Response of Plasmodium falciparum to dihydrofolate reductase inhibitors in Malindi, Kenya

The response of Plasmodium falciparum isolates to dihydrofolate reductase inhibitors (DHFRI) was examined in Malindi, Kenya. All 20 infected children treated with pyrimethamine/sulphadoxine responded. In contrast, after treatment with pyrimethamine, parasitaemia in 9 of 14 infections failed to clear or recrudesced during the seven-day follow-up. In a 48-hour in vitro test, five of six isolates resistant to pyrimethamine in vivo had a minimal inhibitory concentration (MIC) to pyrimethamine greater than or equal to 300 nmoles/1 compared with less than or equal to 100 nmoles/1 for the four sensitive isolates; four isolates did not grow. MIC to M-B 35769, an experimental DHFRI structurally similar to pyrimethamine were the same (six isolates) or 10-fold lower (three isolates). In the laboratory four of five isolates adapted to in vitro culture had the same MICs as in the field while one isolate became less responsive to both drugs. Cycloguanil (the active metabolite of proguanil) was more active in vitro in the laboratory than pyrimethamine or M-B 35769.     

Comparisons of Pooled Polyclonal Rabbit Anti-Human C3d with Four Monoclonal Mouse Anti-Human C3ds

Performance characteristics of pooled rabbit IgG polyclonal anti-C3d are compared with one mouse IgM and three mouse IgG monoclonal anti-C3d antibodies (MAs). IgG MA,s employed singly or in combination, failed to precipitate C3d; by contrast, IgM MA and polyclonal anti-C3d precipitated C3d. Measurements of polyclonal anti-C3d concentration by chemical means and by 125I-C3d radioimmunoassay (RIA) agreed closely. RIA values were 50% of chemical measurement values for three of the four MAs. Use of sucrose density gradient ultracentrifugation to assess MA C3d/anti-C3d molar combining ratios for soluble anti-C3d/C3d was not possible because fast-sedimenting multimeric C3d/anti-C3d complexes did not form. Dissociation and competitive binding studies indicate that (1) two MAs had substantially lower affinities than the other anti-C3d antibodies, and (2) polyclonal anti-C3d recognizes more C3d epitopes than are recognized by individual MAs. The results demonstrate antigenic complexity of C3d fragment and illustrate the difficulties of predicting individual MA performance based on prior experience with polyclonal antibodies.     

A decade of developments in diuretic drug therapy

New diuretics introduced into clinical medicine during the past decade include potent new loop diuretics such as bumetanide and piretanide, the uricosuric indanyloxyacetic acid derivative indacrinone, and a new generation of sulfamoyl diuretics such as indapamide and xipamide, which are recommended primarily for the treatment of hypertension. Pharmacokinetic studies of individual diuretics have demonstrated that the diuretic and natriuretic responses to the newer agents generally follow the plasma drug concentration-time curves and urinary drug excretion rates. Therapeutic monitoring can therefore be achieved in most patients with edema or hypertension by close clinical observation and laboratory analysis of plasma electrolyte and creatinine concentrations and urinary electrolyte excretion rates. Interest in the mechanisms involved in the renal and extrarenal vascular actions of the newer diuretics has led to a better understanding of how changes in venous compliance, peripheral vascular resistance, and renal blood flow distribution may contribute to the overall therapeutic response to these agents, especially in patients with severe congestive heart failure, renal insufficiency with low glomerular filtration rates, and hypertension with cardiorenal complications. Adverse reactions to modern diuretics, which are mainly an extension of their renal pharmacodynamic effects, have proved to be minimal, provided that the dosage is adjusted to meet but not exceed individual patient requirements. However, the long-term consequences of prolonged periods of diuretic-induced alterations in plasma potassium levels, and metabolic effects that include elevated blood lipids, are still under investigation.     

Additive effect of theophylline on the cardiac response to isoproterenol

To ascertain the effect of theophylline on the cardiac chronotropic response to beta-adrenergic stimulation, isoproterenol dose-response curves in healthy young subjects were compared during saline and theophylline maintenance infusions. Each study was repeated 1 to 3 weeks later to evaluate reproducibility. Neither the dose of isoproterenol required to raise the heart rate by 25 bpm (2.32 +/- 0.81 vs. 1.55 +/- 0.46 micrograms on day 1 and 1.28 +/- 0.22 vs. 1.27 +/- 0.25 micrograms on day 2) nor the slopes of the dose-response curves were affected by theophylline. Higher heart rates were observed after isoproterenol bolus dosing during theophylline than during saline infusion because of additive chronotropic effects of theophylline and isoproterenol. Since theophylline does not interact in a synergistic fashion with isoproterenol, phosphodiesterase inhibition appears to be an unlikely mechanism of the chronotropic effect of methylxanthines at therapeutic concentrations.     

Acute hemodynamic effects of piroximone (MDL 19,205) in patients with moderate congestive heart failure: comparison with sodium nitroprusside

Piroximone (MDL 19,205), a new imidazolone derivative, was given intravenously to 14 patients with congestive heart failure (NYHA class II-III), while under constant daily doses of digitalis and diuretics. In the first 3 patients, we determined the dose safely eliciting a favorable hemodynamic response. The subsequent 11 patients received 1 mg/kg of piroximone intravenously, and the hemodynamic effects were compared with those of sodium nitroprusside (SN) at a dose-lowering mean blood pressure by 10-20 mm Hg. Piroximone increased heart rate (13.2 +/- 2.0 beats/min, mean +/- SEM) and lowered mean arterial pressure (9 +/- 2.3 mm Hg). Both agents reduced similarly wedge pressure (6.5 +/- 2.9 and 9 +/- 2.9 mm Hg, respectively, for SN and piroximone) and total peripheral resistance. Cardiac index was increased less by SN (15%) than piroximone (48%) (p less than 0.001), and stroke work index significantly enhanced only by piroximone (p less than 0.001). The changes in loading conditions induced by the two agents being similar, it is likely that piroximone not only acts by peripheral vasodilation, but also possesses positive inotropic properties. Myocardial oxygen demand, assessed indirectly by tension-time index, was not affected by piroximone. Thus, piroximone appears to combine well-balanced vasodilator and inotropic properties which make this new agent potentially very useful for the management of congestive heart failure.     

Prosthetic use in elderly patients with dysvascular above-knee and through-knee amputations

Fifty-five patients with vascular insufficiency resulting in above-knee (AK) and through-knee (TK) amputations were studied to determine factors related to prosthetic candidacy and functional outcome. Chart review showed that the only difference between patients who were fitted with prostheses and those who were not fitted with prostheses was their respective number of medical complications. Twenty-three of 31 patients with prostheses were evaluated 7 to 35 months after receiving the prostheses. Ten (44%) of these patients wore their prostheses all day every day and used wheelchairs minimally or not at all. Over half of the patients evaluated used their wheelchairs most of the time. Two (9%) of the 23 patients had stopped wearing their prostheses. Patients who demonstrated increased walking distances and velocities at follow-up used their prostheses more and their wheelchairs less than did the other patients. Neither gait factors nor hip range of motion at discharge was predictive of continued prosthetic use. Functional outcome and prosthetic use were limited in this group of elderly patients with dysvascular AK and TK amputations. The results of this study may serve as a basis for clinical determination of prosthetic candidacy and functional goals.