Sulfadoxine Research Articles

Quantitation of Fansimef Components (Mefloquine + Sulfadoxine + Pyrimethamine) in Human Plasma by Two High-Performance Liquid Chromatographic Methods

Two simple, precise, and selective high-performance liquid chromatographic methods are described for the simultaneous quantitation of mefloquine (MQ) plus pyrimethamine (PYR) or sulfadoxine (SDX) plus its principal metabolite N4-acetylsulfadoxine (N4SDX) in human plasma. After a single-step extraction, MQ plus PYR and SDX plus N4SDX including internal standards were separated using ion-paired and ion-suppression chromatography. Total run times for the assays were less than 12 min. Intraassay and interassay precision of the methods expressed as the coefficients of variation were less than 9% in plasma for the four compounds. The extraction recovery averaged 98% for MQ, 97% for PYR, 96% for SDX, and 81% for N4SDX. Plasma concentrations of the four compounds in a pediatric patient after a single oral dose of Fansimef (MQ + SDX + PYR) were determined to demonstrate the clinical application of the methods.

Identification and Quantitation of Residual Sulfa Drugs in Meat by High Performance Liquid Chromatography with Photodiode Array Detection

A simple and selective method for the simultaneous determination of sulfadiazine (SDZ), sulfadimidine (SDD), sulfadimethoxine (SDMX), sulfadoxine (SDOX), sulfamerazine (SMR), sulfamethoxazole (SMXZ), sulfamonomethoxine (SMMX), sulfaquinoxaline (SQ), sulfathiazole (STZ), and sulfisomidine (SID) in meat has been developed by high performance liquid chromatography (HPLC) with photodiode array detection.The drugs were extracted from meat with 0.2% metaphosphoric acid-methanol (2:1), followed by a Baker C18 clean-up procedure. The HPLC separation was carried out on a TSK-gel ODS 80TM (150×4.6mm i. d. ) using 0.05M sodium dihydrogenphosphate (pH 4.5)-acetonitrile (2:1) as the mobile phase, with a flow rate of 0.5ml/min, and monitored with a photodiode array detector. The recoveries of drugs from meats fortified at 0.5μg/g were 74.2-89.9%. The limits of detection were 0.05μg/g for each drug. SDD was found in 10 samples of imported pork meat (11.1%) at levels in the range of 0.05-1.05μg/g. SDMX was found in 1 sample of domestic pork meat (2.2%).

Studies on response characteristics of drug ion-selective electrodes (II)--sulpha-drug sensitive electrodes using quaternary phosphonium and arsonium compounds.

Ion-pair complexes of sulphonamide derivatives with quaternary phosphonium and quaternary arsonium have been synthesized and their electrode performances studied. It has been found that the electrode functions depend mainly on the site cation rather than on the anionic species and deteriorate in the order of cetyltrioctylammonium greater than cetyltriphenylphosphonium greater than cetyltriphenylarsonium. The electrode selectivity for different sulpha-drugs decreases in the order of sulphathiazole greater than sulphamethoxazole greater than sulphadimethoxine, sulphadoxine greater than sulphacetamide greater than sulphadiazine greater than sulphanilamide. Selectivity coefficients depend not only on the molecular connectivity index chi, but also on the electronic charge at the ionizing amide nitrogen atom sigma and pKa according to the following formula: logKij = a chi + b sigma - CpKa - d. The quaternary phosphonium type electrodes have been suggested for use in the potentiometric determinations of sulpha-drugs.

Pharmacokinetics of sulfadoxine and pyrimethamine after Fansidar administration in man.

The pharmacokinetics of sulfadoxine (SULF) and pyrimethamine (PYR) were studied in 7 healthy volunteers after a single oral dose of Fansidar. A comparison was made between the pharmacokinetics of the components of Fansidar calculated from whole blood and plasma data. The mean whole blood to plasma concentration ratios of SULF and PYR were 0.62 and 0.87, respectively. The elimination half-lives of SULF and PYR were similar in whole blood and plasma. The apparent volume of distribution and clearance of SULF and PYR in whole blood were significantly higher (p less than 0.01) than the corresponding plasma values. Because malaria-infected erythrocytes appear to concentrate SULF, it may be more relevant to measure drug concentrations in whole blood rather than in plasma in assessing the antimalarial efficacy of Fansidar.

In vitro susceptibility of Plasmodium falciparum malaria to pyrimethamine, sulfadoxine, trimethoprim and sulfamethoxazole, singly and in combination

Two isolates of Plasmodium falciparum (F 32 and K 1) were tested against sulfadoxine (SDX), sulfamethoxazole (SMZ), pyrimethamine (PYR) and trimethoprim (TMP), using a 48 h microtest, with RPMI-1640 low in PABA and folic acid. The IC 50 for F 32 was: PYR 6·1 × 10 −9 m(mol/litre), TMP 1·3 × 10 −7 m, Fansidar ® ( SDX PYR 80:1) < 10 −8 to 1·3 × 10 −10 m and cotrimoxazole ( SMZ TMP 20:1) 2·6 × 10 −7 to 1·3 × 10 −8 m. The IC 50 for K 1 was: PYR > 10 −6 m, TMP 8·2 × 10 −7 m, Fansidar ® 4·1 × 10 −7 to 1·1 × 10 −9 m and cotrimoxazole 1·8 × 10 −6 to 9·0 × 10 −8 m. The difference in IC 50 between F 32 and K 1 against TMP and cotrimoxazole is much less than the difference between the IC 50 values against PYR and Fansidar ®, indicating that cross-resistance between PYR and TMP exists, but is not complete. A method for calculating the IC 50 by linear regression analysis is described.

Effect of pyrimethamine and sulphadoxine on human lymphocyte proliferation

The in vitro effect of pyrimethamine (PYR) on human blood mononuclear cells stimulated with phytohaemagglutinin (PHA), pokeweed mitogen (PWM) and purified protein derivative of tuberculin (PPD) was studied by 14C-thymidine incorporation, by cell counting and by total DNA estimation. PYR in concentrations 10 times higher than serum values obtained in clinical practice inhibited lymphocyte proliferation irreversibly. PYR in concentrations corresponding to clinical practice quickly and irreversibly suppressed the proliferation of PWM-stimulated cells, and more slowly the proliferation of PPD-stimulated cells. The suppression of PHA-stimulated cells was reversed after one week. The increased 14C-thymidine incorporation observed in stimulated cells exposed to PYR in vitro in the early phase of proliferation did not reflect immunopotentiation but rather blocked endogenous thymidine synthesis. Sulphadoxine (SDX), added in vitro, had no effect on the lymphocytes, while SDX plus PYR had the same effect as PYR alone. Oral intake of SDX plus PYR (Fansidar) also blocked the thymidine synthesis of mitogen-stimulated lymphocytes. The possible consequences of the findings for the use of PYR in malaria prophylaxis and therapy are discussed.

Drug displacement from protein binding: source of the sulphadoxine liberated by phenylbutazone.

1. A quantitative study has been made of the redistribution of sulphadoxine produced by phenylbutazone in live sheep.2. From calculations based on plasma measurements, 73% of the sulphadoxine in the body can be accounted for as the sum of the plasma-bound, extracellular-free and intracellular-free drug in the whole animal. This sum is termed the accountable sulphadoxine.3. After the injection of phenylbutazone there was a large shift of sulphadoxine from the plasma-bound form into the free form. The gain in free drug significantly exceeded the loss of bound sulphadoxine from the intravascular compartment, but the discrepancy could easily be explained by displacement of some bound sulphadoxine from extravascular plasma protein.4. Phenylbutazone did not displace sulphadoxine from sheep erythrocytes in vitro, nor from homogenates of liver, kidney or skeletal muscle.5. Although the existence of other susceptible binding sites cannot be entirely excluded, this evidence strongly suggests that all the sulphadoxine liberated by phenylbutazone comes from binding sites on plasma protein.

Drug displacement from protein binding: isolation of a redistributional drug interaction in vivo.

1. The pharmacokinetic interaction between phenylbutazone and sulphadoxine has been studied in live sheep.2. Intravenous injection of phenylbutazone causes a rapid fall in the concentration of total sulphadoxine together with a simultaneous rise in the concentration of free sulphadoxine in plasma. Both processes are complete within 3 min of the injection of phenylbutazone.3. These reciprocal changes in the concentrations of total and free sulphadoxine in plasma do not depend on changes in the absorption, hepatic metabolism or renal excretion of sulphadoxine. By exclusion therefore, it is concluded that the effect of phenylbutazone in this interaction is solely to cause redistribution of the sulphadoxine.