fluoxetine
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fluoxetine
FluoxetineSystematic (IUPAC) nameN-methyl-3-phenyl-3-propan-1-amineIdentifiersCAS number54910-89-3ATC codeN06AB03PubChem3386DrugBankAPRD00530ChemSpider56589Chemical dataFormulaC17H18F3NO Mol. mass309.3 g/mol (345.8 for •HCl)Pharmacokinetic dataBioavailability72%peak at 6-8 hoursProtein binding94.5%MetabolismHepaticHalf life1-3 days (acute); 4-6 days (chronic); Active metabolite Norfluoxetine 4-16 days (acute and chronic)ExcretionKidneys 80%, intestines 15%Therapeutic considerationsLicence dataEU EMEA:link, US FDA:linkPregnancy cat.C(AU) C(US)Legal status℞ Prescription onlyRoutesOralFluoxetine hydrochloride (trade names Prozac, Fontex, Ladose, Sarafem, Solax, Lovan) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine is approved for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder. Despite the availability of newer agents, it remains extremely popular. Over 22.2 million prescriptions for generic formulations of fluoxetine were filled in the United States in 2007, making it the third most prescribed antidepressant.// HistoryAccording to David Wong, the work which eventually led to the discovery of fluoxetine began at Eli Lilly in 1970 as a collaboration between Bryan Molloy and Robert Rathbun. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized dozens of its derivatives. Testing the physiological effects of these compounds in mice resulted in nisoxetine, a selective norepinephrine reuptake inhibitor currently widely used in biochemical experiments.Later, hoping to find a derivative inhibiting only serotonin reuptake, Wong proposed to re-test the series for the in-vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.A controversy ensued after Lilly researchers published a paper entitled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug" claiming fluoxetine to be the first selective serotonin reuptake inhibitor (SSRI). Two years later they had to issue a correction, admitting that the first SSRI was zimelidine developed by Arvid Carlsson and colleagues. Fluoxetine made its appearance on the Belgian market in 1986 and was approved for use by the FDA in the United States in December 1987. Fluoxetine was the fourth SSRI to make it to market, after zimelidine, indalpine and fluvoxamine. However, the first two were withdrawn due to the side effects, and a vigorous marketing campaign by Eli Lilly made sure that in the popular culture fluoxetine has been perceived as a scientific breakthrough and associated with the title of the first SSRI.Eli Lilly's patent on Prozac (fluoxetine) expired in August, 2001, prompting an influx of generic drugs onto the market. IndicationsFluoxetine has been approved by the FDA for the treatment of major depression, obsessive compulsive disorder, bulimia nervosa and panic disorder. Fluoxetine was shown to be effective for depression in 6-week long double-blind controlled trials where it also alleviated anxiety and improved sleep. Fluoxetine was better than placebo for the prevention of depression recurrence when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as pediatric depression was also demonstrated in placebo-controlled trials.The peculiar pharmacokinetics of fluoxetine with its brain levels rising extremely slowly over at least first 5 weeks of treatment (see Pharmacokinetics) makes it unclear whether the 20-mg/day optimal dose established in the short term (6-8 weeks) trials is applicable for the longer term supportive treatment. One 60-mg dose of fluoxetine per week was found to be equivalent to 20 mg/day for the continuation treatment of responders to 20 mg/day of fluoxetine. Furthermore, 5 mg/day fluoxetine was shown to be better than placebo and similar to 20 mg/day, and one weekly dose of 80 mg fluoxetine was equivalent to 60 mg/day fluoxetine or 150 mg/day amitriptyline. On the other hand, increase of the dose to 60 mg/day in non-responders from 20 mg/day brought no additional benefits as compared to continuing the 20 mg/day treatment.The recent research suggests that a significant part of the resistance to the SSRIs paroxetine (Paxil) and citalopram (Celexa) can be explained by the genetic variation of Pgp transporter. Paroxetine and citalopram, which are Pgp substrates, are actively transported from the brain by this protein. Fluoxetine is not a substrate of Pgp, and thus a switch from paroxetine or citalopram to fluoxetine may be beneficial to the non-responders.OCD was successfully treated by fluoxetine in two adult and one pediatric placebo-controlled 13-week trials. The higher doses of fluoxetine appeared to result in better response, while the reverse relationship was observed in the treatment of depression. Fluoxetine dramatically, by 40-50%, decreased the frequency of panic attacks in two controlled trials of panic disorder patients. In three double-blind trials fluoxetine significantly decreased the number of binge-eating and purging episodes of bulimia nervosa. Continued year-long treatment of the patients, who originally responded to fluoxetine, was more effective than placebo for the prevention of bulimia nervosa episodes. PharmacokineticsThe bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6 to 8 hours. It is highly bound to plasma proteins, mostly albumin.Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. Only one metabolite of fluoxetine, norfluoxetine (demethylated fluoxetine), is biologically active.The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life changes from 1 to 3 days, after a single dose—to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use. Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks. Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment. That means that the full benefits of the current dose a patient receives are not realized for at least a month since its initiation. For example, in one 6-week study, the median time to achieving consistent response was 29 days. Likewise, complete excretion of the drug may take several weeks. During the first week after the treatment discontinuation, the brain concentration of fluoxetine decreases only by 50%, The blood level of norfluoxetine 4 weeks after the treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and 7 weeks after the discontinuation norfluoxetine is still detectable in the blood.A PET study compared the action of a single dose of fluoxetine on exclusively heterosexual and exclusively homosexual men who attested that their past and present sexual behavior, desires, and fantasies were directed entirely toward women or men, respectively. The study found that in some areas of the brain the metabolic response in these two groups was different. "Both groups, however, did exhibit similar widespread lateralized metabolic responses to fluoxetine (relative to placebo), with most areas of the brain responding in the same direction." They "did not differ on behavioral measures or blood levels of fluoxetine". Adverse effectsAccording to the manufacturer of Prozac brand of fluoxetine Eli Lilly, fluoxetine is contraindicated in individuals taking monoamine oxidase inhibitors, pimozide (Orap) or thioridazine (Mellaril). The prescribing information recommends that the treatment of the patients with liver impairment "must be approached with caution". The elimination of fluoxetine and its metabolite norfluoxetine is about twice slower in these patients, resulting in the proportionate increase of exposure to the drug.Among the common adverse effects associated with fluoxetine and listed in the prescribing information, the effects with the greatest difference from placebo are nausea (22% vs 9% for placebo), insomnia (19% vs 10% for placebo), somnolence (12% vs 5% for placebo), anorexia (10% vs 3% for placebo), anxiety (12% vs 6% for placebo), nervousness (13% vs 8% for placebo), asthenia (11% vs 6% for placebo) and tremor (9% vs 2% for placebo). Those that most often resulted in interruption of the treatment were anxiety, insomnia, and nervousness (1-2% each), and mania (2%). Sexual side effects are common with fluoxetine, which include sexual dysfunction, anorgasmia, reduced libido and impotence.In addition, rash or urticaria, sometimes serious, was observed in 7% patients in clinical trials; one-third of these cases resulted in discontinuation of the treatment. Postmarketing reports note several cases of complications developed in patients with rash. The symptoms included vasculitis and lupus-like syndrome. Death has been reported to occur in associati
The concept here is that the soldiers are afloat waiting to be pulled out of the flood âwatersâ of the reign. researchers have found that Prozac can fight the resistance of cancer cells to a major Israeli-developed tumor-fighting drug.This is a visual response to the cover story of Time Magazineâs June 2008 issue titled âThe Militaryâs Secret Weaponâ. These results showed that fluoxetine was not effective for reducing repetitive behaviors in children and adolescents with Autistic Disorder as compared to placebo. However, systemic studies on the treatment of depression in patient with cancer have not been well documented. .Scientists have long known that in addition to discouraging synapses from reabsorbing the neurotransmitter serotonin, Prozac (known generically as fluoxetine) also increases the number of neurons (neurogenesis) in the adult brain.New research in specially bred mice has elucidated how the antidepressant Prozac works. Antidepressant treatment has been accepted as one of the new strategies in cancer adjuvant therapy. Basically, Prozac is just another antidepressant.Repetitive behaviors in people with autism serve a function, but studies are being conducted regarding medications to STOP these behaviors. Tel Aviv Univ. Prozac dramatically enhances the effectiveness of a widely used anti-cancer drug doxorubicin.The
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fluoxetine
Fluoxetine hydrochloride (trade names Prozac, Fontex, Ladose, Sarafem, Solax, Lovan) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.
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