<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 Toremifene and can you explain it in depth? [/INST] Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.Side effects of toremifene include hot flashes, sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. It can also cause blood clots, irregular heartbeat, cataracts, visual disturbances, elevated liver enzymes, endometrial hyperplasia, and endometrial cancer. High blood calcium levels can occur in women with bone metastases.The medication is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist–antagonist of the estrogen receptor (ER), the biological target of estrogens like estradiol. It has estrogenic effects in bone, the liver, and the uterus and antiestrogenic effects in the breasts. It is a triphenylethylene derivative and is closely related to tamoxifen.Toremifene was introduced for medical use in 1997. It was the first antiestrogen to be introduced since tamoxifen in 1978. It is available as a generic medication in the United States.

Medical uses
Toremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors. This is its only approved use in the United States. It shows equivalent effectiveness to tamoxifen for this indication. Toremifene has been found to be effective in the treatment of breast pain and may be a more effective medication than tamoxifen for this indication. It also has superior effects on bone mineral density and lipid profile, including levels of cholesterol and triglycerides, compared to tamoxifen. Toremifene has been reported to significantly improve symptoms of gynecomastia in men.

Available forms
Toremifene is provided in the form of 60 mg oral tablets.

Side effects
The side effects of toremifene are similar to those of tamoxifen. The most common side effect is hot flashes. Other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. In women with bone metastases, hypercalcemia may occur. Toremifene has a small risk of thromboembolic events. Cataracts, vision changes, and elevation of liver enzymes have been reported. The drug prolongs the QT interval and hence has a risk of potentially fatal dysrhythmias. The risk of dysrhythmias can be reduced by avoiding use in patients with hypokalemia, hypomagnesemia, pre-existing QT prolongation, and in those taking other QT-prolonging drugs. Because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer.Toremifene appears to be safer than tamoxifen. It has a lower risk of venous thromboembolism (VTE) (e.g., pulmonary embolism), stroke, and cataracts. The lower risk of VTE may be related to the fact tamoxifen decreases levels of the antithrombin III to a significantly greater extent than either 60 or 200 mg/day toremifene.

Interactions
Toremifene is a substrate of CYP3A4, a cytochrome P450 enzyme, and hence drugs that induce or inhibit this enzyme can respectively decrease or increase levels of toremifene in the body.

Pharmacology
Pharmacodynamics
Toremifene is a selective estrogen receptor modulator (SERM). That is, it is a selective mixed agonist–antagonist of the estrogen receptors (ERs), with estrogenic actions in some tissues and antiestrogenic actions in other tissues. The medication has estrogenic effects in bone, partial estrogenic effects in the uterus and liver, and antiestrogenic effects in the breasts.
The affinity of toremifene for the ER is similar to that of tamoxifen. In studies using rat ER, toremifene had about 1.4% and tamoxifen had about 1.6% of the affinity of estradiol for the ER. The affinities (Ki) of toremifene at the human ERs have been reported as 20.3 ± 0.1 nM for the ERα and 15.4 ± 3.1 nM for the ERβ. In other rat ER studies, toremifene had 3–9% of the affinity of estradiol for the ER while its metabolites N-desmethyltoremifene and 4-hydroxytoremifene had 3–5% and 64–158% of the affinity of estradiol for the ER, respectively. The affinity of another metabolite, 4-hydroxy-N-desmethyltoremifene, was not assessed. 4-Hydroxytoremifene showed about 100-fold higher antiestrogenic potency than toremifene in vitro in one study, but not in another. 4-Hydroxy-N-desmethyltoremifene has also been found to be strongly antiestrogenic in vitro. The metabolites of toremifene, particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication. On the other hand, some authorities consider toremifene not to be a prodrug.Toremifene is very similar to tamoxifen and shares most of its properties. There are some indications that toremifene may be safer than tamoxifen as it is not a hepatocarcinogen in animals and may have less potential for genotoxicity. However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of toremifene has been somewhat limited. Toremifene is thought to have about one-third of the potency of tamoxifen; i.e., 60 mg toremifene is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer.Toremifene has been found to have antigonadotropic effects in postmenopausal women, progonadotropic effects in men, to increase sex hormone-binding globulin levels, and to decrease insulin-like growth factor 1 levels by about 20% in postmenopausal women and men.In addition to its activity as a SERM, 4-hydroxytoremifene is an antagonist of the estrogen-related receptor γ (ERRγ).

Pharmacokinetics
Absorption
The bioavailability of toremifene has not been precisely determined but is known to be good and has been estimated to be approximately 100%. Levels of toremifene at steady state with a dosage of 60 mg/day are 800 to 879 ng/mL. Levels of N-desmethyltoremifene at steady state with toremifene were 3,058 ng/mL at 60 mg/day, 5,942 ng/mL at 200 mg/day, and 11,913 ng/mL at 400 mg/day. Levels of 4-hydroxytoremifene at steady state with toremifene were 438 ng/mL at 200 mg/day and 889 ng/mL at 400 mg/day. Concentrations of toremifene increase linearly across a dose range of 10 to 680 mg.

Distribution
Toremifene is 99.7% bound to plasma proteins, with 92% bound specifically to albumin, about 6% to β1 globulin fraction, and about 2% to a fraction between albumin and α1 globulins. The apparent volume of distribution of toremifene ranged from 457 to 958 L.

Metabolism
Toremifene is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation. The metabolites of toremifene include N-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-N-desmethyltoremifene, among others. Ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene.

Elimination
The elimination half-life of toremifene is 3 to 7 days in healthy individuals. In people with impaired liver function, the half-life is 11 days. The elimination half-lives of the metabolites of toremifene are 5 to 21 days for N-desmethyltoremifene, 5 days for 4-hydroxytoremifene, and 4 days for ospemifene. The long elimination half-lives of toremifene and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding. Toremifene is eliminated 70% in the feces, as metabolites.

Chemistry
Toremifene, also known as 4-chlorotamoxifen, is a derivative of triphenylethylene and a close analogue of tamoxifen. It is also closely related to afimoxifene (4-hydroxytamoxifen) and ospemifene (deaminohydroxytoremifene).

History
Toremifene was introduced in the United States in 1997. It was the first antiestrogen to be introduced in this country since tamoxifen in 1978.

Society and culture
Generic names
Toremifene is the generic name of the drug and its INN and BAN, while toremifene citrate is its USAN and JAN and torémifène is its DCF.

Brand names
Toremifene is marketed almost exclusively under the brand name Fareston.

Availability
Toremifene is marketed widely throughout the world and is available in the United States, the United Kingdom, Ireland, many other European countries, South Africa, Australia, New Zealand, and elsewhere throughout the world.

Research
Toremifene was also evaluated for prevention of prostate cancer and had the tentative brand name Acapodene.In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009, and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.Toremifene may be useful in the prevention of bicalutamide-induced gynecomastia.

Phase III Trial Results
A double-blind, placebo-controlled, randomized, 3 year clinical trial of toremifene was conducted using a sample of 1,260 men.  Subjects had a median age of 64 years and were diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN), which is considered premalignant, though Thompson and Leach feel a low grade PIN could also be deemed premalignant.The sponsor, GTx, who designed and managed the study, found 34.7% of the placebo and 32.3% of the toremifene groups had cancer events. No distinction was found in Gleason scores of either group.Previous murine studies using transgenic adenocarcinoma of mouse prostate (TRAMP) mice showed toremifene prevented palpable tumors in 60% of the animals. This study used toremifene as an early prophylactic, which differentiates it from the phase III human studies.

References
Further reading
Taras TL, Wurz GT, Linares GR, DeGregorio MW (2000). "Clinical pharmacokinetics of toremifene". Clin Pharmacokinet. 39 (5): 327–34. doi:10.2165/00003088-200039050-00002. PMID 11108432. S2CID 26647296.
Harvey HA, Kimura M, Hajba A (2006). "Toremifene: an evaluation of its safety profile". Breast. 15 (2): 142–57. doi:10.1016/j.breast.2005.09.007. PMID 16289904.
Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA (2006). "Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy". Expert Opin Investig Drugs. 15 (3): 293–305. doi:10.1517/13543784.15.3.293. PMID 16503765. S2CID 29510508.
Zhou WB, Ding Q, Chen L, Liu XA, Wang S (2011). "Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials". Breast Cancer Res. Treat. 128 (3): 625–31. doi:10.1007/s10549-011-1556-5. PMID 21553116. S2CID 36985808.
Gennari L, Merlotti D, Stolakis K, Nuti R (2012). "Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis". Expert Opin Drug Metab Toxicol. 8 (4): 505–13. doi:10.1517/17425255.2012.665873. PMID 22356442. S2CID 19547631.
Mao C, Yang ZY, He BF, Liu S, Zhou JH, Luo RC, Chen Q, Tang JL (2012). "Toremifene versus tamoxifen for advanced breast cancer". Cochrane Database Syst Rev. 2021 (7): CD008926. doi:10.1002/14651858.CD008926.pub2. PMC 8407374. PMID 22786516.
Vogel CL, Johnston MA, Capers C, Braccia D (2014). "Toremifene for breast cancer: a review of 20 years of data". Clin </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 Flunisolide and can you explain it in depth? [/INST] Flunisolide (marketed as AeroBid among others) is a corticosteroid often prescribed as treatment for allergic rhinitis. Intranasal corticosteroids are the most effective medication for controlling symptoms. The principal mechanism of action of flunisolide is to activate glucocorticoid receptors, meaning it has an anti-inflammatory action. The effects of topical corticosteroids is not immediate and requires regular use and at least a few days to start experiencing noticeable symptom relief.  As-needed use has been shown to be not as effective as regular recommended use.  Flunisolide should not be used in the presence of nasal infection.  It should not be continued if there is no relief of symptoms after regular use over two to three weeks </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 Carbidopa and can you explain it in depth? [/INST] Carbidopa (Lodosyn) is a drug given to people with Parkinsons disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

Pharmacology
Carbidopa inhibits aromatic-L-amino-acid decarboxylase (DOPA decarboxylase or DDC), an enzyme important in the biosynthesis of L-tryptophan to serotonin and in the biosynthesis of L-DOPA to dopamine (DA).  DDC exists both outside of (body periphery) and within the confines of the blood–brain barrier.
Carbidopa is used in the treatment of, among other diseases, Parkinsons disease (PD), a condition characterized by death of dopaminergic neurons in the substantia nigra. Increased dopamine availability may increase the effectiveness of the remaining neurons and alleviate symptoms for a time. The pharmacologic objective is to get an exogenous dopamine-precursor known as levodopa/L-DOPA into the dopamine-deficient brains of PD patients.  Levodopa/L-DOPA can cross the blood–brain barrier, but dopamine cannot.  The use of carbidopa seems counter-intuitive in Parkinsons disease (PD) in that it prevents DDC conversion of levodopa/L-DOPA to dopamine.  However, exogenously provided, levadopa/L-DOPA gets metabolized peripherally to its active metabolite dopamine before reaching the blood–brain barrier. Therefore, the PD brain, which is deficient in dopamine, will not receive as much of its prodrug precursor levodopa/L-DOPA due to peripheral DDC breakdown. However, carbidopa can decrease peripheral DDC conversion of levodopa/L-DOPA before it crosses the blood–brain barrier. Carbidopa acts as a peripheral DDC inhibitor, as carbidopa, itself, cannot cross the blood–brain barrier. In other words, carbidopa has no effect on brain DDC conversion of levodopa/L-DOPA to dopamine. Ultimately, a greater proportion of the exogenously provided levodopa/L-DOPA reaches the brain.  Commercially, carbidopa/levodopa combinations are available in the treatment of central dopamine deficiencies.
Along with carbidopa, other DDC inhibitors are benserazide (Ro-4-4602), difluromethyldopa, and α-methyldopa.

pharmacology 2
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as N-amino-α-methyl-3-hydroxy-L-tyrosine monohydrate. Its empirical formula is C10H14N2O4•H2O. Used in tandem with L-DOPA (also known as levodopa, a dopamine precursor converted in the body to dopamine), it increases the plasma half-life of levodopa from 50 minutes to 1½ hours. CarbiDOPA cannot cross the blood–brain barrier, so it inhibits only peripheral DDC. It thus prevents the conversion of L-DOPA to dopamine peripherally. This reduces the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and dopamine in the brain.
The combination of carbidopa/levodopa carries the brand names of Kinson, Sinemet, Pharmacopa and Atamet; while Stalevo is a combination with entacapone, which enhances the bioavailability of carbidopa and levodopa.
Carbidopa is most commonly used as a method to inhibit the activity of dopamine decarboxylase. This is an enzyme that breaks down L-Dopa in the periphery and converts it to dopamine. This results in the newly formed dopamine being unable to cross the blood–brain barrier and the effectiveness of L-Dopa treatments is greatly decreased. Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid </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 Rifampicin and can you explain it in depth? [/INST] Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires’ disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.Common side effects include nausea, vomiting, diarrhea, and loss of appetite. It often turns urine, sweat, and tears a red or orange color. Liver problems or allergic reactions may occur. It is part of the recommended treatment of active tuberculosis during pregnancy,  though its safety in pregnancy is not known. Rifampicin is of the rifamycin group of antibiotics. It works by decreasing the production of RNA by bacteria.Rifampicin was discovered in 1965, marketed in Italy in 1968, and approved in the United States in 1971. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies rifampicin as critically important for human medicine. It is available as a generic medication. Rifampicin is made by the soil bacterium Amycolatopsis rifamycinica.

Medical uses
Mycobacteria
Rifampicin is used for the treatment of tuberculosis in combination with other antibiotics, such as pyrazinamide, isoniazid, and ethambutol. For the treatment of tuberculosis, it is administered daily for at least six months. Combination therapy is used to prevent the development of resistance and to shorten the length of treatment. Resistance of Mycobacterium tuberculosis to rifampicin develops quickly when it is used without another antibiotic, with laboratory estimates of resistance rates from 10−7 to 10−10 per tuberculosis bacterium per generation.Rifampicin can be used alone in patients with latent tuberculosis infections to prevent or delay the development of active disease because only small numbers of bacteria are present. A Cochrane review found no difference in efficacy between a 3- to 4-month regimen of rifampicin and a 6-month regimen of isoniazid for preventing active tuberculosis in patients not infected with HIV, and patients who received rifampicin had a lower rate of hepatotoxicity. However, the quality of the evidence was judged to be low. A shorter 2-month course of rifampicin and pyrazinamide had previously been recommended but is no longer recommended due to high rates of hepatotoxicity.Rifampicin should be taken on an empty stomach with a glass of water. It is generally taken either at least one hour before meals or two hours after meals.Rifampicin is also used to treat nontuberculous mycobacterial infections including leprosy (Hansens disease) and Mycobacterium kansasii.With multidrug therapy used as the standard treatment of Hansens disease, rifampicin is always used in combination with dapsone and clofazimine to avoid causing drug resistance.It is also used in the treatment of Mycobacterium ulcerans infections as associated with Buruli ulcer, usually in combination with clarithromycin or other antibiotics.

Other bacteria and protozoans
In 2008, tentative evidence showed rifampicin may be useful in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with other antibiotics, including in difficult-to-treat infections such as osteomyelitis and prosthetic joint infections. As of 2012,  if rifampicin combination therapy was useful for pyogenic vertebral osteomyelitis was unclear. A meta-analysis concluded that adding adjunctive rifampicin to a β-lactam or vancomycin may improve outcomes in staphylococcus aureus bacteremia. However, a more recent trial found no benefit from adjunctive rifampicin.It is also used as preventive treatment against Neisseria meningitidis (meningococcal) infections. Rifampicin is also recommended as an alternative treatment for infections by the tick-borne pathogens Borrelia burgdorferi and Anaplasma phagocytophilum when treatment with doxycycline is contraindicated, such as in pregnant women or in patients with a history of allergy to tetracycline antibiotics.It is also sometimes used to treat infections by Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae, and Legionella pneumophila. For these nonstandard indications, antimicrobial susceptibility testing should be done (if possible) before starting rifampicin therapy.
The Enterobacteriaceae, Acinetobacter species, and Pseudomonas species are intrinsically resistant to rifampicin.It has been used with amphotericin B in largely unsuccessful attempts to treat primary amoebic meningoencephalitis caused by Naegleria fowleri.Rifampicin can be used as monotherapy for a few days as prophylaxis against meningitis, but resistance develops quickly during long-term treatment of active infections, so the drug is always used against active infections in combination with other antibiotics.Rifampicin is relatively ineffective against spirochetes, which has led to its use as a selective agent capable of isolating them in materials being cultured in laboratories.

Viruses
Rifampicin has some effectiveness against vaccinia virus.

Pathogen susceptibility
The minimum inhibitory concentrations of rifampicin for several medically significant pathogens are:

Mycobacterium tuberculosis — 0.002 – 64 µg/ml
Mycobacterium bovis — 0.125 µg/ml
Staphylococcus aureus (methicillin resistant) — ≤ 0.006–256 µg/ml
Chlamydia pneumoniae — 0.005 µg/ml

Primary biliary cholangitis
Rifampicin is used to treat itchiness caused by primary biliary cholangitis. The treatment-related adverse effects include hepatotoxicity, nephrotoxicity, hemolysis, and interactions with other drugs. For those reasons as well as some ethical concerns regarding off-label use of antibiotics, rifampin as a very effective preventive antibiotic for meningitis, is not considered appropriate for itchiness.

Hidradenitis suppurativa
Rifampicin with clindamycin has been used to treat the skin disease hidradenitis suppurativa.

Adverse effects
The most serious adverse effect is hepatotoxicity, and people receiving it often undergo baseline and frequent liver function tests to detect early liver damage.The more common side effects include fever, gastrointestinal disturbances, rashes, and immunological reactions. Taking rifampicin usually causes certain bodily fluids, such as urine, sweat, and tears, to become orange-red in color, a benign side effect that nonetheless can be frightening if it is not expected. This may also be used to monitor effective absorption of the drug (if drug color is not seen in the urine, the patient may wish to move the drug dose farther in time from food or milk intake). The discolorization of sweat and tears is not directly noticeable, but sweat may stain light clothing orange, and tears may permanently stain soft contact lenses. Since rifampicin may be excreted in breast milk, breastfeeding should be avoided while it is being taken.Other adverse effects include:

Liver toxicity—hepatitis, liver failure in severe cases
Respiratory—breathlessness
Cutaneous—flushing, pruritus, rash, hyperpigmentation, redness and watering of eyes
Abdominal — nausea, vomiting, abdominal cramps, diarrhea
Flu-like symptoms—chills, fever, headache, arthralgia, and malaise. Rifampicin has good penetration into the brain, and this may directly explain some malaise and dysphoria in a minority of users.
Allergic reaction—rashes, itching, swelling of the tongue or throat, severe dizziness, and trouble breathing

Chemical structure
Rifampicin is a polyketide belonging to the chemical class of compounds termed ansamycins, so named because of their heterocyclic structure containing a naphthoquinone core spanned by an aliphatic ansa chain. The naphthoquinonic chromophore gives rifampicin its characteristic red-orange crystalline color.The critical functional groups of rifampicin in its inhibitory binding of bacterial RNA polymerase are the four critical hydroxyl groups of the ansa bridge and the naphthol ring, which form hydrogen bonds with amino acid residues on the protein.Rifampicin is the 3-(4-methyl-1-piperazinyl)-iminomethyl derivative of rifamycin SV.

Interactions
Rifampicin is the most powerful known inducer of the hepatic cytochrome P450 enzyme system, including isoenzymes CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP3A7. It increases metabolism of many drugs and as a consequence, can make them less effective, or even ineffective, by decreasing their levels. For instance, patients undergoing long-term anticoagulation therapy with warfarin have to increase their dosage of warfarin and have their clotting time checked frequently because failure to do so could lead to inadequate anticoagulation, resulting in serious consequences of thromboembolism.Rifampicin can reduce the efficacy of birth control pills or other hormonal contraception by its induction of the cytochrome P450 system, to the extent that unintended pregnancies have occurred in women who use oral contraceptives and took rifampicin even for very short courses (for example, as prophylaxis against exposure to bacterial meningitis).Other interactions include decreased levels and less effectiveness of antiretroviral agents, everolimus, atorvastatin, rosiglitazone, pioglitazone, celecoxib, clarithromycin, caspofungin, voriconazole, and lorazepam.Rifampicin is antagonistic to the microbiologic effects of the antibiotics gentamicin and amikacin. The activity of rifampicin against some species of mycobacteria can be potentiated by isoniazid (through inhibiting mycolate synthesis) and ambroxol (through host directed effects in autophagy and pharmacokinetics).

Pharmacology
Mechanism of action
Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.Crystal structure data and biochemical data suggest that rifampicin binds to the pocket of the RNA polymerase β subunit within the DNA/RNA channel, but away from the active site. The inhibitor prevents RNA synthesis by physically blocking elongation, and thus preventing synthesis of host bacterial proteins. By this "steric-occlusion" mechanism, rifampicin blocks synthesis of the second or third phosphodiester bond between the nucleotides in the RNA backbone, preventing elongation of the 5 end of the RNA transcript past more than 2 or 3 nucleotides.In a recent study Rifampicin was shown to bind to cytochrome P450 reductase and alter its conformation as well as activity towards supporting metabolism of progesterone via CYP21A2.

Mechanism of resistance
Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin. Resistance mutations map to the rpoB gene, encoding the beta subunit of RNA polymerase. The majority of resistance mutations in E. coli are in 3 clusters on rpoB. Cluster I is amino acids 509 to 533, cluster II is amino acids 563 to 572, and cluster III is amino acid 687.
When describing mutations in rpoB in other species, the corresponding amino acid number in E. coli is usually used. In Mycobacterium tuberculosis, the majority of mutations leading to rifampicin resistance are in cluster I, in a 81bp hotspot core region called RRDR for "rifampcin resistance determining region". A change in amino acid 531 from serine to leucine arising from a change in the DNA sequence of TCG to TTG is the most common mutation. Tuberculosis resistance has also occurred due to mutations in the N-terminal region of rpoB and cluster III.An alternative mechanism of resistance is through Arr-catalyzed ADP-ribosylation of rifampicin. With the assistance of the enzyme Arr produced by the pathogen Mycobacterium smegmatis, ADP-ribose is added to rifampicin at one of its ansa chain hydroxy groups, thereby inactivating the drug.

Resistance in tuberculosis
Mycobacterial resistance to rifampicin may occur alone or along with resistance to other first-line antitubercular drugs. Early detection of such multidrug or extensively drug-resistant tuberculosis is critical in improving patient outcomes by instituting appropriate second-line treatments, and in decreasing transmission of drug-resistant TB. Traditional methods of detecting resistance involve mycobacterial culture and drug susceptibility testing, results of which could take up to 6 weeks. Xpert MTB/RIF assay is an automated test that can detect rifampicin resistance, and also diagnose tuberculosis. A Cochrane review updated in 2014 concluded that for rifampicin resistance detection, Xpert MTB/RIF was accurate, that is (95%) sensitive and (98%) specific.

Pharmacokinetics
Orally administered rifampicin results in peak plasma concentrations in about 2–4 hours. 4-Aminosalicylic acid (another antituberculosis drug) significantly reduces absorption of rifampicin, and peak concentrations may be lower. If these two drugs must be used concurrently, they must be given separately, with an interval of 8 to 12 hours between administrations.
Rifampicin is easily absorbed from the gastrointestinal (GI) tract; its ester functional group is quickly hydrolyzed in bile, and it is catalyzed by a high pH and substrate-specific esterases. After about 6 hours, almost all of the drug is deacetylated. Even in this deacetylated form, rifampicin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and is eliminated from the body. Only about 7% of the administered drug is excreted unchanged in urine, though urinary elimination accounts for only about 30% of the drug excretion. About 60% to 65% is excreted through feces.The half-life of rifampicin ranges from 1.5 to 5.0 hours, though hepatic impairment significantly increases it. Food consumption inhibits its absorption from the GI tract, and the drug is more quickly eliminated. When rifampicin is taken with a meal, its peak blood concentration falls by 36%. Antacids do not affect its absorption. The decrease in rifampicin absorption with food is sometimes enough to noticeably affect urine color, which can be used as a marker for whether or not a dose of the drug has been effectively absorbed.Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including the cerebrospinal fluid. Since the substance itself is red, this high distribution is the reason for the orange-red color of the saliva, tears, sweat, urine, and feces. About 60% to 90% of the drug is bound to plasma proteins.

Use in biotechnology
Rifampicin inhibits bacterial RNA polymerase, thus it is commonly used to inhibit the synthesis of host bacterial proteins during recombinant protein expression in bacteria. RNA encoding for the recombinant gene is usually transcribed from DNA by a viral T7 RNA polymerase, which is not affected by rifampicin.

History
In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan, Italy. There, a research group headed by Piero Sensi and Maria Teresa Timbal discovered a new bacterium. This new species produced a new class of molecules with antibiotic activity </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 Tetracycline and can you explain it in depth? [/INST] Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis.Common side effects include vomiting, diarrhea, rash, and loss of appetite. Other side effects include poor tooth development if used by children less than eight years of age, kidney problems, and sunburning easily. Use during pregnancy may harm the baby. It works by inhibiting protein synthesis in bacteria.Tetracycline was patented in 1953 and came into commercial use in 1978. It is on the World Health Organizations List of Essential Medicines. Tetracycline is available as a generic medication.  Tetracycline was originally made from bacteria of the Streptomyces type.

Medical uses
Spectrum of activity
Tetracyclines have a broad spectrum of antibiotic action. Originally, they possessed some level of bacteriostatic activity against almost all medically relevant aerobic and anaerobic bacterial genera, both Gram-positive and Gram-negative, with a few exceptions, such as Pseudomonas aeruginosa and Proteus spp., which display intrinsic resistance. However, acquired (as opposed to inherent) resistance has proliferated in many pathogenic organisms and greatly eroded the formerly vast versatility of this group of antibiotics. Resistance amongst Staphylococcus spp., Streptococcus spp., Neisseria gonorrhoeae, anaerobes, members of the Enterobacteriaceae, and several other previously sensitive organisms is now quite common. Tetracyclines remain especially useful in the management of infections by certain obligately intracellular bacterial pathogens such as Chlamydia, Mycoplasma, and Rickettsia. They are also of value in spirochaetal infections, such as syphilis, and Lyme disease. Certain rare or exotic infections, including anthrax, plague, and brucellosis, are also susceptible to tetracyclines. Tetracycline tablets were used in the plague outbreak in India in 1994.  Tetracycline is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Lyme disease (B. burgdorferi), Q fever (Coxiella), psittacosis, Mycoplasma pneumoniae, and nasal carriage of meningococci.
It is also one of a group of antibiotics which together may be used to treat peptic ulcers caused by bacterial infections. The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however, protein translation is also disrupted in eukaryotic mitochondria leading to effects that may confound experimental results.The following list presents MIC susceptibility data for some medically significant microorganisms:

Escherichia coli: 1 μg/mL to >128 μg/mL
Shigella spp.: 1 μg/mL to 128 μg/mL

Anti-eukaryote use
The tetracyclines also have activity against certain eukaryotic parasites, including those responsible for diseases such as dysentery caused by an amoeba, malaria (a plasmodium), and balantidiasis (a ciliate).

Use as a biomarker
Since tetracycline is absorbed into bone, it is used as a marker of bone growth for biopsies in humans. Tetracycline labeling is used to determine the amount of bone growth within a certain period of time, usually a period around 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its fluorescence. In "double tetracycline labeling", a second dose is given 11–14 days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the two fluorescent labels.Tetracycline is also used as a biomarker in wildlife to detect consumption of medicine- or vaccine-containing baits.

Side effects
Use of tetracycline antibiotics can:
Discolor permanent teeth (yellow-gray-brown), from prenatal period through childhood and adulthood. Children receiving long- or short-term therapy with a tetracycline or glycylcycline may develop permanent brown discoloration of the teeth.
Be inactivated by calcium ions, so are not to be taken with milk, yogurt, and other dairy products
Be inactivated by aluminium, iron, and zinc ions, not to be taken at the same time as indigestion remedies (some common antacids and over-the-counter heartburn medicines)
Cause skin photosensitivity, so exposure to the sun or intense light is not recommended
Cause drug-induced lupus, and hepatitis
Cause microvesicular fatty liver
Cause tinnitus
Interfere with methotrexate by displacing it from the various protein-binding sites
Cause breathing complications, as well as anaphylactic shock, in some individuals
Affect bone growth of the fetus, so should be avoided during pregnancy
Fanconi syndrome may result from ingesting expired tetracyclines.Caution should be exercised in long-term use when breastfeeding. Short-term use is safe; bioavailability in milk is low to nil. According to the U.S. Food and Drug Administration (FDA),  cases of Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme associated with doxycycline use have been reported, but a causative role has not been established.

Pharmacology
Mechanism of action
Tetracycline inhibits protein synthesis by blocking the attachment of charged tRNA at the P site peptide chain. Tetracycline blocks the A-site so that a hydrogen bond is not formed between the amino acids. Tetracycline binds to the 30S and 50S subunit of microbial ribosomes. Thus, it prevents the formation of a peptide chain. The action is usually not inhibitory and irreversible even with the withdrawal of the drug. Mammalian cells are less vulnerable to the effect of tetracyclines, despite the fact that tetracycline binds to the small ribosomal subunit of both prokaryotes and eukaryotes (30S and 40S, respectively). This is because bacteria actively pump tetracycline in, even against a concentration gradient, whereas mammalian cells are simply not affected by the mechanisms of tetracycline within the cytoplasm. This accounts for the relatively small off-site effect of tetracycline on human cells.

Mechanisms of resistance
Bacteria usually acquire resistance to tetracycline from horizontal transfer of a gene that either encodes an efflux pump or a ribosomal protection protein. Efflux pumps actively eject tetracycline from the cell, preventing the buildup of an inhibitory concentration of tetracycline in the cytoplasm.  Ribosomal protection proteins interact with the ribosome and dislodge tetracycline from the ribosome, allowing for translation to continue.

History
Discovery
The tetracyclines, a large family of antibiotics, were discovered by Benjamin Minge Duggar in 1948 as natural products, and first prescribed in 1948. Benjamin Duggar, working under Yellapragada Subbarow at Lederle Laboratories, discovered the first tetracycline antibiotic, chlortetracycline (Aureomycin), in 1945. The structure of Aureomycin was elucidated in 1952 and published in 1954 by the Pfizer-Woodward group. After the discovery of the structure, researchers at Pfizer began chemically modifying aureomycin by treating it with hydrogen in the presence of a palladized carbon catalyst. This chemical reaction replaced a chlorine moiety with a hydrogen, creating a compound named tetracycline via hydrogenolysis. Tetracycline displayed higher potency, better solubility, and more favorable pharmacology than the other antibiotics in its class, leading to its FDA approval in 1954. The new compound was one of the first commercially successful semi-synthetic antibiotics that was used, and laid the foundation for the development of Sancycline, Minocycline, and later the Glycylcyclines.

Evidence in antiquity
Our modern understanding of tetracyclines dates their discovery to 1948, but there is evidence that early inhabitants of Northeastern Africa consumed tetracycline antibiotics. Nubian mummies from between 350 and 550 C.E. were found to exhibit patterns of fluorescence identical with that of modern tetracycline labelled bone.Tetracycline has a high affinity for calcium and is incorporated into bones during the active mineralization of hydroxyapatite. When incorporated into bones, tetracycline can be identified using ultraviolet light.It is conjectured that the beer brewed at the time was the source of the tetracycline found in these bones.

Society and culture
Price
According to data from EvaluatePharma and published in the Boston Globe, in the USA the price of tetracycline rose from $0.06 per 250-mg pill in 2013 to $4.06 a pill in 2015. The Globe described the "big price hikes of some generic drugs" as a "relatively new phenomenon" which has left most pharmacists "grappling" with large upswings" in the "costs of generics, with overnight price changes sometimes exceeding 1,000%."

Names
It is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others </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 Isatuximab and can you explain it in depth? [/INST] Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell), infusion reactions, pneumonia (infection of the lungs), upper respiratory tract infection (such as nose and throat infections), diarrhoea and bronchitis (inflammation of the airways in the lungs).Isatuximab is an anti-CD38 mAb intended to treat relapsed or refractory multiple myeloma. It entered in Phase II trials for multiple myeloma and T-cell leukemia in 2015.

Medical uses
In the United States it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. It is also indicated in combination with carfilzomib and dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.In the European Union it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (PI) and have demonstrated disease progression on the last therapy.

History
It was granted orphan drug designation for multiple myeloma by the European Medicines Agency (EMA) in April 2014, and by the U.S. Food and Drug Administration (FDA) in December 2016.Researchers started a Phase I study with isatuximab in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM). The results during the Phase I trial showed that 26 out of the 45 patients discontinued the treatment due to progression of the disease. The patients had already been heavily pretreated. The latter lead to a manageable safety profile where the dose of isatuximab in combination with pomalidomide and dexamethasone would be capped to the maximum of 10 mg/kg weekly every two weeks for future studies.Based on the remarkable findings during the Phase I trial, a Phase II trial was launched where researchers investigated isatuximab as a single agent in patients with MM. The heavily pretreated patients reacted well to the single administration of isatuximab during Phase II of the trial.A Phase III combination trial for plasma cell myeloma is comparing pomalidomide and dexamethasone with and without isatuximab is in progress with an estimated completion date of 2021.Additionally, two Phase III trials were added in 2017. The first trial highlights whether there is an added value in the combination of isatuximab with bortezomib, lenalidomide and dexamethasone. The latter will be tested in patients with newly diagnosed MM who are not qualified for a transplant (IMROZ trial). The second trial evaluates the combinations of isatuximab with carfilzomib and dexamethasone compared to carfilzomib with dexamethasone. The second trial was designed for patients who were previously treated with one to three prior lines (IKEMA). There is currently no treatment for MM, however promising improvements have been made and the study is still ongoing.In March 2020, it was approved for medical use in the United States.The U.S. Food and Drug Administration (FDA) approved isatuximab-irfc in March 2020, based on evidence from a clinical trial (NCT02990338) of 307 subjects with previously treated multiple myeloma. The trial was conducted at 102 sites in Europe, North America, Asia, Australia and New Zealand.The trial evaluated the efficacy and side effects of isatuximab-irfc in subjects with previously treated multiple myeloma. Subjects were randomly assigned to receive either isatuximab-irfc (in combination with pomalidomide and low-dose dexamethasone) or active comparator (pomalidomide and low-dose dexamethasone). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Both subjects and health care providers knew which treatment was given. The trial measured the time patients lived without the cancer growing (progression-free survival or PFS).It was approved for medical use in the European Union in May 2020.

Structure and reactivity
The structure of isatuximab consists of two identical immunoglobulin kappa light chains and also two equal immunoglobulin gamma heavy chains. Chemically, isatuximab is similar to the structure and reactivity of daratumumab, hence both drugs show the same CD38 targeting. However, isatuximab shows a more potent inhibition of its ectozyme function. The latter gives potential for some non-cross reactivity. Isatuximab shows action of an allosteric antagonist with the inhibition of the CD38 enzymatic activity. Additionally, isatuximab shows potential where it can induce apoptosis without cross linking. Lastly, Isatuximab reveals direct killing activity when a larger increase in apoptosis is detected in CD38 expressing cancer cells. Furthermore, isatuximab demonstrated a dose dependent inhibition of CD38 enzymatic activity. However, daratumumab with the same experimental conditions shows a more limited inhibition without a dose response.

Reactions
Isatuximab binds uniquely to an epitope on the CD38 receptor and is the only CD38 antibody which can start apoptosis directly. Isatuximab binds to a different CD38 epitope amino-acid sequence than does the anti-CD38 monoclonal antibody daratumumab. The binding with the CD38 receptor is mainly via the gamma heavy chains and are more potent than other CD38 antibodies such as daratumumab which can inhibit the enzymatic activity of CD38. Moreover, isatuximab inhibits the hydrolase activity of CD38.The antibodies show signs of improving antitumor immunity by eliminating regulatory T cells, B cells and myeloid-derived suppressor cells. The difference in binding between isatuximab and daratumumab is in the recognition of the different amino acid groups. Isatuximab identifies 23 amino acids of CD38 to the contrary with daratumumab who has 27. The residue of Glu233 has a flexible sidechain and faces the N-terminal of Asp1 residue in the isatuximab light chain. The latter light chain of isatuximab is also flexible which makes the interaction between CD38/Glu233 and the Asp1 weaker than the other interactions between CD38 and isatuximab. The caspase-dependent apoptotic pathway and the lysosomal mediated cell death pathway in MM cells is induced by isatuximab. The MM cell death follows the downstream reactions of the lysosomal activation. The latter also activates the production of reactive oxygen species.

Available forms
Isatuximab or isatuximab-irfc is available as a drug in an intravenous infusion form. Injection doses are 100 mg/5 mL (20 mg/mL) solution in single-dose vial or 500 mg/25 mL (20 mg/mL) solution in single-dose vial.

Mechanism of action
Cancer of the blood that is distinguished by an overproduction of malignant plasma cells in the bone marrow is called multiple myeloma. The myeloma cells are marked with uniformed overexpression of CD38 surface glycoproteins. Although these proteins are also expressed on other myeloid and lymphoid cells, the extent is relatively minor compared to myeloma cells. The fact that CD38 glycoproteins carry out various important cellular functions, and that they are plentiful on the surface of myeloma cells, has made them an appealing target for multiple myeloma treatment. CD38 was first described as an activation marker, but later the molecule displayed functions in adhesion to endothelial CD31 proteins, e.g. as an aiding component of the synapse complex, as well as an ectoenzyme implicated in the metabolism of extracellular NAD+ and cytoplasmic NADP. The tumour cells can evade the immune system, possibly due to adenosine, an immunosuppressive molecule that arises as a product of the ectoenzymatic activity of CD38.Isatuximab-irfc is an IgG1-derived monoclonal antibody that selectively binds to the CD38 that exists on the exterior of hematopoietic and multiple myeloma cells (as well as other tumor cells). This drug induces apoptosis of tumor cells and activates immune effector mechanisms such as complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). Isatuximab-irfc is able to stimulate natural killer (NK) cells in the absence of CD38-positive target tumor cells and blocks CD38-positive T-regulatory cells. Furthermore, the NADase activity of CD38 is adjusted by isatuximab, similarly to other CD38 antibodies. Contrarily to daratumumab however, isatuximab can incite apoptosis directly without cross-linking, and in its binding epitope. According to the FDA, isatuximab-irfc alone has reduced ADCC and direct tumor cell killing activity in vitro in comparison to when it is combined with pomalidomide. As well as increased anti-tumor activity as opposed to isatuximab-irfc or pomalidomide only in a human multiple myeloma xenograft model.

Metabolism and toxicity
Metabolism
Isatuximab-irfc is likely to be metabolized through catabolic pathways into smaller peptides. When isatuximab is at a constant state it is expected that the ≥99% elimination will occur approximately two months after the last dose was administered. The clearance percentage diminished when the dosages were increased over time, as well as when multiple doses were administered. However, the elimination of isatuximab-irfc did not differ when applied as a single agent or as a combination therapy.

Toxicity
A dose-limiting toxicity (DLT) has been characterized as the development of any of the following: grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia or grade 4 thrombocytopenia lasting more than 5 days; grade ≥ 2 allergic reactions or hypersensitivity (i.e., infusion reactions); or any other toxicity considered to be dose-limiting by the investigators or sponsor. Grade ≤ 2 infusion reactions were excluded from the DLT definition, because, with suitable care, patients that had a grade 2 infusion reaction prior to completion of the infusion were able to finalize isatuximab administration.There is no recommended reduced dose of isatuximab-irfc. In the eventuality of hematological toxicity it may be necessary to delay administration so that the blood count may be recovered. Although there is no counteracting agent for isatuximab, clinical experience with overdoses is seemingly nonexistent as well. Overdose symptoms will probably be in line with the side effects attached to isatuximab. Therefore, infusion reactions, gastrointestinal disturbances and an elevated risk of infections may occur. It is necessary to carefully monitor the patient in case of an overdose and to employ clinically indicated symptomatic and supportive procedures.No studies have been conducted with isatuximab concerning carcinogenicity, genotoxicity or fertility.

Pregnancy
When given to pregnant women isatuximab-irfc can cause fetal injury, due to the mechanism of action. It can precipitate depletion of immune cells as well as decreased bone density in the fetus. Pregnant women are therefore notified of the potential risks to a fetus, and women that are able to reproduce are advised to use effective contraceptives during treatment and at least five months subsequent to the last dose of isatuximab-irfc.
Furthermore, it is not recommended to combine isatuximab-irfc with pomalidomide in women that are carrying a child, because pomalidomide may cause birth defects and death of the unborn child.

Indications
Isatuximab is indicated as a CD38-directed cytolytic antibody. By inhibiting the enzymatic activity of CD38.
The binding of isatuximab to CD38 on multiple myeloma (MM) cells leads to a trigger to several mechanisms leading to direct apoptosis of target cancer cells. The triggered pathways are the caspase-dependent apoptotic and the lysosome-mediated cell death pathway in MM cells.It is used in a combination with dexamethasone and pomalidomide. The drug is thus to treat patients with multiple myeloma. Restrictions for the use of isatuximab is that the patients have to be adults who have at least received two previous treatments with lenalidomide and a proteasome inhibitor.Isatuximab is currently also being tested in a Phase II trial as a monotherapy against refractory/recurrent systemic light-chain amyloidosis.

Efficacy and side effects
Efficacy
A Phase III study of patients with refractory and relapsed MM, who were resistant to lenalidomide and a proteasome inhibitor, and could not have received daratumumab, another anti-CD38 monoclonal antibody was published in 2019 (ICARIA-MM) </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 Peginterferon beta-1a 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 Ifosfamide and can you explain it in depth? [/INST] Ifosfamide (IFO), sold under the brand name Ifex among others, is a chemotherapy medication used to treat a number of types of cancer. This includes testicular cancer, soft tissue sarcoma, osteosarcoma, bladder cancer, small cell lung cancer, cervical cancer, and ovarian cancer. It is administered by injection into a vein.Common side effects include hair loss, vomiting, blood in the urine, infections, and kidney problems. Other severe side effects include bone marrow suppression and decreased level of consciousness. Use during pregnancy will likely result in harm to the baby. Ifosfamide is in the alkylating agent and nitrogen mustard family of medications. It works by disrupting the duplication of DNA and the creation of RNA.Ifosfamide was approved for medical use in the United States in 1987. It is on the World Health Organizations List of Essential Medicines.

Medical uses
It is given as a treatment for a variety of cancers, including:

Testicular cancer
Breast cancer
Lymphoma (Hodgkin and non-Hodgkin)
Soft tissue sarcoma
Osteosarcoma or bone tumor
Lung cancer
Cervical cancer
Ovarian cancer

Administration
It is a white powder which, when prepared for use in chemotherapy, becomes a clear, colorless fluid. The delivery is intravenous.
Ifosfamide is often used in conjunction with mesna to avoid internal bleeding in the patient, in particular hemorrhagic cystitis.
Ifosfamide is given quickly, and in some cases can be given as quickly as an hour.

Side effects
Hemorrhagic cystitis is rare when ifosfamide is given with mesna. A common and dose-limiting side effect is encephalopathy (brain dysfunction). It occurs in some form in up to 50% of people receiving the agent. The reaction is probably mediated by chloroacetaldehyde, one of the breakdown products of the ifosfamide molecule, which has chemical properties similar to acetaldehyde and chloral hydrate. The symptoms of ifosfamide encephalopathy can range from mild (difficulty concentrating, fatigue), to moderate (delirium, psychosis), to severe (nonconvulsive status epilepticus or coma). In children, this can interfere with neurological development. Apart from the brain, ifosfamide can also affect peripheral nerves </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 Butabarbital and can you explain it in depth? [/INST] Butabarbital (brand name Butisol) is a prescription barbiturate sleep aid and anxiety medication. Butabarbital has a particularly fast onset of effects and short duration of action compared to other barbiturates, which makes it useful for certain applications such as treating severe insomnia, relieving general anxiety and relieving anxiety before surgical procedures; however it is also relatively dangerous particularly when combined with alcohol, and so is now rarely used, although it is still prescribed in some Eastern European and South American countries. Its intermediate duration of action gives butabarbital an abuse potential slightly lower than secobarbital. Butabarbital can be hydrolyzed to Valnoctamide.
Butabarbital is also sold in combination with belladonna alkaloids under the brand name Butibel. The belladonna is added for antispasmodic effect. This product contains a low dose of butabarbital combined with a standardised mix of belladonna alkaloids and is used as an antispasmodic taken to relieve cramping and spasms of the stomach and intestines. They are used also to decrease the amount of acid formed in the stomach. Another similar product is Donnatal, which contains belladonna alkaloids combined with phenobarbital.

History
Barbiturates were first discovered to have medical use in 1903, when a research at Bayer showed barbital to be an effective sedative for dogs.  It was not until the mid 20th century that the habit forming nature of barbiturates and behavioral side effects were first notedBenzodiazepines are more commonly administered today for their similar sedative and hypnotic properties, and reduced risk of physical dependence.  Barbiturate drugs such as butabarbital sodium are used now for short-term and acute treatment under strict doctor supervision only

Clinical uses
Barbiturates are non-selective depressants of the central nervous system, inducing drowsiness and mild sedative effects.  Barbiturate hypnotics are used in the treatment of sleep and anxiety disorders for their calming and sedative properties, however are usually restricted to short term use due to risk of dependency.Butabarbital, most commonly known as Butisol commercially, is an approved Schedule III drug in the US and Canada used in the short-term treatment of anxiety disorders and as a pre-surgical sedative aid.  Approved commercial forms are available in tablet or elixir forms. Recently, butabarbital was approved for medical use in 2007 under the brand name Butisol Sodium.  Butisol sodium is manufactured by Meda Pharmaceuticals as a Schedule III controlled substance due to its high risk for abuse and dependence.

Administration
It is most often administered orally as either sodium solution or tablet, however can also be given by intravenous injection.  Tablets contain either 30 mg or 50 mg of butabarbital sodium, or 30 mg/5mL with 7% alcohol/vol in solution.  For preoperative sedation, adults are administered 50–100 mg 60-90min prior to surgery, with varying doses for pediatric and geriatric patients.

Clinical effects & elimination
Effects from oral doses often are felt within an hour of administration, lasting somewhere from six to eight hours in effect.  A non-selective depressant of the CNS, Butabarbital sodium is used as a sedative hypnotic, depending on dose, to induce drowsiness or sleep, or reduce anxiety and tension. Butabarbital sodium can be used as a pre-surgical anesthetic aid or in the short-term treatment of sleep and anxiety disorders.  For short term sleep maintenance and induction butabarbital sodium treatment is recommended to be limited to two weeks, after which it begins to lose efficacy. The half life is approximately 100hrs, eliminated primarily by hepatic microsomal enzymes and excreted in the urine.

Overdose & abuse
Butabarbital sodium is a Schedule III controlled substance in the US and Canada due to risk of abuse and dependence.  A psychoactive substance, butabarbital drugs are often abused with risk of acute intoxication and addiction.  Barbiturates such as butabarbital are thought to be habit-forming and addictive, and have severe risks from withdrawal including death.  Due to the high risk of dependence and overdose, use of butabarbital is highly regulated and has become less common in clinical application.

Side effects
Those taking Butabarbital are asked to watch out for signs of severe allergic reaction, such as swelling or difficulty breathing. Less serious side effects include dizziness or drowsiness, excitation, headache, nausea, vomiting, or constipation. Psychiatric disturbances (hallucinations, agitation, confusion, depression, or memory problems), ataxia, difficulty breathing, or slow heartbeat could be signs of serious adverse effects and should be brought to the attention of a doctor immediately.

Adverse effects
1-10%

Somnolence<1%

Contradictions
Those with a hypersensitivity to barbiturates or a history of porphyria should discuss with a doctor before using butisol sodium treatment.  Butabarbital has also been shown to interact with some medicines; Talk to your doctor if taking Monoamine oxidase inhibitors (MAOIs), beta-blockers, oral-contraceptives, or other medications, as their efficacy may be affected.At low doses Butabarbital has been shown clinically to induce drowsiness, depressing the sensory cortex and motor activity.  In some rare cases Butabarbital has been shown to produce small bursts of excitement or euphoria prior to the sedative effects.  Butabarbital is a highly potent drug however, with addictive properties, and small variations in dose can result in significant escalation of effects.

Pharmacology
Butabarbital is a sedative hypnotic member of the barbiturate family.  It is relatively fast acting, with a short duration, producing a range of effects from mild sedation to hypnosis as a function of dosage. An overdose of butabarbital can result in deep coma or even death.

Absorption, distribution and excretion
Butabarbituates are rapidly distributed and absorbed in the brain, liver and kidneys.  One of the more lipophilic barbiturates, butabarbital crosses the blood brain barrier with relative ease, and is slightly more potent then other less lipophilic barbiturates such as phenobarbital </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 Lifitegrast 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 Icatibant and can you explain it in depth? [/INST] Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication from the ACE inhibitor class.It is a peptidomimetic consisting of ten amino acids, which is a selective and specific antagonist of bradykinin B2 receptors.

Mechanism of action
Bradykinin is a peptide-based hormone that is formed locally in tissues, very often in response to a trauma. It increases vessel permeability, dilates blood vessels and causes smooth muscle cells to contract. Bradykinin plays an important role as the mediator of pain. Surplus bradykinin is responsible for the typical symptoms of inflammation, such as swelling, redness, overheating and pain </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 Sodium picosulfate 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 Cefiderocol and can you explain it in depth? [/INST] Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.In September 2020, cefiderocol (Fetroja) received FDA approval as supplemental New Drug Application (sNDA) for treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) when caused by Gram-negative bacteria resistant to other antibiotics.
Common side effects include diarrhea, infusion site reactions, constipation and rash.It is in the cephalosporin family of medications. Cefiderocol was approved for medical use in the United States in November 2019, and in the European Union in April 2020. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Cefiderocol is used to treat adults with complicated urinary tract infections, including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.In the United States, cefiderocol is indicated in adults 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.For the treatment of severe pneumonia (HABP and VABP), it is indicated in patients 18 years of age and older whose pneumonia is not responding to other, more commonly used antibiotics and is confirmed to be caused by one of the following Gram-negative organisms:

Acinetobacter baumannii complex
Escherichia coli
Enterobacter cloacae complex
Klebsiella pneumoniae
Pseudomonas aeruginosa
Serratia marcescensThis indication is supported by the 2018 APEKS-NP study, where cefiderocol was compared in nosocomial pneumonia caused by Gram-Negative bacteria to meropenem, where it was shown not to be inferior to meropenem. The primary endpoint of the study was all-cause mortality at day 14, where both antibiotics were shown to be almost equally effective. As of 2020, cefiderocol is indicated in the European Union for the treatment of infections due to aerobic Gram-negative bacteria in adults with limited treatment options.

Adverse effects
Cefiderocol may cause serious and life-threatening allergic reactions, severe diarrhea caused by C. difficile and seizures.An increased risk of  all-cause mortality was observed in people treated with cefiderocol as compared to other antibiotics in a separate clinical trial in critically ill people with multidrug-resistant Gram-negative bacterial infections. The higher all-cause mortality rate was observed in people treated for hospital-acquired/ventilator-associated pneumonia (i.e.nosocomial pneumonia), bloodstream infections, or sepsis. The cause of death has not been established, but some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities. The safety and efficacy of cefiderocol has not been established for the treatment of these types of infections.
Hence, cefiderocol label includes a warning regarding the higher all-cause mortality rate.Already in 2021, the first cases of antibiotic resistance were reported, and as of 2022 alarming proportions of up to 50% of resistance in some cohorts have been reported. In September 2022, the German RKI reported victims of the Ukraine War with cefidercol resistant surgical infections (Klebsiella specie. and Acinetobacter baumannii) who had been treated in Germany.

Pharmacology
Its structure is similar to cefepime and ceftazidime, but a chlorocatechol group at the end of the C-3 side chain further enhances its  β-lactamase  stability and renders it a siderophore.This means it enters into bacterial cells by binding to iron, which is actively transported into the bacterial cells. It was the first siderophore antibiotic to be approved by the U.S. Food and Drug Administration (FDA). It bypasses the bacterial porin channels by using the bacterias own iron-transport system for being transported in.

History
Cefiderocol received a Qualified Infectious Disease Product designation from the U.S. Food and Drug Administration (FDA) and was granted priority review. In November 2019, the FDA granted approval of cefiderocol to Shionogi & Co. as an antibacterial drug for treatment of adults 18 years of age or older with complicated urinary tract infections (cUTI), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.The safety and effectiveness of cefiderocol was demonstrated in a study (NCT02321800) of 448 participants with cUTIs. Of the participants who were administered cefiderocol, 72.6% had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% in participants who received an alternative antibiotic. The clinical response rates were similar between the two treatment groups. The trial included participants from Europe, United States and Mexico.In the clinical trial, participants with cUTI were chosen at random to receive cefiderocol, or another antibacterial drug called imipenem/cilastatin. Both treatments were given intravenously for 7–14 days and neither the participants nor the health care professionals knew which drugs were given until after the trial was complete </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 Sevoflurane and can you explain it in depth? [/INST] Sevoflurane is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the  tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

Medical uses
It is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia,  across all ages, as well as in veterinary medicine. Together with desflurane, sevoflurane is replacing isoflurane and halothane in modern anesthesia practice. It is often administered in a mixture of nitrous oxide and oxygen.
Sevoflurane has an excellent safety record, but is under review for potential hepatotoxicity, and may accelerate Alzheimers. There were rare reports involving adults with symptoms similar to halothane hepatotoxicity. Sevoflurane is the preferred agent for mask induction due to its lesser irritation to mucous membranes.
Sevoflurane was discovered by Ross Terrell and independently by Bernard M Regan. A detailed report of its development and properties appeared in 1975 in a paper authored by Richard Wallin, Bernard Regan, Martha Napoli and Ivan Stern. It was introduced into clinical practice initially in Japan in 1990 by Maruishi Pharmaceutical Co., Ltd. Osaka, Japan </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 Prestige Consumer Healthcare and can you explain it in depth? [/INST] Prestige Consumer Healthcare Inc. is an American company that markets and distributes over-the-counter healthcare and household cleaning products. It was formed by the merger of Medtech Products, Inc., Prestige Brands International, and the Spic and Span Company in 1996. The company is headquartered in Tarrytown, New York.Among the brands owned by Prestige Brands are Chloraseptic sore throat products, Clear Eyes, Compound W wart treatment, Dramamine motion sickness treatment, Efferdent denture care, Ludens throat drops, BC Powder and Goodys Headache Powder, Pediacare & Little Remedies childrens OTC products, Beano (dietary supplement), Comet and Spic and Span household cleaning products.
The companys CEO and president is Ron Lombardi, who replaced Matthew Mannelly on June 1, 2015.

History
Prestige Brands Holdings, Inc. was established in 1999 to acquire, revitalize, and line extend leading, often neglected but healthy brands that were considered non-core at major consumer products companies </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 Luliconazole 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 Abametapir and can you explain it in depth? [/INST] Abametapir, sold under the brand name Xeglyze, is a medication used for the treatment of head lice infestation in people six months of age and older.The most common side effects include skin redness, rash, skin burning sensation, skin inflammation, vomiting, eye irritation, skin itching, and hair color changes.Abametapir is a metalloproteinase inhibitor. Abametapir was approved for medical use in the United States in July 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses
Abametapir is indicated for the topical treatment of head lice infestation in people six months of age and older.

Contraindications
Abametapir has no contraindications according to the labeling.

Adverse effects
Common adverse effects are burning skin sensations (in 3% of patients), contact dermatitis (2%), skin redness (4%), rash (3%), and vomiting (2%).

Interactions
Abametapir blocks the liver enzymes CYP3A4, CYP2B6 and CYP1A2 in vitro. A single application of the drug may lead to increased blood concentrations of drugs that are metabolized by these enzymes.

Pharmacology
Mechanism of action
The drug inhibits enzymes called metalloproteinases. In lice, these enzymes play a role in egg development and survival; and consequently, blocking them will disrupt the lices life cycle.

Pharmacokinetics
After application to the scalp, part of the substance reaches the bloodstream, where most of it (91.3–92.3%) is bound to plasma proteins. It is metabolized primarily by the liver enzyme CYP1A2 to abametapir hydroxyl and further to abametapir carboxyl (see structure drawings). Abametapir carboxyl has a plasma protein binding of 96.0–97.5% and is the predominant of the three substances in the circulation, having a Cmax 30 times and an area under the curve (AUC) 250 times that of abametapir itself.The elimination half-life of abametapir is 21 hours. That of abametapir carboxyl is not well known; it is thought to be 71±40 hours or longer. It is not known whether the drug is eliminated via the urine or the faeces.

History
The U.S. Food and Drug Administration (FDA) approved abametapir based on evidence from two identical clinical trials of 699 participants with head lice. The trials were conducted at fourteen sites in the United States.The benefit and side effects of abametapir were evaluated in two clinical trials that enrolled participants with head lice who were at least six months old.About half of all enrolled participants was randomly assigned to abametapir and the other half to placebo. Abametapir lotion or placebo lotion were applied once as a ten-minute treatment to infested hair. The benefit of abametapir in comparison to placebo was assessed after 1, 7 and 14 days by comparing the counts of participants in each group who were free of live lice.

References
Further reading
Bowles VM, VanLuvanee LJ, Alsop H, Hazan L, Shepherd K, Sidgiddi S,  et al </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 Anthim 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 Trabectedin and can you explain it in depth? [/INST] Trabectedin, sold under the brand name Yondelis, is an antitumor chemotherapy medication for the treatment of advanced soft-tissue sarcoma and ovarian cancer.The most common adverse reactions include nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache.It is sold by Pharma Mar S.A. and Johnson and Johnson. It is approved for use in the European Union, Russia, South Korea and the United States. The European Commission and the U.S. Food and Drug Administration (FDA) granted orphan drug status to trabectedin for soft-tissue sarcomas and ovarian cancer.

Discovery and production
During the 1950s and 1960s, the National Cancer Institute carried out a wide-ranging program of screening plant and marine organism material. As part of that program, extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.
Separation and characterization of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984. Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies. Recently, 1774 the biosynthetic pathway responsible for producing the drug has been determined to come from Candidatus Endoecteinascidia frumentensis, a microbial symbiont of the tunicate.
The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success. Yields from the sea squirt are extremely low -  1 tonne of animals is needed to isolate 1 gram of trabectedin - and about 5 grams were believed to be needed for a clinical trial so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996.  This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.  The current supply is based on a semisynthetic process developed by PharmaMar starting from safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens. PharmaMar entered into an agreement with Johnson &  Johnson to market the compound outside Europe.

Approvals and indications
Trabectedin was first trialed in humans in 1996.

Soft tissue sarcoma
In 2007, the European Commission gave authorization for the marketing of trabectedin, under the trade name Yondelis, "for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents". The European Medicine Agencys evaluating committee, the Committee for Medicinal Products for Human Use (CHMP), observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized controlled trial against current best care, and that the clinical efficacy data were mainly based on patients with liposarcoma and leiomyosarcoma. However, the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease, the CHMP considered that marketing authorization could be granted under exceptional circumstances.  As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.Trabectedin is also approved in South Korea and Russia.In 2015, (after a phase III study comparing trabectedin with dacarbazine), the US FDA approved trabectedin (Yondelis) for the treatment of liposarcoma and leiomyosarcoma that is either unresectable or has metastasized. Patients must have received prior chemotherapy with an anthracycline.

Ovarian cancer and other
In 2008, the submission was announced of a registration dossier to the European Medicines Agency and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer.  In 2011, Johnson & Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional phase III study to be done in support of the submission.Trabectedin is also in phase II trials for prostate, breast, and paediatric cancers.

Structure
Trabectedin is composed of three tetrahydroisoquinoline moieties, eight rings including one 10-membered heterocyclic ring containing a cysteine residue, and seven chiral centers.

Biosynthesis
The biosynthesis of trabectedin in Candidatus Endoecteinascidia frumentensis starts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids. A tyrosine residue is modified by the enzymes EtuH, EtuM1, and EtuM2 to add a hydroxyl at the meta position of the phenol, and adding two methyl groups at the para-hydroxyl and the meta carbon position. This modified tyrosine reacts with the original substrate via a Pictet-Spengler reaction, where the amine group is converted to an imine by deprotonation, then attacks the free aldehyde to form a carbocation that is quenched by electrons from the methyl-phenol ring. This is done in the EtuA2 T-domain. This reaction is done a second time to yeid a dimer of modified tyrosine residues that have been further cyclized via Pictet-Spengler reaction, yielding a bicyclic ring moiety. The EtuO and EtuF3 enzymes continue to post-translationally modify the molecule, adding several functional groups and making a sulfide bridge between the original cysteine residue and the beta-carbon of the first tyrosine to form ET-583, ET-597, ET-596, and ET-594 which have been previously isolated </s>