Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.     

Oral trimethoprim-sulfamethoxazole in the treatment of cerebral toxoplasmosis in AIDS patients--a prospective study.

Toxoplasma encephalitis is the commonest cause of intracranial mass lesions in AIDS patients. Effective therapy includes pyrimethamine plus sulfadiazine, clindamycin with pyrimethamine, and co-trimoxazole. This study examines the efficacy of oral co-trimoxazole in 20 AIDS patients with toxoplasmosis and seeks to confirm the experience of Torre et al.     

Environmental and genetic determinants of the hypercoagulable state and cardiovascular disease in renal transplant recipients

Background. Fibrinogen and factor VII coagulant activity (VIIc), risk factors for cardiovascular disease (CVD) in the general population, could contribute to CVD risk in renal transplant recipients (RTR). Methods. We measured fibrinogen and VIIc in 38 RTR and 31 controls, along with prothrombin fragment F1+2 and D-Dimer (markers of coagulation and fibrinolytic activation), plasma lipids and the acute phase response cytokine, interleukin 6. The effect of genetic polymorphisms of {beta}-fibrinogen (G/A^-455) and factor VII (Arg/Gln353) was explored. Results. F1+2, D-Dimer, and fibrinogen were increased in all RTR, indicating a chronic prothrombotic state. Fibrinogen correlated with age, F1+2, and trough cyclosporin A (CsA). RTR carriers of the A^-455 allele had a greater increment in plasma fibrinogen concentration and correlation with CsA than homozygotes for the G^-455 allele. Interleukin 6 was increased in RTR confirming that a persistent low-grade acute-phase response could contribute to increased fibrinogen. Differences in plasma VIIc were associated with factor VII genotype, disease status, and blood lipids. Carriers of the Gln353 allele had 30 lower VIIc when compared with Arg353 homozygotes, which could confer a reduced thrombotic risk. The 12 RTR with CVD or metabolic complications (RTR+) were more hyperlipidaemic and had higher fibrinogen and VIIc than the 26 RTR free of disease complications (RTR-), or the controls. Conclusions. Long-term RTR manifest features of a chronic prothrombotic and persistent inflammatory state. Alterations in fibrinogen and VIIc in RTR arise in part as a result of interactions between common genetic and environmental factors, and these changes could contribute to the increased risk of CVD in RTR.     

New South Wales Nurse Education Project

Abstract: The development of a teaching package for nurse educators on drug and alcohol problems is described and the contents of its 16 modules outlined.     

Nonexclusive solute transport thru protein channels model of the Na,K ATPase complex and similar channels as general transport routes

In earlier work this author put forward a model of the Na,K ATPase complex as a general transport channel. Detailed treatment was limited to anion and monovalent cation transport. Here the functional mechanisms of the Na,K ATPase and similar protein channels as transport routes for all ionic fluxes and also amino acid, sugar and other solutes are presented. Anions, monosaccharide -OH groups and amino acid carboxyls bind to common arginyls and lose hydration water. They combine with cations which bind to adjacent side chain carboxyls, forming neutral ion pairs or positively charged complexes which have minimums in size, hydration and free polar groups. The smaller size and polarity facilitate entry into the tight, structured water channel of some 8-10 A outer bore. Solute fluxes depend on membrane redox activity which maintains channel sulfhydryls in reduced state required for proper transport. ATP binding at channels contributes to transport conformation while ATP hydrolysis gives high efflux of Na+, H+ and Ca2+ as phosphate ion pairs. This cation efflux current clears cations from inner membrane sites, increases negative potential and provides Na+ and H+ about the outer combining sites, while maintaining their inward gradients. Binding of many agents widens the outer bore to give larger, less selective influx.     

Anaesthetic management for surgical cryoablation of accessory conducting pathways: a review and report of 181 cases

Pre-excitation disorders have an estimated prevalence of 0.15 per cent. Advances in electrophysiological mapping and the increasing sophistication of surgical techniques have resulted in an increasing role for definitive surgical treatment. A retrospective chart review of 181 patients undergoing 197 procedures for surgical ablation of accessory atrioventricular pathways between June 1981 to June 1986 was performed. Mean age of the patients was 30 years (range 6-66) with a preponderance of males (59 per cent). Associated cardiac disease was found in 18 (9.9 per cent) patients. Induction of anaesthesia employed either a barbiturate-relaxant (83 per cent) or a narcotic-benzodiazepine-relaxant (17 per cent) and was uneventful in all cases. In 14 per cent of cases a pure narcotic relaxant technique was employed for maintenance of anaesthesia, whereas a balanced technique with isoflurane (29 per cent), enflurane (34 per cent), or halothane (22 per cent) was utilized for the remainder. Muscle relaxation was provided by d-tubocurarine in 35 (18 per cent) procedures and pancuronium in the remaining 162 (82 per cent) procedures. There was no significant correlation between intraoperative arrhythmias and type of anaesthetic used. Although recognizing the potential for malignant arrhythmias, our experience (within the confines of a retrospective analysis) suggests that the majority of these patients can be managed successfully using standard anaesthetic techniques.