Prescrire international
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Prescrire international · Jun 2007
Human papillomavirus vaccine for genotypes 6, 11, 16 and 18: new drug. Cervical cancer prevention: high hopes....
(1) Most cases of high-grade anogenital dysplasia and malignancy are caused by human papillomavirus (HPV) genotypes 16 and 18. Anogenital papilloma and condyloma acuminata are mainly caused by HPV6 and HPV11. (2) A recombinant vaccine covering these four genotypes is now marketed in the European Union for the prevention of condyloma, precancerous lesions, and cancers of the female lower genital tract. (3) A three-dose vaccination schedule (0, 2 and 6 months) elicits an immune response in almost all women, but the minimum antibody titre required for clinical protection is not known. Immune protection lasts at least 5 years, but no one knows what happens after that time. (4) Three double-blind randomised placebo-controlled trials involving a total of about 18 000 women aged 16 to 23 had sufficiently similar designs to pool results for analysis. ⋯ There are no data on efficacy beyond 4.5 years. (6) These results are somewhat undermined by methodological problems, such as follow-up lasting only a maximum of 4.5 years whereas cervical cancer takes much longer to develop. In addition, there were very few cases of dysplasia in each trial, and results were largely based on post hoc subgroup analyses. (7) Apart from local reactions, which occurred in more than 80% of vaccinated women, the only adverse effect of papillomavirus vaccination was fever (12.9% of those on the vaccine versus 11% on placebo). (8) There is no evidence thus far that prenatal exposure due to HPV vaccination during the month preceding conception is harmful. (9) The clinical results are promising but further follow-up is needed to answer ongoing questions, such as the incidence of cervical cancer after vaccination and the duration of protection. Cervical cancer screening remains necessary, even for vaccinated women, and a continued need exists for measures designed to prevent all sexually transmitted diseases.
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Non metastatic prostate cancer: avoid over-interpretation of flawed clinical trial evidence.
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Prescrire international · Apr 2007
Comparative StudySertindole: new drug. Another "atypical" neuroleptic; QT prolongation.
(1) The first-line drug for the treatment of schizophrenic disorders is a neuroleptic such as haloperidol. Amisulpride may be preferable when haloperidol causes unacceptable neurological reactions. Overall, the risk-benefit balance of more recent, so-called atypical neuroleptics is no better. (2) Sertindole, a neuroleptic, was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects. ⋯ However, it causes weight gain. Sertindole also has alpha blocking properties, which can cause postural hypotension and reduce ejaculate volume; it also has atropinic effects (constipation, dry mouth, etc.). (5) Sertindole provokes a dose-dependent increase in the QT interval more frequently than haloperidol in comparative trials, and apparently more frequently than other 'atypical' neuroleptics such as risperidone and olanzapine. Sertindole has been suspected of increasing cardiovascular mortality but this has not been established. (6) Sertindole is metabolised by cytochrome P450 isoenzymes CYP 2D6 and CYP 3A4, hence a high risk of pharmacokinetic interactions. (7) In practice, when haloperidol has to be withdrawn because of adverse effects, especially neurological reactions, it is better to continue to resort to amisulpride, for example, with close monitoring of adverse effects, rather than expose patients to the potential dangers of sertindole.
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Prescrire international · Apr 2007
Comparative StudyIvabradine: new drug. Best avoided in stable angina.
(1) The first-line symptomatic treatment for stable angina is a betablocker such as atenolol. Some calcium channel blockers such as verapamil, and the potassium channel agonist amlodipine, are second-line alternatives. Long-acting nitrate derivatives have poorly documented efficacy but can be used as adjuvants or as third-line treatments. (2) Ivabradine is derived from verapamil but appears to have a different mechanism of action, mainly lowering the heart rate. ⋯ Three double-blind randomised controlled trials lasting 3 to 4 months, based on surrogate exercise endpoints, failed to show that ivabradine was any more effective than atenolol or amlodipine, or even more effective than placebo in patients already treated with amlodipine. (4) In two one-year double-blind randomised controlled trials comparing ivabradine with atenolol or amlodipine in a total of 704 patients, ivabradine was no more effective than the comparators in preventing angina attacks. (5) In head-to-head comparisons, serious coronary events were significantly more frequent with ivabradine than with atenolol (3.8% versus 1.5%). Severe arrhythmias were also more frequent with ivabradine than with atenolol (1.3% versus 0.7%) or amlodipine (0.6% versus 0.2%). (6) Ivabradine provokes phosphenes (flashing lights, etc.) in about 17% of patients in the short term. Information is inadequate to assess possible risks of retinal toxicity in the long term. (7) Ivabradine is metabolised by cytochrome P450 isoenzyme CYP 3A4; there is therefore a potentially high risk of pharmacokinetic interactions. (8) In practice, for long-term preventive treatment of angina it is better to avoid ivabradine and to use better-documented treatments: preferably a betablocker, or, if a betablocker cannot be used, verapamil or amlodipine.
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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.