Ethanol enhances immunosuppression induced by cocaine.

Use of cocaine concurrently with alcohol is prevalent among cocaine addicts. Cocaine has been shown to inhibit phytohemagglutinin- and ConA-induced proliferation of T-lymphocytes, NK cell cytotoxicity, and phagocytic activity of peritoneal macrophages. In some studies no effects of cocaine on the immune response have been observed, although on the contrary, others show it increased the NK cell activity and serum antibody response to T-dependent antigen. Effects of cocaine on the immune system may be mediated by its neurostimulatory action on the hypothalamo-pituitary-adrenal axis. ACTH, beta-endorphine, and corticosterone released under the action of cocaine exert various inhibitory effects on the immune function. We studied the immunotoxic effect of cocaine, combination of cocaine with ethanol, and cocaethylene, a derivative formed from cocaine and ethanol in the body, on the mitogen-stimulated production of cytokines by splenocytes. C57BL mice were injected twice daily with 20 mg/kg cocaine or equivalent dose of cocaethylene and received a liquid Lieber-DeCarli diet containing ethanol (26% of total calories) or isocaloric amount of maltose-dextrin. After 3 weeks of treatment, cocaine and cocaethylene caused a significant decrease of the spleen weight and total number of splenocytes. In splenocytes isolated from the cocaine- or cocaethylene-treated mice, mitogen-stimulated production of gamma-interferon, tumor necrosis factor, and interleukin-2 was suppressed, in all cases more severely when cocaethylene was used. Thus, formation of cocaethylene during simultaneous consumption of cocaine and ethanol may enhance the immunotoxicity of cocaine.     

Evidence for a decrease in sympathetic control of intestinal function in the aged rat.

The ability of carbachol and isoprenaline to contract and relax respectively the longitudinal layer of ileal smooth muscle has been compared in rats aged six and twenty-four months. The concentration response curve to carbachol did not vary with the age of the animal. In contrast, the ability of isoprenaline to relax longitudinal smooth muscle precontracted with carbachol was significantly (p less than 0.02) reduced in the twenty-four month age group. This reduced response was due to a decrease in the maximal relaxation induced by isoprenaline rather than by a shift to the right of its dose-response curve. These results are discussed in the context of previous histochemical and microscopical studies which have shown a marked reduction in the density of the sympathetic innervation of the rat small intestine in old age.     

The preadministration of activated charcoal and aspirin absorption.

There is little information describing the effects of activated charcoal preadministration on drug absorption. This study was undertaken to determine the effect of activated charcoal preadministration at two different times on aspirin absorption. Fifteen volunteer subjects completed three study phases: 1) 975 mg aspirin alone, 2) 975 mg aspirin 30 min after 10 g activated charcoal, and 3) 975 mg aspirin 60 min after 10 g activated charcoal. Urine was collected for 48 h after the initiation of each study phase, and total aspirin recovery determined by HPLC. The aspirin recovery was 88.8% +/- 4.5% for the control phase, and 84.8% +/- 9.4% (Phase 1) and 85.8% +/- 12.6% (Phase 2) for the activated charcoal treatments (p > 0.05). These results suggest that activated charcoal administered 30 and 60 min prior to drug ingestion has little effect on drug absorption. Further studies of the effect of charcoal preadministration on the absorption of other drugs may provide useful information regarding factors important in determining activated charcoal efficacy.     

Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis

BACKGROUND: Patients with cystic fibrosis have received more intravenous antibiotic courses as median survival has steadily increased. A number of centres have adopted a policy of regular (three monthly) rather than on demand intravenous antipseudomonal antibiotics. More widespread bacterial antibiotic resistance has resulted from this increased antibiotic use. Most Pseudomonas aeruginosa strains remain fully sensitive to colistin but its use has been resisted owing to concerns about neurotoxicity and nephrotoxicity. A study was carried out to assess the safety and efficacy of intravenous colistin in the treatment of acute respiratory exacerbations in adult patients with cystic fibrosis. METHODS: Patients with chronic Pseudomonas aeruginosa colonisation who presented with protocol defined respiratory tract exacerbations were randomised to receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti- pseudomonal antibiotic. Comparisons of the absolute values of respiratory function tests on days 1, 5, and 12 and of overnight oxygen saturation on days 1 and 12 were the primary outcome measures. Patient's weight, clinical and chest radiographic scores, and peripheral blood markers of inflammation were also documented. The effect of each treatment regimen individually was assessed by the change in clinical measurements from baseline values. Adverse renal effects were monitored by measurement of serum levels of urea and electrolytes, creatinine clearance, and ward urine testing. Neurotoxicity was monitored by direct questioning for symptoms. RESULTS: Fifty three patients, 18 of whom entered the study twice, were enrolled. The mean forced expiratory volume in one second (FEV1) increased significantly in both groups, mean forced vital capacity (FVC) only with dual therapy. Both groups showed a non-significant increase in overnight oxygen saturation. All patients showed clinical improvement. Thirty seven adverse neurological events (two severe) were reported in 33 patients in the monotherapy group and 37 (none severe) in 36 patients in the dual therapy group. One patient withdrew because of severe weakness and dizziness. All other adverse neurological events were well tolerated and resolved during or shortly after treatment. Significant changes were seen in mean serum urea levels in both groups, but in only four patients to a level above the normal range, and in creatinine clearance in the dual therapy group. At 24 month follow up no long term adverse consequences from intravenous colistin were found in patients who completed the study. CONCLUSIONS: Intravenous colistin is an effective treatment for Pseudomonas aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the pseudomonas shows in vitro sensitivity. Changes in renal function should be monitored.


     

The Effect of Subacute Marijuana Smoke Inhalation on Experimentally Induced Dermonecrosis by S. Aureus Infection

Dermonecrosis was induced in ICR mice by subcutaneous implantation of Staphylococcus aureus absorbed onto sterile cotton pellets. This model was used to assess the effects of marijuana smoke, marijuana placebo smoke and $DL⁹-tetrahydrocan-nabinol ($DL⁹-THC) on the local immune response to bacterial infection. Mice were exposed to 40 or 80 “puffs” of marijuana smoke, marijuana placebo smoke or air daily for 4 consecutive days. The estimated dose of $DL⁹THC per day generated from 40 or 80 puffs of marijuana smoke was 3.2 and 6.4 mg/kg, respectively. A group of sentinel (Shelf) control mice were included in each experiment. The necrotic index (NI) of mice exposed to 40 or 80 puffs of marijuana smoke were 67% and 44% of control, respectively. Air exposed mice showed a necrotic index comparable to the shelf control group. In chronically (60 days) exposed mice (80 puffs per day) the necrotic index was about 12% of control, while air-exposed mice were about 40% of control.

Placebo marijuana smoke exposed mice had a NI comparable to that of marijuana smoke exposed mice which suggested that the reduction in NI was unrelated to the pychomimetic component $DL⁹THC. To further explore which of the constituents of marijuana were responsible for the decreased NI, the ethanol extract from marijuana leaves was partioned between water (cannabinoid free) and chloroform (cannabinoid rich). Injection of the cannabinoid free fraction produced comparable decrease in the NI as observed with whole marijuana smoke, while the cannabinoid rich fraction produced no effect. $DL⁹THC at a dose of 10 mg/kg per day did not alter the NI.