Drugs
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Letrozole is an oral reversible nonsteroidal aromatase inhibitor. Clinical tracer studies show that it inhibits peripheral aromatase by over 98% and suppresses blood and urinary estrogen levels by over 95% after 2 weeks of treatment in postmenopausal women. Letrozole also significantly inhibits intratumoral aromatase in vivo. The action of letrozole appears to be selective for aromatase; long term administration did not affect basal levels of 17 alpha-hydroxyprogesterone or aldosterone, although slight decreases in cortisol levels were observed in 2 studies, these did not appear to be clinically significant. In 2 phase IIb/III trials, letrozole 2.5 mg/day achieved objective response rates of 19.5 and 23.6% which were sustained for a median duration of 24 and 33 months, respectively. The median duration of response compared favourably with both comparator agents, aminoglutethimide and megestrol (15 and 18 months, respectively), as did objective response rates (12.4 and 16.4%). Letrozole 2.5 mg/day was associated with an increase in median survival time of 8 and 3 months compared with aminoglutethimide and megestrol, respectively. According to analyses of overall function, letrozole 2.5 mg/day was significantly superior to both comparators with respect to duration of response and aminoglutethimide with respect to survival. Letrozole has a good short term tolerability profile. The adverse events reported most commonly in association with letrozole 2.5 mg/day in the 2 phase IIb/III trials were headache (1.1 and 7%), nausea (6 and 10.3%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%) and peripheral oedema (6%). Events were usually mild to moderate in severity; adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5 mg/day recipients. ⋯ Letrozole, in common with vorozole and anastrozole, offers greater selectivity and potency of aromatase inhibition than the prototype aromatase inhibitor, aminoglutethimide, and can be administered once daily. Available clinical data suggest that letrozole achieves a significantly longer duration of response than megestrol and aminoglutethimide and longer overall survival than aminoglutethimide. However, direct comparisons are required to distinguish between the newer aromatase inhibitors. For this reason, letrozole should be recommended as a second-line treatment in postmenopausal women with advanced breast cancer whose disease has progressed on or failed to respond to antiestrogen therapy.
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Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise. Mild migraine attacks are treated with antiemetics followed by analgesics such as aspirin (acetylsalicylic acid), paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs (NSAIDs). Moderate to severe attacks are treated by antiemetics combined with ergotamine or dihydroergotamine. ⋯ Substances with proven efficacy include the beta-blockers metoprolol and propranolol and the calcium antagonist flunarizine. Drugs less effective or those with unpleasant adverse effects are the serotonin receptor antagonists (pizotifen, methysergide and lisuride), dihydroergotamine, cyclandelate, NSAIDs, valproic acid (sodium valproate) and amitriptyline. The efficacy of aspirin or magnesium is still under evaluation.
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Ofloxacin is an established fluoroquinolone agent which achieves good concentrations in genitourinary tract tissues and fluids. It has good in vitro activity against most Enterobacteriaceae, Staphylococcus saprophyticus, methicillin-susceptible S. aureus, Neisseria gonorrhoeae, Chlamydia trachomatis and Haemophilus ducreyi, intermediate activity against Ureaplasma urealyticum and most enterococci, but limited or no in vitro activity against enterococci, Serratia marcescens, Pseudomonas aeruginosa and many anaerobes. However, high concentrations achieved in the urine ensure its activity against most urinary tract pathogens. Ofloxacin demonstrates consistent efficacy in a broad range of urinary tract infections, achieving bacteriological response rates in excess of 80% in uncomplicated and 70% in complicated infections. The efficacy of ofloxacin was similar to that of all comparators tested including other fluoroquinolones, cephalosporins and cotrimoxazole (trimethoprim/sulfamethoxazole). Ofloxacin is also effective as a single-dose regimen in the treatment of uncomplicated gonorrhoea, as a 7-day regimen in uncomplicated C. trachomatis infections, and as monotherapy in uncomplicated pelvic inflammatory disease (PID). Again, ofloxacin demonstrated similar efficacy to alternative treatments in each type of infection. The availability of an intravenous formulation and near-complete oral bioavailability allow ofloxacin to be administered as a sequential regimen without loss of activity. The tolerability and drug interaction profile of ofloxacin is consistent with that of other fluoroquinolones. The most commonly reported adverse events with ofloxacin are gastrointestinal, neurological and dermatological. It was associated with a lower incidence of photosensitivity and tendinitis and higher incidence of some neurological events than some other fluoroquinolones. Ofloxacin seems to have a lower propensity to interact with xanthines than other fluoroquinolones. ⋯ ofloxacin has established efficacy in the treatment of a wide variety of urinary tract infections, although, like other fluoroquinolones, it should be used rationally to preserve its activity. Currently, ofloxacin also holds an important place among fluoroquinolones in the treatment of C. trachomatis infections and uncomplicated PID, although its acceptance as monotherapy in PID is likely to depend on clarification of the causative role of anaerobic pathogens in this infection.
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In 1998, over two-thirds of children diagnosed with cancer will be cured of their disease. This has been accomplished by improvements in understanding the biology of the various forms of cancer and stratifying protocol-based therapies (surgery, radiotherapy and chemotherapy) based on predicted treatment outcome and risk of treatment failure. The excellent prognosis of subgroups of malignancies, including acute lymphoblastic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma and Wilms' tumour, has led to the modification of therapies to decrease or minimise long term adverse effects which may have a significant impact on the quality of life of survivors. The lessons learned from the treatment of paediatric cancer may lead to improvements in the treatment of adult cancers.
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Mexiletine is an orally active local anaesthetic agent which is structurally related to lidocaine (lignocaine) and has been used for alleviating neuropathic pain of various origins. Mexiletine has been evaluated in several randomised, placebo-controlled trials in patients with painful diabetic neuropathy. The drug decreased mean visual analogue scale (VAS) pain ratings in all studies that used this measure, although in only 2 studies was this effect significantly greater than the often substantial responses seen with placebo. The clinical significance of these decreases is not clear. Statistically significant (vs placebo) reductions in VAS pain ratings were observed in 16 patients receiving mexiletine 10 mg/kg/day for 10 weeks in 1 study and in nocturnal (but not diurnal) pain in 31 patients receiving mexiletine 675 mg/day for 3 weeks in another. Retrospective analysis of another study revealed that mexiletine recipients (225 to 675 mg/day) who described their pain as stabbing, burning or formication on the pain-rating-index-total instrument of the McGill Pain Questionnaire, experienced statistically significant reductions in VAS pain scores after 5 weeks, compared with placebo recipients. Mexiletine generally did not have a significant influence on the quality of sleep in patients with diabetic neuropathy. In Japanese patients, statistically significant reductions in subjective pain ratings were achieved with mexiletine 300 mg/day in 1 study and with 450 mg/day in a further study. In controlled trials, the frequency of adverse events in patients receiving mexiletine for painful diabetic neuropathy ranged from 13.5 to 50%. Gastrointestinal complaints, of which nausea was the most frequent, were the most common adverse events in mexiletine recipients. Central nervous system complaints were uncommon, but included: sleep disturbance, headache, shakiness, dizziness and tiredness. Serious cardiac arrhythmias have not been reported in patients receiving mexiletine for painful diabetic neuropathy; however, transient tachycardia and palpitations have been reported. There are significant differences in the metabolism of mexiletine between people who have cytochrome P450 2D6 [CYP2D6; extensive metabolisers (EMs)] and those who lack this isoenzyme [poor metabolisers (PMs)]. EMs, but not PMs, are susceptible to drug interactions between mexiletine and drugs that inhibit CYP2D6 (e.g. quinidine). Moreover, mexiletine inhibits CYP2D6-mediated metabolism of metoprolol and cytochrome P450 1A2-mediated metabolism of theophylline. Phenytoin and rifampicin (rifampin) induce the metabolism of mexiletine. Clearance of mexiletine is impaired in patients with hepatic, but not renal, dysfunction. Hence, dosage adjustments may be necessary in patients with liver disease. ⋯ Tricyclic antidepressants (TCAs) are the agents of choice for painful diabetic neuropathy; however, they are ineffective in approximately 50% of patients and are generally not well tolerated. Mexiletine is an alternative agent for the treatment of painful diabetic neuropathy in patients who have not had a satisfactory response to, or cannot tolerate, TCAs and/or other drugs.