What is already known about this subject • Creatinine clearance (CL) is used to assess glomerular filtration rate (GFR). However, it is known to slightly overestimate the true GFR, due to renal tubular secretion of creatinine. • During phase I‐III clinical trials, a 10–15% increase in serum creatinine has been observed both in healthy subjects and patients receiving the new antiarrhythmic agent dronedarone. What this study adds • Dronedarone affects the renal handling of creatinine and N‐methylnicotinamide, two cations, while leaving unchanged GFR, assessed through sinistrin CL, and renal plasma flow and anion secretion, assessed through para‐amino‐hippurate CL. • This suggests a specific action of dronedarone on renal organic cation transport explaining the limited, reversible effect of dronedarone on serum creatinine, which must not be interpreted as reflecting an impairment of renal function, but which may indicate an interaction potential with cationic drugs. Aims To assess the effects of dronedarone on renal function and tubular cation handling. Methods Twelve healthy males were enrolled in a randomized, cross‐over, placebo‐controlled, double‐blind study. They received 400 mg dronedarone or placebo twice daily for 7 days. Baseline and on‐treatment renal function tests were performed under strict standardization of intakes, by assessing creatinine, sinistrin, para‐amino‐hippurate (PAH) and N‐methylnicotinamide (NMN) CLs, and electrolyte excretion. Results Compared with placebo, dronedarone significantly decreased renal creatinine CL (mean 138–119 ml min−1 after dronedarone vs. 142–149 ml min−1 after placebo) and NMN CL (448–368 ml min−1vs. 435–430 ml min−1), but did not alter renal sinistrin CL, PAH CL and other renal parameters. Conclusions Dronedarone reduces renal creatinine and NMN clearance by about 18%, without evidence of an effect on GFR, renal plasma flow or electrolyte exchanges. This suggests a specific partial inhibition of tubular organic cation transporters (OCT). A limited increase in serum creatinine is therefore expected with dronedarone treatment, but does not mean there is a decline in renal function.

Synthetic human pancreatic tumor GH-releasing hormone (hpGRH 1-44-NH2) was given by iv bolus injection to 10 normal men at doses of 75, 150, 300, and 600 micrograms. At all doses the plasma GH responses were similar in an individual subject. Among subjects, however, the responses were significantly different, with peak GH concentrations ranging between 9.0 micrograms/liter and 54.9 micrograms/liter. The GH released in response to GRH was bioactive in the Nb2 lymphoma cell multiplication assay. The circulating GH 30 and 60 min after GRH was detected in 3 molecular forms corresponding to little, big, and big-big GH. These forms averaged 50%, 30%, and 20% of the total immunoreactive GH, respectively. The mean rise of plasma somatomedin-C, from 1.86 U/ml to 2.21 U/ml 24 h after GRH, was not statistically significant. A small but statistically significant GRH dose-dependent rise in plasma PRL (mean PRL concentrations 10 min after 600 micrograms GRH, 11.13 micrograms/liter occurred consistently after GRH injection. The evidence that the GH released by GRH is bioactive supports the potential use of GRH for therapeutic applications.

Clinical studies have shown that acetylsalicylic acid (ASA) or ticlopidine (T) bring a partial clinical benefit in a subset of patients threatened by thrombosis on atherosclerotic plaques. Acetylsalicylic acid and T have different impacts on platelet function and the combination of the drugs seems logical to achieve a greater antiplatelet effect. Healthy volunteers were randomly allocated to any of the three treatment groups: T 250-placebo; T 250-T 250; placebo-placebo (treatment was administered in a double blind manner). Acetylsalicylic acid 40 mg was openly administered once a day to the subjects of the three groups after the first week of treatment. Simplate I bleeding time and platelet aggregation testing were performed before treatment and at the end of the two treatment periods. We confirmed that T alone prolongs bleeding time and impairs, in a dose-dependent manner, ADP-induced aggregation; platelet responses that depend on released ADP were also affected. Inhibition of thromboxane-dependent aggregation, associated with a doubling of the bleeding time, was observed after one week of low-dose ASA inhibition of thromboxane synthesis. An additive effect of ASA 40 mg to T 250 mg on the bleeding time was evidenced. There was also a wider alteration of platelet aggregation, with a trend towards an inhibition of the response to a high concentration of collagen as compared to ASA or T used alone. Such a powerful, logical drug combination is in good agreement with preliminary encouraging results obtained after coronary stent implantation and deserves further studies in patients at high risk for arterial thrombosis to define its benefit-risk profile. Key Words: Aspirin—Ticlopidine— Drug combination—Bleeding time—Platelet aggregation.

Since heart rate (HR) is an important determinant of the duration of systole, systolic time intervals (STI) from 8 healthy subjects were examined after infusion of atropine. As no overall correlation was found between HR and pre-ejection period (PEP), the results confirm the need for individual estimates of the correction of the left ventricular ejection time (LVET) and the total electromechanical systole (OS2). In the same subjects the sensitivity of PEP to minor negative inotropic effects of mexiletine and disopyramide measured at Cmax was confirmed. Thus, in addition to its simplicity and reliability, the sensitivity of the uncorrected PEP should encourage use of this technique as part of any screening system for the early detection of an inotropic effect of new chemical entities.

A placebo-controlled, single blind, crossover study was done to evaluate the inotropic effects of single oral doses of mexiletine and disopyramide assessed by the measurement of Systolic Time Intervals (STI). Each of 8 healthy volunteers received five treatments in random order: 200 and 400 mg mexiletine, 100 and 200 mg disopyramide, and placebo. There was a significant increase in cumulated PEP after 400 mg mexiletine and 200 mg disopyramide. There was no significant change in LVET and QS2. Peak plasma levels were in the lower range of the reputed antiarrythmic levels. Plasma concentration-effect relationships are discussed. Although the study revealed large inter- and intrasubject variability in the measured STIs, it is concluded that a negative inotropic effect was detected despite the low plasma levels of the minor negative inotropic drugs.