Circadian changes in the pharmacokinetics of oral ketoprofen.

Several investigations which have taken treatment time into account have shown that the pharmacokinetic parameters, the therapeutic efficacy and even the toxicity of a large number of products may vary according to the administration schedule. The present study was carried out in order to evaluate any circadian changes in pharmacokinetic parameters of ketoprofen, a new non-steroidal anti-inflammatory drug (NSAID). This randomised crossover study consisted of a single oral dose of ketoprofen 100mg administered to 8 healthy male volunteers, mean age 27.2 years, at 07.00 hours, 13.00 hours, 19.00 hours or 01.00 hours in 4 study periods during the first 3 months of the year. The order of administration was randomised, with each subject acting as his own control. A total of 14 blood and 4 urine samples were taken over a 12-hour period. The peak plasma concentration was twice as high after drug administration at 07.00 hours (13.4 +/- 1 mg/L) than after other administration times (13.00 hours: 6.9 +/- 1; 19.00 hours: 7.2 +/- 0.7; 01.00 hours: 6.3 +/- 0.5 mg/L) [p less than 0.001]. The time to reach peak concentration was much longer after drug administration at 01.00 hours (135 +/- 16.7 min) than at 07.00 (73.1 +/- 14.1 min), 13.00 (75 +/- 16.5 min) or 19.00 hours (82.5 +/- 12.7 min) [p less than 0.05]. The lag time was significantly longer at 01.00 hours than at 13.00 hours (p less than 0.01). The absorption rate constant after treatment at 01.00 hours was less than at the other times of administration (p less than 0.05). The bodyweight-corrected area under the curve (AUC0-12) was greater after 07.00 hours than after 13.00 (p less than 0.01) or 19.00 hours (p less than 0.05) and greater after 01.00 hours than after 13.00 hours (p less than 0.05). The elimination half-life was significantly longer after administration at 01.00 hours than after 19.00 hours (p less than 0.05), while the total clearance was lowest at 07.00 hours. Cosinor analysis demonstrated statistically significant circadian rhythms for all pharmacokinetic parameters described above. The amount of ketoprofen eliminated in the urine was delayed, and was significantly greater after the administration at 01.00 hours than 07.00 hours or 19.00 hours (p less than 0.01). The relationship between absorption, diffusion and/or elimination mechanisms of the drug are discussed.

Relationship between atrial and ventricular rates of fibrillation and cardiac contractile tissue effective refractory periods in the dog.

1 During total cardiopulmonary bypass, acetylcholine-, isoprenaline-, ouabain- and quinidine-induced variations in the atrial and ventricular rates of fibrillation were studied and compared with the variations in effective refractory periods (ERP) of atrial and ventricular contractile tissue obtained under the same experimental conditions. 2 Acetylcholine significantly shortened the ERP and accelerated the rate of fibrillation in the atrium but did not provoke any change in ventricular tissue. A parallel decrease in atrial and ventricular ERP and a parallel increase in atrial and ventricular rates of fibrillation were observed with isoprenaline. 3 Ouabain exerted a biphasic effect on the atrium, with an initial decrease in the ERP and an initial acceleration of the rate of fibrillation. It produced only a slight decrease in the ventricular ERP and no significant variation in the ventricular rate of fibrillation. 4 Quinidine induced a greater increase in the ERP and a greater slowing of the rate of fibrillation in the atrium than in the ventricle. 5 The variations in percentage change of refractoriness and rate of fibrillation were strictly correlated: r = 0.89 (P less than 0.001); the equation of the regression line was y = --0.86 x --2.98.

Effects of mild hyperkalemia on conduction velocity and effective refractory period in various parts of the dog heart in situ.

Effects of mild hyperkalemia on conduction velocity, effective refractory periods (ERPs) and sinus rate were studied on 16 anesthetized dogs, using endocavitary His bundle recordings, the extrastimulus method and standard electrocardiogram. Six dogs were placed under acetylcholine infusion (300 micrograms/kg/min) (ACh group), 10 received atropine sulfate 0.2 mg/kg intravenously (atropine group). Intraventricular conduction time, ventricular ERP and QRS duration of the EKG were studied on 7 other open-chested dogs (ventricular group). During a 60 min potassium chloride infusion (0.025 mmol/kg/min, 30 min, then 0.05 mmol/kg/min, 30 min), following observations were made: - In the ACh group, AV node conduction time (A-H interval) decreased by 20% and AV node ERP by 17%, whereas, in the atropine group, the former parameter was not affected and atrial ERP increased by 29%. - At the same time, sinus rate increased in the ACh group and was unaffected in the atropine group. - Conduction times in atrial contractile tissue (S-A interval), His-Purkinje system (H-V interval) and ventricular contractile tissue, like ventricular ERP, exhibited no variation or very slight, occasionally biphasic variations under both conditions. These results can be accounted for by an "anticholinergic" effect of mild hyperkalemia which is discussed.

Good clinical practices in phase I studies.

In France, official guidelines for good clinical practices in clinical trials were issued in 1987. In December 1988, a law was passed that fixed the requirements for carrying out experiments in healthy subjects. It will be completed by official guidelines for the structures in which experiments on healthy subjects (and patients as well, when the investigation would not benefit the health of the patients) may be conducted. Hence a battery of recent legal instructions precisely state what good clinical practices are in the setting of phase I studies. Of particular importance are: subject recruitment and selection methods and procedures; specific competence of the investigator, in particular to interpret the pre-trial data; necessary and sufficient facilities to guarantee the subjects' safety; careful quality control to check all laboratory procedures; necessity of written standard operating procedures.

[Sucralfate and bezoars: data from the system of pharmacologic vigilance and review of the literature]. / Sucralfate et bézoard: bilan de l'enquête officielle de pharmacovigilance et revue de la littérature.

A bezoar is a mass of undigested material which may form within the lumen of the gut. Some drugs have the potential to form bezoars. In the majority of patients, there is a clear predisposing factor. We present here the data of the French System of Pharmacovigilance on sucralfate and a literature review. Two distinct populations were involved: 16 adults and 5 newborn babies. All were hospitalized in intensive care units. The children were very low birth weight newborn babies, all of whom presented with abdominal distension or acute occlusion. The abdominal radiograph revealed an opaque mass filling the contour of the stomach. Adults presented an oesophageal bezoar around a nasogastric tube. Risk factors for bezoar formation were severe illness, gut hypomotility, dehydration, overdosage, nasogastric tube feeding. Sucralfate is used in the management of peptic ulcer. At pH < 4, extensive polymerization occurs and a sticky viscid gel is formed. In view of this inquiry, the French System of Pharmacovigilance decided to advise caution for adults in intensive care unit being fed by nasogastric tube and contraindication in premature babies and dysmature newborn babies receiving sucralfate.

[Adverse effects of quinine in the treatment of leg cramps]. / Effets indésirables de la quinine dans l'indication de crampes musculaires.

In France, three over-the-counter products containing quinine exist to treat cramps. This study aims to analyse data on spontaneous reports to the French System of Pharmacovigilance of adverse reactions to quinine drug products. From 1985 to 1996, we reviewed 58 adverse reaction reports. Most involved hypersensitivity reactions: rash, pruritus, generalized anaphylaxis, thrombopenia and hepatitis. Cinchonism is rarely observed at the usually low dose of quinine in this indication. No fatal outcome has been notified as described in the USA and Australia. The Food and Drug Administration (FDA) decided that prescription of quinine drug products should not be used any longer in the treatment of muscle cramps. Immuno-allergic reactions are potentially serious and must be avoided by giving clear information to patients and prescribers, and looking into the history of such reactions in patients in respect of the quinine drug and also tonic water.

[Drug prescription for pregnant women in the department of the Loire] . / Prescription médicamenteuse chez la femme enceinte dans le département de la Loire.

A prospective drug prescription and descriptive study was undertaken in a sample of 214 pregnant women in the department of the Loire. This population was randomized using pregnancy declaration files from the French Health Care Centre. Data recording was retrospective. A total of 2064 drugs have been prescribed; 90 per cent of women received at least one drug during the course of pregnancy with an average of 11.5 drugs per woman. Antispasmodics are mainly prescribed in the first trimester while vitamins, mineral supplements, antianemics and vasoactive agents are found in the third trimester. Prescriptions do not rise with age but increase in urban areas. Use of PDD/DDD (Prescribed Daily Dose/Defined Daily Dose) is an estimation of prescription customs. For ketoprofen, it is 1.6 in the last trimester, although this drug is contra-indicated.

[Delayed drug-induced hepatic injury. Evoking the role of amoxicillin-clavulinic acid combination]. / Hépatite médicamenteuse d'apparition retardée. Evoquer le rôle de l'association amoxicilline-acide clavulanique.

Although infrequent, hepatitis associated with amoxicillin and clavulanic acid combination is probably underestimated. Except for cases with few symptoms, a time interval between stopping treatment and the first manifestations (jaundice in most cases), sometimes of several weeks, may hinder diagnosis. We report 9 patients who exhibited this characteristic. The delay between stopping treatment and the onset of hepatitis varied from 13 days to 6 weeks after stopping the drug. Other causes of jaundice were excluded. Male sex, advancing age, or prolonged treatment (more than 10 days) may increase the risk. Complete recovery occurs within 1 to 4 months after discontinuation of treatment. The mechanism is unclear. Clinical and biological signs of hypersensitivity may suggest an immunoallergic reaction.

[Fever caused by fipexide. Evaluation of the national pharmacovigilance survey]. / Les fièvres au fipexide. Bilan de l'enquête nationale de pharmacovigilance.

Fourteen cases of drug fever due to fipexide were reported by a retrospective survey of a National Network of French Pharmacovigilance. 8 women, 6 men (mean age, 52 years), presented a sudden fever with a mean onset delay of 7 days after the first cure (range 2-12 days). In five cases, drug fever was the only manifestation; in other cases, it was associated with systemic or cutaneous signs. Eosinophilia was frequent (8 cases) and once, a chest picture showed an interstitial pneumonitis. Fever disappeared promptly after discontinuation of the drug and for ten patients, the rechallenge was positive within a short time. The clinical picture and laboratory tests are discussed and suggest an hypersensitivity reaction.

[Dextropropoxyphene hepatotoxicity: four cases and literature review]. / Dextropropoxyphène et atteintes hépatiques: à propos de 4 cas et revue de littérature.

We report 4 cases of hepatic injury in patients treated with a dextropropoxyphene-paracetamol combination in which the causal relationship with dextropropoxyphene can be suspected. These four cases show similarities with the 29 cases found in international publications. Hepatotoxicity occurs more frequently among old patients and women. Clinically, this condition can mimic a biliary tract disease with sometimes few or no symptoms. Biochemical criteria can show cholestatic, mixed or cytolytic hepatitis. Intrahepatic cholestasis may be found in liver biopsies sometimes suggesting cholangitis. Outcome is favourable on withdrawal of the drug. The mechanism of action of dextropropoxyphene is discussed.

[Drug-induced taste disorders: analysis of the French Pharmacovigilance Database and literature review]. / Troubles du goût d'origine médicamenteuse: analyse de la Banque Nationale de Pharmacovigilance et revue de la littérature.

Taste disorders, generally poorly studied, have various causes. From 1985 to 1997, 305 observations of taste disorders imputed to drugs were notified to Regional Pharmacovigilance Centres. Patients were on average 54.4 years old and 58 per cent were women. Quantitative as well as qualitative disorders have been observed. Drugs mainly found were: angiotensin converting enzyme inhibitors, terbinafine, zopiclone, D-penicillamine, imidazole derivatives, quinolones, macrolides, carbimazole and calcium channel blockers. The outcome was favourable for 60.3 per cent of patients. The possible efficacy of zinc is discussed. It is generally considered that taste disorders are not a serious side-effect, but they can reduce the quality of life and lead to poor compliance with treatment.

[French pharmacovigilance database system: examples of utilisation]. / La banque de cas du système français de pharmacovigilance: quelques exemples d'exploitation.

UNLABELLED: The French drug surveillance (pharmacovigilance) system is based on a network of 31 regional centres which receive adverse drug reaction (ADR) reports from health professionals and are drug information centers. Cases are entered into a common database, with causality scores. This database contains large amounts of data, which may be used for pharmaco-epidemiological studies. As an example, all cases in which an antihypertensive drug, suspect or not, was cited were identified. ACE-inhibitor cough was also explored. RESULTS: Since 1985, > 70,000 case reports have been entered into the database. 63 per cent were reported by specialists, 20 per cent by GPs. 54 per cent came from University Hospitals, 21 per cent from private practice. The most numerous age group was 60 to 69. The overall sex ratio (F/M) was 1.28, the female preponderance being most marked at < 39 and > 70 years of age. 43 per cent took only one drug, 20 per cent two drugs, 13.4 per cent three, and 24 per cent > three drugs. The most frequently reported effects concerned the skin and appendages (15 per cent), general status and central nervous system (9.5 per cent each), platelets, liver, and GI systems (6 per cent each). Outcome was favourable in 74 per cent. Dechallenge was positive in 71 per cent, rechallence in 6 per cent. 3.4 per cent of the patients died; in 2.2 per cent death was related to a reaction. Causality assessment indicated close temporal relationship (C2 or C3) in 69 per cent of cases; in 51 per cent of cases, no other obvious cause was found. 66 per cent of the reactions were labelled when reported. The database could also be used to explore drug utilisation: as an example, we studied the age and sex distribution of reports containing antihypertensive drugs, irrespective of their possible causal role in the reaction. Antihypertensives were mentioned in 14 per cent of the reports. The age distribution was skewed towards greater age, with a maximum of 70 years. F/M was 1.57, with more M use < 20 and 30-59, whereas F were more common between 20-29 and 60 years. beta-blockers were more often associated with patients under 70, whereas above 70 diuretics and centrally acting antihypertensive drugs were more often reported. This could be related to greater use or worse tolerance of these drugs. As an example of the exploration of a specific drug-reaction relationship, we explored the relationship between the use of ACE inhibitors (ACEI) and cough. ACE inhibitors were present in 6 per cent of cases, but in 75 per cent of reports of cough. F/M was 1.29 (NS) for all reports concerning ACEI, 1.28 for cough unrelated to ACEI, 2.1 for cough with ACEI (P < 0.05). Cough was present in 12 per cent of all reports concerning ACEI. There was no clear difference between ACEI for cough or sex ratio; women cough more with ACEI. This does not seem related to greater ACEI use by women or to greater sensitivity of women to cough. The reason for this sex difference remains to be explained. There are large amounts of essentially underutilized data in drug surveillance databases. How they can or should be used remains to be validated.

[Adverse effects of Disulone; results of the France pharmacovigilance inquiry. Regional Centers of Pharmacovigilance]. / Effets indésirables de la Disulone: résultats de l'enquête française de pharmacovigilance.

Disulone (dapsone + ferrous oxalate) is a sulphone marketed in France since 1958 and authorized in P. Carinii prophylaxis in HIV+ cotrimoxazole intolerant patients, bullous dermatosis, leprosy and polychondritis. Between 1983 and 1998, 249 adverse reactions were reported to French pharmacovigilance centres and Aventis, the manufacturer. Every side-effect was reviewed and the causal relationship was assessed on the basis of the French method for causality assessment. Main side-effects were divided as follows: 117 blood dyscrasias (generally neutropenia and agranulocytosis, rarely methaemoglobinaemia, haemolysis, macrocytosis, anaemia, aplastic anaemia, haemochromatosis and sulphaemoglobinaemia); 29 hypersensitivity syndrome; 39 cutaneous reactions, generally rash; 27 liver injuries (cholestatic, cytolytic and mixed hepatitis); 27 neurological and psychiatric side-effects including 7 axonal neuropathy; 10 gastrointestinal effects, generally nausea and vomiting. Five deaths were reported (4 septicaemia including one case not due to dapsone and 1 digestive bleeding due to underlying disease). In the other cases the outcome was favourable. The results were compared with the published references. It would seem to be important to reinforce information to prescribers about the possible serious adverse reactions with dapsone, particularly hypersensitivity syndrome and agranulocytosis, that can cause death if the drug is not stopped in time.

[Chronopharmacology of fractionated heparin (nadroparin) administrated by subcutaneous route at prophylactic doses in healthy volunteers]. / Chronopharmacologie d'une héparine fractionnée (nadroparine) administrée par voie sous-cutanée à dose prophylactique chez le voluntaire sain.

This study evaluated the effect of injection time on pharmacodynamic of a single subcutaneous bolus of nadroparine (7500 anti-Xa IC U) evaluated by anti-Xa activity (Hepaclot and Heptest) and by activated partial thromboplastin time (APTT by auto PTT reagent). 10 healthy male volunteers were studied at 4 different 24 hours periods with 4 different injection times (6 am, 12 am, 6 pm, 12 pm) and with a one week wash-out period between each period. No chronopharmacological variation of the anti-Xa activity evaluated by Hepaclot was found. However the anti-Xa activity evaluated by Heptest was higher at the sixth hour after 12 am injection (p = 0.0022). No difference on APTT values was observed whatever the injection time. So the injection time of nadroparine has a weak influence on anti-Xa activity and no effect on APTT; Before to conclude on the lack of chronopharmacological effect of nadroparine, it seems necessary to evaluate such a possibility with higher dosage, with sick and older subjects.

[Good practices of publication of clinical cases of pharmacovigilance: comments, Groupe de Travail sur les Bonnes Pratiques de Publication de Cliniques en Pharmacovigilance: commentary]. / Les bonnes pratiques de publication de cas cliniques de pharmacovigilance: commentaires. Groupe de Travail sur les Bonnes Pratiques de Publication de Cliniques en Pharmacovigilance: commentaires.

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.

[Cyclines and acne: pay attention to adverse drug reactions! A recent literature review]. / Cyclines et acné: attention aux effets indésirables! Aspects récents de la littérature.

PURPOSE: Cyclines are broad-spectrum antibiotics often used in acne. Side effects might occur precociously or more insidiously during long term treatment such in acne. The aim of this study is to review all adverse effects recently reported in this indication. CURRENT KNOWLEDGE AND KEY POINTS: A literature review from 1997 to 2001 has been conducted. Seventy-six articles reporting 250 cases have been found. Data analysis indicated that minocycline is the most widely incriminated molecule. Seventy-two cases revealed autoimmune disorders : lupus like syndrome associated or not with autoimmune hepatitis, 5 cases developed vasculitis. These reactions occurred in long term treatment (several weeks to several months). Fifteen cases of hypersensitivity syndromes and 3 cases of serum sickness like illness have been reported. These reactions occurred within the first weeks of exposure. Twenty-four cases of pseudotumor cerebri and 123 cases of abnormal pigmentations (skin, nails, mouth, bones or organs) have also been found. Eight cases presented other diseases. FUTURE PROSPECTS AND PROJECTS: Adverse effects of cyclines might be serious and sometimes unknown. Long term treatment by tetracyclines must be researched in patients presenting such symptoms. Moreover, several adverse drug reactions might be avoided by an optimal use of the drug (oesophageal ulcerations, photosensitivity) or by shorter periods of treatment (autoimmune disorders, pigmentations); only DRESS are drug adverse reactions unpredictable and sometimes severe.

[Unexplained chronic diarrhea, apropos of 4 new cases under Cyclo 3 fort and review of the literature]. / Diarrhées chroniques inexpliquées, à propos de quatre nouveaux cas sous Cyclo 3 fort et revue de la littérature.

We report 4 cases of chronic diarrhoea in patients treated with Cylclo 3 fort. This side-effect was not mentioned in the French list of therapeutic drugs until 1992. The diarrhoea was without faeces and without glairy mucus or blood. Symptomatic treatments were totally ineffective. The diarrhoea itself was well tolerated, but 3 patients lost weight, with hypokalaemia in 2 of them, and 1 had regressive acute renal failure. The time elapsed between the first dose of Cyclo 3 fort and the diarrhoea ranged from 1 to 3 months, and it took 5 months to make the aetiological diagnosis. Two patients were hospitalized. Withdrawal of the drug always resulted in cure. One patient taking enemas developed a regressive subocclusion of the bowel. The physiopathological mechanism of this diarrhoea is unknown. These cases are similar to the 5 other cases reported in the literature.

[Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants. Seven case reports and review of the literature]. / Syndromes hémorragiques sous antidépresseurs inhibiteurs sélectifs de la recapture de la sérotonine (ISRS). A propos de sept cas et revue de la littérature.

PURPOSE: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed. Since their release unexpected adverse effects such as bleeding disorders have been described. METHODS: Thirty patients with either hematoma or muco-cutaneous bleeding have been selected from case reports of the Saint-Etienne Pharmacovigilance center and from a literature review. RESULTS: The female/male sex-ratio was 3:4 and the mean age 42 years. Two newborns who had been exposed in utero to SSRIs were also included in the study. Eleven patients presented an underlying disease or were at risk. Various adverse effects such as bruising, hematoma, petechiae or purpura, epistaxis, and more rarely intestinal hemorrhage, ocular bleeding or cerebral hemorrhage were encountered. Symptoms were sometimes associated with prolonged bleeding time and platelet aggregation disorders and usually resolved within two days to four months after treatment discontinuation. CONCLUSION: Hematoma and muco-cutaneous bleeding would therefore be related to treatment, including selective serotonin reuptake inhibitors. However, these adverse effects are still poorly known and rarely reported. The main mechanism suggested would be a decrease in serotonin platelet leading to a defect in platelet aggregation. However, an increase in capillary fragility or susceptibility related to the patient's condition might be involved. Study of hemostasis history in patients requiring treatment with SSRIs might be of value.

[Roles of arterial dysplasia, chronic ergotism and other factors in a case multiple spontaneous arterial dissections]. / Rôles d'une dysplasie artérielle, d'un ergotisme chronique et d'autres facteurs dans un cas de dissections artérielles multiples spontanées.

INTRODUCTION: Spontaneous dissection of cervical and visceral arteries are rare and usually associated with an underlying arterial disease. EXEGESIS: The authors report the unusual case of a 50-year-old woman with high blood pressure who presented spontaneous dissection of cervico-cephalic, renal and hepatic arteries and of the descending aorta. She had been taking ergotamine tartrate for ten years for migraine. She also suffered from Raynaud's syndrome worsened by treatment. CONCLUSION: The respective roles of arterial dysplasia, chronic ergotism, renovascular hypertension and migraine are discussed.

[Evaluation of the potential cardiotoxicity of propranolol-lithium gluconate association (author's transl)]. / Association propranolol-gluconate de lithium et conduction cardiaque. Evaluation expérimentale d'un effect dépresseur éventuel.

The association B blocking agent-lithium salt is used for the therapy of some severe hyperthyroidism with cardiotoxicosis. Separately, both drugs depress intracardiac conduction. However by recording the potentials of the His bundle in anesthetized dogs, a potential cardiotoxicity of this association is unlikely since sinusal automaticity alone is importantly slowed. But, these results need further confirmation in man.