Therapeutic efficacy of generic artemether-lumefantrine in the treatment of uncomplicated malaria in Ghana: assessing anti-malarial efficacy amidst pharmacogenetic variations.

BACKGROUND: Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether-lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy. METHODS: Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR-RFLP. RESULTS: A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0-2666/µL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors. CONCLUSIONS: The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

Introducing an lsoprenaline Eluting Guidewire: Report on its Design and the Results of the Dose-Determining Pilot Study.

Introduction: Retrograde intrarenal surgery (RIRS) is associated with complications, many of which are related to the intrarenal pressure (IRP). We aim to describe the design of a novel isoprenaline-eluting guidewire ("IsoWire") and present the results from the first in vitro release studies and the first animal studies showing its effect on IRP. Materials and Methods: The IsoWire comprises a Nitinol core surrounded by a stainless-steel wire wound into a tight coil. The grooves created by this coil provided a reservoir for adding a hydrogel coating into which isoprenaline, a beta-agonist, was loaded. Animal studies were performed using a porcine model. For the control, IRP, heart rate (HR), and mean arterial pressure (MAP) were measured continuously for 6 minutes with a standard guidewire in place. For the experiment, the standard hydrophilic guidewire was removed, the IsoWire was inserted into the renal pelvis, and the same parameters were measured. Results: In vitro analysis of the isoprenaline release profile showed that most (63.9 ± 5.9%) of the loaded drug mass was released in the 1st minute, and almost all of the drug was released in the first 4 minutes exponentially. Porcine studies showed a 25.1% reduction in IRP in the IsoWire that released 10 µg in the 1st minute; however, there was a marked increase in HR. The average percentage reduction in IRP was 8.95% and 21.3% in the IsoWire that released 5 and 7.5 µg of isoprenaline, respectively, with no changes in HR or MAP. Conclusions: The IsoWire, which releases 5 and 7.5 µg of isoprenaline in the 1st minute, appears to be safe and effective in reducing the IRP. Further studies are needed to establish whether the isoprenaline-induced ureteral relaxation will render easier insertion of a ureteral access sheath, reduce IRP during sheathless RIRS, or even promote the practice of sheathless RIRS.