<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 Elagolix and can you explain it in depth? [/INST] Elagolix, sold under the brand name Orilissa, is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication which is used in the treatment of pain associated with endometriosis in women. It is also under development for the treatment of uterine fibroids and heavy menstrual bleeding in women. The medication was under investigation for the treatment of prostate cancer and enlarged prostate in men as well, but development for these conditions was discontinued. Elagolix is taken by mouth once or twice per day. It can be taken for up to 6 to 24 months, depending on the dosage.Side effects of elagolix include menopausal-like symptoms such as hot flashes, night sweats, insomnia, amenorrhea, mood changes, anxiety, and decreased bone density, among others. Elagolix is a GnRH antagonist, or an antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic hormone gonadotropin-releasing hormone (GnRH). By blocking the GnRHR, it dose-dependently suppresses the gonadal production and hence circulating levels of sex hormones such as estradiol, progesterone, and testosterone. Elagolix is a short-acting GnRH antagonist, and can be used to achieve either partial or more substantial suppression of sex hormone levels. Reduced estrogen levels in the endometrium are responsible for the efficacy of elagolix in the treatment of endometriosis.Elagolix was first described in 2008 and was approved for medical use in July 2018. It has been described as a "second-generation" GnRH modulator due to its non-peptide and small-molecule nature and its oral activity. Unlike GnRH agonists and older GnRH antagonists, which are peptides and first-generation GnRH modulators, elagolix is not a GnRH analogue as it is not structurally related to GnRH. Elagolix was the first second-generation and orally active GnRH modulator to be introduced for medical use. The introduction of elagolix in the United States and Canada was followed by that of relugolix (brand name Relumina), the next second-generation GnRH antagonist, in Japan in January 2019. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses
Elagolix is used in the treatment of moderate to severe pain associated with endometriosis in premenopausal women. Endometriosis is a condition in which the endometrium, the inner lining of the uterus, grows outside of the uterus into surrounding tissues and causes symptoms such as pelvic pain and infertility. Around 10% of women may be affected by endometriosis. Elagolix significantly decreases symptoms of dysmenorrhea (menstrual pelvic pain), non-menstrual pelvic pain, and dyspareunia (pain during sexual intercourse) in women with endometriosis. The medication is used at a lower dosage of 150 mg once per day or at a higher dosage of 200 mg twice per day, depending on the severity of symptoms.The effectiveness of elagolix in the treatment of symptoms of endometriosis was demonstrated in the 6-month Elaris Endometriosis I and II (EM-I and EM-II) phase III clinical trials. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P < 0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to non-menstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P < 0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P = 0.003 and P < 0.001, respectively). The reductions in symptoms of endometriosis with elagolix resulted in an improved quality of life.The duration of use of elagolix in the treatment of endometriosis should be limited due to a progressive risk of bone loss, and the lowest effective dosage should be used. Elagolix can be used for up to 24 months at the 150 mg once per day dosage and for up to 6 months at the 200 mg twice per day dosage.Because of its relatively short duration, elagolix should be taken at approximately the same time each day. In the case of twice-daily administration, elagolix should be taken at approximate 12-hour intervals, for instance once in the morning and once at night. It can be taken with or without food.Elagolix is approved only for the treatment of endometriosis. Other approved and off-label uses of GnRH antagonists in general are the same as those of GnRHR desensitization therapy with GnRH agonists such as leuprorelin, and include uterine fibroids and breast cancer in premenopausal women, prostate cancer in men, precocious puberty in children, and hormone therapy in transgender adolescents and adults, among others.

Available forms
Elagolix is available in the form of Orilissa 150 and 200 mg oral tablets. The 150 mg tablets are light pink, oblong, and film-coated with "EL 150" debossed on one side, while the 200 mg tablets are light orange, oblong, and film-coated with "EL 200" debossed on one side. The inactive ingredients in the tablets include mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and a distinct color additive (carmine high tint in the 150 mg tablets and iron oxide red in the 200 mg tablets).

Contraindications
Contraindications of elagolix include pregnancy, known osteoporosis, severe hepatic impairment, and concomitant use with strong organic anion-transporting polypeptide (OATP) 1B1 inhibitors such as ciclosporin and gemfibrozil. Elagolix may increase the risk of miscarriage in early pregnancy. Women should avoid pregnancy while taking elagolix, for instance by using birth control, and should discontinue the medication if they become or wish to become pregnant. Elagolix should not be used in women with osteoporosis because it may increase the risk of further bone loss. Severe hepatic impairment is associated with 7-fold increased exposure to elagolix, which may increase the risk of bone loss. In women with moderate hepatic impairment, which is associated with 3-fold increased exposure to elagolix, the medication at 200 mg twice per day should not be used, while 150 mg once per day should be used for no more than 6 months. OATP1B1 inhibitors are likely to greatly increase exposure to elagolix similarly to moderate to severe hepatic impairment.Combined birth control is not contraindicated with elagolix, but because of the estrogen component, is expected to decrease the effectiveness of elagolix in the treatment of endometriosis, and hence is not recommended. Other forms of birth control, such as non-hormonal birth control, can be used instead. Elagolix is not contraindicated in women who are breastfeeding, but it is unknown whether the medication is excreted in breast milk or if it has adverse effects on milk production or the breastfed child. The use of elagolix in women who are breastfeeding should be considered carefully, weighing both benefits and risks.

Side effects
The side effects of elagolix are in general similar to menopausal symptoms. The most common side effects of elagolix (incidence ≥10%) are hot flashes, night sweats, headaches, nausea, and amenorrhea (cessation of menstruation). The next most frequent side effects of elagolix (incidence ≥5%) are insomnia, anxiety, arthralgia (joint pain), depression, and mood changes. Less common side effects of elagolix (incidence ≥3% and <5%) include decreased sex drive, diarrhea, abdominal pain, weight gain, dizziness, constipation, and irritability. Other common side effects of elagolix include decreased bone mineral density (BMD) and changes in the blood lipid profile. Rare but serious adverse effects that were observed during elagolix therapy in clinical trials included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%), though it is unknown if these were due to elagolix. Other serious adverse effects of elagolix may include bone loss, miscarriage, suicidality, and elevated liver enzymes. Elagolix was discontinued due to side effects by 5 to 10% of women in clinical trials, with the most common reasons being hot flashes or night sweats, nausea, and decreased BMD.Elagolix dose- and duration-dependently decreases BMD in premenopausal women with long-term therapy. After 6 months of treatment with elagolix, lumbar spine BMD was decreased by 0.3 to 1.3% with 150 mg once per day and by 2.5 to 3.1% with 200 mg twice per day. The decrease in BMD during elagolix therapy may not be fully reversible with discontinuation, as only partial recovery was observed 12 months after discontinuation of therapy. The cause of the decrease in BMD with elagolix is estrogen deficiency, and is analogous to that associated with postmenopause. The consequences of the effects of elagolix on BMD are unknown, but may be an increase in the risk of bone loss and fractures. This is why the duration of use of elagolix should be limited. In women with risk factors for bone loss and osteoporosis, such as a history of low-trauma fracture, assessment of BMD may be considered. Elagolix should not be used in premenopausal women with known osteoporosis. Supplementation with calcium and/or vitamin D during treatment with elagolix has not been studied, but may be beneficial for helping to maintain bone health.Elagolix decreases the amount, intensity, and duration of menstrual bleeding. Amenorrhea, the cessation of menstruation, was observed in 4 to 17% of women with 150 mg once per day and in 7 to 57% of women with 200 mg twice per day, compared to less than 1% of women given placebo. The decreased menstrual bleeding caused by elagolix may impede the ability to recognize pregnancy in a timely manner. Based on its mechanism of action, elagolix may increase the risk of miscarriage in early pregnancy, and so should be discontinued if pregnancy occurs. If pregnancy is suspected, pregnancy testing can be performed. Elagolix decreases the rate of ovulation and thereby decreases the likelihood of pregnancy, but has not been shown to be a fully effective contraceptive and should not be relied on to prevent pregnancy.The incidence of depression and mood changes in clinical trials with elagolix was increased in premenopausal women taking elagolix relative to placebo. Mood- and depression-type side effects such as altered mood, mood swings, depressed mood, depression, depressive symptoms, and tearfulness occurred in 3 to 6% of women with 150 mg per day and in 5 to 6% of women with 200 mg twice per day, compared to 2 to 3% in women given placebo. Suicidal ideation and behavior occurred in a few women (0.2–0.4%), with one suicide observed. People taking elagolix with new or existing depressive symptoms should be promptly evaluated to determine whether the benefits of treatment outweigh the risks. In those with new or existing depressive symptoms, referral to a mental health professional, as appropriate, may be warranted. Immediate medical attention should be sought for those with suicidal ideation and behavior.Elagolix dose-dependently produced elevated liver enzymes, including elevations of serum alanine aminotransferase of at least 3-fold the upper limit, in clinical trials. This was observed in one woman (0.2%) with 150 mg once per day and in five women (1.1%) with 200 mg twice per day, compared to one woman (0.1%) given placebo. Medical attention should be sought if signs or symptoms of liver injury, such as jaundice, are noticed. The lowest effective dosage of elagolix may be used to minimize the risk of liver problems, and in those who develop elevated liver enzymes during elagolix therapy, prompt evaluation should be done to determine whether the benefits of treatment outweigh the risks.

Overdose
In the event of an overdose of elagolix, the person should be monitored for any signs or symptoms of adverse reactions and should be treated on a symptomatic basis as needed. Elagolix has been assessed in clinical studies at a dose as high as a single administration of 1,200 mg, which resulted in concentrations of the medication that were 17 times higher than with the typical high clinical dosage of 200 mg twice per day. No adverse effects were mentioned. Chronic overdosage of elagolix may result in greater suppression of estradiol levels and a consequent increased risk of bone loss with long-term therapy.

Interactions
Elagolix has a number of potential drug interactions with other medications. Elagolix is a substrate of the cytochrome P450 (CYP450) enzyme CYP3A, and inhibitors and inducers of CYP3A4 may alter the metabolism of elagolix and increase or decrease its circulating levels. The strong CYP3A4 inhibitor ketoconazole has been found to increase peak levels of and total exposure to a single 150 mg dose of elagolix by about 2-fold. Paradoxically, rifampin, a strong inducer of CYP3A4 and other CYP450 enzymes, increased peak levels of and total exposure to a single 150 mg dose of elagolix as well. A single dose of rifampin increased peak levels of elagolix by 4.4-fold and total exposure by 5.6-fold, whereas continuous rifampin therapy increased peak levels of elagolix by 2-fold and total exposure by 1.7-fold. The use of elagolix at 200 mg twice per day concomitantly with rifampin is not recommended, whereas the concomitant use of elagolix at 150 mg once per day with rifampin should be limited to 6 months. No significant changes in exposure to elagolix were observed with concomitant administration of rosuvastatin (a substrate of OATP1B1, OATP1B3, and BCRP), sertraline (a moderate inhibitor of CYP2D6 and CYP2B6), or fluconazole (a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4).Elagolix is a substrate of the hepatic OATP1B1 transporter. Levels of elagolix have been found to be increased by 78% in people with a genotype characterized by reduced OATP1B1 transporter function. The concomitant use of elagolix with medications that inhibit OATP1B1 may increase elagolix levels, and the use of elagolix with strong OATP1B1 inhibitors like ciclosporin and gemfibrozil, which may markedly increase elagolix exposure, is contraindicated.Elagolix is a weak to moderate inducer of CYP3A, and may decrease levels of medications that are substrates of CYP3A4. In addition, elagolix is an inhibitor of P-glycoprotein, and may increase levels of medications that are substrates of P-glycoprotein, such as digoxin. Elagolix has been found to increase exposure to digoxin and ethinylestradiol, whereas it has been found to decrease exposure to rosuvastatin, midazolam, norethisterone, norelgestromin, and norgestrel.Because combined birth control pills and other forms of combined birth control contain an estrogen, and because elagolix treats endometriosis by decreasing estrogen levels in the endometrium, these form of hormonal birth control are likely and expected to decrease the effectiveness of elagolix in the treatment of this condition. The effect of progestogen-only birth control on the effectiveness of elagolix in endometriosis is unknown. However, progestogens are antiestrogenic in the uterus, and high-dose progestin therapy is known to be effective in the treatment of endometriosis similarly to GnRH antagonists. On the basis of limited clinical research, combined birth control pills have also been found to be effective in the treatment of endometriosis, but are likely not as effective as GnRH modulator monotherapy. It is advised that women use non-hormonal methods of birth control during elagolix therapy and for one week following discontinuation of elagolix.

Pharmacology
Pharmacodynamics
Elagolix acts as a potent and selective competitive antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic peptide hormone gonadotropin-releasing hormone (GnRH). As such, it is a GnRH antagonist. The affinity (KD) of elagolix for the GnRHR is 54 pM. By blocking the GnRHR in the pituitary gland, elagolix suppresses the GnRH-induced secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, and thereby decreases the production of sex hormones by the gonads. In women, elagolix dose-dependently suppresses the production of ovarian hormones including estradiol, progesterone, and testosterone, and thereby decreases the circulating levels of these hormones. In men, GnRH modulators suppress the testicular production of testosterone and estradiol, decreasing the circulating levels of these hormones similarly. Unlike previous GnRH agonists and antagonists, referred to collectively as GnRH analogues, elagolix is a non-peptide and small-molecule compound that can be taken orally.Estrogens like estradiol stimulate the growth of the endometrium, and thereby aggravate symptoms of endometriosis. By suppressing estrogen production and levels, elagolix decreases the growth of the endometrium and decreases endometriosis symptoms such as pelvic pain.Elagolix is a short-acting GnRH antagonist, with a terminal half-life of typically about 4 to 6 hours. Because of the short duration of elagolix in the body, the activation of the GnRHR by GnRH is not fully blocked throughout the day with once-daily administration of elagolix. As a result, gonadotropin and sex hormone levels are only partially suppressed when elagolix is taken once per day. In addition, the degree of suppression can be dose-dependently adjusted as needed, for instance with higher-dose twice-daily administration to achieve greater hormonal suppression. Because of its short duration in the body, the effects of elagolix are rapidly reversible upon discontinuation. In addition, due to its partial and incomplete suppression of estradiol levels, the side effects of elagolix, such as hot flashes and decreased BMD, are lower than with first-generation GnRH modulators.
In clinical trials, elagolix produced dose-dependent decreases in gonadotropin, estradiol, and progesterone levels in women. Median levels of estradiol were partially suppressed to 42 pg/mL (follicular phase levels) with 150 mg once daily and were fully or near-fully suppressed to 12 pg/mL (postmenopausal levels) with 200 mg twice daily. In a 21-day study in premenopausal women, the effects of elagolix on FSH levels were found to be maximal at a dosage of 300 mg twice per day or above, whereas its effects on LH and estradiol levels were maximal at a dosage of 200 mg twice per day or above. Levels of progesterone were maintained at anovulatory levels (<2 ng/mL) across the 21-day study period at dosages of elagolix of 100 mg twice per day and above. A dosage of elagolix of 400 mg twice per day appears to produce no greater suppression in gonadotropin or estradiol levels than a dosage of 300 mg twice per day in premenopausal women. Suppression of gonadotropin and sex hormone levels with elagolix occurs rapidly, within hours, and upon discontinuation of elagolix, gonadotropin and sex hormone levels remain suppressed for at least 12 hours, but show recovery within 24 to 48 hours. As a consequence of its suppression of gonadotropin and sex hormone levels, elagolix inhibits ovulation in women. Over the course of three menstrual cycles, the ovulation rate with elagolix was 50% at 150 mg once daily and 32% at 200 mg twice daily. Because ovulation is triggered by a surge in estradiol levels at mid-cycle, estrogen exposure during elagolix therapy might be greater around this time in some women.In addition to its activity as a GnRH antagonist, elagolix is a weak to moderate inducer of CYP3A and an inhibitor of P-glycoprotein. As a result, elagolix may affect the metabolism and/or transport of other medications, and this may contribute to drug interactions with elagolix.

Pharmacokinetics
Elagolix is taken by the oral route of administration, in contrast to other GnRH modulators. The oral bioavailability of elagolix in humans is not described in the Food and Drug Administration (FDA) label for the medication, but in animal research elagolix showed a low oral bioavailability of 5.8% in rats and 11% in monkeys. Following administration, elagolix is rapidly absorbed, with peak concentrations occurring after 0.5 to 1.5 hours. The drug accumulation ratio of elagolix at 150 mg once per day is 0.98 and at 200 mg twice per day is 0.89, indicating that it is not accumulated in the body with continuous administration. At steady state, peak levels of elagolix at 150 mg once per day are 574 ng/mL and at 200 mg twice per day are 774 ng/mL while area-under-the-curve levels of elagolix at 150 mg once per day are 1,292 ng•hour/mL and at 200 mg twice per day are 1,725 ng•hour/mL. A toxicology study found that levels of elagolix in women after a single dose of 1,200 mg were 17 times higher than in women taking 200 mg twice daily. Taking elagolix with a high-fat meal has been found to decrease its peak levels by 36% and its area-under-the-curve levels by 24%. In terms of distribution, the plasma protein binding of elagolix is 80% and its blood-to-plasma ratio is 0.6. The volume of distribution at steady state is 1,674 L at 150 mg once per day and 881 L at 200 mg twice per day.Elagolix is metabolized in the liver, with the major pathway being by CYP3A and minor pathways including by CYP2D6, CYP2C8, and UDP-glucuronosyltransferases. The terminal half-life of elagolix is typically about 4 to 6 hours. A study found that its half-life was 2.4 to 6.3 hours with a single dose and was 2.2 to 10.8 hours with continuous administration. The oral clearance of elagolix is 123 L/hour at 150 mg once per day and 144 L/hour at 200 mg twice per day. The major pathway of elimination of elagolix is hepatic metabolism. Elagolix is taken up from the circulation into the liver by the hepatic OATP1B1 carrier. In people with two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C; SLCO1B1 521 C/C genotype), plasma levels of elagolix have been found to be increased by 78% relative to in people with normal OATP1B1 function (SLCO1B1 521T/T genotype). The frequency of this reduced function OATP1B1 genotype is generally less than 5% in most racial and ethnic groups. Elagolix is excreted less than 3% in urine and 90% in feces.Exposure to elagolix is not affected by renal impairment or mild hepatic impairment, but is increased by approximately 3-fold in women with moderate hepatic impairment and by approximately 7-fold in women with severe hepatic impairment. There were no differences in the pharmacokinetics of elagolix between individuals of different racial and ethnic groups. Similarly, the pharmacokinetics of elagolix were unaffected by body weight and body mass index. Peak and area-under-the-curve levels of elagolix have been shown to be altered by CYP3A4 inhibitors like ketoconazole and CYP3A4 inducers like rifampin. Inhibitors of OATP1B1 may increase circulating levels of elagolix, and elagolix is considered to be contraindicated in combination with strong OATP1B1 inhibitors. Elagolix is a substrate of P-glycoprotein, but the effect of inhibitors and inducers of P-glycoprotein on the pharmacokinetics of elagolix is unknown. Elagolix itself is an inhibitor of P-glycoprotein.

Chemistry
Elagolix is a small-molecule and non-peptide compound. This is in contrast to GnRH analogues such as leuprorelin and cetrorelix, which are peptides and analogues of GnRH. Other small-molecule and non-peptide orally active GnRH antagonists besides elagolix include linzagolix, opigolix, relugolix, and sufugolix, although none of these compounds have been introduced for medical use at this time.Elagolix is used as elagolix sodium, the sodium salt of elagolix. It is a white to off white to light yellow powder. The compound is freely soluble in water. The chemical name of elagolix sodium is sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate. It has a molecular formula of C32H29F5N3O5Na and a molecular weight of 653.58 g/mol. The free acid form of elagolix has a molecular formula of C32H29F5N3O5 and a molecular weight of 631.60 g/mol.

History
Elagolix was first described in the literature in 2005. It was originally developed by the pharmaceutical company Neurocrine Biosciences, and was later developed together by Neurocrine Biosciences and AbbVie (previously Abbott Laboratories). In June 2010, Neurocrine Biosciences and Abbott announced a global agreement to develop and commercialize elagolix for the treatment of endometriosis. The medication completed phase III clinical trials for endometriosis in November 2016. Two phase III clinical trials, the Elaris Endometriosis I and II (EM-I and EM-II) studies, were conducted. The studies included almost 1,700 women, about 950 of whom were treated with elagolix. In September 2017, AbbVie filed a New Drug Application (NDA) for elagolix for the treatment of pain associated with endometriosis in the United States. The medication was approved by the FDA for the treatment of endometriosis-associated pain in the United States on 23 July 2018. It was the first new medication to be approved by the FDA for the treatment of endometriosis in more than a decade. Elagolix was the first member of a new class of GnRH modulators described as "second-generation" due to their non-peptide and small-molecule nature and oral activity to be marketed. A second member of this group, relugolix (brand name Relumina), was introduced in Japan in January 2019. In addition to endometriosis, elagolix is under development for the treatment of uterine fibroids and menorrhagia. It is in phase III clinical trials for these indications.

Society and culture
Generic names
Elagolix is the generic name of the drug and its INN and USAN. It is also known by its former developmental code names NBI-56418 and ABT-620.

Brand names
Elagolix is marketed under the brand name Orilissa.

Availability
Elagolix is available in the United States and Canada.  A similar medication, relugolix, is available in Japan.

Economics
Prior to its introduction, elagolix was estimated to cost about US$850 per month. It is not available as a generic medication.

Research
As of November 2018, elagolix in phase III clinical trials for the treatment of uterine fibroids (uterine leiomyoma) and menorrhagia (abnormally heavy bleeding during menstruation) in women. An efficacy and safety study of elagolix in combination with add-back estradiol, an estrogen, and norethisterone acetate, a progestin, for the treatment of menorrhagia associated with uterine fibroids in premenopausal women has been published. The medication was also under investigation for the treatment of prostate cancer and benign prostatic hyperplasia (enlarged prostate) in men, but development for these indications was discontinued.

References
Further reading
Ezzati M, Carr BR (January 2015). "Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain". Womens Health. 11 (1): 19–28. doi:10.2217/whe.14.68. PMID 25581052.
Melis GB, Neri M, Corda V, Malune ME, Piras B, Pirarba S, Guerriero S, Orrù M, DAlterio MN, Angioni S, Paoletti AM (May 2016). "Overview of elagolix for the treatment of endometriosis". Expert Opin Drug Metab Toxicol. 12 (5): 581–8. doi:10.1517/17425255.2016.1171316. PMID 27021205. S2CID 28684228.
Alessandro P, Luigi N, Felice S, Maria PA, Benedetto MG, Stefano A (April 2017). "Research development of a new GnRH antagonist (Elagolix) for the treatment of endometriosis: a review of the literature". Arch. Gynecol. Obstet. 295 (4): 827–832. doi:10.1007/s00404-017-4328-6. PMID 28255765. S2CID 26422467.
Perricos A, Wenzl R (September 2017). "Efficacy of elagolix in the treatment of endometriosis". Expert Opin Pharmacother. 18 (13): 1391–1397. doi:10.1080/14656566.2017.1359258. PMID 28737050. S2CID 32467159.
Surrey E, Taylor HS, Giudice L, Lessey BA, Abrao MS, Archer DF, Diamond MP, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Singh SS, Rechberger T, Agarwal SK, Duan WR, Schwefel B, Thomas JW, Peloso PM, Ng J, Soliman AM, Chwalisz K (July 2018). "Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies". Obstet Gynecol. 132 (1): 147–160. doi:10.1097/AOG.0000000000002675. PMID 29889764.
Taylor HS (July 2018). "Use of Elagolix in Gynaecology". J Obstet Gynaecol Can. 40 (7): 931–934. doi:10.1016/j.jogc.2018.01.004. PMID 29921430.
Lamb YN (September 2018). "Elagolix: First Global Approval". Drugs. 78 (14): 1501–1508. doi:10.1007/s40265-018-0977-4. PMC 6244606. PMID 30194661.
Vercellini P, Viganò P, Barbara G, Buggio L, Somigliana E (February 2019). "Elagolix for endometriosis: all that glitters is not gold". Hum. Reprod. 34 (2): 193–199. doi:10.1093/humrep/dey368 </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 Travoprost and can you explain it in depth? [/INST] Travoprost, sold under the brand name Travatan among others, is a medication used to treat high pressure inside the eye including glaucoma. Specifically it is used for open angle glaucoma when other agents are not sufficient. It is used as an eye drop. Effects generally occur within two hours.Common side effects include red eyes, blurry vision, eye pain, dry eyes, and change in color of the eyes. Other significant side effects may include cataracts. Use during pregnancy or breastfeeding is generally not recommended </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 Tioguanine and can you explain it in depth? [/INST] Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth.Common side effects include bone marrow suppression, liver problems and inflammation of the mouth. It is recommended that liver enzymes be checked weekly when on the medication. People with a genetic deficiency in thiopurine S-methyltransferase are at higher risk of side effects. Avoiding pregnancy when on the medication is recommended for both males and females. Tioguanine is in the antimetabolite family of medications. It is a purine analogue of guanine and works by disrupting DNA and RNA.Tioguanine was developed between 1949 and 1951. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Acute leukemias in both adults and children
Chronic myelogenous leukemia
Inflammatory bowel disease, especially ulcerative colitis
Psoriasis

Side effects
Leukopenia and neutropenia
Thrombocytopenia
Anemia
Anorexia
Nausea and vomiting
Hepatotoxicity: this manifests as:

Hepatic veno-occlusive disease
The major concern that has inhibited the use of thioguanine has been veno-occlusive disease (VOD) and its histological precursor nodular regenerative hyperplasia (NRH). The incidence of NRH with thioguanine was reported  as between 33 and 76%. The risk of ensuing VOD is serious and frequently irreversible so this side effect has been a major concern.
However, recent evidence using an animal model for thioguanine-induced NRH/VOD has shown that, contrary to previous assumptions, NRH/VOD is dose dependent and the mechanism for this has been demonstrated. This has been confirmed in human trials, where thioguanine has proven to be safe but efficacious for coeliac disease when used at doses below those commonly prescribed. This has led to a revival of interest in thioguanine because of its higher efficacy and faster action compared to other thiopurines and immunosuppressants such as mycophenylate.

Contraindications
Pregnancy
Lactation: The safety warning against breastfeeding may have been a conservative assessment, but research evidence suggests that thiopurines do not enter breastmilk.

Interactions
Cancers that do not respond to treatment with mercaptopurine do not respond to thioguanine. On the other hand, some cases of IBD that are resistant to mercaptopurine (or its pro-drug azathioprine) may be responsive to thioguanine.

Pharmacogenetics
The enzyme thiopurine S-methyltransferase (TPMT) is responsible for the direct inactivation of thioguanine to its methylthioguanine base – this methylation prevents thioguanine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving thioguanine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT activity, allowing for the adjustment of thiopurine dose or avoidance of the drug entirely. The FDA-approved drug label for thioguanine notes that patients who are TPMT-deficient may be prone to developing myelosuppression and that laboratories offer testing for TPMT deficiency. Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care.

Metabolism and pharmacokinetics
A single oral dose of thioguanine has incomplete metabolism, absorption and high interindividual variability. The bioavailability of thioguanine has an average of 30% (range 14-46%). The maximum concentration in plasma after a single oral dose is attained after 8 hours.
Thioguanine, like other thiopurines, is cytotoxic to white cells; as a result it is immunosuppressive at lower doses and anti-leukemic/anti-neoplastic at higher doses. Thioguanine is incorporated into human bone marrow cells, but like other thiopurines, it is not known to cross the blood-brain barrier. Thioguanine cannot be demonstrated in cerebrospinal fluid, similar to the closely related compound 6-mercaptopurine which also cannot penetrate to the brain.
The plasma half-life of thioguanine is short, due to the rapid uptake into liver and blood cells and conversion to 6-TGN. The median plasma half-life of 80-minutes with a range of 25–240 minutes. Thioguanine is excreted primarily through the kidneys in urine, but mainly as a metabolite, 2-amino-6-methylthiopurine.  However, the intra-cellular thio-nucleotide metabolites of thioguanine (6-TGN) have longer half-lives and can therefore be measured after thioguanine is eliminated from the plasma.
Thioguanine is catabolized (broken down) via two pathways. One route is through the deamination by the enzyme guanine deaminase to 6-thioxanthine, which has minimal anti-neoplastic activity, then by oxidation by xanthine oxidase of the thioxanthine to thiouric acid. This metabolic pathway is not dependent on the efficacy of xanthine oxidase, so that the inhibitor of xanthine oxidase, the drug allopurinol, does not block the breakdown of thioguanine, in contrast to its inhibition of the breakdown of the related thiopurine 6-mercaptopurine. The second pathway is the methylation of thioguanine to 2-amino-6-methylthiopurine, which is minimally effective as an anti-neoplastic and significantly less toxic than thioguanine. This pathway also is independent of the enzyme activity of xanthine oxidase.

Mechanism of action
6-Thioguanine is a thio analogue of the naturally occurring purine base guanine. 6-thioguanine utilises the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) to be converted to 6-thioguanosine monophosphate (TGMP). High concentrations of TGMP may accumulate intracellularly and hamper the synthesis of guanine nucleotides via the enzyme Inosine monophosphate dehydrogenase (IMP dehydrogenase), leading to DNA mutations.TGMP is converted by phosphorylation to thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP). Simultaneously deoxyribosyl analogs are formed, via the enzyme ribonucleotide reductase. The TGMP, TGDP and TGTP are collectively named 6-thioguanine nucleotides (6-TGN). 6-TGN are cytotoxic to cells by: (1) incorporation into DNA during the synthesis phase (S-phase) of the cell; and (2) through inhibition of the GTP-binding protein (G protein) Rac1, which regulates the Rac/Vav pathway.

Chemistry
It is a pale yellow, odorless, crystalline powder.

Names
Tioguanine (INN, BAN, AAN), or thioguanine (USAN).
Thioguanine is administered by mouth (as a tablet – Lanvis).

References
Further reading
Dean L (2012) </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 Fidaxomicin and can you explain it in depth? [/INST] Fidaxomicin, sold under the brand name Dificid among others, is the first member of a class of narrow spectrum macrocyclic antibiotic drugs called tiacumicins. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.
Fidaxomicin is minimally absorbed into the bloodstream when taken orally, is bactericidal, and selectively eradicates pathogenic Clostridioides difficile with relatively little disruption to the multiple species of bacteria that make up the normal, healthy intestinal microbiota. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridioides difficile infection.It is marketed by Merck, which acquired Cubist Pharmaceuticals in 2015, and had in turn bought the originating company, Optimer Pharmaceuticals.  It is used for the treatment of Clostridioides difficile infection, which is also known as Clostridioides difficile-associated diarrhea or Clostridioides difficile-associated illness (CDI), and can develop into Clostridioides difficile colitis and pseudomembranous colitis.
Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patients clinical status. It is currently one of the most expensive antibiotics approved for use. A standard course costs upwards of £1350.

Mechanism
Fidaxomicin binds to and prevents movement of the "switch regions" of bacterial RNA polymerase. Switch motion occurs during the opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but is especially important in the opening of double-stranded DNA during the initiation of transcription. It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria, especially clostridia.  The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.

Clinical trials
Good results were reported by the company in 2009, from a North American Phase III clinical trial comparing it with oral vancomycin for the treatment of Clostridioides difficile infection.  The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin) </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 Anagrelide and can you explain it in depth? [/INST] Anagrelide (Agrylin/Xagrid, Shire and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of essential thrombocytosis (also known as essential thrombocythemia), or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.Anagrelide controlled release (GALE-401) is in phase III clinical trials by Galena Biopharma for the treatment of essential thrombocytosis.

Medical uses
Anagrelide is used to treat essential thrombocytosis, especially when the current treatment of the patient is insufficient. Essential thrombocytosis patients who are suitable for anagrelide often meet one or more of the following factors:
age over 60 years
platelet count over 1000×109/L
a history of thrombosisAccording to a 2005 Medical Research Council randomized trial, the combination of hydroxyurea with aspirin is superior to the combination of anagrelide and aspirin for the initial management of essential thrombocytosis.  The hydroxyurea arm had a lower likelihood of myelofibrosis, arterial thrombosis, and bleeding, but it had a slightly higher rate of venous thrombosis.  Anagrelide can be useful in times when hydroxyurea proves ineffective.

Side-effects
Common side effects are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea.
The same MRC trial mentioned above also analyzed the effects of anagrelide on bone marrow fibrosis, a common feature in patients with myelofibrosis. The use of anagrelide was associated with a rapid increase in the degree of reticulin deposition (the mechanism by which fibrosis occurs), when compared to those in whom hydroxyurea was used. Patients with myeloproliferative conditions are known to have a very slow and somewhat variable course of marrow fibrosis increase </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 Rufinamide and can you explain it in depth? [/INST] Rufinamide is an anticonvulsant medication.  It is used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders </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 Diosmin and can you explain it in depth? [/INST] Diosmin (diosmetin 7-O-rutinoside), a flavone glycoside of diosmetin, is manufactured from citrus fruit peels as a phlebotonic non-prescription dietary supplement used to aid treatment of hemorrhoids or chronic venous diseases, mainly of the legs.

Uses
Diosmin is a dietary supplement used to aid treatment of hemorrhoids and venous diseases, i.e., chronic venous insufficiency including spider and varicose veins, leg swelling (edema), stasis dermatitis and venous ulcers. The mechanism of action of Diosmin and other phlebotonics is undefined, and clinical evidence of benefit is limited.  Diosmin is not recommended for treating the rectal mucosa, skin irritations, or wounds, and should not be used to treat dermatitis, eczema, or urticaria </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 Brincidofovir and can you explain it in depth? [/INST] Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses, as well as oral bioavailability.The most common side effects include diarrhea, nausea, vomiting, and abdominal pain.Brincidofovir was approved for medical use in the United States in June 2021.

Medical uses
Brincidofovir is indicated for the treatment of human smallpox disease caused by variola virus.

Mechanism of Action
Brincidofovir is a pro-drug that is composed of cidofovir, conjugated with a lipid molecule. The lipid aspect of the molecule takes on the action of endogenous lysopghosphatidyl choline, which then is able to enter cells in the body which are infected with smallpox. Once the infected cell takes in the drug, the drug cleaves to generate cidofovir. Cidofovir is then consequently phosphorylated to yield Cidofovir Diphosphate, which is the active drug.Cidofovir diphosphate arises from two key mechanisms. Firstly, cidofovir diphosphate inhibits the variola viruss DNA-polymerase mediated DNA synthesis.The second mechanism is that the drug acts as an acyclic nucleotide and incorporates itself into the viral DNA chain, which then stops viral DNA synthesis.

Pharmacokinetics
The oral bioavailability of Brincidofovir is 13.4% as a tablet and 16.8% in a suspension. The metabolism of the drug is as such: once the drug enters the target infected cell, Brincidofovirs phosphodiester bond is then hydrolyzed to generate cidofovir which is then phosphorylated to the active cidofovir diphosphate. The volume of distribution of the drug is 1230 L. Brincidofovir is almost entirely absorbed in plasma.

History
Because smallpox is eradicated, the effectiveness of brincidofovir was studied in animals infected with viruses that are closely related to the variola virus. Effectiveness was determined by measuring animals survival at the end of the studies.Safety information to support approval of brincidofovir was derived from clinical trials of the drug for a non-smallpox indication, primarily from patients who received hematopoietic stem cell transplants.The U.S. Food and Drug Administration (FDA) granted the application for brincidofovir priority review, fast track, and orphan drug designations. The FDA approved brincidofovir under the agencys Animal Rule, which allows findings from adequate and well-controlled animal efficacy studies to serve as the basis of an approval when it is not feasible or ethical to conduct efficacy trials in humans.

Ethical considerations
Brincidofovir (CMX001) was the subject of widespread social media campaigning in 2014, which was then picked up by national news sources about a boy with an adenovirus infection following a bone marrow transplant.  The family requested legal access to the still-unapproved drug outside of any clinical trial, and Chimerix initially denied the request.  After a short and intense media campaign, Chimerix got permission from the FDA to start a limited open-label trial which allowed the boy to receive the drug.  This media event sparked a debate on the ethics of using social media, the allocation of limited resources of a small company, and the emphasis on the individual over the group. The new use of any drug has the potential to interfere with the process to get the drug approved and widely marketed, through means such as consuming limited staff time that may be needed elsewhere – staff time that has the potential to save thousands of lives in the long-term, rather than one life now – overwhelming manufacturing capabilities, or by causing adverse effects or even death.  These adverse events are more likely during these programs, because the people seeking access are usually much sicker than most, and problems experienced by these people can result in an unfavorable and inaccurate perception of the drugs safety profile.  In this case, the boy recovered from the infection in 2014, and died in 2016 from complications of cancer.Brincidofovir is one of several experimental drugs administered to a small number of patients to treat Ebola virus disease during the 2014 outbreak. The WHO published a report on the ethics of using unregistered interventions to treat Ebola, where they concluded that "In the particular context of the current Ebola outbreak in West Africa, it is ethically acceptable to offer unproven interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans as potential treatment or prevention."

Research
Brincidofovir is under investigation for the treatment of cytomegalovirus, adenovirus, poxvirus, and ebolavirus infections. It has been used off-label for the treatment of monkeypox.

Adenovirus and cytomegalovirus
As of 2014, brincidofovir is in Phase III clinical trials for use in humans against cytomegalovirus and adenovirus. Preliminary safety data from a database of 1000 patients supported progression into later phase trials, Chimerix announced in December 2015 that the Phase III trials for use of the drug in preventing cytomegalovirus infection in stem cell transplant patients had failed, and in February 2016 shut down two other late-stage trials for use of the drug in preventing infection after kidney transplants. Brincidofovir is not yet FDA approved for adenovirus or cytomegalovirus due to lack of efficacy in clinical trials. In a trial of brincidofovir for patients with CMV brincidofovir was associated with a 15.5% week 24 all-cause mortality compared with 10.1% among placebo recipients. Additionally brincidofovir was associated with increased serious adverse events (57.1% versus 37.6%) compared with placebo. Brincidofovir was initially offered via an FDA expanded access trial; however as of May 9, 2019, Chimerix discontinued clinical trials of brincidofovir for the treatment of adenovirus and discontinued the expanded access program in 2019.

Ebola
After initial studies by the Centers for Disease Control and Prevention (CDC, Atlanta, GA, USA) in cell culture models, on October 6, 2014, Chimerix received an FDA authorization for emergency investigational new drug applications of brincidofovir for the treatment of Ebola virus disease. Brincidofovir was administered to the first patient diagnosed in the Ebola virus disease outbreak in the US in 2014. The patient was given the drug starting six days after hospital admission when he was already critically ill; he died four days later. Brincidofovir was also given to Ebola patient Ashoka Mukpo at the Nebraska Medical Center, who had developed the disease and then was pronounced Ebola-free and released from the center on 22 October 2014.In October 2014, Chimerix reported it had been given approval by the FDA to start Phase 2 trials in patients infected with ebolaviruses for brincidofovirs safety, tolerability, and efficacy. Organised by a team of scientists at the University of Oxford, including Peter Horby, Jake Dunning, Laura Merson and Trudie Lang, a trial commenced during January 2015 in Liberia, but was subsequently discontinued. Because of a lack of suitable subjects in Liberia, Oxford University and Médecins Sans Frontières planned to extend the trial to Sierra Leone, where there were still Ebola cases; but on the 30th of January 2015, the manufacturer decided to withdraw support for the trial and end discussion of future trials.

Animals
In animal trials brincidofovir has shown activity against cytomegalovirus, adenoviruses, BK virus, poxviruses, and herpes simplex viruses </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 Iron(III) pyrophosphate and can you explain it in depth? [/INST] Iron(III) pyrophosphate is an inorganic chemical compound with the formula Fe4(P2O7)3.

Synthesis
Anhydrous iron(III) pyrophosphate can be prepared by heating the mixture of iron(III) metaphosphate and iron(III) phosphate under oxygen with the stoichiometric ratio 1:3 </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 Lactulose and can you explain it in depth? [/INST] Lactulose is a non-absorbable sugar used in the treatment of constipation and hepatic encephalopathy. It is used by mouth for constipation and either by mouth or in the rectum for hepatic encephalopathy. It generally begins working after 8–12 hours, but may take up to 2 days to improve constipation.Common side effects include abdominal bloating and cramps. A potential exists for electrolyte problems as a result of the diarrhea it produces. No evidence of harm to the baby has been found when used during pregnancy. It is generally regarded as safe during breastfeeding. It is classified as an osmotic laxative.Lactulose was first made in 1929, and has been used medically since the 1950s. It is on the World Health Organizations List of Essential Medicines. It is available as a generic and brand-name product.  Lactulose is made from the milk sugar lactose, which is composed of two simple sugars, galactose and glucose.

History
In 1957, Peitele discovered that lactulose is a bifidobacterium proliferation factor. In 1964, Hoffman found that only bifidobacteria, Lactobacillus and Streptococcus could metabolise lactulose into lactic acid and acetic acid. In 1966, Baicier found that lactulose can promote the growth of basophilic gram-positive bacteria lacking urease (e.g. Escherichia coli) and reduce ammonia production. It has been proven that lactulose reduces blood ammonia, and it has been successfully used in the treatment of hepatic encephalopathy. In 1979, Nianmoleyou treated viral hepatitis with lactulose and he found that lactulose has the effect of reducing plasma endotoxin. From 1980 to 1981, Leicier found that the limulus test agglutination reaction of lactulose inhibits endotoxin in vitro, alleviating the liver injury of rats induced by D-amino galactose. He believed that lactulose had anti-endotoxin activity, meaning that and it can be used in the treatment of liver and kidney syndrome.

Medical uses
Constipation
Lactulose is used in the treatment of chronic constipation in patients of all ages as a long-term treatment. The dosage of lactulose for chronic idiopathic constipation is adjusted depending on the constipation severity and desired effect, from a mild stool softener to causing diarrhea. Lactulose is contraindicated in case of galactosemia, as most preparations contain the monosaccharide galactose due to its synthesis process.Lactulose may be used to counter the constipating effects of opioids, and in the symptomatic treatment of hemorrhoids as a stool softener.Lactulose is commonly prescribed for children who develop fear of their bowel movements and are withholders. This is because lactulose, when dosed in the proper amount, causes a bowel movement that is impossible to retain for very long. Lactulose is also used for the elderly because of its gentle and consistent results.

Hyperammonemia
Lactulose is useful in treating hyperammonemia (high blood ammonia), which can lead to hepatic encephalopathy. Lactulose helps trap the ammonia (NH3) in the colon and bind to it.  It does this by using gut flora to acidify the colon, transforming the freely diffusible ammonia into ammonium ions (NH+4), which can no longer diffuse back into the blood. It is also useful for preventing hyperammonemia caused as a side effect of administration of valproic acid.

Small intestine bacterial overgrowth
Lactulose is used as a test of small intestine bacterial overgrowth (SIBO). Recently, the reliability of it for diagnosing SIBO has been seriously questioned. A large amount of it is given with subsequent testing of molecular hydrogen gas in the breath. The test is positive if an increase in exhaled hydrogen occurs before that which would be expected by normal  digestion by the normal gut flora in the colon. An earlier result has been hypothesized to indicate digestion occurring within the small intestine. An alternate explanation for differences in results is the variance in small bowel transit time among tested subjects.

Pregnancy
No evidence of harm to the baby has been found when used during pregnancy. It is generally regarded as safe during breastfeeding.

Side effects
Common side effects of lactulose are abdominal cramping, borborygmus, and flatulence. In normal individuals, overdose is considered uncomfortable, but not life-threatening. Uncommon side effects are nausea and vomiting.  In sensitive individuals, such as the elderly or people with reduced kidney function, excess lactulose dosage can result in dehydration and electrolyte disturbances such as low magnesium levels.  Ingestion of lactulose does not cause a weight gain because it is not digestible, with no nutritional value. Although lactulose is less likely to cause dental caries than sucrose, as a sugar, a potential for this exists. This should be taken into consideration when taken by people with a high susceptibility to this condition.

Mechanism of action
It is a disaccharide formed from one molecule each of the simple sugars (monosaccharides) fructose and galactose. Lactulose is not normally present in raw milk, but is a product of heat processes: the greater the heat, the greater amount of this substance (from 3.5 mg/L in low-temperature pasteurized milk to 744 mg/L in in-container sterilized milk). It is produced commercially by isomerization of lactose.Lactulose is not absorbed in the small intestine nor broken down by human enzymes, thus stays in the digestive bolus through most of its course, causing retention of water through osmosis leading to softer, easier-to-pass stool. It has a secondary laxative effect in the colon, where it is fermented by the gut flora, producing metabolites which have osmotic powers and peristalsis-stimulating effects (such as acetate), but also methane associated with flatulence.Lactulose is metabolized in the colon by bacterial flora into short-chain fatty acids, including lactic acid and acetic 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 Castor oil and can you explain it in depth? [/INST] Castor oil is a vegetable oil pressed from castor beans.
It is a colourless or pale yellow liquid with a distinct taste and odor. Its boiling point is 313 °C (595 °F) and its density is 0.961 g/cm3. It includes a mixture of triglycerides in which about 90% of fatty acids are ricinoleates. Oleic acid and linoleic acid are the other significant components.
Castor oil and its derivatives are used in the manufacturing of soaps, lubricants, hydraulic and brake fluids, paints, dyes, coatings, inks, cold-resistant plastics, waxes and polishes, nylon, and perfumes.

Etymology
The name probably comes from a confusion between the Ricinus plant that produces it and another plant, the Vitex agnus-castus. An alternative etymology, though, suggests that it was used as a replacement for castoreum.

Composition
Castor oil is well known as a source of ricinoleic acid, a monounsaturated, 18-carbon fatty acid. Among fatty acids, ricinoleic acid is unusual in that it has a hydroxyl functional group on the 12th carbon atom. This functional group causes ricinoleic acid (and castor oil) to be more polar than most fats. The chemical reactivity of the alcohol group also allows chemical derivatization that is not possible with most other seed oils. Because of its ricinoleic acid content, castor oil is a valuable chemical in feedstocks, commanding a higher price than other seed oils. As an example, in July 2007, Indian castor oil sold for about US$0.90/kg ($0.41/lb), whereas U.S. soybean, sunflower, and canola oils sold for about $0.30/kg ($0.14/lb).

Uses
Annually, 270,000–360,000 tonnes (600–800 million pounds) of castor oil are produced for a variety of uses.

Food and preservative
In the food industry, food-grade castor oil is used in food additives, flavorings, candy (e.g., polyglycerol polyricinoleate in chocolate), as a mold inhibitor, and in packaging. Polyoxyethylated castor oil (e.g., Kolliphor EL) is also used in the food industries.In India, Pakistan, and Nepal, food grains are preserved by the application of castor oil. It stops rice, wheat, and pulses from rotting. For example, the legume pigeon pea is commonly available coated in oil for extended storage.

Traditional medicine
Use of castor oil as a laxative is attested to in the circa 1550 BCE Ebers Papyrus, and was in use several centuries earlier.Although used in traditional medicine to induce labor in pregnant women, there is no clinical evidence that castor oil is effective for dilating the cervix or inducing labor.According to the American Cancer Society, "available scientific evidence does not support claims that castor oil on the skin cures cancer or any other disease."

Skin and hair care
Castor oil has been used in cosmetic products included in creams and as a moisturizer. Small amounts of castor oil are frequently used in cold-process soap to increase lathering in the finished bar. It also has been used to enhance hair conditioning in other products and for supposed anti-dandruff properties.

Coatings
Castor oil is used as a biobased polyol in the polyurethane industry. The average functionality (number of hydroxyl groups per triglyceride molecule) of castor oil is 2.7, so it is widely used as a rigid polyol and in coatings. One particular use is in a polyurethane concrete where a castor-oil emulsion is reacted with an isocyanate (usually polymeric methylene diphenyl diisocyanate) and a cement and construction aggregate. This is applied fairly thickly as a slurry, which is self-levelling. This base is usually further coated with other systems to build a resilient floor.Castor oil is not a drying oil, meaning that it has a low reactivity with air compared with oils such as linseed oil and tung oil. Dehydration of castor oil yields linoleic acids, which do have drying properties. In this process, the OH group on the ricinoleic acid along with a hydrogen from the next carbon atom are removed yielding a double bond which then has oxidative cross-linking properties yielding the drying oil.

Precursor to industrial chemicals
Castor oil can react with other materials to produce other chemical compounds that have numerous applications. Transesterification followed by steam cracking gives undecylenic acid, a precursor to specialized polymer nylon 11, and heptanal, a component in fragrances. Breakdown of castor oil in strong base gives 2-octanol, both a fragrance component and a specialized solvent, and the dicarboxylic acid sebacic acid. Hydrogenation of castor oil saturates the alkenes, giving a waxy lubricant. Castor oil may be epoxidized by reacting the OH groups with epichlorohydrin to make the triglycidyl ether of castor oil which is useful in epoxy technology. This is available commercially as Heloxy 505.The production of lithium grease consumes a significant amount of castor oil. Hydrogenation and saponification of castor oil yields 12-hydroxystearic acid, which is then reacted with lithium hydroxide or lithium carbonate to give high-performance lubricant grease.Since it has a relatively high dielectric constant (4.7), highly refined and dried castor oil is sometimes used as a dielectric fluid within high-performance, high-voltage capacitors.

Lubrication
Vegetable oils such as castor oil are typically unattractive alternatives to petroleum-derived lubricants because of their poor oxidative stability. Castor oil has better low-temperature viscosity properties and high-temperature lubrication than most vegetable oils, making it useful as a lubricant in jet, diesel, and racing engines. The viscosity of castor oil at 10 °C is 2,420 centipoise, but it tends to form gums in a short time, so its usefulness is limited to engines that are regularly rebuilt, such as racing engines. Lubricant company Castrol took its name from castor oil.
Castor oil has been suggested as a lubricant for bicycle pumps because it does not degrade natural rubber seals.

Early aviation and aeromodelling
Castor oil was the preferred lubricant for rotary engines, such as the Gnome engine after that engines widespread adoption for aviation in Europe in 1909. It was used almost universally in rotary-engined Allied aircraft in World War I. Germany had to make do with inferior ersatz oil for its rotary engines, which resulted in poor reliability.The methanol-fueled, two-cycle, glow-plug engines used for aeromodelling, since their adoption by model airplane hobbyists in the 1940s, have used varying percentages of castor oil as lubricants. It is highly resistant to degradation when the engine has its fuel-air mixture leaned for maximum engine speed. Gummy residues can still be a problem for aeromodelling powerplants lubricated with castor oil, however, usually requiring eventual replacement of ball bearings when the residue accumulates within the engines bearing races. One British manufacturer of sleeve-valved four-cycle model engines has stated the "varnish" created by using castor oil in small percentages can improve the pneumatic seal of the sleeve valve, improving such an engines performance over time.

Turkey red oil
Turkey red oil, also called sulphonated (or sulfated) castor oil, is made by adding sulfuric acid to vegetable oils, most notably castor oil. It was the first synthetic detergent after ordinary soap. It is used in formulating lubricants, softeners, and dyeing assistants.

Biodiesel
Castor oil, like currently less expensive vegetable oils, can be used as feedstock in the production of biodiesel. The resulting fuel is superior for cold winters, because of its exceptionally low cloud point and pour point.Initiatives to grow more castor for energy production, in preference to other oil crops, are motivated by social considerations. Tropical subsistence farmers would gain a cash crop.

Punishment
Some parents punished children with a dose of castor oil. Physicians recommended against the practice because they did not want medicines associated with punishment.A heavy dose of castor oil could be used as a humiliating punishment for adults. Colonial officials used it in the British Raj (India) to deal with recalcitrant servants. Belgian military officials prescribed heavy doses of castor oil in Belgian Congo as a punishment for being too sick to work.The most famous use as punishment came in Fascist Italy under Benito Mussolini. It was a favorite tool used by the Blackshirts to intimidate and humiliate their opponents. Political dissidents were force-fed large quantities of castor oil by Fascist squads </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 Cangrelor and can you explain it in depth? [/INST] Cangrelor, sold under the brand name Kengreal in the United States, CANREAL in India ( MSN Labs ) and Kengrexal in the European Union) is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.
Poor interim results led to the abandonment of the two CHAMPION clinical trials in mid-2009.  The BRIDGE study, for short term use prior to surgery, continues. The CHAMPION PHOENIX trial was a randomized study of over 11,000 patients published in 2013.  It found usefulness of cangrelor in patients getting cardiac stents.  Compared with clopidogrel given around the time of stenting, intravenous ADP-receptor blockade with cangrelor significantly reduced the rate of stent thrombosis and myocardial infarction. Reviewers have questioned the methodology of the trial.

Medical use
According to recent phase 3 randomized trials, a cangrelor–clopidogrel combination is safe and has been found to be more effective than standard clopidogrel treatment at reducing ischemic events in the heart, without increasing major bleeding in the treatment of stenotic coronary arteries. The advantages of this drug combination are most prominent in patients with myocardial infarction.Available antiplatelet drugs have delayed onset and offset of action. Since cangrelors effects are immediate and quickly reversed, it is a more desirable drug for elective treatment of stenotic coronary arteries, high risk acute coronary syndromes treated with immediate coronary stenting, and for bridging those surgery patients who require P2Y12 inhibition.Current evidence regarding cangrelor therapy is limited by the lack studies assessing cangrelor administration in conjunction with either prasugrel or ticagrelor.Recently, its been approved for adult patients undergoing percutaneous coronary intervention (PCI).

Pharmacology
Cangrelor is a high-affinity, reversible inhibitor of P2Y12 receptors that causes almost complete inhibition of ADP-induced platelet aggregate. It is a modified ATP derivative stable to enzymatic degradation. It does not require metabolic conversion to an active metabolite. This allows cangrelors immediate effect after infusion, and the therapeutic effects can be maintained with continuous infusion </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 Tolvaptan and can you explain it in depth? [/INST] Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca. Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.The U.S. Food and Drug Administration (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of polycystic kidney disease. The FDA granted Jynarque an orphan drug designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.Tolvaptan is available as a generic medication.

Medical uses
Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.Tolvaptan (Jynarque) is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).Tolvaptan phosphate is a prodrug of tolvaptan, developed for intravenous administration.   Tolvaptan phosphate is converted into the active drug tolvaptan in the human body following administration.

Side effects
The FDA has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure </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 Faricimab and can you explain it in depth? [/INST] Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody, to target both vascular endothelial growth factor (VEGF), and angiopoietin 2 (Ang-2) inhibitor. By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection (injection into the eye) by an ophthalmologist.Faricimab was developed by Roche. Faricimab was approved for medical use in the United States in January 2022, and in the European Union in September 2022.

Medical uses
Faricimab is indicated for treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME).

Adverse effects
The most common adverse reaction reported in people receiving faricimab include conjunctival bleeding.

Contraindications
Contraindications to injection of faricimab include active infection in or around the eye, active inflammation in the eye (uveitis), and prior allergic reactions to receiving the drug (hypersensitivity).

Special populations
Pregnancy
There are no adequate and well-controlled studies of faricimab administration in pregnant women.

Breast feeding
There is no information regarding faricimab accumulation in breast milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, the drug company states that many drugs are transferred in human milk with the potential for absorption and adverse reactions in the breastfed child.

Fertility
No studies on the effects of faricimab on human fertility have been conducted and it is not known whether faricimab can affect reproduction. Based on its mechanism of action, treatment with may pose a risk to reproductive capacity.

Pharmacology
Faricimab is a 150kDa-sized bispecific antibody whose molecular structure allows a high affinity bond to both vascular endothelial growth factor A (VEGF-A) and Angiopoietin (Ang-2). By blocking the action of these two growth factors, faricimab decreases migration and replication of endothelial cells allowing for stabilization of vascular structures, thereby decreasing vascular leakage </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 Plerixafor and can you explain it in depth? [/INST] Plerixafor (INN and USAN, trade name Mozobil) is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients into the bloodstream. The stem cells are then extracted from the blood and transplanted back to the patient. The drug was developed by AnorMED, which was subsequently bought by Genzyme.

Medical uses
Peripheral blood stem cell mobilization, which is important as a source of hematopoietic stem cells for transplantation, is generally performed using granulocyte colony-stimulating factor (G-CSF), but is ineffective in around 15 to 20% of patients. Combination of G-CSF with plerixafor increases the percentage of persons that respond to the therapy and produce enough stem cells for transplantation. The drug is approved for patients with lymphoma and multiple myeloma.Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, a CXCL2 ligand.

Contraindications
Pregnancy and lactation
Studies in pregnant animals have shown teratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use contraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.

Adverse effects
Nausea, diarrhea and local reactions were observed in over 10% of patients. Other problems with digestion and general symptoms like dizziness, headache, and muscular pain are also relatively common; they were found in more than 1% of patients. Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and transient.The European Medicines Agency has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells has occurred in patients with leukaemia treated with plerixafor.

Interactions
No interaction studies have been conducted. The fact that plerixafor does not interact with the cytochrome system indicates a low potential for interactions with other drugs.

Pharmacology
Mechanism of action
In the form of its zinc complex, plerixafor acts as an antagonist (or perhaps more accurately a partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist of CXCR7.
The CXCR4 alpha-chemokine receptor and one of its ligands, SDF-1, are important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. The in vivo effect of plerixafor with regard to ubiquitin, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells. Additionally, plerixafor inhibits CD20 expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression.

Pharmacokinetics
Following subcutaneous injection, plerixafor is absorbed quickly and peak concentrations are reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides in extravascular compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoproteins has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidneys, with 70% of the drug being excreted within 24 hours.

Chemistry
Plerixafor is a macrocyclic compound and a bicyclam derivative, the cyclam rings being linked at the amine nitrogen atoms by a 1,4-xylyl spacer. It is a base; all eight nitrogen atoms accept protons readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinc, copper and nickel, as well as  cobalt and rhodium. The biologically active form of plerixafor is its zinc complex.

Synthesis
Three of the four nitrogen atoms of the macrocycle cyclam... (1,4,8,11-tetraazacyclotetradecane) are protected with tosyl groups. The product is treated with 1,4-bis(brommethyl)benzene and potassium carbonate in acetonitrile. After cleaving of the tosyl groups with hydrobromic acid, plerixafor octahydrobromide is obtained.

History
The molecule was first synthesised in 1987 to carry out basic studies on the redox chemistry of dimetallic coordination compounds. Then, it was serendipitously discovered by another chemist that such a molecule could have a potential use in the treatment of HIV because of its role in the blocking of CXCR4, a chemokine receptor which acts as a co-receptor for certain strains of HIV (along with the viruss main cellular receptor, CD4). Development of this indication was terminated because of lacking oral availability and cardiac disturbances </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 Gabapentin and can you explain it in depth? [/INST] Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.Sleepiness and dizziness are the most common side effects. Serious side effects include an increased risk of suicide, respiratory depression, and allergic reactions. Lower doses are recommended in those with kidney disease. Gabapentin acts by decreasing activity of a subset of calcium channels.Gabapentin was first approved for use in 1993. It has been available as a generic medication in the United States since 2004. In 2020, it was the tenth most commonly prescribed medication in the United States, with more than 49 million prescriptions. During the 1990s, Parke-Davis, a subsidiary of Pfizer, used a number of illegal techniques to encourage physicians in the United States to prescribe gabapentin for unapproved uses. They have paid out millions of dollars to settle lawsuits regarding these activities.

Medical uses
Gabapentin is recommended for use in focal seizures and neuropathic pain. Gabapentin is widely prescribed off-label in the US and UK, for example, for the treatment of non-neuropathic pain, anxiety disorders and bipolar disorder.

Seizures
Gabapentin is approved for the treatment of focal seizures; however, it is not effective for generalized epilepsy.

Neuropathic pain
Gabapentin is recommended as a first-line treatment for chronic neuropathic pain by various medical authorities. This is a general recommendation applicable to all neuropathic pain syndromes except for trigeminal neuralgia.In regard to the specific diagnoses, the best evidence exists for gabapentin treatment of postherpetic neuralgia and diabetic neuropathy. Gabapentin is approved for the former indication in the US. In addition to these two neuropathies, European Federation of Neurological Societies guideline notes gabapentin effectiveness for central pain. A combination of gabapentin with an opioid or nortriptyline may work better than either drug alone.Overall, gabapentin shows moderate effectiveness for neuropathic pain. Only a minority of patients obtain meaningful relief. Out of 10 persons treated with gabapentin, three to four benefit substantially as compared to one to two persons treated with placebo.Evidence finds little or no benefit and significant risk in those with chronic low back pain or sciatica. Gabapentin is not effective in HIV-associated sensory neuropathy and neuropathic pain due to cancer.

Anxiety
There is a small amount research on the use of gabapentin for the treatment of anxiety disorders. In a controlled trial of breast cancer survivors with anxiety, and in a trial for social phobia, gabapentin significantly reduced anxiety levels. For panic disorder, gabapentin is ineffective. Conversely, some psychiatric textbooks see "a possible role for gabapentin in anxiety disorders, particularly social phobia and panic disorder" based on "case reports and double-blind studies" or state that controlled studies have not shown gabapentin to be very effective for psychiatric indications; "however, clinically it is effective".

Sleep
Gabapentin is effective in treating sleep disorders such as insomnia and restless legs syndrome. Gabapentin enhances slow-wave sleep in patients with primary insomnia. It also improves sleep quality by elevating sleep efficiency and decreasing spontaneous arousal. The results suggest that gabapentin may be beneficial in the treatment of primary insomnia.

Drug dependence
Gabapentin is moderately effective in reducing the symptoms of alcohol withdrawal and associated craving. The evidence in favor of gabapentin is weak in the treatment of alcoholism: it does not contribute to the achievement of abstinence, and the data on the relapse of heavy drinking and percent of days abstinent do not robustly favor gabapentin; it only decreases the percent days of heavy drinking.Gabapentin is ineffective in cocaine dependence and methamphetamine use, and it does not increase the rate of smoking cessation. Gabapentin does not significantly reduce the symptoms of opiate withdrawal. There is insufficient evidence for its use in cannabis dependence.

Other
Gabapentin is recommended as a first-line treatment of the acquired pendular nystagmus, torsional nystagmus, and infantile nystagmus; however, it does not work in periodic alternating nystagmus.Gabapentin decreases the frequency of hot flashes in both menopausal women and patients with breast cancer. However, antidepressants have similar efficacy, and treatment with estrogen more effectively prevents hot flashes.Gabapentin reduces spasticity in multiple sclerosis and is prescribed as one of the first-line options. It is an established treatment of restless legs syndrome. Gabapentin alleviates itching in kidney failure (uremic pruritus) and itching of other causes. It may be an option in essential or orthostatic tremor. Although the efficacy of gabapentin for insomnia has not been established, it does alleviate sleep disorder in patients with medical illness.Gabapentin does not appear to provide benefit for bipolar disorder, complex regional pain syndrome, post-surgical pain, or tinnitus, or prevent episodic migraine in adults.

Contraindications
Gabapentin should be used carefully and at lower doses in people with kidney problems due to possible accumulation and toxicity. It is unclear if it is safe during pregnancy or breastfeeding.

Side effects
Dizziness and somnolence are the most frequent side effects. Fatigue, ataxia, peripheral edema (swelling of extremities), and nystagmus are also common. Gabapentin is associated with a weight gain of 2.2 kg after 1.5 months of use. Case studies indicate that it may cause anorgasmia and erectile dysfunction, as well as myoclonus that disappear after discontinuing gabapentin or replacing it with other medication. DRESS, anaphylaxis, respiratory depression, and increased suicide behavior are the rare but serious side effects.

Suicide
The gabapentin label contains a warning of an increased risk of suicidal thoughts and behaviors. According to an insurance claims database study, gabapentin use is associated with about 40% increased risk of suicide, suicide attempt and violent death as compared with a reference anticonvulsant drug topiramate. The risk is increased for both bipolar disorder and epilepsy patients. Another study has shown an approximately doubled rate of suicide attempts and self-harm in patients with bipolar disorder who are taking gabapentin versus those taking lithium.
A large Swedish study suggests that gabapentinoids are associated with an increased risk of suicidal behaviour, unintentional overdoses, head/body injuries, and road traffic incidents and offences.

Respiratory depression
Serious breathing suppression, potentially fatal, may occur when gabapentin is taken together with opioids, benzodiazepines, or other depressants, or by people with underlying lung problems such as COPD. Gabapentin and opioids are commonly prescribed or abused together, and research indicates that the breathing suppression they cause is additive. For example, gabapentin use before joint replacement or laparoscopic surgery increased the risk of respiratory depression by 30–60%.

Withdrawal and dependence
Withdrawal symptoms typically occur 1–2 days after abruptly stopping gabapentin. Agitation, confusion and disorientation are the most frequently reported, followed by gastrointestinal complaints and sweating, and more rare tremor, tachycardia, hypertension and insomnia. In some cases, users experience withdrawal seizures. All these symptoms subside when gabapentin is re-instated.On its own, gabapentin appears to not have a substantial addictive power. In human and animal experiments, it shows limited to no rewarding effects. The vast majority of people abusing gabapentin are current or former abusers of opioids or sedatives. In these persons, gabapentin can boost the opioid "high" as well as decrease commonly experienced opioid-withdrawal symptoms such as anxiety.

Overdose
Through excessive ingestion, accidental or otherwise, persons may experience overdose symptoms including drowsiness, sedation, blurred vision, slurred speech, somnolence, uncontrollable jerking motions, and anxiety. A very high amount taken is associated with breathing suppression, coma, and possibly death, particularly if combined with alcohol or opioids.

Pharmacology
Pharmacodynamics
Gabapentin is a ligand of the α2δ calcium channel subunit. α2δ is an auxiliary protein connected to the main α1 subunit (the channel-forming protein) of high voltage activated voltage-dependent calcium channels (L-type, N-type, P/Q type, and R-type). Gabapentin is not a direct channel blocker: it exerts its actions by disrupting the regulatory function of α2δ and its interactions with other proteins. Gabapentin prevents delivery of the calcium channels to the cell membrane, reduces the activation of the channels by the α2δ subunit, decreases signaling leading to neurotransmitters release, and disrupts interactions of α2δ with NMDA receptors, neurexins, and thrombospondins. Out of the four known isoforms of α2δ protein, gabapentin binds with similar high affinity to two: α2δ-1 and α2δ-2. Most of the pharmacological properties of gabapentin are explained by its binding to just one isoform – α2δ-1.The endogenous α-amino acids L-leucine and L-isoleucine, which resemble gabapentin in chemical structure, bind α2δ with similar affinity to gabapentin and are present in human cerebrospinal fluid at micromolar concentrations. They may be the endogenous ligands of the α2δ subunit, and they competitively antagonize the effects of gabapentin. Accordingly, while gabapentin has nanomolar affinity for the α2δ subunit, its potency in vivo is in the low micromolar range, and competition for binding by endogenous L-amino acids is likely to be responsible for this discrepancy.Gabapentin is a potent activator of voltage-gated potassium channels KCNQ3 and KCNQ5, even at low nanomolar concentrations. However, this activation is unlikely to be the dominant mechanism of gabapentins therapeutic effects.Despite the fact that gabapentin is a structural GABA analogue, and in spite of its name, it does not bind to the GABA receptors, does not convert into GABA or another GABA receptor agonist in vivo, and does not modulate GABA transport or metabolism.

Pharmacokinetics
Gabapentin is absorbed from the intestines by an active transport process mediated via an amino acid transporter, presumably, LAT2. As a result, the pharmacokinetics of gabapentin is dose-dependent, with diminished bioavailability and delayed peak levels at higher doses.The oral bioavailability of gabapentin is approximately 80% at 100 mg administered three times daily once every 8 hours, but decreases to 60% at 300 mg, 47% at 400 mg, 34% at 800 mg, 33% at 1,200 mg, and 27% at 1,600 mg, all with the same dosing schedule. Drugs that increase the transit time of gabapentin in the small intestine can increase its oral bioavailability; when gabapentin was co-administered with oral morphine, the oral bioavailability of a 600 mg dose of gabapentin increased by 50%.Gabapentin at a low dose of 100 mg has a Tmax (time to peak levels) of approximately 1.7 hours, while the Tmax increases to 3 to 4 hours at higher doses. Food does not significantly affect the Tmax of gabapentin and increases the Cmax and area-under-curve levels of gabapentin by approximately 10%.Gabapentin can cross the blood–brain barrier and enter the central nervous system. Gabapentin concentration in cerebrospinal fluid is approximately 9–14% of its blood plasma concentration. Due to its low lipophilicity, gabapentin requires active transport across the blood–brain barrier. The LAT1 is highly expressed at the blood–brain barrier and transports gabapentin across into the brain. As with intestinal absorption mediated by an amino acid transporter, the transport of gabapentin across the blood–brain barrier by LAT1 is saturable. Gabapentin does not bind to other drug transporters such as P-glycoprotein (ABCB1) or OCTN2 (SLC22A5). It is not significantly bound to plasma proteins (<1%).Gabapentin undergoes little or no metabolism.Gabapentin is eliminated renally in the urine. It has a relatively short elimination half-life, with the reported average value of 5 to 7 hours. This value changes with increasing doses, from 5.4 hours for a 200 mg single dose, to 8.3 hours for a 1,400 mg dose. Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels. Gabapentin XR (brand name Gralise) is taken once a day.

Chemistry
Gabapentin is a 3,3-disubstituted derivative of GABA. Therefore, it is a GABA analogue, as well as a γ-amino acid. Specifically, it is a derivative of GABA with a pentyl disubstitution at 3 position, hence, the name - gabapentin, in such a way as to form a six-membered ring. After formation of the ring, the amine and carboxylic groups are not in the same relative positions as they are in the GABA; they are more conformationally constrained.

Synthesis
A chemical synthesis of gabapentin has been described starting from 1,1-diacetyl hexane anhydride.

History
Gabapentin was designed by researchers at Parke-Davis to be an analogue of the neurotransmitter GABA that could more easily cross the blood–brain barrier and was first described in 1975 by Satzinger and Hartenstein. Under the brand name Neurontin, it was first approved in May 1993, for the treatment of epilepsy in the United Kingdom. Approval by the U.S. Food and Drug Administration followed in December 1993, for use as an adjuvant (effective when added to other antiseizure drugs) medication to control partial seizures in adults; that indication was extended to children in 2000. Subsequently, gabapentin was approved in the United States for the treatment of postherpetic neuralgia in 2002. A generic version of gabapentin first became available in the United States in 2004. An extended-release formulation of gabapentin for once-daily administration, under the brand name Gralise, was approved in the United States for the treatment postherpetic neuralgia in January 2011.

Society and culture
Legal status
United Kingdom
Effective April 2019, the United Kingdom reclassified the drug as a class C controlled substance.

United States
Effective 1 July 2017, Kentucky classified gabapentin as a schedule V controlled substance statewide. Effective 9 January 2019, Michigan also classified gabapentin as a schedule V controlled substance. Gabapentin is scheduled V drug in other states such as West Virginia, Tennessee, Alabama.

Off-label promotion
Although some small, non-controlled studies in the 1990s—mostly sponsored by gabapentins manufacturer—suggested that treatment for bipolar disorder with gabapentin may be promising, the preponderance of evidence suggests that it is not effective. Subsequent to the corporate acquisition of the original patent holder, the pharmaceutical company Pfizer admitted that there had been violations of FDA guidelines regarding the promotion of unproven off-label uses for gabapentin in the Franklin v. Parke-Davis case (see below).
Reuters reported on 25 March 2010, that "Pfizer Inc violated federal racketeering law by improperly promoting the epilepsy drug Neurontin ... Under federal RICO law the penalty is automatically tripled, so the finding will cost Pfizer $141 million." The case stems from a claim from Kaiser Foundation Health Plan Inc. that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians still recommend the drug for those uses", and that "the insurers website also still lists Neurontin as a drug for neuropathic pain."The Wall Street Journal noted that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal." He later added that "the verdict and the judges rulings are not consistent with the facts and the law."

Franklin v. Parke-Davis case
While off-label prescriptions are common for a number of drugs, marketing of off-label uses of a drug is not. In 2004, Warner-Lambert (which subsequently was acquired by Pfizer) agreed to plead guilty for activities of its Parke-Davis subsidiary, and to pay $430 million in fines to settle civil and criminal charges regarding the marketing of Neurontin for off-label purposes. The 2004 settlement was one of the largest in U.S. history, and the first off-label promotion case brought successfully under the False Claims Act.

Brand names
Gabapentin was originally marketed under the brand name Neurontin. Since it became generic, it has been marketed worldwide using over 300 different brand names. An extended-release formulation of gabapentin for once-daily administration was introduced in 2011, for postherpetic neuralgia under the brand name Gralise.

Related drugs
Parke-Davis developed a drug called pregabalin, which is related in structure to gabapentin, as a successor to gabapentin. Another similar drug atagabalin has been unsuccessfully tried by Pfizer as a treatment for insomnia. A prodrug form (gabapentin enacarbil) was approved by the U.S. Food and Drug Administration (FDA).

Recreational use
Gabapentin when taken in excess can induce euphoria, a sense of calm, a marijuana-like high, improved sociability, and reduced alcohol or cocaine cravings. Also known on the streets as "Gabbies", gabapentin is increasingly being abused and misused for these euphoric effects. About 1 percent of the responders to an internet poll and 22 percent of those attending addiction facilities had a history of abuse of gabapentin </s>