<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Prednisone and can you explain it in depth? [/INST] Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and adrenal insufficiency along with other steroids. It is taken by mouth.Common side effects with long-term use include cataracts, bone loss, easy bruising, muscle weakness, and thrush. Other side effects include weight gain, swelling, high blood sugar, increased risk of infection, and psychosis. It is generally considered safe in pregnancy and low doses appear to be safe when breastfeeding. After prolonged use, prednisone needs to be stopped gradually.Prednisone is a prodrug and must be converted to prednisolone by the liver before it becomes active. Prednisolone then binds to glucocorticoid receptors, activating them and triggering changes in gene expression.Prednisone was patented in 1954 and approved for medical use in the United States in 1955. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 30th most commonly prescribed medication in the United States, with more than 19 million prescriptions.

Medical uses
Prednisone is used for many different autoimmune diseases and inflammatory conditions, including asthma, gout, COPD, CIDP, rheumatic disorders, allergic disorders, ulcerative colitis and Crohns disease, granulomatosis with polyangiitis, adrenocortical insufficiency, hypercalcemia due to cancer, thyroiditis, laryngitis, severe tuberculosis, hives, lipid pneumonitis, pericarditis, multiple sclerosis, nephrotic syndrome, sarcoidosis, to relieve the effects of shingles, lupus, myasthenia gravis, poison oak exposure, Ménières disease,  autoimmune hepatitis, giant-cell arteritis, the Herxheimer reaction that is common during the treatment of syphilis, Duchenne muscular dystrophy, uveitis, and as part of a drug regimen to prevent rejection after organ transplant.Prednisone has also been used in the treatment of migraine headaches and cluster headaches and for severe aphthous ulcer. Prednisone is used as an antitumor drug. It is important in the treatment of acute lymphoblastic leukemia, non-Hodgkin lymphomas, Hodgkins lymphoma, multiple myeloma, and other hormone-sensitive tumors, in combination with other anticancer drugs.
Prednisone is often also prescribed as a form of treatment for Sudden Sensorineural Hearing Loss (SSNHL).Prednisone can be used in the treatment of decompensated heart failure to increase renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large doses of loop diuretics. In terms of the mechanism of action for this purpose: prednisone, a glucocorticoid, can improve renal responsiveness to atrial natriuretic peptide by increasing the density of natriuretic peptide receptor type A in the renal inner medullary collecting duct, thereby inducing a potent diuresis.At high doses it may be used to prevent rejection following organ transplant.

Side effects
Short-term side effects, as with all glucocorticoids, include high blood glucose levels (especially in patients with diabetes mellitus or on other medications that increase blood glucose, such as tacrolimus) and mineralocorticoid effects such as fluid retention. The mineralocorticoid effects of prednisone are minor, which is why it is not used in the management of adrenal insufficiency, unless a more potent mineralocorticoid is administered concomitantly.
It can also cause depression or depressive symptoms and anxiety in some individuals.Long-term side effects include Cushings syndrome, steroid dementia syndrome, truncal weight gain, glaucoma and cataracts, diabetes mellitus type 2, and depression upon dose reduction or cessation. Long-term steroids can also increase the risk of osteoporosis, but research has found that few of these people were taking medications to protect bones. Prednisone also results in leukocytosis.When used as treatment for sudden deafness or sudden sensorineural hearing loss, it can cause or exacerbate Tinnitus or a ringing in the ears.

Major
Source:

Minor
Source:

Dependency
Adrenal suppression will begin to occur if prednisone is taken for longer than seven days. Eventually, this may cause the body to temporarily lose the ability to manufacture natural corticosteroids (especially cortisol), which results in dependence on prednisone. For this reason, prednisone should not be abruptly stopped if taken for more than seven days; instead, the dosage should be gradually reduced. This weaning process may be over a few days if the course of prednisone was short, but may take weeks or months if the patient had been on long-term treatment. Abrupt withdrawal may lead to an Addisonian crisis. For those on chronic therapy, alternate-day dosing may preserve adrenal function and thereby reduce side effects.Glucocorticoids act to inhibit feedback of both the hypothalamus, decreasing corticotropin-releasing hormone (CRH), and corticotrophs in the anterior pituitary gland, decreasing the amount of adrenocorticotropic hormone (ACTH). For this reason, glucocorticoid analogue drugs such as prednisone down-regulate the natural synthesis of glucocorticoids. This mechanism leads to dependence in a short time and can be dangerous if medications are withdrawn too quickly. The body must have time to begin synthesis of CRH and ACTH and for the adrenal glands to begin functioning normally again.
Prednisone may start to result in the suppression of the hypothalamic-pituitary-adrenal (HPA) axis if used at doses 7–10 mg or higher for several weeks. This is approximately equal to the amount of endogenous cortisol produced by the body every day. As such, the HPA axis starts to become suppressed and atrophy. If this occurs the patient should be tapered off prednisone slowly to give the adrenal gland enough time to regain its function and endogenous production of steroids. Supplemental doses, or "stress doses" may be required in those with HPA axis suppression who are experiencing a higher degree of stress (e.g., illness, surgery, trauma, etc.). Failing to do so in such situations could be life-threatening.

Withdrawal
The magnitude and speed of dose reduction in corticosteroid withdrawal should be determined on a case-by-case basis, taking into consideration the underlying condition being treated, and individual patient factors such as the likelihood of relapse and the duration of corticosteroid treatment. Gradual withdrawal of systemic corticosteroids should be considered in those whose disease is unlikely to relapse and have:

received more than 40 mg prednisone (or equivalent) daily for more than 1 week
been given repeat doses in the evening
received more than 3 weeks of treatment
recently received repeated courses (particularly if taken for longer than 3 weeks)
taken a short course within 1 year of stopping long-term therapy
other possible causes of adrenal suppressionSystemic corticosteroids may be stopped abruptly in those whose disease is unlikely to relapse and who have received treatment for 3 weeks or less and who are not included in the patient groups described above.
During corticosteroid withdrawal, the dose may be reduced rapidly down to physiological doses (equivalent to prednisolone 7.5 mg daily) and then reduced more slowly. Assessment of the disease may be needed during withdrawal to ensure that relapse does not occur.

Pharmacology
Prednisone is a synthetic glucocorticoid used for its anti-inflammatory and immunosuppressive properties. Prednisone is a prodrug; it is metabolised in the liver by 11-β-HSD to prednisolone, the active drug. Prednisone has no substantial biological effects until converted via hepatic metabolism to prednisolone.

Pharmacokinetics
Prednisone is absorbed in the gastrointestinal tract and has a half life of 2–3 hours. it has a volume of distribution of 0.4–1 L/kg. The drug is cleared by hepatic metabolism using cytochrome P450 enzymes. Metabolites are excreted in the bile and urine.

Lodotra
"Lodotra" is the brand name of an oral formulation, which releases prednisone four hours after ingestion. It is indicated for rheumatoid arthritis with morning stiffness </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Homatropine and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Benzoyl peroxide and can you explain it in depth? [/INST] Benzoyl peroxide is a chemical compound (specifically, an organic peroxide) with structural formula  (C6H5−C(=O)O−)2, often abbreviated as (BzO)2.  In terms of its structure, the molecule can be described as two benzoyl (C6H5−C(=O)−, Bz) groups connected by a peroxide (−O−O−).  It is a white granular  solid with a faint odour of benzaldehyde, poorly soluble in water but soluble in acetone, ethanol, and many other organic solvents. Benzoyl peroxide is an oxidizer, which is principally used as in the production of polymers.As a bleach, it has been used as a medication and a water disinfectant. In specialized contexts, the name may be abbreviated as BPO.
As a medication, benzoyl peroxide is mostly used to treat acne, either alone or in combination with other treatments. Some versions are sold mixed with antibiotics such as clindamycin. It is on the WHO List of Essential Medicines, and, in the US, it is available as an over-the-counter and generic medication. It is also used in dentistry for teeth whitening.
Benzoyl peroxide is also used in the plastics industry and for bleaching flour, hair, and textiles. It is also used to remove stubborn stains from dolls and other plastic toys, although some users have claimed that the product has unwanted long-term effects of discolouring the item, particularly with the My Little Pony brand.

History
Benzoyl peroxide was first prepared and described by Liebig in 1858.  It was the first organic peroxide prepared intentionally.In 1901, J. H. Kastle and his graduate student A. S. Loevenhart observed that the compound made the tincture of guaiacum tincture turn blue, a sign of oxygen being released.  Around  1905, Loevenhart reported on the successful use of BPO to treat various skin conditions, including burns, chronic varicose leg tumors, and tinea sycosis. He also reported animal experiments that showed the relatively low toxicity of the compound.Treatment with benzoyl peroxide was proposed for wounds by Lyon and Reynolds in 1929, and for sycosis vulgaris and acne varioliformis by Peck and Chagrin in 1934. However, preparations were often of questionable quality.  It was officially approved for the treatment of acne in the US in 1960.

Medical uses
Acne treatment
Benzoyl peroxide is effective for treating acne lesions. It does not induce antibiotic resistance. It may be combined with salicylic acid, sulfur, erythromycin or clindamycin (antibiotics), or adapalene (a synthetic retinoid).  Two common combination drugs include benzoyl peroxide/clindamycin and adapalene/benzoyl peroxide, adapalene being a chemically stable retinoid that can be combined with benzoyl peroxide unlike tezarotene and tretinoin. Combination products such as benzoyl peroxide/clindamycin and benzoyl peroxide/salicylic acid appear to be slightly more effective than benzoyl peroxide alone for the treatment of acne lesions. The combination tretinoin/benzoyl peroxide was approved for medical use in the United States in 2021.
Benzoyl peroxide for acne treatment is typically applied to the affected areas in gel, cream, or liquid, in concentrations of 2.5% increasing through 5.0%, and up to 10%. No strong evidence supports the idea that higher concentrations of benzoyl peroxide are more effective than lower concentrations.

Mechanism of action
Classically, benzoyl peroxide is thought to have a three-fold activity in treating acne. It is sebostatic, comedolytic, and inhibits growth of  Cutibacterium acnes, the main bacterium associated with acne.  In general, acne vulgaris is a hormone-mediated inflammation of sebaceous glands and hair follicles. Hormone changes cause an increase in keratin and sebum production, leading to blocked drainage. C. acnes has many lytic enzymes that break down the proteins and lipids in the sebum, leading to an inflammatory response. The free-radical reaction of benzoyl peroxide can break down the keratin, therefore unblocking the drainage of sebum (comedolytic). It can cause nonspecific peroxidation of C. acnes, making it bactericidal, and it was thought to decrease sebum production, but  disagreement exists within the literature on this.Some evidence suggests that benzoyl peroxide has an anti-inflammatory effect as well. In micromolar concentrations it prevents neutrophils from releasing reactive oxygen species, part of the inflammatory response in acne.

Side effects
Application of benzoyl peroxide to the skin may result in redness, burning, and irritation. This side effect is dose-dependent.Because of these possible side effects, it is recommended to start with a low concentration and build up as appropriate, as the skin gradually develops tolerance to the medication. Skin sensitivity typically resolves after a few weeks of continuous use. Irritation can also be reduced by avoiding harsh facial cleansers and wearing sunscreen prior to sun exposure.One in 500 people experience hypersensitivity to BPO and are liable to experience burning, itching, crusting, and possibly swelling.  About one-third of people experience phototoxicity under exposure to ultraviolet (UVB) light.

Dosage
In the U.S., the typical concentration for benzoyl peroxide is 2.5% to 10% for both prescription and over-the-counter drug preparations that are used in treatment for acne.

Other medical uses
Benzoyl peroxide is used in dentistry as a tooth whitening product.

Non-medical uses
Bleaching
Like most peroxides, it is a powerful bleaching agent. It has been used for the bleaching of flour, fats, oils, waxes, and cheeses, as well as a stain remover.

Polymerization
Benzoyl peroxide is also used as a radical initiator to induce chain-growth polymerization reactions, such as for polyester and poly(methyl methacrylate) (PMMA) resins and dental cements and restoratives. It is the most important among the various organic peroxides used for this purpose, a relatively safe alternative to the much more hazardous methyl ethyl ketone peroxide.  It is also used in rubber curing and as a finishing agent for some acetate yarns.

Safety
Explosion hazard
Concentrated benzoyl peroxide is potentially explosive like other organic peroxides, and can cause fires without external ignition. The hazard is acute for the pure material, so the compound is generally used as a solution or a paste. For example, cosmetics contain only a small percentage of benzoyl peroxide and pose no explosion risk.

Toxicity
Benzoyl peroxide breaks down in contact with skin, producing benzoic acid and oxygen, neither of which is very toxic.The carcinogenic potential of benzoyl peroxide has been investigated. A 1981 study published in the journal Science found that although benzoyl peroxide is not a carcinogen, it does promote cell growth when applied to an initiated tumor. The study concluded, "caution should be recommended in the use of this and other free radical-generating compounds".A 1999 IARC review of carcinogenicity studies found no convincing evidence linking BPO acne medication to skin cancers in humans.  However, some animal studies found that the compound could act as a carcinogen and enhance the effect of known carcinogens.

Skin irritation
In a 1977 study using a human maximization test, 76% of subjects acquired a contact sensitization to benzoyl peroxide. Formulations of 5% and 10% were used.The U.S. National Institute for Occupational Safety and Health has developed criteria for a recommended standard for occupational exposure to benzoyl peroxide.

Cloth staining
Contact with fabrics or hair, such as from still-moist acne medication, can cause permanent color dampening almost immediately. Even secondary contact can cause bleaching, for example, contact with a towel that has been used to wash off benzoyl peroxide-containing hygiene products.

Reactivity
The original 1858 synthesis by Liebig reacted benzoyl chloride with barium peroxide, a reaction that probably follows this equation:

2 C6H5C(O)Cl + BaO2 → (C6H5CO)2O2 + BaCl2Benzoyl peroxide is usually prepared by treating hydrogen peroxide with benzoyl chloride under alkaline conditions.

2 C6H5COCl + H2O2 + 2 NaOH → (C6H5CO)2O2 + 2 NaCl + 2 H2OThe oxygen–oxygen bond in peroxides is weak </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Amiloride and can you explain it in depth? [/INST] Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.Common side effects include high blood potassium, vomiting, loss of appetite, rash, and headache. The risk of high blood potassium is greater in those with kidney problems, diabetes, and those who are older. Amiloride blocks the epithelial sodium channel (ENaC) in the late distal tubule, connecting tubule, and collecting duct of the nephron, which both reduces absorption of sodium ion from the lumen of the nephron and reduces excretion of potassium ion into the lumen.Amiloride was developed in 1967. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Amiloride may be used in combination with a thiazide diuretic for treatment of high blood pressure or (less commonly) in combination with a loop diuretic for treatment of heart failure. The potassium-sparing effects of amiloride offset the low blood potassium (hypokalemia) that is often induced by thiazides or loop diuretics, which is of particular importance in people for whom maintaining a normal level of potassium is critically important. For example, people that are taking Digitalis (i.e. digoxin) are at higher risk for changes in heart rhythm if their potassium levels get too high. The 2017 clinical practice guidelines of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines list amiloride as a "secondary" oral antihypertensive, with minimal efficacy. For people with resistant hypertension, already taking a thiazide diuretic, an angiotensin converting enzyme inhibitor (ACE-i) or an angiotensin II receptor blocker (ARB), and a calcium channel blocker, the addition of amiloride (or spironolactone) was better at reducing blood pressure than adding a beta-blocker (bisoprolol) or an alpha-1 blocker (doxazosin). When combined with hydrochlorothiazide, the addition of amiloride had positive effects on blood pressure and blood sugar tolerance. Amiloride may therefore be useful for preventing the metabolic side effects of thiazide diuretics, allowing for the use of higher thiazide doses (in line with how they were originally studied).Amiloride is the treatment of choice for Liddle phenotype, which is characterized by high blood pressure, low blood potassium, and metabolic alkalosis in conjunction with a low plasma renin activity and a low aldosterone. Some people with the Liddle phenotype have Liddle syndrome, which involves a genetic mutation resulting in upregulation of the epithelial sodium channel (ENaC), located in the apical membrane of polarized epithelial cells in the late distal tubule and collecting duct of the kidney. Because Liddle phenotype usually involves an upregulation of ENaC channels, leading to retention of sodium and water and to hypokalemia, amiloride is useful as an ENaC channel inhibitor due to its promotion of sodium excretion and its potassium-sparing effects, restoring potassium to normal levels.Amiloride can be used as a monotherapy (single-drug therapy) or an adjunctive therapy alongside other diuretics (e.g. hydrochlorothiazide, furosemide) for the treatment of ascites and edema (swelling) due to cirrhosis of the liver. The 2012 clinical practice guidelines by the American Association for the Study of Liver Diseases (AASLD) states that amiloride can be used to treat ascites in place of spironolactone if it isnt tolerated (e.g. due to the side effect of gynecomastia), though amiloride isnt a preferred drug due to cost and lack of efficacy.

Specific populations
Diabetics
People with diabetes are at higher risk for kidney problems, which increases their risk for hyperkalemia (high blood potassium). The use of amiloride in people with diabetes requires careful potassium and kidney function monitoring to prevent toxicity. Amiloride must be discontinued for at least 3 days prior to glucose tolerance testing, due to the risk for fatal hyperkalemia.

Poor kidney function
People with poor kidney function (e.g. blood urea nitrogen >30 mg/dL, or serum creatinine >1.5 mg/dL) are at high risk for hyperkalemia.

Lactation
There is no data on the use of amiloride in women that are breastfeeding. While diuretics can make lactation difficult, it is unlikely that amiloride would induce this effect in the absence of other diuretics.

Pregnancy
Data from the use of amiloride in animals suggests that it does not pose a risk to the developing fetus. However, when used in combination with the drug acetazolamide during the process of organ formation, amiloride increases the risk for kidney and ureter abnormalities. Limited human data from use during pregnancy suggests an association with a specific congenital penis abnormality if taken during the first trimester, as well as a risk for mild intrauterine growth restriction if taken throughout pregnancy.

Contraindications
Amiloride is contraindicated in people with kidney problems (e.g. anuria, acute or chronic kidney disease, or diabetic nephropathy), elevated blood potassium (≥5.5 mEq/L), or people that are hypersensitive to amiloride or any ingredients within the specific formulation. Use is also contraindicated in people that are already taking potassium-sparing drugs (e.g. spironolactone and triamterene) or whom are taking potassium supplements (e.g. potassium chloride) in most circumstances.

Adverse effects
Amiloride is generally well tolerated. Common adverse effects to the use of amiloride include elevated blood potassium, mild skin rashes, headaches, and gastrointestinal side effects (nausea, vomiting, diarrhea, decreased appetite, flatulence, and abdominal pain). Mild symptoms of high blood potassium concentrations include unusual skin sensations, muscle weakness, or fatigue, but more severe symptoms such as flaccid paralysis of the limbs, slow heart rate, and even shock can occur.

Overdose
There exists no overdose data on amiloride in humans, though it is expected than an overdose would produce effects consistent with its therapeutic effects; e.g. dehydration due to over-diuresis, and electrolyte disturbances related to hyperkalemia. It is unknown if amiloride can be dialyzed off, and no specific antidote against it exists. Treatment is generally supportive, though hyperkalemia can be treated.

Interactions
Amiloride may have important drug-drug interactions when combined with other medications that also increase potassium levels in the blood, leading to hyperkalemia. For example, the combination of amiloride with angiotensin-converting enzyme (ACE) inhibitors like lisinopril, or angiotensin II receptor type 1 (AT1) antagonists like losartan, may lead to high levels of potassium in the blood, requiring frequent monitoring.

Pharmacology
Mechanism of action
Diuresis
Amiloride works by directly blocking the epithelial sodium channel (ENaC) with an IC50 around 0.1 μM, indicating potent blockade. Antagonism of ENaC thereby inhibits sodium reabsorption in the late distal convoluted tubules, connecting tubules, and collecting ducts in the nephron. This promotes the loss of sodium and water from the body, and reduces potassium excretion. The drug is often used in conjunction with a thiazide diuretic to counteract with a potassium-losing effect. Due to its potassium-sparing capacities, hyperkalemia (elevated potassium concentration in the blood) can occur. The risk of developing hyperkalemia is increased in patients who are also taking ACE inhibitors, angiotensin II receptor antagonists, other potassium-sparing diuretics, or any potassium-containing supplements.

Miscellaneous
A fraction of the effects of amiloride is inhibition of cyclic GMP-gated cation channels in the inner medullary collecting duct.Amiloride has a second action on the heart, blocking Na+/H+ exchangers sodium–hydrogen antiporter 1 or NHE-1.
Amiloride also blocks the Na+/H+ antiporter on the apical surface of the proximal tubule cells in the nephron, abolishing more than 80% of the action of angiotensin II on the secretion of hydrogen ions in proximal tubule cells. Note that amiloride is not an angiotensin II receptor blocker (like losartan, for example). The Na-H transporter is also found in the Jejunum of the small intestine, as a result, amiloride also blocks the reabsorption of Na, and thereby water in the intestines.Amiloride is considered to be a reversible, pan-acid-sensing ion channel (ASIC) inhibitor that prevents the transient flow of ions but not the sustained flow of ions. ASICs are members of the ENaC family of protein channels, and are found in the nervous system, the cardiovascular system, the gastrointestinal system, and  the skin. Broadly, ASICs are involved in harm detection, chemosensation (pH changes specifically), and touch.

Pharmacokinetics
Absorption
Amiloride has an oral bioavailability of 50%, meaning that about 50% of an oral dose is absorbed into the blood stream. Coadministration with food reduces the amount of amiloride that is absorbed by the body by about 30%, though it does not affect the rate of absorption. However, taking amiloride with food helps to reduce the incidence of its gastrointestinal side effects. After being taken, amilorides diuretic effect occurs within 2 hours, with peak diuresis within 6–10 hours. The diuretic effects of amiloride persist for about 24 hours after administration.

Distribution
Amiloride cross the placenta and distributes into breast milk in vivo.

Metabolism
Amiloride is not metabolized by the liver. In comparison, the ENaC inhibitor triamterene is metabolized by the liver.

Excretion
About 50% of amiloride is excreted unchanged by the kidneys, while around 40% is excreted in the feces (likely drug that wasnt absorbed). The half-life of amiloride in humans is between 6 and 9 hours, which may be prolonged in people with poor kidney function.

Pharmacogenomics
A single nucleotide polymorphism (SNP) in the protein NEDD4L may impact how amiloride affects a persons blood pressure in people with high blood pressure.

Chemistry
Amiloride is a pyrazinoylguanidine, composed of a substituted pyrazine ring structure with a carbonylguanidinium substituent. Amilorides pKa is 8.67, which is due to the guanidinium group. In high pH (alkaline, low hydrogen concentration) environments, the guanidinium group is deprotonated and the compound is rendered neutral, depleting its activity on sodium channels. Amiloride, as a pure substance, is highly fluorescent, with excitation wavelengths at 215, 288, and 360 nm, emitting light at 420 nm.

History
Amiloride was first synthesized and discovered by the Merck Sharp and Dohme Research Laboratories in the late 1960s. The drug was discovered as part of a screening process of chemicals that reversed the effects of mineralocorticoids in vivo. Amiloride was the only drug in the screen that was capable of causing the excretion of sodium (natriuresis) without a concomitant urinary excretion of potassium (kaliuresis). Thousands of amiloride analogues have been studied since its initial discovery, which have been used to study the effects of sodium transporters.Amiloride was approved by the U.S. Food and Drug Administration (FDA) on October 5, 1981.

Society and culture
It is on the World Health Organizations List of Essential Medicines.Amiloride is on the World Anti-Doping Agencys list of banned substances, as it is considered a masking agent. Diuretics like amiloride act as masking agents by reducing the concentration of other doping agents due to promoting diuresis, increasing the total volume of the urine. The list includes other potassium-sparing diuretics, such as triamterene and spironolactone. In 2008, amiloride and the potassium-sparing diuretic triamterene were found in 3% of positive diuretic doping samples.

Formulations and trade names
Amiloride hydrochloride
Midamor (U.S.)
Co-amilozide (amiloride hydrochloride with hydrochlorothiazide)
Co-amilofruse (amiloride hydrochloride with furosemide)
Amiloride hydrochloride with cyclopenthiazide
Amiloride hydrochloride with bumetanide

Research
Amiloride is an inhibitor of NHE-1, which helps to maintain normal pH within cells. Cancer cells in leukemia, a type of blood cancer, have higher pH compared to normal cells. Amiloride affects the splicing and regulation of multiple genes involved in cancer, though they do not appear to be directly related to its effects on pH. Amiloride has been tested in vitro as an adjunct to the anticancer drug imatinib, which appeared to show a synergistic effect </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Moxetumomab pasudotox and can you explain it in depth? [/INST] Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox is a CD22-directed cytotoxin and is the first of this type of treatment for adults with HCL. The drug consists of the binding fragment (Fv) of an anti-CD22 antibody fused to a toxin called PE38. This toxin is a 38 kDa fragment of Pseudomonas exotoxin A.
Hairy cell leukemia (HCL) is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

Medical uses
Moxetumomab pasudotox as monotherapy is indicated for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) after receiving at least two prior systemic therapies, including treatment with a purine nucleoside analogue (PNA).

Adverse effects
Common side effects include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.The prescribing information for moxetumomab pasudotox includes a boxed warning about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The boxed warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells.Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities.Women who are breastfeeding should not be given moxetumomab pasudotox.

Discovery and ownership background
On 1 November 2005, Cambridge Antibody Technology (CAT) announced it was acquiring two anti-CD22 immunotoxin products from Genencor, namely GCR-3888 and GCR-8015. Genencor is the biotechnology division of Danisco and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes.GCR-3888 and GCR-8015 were discovered and initially developed by the National Cancer Institute, which is part of the U.S. National Institutes of Health.  Genencor licensed the candidates for hematological malignancies and entered into a Cooperative Research and Development Agreement (CRADA) with the NIH, which will now be continued by CAT.  Under the original
license agreement with the NIH, CAT gained the rights to a portfolio of intellectual property associated with the programs and would pay future royalties to the NIH.
CAT intended to file an Investigational New Drug (IND) application for GCR-8015 in various CD22 positive B-cell malignancies, including Non-Hodgkin lymphoma and chronic lymphocytic leukemia, following a period of manufacturing development which is expected to be complete by the end of 2006 and to support the NCIs ongoing development of GCR-3888 in Hairy cell leukemia (HCL) and pediatric acute lymphoblastic leukemia (pALL).CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888 and CATs language such as "CAT will support the NCIs ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate.CAT was acquired by AstraZeneca, who also acquired MedImmune, combining the two into a biologics division. MedImmune renamed CAT-8015 to moxetumomab pasudotox.On 16 May 2013, AstraZeneca announced that CAT-8015 had started Phase III clinical trials.

History
On 5 December 2008, orphan designation (EU/3/08/592) was granted by the European Commission to Medimmune Limited, United Kingdom, for murine anti-CD22 antibody variable region fused to truncated Pseudomonas exotoxin 38 for the treatment of hairy cell leukaemia. It was renamed to Moxetumomab pasudotox. The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.On 17 July 2013, orphan designation (EU/3/13/1150) was granted by the European Commission to MedImmune Ltd, United Kingdom, for moxetumomab pasudotox for the treatment of B-lymphoblastic leukaemia / lymphoma. The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.Moxetumomab pasudotox was approved for use in the United States in September 2018.The efficacy of moxetumomab pasudotox was studied in a single-arm, open-label clinical trial of 80 subjects who had received prior treatment for hairy cell leukemia with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of subjects in the trial achieved durable CR, and the overall response rate (number of subjects with partial or complete response to therapy) was 75 percent.The US Food and Drug Administration (FDA) granted the application for moxetumomab pasudotox fast track, priority review, and orphan drug designations. The FDA granted the approval of a Biologics License Application for Lumoxiti to AstraZeneca Pharmaceuticals. This was subsequently transferred to Innate Pharma in March 2020.On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Lumoxiti, intended for the treatment of relapsed or refractory hairy cell leukemia after two prior systemic therapies including a purine nucleoside analog. The orphan designation for Lumoxiti for treatment of hairy cell leukaemia was also maintained </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tobi and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Motofen and can you explain it in depth? [/INST] Motofen is the brand name for an antiperistaltic anti-diarrheal medication, containing 1.0 mg difenoxin HCl and 0.025 mg atropine (U.S. Food and Drug Administration: Schedule IV Combination). It was invented by Kendra Clark. Atropine is purposely added at 25 micrograms per tablet, or 1/24 to 1/40 of the usual therapeutic dose for atropine to minimize the potential of misuse by swallowing large numbers of tablets or preparing them for injection since difenoxin is chemically related to the pethidine-piritramide subgroup of the opioid family, and could theoretically be misused.  Although unlikely, physical and mental withdrawal symptoms (from both anticholinergic rebound caused by atropine, and opiate withdrawal caused by the difenoxin) are possible if taken for long periods of time.  However, both of these compounds are responsible for the medicinal effects of the medicine (both atropine and difenoxin slow gut movement).
This combination medication should not be confused with Lomotil (2.5 mg diphenoxylate and 0.025 mg atropine – a Schedule V combination), because the active ingredients in the two medications are different compounds, except for the inclusion of atropine.  Motofen is approximately 2 to 4 times more effective in treating symptoms than Lomotil.

Indications and uses
Although Motofen is officially indicated by the U.S. Food and Drug Administration (FDA) for diarrhea, it has also been successfully used by physicians for irritable bowel syndrome (IBS), and hyperhidrosis (chronic, severe sweating).

Side effects, interactions, and misuse potential
Side effects include drowsiness, nausea, vomiting, burning eyes, blurred vision, dry eyes, dizziness, dry mouth, epigastric distress, and constipation.  Side effects attributed to the atropine content (especially when taken in excess doses, or in children), include: flushing, dryness in many areas, urinary retention, insomnia, headache, anxiety, hyperthermia, and tachycardia.  It is these side effects that make it undesirable for most patients to take higher amounts of the medicine.

Dosing and administration
The recommended initial dosing is two tablets, and one tablet to be taken after each loose stool thereafter.  The therapeutic dosage for Motofen should not exceed 8 tablets (8 milligrams of Difenoxin).  There are currently no instructions indicating usage for irritable bowel syndrome (IBS) and Hyperhidrosis, although as stated above, it has been used successfully in treating symptoms of both disorders (which can accompany each other).  There was a "Motofen half-strength" tablet, containing only 0.5 milligram of difenoxin, but it has since been discontinued.  Only standard 1.0 milligram strength tablets are available by prescription.

Availability, price, and supply
There is currently only one manufacturer of Motofen tablets: Valeant Pharmaceuticals. It acquired the drug from Amarin Pharmaceuticals in 2004.  Valeants tablets are pentagonal shaped, impressed with a "V" on one side, and vertically scored on the other side.  In addition, the number "0500" is impressed bisecting the score line perpendicularly.  The aforementioned bisection renders "05" and "00" on the left and right side of the score, respectively.  Amarins version were also pentagonal shaped, but impressed with an "A" on one side with "74" on the opposing.
Motofen is higher priced than both Imodium and Lomotil, does not have a generic equivalent, and is only available by prescription in the United States.  Many United States insurance companies do not include Motofen as one of their formulary drugs, causing consumers to pay the highest copay, if it is covered by their health insurance at all.  This is most likely due to the high cost of the medication itself, and the fact that similar lower-priced medicines can help ease symptoms of diarrhea.  The United States is currently the only country where Motofen tablets are prescribed, approved by the government, and sold.

Miscellaneous information
Strangely, Motofen is only included in the Physicians Desk Reference (PDR) for the years 2005 and 2006 as a literal snippet entry.  Nothing is said about the indications and usage, only the ingredients, current appearance (at the time of publishing), NDC#, and the quantities in which it is supplied.  As of August 1, 2008, Motofen appears to have been discontinued by Valeant Pharmaceuticals </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tamsulosin and can you explain it in depth? [/INST] Tamsulosin, sold under the brand name Flomax among others, is a medication used to treat symptomatic benign prostatic hyperplasia (BPH) and chronic prostatitis and to help with the passage of kidney stones. The evidence for benefit with a kidney stone is better when the stone is larger. It is taken by mouth.Common side effects include dizziness, headache, sleeplessness, nausea, blurry vision, and sexual problems. Other side effects may include feeling lightheaded with standing and angioedema. Tamsulosin is an alpha blocker and works by relaxing muscles in the prostate. Specifically it is an α1 adrenergic receptor blocker.Tamsulosin was approved for medical use in the United States in 1997. It is available as a generic medication. In 2020, it was the 24th most commonly prescribed medication in the United States, with more than 24 million prescriptions.

Medical uses
Tamsulosin is primarily used for benign prostatic hyperplasia and to help with the passage of kidney stones. Tamsulosin, however, appears to be effective only for stones over 4 mm and less than 10 mm in size.Tamsulosin is also used as an add-on treatment for acute urinary retention. People may void more successfully after catheter removal if they are taking tamsulosin. People taking tamsulosin also are less likely to need re-catheterization.Tamsulosin does not decrease the overall size of the prostate in men with benign prostatic hyperplasia (BPH), and is not recommended for prevention of prostate cancer.

Combination therapy
The results of the CombAT (combination of dutasteride (Avodart) and tamsulosin, under the brand name Duodart) trial in 2008 demonstrated that treatment with the combination of dutasteride and tamsulosin provides greater symptom benefits compared to monotherapy with either agent alone for treatment of benign prostatic hyperplasia.
The CombAT trial became the medication Jalyn.  It was approved by the FDA on 14 June 2010.  This combination can be useful because it may take up to six months for symptomatic relief to be found when using 5-alpha-reductase inhibitors such as dutasteride compared to alpha-1 receptor blockers, which can provide relief in some cases within 48 hours.

Adverse effects
Eyes: People taking tamsulosin are prone to a complication known as floppy iris syndrome during cataract surgery. Adverse outcomes of the surgery are greatly reduced by the surgeons prior knowledge of the persons history with this drug, and thus having the option of alternative techniques.
Severe hypotension.
Persons with cardiac conditions including hypotension, mechanical heart failure (valvular, pulmonary embolism, pericarditis), and congestive heart failure should be monitored carefully while taking tamsulosin.
Alpha blockers, including prazosin, terazosin, doxazosin, or tamsulosin, do not appear to affect all-cause mortality in heart failure re-hospitalization in those also receiving β-blockers.
Tamsulosin can also cause retrograde ejaculation, which occurs when semen is redirected to the urinary bladder instead of being ejaculated normally. This is because tamsulosin relaxes the muscles of the urethral sphincters, which are normally closed during ejaculation. This side effect can be mitigated by regular pelvic floor (Kegel) exercise and contracting the pelvic floor during ejaculation.

Mechanism
Tamsulosin is a selective α1 receptor antagonist that has preferential selectivity for the α1A receptor in the prostate versus the α1B receptor in the blood vessels.When alpha 1 receptors in the bladder neck, the prostate, the ureter, and the urethra are blocked, a relaxation in smooth muscle tissue results. This mechanism decreases resistance to urinary flow, reduces discomfort associated with BPH, and facilitates passage of kidney stones.Selective action of tamsulosin in alpha 1A/D receptors is controversial and over three quarters of tamsulosin registered human studies are unpublished.

Brand names
Tamsulosin was first marketed in 1996 under the trade name Flomax. The U.S. patent expired in October 2009. The U.S. Food and Drug Administration (FDA) approved generics in March 2010. In 2010, tamsulosin was available as OTC medication in UK.It is marketed by various companies under licence, including Boehringer Ingelheim and CSL. Tamsulosin hydrochloride extended-release capsules are marketed under the trade names Urimax 0.4(India), Flomax, Flomaxtra, Contiflo XL, bestflo, Mecir LP (France), Urimax, Pamsvax, and Pradif, although generic, non-modified-release capsules are still approved and marketed in many countries (such as Canada). Generic extended-release tablets are marketed in most countries of the EEA </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Oxacillin and can you explain it in depth? [/INST] Oxacillin (trade name Bactocill) is a narrow-spectrum beta-lactam antibiotic of the penicillin class developed by Beecham.It was patented in 1960 and approved for medical use in 1962.

Medical uses
Oxacillin is a penicillinase-resistant β-lactam. It is similar to methicillin, and has replaced methicillin in clinical use.  Other related compounds are nafcillin, cloxacillin, dicloxacillin, and flucloxacillin.  Since it is resistant to penicillinase enzymes, such as that produced by Staphylococcus aureus, it is widely used clinically in the US to treat penicillin-resistant Staphylococcus aureus.   However, with the introduction and widespread use of both oxacillin and methicillin, antibiotic-resistant strains called methicillin-resistant and oxacillin-resistant Staphylococcus aureus (MRSA/ORSA) have become increasingly prevalent worldwide.  MRSA/ORSA can be treated with vancomycin or other new antibiotics.

Contraindications
The use of oxacillin is contraindicated in individuals that have experienced a hypersensitivity reaction to any medication in the penicillin family of antibiotics. Cross-allergenicity has been documented in individuals taking oxacillin that experienced a previous hypersensitivity reaction when given cephalosporins and cephamycins.

Adverse effects
Commonly reported adverse effects associated with the use of oxacillin include skin rash, diarrhea, nausea, vomiting, hematuria, agranulocytosis, eosinophilia, leukopenia, neutropenia, thrombocytopenia, hepatotoxicity, acute interstitial nephritis, and fever. High doses of oxacillin have been reported to cause renal, hepatic, and nervous system toxicity </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Zaleplon and can you explain it in depth? [/INST] Zaleplon, sold under the brand names Sonata among others, is a sedative-hypnotic, used to treat insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class.It is manufactured by King Pharmaceuticals and Gedeon Richter Plc. It has been discontinued in Canada but can be manufactured if a prescription is brought to a compounding pharmacy. It was prescribed rarely in the United Kingdom, with zopiclone being the preferred Z-drug by the National Health Service (NHS) and is now unavailable.

Medical uses
Zaleplon is slightly effective in insomnia, primarily characterized by difficulty falling asleep. Zaleplon significantly reduces the time required to fall asleep by improving sleep latency and may therefore facilitate sleep induction rather than sleep maintenance. Due to its ultrashort elimination half-life, zaleplon may not be effective in reducing premature awakenings; however, it may be administered to alleviate middle-of-the-night awakenings. However, zaleplon has not been empirically shown to increase total sleep time.It may result in an impaired ability to drive the next day, though it has proven promising when compared to other sedative/hypnotics in terms of next-day residual sedation. It may have advantages over benzodiazepines with fewer adverse effects.Neither zaleplon, nor any nonbenzodiazepine hypnotic class medication should be combined with alcohol, as both modulate GABAA receptor sites, and in a synergistic manner increase the chances of fatal respiratory depression and asphyxiation from vomiting.

Special populations
Zaleplon is not recommended for chronic use in the elderly. The elderly are more sensitive to the adverse effects of zaleplon such as cognitive side effects. Zaleplon may increase the risk of injury among the elderly. It should not be used while in pregnancy or lactation, and in patients with a history of alcohol or drug abuse, psychotic illness or depression, clinicians should devote more attention.When compared with benzodiazepines, nonbenzodiazepines (including zaleplon) offer few significant advantages in efficacy and tolerability among elderly individuals. Long-term use of sedative/hypnotics for insomnia has traditionally been discouraged for reasons that include concerns about addiction and rebound insomnia, as well to the risk of side effects associated to GABAA agonists, such as cognitive impairment, anterograde amnesia, daytime sedation, musculoskeletal impairment, and subsequently an increased risk of harm to oneself (e.g. falling) and to others (e.g. automotive accidents). Though, quite obviously as the body and brain age, these aforementioned phenomena are expected events, as they occur daily regardless of ingestion of a sedative/hypnotic. Thus, statistically significant and empirical evidence are arguably still absent as dramatic precautions and conclusions are drawn irrespective of the debilitating realities that accompany insomnia and the fact that these medicines do indeed provide assistance to millions of elderly individuals. It is important to distinguish between the extrapolation of potential side effects relative to the vast number of examples, wherein the sedative/hypnotic has proven therapeutically beneficial and appropriate.
In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but nothing concrete suggests long-term use poses any direct harm to a person. Still, as of today neither benzodiazepines nor nonbenzodiazepines are recommended for the long-term treatment of insomnia.

Adverse effects
The adverse effects of zaleplon are similar to the adverse effects of benzodiazepines, although with less next-day sedation, and in two studies zaleplon use was found not to cause an increase in traffic accidents, as compared to other hypnotics currently on the market.Sleeping pills, including zaleplon, have been associated with an increased risk of death.Available data cannot provide a reliable estimate of the incidence of dependence during treatment at recommended doses of zaleplon (typically 5–20 mg before bed).  Other sedative/hypnotics have been associated with various signs and symptoms of a withdrawal syndrome, following abrupt discontinuation, ranging from mild dysphoria and insomnia to more serious cases that include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Following abrupt cessation, the seizure threshold is further lowered, wherein coma and death are possible outcomes if untreated.
Some evidence suggests zaleplon is not as chemically reinforcing and exhibits far fewer rebound effects when compared with other nonbenzodiazepines, or Z-drugs.

Interactions
Cimetidine, rifampicin, and thioridazine cause interactions with zaleplon.Cimetidine and grapefruit are known to increase blood plasma concentrations of benzodiazepines metabolized by the P450 CYP3A4 liver enzyme (e.g. alprazolam) by extending the time by which the drug leaves the body, effectively extending the half-life and enhancing effects to potentially toxic levels. Thus, given the similarities between zaleplon and benzodiazepines, particularly in effect and not just chemical structure, it is reasonable to take precautions (e.g. inquire at a pharmacy) before one consumes cimetidine (or grapefruit) while also taking zaleplon.

Pharmacology
Mechanism of action
Zaleplon is a high-affinity ligand of positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills. Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the natural sleep architecture.A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.Zaleplon has a pharmacological profile similar to benzodiazepines, characterized by an increase in slow wave deep sleep (SWDS) with rapid onset of hypnotic action. Zaleplon is a full agonist for the benzodiazepine α1 receptor located on the GABAA receptor complex in the body, with lower affinity for the α2 and α3 subsites. It selectively enhances the action of GABA similar to, but more selectively than benzodiazepines. Zaleplon, although not a benzodiazepine, maintains a very similar pharmacological profile nonetheless, known for inducing hypnotic effects by α1 subreceptor sites, anxiolytic and muscle relaxant effects via α2 and α3 subsites, with negligible anticonvulsant properties (via α5 subsite), as zaleplon action is modulated at benzodiazepine receptor sites. The elimination half-life of zaleplon is about 1–1.5 hours. The absorption rate of zaleplon is rapid and the onset of therapeutic effects is typically breached within 5–15 minutes following ingestion.
Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band

Pharmacokinetics
Zaleplon is primarily metabolised by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase. Taken orally, zaleplon reaches full concentration in about one hour.  It is extensively metabolised into 5-oxozaleplon and 5-oxodesethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine.

Chemistry
Pure zaleplon in its solid state is a white to off-white powder with very low solubility in water, as well as low solubility in ethanol and propylene glycol. It has a constant octanol-water partition coefficient of log P = 1.23 in the pH range between 1 and 7.
It is classified as a pyrazolopyrimidine.

Synthesis
The synthesis starts with the condensation of 3-acetylacetanilide (1) with N,N-dimethylformamide dimethyl acetal (DMFDMA) to give the eneamide (2). The anilide nitrogen is then alkylated by means of sodium hydride and ethyl iodide to give 3 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Protein-bound paclitaxel and can you explain it in depth? [/INST] Protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel or  nab-paclitaxel, is an injectable formulation of paclitaxel used to treat breast cancer, lung cancer and pancreatic cancer, among others. Paclitaxel kills cancer cells by preventing the normal breakdown of microtubules during cell division. In this formulation, paclitaxel is bonded to albumin as a delivery vehicle. It is manufactured and sold in the United States by Celgene under the trade name Abraxane where it is designated as an orphan drug as first-line treatment, in combination with gemcitabine, for the orphan disease "metastatic adenocarcinoma of the pancreas".This treatment was approved in the United States in 2005, and the European Union in 2008, for breast cancer cases where cancer did not respond to other chemotherapy or has relapsed. In 2012, the FDA widened the approved uses to include treatment for NSCLC. In 2013, the FDA approved protein-bound paclitaxel for use in treating advanced pancreatic cancer as a less toxic (although less effective) alternative to FOLFIRINOX.

Society and culture
Abraxane is registered on the Australian Register of Therapeutic Goods for the treatment of metastatic carcinoma of the breast after failure of anthracycline therapy. Abraxane is also included on the Schedule of the Australian Pharmaceutical Benefits Scheme although the manufacturer was unable to convince the independent Pharmaceutical Benefits Advisory Committee that the drug warranted a higher price than existing comparator drugs.

Protein-bound paclitaxel was developed by VivoRx which became Abraxis BioScience as the first in its class of drugs to use the nanoparticle albumin bound (nab) technology platform.In 2010, Abraxis was acquired by Celgene, which now markets Abraxane. Total revenue from the sales of Abraxane for 2009 were $314.5 million.  In 2013, Abraxane was FDA approved for the treatment of pancreatic cancer.  In 2014, Abraxanes sales were $848 million, 31 percent year-over-year increase.The British National Institute for Health and Care Excellence (NICE) announced in 2015, that it would not support the routine use of protein-bound paclitaxel in advanced pancreatic cancer on the NHS.

References
Further reading
Miele E, Spinelli GP, Miele E, Tomao F, Tomao S (2009). "Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer". International Journal of Nanomedicine. 4: 99–105. doi:10.2147/ijn.s3061. PMC 2720743. PMID 19516888.
Stinchcombe, Thomas E (2007). "Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL®-free formulation of paclitaxel". Nanomedicine. 2 (4): 415–423. doi:10.2217/17435889.2.4.415. ISSN 1743-5889. PMID 17716129.
Gradishar, William J (2006). "Albumin-bound paclitaxel: a next-generation taxane". Expert Opinion on Pharmacotherapy. 7 (8): 1041–1053 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Allergen immunotherapy and can you explain it in depth? [/INST] Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies, such as insect bites, and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergen in an attempt to change the immune systems response.Meta-analyses have found that injections of allergens under the skin are effective in the treatment in allergic rhinitis in children and in asthma. The benefits may last for years after treatment is stopped. It is generally safe and effective for allergic rhinitis, allergic conjunctivitis, allergic forms of asthma, and stinging insects. The evidence also supports the use of sublingual immunotherapy against rhinitis and asthma, but it is less strong. In this form the allergen is given under the tongue and people often prefer it to injections. Immunotherapy is not recommended as a stand-alone treatment for asthma.Side effects during sublingual immunotherapy treatment are usually local and mild and can often be eliminated by adjusting the dosage. Anaphylaxis during sublingual immunotherapy treatment has occurred on rare occasions.Potential side effects related to subcutaneous immunotherapy treatment for asthma and allergic rhinoconjunctivitis include mild or moderate skin or respiratory reactions. Severe side effects such as anaphylaxis during subcutaneous immunotherapy treatment are relatively uncommon.Discovered by Leonard Noon and John Freeman in 1911, allergen immunotherapy is the only medicine known to tackle not only the symptoms but also the causes of respiratory allergies. A detailed diagnosis is necessary to identify the allergens involved.

Types
Subcutaneous
Subcutaneous immunotherapy (SCIT), also known as allergy shots, is the historical route of administration and consists of injections of allergen extract, which must be performed by a medical professional. Subcutaneous immunotherapy protocols generally involve weekly injections during a build-up phase, followed by monthly a maintenance phase that consists of injections for a period of 3–5 years. The build-up phase involves the patient being administered injections which contain increasing amounts of allergens about one to two times per week. The length of the build-up phase is dependent upon how often injections are administered, but normally ranges from three to six months. After the effective dose is reached, the maintenance phase is implemented, which varies depending upon an individuals response to the build-up phase.When accounting for a persons age, type of allergen, and severity of allergy, there is a high probability that subcutaneous allergen immunotherapy may provide greater clinical and immunological responses than sublingual allergen immunotherapy. Compared to sublingual allergen immunotherapy, there are no significant differences observed in quality of life.It is possible, but rare (1/2.5 million), that people undergoing subcutaneous allergen immunotherapy may experience a fatal anaphylactic event. Subcutaneous allergen immunotherapy adverse events vary significantly depending on different allergenic extracts and the application of different allergen immunotherapy schedules.Allergen immunotherapy schedules include the "cluster" approach, which involves administering several doses sequentially in a single day; a "conventional" approach, which involves incrementally increasing the dose over approximately 15 weeks; and the "rush" approach, which involves administering incremental doses at intervals of 15–60 minutes over 1–3 days).It is challenging to perform an adequate risk assessment on the use of subcutaneous allergen immunotherapy compared to other forms of allergen immunotherapy administration due to the variability of immunotherapy schedules and further research is required.

Sublingual
Sublingual immunotherapy involves putting drops or a tablet of allergen extracts under the tongue, which are then absorbed through the lining of the mouth. Sublingual immunotherapy has been demonstrated to be effective against rhinoconjuctivitis and asthma symptoms. This effectiveness, however, varies depending on the type of allergen. The strongest evidence for the efficacy of sublingual immunotherapy comes from studies that used grass allergens or mite allergens to alleviate allergic rhinitis symptoms; the evidence shows modest improvement.Sublingual immunotherapy is used to treat allergic rhinitis, often from seasonal allergies, and is typically given in several doses over a 12-week period. It works best when given 12 weeks before the start of the pollen season. The first dose is given by a physician to monitor for any rare reactions or anaphylaxis. Subsequent doses can be taken at home which makes this a convenient alternative to subcutaneous immunotherapy.
While a number of side effects have been associated with sublingual immunotherapy, serious adverse effects are very rare (about 1.4/100000 doses), and there has not been a reported fatality. There have been a small number of reports of anaphylaxis. The majority of side effects are local and usually resolve within a few days. They include swelling of the mouth, tongue or lip, throat irritation, nausea, abdominal pain, vomiting, diarrhea, heartburn, and uvular edema. It is not yet clear if there are any risk factors that might increase a persons susceptibility to these adverse effects. Sublingual immunotherapy appears to be better tolerated than subcutaneous immunotherapy and causes fewer side effects. The safety of sublingual immunotherapy has not been studied extensively in people with chronic immunodeficiency or autoimmune disorders.

Oral
Oral immunotherapy (OIT) involves feeding an allergic individual increasing amounts of a food allergen in order to raise the threshold which triggers a reaction. Long-term, many study participants still experienced mild allergic reactions or needed to regularly consume the allergen to maintain desensitivity. Additionally, oral immunotherapy is known to have an increased risk in the probability of needing epinephrine in patients who take it.

Transdermal
Transdermal immunotherapy (TDIT) involves skin-induced suppression via epicutaneous (EC) application of an antigen in order to raise the threshold which triggers a reaction.

Mechanism of action
In desensitization immunotherapy the aim is to induce or restore tolerance to the allergen by reducing its tendency to induce IgE production. People are desensitized through the administration of escalating doses of allergen that gradually decreases the IgE-dominated response. The objective of immunotherapy is to direct the immune response away from humoral immunity and toward cellular immunity, thereby encouraging the body to produce fewer IgE antibodies and more CD4+ T regulatory cells that secrete IL-10 and TGF-β, which skews the response away from IgE production.Oral immunotherapy also creates an increase in allergen-specific IgG4 antibodies and a decrease in allergen-specific IgE antibodies, as well as diminished mast cells and basophils, two cell types that are large contributors to allergic reaction.

Protocol
Reactivity is tested using oral food challenges or with skin prick tests. Phases 1 & 2 of sublingual immunotherapy are conducted in a supervised clinical setting. However, phase 3 can be done at home.

History
In the late 19th century and early 20th century, allergic conditions were increasingly attracting both medical attention (as an emerging public health problem) and scientific interest (aided by progress in biochemical techniques and the development of molecular and pathogenic theories). However, the many and varied treatment approaches were very unscientific.The British physicians Noon and Freeman were the first researchers to test pollen allergen immunotherapy in humans. Noon and Freeman, researchers at the Department of Therapeutic Inoculation at St. Marys Hospital in London, published their findings in The Lancet in 1911. Building on the observations of his predecessors Bostock, Blackley and Dunbar, Noon noted that people with hay fever "sometimes become cured" and that this was possibly because they "have had the good fortune to develop an active immunity against the toxin." He hypothesized that by injecting people with hay fever with small amounts of a pollen "toxin", a state of immunity could be achieved.Allergen immunotherapy was part of mainstream medical practice for hay fever treatment in the 1930s.

Society and culture
Sublingual immunotherapy drops are currently commercialized and used in most European and South American countries, and in Australia and Asian countries. In most European countries, national regulations allow marketing of allergen products as "named patient preparations" (NPPs). In the United States, drop formulations have not yet received FDA approval, though off-label prescription is becoming common. In 2014, the FDA approved a once-daily sublingual tablet containing allergen extracts for the treatment of "hay fever" (allergic rhinitis with or without conjunctivitis).

Recognition by international agencies
The use of subcutaneous immunotherapy for treatment of environmental-based allergies and asthma is well supported by the majority of national and international allergy groups such as the World Allergy Organization, Canadian Society of Allergy and Immunology, European Academy of Allergy and Clinical Immunology, and the American Academy of Allergy, Asthma and Immunology. The use of sublingual immunotherapy is supported by few allergy agencies in order to allow for more investigation to occur on its practical use. Oral immunotherapy is generally not recommended, however the EAACI recommends that this treatment only be administered at specialized centres with expert professionals.Subcutaneous immunotherapy is both approved and regulated by the American Food and Drug Administration (FDA) and the European Medicinal Agency (EMEA). The FDA currently allows individual allergists to create the formula for each dosage, whereas the EMEA requires treatment extracts to be prepared at manufacturing sites. The FDA has approved sublingual therapy through the use of tablets, but has not approved specific formulation. The EMEA has also approved sublingual therapy through both tablets and solution, and this administration now accounts for 45% of immunotherapy treatments.The FDA advisory board has supported the use of AR101, an oral immunotherapy, for patients with peanut allergies in 2019.

Science communication
Allergen immunotherapy is viewed as a beneficial way to curb allergies in the perspective of the media. It is seen where it can be covered by insurance and offer a more permanent solution than antihistamines or nasal steroids that treat symptoms, not the bodys reaction. Communication about allergen immunotherapy is not described very often in the news media; it is usually only communicated by the science community. The scientific community describes allergen immunotherapy as a scientific solution that helps not only patients with allergies but also positively impacts the quality of life of them and others around them. As temperatures increase due to changing climates, pollen levels also increase. Allergies are becoming a more common problem among the public, which is why the science community advocates for allergen immunotherapy. Subcutaneous allergen immunotherapy, according to the scientific community, is an effective solution to allergies due to numerous positive studies.

Research
Oral immunotherapy
As of 2015, oral immunotherapys balance of risk to benefit for food allergies was not well studied. As of 2011, OIT was under investigation as a treatment for a variety of common food allergies including peanuts, milk, and eggs. Studies involving OIT have shown desensitization towards the allergen. However, there are still questions about longevity of tolerance after the study has ended. However, almost every study has excluded people with severe allergen-induced anaphylaxis.One approach being studied is in altering the protein structure of the allergen to decrease immune response but still induce tolerance. Extensive heating of some foods can change the conformation of epitopes recognized by IgE antibodies. In fact, studies show that regular consumption of heated food allergens can speed up allergy resolution </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Naldemedine and can you explain it in depth? [/INST] Naldemedine (brand name Symproic in the US and Rizmoic in the European Union) is a medication that is used for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. It is a peripherally acting μ-opioid receptor antagonist and was developed by Shionogi. Clinical studies have found it to possess statistically significant effectiveness for these indications and to be generally well tolerated, with predominantly mild to moderate gastrointestinal side effects. Effects indicative of central opioid withdrawal or impact on the analgesic or miotic effects of co-administered opioids have only been observed in a small number of patients.

Medical uses
In the US, naldemedine is approved for the treatment of opioid induced constipation in adults with chronic non-cancer pain, including those who have chronic pain related to prior cancer or its treatment and do not need frequent opioid dosage escalation.In the European Union, naldemedine is also approved for the treatment of opioid induced constipation in adults, but as a second-line therapy after treatment with a laxative.

Contraindications
The drug is contraindicated in patients with gastrointestinal obstruction or perforation, or those at risk for these problems.

Side effects
Side effects in studies were abdominal pain (8–11% of patients as compared to 2–5% under placebo, depending on the study), diarrhea (7% versus 2–3%), nausea (4–6% versus 2–5%), vomiting (3% versus 2%), gastroenteritis (2–3% versus 1%), and opioid withdrawal syndrome (1.5–3.2% versus 0.5–1.5%). The latter was severe but manageable in one patient, and otherwise mild to moderate. Hypersensitivity reactions were rare; they occurred in two patients.

Overdose
Single doses up to 500 times the recommended dose, as well as multiple doses up to 150 times the recommended dose for ten days, resulted in an increase of the mentioned side effects. Theses side effects were mild to moderate.

Interactions
As naldemedine is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme can increase its concentrations in the body and thus its potential for side effects. Examples include itraconazole (which increased naldemedine exposure 2.9-fold in a study), ketoconazole, clarithromycin and grapefruit juice. Conversely, CYP3A4 inducers such as rifampicin and St Johns wort decrease naldemedine concentrations; with rifampicin, the reduction was 83% in a study.Strong inhibitors of the pump P-glycoprotein such as ciclosporin may increase naldemedine concentrations in the blood plasma.

Pharmacology
Mechanism of action
Naldemedine is a derivative of naltrexone and, like this substance, blocks opioid receptors of the types μ (mu), δ (delta) and κ (kappa). While naltrexone is able to cross the blood–brain barrier and can therefore be used to treat opioid dependence, the large hydrophilic side chain of naldemedine and its affinity to P-glycoprotein result in negligible concentrations in the central nervous system when recommended doses are applied. Instead, it acts mainly on μ-receptors in the gastrointestinal tract, where it counteracts the constipation inducing effects of opioid drugs.

Pharmacokinetics
After oral intake, naldemedine has an absolute bioavailability in the range of 20% to 56% and reaches highest blood plasma levels after 0.75 hours when taken without food and 2.5 hours when taken with a high-fat meal. As the area under the curve is not significantly different with or without a meal, the drug can be taken independently of food. Once in the bloodstream, 93 to 94% of the substance is bound to plasma proteins, mainly to albumin.Naldemedine is mainly metabolized by the enzyme CYP3A4 to nor-naldemedine (which makes up about 9–13% of the circulating substance), and to a much lesser extent by UGT1A3 to naldemedine 3-glucuronide. Minor metabolites are the 6-glucuronide, the 7-(R/S)-hydroxy-derivates, and two products formed by enterobacteria through cleaving the oxadiazole ring: naldemedine carboxylic acid and benzamidine. Nor-naldemedine, the glucuronides, and the carboxylic acid are opioid receptor antagonists, but less potent than the original substance.

Naldemedine and its metabolites are excreted via urine and faeces. The part of the molecule "left" of the cleavage line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and carboxylic acid) is found to 20.4% in the urine and to 64.3% in the faeces, while the part "right" to the line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and benzamidine) is found to 57.3% in the urine and to 34.8% in the faeces. This indicates that benzamidine is predominantly excreted in the urine and the carboxylic acid is predominantly excreted in the faeces. The terminal half-life is about 11 hours.

Chemistry
Naldemedine is used in form of the tosylate, a white to light tan powder. It is not hygroscopic and has a high water solubility at a physiologic pH.

Society and culture
Commercialization
Naldemedine is manufactured by Shionogi Inc., a United States-based subsidiary of Shionogi & Co., Ltd. Shionogi & Co., Ltd. (SGIOF) is a pharmaceutical company founded in 1878 based in Osaka, Japan. Shionogi Inc. is fully funded by its parent company, Shionogi & Co., Ltd. The parent company specializes in pharmaceuticals, diagnostic reagents and medical devices in Japan and internationally. Naldemedine is their only gastroenterology product in the United States.
In the US market, Shionogi Inc. has partnered with Purdue Pharma in a joint venture for US commercialization of Symproic. Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders.Purdue Pharma appealed to remove the Class II scheduling of Symproic as accordant to the Controlled Substances Act. The appeal was posted to the Federal Register on July 12, 2017. The Drug Enforcement Administration officially removed the Class II scheduling in September 2017.

Manufacturer finances
Since 2015, Shionogi & Co., Ltd. has produced increasing net income. At the end of fiscal year 2016, Shionogi & Co., Ltd. had a net income of $66,687,000. At the end of fiscal year 2017, they increased their net income to $83,879,000. How much of this is attributed to sales of Symproic is unknown. Shionogi & Co., Ltd. ends their fiscal year on March 31 of each year. Considering the drug was only FDA approved on March 23 of 2017, the true valuation of the drug is yet to be seen. Purdue Pharma has begun advertising for the medication to be available by October 2017.

Intellectual property
There are currently three patents issued for naldemedine tosylate by the United States Patent and Trademark Office. All patents are owned by Shionogi Inc. and will expire from 2026 to 2031. Naldemedine tosylate has 46 other patents in 18 different countries.

Clinical trials
The approval of naldemedine came from the results of the COMPOSE program, a phase three clinical studies program conducted in adults 18–80 years of age with chronic non-cancer pain opioid induced constipation. COMPOSE-I and COMPOSE-II were 12-week double blind randomized controlled trials comparing the use of naldemedine to placebo in the patient population. COMPOSE-I began in August 2013 until January 2015 in 68 outpatient clinic in seven countries </s>