Parachloroamphetamine toxicity in mice: influence of body weight, sex and dose

Five doses of d,l-para-chloroamphetamine (0.0, 15,0, 30.0, 45.0 and 60.0 mg/kg) were used to challenge 10 groups of 16 male and 10 groups of 16 female CF-1 mice weighing either 16 to 25 g or 40 to 55 g. Twenty-four hours after intraperitoneal injection, rates of lethal toxicity were assessed. Effects for body weight and dose were found. In addition, a sex by dose interaction was demonstrated. It was hypothesized that the influence of weight might be related to thermoregulatory processes, since as weight rises, surface-to-volume ratios decline, and with them the efficiency of heat exchange. Caution is suggested in the interpretation of ontological studies of drug response.     

Does the choice of antihypertensive therapy influence haemodynamic responses to induction, laryngoscopy and intubation?

We have measured haemodynamic responses to induction of anaesthesia, laryngoscopy and intubation in 103 mild-moderate hypertensive patients (83 patients (diastolic pressures < or = 110 mm Hg) currently receiving one of four monotherapies (ACE inhibitors, group A; beta adrenoceptor blocking drugs, group B; calcium channel antagonists, group C; diuretics, group D) and 24 were untreated hypertensive patients). Anaesthesia was induced with fentanyl 1.5-2.0 micrograms kg-1 and thiopentone 3-5 mg kg-1. Tracheal intubation was facilitated by vecuronium 0.1 mg kg-1 and anaesthesia maintained with enflurane and nitrous oxide in oxygen. Systolic and diastolic pressures (SAP, DAP) were measured at 1-min intervals by a non-invasive oscillometric method and cardiac output (CO) and stroke volume (SV) by thoracic bioimpedance. Induction of anaesthesia was associated with a decrease in SAP, DAP and CO in groups A-D (P < 0.05). Heart rate (HR) decreased in groups A and D (P < 0.01) and systemic vascular resistance (SVR) decreased in groups A and B (P < 0.05). SAP and HR increased in all groups after laryngoscopy and intubation (P < 0.01) as did SVR in groups A, B and D (P < 0.02). CO was unaltered. Similar changes occurred in the untreated hypertensive patients, although nine of 24 patients exhibited HR > or = 100 beat min-1 after laryngoscopy and intubation. Comparison of the changes in SAP, DAP, CO and SVR with time showed no differences in the five treatment groups; changes in HR were significantly less in group B compared with the other groups (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-dose cyclosporine for the treatment of Crohn's disease. The Canadian Crohn's Relapse Prevention Trial Investigators

BACKGROUND: Long-term corticosteroid therapy for Crohn's disease is associated with important types of morbidity, such as osteoporosis. Safe and effective alternative treatments are required. Although a short-term benefit of cyclosporine in active Crohn's disease has been suggested, the long-term safety and efficacy of this treatment have not been established. METHODS: We conducted a randomized, double-blind, placebo-controlled evaluation of the effect of 18 months of low-dose cyclosporine treatment on the course of Crohn's disease. Adult patients whose disease had been active within the previous two years were randomly assigned to receive cyclosporine (151 patients) or placebo (154 patients) in addition to their usual therapy. Randomization was stratified according to center and score on the Crohn's Disease Activity Index (193 patients had scores of 150 or less, and 112 had scores greater than 150). The primary outcome measure was clinically important worsening of Crohn's disease, defined as a 100-point increase in the Crohn's Disease Activity Index from the patient's base-line value. Secondary outcomes were the use of prednisone and 5-amino-salicylates, mean score on the Crohn's Disease Activity Index and mean quality-of-life score, and the need for surgery. RESULTS: The condition of more patients worsened with cyclosporine than with placebo (91 of 151, or 60.3 percent, vs. 80 of 154, or 51.9 percent; P = 0.10). The median time to worsening of disease in patients receiving cyclosporine was 338 days, as compared with 492 days in patients receiving placebo (P = 0.25; relative risk, 1.22; 95 percent confidence interval, 0.86 to 1.72). Analyses of the mean Crohn's Disease Activity Index and quality-of-life scores and of the use of prednisone and 5-aminosalicylates also failed to demonstrate benefit. CONCLUSIONS: In our patient population, the addition of low-dose cyclosporine to conventional treatment for Crohn's disease did not improve symptoms or reduce requirements for other forms of therapy.     

Studies of 5-fluorodeoxyuridine 5'-monophosphate binding to carboxypeptidase A-inactivated thymidylate synthase from Lactobacillus casei

The binding of 5-fluorodeoxyuridylate (FdUMP) to carboxypeptidase-inactivated thymidylate synthase obtained from methotrexate-resistant Lactobacillus casei was investigated using [3H]FdUMP in a trichloroacetic acid precipitation assay and by 19F nuclear magnetic resonance spectroscopy. The cleavage of 1 valine residue from the carboxyl terminus of one of the identical subunits of the enzyme dimer correlates with complete loss of thymidylate synthesis (Aull, J. L., Loeble, R. B., and Dunlap, R. B. (1974) J. Biol. Chem. 249, 1167-1172). We have further investigated the phenomenon of carboxypeptidase A-dependent inactivation of thymidylate synthase by employing immobilized carboxypeptidase A in order to facilitate the isolation and characterization of the inactivated enzyme. The time course of carboxypeptidase treatment of thymidylate synthase has been profiled by the spectrophotometric assay, tritium release assay, trichloroacetic acid precipitation assay (covalent adduct analysis), 19F nuclear magnetic resonance spectroscopy, and amino acid analysis. The techniques utilized in this study yielded results which showed that the completely inactivated enzyme (failure to catalyze thymidylate formation) continued to catalyze both covalent FdUMP-enzyme interactions and the formation of the covalent inhibitory ternary complex with the cofactor, 5,1O-methylenetetrahydrofolate, although to a reduced extent, thus effectively uncoupling these processes from thymidylate synthesis activity.