Single-dose pharmacokinetics and dose proportionality of oral cibenzoline

The pharmacokinetics of cibenzoline were evaluated in four young healthy volunteers who received ascending oral doses of 65, 97.5, 130, 162.5, 195, 227.5, and 260 mg separated by one week. Cibenzoline plasma concentrations exhibited an apparent biexponential decline following oral absorption. Maximum plasma concentrations and area under the plasma concentration-time curve increased in proportion to the dose. The mean elimination half-life among subjects was independent of dose and ranged from 7.3 to 8.7 hours. Oral clearance ranged from 380 to 575 ml/min and was also independent of dose. A single pharmacokinetic equation was used to adequately describe the plasma concentration data over the entire range of doses for each subject, indicating dose-proportional and linear pharmacokinetics.     

The influence of nutritional factors on lead absorption

The nutritional factors which affect lead absorption have been studied. Synthetic diets of known composition were compounded to contain 0·075% Pb as PbCl₂ labelled with ²⁰³Pb. Rats were exposed to lead for periods of 48 hr. The dietary intake was then measured and the absorption of lead determined by means of a whole-body counter. Lead absorption was increased by high fat, low mineral, low protein and high protein diets but was decreased by high mineral diet. Low fat, low fibre, high fibre, low vitamin and high vitamin diets had no effects on lead absorption.     

Reactions in rabbit Fallopian tube after plastic reconstruction. I. Gross pathology, tubal patency, and pregnancy

Rabbit tubal repair surgery was aseptic with Nembutal and ether anesthesia. Both tubes were cut at the uterotubal junction, a .61 mm thick polyethylene splint was inserted, sutured to the myometrium, and the junction sutured. At 2, 6, 10, 16, and 24 weeks the splint was removed through an incision. After a dye test for patency, 1 tube was removed and the rabbit was mated 1 week later. Results were 30% distorted placement of tube, 30% fibrose tubes (especially after 16 weeks), 47% adhesion (particularly after 6 weeks), some infection, and 55% positive dye flow test. 3 out of 7 rabbits delivered, all in those of the 2-week group that had no adhesions. 2 of the pregnancies occurred in rabbits with no dye passage.     

Transplantation of neonatal porcine islets and sertoli cells into nonimmunosuppressed nonhuman primates

A Mexican group reported transplantation of cocultured neonatal porcine islets and Sertoli cells resulting in insulin independence in nonimmunosuppressed type 1 diabetes patients. We have transplanted similar islets alone (naked islets) or cocultured islets with sertoli cells (islet/sertoli cells) into an omental site and other locations of seven nondiabetic, nonimmunosuppressed, nonhuman primates. Porcine endogenous retrovirus was not detected in recipient blood 8 weeks after porcine islet grafts, and porcine C-peptide was detected at a very low level in all animals. Histology examination failed to demonstrate obviously recognizable islets, but in the animals transplanted with islet/Sertoli cells at the omentum site, there were some surviving glucagons, pan-cytokeratin, and inhibin stained cells at 8 weeks.     

In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo.