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.     

MRP8 and MRP14, S-100-like proteins associated with myeloid differentiation, are translocated to plasma membrane and intermediate filaments in a calcium-dependent manner

MRP8 and MRP14 are two Ca(2+)-binding proteins of the S-100 family expressed by myelomonocytic cells. Both proteins assemble to noncovalently associated complexes in a Ca(2+)-dependent manner. Members of the S-100 family are known to play a role in cytoskeletal- membrane interactions; therefore, we investigated the subcellular distribution of MRP8/MRP14 and their complexes in human monocytes. Using differential centrifugation and subsequent Western blot or enzyme- linked immunosorbent assay analysis, we found that MRP8/MRP14 were almost completely translocated from the cytoplasma to membrane and cytoskeletal structures in a Ca(2+)-dependent manner. Using a cross- linking technique, complexed forms of MRP8/MRP14 were found to be associated with the plasma membrane. Analysis of MRP-transfected L132 cells showed that the MRP8 as well as the MRP14 component of the MRP8/MRP14 complex may independently bind to membrane and cytoskeletal structures. Furthermore, immunogold electron microscopy showed a colocalization of MRP8/MRP14 and the intermediate filament type III protein vimentin in A23187-treated monocytes. Our data indicate that, in analogy to other S-100-like proteins, MRP8 and MRP14 play a role in Ca(2+)-dependent cytoskeletal-membrane interactions. Restriction of MRP8/MRP14 expression to distinct stages of myelomonocytic differentiation suggests that these proteins are involved in highly specific pathways of intracellular signaling in phagocytes.     

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.     

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.     

Down-regulation of tenascin expression by antiprogestins during terminal differentiation of rat mammary tumors.

Studies on tenascin expression in hormonally dependent growing tissues of breast and endometrium suggested that its expression parallels the progression of normal or malignant proliferative alteration of the tissue. With the study presented here we addressed the question of whether antiprogestin-induced terminal differentiation down-regulates tenascin expression. By comparative immunolocalization of tenascin in sections of untreated 7,12-dimethylbenz[alpha]anthracene-induced tumors, tumors grown in ovariectomized animals, tamoxifen-treated tumors, and antiprogestin-treated tumors, we obtained the following results. (a) The entire extracellular space of the stromal mesenchyme was filled by tenascin immunoreactivity in cases of untreated control tumors. (b) Both ovariectomy and antiestrogen treatment with tamoxifen did not affect the overall staining pattern and resulted in a slight increase of the arbitrarily judged staining intensity. (c) Within antiprogestin-treated tumors tenascin-like immunoreactivity predominantly was restricted to fiber-like, collagenous connective tissue structures, which appeared in the stromal compartment as a result of the antiprogestin treatment. In large areas of the tumor composed of apparently secretory active tumor cells we failed to immunolocalize tenascin. Our results provide further evidence that expression of tenascin reflects both benign and malignant proliferative alterations of the tissue, whereas its down-regulation is correlated to differentiation of the tissue. Additionally, evidence is provided that the mechanism of tumor growth inhibition by antiprogestins indeed is induction of terminal differentiation of tumor cells.