Experimentally Induced Hypervolemia During Ganglionic Blockade: The Effect on Cardiac Functios in Patients with Mitral Disease

The hemodynamic effects of hypervolemia, induced by dextran infusion during simultaneous ganglionic blockade with arfonad, have been investigated in 13 patients with mitral disease.

In Series I (5 patients), where dextran infusion was started before the ganglionic blockade, arfonad caused a decrease in blood pressures, but cardiac output remained unaltered. This could possibly be clue to dextran continuously sustaining the filling d the heart.

In Series II (8 patients), where ganglionic blockade preceded the dextran infusion, the hypervolemia caused a rise of right atrial and pulmonary arterial blood pressures toward or above the basal values. Cardiac output and stroke volume increased. There was a good correlation between right ventricular stroke work index and mean right atrial pressure during the autonomic blocking with arfonad. No such correlation could be found when the basal values were compared to the last values without autonomic blocking.

It is concluded that other factors than the filling pressure govern the cardiac output and work of the heart, as long as myocardial failure has not supervened.     

Indomethacin: Plasma concentrations and protein binding in man

Summary The fluorometric method of Holt & Hawkins (1965) has been modified to permit determination of 50 ng indomethacin in 0.5 ml plasma, by measuring its fluorescence in a phosphate buffer at pH 11.6 instead of sodium hydroxide. The method has also been adapted to show the presence of salicylic acid and a column chromatographic method has been devised for its removal. The protein binding of indomethacin in human plasma was calculated to be about 90% from an association constant of 0.86×10³ M^–1 (M=molarity). The number of binding sites on albumin is about 15. The plasma levels of indomethacin in patients receiving continuous treatment with Indocid^® were between 0.5 and 3 µg/ml during the 4–5 h immediately after the last dose of 25 mg. The disappearance of indomethacin from plasma appears to consist of a fast primary phase at plasma concentrations greater than 1 µg/ml (T 1/2 about 90 min.), and a slower secondary phase.     

Lack of relationship between serum free fatty acids and impaired plasma protein binding of diphenylhydantoin in chronic renal failure

Summary The plasma protein binding of diphenylhydantoin (DPH) in 13 patients with varying degrees of renal failure was considerably less than in normal healthy subjects confirming earlier studies. The fraction of unbound DPH was correlated with serum creatinine (r=0.81, p<0.001), but there was no significant correlation with the serum concentration of free fatty acids, triglycerides or cholesterol.     

Unexpected relationship between plasma protein binding and the pharmacodynamics of 2-NAP, a CCK1-receptor antagonist

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?: * Two chemically diverse CCK1 receptor antagonists have been shown clinically to inhibit CCK-evoked contraction of human gallbladder [2, 3]. These studies have not examined the relationship between plasma concentration and effect, the latter usually considered to be predictive from the free drug concentration [8]. * We wanted to examine our novel CCK1 receptor antagonist in this validated model and also to explore its PK-PD relationship. WHAT THIS STUDY ADDS: * 2-NAP inhibited CCK-evoked human gallbladder contraction in vivo but at a plasma free concentration that was, in theory, too low to have achieved adequate CCK1 receptor occupancy. * The study serves as a caveat to the assumption that free plasma concentration can be used to predict pharmacological effect. AIMS: To study the pharmacokinetics and pharmacodynamics of 2-NAP (2-naphthalenesulfonyl-L-aspartyl-(2-phenethyl)amide), a selective CCK1 receptor antagonist in healthy volunteers. METHODS: 2-NAP was given to 12 healthy male volunteers in an ascending dose, safety and PK phase 1a study by 1 h i.v. infusion (0.6-9.6 mg kg(-1) h(-1)). A further 12 healthy male volunteers received i.v. CCK-8S (6.25 pmol kg(-1) h(-1)) to produce gallbladder contraction, measured by ultrasound recordings of gallbladder volume, and the effect of concurrent i.v. 2-NAP administration was studied. Plasma protein binding in vitro and ex vivo was measured by ultrafiltration and by equilibrium dialysis. RESULTS: 2-NAP was generally well tolerated, displayed linear pharmacokinetics and a very high degree of plasma protein binding (99.9%). A 105 min i.v. CCK-8S infusion induced a reduction in gallbladder volume of 14.9 (+/-7.0) ml during placebo co-infusion and this was reduced to 2.4 (+/-5.9) ml when 2-NAP was co-infused with CCK-8S (P = 0.00024, paired t-test, mean change 12.5 ml; 95% CI For mean 7.4, 18.3 ml). This extent of inhibition was consistent with a 2-NAP total plasma concentration of 36 microm, but when protein binding corrections were made, the 'free concentration' of 2-NAP was only 0.04 microm, a value much less than the average equilibrium dissociation constant of 2-NAP for human CCK1 receptors ( approximately 0.7 microm). CONCLUSIONS: The pharmacological effect of a drug is usually considered to be determined by its free concentration. However, the complete inhibition of CCK-8S-evoked gallbladder contraction by a free plasma concentration of 0.04 microm 2-NAP was much greater than would have been predicted from simple drug-receptor occupancy theory and cautions against the general use of free concentration of drug for predicting pharmacological effect.