Natural cell-mediated cytotoxicity in cutaneous T-cell lymphomas.

Natural cell-mediated cytotoxicity was studied in 24 patients with cutaneous T-cell lymphomas and in 18 age- and sex-matched controls studied concomitantly. Percent cytotoxicity was determined by 4-h 51Cr release assay using K562 targets at effector to target ratios of 100:1, 50:1, and 25:1. Mean percent cytotoxicity was significantly lower in patients than in controls at an effector to target cell ration of 100:1. Likewise, decreased cytotoxicity was found at effector to target ratios of 50:1 and 25:1, although this difference was not significant. When natural killer activity was analyzed separately for males and females, cytotoxicity was lower in both, although the decrease was significant only for male patients. Impairment of natural killer activity did not correlate with blood zinc levels, but appeared to correlate with stage of disease.

Uptake of inorganic lead in vitro by isolated mitochondria and tissue slices of rat renal cortex.

Slices of rat renal cortex were shown to take up Pb2+ during incubation in vitro; Pb2+ was also shown to enter mitochondria within the slices. The uptake of Pb2+ by isolated mitochondria was inhibited by N-3, La3+ and ruthenium red. A steady state of uptake was attained within 60 sec. The concentration dependence of uptake was complex; maximum uptake was attained at 25 microM and inhibition ensued at higher concentrations. A substantial inhibitor-resistant component of Pb2+ uptake was noted, especially at medium Pb2+ concentrations greater than 25 microM, and these concentrations also inhibited respiration state 3. The effects on respiration were reduced if the mitochondria had been preincubated with ruthenium red. Slices of renal cortex incubated at 1 degree in medium with various concentrations of Pb2+ showed two fractions of uptake, one saturating at 50-100 microM external Pb2+ and the other at 150-200 microM. Subsequent incubation for 60 min at 25 degrees led to further uptake at all concentrations. Upon isolation of mitochondria from incubated slices, significant amounts of Pb2+ were detected in the mitochondria within 5 min of addition of Pb2+ (200 microM), with maximum attained at 30 min. Electron microscopy of slices showed electron-dense particles, apparently of Pb2+, in the cortical cells but the greatest concentration was deposited in the basement membranes. The results indicate the importance of the basement membrane in limiting access of Pb2+ to cortical cells, and of mitochondria in accumulating Pb2+ once it is in the cells. They also illustrate the importance of interactions between Pb2+ and Ca2+.

3-Carbamyl-N-allylquinuclidinium bromide. Effects on cholinergic activity and protection against soman.

3-Carbamyl-N-allylquinuclidinium bromide (CAB) was synthesized and evaluated for its pharmacological effects on cholinergic activity and for protection in vivo against soman toxicity in guinea pigs. This carbamylated derivative of N-allyl-3-quinuclidinol (NAQ), a potent inhibitor of high-affinity choline uptake, demonstrated stereospecific alterations of cholinergic function as well as protection against soman. The R-isomer, but not the S-isomer, of CAB inhibited erythrocyte acetylcholinesterase (AChE) and plasma pseudocholinesterase (pChE) in a concentration-response manner (IC50 = 25 and 29 microM, respectively). The R-isomer of CAB was also a more potent inhibitor of high-affinity choline uptake (IC50 = 4.8 microM) than S-CAB (IC50 = 63 microM). When R-CAB (10 mumol/kg, i.m.) was administered to guinea pigs 30 min prior to soman in conjunction with atropine (16 mg/kg, i.m.) given 1 min post-soman, the compound significantly reduced lethality up to 5 LD50S. This represents enhanced protection when compared to NAQ (up to 100 mumol/kg); the S-isomer of CAB failed to protect against soman intoxication. The results demonstrate that reversible inhibition of AChE with suppression of acetylcholine synthesis into a single compound, CAB, enhances the protection against organophosphates.

Microemulsions as topical drug delivery vehicles: in-vitro transdermal studies of a model hydrophilic drug.

Microemulsions with a 58:42 weight ratio of dioctyl sodium sulphosuccinate: octanol and containing 15, 35, and 68% water have been tested for their ability to transport glucose across human cadaver skin. A flow-through multisample skin diffusion cell showed that both the 35 and 68% water microemulsions caused enhanced (approximately 30-fold) transport of glucose. No transport was discernible for the 15% water microemulsion. Differences in percutaneous glucose transport were shown to parallel differences in the diffusion of water within the microemulsion vehicles before application to the skin.

Effect of chronic lead ingestion by rats on glucose metabolism and acetylcholine synthesis in cerebral cortex slices.

The effect of chronic low-level lead (Pb2+) ingestion on the metabolic pathways leading to the acetyl moiety of acetylcholine (ACh) was examined. Cerebral cortex slices, prepared from untreated or Pb2+-exposed rats (600 ppm lead acetate in the drinking water for 20 days), were incubated in Krebs-Ringer bicarbonate buffer with 10 mM glucose and tracer amounts of [6-3H]glucose and either [6-14C]glucose or [3-14C] beta-hydroxybutyrate. Altering the concentration of Pb2+ in the drinking water produced a dose-related increase in blood and brain lead levels. When tissue from Pb2+-exposed rats was incubated with mixed-label glucose, incorporation into lacate, citrate, and ACh was considerably decreased, although no changes occurred in the 3H/14C rations. Similar effects of Pb2+ were found when 14C-labeled beta-hydroxybutyrate was substituted for the [14C]glucose. It appears from these data that Pb2+ exerts a generalized effect on energy metabolism and not on a specific step in glucose metabolism. The impairment of glucose metabolism may explain partially the Pb2+-induced changes observed in cholinergic function.

Effect of inorganic lead on rat brain mitochondrial respiration and energy production.

Toxicologically significant amounts of inorganic lead were added to rat brain mitochondrial preparations that did not contain EDTA or Pi. The binding of the lead to the mitochondria was measured by anodic stripping voltometry. In the presence of lead, the respiratory control ratios decreased, implying a decrease in the degree of dependence of respiration on a phosphate acceptor. Nucleotide contents were also measured, and in the presence of inorganic lead the actual amounts of ATP formed from ADP were found to be significantly decreased as well.