Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets

The interaction of the heparin-dependent antibody with heparin and platelets has been studied using the sera and purified IgG of four patients with heparin-induced thrombocytopenia. Both normal platelets and Bernard-Soulier syndrome (BSS) platelets which lack glycoprotein (GP) Ib. GPV and GPIX, aggregated in response to patient serum or IgG, but only in the presence of heparin. A monoclonal antibody (Mab) against platelet Fc II receptor (IV.3) strongly inhibited the heparin-dependent aggregation of both normal and BSS platelets induced by patient sera/IgG. Inhibition by the anti-GPIb Mab (AK2) was variable and occurred only with normal platelets. Anti-GPIX Mab (FMC 25) was not inhibitory with either normal or BSS platelets. Similar results were obtained using 14C-serotonin release instead of platelet aggregation as a measure of platelet activation. These findings suggest that (1) the reaction of the heparin-dependent antibody with platelets and heparin is mediated by a Fc-dependent mechanism, (2) GPIb, GPV and GPIX are not involved in this reaction, and (3) the inhibitory effect of anti-GPIb Mab on normal platelets is due to steric interference consistent with the platelet Fc receptor being in close proximity to GPIb.     

Influence of Poly(DL-Lactide) Nanocapsules on the Biliary Clearance and Enterohepatic Circulation of Indomethacin in the Rabbit

Following intravenous administration, the uptake of colloidal drug carriers by cells of the mononuclear phagocyte system, mainly the Kuppfer cells, may concentrate an encapsulated drug close to the liver parenchymal cells and facilitate its biliary excretion and enterohepatic circulation. To test this hypothesis indomethacin was administered (10 mg/kg) in four groups of 10 rabbits each by intravenous infusion at a constant rate over 2 hr, either in its free form (aqueous solution) or as nanocapsules prepared from preformed poly(DL-lactide). Unchanged drug was assayed in plasma of the two control (sham-operated) groups and in both plasma and bile of the two bile-cannulated groups. Pharmacokinetic analysis led to the conclusion that the uptake of nanocapsules by liver macrophages reduces the concentration of the drug by enhancing its total clearance. This enhancement was due to an increase in biliary clearance, as a result of parallel increases in bile concentration and biliary excretion of the drug. It was also demonstrated that nanocapsules enhance the enterohepatic circulation of indomethacin.     

The effect of dinitrophenol, hypoxaemia and ischaemia on the phosphorus compounds of the dog heart

The results reported in this paper indicate that dinitrophenol acts directly on the isolated heart, increasing its metabolic rate. It also produces heart failure associated with a low phosphocreatine content of the muscle but with no change in adenosine triphosphate, which may or may not be due to a relative hypoxia of the cardiac tissue. Experimental arterial hypoxaemia, if severe, produces a similar picture of heart failure with a decrease in phosphocreatine and no change in adenosine triphosphate. Ligation of the coronary arteries results in disappearance of the major part of the phosphocreatine within a few minutes regardless of whether or not ventricular fibrillation ensues; the adenosine triphosphate remains unchanged.     

Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators

Pentahydroxyflavone dihydrate, quercetin (QU) is one of common flavonols biosynthesized by plants and has been suggested to modulate inflammatory responses in various models. In the present study, we investigated in vivo effects of oral or intra-cutaneous QU in chronic rat adjuvant-induced arthritis (AA). Growth delay and arthritic scores were evaluated daily after AA induction in Lewis rats. Oral administration of QU (5 x 160 mg/kg) to arthritic rats resulted in a clear decrease of clinical signs compared to untreated controls. Intra-cutaneous injections of lower doses (5 x 60 mg/kg) of QU gave similar anti-arthritic effects, while 5 x 30 mg/kg concentrations were inefficient in this respect. Finally, injection of relatively low QU doses (5 x 30 mg/kg) prior to AA induction significantly reduced arthritis signs. As QU was suggested to inhibit macrophage-derived cytokines and nitric oxide (NO), we then analyzed macrophage response ex vivo. Anti-arthritic effects of QU correlated with significant decrease of inflammatory mediators produced by peritoneal macrophages, ex vivo and in vitro. These data indicate that QU is a potential anti-inflammatory therapeutic and preventive agent targeting the inflammatory response of macrophages.     

The effect of theophylline alone and in combination with ouabain on the isolated dog heart

Summary A comparative study of the inotropic effects of theophylline and ouabain as well as a study of the interaction between the two pharmacological agents were carried out in the nonfailing Starling heart-lung preparation modified to permit metabolic studies. Single doses of theophylline ranging between 100 to 200 mg added to the venous reservoir produced consistent increases in myocardial contractile force, as gauged by the maximal rate of rise of left ventricular pressure, dp/dt, 73%; systemic output, 28%; coronary output, 277%; total cardiac output, 41%; heart rate, 27%; left ventricular work, 45% and myocardial oxygen consumption, 43%. In addition, systolic time decreased consistently by 15%. 20 min and 30 min after the onset of an ouabain infusion of 5g per min, which was started 15 min after the addition of theophylline, there was further increase in dp/dt to 87% and 107%, respectively, with no significant change in the remaining parameters from the levels attained 15 min after the administration of theophylline. As compared to ouabain administered alone, ouabain administered at peak effect of theophylline led to an earlier occurence of ventricular arrhythmias and death. It may be concluded from this study that maximally effective doses of theophylline brought about an increase in dp/dt which is greater than that brought about by maximal therapeutic doses of ouabain. Secondly, ouabain administered after the peak effect of theophylline was exerted led to an additional increase in dp/dt implying that the mechanisms underlying the inotropic action of each drug are different. Thirdly, at constant aortic pressure, heart rate, left ventricular enddiastolic and left atrial pressures, ouabain in the presence of theophylline brought about an increase in myocardial contractility, as gauged by an increase in dp/dt, without a concomitant increase in myocardial oxygen consumption, thus confirming earlier results obtained with ouabain alone. Fourthly, ouabain administered at peak effect of theophylline led to an earlier occurrence of ventricular arrhythmias and death.This work was supported by a grant from the Lebanese National Research Council.     

The mechanism of dinitrophenol heart failure

Hypoxaemia, resulting from increased tissue metabolism, is an important factor in dinitrophenol failure in the conventional heart-lung preparation. Improved oxygenation of the blood by a technique described in this paper prolongs the life of dinitrophenol-treated hearts. Dinitrophenol acts very rapidly; oxygen consumption and coronary flow increase in a few minutes and the increase is proportional to the dose. The increase in oxygen consumption diminishes with time. Dinitrophenol decreases the phosphocreatine content of the heart, even when there is no failure or hypoxia. There is no evidence that dinitrophenol failure can be due to a decrease of phosphocreatine or adenosine triphosphate content of the heart, although this is to be expected in view of the observed “uncoupling” action of dinitrophenol.