Diflunisal, a new-acting analgesic and prostaglandin inhibitor: effect of concomitant acetylsalicylic acid therapy on ototoxicity and on disposition of both drugs.

Intermittent and concomitant acetylsalicylic acid (ASA) therapy was superimposed onto a 21-day regimen with diflunisal 250 mg b.i.d. Low doses of ASA (600 mg single dose or 300 mg q.i.d.) did not influence signficantly diflunisal blood levels whereas a 600 mg q.i.d. dosing caused a small significant drop, especially at trough level. This drop is not expected to be clinically significant. No ototoxicity could be demonstrated with any treatment of diflunisal though four of fourteen subjects reported mild tinnitus during concomitant therapy at the higher doses of ASA. Diflunisal at 375 mg b.i.d. failed to alter the metabolism of a single dose of labelled ASA (600 mg) as judged by plasma levels, urinary excretion and plasma binding. Daily urinary excretion of prostaglandins E1 and E2 major metabolite was decreased by about 70% by diflunisal.

[Demography and medicine in Switzerland: medical manpower and project "DEMOMED"]. / Démographie et médecine en Suisse: l'effectif médical désirable et le projet "DEMOMED"

The situation as regards medical manpower in Switzerland in 1975 is characterized by high enrollment in the medical schools and a doubling time for the number of physicians in practice of approximately twenty years. A federal commission concerned with problems related to medical studies (CEPREM) conducted a study aiming at defining an optimum figure for intake of students into the medical schools. A survey of the international literature and a statistical study of availability of physician services region by region in Switzerland were conducted. The results show that it is impossible to define with precision an optimum "medical density" for Switzerland. The system of health and the functions of its various professions are not defined, and powers of decision in this field are not uniformly attributed. In the national survey, the most striking feature was disparity between various regions as regards access to medical or paramedical services. This disparity is parallel to state of economical development, and unlikely to be corrected even by an excess of overall medical manpower. Four hypotheses are presented on the consequences of increase, decrease, or stable enrolment in the medical schools. We conclude that there is no technical basis for defining an optimal medical density, but that it would be reasonable to decrease the number of second-year students by a factor of the order of 25% on the basis of a political decision.

Action of H1 and H2 inhibitors on the response of histamine sensitive adenyly cyclase from guinea-pig mucosa.

In the guinea-pig, it has been shown that homogenates of mucosa from the fundus contain an adenylyl cyclase system that is activated by histamine as well as by prostaglandins PGE1 and PGA1. The effects of burimamide, an H2-inhibitor, and mepyramine and chlorpheniramide, both H1-inhibitors, were tested. Both H1 and H2 inhibitors behaved kinetically as competitive inhibitors of histamine, but the Km derived for burimamide (2.5 - 4.1 . 10(-5)) was significantly lower than that for either chlorpheniramine (0.9 - 1.9 . 10(-4)) or mepyramine (1.3 - 1.4 . 10(-4)). On the other hand none of the three inhibitors influenced the cyclase activation by PGE1 and PGA1. These results suggest that there are at least two types of receptors in the preparation studied, one responsive to histamine and the other to the prostaglandins, and that the specificity of H1- and H2-receptors is not absolute in the broken cell preparation.

Inadequacy of information about drugs.

A questionary was sent back by 52 interns in three internal medicine services. It showed that approximately 60% of doctors lack "often" or "very often" pharmacological facts. Information about comparative efficacy is the most difficult to obtain.

Pharmacokinetic and metabolic pathways of dimethophrine in man.

Pharmacokinetics and metabolism of dimethophrine labelled with tritium have been investigated on 5 subjects treated orally with a single dose of 100 mg. The results obtained have shown that: 1. the absorption and urinary elimination are rather slow; 2. no metabolic transfromation of the drug occurs, except conjugation.

A strategy of approaching the fit of a compartmental model applied to the behaviour of aspirins in humans.

A compartmental model has been set up with five parts. Formulation and testing of the model have been performed by simultaneous experiments involving measurement of blood levels of ASA and SA for four different preparations of aspirin investigated in four different patients. The hypotheses of the present study had been based upon a four-compartment model. However, such a model did not appear to be adequate and a new model with five compartments has been substituted for the former one. The five-compartment model has led to the formulation and testing of new physiological hypotheses; it has also provided the development of a fitting method using powerful convergence algorithms. A general analytical formulation has been set up which has made it possible to circumscribe the multiple roots of the characteristic polynomial when they have to be taken into consideration.

Physiological disposition and metabolism of 5-(2',4'-difluorophenyl)salicyclic acid, a new salicylate.

5-(2'4'-Difluorophenyl) [carboxy-14C]salicyclic acid (MK-647) was quickly and completely absorbed in rats, dogs, and man. Peak levels of plasma radioactivity occurred in 1-2 hr after oral administration. The dose was 10 mg/kg in rats and dogs, and 50 or 500 mg in man. Most of the drug in plasma was intact MK-647 which was extensively bound to plasma protein. In man the peak concentration following the 500-mg dose was approximately 10 times that after the lower dose, which suggests that absorption rates of both doses were similar. Elimination of drug from plasma was dose-dependent. The area under the curve for MK-647-14C in plasma was 18 times higher following the 500-mg dose than the 50-mg dose. Dogs given 10 mg/kg orally or intravenously excreted 44% of the dose in the urine and 42% in the feces in 72 hr. Rats given the same dose level by either route of administration excreted 80% in the urine and 11% in the feces. In man approximately 95% of a 50- or 500-mg oral dose was excreted in the urine and 3% in the feces, in 96 hr. MK-647 and two metabolites were present in the urine of three species. The ether and ester glucuronides were identified in human urine. The latter metabolite was also identified in rat and dog urine. The glycine conjugate of MK-647 was not observed in the urine of the three species. No interaction was observed between MK-647 and bishydroxycoumarin in the prothrombin time test nor with tolbutamide in the glucose tolerance test. A significant lowering of hexobarbital sleeping time was observed in female, but not male rats after four consecutive daily doses of MK-647. After repeated daily administration of MK-647 (12.5-100 mg/kg), the diurnal plasma level in dogs was not significantly altered, indicating that no saturation, induction, or inhibition of its own metabolism took place.