Prescrire international
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(1) Worldwide, there are an estimated 6000 to 7000 rare diseases. Patients face special difficulties in obtaining an accurate diagnosis, adequate information about the disease, and access to qualified specialists. (2) Drug companies do not spontaneously conduct research on drugs for rare diseases, mainly because of the limited market for each indication. Only a few dozen of these drugs were available in France before 2000. (3) In 2000 the European Union adopted a Regulation, based on experience in the United States, aimed at promoting the development of drugs for patients suffering from rare diseases, i.e. 'orphan drugs'. (4) In Europe, orphan drug status can be granted when the prevalence of the disease does not exceed 5 cases per 10 000 inhabitants (or when it is more frequent but profitability is likely to be inadequate). (5) Companies that market an orphan drug receive a variety of financial assistance as well as a 10-year marketing monopoly. (6) Between April 2000 and April 2005, 268 medicinal products received European orphan drug status and 22 were granted European marketing authorization. (7) Access to these drugs varies greatly from one European Union Member State to another, mainly because of the high annual treatment costs (up to 300 000 euros per patient). ⋯ Clinical research and evaluation should continue after marketing authorization has been granted. (11) More drugs, with better-documented efficacy and safety, are now available for patients who previously had no effective treatment options. Yet there is too much duplication and too little evaluation, and too many drugs are extremely expensive, meaning that patients in many European countries cannot benefit. And many rare diseases are still neglected.
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Prescrire international · Feb 2007
Comparative StudyDrotrecogin alfa: a second look. More clinical trials in severe sepsis: mostly negative results.
(1) The initial evaluation of drotrecogin alfa in the treatment of severe sepsis did not convincingly demonstrate the therapeutic potential of this recombinant form of activated protein C. It mainly included one study (PROWESS), a double-blind placebo-controlled trial, involving 1690 patients with sepsis of varying severities. In this trial, drotrecogin alfa seemed to reduce the overall mortality rate at 28 days from 31% to 25%. ⋯ There was no evidence of a reduction in mortality with drotrecogin alfa (overall mortality rate 18%). (5) A paediatric placebo-controlled trial was interrupted after 477 children had been enrolled, because drotrecogin alfa was ineffective and caused severe bleeding. (6) Data from ongoing comparative and non comparative studies confirm the increased risk of severe bleeding during drotrecogin alfa therapy, affecting about 7% of patients. (7) In practice, despite trials involving thousands of patients, there are still no firmly identified patient subgroups in which drotrecogin alfa is clearly beneficial. In contrast, the increased bleeding risk is well documented. Drotrecogin alfa should not be routinely used in the management of patients with severe sepsis.
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(1) Domperidone, a "hidden" neuroleptic, is widely used as an oral antiemetic yet its efficacy has not been adequately documented. (2) In a case-control study domperidone was associated with an estimated relative risk of sudden cardiac death of 3.8 (95% confidence interval 1.5-9.7). (3) QT interval prolongation has been reported in an infant on domperidone, with normalisation after domperidone withdrawal. Serious cardiac arrhythmias led to the market withdrawal of the intravenous form of domperidone in the 1980s. (4) In practice, these data represent an additional reason not to use domperidone, or other antiemetics, for mild and transient health problems. Special care is required when other risk factors for QT interval prolongation are present.
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Prescrire international · Oct 2006
Comparative StudyDuloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects.
(1) Several classes of antidepressants are available. The main difference between these classes is in their short-term pharmacological effects, leading to different patterns of adverse effects. Some antidepressants, especially tricyclics, have positive risk-benefit balances in the treatment of diabetic neuropathy. (2) Duloxetine, a compound chemically related to fluoxetine, appears to have a short-term mechanism of action similar to that of venlafaxine. ⋯ It is therefore appropriate that this use is not mentioned in the "Indications" section of the summary of product characteristics (SPC). (6) The assessment of duloxetine in depression and neuropathic pain confirms existing data on its gastrointestinal, neuropsychological and hepatic adverse effects. In these trials, duloxetine increased blood pressure in a dose-dependent manner. (7) Duloxetine is metabolized by cytochrome P450 isoenzymes CYP 1A2 and CYP 2D6, creating an important risk of interactions with other drugs. (8) In practice, duloxetine currently has no place in the treatment of depression or diabetic neuropathy. Its efficacy has not yet been demonstrated to be even equivalent to that of other available drugs, and it has too many adverse effects, given this degree of uncertainty.
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Prescrire international · Oct 2006
Pharmacological prevention of migraine: to be considered case by case.
(1) Migraines are characterized by recurrent headaches generally lasting between 4 and 72 hours and disappearing without complication. They can be incapacitating, owing to their frequency and/or intensity. (2) Many drugs have been used to prevent migraines. One of the most common outcome measures used in clinical trials is the proportion of responder patients, defined as those in whom the monthly frequency of migraines is at least halved. ⋯ Amitriptyline can also have a sedative effect. (6) Flunarizine also has documented efficacy, but this "hidden neuroleptic" can cause extrapyramidal disorders and weight gain. (7) Among the serotonergic antagonists, methysergide has documented efficacy but long-term treatment can lead to serious retroperitoneal, pulmonary or cardiac fibrosis. Pizotifen causes drowsiness or weight gain in about 50% of patients. (8) The choice of preventive treatment for migraine must be based on the balance between efficacy (compared to placebo) and adverse effects. In practice, the first choice drug is propranolol. (9) Because the frequency of migraines fluctuates over time, withdrawal of prophylaxis should be attempted on a regular basis, with the patient's consent.