The new steroid analog RU 486 inhibits glucocorticoid action in man.

RU 486 [17 beta-hydroxy-11 beta-(4- dimethylaminophenyl )-17 alpha-(prop-1- ynyl )-estra-4,9-dien-3-one] is a new steroid analog which antagonizes glucocorticoid action at the receptor level in animals. To assess its potential antiglucocorticoid activity in man we studied the pituitary-adrenal response to RU 486 in normal men. The compound was administered at 0200 h and plasma cortisol and lipotropins (LPH) were measured hourly for 10 h. After 400 mg RU 486 significant and sustained elevation of both hormones occurred during the 0700-1200 h period: mean (+/- SE) plasma levels after placebo or RU 486 during this interval were, respectively, for cortisol (ng/ml), 63.4 +/- 8.2 and 112.7 +/- 2.9 (P less than 0.02); and for LPH (pg/ml), 34.8 +/- 11.3 and 71.6 +/- 15.4 (P less than 0.01). The 200- and 100-mg doses induced only transient cortisol and LPH increases. Administration of RU 486 (400 mg) at 1400 h induced no increase in plasma cortisol compared to placebo in the corresponding 2000 to 2400 h period. When RU 486 was administered concomitantly with dexamethasone (1 mg) at 2400 h, dose-dependent blockade of the dexamethasone-induced cortisol suppression at 0900 h was found (r = 0.62, P less than 0.01); this blockade was partial after the 100-mg dose, but complete after the 400-mg dose. Plasma LPH and ACTH showed parallel variations. We conclude that RU 486 antagonizes the negative pituitary feedback of both the nocturnal endogenous cortisol rise and exogenously administered dexamethasone. These actions are consistent with an antiglucocorticoid activity of this compound in man.

Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing's syndrome.

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a steroid analog which antagonizes glucocorticoid action at the receptor level. The pituitary-adrenal response to RU 486 was evaluated in patients with Cushing's syndrome. The acute administration of 400 mg RU 486 at 0800 h in five patients with Cushing's disease induced no significant change in plasma cortisol during the next 10 h compared with the administration of placebo. However, prolonged administration (400 mg daily for 3 days) caused activation of the pituitary-adrenal axis; urinary cortisol increased the most from 727 to 5720, 830 to 8200, 610 to 1020, 110 to 570, and 300 to 990 micrograms/day. Plasma cortisol and lipotropins increased to a lesser extent. Hormone changes appeared on the second day of drug administration and lasted up to 3-4 days after the drug was discontinued. In two patients with nonpituitary-dependent Cushing's syndrome, RU 486 induced no significant change in steroid secretion. We conclude that RU 486 induced a delayed and prolonged pituitary-adrenal response in Cushing's disease; whether the resulting cortisol overproduction will overcome the peripheral effect of RU 486 remains to be determined.

Interaction between roxithromycin and cyclosporin in heart transplant patients.

Cyclosporin is an immunosuppressive agent commonly used in transplant patients. It is actively metabolised by the cytochrome P450 system and interactions with drugs metabolised by the same system are predictable. This is particularly relevant since cyclosporin has a low therapeutic index and its renal toxicity is concentration-related. Roxithromycin, a new, well-tolerated macrolide with a weak interactive profile, uses the same isoenzyme of the P450 system as cyclosporin. To evaluate its interaction potential in clinical practice, 8 heart transplant recipients treated with cyclosporin for at least 1 month received roxithromycin for 11 days (150 mg twice daily). Bi-weekly controls of plasma cyclosporin concentrations and creatinine levels were carried out before, during and after roxithromycin treatment. A slight nonsignificant rise in cyclosporin concentrations was observed, but creatinine levels remained stable during roxithromycin treatment. Values of cyclosporin concentrations diminished after withdrawal of roxithromycin. Cyclosporin dosage adjustment was not necessary. There was a minor pharmacokinetic interaction, which can be considered safe for the usual therapeutic dosage of roxithromycin used.

Effects of RU16117, an orally active weak oestrogenic compound, in postmenopausal women.

Daily oral administration of 1, 3 or 10 mg of RU16117 (11 alpha-methoxy ethinyl oestradiol) to normal postmenopausal women led to a progressive decrease of basal serum LH levels to 60.4 +/- 17.0, 35.1 +/- 9.1 and 20.1 +/- 2.8% of control (pretreatment values, P less than 0.01), respectively, after 4 wk of drug administration. Although the pattern was similar, the inhibitory effect of RU16117 was even more pronounced on FSH than LH levels: a 50% decrease of basal LH and FSH levels was obtained at the daily 1.8 and 1.2 mg doses of RU16117, respectively. No significant change of basal serum gonadotrophin levels was observed with the daily 0.3 mg dose. Administration of 1 mg of RU16117 every second day or 10 mg once a week led to a relatively small but significant (P less than 0.05) 20--25% decrease of basal serum LH levels after 4 wk of treatment in four out of five women. While daily 0.3 and 1.0 mg doses of RU16117 had no significant effect on the LH response to 100 microgram LHRH, the 3.0 mg dose delayed the response up to 90 min. The 10 mg dose, on the other hand, led to a markedly delayed and reduced response. Treatment for the same period (4 wk) with 1 mg RU16117 every second day or 10 mg once a week led to a small (20--25%, P less than 0.05) inhibition of the LH response to LHRH. At the dose of 10 mg once a week, RU16117 had no or minimal effect on endometrial histology. Since RU16117, an orally active weak oestrogenic compound, has been shown to have anticarcinogenic activity in the rat, the present findings suggest that this new steroid could be useful for the treatment of climacteric symptoms.

PIP: Daily oral administration of 1, 3, or 10 mg of RU16117 (11alpha-methoxy ethiyl estradiol) to normal postmenopausal women led to a progressive decrease of basal serum LH levels to 60.4 + or - 17.0, 35.1 + or - 9.1 and 20.1 + or - 2.8% of control (pretreatment values, P 0.01), respectively, after 4 weeks of drug administration. Although the pattern was similar, the inhibitory effect of RU16117 was even more pronounced on FSH than LH levels: a 50% decrease of basal LH and FSH levels was obtained at the daily 1.8 and 1.2 mg doses of RU16117, respectively. No significant change of basal serum gonadotrophin levels was observed with the daily 0.3 mg dose. Administration of 1 mg of RU16117 every 2nd day or 10 mg once a week led to a relatively small but significant (P 0.05) 20-25% decrease of basal serum LH levels after 4 weeks of treatment in 4 out of 5 women. While daily 0.3 and 1.0 mg doses of RU16117 had no significant effect on the LH response to 100 mcg LHRH, the 3.0 mg dose delayed the response up to 90 minutes. The 10 mg dose, on the other hand, led to a markedly delayed and reduced response. Treatment for the same period (4 weeks) with 1 mg RU16117 every 2nd day or 10 mg once a week, led to a small (20-25%, P 0.05) inhibition of the LH response to LHRH. At the dose of 10 mg once a week, RU16117 had no or minimal effect on endometrial histology. Since RU16117, an orally active weak estrogenic compound, has been shown to have anticarcinogenic activity in the rat, the present findings suggest that this new steroid could be useful for the treatment of climacteric synptoms.

A radioreceptor assay for benzodiazepines.

A simple, rapid and sensitive radioreceptor assay for determining benzodiazepines in serum is based on the displacement by the drug of specific [3H]diazepam binding to a membrane fraction from rat brain. The limit of detection of the more active benzodiazepines is about 0.5 ng. Diazepam, nitrazepam, clobazam and HR 458 have been assayed in human serum after a single oral clinical dose. The results can be used for determining pharmacokinetic parameters. The technique measures not only the parent benzodiazepine but also clinically active metabolites.

Streptokinase after late failure of reconstructive surgery for peripheral arteriosclerosis.

After the failure of reconstructive surgery for arterial occlusions of the lower limbs, 25 patients with severe ischemia were treated with streptokinase (SK) to avoid amputation of the limbs and sometimes death, in the absence of any other possible treatment. In 16 subjects, thrombolysis, assessed by the Doppler ultrasound technique, occurred rapidly; in 12 cases, SK combined with surgery or with symptomatic medical treatment gave good results saving limbs and improving the quality of life. Three of the 16 patients died from a cerebral vascular accident which occurred before the 10th hour. Whatever the type and the number of surgical operations performed before the use of SK, the indications and the results of the treatment are governed by the condition of the vascular tree below the arterial lesions. SK seems to be justified in endarterectomy or venous grafts with severe ischemia less than two months old. For dacron by-passes, the possibility of prosthesis dissection makes SK debatable in spite of frequent lysis. In axillofemoral by-passes, the risk of embolism of the upper limbs makes the use of SK inadvisable.

[Epidemiologic relations between arteriopathy of the lower extremities and chronic gastroduodenal ulcer]. / Relations épidémiologiques entre artériopathie des membres inférieurs et ulcère gastro-duodénal chronique.

The authors report the results of a study of 3 565 consecutive patients over 30 years of age, of French nationality living in the Paris region, hospitalised over a 5 year period in a Department of internal medicine and vascular pathology. The incidence of gastroduodenal ulcer was compared in each sex in 10 year age groups in 764 patients with arterial disease and 2 801 patients without arterial disease. The incidence of ulcers was higher in patients with occlusive arterial disease in men in the 50 to 59 year age group (20,4 p. 100 compared to 9 p. 100, p less than 0,01), and in the 60 to 69 year age group (20,3 p. 100 compared to 9,8 p. 100, p less than 0,001), and after 70 years of age in females (12,8 p. 100 compared to 4 p. 100, p less than 0,01). The overall incidence in all patients with arterial disease (16,7 p. 100 of all 591 males, and 12,1 p. 100 of all females) was higher than in a corresponding control group (9,7 p. 100, p less than 0,0001, and 4,8 p. 100, p less than 0,001 respectively). These results only concern chronic ulcers. There was no difference in the incidence of acute ulcers.

[Contribution of explanatory notes. Efficacy of the ICH plan for international clinical development of a new drug]. / Contribution des notes explicatives. Efficacité d'ICH au plan de développement clinique international d'un nouveau médicament.

After the achievement of the Phase 1 of the ICH process (ICH4, Brussels, July 1997) and the recent adoption of two new Efficacy Guidelines (E5, E9) by the ICH Steering Committee, the Pharmaceutical Industry and CROs have today the necessary tools and standards of reference, to set up a Global Plan of Clinical Development for any New Molecular Entity for Human Use, within the three ICH Regions, Europe, Japan and the USA. However to achieve such a goal, the Efficacy Guidelines must officially be integrated in the Regulatory requests of each of the 3 ICH Regions ans implemented by Industry. The use of these Guidelines which concern the Clinical Development Plan and most of the content of the Clinical Documentation for Registration of New Medicinal Products, will show the qualities and defects of ICH texts, leading in the future to possible amendments, during the maintenance phase of these Guidelines (Step6 of ICH process?). The Efficacy texts cannot be separated from other ICH Guidelines concerning Quality, Safety ans above all the Multidisciplinary texts which are of great interest for the clinical development plan, registration and follow up after MAA of any New Medicinal Product. Referring to Ethnic differences between the three ICH Regions, topic E5 is the most innovative of Efficacy Guidelines for both Regional Regulatory Authorities, accepting or not foreign clinical data and International Companies, setting up Global Clinical Plan and Registration Dossier. The paper is also looking at the future impact of the other Efficacy (E10) and Multidisciplinary (M1 to M4) Guidelines which are still under consideration.

Guidance synthesis. Medical research for and with older people in Europe: proposed ethical guidance for good clinical practice: ethical considerations.

INTRODUCTION: In Europe the population is ageing rapidly. Older people are taking many medicinal products daily and these may not necessarily be suitable for them. Publications show that older patients are underrepresented in clinical trials, especially those over 75 years, with multiple co-morbidities, concomitant treatments and/or frailty. This document provides a summary of recommendations on ethical aspects of clinical trials with older people, who may in some cases be considered a vulnerable patient population. The EFGCP's Geriatric Medicine Working Party (GMWP) has developed this guidance to promote such research and to support health care professionals in their efforts. ETHICAL, SCOPE AND CONTEXT: The definition of a geriatric patient is reviewed. Frail and vulnerable patients, who are a minority of geriatric patients, should be included whenever it is relevant. The legal context is described. THE PROCESS OF INFORMED CONSENT: All adults should be presumed capable of consent, unless proven otherwise; informed consent must be sought for all older people who are able to consent. A simple, short and easy-to-understand information sheet and consent form will contribute to improving the readability and understanding of the older participant. A participant guide and the use of a simple tool to ensure decision making capacity, are recommended. Whenever older people are unable to consent, their assent should be sought systematically using adequate information, in addition to seeking the consent of their legal or authorised representative as appropriate. ETHICS COMMITTEES: Research ethics committees need internal and/or external geriatric expertise to balance the benefits and risks of research in older people and to appreciate and recognise their autonomy. DESIGN AND ANALYSES: Design and Analyses should be adapted to the objectives with appropriate outcomes and are not different from other clinical trials. CONCLUSIONS: The absence of proper recruitment or insufficient presence of older patients in clinical development plans for new medicinal products is detrimental; there is a need to improve evidence-based knowledge, understanding and management of their conditions and treatment. The aim of this guidance is to facilitate clinical research for and with the older patient population. The long version of the guidance will be available on the EFGCP's website: www.efgcp.be/.

Guiding Principles for Pharmaceutical Physicians from the Ethical Issues Committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK.

Medical practitioners practising in the field of pharmaceutical medicine, whether in industry, regulatory bodies or an academic environment, are bound by the same ethical standards which apply to all doctors. Their work, however, leads to some very specific ethical considerations which may not be fully explored in ethical codes based in clinical medicine. This document aims to establish some guiding principles which should underpin a working ethical framework for pharmaceutical physicians. It clearly places the protection of patients (and research subjects) and the doctor's duties to wider society ahead of responsibilities to an individual employer while emphasising the importance of adherence to high standards of research, including dissemination of findings. These principles form the basis of a fuller report which offers more specific practical advice on possible ethical conflicts or dilemmas.

Ethics and pharmaceutical medicine -- the full report of the Ethical Issues Committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK.

The practice of pharmaceutical medicine brings with it ethical challenges and dilemmas often very different from those encountered in the practice of clinical medicine. Having established a framework of guiding ethical principles, this report aims to look in some detail at specific areas of possible ethical concern to pharmaceutical physicians, offering practical advice and guidance on good practice. The report covers issues related to pharmaceutical research, including dissemination of research findings, communication with other health professionals and patients and involvement of pharmaceutical physicians and companies in the provision of patient services. The primacy of the interests of patients and the wider public is emphasised, and the possible impact of new developments in pharmaceutical technology is explored. It is hoped that the report will help those working in pharmaceutical medicine and act as a stimulus for wider discussion and debate.

[Encapsulating peri-hepatitis. Apropos of 4 cases]. / La périhépatite encapsulante. A propos de quatre observations

The authors report 4 cases of encapsulating peri-hepatitis, including an angiographic study. Selective arteriography of the coeliac trunk showed extremely sinuous intra-hepatic arteries in 3 of these cases, and obstruction of the portal vein, in one case. Catheterisation of the hepatic veins showed a pressure gradient between the obstructed hepatic vein and the free supra-hepatic pressure, showing a post-sinusoidal block. In 2 of the 4 cases, ascites was chylous. Lymphography carried out via lymphatics in the foot was negative in 3 cases where it was carried out. One case showed, on two successive laparoscopies, that micro-nodular cirrhosis was present before the development of encapsulating peri-hepatitis.

Franco-Belgian cooperative study of ursodeoxycholic acid in the medical dissolution of gallstones: a double-blind, randomized, dose-response study, and comparison with chenodeoxycholic acid.

A double-blind randomized, multicenter study was carried out to determine the efficacy and safety of ursodeoxycholic acid (UDCA) at 4 doses of 2.1 to 16.2 mg X kg-1 X day-1, and chenodeoxycholic acid (CDCA) at the dose of 16.9 mg X kg-1 X day-1, in 197 patients treated for up to 1 year for radiolucent gallstones in functioning (opacified) gallbladders. There was confirmed complete dissolution in 5.9% of patients receiving UDCA at the dose of 2.1 mg X kg-1 X day-1, 18.9% in those receiving 4.2, 28.9% in those receiving 8.4, 14.6% in those receiving 16.2, and 20.0% in patients receiving CDCA. Partial (over 50%) or complete dissolution occurred in 29.4% of patients receiving 2.1 mg X kg-1 X day-1 of UDCA, 37.8% of those receiving 4.2, 55.2% in those receiving 8.4, 48.7% in those receiving 16.2, and 50.0% in patients receiving CDCA. Complete dissolution occurred significantly more frequently in small (less than 5 mm in diameter) than in large (5 to 15 and more than 15 mm) stones. There was no significant influence of treatment on serum cholesterol and triglycerides in any of the groups. Serum aminotransferases remained normal (or lower than twice the upper normal limit) in all patients treated with UDCA. Diarrhea leading to cessation of treatment occurred in 5% of patients receiving UDCA, but was significantly less frequent than in those receiving CDCA. These results confirm that, within a 1-year period, UDCA is equally effective and induces diarrhea less frequently than CDCA, with an optimal dose (8 mg X kg-1 X day-1) approximately twice lower than that of CDCA.

Hormonal and metabolic effects of somatostatin in diabetic patients submitted to an i.v. arginine infusion.

Hormonal and metabolic effects of a synthetic linear somatostatin were tested in insulin-dependent subjects submitted to an intravenous arginine infusion. Arginine alone induced a rise in plasma growth hormone (HGH) and glucagon (IRG) concentrations but did not affect the spontaneous diurnal decrease of plasma cortisol; blood glucose concentration rose while that of alanine decreased suggesting enhanced gluconeogenesis; concentrations of plasma free fatty acids (FFA) and 3-hydroxybutyrate decreased. Somatostatin, at three different dosages, markedly influenced these patterns: HGH response to arginine was suppressed by the lowest somatostatin dose; IRG response was progressively inhibited by increasing doses of somatostatin but never reached zero; cortisol level was not decreased but slightly increased by somatostatin. Substrate responses to arginine were also modified by somatostatin: alanine disappearance was impaired, this effect being dose-related; plasma FFA and 3-hydroxybutyrate concentrations showed a significant increase rather than decrease, consistent with somatostatin suppression of residual insulin secretion. Tolerance to somatostatin was good and no alteration of hemostasis was observed.

Assessment of the antimineralocorticoid effect of RU 28318 in healthy men with induced exogenous and endogenous hypermineralocorticism.

The antimineralocorticoid effect of a single dose of RU 28318, has been assessed in healthy men with exogenous or endogenous hypermineralocorticism. For exogenous hypermineralocorticism induced by ingestion of 9 alpha-fluorohydrocortisone (9 alpha-FHC) and aldosterone infusion, RU 28318 100 mg (9 alpha-FHC ingestion) or 200 mg (aldosterone infusion) was administered, and its effect compared with identical doses of spironolactone or a placebo. For endogenous hypermineralocorticism induced by ingestion of furosemide, RU 28318 100 and 300 mg was tested in comparison with 100 mg spironolactone or placebo. In all 3 studies, both RU 28318 and spironolactone significantly raised the urinary Na/K ratio when compared to placebo administration. No significant difference was apparent between RU 28318 and spironolactone. Thus, a single dose of RU 28318 in man has an antimineralocorticoid effect identical to those produced by the identical molar dose of spironolactone. In addition, the results show that furosemide-induced hyperaldosteronism constitutes a simple and reproducible test for assessing the antimineralocorticoid effect of a drug.

[Does the hepatitis of secondary syphilis exist? Two cases (author's transl)]. / L'hépatite de la syphilis secondaire existe-t-elle? 2 observations.

Two patients are presented as new cases of secondary syphilitic hepatitis. The closely resemble descriptions in the literature with the same clinical and laboratory "profile" and the same course spectaculary influenced by anti-syphilitic penicillin therapy. The presence of treponemes in the liver, which would definitely confirm the diagnosis, was not demonstrated. This is a particularly important diagnosis, which should not be missed since it leads to treatment of fundamental importance to the patient's future.

Hepatocyte giant mitochondria: an almost constant lesion in systemic scleroderma.

Liver electron microscopic studies were performed in 14 patients with systemic scleroderma. In 13 of these patients, giant mitochondria were demonstrated in the hepatocytes. This ultrastructal abnormality was present whatever the type and duration of the disease and was also present even when the liver was histologically normal. The mechanism of formation of giant mitochondria in systemic scleroderma is unknown.