Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?

Background  

Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies.     

Use of alveolar cell monolayers of varying electrical resistance to measure pulmonary peptide transport

The apparent permeability coefficient (P(app)) of two fluorescently tagged model hydrophilic peptides, acXASNH(2) and acXAS(GAS)(7)NH(2), and (14)C-mannitol across monolayers of cultured rat alveolar epithelial cells of varying transepithelial electrical resistance (TER) has been examined. In line with their design features, the peptides were not degraded under the conditions of the test. Furthermore, no concentration dependence of transport of the tripeptide acXASNH(2) was observed over the concentration range studied, nor was any directional transport seen for either of the model peptides, indicating that under the conditions of the test they were not substrates for any transporters or efflux pumps. From the hydrophilic nature of the peptides (as assessed by their log P), and their inverse dependence of transport with molecular weight and TER, it was assumed that the peptides were transported across the cell monolayer passively via the paracellular route. The observed P(app) for the transport of (14)C-mannitol and the peptides across rat alveolar epithelial cell monolayers were found to be inversely (though not linearly) related to the measured TER and could be well-modeled assuming the presence of two populations of "pores" in the cell monolayer, namely, cylindrical pores of diameter 1.5 nm and large pores of diameter 20 nm. The relative populations of the two types of pores varied with the TER of the monolayer, with the number of large pores decreasing with an increase in TER (and the number of small pores taken as fixed). These results suggest that if the cell monolayer is well characterized with respect to the passage of a range of probe molecules across monolayers of varying electrical resistance, it should be possible to predict the P(app) of any hydrophilic peptide or drug crossing the membrane by the paracellular route at any desired TER using a monolayer of any electrical resistance, above a minimum value.     

Physician distribution and access: workforce priorities

Most Primary Health Professional Shortage Areas (HPSAs) exceed federal population-to-physician designation criteria, yet struggle to maintain access to primary care physicians. Policy options for recruiting and retaining primary care physicians to HPSAs, and new HPSA criteria that support access to primary care practices, should be considered.     

The Effect of some Selected Pesticides on the Growth and Reproduction of Fresh Water <Emphasis Type="Italic">Oreochromis niloticus</Emphasis>, <Emphasis Type="Italic">Chrysicthys nigrodigitatus</Emphasis> and <Emphasis Type="Italic">Clarias gariepinus</Emphasis>

Studies were carried out to determine the toxicity of some selected pesticides on fresh water fish in a tropical environment. The uptake of the pesticides lindane, pentachlorophenol (PCP), and propoxur, which are frequently used on farms, and in industries as well as by loggers and timber men on wood were studied in concrete ponds at the University of Cape Coast, in Ghana. The fish used for the study were Oreochromis niloticus, Clarias gariepinus, and Chrysicthys nigrodigitatus. They were obtained from cultured ponds in the Cape Coast and Mankessim districts in the Central Region and Weija Dam, in the Greater Accra region of Ghana. Single high lethal concentration (SD) or acute treatment and cumulative/chronic (or multiple minor) lethal concentration (CD) treatment were employed in administering the pesticides to the fish via water. Gas chromatograph electron capture detector analysis was done on the dead fish to see the extent of ingestion. The LC₅₀ values obtained for lindane on the three fish samples were as follows: Chrysicthys – 0.38 mg L⁻¹; Oreochromis – 0.42 mg L⁻¹, and Clarias – 1.2 mg L⁻¹. Mortalities occurred in fish within 3–5 days of application. For the PCP on Chrysicthys, Oreochromis, and Clarias species the LC₅₀ values were 0.42, 0.32 and 0.64 mg L⁻¹, respectively, for over a 2- to 3-day period. For a three-time influx period of propoxur the LC₅₀ for Chrysicthys, Oreochromis, and Clarias, were 22.0, 30.40, and 45.04 (all in mg L⁻¹), respectively. The results obtained indicated that the pesticides had adverse effects on the general growth and reproduction of fish as shown by gonadosomatic indices.     

COGME's 16th Report to Congress: too many physicians could be worse than wasted

Departing from past reports, the latest Council on Graduate Medical Education (COGME) report warns of a physician deficit of 85,000 by 2020 and recommends increases in medical school and residency output. COGME notes that contributions of other clinicians and changes in how medical care is delivered in the future would likely offset physician deficits but chose not to modify their recommendations. COGME offers a relatively minor workforce correction in an otherwise flawed system of health care; however, the nation awaits a reassessment of its physician workforce based on what the nation wants and needs from physicians working in modern systems of care. Great caution should be exercised in expanding the physician workforce. Producing a physician surplus could be far worse than wasted, because the investment required and resulting rise in health care cost may harm, not help, the health of people in the United States. Instead, these resources could be applied in ways that improve health.     

Pharmacogenetics in ghana: reviewing the evidence

Different clinical response of different patients to the same medicine has been recognised and documented since the 1950's. Variability in response of individuals to standard doses of drug therapy is important in clinical practice and can lead to therapeutic failures or adverse drug reactions. Pharmacogenetics seeks to identify individual genetic differences (polymorphisms) in drug absorption, metabolism, distribution and excretion that can affect the activity of a particular drug with the view of improving efficacy and reducing toxicity. Although knowledge of pharmacogenetics is being translated into clinical practice in the developed world, its applicability in the developing countries is low. Several factors account for this including the fact that there is very little pharmacogenetic information available in many indigenous African populations including Ghanaians. A number of genes including Cytochrome P450 (CYP) 2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, MDR1 and TPMT have been genotyped in the Ghanaian population since the completion of the Human genome project. There is however, an urgent need to increase pharmacogenetic research in Ghana to increase availability of data. Introducing Pharmacogenetics into the curriculum of Medical and Pharmacy training institutions will influence translating knowledge of pharmacogenetics into clinical practice. This will also equip health professionals with the skill to integrate genetic information into public health decision making.     

Evaluation of lead and mercury neurotoxic health risk by resident children in the Obuasi municipality, Ghana

This study assesses neurotoxic effects associated with exposure to lead and mercury in borehole, tap and surface water by resident children in the Obuasi municipality in accordance with USEPA risk assessment guidelines. From the results of the study, the hazard quotient for oral ingestion of mercury in tap water in Obuasi is 7.4 and 15 respectively via both central tendency exposure (CTE) and reasonable maximum exposure (RME) parameters, respectively. This means that approximately 7 and 15 (by both CTE and RME parameters, respectively) resident children in Obuasi are likely to show neurologic effects associated with exposure to mercury and lead such as increased nervousness, loss of memory and/or decrease in concentration, impaired writing ability and tremor.