RESUMEN
Endogenous biomarkers are emerging to advance clinical drug-drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates (creatinine and N1 -methylnicotinamide (1-NMN)), N1 -methyladenosine (m1 A) was included as novel biomarkers. 1-NMN and m1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CLr ) along with pyrimethamine dose were well-correlated with metformin CLr changes. The CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki ) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1-NMN) and MATE2-K (1-NMN and m1 A). It is concluded that 1-NMN and m1 A CLr can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.
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Biomarcadores/metabolismo , Interacciones Farmacológicas/fisiología , Proteínas de Transporte de Catión Orgánico/metabolismo , Adulto , Pueblo Asiatico , Línea Celular , Creatinina/metabolismo , Estudios Cruzados , Células HEK293 , Voluntarios Sanos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/metabolismo , Riñón/metabolismo , Masculino , Metformina/uso terapéutico , Pirimetamina/administración & dosificación , Pirimetamina/sangre , Pirimetamina/metabolismo , Medición de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Dosing recommendations for the treatment of pregnancy-acquired toxoplasmosis are empirical and widely based on experimental data. There are no pharmacological data on pregnant women with acute Toxoplasma gondii infection under treatment with pyrimethamine (PY) and sulfadiazine (SA) and our study intends to tighten this gap. METHODS: In this retrospective case-control study, we included 89 pregnant women with primary Toxoplasma infection (PT) treated with PY (50 mg first dose, then 25 mg/day), SA (50 mg/kg of body weight/day), and folinic acid (10-15 mg per week). These were compared to a group of 17 women with acute ocular toxoplasmosis (OT) treated with an initial PY dose of 75 mg, thereafter 25 mg twice a day but on the same SA and folinic acid regimen. The exact interval between drug intake and blood sampling and co-medication had not been recorded. Plasma levels of PY and SA were determined 14 ± 4 days after treatment initiation using liquid chromatography-mass spectrometry and compared using the Mann-Whitney U test at a p < 0.05 level. RESULTS: In 23 PT patients (26%), SA levels were below 20 mg/l. Fifteen of these 23 patients (17% of all patients) in parallel presented with PY levels below 700 µg/l. Both drug concentrations differed remarkably between individuals and groups (PY: PT median 810 µg/l, 95% CI for the median [745; 917] vs. OT 1230 µg/l [780; 1890], p = 0.006; SA: PT 46.2 mg/l [39.9; 54.4] vs. OT 70.4 mg/l [52.4; 89], p = 0.015) despite an identical SA dosing scheme. CONCLUSIONS: SA plasma concentrations were found in the median 34% lower in pregnant women with PT compared to OT patients and fell below a lower reference value of 50 mg/l in a substantial portion of PT patients. The interindividual variability of plasma concentrations in combination with systematically lower drug levels and possibly a lower compliance in pregnant women may thus account for a still not yet supportable transmission risk. Systematic drug-level testing in PT under PY/SA treatment deserves to be considered.
Asunto(s)
Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Pirimetamina/uso terapéutico , Sulfadiazina/uso terapéutico , Toxoplasma/efectos de los fármacos , Toxoplasmosis Ocular/tratamiento farmacológico , Toxoplasmosis/tratamiento farmacológico , Adolescente , Adulto , Antiprotozoarios/sangre , Antiprotozoarios/uso terapéutico , Estudios de Casos y Controles , Quimioterapia Combinada , Femenino , Humanos , Embarazo , Complicaciones Parasitarias del Embarazo/parasitología , Pirimetamina/sangre , Estudios Retrospectivos , Sulfadiazina/sangre , Toxoplasma/fisiología , Toxoplasmosis/parasitología , Toxoplasmosis Ocular/parasitología , Resultado del Tratamiento , Adulto JovenRESUMEN
Despite the clinically proven advantages of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), utilisation has been low in many African countries. To increase uptake and achieve the desired effect, the World Health Organization revised the policy to a monthly administration. Assessing the coverage and impact of the revised policy on pregnancy and neonatal outcomes is, therefore, a necessity. A 2-parallel cross-sectional hospital-based study was carried out among pregnant women attending first antenatal care (ANC) and delivery. Maternal and cord blood samples were assayed for malaria parasites by quantitative PCR targeting both the 18S rDNA and the acidic terminal segment of Plasmodium falciparum var genes, and plasma SP levels were measured by liquid chromatography coupled to tandem mass spectrometry. Parasite prevalence was similar between the two study sites but decreased significantly between the first ANC (9% or 43%) and delivery (4% or 11%) based on the qPCR target. At delivery, 64.5% of women received ≥3 IPTp-SP dose, 15.5% received 2 doses and 6% had 1 dose. Taking ≥3 IPTp-SP doses was associated with an average birth weight increase of more than 0.165 kg. IPTp-SP uptake was associated with plasma SP level at delivery (OR = 32.3, p ≤ 0.005, 95% CI (13.3;78.4) for those that reported ≥3 IPTp-SP doses) while the same trend of improved birth weight was observed with high plasma SP levels. The new IPTp policy is well implemented and well utilised by women in the sites considered in this study and translates to the improved birth weight observed. This study confirms the interest and the clinical benefit expected from this policy change.
Asunto(s)
Peso al Nacer/fisiología , Malaria/prevención & control , Complicaciones Parasitarias del Embarazo/prevención & control , Adolescente , Adulto , Estudios de Cohortes , Combinación de Medicamentos , Femenino , Ghana/epidemiología , Humanos , Modelos Lineales , Malaria/sangre , Malaria/tratamiento farmacológico , Malaria/epidemiología , Persona de Mediana Edad , Análisis Multivariante , Plasmodium falciparum , Embarazo , Complicaciones Parasitarias del Embarazo/sangre , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Complicaciones Parasitarias del Embarazo/epidemiología , Prevalencia , Pirimetamina/sangre , Pirimetamina/uso terapéutico , Sulfadoxina/sangre , Sulfadoxina/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: The intermittent preventive treatment in infants (IPTi) trial that took place in Papua New Guinea showed an overall reduction of 29% of the risk of malaria when delivering single-dose sulfadoxine-pyrimethamine (SP) associated to 3 days of amodiaquine (AQ) every three months to children during the first year of life. The aim of the present study was to assess if the last two doses of AQ were truly administered as prescribed by the parents at home based on drug level measurement and PK modelling, which is a good proxy of medication adherence. It provides also important information to discuss the efficacy of the intervention and on feasibility of self-administered preventive malaria treatment. METHODS AND FINDINGS: During the three-arm randomized double-blinded IPTi trial, each child was prescribed one dose of SP (day 0) and 3 doses of either AQ or artesunate (AS) at day 0, 1 & 2 adjusted to weight or placebo. Treatments were given at 3, 6, 9 and 12 months of age. The first day of treatment was delivered by nursing staff (initiation under directly observed treatment (DOT)) and the two last doses of AQ or AS by parents at home without supervision. For this cross-sectional study, 206 consecutive children already involved in the IPTi trial were enrolled over a 2-month period. At the time of the survey, allocation of the children to one of the three arms was not known. Blood samples for drug level measurement were collected from finger pricks one day after the planned last third dose intake. Only children allocated to the SP-AQ arm were included in the present analysis. Indeed, the half-life of AS is too short to assess if drugs were given on not. Because of the short half-life of AQ, desethyl-AQ (metabolite of AQ (DAQ)) measurements were used to investigate AQ medication adherence. Two PK (PK) models from previously published studies in paediatric populations were applied to the dataset using non-linear mixed effect modelling (NONMEM) to estimate the number of doses really given by the parents. The study nurse reported the administration time for the first AQ dose while it was estimated by the parents for the remaining two doses. Out of 206 children, 64 were in the SP-AQ arm. The adjusted dosing history for each individual was identified as the one with the lowest difference between observed and individual predicted concentrations estimated by the two PK models for all the possible adherence schemes. The median (range) blood concentration AQ in AQ arm was 9.3 ng/mL (0-1427.8 ng/mL), (Quartiles 1-3: 2.4 ng/mL -22.2 ng/mL). The median (range) for DAQ was 162.0 ng/mL (0-712 ng/mL), (Quartiles 1-3: 80.4 ng/mL-267.7 ng/mL). Under the assumption of full adherence for all participants, a marked underprediction of concentrations was observed using both PK models. Our results suggest that only 39-50% of children received the three scheduled doses of AQ as prescribed, 33-37% two doses and 17-24% received only the first dose administered by the study nurse. Both models were highly congruent to classify adherence patterns. CONCLUSIONS: Considering the IPTi intervention, our results seem to indicate that medication adherence is low in the ideal trial research setting and is likely to be even lower if given in day-to-day practice, questioning the real impact that this intervention might have. More generally, the estimation of the number of doses truly administered, a proxy measure of adherence and an assessment of the feasibility of the mode of administration, should be more thoroughly studied when discussing the efficacy of the interventions in trials investigating self-administered malaria preventive treatments.
Asunto(s)
Antimaláricos/administración & dosificación , Malaria/prevención & control , Cumplimiento de la Medicación/estadística & datos numéricos , Pirimetamina/administración & dosificación , Autoadministración/estadística & datos numéricos , Sulfadoxina/administración & dosificación , Antimaláricos/sangre , Estudios Transversales , Combinación de Medicamentos , Estudios de Factibilidad , Femenino , Humanos , Lactante , Malaria/epidemiología , Masculino , Papúa Nueva Guinea/epidemiología , Padres , Pirimetamina/sangre , Pirimetamina/farmacocinética , Sulfadoxina/sangre , Sulfadoxina/farmacocinéticaRESUMEN
Antimalarial drug combination therapy is now being widely used for the treatment of uncomplicated malaria. The objective of the present study was to investigate the effects of coadministration of intramuscular α/ß-arteether (α/ß-AE) and oral sulfadoxine-pyrimethamine (SP) on the pharmacokinetic properties of each drug as a drug-drug interaction study to support the development of a fixed-dose combination therapy. A single-dose, open-label, crossover clinical trial was conducted in healthy adult Indian male volunteers (18 to 45 years, n = 13) who received a single dose of AE or SP or a combination dose of AE and SP. Blood samples were collected up to 21 days postadministration, and concentrations of α-AE, ß-AE, sulfadoxine, and pyrimethamine were determined by using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and statistically analyzed to calculate the geometric mean ratio and confidence interval. Following single-dose coadministration of intramuscular AE and oral SP, the pharmacokinetic properties of α/ß-AE were not significantly affected, and α/ß-AE had no significant effect on the pharmacokinetic properties of SP in these selected groups of healthy volunteers. However, more investigations are needed to explore this further. (This study has been registered in the clinical trial registry of India under approval no. CTRI/2011/11/002155.).
Asunto(s)
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Pirimetamina/farmacocinética , Sulfadoxina/farmacocinética , Adolescente , Adulto , Antimaláricos/sangre , Antimaláricos/uso terapéutico , Artemisininas/sangre , Artemisininas/uso terapéutico , Cromatografía Liquida , Combinación de Medicamentos , Interacciones Farmacológicas/fisiología , Voluntarios Sanos , Humanos , Malaria Falciparum/parasitología , Masculino , Persona de Mediana Edad , Pirimetamina/sangre , Pirimetamina/uso terapéutico , Sulfadoxina/sangre , Sulfadoxina/uso terapéutico , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effects modeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight and hematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold for sulfadoxine but decreased by 18% for pyrimethamine. Postpartum sulfadoxine clearance decreased gradually over 13 weeks. This finding, together with hematocrit-based scaling of plasma to whole-blood concentrations and allometric scaling of pharmacokinetics parameters with body weight, enabled site-specific differences in the pharmacokinetic profiles to be reduced significantly but not eliminated. Further research is necessary to explain residual site-specific differences and elucidate whether dose-optimization, to address the 3-fold increase in clearance of sulfadoxine in pregnant women, is necessary, viable, and safe with the current fixed dose combination of sulfadoxine/pyrimethamine.
Asunto(s)
Antimaláricos/farmacocinética , Modelos Biológicos , Pirimetamina/farmacocinética , Sulfadoxina/farmacocinética , Adulto , África , Antimaláricos/sangre , Antimaláricos/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Malaria/prevención & control , Periodo Posparto/sangre , Periodo Posparto/metabolismo , Embarazo/sangre , Embarazo/metabolismo , Pirimetamina/sangre , Pirimetamina/uso terapéutico , Sulfadoxina/sangre , Sulfadoxina/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVE: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1). METHODS: A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale-Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9. RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p < 0.001) with a mean reduction of 13.5% (95% confidence interval [CI] = 8.4-18.5) and at visit 9 (p < 0.001) with a mean reduction of 10.5% (95% CI = 5.2-15.8). INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. Ann Neurol 2017;81:837-848.
Asunto(s)
Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Antagonistas del Ácido Fólico/farmacología , Pirimetamina/farmacología , Índice de Severidad de la Enfermedad , Superóxido Dismutasa-1/líquido cefalorraquídeo , Superóxido Dismutasa-1/efectos de los fármacos , Adulto , Anciano , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/genética , Femenino , Antagonistas del Ácido Fólico/efectos adversos , Antagonistas del Ácido Fólico/sangre , Antagonistas del Ácido Fólico/líquido cefalorraquídeo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pirimetamina/efectos adversos , Pirimetamina/sangre , Pirimetamina/líquido cefalorraquídeo , Superóxido Dismutasa-1/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
A simple, sensitive, and rapid liquid chromatographic method was developed and validated using diode array detection for the determination of five commonly used antimalarial drugs in pharmaceutical formulations and in human plasma. Chromatographic separation of antimalarial drugs and internal standard (ibuprofen) was achieved on a C18 column with a mobile phase composed of 10 mM dipotassium orthophosphate at pH 3.0, methanol, and acetonitrile in a ratio of 20:38:42 v/v, at a flow rate of 1 mL/min. The analytes were monitored at 220 nm and separated in Ë10 min. The method was validated for linearity, accuracy, precision, limit of quantification, and robustness. Both intra- and interday precisions (in terms of %RSD) were lower than 3% and accuracy ranged from 98.1 to 104.5%. Extraction recoveries were ≥96% in plasma. The limits of quantitation for artemether, lumefantrine, pyrimethamine, sulfadoxine, and mefloquine were 0.3, 0.03, 0.06, 0.15, and 0.15 µg/mL in human plasma. Stability under various conditions was also investigated. The method was successfully applied for quantification of antimalarial drugs in marketed formulations and in spiked human plasma. The method can be employed for routine QC purposes and in pharmacokinetic investigations.
Asunto(s)
Antimaláricos/análisis , Artemisininas/análisis , Etanolaminas/análisis , Fluorenos/análisis , Mefloquina/análisis , Pirimetamina/análisis , Sulfadoxina/análisis , Antimaláricos/sangre , Arteméter , Artemisininas/sangre , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Etanolaminas/sangre , Fluorenos/sangre , Voluntarios Sanos , Humanos , Lumefantrina , Mefloquina/sangre , Pirimetamina/sangre , Reproducibilidad de los Resultados , Sulfadoxina/sangre , ComprimidosRESUMEN
BACKGROUND: Intermittent preventive treatment in infants (IPTi) is the administration of sulfadoxine-pyrimethamine (SP) at 2, 3, and 9 months of age to prevent malaria. We investigated the influence of IPTi on drug resistance. METHODS: Twenty-four areas were randomly assigned to receive or not receive IPTi. Blood collected during representative household surveys at baseline and 15 and 27 months after implementation was tested for SP and resistance markers. RESULTS: The frequency of SP in blood was similar in the IPTi and comparison areas at baseline and at 15 months. dhfr and dhps mutations were also similar at baseline and then increased similarly in both arms after 15 months of SP-IPTi. First-line treatment was switched from SP to artemether-lumefantrine before the final survey, when SP positivity fell among infants in comparison areas but increased in IPTi areas. This was accompanied by an increase in dhfr but not dhps mutations in IPTi areas (P = .004 and P = .18, respectively). CONCLUSIONS: IPTi did not increase drug pressure or the selection on dhfr and dhps mutants, when SP was the first-line malaria treatment. Introduction of artemether-lumefantrine was followed by an increase in dhfr mutations, consistent with weak selection attributable to SP-IPTi, but not by an increase in dhps mutations, suggesting a fitness cost of this mutation.
Asunto(s)
Antimaláricos/administración & dosificación , Esquema de Medicación , Resistencia a Medicamentos , Malaria/prevención & control , Malaria/parasitología , Plasmodium/efectos de los fármacos , Pirimetamina/administración & dosificación , Sulfadoxina/administración & dosificación , Antimaláricos/sangre , Antimaláricos/farmacología , Combinación de Medicamentos , Femenino , Humanos , Lactante , Masculino , Mutación , Péptido Sintasas/genética , Pirimetamina/sangre , Pirimetamina/farmacología , Selección Genética , Sulfadoxina/sangre , Sulfadoxina/farmacología , Tanzanía , Tetrahidrofolato Deshidrogenasa/genéticaRESUMEN
BACKGROUND: Sulfadoxine/pyrimethamine fixed-dose combination (FDC) tablet is the long-acting portion of the antimalaria product Artecospe(®), coblister containing artesunate tablets plus sulfadoxine/pyrimethamine FDC tablets. This study was conducted to support the efficacy and tolerability of the sulfadoxine/pyrimethamine FDC tablet in the World Health Organization's (WHO) Prequalification of Medicines Programme, as well as to obtain marketing authorization in China. OBJECTIVE: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and the branded reference formulation of sulfadoxine/pyrimethamine FDC tablets, and to assess the bioequivalence of the 2 products in healthy Chinese volunteers. METHODS: This single-dose, open-label, randomized, parallel-group study was conducted in healthy Chinese male volunteers who were randomly assigned (1:1) to receive a single 1500/75-mg dose (3 × 500/25-mg tablets) of either the test or reference formulation after a 12-hour overnight fast. Seventeen blood samples were obtained over a 168-hour interval, and plasma concentrations of sulfadoxine and pyrimethamine were determined by 2 separate validated liquid chromatography-isotopic dilution mass spectrometry methods. Pharmacokinetic properties (C(max), AUC(0-72), AUC(0-168), and T(max)) were calculated and analyzed statistically. The 2 formulations were to be considered bioequivalent if 90% CIs for the log-transformed ratios of C(max) and AUC(0-72) were within the predetermined bioequivalence range of 80% to 125%, in accordance with the guidelines of WHO and China's Food and Drug Administration (FDA). Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead ECGs, and subject interviews on adverse events (AEs). RESULTS: Forty-six healthy subjects completed the study. The mean values of sulfadoxine C(max) (183.07 and 165.15 mg/L), AUC(0-72) (11,036.52 and 10,536.78 mg/L/h), and AUC(0-168) (22,247.05 and 21,761.02 mg/L/h) were not significantly different between the test and reference formulations, respectively. The same was true for pyrimethamine (0.55 and 0.58 mg/L, 29.85 and 31.44 mg/L/h, and 56.18 and 59.27 mg/L/h, respectively). The 90% CIs for the log-transformed ratios of C(max), AUC(0-72), and AUC(0-168) of both sulfadoxine (105.4%-116.6%, 99.3%-110.6%, and 96.4%-108.1%) and pyrimethamine (88.8%-100.9%, 89.5%-101.0%, and 88.3%-101.6%) were within the acceptance limits for bioequivalence. A total of 7 mild AEs were reported in 7 subjects (15.2%). CONCLUSIONS: The findings from this single-dose (1500/75-mg) study suggest that the test and reference formulations of sulfadoxine/pyrimethamine FDC 500/25-mg tablet have similar pharmacokinetic profiles both in terms of rate and extent of absorption. The formulations met WHO's and China's FDA regulatory criteria for bioequivalence in these healthy Chinese volunteers under fasting conditions. Both formulations were generally well-tolerated.
Asunto(s)
Antimaláricos/farmacocinética , Pueblo Asiatico , Medicamentos Genéricos/farmacocinética , Pirimetamina/farmacocinética , Sulfadoxina/farmacocinética , Administración Oral , Adolescente , Adulto , Análisis de Varianza , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/sangre , Antimaláricos/química , Química Farmacéutica , Distribución de Chi-Cuadrado , China , Cromatografía Liquida , Combinación de Medicamentos , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Medicamentos Genéricos/química , Humanos , Técnicas de Dilución del Indicador , Modelos Lineales , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Modelos Biológicos , Pirimetamina/administración & dosificación , Pirimetamina/efectos adversos , Pirimetamina/sangre , Pirimetamina/química , Sulfadoxina/administración & dosificación , Sulfadoxina/efectos adversos , Sulfadoxina/sangre , Sulfadoxina/química , Comprimidos , Equivalencia Terapéutica , Adulto JovenRESUMEN
In Rwanda, frequent mutations in the pfdhfr and pfdhps genes of Plasmodium falciparum have suggested intense sulfadoxine-pyrimethamine resistance. However, data on pfmdr1 are not available but might be important in the context of the first-line treatment with artemether-lumefantrine. During a survey among 749 children under five years of age in southern highland Rwanda, 104 P. falciparum isolates were obtained. Parasite polymorphisms associated with drug sensitivity were typed including the genes pfdhfr, pfdhps, pfmdr1, and pfcrt. Plasma concentrations of chloroquine and pyrimethamine were measured by ELISA. Treatment with artemether-lumefantrine within the preceding two weeks was stated by 12.5% of the respondents; chloroquine in plasma was detected in 17.6%, pyrimethamine in none. Isolates with pfdhfr triple and pfdhps double/triple mutations occurred in 75% and 93%, respectively; 69% of the isolates comprised pfdhfr/pfdhps quintuple or sextuple mutations associated with high-grade sulfadoxine-pyrimethamine resistance. Pfdhfr L164 was absent. The pfmdr1 pattern revealed more than 50% of the F184 polymorphism and almost 40% of the N86-F184-D1246 allele combination known to be selected in infections reappearing following artemether-lumefantrine treatment. Molecular markers demonstrate intense antifolate drug resistance of P. falciparum in southern Rwanda. The present, first-time data on pfmdr1 alleles from Rwanda reveal a pattern which might reflect a predominance of wild types for some alleles or, alternatively, substantial artemether-lumefantrine pressure on the local parasite population.
Asunto(s)
Antimaláricos/farmacología , Resistencia a Medicamentos , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas Protozoarias/genética , Antimaláricos/sangre , Preescolar , Cloroquina/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Lactante , Malaria Falciparum/parasitología , Masculino , Mutación Missense , Plasmodium falciparum/aislamiento & purificación , Pirimetamina/sangre , RwandaRESUMEN
The study objective was to determine plasma concentration of pyrimethamine in 24 infants aged 1-5 months, treated for congenital toxoplasmosis. Pyrimethamine was used in a single daily dose at an amount of 0.35-0.98 mg/kg daily, with sulfadiazine (50-100 mg/kg/day) in divided doses 2-3 times a day, and folinic acid given twice a week (7.5 mg). This regimen was continued for 2-6 months, then Fansidar was administered. Pyrimethamine concentration in plasma was measured using high-performance liquid chromatography method (HPLC). A total of 70 tests were performed. Concentration of pyrimethamine ranged from 0.01 to 1.2 microg/ml. In 14 children (58 tests) the concentration of pyrimethamine achieved therapeutic value. In 7 patients (8 tests) the concentration was below therapeutic level, and in 3 patients (4 tests) above therapeutic level. In 11/24 (46%) children transient moderate neutropenia was observed. Modification of therapy was necessary in 12 patients. Monitoring of pyrimethamine concentration in plasma improves safety and effectiveness of the therapy and is useful in obtaining correct individual dose of the drug. Neutropenia is the most common side-effect of pyrimethamine observed even when using the recommended dose.
Asunto(s)
Antiprotozoarios/sangre , Pirimetamina/administración & dosificación , Pirimetamina/sangre , Toxoplasmosis Congénita/congénito , Toxoplasmosis Congénita/tratamiento farmacológico , Antiprotozoarios/administración & dosificación , Esquema de Medicación , Monitoreo de Drogas , Quimioterapia Combinada , Femenino , Humanos , Lactante , Leucovorina/administración & dosificación , Masculino , Sulfadiazina/administración & dosificación , Toxoplasmosis Congénita/sangreRESUMEN
Intermittent preventive treatment in infancy (IPTi) entails routine administration of antimalarial treatment doses at specified times in at-risk infants. Sulfadoxine-pyrimethamine (SDX/PYR) is a combination that has been used as first-line IPTi. Because of limited pharmacokinetic data and suggestions that higher milligram/kilogram pediatric doses than recommended should be considered, we assessed SDX/PYR disposition, randomized to conventional (25/1.25 mg/kg of body weight) or double (50/2.5 mg/kg) dose, in 70 Papua New Guinean children aged 2 to 13 months. Blood samples were drawn at baseline, 28 days, and three time points randomly selected for each infant at 4 to 8 h or 2, 5, 7, 14, or 21 days. Plasma SDX, PYR, and N(4)-acetylsulfadoxine (NSX, the principal metabolite of SDX) were assayed by high-performance liquid chromatography (HPLC). Using population modeling incorporating hepatic maturation and cystatin C-based renal function, two-compartment models provided best fits for PYR and SDX/NSX plasma concentration profiles. The area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) was greater with the double dose versus the conventional dose of PYR (4,915 versus 2,844 µg/day/liter) and SDX (2,434 versus 1,460 mg/day/liter). There was a 32% reduction in SDX relative bioavailability with the double dose but no evidence of dose-dependent metabolism. Terminal elimination half-lives (15.6 days for PYR, 9.1 days for SDX) were longer than previously reported. Both doses were well tolerated without changes in hemoglobin or hepatorenal function. Five children in the conventional and three in the double-dose group developed malaria during follow-up. These data support the potential use of double-dose SDX/PYR in infancy, but further studies should examine the influence of hepatorenal maturation in very young infants.
Asunto(s)
Antimaláricos/uso terapéutico , Malaria Falciparum/prevención & control , Pirimetamina/uso terapéutico , Sulfadoxina/uso terapéutico , Antimaláricos/sangre , Combinación de Medicamentos , Femenino , Humanos , Lactante , Recién Nacido , Malaria Falciparum/tratamiento farmacológico , Masculino , Pirimetamina/sangre , Sulfadoxina/análogos & derivados , Sulfadoxina/sangreRESUMEN
Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or ß subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ß-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy.
Asunto(s)
Gangliosidosis GM2/tratamiento farmacológico , Pirimetamina/uso terapéutico , Adulto , Pruebas de Enzimas , Femenino , Glucosilceramidasa/sangre , Hexosaminidasa A/sangre , Hexosaminidasa B/sangre , Humanos , Masculino , Persona de Mediana Edad , Pirimetamina/efectos adversos , Pirimetamina/sangre , Adulto Joven , beta-Galactosidasa/sangreRESUMEN
OBJECTIVE: To determine the relationship between mutations in dhfr and dhps and SP treatment failure in Plasmodium falciparum malaria in the Democratic Republic of the Congo (DRC). METHODS: Therapeutic efficacy trial was conducted in Rutshuru, Eastern DRC, between June and September 2002, comparing sulfadoxine-pyrimethamine (SP), SP plus amodiaquine (AQSP) and artesunate plus SP (ASSP) regimens for treating malaria in children under 5 years old. We genotyped 212 samples for mutations associated with SP resistance and investigated their association with treatment failure. RESULTS: In the SP arm, 61% of the subjects experienced treatment failure after 14 days. The failure rate was lower in the combination arms (AQSP: 32%, ASSP: 21%). The dhfr-108 and dhfr-51 mutations were nearly universal while 89% of the samples had at least one additional mutation at dhfr-59, dhps-437 or dhps-540. Dhps mutations had a bigger impact on treatment failure in children with high parasite density: for children with a parasite density <45 000 parasites/microl, the risk of treatment failure was 37% for mutations at dhps-437 and dhps-540 mutation and 21% for neither mutation [risk difference (RD) = 17%, 95% CI: -3%, 36%]. In children with a parasite density >45 000 parasites/microl, the treatment failure risk was 58% and 8% for children with both mutations or neither mutation, respectively (RD = 51%, 95% CI: 34%, 67%). CONCLUSIONS: Dhps-437 and dhps-540 are strongly associated with SP treatment failure and should be evaluated further as a method for surveillance of SP-based therapy in DRC.
Asunto(s)
Antimaláricos/uso terapéutico , Dihidropteroato Sintasa/genética , Malaria Falciparum/tratamiento farmacológico , Mutación Puntual/genética , Pirimetamina/uso terapéutico , Sulfadoxina/uso terapéutico , Tetrahidrofolato Deshidrogenasa/genética , Amodiaquina/uso terapéutico , Antimaláricos/sangre , Artemisininas/uso terapéutico , Artesunato , Preescolar , República Democrática del Congo , Combinación de Medicamentos , Resistencia a Medicamentos/genética , Quimioterapia Combinada , Femenino , Marcadores Genéticos , Genotipo , Humanos , Lactante , Malaria Falciparum/genética , Masculino , Pirimetamina/sangre , Salud Rural , Sulfadoxina/sangre , Insuficiencia del TratamientoRESUMEN
We assessed the efficacy of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania, 3 years after their introduction as first- and second-line treatments for uncomplicated malaria, respectively. Under five children with uncomplicated malaria were given standard treatments of either SP (n=66) or AQ (n=30) and treatment outcomes after 14 and 28 days were determined. Total treatment failure of 18 and 42.5% was observed for SP on days 14 and 28, respectively. For AQ, total treatment failure of 27 and 53% was found on day 14 and 28, respectively. On day 14, significantly lower SP total treatment failures were observed in 2004 compared with results from a study conducted in 1999 in the same location. No relationship was detected between clinical outcome and DHFR/DHPS genotypes, but the point mutation prevalence in parasites was higher than in 1999. Pre-treatment blood levels of SP were detected in a quarter of the study children: less than expected. We report unacceptably high levels of total treatment failures, both for first- and second-line treatments for uncomplicated malaria in Tanzania 3 years after their introduction, supporting the decision to replace them with artemisinin-based combination therapy.
Asunto(s)
Amodiaquina/uso terapéutico , Antimaláricos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Pirimetamina/uso terapéutico , Sulfadoxina/uso terapéutico , Animales , Preescolar , Dihidropteroato Sintasa/genética , Combinación de Medicamentos , Resistencia a Medicamentos , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Lactante , Malaria Falciparum/parasitología , Masculino , Plasmodium falciparum/genética , Mutación Puntual , Pirimetamina/sangre , Salud Rural , Sulfadoxina/sangre , Tanzanía , Tetrahidrofolato Deshidrogenasa/genética , Insuficiencia del TratamientoRESUMEN
This article describes high-performance liquid chromatographic assays for the quantification of sulfadoxine (SDX), pyrimethamine (PYM), chloroquine (CQ), amodiaquine (AQ) and desethylamodiaquine (AQM) from whole blood. All four assays were set up and validated in Malawi using a common high-performance liquid chromatography platform and column and involved the use of simple mobile phase and extraction reagents. Calibration curves were linear (r(2)>0.95) in the ranges 5-100microg/ml, 50-1000, 150-1500, 100-1000 and 100-1000ng/ml for SDX, PYM, CQ, AQ and AQM, respectively. Intra-assay and inter-assay coefficients of variation were <15% at 3 points spanning the concentration range and <20% at the lower limit of quantification. The assays were specific with no interference from the other antimalarials described in this report. All four assays use liquid-liquid extraction, reversed-phase chromatography and UV detection and require between 50 and 200microl of blood. Because the assays share common instruments and reagents, they are cost-efficient and could be used to optimise antimalarial drug therapies in other resource poor settings.
Asunto(s)
Antimaláricos/sangre , Cromatografía Líquida de Alta Presión/métodos , África , Amodiaquina/análogos & derivados , Amodiaquina/sangre , Cloroquina/sangre , Humanos , Pirimetamina/sangre , Reproducibilidad de los Resultados , Sulfadoxina/sangreRESUMEN
Placental sequestration of Plasmodium falciparum in pregnancy may impair the usefulness of molecular markers of sulfadoxine-pyrimethamine resistance. In 300 infected, delivering women, the concordance of PCR-restriction fragment length polymorphism-derived parasite resistance alleles in matched samples from placenta and circulation was 83 to 98%. Sulfadoxine-pyrimethamine resistance typing in peripheral blood is reasonably representative of P. falciparum infecting pregnant women.
Asunto(s)
Resistencia a Medicamentos/genética , Malaria Falciparum/tratamiento farmacológico , Placenta/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirimetamina/farmacología , Sulfadoxina/farmacología , Adolescente , Adulto , Animales , Antimaláricos/farmacología , Biomarcadores/análisis , Biomarcadores/sangre , Combinación de Medicamentos , Femenino , Genotipo , Humanos , Malaria Falciparum/sangre , Malaria Falciparum/parasitología , Persona de Mediana Edad , Mutación , Placenta/metabolismo , Placenta/parasitología , Plasmodium falciparum/genética , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Embarazo , Complicaciones Parasitarias del Embarazo/sangre , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Pirimetamina/sangre , Sulfadoxina/sangre , Tetrahidrofolato Deshidrogenasa/genéticaRESUMEN
The work presented here deals with the development of a quantitative tool for the simultaneous determination of sulfamethoxypyrazine (sulfalene)/pyrimethamine in plasma. The chromatography used only takes 12.5 min, allowing a fast sample turnover time. Relative standard deviation of retention times was never above 3.48% (n = 66). Adequate sample clean-up was achieved by a simple and relatively fast liquid/liquid extraction. In this way, ionisation suppression effects, typical for more simple sample clean-up procedures, could be avoided resulting in absolute plasma effects of maximum -17.1% for sulfalene, -16.1 for the internal standard (IS), and 12% for pyrimethamine. For both pyrimethamine and sulfalene, quadratic calibration curves from 0.00101 to 0.807 microg/mL for pyrimethamine and from 0.271 to 216 microg/mL for sulfalene gave the best fit. Mean coefficients of determination (R2) were 0.9951 (n = 6, CV% 0.39) for pyrimethamine and 0.9942 (n = 6, CV% 0.13) for sulfalene. Precision was below 9.35% for pyrimethamine and 13.9% for sulfalene. Inaccuracy remained below 15% at all cases. The optimised method was used for a time-course study of the sulfalene/pyrimethamine combination concentration in plasma of patients treated with Co-Arinate, a new curative antimalaria-medicine.
Asunto(s)
Antimaláricos/sangre , Cromatografía Líquida de Alta Presión , Pirimetamina/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Sulfaleno/sangre , Espectrometría de Masas en Tándem/métodos , Reproducibilidad de los ResultadosRESUMEN
The efficacy of sulfadoxine-pyrimethamine (SP) in East Timor is unknown. We treated 38 individuals with uncomplicated Plasmodium falciparum malaria with SP and monitored the outcome for 28 days. Recrudescent parasitemia, confirmed by genotyping, were detected in three individuals resulting in a late treatment failure rate of 7.9% (95% confidence interval = 1.7-21.4%). The results suggest that SP is still efficacious in treating uncomplicated P. falciparum malaria in East Timor. However, the useful life of SP in East Timor may be limited because 80% of the parasites in our samples were found to already carry double mutations in P. falciparum dihydrofolate reductase (S108N/C59R). The data from this study also highlights that the presence of gametocytes may significantly influence the estimate of SP efficacy determined by genotyping.