Selective, histamine-mediated immunosuppression in laryngeal cancer

Immunosuppression observed even in the earliest laryngeal cancers can be, in part, reversed with H2 histamine antagonists. In an effort to explain this, we tested whether histamine could evoke changes in endogenous antitumor lymphokine production using tonsil lymphocytes as test cells. We have observed that lymphocytes, treated in vitro with histamine, display a significant suppression of lymphokine production and mixed lymphocyte proliferation response following galactose oxidase treatment. Interferon gamma production was reduced to less than 2% of control value in the presence of histamine. In contrast, the lymphokine-activated killer cell activity induced by purified, natural interleukin-2 was not affected by similar concentrations of histamine. Histamine appears to exert its inhibitory effect by stimulating the production of a substance released by suppressor T cells. The suppressive effects observed could be reversed by concomitant or sequential treatment with cimetidine or ranitidine and not by H1 histamine antagonists, indicating that it occurs through an H2 histamine receptor. These experiments suggest that histamine may have a profound suppressive effect on the lymphocyte population studied.     

Effect of short-term training cessation on performance measures in distance runners.

This study examined if measures associated with distance running performance were affected by short-term (14 d) training cessation in 12 distance runners. VO2max decreased by approximately 3 ml.kg-1.min-1 (mean +/- SE, 61.6 +/- 2.0 vs 58.7 +/- 1.8 ml.kg-1.min-1, p < 0.05) with training cessation. Time to exhaustion (TTE) during the incremental VO2max test decreased by 1.2 min (13.0 +/- 0.5 vs 11.8 +/- 0.5 min, p < 0.001) and maximal heart rate increased (p < 0.001) by 9 beats per minute (BPM). No changes in running economy (75 and 90% VO2max) were evident, although submaximal heart rate increased by 11 BPM (p < 0.001) at both running speeds. Other evidence for detraining were decreases in estimated resting plasma volume (-5.1 +/- 1.9%) and muscle citrate synthase activity (-25.3 +/- 2.6%, p < 0.05). Muscular atrophy (muscle fiber cross-sectional area) was not evident. TTE and submaximal heart rate exhibited relatively large percent changes (-9 and +6%, respectively) compared to VO2max (-4%). These findings indicate that the reduction in VO2max with short-term training cessation is relatively small. TTE and submaximal heart rate may be easily measured, yet more sensitive indicators of decrements in distance running performance.     

The action of atriopeptin III on renal function in two models of chronic renal failure in the rat.

1. The natriuretic and diuretic effects of atriopeptin III (125, 250 and 500 ng kg-1, i.v.) were studied in groups of rats anaesthetized with pentobarbitone which were either sham controls, unilaterally nephrectomized controls, adenine-fed or subtotal nephrectomy chronic renal failure models. 2. Atriopeptin III given at these doses to the sham control animals had no effect on blood pressure, renal blood flow or glomerular filtration rate but reversibly increased urine flow, between 46% to 54%, absolute sodium excretion, between 52% to 61%, and fractional sodium excretion, between 48% to 54% (all P values less than 0.05) from the lowest to the highest dose. The adenine-fed chronic renal failure group of rats had a reduced renal blood flow of between 30 and 75%, and glomerular filtration rate of approximately 20%, compared to the sham controls. Administration of atriopeptin at 125, 250 and 500 ng kg-1 to the animals with renal failure increased water and sodium excretion to the same degree as observed in the sham group of rats. 3. In the group of unilaterally nephrectomized rats, atriopeptin III, at 125, 250 and 500 ng kg-1 increased urine flow by 36%, 47% and 72%, respectively, absolute sodium excretion by 37%, 57% and 106%, respectively, and fractional sodium excretion by 46%, 45% and 102%, respectively. A similar pattern of responses was observed in the subtotal nephrectomy, chronic renal failure group in which filtration rate was approximately 4 times less than the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of varying doses of nicotinamide and tumour radiosensitisation with carbogen and nicotinamide: clinical considerations.

Plasma concentrations, after administration of varying doses of nicotinamide, were measured in CBA male mice using a newly-developed high performance liquid chromatography assay. In all dose groups, peak levels were observed within the first 15 min after an i.p. administration of 0.1, 0.2, 0.3 or 0.5 mg g-1 of nicotinamide. There was a clear dose-dependent increase in plasma concentration with increasing dose, with almost a five-fold lower concentration (1.0 vs 4.9 mumol ml-1) achieved with a dose of 0.1 mg g-1 compared with 0.5 mg g-1, respectively. The half-life of nicotinamide increased from 1.4 h to 2.2 h over the dose range (P < 0.01). Comparisons with previous pharmacokinetic data in humans show that clinically-relevant oral doses of 6 and 9 g in humans give plasma levels slightly higher than those achieved at 1 h with doses of 0.1 to 0.2 mg g-1 in mice. Tumour radiosensitisation with carbogen alone, and with carbogen combined with varying doses of nicotinamide (0.05 to 0.5 mg g-1), was investigated using a 10-fraction in 5 days X-ray schedule. Relative to air-breathing mice, a statistically significant increase in sensitisation was observed with both a local tumour control and with an in vivo/in vitro excision assay (P < or = 0.007). With the local control assay, a trend was observed towards lower enhancement ratios (ERs) with decreasing nicotinamide dose (from 1.85 to 1.55); carbogen alone was almost as effective as when combined with 0.1 mg g-1 of nicotinamide. With the excision assay, ERs for carbogen combined with nicotinamide increased with decreased levels of cell survival. At a surviving fraction of 0.02, enhancement ratios of 1.39-1.48 were obtained for carbogen plus 0.1 to 0.3 mg g-1 of nicotinamide. These were lower than those seen with the two higher doses of 0.4 to 0.5 mg g-1 (ERs = 1.63-1.69).