Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria

Abstract

BackgroundDespite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high. Adjunctive therapies that target the host response to malaria infection may further decrease mortality over that of anti-malarial agents alone. Peroxisome proliferator-activated receptor-gamma agonists (e.g. rosiglitazone) have been shown to act on several pathways implicated in the pathogenesis of severe malaria and may improve clinical outcome as an adjunctive intervention.MethodsIn this study, the safety and tolerability of adjunctive rosiglitazone in paediatric uncomplicated malaria infection was evaluated in Mozambique, as a prelude to its evaluation in a randomized controlled trial in paediatric severe malaria. The study was a prospective, randomized, double-blind, placebo-controlled, phase IIa trial of rosiglitazone (0.045 mg/kg/dose) twice daily for 4 days versus placebo as adjunctive treatment in addition to Mozambican standard of care (artemisinin combination therapy Coartem®) in children with uncomplicated malaria. The primary outcomes were tolerability and safety, including clinical, haematological, biochemical, and electrocardiographic evaluations.ResultsThirty children were enrolled: 20 were assigned to rosiglitazone and 10 to placebo. Rosiglitazone treatment did not induce hypoglycaemia nor significantly alter clinical, biochemical, haematological, or electrocardiographic parameters.ConclusionsAdjunctive rosiglitazone was safe and well-tolerated in children with uncomplicated malaria, permitting the extension of its evaluation as adjunctive therapy for severe malaria.The trial is registered with Clinicaltrials.gov, NCT02694874

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

“…However, serum AST or ALT levels did not improve in comparison to placebo-treated patients [265]. In contrast, adjunctive treatment with rosiglitazone in another Phase II trial was not superior to placebo in improving AST, ALT, hematocrit, hemoglobin, mean parasite density, and the median time to parasite clearance, despite its safety and well-tolerance [266]. These studies suggest that rosiglitazone is well-tolerated among malaria patients.…”

“…Unlike PPARγ agonists, clinical evidence of the anti-inflammatory effect of other PPAR modulators is scarce. 140Enhanced parasite clearanceReduced inflammatory response [265] II (30) Rosiglitazone was well-tolerated in children with uncomplicated malaria [266] Ulcerative colitis PPARγ Rosiglitazone II (105) Increased clinical response and quality of lifeMore patients on rosiglitazone achieved remission [267] NA 14Reduced disease activity scoreIncreased adipophilin level [268] Asthma PPARγ Rosiglitazone I (34) Mild reduction of late asthmatic reaction [270] Pioglitazone IV (68) No effect on asthma control, airway inflammation, and quality of life [271] II (23) No effect on asthma control, lung infection, and exhaled nitric oxide [272] NA (34) No effect on severe asthma [273] Plaque (36) No effect on cytokines, chemokines, and acute-phase proteins [281] 13. Malignancy…”

Synthetic oleanane triterpenoids enhance blood brain barrier integrity and improve survival in experimental cerebral malaria

“…To mimic a more clinically relevant scenario where patients often seek treatment late in the course of disease, mice were treated after the onset of neurological symptoms with adjunctive CDDO-EA co-administered with artesunate. We did not assess CDDO-EA as a monotherapy at this stage as parenteral artesunate is the current first line treatment for severe malaria [ 72 , 73 ]. This treatment increased survival and improved the neurological outcome of mice already displaying neurological signs, suggesting that adjunctive CDDO-EA may not only prevent BBB leak but also restore its function and mitigate associated neurological injury.…”

A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration

“…Rosiglitazone, a direct PPAR-ɣ agonist, is effective in preventing death from ECM when given together with artesunate at days 5/6 post-infection [ 9 , 39 ]. Rosiglitazone increases survival and phagocytosis of infected erythrocytes via upregulation of CD36 expression on macrophages [ 9 , 39 ], and has proven safe in patients with uncomplicated P. falciparum malaria, thus prompting its use as an adjuvant therapy against CM [ 9 , 40 , 41 ].…”