Maternotoxicity and Fetotoxicity of an Angiotensin-Converting Enzyme Inhibitor, Enalapril, in Rabbits

Maternotoxicity and Fetotoxicity of an Angiotensin-ConvertingEnzyme Inhibitor, Enalapril, in Rabbits. MINSKER, D. H., BAGDON,W. J., MACDONALD, J. S., ROBERTSON, R. T., AND BOKELMAN, D.L. (1990). Fundam. Appl. Toxicol 14, 461–470. When enalapril,an angiotensin-converting enzyme (ACE) inhibitor, was orallyadministered to inseminated rabbits at dosages of 0.1 to 30mg/kg/day for 13 days in a range-finding study, nephrotoxicity,as measured by elevated serum urea nitrogen concentrations,occurred at 1 mg/kg/day and higher dosages and significant (p 0.05) increases in fetal wastage were observed at dosages aslow as 3 mg/kg/day. Saline supplementation during treatmentprevented this rise in urea nitrogen. Fetal wastage was significantly(p 0.05) increased in the absence of maternotoxicity when saline-supplementedfemales were treated with enalapril at 30 mg/kg/day. A developmentaltoxicity study of enalapril in saline-supplemented rabbits producedno evidence of teratogenicity at 3, 10, and 30 mg/kg/ day. Theperiod of sensitivity of fetuses to the toxic effects of enalaprilwas found to be limited to middle-to-late gestation (GestationalDays 14-27). A single oral dose of enalapril (30 mg/kg) on Day26 of gestation resulted in 100% fetal deaths. On the basisof the work done by Broughton Pipkin el al. [1982, J. Physiol.(London) 323, 415–422] and Broughton Pipkin and Wallace(1986, Brit. J. Pharmacol 87, 533–542), which demonstratedthat the sheep fetus becomes markedly hypotensive when the damis treated with captopril or enalapril during late pregnancy,we believe that the observed fetotoxicity of enalapril in rabbitsis also due to fetal hypotension. On the basis of publishedevidence indicating that the renin-angiotensin system in rabbitsand in humans is not developed until middle-to-late gestation,we believe our results support the premise that incidental exposureto enalapril early in human pregnancy is unlikely to be associatedwith an increased risk of fetotoxicity. However, our resultsand those cited above demonstrate that ACE inhibitors are fetotoxicin late gestation in rabbits and sheep, and should be givenin pregnancy only if the potential benefit justifies the potentialrisk to the fetus.     

Oral premedication with midazolam in paediatric anaesthesia. Effects on sedation and gastric contents

The aim of this study was to assess oral premedication with midazolam in paediatric anaesthesia. Sedation, quality of induction, recovery time, acceptance and effects on gastric contents were analysed. This prospective, double blind, at random and controlled study was performed in 107 children, aged between three and ten years. They were divided into: group 1 (control, n=29), group 2 (placebo) receiving 5 ml of water in the preoperative stage (n=40), and group 3 (midazolam) with 0.75 mg·kg^-1 midazolam by mouth (n=38). Two children refused to take medication. In children aged five years or more (n=48) of groups 2 and 3, acceptance of premedication was evaluated. The midazolam group showed a better level of sedation as compared with the placebo (P<0.05). The recovery time was similar for the two groups. There were no statistically significant differences in gastric pH or residual volume among the three groups. It is concluded that midazolam given by mouth is an efficient and safe drug for premedication in paediatric anaesthesia.     

Independent Regulation of Periarteriolar and Perivenular Nitric Oxide Mechanisms in the In Vivo Hamster Cheek Pouch Microvasculature

Objective: We tested the hypothesis that differential stimulation of nitric oxide (NO) production can be induced in pre‐ and postcapillary segments of the microcirculation in the hamster cheek pouch. Materials and Methods: We applied acetylcholine (ACh) or platelet‐activating factor (PAF) topically and measured perivascular NO concentration ([NO]) with NO‐sensitive microelectrodes in arterioles and venules of the hamster cheek pouch. We also measured NO in cultured coronary endothelial cells (CVEC) after ACh or PAF. Results: ACh increased periarteriolar [NO] significantly in a dose‐dependent manner. ACh at 1 μM increased [NO] from 438.1±43.4 nM at baseline to 647.9±66.3 nM, while 10 μM of ACh increased [NO] from baseline to 1,035.0±59.2 nM (P<0.05). Neither 1 nor 10 μM of ACh changed perivenular [NO] in the hamster cheek pouch. PAF, at 100 nM, increased perivenular [NO] from 326.6±50.8 to 622.8±41.5 nM. Importantly, 100 nM of PAF did not increase periarteriolar [NO]. PAF increased [NO] from 3.6±2.1 to 455.5±19.9 in CVEC, while ACh had no effect. Conclusions: We conclude that NO production can be stimulated in a differential manner in pre‐ and postcapillary segments in the hamster cheek pouch. ACh selectively stimulates the production of NO only in arterioles, while PAF stimulates the production of NO only in venules.     

Beat-to-Beat Repolarization Lability Identifies Patients at Risk for Sudden Cardiac Death

QT Interval Variability and Sudden Death. Introduction : Recent studies have implicated repolarization lability in the genesis of malignant ventricular arrhythmias. However, few data exist on assessment of temporal QT interval variability and its relation to arrhythmogenesis. We tested the ability of the QT variability index (QTVI), a measure of beat-to-beat QT interval fluctuations measured on a single ECG lead, to identify patients presenting with malignant ventricular arrhythmias and predict their subsequent occurrences.
Methods and Results : We measured the QTVI in 95 patients presenting for electrophysiologic study (EPS). The ability of the QTVI to identify patients with sudden cardiac death (SCD) or sustained monomorphic ventricular tachycardia (MVT) on presentation and during follow-up of 23.7 ± 14.3 months was compared with spatial QT dispersion, T wave alternans ratio during atrial pacing, MVT inducibility at EPS, signal-averaged ECG, heart rate variability, and ejection fraction. The QTVI was higher in patients with heart disease than in controls (-0.7 ± 0.7 vs −1.1 ± 0.5, P < 0.05), and higher in patients presenting with SCD than in other patients with heart disease (0.0 ± 0.6 vs −0.8 ± 0.5, P < 0.05). The QTVI was the only clinical variable that identified patients who presented with SCD ( P = 0.004, odds ratio = 12.5) on stepwise, logistic multiple regression. Fourteen patients had arrhythmic events during follow-up. In a Kaplan-Meier analysis of arrhythmic events, QTVI ≥ 0.1 was a discriminator for higher risk of arrhythmic events ( P < 0.05).
Conclusions : (1) This noninvasive measure of temporal repolarization lability identified patients with SCD and predicted arrhythmia-free survival. (2) Further studies are needed to determine the mechanisms that mediate beat-to-beat QT interval variability.     

Induction Ovens and Electromagnetic Interference:

Electromagnetic fields may interfere with normal pacemaker function. Despite the introduction of modern pacemakers and bipolar lead systems, electromagnetic interference (EMI) still remains to be a concern during daily lives when patients are exposed to cellular phones, electronic security systems, and several household appliances. The aim of this study was to evaluate potential EMI risk of induction ovens, which are increasingly used in private households. The study included 40 consecutive patients (22 men, 18 women; age   73 ± 11  years   ) with implanted DDD, VVI, VDD, and AAI pacemaker systems. The pacemakers were programmed to unipolar sensing and pacing. Sensitivity remained unchanged, if the measured sensing threshold was more than twice the programmed value; otherwise, it was set at half of the measured sensing threshold. Patients were placed in a sitting position at the closest possible distance of about 20 cm between two cooking pots and pacemaker bending the upper part of the body slightly over the induction oven. The energy was increased stepwise to the maximum. One pot was removed and placed again at the highest oven level. Potential interference was monitored continuously. The study showed no incidence of pacemaker malfunction during the entire test while the patients with intrinsic cardiac rhythms were exposed to the induction oven at varying energy strengths. Likewise, there was no external interference when the patients were paced at heart rates of 10–15 beats/min above their heart rates. The programmed parameters remained unchanged after the study. In conclusion, this study shows no EMI risk of an induction oven in patients with bipolar or right-sided unipolar pacemakers. (PACE 2003; 26[Pt. I]:1494–1497)     

Views of Australian mental health stakeholders on clients' problematic drug and alcohol use

Introduction and Aims. Substance misuse by people with a serious mental illness may exacerbate psychiatric symptoms and contribute to relapse. The aim of the study was to ascertain the views of a wide range of Australian mental health service providers on staff education and training, client contact and management, assessment, and treatment effectiveness and service delivery. Design and Methods. A survey was sent to a sample of 171 mental health stakeholders in Australia identified through internet searches, state and territory mental health departments and professional organisations. Results. Of the 66 respondents (39% response rate), the substances identified to be most problematic were alcohol and cannabis. Integrated service models of treatment were identified as the most preferable and effective. Barriers to treatment included client motivation to reduce substance use, poor communication and coordination between treatment services, and lack of specific services for dual diagnosis clients. Almost all indicated a need for further training in the area of dual diagnosis. Discussion and Conclusions. Dual diagnosis is common and the reality is that this vulnerable clientele will continue to challenge service providers and treatment approaches into the foreseeable future. Issues include the organization and delivery of treatment services, education and training, resource allocation, collaboration between treatment agencies and clinically relevant research evaluating the effectiveness of practice. It is thus surprising that with so much investment in this area the majority of stakeholders are still dissatisfied with access to and the level of care for dual diagnosis clients.[Cleary M, Hunt GE, Matheson S, Walter G. Views of Australian mental health stakeholders on clients' problematic drug and alcohol use. Drug Alcohol Rev 2009;28:122–128]