Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy

Gutman, Julie; Kachur, S. Patrick; Slutsker, Laurence; Nzila, Alexis; Mutabingwa, Theonest K.

doi:10.1186/1475-2875-11-39

Cited by 15 publications

(7 citation statements)

References 86 publications

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“…Possible ways around this challenge would be more frequent dosing of SP or coadministration of SP with drugs that decrease its renal clearance. The use of probenecid to retard renal clearance of SP has been proposed [ 52 ] and may warrant further research.…”

Section: Discussionmentioning

confidence: 99%

Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine–Pyrimethamine Disposition Among Ugandan Pregnant Women

et al. 2015

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BackgroundSulphadoxine–pyrimethamine (SP) is widely used as an intermittent preventive treatment for malaria in pregnancy (IPTp). However, pharmacokinetic studies in pregnancy show variable and often contradictory findings. We describe population and trimester-specific differences in SP pharmacokinetics among Ugandan women.MethodsSP (three tablets) were administered to 34 nonpregnant and 87 pregnant women in the second trimester. Seventy-eight pregnant women were redosed in the third trimester. Blood was collected over time points ranging from 0.5 h to 42 days postdose. Data on the variables age, body weight, height, parity, gestational age, and serum creatinine, alanine transaminase and albumin levels were collected at baseline. Plasma drug assays were performed using high-performance liquid chromatography with ultraviolet detection. Population pharmacokinetic analysis was done using NONMEM software.ResultsA two-compartment model with first-order absorption and a lag time best described both the sulphadoxine and pyrimethamine data. Between trimesters, statistically significant differences in central volumes of distribution (V2) were observed for both drugs, while differences in the distribution half-life and the terminal elimination half-life were observed for pyrimethamine and sulphadoxine, respectively. Significant covariate relationships were identified on clearance (pregnancy status and serum albumin level) and V2 (gestational age) for sulphadoxine. For pyrimethamine, clearance (pregnancy status and age) and V2 (gestational age and body weight) were significant. Considering a 25 % threshold for clinical relevance, only differences in clearance of both drugs between pregnant and nonpregnant women were significant.ConclusionWhile clinically relevant differences in SP disposition between trimesters were not seen, increased clearance with pregnancy and the increasing volume of distribution in the central compartment with gestational age lend support to the revised World Health Organization guidelines advocating more frequent dosing of SP for IPTp.

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Section: Discussionmentioning

confidence: 99%

Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine–Pyrimethamine Disposition Among Ugandan Pregnant Women

et al. 2015

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“…In addition, statistical analysis of the ciprofloxacin P app in the presence of probenecid showed no significant difference in the absorptive (A-B) and secretory (B-A) directions (P ϭ 0.07), suggesting MRP involvement in the active transport of ciprofloxacin across the Calu-3 lung epithelial model. However, there is conflicting evidence suggesting that probenecid may also interact with not only MRPs but also OAT and OATP due to its anionic nature (34,35). Hence, the involvement of these influx transporters could also contribute to the decrease in ciprofloxacin permeation when probenecid is used.…”

Section: Resultsmentioning

confidence: 94%

Ciprofloxacin Is Actively Transported across Bronchial Lung Epithelial Cells Using a Calu-3 Air Interface Cell Model

Ong

Traini

Bebawy

et al. 2013

Antimicrob Agents Chemother

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cCiprofloxacin is a well-established broad-spectrum fluoroquinolone antibiotic that penetrates well into the lung tissues; still, the mechanisms of its transepithelial transport are unknown. The contributions of specific transporters, including multidrug efflux transporters, organic cation transporters, and organic anion-transporting polypeptide transporters, to the uptake of ciprofloxacin were investigated in vitro using an air interface bronchial epithelial model. Our results demonstrate that ciprofloxacin is subject to predominantly active influx and a slight efflux component.

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“…In humans, the recommended dosage for verapamil and probenecid is 80mg/kg and 500mg/kg, respectively (www.medscape.com). Studies have supported a combination of probenecid and SP for intermittent prevention of malaria in pregnancy (IPTp) 13 . Here, we have used a lower dose to restore the activity of LM against PQ R parasites.…”

Section: Discussionmentioning

confidence: 99%

“…One archetypical method of studying the mechanisms by which parasites evade drug action and simultaneously generate new drugs is the use of a chemosensitizer (a drug with the ability to enhance/restore activity) in association with antimalarial drugs for which the parasite is resistant 12 . This approach has been utilized previously to generate prophylactic drugs against malaria parasites 13,14 . Although many chemosensitizers have no intrinsic antimalarial potency, an antihistamine cyproheptadine can reverse resistance and kill asexual blood-stage malaria parasite 15 .…”

Section: Introductionmentioning

confidence: 99%

Genetic alteration of ferredoxin NADP⁺-reductase or cysteine desulfurase in piperaquine-resistant Plasmodium berghei restores susceptibility to lumefantrine and abolishes the impact of probenecid, verapamil, and cyproheptadine

Bara

Ndung'u

Onchieku³

et al. 2019

Preprint

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The ability of the human malaria parasite, Plasmodium falciparum to develop resistance against mainstay drugs remains a public health problem. Currently, the antimalarial drugs, lumefantrine (LM), and piperaquine (PQ) are essential components of the mainstay artemisinin-based therapies used for the treatment of malaria globally. Here, we used a model parasite Plasmodium berghei, to investigate the mechanisms of LM and PQ resistance. We employed known resistance reversing agents (RA): probenecid, verapamil, or cyproheptadine to study the mechanisms of LM and PQ resistance in the standard 4-day suppressive test. We then employed reverse genetics to assess the impact of deleting or over-expressing plausible genes associated with the metabolism and transport of drugs. We show that only, cyproheptadine at 5mgkg-1 restored LM activity by above 65% against LM-resistant parasites (LMr) but failed to reinstate PQ activity against PQ-resistant parasites (PQr). Whereas the PQr had lost significant susceptibility to LM, the three RA, cyproheptadine verapamil, and probenecid restored LM potency by above 70%, 60%, and 55% respectively against the PQr. We thus focused on the mechanisms of LM resistance in PQr. Here we show the partial deletion of the cysteine desulfurase (SUFS) and overexpression of the Ferredoxin NADP+ reductase (FNR) genes in the PQr parasite achieved two results; i) abolished the impact of RA on LM activity; ii) restored the susceptibility of PQr to LM alone. Our findings associated SUFS and FNR protein with the action of LM and RA action in P. berghei. We demonstrate that the incorporation of any of the RA into an antimalarial combination that comprises LM would augment LM activity and concomitantly antagonize the emergence of LM resistance derived from PQ pressure. The impact of RA, deletion of SUFS, and overexpression of FNR on LM activity need to be tested in Plasmodium falciparum.Author summaryLumefantrine (LM) and piperaquine (PQ) are essential drugs for the treatment of malaria globally. Here, we used Plasmodium berghei, a model parasite that infects rodents to study how parasites escape killing by PQ and LM. We first used a second drug: probenecid, verapamil, or cyproheptadine to enhance the activity of LM or PQ. We show that cyproheptadine restores LM activity against LM-resistant parasites (LMr) but failed to reestablish PQ activity against PQ-resistant parasites (PQr). Since PQr is resistant to LM, combining LM with either cyproheptadine, verapamil, or probenecid reinstates LM activity against PQr. We then focused mainly on LM resistance in PQr. After genetically manipulating the PQr, we reveal that cysteine desulfurase (SUFS) and ferredoxin NADP+reductase (FNR) regulate LM capacity to kill parasites. Decreasing the level of SUFS or increasing FNR levels in the PQr makes the parasites susceptible to LM but abolishes the impact of probenecid, verapamil, and cyproheptadine on LM activity. Overall, we provide clues on the link between SUFS and FNR in the action of LM and RA in P. berghei. This study provides a basis for an in-depth analysis of how LM mediates parasites kill and how the parasite escapes LM action in Plasmodium falciparum.

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Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy

Cited by 15 publications

References 86 publications

Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine–Pyrimethamine Disposition Among Ugandan Pregnant Women

Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine–Pyrimethamine Disposition Among Ugandan Pregnant Women

Ciprofloxacin Is Actively Transported across Bronchial Lung Epithelial Cells Using a Calu-3 Air Interface Cell Model

Genetic alteration of ferredoxin NADP⁺-reductase or cysteine desulfurase in piperaquine-resistant Plasmodium berghei restores susceptibility to lumefantrine and abolishes the impact of probenecid, verapamil, and cyproheptadine

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Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy

Cited by 15 publications

References 86 publications

Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine–Pyrimethamine Disposition Among Ugandan Pregnant Women

Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine–Pyrimethamine Disposition Among Ugandan Pregnant Women

Ciprofloxacin Is Actively Transported across Bronchial Lung Epithelial Cells Using a Calu-3 Air Interface Cell Model

Genetic alteration of ferredoxin NADP+-reductase or cysteine desulfurase in piperaquine-resistant Plasmodium berghei restores susceptibility to lumefantrine and abolishes the impact of probenecid, verapamil, and cyproheptadine

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Genetic alteration of ferredoxin NADP⁺-reductase or cysteine desulfurase in piperaquine-resistant Plasmodium berghei restores susceptibility to lumefantrine and abolishes the impact of probenecid, verapamil, and cyproheptadine