The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole

1 Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine.
2 Ten healthy male volunteers were given co-trimoxazole (800  mg sulphamethoxazole and 160  mg trimethoprim) alone or 1  h after either fluconazole (150  mg) or ketoconazole (200  mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24  h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N₄-acetyl sulphamethoxazole, or sulphamethoxazole N₁-glucuronide excreted in urine.
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points.     

CHWs: are national programmes in crisis?

Community health workers (CHWs) have become the distinguishingfeature of many primary health care schemes. CHW programmesexpanded during the 1970s and early 1980s as long-term evidencefor the effectiveness of small-scale programmes grew. However,there is a growing suggestion of a decline in support for CHWs.Criticisms have grown, evaluations of existing programmes havepointed to difficulties in implementation and a number of reviewshave highlighted weaknesses in key areas. Training of CHWs hasbeen suspended in some countries, and fewer than originallyplanned are being trained in others. In this paper it is arguedthat although the financial recession has affected support forCHW programmes, there are other reasons why they are now underpressure. On the whole they have been implemented as ‘vertical’programmes, against a background of unrealistic expectationsand minimal professional interest. Structural political andeconomic factors have been neglected. Lessons have not beendrawn from the experience of community workers in other sectorssuch as agriculture and community development. The paper analysesall these issues within a health policy perspective concludingthat, unless adjustments are made, CHW programmes will drifttowards demise, not because CHWs themselves cannot deliver,but because the support that makes them effective is, in general,absent.     

A randomized controlled trial of sedation in the critically ill

A randomized controlled trial comparing: a) a combination of oral chloral hydrate and promethazine to b) a continuous intravenous midazolam infusion, for maintenance sedation in critically ill children, was carried out. The level of sedation was assessed four hourly using a specifically devized sedation scale. Forty-four children entered the study of whom two were subsequently excluded. The number of satisfactory assessments (desired and actual levels of sedation equal) was significantly greater in the chloral hydrate and promethazine group (Chi-squared P <0.01; confidence intervals of the difference 0.06 to 0.20). The number of assessments at level 5 on the sedation scale (patient restless/distressed) was significantly greater in the midazolam group (Chi-squared P <0.05). The total number of satisfactory assessments in the two groups were only 61 and 48% respectively, suggesting that sedation can be considerably improved. Chloral hydrate and promethazine are more effective than midazolam as maintenance sedation in critically ill children. It is possible to prospectively study the efficacy of sedative drugs in critically ill children.     

Sickness Absence from Work and Influenza Immunization

The worth of influenza immunization for employees in U.K. industryhas been debated for more than a decade. In this study no evidencecould be found of a protective effect for sickness absence patterns.Other evidence is also cited that suggests routine influcnzalimmunization programmes for healthy adults of working age areno longer justilied. *Requests for reprints should be addressed to: Dr Robin Philipp, Department of Epidemiology and Community Medicine, University of Bristol, Bristol BS8 2PR.     

Seminal Fluid and the Expression of MHC Class I Antigens in the Placenta of the Rat

PROBLEM : To determine whether seminal fluid influences the expression of MHC class I antigens on the surface of basal trophoblast cells in the placenta of the rat. METHODS : Transfer of DA × DA embryos into a WF (allogeneic) or DA (syngeneic) recipient made pseudopregnant by hormonal treatment followed by mating with a vasectomized male (seminal fluid) or by mechanical stimulation (no seminal fluid). Antigen expression was determined by electron microscopic immunocytochemistry using the appropriate gold-labeled monoclonal antibodies. RESULTS : Seminal fluid did not affect the expression of MHC class I antigens on the surface of the basal trophoblast in either allogeneic or syngeneic matings. CONCLUSIONS : The suppression of the expression of paternal class I antigens on the surface of the basal trophoblast cells in allogeneic pregnancies most likely occurs at the genome level shortly after fertilization.     

ALCOHOL PROBLEMS IN EMPLOYMENT: EPIDEMIOLOGY AND RESPONSES

A review is presented of evidence related to the epidemiologyof alcohol-related problems in employment and of policies toprevent or curb such problems. It is concluded that, althoughalcohol use is associated with accidents, absenteeism and inefficiency,epidemiological data from most countries are scarce. Availableevidence is so limited that estimates of the extent or costof alcohol-related problems in the workplace are of dubiousvalue. National responses to alcohol problems in employmenthave been variable. A significant proportion of relevant publishedevidence relates to the U.S.A. It appears that even there veryfew workplace initiatives have been subjected to rigorous assessment.Limited evidence suggests that Employee Assistance Programmesfor problem drinkers have reduced subsequent health-care costs.     

PHARMACOKINETIC INTERACTION OF PROPOFOL AND FENTANYL: SINGLE BOLUS INJECTION STUDY

The effect of pretreatment with fentanyl on the pharmacokineticsof a single bolus of propofol was studied in 17 female patients(mean age 35 yr), ASA grade l. Eight patients received fentanyl1.5 µg kg^–1 5 min before induction of anaesthesia.In all patients anaesthesia was induced with propofol 2.5 mgkg^–1 and maintained with halothane and nitrous oxide inoxygen. Pretreatment with fentanyl resulted in prolonged apnoeain all eight patients compared with three of nine patients inthe control group. The pharmacokinetic values for propofol weredescribed by a three-compartment mammillary model with rapiddistribution phases (T mean (SEM) 3.1 (2.0) min and ß44 (9.1) min) and a slower final phase of <<520 (96)min. The clearance of propofol was rapid (mean 1.6 (0.24) litremin^–1). Propofol was distributed initially into a relativelylarge central compartment (mean 23.7 (6.6) litre) and was extensivelyredistributed (mean V^ss 593 (157) litre). There was no differencein the pharmacokinetic profile of propofol between the two groups.     

Developmental Neurotoxicity Evaluation of Orally Administered Isopropanol in Rats

Isopropanol was administered by gavage to timed-mated rats fromGestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administeredwere 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg.The dams were allowed to deliver and body weights and food consumptionwere recorded during gestation and lactation. Pups were counted,examined, sexed, and weighed on PND 0, 4, 7, 13, 17, 21, 36,49, and 68. Litters were culled to eight pups (4:4 or 5:3 sexratio) on PND 4 and litters without acceptable numbers of maleand female pups were eliminated from the study. Pups were weanedon PND 22, and two pups from each litter and their dams werekilled. Six of these pups from each dose group were perfusedin Situ for histopatho logical examination of the central andperipheral nervous sys tem. Brains of the remaining pups weredivided into four regions and weighed. Maternal liver and kidneyweights were re corded. Weaned pups were assessed for day oftestes descent or vaginal opening and for motor activity onPNDs 13, 17, 21, 47, and 58; auditory startle on PNDs 22 and60; and active avoidance on PNDs 60–64. These pups wereeuthanized and examined on PND 68. One high-dose dam died onPND 15, but there were no other clinical observations or effectson maternal weight, food consumption, or gestation length. Pupsurvival, weight, sex ratio, and sexual maturation were unaffected.There were no biologically significant findings in the behavioraltests, no changes in organ weights, and no pathological findingsthat could be attributed to isopropanol exposure. In conclusion,there was no evidence of developmental neurotoxicity associatedwith isopropanol exposure as high as 1200 mg/kg/day.