Opiate maintenance with buprenorphine in ambulatory care: a 24-week follow-up study of new users.

BACKGROUND: Many studies suggest that buprenorphine, a long acting partial opioid agonist, may be comparable to methadone in efficacy, with fewer withdrawal symptoms and a lower risk of overdose. The aim of this study was to assess the patterns of buprenorphine prescription use in ambulatory care and retention rate under treatment during a 24-week follow-up period. METHODS: This observational cohort study included buprenorphine users identified from the French Health System prescription database in an area of 1 million inhabitants and followed for 24 weeks. RESULTS: We selected 282 users of buprenorphine defined as "new users" (74% male, mean age 32.4+/-6.2 years). Three groups were defined: 50% of "rational users" (141 subjects, no more than 2 prescribers), 24% of "occasional users" (67 subjects, less than 2 buprenorphine prescriptions) and 26% of "non-rational users" (74 subjects, 3 or more prescribers). The overall 24-week treatment retention rate was 37%. Misuse of buprenorphine or benzodiazepines was significantly more frequent in "non-rational" than "rational users". CONCLUSION: The retention rate with buprenorphine estimated in this observational study was very similar to that obtained in controlled trials. A majority of regular users of buprenorphine could be regarded as "rational users" in this area of France.

Incidence of Reye's syndrome in France: a hospital-based survey.

At the time of the study no information was available in France about the incidence of Reye's Syndrome (RS) and no warnings about RS and aspirin. The objective was to evaluate the incidence of RS in France by a hospital-based study. For a period of 1 year from November 1995 to November 1996, all French paediatric departments were required to report any child under 15 years with unexplained noninflammatory encephalopathy (i.e., CDC consciousness level stage I or deeper with normal CSF) and a threefold (or greater) increase in serum aminotransferase and/or ammonia. All suspected cases were classified by a panel of experts as probable RS or excluded RS. In 10% of randomly selected paediatric departments we checked that every suspected case had been reported. Forty-six suspected cases were reported during the year of the survey, of which 14 were classified as RS. Five of these 14 cases had a metabolic disorder. Nine children were definitively diagnosed as having RS (i.e., an estimated incidence of RS of 0.79/1,000,000 children, i.e., below 15/year). Eight children had been exposed to aspirin, four to aspirin alone and four to aspirin and acetaminophen. On the basis of these results the incidence of RS in France in 1996-1997 was not substantially different from that of countries where warning labels were already in use, but it was higher than in the US after 1994. This was probably due to the reduction in aspirin prescription in France because of warnings in Europe and the US and also because many cases of RS are now identified as metabolic disease. On the basis of these results and because the relationship between aspirin and RS has already been proved, public and professional warnings concerning RS on aspirin-containing products in cases of varicella and viral febrile illness have been adopted by the French Drugs Agency.

A study of dopaminergic sensitivity in Parkinson's disease: comparison in "de novo" and levodopa-treated patients.

The present study investigates dopaminergic sensitivity in Parkinson's disease (PD) through the measurement of neuroendocrine (growth hormone: GH, prolactin: PRL) and cardiovascular (blood pressure: BP, heart rate: HR) responses to low doses of apomorphine (5 micrograms/kg s.c.) in three groups of subjects: 13 normal volunteers (controls), 19 "de novo" never-treated PD patients, and 14 levodopa-treated PD patients. Apomorphine did not change BP and HR but significantly decreased PRL plasma levels in controls as well as in the two groups of PD patients. GH plasma levels significantly increased after apomorphine. There was no significant difference in the changes in neuroendocrine (GH, PRL) parameters in the two groups of PD patients in comparison with controls. However, "de novo" patients exhibited a significantly higher number of apomorphine-induced orthostatic symptoms (7 of 19) than did controls (0 of 13) or treated PD patients (2 of 14). These results show that hypothalamic dopaminergic sensitivity (studied through GH and PRL responses to apomorphine) is normal in PD. In contrast, because apomorphine-induced orthostatic hypotension is mainly due to the stimulation of peripheral dopaminergic receptors, our study suggests a peripheral dopaminergic hypersensitivity in some "de novo" never treated (but not in treated) PD patients.

A study of tolerance to apomorphine.

1. The present study was designed to investigate tolerance to several pharmacological effects of apomorphine. 2. Changes in blood pressure, heart rate, plasma noradrenaline levels, rectal temperature, respiratory rate and retching plus vomiting were compared after administration of apomorphine (200 micrograms kg-1, i.v. as a bolus) or saline at different time intervals (30, 120 and 720 min) in four groups of chloralose-anaesthetized dogs. 3. The first administration of apomorphine induced a significant decrease in blood pressure and rectal temperature, a marked rise in heart rate with no change in noradrenaline plasma levels or respiratory rate. Emesis occurred in 71% of the animals. 4. A second administration of apomorphine 30 min later failed to modify blood pressure or heart rate. In contrast, the magnitude of apomorphine-induced changes in blood pressure and heart rate was similar to that observed after the first administration when apomorphine was given 120 or 720 min later. 5. The apomorphine-induced decrease in rectal temperature evoked by a second dose of apomorphine was less marked when given 30 and 120 min after the first dose and unchanged when given 720 min later. 6. The number of animals exhibiting retching and vomiting was lower when apomorphine was reinjected after 30 min than when the time between two successive injections of apomorphine was 120 or 720 min. 7. These results show that tolerance to apomorphine involves its cardiovascular, hypothermic and emetic effects. The time course of tolerance to repeated injections of apomorphine is longer for its hypothermic than for its hypotensive or emetic effects. This suggests a tissue-specific regulation of D2 dopamine receptors to repeated injections of apomorphine.

[Movement disorders induced by drugs: experience at a pharmaco-vigilance center over five years]. / Mouvements anormaux d'origine médicamenteuse: l'expérience d'un centre de pharmacovigilance sur cinq ans.

The present retrospective study investigates the characteristics of drug-induced movement disorders notified to a Regional Drug Surveillance Centre. Among 4000 general side effects spontaneously reported to the Centre between 1989 and 1993, 122 were drug-induced movement disorders. Drug-induced parkinsonism (40 per cent) was mainly due to antidopaminergic agents (neuroleptics but also antiemetics or calcium channel blockers). Acute dyskinesia and dystonia (25 per cent) as well as tardive dyskinesia (14 per cent) involved mainly neuroleptics or antiemetics. Non-parkinsonian tremors (11 per cent) were related mostly to tricyclic antidepressants. Involvement of other less often suspected drugs (non-imipramine antidepressants, cardiac or hypolipidaemic drugs, etc) is discussed.

[Drug-induced alopecia: review of the literature]. / Les alopécies médicamenteuses: revue de la littérature.

Drugs are capable of producing a wide spectrum of hair loss, ranging from barely detectable shedding to irreversible baldness. Drug-induced alopecia is usually described as a diffuse non-scarring alopecia which is reversible upon withdrawal of the drug. Only a few drugs (mainly antimitotic agents) routinely cause hair loss whereas many drugs may be the cause of isolated cases of alopecia. Some psychotropic drugs are likely to induce a drug-related alopecia. Case reports with tricyclic antidepressants rarely appear in the literature. It has been reported that 15 per cent of patients taking lithium developed hair thinning. Hair loss is reported secondary to some anticonvulsant agents mainly valproic acid. Among antihypertensive drugs, systemic or topic beta-adrenoceptor antagonists should be considered as possible causes of hair loss. Hair loss from salicylates or nonsteroidal analgesics occurs in a very small percentage of patients. All anticoagulant and antithyroid drugs can produce hair loss. Diffuse hair loss can also be associated with the use of oral contraceptives, while receiving the pill and after stopping the drug. There is a long list of drugs that on occasion have been cited as causing hair loss: cimetidine, retinoids, amphetamines, bromocriptine and levodopa. A few isolated cases have been reported with some hypocholesterolaemic or anti-infectious agents. Diagnosis of drug-induced alopecia remains difficult. The only way to confirm it is to see if an improvement occurs after cessation of the suspected drug. This side effect must be recognized because it may be a source of poor compliance in some patients.

Naloxone does not prevent apomorphine-induced emesis or hypotension in dogs.

Previous data have shown that apomorphine-induced respiratory depression can be reversed by the opiate antagonist, naloxone. The present study investigates the influence of naloxone on cardiovascular changes and vomiting elicited by apomorphine in dogs. In chloralose-anaesthetized animals, naloxone (0.02 mg/kg i.v.) failed to modify either the decrease in blood pressure and the biphasic changes (bradycardia followed by a long-lasting tachycardia in heart rate or the characteristics (occurrence, latency, duration) of the emesis elicited by apomorphine (200 micrograms/kg i.v.). In contrast, in conscious animals, naloxone (0.02 mg/kg i.v.) increased both the number and the duration (but not latency) of vomiting induced by a lower dose of apomorphine (30 micrograms/kg i.v.). These data show that apomorphine-induced vomiting and arterial hypotension do not involve opiate receptors.

[Drug-induced parkinsonian syndromes: a 10-year experience at a regional center of pharmaco-vigilance]. / Syndromes parkinsoniens d'origine médicamenteuse: expérience d'un centre régional de pharmacovigilance sur dix ans.

Besides classical neuroleptics, several drugs can induce parkinsonian symptoms. The present retrospective study investigates the characteristics of drug-induced parkinsonism notified to the Midi-Pyrénées Pharmacovigilance Centre between 1983 and 1992. Among 3,923 side effects spontaneously reported between 1983 and 1992 to the center, 53 (1.4%) were drug-induced parkinsonism. Mean age was 65 +/- 2 (s.e.m.) years (range 21-88). Drug-induced parkinsonism appeared after a mean treatment duration of 473 +/- 142 days (range 1 day to 15 years) and occurred most frequently in women (63%). The occurrence onset of drug-induced Parkinsonism exhibited a bimodal pattern with a first peak (between 0 and 6 months) mainly due to peripheral or central antidopaminergic drugs and a second one later (between 9 and 12 months) due mostly to calcium channel blockers. Involved drugs were mostly antidopaminergic agents: neuroleptics (antipsychotic drugs: 39%) but also agents used for nausea or vomiting (domperidone, metoclopramide, metopimazine or triethylperazine: 12%) or symptoms associated with menopause (veralipride: 6%). Other cases were related mainly to drugs with "calcium channel blocker" properties (flunarizine and cinnarizine: 30%), H1 antihistamine (1 case), fluoxetine (1 case), alphamethyldopa (1 case) or reserpine (1 case) whereas 3 cases were due to drug interactions. Imputability scores (according to the method of assessment of unexpected drug reactions used in France) were "doubtful" (11%), "plausible" (34%) and "probable" (53%). The complete triad (tremor, akinesia plus rigidity) was seen in 13 (25%) cases. Symmetrical symptoms occurred in 41 (77%) patients. A total disappearance of the clinical feature occurred in 39 (74%) patients whereas in 8 cases (15%), drug-induced parkinsonism led to the diagnosis of underlying idiopathic Parkinson's disease. The present study shows that around 80% of drug-induced parkinsonism are due to two pharmacological classes: central and peripheral antidopaminergic agents and calcium channel blockers.

[Pharmacovigilance of antibiotics. Evaluation by the Midi-Pyrénées Pharmacovigilance Center between 1989 and 1992]. / Pharmacovigilance des antibiotiques. Bilan du Centre Midi-Pyrénées de Pharmacovigilance de 1989 à 1992.

The present retrospective study investigates the antibiotic-induced side effects in a regional French Pharmacovigilance Center between 1989 and 1992. Five-hundred and seventy six side effects were reported, involving 611 drugs and accounting for 18% of the total activity of the pharmacovigilance center. Most of the side effects involved penicillins and systemic quinolones followed by sulfonamides, cephalosporines and glycopeptides. When expressed in number of adverse effects in Defined Daily Dose, the maximal frequency of side effects was observed with sulfonamides. In contrast, the frequency of penicillin-induced adverse events was low. The most frequently reported side effects were cutaneous and/or immunologic (54%) and digestive (24%) disturbances. Among serious side effects, 3 toxic epidermal necrolysis (2 with cotrimoxazole), 16 pseudomembranous colitis (11 with beta-lactam antibiotics, 4 with macrolides and lincomycines and 1 with vancomycin), 14 neuropsychiatric reactions (seizures, confusions and hallucinations with beta-lactam antibiotics and fluoroquinolones) were notified. Five antibiotic-induced side effects led to the death.

Drug-induced parkinsonism: a review.

The main clinical features, pathophysiology and underlying mechanisms of drug-induced parkinsonism are reviewed. The clinical manifestations of drug-induced parkinsonism are often indistinguishable from idiopathic Parkinson's disease. However, some subtle differences may exist: for example drug-induced parkinsonism is often associated with tardive dyskinesias, bilateral symptoms and the absence of resting tremor, etc. Besides toxins (eg manganese, carbon monoxide or MPTP), many drugs are known to produce parkinsonism: dopamine blocking drugs (true neuroleptics used as antipsychotics: phenothiazines, butyrophenones, thioxanthenes but also sulpiride, "hidden" neuroleptics prescribed as anti-nausea or anti-vomiting drugs (such as metoclopramide and other benzamide derivatives), dopamine depleting drugs (reserpine, tetrabenazine), alpha-methyldopa, calcium channel blockers (flunarizine, cinnarizine, etc). The putative role of other drugs (eg fluoxetine, lithium, amiodarone) as well as the therapeutic management of this side effect are reviewed.

The effect of yohimbine on sympathetic responsiveness in essential hypertension.

We have studied the sympathetic response to blockade of presynaptic alpha 2-adrenoceptors in essential hypertension by measuring plasma concentrations of noradrenaline after a single oral dose of yohimbine, an alpha 2-adrenoceptor antagonist. Mean baseline plasma noradrenaline and adrenaline concentrations were similar in the hypertensive and normotensive groups. Yohimbine (0.2 mg x kg-1 orally) caused a lesser increase in the plasma concentrations of noradrenaline in hypertensive patients (+67%) than in normotensive subjects (+178%) and a pressor response in hypertensive (but not in normotensive) patients. These results are consistent with an alteration in the balance of alpha-adrenoceptors (for example presynaptic alpha 2-adrenoceptor desensitization and post-synaptic alpha 1-adrenoceptor hyper-responsiveness) which would help to develop and/or maintain arterial hypertension.

[Is there any desensitization of presynaptic alpha 2-adrenergic receptors in hypertension? Experimental and clinical studies]. / Existe-t-il une désensibilisation des récepteurs alpha 2-adrénergiques présynaptiques dans l'hypertension artérielle? Etudes expérimentales et cliniques.

Several authors have discussed an alteration of adrenergic receptivity in arterial hypertension. De Champlain (Hypertension 1990; 8: S77-S85) suggested that postsynaptic alpha 1-adrenergic functions became dominant while beta-adrenergic functions are attenuated in arterial hypertension. However, the status of presynaptic alpha 2-adrenoceptors remains unknown. The present study investigates presynaptic alpha 2-adrenoceptors in hypertension through the measurement of plasma levels of noradrenaline after administration of yohimbine, an alpha 2-adrenoceptor antagonist, in essential hypertension. Yohimbine (0.2 mg/kg per os) induced a 73% increase of plasma levels of noradrenaline in hypertensive patients (n = 12) and a 178% one in normotensive subjects (n = 6, p < 0.05). A similar significant difference was found in experimental neurogenic hypertension observed in awake dogs 3 weeks after sinoaortic denervation: the increase in plasma concentrations of noradrenaline after yohimbine (0.5 mg/kg i.v.) was +279% in hypertensive versus +642% in normotensive dogs (p < 0.05). The results show that the magnitude of the yohimbine-induced sympathetic activation is lower in hypertensives than in normotensives. They suggest the existence of a presynaptic alpha 2-adrenoceptor desensitization in arterial hypertension. The abnormality of this presynaptic inhibitory mechanism can increase the sympathetic tone and help to develop and maintain arterial hypertension.

Parkinson's disease and weight loss: a study with anthropometric and nutritional assessment.

In order to investigate a putative weight loss in patients with Parkinson's disease, an anthropometric and biochemical study was undertaken. We compared body weight and indexes of fat [body mass index (BMI), tricipital skinfold] and lean [midarm muscle area (MMA), calf circumference] mass in men and women suffering from idiopathic Parkinson's disease with normal controls. We found that women suffering from Parkinson's disease exhibited a significant weight loss (-8.5%) and decreased calf circumference when compared with controls. A decrease (-4.3%) in total body weight was also found in men with Parkinson's disease but the difference did not reach the level of significance. Protein biochemical markers of nutritional status (albumin, prealbumin, retinol binding protein, transferrin) were normal in Parkinson's disease patients. The present study demonstrates the occurrence of weight loss in a large population of patients with Parkinson's disease. The putative mechanisms involved in the weight loss are discussed.