R.B. Taylor

Assessment of the incidence of substandard drugs in developing countries

In a number of developing countries there is reportedly a high incidence of the availability of substandard drugs. The majonty of these reports do not contain quantitative data to support these claims, nor do they describe the methodology employed for the quality assessment. Many assume counterfeiting as the reason for the poor quality and in some cases this is not justified. We collected 96 samples of chloroquine and selected antibacterials from Nigeria and Thailand in a controlled and methodical manner and analysed them using appropriately validated methods based on high‐performance liquid chromatography capable of detecting drug‐related impurities and quantifying active drug(s). The results indicate that 36.5% of the samples were substandard with respect to pharmacopoeial limits. Decomposition was the cause of poor quality in a number of the samples but overall, poor manufacturing appeared to be prevalent. The analyses generated little evidence to indicate fraudulent manufacturing. Treatment failure and drug‐resistance are possible consequences of the use of substandard drugs.

Pharmacopoeial quality of drugs supplied by Nigerian pharmacies

BACKGROUND The quality of medicines available in some less-developed countries is inadequate in terms of content of active ingredient. Reasons for the poor quality of drugs include widespread counterfeiting of medicines in less-developed countries, excessive decomposition of active ingredient as a result of high temperature and humidity, and poor quality assurance during the manufacture of medicinal products. Our aim was to investigate the quality of different drugs obtained from retail pharmacies in two urban areas of Nigeria, and, in instances of poor quality, to ascertain the reason why. METHODS We randomly collected 581 samples of 27 different drugs from 35 pharmacies in Lagos and Abuja in Nigeria. We analysed the medicines for drug content by validated chromatographic methods, and compared our results with pharmacopoeial requirements. FINDINGS 279 (48%) samples did not comply with set pharmacopoeial limits, and this proportion was uniform for the various types of drugs tested. Although some preparations contained no active ingredient, most had amounts just outside the pharmacopoeial limits. We identified samples with both too much and too little active drug content. INTERPRETATION The most probable cause of the poor quality of drugs is absence of adequate quality assurance during manufacture. Substandard drugs sold in the pharmacies of less-developed countries could contribute to global microbial resistance and therapeutic failure of infectious diseases.

Determination of opiates in urine by capillary electrophoresis.

A method for the separation of a mixture of opiates comprising pholcodine, 6-monoacetylmorphine, morphine, heroin, codeine and dihydrocodeine by capillary electrophoresis using a running buffer of 100 mM disodium hydrogenphosphate at pH 6 is described. The characteristics of an analytical method based on this separation for the determination of these drugs following extraction from urine and using levallorphan as internal standard are reported. Detection limits in the region of 10 ng cm-3 are achieved when using electrokinetic injection. A comparison is made of the sensitivity and reproducibility of electrokinetic and hydrodynamic injection for these drugs. Data are presented to show the results obtained when the proposed method is applied to urine spiked with all the above opiates and also to urine from a subject following consumption of dihydrocodeine and pholcodine. The concentrations found are compared with those obtained by LC.

Analysis of proguanil and its metabolites by application of the sweeping technique in micellar electrokinetic chromatography

The method of applying large sample volumes in micellar electrokinetic chromatography termed sweeping is applied to determine the conservative limits of detection of some basic drugs in plasma and urine. The biguanides proguanil, 4-chlorophenylbiguanide and cycloguanil are used as models of basic drugs and the limits of detection obtained compared with those previously reported for capillary zone electrophoresis using field-amplified sample injection (FASI) and also by LC using off-line preconcentration. It is found that the sweeping method can be applied to extracts of such biological matrices. The limits of detection obtained by sweeping are improved over FASI for plasma but not for urine and the limits of detection are higher than those reported for LC, for these compounds.

Analysis of basic antimalarial drugs by CZE; Part 2. Validation and application to bioanalysis

This report describes some of the quantitative aspects of the CZE separation of proguanil, chloroquine and their respective metabolites, the separations of which, by CE and MEKC, were reported in Part 1. Results obtained on the precision of migration time and peak areas using the alternative injection methods of vacuum and electrokinetic are described and discussed. The increase in concentration sensitivity using electrokinetic injection with an organic injection solvent reported in Part 1 is confirmed and the resultant limits of detection in urine reported. An assay method for these compounds in urine is described which incorporates a pretreatment stage of solid phase extraction and the main analytical parameters used in the validation of such an assay are reported. The limitation of the sample pretreatment used when applied to matrices of plasma and saliva are reported and discussed in the context of the electrokinetic injection method used.

Determination of sodium artesunate in plasma using ion-pairing high-performance liquid chromatography.

A chromatographic method is described for the determination of sodium artesunate in plasma. This includes cetyltrimethylammonium bromide as a cationic pairing ion in a reversed-phase system using an octadecylsilica 100 x 4.6 mm I.D. 3 microm analytical column with a mobile phase of acetonitrile/acetate buffer at pH7. Column switching incorporating a 5 microm octadecylsilica 100 x 4.6 mm I.D. precolumn is used in addition to off-line solid-phase extraction for pretreatment of plasma samples in order to eliminate interference from endogenous components. Detection is by post-column derivatisation with 1.0 M methanolic KOH followed by UV detection at 289 nm. Calibration is linear over the range 100-1600 ng ml(-1) and the limit of detection is estimated as 20 ng ml(-1). Illustrative results are shown of the artesunate plasma levels determined by the proposed method following the administration of artesunate as tablets and as suppositories to healthy volunteers.

Traveller's diarrhoea; a controlled study of its effect on chloroquine and proguanil absorption

The potential for travellers diarrhoea to impair proguanil and chloroquine absorption and cause chemoprophylaxis failure was investigated in a study involving recently returned travellers who were either asymptomatic or presented with diarrhoea. A routine dose of chemoprophylaxis was administered to 12 travellers with diarrhoea and 12 asymptomatic subjects. The subjects undertook a lactulose-mannitol intestinal permeability test and were bled hourly after prophylaxis ingestion. Plasma analysis of chloroquine and proguanil from serial samples revealed a significantly lower proguanil Cmax (146 ng/mL vs. 196 ng/mL, P = 0.05), and longer tmax (3.1 h vs. 2.6 h, P = 0.05) in the diarrhoea cohorts. The absorption coefficient was lower for proguanil (0.57 vs. 0.76) but the difference did not quite reach levels of significance. Chloroquine kinetics were similar in both groups. The diarrhoea cohort had a three-fold higher lactulose absorption, influencing the mean lactulose mannitol:ratio, 0.114 +/- 0.17 compared to the control ratio of 0.02 +/- 0.01 (P = 0.04). Symptomatic subjects had impaired mucosal function which reduced the absorption of proguanil but not chloroquine, a phenomenon which may reduce prophylactic efficacy.

Multidrug assay method for antimalarials

A general separation strategy, involving solid-phase extraction followed by reversed-phase ion-pairing HPLC with an organic counter ion for a set of 11 widely used antimalarial drugs and metabolites has been developed. The basis underlying the separation has been explored and work, including quantitative data, has been carried out on illustrative separations which form the basis of novel quantitative assays of groups of antimalarials which are relevant to current prophylaxis and treatment of malaria.

Effects of cimetidine on the pharmacokinetics of proguanil in healthy subjects and in peptic ulcer patients

The pharmacokinetics of orally administered proguanil and its metabolites were determined in six healthy volunteers and in six peptic ulcer patients, before and after a 3-day course of cimetidine (400 mg given two times daily for 2 days and 400 mg on the third day 1 h before proguanil). Cimetidine significantly increased Cmax (P < 0.05), AUCo-alpha (P < 0.005) and elimination half-life t 1/2b of proquanil in plasma of healthy subjects. In ulcer patients, cimetidine significantly increased, AUCo-alpha (P < 0.05), elimination half life (P < 0.005) and Cmax. Cimetidine significantly reduced (P < 0.05) Total body clearance in both healthy subjects and in peptic ulcer patients. The Cmax and AUCo-alpha of the active metabolite cycloguanil was significantly decreased (P < 0.05) in both the healthy subjects and in the peptic ulcer patients. The Cmax of the inactive metabolite, 4-CPB was significantly decreased in healthy subjects and AUCo-alpha significantly decreased in peptic ulcer patients.

HEROIN: LIQUID CHROMATOGRAPHY AND CAPILLARY ELECTROPHORESIS

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