Randomized controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction: safety and haemodynamic effects: ISIS-4 (Fourth International Study of Infarct Survival) Pilot Study Investigators

The purpose of this randomized controlled study was to assessthe haemodynamic effects, safety and tolerability in acute myocardialinfarction (AMI) of one month of oral captopril, one month oforal isosorbide mononitrate and 24 h of intravenous magnesium.It was carried out in four United Kingdom and six Polish hospitalsin consecutive phases; oral captopril vs oral mononitrate vsplacebo were compared among 400 patients in a ‘three-way’study; and then oral captopril vs placebo and oral mononitratevs placebo were compared among 474 patients in ‘2x2’and ‘2 x 2 x 2’ factorial studies (with 208 patientsin the latter study also randomized between intravenous magnesiumand open control). The factorial studies differed from the three-waystudy in that one group of patients was allocated both oralcaptopril and oral mononitrate, a higher maintenance dose ofcaptopril was used (following the same initial dose), and oncedaily controiled-release mononitrate was used. In the three-waystudy, the mean of the lowest systolic blood pressures recordedduring the first 4 h after randomization were (mmHg ±standard error): 104 ± 2 captopril vs 105 ± 1mononitrate vs 112 ±2 placebo (P<0.001 for captoprilor for mononitrate vs placebo), and in the factorial studieswere 105 ± 1 captopril vs 110 ± 1 placebo (P<0.01)and 106 ± 1 mononitrate vs 108 ±1 placebo (NS).There was an excess of hypotension recorded among patients allocatedactive treatment (captopril>mononitrate>placebo) and therewas a small, but significant, excess of cardiogenic shock withcaptopril compared with control in the factorial study. However,in these studies, neither captopril nor mononitrate were associatedwith any overall increase in the incidence of hypotension consideredsevere enough to lead to treatment being stopped. No other seriouscomplications were observed, and compliance with study tabletsat hospital discharge was not significantly different betweenthe active and placebo groups. Patients allocated magnesiumin the 2 x 2 x 2 factorial study had a slightly lower mean systolicblood pressure just after the initial 15 min bolus injection(126 ± 2 magnesium vs 134 ± 3 control; P<0.05)but there were no significant differences during the subsequent24 h maintenance infusion period. Apart from some facial flushing,magnesium did not appear to be associated with any complications.These pilot studies indicate that, although the study treatmentregimens produced moderate early reductions in blood pressure,they were all generally well tolerated when started in the acutephase of MI.     

Evaluation of Changes in the Secretion of Immunoactive Inhibin by Adult Rat Seminiferous Tubules in Vitro as an Indicator of Early Toxicant Action on Spermatogenesis

Evaluation of Changes in the Secretion of Immunoactive Inhibinby Adult Rat Seminiferous Tubules in Vitro as an Indicator ofEarly Toxicant Action on Spermatogenesis. Allenby, G., Foster,P. M. D., and Sharpe, R. M. (1991). Fundam. Appl. Toxicol 16,710–724. A method for culturing isolated seminiferoustubules (ST) from adult rats for 1–3 days has been developedand optimized rigorously on the basis of the secretion of immunoactiveinhibin under basal conditions and after maximal stimulationwith rat FSH or dibutyryl cyclic AMP. The effect on these culturesof three known testicular toxicants was assessed. Of these,two are thought to act on the Sertoli cell, meta-dinitrobenzene(mDNB) and nitrobenzene (NB), while the third, methoxy aceticacid (MAA), is thought to act on pachytene spermatocytes. Inaddition, the effect of a possible testicular toxicant, 3-mononitrotoluene(3-MNT), was investigated. These data were compared with thoseobtained using cultures of immature rat Sertoli cells (SC) orSC + germ cells and with data on the effect of equivalent dosesof the compounds on the secretion of immunoactive inhibin invivo. In studies designed to optimize conditions for the secretionof immunoactive inhibin by ST in culture, significant effectswere found of the type of culture medium used, the durationof culture, the total and individual length of tubules used,etc. All subsequent studies with toxicants utilized optimalconditions. Addition of either mDNB or NB to ST cultures at10^–5 or 10^–3 m, or MAA at 10^–4 m, stimulatedbasal secretion of immunoactive inhibin by two- to fourfoldon Days 1, 2, or 3 of culture while FSH or dibutyryl cyclicAMP-stimulated secretion of immunoactive inhibin was eitherunaffected or was enhanced to a small extent. At the same doses,mDNB or NB also enhanced secretion of immunoactive inhibin bySC cultures, although these effects were more variable and ofsmaller magnitude than the effects on ST cultures. In contrast,addition of up to 10^–3 m MAA to cocultures of SC + germcells had no effect on the secretion of immunoactive inhibin.Exposure of rats in vivo to levels of mDNB, NB, or MAA similarto those which stimulated secretion of immunoactive inhibinin vitro resulted in a two-to fourfold increase in the levelsof immunoactive inhibin in testicular interstitial fluid (IF)at 1 and 3 days post-treatment, and this was associated withearly impairment of spermatogenesis (as judged by testis weight).In contrast to these effects, addition of 3-MNT to ST or SCcultures had no effect except at 10^–3 m, when the secretionof immunoactive inhibin was increased marginally. Treatmentof rats with an equivalent dose of 3-MNT in vivo resulted indeath, but exposure to the highest nonlethal dose (1 g/kg) hadno significant effect either on spermatogenesis or on the levelsof immunoactive inhibin in testicular IF. In view of these findings,it is concluded that modulation of the secretion of immunoactiveinhibin by isolated ST from adult rats has considerable potentialas an in vitro screening method for investigating potentialadverse effects of chemicals on spermatogenesis, and thus meritsmore detailed evaluation. Moreover, because of the agreementbetween in vitro and in vivo findings, measurement of the levelsof immunoactive inhibin levels in vivo in testicular IF (orblood) may also be useful in the detection of early adverseeffects of chemicals on spermatogenesis.     

The use of monosodium glutamate in identifying neuronai populations in mice infected with scrapie

The excitatory amino-acid, monosodium glutamate, which causes degeneration in the retinal ganglion cells in neonatal mice, was used to investigate the transport of scrapie within optic nerve axons. In treated mice, there was prolongation of the incubation period following intraocular infection with the ME7 strain of scrapie, and a decrease in the severity of retinopathy after intracerebral infection with the 79A strain. These data confirm that scrapie infection spreads along neural pathways, and demonstrate the potential use of selective neurotoxins to study pathogenesis.