Enhancement of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor efficacy through administration of a controlled-porosity osmotic pump dosage form.

An extended-release osmotic dosage form was designed for gastrointestinal delivery of the water-soluble tromethamine salt of the beta-hydroxyacid form of simvastatin, a potent HMG-CoA reductase inhibitor and cholesterol lowering agent. The cholesterol lowering efficacy and systemic plasma drug levels resulting from peroral administration of this dosage form, relative to a powder-filled capsule oral bolus, were evaluated in dogs. A twofold improvement in cholesterol lowering efficacy was realized with the controlled-release dosage form that was accompanied by a drug AUC and Cmax that were 67 and 16%, respectively, of those achieved with the bolus dosage form. These results suggest that extended-release dosage forms have the potential for a dose-sparing advantage in the administration of HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia.

The solubility-modulated osmotic pump: in vitro/in vivo release of diltiazem hydrochloride.

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem.HCl as a model drug. Diltiazem.HCl has an aqueous solubility greater than 590 mg/ml (37 degrees C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ml; 37 degrees C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of greater than 80% of an initial diltiazem.HCl load. Devices were prepared with cores that contained diltiazem.HCl and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of approximately 75% of the initial diltiazem.HCl load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.

Diel periodicity in the landing of Aedes aegypti on man.

The dynamics of transmission of disease agents by vectors depends, in part, on the probability of host-vector contact, which can vary with fluctuations of both host and vector. As important as seasonal variations is 24-hour periodicity in activity. Periodicity in the landing of males and females of Aedes aegypti on man has been assessed by means of catches of 15 hours or longer, with several persons as a bait. The assessments were made in a suburban area of Tanzania and continued throughout one year. Activity was observed to be almost entirely diurnal and diphasic. Whereas the detailed activity pattern of males agreed closely with that found elsewhere in East Africa, that of the females was unusual on account of the symmetry of the morning and afternoon peaks. Possible causes of differences among studies are discussed.

Subtle periodicity of pupation in rapidly developing mosquitos: with particular reference to Aedes vittatus and Aedes aegypti.

Aedes vittatus and Ae. aegypti are important vectors of yellow fever and other arbovirus diseases in Africa and they complete many generations, through all developmental stages, in a single year. Recent studies on Drosophila have offered precise techniques for analysing periodicities in populations of single developmental events in individuals. If the variability of pupation times is low, periodicities may not be recognizable by an obviously polymodal pattern in a single synchronized population. Analysis of 8 synchronized populations of Ae. vittatus and Ae. aegypti, evenly spaced through 24 hours, provided a sensitive method of recognizing even subtle periodicities in rapidly developing mosquitos. By this means Ae. vittatus has been shown to exhibit a weak diurnal periodicity of pupation while a strain of Ae. aegypti showed not the slightest periodicity of pupation under the same light-dark cycle. The authors stress that periodicity of emergence or pupation in mosquitos can have important consequences for epidemiology and vector control and should be verified for each vector species for which control measures are envisaged.