Onchocerciasis control in the Democratic Republic of Congo (DRC): challenges in a post-war environment.

OBJECTIVE: To evaluate onchocerciasis control activities in the Democratic Republic of Congo (DRC) in the first 12 years of community-directed treatment with ivermectin (CDTI). METHODS: Data from the National Programme for Onchocerciasis (NPO) provided by the National Onchocerciasis Task Force (NOTF) through the annual reports of the 21 CDTI projects for the years 2001-2012 were reviewed retrospectively. A hypothetical-inputs-process-outputs-outcomes table was constructed. RESULTS: Community-directed treatment with ivermectin expanded from 1968 communities in 2001 to 39 100 communities by 2012 while the number of community-directed distributors (CDD) and health workers (HW) multiplied. By 2012, there were ratios of 1 CDD per 262 persons and 1 HW per 2318 persons at risk. More than 80% of the funding came from the fiduciary funds of the African Programme for Onchocerciasis Control. The cost of treatment per person treated fell from US$ 1.1 in 2001 to US$ 0.1 in 2012. The therapeutic coverage increased from 2.7% (2001) to 74.2% (2012); the geographical coverage, from 4.7% (2001) to 93.9% (2012). Geographical coverage fell in 2005 due to deaths in loiasis co-endemic areas, and the therapeutic coverage fell in 2008 due to insecurity. CONCLUSIONS: Challenges to CDTI in DRC have been serious adverse reactions to ivermectin in loiasis co-endemic areas and political conflict. Targets for personnel or therapeutic and geographical coverages were not met. Longer term funding and renewed efforts are required to achieve control and elimination of onchocerciasis in DRC.

Immunological and C-peptide studies of patients with diabetes in northern Ethiopia: existence of an unusual subgroup possibly related to malnutrition.

AIMS/HYPOTHESIS: Surveys in northern Ethiopia have demonstrated that apparent type 1 diabetes occurs more frequently than elsewhere in Africa and, indeed, in other parts of the world. We therefore investigated in detail a cohort of diabetic patients from this region to clarify the nature of this type of diabetes. METHODS: All patients attending the diabetic clinic at Mekelle Hospital in the Tigray region of northern Ethiopia were investigated over a 6 week period. Clinical, demographic and anthropometric data were collected, as well as measurements of HbA(1c), fasting lipid profile, fasting serum C-peptide and serum markers of beta cell autoimmunity, i.e. islet antigen-2 and GAD antibodies (GADA). RESULTS: Of 105 patients seen, 69 (66%) were on insulin treatment and had been from or close to diagnosis. Their median age and diabetes duration were 30 and 5 years, respectively, with a male excess of 2:1. Median BMI was 20.6 kg/m². Despite these clinical characteristics suggestive of type 1 diabetes, only 42 of 69 (61%) patients were C-peptide-negative and 35% GADA-positive. Overall, 38 (36%) of the total group (n = 105) had immunological or C-peptide characteristics inconsistent with typical type 1 or type 2 diabetes. The clinical characteristics, local prevalence of undernutrition, and GADA and C-peptide heterogeneity suggest a malnutrition-related form of diabetes. CONCLUSIONS/INTERPRETATION: Not all patients in northern Ethiopia with apparent type 1 diabetes appear to have the form of disease seen in Europids; their disease may, in fact, be related to malnutrition.

Ulysses radio and plasma wave observations in the jupiter environment.

The Unified Radio and Plasma Wave (URAP) experiment has produced new observations of the Jupiter environment, owing to the unique capabilities of the instrument and the traversal of high Jovian latitudes. Broad-band continuum radio emission from Jupiter and in situ plasma waves have proved valuable in delineating the magnetospheric boundaries. Simultaneous measurements of electric and magnetic wave fields have yielded new evidence of whistler-mode radiation within the magnetosphere. Observations of aurorallike hiss provided evidence of a Jovian cusp. The source direction and polarization capabilities of URAP have demonstrated that the outer region of the lo plasma torus supported at least five separate radio sources that reoccurred during successive rotations with a measurable corotation lag. Thermal noise measurements of the lo torus densities yielded values in the densest portion that are similar to models suggested on the basis of Voyager observations of 13 years ago. The URAP measurements also suggest complex beaming and polarization characteristics of Jovian radio components. In addition, a new class of kilometer-wavelength striated Jovian bursts has been observed.

A rapid liquid chromatographic method for the determination of lamotrigine in plasma.

A rapid sensitive and simple high-performance liquid chromatographic (HPLC) method for the determination of lamotrigine in plasma is described. The drug was extracted from 100 microliters of plasma with chloroform:isopropanol (95:5% v/v) in the presence of 100 microliters of phosphate buffer (10 mM). The extract was evaporated and the residue was reconstituted with mobile phase and injected onto the HPLC system. The drug and the internal standard (chloramphenicol) were eluted from a Symmetry C18 stainless steel column at ambient temperature with a mobile phase consisting of 0.01 M potassium-acetonitrile-methanol (70.20:10% v/v/v), adjusted to pH 6.7, at a flow rate of 1.3 ml min-1 and the detector was monitored at 214 nm. Quantitation was achieved by measurement of the peak-area ratio of the drug to the internal standard and the lower limit of detection for lamotrigine in plasma was 20 ng ml-1. The intraday precision ranged from 3.34 to 6.12% coefficient of variation (CV) and the interday precision ranged from 2.15 to 8.34% CV. The absolute and relative recoveries of lamotrigine ranged from 86.93 to 90.71% and from 95.18 to 107.13%, respectively. The method was applied in studying the pharmacokinetics of lamotrigine administered orally to rabbits. This reliable micro-method would have application in pharmacokinetic studies of lamotrigine where only small sample sizes are available, e.g. paediatric patients.

Phenytoin-bupropion interaction: effect on plasma phenytoin concentration in the rat.

The effect of coadministration of bupropion (50 mg kg-1, p.o.) on the disposition profile of phenytoin has been studied in the rat. Plasma phenytoin concentration was measured serially for 10 h by HPLC. Bupropion had little or no effect on the pharmacokinetic parameters of an acutely administered dose of phenytoin. Following multiple doses of phenytoin however (i.e. steady state) the coadministration of bupropion resulted in significant increases in the elimination half-life (t 1/2), the area under the plasma concentration-time curve (AUC) and the time to maximum plasma concentration (tmax). Allowing for the limitations of single dose studies, these results point to a possible pharmacokinetic interaction between bupropion and phenytoin--the clinical significance of which needs to be assessed.

The effect of stress on the pharmacokinetics and pharmacodynamics of glibenclamide in diabetic rats.

Optimal management of the diabetic patient includes normalization of glucose concentration. Attainment of this goal is difficult because stress has long been shown to have a major effect on metabolic activity. The aim of this study was to assess the effect of stress on the pharmacokinetics and dynamics of glibenclamide in normal and diabetic rats. In this respect, administration of glibenclamide (1.4 mg/kg, p.o.) significantly reduced the blood glucose level estimated after an intravenous challenge dose (4 ml/kg) of 50% dextrose. Peak drug effect occurred at about 2 h in the control on diabetic group and this effect was clearly evident over a 6 h period in the diabetic group. The stressed diabetic group showed consistently higher blood glucose level at all time points than the nonstressed diabetic controls. Stress was also associated with significant reductions in glibenclamide Cp-max and AUC0-infinity and an increase in the Tmax. These results suggest that the response to glibenclamide in diabetics may be strongly modified by stress through a number of mechanisms. Changes in the bioavailability of the drug and activation of sympathetic nervous system and the hypothalamic-pituitary-adrenocortical axis are potential candidates. Further clinical and experimental studies in relevant models may, however, be needed to characterize fully and relate this effect to rational pharmacotherapy of type II diabetes.

Assessment of pharmacokinetic interaction between theophylline and loperamide in the rat.

The effect of loparamide (1 mgkg-1, p.o.) on the pharma-cokinetics of theophylline was studied in the rat. Theophylline (as aminophylline-25 mgkg-1, p.o.) was administered either alone, in combination with, or 1 hr after loperamide. Plasma levels of theophylline were serially measured over a period of 12 hr using HPLC. The disposition kinetics of theophylline was markedly altered by loperamide. This was evident from the significant differences obtained between the control and drug combination groups in most of the parameters studied (Cpmax, tmax, Ka, t1/2 and AUC). Allowing for the limitations of single dose studies, the data presented here suggest that pharma-cokinetic interaction between theophylline and loperamide is possible during their concomitant use.

Effect of vigabatrin and gabapentin on phynytoin pharmacokinetics in the dog.

The study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A group of five beagle dogs were given a daily dose of PT (12 mg/kg, i.v.) for a period of 1 week. On day 8, plasma samples were serially collected over 24 hr. after administration of the PT dose. PT administration was continued with oral supplementary dose of VGB (60 mg/kg) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mg/kg, i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n = 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parental PT. VGB, however markedly changed the drug's kinetics as evidenced by a 31% (P = 0.015) reduction in total body clearance (CL) and increase of over 45% in half-life (t1/2), (P = 0.013) and area under the plasma PT concentration-time curve (AUC), (P = 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in marked reduction in systemic clearance of the latter in the dog.

Bioavailability of ibuprofen from oral and suppository preparations in rats.

Bioavailability of ibuprofen (15 mgkg-1) from oral and suppository dosage forms was investigated. Three different combinations of PEG 4000 and 1000 and theobroma oil were used as suppository bases. Oral administration gave higher values for mean residence time (MRT) and absolute bioavailability (F) compared to suppository dosage forms. The theobroma oil base was associated with lower maximum plasma concentration (cpmax), area under the concentration time curve (AUC) and F values compared to the other bases but differences were not significant (P greater than 0.05). Ibuprofen appears to be strongly retained by the lipophilic base, thereby limiting its diffusion through the rectal mucosal membrane. The absorption profile was slightly improved for the three PEG combination bases but were inferior to oral dosing. It is suggested that the relatively smaller size of the rectal mucosal membrane compared to the small intestine was primarily responsible for limiting the rate/extent of ibuprofen absorption. The absorption profile from the suppository preparations may be enhanced by the appropriate selection of the bases and their additives.

Comparison of high-performance liquid chromatography with fluorescence polarization immunoassay for the analysis of vancomycin in patients with chronic renal failure.

Eighty-two plasma samples from patients with chronic renal failure undergoing vancomycin treatment and hemodialysis (HD) were analyzed with fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). Vancomycin was infused once and the samples were collected during three subsequent HD sessions at 2 h, 3 days and 5 days post-infusion. The HPLC method, modified from an earlier assay, was simple. There was a wide variation in the estimated concentration between the two assay methods. The results obtained by HPLC were 69% lower than those obtained by FPIA. This difference in vancomycin concentration was independent of the sampling time after vancomycin infusion. HPLC analysis commenced approximately 1.5 year after that of FPIA. To study the effect of in vitro degradation, the vancomycin concentration in ten of the samples was redetermined with FPIA during HPLC analysis. The concentrations of those samples decreased to 78-98% (average 92%) of the original concentration. Because FPIA appears to lack specificity, there is a need of other methods such as HPLC for vancomycin measurements, particularly in samples from patients with end-stage renal failure.

Subacute benzodiazepine treatment: observations on behavioural tolerance and withdrawal.

The acute and subchronic actions of the benzodiazepines triazolam, oxazepam and diazepam have been examined using three behavioural tests. In the accelerating rotarod motor coordination test both diazepam and oxazepam on acute administration produced dose-related discoordination or motor impairment in mice. After chronic administration (50 mg/kg per day i.p. for 14 days) the corresponding dose-response lines were shifted to the right suggesting tolerance development. In a test for conflict behaviour in rats (conditioned suppression of drinking) oxazepam (20 mg/kg i.p.), triazolam (1 mg/kg i.p.) and diazepam (10 mg/kg i.p.) all augmented punished responding rates with no effect on unpunished responses and this has been speculated to reflect anxiolytic activity. These initial elevations in punished responding displayed a gradual decline during repeated daily administration over 20 days, there being little alteration in the unpunished response levels. In separate studies, chronic treatment of mice with triazolam in the drinking water over 30 days showed diminished pentylenetetrazol-induced seizure latencies compared to the level of protection afforded by triazolam at the beginning of the schedule. In additional experiments, mice injected daily with triazolam (1 mg/kg i.p. for 14 days) exhibited a higher seizure susceptibility than their corresponding controls. The results are discussed in relation to tolerance to the anxiolytic, anticonvulsant and neurological impairment properties of benzodiazepines.

Rapid micromethod for simultaneous measurement of oxcarbazepine and its active metabolite in plasma by high-performance liquid chromatography.

A rapid method for the simultaneous determination of oxcarbazepine (OXC) and its active metabolite (10-hydroxycarbazepine) in human and rat plasma by reversed phase high-performance liquid chromatography is described. The method involves a simple one-step extraction of the drugs from plasma with dichloromethane. The extract was evaporated and the residue was reconstituted with mobile phase and injected onto a Novapak C18 column. The eluting solvent was 20% acetonitrile in water at a flow rate of 1.5 ml/min and the detector was monitored at 215 nm. The detection limit of OXC and 10-hydroxycarbazepine was 50 and 20 ng/ml, respectively. The within-day and between-day coefficients of variation for OXC and its active metabolite were 2.57-6.95% and 4.21-8.3%, respectively. The relative and absolute recoveries varied between 71.4% and 104.0%. The applicability of the analytical procedure to pharmacokinetic studies was illustrated.

The effect of domperidone on theophylline disposition in the rat.

The effect of domperidone (2 mg kg-1) on the pharmacokinetics of a single oral dose of theophylline (25 mg kg-1) was studied in the rat. Theophylline concentrations were measured serially for 12 h using an HPLC technique. Domperidone did not have any significant effect on any of the four parameters studied: peak plasma levels (Cpmax), the time these were attained (tmax), elimination half-life (t1/2) and area under the plasma concentration-time curve (AUC). Our data preliminarily suggests that domperidone may be safely coadministered with theophylline but clearly further studies in patients or relevant animal models of gastric motility disturbances are needed to reliably rule out any potential interaction between these agents.

Evaluation of reagent strips in urine tests for detection of Schistosoma haematobium infection: a comparative study in Ghana and Zambia.

The presence of haematuria and proteinuria, detected by reagent strips, was compared with Schistosoma haematobium egg counts in the urines of human subjects from two epidemiologically distinct areas in Ghana and Zambia. In children and adults in both areas, the individual or combined semiquantitative levels of proteinuria and haematuria were related directly to increasing urinary egg counts. In both areas the presence of blood in the urine was highly specific (greater than 85%) and sensitive, being positive in 97% of urine specimens with more than 64 eggs per 5-ml sample of urine. The sensitivity of the protein indicator was also high, but its specificity was less than the blood indicator. The specificity of combined proteinuria and haematuria was higher than either alone; on the other hand, the sensitivity was lower than either alone. At each level of proteinuria and haematuria, the geometric mean urinary egg count was higher in Ghana than in Zambia. This study confirms the necessity to evaluate indirect diagnostic techniques in each endemic country, in order to establish criteria for their interpretation, before wide-scale use.

Indirect screening for Schistosoma haematobium infection: a comparative study in Ghana and Zambia.

Four indirect approaches, based on inquiry into a past history of haematuria, visual inspection for blood in the urine specimens, and the use of reagent strips to detect haematuria and proteinuria, were evaluated to identify persons with Schistosoma haematobium infection. These approaches were applied individually and in three different screening sequences on two populations in Ghana and Zambia in order to identify infected children and adults for subsequent treatment in both areas. Detection of haematuria using reagent strips was the single approach with the highest sensitivity and specificity. The observation of gross haematuria (bloody urine), followed by detection of blood by reagent strips, identified 87% of infected children in both areas. This screening sequence showed the highest combined sensitivity and specificity in the identification of infected children as well as adults for treatment in both areas. Differences in the results between the two countries are discussed. This study emphasizes the need for evaluation of indirect screening procedures for the diagnosis of S. haematobium infection in each endemic area so as to establish criteria for their interpretation, prior to large-scale field application.

Effect of vigabatrin and gabapentin on phenytoin pharmacokinetics in the dog.

This study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A daily dose of PT (12 mgkg(-1)i.v.) was given to a group of five beagle dogs for a period of 1 week. On day eight, plasma samples were serially collected over 24 h, after administration of the PT dose. PT administration was continued, along with supplementary oral VGB (60 mgkg(-1)) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mgkg(-1), i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n= 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parenteral PT. However VGB markedly changed the drug's kinetics, as evidenced by a 31% (P= 0.015) reduction in total body clearance (CL) and an increase of over 45% in half-life (t(1/2)), (P= 0.013) and area under the plasma PT concentration-time curve (AUC), (P= 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in a marked reduction in systemic clearance of the latter in the dog.

Liquid chromatographic determination of six antiepileptic drugs and two metabolites in microsamples of human plasma.

A simple, rapid, sensitive, and reproducible high-performance liquid chromatographic (HPLC) method for simultaneous determination of the antiepileptic drugs (ethosuximide, primidone, lamotrigine, phenobarbital, phenytoin, and carbamazepine) and two metabolites (carbamazepine-diol and carbamazepine-epoxide) in human plasma is described. The procedure involves extraction of the drugs from human plasma (100 microL) with ether using 9-hydroxymethyl-10-carbamyl acridan as an internal standard. The extract was evaporated and reconstituted with mobile phase and then injected onto the chromatograph. The drugs and the internal standard were eluted from a Supelcosil LC-18 stainless steel column at ambient temperature with a mobile phase consisting of a 0.01M phosphate buffer/methanol/acetonitrile (65/18/17, v/v/v) adjusted to a pH of 7.5 with phosphoric acid and a flow rate of 1 mL/min. The effluent was monitored at 220 nm. Quantitation was achieved by using peak area ratio of each drug to the internal standard. The intraassay and interassay coefficients of variation (CV) ranged from 2.43% to 6.25% and from 3.02% to 5.85%, respectively. The absolute (extraction) and relative (analytical) recoveries for the drugs ranged from 70.7% to 104.4% and from 88.3% to 106.1%, respectively. Stability tests showed that the drugs were stable in plasma for at least 4 weeks when stored at -20 degrees C. The method was applied clinically for monitoring the AEDs in epileptic patients.

Effect of valproic acid on the pharmacokinetic profile of oxcarbazepine in the rat.

The pharmacokinetics of oxcarbazepine (30 mg kg-1, po), administered for 1 week, was studied in rats pre-treated for 2 weeks with valproic acid (100 mg kg-1, po). Oxcarbazepine (OXC) plasma levels were measured over a period of 24 h from dosing, using a sensitive HPLC method. No significant changes were observed in the mean values of OXC pharmacokinetic parameters (Cmax, Tmax, t1/2 and AUC0-infinity) between the control and the pre-treated groups. The findings of this study suggest that OXC metabolism in the rat is apparently not affected by valproic acid, and the lack of effect may be attributed to the different pathways of biotransformation of the two drugs.

Effects of pregnancy on the pharmacokinetics of lamotrigine in dogs.

PURPOSE: This study was designed to evaluate the effects of pregnancy on the kinetics of lamotrigine (LTG). METHODS: Five pregnant dogs were given a daily dose of LTG (100 mg) for a period of 1 week. Two months after parturition, the same subjects were given the LTG dose (100 mg) over the same period. On both occasions, plasma LTG concentrations were determined by a sensitive, high-performance liquid chromatographic (HPLC) method, over a 30-h period after the last dose. RESULTS: The mean maximum plasma concentration (Cmax), volume of distribution (Vd/F), and oral body clearance (Cl/F) for LTG (+/- SD) during pregnancy were 7.63+/-2.46 microg/ml 1.74+/-0.29 L/kg, and 0.19+/-0.04 L/h/kg, respectively. After pregnancy, the same variables were 6.12+/-2.24 microg/ml, 2.36+/-1.10 L/kg, and 0.30+/-0.13 L/h/kg, respectively. None of these pharmacokinetic parameters was found to be significantly different between the two groups. CONCLUSIONS: The apparent lack of change in the relevant pharmacokinetic parameters of LTG during pregnancy may indicate that pregnancy has little or no effect on glucuronidation; the principal pathway for the drug's elimination.