Quinacrine has been reported as an antiprion agent and proposed as an immediately applicable treatment for Creutzfeldt-Jakob disease (CJD). The authors report the results of an open compassionate procedure to which 32 CJD patients had access. In some genotypic subgroups, a slight but nonsignificant increase in survival was observed, likely due to biased inclusion of long-term surviving patients. There was no pathologic evidence of a beneficial effect of quinacrine treatment.
Creutzfeldt-Jakob Syndrome/drug therapy , Quinacrine/therapeutic use , Brain/pathology , Creutzfeldt-Jakob Syndrome/mortality , Creutzfeldt-Jakob Syndrome/pathology , Disease Progression , Drug Evaluation , Humans , Quinacrine/administration & dosage , Quinacrine/adverse effects , Survival Analysis , Treatment Failure
BACKGROUND: The risk of occurrence of medical events in a clinical trial is competitive in nature; that is, in a given patient the risk of having a critical event depends on the amount of time elapsed since random assignment and on the previous events that may have occurred in the patient. The purpose of this study was to examine the relations between baseline variables, the interactions between treatment, bisoprolol, or placebo, and the occurrence of critical events during the CIBIS trial, a mortality and morbidity trial of beta-blockade in patients with heart failure. METHODS AND RESULTS: A Cox model for censored data was used to analyze the relations between baseline variables, total deaths, permanent treatment withdrawals, nonlethal cardiovascular events, and their interactions with bisoprolol or placebo. We examined the influence of treatment on the occurrence of deaths, permanent treatment withdrawals, and nonlethal cardiovascular events by using the technique of event history analysis, which takes into account competitive risks between events. Compared with placebo, bisoprolol reduced mortality rates in patients with a left ventricular ejection fraction < or =20% (relative risk [RR] 0.49; 95% confidence interval [CI] 0.27 to 0.88; P =.02). In patients whose baseline heart rate was in the upper tertile of distribution, permanent treatment withdrawals were less frequent in patients randomly assigned to bisoprolol than in patients randomly assigned to placebo (RR 0.50; 95% CI 0.28 to 0.88; P =.02). Bisoprolol reduced the incidence of nonlethal cardiac events in patients in whom heart failure was present for at least 4 years (RR 0.44; 95% CI 0.27 to 0.71; P <.01). Event history analysis revealed that among patients who died under treatment after having at least 1 nonlethal cardiovascular event, 20 patients were treated with placebo but only 7 patients were treated with bisoprolol (RR 0.41; 95% CI 0.17 to 0.98; P <.05). CONCLUSIONS: Some patients with heart failure derive more benefit from beta-blocker therapy than others. In the CIBIS trial, they are those patients with the lower left ventricular ejection fractions and those who have nonlethal cardiovascular events but in whom beta-blocker therapy is not permanently discontinued.
Adrenergic beta-Antagonists/therapeutic use , Bisoprolol/therapeutic use , Heart Failure/drug therapy , Heart Failure/mortality , Aged , Female , Heart Failure/physiopathology , Humans , Male , Middle Aged , Prognosis , Randomized Controlled Trials as Topic , Risk Assessment , Survival Analysis
The carrying out of clinical trials with a view to the marketing of drugs for human use is directly related to results of some animal studies. This workshop was devoted to evaluation of the quality and interest of these experimental models in reproductive toxicology. The predictive ability of preclinical trials to make extrapolations from animals to man decreases from foetotoxic to tetratogenic risks respectively and from the effects on fertility in both sexes to postnatal risks. As a result of this workshop, we propose the following improvements: (1) standardization and generalization of fertility test evaluations, especially the spermogram, in order to improve animal and human correlations; (2) development of knowledge and standardization of the follow up of the oestral cycle; (3) improvement of standardization, harmonization and diffusion of postnatal tests that prove relevant in animals; (4) increase in initiatives aimed at better mutual understanding of all drug partners; (5) creation of registers for new drugs, as soon as possible during clinical trials, to study their effects on the whole reproductive process; (6) recommendations for the creation of guidelines for International Conference on Harmonisation (ICH) to enable classification of observed effects in experimental models. This could lead to specific (potentially for each phase of the reproductive cycle) guidelines, precautions for use and/or contraindications which are listed in the summary of product characteristics.
Drug Evaluation/standards , Reproduction/drug effects , Teratogens/toxicity , Toxicology/standards , Animals , Drug Evaluation/methods , Female , Fertility/drug effects , Humans , Male , Predictive Value of Tests , Risk Factors , Toxicology/methods
This paper introduces some comments on the complete text of Good Pharmacovigilance Publishing Practices, which forms appendix number 2 of the Good Pharmacovigilance Practices now published by the French Drug Agency, as was Good Clinical Practices. Each good practice is printed in italic and presented in a frame; the following comments are designed to facilitate its application. The technical terms that are used in this text are presented according to the glossary in Good Pharmacovigilance Practices.
Adverse Drug Reaction Reporting Systems , Periodicals as Topic , Product Surveillance, Postmarketing , France
We diagnosed Cruetzfeldt-Jakob disease in 34 patients (16 definite, 18 probable) who had received human growth hormone extract for various period of time (mean +/- SD, 2.9 years), but particularly during the period between January 1984 and July 1985, a potential high-risk factor. Disease duration for deceased patients (n = 30) was 17 +/- 9 months. The clinical picture was homogeneous, starting with cerebellar ataxia and ocular motor disorders in about 90% of the patients. Neurologic deterioration, including dementia and myoclonic jerks, occurred within months. The high number of cases (1.5% of those treated between 1959 and 1988, 3% of those treated during the putative high-risk period) is still unexplained. We discuss the possibility that new cases will be detected,the risk of contaminating the general public, and the sanitary measures undertaken to prevent this.
Creutzfeldt-Jakob Syndrome/etiology , Drug Contamination , Human Growth Hormone/adverse effects , Adolescent , Adult , Female , France , Humans , Male
Evaluating a teratogenic risk remains a difficult problem, since the existing data in this field is fragmentary. One can consider using the material obtained by the follow-up of pregnancies which have motivated a telephone consultation to an Information Center. The material could, within limits, be used to give some security. If the present numbers do not change, it would take around four years to obtain data concerning 150 women exposed during the first trimester of their pregnancy.
Abnormalities, Drug-Induced/epidemiology , Drug Information Services , Prenatal Exposure Delayed Effects , Abnormalities, Drug-Induced/etiology , Data Collection/methods , Drug Information Services/statistics & numerical data , Female , Follow-Up Studies , Humans , Pregnancy , Pregnancy Trimester, First , Product Surveillance, Postmarketing , Risk Factors , Teratogens
A knowledge of pharmacokinetic data is particularly important with drugs that have a narrow margin of safety. Exhaustive pre-marketing pharmacokinetic investigations and pharmacokinetic studies in populations are the two principal means of acquiring such knowledge. Although popular, the concept of half-life which decreases with age for many drugs is insufficient to calculate dosage in elderly people. Measurements of creatinine clearance provide an almost mathematical approach to the dosage of drugs that are excreted exclusively by the kidneys. In contrast, changes in hepatic metabolism with age and pathology are difficult to evaluate, and their consequences are often vaguely perceived. Our knowledge of relationships between age and pharmacodynamics is still in infancy. Owing to the wide consumption of medicine by elderly people, drug interactions are frequent at all stages, including absorption, metabolization, transport and site of action.
Pharmacokinetics , Administration, Oral , Age Factors , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Female , Humans , Male , Metabolic Clearance Rate , Pharmaceutical Preparations/administration & dosage
Disopyramide is a group I antiarrhythmic drug which is mainly used for the treatment of ventricular and supraventricular rhythm disturbances. Commonest side effects result from disopyramide's anticholinergic activity. Other side effects such as hypoglycemia have been reported less frequently. We report one observation of disopyramide induced hypoglycemia, and a review of the literature is presented. Including our observation, 14 cases (9 men and 5 women, aged from 41 to 88) have so far been reported. Doses of disopyramide ranged from 200 to 1,200 mg per day, administered from one day to one year. Symptomatology was mainly neurologic (12 patients) and two patients were clinically asymptomatic. The outcome was favorable in all but the 2 patients who died with persistent hypoglycemia after a single dose of 250 mg in one patient and after 400 mg daily during 4 days in the other (without stopping the drug). Renal function was markedly impaired in 9 patients, two of these patients being on a long term dialysis therapy. Blood levels of disopyramide were measured in 7 patients and ranged from 1 to 11.4 ng/ml. In five patients it was in the normal range (1-4 ng/ml). Three patients were rechallenged for disopyramide: hypoglycemia occurred in all, without clinical symptoms in two of them. The main risk factors of disopyramide induced hypoglycemia are a preexisting chronic renal failure, advanced age, and malnutrition. In these patients normally non toxic disopyramide blood levels, as defined in normal subjects, seem to be inappropriately high. We suggest that in patients at risk, disopyramide blood levels should be maintained at the lower range of therapeutic level.(ABSTRACT TRUNCATED AT 250 WORDS)
Disopyramide/adverse effects , Hypoglycemia/chemically induced , Aged , Blood Glucose/metabolism , C-Peptide/blood , Disopyramide/therapeutic use , Humans , Insulin/blood , Kidney Failure, Chronic/blood , Male
Foscarnet (FC) is a new antiviral agent which has been recently proposed for the treatment of severe cytomegalovirus (CMV) infections in immunocompromised patients. When used intravenously (i.v.), main adverse effects of FC are a fall in hemoglobin, and an increase in liver enzymes and serum calcium. Although increased serum creatinine have been noted in several patients, deterioration of renal function is often accounted for by the concomitant use of other nephrotoxic drugs, the severity of underlying disease or the presence of graft rejection. Consequently FC is often considered as a non or poorly nephrotoxic drug. We report 4 cases of acute renal failure (ARF) which can be exclusively attributed to FC. FC was used for CMV chorioretinitis in 3 AIDS patients and in one non-immunocompromised patient. ARF was diagnosed between the 6th and 15th day of treatment, with oligoanuria in two patients (one of whom required two hemodialysis periods). ARF was most likely secondary to acute toxic tubulopathy. Three patients did not receive any other nephrotoxic drug. The fourth patient received concomitantly sulfadiazine but renal function returned to baseline value after FC completion although sulfadiazine was continued. In conclusion, our 4 observations suggest that FC may be responsible for acute tubulopathy. We suggest that in these patients renal function should be carefully monitored and dehydration promptly corrected to limit the risk of nephrotoxicity.
Acquired Immunodeficiency Syndrome/complications , Acute Kidney Injury/chemically induced , Antiviral Agents/adverse effects , Organophosphorus Compounds/adverse effects , Phosphonoacetic Acid/adverse effects , Adult , Antiviral Agents/therapeutic use , Chorioretinitis/drug therapy , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/etiology , Female , Foscarnet , Humans , Immune Tolerance , Male , Middle Aged , Phosphonoacetic Acid/analogs & derivatives , Phosphonoacetic Acid/therapeutic use
A 68 year-old woman had been taking flunarizine 10 mg daily for 10 weeks when she developed severe bradykinesia and rigidity, resting tremor of both hands, akathisia, buccolinguofacial dyskinesias and depressed mood. Flunarizine was discontinued. After 3 months the patient was asymptomatic. This case and data from the literature suggest that extrapyramidal symptoms and depression may be observed even at the recommended daily dose of 10 mg. Flunarizine should be avoided in patients with Parkinson's disease. Patients on flunarizine should be watched for depressive and extrapyramidal signs, especially those aged over 60.
Basal Ganglia Diseases/chemically induced , Flunarizine/adverse effects , Aged , Female , Humans
