Fluoride salts are no better at preventing new vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis: the FAVOStudy.

Although fluoride salts have been shown to be capable of linearly increasing spinal bone mineral density (BMD) in postmenopausal osteoporosis, the effects of this gain in density on the vertebral fracture rate remain controversial. We conducted a 2-year multicenter, prospective, randomized, double-masked clinical trial in 354 osteoporotic women with vertebral fractures (mean age 65.7 years). They received either fluoride (208 patients), given as sodium fluoride (50 mg/day) or as monofluorophosphate (200 mg/day or 150 mg/day), or a placebo (146 patients). All patients received daily supplements of 1 g of calcium (Ca) and 800 IU of vitamin D2 (D). A 1-year open follow-up on Ca-D was obtained in 124 patients. After 2 years the fluoride group and the Ca-D group had increased their lumbar BMD by 10.8% and 2.4% respectively (p = 0.0001). However, the rate of patients with at least one new vertebral fracture, defined by semiquantitative assessment and evaluable on an intention-to-treat basis in 89% of patients, was similar in the fluoride groups and the Ca-D group. No difference between the three fluoride regimens was found. The percentage of patients with nonvertebral fractures was not different in the fluoride and Ca-D groups (1.9% and 1.4% respectively for hip fractures). A lower limb pain syndrome occurred more frequently in the fluoride groups. In the 124 patients followed for 1 year after cessation of fluoride therapy, the percentage of patients with at least one new vertebral fracture after 36 months was identical to the percentages in the previous fluoride group and the Ca-D group. We conclude that fluoride-Ca-D regimen was no more effective that Ca-D supplements for the prevention of new vertebral fractures in women with postmenopausal osteoporosis.

[Cardiac accidents of locoregional anesthesia: experimental study of risk factors with bupivacaine]. / Accidents cardiaques de l'anesthésie locorégionale: étude expérimentale des facteurs de risque avec la bupivacaïne.

Cardiac disorders are observed when excessive plasma concentrations of local anaesthetics are reached, following for instance intravascular accidental injection for epidural anaesthesia or brachial plexus block. Bupivacaine particularly, which is one of the most used local anaesthetics, adversely affects intraventricular conduction and cardiac contractile strength from the 3.0-4.0 micrograms/ml blood levels. Depression of conduction is especially to be feared, for it can result in reentrant arrhythmias likely to degenerate into often fatal ventricular fibrillation. Such accidents may sometimes occur at far lower concentrations, subsequent to diffusion into systemic circulation from the injection site (0.4-1.2 micrograms/ml). These accidents were probably due to various factors which concomitantly intervene during the anaesthesia. We could identify a number of these factors by associating them to an intravenous infusion of bupivacaine (0.04 mg/kg/min after a loading dose of 1.00 mg/kg) in animals (dogs and pigs) under electrocardiographic monitoring, in which conduction time, monophasic action potential duration, effective refractory period and electrical fibrillation threshold were determined in the ventricular fibres. The electrophysiological changes due to bupivacaine may be enhanced by 1) dilution hyponatremia (115-110 mmol/l) induced by a short (5 min) intravenous 10 ml/kg/min infusion of hypotonic solution and/or hyperkalemia (7-8 mmol/l) induced by 0.05 mmol/kg/min infusion of potassium chloride; 2) the acceleration of cardiac contractions (180-210 beats/min) induced by ventricular pacing; 3) mild hypothermia (35-34 degrees C) induced by blood cooling in an extracorporeal circuit; 4) myocardial ischaemia induced by complete temporary occlusion of the left anterior descending coronary artery near its origin. The risk of cardiac accidents, possibly severe, is therefore enhanced by each of these factors capable of lowering the concentration required for their triggering and, of course, the combination of two or several of them. On the contrary, the knowledge of these factors should allow to prevent most of cardiac accidents of locoregional anaesthesia.

[Drug-induced fever caused by hydroxyurea. Apropos of 3 new cases]. / Fièvre médicamenteuse induite par l'hydroxyurée. A propos de trois nouveaux cas.

Drug-induced fever is a frequent (3-5% of all adverse effects) but under recognized adverse effect of several drugs. Hydroxyurea, an antimetabolite cytostatic agent, has rarely been involved in the occurrence of fever. We report three additional cases of hydroxyurea-induced fever including one case with pulmonary involvement (acute alveolitis). In these cases, the role of hydroxyurea was strongly suggested by the delay to onset of symptoms (16-36 days), the disappearance of fever within a few hours after drug withdrawal, the recurrence of fever shortly after rechallenge in two patients, and the absence of any other obvious cause.

Calcium antagonists and prevention of ventricular fibrillation induced by transient or persistent ischemia.

Experimental studies have shown the limitation by calcium antagonists of the propensity to fibrillation secondary to the occlusion of a large coronary artery. However, this capacity, studied in the acute phase of infarction, is less obvious and still under debate. Ischemia was therefore produced in anesthetized, open-chest pigs by complete occlusion of the left anterior descending coronary artery according to two modes, either near its origin during brief but increasing periods (30, 60, 120, 180 s, etc) or half-way from this origin for a much longer time (60 min). The time course of vulnerability to fibrillation was monitored by ventricular fibrillation threshold (VFT), measured by trains of diastolic stimuli of 100 ms. Verapamil was administered in a 50 micrograms/kg dose followed by 2 micrograms/kg/min infusion. 1) In the case of brief proximal occlusions under pacing at a constant high rate (180 beats/min), verapamil slowed the decline of VFT from 6-8 mA to nearly 0 mA. VFT was 4.4 +/- 0.4 mA after 60 s ischemia, whereas it had already fallen to 1.8 +/- 0.3 mA (p < 0.001) in the absence of the drug. Accordingly, the onset of spontaneous fibrillation which depends on the decrease in VFT to about 0 mA was prolonged from 2-3 to 6-9 min. Bradycardia, concurrently produced by verapamil, is a factor which enhances these alterations. 2) In the case of a persistent midportion occlusion of the artery under sinus rate, fibrillations were similarly delayed by verapamil from 14-25 to 23-49 min after occlusion, but they were more numerous. VFT was lowered to critical values later, but also for a longer time. The period propitious to fibrillation was prolonged because the return of VFT to higher values reflecting hypoexcitability subsequent to the first cell injury was substantially delayed. Consequently, calcium antagonists should often prevent ventricular fibrillation when transient ischemia disappears before VFT falls to the vicinity of 0 mA. In contrast, a real benefit could not be expected from these drugs when ischemia is persistent since they then only delay fibrillations, the number of which is increased.

[Acute drug-induced agranulocytosis: experience of the Regional Center of Pharmacovigilance of Lyon over 7 years]. / Agranulocytoses aïgues médicamenteuses: expérience du Centre Régional de Pharmacovigilance de Lyon sur 7 ans.

Sixty-two cases of drug-induced agranulocytosis, spontaneously reported to the regional drug monitoring centre in Lyon from 1988 to 1994, have been analysed. The mean age of patients was 58.6 years, and sex ratio was 1:1. The mean delay of onset was 46.2 days and absolute neutrophil counts (ANC) dropped below 0.1 x 10(9)/l in 73 per cent of patients. Bone marrow aspirates disclosed absence of myeloid series in 28 per cent of investigated cases. Neutrophil recovery occurred after a mean of 9.3 days, and the overall fatality rate was 6.5 per cent. Haematopoietic growth factors (HGF) were used in 11 patients with an ANC below 0.1 x 10(9)/l and/or a hypoplastic bone marrow. We have found no clear indication for a potential benefit of HGF treatment, but HGF were usually administered late during the course of neutropenia, i.e., after a mean of 6 days. The incidence rate estimated for people living in the Rhône administrative division was 3.3 per million per year, similar to that found in epidemiological studies. Drugs most frequently involved were anti-infective agents and psychotropic drugs.

[Neutropenia during treatment with fusidic acid: analysis of 5 cases]. / Neutropénies au cours de traitements par l'acide fusidique: analyse de cinq observations.

Two cases of moderate neutropenia and 3 cases of severe neutropenia in the course of fusidic acid treatment for sepsis related to a hip prothesis or septic osteitis are reported. Neutropenia was always observed following routine blood cell count, after a mean of 21 days' treatment (16 to 27 days). Moderate fever was observed only once, in a patient with profound neutropenia. A complete recovery of blood cell count was noted in all cases, 5 to 9 days upon discontinuation of fusidic acid. A sternal bone-marrow aspiration was performed in 4 cases, showing normocellularity or hypercellularity in two cases, and moderate hypoplasia of granulocytic cells. The respective roles of other treatments are discussed. Overall, these five cases suggest that reversible granulocytopenia can be caused by protracted treatment with fusidic acid. Although nine different associated drugs could also have been involved in four patients, the causal relationship was less suggestive for three of them due to chronological events. In other cases, the drugs never or very rarely caused neutropenia. Finally, the possibility of vancomycin-induced neutropenia cannot be excluded in one case.

[Exacerbation of myasthenia gravis by pefloxacin]. / Aggravation d'une myasthénie sous péfloxacine.

Pefloxacine 800 mg single dose was given as routine treatment after a cystomanometric examination to a 45-year-old woman with a 30-month history of generalized myasthenia gravis. One hour after, the patient developed exacerbation of myasthenia gravis with bilateral ptosis and an increased generalized weakness. She experienced a rapid improvement during the next 8 hours and physical examination returned to normal within one day. No additional factors which might have contributed to the exacerbation of myasthenia gravis were found. The report of exacerbation of myasthenia gravis with other antibiotic belonging to the group of fluoroquinolones (ciprofloxacin, norfloxacin and ofloxacin) prompt us to recommend caution with the use of all fluoroquinolones in myasthenic patients.

[Follow-up of 151 pregnant women exposed to antidepressant treatment (MAOI excluded) during organogenesis]. / Suivi de 151 grossesses exposées à un traitement antidépresseur (IMAO exclus) au cours de l'organogenèse.

The Pharmacovigilance and Poisons Center in Lyon undertook an analysis of their data on antidepressant (MAOI excluded) exposure during the first trimester of pregnancy. From 1986 to 1991, 151 prospective enquiries were collected of which 145 exposures occurred during the first trimester of pregnancy. The outcome of pregnancy was known for 114 of these cases. Voluntary or medical abortion was decided in 24 cases, spontaneous abortion occurred in 11 patients and fetal death, unrelated to drug exposure, was noted in one case. Delivery was reported in 78 cases including 69 (88.5%) normal infants, with obstetrical complications not related to the treatment in 7 of these cases. Neonatal complications were noted in 5 (6.4%) cases, including withdrawal symptoms possibly related to the treatment in 3 cases. Congenital abnormalities were identified in 4 cases (5.1%) with one case of major malformation (membranous ventricular septal defect). Such a study is not an exhaustive survey of antidepressant exposure during pregnancy, but a collection of inquiries received by our centre. Even though our study's ability to detect an overall increase in the risk of malformations is too low and limited the extent of our conclusion, our results are in agreement with the literature data as no important increased in major birth defect was observed.

[Hypoglycemia induced by oral hypoglycemic agents. Records of the French Regional Pharmacovigilance Centers 1985-1990]. / Hypoglycémies induites par les sulfamides hypoglycémiants. Recensement par les Centres Régionaux de Pharmacovigilance français de 1985 à 1990.

All 98 cases of sulfonylurea-induced hypoglycemia reported by the 30 regional drug-monitoring centers between 1985 and 1990 were analyzed: 46 with gliclazide, 40 with glibenclamide, 5 with glipizide, 1 with glibornuride and 6 with first-generation sulfonylureas. These cases of hypoglycemia were often serious. The patients were 61% female and their mean age was 78.9 years. The average number of medications being taken was 3.4, but ranged up to 14. The risk factors were: reduced food intake (4.2%), renal failure (4.2%), prescription error (3.2%), voluntary or accidental overdose (5.2%), alcohol (1.1%), suspected drug interactions (50%), unknown (32.6%). The most frequent drug interactions involved miconazole (8 cases), angiotensin-converting enzyme inhibitors (9 cases), lipid-regulating agents (fibrates) (7 cases), co-trimoxazole (trimethoprim-sulfamethoxazole; 5 cases), metformin (4 cases), histamine H2-receptor antagonists (4 cases). The mechanisms of these interactions are discussed.

Side effects of ranitidine.

Ranitidine was first marketed in 1981; since then many patients have been treated such that much experience has been accumulated on the safety of this histamine H2-receptor antagonist in the treatment of gastroduodenal disease. A wide array of ranitidine-associated side effects has been described, but infrequently. As so much information is now available, the aim of this review is to assess the weight of evidence for a causal link between ranitidine and the reported side effects. Overall, ranitidine is well tolerated. The incidence of general side effects at less than 2% is very similar to placebo. Headaches, tiredness, dizziness and mild gastrointestinal disturbance (e.g. diarrhoea, constipation and nausea) are among the most frequent complaints, but have very seldom resulted in stopping treatment. Cardiovascular side effects are extremely rare and unpredictable with the usual doses of oral ranitidine (at most 1 in 1 million patients). They mostly comprise sinusal bradycardia and atrioventricular blockade, especially after rapid intravenous administration, receding after cessation of the drug. Clinical studies, however, have not shown a significant pharmacological effect of ranitidine on the cardiovascular system via H2-receptors, even though individual sensitivities cannot be ruled out in a few isolated reports. Ranitidine is unlikely to be directly hepatotoxic: a transient change in liver function tests has been noted in only 1 in 100 to 1 in 1000 patients. Several cases of mixed hepatitis have been reported, but very few were fully documented. The incidence of ranitidine-associated acute hepatitis has been estimated to be less than 1 in 100,000 patients. Neuropsychiatric complications may be less common and clinically quite similar to those reported with cimetidine, i.e. confusion, disorientation, hallucinations, delirium. These side effects have occurred especially in critically ill and multiple-therapy patients, or patients with chronic renal or hepatic failure, so that the direct causal link with ranitidine treatment was often difficult to ascertain. Even though an H2-receptor-mediated effect is an attractive hypothesis (since similar complications were noted with other H2-receptor antagonists), other mechanisms have been suggested to play a role, e.g. cholinergic or histaminic effects. The overall incidence of neuropsychiatric complications is probably markedly less than 1%. White cell injury (i.e. agranulocytosis) appears to be the most frequent haematological complication, even though case reports are very few and poorly documented.(ABSTRACT TRUNCATED AT 400 WORDS)

[Retroperitoneal fibrosis with eye-drops containing timolol]. / Fibrose rétropéritonéale et timolol en collyre.

Retroperitoneal fibrosis occurred in a 62-year-old man who had been treated during 4 years eye-drops containing timolol. The disease was diagnosed after a sudden episode of nephritic colic. The recovery was progressive and uneventful. No corticosteroid therapy was used. Six months later the patient remained free of symptoms. Although an idiopathic origin could not be excluded, the causal relationship with timolol treatment is likely due to the chronology of events and the lack of other causes.

[The caffeine test]. / Le test á la caféine.

The inhibition of oxidative drug metabolism is a major cause of clinically significant drug interactions. Among the possible modalities for exploring the enzyme inhibiting potential of drugs, the caffeine test is a valuable addition to the antipyrine test in man. Indeed, microsomal enzymes explored by the caffeine test differ from those attainable by the antipyrine test. After a short overview of caffeine pharmacokinetics, the features of the caffeine test are tentatively described. The results of published studies indicate the usefulness of this simple test for detecting those new drugs endowed with an enzyme inhibiting potential.