Disclaimer: This discussion on Medical Drugs (prescription or OTC) is not a comprehensive analyses of all the clinical and scientific data. We are concerned here with with meta analyses of clinical studies on the risk versus benefit ratio. Always discuss your medication with your Medical Provider. This website is for informational purpose only and does not replace professional medical advice. No statements of efficacy of any drug or treatment are made here.
If you want to look up the FDA listing of side effects of a specific drug taking look here: simply enter your drug name in the search bar, eg. LEVOTHYROXINE
Please do refer to the discussion on statistics, placebo effect and meta analyses here. https://omega3health.us/science/#statistics
Disclaimer: Always talk to your MD/PCP about changing or using medication drugs!
Some questions to ask your medical provider:
- What are the risk vs benefit ratios of using a drug long term?
- What is the NNT and sNNH value of the drug you are prescribing?
- What are the exact studies that really show the absolute (not relative) numbers of benefits vs risks? How many people are really helped?
- Which studies really used proper placebo control (not comparing one drug to another)?
- What is an OR (odds ratio)?
- What are the biochemical tests including blood marker tests that verify the clinical efficacy?
In summary, Can you make an educated decision on recent meta analyses and tell me if this drug efficacy is outweighing its short and long term adverse effects? Please visit the discussion on OR, RR, HR!
Terminology and abbreviations: FO= fish oil.; PUFA=polyunsaturated fatty acids; Omega-3= ω-3 fatty acids; DHA=Docosahexaenoic acid; RCT=randomly controlled trial (placebo controlled study); MUFA=monounsaturated fatty acids; n6= ω-6=omega6; n3=omega3; SFA=saturated fatty acids; HSF=high saturated fatty acids; EPA=Eicosapentaenoicacid; ALA= Alpha-linolenic acid; Linoleicacid(LA); Arachidonicacid(AA); LT4 = exogenous (external drug) vs. natural intra-body gland produced thyroxine; (SBP) systolic blood pressure; (DBP) diastolic blood pressure; cardiovascular disease = (CVD); CVE=cardiovascular events
Prescription Drugs
It’s difficult to give an exact number for the total number of prescription drugs on the market, as new drugs are constantly being approved and existing drugs may be discontinued or removed from the market.
In addition many drugs are re-named and re-labeled under different names but they are essentially very similar chemically. This makes the comparison of clinical studies difficult in some cases.
According to the U.S. Food and Drug Administration (FDA), as of 2022, there were over 30,000 prescription drugs approved for use in the United States. This number includes brand-name drugs, generic drugs, and biologic drugs. It’s important to note that the number of prescription drugs available in a particular country can vary depending on a number of factors, including the regulatory process for drug approval, healthcare policies, and pharmaceutical market conditions. Additionally, different drugs may be approved for different uses or indications, and may be available in different strengths, formulations, or combinations.
The number of over-the-counter (OTC) drugs available can vary depending on the country and regulatory system in place. The United States, the U.S. Food and Drug Administration (FDA) estimates that there are over 300,000 OTC drug products available. This includes a wide range of products, such as pain relievers, cold and flu medications, allergy medications, antacids, and topical treatments for skin conditions. OTC drugs are ‘generally considered safe’ and effective when used as directed, and can be purchased without a prescription.
The most commonly prescribed drugs can vary depending on factors such as the region, population, and year. Here is a list of some of the most commonly prescribed prescription drugs in the United States as of 2022, based on data from the IQVIA Institute for Human Data Science; note of these 20 drugs: 5 are among blood pressure medications, 3 cholesterol and 3 asthma !
- Atorvastatin – cholesterol-lowering medication
- Levothyroxine – thyroid hormone replacement
- Lisinopril – blood pressure medication
- Metformin – diabetes medication
- Amlodipine – calcium channel blocker
- Albuterol – asthma medication
- Omeprazole – heartburn medication
- Simvastatin- cholesterol-lowering medication
- Hydrochlorothiazide – water pill (diuretic) for blood pressure control
- Sertraline – antidepressant
- Metoprolol, Altenolol – beta blockers
- Furosemide – water pill (diuretic) for fluid retention
- Losartan – blood pressure medication
- Gabapentin – anticonvulsant used for nerve pain?
- Montelukast – asthma medication
- Amoxicillin – antibiotic
- Fluticasone/salmeterol – combination asthma medication
- Escitalopram – antidepressant
- Tramadol – pain medication
- Rosuvastatin – cholesterol-lowering medication
More of the top 300 prescription drugs that are of concern:
- Alprazolam
- Adderall
- Amitriptyline
- Baclofen
- benzodiazepine
- Clopidogrel
- Cortisone
- Insulin glargine
- Estrogen and Progesterone treatment for hot flashes
- Ezetimibe
- Flowmax (Tamsulosin®)-BPH drugs
- Fluticasone
- Fluoxetine
- Gabapentin prescribed off-label
- Levadopa (Parkinson’s)
- Oxycodone
- Prednisone
- Semaglutide (ozempic®)
- Blood thinners – Warfarin, Eliquis, Plavix, Rivaroxaban
- Vascepa® (artificial omega3)
- Vicodin®
Disclaimer: This is not an exhaustive list and the most commonly prescribed drugs can vary over time and across different populations.
Topics in detail:
- Acetaminophen (Tylenol®) – pain reliever/fever reducer
- Ibuprofen (Advil, Motrin®) – pain reliever/fever reducer
- Aspirin – pain reliever/fever reducer/antiplatelet agent
- Diphenhydramine (Benadryl®) – antihistamine/sleep aid
- Loratadine (Claritin®) – antihistamine
- Naproxen (Aleve®) – pain reliever/anti-inflammatory
- Famotidine (Pepcid) – heartburn medication
- Ivermectin
- Omeprazole (Prilosec®) – heartburn medication
- Loperamide (Imodium) – anti-diarrheal
- Polyethylene glycol (MiraLAX) – laxative
- Psyllium (Metamucil) – fiber supplement/laxative
- Calcium carbonate (Tums) – antacid
- Vitamin D – dietary supplement
- Magnesium hydroxide (Milk of Magnesia) – laxative/antacid
- Ranitidine (Zantac) – heartburn medication
- Phenylephrine (Sudafed PE) – nasal decongestant
- Guaifenesin (Mucinex) – expectorant
- Pseudoephedrine (Sudafed) – nasal decongestant
- Chlorpheniramine (Chlor-Trimeton) – antihistamine
- Saline nasal spray (Ocean, Simply Saline) – nasal moisturizer/decongestant
- paxlovid®
Disclaimer: This is not an exhaustive list and the most commonly purchased OTC medications can vary depending on the source and time period. It’s important to note that OTC medications should be used as directed and patients should always consult with their healthcare provider if they have questions or concerns about OTC medications.
Some history on drug milestones!
New Drugs on the Horizon
Suzetrigine – a Milestone:
- Non-Opioid Pain Relief:
- With the ongoing opioid crisis, there’s a critical need for effective, non-addictive pain relief options. Suzetrigine’s selective inhibition of the Nav1.7 sodium channel offers a promising alternative that could reduce dependence on opioids.
- Selective Targeting:
- The ability of Suzetrigine to selectively target sodium channels involved in pain transmission (Nav1.7) without affecting those critical for muscle function or cardiac activity is a breakthrough in achieving pain relief with minimal side effects. This selectivity reduces the risk of paralysis, muscle weakness, or other severe neurological side effects.
- Innovation in Sodium Channel Modulation:
- Traditionally, sodium channel blockers that were not selective often led to widespread nerve and muscle function suppression, leading to undesirable side effects like paralysis. Suzetrigine’s design represents an innovative step forward in precision medicine, where drugs can be tailored to target specific pathways involved in disease or pain, minimizing unintended effects.
- Potential Impact on Chronic Pain Treatment:
- Chronic pain is a complex and often debilitating condition that affects millions worldwide. The introduction of a drug like Suzetrigine, which can provide pain relief without the risks associated with long-term opioid use or the systemic effects of non-selective sodium channel blockers, could dramatically improve quality of life for chronic pain sufferers.
If clinical trials continue to demonstrate the safety and efficacy of Suzetrigine, it could set a new standard for pain management. It would also encourage further research into selective ion channel modulators, potentially opening the door for new treatments across a range of neurological conditions.
This kind of advancement in drug design underscores the growing potential of targeted therapies in treating complex conditions with greater precision and fewer side effects, marking it as a milestone in both pain management and pharmaceutical innovation.
Suzetrigine (VX-548) is a selective inhibitor of Nav1.8, targeting this specific sodium channel to provide pain relief with reduced risks of side effects. Nav1.8 plays a crucial role in the transmission and maintenance of pain signals in the peripheral nervous system, making it a valuable target for new pain therapies, especially for chronic pain conditions. By selectively inhibiting Nav1.8, Suzetrigine could offer a more precise and effective pain management option.
Nav1.8: Role in Pain Perception
Nav1.8 channels are expressed predominantly in peripheral sensory neurons, especially in dorsal root ganglion (DRG) neurons, which are involved in the transmission of pain and temperature sensations. These channels are responsible for the propagation of action potentials in response to noxious stimuli.
Specificity in Pain:
Nav1.8 is particularly important in mediating the persistent pain associated with chronic inflammatory and neuropathic conditions. Unlike Nav1.7, which is involved in setting the threshold for pain signals, Nav1.8 is crucial for sustaining the pain signal and transmitting it to the central nervous system.
Why Nav1.8 Inhibition is Significant:
By selectively targeting Nav1.8, Suzetrigine (VX-548) can specifically disrupt the pain signaling pathway without affecting other sodium channels involved in critical functions like heart rhythm (Nav1.5) or muscle contraction (Nav1.4). This specificity reduces the risk of side effects such as paralysis or cardiac issues.
Suzetrigine (VX-548) and Nav1.8:
Selective Inhibition:
Suzetrigine’s ability to selectively inhibit Nav1.8 makes it a promising candidate for treating conditions involving chronic pain, such as neuropathic pain, without the adverse effects that result from broader sodium channel blockade. This selectivity allows for effective pain relief while maintaining the function of other sodium channels that are crucial for the body’s normal physiological activities.
Therapeutic Potential:
Since Nav1.8 is less widely expressed in the nervous system compared to Nav1.7, targeting Nav1.8 with Suzetrigine offers a more focused approach to pain management. This can be particularly beneficial for patients with conditions that involve chronic pain, where other treatments may be less effective or cause significant side effects.
Atorvastatin (Lipitor), Zocor and other statins
Lipitor is the brand name for the medication atorvastatin, which is a type of drug called a statin. It is used to lower “high levels of cholesterol” and triglycerides in the blood. Lipitor works by blocking an enzyme in the liver that is responsible for producing cholesterol, thereby reducing the amount of cholesterol in the bloodstream. It is typically prescribed to patients with high cholesterol levels, which can increase the risk of heart disease, stroke, and other related conditions. Lipitor is available only by prescription and is typically taken once a day with or without food.
What do these numbers really mean? Is there really a link between cholesterol and heart disease and stroke?
On the contrary, massive side effects are lowering benefit to risk ratios are becoming evident with every year.
from the FDA website:
Why would statins increase the risk of diabetes if cholesterol is allegedly responsible for arterial disease? These problems are all related under the umbrella of metabolic syndrome.
Statins long term use cause jaundice and possible liver damage. Statins inhibit a vital reaction in the liver namely the synthesis of cholesterol! “Healthcare professionals should perform liver enzyme tests before initiating statin therapy in patients and as clinically indicated thereafter. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, therapy should be interrupted. If an alternate etiology is not found, the statin should not be restarted.”
“Healthcare professionals should follow the recommendations in the lovastatin label regarding drugs that may increase the risk of myopathy/rhabdomyolysis when used with lovastatin ”
Non-statin drugs
Ezetimibe and statins are both medications used to lower cholesterol levels, but they work in different ways and have distinct roles in ‘managing’ cardiovascular health. Here’s a comparison of the two:
Mechanism of Action
- Ezetimibe: Ezetimibe works by inhibiting the absorption of cholesterol from the small intestine. It blocks a specific protein (Niemann-Pick C1-Like 1, or NPC1L1) that is responsible for absorbing cholesterol from the diet. This reduces the amount of cholesterol entering the bloodstream.
- Statins: Statins work by inhibiting an enzyme called HMG-CoA reductase, which is crucial for cholesterol production in the liver. By reducing the liver’s production of cholesterol, statins lead to an increased uptake of LDL (low-density lipoprotein) cholesterol from the blood, thereby lowering overall cholesterol levels.
Efficacy
- Ezetimibe: Ezetimibe is effective at lowering LDL cholesterol, typically reducing levels by 15-20%. It is often used in combination with statins for additional cholesterol reduction, especially in patients who do not achieve their target LDL levels with statins alone.
- Statins: Statins are generally more potent in lowering LDL cholesterol, with reductions ranging from 20% to 60%, depending on the type and dose of statin. Statins are also proven to reduce the risk of heart attacks, strokes, and other cardiovascular events.
Side Effects
- Ezetimibe: Gastrointestinal symptoms like diarrhea, fatigue, and muscle pain (though less common than with statins).
- Statins: Muscle pain (myopathy), liver enzyme abnormalities, and, rarely, an increased risk of diabetes. The severity of side effects can vary depending on the specific statin and dose.
Usage
- Ezetimibe: Often prescribed as an add-on therapy to statins in patients who need additional cholesterol lowering or who cannot tolerate high doses of statins. It may also be used alone in patients who are statin-intolerant.
- Statins: Typically the first-line treatment for lowering LDL cholesterol and reducing cardiovascular risk. They are widely prescribed for patients with high cholesterol, a history of cardiovascular disease, or those at high risk for cardiovascular events.
Impact on Cardiovascular Outcomes
The numbers are small! here you can find them:
A detailed discussion of Cholesterol
Levothyroxin
Levothyroxine is a medication that is used to treat an underactive thyroid gland (hypothyroidism). The thyroid gland produces hormones that help regulate the body’s metabolism. When the thyroid gland is not producing enough hormones, it can cause a range of symptoms including fatigue, weight gain, cold intolerance, constipation, and dry skin.
Levothyroxine is a synthetic form of the thyroid hormone thyroxine (T4) that is normally produced by the thyroid gland. It works by increasing the levels of thyroid hormone in the body, which can help alleviate the symptoms of hypothyroidism.
Levothyroxine is usually taken orally, typically on an empty stomach, and it is important to follow the dosage instructions provided by a doctor or healthcare professional. It may take several weeks or months of treatment to see the full benefits of levothyroxine, and regular blood tests may be needed to monitor thyroid hormone levels.
The efficacy of thyroxine (T4) treatment is usually measured by monitoring the levels of thyroid stimulating hormone (TSH) in the blood.
TSH is produced by the pituitary gland and stimulates the thyroid gland to produce more thyroid hormones. When T4 levels are low, the pituitary gland produces more TSH in an attempt to stimulate the thyroid gland to produce more thyroid hormones. Conversely, when T4 levels are high, the pituitary gland reduces its production of TSH.
In people with hypothyroidism who are being treated with T4 medication like levothyroxine, the goal is to keep TSH levels within a normal range. If TSH levels remain high, it may indicate that the T4 dosage needs to be increased. On the other hand, if TSH levels are low, it may indicate that the T4 dosage is too high and needs to be reduced.
In addition to monitoring TSH levels, doctors may also assess the efficacy of T4 treatment by evaluating symptoms and monitoring other thyroid hormone levels, such as free thyroxine (FT4) and triiodothyronine (T3). However, TSH levels are the most commonly used indicator of thyroid hormone replacement therapy efficacy.
Note1: obviously if the thyroid gland was removed fully, this discussion does not apply.
Note2: there is also a variation in synthetic and “bio-identical” sources of thyroxine.
Problem #1:
When T4 levels are low, the pituitary gland produces more TSH to stimulate the thyroid gland to produce more thyroid hormones. Conversely, when T4 levels are high, the pituitary gland reduces its production of TSH. By measuring TSH levels, doctors can indirectly assess whether the T4 treatment is effectively regulating thyroid hormone levels in the body.
However, T4 has many important functions in the body beyond regulating TSH levels, including regulating metabolism, growth, and development. In addition to monitoring TSH levels, doctors may also evaluate the effectiveness of T4 treatment by assessing symptoms and monitoring other thyroid hormone levels, such as free thyroxine (FT4) and triiodothyronine (T3), which are more direct measures of the effects of thyroid hormones on the body.
TSH (green) is produced by the pituitary if there is not enough T4/T3 in the body. However it does not tell you how effective T4/T3 act inside the target cells.
Problem #2
Total T4 (thyroxine) is the measurement of the total amount of T4 circulating in the bloodstream, including both the bound and unbound (free) forms. Most of the T4 in the bloodstream is bound to proteins, particularly to thyroxine-binding globulin (TBG), but a small amount of T4 is unbound and available for use by the body’s tissues.
Free T4 (FT4) is the measurement of the unbound (free) T4 circulating in the bloodstream. Free T4 is the biologically active form of T4 and is the fraction of T4 that is immediately available to tissues. Measuring FT4 is important in diagnosing and monitoring thyroid disorders because it reflects the amount of T4 that is actually available to the body’s tissues.
The T4/T3 ratio is a comparison of the amount of T4 to T3 (triiodothyronine) in the bloodstream. T3 is a more biologically active thyroid hormone than T4, and it is thought to be responsible for many of the effects of thyroid hormones on the body. However, most of the T3 in the bloodstream is not directly secreted by the thyroid gland but is instead produced by the conversion of T4 to T3 in peripheral tissues.
In some cases, a low T4/T3 ratio can indicate a problem with the conversion of T4 to T3, such as in cases of peripheral thyroid hormone resistance or in certain types of thyroid disease. However, a low T4/T3 ratio can also occur in people who are taking T4 replacement therapy, particularly if their dose is too high, which can lead to a decrease in T3 levels. It is important to interpret T4/T3 ratio measurements in the context of other thyroid function tests and clinical symptoms.
Problem #3
There is still no way of assessment of the actual cellular effects of T4/3. In the end decisions of dosage and continued use by the MD are based on symptoms and how you feel! Again TSH is only an indirect feedback hormone. So in other words you give someone thyroid hormone externally of course your TSH is going down with it but it tells you nothing about how effective the T4/3 in the blood really is. In the end the dosage and continued usage depends on subjective symptoms or the MD asking you “how do you feel”>
Problem #4
Taking thyroxine (T4) for a long time is considered safe when used as directed by a healthcare provider. In fact, for people with hypothyroidism (an underactive thyroid gland), taking thyroid hormone replacement therapy like thyroxine is necessary to maintain normal metabolism and avoid serious complications.
However, it is important to have regular follow-up with a healthcare provider to monitor thyroid hormone levels and adjust the dosage as needed. Too much thyroxine can cause hyperthyroidism, which can lead to symptoms such as anxiety, rapid heartbeat, weight loss, and fatigue. On the other hand, too little thyroxine can lead to hypothyroidism, which can cause symptoms such as fatigue, weight gain, depression, and constipation.
Additionally, like with any medication, there may be some side effects associated with long-term use of thyroxine, although they are typically mild and go away with time. Some possible side effects include hair loss, headaches, and changes in appetite.
Problem #5
Many other aspects of metabolism and thyroid health are overlooked such as iodine which is an essential mineral that is required for the production of thyroid hormones, including thyroxine (T4). In cases where low T4 levels are due to iodine deficiency, iodine supplementation can help increase T4 levels. This is because iodine is necessary for the thyroid gland to produce T4.
However, it is important to note that not all cases of low T4 levels are due to iodine deficiency. In some cases, low T4 levels may be due to other factors such as autoimmune disorders, radiation exposure, certain medications, or pituitary gland disorders. In these cases, iodine supplementation may not be effective in increasing T4 levels. In addition, it is important to be cautious when supplementing with iodine, as too much iodine can also have negative effects on thyroid function. In individuals with normal thyroid function, excessive iodine intake can actually suppress thyroid hormone production, leading to hypothyroidism.
Problem #6
Taking levothyroxine is adding a hormonal messenger that should be produced internally. After years of this administration the thyroid gland gives up and falls “asleep”. So a revival becomes more and more unlikely. In other words the drug never fixes anything but simply masks the real underlying problems.
Lets look at the studies: The main problem when looking at studies are all of the above but especially problem#3 : If you are giving someone LT4 then measuring the same within the blood and that is the only way of assessing outcomes in a study = you have no study. So the bottom line here is that there are not a lot of proper statistical studies but just opinions based on peoples subjective symptoms.
Cancer risk taking LT4:
-A population-based case-control study from Taiwan (65,491 breast cancers, 261,964 controls) found that LT4 administration vs. no LT4 use was associated with a modestly higher risk of breast cancer, with a greater effect in older (≥65 years) patients (odds ratio [OR] 1.45 [95%CI 1.23–1.71], p < 0.01)
Lisinopril and other ACE inhibitors
Taking blood pressure medications is a bit like plumbing 101; “the less water in the system- means less pressure in the pipe”. this is done initially by ‘water pills’, then ACE inhibitors and Beta blockers:
- ACE-inhibitors: You can reduce the amount of water in the blood by reducing the the amount of angiotensin II. Angiotensin II is a potent vasoconstrictor, meaning it causes blood vessels to narrow, increasing blood pressure; so the less angiotensin II is in the blood the lower the blood pressure.
- With less angiotensin II in the system, there is also less aldosterone released, resulting in decreased sodium and water retention in the kidneys. This, in turn, helps to reduce blood volume and further contributes to lowering blood pressure.
- “Waterpills”: eg Thiazide diuretics are a class of medications commonly used to treat high blood pressure (hypertension) and edema (fluid retention). They work by acting on the kidneys to increase the excretion of sodium, chloride, and water, leading to a reduction in blood volume and a subsequent decrease in blood pressure. Thiazide diuretics inhibit the action of the sodium-chloride symporter, preventing the reabsorption of sodium and chloride ions. Consequently, more sodium and chloride remain in the tubule, creating an osmotic gradient that prevents water from being reabsorbed.
Hydrochlorothiazide is a diuretic, often referred to as a “water pill,” that is commonly used to treat high blood pressure and fluid retention due to various conditions like congestive heart failure, liver disease, or kidney disorders. As with any medication, it comes with potential benefits and risks that must be considered.
Claimed Benefits:
- The effects of Lowered Blood Pressure are small: Hydrochlorothiazide effectively reduces blood pressure, which decreases the risk of strokes, heart attacks, and kidney problems. In 33 trials, hydrochlorothiazide (HCTZ) lowered blood pressure based on dose. The doses of 6.25 mg, 12.5 mg, 25 mg, and 50 mg/day lowered blood pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderate-quality evidence)/2 mmHg (95% CI 1 to 4, moderate-quality evidence).
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In essential hypertension, thiazides reduce systolic pressure by only 8 to 10 mm Hg.A systematic review published in the Journal of the American Medical Association (JAMA) in 2003 found that diuretics like HCTZ reduced systolic blood pressure by an average of 11-15 mmHg and diastolic blood pressure by 6-8 mmHg when used as the first-line treatment for hypertension.
A 2010 review published in the Cochrane Database of Systematic Reviews found that low-dose thiazide diuretics (like HCTZ) reduced systolic blood pressure by 8-10 mmHg and diastolic blood pressure by 4-5 mmHg compared to placebo in patients with mild to moderate hypertension.
- Decreased Swelling: It helps the body get rid of excess salt and water, reducing swelling and water retention. While there are many clinical trials and studies that have demonstrated the effectiveness of HCTZ and other diuretics in treating edema, most of these studies measure success based on improvement in symptoms (like reduced swelling and shortness of breath), rather than specific measurements of fluid volume.In a meta-analysis published in the Cochrane Database of Systematic Reviews, diuretics like HCTZ were found to be effective in reducing the symptoms of acute and chronic heart failure, which often includes edema.
Risks/Side Effects:
- Dehydration: Hydrochlorothiazide increases urination, which can lead to dehydration. Symptoms include dry mouth, increased thirst, confusion, and dizziness.
- Electrolyte Imbalance: By causing the kidneys to excrete more sodium, potassium may also be lost leading to electrolyte imbalances. Low potassium levels can result in muscle cramps, weakness, or heart rhythm abnormalities.
- Photosensitivity: This medication can make you more sensitive to the sun, increasing your risk of sunburn.
- Gout: Long-term use can increase uric acid levels, leading to gout.
- Blood Sugar Levels: It may affect blood sugar levels, making control of diabetes more difficult.
- Kidney Problems: It can occasionally cause kidney problems, which are usually reversible with discontinuation of the medication.
- Lipid Levels: There can be a slight increase in cholesterol and triglyceride levels.
- HCTZ can cause a loss of potassium and bicarbonate.
Angiotensin-converting enzyme (ACE) inhibitors are a class of medications primarily used to treat high blood pressure (hypertension) and heart failure. They work by inhibiting the action of the angiotensin-converting enzyme, which is responsible for converting angiotensin I to angiotensin II in the body. Angiotensin II is a potent vasoconstrictor, meaning it narrows blood vessels, leading to an increase in blood pressure. By inhibiting the production of angiotensin II, ACE inhibitors help relax blood vessels, which in turn lowers blood pressure and reduces the workload on the heart.
Some common ACE inhibitors include:
- Captopril (Capoten)
- Enalapril (Vasotec)
- Lisinopril (Prinivil, Zestril)
- Ramipril (Altace)
- Perindopril (Coversyl)
- Quinapril (Accupril)
- Benazepril (Lotensin)
ACE inhibitors are often prescribed for patients with hypertension, heart failure, diabetic kidney disease, or those who have suffered a heart attack. “They have been shown to be particularly effective in reducing the risk of stroke, heart attack, and other cardiovascular events.”
However, ACE inhibitors may cause side effects in some patients. Common side effects include dry cough, dizziness, headache, fatigue, and increased potassium levels in the blood (hyperkalemia). In rare cases, they can cause angioedema, a serious allergic reaction characterized by rapid swelling of the face, lips, tongue, or throat. ACE inhibitors are typically not recommended for pregnant women, as they can cause harm to the developing fetus.
As with any medication, it is essential to follow the prescribed dosage and consult with a healthcare professional about any concerns or potential side effects.
What do the studies show: How many heart attacks or strokes are prevented?
Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor commonly prescribed to treat high blood pressure (hypertension) and heart failure, as well as to provide protection for the kidneys in patients with diabetes. It has been shown in various clinical trials and meta-analyses to reduce the risk of heart attacks, strokes, and other cardiovascular events.
The exact number of heart attacks or strokes prevented by lisinopril can vary depending on the study and the population included. However, evidence from large clinical trials and meta-analyses demonstrates the benefits of ACE inhibitors, including lisinopril, in reducing cardiovascular events.
One notable study is the Heart Outcomes Prevention Evaluation (HOPE) trial, which assessed the effects of the ACE inhibitor ramipril on the risk of cardiovascular events in high-risk patients. While this study focused on ramipril, the results are generally applicable to other ACE inhibitors, including lisinopril. The HOPE trial found that ramipril reduced the risk of heart attacks by 20%, stroke by 32%, and cardiovascular death by 26% when compared to placebo.
Is that really true? Let look at these studies in detail?
Here is the discussion on the NNT ; your improved chance of preventing a heart attack is less that 1%; your improved chance of preventing a stroke is less than 2%.
Possible Causes of Skin Blistering with Candesartan:
Candesartan, an angiotensin II receptor blocker (ARB) used primarily for the treatment of high blood pressure and heart failure, can have various side effects. Skin blistering, after sun exposure, may occur as an adverse reaction.
- Allergic Reaction: Skin blistering could be a manifestation of a severe allergic reaction or hypersensitivity to candesartan.
- Drug-induced Bullous Pemphigoid: Candesartan has been implicated in some cases of bullous pemphigoid, a skin condition characterized by large, fluid-filled blisters.
- Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN): These are rare but serious conditions that can cause severe skin blistering and detachment.
Cancer Risk taking lisinopril
Although there is a body of meta analyses that states that your cancer risk is not increased taking lisinopril there is evidence that it at least increases your risk of metastases and it increases CRP levels.
Diabetes Risk taking lisinopril
Again: This is not a true statement: “the odds of developing DM were reduced by 28% (OR 0.72, 95% CI 0.63 to 0.84, p<0.001)” = it should be: the odds of developing DM were reduced by 28% compared to the risk of the control group (not specified here)>.. here are the real numbers “Renin-angiotensin system antagonists reduced the incidence of DM from 9% in nontreated patients to 7.1% in those treated”, so that is a reduced relative risk of 1.9%! In addition these large studies are difficult to do because we dont really know the life style of the non-treated and there was no placebo included.
Again, look a the absolute numbers, only a few dozen incidence out of thousands of participants are used to draw conclusions on the outcome.
Losartan is a prescription drug that is used to treat high blood pressure (hypertension). It is also used to lower the risk of stroke in certain people with heart disease and to slow long-term kidney damage in people with type 2 diabetes who also have high blood pressure.
Losartan belongs to a class of drugs called angiotensin II receptor antagonists (or blockers). Angiotensin II is a substance in the body that narrows blood vessels and releases a hormone that can increase the amount of sodium and water the body retains. By blocking the effects of angiotensin II, losartan relaxes and widens the blood vessels, allowing blood to flow more easily, reducing blood pressure, and reducing the amount of sodium and water the body retains.
Like all medications, losartan can have side effects. The most common ones include dizziness, back pain, and cold or flu symptoms such as sneezing or a stuffy nose. More serious side effects, although rare, can include kidney problems, high potassium levels, and allergic reaction.
According to eHealthMe, a study based on reports of 70,992 people who have side effects when taking Losartan from FDA, bladder cancer is found among people who take Losartan1. However, it is important to note that this does not mean that Losartan causes bladder cancer. The study only shows an association between the two.
It is also important to note that Losartan has been recalled several times due to the presence of impurities that may increase the risk of cancer234.
Beta blockers
Beta blockers, also known as beta-adrenergic blocking agents, are a class of medications used to treat various cardiovascular conditions, including high blood pressure (hypertension), angina, heart failure, and abnormal heart rhythms. They work by blocking the effects of certain stress hormones, such as epinephrine (adrenaline), on beta receptors found in the heart and blood vessels.
Here’s how beta blockers lower blood pressure:
- Reduced heart rate: By blocking the beta-1 receptors in the heart, beta blockers decrease the rate at which the heart beats (heart rate). This reduces the amount of blood pumped by the heart per minute (cardiac output) and lowers the overall workload on the heart.
- Decreased contractility: Beta blockers also reduce the force with which the heart muscle contracts. This further reduces the workload on the heart and helps to lower blood pressure.
- Vasodilation: Some beta blockers, particularly those that block both beta-1 and beta-2 receptors, can cause blood vessels to relax and widen (vasodilation) by blocking the action of stress hormones on the smooth muscle cells of the blood vessels. This can lead to a reduction in peripheral vascular resistance, which also contributes to lowering blood pressure.
- Decreased renin release: Beta blockers can also inhibit the release of renin from the kidneys. Since renin is a key component of the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure, a reduction in renin levels can lead to lower blood pressure.
Some common beta blockers include:
- Atenolol (Tenormin)
- Metoprolol (Lopressor, Toprol-XL)
- Propranolol (Inderal)
- Bisoprolol (Zebeta)
- Carvedilol (Coreg)
- Nebivolol (Bystolic)
Beta blockers can cause side effects such as fatigue, dizziness, cold hands and feet, slow heart rate, and, in some cases, weight gain. They may also worsen symptoms of asthma and other respiratory conditions due to their effect on beta-2 receptors in the lungs. Also patients should not abruptly stop taking beta blockers, as this can lead to a sudden increase in heart rate and blood pressure, increasing the risk of a heart attack or other complications.
In summary, Beta blockers are a class of medications used to treat various cardiovascular conditions by blocking the effects of certain stress hormones, such as epinephrine (adrenaline), on beta receptors found in the heart and blood vessels. Beta blockers decrease the rate at which the heart beats (heart rate). This reduces the amount of blood pumped by the heart per minute (cardiac output) and lowers the overall workload on the heart. Beta blockers also reduce the force with which the heart muscle contracts. This further reduces the workload on the heart and helps to lower blood pressure. But they can also work as vasodilators via blocking renin release via the kidneys.
There is no evidence the use of beta blockers can prevent heart attacks or stroke.
Wiysonge 2017: They compared beta-blockers to placebo (4 RCTs, 23,613 participants), diuretics (5 RCTs, 18,241 participants), calcium-channel blockers (CCBs: 4 RCTs, 44,825 participants), and renin-angiotensin system (RAS) inhibitors (3 RCTs, 10,828 participants). These RCTs were conducted between the 1970s and 2000s and most of them had a high risk of bias resulting from limitations in study design, conduct, and data analysis. There were 40,245 participants taking beta-blockers, three-quarters of them taking atenolol. We found no outcome trials involving the newer vasodilating beta-blockers (e.g. nebivolol).There was no difference in all-cause mortality between beta-blockers and placebo (RR 0.99, 95% CI 0.88 to 1.11), diuretics or RAS inhibitors, but it was higher for beta-blockers compared to CCBs (RR 1.07, 95% CI 1.00 to 1.14).
When the researchers looked at specific types of cancer, they found a slight increase in risk for brain cancer among beta-blocker users, but this finding was based on a small number of cases and might have been due to chance.
Similarly, another meta-analysis published in 2014 in the Journal of the American College of Cardiology found no overall association between beta-blocker use and cancer risk.
Evidence does not conclusively show a strong link between beta blockers and cancer risk. Any individual concerned about this issue should diligently do their own research and present it to their healthcare provider.
References:
- Hicks BM, Murray LJ, Hughes C, Cardwell CR. Beta-blocker usage and colorectal cancer mortality: a nested case-control study in the UK Clinical Practice Research Datalink cohort. Ann Oncol. 2013;24(2):310-316.
- Assayag J, Pollak MN, Azoulay L. The use of beta-blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax. 2014;69(8):785-787.
- Gandhi S, Fleet JL, Bailey DG, et al. Calcium-Channel Blocker-Clarithromycin Drug Interactions, Kidney Injury, and Hospitalization for Acute Kidney Injury: A Cohort Study. Medicine (Baltimore). 2015;94(34):e1370.
Types of Antiarrhythmics
Here’s a breakdown of oral antiarrhythmic drugs based on their primary molecular targets and additional considerations for agents with multiple targets:
Class I: Sodium Channel Blockers
These agents are further subdivided into Ia, Ib, and Ic based on their effects on the action potential duration and kinetics of sodium channel blockade.
- Class Ia: Moderate Na⁺ channel blockade and prolonged repolarization (increased action potential duration).
- Examples: Quinidine, Procainamide, Disopyramide
- Class Ib: Weak Na⁺ channel blockade and shortened repolarization (decreased action potential duration).
- Examples: Lidocaine (primarily used intravenously), Mexiletine
- Class Ic: Strong Na⁺ channel blockade with minimal effect on repolarization (no significant change in action potential duration).
- Examples: Flecainide, Propafenone (also has beta-blocking activity)
Class II: Beta-Adrenergic Receptor Blockers
These drugs block the effects of adrenaline on the heart, reducing heart rate and contractility.
- Examples: Atenolol, Metoprolol, Propranolol (non-selective), Bisoprolol, Esmolol (primarily used intravenously)
Class III: Potassium Channel Blockers
These agents primarily prolong repolarization by blocking potassium channels, thus increasing the action potential duration and refractory period.
- Examples: Amiodarone (also has Class I, II, and IV effects), Sotalol (also a beta-blocker), Dofetilide, Ibutilide (primarily used intravenously), Dronedarone
Class IV: Calcium Channel Blockers
These drugs primarily inhibit L-type calcium channels, slowing the heart rate and reducing contractility, particularly effective in the atria and AV node.
- Examples: Verapamil, Diltiazem
Agents with Multiple Targets
Some antiarrhythmics do not fit neatly into a single class because they affect multiple ion channels or receptors.
- Amiodarone: Exhibits properties of all four classes (sodium, potassium, calcium channels, and beta-adrenergic receptors).
- Sotalol: Has both Class III (potassium channel blockade) and Class II (beta-blockade) effects.
- Propafenone: Primarily a Class Ic agent but also has beta-blocking activity.
- Dronedarone: Similar to amiodarone but with fewer side effects; affects multiple channels but primarily classified as Class III.
In summary, Antiarrhythmic drugs are classified based on their primary molecular targets, but many have multiple actions that can affect their overall clinical use and side effect profiles. Understanding these classifications helps guide appropriate therapy for different types of arrhythmias.
More detailed Mechanisms
Flecainide or Tambocor® is a class Ic antiarrhythmic agent primarily used to treat certain types of serious ventricular and supraventricular arrhythmias. Its mechanism of action involves blocking the sodium channels in the heart. Here’s a more detailed look at how it works:
- Sodium Channel Blockade: Flecainide inhibits the fast inward sodium (Na⁺) current in cardiac cells. This blockade prolongs the phase 0 depolarization of the cardiac action potential, which slows the conduction of electrical impulses in the heart.
- Reduction of Conduction Velocity: By slowing down the rate at which electrical impulses travel through the heart, flecainide can prevent or reduce the occurrence of abnormal, rapid heart rhythms (arrhythmias).
- Prolongation of the Effective Refractory Period: Flecainide increases the effective refractory period in the atria, ventricles, and His-Purkinje system. This means that the cells are less likely to respond to premature or inappropriate electrical impulses.
- Use Dependence: Flecainide exhibits use-dependent blockade, meaning its effects are more pronounced at higher heart rates. This makes it particularly effective in treating tachyarrhythmias (abnormally fast heart rates) without significantly affecting the heart’s function at normal rates.
Because of these effects, flecainide is often used to manage conditions like atrial fibrillation, atrial flutter, and ventricular tachycardia. However, due to its potent effects and potential for proarrhythmia (the induction of new arrhythmias), its use is generally reserved for patients without significant structural heart disease and under careful medical supervision.
Flecainide and Atenolol Comparison
Flecainide and atenolol are both used to manage cardiac conditions, but they have different mechanisms of action, therapeutic uses, and potential side effects. Here’s a comparison:
- Flecainide:
- Class: Class Ic antiarrhythmic.
- Action: Blocks fast sodium channels, slowing the conduction of electrical impulses in the heart and prolonging the refractory period.
- Effect: Primarily affects the atria, ventricles, and His-Purkinje system.
- Atenolol:
- Class: Beta-blocker (specifically a beta-1 selective antagonist).
- Action: Blocks beta-1 adrenergic receptors, reducing the effects of adrenaline and noradrenaline.
- Effect: Decreases heart rate, reduces myocardial contractility, and lowers blood pressure.
Therapeutic Uses
- Flecainide:
- Used for treating certain serious ventricular and supraventricular arrhythmias, such as atrial fibrillation, atrial flutter, and ventricular tachycardia.
- Reserved for patients without significant structural heart disease.
- Atenolol:
- Used to treat hypertension, angina pectoris, and for secondary prevention of myocardial infarction.
- Also used for managing certain types of arrhythmias, though not as a first-line treatment for arrhythmias like flecainide.
Side Effects
- Flecainide:
- Proarrhythmic effects (can induce new arrhythmias).
- Dizziness, visual disturbances, dyspnea.
- Can exacerbate heart failure in patients with structural heart disease.
- Atenolol:
- Bradycardia, hypotension, fatigue.
- Cold extremities, depression, and erectile dysfunction.
- Less likely to cause bronchospasm compared to non-selective beta-blockers, but caution is still advised in asthmatic patients.
Contraindications
- Flecainide:
- Contraindicated in patients with pre-existing second- or third-degree AV block, right bundle branch block when associated with a left hemiblock (bifascicular block), and in patients with significant structural heart disease.
- Atenolol:
- Contraindicated in patients with severe bradycardia, second- or third-degree heart block, overt cardiac failure, and cardiogenic shock.
- Should be used with caution in patients with asthma or other obstructive airway diseases, though it is relatively cardioselective (targeting the heart only).
Another common drug class is Dofetilide(TIKOSYN ® )but they belong to different classes and have distinct mechanisms of action, indications, and side effect profiles. Here’s a detailed comparison:
Dofetilide Mechanism of Action
-
- Class: Class III antiarrhythmic.
- Action: Blocks the rapid component of the delayed rectifier potassium current (I_Kr).
- Effect: Prolongs the action potential duration and refractory period in the cardiac tissue without affecting conduction velocity.
Therapeutic Uses
- Dofetilide:
- Used specifically for the conversion and maintenance of sinus rhythm in patients with atrial fibrillation and atrial flutter.
- Often used in patients with persistent or recurrent atrial fibrillation.
Side Effects
- Dofetilide:
- Risk of Torsades de Pointes (a type of ventricular tachycardia).
- Headache, dizziness, and gastrointestinal disturbances.
- Requires hospitalization or heart monitor for initiation and close monitoring of the QT interval.
Contraindication comparison
- Flecainide:
- Contraindicated in patients with pre-existing second- or third-degree AV block, right bundle branch block when associated with a left hemiblock (bifascicular block), and in patients with significant structural heart disease.
- Dofetilide:
- Contraindicated in patients with congenital or acquired long QT syndromes, severe renal impairment, and concurrent use of other QT-prolonging drugs.
- Should be used with caution in patients with electrolyte imbalances.
Monitoring and Administration
- Flecainide:
- Can be initiated on an outpatient basis in some cases, but monitoring for proarrhythmia is essential.
- Regular ECG monitoring may be required, especially during dose adjustments.
- Dofetilide:
- Requires inpatient initiation to monitor for Torsades de Pointes.
- Continuous ECG monitoring and regular measurement of renal function are necessary due to the risk of QT prolongation and renal excretion.
proarrhythmia is a known adverse effect.
Comparison Summary
- Flecainide (Tambocor) is primarily an antiarrhythmic agent used for managing specific arrhythmias.
- Atenolol (Tenormin) is primarily a beta-blocker used for treating hypertension, angina, and in some cases, arrhythmias.
- Dofetilide (Tikosyn) is a Class III antiarrhythmic used primarily for atrial fibrillation and atrial flutter by prolonging the action potential and refractory period.
These drug mechanisms are quite different as they b and so are the side effects.
Their use depends on the specific arrhythmic condition, underlying patient health, and the need for close monitoring due to potential side effects. Flecainide is more versatile but carries a risk for proarrhythmia, especially in patients with structural heart disease. Dofetilide, while effective for atrial fibrillation, may require hospitalization for initiation and careful heart monitoring to avoid severe ventricular arrhythmias.
Calcium Channel blockers
Flowmax and BPH
One of the most frustrating age related diseases in older men is BPH. After the restriction of the urether becomes apparent many men start taking alpha blockers. However after several years on the drug the problem becomes worse because they never address the root of the disease. Many men end up getting surgery and a TURP.
There are two sphincters that control the flow of urine out of the bladder in humans: the internal urethral sphincter and the external urethral sphincter.
The internal urethral sphincter is an involuntary smooth muscle located at the base of the bladder where it connects to the urethra. When the bladder is filling with urine, this sphincter is contracted, which helps to prevent urine from leaking out. When the bladder is full and it’s time to urinate, the internal sphincter relaxes and allows urine to flow out of the bladder and into the urethra.
The external urethral sphincter is a voluntary skeletal muscle located just below the internal sphincter. This sphincter is under conscious control and can be contracted or relaxed at will. When it is contracted, it acts as a secondary barrier to prevent urine from leaking out. When it is relaxed, urine is allowed to flow out of the body through the urethra.
Both of these sphincters work together to control the flow of urine out of the bladder and prevent urinary incontinence. Dysfunction of either of these sphincters can lead to problems with bladder control and urinary incontinence.
The prevalence of BPH increases with age, and it is estimated that approximately 50% of men aged 50 years and older have histological evidence of BPH. The prevalence increases to 80-90% among men aged 80 years and older. However, not all men with BPH will experience symptoms that require treatment, and the proportion who ultimately undergo TURP is much lower.
Historically, TURP has been considered the gold standard treatment for BPH, particularly for men with moderate to severe symptoms. However, the widespread use of medical therapies, such as alpha-adrenergic antagonists and 5-alpha reductase inhibitors, has led to a decrease in the number of TURPs performed. Medical therapies can often effectively manage symptoms, improve urinary flow rates, and reduce the risk of BPH-related complications.
In recent years, the introduction of minimally invasive procedures, such as laser prostatectomy, transurethral microwave thermotherapy (TUMT), transurethral needle ablation (TUNA), and prostate artery embolization (PAE), has provided alternative treatment options for men with BPH, further reducing the reliance on TURP.
Holmium Laser Enucleation of the Prostate (HoLEP) and Transurethral Resection of the Prostate (TURP) are both surgical procedures used to treat benign prostatic hyperplasia (BPH). While TURP has been the gold standard for many years, HoLEP has emerged as a minimally invasive alternative with some advantages. Below is a comparison of HoLEP and TURP:
- Technique: TURP involves the use of a resectoscope, which is inserted through the urethra to remove excess prostate tissue by cutting it away in small pieces. In contrast, HoLEP uses a high-powered holmium laser to enucleate (remove) the excess prostate tissue, which is then morcellated (cut into smaller pieces) and removed.
- Blood loss: HoLEP generally results in less blood loss compared to TURP due to the laser’s ability to coagulate blood vessels during the procedure. This reduced blood loss may lead to a lower risk of complications, such as blood transfusions.
- Operative time: HoLEP can take longer to perform than TURP, particularly in the hands of less experienced surgeons. However, the operative time for HoLEP tends to decrease as the surgeon gains more experience with the technique.
- Hospital stay and recovery: Patients who undergo HoLEP typically have a shorter hospital stay and a quicker return to normal activities compared to those who undergo TURP. HoLEP patients may also experience a shorter duration of postoperative catheterization.
- Effectiveness and durability: Both HoLEP and TURP are effective in relieving BPH symptoms and improving urinary flow rates. Studies have shown that HoLEP may provide better long-term outcomes, especially for larger prostates, with a lower risk of recurrence and need for reoperation.
- Complications: HoLEP has a lower risk of certain complications, such as bleeding and TUR syndrome (a rare but potentially life-threatening complication caused by the absorption of irrigating fluid during TURP). However, both procedures can lead to complications like urinary incontinence, retrograde ejaculation, and erectile dysfunction.
In summary, both HoLEP and TURP are effective treatments for BPH. HoLEP has some advantages over TURP, such as reduced blood loss, shorter hospital stay, and potentially better long-term outcomes, especially for larger prostates. However, the choice between the two procedures depends on several factors, including the size of the prostate, the surgeon’s experience, and the patient’s overall health and preferences.
Ultimately, the odds ratio or relative risk of a man with BPH requiring TURP or other surgery depends on various factors and the effectiveness of alternative treatment options. It is essential for men with BPH to work closely with their healthcare providers to determine the most appropriate treatment plan based on their individual needs and medical history.
Flomax (tamsulosin) is an alpha-1 adrenergic antagonist commonly prescribed for the treatment of benign prostatic hyperplasia (BPH), which is an enlargement of the prostate gland. BPH can cause urinary symptoms such as frequent urination, difficulty starting urination, weak urine stream, and the sensation of not completely emptying the bladder.
Flomax and other alpha-blockers work by relaxing the smooth muscle in the prostate and bladder neck, making it easier to urinate and relieving BPH symptoms. Besides Flomax, other alpha-blockers used for BPH treatment include:
- Terazosin (Hytrin)
- Doxazosin (Cardura)
- Alfuzosin (Uroxatral)
- Silodosin (Rapaflo)
In addition to alpha-blockers, other treatments for BPH include:
- 5-alpha reductase inhibitors: These medications shrink the prostate by inhibiting the conversion of testosterone to dihydrotestosterone (DHT), which plays a role in prostate growth. Common 5-alpha reductase inhibitors include finasteride (Proscar) and dutasteride (Avodart). These drugs may take several months to show significant improvement in symptoms.
- Combination therapy: In some cases, a combination of an alpha-blocker and a 5-alpha reductase inhibitor may be prescribed to treat BPH more effectively.
- Phosphodiesterase-5 inhibitors: Tadalafil (Cialis) is a phosphodiesterase-5 inhibitor, primarily used for erectile dysfunction, but can also help with BPH symptoms by relaxing smooth muscle in the prostate and bladder.
- Beta-3 adrenergic agonists: Mirabegron (Myrbetriq) is a beta-3 adrenergic agonist, which relaxes the bladder’s detrusor muscle, allowing it to store more urine and reducing urinary urgency and frequency. This medication is primarily used for overactive bladder but may also be helpful for some BPH symptoms.
As there is is some published data on short term outcomes less than 5 years – There simply are no meta analyses studies available looking at these pressing questions:
- how many men end up with a TURP after taking tamsulosin for several years vs no treatment or even how many men with diagnosed BPH end up with a TURP compared to men that took α-adrenergic antagonists, how many get a TURP or other surgery?
- there are no meta study available to tell what is the odds ratio or relative risk as a man developing BPH and getting a TURP
The limitations of studies:
Here are the actual results published on the tamsulosin efficacy:
So in a very small sample size placebo controlled study (no study details available) showed an effect over 4 years. Roughly 57 people out of 1500 were helped. Is that worth the risk of side effects?
That is if you divide 4.5 participants out (of a 100) in the placebo group divided by 2.9 (of a 100) Finasteride – However the final results are pending publication? These are very small numbers. Can you truly conclude that your risk for surgery is reduced?
Most clinical trials such as this one have a small sample size and very short duration!
=with the estimate of 50% to 80% of men develop BPH depending on age and given the large number of prescriptions it is unlikely that taking alpha-blocker and a 5-alpha reductase inhibitors has any long term beneficial effects.
None where helped in the NNT analyses of kidney stone surgery prevention.
Other side effects:
In Conclusion, as clinical studies show that alpha-blocker and a 5-alpha reductase inhibitors certainly initially help with reducing the symptoms of BPH – shockingly the long term side effects are not not available at this time. As such the risk to benefit ratio is not established.
Other alternative treatments to surgery:
PSH Testing:
Levodopa, dopamine agonists and Parkinson’s
First things first – Diagnosis:
Parkinson’s disease (PD) and essential tremor (ET) are two distinct neurological disorders that can sometimes be challenging to differentiate based on clinical presentation alone, as both conditions can cause tremors. However, they have different characteristics and underlying pathophysiology. While there is no single test or marker that can definitively distinguish PD from ET, a combination of clinical features, imaging studies, and response to treatment can help differentiate the two conditions.
Some factors that can help distinguish PD from ET include:
- Tremor characteristics: In PD, the tremor is typically a resting tremor that occurs when the affected body part is at rest and diminishes with voluntary movement. The tremor in ET is usually an action or postural tremor, which worsens with voluntary movement or when maintaining a posture.
- Associated symptoms: In addition to tremors, PD often presents with other motor symptoms such as bradykinesia (slowness of movement), rigidity, and postural instability. Non-motor symptoms, such as constipation, loss of smell, and sleep disturbances, can also occur in PD. ET typically presents with tremors as the primary symptom, and other motor symptoms are usually absent.
- Asymmetry: PD symptoms often begin asymmetrically, affecting one side of the body more than the other. In ET, the tremor is usually symmetrical, affecting both sides of the body.
- Response to treatment: PD tremors usually respond well to levodopa or other dopamine agonist medications. ET tremors, on the other hand, typically do not respond to these medications and are more likely to improve with other treatments such as beta-blockers or anticonvulsant medications.
- Imaging studies: While not routinely used for diagnosis, imaging studies like DaTscan (a dopamine transporter imaging technique) can help differentiate PD from ET by showing reduced dopamine transporter uptake in the brain’s basal ganglia in PD patients, which is not seen in ET patients.
- Genetic factors: Although not definitive, genetic factors can help differentiate PD from ET in some cases. For example, a family history of ET is more likely to suggest ET, whereas specific genetic mutations are associated with some forms of PD.
It is important to remember that the diagnosis of PD or ET should be made by a neurologist or movement disorder specialist who can take into account the full clinical picture, medical history, and response to treatment to arrive at the most accurate diagnosis.
Biochemistry- you cannot measure dopamine!
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in a specific region of the brain called the substantia nigra pars compacta. This neuronal loss leads to alterations in brain biochemistry that contribute to the motor and non-motor symptoms of the disease.
Measuring endogenous dopamine levels in the human brain is challenging and typically requires advanced imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT). These methods can provide indirect measurements of dopamine levels by assessing the density of dopamine receptors or the activity of enzymes involved in dopamine synthesis and metabolism. However, these techniques are not routinely used in clinical practice and are mainly utilized in research settings.
The primary biochemical change in Parkinson’s disease is the depletion of dopamine, a neurotransmitter that plays a crucial role in the regulation of movement, reward, and motivation. The loss of dopaminergic neurons results in reduced dopamine production, leading to imbalances in the basal ganglia’s neural circuits, which are responsible for coordinating movement.
Some of the key biochemical changes in Parkinson’s disease include:
- Dopamine depletion: The progressive loss of dopaminergic neurons leads to a significant reduction in dopamine levels in the brain, particularly in the striatum. This disruption in dopaminergic signaling impairs the normal functioning of the basal ganglia’s motor circuits, leading to the characteristic motor symptoms of PD, such as bradykinesia, rigidity, and resting tremor.
- Alpha-synuclein accumulation: One of the hallmarks of Parkinson’s disease is the presence of Lewy bodies, which are abnormal protein aggregates mainly composed of alpha-synuclein. The exact role of alpha-synuclein in the development of PD is not fully understood, but its accumulation is believed to contribute to neurodegeneration and neuroinflammation.
- Neuroinflammation: Chronic inflammation is thought to play a role in the progression of PD. Microglia, the immune cells of the brain, become activated in response to neuronal damage and can release pro-inflammatory cytokines and reactive oxygen species, which can further exacerbate neuronal injury and contribute to the degeneration of dopaminergic neurons.
- Oxidative stress: The substantia nigra is particularly vulnerable to oxidative stress due to its high metabolic rate and the presence of dopamine, which can generate reactive oxygen species when it is metabolized. The accumulation of reactive oxygen species can damage cellular structures, such as proteins, lipids, and DNA, and contribute to the degeneration of dopaminergic neurons.
- Imbalances in other neurotransmitter systems: In addition to dopamine, other neurotransmitter systems, such as serotonin, norepinephrine, and glutamate, can also be affected in PD. Changes in these neurotransmitter systems can contribute to both motor and non-motor symptoms of the disease.
These biochemical changes in the brain are intricately linked and can influence each other, resulting in a complex and multifaceted disease process. Understanding the underlying biochemistry of Parkinson’s disease is crucial for the development of new therapeutic strategies aimed at slowing or halting the progression of the disease.
While it is not possible to directly measure dopamine levels in the living human brain, there are several non-invasive imaging techniques that can be used to assess the integrity of the dopaminergic system and the substantia nigra in living individuals. These imaging techniques can provide valuable insights into the changes that occur in the brain in Parkinson’s disease (PD) and help in the diagnosis and monitoring of the condition.
Some of the commonly used imaging techniques in PD include:
- DaTscan (Ioflupane I123): This is a type of single-photon emission computed tomography (SPECT) imaging that specifically targets the dopamine transporter (DAT). It can visualize the dopamine transporter in the brain’s basal ganglia and provide indirect evidence of the dopaminergic system’s integrity. A reduction in DAT binding in the striatum is suggestive of dopamine depletion and can help support a diagnosis of PD.
- Magnetic Resonance Imaging (MRI): Conventional MRI can be used to visualize the brain’s anatomy and exclude other structural causes of parkinsonism, such as tumors or vascular lesions. Although it cannot directly assess dopamine levels or the substantia nigra’s functionality, advanced MRI techniques like neuromelanin-sensitive MRI or susceptibility-weighted imaging (SWI) can help visualize changes in the substantia nigra related to PD, such as atrophy or iron accumulation.
- Positron Emission Tomography (PET): PET imaging can provide insights into the brain’s metabolic and molecular processes. In PD, PET imaging can be used to assess the dopaminergic system by targeting specific molecules, such as dopamine receptors or the enzyme responsible for dopamine synthesis (aromatic L-amino acid decarboxylase, AADC). PET imaging can help visualize the dopaminergic system’s functionality and provide information about the severity and progression of PD.
- Functional MRI (fMRI): fMRI measures changes in blood oxygenation levels as an indirect indicator of neural activity. While it cannot directly assess dopamine levels or the substantia nigra’s functionality, fMRI can help evaluate the brain’s functional connectivity and identify changes in the neural networks involved in motor and cognitive processes in PD.
While these imaging techniques can provide valuable information about the dopaminergic system and the substantia nigra in living individuals, they do have limitations. Direct assessment of dopamine levels, Lewy bodies, and detailed cellular changes can only be performed post-mortem through histopathological examination of brain tissue. Nonetheless, the available in vivo imaging techniques can offer important insights into the changes that occur in the brain in PD and help guide diagnosis and treatment.
Levodopa (L-DOPA) has been the gold standard treatment for Parkinson’s disease (PD) since the 1960s. It is a precursor to dopamine that can cross the blood-brain barrier and be converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC) in the brain. This helps to increase dopamine levels and alleviate motor symptoms of PD.
Long-term use of levodopa in Parkinson’s disease can lead to several complications. While levodopa is the most effective medication for controlling the motor symptoms of Parkinson’s disease, its chronic use is associated with adverse effects such as fluctuations, dyskinesias (involuntary movements), toxicity, or loss of efficacy. After about 5 years of treatment, the majority of patients experience these side effects, which can impact their quality of life. However, these adverse effects can be managed to some extent by adjusting the drug regimen, adding other medications, or addressing factors like gastric emptying and dietary influences. Despite these challenges, levodopa remains a key component of therapy for Parkinson’s disease, and its long-term effectiveness maybe maintained with careful management.
The question of whether levodopa may cause more harm than good has been debated, especially concerning the potential for long-term side effects and the development of motor complications, such as dyskinesias (involuntary movements) and motor fluctuations (“wearing off” effect). However, numerous clinical trials and meta-analyses have provided evidence for the efficacy and safety of levodopa in the management of PD.
A meta-analysis published in 2018 by the Cochrane Collaboration reviewed the evidence on the effectiveness of levodopa for treating early-stage Parkinson’s disease (Katzenschlager et al., 2018). The analysis included 44 trials with 7,384 participants and found that levodopa significantly improved motor symptoms and overall quality of life in PD patients compared to placebo or other active treatments, such as dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors.
While the study acknowledged the increased risk of dyskinesias and motor fluctuations with levodopa use, the authors concluded that the benefits of levodopa in terms of motor symptom control and quality of life outweighed the risks of these side effects.
It is essential to note that the management of PD is individualized, and treatment plans should be tailored to each patient’s specific needs and symptoms. The decision to initiate levodopa therapy is typically based on the severity of motor symptoms and the impact on the patient’s quality of life. In some cases, healthcare professionals may opt to start with other medications, such as dopamine agonists or MAO-B inhibitors, to delay the initiation of levodopa and potentially reduce the risk of long-term side effects.
In conclusion, levodopa does have potential side effects, particularly with long-term use and as the overall evidence may support its efficacy and safety in managing Parkinson’s disease short term there is no evidence of its harm vs benefit ratio. Do the benefits of levodopa in improving motor symptoms and quality of life generally outweigh the risks after 10 years of use?
Clinical Studies:
There is a shocking lack of long term studies:
Clinical studies of Levodopa are convoluted by false or missing diagnosis and the use of dopamine agonists as a control. In other words comparing levodopa to other drugs tells you nothing about how effective levodopa is long term:
Anti-depressants
Anti-depressants are a very large topic. It is critical to distinguish between the various classes of medications used in the treatment of psychosis and other mental health disorders. Each class of drug works differently and is used to manage different symptoms or disorders. Here are a few major classes:
- Antipsychotics: Also known as neuroleptics, these drugs are primarily used to treat psychosis, including delusions, hallucinations, and disordered thinking seen in conditions like schizophrenia. Examples include risperidone (Risperdal), olanzapine (Zyprexa), and aripiprazole (Abilify). There are both typical (first generation) and atypical (second generation) antipsychotics.
- Mood Stabilizers: These drugs are mainly used in the treatment of bipolar disorder, which involves episodes of mania and depression. They help to balance mood swings. Lithium and certain anticonvulsants like valproic acid (Depakote) are examples.
- Antidepressants: These medications are used to treat depression, anxiety disorders, and sometimes other conditions. They work by affecting neurotransmitters in the brain, particularly serotonin, norepinephrine, and dopamine. Classes of antidepressants include selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac), serotonin and norepinephrine reuptake inhibitors (SNRIs) like venlafaxine (Effexor), and tricyclic antidepressants (TCAs) like amitriptyline (Elavil).
- Anxiolytics: These drugs are used to relieve anxiety. Benzodiazepines such as diazepam (Valium) and alprazolam (Xanax) are examples. They are typically used for short-term relief of acute symptoms, as they have potential for dependence and withdrawal symptoms.
- Stimulants: Used primarily to treat attention deficit hyperactivity disorder (ADHD), these medications increase the activity of certain neurotransmitters in the brain, enhancing focus, attention, and alertness. Examples include methylphenidate (Ritalin, Concerta) and amphetamine/dextroamphetamine (Adderall).
Each of these drug classes has different side effects, contraindications, and interactions, so healthcare providers take into account a patient’s specific symptoms, overall health, the presence of any other mental or physical health conditions, and other factors when choosing the most appropriate medication.
Depression is typically diagnosed through clinical evaluation rather than direct biological markers. So in essence there is “no biological test”.
Some biological factors have been associated with depression, and ongoing research suggests potential biological markers. Some of these include:
- Hormones: Alterations in cortisol levels, often assessed through a dexamethasone suppression test or measurement of cortisol in saliva, have been linked to depression. However, these findings are not specific or sensitive enough to serve as reliable diagnostic tools for depression.
- Inflammatory markers: Some studies have found associations between depression and increased levels of inflammatory markers, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha). However, these are not specific to depression and can be elevated in many physical health conditions.
- Brain-derived neurotrophic factor (BDNF): Lower levels of BDNF, a protein that supports the survival of existing neurons and encourages the growth of new neurons and synapses, have been linked to depression.
- Genetic markers: Various genes and gene expressions have been linked to an increased risk of developing depression. However, depression is a complex condition thought to result from the interplay of many genes with each other and with environmental factors.
- Neuroimaging: Certain patterns on MRI or PET scans, such as decreased hippocampal volume or altered activity in certain brain regions, have been associated with depression.
The bottom line is that the diagnosis most often involves a mental health professional assessing the person’s symptoms, mental and physical health history, and degree of functional impairment in a subjective way.
“Anti-Depressants”
If there is no test – how do you know how effective anti-depressants really are?
The effectiveness of antidepressants is generally evaluated through symptom-based rating scales and patient self-reports rather than biological markers. These assessment methods aim to measure changes in the severity and frequency of depressive symptoms.
For instance, health professionals commonly use tools like the Hamilton Depression Rating Scale (HDRS), the Beck Depression Inventory (BDI), or the Patient Health Questionnaire (PHQ-9). These scales consist of questions related to the symptoms of depression such as mood, interest in activities, sleep, appetite, concentration, and suicidal thoughts. The patient’s responses to these questions allow clinicians to evaluate the severity of their depression and monitor changes over time.
In clinical trials for antidepressants, patients’ depression levels are measured before and after treatment to determine the drug’s effectiveness. The gold standard for these trials is the randomized controlled trial, where patients are randomly assigned to receive either the drug being tested or a placebo. This design allows researchers to compare the drug’s effects to changes that occur naturally or due to placebo effects.
These scales don’t measure biological changes, its all about subjectively assessing changes in symptoms that matter most to patients—how they feel and function in their daily lives.
The field recognizes that the reliance on patient self-report and clinical evaluation has its limitations, and there’s ongoing research aimed at finding more objective measures (biomarkers) to supplement these traditional assessment methods. As of September 2021, no such biomarkers have been definitively identified or widely adopted in clinical practice.
In 2021, the most commonly prescribed classes of antidepressants include:
- Selective serotonin reuptake inhibitors (SSRIs) – These tend to have fewer side effects than other types of antidepressants and are typically first-line treatment options. Examples include fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro).
- Serotonin and norepinephrine reuptake inhibitors (SNRIs) – These may be an option if an SSRI isn’t effective. Examples include venlafaxine (Effexor), duloxetine (Cymbalta), and desvenlafaxine (Pristiq).
- Tricyclic antidepressants (TCAs) – While these can be as effective as SSRIs, they tend to have more side effects and are usually considered after other options. Examples include amitriptyline (Elavil), imipramine (Tofranil), and nortriptyline (Pamelor).
- Monoamine oxidase inhibitors (MAOIs) – These are typically considered as a last resort, due to necessary dietary restrictions when taking them and potential interactions with other drugs. Examples include phenelzine (Nardil) and tranylcypromine (Parnate).
- Atypical antidepressants – These don’t fit neatly into the other categories. Examples include bupropion (Wellbutrin), mirtazapine (Remeron), and vilazodone (Viibryd).
- Novel drugs like esketamine (Spravato) and ketamine are also used in specific circumstances for treatment-resistant depression.
Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It’s primarily used for major depressive disorder in adult outpatients as well as obsessive-compulsive disorder, panic disorder, and social anxiety disorder in both adults and children. In 2013, it was the most prescribed antidepressant and second most prescribed psychiatric medication (after alprazolam) in the U.S. outpatient sector.
It works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance.
Side effects of sertraline can include nausea, upset stomach, diarrhea, dry mouth, changes in appetite, sleep problems, drowsiness, dizziness, sweating, nervousness, or weight changes.
Like all antidepressants, sertraline carries a black box warning from the FDA about an increased risk of suicidal thinking and behavior in children, adolescents, and young adults, particularly within the first few months of treatment or when the dose is changed.
Number Needed to Treat (NNT) is a measurement that’s often used in healthcare statistics. It refers to the number of patients you need to treat to prevent one additional bad outcome (like hospitalization, or in this case, one additional patient having an improvement in their depression symptoms).
As of September 2021, there is no specific NNT value for sertraline because it can vary widely depending on the specifics of the patient population and how their subjective symptoms are interpreted.
In summary, The effectiveness of antidepressants has been scrutinized, especially considering the closeness of results between these drugs and placebos in clinical trials.
- The placebo effect: In clinical trials, it is indeed possible that the placebo effect contributes to the observed benefits of antidepressants. Participants may report feeling better due to the expectation of improvement, not the drug itself. Moreover, side effects from the medication could potentially lead to ‘unblinding’, where patients and doctors deduce who is on the active drug versus the placebo, further complicating interpretation of the results.
- The serotonin theory: The hypothesis that depression is caused by a deficiency of serotonin in the brain has been influential in depression research for decades. This theory has indeed faced criticism, as it is an oversimplification and doesn’t account for the complexity of depression, including its causes, symptoms, and treatments. Many researchers now believe depression involves a range of biological, psychological, and social factors, not just a single neurotransmitter deficiency.
These debates underscore the complexity of depression as a disorder and the challenges in developing effective treatments. As seen above, it is far more important to address biomarkers such as hormones and inflammation and over-all health and nutrition and life style than the though that ‘a pill can cure depression’.
Omeprazole and other proton pump inhibitors
Some studies have suggested a possible association between long-term use of proton pump inhibitors (PPIs) like omeprazole and an increased risk of certain types of cancer, including gastric (stomach) cancer. The theory behind this possible connection relates to the fact that PPIs reduce the production of stomach acid, which can lead to an overgrowth of bacteria in the stomach and changes in the stomach lining that could potentially increase cancer risk.
However, it’s important to understand that this is a complex issue and the evidence is not definitive. The overall risk is still considered to be low, and many people use PPIs for long periods without developing cancer. Furthermore, it’s not clear whether the increased risk is due to the PPIs themselves or other factors. For example, people who use PPIs are more likely to have other risk factors for stomach cancer, such as infection with Helicobacter pylori bacteria or long-term inflammation of the stomach.
Long term use of Oxycodone, Tramadol and Gabapentin
Although certainly used for different purposes both Oxycodone and Gabapentin are affecting pain receptors in the brain and have profound affects on brain chemistry when used long term.
=> Brain and nerve chemistry is changed in such a way that normal thresholds of pain levels are now producing pain in many parts of the body even if there is no apparent physical reason for the pain
=> Inflammatory processes directed by the brain pain centers are never controlled and may increase
=> normal nerve signals are becoming dysfunctional and creating a confusing signal in the CNS processing of pain signals and hyperalgesia
While both oxycodone and gabapentin are used to manage pain, they have different mechanisms of action and affect the brain in different ways.
Oxycodone is an opioid analgesic, which works by binding to opioid receptors in the brain, spinal cord, and other areas of the central nervous system. By binding to these receptors, oxycodone alters the perception of pain and produces a sense of euphoria. Long-term use of opioids like oxycodone can lead to dependence, addiction, and significant changes in brain chemistry, such as the downregulation of endogenous opioid receptors and neurotransmitter systems. This may result in increased pain sensitivity (hyperalgesia) and a reduced ability to experience pleasure (anhedonia) when the drug is discontinued.
Gabapentin, on the other hand, is an anticonvulsant medication primarily used to treat seizures, neuropathic pain, and restless legs syndrome. Its mechanism of action involves binding to the alpha-2-delta subunit of voltage-gated calcium channels, reducing calcium influx into nerve cells, and decreasing the release of excitatory neurotransmitters. This reduces neuronal hyperexcitability and the abnormal electrical activity associated with neuropathic pain. While long-term use of gabapentin can lead to some changes in brain chemistry, the risk of dependence and addiction is considered to be lower than with opioid medications.
Both medications can have profound effects on brain chemistry when used long-term, but the specific ways in which they interact with the brain and their potential for causing dependence or addiction are different. It is essential to use these medications under the supervision of a healthcare professional who can monitor for side effects, adjust dosages, and ensure appropriate use.
Gabapentin has side effects, especially if taken for a long time or in high doses. Some of the possible long-term effects of gabapentin are:
- Kidney problems: Gabapentin can cause toxicity in people with kidney disease, which can be fatal1. It can also affect the kidney function and increase the risk of kidney stones2.
- Memory loss: Gabapentin can impair the cognitive function and cause memory problems, especially in older adults23.
- Muscle weakness: Gabapentin can reduce the muscle strength and cause fatigue, tiredness, or weakness23.
- Respiratory failure: Gabapentin can affect the breathing and cause respiratory depression, which can be life-threatening23.
It’s important to remember that while gabapentin can help manage symptoms short term, it doesn’t treat the underlying cause of the nerve damage nor is it really a pain medication. It’s crucial to identify the underlying cause of the nerve damage, as different causes can require different treatments. For example, nerve damage due to diabetes might require tighter blood sugar control, while nerve damage due to a vitamin B12 deficiency might require B12 supplementation.
In summary, gabapentin is often used off-label and is not meant to be a pain medication nor should it be prescribed for insomnia. It has severe side effects and a risk for Hyperalgesia discussed below.
Vicodin is a combination of two drugs:
- Hydrocodone: This is an opioid pain medication, or sometimes called a narcotic.
- Acetaminophen: This is a less potent pain reliever that increases the effects of hydrocodone.
Hydrocodone works in the brain to change how your body feels and responds to pain. Acetaminophen can also reduce a fever. This combination medication is not typically used for long-term treatment or for ongoing pain unless specifically directed by your doctor due to the risk of addiction and other potential side effects.
As of my knowledge cutoff in 2021, Vicodin is classified as a Schedule II drug in the United States, which means it’s considered to have a high potential for abuse, potentially leading to severe psychological or physical dependence.
Possible side effects of Vicodin can include dizziness, lightheadedness, nausea, vomiting, constipation, and addiction, among others. Overdose or misuse can lead to severe liver damage, respiratory distress, or death. Always use Vicodin under the supervision of a healthcare professional and according to the prescribed directions.
Vicodin enhances the relationship between chronic pain and a systemic inflammatory state of the body.
Tramadol (brand name Ultram, among others) is a centrally acting opioid analgesic used in the treatment of moderate to moderately severe pain. It was first launched in Germany in 1977 and has since been used to treat pain in over 100 countries.
Tramadol is somewhat unique among opioids due to its dual mechanism of action. It works by both binding to the µ-opioid receptor and by inhibiting the reuptake of serotonin and norepinephrine. This combination is thought to provide more comprehensive pain relief than opioids that work through only one of these mechanisms.
Common side effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, headache, and somnolence.
Like all opioid medications, tramadol is no different and has the potential for abuse and addiction, and it should be used with caution in individuals with a history of substance abuse. Furthermore, it has been associated with a risk of serotonin syndrome when combined with other drugs that increase the levels of serotonin in your body, and it can interact with a number of other medications, so it’s important to discuss all the medications you are taking with your doctor or pharmacist.
Tramadol, like all opioids, has the potential to cause hyperalgesia.
Hyperalgesia – systemic pain
Long-term use of opioids like oxycodone can lead to a phenomenon known as opioid-induced hyperalgesia (OIH). OIH is a paradoxical increase in pain sensitivity that occurs in some individuals after prolonged exposure to opioids. The exact mechanism behind OIH is not fully understood, but several factors are thought to contribute to this phenomenon:
- Changes in opioid receptors: Long-term opioid use can lead to changes in the number and sensitivity of opioid receptors in the central nervous system. This can result in the downregulation of receptors, making them less responsive to the effects of opioids and potentially contributing to increased pain sensitivity.
- Activation of pronociceptive pathways: Opioids like oxycodone can activate certain pain-signaling pathways in the central nervous system, known as pronociceptive pathways. These pathways can counteract the pain-relieving effects of opioids and contribute to the development of OIH.
- Neuroplasticity and central sensitization: Long-term opioid use can cause changes in the structure and function of neurons in the brain and spinal cord. This can result in central sensitization, a phenomenon where the central nervous system becomes more responsive to pain signals, leading to increased pain sensitivity.
- Changes in neurotransmitter systems: Opioids can affect the balance of neurotransmitters like dopamine, serotonin, and glutamate in the brain. Prolonged use of opioids can alter these neurotransmitter systems, potentially contributing to increased pain sensitivity.
- Inflammation: Some research suggests that long-term opioid use may increase the release of inflammatory substances in the central nervous system, which could contribute to increased pain sensitivity.
It is important to note that not everyone who uses opioids long-term will develop OIH, and the risk factors for this phenomenon are not fully understood. However, the potential for OIH highlights the need for careful monitoring and appropriate management of pain in individuals using opioids for extended periods. In some cases, alternative pain management strategies or a reduction in opioid dosage may be necessary to address OIH and optimize pain control.
Opioid-induced hyperalgesia (OIH) is a condition where exposure to opioids causes an increased sensitivity to pain. It is a paradoxical effect of opioid therapy, meaning that the drugs that are supposed to relieve pain may actually make it worse in some cases. OIH has been well documented in animal studies, but the evidence in human studies is less consistent1. Some factors that may affect the development of OIH include the type, dose, and duration of opioid use, as well as the individual characteristics of the patient2. The exact mechanism of OIH is not fully understood, but it may involve changes in the brain and spinal cord that enhance the transmission of pain signals2. Some possible ways to prevent or treat OIH include reducing the opioid dose, switching to a different opioid, or adding other medications that block certain receptors involved in pain processing3.
More References discussing opioid-induced hyperalgesia and the potential mechanisms behind it:
- Lee, M., Silverman, S. M., Hansen, H., Patel, V. B., & Manchikanti, L. (2011). A comprehensive review of opioid-induced hyperalgesia. Pain Physician, 14(2), 145-161.
- Raffa, R. B., Pergolizzi, J. V., & Taylor, R. (2018). Opioid-induced hyperalgesia: clinical implications for the pain practitioner. Pain Management, 8(3), 215-223.
- Tompkins, D. A., Campbell, C. M. (2011). Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Current Pain and Headache Reports, 15(2), 129-136.
- Roeckel, L. A., Le Coz, G. M., Gavériaux-Ruff, C., & Simonin, F. (2016). Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience, 338, 160-182.
These articles discuss the phenomenon of opioid-induced hyperalgesia, its clinical implications, and the potential mechanisms that contribute to its development. These references should provide you with a solid overview of the topic and a starting point for further research if desired.
Pregabalin-lyrica
Lyrica (pregabalin) is an anticonvulsive drug that inhibits voltage gated calcium channels. However it is used to treat various conditions, including nerve pain (neuropathic pain) associated with diabetes or shingles, fibromyalgia, and partial onset seizures in adults with epilepsy. It works by affecting chemicals in the brain that send pain signals across the nervous system. Lyrica can have serious side effects and may not be suitable for everyone, so it’s important to use it under the guidance of a healthcare professional.
Some common side effects of Lyrica (pregabalin) include dizziness, sleepiness, dry mouth, swelling of the hands and feet, blurred vision, weight gain, and difficulty concentrating. In rare cases, it can cause more serious side effects like allergic reactions, muscle pain, and changes in mood or behavior. It’s important to discuss any side effects with a healthcare professional and to follow their guidance when taking Lyrica. For more detailed information, you can refer to the official prescribing information.
In placebo-controlled trials for pain medications like Lyrica (pregabalin), pain scores are typically calculated using standardized pain rating scales. These scales can be numerical (e.g., 0-10, with 0 being no pain and 10 being the worst pain imaginable) or descriptive (e.g., mild, moderate, severe). Patients are asked to rate their pain at various intervals during the study. The difference in pain scores between the active medication group and the placebo group is then analyzed to assess the medication’s effectiveness.
So in summary out of a 10 of 10 pain score you are gaining 0.5 subjective points over placebo. But at the same time studies show a 33% higher risk of adverse effects!
Amitriptyline is a medication that belongs to a class of drugs known as tricyclic antidepressants (TCAs). It is primarily used to treat depression, but it is also commonly prescribed for other conditions, including:
- Neuropathic Pain: Amitriptyline is often used to manage chronic pain conditions, such as neuropathic pain, fibromyalgia, and postherpetic neuralgia.
- Migraine Prevention: It can be prescribed as a preventive treatment for migraines and chronic tension-type headaches.
- Insomnia: Amitriptyline is sometimes used off-label to treat insomnia, especially when the sleep disturbance is associated with depression or anxiety.
- Anxiety Disorders: Although not a first-line treatment, it can be used for certain anxiety disorders.
The exact mechanism of action of amitriptyline is not fully understood, but it is believed to work by increasing the levels of certain neurotransmitters in the brain, such as serotonin and norepinephrine, which help regulate mood and pain perception.
Amitriptyline can cause serious side effects, some of which include dry mouth, drowsiness, weight gain, constipation, and blurred vision and neuropathy. Due to its potential side effects and interactions with other medications, it should be used under the guidance of a healthcare professional. It’s also important to note that it can take several weeks for the full effects of amitriptyline to be felt.
Xanax-Alprazolam-tranquilizers
Alprazolam is a medication in the benzodiazepine family. The history of benzodiazepines begins in the mid-20th century with the discovery of the first benzodiazepine, chlordiazepoxide (Librium), in the late 1950s.
Chlordiazepoxide was discovered accidentally by the Austrian scientist Leo Sternbach while he was working for the pharmaceutical company Hoffmann-La Roche. The medication had a calming effect and was found to be safer and less addictive than barbiturates, the prevailing anti-anxiety medication at the time.
The success of Librium led to the development of other benzodiazepines, including diazepam (Valium), which was introduced in 1963 and quickly surpassed Librium in popularity due to its greater potency.
Alprazolam (Xanax) is a more recent addition to the benzodiazepine family. It was first patented in 1969 and later approved for medical use in the United States in 1981. Since then, it has become one of the most commonly prescribed medications for anxiety and panic disorders.
Over the years, the use of benzodiazepines has been marked by cycles of popularity and controversy. While they are effective for many people in managing anxiety, insomnia, seizures, and a few other conditions, they also have a high potential for abuse and dependence, especially with long-term use. There has been increasing attention in recent years to the risks of overprescription and misuse of these medications.
Alprazolam, sold under the brand name Xanax among others, is a short-acting tranquilizer of the benzodiazepine class, which produces a calming effect. It is used to manage conditions like anxiety and panic disorders. However, long-term use of alprazolam may lead to a number of negative effects.
Here are some potential side effects and risks of long-term alprazolam use:
- Physical Dependence and Withdrawal: This is a major concern with long-term use. Over time, the body becomes accustomed to the presence of the drug, and if it’s abruptly discontinued, withdrawal symptoms can occur. These can include seizures, anxiety, restlessness, and in severe cases, hallucinations and psychosis.
- Tolerance: The body may become tolerant to the effects of alprazolam over time, which means higher doses may be required to achieve the same effects.
- Cognitive Impairment: Long-term use of alprazolam can affect cognition, causing problems with memory, concentration, and decision-making.
- Emotional Effects: Alprazolam can cause mood swings, depression, and emotional blunting or numbing over the long term.
- Risk of Overdose: The risk of overdose increases with long-term use, particularly if alprazolam is used in combination with other depressant substances like alcohol.
- Rebound Symptoms: Upon discontinuation, especially abruptly, symptoms of the initial disorder (anxiety, panic attacks) may return and could potentially be worse than before.
It’s important to note that alprazolam should always be used under the guidance of a healthcare provider. If a person wishes to stop using alprazolam, it should be done slowly under a doctor’s supervision to manage withdrawal symptoms and avoid rebound effects.
In summary, given the large number of prescriptions over 80 years history, this is a “safe” drug. However it is a psychotropic and the price on brain chemistry of long term use is high. Benzos are very effective on short term anxiety attacks when nothing else helps. Then they should be used continuously for a week or 2 every 3-5 hours (depending on the exact prescription) to avoid a rebound effect. Taking benzos irregular for eg. insomnia is only counter productive and the underlying causes are never addressed.
Many people take Benzos on and off for insomnia. Here is what that does to you:
Temazepam is a benzodiazepine used primarily for the treatment of insomnia. Like other benzodiazepines, temazepam works by enhancing the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain, leading to sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties.
There is evidence to suggest that benzodiazepines, in general, can affect the secretion of melatonin:
- Melatonin Secretion: Some studies have suggested that benzodiazepines might suppress melatonin secretion. However, the exact effect might vary depending on the specific benzodiazepine and the timing of its administration.
- Sleep Architecture: Benzodiazepines can alter sleep architecture, which includes changes in the proportions of different sleep stages such as reduced proportion of REM (rapid eye movement) sleep. Since melatonin plays a role in regulating sleep-wake cycles, any medication that affects sleep can potentially impact the natural rhythm of melatonin release indirectly.
- Circadian Rhythm: Benzodiazepines might also have an effect on the body’s circadian rhythm. Since melatonin is a key hormone involved in regulating the circadian rhythm, there could be indirect effects on melatonin secretion.
It’s essential to remember that the relationship between benzodiazepines, sleep, and melatonin is complex. Alternatively we suggest mental training such as silvamethod.com or NVC to help with sleep issues. Good “sleep hygiene” needs to be practiced, e.g. no electronics or food in bed.
Adderall
Adderall is a stimulant medication that primarily affects chemicals in the brain, such as dopamine and norepinephrine, which contribute to hyperactivity and impulse control. However, it can also have peripheral effects on the body, including impacts on the cardiovascular system.
Stimulants like Adderall can cause increased heart rate, increased blood pressure, and vasoconstriction (narrowing of blood vessels), all of which are normal responses to stimulant medications.
Raynaud’s disease is a condition where the small blood vessels in the extremities (like fingers and toes) constrict excessively in response to cold or stress, leading to episodes of reduced blood flow, causing pallor (whiteness), cyanosis (blueness), pain and discomfort in the affected areas.
Given that both Adderall and Raynaud’s disease can cause vasoconstriction, it’s theoretically possible that taking Adderall could exacerbate the symptoms of Raynaud’s disease. Therefore, individuals with Raynaud’s disease should discuss the potential risks and benefits with their healthcare provider before starting a medication like Adderall.
Long-term use of Adderall, a prescription stimulant primarily used to treat attention deficit hyperactivity disorder (ADHD), has been subject to numerous studies, but the overall evidence base is mixed. While some studies suggest that long-term use can be safe and effective, others highlight potential concerns about dependence, cardiovascular effects, and other adverse outcomes.
- Dependence and Addiction: Some studies suggest that long-term use of Adderall can lead to physical dependence and, in some cases, addiction, particularly when the drug is used improperly (such as being taken in higher doses or by methods other than prescribed).
- Cardiovascular Effects: While rare, there are potential risks of serious cardiovascular events, such as stroke or heart attack, particularly in those with pre-existing heart conditions.
- Psychiatric Effects: There are also concerns about potential psychiatric effects, such as increased anxiety, depression, and sleep disturbances. Some people may experience a worsening of these symptoms over time.
- Efficacy: Some studies show that the benefits of Adderall for treating ADHD can persist over the long term, but these studies often rely on subjective self-reports rather than objective measures.
Given the potential risks associated with long-term use, it’s important that individuals taking Adderall do so under the supervision of a healthcare provider, who can monitor for any adverse effects and adjust treatment as necessary. Long-term users should have regular check-ups to monitor their physical and mental health.
In Summary, again there is very little science behind the use of this drug and no biomarkers. The risk vs benefit is difficult to decide and depends on subjective measure.
Warfarin and other blood thinners
Warfarin (Coumadin) and several other anticoagulants, or “blood thinners,” are commonly used in clinical practice. These include:
- Direct Oral Anticoagulants (DOACs): These are a newer class of anticoagulants that directly inhibit either thrombin or factor Xa, two key enzymes involved in the blood clotting process.
- Dabigatran (Pradaxa): Dabigatran is a direct thrombin inhibitor.
- Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa): These are Factor Xa inhibitors.
- Antiplatelet Drugs: These are medications that prevent platelets in the blood from sticking together and forming clots. They’re often used for different indications than anticoagulants.
- Aspirin: Aspirin inhibits the function of platelets to prevent clots from forming.
- Clopidogrel (Plavix), Prasugrel (Effient), Ticagrelor (Brilinta): These drugs are often used to prevent clotting after a heart attack or stroke, or in people with certain heart or blood vessel conditions.
- Injectable Anticoagulants: These are often used in hospitals and for short-term use at home.
- Heparin and Low-Molecular-Weight Heparins (LMWHs) like Enoxaparin (Lovenox): These are often used in the hospital setting or in the initial treatment of conditions like deep vein thrombosis (DVT) or pulmonary embolism (PE).
- Fondaparinux (Arixtra): This is a synthetic anticoagulant that specifically inhibits Factor Xa.
All blood thinners have the potential for side effects, including an increased risk of bleeding.
This is where blood thinners inhibit the natural clotting cascade!
Harms in NNT
- Bleeding: This is the most common and serious side effect of warfarin use. It can occur in any tissue or organ. The signs and symptoms of bleeding may include pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow, or unexplained nosebleeds.
- Skin necrosis: This refers to damage and death of skin tissue, which can happen when blood clots form in the blood vessels of the skin. It is a rare side effect, but it can be serious.
- Purple toes syndrome: This is another rare side effect of warfarin use, causing a person’s toes to turn purple due to cholesterol emboli that occur during treatment.
- Allergic reactions: Some people might have allergic reactions to warfarin, which can include hives, rash, itching, difficulty breathing, or swelling of the face, lips, tongue, or throat.
- Other side effects can include nausea, vomiting, diarrhea, bloating, and changes in the way food tastes.
An odds ratio (OR) of 0.39 implies that the odds of the outcome (in this case, having a stroke) in the treatment group is 0.39 times compared to the odds in the control (or placebo) group. In other words, the odds of having a stroke are 61% lower in the treatment group than in the placebo group. This is a relative measure of effect and you have to look at the absolute numbers. In addition the question remains what was used as placebo. EG. Aspirin is not a placebo – its a drug with massive side effects!
According to Heart 2005: The inherent risk of stroke should be considered in the decision to use OACs in AF patients, selecting those who stand to benefit most for this therapy (Hart 1998, Laupacis 1998). For example, among high‐risk AF patients with prior stroke or TIA who have stroke rates of about 12% per year, about 70 strokes would be prevented yearly per 1000 AFib patients given warfarin, whereas for low‐risk AF patients (with a stroke rate of about 2% per year), only 12 strokes would be prevented per 1000. These numbers leave the risk to benefit ratio very questionable and certainly not 39% effective.
In addition many studies included in the meta analyses are biased: “Several potential caveats pertain to generalizing these results from clinical research to clinical practice. Participants in these trials were, on average, younger than AF patients in the general population (Feinberg 1995; Go 2001). Older AF patients have higher rates of ischemic stroke, but also higher rates of bleeding associated with anticoagulation, so that the risk‐benefit equation may not be identical to that characterized in this meta‐analysis. ”
Once again the absolute numbers of strokes is very small: “With the annualized rate of ischemic stroke in the control group of about 4% per year, the absolute reduction by OACs was about 2.6% per year for participants without prior stroke or TIA, or about 25 ischemic strokes saved yearly per 1000 participants given warfarin.”
The question one has to answer is if saving 25 strokes per 1000 is worth the serious side effects mentioned above.
Salah2023: ” Eleven studies fulfilled all the inclusion criteria and were included in the present meta-analysis enrolling 144,502 patients. However this meta analyses is an example in deception. It says nothing other than which anticoagulants are potentially more effective than others…
_No absolute numbers are given how many strokes where saved.
_Instead of a placebo control a ‘comparator’ is used
In this study, relative risk was chosen and the lowered risk for apixaban overall is 17% lower than taking rivaroxaban; again no absolute numbers are given other than out of about 550,000 participants there were 4750 ‘events’ (0.87%) on apixaban vs 5850 on rivaroxaban [see Fig. 5]. The assumption can be made that the odds ratio was not used here because it was not statistically significant.
It is very difficult to get some absolute numbers of your “non-medicated” stroke risk:
But Here you can clearly see how small the effects of rivaroxaban vs Aspirin really are. Out of 9,100 participants only ~30 less events were recorded. As a matter of fact your risk of hemorrhagic stroke increases on rivaroxaban.
In conclusion, always look at the absolute numbers: “how many strokes are prevented and weigh the risks when making a decision on taking blood thinners.”
Blood-thinners for AFib
Atrial fibrillation (AFib) is not typically considered immediately life-threatening, but it is a serious medical condition that can lead to significant health complications if left untreated. The main concern with AFib is its association with an increased risk of stroke, which can be life-threatening. In theory the irregular heartbeats of AFib can cause blood to pool and form clots in the atria, and these clots can travel to the brain, leading to a stroke.
Here are the stats: Atrial fibrillation (AFib) significantly increases the risk of both heart failure and stroke:
- Stroke: AFib is a major risk factor for stroke, increasing the risk by about 4-5 times compared to those without AFib. This heightened risk is due to the irregular heartbeats associated with AFib, which can lead to the formation of blood clots in the heart. These clots can then travel to the brain, causing a stroke.
- Heart Failure: AFib is also associated with an increased risk of developing heart failure. The irregular and often rapid heart rate in AFib can impair the heart’s ability to pump blood effectively, leading to heart failure. The exact increase in risk varies depending on other factors such as age, the presence of other heart conditions, and the duration of AFib. Some research studies have consistently shown that AFib is associated with an increased risk of heart failure. For example, In subjects from the original cohort of the Framingham Heart Study, AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related. The specific RR values reported in different studies may vary, but the overall conclusion is that AFib is a significant risk factor for heart failure.
The increased risks of stroke and heart failure highlight the importance of managing AFib through appropriate treatment strategies, including anticoagulation to prevent stroke and medications to control heart rate and rhythm, as well as addressing any underlying conditions.
But what does “Effective management” of AFib look like? It usually includes the use of anticoagulants to “reduce” the risk of stroke and medications to control heart rate and rhythm, can help mitigate these risks. So this essentially ties into the discussion above.
Patients with non-valvular atrial fibrillation with diabetes face increased stroke and cardiovascular risks. Why is that? =metabolic disease
First of all again: using blood thinners has a small measurable effect on stroke and hemorrhage:
HR of 0.37 DOES NOT mean that your risk is lowered by 73% percent. Similar to OR:
The hazard ratio (HR) and the relative risk (RR) are both measures used in epidemiological studies to compare the risk of an event between two groups, but they are not the same.
- Relative Risk (RR): This is a measure used primarily in cohort studies. It represents the ratio of the probability of an event occurring in the exposed group to the probability of the event occurring in the unexposed (control) group. For example, if the risk of developing lung cancer in smokers is 20% and in non-smokers is 5%, the RR of developing lung cancer for smokers compared to non-smokers is 20% / 5% = 4. This means that smokers are 4 times as likely to develop lung cancer as non-smokers.
- Hazard Ratio (HR): This is a measure used primarily in survival analysis, particularly in the context of time-to-event data. It represents the ratio of the hazard rates (the instantaneous rate of the event occurring at a given point in time) between two groups. The HR is often estimated using the Cox proportional hazards model. An HR of 1 indicates no difference in risk between the two groups, an HR greater than 1 indicates a higher risk in the exposed group, and an HR less than 1 indicates a lower risk in the exposed group.
While both RR and HR provide information about the strength of association between an exposure and an outcome, they are used in different contexts and are not interchangeable. The choice between using RR or HR depends on the study design and the nature of the data being analyzed.
That is why the all cause mortality is about the same in the above analyses.
Now what about AFIB itself…
Non-vitamin K antagonist oral anticoagulants (NOACs), also known as direct oral anticoagulants (DOACs), are a class of medications used to prevent and treat blood clots. Unlike traditional anticoagulants like warfarin, which work by inhibiting vitamin K-dependent clotting factors, NOACs directly target specific proteins in the clotting cascade.
The main NOACs include:
- Dabigatran (Pradaxa): Directly inhibits thrombin (factor IIa), which is a key protein in the final step of the clotting cascade.
- Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa): Directly inhibit factor Xa, an important protein in the middle of the clotting cascade.
NOACs are used for various indications, including:
- Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
- Treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE).
- Prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery.
Advantages of NOACs over warfarin include a more predictable anticoagulant effect, fewer dietary and drug interactions, and no need for routine blood monitoring. However, NOACs may not be suitable for all patients, and their use should be guided by a healthcare professional based on individual patient factors and clinical guidelines.
This means that some NOACs have a slight advantage over warfarin in patients with valve disease. However rivaroxaban versus warfarin increased major bleeding (HR: 1.56; 95% CI, 1.20–2.04) by almost twice.
In summary, the the “treatment” of AFIB is questionable and there maybe no relationship with stroke. Why else would you employ blood thinners? The underlying causes such as coronary heart disease an valve disease not addressed.
On the contrary : “The combined overall rate of warfarin-related adverse events and potential events was 25.5 per 100 resident months on warfarin therapy.”
Given the small effect on life threatening events this benefit to risk ratio is questionable.
Antiarrhythmics
Antiarrhythmic drugs can be lifesaving in managing arrhythmias short term, but they come with a range of potential side effects used long term.
These drugs are never specific to just the heart muscle channels. As an example Dofetilide blocks the hERG potassium channel which delays the repolarization of cardiac myocytes. The IKr current is crucial in cardiac tissues but is also found in the CNS, smooth muscle cells, and some endocrine and gastrointestinal tissues. While drugs like dofetilide aim to selectively inhibit the IKr current, complete specificity is challenging. Therefore, at higher doses or with certain drugs like amiodarone, there can be cross-affinity to other ion channels, including sodium, calcium, and other potassium channels.
These effects vary depending on the specific class of antiarrhythmic and individual patient factors. Below is an overview of the common side effects associated with different classes of antiarrhythmics:
- 1. Class I Antiarrhythmics (Sodium Channel Blockers)
Examples: Quinidine, Procainamide, Disopyramide, Flecainide
Side Effects:
Cardiac Toxicity: These drugs can exacerbate existing arrhythmias or cause new ones, particularly in patients with underlying heart disease. Quinidine and procainamide are known to cause Torsades de Pointes.
Gastrointestinal Issues: Quinidine is associated with nausea, diarrhea, and abdominal discomfort.
Autoimmune Reactions: Procainamide can lead to drug-induced lupus in some patients, characterized by joint pain, fever, and a positive ANA test.
Anticholinergic Effects: Disopyramide can cause dry mouth, urinary retention, and blurred vision due to its anticholinergic activity.
2. Class II Antiarrhythmics (Beta-Blockers)
Examples: Propranolol, Metoprolol, Atenolol
Side Effects:
Bradycardia: Excessive slowing of the heart rate, leading to fatigue, dizziness, and hypotension.
Bronchospasm: Particularly in non-selective beta-blockers (like propranolol), which can trigger asthma symptoms in predisposed individuals.
Hypoglycemia: Beta-blockers can mask the symptoms of hypoglycemia, which is especially concerning for diabetic patients.
Sexual Dysfunction: Reduced libido and erectile dysfunction are possible with long-term use.
3. Class III Antiarrhythmics (Potassium Channel Blockers)
Examples: Amiodarone, Sotalol, Dofetilide
Side Effects:
Pulmonary Toxicity: Amiodarone can cause pulmonary fibrosis, presenting as a chronic cough or shortness of breath, which can be life-threatening if not managed.
Thyroid Dysfunction: Amiodarone contains iodine and can cause both hypothyroidism and hyperthyroidism.
Ocular Toxicity: Corneal deposits, optic neuropathy, and blurred vision can occur with amiodarone.
Hepatotoxicity: Elevated liver enzymes and, in rare cases, liver failure.
Torsades de Pointes: Particularly with sotalol and dofetilide, due to significant QT prolongation.
4. Class IV Antiarrhythmics (Calcium Channel Blockers)
Examples: Verapamil, Diltiazem
Side Effects:
Bradycardia and AV Block: Due to the suppression of the AV node, which can slow down the heart rate excessively.
Peripheral Edema: Common in calcium channel blockers, causing swelling of the legs and feet.
Constipation: More common with verapamil due to its effect on smooth muscle relaxation.
Hypotension: Resulting in dizziness or fainting episodes.
5. Miscellaneous (e.g., Digoxin, Adenosine)
Digoxin:
Toxicity: Digoxin toxicity can present with nausea, vomiting, confusion, and visual disturbances such as seeing “yellow halos.” It can also trigger arrhythmias, especially in patients with low potassium levels.
Adenosine:
Transient Effects: Adenosine is administered rapidly and can cause transient effects like flushing, chest discomfort, shortness of breath, and a feeling of impending doom due to its brief, intense slowing of the heart rate.Summary:
Using beta-blockers long term and blocking sodium and potassium channel long term cant be a good idea. The side effects of antiarrhythmics are often related to their mechanisms of action. For example, drugs that block sodium or potassium channels can prolong repolarization, increasing the risk of dangerous arrhythmias. Those that affect beta or calcium channels can cause bradycardia or heart block. Additionally, some drugs like amiodarone have effects on multiple organs, requiring careful monitoring and dose adjustment.
Long QT Syndrome With Drugs Used in the Management of Arrhythmias: A Systematic Review
Long QT syndrome (LQTS) is a heart rhythm condition that can cause fast, chaotic heartbeats, leading to fainting, seizures, or even sudden death. It is often triggered by certain medications, including antiarrhythmic drugs. These medications can prolong the QT interval on an ECG, increasing the risk of potentially life-threatening arrhythmias like Torsades de Pointes (TdP). Here’s how each of the mentioned medications contributes to this risk:
1. Amiodarone:
- Mechanism: Amiodarone is a class III antiarrhythmic that works by blocking potassium channels, which delays repolarization of the heart muscle cells and increases the QT interval. It is used to treat a variety of arrhythmias but carries a risk of inducing LQTS.
- Risk Profile: Although amiodarone is associated with QT prolongation, its propensity to cause Torsades de Pointes is lower compared to other class III agents due to its multiple effects on different ion channels. Still, prolonged use or high doses increase the risk.
2. Sotalol:
- Mechanism: Sotalol is another class III antiarrhythmic with additional beta-blocker activity. It prolongs the QT interval by blocking potassium channels responsible for repolarization.
- Risk Profile: Sotalol is one of the more commonly cited drugs in causing drug-induced LQTS and Torsades de Pointes. This risk is dose-dependent, increasing significantly at higher doses or with renal impairment, which affects the drug’s clearance.
3. Dofetilide:
- Mechanism: Dofetilide is a pure class III antiarrhythmic that specifically blocks the delayed rectifier potassium current (IKr), leading to significant prolongation of the QT interval.
- Risk Profile: Due to its specific mechanism, dofetilide is strongly associated with the risk of Torsades de Pointes and is therefore used with caution. Its use often requires hospitalization and monitoring during initiation to minimize the risk of life-threatening arrhythmias.
4. Procainamide:
- Mechanism: Procainamide is a class IA antiarrhythmic that blocks sodium channels and IKr potassium channels. This dual effect prolongs the action potential and the QT interval.
- Risk Profile: The combination of sodium and potassium channel blocking effects gives procainamide a relatively high risk of inducing QT prolongation and subsequent Torsades de Pointes, particularly with high doses or in cases of renal impairment.
5. Quinidine:
- Mechanism: Quinidine is another class IA antiarrhythmic, which prolongs the QT interval by blocking both sodium and potassium channels. It is also known to block calcium channels to some extent.
- Risk Profile: Quinidine is associated with a high risk of causing Torsades de Pointes, especially when used in combination with other QT-prolonging medications or in the presence of electrolyte imbalances (like low potassium or magnesium).
6. Flecainide:
- Mechanism: Flecainide is a class IC antiarrhythmic that primarily blocks sodium channels and has minimal effect on potassium channels. However, it can still prolong the QT interval in some patients, particularly at higher doses.
- Risk Profile: Flecainide has a lower risk of causing Torsades de Pointes compared to the other drugs mentioned, but it can cause other arrhythmias, especially in patients with underlying structural heart disease.
Summary:
Each of these medications can prolong the QT interval through different mechanisms, primarily by blocking potassium channels responsible for cardiac repolarization. This prolongation increases the risk of dangerous arrhythmias like Torsades de Pointes. The degree of risk varies based on the drug’s specific mechanism, dosage, patient factors (such as age, electrolyte levels, or renal function), and concurrent use of other QT-prolonging drugs.
Acetaminophen
Acetamenophen is not an NSAID. Tylenol is the brand name for the drug acetaminophen, and it can work by disrupting pain signals in the body although it may also work as a weak inhibitor (in vitro) of both cyclooxygenase (COX)-1 and COX-2. Recent reviews on acetaminophen (paracetamol) mechanisms have revealed significant insights into both its therapeutic and toxicological actions:
- Mechanism of Action in Pain Relief: A review highlighted that despite its wide use and status as a first-line option for mild-to-moderate acute pain, there’s ongoing debate about the analgesic mechanism of acetaminophen. Recent evidence challenges the previously held notion that its analgesic effect is solely through the cyclooxygenase (COX)-dependent pathway. It’s now understood that acetaminophen’s analgesia involves multiple pathways, particularly mediated by the formation of the bioactive metabolite AM404 in the central nervous system (CNS). This metabolite activates the TRPV1 channel and contributes to the neuronal response to pain in the brain and spinal cord. This review establishes acetaminophen as a central, COX-independent antinociceptive medication, distinct from non-steroidal anti-inflammatory drugs (NSAIDs) and with a more tolerable safety profile.
- Toxicity Mechanisms: Another review focuses on the mechanisms of toxicity in cases of acetaminophen poisoning, which is a common cause of acute liver injury due to self-harm or repeated supratherapeutic (higher dosage) ingestion. This study highlights the roles of metabolic and oxidative phases in acetaminophen toxicity and discusses the utility of novel biomarkers and adjunct treatments in managing these cases. It notes that acetylcysteine, the mainstay treatment for acetaminophen poisoning, is most effective when administered early, but can fail in cases of massive overdoses or in high-risk patients. The review also mentions the increasing use of newly proposed adjunct treatments like fomepizole, and the potential of novel biomarkers (not yet clinically available) for better assessment and treatment of acetaminophen toxicity, indicating advancements in the understanding of acetaminophen-related liver injury and its treatment.
These reviews underscore a growing understanding of acetaminophen’s complex actions, both therapeutically and in terms of toxicity, revealing nuances in its mechanism that impact clinical practice.
TRPV1, short for “Transient Receptor Potential Vanilloid 1”, is a protein that plays a critical role in the body’s sensory system. It is a type of ion channel found on the membrane of certain cells, including sensory nerve cells, where it is involved in the detection and regulation of body temperature, as well as in the perception of pain. Here are some key points about TRPV1:
- Pain Perception: TRPV1 is known for its role in transmitting signals of pain to the brain, particularly in response to high temperatures (heat) and certain chemical stimuli, like capsaicin (the compound that makes chili peppers hot).
- Thermoregulation: It also helps regulate body temperature by sensing heat and triggering responses to maintain a balance.
- Activation by Various Stimuli: TRPV1 can be activated by a variety of stimuli, including heat, acidic conditions, and certain natural and synthetic compounds.
- Role in Inflammation and Pain Treatment: TRPV1 is a target for developing new pain medications, especially for conditions like neuropathic pain and inflammation, as it is involved in the pain pathway.
- Involvement in Acetaminophen Mechanism: Recent research suggests that the bioactive metabolite of acetaminophen, AM404, activates the TRPV1 channel in the central nervous system, contributing to its pain-relieving effects. This discovery marks a shift in understanding how acetaminophen works, indicating it’s not solely through inhibiting COX enzymes but also involves modulation of pain perception at the neuronal level through TRPV1 activation.
The discovery of the role of TRPV1 in pain perception does add complexity to, but doesn’t fundamentally change, the gate control theory of pain. The gate control theory, proposed by Ronald Melzack and Patrick Wall in 1965, is a foundational concept in understanding pain. It suggests that pain signals are modulated by a “gate” in the spinal cord: certain types of nerve fibers can either inhibit or facilitate the transmission of pain signals to the brain.
TRPV1’s role in pain perception can be seen as an additional layer to this theory:
- Specificity in Pain Sensation: TRPV1 is involved in the direct sensation of pain, particularly in response to high temperatures and certain chemicals. It’s a specific type of receptor that responds to a particular kind of painful stimulus.
- Peripheral and Central Roles: TRPV1 receptors are located peripherally on sensory neurons but also have roles centrally within the nervous system. Their activation leads to the initiation of pain signals that are then modulated by the spinal cord’s gating mechanisms.
- Integration with Gate Control Theory: The activity of TRPV1 and similar receptors fits within the broader context of the gate control theory. These receptors are part of the mechanism by which pain signals are generated and sent to the spinal cord. The gate control theory then explains how these signals are modulated on their way to the brain.
- Expanding Understanding of Pain Mechanisms: The discovery of receptors like TRPV1 expands our understanding of how pain is perceived and processed. It highlights that pain is a complex phenomenon involving various receptors, nerve fibers, and central nervous system processes.
In summary, TRPV1 contributes to our understanding of how pain signals are initiated and highlights the complexity of pain mechanisms, but it doesn’t contradict the gate control theory. Instead, it provides more detail about the types of stimuli that can initiate pain signals that are then modulated by the spinal gating mechanisms described in the gate control theory.
Liver damage
Acetaminophen (paracetamol) is a widely used over-the-counter medication for pain relief and fever reduction. While it’s safe when used as recommended, acetaminophen overdose is a leading cause of acute liver failure in many countries. This is due to the way acetaminophen is metabolized in the liver and its toxic effects when taken in large doses. Here’s how this happens and the role of N-acetylcysteine (NAC) in treating acetaminophen overdose:
- Acetaminophen Metabolism and Toxicity: In normal doses, acetaminophen is safely metabolized in the liver and excreted from the body. However, in an overdose, the normal metabolic pathways become saturated, and more acetaminophen is shunted into an alternate pathway involving the cytochrome P450 enzyme system. This results in the formation of a toxic metabolite called N-acetyl-p-benzoquinone imine (NAPQI).
- NAPQI and Liver Damage: NAPQI is highly reactive and can cause oxidative stress and cellular damage, particularly in liver cells. Normally, NAPQI is detoxified by glutathione, a powerful antioxidant found in liver cells. However, in the case of an overdose, the stores of glutathione can be depleted, leaving the liver cells vulnerable to damage from NAPQI.
- Role of N-Acetylcysteine (NAC): NAC is the antidote for acetaminophen overdose. It works by replenishing glutathione levels in the liver, helping to detoxify NAPQI. NAC is most effective when administered within 8 to 10 hours of the overdose, but it can still be beneficial if given later. It can be administered orally or intravenously.
- NAC Treatment Protocol: The decision to treat with NAC is usually based on the amount of acetaminophen ingested and the time elapsed since ingestion. Blood tests are also used to measure acetaminophen levels and liver function. The treatment typically involves a loading dose followed by several maintenance doses over a period of hours to days, depending on the severity of the overdose and the patient’s response.
- Prevention of Liver Damage: Early treatment with NAC is crucial to prevent or minimize liver damage. In many cases, if NAC is administered promptly, liver damage can be avoided, and the patient can recover fully.
In summary, while acetaminophen is generally safe when used as directed, overdose can lead to severe liver damage due to the formation of the toxic metabolite NAPQI. N-acetylcysteine is an effective antidote that works by replenishing glutathione in the liver, helping to detoxify NAPQI and prevent liver damage. Prompt treatment is crucial for the best outcomes.
Aspirin as a blood thinner
Aspirin is a common medication used for various purposes, one of which is the prevention of heart disease. Aspirin works by inhibiting the production of substances that promote clotting, thereby reducing the risk of heart attacks and strokes.
For a detailed discussion on NSAIDS look here.
However, because aspirin inhibits clotting, it can also increase the risk of bleeding, including hemorrhagic stroke (a stroke caused by bleeding in the brain), gastrointestinal bleeding, and other bleeding complications.
There have been numerous studies on this topic, with varying results due to differences in study design, populations studied, aspirin dose, and other factors.
One large study, the ASPREE (Aspirin in Reducing Events in the Elderly) trial, found that in a healthy elderly population, the risks of aspirin, including increased risk of major hemorrhage, outweighed the benefits in terms of cardiovascular disease prevention.
The American Heart Association and American College of Cardiology updated their guidelines in 2019 and now suggest that aspirin should not be used in the routine prevention of heart disease due to the risk of bleeding.
Suggestions that individuals who have already had a heart attack or stroke, or who have a high risk of having such an event, the benefits of aspirin use may outweigh the risks are questionable. In general, the decision to use aspirin for heart disease prevention should be discussed in the context of their risk of heart disease and their risk of bleeding.
The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14)
Baclofen
Baclofen is a muscle relaxer and an antispasmodic agent that is primarily used for the treatment of muscle symptoms caused by multiple sclerosis, including spasm, pain, and stiffness.
Off-label use for Stroke or Parkinson’s:
However, use of baclofen in patients who have had a stroke or have Parkinson’s disease is generally not recommended due to lack of evidence supporting its efficacy and the potential for side effects, including muscle weakness and fatigue.
Additionally, while baclofen can be used to help reduce spasticity in conditions like spinal cord injury and cerebral palsy, it’s important to remember that all medication use should be under the supervision and direction of a healthcare provider, and individual responses to medications can vary.
It’s also worth noting that while baclofen is primarily used for these indications, it may also be used off-label for conditions such as hiccups, alcohol withdrawal syndrome, and certain types of neuropathic pain. However, the evidence supporting these uses can be limited and may not be as robust as for its primary indications.
For spasms:
The author has been unable to find exact statistics to verify the above statements (more research is needed); eg. what were the risks vs benefit absolute numbers and what was used as a placebo. Many times Baclofen is just compared to Tizanidine and vs versa. The incidence of adverse effects is reported to range from 10% to 75%.
Steroids and Cortisone
Long-term use of cortisone or other corticosteroids can have several potential side effects and health risks, including:
- Osteoporosis: Prolonged use of corticosteroids can lead to a decrease in bone density, increasing the risk of fractures.
- Adrenal Suppression: Long-term corticosteroid use can suppress the function of the adrenal glands, which produce natural corticosteroids. This can lead to a condition called adrenal insufficiency.
- Weight Gain and Fat Redistribution: Corticosteroids can cause an increase in appetite and lead to weight gain, particularly around the abdomen, face (moon face), and back of the neck (buffalo hump).
- Muscle Weakness: Prolonged use can lead to muscle weakness and wasting.
- Skin Thinning and Bruising: The skin may become thinner and more prone to bruising and other injuries.
- Increased Risk of Infections: Corticosteroids can suppress the immune system, making the body more susceptible to infections.
- Cataracts and Glaucoma: Long-term use of corticosteroids can increase the risk of developing cataracts and glaucoma.
- High Blood Pressure and Cardiovascular Risks: Corticosteroids can lead to increased blood pressure and may increase the risk of heart disease and stroke.
- Blood Sugar Changes: Corticosteroids can affect blood sugar levels, which can be particularly concerning for individuals with diabetes.
- Mood Changes: Some individuals may experience mood swings, anxiety, or depression with long-term corticosteroid use.
Skin thinning (atrophy) is a common side effect of long-term topical corticosteroid use. The mechanism behind this involves several factors:
- Decreased Collagen Production: Corticosteroids can inhibit the production of collagen, a key protein that provides structure and strength to the skin. Reduced collagen leads to a thinner dermis (the middle layer of the skin).
- Reduced Skin Cell Proliferation: Corticosteroids can slow down the rate at which skin cells (keratinocytes) proliferate and renew, resulting in a thinner epidermis (the outer layer of the skin).
- Vasoconstriction: Corticosteroids can cause the blood vessels in the skin to constrict, reducing blood flow and nutrients to the skin, which can contribute to thinning.
- Inhibition of Fibroblast Function: Fibroblasts are cells that produce collagen and other extracellular matrix components. Corticosteroids can inhibit fibroblast function, further reducing collagen production.
- Altered Lipid Metabolism: Corticosteroids can affect the metabolism of lipids in the skin, leading to changes in the skin barrier and a reduction in skin thickness.
Steroids, specifically corticosteroids, are a class of medications that are widely used to reduce inflammation and immune responses. They work by mimicking the effects of hormones that are naturally produced by the adrenal glands, which sit on top of the kidneys.
Steroids can be beneficial in treating a variety of conditions that involve inflammation and overactive immune responses. These include but are not limited to:
- Asthma: Inhaled corticosteroids help reduce inflammation in the airways and prevent asthma attacks.
- Arthritis: Steroids can help reduce joint inflammation and pain.
- Allergies: Steroids are used to reduce the immune system’s response to allergens.
- Autoimmune Diseases: Conditions like lupus, multiple sclerosis, and inflammatory bowel disease involve overactive immune responses, and steroids can help control these responses.
- Skin Conditions: Conditions such as eczema and psoriasis that involve inflammation and immune responses can also be treated with steroids.
While steroids can be very effective, they can also cause side effects, especially with long-term use. These side effects can include osteoporosis, weight gain, increased risk of infections, and changes in mood or behavior. Because of this, doctors usually aim to prescribe the lowest effective dose for the shortest possible time, and will monitor patients closely for potential side effects.
Fluticasone is a corticosteroid that is commonly used to treat conditions such as asthma and allergic rhinitis. It’s typically administered via inhalation or as a nasal spray. It can help to reduce inflammation, swelling, and irritation in the airways or nasal passages.
Long-term use of fluticasone, particularly at high doses, can potentially lead to certain side effects. These may include:
- Throat irritation or dryness: This is a common side effect of inhaled or nasal fluticasone.
- Hoarseness or changes in voice: Inhaled fluticasone can cause these symptoms.
- Fungal infections (oral thrush): These can occur in the mouth and throat from inhaled fluticasone. Rinsing your mouth after using the inhaler can help prevent this.
- Nosebleeds: This is a potential side effect of nasal fluticasone.
- Glaucoma or cataracts: Long-term use of inhaled corticosteroids may increase the risk of these eye conditions.
- Adrenal insufficiency: This is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. It is a rare but potential side effect of long-term, high-dose use of inhaled corticosteroids.
- Decreased bone mineral density: Prolonged use of high doses of inhaled corticosteroids may contribute to osteoporosis.
- Growth reduction in children and adolescents: Long-term use of high-dose inhaled corticosteroids has been associated with reduced growth in some children and adolescents.
The risks of long-term side effects must be weighed against the benefits of controlling symptoms and reducing exacerbations of conditions like asthma.
If fluticasone or other corticosteroids are discontinued suddenly after prolonged use, a “rebound effect” can occur. This term refers to the return or worsening of symptoms that were being managed with the medication.
In the context of nasal fluticasone (a nasal spray), for example, a rebound effect could result in the return or worsening of nasal congestion. This is also known as rhinitis medicamentosa. It can occur if the medication is overused or suddenly stopped, leading to a return of swelling in the nasal passages.
In cases where fluticasone has been used for asthma management, stopping the medication abruptly could potentially lead to an asthma attack or other serious complications.
Montelukast is a medication that is typically used to treat asthma, exercise-induced bronchoconstriction, and allergic rhinitis. It is a leukotriene receptor antagonist, which means it works by blocking inflammatory substances in the body called leukotrienes. Leukotrienes are chemicals your body releases when you breathe in an allergen (such as pollen). These chemicals cause swelling in your lungs and tightening of the muscles around your airways, which can result in asthma symptoms.
Montelukast is usually prescribed to help prevent asthma attacks and for long-term treatment of asthma in adults and children ages 1 year and older. It is also used to prevent bronchospasm (breathing difficulties) during exercise in adults and children ages 6 years and older.
Common side effects of montelukast include:
- Stomach pain, diarrhea, dyspepsia, nausea, or vomiting.
- Headache.
- Fever, sore throat, or cough.
- Nasal congestion.
- Fatigue.
In some rare cases, patients taking montelukast have experienced changes in mood or behavior, including suicidal thoughts or actions. As a result, the U.S. Food and Drug Administration has required a boxed warning – the agency’s most prominent warning – for montelukast to strengthen an existing warning about the risk of neuropsychiatric events associated with the drug.
Montelukast is not a steroid but that doesn’t mean its safer. It’s a type of drug known as a leukotriene receptor antagonist. Leukotrienes are chemicals in the body that are released during an allergic reaction and contribute to inflammation in the airways and tightness in the chest. By blocking leukotrienes, montelukast also blocks inflammation and can help to relieve the symptoms of asthma and allergies.
Steroids, on the other hand, work by reducing inflammation throughout the body, not just in the airways. They’re a more broad-based anti-inflammatory medication, and while they can be used to treat severe asthma symptoms, they also have a wide range of other uses.
There have been several studies evaluating the long-term use of montelukast, particularly in asthma management. Some studies and case reports have suggested a possible association between montelukast and neuropsychiatric events, such as agitation, aggression, depression, and sleep disturbances, though these are relatively rare.
Montelukast studies, most side effects reported were the same in children as those seen in adults. But certain side effects were reported in children ages 2 to 5 years who took montelukast to treat asthma. They include: eczema, chickenpox, pneumonia, pink eye1.
Serious side effects that have been reported with montelukast include high levels of eosinophils (a type of white blood cells), risk of serious mood and behavior changes, liver-related side effects, severe allergic reaction and low level of platelets (cells that help with blood clotting)2. The FDA has required a boxed warning about serious mental health side effects for asthma and allergy drug3
In Summary, steroidal and non-steroidal anti-inflammatory drugs have serious side effects when used long term. They are very effective almost instantly but never address the root cause of inflammation which is generally the up to 95% omega3 deficiency.
more info on cortisone injections
CYP1A2 inhibitors – VEOZAH
CYP1A2 (Cytochrome P450 1A2) is an enzyme involved in the metabolism of various drugs and substances in the body, including some inflammatory markers and chemicals. When we discuss CYP1A2 inhibitors in the context of inflammatory markers, it usually means substances that can inhibit the activity of this enzyme. The effects of CYP1A2 inhibitors on inflammatory markers can vary depending on the specific marker and the drug or compound involved.
Here’s a general overview of how CYP1A2 inhibitors might interact with inflammatory markers:
- Caffeine: Caffeine is metabolized by CYP1A2, and some studies have suggested that CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin, can increase caffeine levels in the bloodstream by inhibiting its metabolism. Increased caffeine levels can have various effects on the body, including potential effects on inflammation. High caffeine intake may influence certain inflammatory markers, but the overall impact can be complex and vary among individuals.
- Potential Interactions with Inflammatory Drugs: CYP1A2 inhibitors might affect the metabolism of drugs commonly used to manage inflammation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids. Altering the metabolism of these drugs could impact their effectiveness or side effects.
- Inflammatory Marker Metabolism: Some inflammatory markers, such as prostaglandins and certain cytokines, can be metabolized by enzymes in the body, including CYP1A2. Inhibiting CYP1A2 could potentially influence the clearance or levels of these markers in the bloodstream.
It’s essential to keep in mind that the effects of CYP1A2 inhibitors on inflammatory markers are not straightforward, and the specific outcomes can vary depending on many factors, including the individual’s genetics, the specific inhibitor and marker in question, and the overall context of their health and medication regimen.
CYP1A2 (Cytochrome P450 1A2) is an enzyme involved in the metabolism of various substances in the body, including drugs and some naturally occurring compounds. It plays a role in breaking down certain chemicals, making them more water-soluble and easier to eliminate from the body.
Hot flashes are a common symptom experienced by many women during menopause. They are characterized by sudden, intense feelings of warmth, flushing of the skin, and sweating. Hot flashes are primarily attributed to hormonal changes, particularly a decrease in estrogen levels, which affect the body’s temperature regulation.
There isn’t direct evidence to suggest that CYP1A2 inhibitors or inducers have a significant role in the regulation of hot flashes. Hot flashes are primarily driven by hormonal factors, and their exact mechanisms are not fully understood. Estrogen replacement therapy is one of the most effective treatments for relieving hot flashes in menopausal women because it helps compensate for the decline in estrogen levels.
CYP1A2 inhibitors or inducers are more commonly associated with drug interactions and the metabolism of various medications and substances in the body. They may affect the clearance and levels of drugs, which can have implications for drug efficacy and potential side effects.
Neurokinin 3 (NK3) receptor antagonists are a class of drugs that target the neurokinin 3 receptor in the central nervous system. These drugs are primarily being investigated and developed for the treatment of various conditions related to hormone regulation, including menopausal symptoms, particularly hot flashes.
NK3 receptor antagonists, like fezolinetant and MLE4901, work by blocking the action of substance P, a neurotransmitter involved in temperature regulation and hormonal control. Substance P is believed to play a role in the mechanism of hot flashes. By blocking the NK3 receptor and reducing the activity of substance P, these antagonists may help alleviate hot flashes and other symptoms associated with hormonal changes.
Clinical trials have shown little effect over placebo. In contrast these drug classes have serious side effects.
There is a potential risk of adverse effects, including liver damage, associated with the use of certain drugs, including neurokinin 3 (NK3) receptor antagonists. It’s essential to be aware of these risks and to use these medications under the guidance and supervision of a healthcare provider who can monitor your health and assess the potential benefits and risks on an individual basis.
Liver damage, though relatively rare, can occur with the use of medications. Symptoms of liver damage may include:
1. Yellowing of the skin or eyes (jaundice)
2. Dark urine
3. Unexplained fatigue or weakness
4. Abdominal pain or discomfort, especially in the upper right side
5. Loss of appetite
6. Nausea and vomiting
If you experience any of these symptoms while taking a medication, including an NK3 receptor antagonist, it’s crucial to contact your healthcare provider promptly.
Before starting any new medication, your healthcare provider should perform a comprehensive evaluation of your medical history, current health status, and potential risk factors for liver damage. They may order baseline liver function tests to assess the health of your liver before initiating treatment and may continue to monitor your liver function throughout your medication course.
It’s also essential to follow your healthcare provider’s instructions carefully, including dosing recommendations and any specific guidelines related to liver monitoring. If you have a pre-existing liver condition or other risk factors for liver problems, your healthcare provider will consider these factors when prescribing medications and may choose alternative treatments or closely monitor your liver function.
Overall, while there is a potential risk of liver damage associated with certain medications, including NK3 receptor antagonists, this risk should be weighed against the potential benefits of treatment. Your healthcare provider can help you make an informed decision about whether these medications are appropriate for your specific situation and ensure that you receive appropriate monitoring and care to minimize any potential risks.
VASCEPA
VASCEPA (icosapent ethyl) is a prescription medication derived from the omega-3 fatty acid eicosapentaenoic acid (EPA). It is used to reduce the risk of cardiovascular events in adults with elevated triglyceride levels (≥ 150 mg/dL) and other risk factors for heart disease. The most notable study on VASCEPA is the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) study, which has significantly influenced the use of icosapent ethyl in clinical practice.
REDUCE-IT Study:
Study Design: REDUCE-IT was a large, randomized, double-blind, placebo-controlled trial that involved over 8,000 participants. The participants were adults with established cardiovascular disease or diabetes and other risk factors, all of whom had elevated triglyceride levels despite being on statin therapy.
Dosage: Participants in the treatment group received 4 grams of icosapent ethyl per day, while the control group received a placebo.
Primary Outcome: The primary endpoint was a composite of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction (heart attack), nonfatal stroke, coronary revascularization (procedures like angioplasty or bypass surgery), and hospitalization for unstable angina (chest pain).
Key Findings:
The study showed a significant reduction in the primary endpoint among participants taking icosapent ethyl compared to the placebo group. There was a 25% relative risk reduction in the primary composite endpoint.
Significant reductions were also observed in key secondary endpoints, including a 20% reduction in cardiovascular death, a 31% reduction in myocardial infarction, and a 28% reduction in stroke.
The medication was generally well-tolerated, with a higher incidence of atrial fibrillation and bleeding events in the icosapent ethyl group compared to the placebo group, but these were not associated with increased mortality.
Clinical Implications:
The results of the REDUCE-IT study have led to the inclusion of icosapent ethyl in clinical guidelines for the management of patients with elevated triglyceride levels and a high risk of cardiovascular events. It has been recognized as an important therapeutic option for reducing cardiovascular risk in this patient population.
Other Studies:
In addition to REDUCE-IT, other studies and analyses have been conducted to further evaluate the efficacy, safety, and potential mechanisms of action of icosapent ethyl in cardiovascular risk reduction. These studies continue to support the role of icosapent ethyl as a valuable addition to cardiovascular risk management strategies.
Overall, the REDUCE-IT study and subsequent research have established icosapent ethyl as an effective treatment for reducing cardiovascular risk in patients with elevated triglycerides and other risk factors, when used in conjunction with statin therapy and lifestyle modifications.
VASCEPA (icosapent ethyl) is a prescription medication derived from the omega-3 fatty acid eicosapentaenoic acid (EPA). It is used to reduce the risk of cardiovascular events in adults with elevated triglyceride levels (≥ 150 mg/dL) and other risk factors for heart disease. The most notable study on VASCEPA is the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) study, which has significantly influenced the use of icosapent ethyl in clinical practice.
REDUCE-IT Study:
- Study Design: REDUCE-IT was a large, randomized, double-blind, placebo-controlled trial that involved over 8,000 participants. The participants were adults with established cardiovascular disease or diabetes and other risk factors, all of whom had elevated triglyceride levels despite being on statin therapy.
- Dosage: Participants in the treatment group received 4 grams of icosapent ethyl per day, while the control group received a placebo.
- Primary Outcome: The primary endpoint was a composite of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction (heart attack), nonfatal stroke, coronary revascularization (procedures like angioplasty or bypass surgery), and hospitalization for unstable angina (chest pain).
- Key Findings:
- The study showed a significant reduction in the primary endpoint among participants taking icosapent ethyl compared to the placebo group. There was a 25% relative risk reduction in the primary composite endpoint.
- Significant reductions were also observed in key secondary endpoints, including a 20% reduction in cardiovascular death, a 31% reduction in myocardial infarction, and a 28% reduction in stroke.
- The medication was generally well-tolerated, with a higher incidence of atrial fibrillation and bleeding events in the icosapent ethyl group compared to the placebo group, but these were not associated with increased mortality.
Clinical Implications:
The results of the REDUCE-IT study have led to the inclusion of icosapent ethyl in clinical guidelines for the management of patients with elevated triglyceride levels and a high risk of cardiovascular events. It has been recognized as an important therapeutic option for reducing cardiovascular risk in this patient population.
Other Studies:
In addition to REDUCE-IT, other studies and analyses have been conducted to further evaluate the efficacy, safety, and potential mechanisms of action of icosapent ethyl in cardiovascular risk reduction. These studies continue to support the role of icosapent ethyl as a valuable addition to cardiovascular risk management strategies.
Overall, the REDUCE-IT study and subsequent research have established icosapent ethyl as an effective treatment for reducing cardiovascular risk in patients with elevated triglycerides and other risk factors, when used in conjunction with statin therapy and lifestyle modifications.
These numbers are not high and far below what proper omega3 treatment can do. Higher dosages are required due to rancidity and numbers are lowered due the side effects of Vacepa itself and co-administration of statins.
VASCEPA (icosapent ethyl) is generally well-tolerated, but like all medications, it can have side effects and high likelihood of rancidity. Some side effects may be reflected in blood work or laboratory tests. Here are a few potential side effects of VASCEPA that could be detected through blood work:
- Increased Bleeding Time: VASCEPA can have an anticoagulant effect, potentially increasing bleeding time. This effect might be observed in blood tests that measure clotting time, such as prothrombin time (PT) or international normalized ratio (INR).
- Liver Function Tests: Although rare, VASCEPA can affect liver function. Regular monitoring of liver enzymes (such as AST and ALT) through blood tests is recommended to detect any potential liver damage.
- Creatine Kinase Levels: In some cases, VASCEPA may increase creatine kinase levels, which is an enzyme found in the heart, brain, and skeletal muscle. Elevated levels can indicate muscle damage, including a rare side effect called myopathy.
- Blood Urea Nitrogen (BUN) and Creatinine: VASCEPA may cause changes in kidney function, which can be detected through increased levels of BUN and creatinine in the blood.
- Blood Lipid Levels: While VASCEPA is used to lower triglyceride levels, it’s important to monitor other lipid levels, such as LDL cholesterol, as some patients may experience an increase in LDL levels while on VASCEPA.
- White Blood Cell Count: In clinical trials, a small percentage of patients experienced a decrease in white blood cell count, which could be detected in a complete blood count (CBC) test.
An analyses of a client taking Vascepa shows the omega3 index is only 3.9%, far below the desired 8%! This shows the prescription is very likely rancid.
IN summary why risk low outcomes and serious side effects when you simply can take a natural stabilized fish oil or algae product.
Antibiotics
There is no doubt that in true systemic blood infections antibiotics can be life saving but the overuse of antibiotics and the result of multiple strain resistance is a big topic. Of course there are many different antibiotics with different applications that have to be studied separately.
The overuse of antibiotics has led to a significant public health issue: the development of multiple strain resistance, or antibiotic resistance. This occurs when bacteria evolve in response to the use of these drugs, becoming resistant to them and thus harder to treat. Over-prescription of antibiotics, their use in agriculture, and inadequate patient adherence to treatment regimens have all contributed to this problem. As a result, many antibiotics have become less effective, and infections that were once easily treatable are now more challenging to cure, leading to increased medical costs, longer hospital stays, and higher mortality rates.
The term “antibiotics” was chosen to describe these substances because it originates from the Greek words “anti,” meaning “against,” and “bios,” meaning “life.” This term reflects the primary function of antibiotics, which is to fight against bacterial life forms that cause infections in humans and animals. The name aptly describes the nature of these substances as agents that inhibit the growth and survival of bacteria.
In many instances antibiotics are prescribed for allergic or viral cases. Testing for bacterial ‘overgrowth’ and ‘bad strains’ is rarely done. It’s true that antibiotics are often prescribed for conditions where they may not be effective, such as viral infections or allergic reactions. This is partly due to the difficulty in quickly distinguishing bacterial infections from other types of illnesses in clinical settings. Routine testing for specific bacterial strains or “overgrowth” is not always feasible due to time, cost, and resource constraints. This practice contributes to the inappropriate use of antibiotics, which, in turn, accelerates the development of antibiotic resistance. Addressing this issue requires better diagnostic tools, increased awareness about the appropriate use of antibiotics, and more stringent prescribing practices.
But what do the studies show?
Ivermectin
Ivermectin, a widely used antiparasitic drug, was discovered as a result of a collaborative research effort between the pharmaceutical company Merck & Co. and the Kitasato Institute in Japan. The discovery of ivermectin is an interesting story of scientific exploration and serendipity.
Discovery Timeline:
- Origins of the Discovery: The story began in the early 1970s when Satoshi Ōmura, a microbiologist at the Kitasato Institute in Japan, collected soil samples from around Japan. He was searching for novel strains of Streptomyces bacteria, known for producing a variety of medicinal compounds.
- Collaboration with Merck: Ōmura entered into a research collaboration with Merck & Co., specifically with a parasitologist named William C. Campbell. The partnership aimed to discover new compounds that could effectively treat parasitic infections in animals and humans.
- Screening for Active Compounds: From Ōmura’s collection, thousands of Streptomyces cultures were screened at Merck’s research facility in the United States. The goal was to identify substances that were effective against parasites in domestic and farm animals.
- Discovery of Avermectins: In 1975, the screening program led to the discovery of a compound, later named “avermectin,” produced by a bacterium isolated from a soil sample collected near a golf course in Kawana, Japan. This bacterium was later named Streptomyces avermitilis.
- Development of Ivermectin: Merck chemists modified avermectin to increase its effectiveness and safety. The derivative they created was named “ivermectin.” It proved to be highly effective against a broad range of parasites in animals.
- Human Use and River Blindness: Following the success in veterinary medicine, researchers found that ivermectin was also effective against parasites in humans. A notable application was for the treatment of onchocerciasis, also known as river blindness, a devastating tropical disease caused by a parasitic worm and transmitted by black flies.
- Philanthropic Efforts: In a remarkable philanthropic gesture, Merck & Co. decided in 1987 to provide ivermectin (under the brand name Mectizan) for free “as much as needed, for as long as needed” to combat river blindness in affected countries. This decision led to one of the most successful public health initiatives against a parasitic disease, significantly reducing the incidence of river blindness and improving the lives of millions of people in Sub-Saharan Africa, Latin America, and Yemen.
Recognition and Impact:
- Nobel Prize in Physiology or Medicine: The significance of this discovery was recognized globally when, in 2015, Satoshi Ōmura and William C. Campbell were awarded the Nobel Prize in Physiology or Medicine for their work leading to the discovery of ivermectin. Their discovery was hailed for its profound impact on improving the health and wellbeing of millions of people affected by parasitic diseases.
- Broader Applications: Beyond river blindness, ivermectin has been used to treat other parasitic infections, such as strongyloidiasis and lymphatic filariasis. It’s also widely used in veterinary medicine for the control of a variety of internal and external parasites.
Paxlovid
Paxlovid is a prescription medication used for the treatment of mild to moderate COVID-19 in adults and pediatric patients aged 12 years or older weighing at least 40 kg. It is a combination of two drugs: nirmatrelvir and ritonavir.
Nirmatrelvir is a protease inhibitor that works by inhibiting an enzyme called the main protease (Mpro) of the SARS-CoV-2 virus, which is responsible for the replication of the virus. Ritonavir is another protease inhibitor that works by inhibiting an enzyme called cytochrome P450 3A4 (CYP3A4), which breaks down nirmatrelvir in the body, allowing it to remain effective for a longer period of time.
The development of Paxlovid was a collaboration between Pfizer and the US government’s Operation Warp Speed program, which was established in 2020 to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. Clinical trials for Paxlovid began in 2020, and the drug was granted emergency use authorization (EUA) by the US Food and Drug Administration (FDA) in November 2021 (normally this process involves years of rigorous phase3 trials).
It is important to look at the absolute changes: Rosenberg 2023: Hospitalization or death occurred in 0.55% (n = 69) of patients who received nirmatrelvir plus ritonavir compared with 0.97% (n = 310) of patients who did not receive the treatment.
Evaluating the absolute changes of “treated vs placebo” helps you to draw conclusions if small effects of a drug treatment are worth side effects. In addition possible long term safety data is often not available. In addition, always verify if the placebo used in the study was actually saline.
ODDs Ratio: This meta analyses shows an effect however they are using OR: Three RCTs involving 4241 patients were included. Overall, anti-viral agents were associated with a significantly lower risk of COVID-19 related hospitalization or death compared with the placebo (OR, 0.23; 95% CI: 0.06-0.96; p = 0.04)
So treating people with paxlovid does not mean they have only a “23% chance” of eg not getting hospitalized. OD 0.23 means that the odds of the outcome occurring in the exposed group are about a quarter (or 23%) of the odds of the outcome occurring in the control group. So, if the odds of the outcome in the untreated group were 20%, then the odds of the outcome in the treated group would be 5% (i.e. 25% of 20%). Now it is important to know what are the odds or better the relative risk of the control group to evaluate this data. This number is not easily obtainable and fluctuates!
To be fair, the analyses shows 69 vs 160 people had serious adverse effects and it is not full clear to the author how 160 people ~3% receiving a placebo ended up with severe effects in these studies. Generally “adverse effects” are defined as any new symptoms, clinical or laboratory abnormalities, or complications that occurred after the start of treatment.
The Flu Vaccine Effectiveness
How the Flu Vaccine Works
The flu vaccine claims to be designed to protect against the influenza virus. Here’s how should work:
- Introduction of Antigens: The vaccine contains inactivated (killed) flu viruses or pieces of the virus (such as proteins). These components are called antigens. However these antigens have to be correctly guessing the new strain mutations.
- Immune Response: When the vaccine is administered, the body’s immune system recognizes these antigens as foreign invaders and responds by producing antibodies. This is very similar to actually getting the flu.
- Building Immunity: These antibodies are specific ONLY to the flu virus strains INCLUDED in the vaccine. If the person is later exposed to the actual flu virus, their immune system can quickly recognize and fight the virus, either preventing illness or reducing the severity of symptoms.
- Updating the Vaccine: Because flu viruses MUTATE frequently, the flu vaccine is updated annually to match the most common strains circulating in that flu season. This is why it’s recommended to get a flu shot every year.
How is it made?
Traditionally, inactivated (killed) influenza vaccines are produced using chicken eggs. This method has been the standard for many decades and is still widely used today. However, it’s important to note that there are alternative methods for producing flu vaccines that do not rely on eggs. Here’s a detailed overview of the production processes:
1. Egg-Based Production (Traditional Method):
Process:
- Virus Selection: Each year, scientists select the influenza virus strains expected to be the most prevalent in the upcoming flu season.
- Virus Inoculation: These selected viruses are injected into fertilized chicken eggs.
- Incubation: The eggs are incubated to allow the viruses to replicate.
- Harvesting: After several days, the fluid containing the replicated viruses is harvested from the eggs.
- Inactivation: The harvested viruses are then inactivated (killed) using chemicals such as formaldehyde, ensuring they cannot cause disease.
- Purification and Formulation: The inactivated viruses are purified and formulated into vaccines, often combined with adjuvants to enhance immune response.
Predicting the influenza strains for the next season is a complex process involving global surveillance, data analysis, and expert judgment. Here’s how it generally works:
1. Global Surveillance:
- World Health Organization (WHO) Coordination: The WHO collaborates with over 140 national influenza centers in over 100 countries to collect data on circulating flu viruses. These centers analyze thousands of flu virus samples from patients around the world.
- Flu Types and Subtypes: The collected data includes information on the types (Influenza A and B) and subtypes (such as H1N1, H3N2) of the viruses, as well as any mutations or variations observed in these strains.
2. Data Collection and Analysis:
- Genetic Sequencing: The flu viruses are genetically sequenced to understand the specific changes (mutations) in the viral genome. This helps in identifying new variants that might be emerging.
- Epidemiological Data: Researchers also study how widely the flu strains are spreading, the severity of the illnesses they cause, and the effectiveness of the current season’s vaccine against them.
3. Strain Selection:
- Twice-Yearly Meetings: Experts from the WHO, along with representatives from national health organizations like the CDC (Centers for Disease Control and Prevention) and other partners, meet twice a year (in February for the Northern Hemisphere and in September for the Southern Hemisphere) to review the surveillance data.
- Predictive Models: Scientists use predictive models that incorporate factors like mutation trends, population immunity, and historical patterns to forecast which strains are most likely to be dominant in the upcoming season.
- Expert Consensus: Based on the data and models, experts select the strains to include in the next season’s flu vaccine. Typically, they choose three or four strains (trivalent or quadrivalent vaccines) that they believe are most likely to circulate.
4. Vaccine Production:
- Vaccine Manufacturing: Once the strains are selected, vaccine manufacturers begin producing the flu vaccine for the upcoming season. This process takes several months, which is why strain selection happens well in advance of the flu season.
- Adjustments: If a significant mutation occurs after strain selection (referred to as “antigenic drift”), there may be a mismatch between the vaccine and the circulating strains, which can reduce vaccine effectiveness.
5. Ongoing Monitoring:
- Post-Season Review: After each flu season, health organizations review the effectiveness of the vaccine and the accuracy of the strain predictions. This feedback helps refine the predictive process for future seasons.
Challenges:
- Rapid Mutation: Influenza viruses mutate rapidly, making it challenging to predict exactly which strains will be dominant.
- Global Variability: Flu viruses can behave differently in different regions, complicating predictions.
- Vaccine Mismatch: Occasionally, the selected strains don’t match well with the circulating strains, leading to lower vaccine effectiveness.
In summary, predicting influenza strains involves a combination of global surveillance, genetic analysis, epidemiological data, predictive modeling, and expert judgment to forecast which strains are most likely to circulate in the upcoming flu season. Despite the challenges, this method has been effective in reducing the impact of influenza worldwide.
Does the Flu Vaccine Contain Mercury?
Some flu vaccines contain a preservative called thimerosal, which is a mercury-based compound used to prevent contamination in multi-dose vials of the vaccine. However:
- Thimerosal-Free Options: Single-dose vials and pre-filled syringes of the flu vaccine typically do not contain thimerosal. There are also thimerosal-free versions of the vaccine available for people who are concerned about mercury exposure.
- Mercury Content: Thimerosal contains ethylmercury, which is different from the more toxic methylmercury found in some fish. Ethylmercury is processed and eliminated from the body more quickly and has not been shown to cause harm at the levels used in vaccines.
- ethylmercury has A half-life of 6.9 days, that means that after about 7 days, 50% of the ethylmercury from thimerosal would still be present in the blood. Over time, the amount continues to decrease, with roughly 25% remaining after two half-lives (around 14 days), 12.5% after three half-lives (around 21 days), and so on.
In summary, while some flu vaccines do contain thimerosal, there are also many thimerosal-free options available. The use of thimerosal in vaccines has been extensively studied, and it has been found to be safe in the amounts used!
37% Effectiveness – The Vaccine nocebo effect?
The flu vaccine’s effectiveness, including a 37% effectiveness against hospitalization, is not merely a nocebo effect? The effectiveness of the flu vaccine is based on rigorous clinical studies and real-world data that demonstrate its ability to reduce the severity of illness, the likelihood of hospitalization, and the overall burden of flu-related complications.
Here is the real data – you decide:
Once again the studies are small!
Overall out of 900 vaccinated 138 (15.3%) were hospitalized
Out of 1,880 non-vaccinated 526 (28.0%) were hospitalized.
That means: 252(28%)-138 (15%) = 114 out of 900 where kept out of the hospital. This still says nothing about who actually got the flu at home? Flu Incidence vs. Severity: These numbers focus on severe cases requiring hospitalization, not on how many people contracted the flu but managed it at home. To understand the vaccine’s impact on overall flu incidence (including mild and moderate cases), you would need data on flu diagnoses or flu-like illnesses in both vaccinated and unvaccinated individuals.
It is very difficult to get to the real number and assess how effective a vaccine really is. There are few meta analyses and they are funded by the vaccine manufacturers.
Anti-parasitic
Mebendazole and Fenbendazole are both antiparasitic drugs commonly used in veterinary medicine and, in the case of mebendazole, in human medicine. Despite their similarities, they have distinct differences in their uses, effectiveness, and safety profiles. Here’s a comparison:
1. Chemical Structure and Class:
- Mebendazole: It is a benzimidazole derivative and is used as a broad-spectrum anthelmintic. It works by inhibiting the formation of microtubules in the parasitic worms, leading to their death.
- Fenbendazole: Also a benzimidazole, fenbendazole works similarly by disrupting the microtubule function in parasites. However, it is typically used more in veterinary medicine than in humans.
2. Uses:
- Mebendazole:
- Human Medicine: Mebendazole is widely used to treat a variety of helminth infections in humans, including those caused by pinworms, roundworms, whipworms, and hookworms.
- Veterinary Medicine: Less commonly used in animals but can be prescribed for similar parasitic infections.
- Fenbendazole:
- Veterinary Medicine: Fenbendazole is primarily used to treat gastrointestinal parasites in animals, including dogs, cats, horses, and livestock. It is effective against a range of parasites such as roundworms, hookworms, whipworms, and certain tapeworms.
- Off-label Use in Humans: There has been some anecdotal and preliminary scientific interest in the potential use of fenbendazole in cancer therapy, but this is not an approved or widely recognized use in human medicine.
3. Effectiveness:
- Mebendazole: Highly effective against common gastrointestinal parasites in humans. It is typically taken in a single dose or in a short course, depending on the type of infection.
- Fenbendazole: Effective in animals, particularly because it is metabolized more slowly than mebendazole, allowing for a longer duration of action. This makes it particularly useful in veterinary applications where prolonged exposure to the drug is needed.
4. Safety and Side Effects:
- Mebendazole: Generally well-tolerated in humans, with mild side effects such as gastrointestinal discomfort or allergic reactions. However, it is not recommended for use in pregnant women due to potential teratogenic effects.
- Fenbendazole: Generally safe for use in animals, with minimal side effects. In humans, its safety profile is less well-studied, but it has been used off-label in some experimental cancer treatments without significant adverse effects reported. However, its long-term safety in humans is not well-established.
5. Regulatory Status:
- Mebendazole: Approved by the FDA for human use in treating parasitic infections.
- Fenbendazole: Approved by the FDA for use in animals, but not in humans. Any human use would be considered off-label and experimental.
6. Recent Interest and Research:
- Cancer Treatment:
- Fenbendazole has garnered attention for its potential off-label use in cancer therapy. Some studies and anecdotal reports suggest it may have anti-cancer properties, particularly in disrupting cancer cell metabolism and inducing cell death in certain types of cancer cells. However, this use is still experimental and not clinically approved.
- Mebendazole has also been explored for its potential anti-cancer properties, particularly because of its ability to inhibit microtubule formation, which is similar to the action of some chemotherapy drugs. However, this is also not an approved use, and research is ongoing.
Conclusion:
- Mebendazole is primarily used in humans for treating parasitic infections, while fenbendazole is more commonly used in animals but has gained attention for its potential use in cancer therapy. Both drugs have similar mechanisms of action but are used in different contexts and have different safety profiles. Any off-label use, particularly in humans, should be approached with caution and under medical supervision.
The distinction between mebendazole and fenbendazole involves differences in their chemical structures:
Chemical Structure: Mebendazole has a benzimidazole ring structure with a carbamate side chain. Specifically, it has a ketone group as part of its molecular structure.
- Chemical Formula: C16H13N3O3
- Functional Groups:
- Ketone: The carbonyl group (C=O) within the structure is characteristic of a ketone.
- Benzimidazole ring: This fused heterocyclic compound consists of benzene fused to imidazole, forming the core of the molecule.
Fenbendazole:
- Chemical Structure: Fenbendazole also belongs to the benzimidazole class but differs from mebendazole by having a sulfoxide functional group, making it a sulfoxide derivative rather than a ketone.
- Chemical Formula: C15H13N3O2S
- Functional Groups:
- Sulfoxide: This contains a sulfur atom double-bonded to an oxygen atom (S=O), and this group is crucial for the drug’s activity.
- Benzimidazole ring: Like mebendazole, it also has a benzimidazole ring, but the presence of the sulfoxide group differentiates it structurally.
Summary of Key Differences:
- Mebendazole contains a ketone group as part of its molecular structure.
- Fenbendazole features a thioester group instead of a ketone.
This difference in chemical structure contributes to their distinct pharmacokinetics and possibly their varying efficacies and side effect profiles in both veterinary and potential human uses.
Is Ivermectin anti-viral?
The topic of ivermectin’s potential antiviral effects, particularly against COVID-19, has been a subject of significant debate and research. Initially, there was some interest in the possibility that ivermectin, an antiparasitic drug, might have efficacy against SARS-CoV-2, the virus responsible for COVID-19. This interest was sparked by early laboratory studies that suggested ivermectin could inhibit the replication of the virus in cell cultures. However, subsequent research, including clinical trials, has provided more nuanced insights:
- In Vitro Studies: Early laboratory (in vitro) studies indicated that ivermectin might inhibit the replication of SARS-CoV-2 in cell cultures. However, these studies often used concentrations of ivermectin far higher than what is safe or achievable in humans.
- Clinical Trials and Observational Studies: Numerous clinical trials and observational studies have been conducted to assess the effectiveness of ivermectin in treating COVID-19. The results have been mixed, with some studies suggesting a potential benefit and others showing no significant effect.
- Meta-Analyses and Reviews: Several meta-analyses and systematic reviews, which combine data from multiple studies, have been conducted. Some of these analyses initially suggested a possible benefit of ivermectin in reducing mortality or the severity of COVID-19, but these findings were often based on studies with methodological limitations.
- Concerns About Data Quality: Some of the studies reporting positive effects of ivermectin on COVID-19 outcomes have faced scrutiny regarding data quality, methodology, and potential biases. This has led to caution in interpreting these results.
- Health Authority Guidelines: Major health authorities, including the World Health Organization (WHO), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA), have generally advised against the use of ivermectin for COVID-19 outside of clinical trials, citing insufficient evidence for its efficacy and concerns about potential misuse and side effects.
- Ongoing Research: Research into ivermectin’s potential antiviral effects, especially against COVID-19, is ongoing. Some clinical trials are still in progress or under review, aiming to provide more definitive answers regarding its efficacy and safety in this context.
- Use in Other Viral Infections: Apart from COVID-19, ivermectin has been studied for potential effects against other viruses. While there is some evidence suggesting antiviral activity in vitro, translating these findings to effective clinical treatments for viral diseases has been challenging. The concentrations of ivermectin required to achieve antiviral effects in cell cultures are often much higher than what can be safely administered to humans.
- Mechanism of Action: The proposed antiviral mechanisms of ivermectin include inhibiting viral entry into cells, interfering with viral replication machinery, and modulating the host’s immune response. However, these mechanisms are not fully understood and may vary depending on the virus and the context of treatment.
In conclusion, while initial studies sparked interest in the potential antiviral properties of ivermectin, especially against COVID-19, subsequent research has provided mixed results, and major health organizations currently recommend against its use for COVID-19 outside of clinical trials. The scientific community continues to evaluate the evidence through ongoing research and clinical trials to determine the efficacy and safety of ivermectin in treating COVID-19 and other viral infections.
More on Streptomyces
The production of anti-parasitic compounds like ivermectin by soil bacteria such as Streptomyces is an interesting aspect of microbial ecology. While the exact reasons for these bacteria to produce such compounds are not fully understood, there are several theories and ecological justifications:
- Chemical Warfare in Soil Microbiome: The soil is a highly competitive environment where countless microorganisms, including bacteria, fungi, and microfauna, coexist and compete for resources. Streptomyces and other soil bacteria produce a variety of bioactive compounds, including antibiotics and anti-parasitic agents, as a means of chemical warfare to inhibit the growth of competing organisms. This helps them secure necessary resources like nutrients and space.
- Defense Mechanism: These compounds may act as defense mechanisms against predation by soil-dwelling microorganisms and invertebrates. By producing anti-parasitic and antibacterial substances, Streptomyces can protect themselves from being consumed or overpowered by other microorganisms or small invertebrates in the soil.
- Secondary Metabolites for Survival: Anti-parasitic compounds are classified as secondary metabolites, which are not directly involved in the basic growth, development, or reproduction of the organism. These metabolites often play a role in interactions with other organisms in the environment, and in the case of Streptomyces, they may provide an evolutionary advantage in certain ecological niches
- Communication and Signaling: Some secondary metabolites, including anti-parasitic compounds, can function in communication and signaling within microbial communities. These compounds might influence the behavior or development of other organisms in the soil ecosystem, contributing to the complex interplay of microbial interactions.
- Accidental Discovery for Human Use: From an ecological perspective, the fact that these compounds have anti-parasitic effects in humans and animals is more of an accidental discovery than a specific ecological function. Humans have harnessed these natural products for medical purposes, but their original role in the soil may have little to do with how they interact with human pathogens or parasites. The discovery and application of such compounds in medicine is a result of bioprospecting – exploring the natural world, particularly microorganisms, for novel compounds that may have therapeutic potential.
- Genetic Diversity and Adaptability: The genetic diversity of Streptomyces, along with their ability to adapt to various environments, allows them to produce a wide array of secondary metabolites. This diversity is a survival mechanism, enabling these bacteria to thrive in competitive and changing environments.
In summary, the production of anti-parasitic compounds by Streptomyces can be seen as part of their survival strategy in the competitive soil environment. These compounds may serve multiple functions, including defense against predators, suppression of competing microorganisms, and communication within microbial communities. The utility of such compounds in human and veterinary medicine is a fortunate benefit derived from the complex and diverse chemical ecology of soil microbes.
Even more: Streptomyces is a genus of Gram-positive bacteria that plays a significant role in natural environments, particularly soil. These bacteria are notable for their complex life cycle and their ability to produce a wide array of bioactive compounds, including antibiotics. Understanding the habitat of Streptomyces involves looking at various aspects of their environmental presence:
Soil Environment
- Dominant Soil Inhabitants: Streptomyces species are predominantly found in soil, where they play a crucial role in decomposing organic materials. This decomposition helps in nutrient cycling, making them vital for soil health.
- Diverse Soil Types: They thrive in a variety of soil types, from agricultural lands to forests, and are well-adapted to different soil conditions, including various pH levels and moisture content.
- Role in Soil Ecology: In the soil, Streptomyces bacteria act as decomposers, breaking down complex organic matter such as decaying plant material, which recycles nutrients back into the ecosystem.
Adaptation and Survival
- Filamentous Growth: Streptomyces are characterized by their filamentous growth, similar to fungi, which allows them to colonize and adapt to the soil environment effectively.
- Spore Formation: They form spores that can withstand harsh environmental conditions, aiding in their survival and dispersal. Spore formation also allows them to remain dormant until conditions are favorable for growth.
Interaction with Other Organisms
- Symbiotic Relationships: Streptomyces species often engage in symbiotic relationships with plants and animals. For example, they can provide plants with growth-promoting substances and protection against pathogens.
- Antagonistic Interactions: They produce a variety of secondary metabolites, including antibiotics and antifungals, which can inhibit the growth of competing microorganisms in the soil.
Other Habitats
- Beyond Soil: While soil is their primary habitat, Streptomyces species can also be found in other environments, including fresh and saltwater, decomposing vegetation, and even in association with animals and humans.
- Industrial and Research Importance: Due to their ability to produce various useful compounds, Streptomyces is extensively studied in industrial biotechnology for the production of antibiotics, enzymes, and other pharmaceuticals.
Genetic Adaptability
- Genetic Diversity: Streptomyces has a large and diverse genome, which provides them with the genetic adaptability
to respond to different environmental conditions and challenges. This genetic diversity is also the reason behind their capability to synthesize a wide range of secondary metabolites.
- Natural Genetic Engineering: Streptomyces are known for their sophisticated genetic system that allows for natural genetic recombination. This capability enables them to evolve and adapt rapidly, enhancing their survival in various environments.
In summary, Streptomyces primarily inhabit soil environments where they play a key role in organic matter decomposition and nutrient cycling. Their ability to produce a wide range of bioactive compounds, including antibiotics, is a result of their adaptive genetic makeup and their interactions with other organisms in their environment. These interactions range from symbiotic relationships that benefit both the bacteria and their hosts, to antagonistic ones where they inhibit competing microbes, showcasing their ecological versatility. Streptomyces’ filamentous growth and spore-forming capability also contribute to their resilience and widespread presence in diverse habitats beyond just soil, making them a subject of great interest in both ecological studies and biotechnological applications.
Antihistamine
Antihistamines are a class of drugs used to treat symptoms of allergies and conditions such as hay fever, hives, conjunctivitis, reactions to insect bites or stings, and some types of rashes. They can also help to relieve symptoms of the common cold, like a runny nose and sneezing. However the underlying cause for the allergic reaction is never addressed and these drugs have a strong rebound effect.
Histamine is a chemical that the body naturally produces in response to an allergen. When the body encounters something it’s allergic to, it releases histamines that bind to specific receptors on cells, causing them to swell or expand. This inflammation results in common allergy symptoms like itching, sneezing, nasal congestion, and eye irritation.
Antihistamines work by blocking the binding of histamine to these receptors, which helps to alleviate the symptoms associated with an allergic reaction.
There are two main types of antihistamines:
- First-generation antihistamines, such as diphenhydramine (Benadryl), can cause drowsiness and other side effects like dry mouth, blurred vision, constipation, and urinary retention.
- Second-generation antihistamines, such as loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec), are less likely to cause drowsiness and are generally long-acting, often providing relief for 24 hours with a single dose.
Loratadine is an antihistamine that is used to relieve symptoms of allergies, such as runny nose, sneezing, itchy or watery eyes, and itching of the nose or throat. It works by blocking a certain natural substance (histamine) that your body makes during an allergic reaction.
Loratadine is commonly found under the brand names Claritin, Alavert, and others. It’s available over-the-counter in most countries, which means you can buy it without a prescription.
Side effects of loratadine are usually mild and can include:
- Headache
- Dry mouth
- Feeling tired or drowsy
- Stomach pain
- Nausea
- Diarrhea
Severe side effects are rare, but can include:
- Fast or uneven heart rate
- Feeling like you might pass out
- Jaundice (yellowing of your skin or eyes)
- Seizures (convulsions)
Again although these drugs are concluded to be safe, the long term use effects are not well studied.
Chemotherapy
The topic of cancers and malignancies is very complex and has to be discussed with a trained medical provider. Ever cancer is different and it is beyond the scope of this website to discuss all malignancies. This is by no means a comprehensive discussion on all Chemo drugs or all forms of cancers. This discussion will be updated frequently so keep on checking in.
Do not use this information to treat yourself!
The Problems:
- There are no placebo controlled studies available (using saline) on the efficacy statistics of chemotherapy.In the field of oncology, it’s considered unethical to give patients a placebo when an effective treatment is available. Since chemotherapies can have a measurable effects on tumor size and progression that would not be seen with a placebo, making such a study design unnecessary and inappropriate.
- Meta-analyses studies comparing survival rates of people who “opt-out” of chemo show similar or even higher survival rates.
- Just because a tumor shrinks does not mean the root of the cancer problem is treated. A median life expectancy prolonged by a few weeks or month compared to “supportive” care is not a cure.
- Chemotherapy generally inhibits DNA replication or cell division which causes a massive deaths’ of all active cells including white blood cells.
- The problem of the cancerous stem cell is never addressed. The tumor can shrink but the cancer persists.
- Chemo kills your white blood cells, the very cells that your body is using to fight the tumor, eg. NK-cells. For that matter CAR-NK can be a very effective immune therapy. Of course Leukemia is not part of this discussion.
- Any studies on chemo drugs usually compare them to other drugs such as tamoxifen-only. These are not placebos and have side effects. New chemotherapy drugs or treatment strategies are often tested against the current standard of care in what are known as randomized controlled trials (RCTs). In these studies, patients are randomly assigned to receive either the new treatment or the current standard treatment. This allows researchers to compare the effectiveness and side effects of the new treatment with those of the existing one but they say nothing about the overall efficacy of the drug use.
- Studies are usually short term and generally stop before re-occurrence of the original or 2ndary cancers.
- Chemo drugs can cause 2ndary cancers, not related to the “originally diagosed” cancers. This is because chemotherapy drugs work by killing rapidly dividing cells, a hallmark of cancer. However, these drugs can also affect normal cells in the body that divide rapidly, such as cells in the bone marrow that produce new blood cells. In some cases, damage to these normal cells can lead to changes (mutations) in their DNA, which may eventually cause a new, separate cancer to develop. This is known as a treatment-related or secondary cancer. The risk of secondary cancer is influenced by several factors, including the type and dose of chemotherapy received, the duration of treatment, the patient’s age at treatment, and the patient’s individual genetic susceptibility to cancer.
- Many Chemo drugs are studied for specific cancers only and are often mixed in cocktails with other drugs, so it becomes difficult or impossible to compare meta analyses of clinical studies.
- Even for a trained scientist study results are so convoluted and not clearly presented in statistical valuable plots so to avoid any reasonable conclusions.
- Immuno-assisted therapies are largely unavailable
Cyclophosphamide – survival rate is about 60% = marginally above placebo
Topotecan – survival rate is about 20-30% = ca 20% below placebo (nocebo); Topotecan is one of the oldest chemotherapy drugs that is often used to treat small cell lung cancer, ovarian cancer, and cervical cancer.
For example, in the treatment of recurrent small cell lung cancer, a disease for which topotecan is commonly used, the drug has been found to increase median survival to around 25-30 weeks, compared with supportive care alone which has a median survival of 13-20 weeks. In relapsed ovarian cancer, studies have shown overall response rates of approximately 20% with a median survival of around 12 to 24 months.
Mammograms save lives?
CISNET study 2024: For 32 life exams: 32 exams * 0.007 life-years per exam = 0.224 life-years (approximately 82 days) saved!
Look at the absolute numbers!
11 breast cancer death less per 1000 women? what exactly does that mean? they typically stop counting after 5 years? If a study follows 100,000 women over 30 years, it might find that 400 women die from breast cancer in the screened group, compared to 511 in the unscreened group. This yields a reduction of 11 deaths per 1,000 women (511 – 400 = 111 fewer deaths per 100,000 women, or 11 fewer deaths per 1,000 women).
Aromatase Inhibitors
Aromatase inhibitors (AIs) are drugs used to reduce estrogen production by inhibiting the enzyme aromatase, which is responsible for converting androgens (testosterone and androstenedione) into estrogens (estradiol and estrone). They are most commonly used in the treatment of hormone receptor-positive breast cancer in postmenopausal women, where reducing estrogen levels helps slow or stop the growth of estrogen-dependent cancer cells.
As like most everything in cancer therapy, Aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemestane, have shown the ability to shrink tumors and improvements in disease-free survival (DFS) when compared to placebo or no treatment, particularly in postmenopausal women with hormone receptor-positive breast cancer. Their impact on overall survival (OS) is less pronounced when compared to no treatment or placebo. The question of whether they significantly improve overall survival (OS) after 10 years is complex.
‘Long term Meta studies’ results shown below show little effect.
There are different types of aromatase inhibitors, and they vary in their chemical structure, mechanism of action, and potential side effects.
Types of Aromatase Inhibitors:
- Non-Steroidal Aromatase Inhibitors (Reversible)
- Examples: Anastrozole (Arimidex) and Letrozole (Femara)
- Mechanism: These inhibitors bind reversibly to the aromatase enzyme’s active site, preventing it from converting androgens into estrogens. The inhibition is competitive and reversible, meaning that the inhibitor can dissociate from the enzyme, and the enzyme’s function can potentially be restored if the drug is stopped.
- Usage: These drugs are commonly used in the treatment of postmenopausal women with hormone receptor-positive breast cancer. They are also used off-label for conditions related to high estrogen levels.
- Advantages: They are generally well-tolerated, with fewer hormonal side effects than some steroidal AIs.
- Side Effects: Common side effects include hot flashes, joint pain, fatigue, and bone thinning (osteopenia/osteoporosis) due to lower estrogen levels.
- Steroidal Aromatase Inhibitors (Irreversible)
- Example: Exemestane (Aromasin)
- Mechanism: Exemestane is a steroidal aromatase inhibitor that binds irreversibly to the aromatase enzyme. It permanently deactivates the enzyme by forming a covalent bond, meaning the enzyme cannot regain function even after the drug is cleared from the body.
- Usage: Exemestane is used similarly to non-steroidal AIs for hormone receptor-positive breast cancer in postmenopausal women. It can be preferred in certain cases where irreversible inhibition may be more effective.
- Advantages: Since it irreversibly binds to the enzyme, exemestane can be more potent in some scenarios, particularly in individuals whose cancer cells are highly dependent on estrogen.
- Side Effects: Similar to non-steroidal AIs, but some research suggests that exemestane may have a slightly lower risk of bone loss due to its partial androgenic properties.
Key Differences Between Non-Steroidal and Steroidal Aromatase Inhibitors:
| Feature | Non-Steroidal AIs (Anastrozole, Letrozole) | Steroidal AIs (Exemestane) |
|---|---|---|
| Mechanism | Reversible inhibition of aromatase | Irreversible inhibition (suicide inhibitor) |
| Chemical Structure | Non-steroidal, synthetic molecules | Steroid-based structure |
| Enzyme Binding | Competitively and reversibly binds to aromatase | Permanently deactivates aromatase |
| Bone Health Effects | Higher risk of bone loss (osteoporosis) | Slightly lower risk due to mild androgenic effects |
| Side Effects | Hot flashes, joint pain, fatigue, osteoporosis | Similar, but may have less severe bone effects |
| Duration of Inhibition | Temporary (can be reversed if drug is stopped) | Permanent (enzyme remains deactivated) |
Other Aromatase Inhibitor Considerations:
- Effectiveness: Both non-steroidal and steroidal AIs are effective at reducing estrogen levels in postmenopausal women, but individual responses to the drugs may vary. The choice of an AI can depend on factors such as side effect profiles, cancer progression, and patient tolerance.
- Use in Premenopausal Women: Aromatase inhibitors are generally not used in premenopausal women because their ovaries continue to produce significant amounts of estrogen. In these cases, drugs that directly suppress ovarian function (such as gonadotropin-releasing hormone analogs) are preferred. In some cases, AIs may be used in combination with ovarian suppression therapy in premenopausal women.
- Resistance: Some patients may develop resistance to aromatase inhibitors over time. This can be due to changes in tumor biology, such as mutations in estrogen receptors or upregulation of other estrogen production pathways.
The main differences between the types of aromatase inhibitors lie in their chemical structure, mechanism of enzyme inhibition, and side effect profiles. Non-steroidal AIs (like anastrozole and letrozole) act by reversibly binding to aromatase, while steroidal AIs (like exemestane) permanently inactivate the enzyme. Both types are effective in reducing estrogen levels for the treatment of hormone receptor-positive breast cancer, but the choice of AI depends on the patient’s individual needs, cancer progression, and how well they tolerate the drugs.
Studies on the impact of aromatase inhibitors (AIs) on mortality, particularly in the context of hormone receptor-positive breast cancer, have been a major area of research. These studies primarily focus on the comparison between aromatase inhibitors and other endocrine therapies, such as tamoxifen, to assess survival rates, disease recurrence, and overall mortality. Here’s a summary of key findings from studies on the effect of aromatase inhibitors on mortality:
Key Studies on Aromatase Inhibitors and Mortality in Breast Cancer
- ATAC Trial (Arimidex, Tamoxifen, Alone or in Combination)
- Overview: The ATAC trial compared anastrozole (an aromatase inhibitor) to tamoxifen (a selective estrogen receptor modulator) in postmenopausal women with early hormone receptor-positive breast cancer.
- Results:
- Anastrozole showed a significant reduction in recurrence rates compared to tamoxifen after 5 years of follow-up.
- After 10 years, the overall survival rates were comparable, but disease-free survival and the incidence of contralateral breast cancer were improved with anastrozole.
- Conclusion: While the overall mortality did not differ significantly between the two groups, AIs showed better control of disease recurrence, suggesting a long-term benefit in preventing cancer progression.
- BIG 1-98 Trial (Letrozole vs. Tamoxifen)
- Overview: This study compared letrozole (an AI) to tamoxifen in postmenopausal women with hormone receptor-positive breast cancer.
- Results:
- Letrozole was associated with a reduction in the risk of breast cancer recurrence compared to tamoxifen.
- Letrozole demonstrated an improved overall survival in patients at higher risk of recurrence (e.g., those with lymph node involvement).
- Conclusion: Letrozole showed better outcomes in terms of disease-free survival and overall survival in certain subgroups of patients, making it a preferable choice for high-risk individuals.
- MA.17 Trial (Exemestane after Tamoxifen)
- Overview: The MA.17 trial looked at the effect of using exemestane (a steroidal AI) following 5 years of tamoxifen therapy in postmenopausal women.
- Results:
- Women who switched to exemestane after tamoxifen had a lower risk of breast cancer recurrence compared to those who continued on placebo.
- Overall survival was improved, especially in patients with node-positive disease.
- Conclusion: This trial demonstrated the benefit of extending AI therapy after tamoxifen to reduce recurrence and improve survival in some women.
- TEAM Trial (Exemestane vs. Tamoxifen)
- Overview: The TEAM trial compared exemestane with tamoxifen, followed by exemestane after 2.5 years of tamoxifen treatment.
- Results:
- The use of exemestane alone or following tamoxifen was associated with a reduction in breast cancer recurrence compared to tamoxifen alone.
- No significant difference in overall survival was observed, but disease-free survival was significantly better in the exemestane group.
- Conclusion: Exemestane reduced the risk of recurrence, but like other AIs, did not consistently demonstrate significant improvements in overall mortality when compared to tamoxifen in the broader population.
- Meta-Analyses of Aromatase Inhibitors vs. Tamoxifen
- Overview: Multiple meta-analyses have compared AIs (including anastrozole, letrozole, and exemestane) to tamoxifen in terms of survival and recurrence outcomes.
- Results:
- Disease-free survival: AIs consistently showed an advantage over tamoxifen in terms of reducing the risk of breast cancer recurrence.
- Overall survival: In some analyses, AIs showed a slight improvement in overall survival, particularly in high-risk patients, but the difference was not always statistically significant.
- Conclusion: AIs are more effective in preventing breast cancer recurrence, but the overall survival benefit remains modest in certain groups, with tamoxifen still being a valuable option for some women.
Other Factors Influencing Mortality in AI Studies
- Cardiovascular and Bone Health:
- AIs are associated with a higher risk of bone loss (osteoporosis) and fractures compared to tamoxifen, which can reduce the overall survival benefit in some patients.
- However, tamoxifen has been linked to an increased risk of venous thromboembolism and uterine cancer, while AIs have a more favorable profile in these areas.
- Adherence to Therapy:
- Adherence to AI therapy is crucial for its effectiveness. Some studies have shown that side effects like joint pain (arthralgia) can lead to discontinuation of therapy, which can negatively impact survival outcomes.
- Duration of Treatment:
- Longer durations of AI therapy (e.g., 5-10 years) have shown better outcomes in terms of recurrence prevention, but the impact on overall survival is still being studied, and extended treatment may increase side effects such as bone thinning.
Summary of Findings on Mortality and Aromatase Inhibitors
- Recurrence Prevention: AIs consistently reduce the risk of breast cancer recurrence compared to tamoxifen, which can have long-term benefits in reducing cancer-related mortality.
- Overall Survival: AIs may provide a slight overall survival advantage in certain high-risk subgroups (e.g., node-positive patients), but across broad populations, the difference in mortality between AIs and tamoxifen is modest.
- Side Effects and Comorbidities: The benefits of AIs must be weighed against their side effects, particularly on bone health and cardiovascular risk, which can influence long-term outcomes and mortality.
Caveats: Meta-analyses on anastrozole often focus on its use as an aromatase inhibitor in treating postmenopausal women with hormone receptor-positive breast cancer. However, most studies compare it to tamoxifen, a common treatment. Still, there is valuable data from studies where anastrozole is evaluated independently or compared to other therapies like megestrol acetate.
Major side-effects:
- Bone density loss, which can lead to osteoporosis and bone fractures
- Muscle pain
- Joint pain
- Menopausal symptoms, such as hot flashes
In conclusion, aromatase inhibitors are highly effective in reducing breast cancer recurrence, and they may provide a survival advantage in specific subgroups of patients. However, the impact on overall mortality remains nuanced and influenced by various factors, including patient characteristics, treatment adherence, and side effect management.
CAR-T vs. adoptive T cell therapy
The concept of T-cell-based immunotherapy for cancer, where T cells are used to fight tumors, dates back several decades, but it began gaining real momentum in the 1980s. Early studies, particularly from researchers like Dr. Steven Rosenberg at the National Cancer Institute (NCI), pioneered the development of tumor-infiltrating lymphocytes (TILs), which laid the groundwork for modern TIL-based therapies like Lifileucel. These early trials showed that T cells isolated from tumors could be expanded in the lab and re-infused into patients to combat cancer, particularly melanoma.
Throughout the 1990s and early 2000s, researchers made significant advances in the understanding of how the immune system, particularly T cells, could recognize and attack tumors. This era saw the development of more refined techniques for isolating and expanding T cells, improving patient outcomes. By the 2010s, TIL therapy was refined to the point where clinical trials began showing promising results in treating advanced cancers.
While these early efforts were pioneering, the first FDA approval of a T-cell-based therapy, CAR-T therapy, for blood cancers happened only in 2017. Lifileucel, a TIL-based therapy, was approved for melanoma in 2024, marking a key milestone for T-cell-based therapies targeting solid tumors.
In summary, T-cell selection for cancer therapy has been studied for over 40 years, but its clinical applications and FDA approvals have become prominent only in the last decade.
Lifileucel (TIL therapy) and CAR-T cell therapy are both forms of cell-based immunotherapy, but they differ significantly in how the immune cells are prepared and function.
Key Differences: Source of Immune Cells:
Lifileucel (TIL therapy): Uses tumor-infiltrating lymphocytes (TILs) that are naturally present in the patient’s tumor. These TILs are collected, expanded in a lab, and re-infused into the patient to attack the tumor.
CAR-T Therapy: Involves the genetic modification of T cells (usually from the patient’s blood), which are engineered to express a chimeric antigen receptor (CAR) that specifically targets certain proteins on cancer cells.
Genetic Engineering:
Lifileucel: Does not involve genetic engineering. The patient’s T cells are simply expanded outside the body and then reintroduced to enhance their natural tumor-fighting ability
CAR-T: Requires genetic engineering to create T cells that specifically target cancer cells. CAR-T cells are reprogrammed to recognize specific antigens (such as CD19 in B-cell leukemias) on cancer cells
Targeting Mechanism:
Lifileucel: Relies on naturally occurring T cells that are already recognizing cancer cells within the tumor. It enhances the patient’s existing immune response but does not introduce new specificity
CAR-T: Uses engineered T cells that are designed to specifically target cancer cells by recognizing surface proteins. This makes CAR-T cells highly specific for certain cancers.
Type of Cancer Treated:
Lifileucel: Primarily used for solid tumors, such as melanoma
CAR-T: Most effective in blood cancers like leukemia and lymphoma
Side Effects:
Lifileucel: Generally has more manageable side effects compared to CAR-T, as it does not cause severe immune-related reactions like cytokine release syndrome (CRS) or neurotoxicity
Comprehensive Cancer Information
CAR-T: Often causes CRS and neurotoxicity due to the aggressive immune response it triggers
In summary, while both therapies harness the power of the immune system to fight cancer, CAR-T therapy uses genetically engineered cells for a highly targeted approach, primarily for blood cancers, while Lifileucel leverages naturally occurring immune cells from the tumor environment to treat solid tumors like melanoma.
CRISPR and viral vector gene therapy
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a powerful genome editing tool that has revolutionized genetics and molecular biology. It originally evolved as a bacterial defense mechanism against phages (viruses that infect bacteria). The system has been adapted for genome editing in various organisms, including humans.
Traditional gene therapy such as Libmeldy does not use CRISPR technology. Instead, it employs viral vector-based gene therapy. The process involves using a lentiviral vector to introduce a functional copy of the ARSA gene into the patient’s hematopoietic stem cells. These modified stem cells are then reintroduced into the patient, where they produce the necessary enzyme to prevent the progression of metachromatic leukodystrophy (MLD).
The central component in the CRISPR system for genome editing is the Cas9 protein (or other variations, like Cpf1/Cas12a), which can be guided to specific DNA sequences by a molecule called single-guide RNA (sgRNA). When the Cas9 protein, guided by the sgRNA, finds its target DNA sequence, it induces a double-strand break (DSB) at that site.
Once the DNA is cleaved (both strands), the cell’s repair mechanisms kick in. A word of caution! Nature is trying to avoid DNA double strand breakage under normal circumstances. These disruptions are very rare but can be cause by eg. reactive oxygen species. Under normal circumstances only single strand breaks happen. They can easily be repaired and usually are not a disruption. DSB however can be devastating to the cellular function. There are mainly two pathways the cell uses to repair DSBs:
- Non-Homologous End Joining (NHEJ): This pathway can be error-prone. It often results in the insertion or deletion (indel) of small numbers of DNA base pairs. If this occurs within a gene, especially in a critical region like the coding sequence, it can disrupt the function of the gene, effectively “knocking it out.”
- Homology Directed Repair (HDR): This is a more precise repair mechanism that requires a DNA template with sequences homologous to the regions flanking the DSB. If a researcher provides a custom DNA template with desired changes (along with the CRISPR-Cas9 components), the cell can use this template to repair the DSB, incorporating the changes in the process. This is the basis for the “new DNA introduction” or precise gene editing.
Here’s a simplified breakdown of how the “new DNA introduction” using HDR works:
- Design the sgRNA: First, researchers design an sgRNA that targets the desired location in the genome.
- Provide the DNA Template: Along with the Cas9 protein and sgRNA, researchers introduce a piece of DNA that contains the desired changes (mutations, insertions, deletions, etc.). This piece of DNA also contains sequences on its ends that are homologous to the regions immediately flanking the target DNA site.
- DNA Cleavage: The Cas9-sgRNA complex finds the target DNA sequence and induces a DSB.
- Cellular Repair with HDR: If the cell chooses the HDR pathway for repair (and is provided with the custom DNA template), it will use this template as a guide to repair the break, integrating the desired changes in the process.
A couple of important things to note:
- The efficiency of HDR is generally lower than NHEJ in many cell types, so obtaining the desired edit using HDR can be challenging.
- Since NHEJ can occur more frequently than HDR, there’s often a mix of outcomes, with some cells having indels (due to NHEJ) and some cells incorporating the desired changes (due to HDR).
Efforts are ongoing to enhance the efficiency of HDR and reduce off-target effects to make CRISPR-based genome editing more precise and reliable.
Concerns in the CRISPR/Cas9 system
- Targeting with sgRNA: The specificity of CRISPR/Cas9 largely depends on the sgRNA sequence. The sgRNA is designed to be complementary to the target DNA site. This complementarity ensures that the Cas9 protein, guided by the sgRNA, binds to the correct location. The region at the 3′ end of the sgRNA (typically the last 20 nucleotides) is what defines the specificity. Additionally, many versions of Cas9 also require an adjacent motif (e.g., NGG for the most common Cas9 from S. pyogenes) called a protospacer adjacent motif (PAM) next to the target site, which further enhances specificity.
- Errors and Off-Targets: No system is perfect, and CRISPR/Cas9 is no exception. Off-target edits (edits at unintended locations) can happen, especially if other sites in the genome are similar to the target site. To minimize off-target effects:
- sgRNAs are carefully designed using computational tools to minimize potential off-targets.
- Modified versions of Cas9 with higher specificity have been developed.
- Using a lower amount of CRISPR/Cas9 components or controlling the duration of their activity can also reduce off-target edits.
- After editing, techniques like whole-genome sequencing can be used to check for unintended modifications, especially in applications like gene therapy.
- Concerns About Double-Strand Breaks (DSBs): Introducing DSBs into the genome is indeed a concern because they are potentially mutagenic and cytotoxic.
- As mentioned, cells can repair DSBs via NHEJ, which can introduce indels. If this happens in a functional gene, it might disrupt that gene’s function or, in worse cases, lead to potential oncogenic transformations.
- Some strategies aim to avoid DSBs altogether. For instance, base editing and prime editing are newer CRISPR-derived technologies that can introduce specific DNA changes without causing DSBs.
- Unrepaired DSBs: Continuous expression or presence of CRISPR/Cas9 components can result in persistent DNA breaks, which are undesirable. To address this:
- Temporal control of CRISPR/Cas9 activity is crucial. Systems where the Cas9 and sgRNA are only transiently available, such as using ribonucleoprotein (RNP) complexes instead of plasmid DNA, can help.
- If a DSB is not repaired, it can lead to cell cycle arrest or cell death, a natural safeguard. But in cases where it doesn’t, and the break becomes stabilized (e.g., through chromosomal translocations or large deletions), that poses risks.
The CRISPR/Cas9 system, while revolutionary, has complexities and potential pitfalls. Thorough experimental design, careful consideration of target sites, and post-editing analyses are essential to maximize benefits and minimize risks.
- Role of Homology Arms: The donor DNA template, which contains the desired sequence to be introduced into the genome, typically has flanking sequences called “homology arms.” These homology arms are designed to be identical to the sequences adjacent to the cleavage site in the genome. The presence of these homologous sequences is crucial for guiding the donor DNA to the correct location.
- Cell’s Inherent Repair Machinery: When the CRISPR/Cas9 system introduces a double-strand break (DSB) in the target DNA, the cell naturally tries to repair it. One of the pathways it can use is the homology-directed repair (HDR) pathway. In HDR, the cell looks for a homologous sequence to use as a template to guide the repair. If the donor DNA with the homology arms is present in the cell, the cellular machinery will recognize the homology between the arms of the donor DNA and the sequences adjacent to the DSB. This recognition ensures the donor DNA is used as a template for repair, leading to the insertion of the desired sequence at the cleavage site.
- Importance of Co-delivery: For successful HDR-mediated insertion of the donor DNA, it’s essential that the donor DNA is present in the cell around the same time the DSB is introduced. Thus, in genome editing experiments, researchers often co-deliver the CRISPR/Cas9 components and the donor DNA template to ensure their concurrent presence in the cell.
- Limitations of Efficiency: It’s worth noting that while the above mechanism describes how the donor DNA can be integrated at the target site, the efficiency of this process can be quite low. Cells more often use the NHEJ pathway, which doesn’t rely on a homologous template and can result in small insertions or deletions at the break site. Because of this preference for NHEJ over HDR in many cell types, achieving high-efficiency insertion of donor DNA can be challenging.
- Enhancing HDR Efficiency: Various strategies are being explored to enhance the efficiency of HDR over NHEJ. For example, inhibiting key proteins involved in the NHEJ pathway can tip the balance in favor of HDR. Similarly, synchronizing cells in a particular phase of the cell cycle where HDR is more active (e.g., the S/G2 phase) can improve donor DNA insertion rates.
In essence, the precise insertion of the new DNA sequence relies on the cell’s inherent DNA repair mechanisms, guided by the homologous sequences on the donor DNA template. This is a carefully orchestrated process that researchers can harness and manipulate for genome editing purposes.
Cancer Risk:
Unrepaired or improperly repaired double-strand breaks (DSBs) can pose a cancer risk. Here’s why:
- Genomic Instability: DSBs are among the most deleterious types of DNA damage because they can lead to genomic instability if not correctly repaired. Genomic instability, characterized by an increased tendency of the genome to acquire mutations, is a hallmark of cancer.
- Chromosomal Translocations: Unrepaired DSBs or those repaired by the error-prone non-homologous end joining (NHEJ) pathway can lead to chromosomal translocations, where parts of one chromosome become attached to another. Some chromosomal translocations are known to be oncogenic. For example, the Philadelphia chromosome, a result of a translocation between chromosomes 9 and 22, is associated with certain types of leukemia.
- Activation of Oncogenes or Inactivation of Tumor Suppressors: If DSBs occur within or near critical genes, their repair might lead to the activation of oncogenes (genes that have the potential to cause cancer when activated) or the inactivation of tumor suppressor genes (genes that protect a cell from progressing to cancer).
- Escape from Cell Cycle Checkpoints: Normally, cells have mechanisms (checkpoints) to detect DNA damage and either halt the cell cycle to allow repair or, if the damage is too severe, initiate programmed cell death (apoptosis). If these mechanisms fail, cells with DSBs can continue to divide, propagating the damage and increasing the risk of malignant transformation.
- Potential for Clonal Expansion: If a cell with a DSB survives and gains a growth advantage (e.g., through activation of an oncogene), it might proliferate more than its neighbors, leading to clonal expansion of a potentially precancerous or cancerous cell population.
Given these risks, it’s crucial to be cautious when using tools like CRISPR/Cas9 that introduce DSBs, especially in therapeutic contexts where the edited cells will be reintroduced into patients. It’s essential to thoroughly analyze edited cells for unwanted mutations and other genomic alterations before any clinical application. The field is also working on refining genome editing techniques to reduce the chances of off-target DSBs and to develop methods that don’t rely on DSBs at all, like base editing and prime editing.