Pharmacokinetics and pharmacodynamics of fosmidomycin monotherapy and combination therapy with clindamycin in the treatment of multidrug resistant falciparum malaria

Na‐Bangchang, Kesara; Ruengweerayut, Ronnatrai; Karbwang, Juntra; Chauemung, Anurak; Hutchinson, David K.

doi:10.1186/1475-2875-6-70

Cited by 53 publications

(45 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is possible that the shorter course of clindamycin used in this study may have insufficiently complemented fosmidomycin and that, as a result, parasite clearance may have been incomplete or delayed. However, neither the good cure rates observed on day 7 (35/37; 94.6%) nor the good results obtained with the F/C combination elsewhere (3,5,6,18,20,23) support this hypothesis, and as previously mentioned, the significantly prolonged parasite clearance times instead support the hypothesis that clindamycin worked better than fosmidomycin. The roles of other partner drugs, such as piperaquine, with longer half-lives and the prospect of requiring shorter dosing courses should be explored.…”

Section: Discussionmentioning

confidence: 74%

“…Furthermore, in vitro synergistic activity between fosmidomycin and clindamycin against various strains of P. falciparum has been demonstrated (27). Different clinical trials have confirmed the safety and efficacy of fosmidomycin alone (15) or combined with clindamycin for the treatment of uncomplicated P. falciparum both in adults (17,18,20,23) and in older children (3,5,6,20). However, data on the efficacy of this combination in younger children, the age group most affected by malaria worldwide, are scarce.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inadequate Efficacy of a New Formulation of Fosmidomycin-Clindamycin Combination in Mozambican Children Less than Three Years Old with Uncomplicated Plasmodium falciparum Malaria

Lanaspa

Moraleda

Machevo

et al. 2012

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

fThe combination of fosmidomycin and clindamycin (F/C) is effective in adults and older children for the treatment of malaria and could be an important alternative to existing artemisinin-based combinations (ACTs) if proven to work in younger children.We conducted an open-label clinical trial to assess the efficacy, safety, and tolerability of F/C for the treatment of uncomplicated P. falciparum malaria in Mozambican children <3 years of age. Aqueous solutions of the drugs were given for 3 days, and the children were followed up for 28 days. The primary outcome was the PCR-corrected adequate clinical and parasitological response at day 28. Secondary outcomes included day 7 and 28 uncorrected cure rates and fever (FCT) and parasite (PCT) clearance times. Fifty-two children were recruited, but only 37 patients were evaluable for the primary outcome. Day 7 cure rates were high (94.6%; 35/37), but the day 28 PCR-corrected cure rate was 45.9% (17/37). The FCT was short (median, 12 h), but the PCT was longer (median, 72 h) than in previous studies. Tolerability was good, and most common adverse events were related to the recurrence of malaria. The poor efficacy observed for the F/C combination may be a consequence of the new formulations used, differential bioavailability in younger children, naturally occurring variations in parasite sensitivity to the drugs, or an insufficient enhancement of their effects by naturally acquired immunity in young children. Additional studies should be conducted to respond to the many uncertainties arising from this trial, which should not discourage further evaluation of this promising combination.

show abstract

Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 99%

Inadequate Efficacy of a New Formulation of Fosmidomycin-Clindamycin Combination in Mozambican Children Less than Three Years Old with Uncomplicated Plasmodium falciparum Malaria

Lanaspa

Moraleda

Machevo

et al. 2012

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…Due to its short half-life in plasma, FOS is not suitable for monotherapy; however, combination therapy studies in humans revealed success in maintaining total parasite clearance when FOS was used with artesunate or clindamycin (37)(38)(39)(40)(41)(42)(43). Thus far, our results indicate that MMV008138 affects apicoplast function and that its molecular target may differ from current antiapicoplast drugs, like FOS.…”

Section: Discussionmentioning

confidence: 78%

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

Bowman

Merino

Brooks

et al. 2014

Antimicrob Agents Chemother

129

View full text Add to dashboard Cite

cMalaria remains a significant infectious disease that causes millions of clinical cases and >800,000 deaths per year. The Malaria Box is a collection of 400 commercially available chemical entities that have antimalarial activity. The collection contains 200 drug-like compounds, based on their oral absorption and the presence of known toxicophores, and 200 probe-like compounds, which are intended to represent a broad structural diversity. These compounds have confirmed activities against the asexual intraerythrocytic stages of Plasmodium falciparum and low cytotoxicities, but their mechanisms of action and their activities in other stages of the parasite's life cycle remain to be determined. The apicoplast is considered to be a promising source of malaria-specific targets, and its main function during intraerythrocytic stages is to provide the isoprenoid precursor isopentenyl diphosphate, which can be used for phenotype-based screens to identify compounds targeting this organelle. We screened 400 compounds from the Malaria Box using apicoplast-targeting phenotypic assays to identify their potential mechanisms of action. We identified one compound that specifically targeted the apicoplast. Further analyses indicated that the molecular target of this compound may differ from those of the current antiapicoplast drugs, such as fosmidomycin. Moreover, in our efforts to elucidate the mechanisms of action of compounds from the Malaria Box, we evaluated their activities against other stages of the life cycle of the parasite. Gametocytes are the transmission stage of the malaria parasite and are recognized as a priority target in efforts to eradicate malaria. We identified 12 compounds that were active against gametocytes with 50% inhibitory concentration values of <1 M.

show abstract

“…Compounds 4, 9 and 15 (fosmidomycin) exhibited low BBB penetration due to their negative logD values (À0.423, À0.404 and À2.244, respectively). However, there are some reports of headache and vertigo from Fosmidomycin mono-therapy to patients and these adverse effects are considered due to its MW (<300 Da) and some amount of fosmidomycin molecule squeezing along the gap junctions of BBB (Na-Bangchang et al 2007;Meyers 2008).…”

Section: Computational Pharmacokinetic Studiesmentioning

confidence: 99%

“…Similarly, the highest log D value possessed by the lead compound 1 > 8 > 6 >13 also conferred them to be released metabolically via bile canaliculi and faecal route (Smith et al 1996). Fosmidomycin will be released solely by the renal clearance due to MW less than 250 Da (Na-Bangchang et al 2007). …”

Section: Computational Pharmacokinetic Studiesmentioning

confidence: 99%

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Wadood

Ghufran

Hassan

et al. 2016

Pharmaceutical Biology

View full text Add to dashboard Cite

Fosmidomycin is a promising DXR inhibitor, which showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. However, due to its poor oral bioavailability and non-drug-like properties, the focus of medicinal chemists is to develop inhibitors with improved pharmacological properties. Objective: This study described the computational design of new and potent inhibitors for deoxyxylulose 5-phosphate reductoisomerase and the prediction of their pharmacokinetic and pharmacodynamic properties. Material and methods: A complex-based pharmacophore model was generated from the complex X-ray crystallographic structure of PfDXR using MOE (Molecular Operating Environment). Furthermore, MOE-Dock was used as docking software to predict the binding modes of hits and target enzyme.Results: Finally, 14 compounds were selected as new and potent inhibitors of PfDXR on the basis of pharmacophore mapping, docking score, binding energy and binding interactions with the active site residues of the target protein. The predicted pharmacokinetic properties showed improved permeability by efficiently crossing blood-brain barrier. While, in silico promiscuity binding data revealed that these hits also have the ability to bind with other P. falciparum drug targets. Discussion and conclusion: In conclusion, innovative scaffolds with novel modes of action, improved efficacy and acceptable physiochemical/pharmacokinetic properties were computationally identified.ARTICLE HISTORY

show abstract

Pharmacokinetics and pharmacodynamics of fosmidomycin monotherapy and combination therapy with clindamycin in the treatment of multidrug resistant falciparum malaria

Abstract: Background: The study investigated the pharmacokinetics of fosmidomycin when given alone and in combination with clindamycin in patients with acute uncomplicated falciparum malaria.

Cited by 53 publications

References 21 publications

Inadequate Efficacy of a New Formulation of Fosmidomycin-Clindamycin Combination in Mozambican Children Less than Three Years Old with Uncomplicated Plasmodium falciparum Malaria

Inadequate Efficacy of a New Formulation of Fosmidomycin-Clindamycin Combination in Mozambican Children Less than Three Years Old with Uncomplicated Plasmodium falciparum Malaria

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Contact Info

Product

Resources

About