Host ABC transporter proteins may influence the efficacy of ivermectin and possibly have broader implications for the development of resistance in parasitic nematodes.

ABC transporter proteins function to extrude compounds from the cell. These proteins present an obstacle for treatment and for overcoming drug resistance as they are expressed by both host and parasite, and function similarly. The contribution of host ABC proteins to drug efficacy was examined using ivermectin and a Brugia malayi model system. Parallel in vitro and in vivo experiments were conducted using equal concentrations of ivermectin. The motilities and fecundity of B. malayi exposed to ivermectin in vitro were significantly lower than those treated in vivo. The higher motilities were correlated with low concentrations of ivermectin in worms extracted from treated hosts. The expression of ABC proteins was significantly higher in worms treated in vitro compared to those treated in vivo as well as in gerbils treated with ivermectin than in non-treated controls. The results suggest that host ABC transporters may influence the efficacy of ivermectin.

[The use of assessment instruments in the rehabilitation of accident victims]. / Der Einsatz von Assessmentverfahren in der Rehabilitation von Unfallverletzten.

Within the course of rehabilitation management the Verwaltungs-Berufsgenossenschaft (VBG) has started to measure the outcomes to assure the quality of rehabilitation processes using assessment instruments. The measures included some aspects of activity and participation in accordance with the International Classification of Functioning, Disability and Health (ICF). The present paper describes the generic and condition-specific instruments used in the this study to assess the health-related quality-of-life, discusses their selection and illustrates their incorporation into management practice. The assessment process constitutes a consistent system to prove the effects of rehabilitation and their persistence. The first experience shows that the assessment-based quality management system can be recommended for permanent modelling of structures, processes and outcomes to improve the efficacy and cost-effectiveness of rehabilitation.

The profession of pharmacy in Zimbabwe.

Zimbabwe (formerly Rhodesia) is a developing country in central southern Africa where great strides have been made in healthcare since black-majority rule began in 1980. Shortages of personnel, equipment, and drugs continue to be a problem. Challenges facing the pharmacy profession include improving drug supply, promoting rational use of essential drugs, and educating healthcare professionals and the public. Persuading pharmacists to practice in the government sector of healthcare rather than to serve the small percentage of the public that can afford private healthcare should be a major priority. Zimbabwe is a land of opportunity for pharmacy practice but the financial constraints are formidable.

Meeting the pharmaceutical needs of a developing country.

Zimbabwe is making advances in the selection, procurement, distribution, storage, management and use of pharmaceutical products. The periodic updating of the country's essential drugs list is a vital part of this process.

PIP: Zimbabwe is unique among African countries in terms of its strong drug control procedures and ban on nonessential products. Zimbabwe's Drug Control Council has devised guidelines on the efficacy, safety, quality, appropriateness, and advertising of pharmaceuticals, and package inserts are monitored to ensure that necessary information on dosage and adverse reactions is included. The Council further operates a quality control laboratory that monitors both imported and locally manufactured drugs. Since the country has excellent drug manufacturing facilities, proposals are under consideration for the production of raw materials for 12 widely prescribed drugs. The University of Zimbabwe's Medical School's Pharmacy Unit operates a drug and toxicology information service and published a bulletin on current research findings. 17 training manuals have been prepared for health workers, and the mass media are being used for patient education. To improve the availability of essential drugs in outlying rural areas, the government's medical stores network is being expanded. Finally, the country makes regular updates in its essential drugs list. The 1984 update included guidelines on the drug treatment of common medical conditions, and these norms were further updated in 1988. The number of drugs used in rural health centers has been reduced from over 200 to 90.

A 10-year review of the Teaching Hospital-Based National Drug and Toxicology Information Service in Zimbabwe.

The drug and toxicology information service (DaTIS), at the Department of Pharmacy, University of Zimbabwe Medical School, was set up in 1979. The service is mainly delivered to health professionals and to a lesser extent to the community. The DaTIS is designed to help solve complex clinical questions. Most of the requests are made by telephone. Urgent questions may be initially answered by telephone, or a phone call can be returned after in-depth documentation. A complete answer with references may be written and sent to the enquirer. Written non-urgent questions may be sent a few days to a few weeks later. This report is based on a systematic review of records compiled over the period between January 1983 and July 1988. Of the 1,000 requests received and recorded during the period under consideration, approximately 750 (75%) were on drug information and 250 (25%) were on poisoning or toxicological information. The most common causes of poisonings were due to organophosphate pesticides and fertilizers, Elephant's Ear, Amanita Phalloides mushroom, medicines affecting the central nervous system, e.g. tranquilizers, psychotropics, and chemicals, especially those used for hair relaxing. Only the first three causes of poisoning are discussed in detail. Most of the queries relating to poisoning, especially those received during the night, were not recorded. These results confirm the need for an adequate number of qualified and committed manpower to share the work-load in DaTIS as well as in teaching, research and in the continuous health education of the community. The results obtained by DaTIS and a recent survey (14) indicate that Zimbabwe has a big poisoning problem, especially with regard to pesticides and treatments recommended by the traditional healer. Education and information dissemination to health professionals, workers and the general public on the toxic agents concerned are vital and, although steps have been taken in this direction, much still remains to be done. Moreover, the report confirms the importance of the service to health professionals and the community in the country and the SADCC (Southern African Development Conference Committee) region as a whole.

Mechanical measures during maximal velocity knee extension exercise and their relation to fibre composition of the human vastus lateralis muscle.

A method for measuring the maximal velocity of knee extension exercise is described using a very light lever arm. Instrumentation of the lever arm with a potentiometer and accelerometer also allows for the measurement of peak acceleration, time to peak acceleration, the average rate of development of acceleration (jerk) and peak torque. With this apparatus and surface electromyography, electromechanical delay (EMD) was also determined. This apparatus was tested using 17 female and 10 male subjects, and the measures obtained were related to the percentage of fast twitch fibres (% FT) and the relative area of fast twitch fibres (% FTA) in the vastus lateralis determined from duplicate muscle biopsy samples. Peak velocity of unloaded knee extension averaged 12.1 +/- 1.2 and 12.2 +/- 1.7 rad.s-1 for females and males, respectively, and were not significantly different. As well, peak acceleration, time to peak acceleration jerk and EMD values were not significantly different between the female and male subjects, but the mean peak torque for the female subjects (73.5 +/- 14.7 N.m) was significantly lower than that for the males (98.4 +/- 31.5 N.m). Peak acceleration was significantly correlated with %FT (r = 0.40, P = 0.04) for the total subject population. None of the other measures was significantly related to either %FT or %FTA for the male and female subjects or the combined population of subjects.

Performance during the Wingate anaerobic test and muscle morphology in males and females.

Performance indices during the Wingate 30-s anaerobic test and their relationship to muscle morphology of the vastus lateralis muscle were studied in 30 untrained male and female subjects. Absolute values for peak power (P05), total work performed (TW), power decrease (PD), and post-test blood lactate concentration were significantly greater for the male subjects. When expressed per unit of body mass or leg volume, both P05 and TW were larger for the males than the females (P less than 0.05). Significant correlations were noted for P05, TW, PD, and blood lactate and the percent of fast-twitch (FT) fibers and the percent relative area of FT fibers for the male but not the female subjects. The results from this experiment reveal a significant influence of muscle morphology on short-term anaerobic work performance for these male subjects. The absence of a similar relationship for the women subjects was likely due to the use of an inappropriately high resistance setting.

Torque-velocity characteristics and muscle fiber type in human vastus lateralis.

The relationship between torque-velocity characteristics of the knee extensors during isokinetic contractions and muscle fiber type of the vastus lateralis, determined from two muscle biopsy samples, was investigated in 12 male and 18 female subjects. Peak torque, corrected for the effect of gravity and impact artifact, was classified as corrected peak torque. The torque measured 30 degrees from full extension and, corrected for gravity, was classified as corrected torque at 30 degrees. No significant correlations were found between the percentage of fast-twitch fibers (%FT) or the relative area of FT fibers (%FTA) and corrected peak torque values for any of the velocities tested or the knee angles where corrected peak torques were measured. However, significant inverse relationships were determined for corrected torque at 30 degrees at all but the fastest velocity (270 degrees/s) and both %FT and %FTA for the male subjects. These results reveal that muscle fiber type of the vastus lateralis, based on duplicate muscle samples, is not related to the peak torque actually generated by the knee extensors but may influence the shape of the torque output for maximal contractions sustained over the entire range of motion.

Antagonism of the cytocidal activity and uptake of melphalan by tamoxifen in human breast cancer cells in vitro.

The effect of the antiestrogen tamoxifen on the cytocidal activity and uptake of melphalan in human breast cancer cells was investigated. A clonogenic assay was used to obtain dose-survival curves of estrogen receptor-positive MCF-7 cells and of estrogen receptor-negative Evsa T cells following treatment with melphalan and/or tamoxifen. Isobolograms derived from these dose-survival curves were concave downward, suggesting that the drug interaction was antagonistic. The effect of tamoxifen on melphalan uptake by breast cancer cells was evaluated at steady-state conditions. Thin-layer chromatography revealed that the intracellular level of free intact melphalan (mean +/- S.E.) in control cells was 6.47 +/- 1.21 fmoles/cell and that in cells treated with tamoxifen was 3.60 +/- 0.35 fmoles/cell; this 44% reduction in cellular melphalan was statistically significant (P = 0.006). Thus, the antagonistic cytocidal effect of melphalan and tamoxifen against breast cancer cells appeared to be due to inhibition of melphalan uptake at the steady state by the antiestrogen. Further investigation revealed that tamoxifen inhibited unidirectional melphalan influx in human breast cancer cells both by the sodium-independent system L and by the sodium-dependent system ASC. Tamoxifen also appeared to stimulate melphalan efflux from human breast cancer cells. The first-order rate constant K for melphalan efflux from control cells was 0.085 +/- 0.008 and that from cells treated with tamoxifen was 0.129 +/- 0.005; the difference was highly significant (P less than 0.001). Therefore, the antagonistic effect of tamoxifen on the uptake and cytocidal activity of melphalan in breast cancer cells appeared to be due to inhibition of melphalan influx and stimulation of drug efflux.

Induction of DNA single- and double-strand breaks by diethylstilbestrol in murine L5178Y lymphoblasts in vitro.

The mechanism of action of the synthetic estrogen diethylstilbestrol (DES) was investigated in murine L5178Y lymphoblasts. The dose-survival curve of cells treated with DES in serum-free medium for 1 hr was characterized by a prominent shoulder followed by a simple exponential decline; the Do, the dose of DES reducing cell survival to 1/e, was 1.52 nmoles/ml. DNA single-strand breaks, as measured by the alkaline elution method, were observed in DES-treated cells, and these followed a dose-response relationship after an apparent threshold of 10 microM DES was exceeded. Protein-associated strand breaks, which represent the increment in single-strand breaks that occurs by exposing drug-treated cells to proteinase K, were also noted. DNA double-strand breaks as measured by filter elution technology at pH 9.6 were observed and increased markedly to reach a level of approximately 9000 rad equivalents at a DES concentration of 20 microM. The measured ratio (mean +/- S.E.) of single- to double-strand breaks induced by DES in L5178Y limphoblasts was 0.09 +/- 0.035. A comparison of the ratio of single- to double-strand breaks induced by DES to that observed following radiation suggested that all of the single-strand breaks produced by DES could be attributed to double-strand breaks. The close correspondence of the dose-response curve for cytocidal activity of DES with that obtained for induction of DNA double-strand breaks suggested that such breaks may play an important role in the mechanism of cell kill by DES.

Liposomes as immune adjuvants: T cell dependence.

The T cell dependence of the immune adjuvant action of liposomes containing the soluble antigens bovine serum albumin (BSA) and chicken immunoglobulin (CIgG) was studied with use of a quantitative enzyme-linked immunosorbent assay to measure serum antibody levels. Normal BALB/c mice, adult thymectomized mice, and congenitally athymic (nu+/nu+) mice were intravenously inoculated with liposomes containing BSA (Lip-BSA). The high levels of serum anti-BSA antibody that were seen in the normal group were decreased in the adult thymectomized group and were almost completely abrogated in the nu+/nu+ group. Reconstitution of nu+/nu+ mice with normal thymocytes and cortisone-resistant thymocytes led to a partial restoration of the anti-BSA antibody production after Lip-BSA immunization. Examination of the class of immunoglobulin produced in normal mice, immunized with Lip-BSA, showed an early low IgM response and a sustained higher IgG response that was primarily due to the IgG1 subclass. Trypsin removal of BSA exposed on the liposome surface decreased the resulting serum anti-BSA antibody level by 30% to 50%. Animals could be primed equally with a very low dose (0.2 micrograms) of Lip-BSA or with peritoneal macrophages that had phagocytosed the same dose of Lip-BSA. The adjuvant effect of liposomes containing CIgG on the number and type of specific anti-CIgG antibody-producing cells in the spleen was an early increase in IgM-producing cells followed by a substantially higher increase in IgG-producing cells. These observations suggest that liposome encapsulation of a soluble T-dependent antigen stimulates the helper T cell, not the suppressor T cell population, and that this stimulation involves uptake by macrophages.