Sulfadoxine Research Articles

In vitro sensitivity to antimalarial drugs and polymorphisms in Pfg377 gene in Plasmodium falciparum field isolates from Mewat, India

The malaria infection is the interplay of several complex factors, among which drug resistance and gametocyte biology are the crucial ones. Measurements of the drug sensitivity assays and prevalence of gametocyte genes play a major role in malaria eradication programmes. The purpose of this study was to assess the current drug sensitivity profile in the field isolates and type the Pfg377 gene. In vitro drug sensitivity assay was used to assess the susceptibility of Plasmodium falciparum field isolates collected from Mewat (Haryana), located in Northern region of India to four anti-malarial drugs. The inhibitory concentrations (IC50) for the four drugs viz Chloroquine (CQ), Artesunate (AS), Sulphadoxine (SD) and Pyrimethamine (PYR) were in the range of 10.11–113.2, 2.26–4.08, 13.31–43.91 and 0.76–4.91 nM respectively in the evaluated 25 field isolates. The Pfg377 allele typing in the 26 field isolates revealed different types of haplotypes (A, B, C and D) varying by the size and number of repeats and deletions. The Pfg377 allelic types in the cryopreserved and adapted isolates of P. falciparum were compared to determine the parasite lines in them. The allele types or presence of different clones in the same sample could not be correlated significantly with resistance to any of the four drugs tested in the study. Our study revealed different drug sensitivity profiles of field isolates from Mewat region and allele typing of Pfg377 gene revealed different haplotypes of field isolates were circulating in parasite population.

Optimal Antimalarial Dose Regimens for Sulfadoxine-Pyrimethamine with or without Azithromycin in Pregnancy Based on Population Pharmacokinetic Modeling.

Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when coadministered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 nonpregnant and 45 pregnant women treated with SP-AZI (n = 15 in each group) and SP-chloroquine (n = 30 in each group) were analyzed. Population nonlinear mixed-effect pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX), and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX, and NASDOX by 48, 29, and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46 and 99%) and NASDOX (46%). Coadministration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design, including the use of an early postpartum follow-up study rather than a nonpregnant comparator group. Simulations based on the final population model demonstrated that, compared to conventional single-dose SP in nonpregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure, while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials using recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings and consideration given to using increased doses in future trials.

Silver sulfadoxinate: Synthesis, structural and spectroscopic characterizations, and preliminary antibacterial assays in vitro

The sulfa drug sulfadoxine (SFX) reacted with Ag+ ions in aqueous solution, affording a new silver(I) complex (AgSFX), which was fully characterized by chemical, spectroscopic and structural methods. Elemental, ESI-TOF mass spectrometric and thermal analyses of AgSFX suggested a [Ag(C12H13N4O2S)] empirical formula. Infrared spectroscopic measurements indicated ligand coordination to Ag(I) through the nitrogen atoms of the (deprotonated) sulfonamide group and by the pyrimidine ring, as well as through oxygen atom(s) of the sulfonamide group. These hypotheses were corroborated by 13C and 15N SS-NMR spectroscopy and by an unconventional structural characterization based on X-ray powder diffraction data. The latter showed that AgSFX crystallizes as centrosymmetric dimers with a strong Ag⋯Ag interaction of 2.7435(6) Å, induced by the presence of exo-bidentate N,N′ bridging ligands and the formation of an eight-membered ring of [AgNCN]2 sequence, nearly planar. Participation of oxygen atoms of the sulfonamide residues generates in the crystal a 1D coordination polymer, likely responsible for its very limited solubility in all common solvents. Besides the analytical, spectroscopic and structural description, the antibacterial properties of AgSFX were assayed using disc diffusion methods against Escherichia coli and Pseudomonas aeruginosa (Gram-negative), and Staphylococcus aureus (Gram-positive) bacterial strains. The AgSFX complex showed to be active against Gram-positive and Gram-negative bacterial strains, being comparable to the activities of silver sulfadiazine.

Confirmation of 13 sulfonamides in honey by liquid chromatography–tandem mass spectrometry for monitoring plans: Validation according to European Union Decision 2002/657/EC

A rapid and reliable liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous confirmation of 13 sulfonamides in honey was developed and fully validated in accordance with the European Commission Decision No 2002/657/EC. The validation scheme was built in accordance with the target level of 50μgkg−1 for all analytes. The sulfonamides investigated were as follows: sulfaguanidine (SGN), sulfanilamide (SNL), sulfadiazine (SDZ), sulfathiazole (STZ), sulfamerazine (SMR), sulfamethizole (SMZ), sulfadimerazine (SDM), sulfamonomethoxine (SMNM), sulfamethoxypiridazine (SMP), sulfadoxine (SDX), sulfamethoxazole (SMX), sulfaquinoxaline (SQX) and sulfadimethoxine (SDT). Several extraction procedures were investigated during the development phase. Finally, the best results were obtained with a procedure using acidic hydrolysis and cation exchange purification. Chromatographic separation was achieved on a C18 analytical column. Matrix effects were also investigated. Data acquisition implemented for the confirmatory purpose was performed by monitoring 2 MRM transitions per analyte under the positive electrospray mode. Mean relative recoveries ranged from 85.8% to 110.2% and relative standard deviations lying between 2.6% and 19.8% in intra-laboratory reproducibility conditions. The decision limits (CCα) ranged from 1.8 to 15.5μgkg−1. High resolution mass spectrometry was used to investigate the possible formation of sulfonamide metabolites in honey. The validation results proved that the method is suitable for the screening and confirmatory steps as implemented for the French monitoring residue plan for sulfonamides residue control in honeybees.

New spectrophotometric methods for the determination of sulfadoxine by the formation of Co(II) complexes

New sensitive spectrophotometric methods are developed for the determination of sulfadoxine (SFD). Proposed methods are based on the reaction of drug with aryl aldehyde followed by Co(II) chloride in the acidic medium. The reaction of aryl aldehyde with drug results in the formation of Schiff base which acts as a ligand for the formation of complex with Co(II). Different aryl aldehydes are tested, out of which p-dimethylaminobenzaldehyde (used in method A) and vanillin (used in method B) gave stable green colored complexes. The complexes formed due to p-dimethylaminobenzaldehyde and vanillin are measured at 672 and 665nm for method A and method B, respectively. The molar absorptivity and Sandell’s sensitivity of method A and method B are 0.1264×104, 0.2453 and 0.6982×104, 0.4444, respectively. The optical reaction condition and their analytical parameters are evaluated. Both the methods are free from interference of the ingredients such as lactose, sucrose and starch, thus it is successfully applied to pharmaceutical formulations.

Validated HPTLC Method for Simultaneous Analysis of Pyrimethamine and Sulphadoxine in Pharmaceutical Dosage Forms

A simple, specific, precise, and accurate HPTLC method for analysis of pyrimethamine (PYR) and sulphadoxine (SUL) both in bulk drugs and tablet formulation was developed and validated. The method uses haloperidol as an internal standard (IS). Chromatography was performed on TLC plates with precoated silica gel 60F254 using chloroform‐n‐butanol‐acetone (6 : 1.5 : 2, v/v/v) as a mobile phase. Densitometric evaluation was performed at 254 nm. The RF values were 0.27 for PYR, 0.63 for IS, and 0.75 for SUL. Linear regression analysis data for calibration plots revealed good linearity over the concentration ranges 100–500 ng per band for PYR and 2000–10000 ng per band for SUL. The method was validated for linearity, accuracy (from 98.12 to 101.24%), precision, robustness, and specificity in accordance with ICH guidelines. The limits of detection and quantification for PYR were 14.15 and 43.07 ng per band; for SUL, 58.37 and 152.26 ng per band, respectively. Statistical analysis showed the method enables repeatable and selective simultaneous analysis of these drugs in tablet formulation and routine quality control of the bulk drug raw material.

Pharmacokinetic Disposition of Sulfadoxine in Children with Acute Uncomplicated Falciparum Malaria Treated with Sulfadoxine–Pyrimethamine in South West Nigeria

Sulfadoxine (SDX)-pyrimethamine is currently recommended as a partner drug with artesunate in the chemotherapy of malaria. However, information on pharmacokinetic disposition of SDX-pyrimethamine in children is limited. Efforts in this study were thus devoted to evaluation of pharmacokinetic disposition of SDX using high-pressure liquid chromatographic techniques and effects of pharmacokinetic variability on treatment outcome in Nigerian children with falciparum malaria. The blood concentration profile of SDX was similar in patients whose infection responded to treatment and those who failed treatment; mean SDX concentration values were similar for day 3 (179 vs 157 μg/mL, P = 0.734), day 7 (84 vs 51 μg/mL, P = 0.365), and day 14 (50 vs 14 μg/mL, P = 0.151). Extent of exposure (area under the curve) to SDX was also similar in the patients (1196 vs 1013 μg d/mL, P = 0.561). Pearson's correlation, showed significant correlation between area under the curve and D3 or D7 concentration of SDX (P = 0.001, r = 0.702 or P = 0.001, r = 0.835, respectively). Age-stratified analysis showed that SDX concentrations were significantly higher in older children (older than 5 years); the mean maximum concentration (125 vs 295 μg/mL, P = 0.001), extent of exposure (812 vs 1562 μg d/mL, P = 0.001), day 3 concentration (98 vs 250 μg/mL, P = 0.001), and day 7 concentration (54 vs 128 μg/mL, P = 0.007) were higher. The study revealed no differences in posttreatment blood SDX concentrations in patients who responded to treatment and those who failed to respond to treatment. Furthermore, there was an age-related pharmacokinetic variability of SDX in the group of children studied with potential impact on treatment outcome.

Evaluation of dihydrofolate reductase and dihydropteroate synthetase genotypes that confer resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum in Haiti

BackgroundMalaria caused by Plasmodium falciparum infects roughly 30,000 individuals in Haiti each year. Haiti has used chloroquine (CQ) as a first-line treatment for malaria for many years and as a result there are concerns that malaria parasites may develop resistance to CQ over time. Therefore it is important to prepare for alternative malaria treatment options should CQ resistance develop. In many other malaria-endemic regions, antifolates, particularly pyrimethamine (PYR) and sulphadoxine (SDX) treatment combination (SP), have been used as an alternative when CQ resistance has developed. This study evaluated mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes that confer PYR and SDX resistance, respectively, in P. falciparum to provide baseline data in Haiti. This study is the first comprehensive study to examine PYR and SDX resistance genotypes in P. falciparum in Haiti.MethodsDNA was extracted from dried blood spots and genotyped for PYR and SDX resistance mutations in P. falciparum using PCR and DNA sequencing methods. Sixty-one samples were genotyped for PYR resistance in codons 51, 59, 108 and 164 of the dhfr gene and 58 samples were genotyped for SDX resistance codons 436, 437, 540 of the dhps gene in P. falciparum.ResultsThirty-three percent (20/61) of the samples carried a mutation at codon 108 (S108N) of the dhfr gene. No mutations in dhfr at codons 51, 59, 164 were observed in any of the samples. In addition, no mutations were observed in dhps at the three codons (436, 437, 540) examined. No significant difference was observed between samples collected in urban vs rural sites (Welch’s T-test p-value = 0.53 and permutations p-value = 0.59).ConclusionThis study has shown the presence of the S108N mutation in P. falciparum that confers low-level PYR resistance in Haiti. However, the absence of SDX resistance mutations suggests that SP resistance may not be present in Haiti. These results have important implications for ongoing discussions on alternative malaria treatment options in Haiti.

Novel coupling reactions of phytochemicals with sulfa drugs and their applications in the determination of nitrite at trace level in environmental samples

Twelve spectrophotometric methods based on new reactions for the determination of trace amounts of nitrite in environmental samples were developed. Replacement of toxic reagents was explored to attain the standards of clean chemistry. These methods utilize two classes of compounds namely; phytochemicals and sulfonamides, in the presence of limited amounts of sodium hydroxide. The methods were based on the oxidation of sulfanilamide (SAA), sulfadoxine (SDX), sulfamethoxazole (SMX) or sulfadiazine (SDZ) by nitrite in sodium hydroxide medium and coupling with cardol, cardanol or anacardic acid which yielded yellow, orange and orange red color derivatives having an absorbance maximum in the range 430, 460 and 470nm, respectively. The colors developed were stable for about 3h. Beer’s law was obeyed for nitrite in the concentration range 0.08–0.90, 0.16–1.04, 0.08–0.80 and 0.08–0.80μgml−1 for cardol; 0.80–4.40, 1.60–5.72, 0.52–5.20 and 0.80–4.40μgml−1 for cardanol and 0.80–5.70, 1.04–6.20, 1.30–5.20 and 0.80–4.00μgml−1 for anacardic acid, respectively. The reaction conditions and other important analytical parameters were optimized to enhance the sensitivity of the methods. Interference if any, by non-target ions was also investigated. The methods were applied determining nitrite in environmental samples. The performances of these methods were evaluated in terms of Student’s t-test and variance ratio F-test to find out the significance of the proposed methods over the reference spectrophotometric method.

Population Pharmacokinetics of Sulfadoxine and Pyrimethamine in Malawian Children With Malaria

In addition to parasite resistance, inadequate levels of exposure to antimalarial drugs may contribute to treatment failure. We developed population pharmacokinetic (PK) models to describe the distribution of sulfadoxine (SDX) and pyrimethamine (PYM) in children with uncomplicated malaria in Malawi. The concentration levels of antimalarial drugs in whole blood were determined using high-performance liquid chromatography. We found no evidence of underdosing in children as compared with adults; the children had drug exposure levels similar to those described in adults. Treatment failure was more likely in children with lower PYM concentrations on day 14 (P = 0.024), and there was a trend for lower SDX concentrations on day 14 (P = 0.061). SDX and PYM concentrations at levels predictive of treatment failure have been identified at day 14. Less than one-third of the children displayed drug concentration levels above these thresholds after receiving the recommended SDX-pyrimethamine (SP) dose. Our findings suggest that PK factors contributed to the observed high rate of treatment failure, and we therefore recommend a higher SP dose for children under the age of 5 years.

Spectroscopic and thermal investigations of charge-transfer complexes formed between sulfadoxine drug and different types of acceptors

Charge-transfer reactions between sulfadoxine (SDOX) as a donor with iodine (I 2), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), p-chloranil (CHL) and picric acid (PA) have been studied in solid and solution forms. The stoichiometry of all complexes was found to be 1:1 by molar ratio method between donor and acceptor at a CT-band absorption bands. The data are discussed in terms of formation constant ( K CT), molar extinction coefficient ( ε CT), standard free energy (Δ G o), oscillator strength (ƒ), transition dipole moment ( μ), resonance energy ( R N) and ionization potential ( I D). The results indicate that the formation constant ( K CT) for the complexes were shown to be dependent upon the nature of electron acceptor, donor and polarity of solvents which were used. IR, 1H NMR and UV–Vis spectroscopic techniques, Elemental analyses (CHN) and TG–DTG investigation were used to characterize the four sulfadoxine charge-transfer complexes.

Haematological changes and recovery associated with treated and untreated Plasmodium falciparum infection in children in the Mount Cameroon Region

Pre-hospital antimalarial treatment of febrile children remains a significant common practice among individuals in the Mount Cameroon region. To evaluate the effect of routinely administered monotherapy sulphadoxine pyrimethamine (SP), treatment using amodiaquine artesunate (AQAS) combination therapy and untreated malaria on haematological and parasitological parameters, 332 malaria positive subjects were assigned to three groups comprising 138 children treated with AQAS, 43 treated with SP and 151 untreated. The changes and recovery in red cell indices, white blood cell and differential and platelets counts were compared. The highest haematological recovery (39.1%) occurred in the AQAS treatment group. The majority (94%) of the untreated cases never achieved haematological recovery even though there was spontaneous clearance of parasites in some cases. Haematological insult was greatest in untreated children followed by those treated with SP, the 1.1 - 3 year age group whether or not they received treatment and in those with high parasitaemia. Delayed parasite clearance observed in the untreated and SP treatment group may be responsible for the occurrence of haematological insult. Treatment type and parasitological cure was associated with haematological recovery. Prompt use of effective arthemisinin combination therapy reduced the burden of malaria, hence the greater clinical and haematological benefits observed in our study. Key words: Malaria, children, anaemia, haemoglobin, treatment, haematological recovery.

The effect of intermittent preventive treatment using sulphadoxine pyrimethamine in the control of malaria in pregnancy: A cross-sectional study in the Offinso district of Ghana

Malaria infection during pregnancy causes maternal anaemia and placental parasitaemia both of which pose substantial risks to the mother, the foetus and the newborn. This study assessed the effects of intermittent preventive treatment (IPTp) using sulphadoxine-pyrimethamine (SP) to control malaria in pregnancy in the Offinso district, Ghana. Pregnant women attending antenatal clinics (ANC) between October 2005 and June 2006 in five health facilities in the District were studied. The effects of SP on parasitaemia, haemoglobin level and adverse effects on pregnant women were assessed. Of the 444 pregnant women studied, 190 (43%) took SP. The influence of SP intake on malaria infection was insignificant (r = 0.0008, p = 0.986). However, there was a tendency towards reduced parasitaemia as number of SP doses increased; one dose: 29/82 (35%), two doses: 18/57 (32%) and three doses: 11/57 (22%). The mean Hb level (10.4 ± 1.69 g/dl) for the SP group (all doses combined) was significantly higher than that (9.9 ± 1.64 g/dl) in the no SP group (p = 0.002). Further, there was a significant association between IPTp using SP and haemoglobin level (p = 0.01) with a dose-response relationship. SP usage had no significant adverse effects on the pregnant women. Effective implementation of IPTp using SP is an evidence-based measure for control of malaria-related anaemia in pregnancy. Key words: Malaria, intermittent preventive treatment, pregnant women, sulphadoxine-pyrimethamine.

Trimethoprim and Sulphadoxine in Swine

Summary In experiments on swine it was found that the half-lives for trimethoprim and sulphadoxine are 2 hours and 8 hours, respectively. The apparent volume of distribution is about 1.5 for trimethoprim and 0.3 for sulphadoxine. These parameters are the same whether trimethoprim and sulphadoxine are given alone or in combination. The concentrations of thesedrugs in tissues 2 hours after administration are for trimethoprim equal to or higher than in plasma while the concentrations of sulphadoxine in tissues are lower than in plasma. Zusammenfassung Das Verhalten von Trimethoprim und Sulphadoxin beim Schwein Halbwertszeit, scheinbares Verteilungsvolumen und Gewebskonzentrationen Die Halbwertszeiten von Trimethoprim und Sulphadoxin betragen beim Schwein 2 bzw. 8 Stunden. Die scheinbaren Verteilungsvolumina (Verhältnis Verteilungsvolumen: Körpergewicht) betragen etwa 1,5 für Trimethoprim und 0,3 für Sulphadoxin. Die Parameter sind die gleichen, ungeachtet dessen, ob die Wirkstoffe allein oder kombiniert verabreicht werden. Zwei Stunden nach der Verabreichung ist die Konzentration von Trimethoprim in den Geweben gleich groß oder höher als im Plasma, während die Sulphadoxinkonzentration in den Geweben geringer ist als im Plasma. Résumé Comportement du Trimethoprim et de Sulphadoxin chez le porc Temps moyen d'activité, volume de répartition apparent et concentrations dans les tissus Le temps moyen d'activité du Trimethoprim et de Sulphadoxin est de 2 et 8 heures chez le porc. Les volumes de répartition apparents (rapport volume de répartition/poids corporel) sont d'environ 1,5 pour le Trimethoprim et 0,3 pour Sulphadoxin. Les paramètres sont les mêmes indépendamment du fait que les substances sont administrées individuellement ou ensemble. La concentration du Trimethoprim est égale ou plus élevée dans les tissus que dans le plasma deux heures après l'administration, alors que la concentration de Sulphadoxin est plus faible dans les tissus que dans le plasma. Resumen Porte de la trimetoprima y sulfadoxina en el cerdo Tiempo semivalor, volumen aparente de distribución y concentraciones hísticas Los tiempos semivalor de trimetoprima y sulfadoxina son en el cerdo del orden de 2 resp. 8 horas. Los volúmenes aparentes de distribución (relación volumen de distribución: peso corporal) ascienden a 1,5 aprox. para trimetoprima y 0,3 para sulfadoxina. Los parámetros son los mismos, dando lo mismo el que los principios activos se administren solos o en combinación. Dos horas después de la aplicación es la concentración de trimetoprima en los tejidos igual de grande o mayor que en el plasma, mientras que la concentración de sulfadoxina es menor en los tejidos que en el plasma.

Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women

To determine the pharmacokinetic disposition of sulfadoxine (SDOX) and pyrimethamine (PYR) when administered as intermittent presumptive treatment during pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were given a single dose of 1,500 mg of SDOX plus 75 mg of pyrimethamine PYR. Blood was taken at baseline and 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h and at 7, 10, 14, 28, and 42 days posttreatment in all women. Plasma samples were assayed for SDOX, N-acetylsulfadoxine (NASDOX), and PYR by high-performance liquid chromatography. Population pharmacokinetic modeling was performed using NONMEM v6.2.0. Separate user-defined mamillary models were fitted to SDOX/NASDOX and PYR. When the covariate pregnancy was applied to clearance, there was a significant improvement in the base model for both treatments. Pregnancy was associated with a significantly lower area under the concentration-time curve from 0 to infinity for SDOX (22,315 versus 33,284 mg x h/liter), NASDOX (801 versus 1,590 mg x h/liter), and PYR (72,115 versus 106,065 microg x h/liter; P < 0.001 in each case). Because lower plasma concentrations of SDOX and PYR could compromise both curative efficacy and posttreatment prophylaxis in pregnant patients, IPTp regimens incorporating higher mg/kg doses than those recommended for nonpregnant patients should be considered.

Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen

* Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria. * The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults. * No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria. * This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria. * The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor. * The study proposes dose modification to improve response with the CQ + SDx/PYR combination. To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination. Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 microl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis. A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (V(C)/F) values were estimated to be 2.84 l h(-1) and 230 l. The typical CL/F for SDx was 0.023 l h(-1), while the factor relating its V(C)/F to normalized body weight was 1.6 l kg(-1). Post hoc parameter estimates for both drugs showed lower maximum concentrations (C(max)) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome. The study results suggest that full-strength combination to all children would improve the cure rate.

Pregnancy appears to affect the pharmacokinetics of sulfadoxine, but not necessarily pyrimethamine,

Pregnancy appears to affect the pharmacokinetics of sulfadoxine, but not necessarily pyrimethamine,

Simple Multiresidue Method for Monitoring of Trimethoprim and Sulfonamide Residues in Buffalo Meat by High-Performance Liquid Chromatography

A simple, specific, and rapid analytical method for the determination of trimethoprim (TMP) and three sulfonamide (SA) antimicrobial drug residues in buffalo meat is developed and validated. This method is based on a solid-phase extraction technique followed by high-performance liquid chromatography (HPLC)-photodiode array (PDA) detection. Target compounds were extracted from the meat by acetonitrile and water, cleaned up on a Bond Elute C 18 cartridge column, and separated on a RP-C 18 column during HPLC analysis. Acetonitrile along with water appears to be an excellent extractant as recovery of the analytes at maximum residues levels (MRLs) in spiked sample was in the range of 75-108%, with coefficient of variations (CVs) ranging between 1.34 and 22%. The limit of detection (LOD) and the limit of quantification (LOQ) were 0.031 and 0.062 microg/g, respectively, for all of the compounds. Intra- and interday assay precisions of the method at 0.125 microg/g concentrations for any drug ranged between 3 and 4%. The linearities of the TMP, sulfadimidine (SDM), sulfadoxine (SDO), and sulfamethoxazole (SMX) were 0.9989, 0.9999, 0.9998, and 0.9997, respectively. For robustness, the analytical method was applied to 122 buffalo meat samples obtained from export meat processing plants.

Molecular analysis of chloroquine resistance in Plasmodium falciparum in Yunnan Province, China

Resistance of Plasmodium falciparum to chloroquine (CQ) is determined by the mutation at K76T of the P. falciparum chloroquine resistance transporter (pfcrt) gene and modified by other mutations in this gene and in the P. falciparum multidrug resistance 1 (pfmdr1) gene. To determine the extent of polymorphisms in these genes in field P. falciparum isolates from Yunnan province of China, we genotyped the pfcrt codon 76, pfmdr1 codons 86 and 1246. Our results showed that although CQ has been withdrawn from treating falciparum malaria for over two decades, 90.3% of the parasites still carried the pfcrt K76T mutation. In contrast, mutations at pfmdr1 codons 86 and 1246 were rare. Sequencing analysis of the pfcrt gene in 34 parasite field isolates revealed CVIET at positions 72-76 as the major type, consistent with the theory of Southeast Asian origin of CQ resistance in the parasite. In addition, two novel pfcrt haplotypes (75D/144Y/220A and 75E/144Y/220A) were identified. Real-time polymerase chain reaction was used to determine pfmdr1 gene amplification, which is associated with mefloquine resistance. Our result indicated that in agreement with that mefloquine has not been used in this area, most (>90%) of the parasites had one pfmdr1 copy. Genotyping at two hypervariable loci showed relatively low levels of genetic diversity of the parasite population. Meanwhile, 28.4% of cases were found to contain mixed clones, which favour genetic recombination. Furthermore, despite a unique history of antimalarial drugs in Yunnan, its geographical connections with three malarious countries facilitate gene flow among parasite populations and evolution of novel drug-resistant genotypes. Therefore, continuous surveillance of drug resistance in this area is necessary for timely adjustment of local drug policies and more effective malaria control.

Lack of impact of artesunate on the disposition kinetics of sulfadoxine/pyrimethamine when the two drugs are concomitantly administered

To determine the effect of artesunate (AT) on the disposition kinetics of sulfadoxine/pyrimethamine (SP) in humans. In a randomized cross-over study, 16 healthy volunteers were given a dose of three SP tablets containing 500 mg of sulfadoxine (SDX) and 25 mg of pyrimethamine (PYR) (=SP group), while the second arm received three SP tablets + two AT tablets of 200 mg in total followed by 100 mg AT for the next 4 days (SP+AT group). Blood samples (100 microl) were collected by means of a finger prick and dried on filter paper. The blood spots were wrapped in polythene folders and stored at room temperature until analysis. The samples were assayed using high-performance liquid chromatographic methods. The peak concentration C(max)), time required to attain peak concentration (T(max)), half-life (t ((1/2))) and area under the plasma concentration-time curve (AUC) were determined. The C(max) of SDX were 92.9 and 98.9 microg/ml for the SP and SP+AT arms, respectively; for PYR, these were 0.86 and 0.79 microg/ml, respectively. The T(max) of SDX were 10 and 8 h for the SP and SP+AT arms, respectively; for PYR, these were 4.0 and 3.0 h, respectively. The AUC(0-288) of SDX were 15,840 and 18,876 microg/ml h for the SP and SP+AT arms, respectively; for PYR, they were 124 and 112 microg/ml h, respectively. The t ((1/2)) of values for SDX were 165 and 180 h for the SP and SP+AT arms, respectively; for PYR, these were 158 and 177 h, respectively. There was no statistically significant difference between the C(max), T(max), AUC(0-288) and t ((1/2)) between the two arms (p > 0.05). Taking AT concomitantly with SP does not have any impact in the disposition of SP.