[The origins of clinical pharmacology in France]. / Origines de la pharmacologie clinique en France.

This text is a history of the early development of clinical pharmacology in France in the 60s and 70s. It relates the obstacles that needed to be surmounted to impose clinical trials, pharmacovigilance, therapeutic drug monitoring. It follows the evolution of regulations, and the constitution of a new hospital and academic discipline. This study shows the obstacles raised by an established medical tradition against a change in paradigm towards a scientific approach to the evaluation and clinical use of drugs. It relates a crucial moment of the history of French pharmacology, when French medicine entered the modern era.

[Drug evaluation in France: comparison of two approaches]. / L'évaluation des médicaments en France: comparaison de deux approches.

Two independent expert groups assess new medicines in France: that of the journal Prescrire (P), and the official Transparency Commission (CT). Each uses its own 5-level scale to assess its contribution to therapeutics (P: (1) bravoi, (2) interesting, (3) adds something, (4) possibly useful, (5) nothing new; CT: (1) major, (2) important, (3) moderate, (4) modest, (5) none). We have compared the gradings for new drugs in P from 1993 to 1998 (except vaccines, generics and items for exclusive hospital use) to those of CT. Of 414 P gradings, 14 were without opinion, 54 were not found in CT (old or unexamined products), and 82 had been examined but not graded. The 264 graded pairs were 99 new substances (NS), 17 new combinations (NA), 50 new indications (NI), 56 new formulations (NF), 27 new dosages (ND), 10 new forms of packaging (NC), and 5 late gradings or reregardings (CR). For NS and NA, there were 21 discordances (2 degrees difference or more) between P and CT. When P is shifted one point to the left (better gradings), the number of discordances decreases to 2. NI, NF, ND, NC were less often graded by CT (respectively 63 per cent, 67 per cent, 54 per cent, 31 per cent of gradings). For NI, high CT grading results in 15 discordances (30 per cent). For NF, ND, NC the concordance is good (respectively 3, 1, 0 discordances). For CR, 13 of 18 products (72 per cent) are downgraded for P, and are discordant with the 5 initial CT grades. In 3 per cent of cases, P emits no opinion, CT gives a high grading in 2/3, never null (these are for severe diseases). In conclusion, the two groups of experts come to similar conclusions considering different objectives (use or not a new drug vs. give indications for reimbursement) and the time distortion. Discrepancies can also be explained thus, but some can result from differences in appreciation of the data.

Benzodiazepines and hip fractures in elderly people: case-control study.

OBJECTIVE: To determine whether benzodiazepines are associated with an increased risk of hip fracture. DESIGN: Case-control study. PARTICIPANTS: All incident cases of hip fracture not related to traffic accidents or cancer in patients over 65 years of age. 245 cases were matched to 817 controls. SETTING: Emergency department of a university hospital. MAIN OUTCOME MEASURES: Exposure to benzodiazepines and other potential risk or protective factors or lifestyle items. RESULTS: The use of benzodiazepines as determined from questionnaires, medical records, or plasma samples at admission to hospital was not associated with an increased risk of hip fracture (odds ratio 0.9, 95% confidence interval 0.5 to 1.5). Hip fracture was, however, associated with the use of two or more benzodiazepines, as determined from questionnaires or medical records but not from plasma samples. Of the individual drugs, only lorazepam was significantly associated with an increased risk of hip fracture (1.8, 1.1 to 3.1). CONCLUSION: Except for lorazepam, the presence of benzodiazepines in plasma was not associated with an increased risk of hip fracture. The method used to ascertain exposure could influence the results of case-control studies.

[Pharmacoepidemiology: definitions, problems, methodology]. / Pharmaco-épidémiologie: définition, problèmes, méthodologie.

Pharmacoepidemiology aims to complete the evaluation of drugs made before approval, by providing reliable information concerning effectiveness, safety and utilization of medicines in realistic conditions. The goal may be only descriptive or aetiological. In the latter, the conclusions from observational studies can be jeopardized by systematic errors and cannot achieve the robustness of experimental designs. According to directionality, three main types of studies can be identified: cross-sectional, prospective and retrospective. Prospective and retrospective studies can be based on a single group (descriptive studies) or include a reference group (comparative or aetiologic studies). The interest of prospective studies is reduced when (1) the incidence of the considered event becomes low or (2) one intends to assess the effects of various causal factors. Retrospective studies are approaching their limits when (1) the prevalence of the exposure is low in the source-population or (2) several events or outcomes are concerned.

Adverse drug reactions: physicians' opinions versus a causality assessment method.

Since spontaneous reporting of adverse drug reactions depends on the physician's opinion of the relationship between the drug and the adverse event, we compared physicians' opinions with the scores obtained by the causality assessment method used in France. During a 2 month period, all physicians who reported adverse drug reactions (ADRs) to our pharmacovigilance centre expressed their opinions on the causal link by means of visual analogue scales. ADR reports were then assessed with the French causality assessment method by a clinical pharmacologist who was blind to physicians' opinions. The assessment by both physicians and the standardized method was performed for 75 ADR cases involving 120 drugs. Physicians used a wide range of assessments, with a preponderance of extreme scores, resulting in a U-shaped distribution, while the standardized method gave generally low scores. Scores given by physicians were very high (causality considered very likely or likely) in 60% of cases and very low (causality considered unlikely or dubious/possible) in 32% of cases. Scores obtained using the causality assessment method were low (causality dubious/possible) in 89% of cases and causality considered likely in only 11 cases, essentially in cases with positive rechallenge. Complete agreement occurred in only 6% of cases. Adding complete agreement and minor discrepancies raised the percentage to 49%.

Pharmacokinetics of intravenous and intraperitoneal ceftazidime in chronic ambulatory peritoneal dialysis.

The pharmacokinetics of ceftazidime have been investigated in eight patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis. Each subject was given ceftazidime 1 g intravenously and 1 g intraperitoneally at an interval of 1 week. Ceftazidime was assayed by high-pressure liquid chromatography. After intravenous administration, the pharmacokinetic parameters of ceftazidime were: elimination plasma half-life (t1/2 beta) = 24.6 +/- 4.6 hours; apparent volume of distribution (V(area)): 0.37 +/- 0.09 1/kg, total plasma clearance (CL): 11.9 +/- 3.3 mL/minute, peritoneal clearance (CLp): 1.7 +/- 0.3 mL/minute. Over 72 hours, only 15.6 +/- 4.7% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftazidime appeared in the plasma rapidly, and the peak plasma concentration of 24.5 +/- 5.2 mg/L was achieved at the fourth hour; the elimination half-life (t1/2ke) was 20.8 +/- 1.7 hours. The absorption of ceftazidime from the peritoneal space was 74.1 +/- 7.4%. These data suggest that ceftazidime has bidirectional exchange characteristics through the peritoneal membrane. A single 1-g intraperitoneal dose led to serum and dialysate concentrations of ceftazidime above the minimum concentrations for susceptible pathogen germs for 24 hours.

[Imputability of drug side effects]. / Imputabilité des effets indésirables des médicaments.

By imputability it is meant the assessment of the probable responsability of a drug in the development of undesirable effect. Its principle is based on the evaluation of some criteria derived from observation (intrinsic imputability) or relevant literature (extrinsic imputability). Around ten imputability methods have so far been reported; although they are not comparable, personnel differences in evaluation may be avoided.

[Effect of temperature on the kinetics of propranolol, theophylline, phenytoin and digoxin in rats (author's transl)]. / Influence de la température sur la cinétique du propranolol, de la theophylline, de la phenytoine et de la digoxine chex le rat.

1. The effect of chronic hyperthermia (35 degree C for 1 month) on the kinetics of propranolol, theophylline, diphenylhydantoin and digoxin was studied in groups of male Wistar rats. 2. Each compound was administered by intravenous injection, dosage being 2 mg/kg for propranolol, 3 mg/kg for theophylline, 10 mg/kg for phenytoin, and 0.01 mg/Kg for digoxin. 3. Total body clearance was diminished, mainly by an increase in the elimination half-life, for propranolol, theophylline, and digoxin. That of phenytoin remained unchanged. 4. Distribution volume increased slightly with propranolol, theophylline, digoxin.