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Journal of Korean Medical Science Sep 2020Oxidative stress induced by chronic hyperglycemia is recognized as a significant mechanistic contributor to the development of diabetic kidney disease (DKD)....
BACKGROUND
Oxidative stress induced by chronic hyperglycemia is recognized as a significant mechanistic contributor to the development of diabetic kidney disease (DKD). Nonphagocytic nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in many cell types and in the kidney tissue of diabetic animals. We designed this study to explore the therapeutic potential of chloroquine (CQ) and amodiaquine (AQ) for inhibiting mitochondrial Nox4 and diabetic tubular injury.
METHODS
Human renal proximal tubular epithelial cells (hRPTCs) were cultured in high-glucose media (30 mM D-glucose), and diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57BL/6J mice. CQ and AQ were administered to the mice via intraperitoneal injection for 14 weeks.
RESULTS
CQ and AQ inhibited mitochondrial Nox4 and increased mitochondrial mass in hRPTCs under high-glucose conditions. Reduced mitochondrial ROS production after treatment with the drugs resulted in decreased endoplasmic reticulum (ER) stress, suppressed inflammatory protein expression and reduced cell apoptosis in hRPTCs under high-glucose conditions. Notably, CQ and AQ treatment diminished Nox4 activation and ER stress in the kidneys of STZ-induced diabetic mice. In addition, we observed attenuated inflammatory protein expression and albuminuria in STZ-induced diabetic mice after CQ and AQ treatment.
CONCLUSION
We substantiated the protective actions of CQ and AQ in diabetic tubulopathy associated with reduced mitochondrial Nox4 activation and ER stress alleviation. Further studies exploring the roles of mitochondrial Nox4 in the pathogenesis of DKD could suggest new therapeutic targets for patients with DKD.
Topics: Amodiaquine; Animals; Apoptosis; Cells, Cultured; Chloroquine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; Glucose; Humans; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Mitochondria; NADPH Oxidase 4; Reactive Oxygen Species
PubMed: 32924342
DOI: 10.3346/jkms.2020.35.e305 -
Tropical Medicine and Infectious Disease Jul 2022Malaria infection during pregnancy is an important driver of maternal and neonatal health in endemic countries. Intermittent preventive treatment in pregnancy (IPTp)... (Review)
Review
Malaria infection during pregnancy is an important driver of maternal and neonatal health in endemic countries. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention at each scheduled antenatal care visit, starting at the second trimester, in areas of high and moderate transmission. However, the increased resistance to SP in some endemic areas challenges its effectiveness. Furthermore, SP is contraindicated in the first trimester of pregnancy and in HIV-infected women on co-trimoxazole prophylaxis due to potential drug-drug interactions. Thus, in recent last decades, several studies evaluated alternative drugs that could be used for IPTp. A comprehensive literature review was conducted to summarize the evidence on the efficacy and safety of antimalarial drugs being evaluated for IPTp. Chloroquine, amodiaquine, mefloquine and azithromycin as IPTp have proven to be worse tolerated than SP. Mefloquine was found to increase the risk of mother-to-child transmission of HIV. Dihydroartemisin-piperaquine currently constitutes the most promising IPTp drug alternative; it reduced the prevalence of malaria infection, and placental and clinical malaria in studies among HIV-uninfected women, and it is currently being tested in HIV-infected women. Research on effective antimalarial drugs that can be safely administered for prevention to pregnant women should be prioritized. Malaria prevention in the first trimester of gestation and tailored interventions for HIV-infected women remain key research gaps to be addressed.
PubMed: 36006244
DOI: 10.3390/tropicalmed7080152 -
Malaria Journal Jul 2021Burundi has experienced an increase in malaria cases since 2000, reaching 843,000 cases per million inhabitants in 2019, a more than twofold increase compared to the... (Review)
Review
Burundi has experienced an increase in malaria cases since 2000, reaching 843,000 cases per million inhabitants in 2019, a more than twofold increase compared to the early 2000s. Burundi thus contrasts the decreasing number of cases in many other African countries. To evaluate the impact of malaria control on this increase, data on interventions from 2000 to 2019 were compiled. Over this period, the number of health facilities increased threefold, and the number of tests 20-fold. The test positivity rate remained stable at around 50-60% in most years. Artemisinin-based combination therapy was introduced in 2003, initially using artesunate-amodiaquine and changed to artemether-lumefantrine in 2019/2020. Mass distribution campaigns of insecticide-treated bed nets were conducted, and indoor residual spraying and intermittent preventive treatment in pregnancy introduced. Thus, the increase in cases was not the result of faltering control activities. Increased testing was likely a key contributor to higher case numbers. Despite the increase in testing, the test positivity rate remined high, indicating that current case numbers might still underestimate the true burden.
Topics: Antimalarials; Burundi; Humans; Insecticide-Treated Bednets; Malaria, Falciparum
PubMed: 34215270
DOI: 10.1186/s12936-021-03830-y -
Scientific Reports Jun 2020In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the... (Comparative Study)
Comparative Study Randomized Controlled Trial
In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the status of antimalarial efficacy more than ten years after their first introduction. This was a randomized, three-arm, open-label study to evaluate the efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP) in Senegal. Malaria suspected patients were screened, enrolled, treated, and followed for 28 days for AL and ASAQ arms or 42 days for DP arm. Clinical and parasitological responses were assessed following antimalarial treatment. Genotyping (msp1, msp2 and 24 SNP-based barcode) were done to differentiate recrudescence from re-infection; in case of PCR-confirmed treatment failure, Pfk13 propeller and Pfcoronin genes were sequenced. Data was entered and analyzed using the WHO Excel-based application. A total of 496 patients were enrolled. In Diourbel, PCR non-corrected/corrected adequate clinical and parasitological responses (ACPR) was 100.0% in both the AL and ASAQ arms. In Kedougou, PCR corrected ACPR values were 98.8%, 100% and 97.6% in AL, ASAQ and DP arms respectively. No Pfk13 or Pfcoronin mutations associated with artemisinin resistance were found. This study showed that AL, ASAQ and DP remain efficacious and well-tolerated in the treatment of uncomplicated P. falciparum malaria in Senegal.
Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Microfilament Proteins; Mutation; Plasmodium falciparum; Protozoan Proteins; Quinolines; Senegal; Sequence Analysis, DNA; Treatment Failure
PubMed: 32483161
DOI: 10.1038/s41598-020-65553-5 -
Parasites & Vectors Apr 2018Co-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to...
BACKGROUND
Co-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to Loa loa infected people are not well documented. This study compared the in vitro activity of several of these drugs on the viability of L. loa microfilariae (mf).
METHODS
Human strain L. loa mf were isolated from baboon blood using iso-osmotic Percoll gradient, and cultured in RPMI 1640/10% FBS with antimalarial drugs (mefloquine, amodiaquine, artesunate, chloroquine and quinine), anthelmintics (ivermectin, praziquantel, flubendazole and its reduced and hydrolyzed metabolites), two potential trypanocidal agents (fexinidazole and Scynexis-7158) and the anticancer drug imatinib. The drug concentrations used varied between 0.156 μg/ml and 10 μg/ml. Mf motility (CR = 50% immotility) and a metabolic viability assay (MTT) were used to assess the effects of these drugs on the parasites.
RESULTS
Mf in control cultures showed only a slight reduction in motility after 5 days of culture. Active inhibition of Loa loa motility was seen with mefloquine and amodiaquine (CR values of 3.87 and 4.05 μg/ml, respectively), immobilizing > 90% mf within the first 24 hours: mefloquine killed the mf after 24 hours of culture at concentrations ≥ 5 μg/ml. SCYX-7158 also induced a concentration-dependent reduction in mf motility, with > 50% reduction in mf motility seen after 5 days at 10 μg/ml. The anticancer drug imatinib reduced mf motility at 10 μg/ml from the first day of incubation to 55% by day 5, and the reduction in motility was concentration-dependent. Praziquantel and fexinidazole were inactive, and FLBZ and its metabolites, as well as ivermectin at concentrations > 5 μg/ml, had very minimal effects on mf motility over the first 4 days of culture.
CONCLUSIONS
The considerable action of the anti-malarial drugs mefloquine and amodiaquine on Loa mf in vitro highlights the possibility of repurposing the existing anti-infectious agents for the development of drugs against loiasis. The heterogeneity in the activity of anti-parasitic agents on Loa loa mf supports the need for further investigation using animal models of loiasis.
Topics: Animals; Antineoplastic Agents; Antiparasitic Agents; Loa; Movement; Parasitic Sensitivity Tests; Survival Analysis
PubMed: 29615094
DOI: 10.1186/s13071-018-2799-3 -
Malaria Journal Jul 2020Artemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine. Plasmodium falciparum isolates with...
BACKGROUND
Artemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine. Plasmodium falciparum isolates with reduced susceptibility to these partner drugs may affect treatment outcome. Mutations in pfmdr1 gene is linked to reduced parasite susceptibility to amodiaquine and lumefantrine. In addition, the potency of the partner drugs in vivo depends on the metabolism by the cytochrome P450 (CYP) enzyme in the host. Mutations in the CYP2C8 and CYP3A4 genes are linked to reduced metabolism of amodiaquine and lumefantrine in vitro, respectively. This study investigated the host and parasite genetic factors affecting the susceptibility of the malaria parasite to ACT partner drugs.
METHODS
Archived samples from 240 patients age ≤ 9 years participating in anti-malarial drug resistance survey in Ghana, and given artemether with lumefantrine (AL) or artesunate with amodiaquine (AA), were selected and analysed. Polymerase chain reaction (PCR) followed by Sanger sequencing was used to determine the polymorphisms in CYP2C8, CYP3A4 and pfmdr1 genes.
RESULTS
For CYP3A4, all had wild type alleles, suggesting that the hosts are good metabolizers of lumefantrine. For CYP2C8 60% had wild type alleles, 35% heterozygous and 5% homozygous recessive alleles suggesting efficient metabolism of amodiaquine by the hosts. For pfmdr1 gene, at codon 86, 95% were wild type (N86) and 5% mutant (Y86). For codon 184, 36% were wild type (Y184) and 64% mutant (F184) while for codons 1034, 1042 and 1246, 100% (all) were wild type. The high prevalence of N86-F184-D1246 haplotype (NFD) suggest presence of parasites with reduced susceptibility to lumefantrine and not amodiaquine. Delayed clearance was observed in individuals with mutations in the pfmdr1 gene and not cytochrome 450 gene. Both synonymous and non-synonymous mutations were observed in the pfmdr1 at low prevalence.
CONCLUSION
The outcome of this study indicates that the parasite's genetic factors rather than the host's are likely to drive resistance to ACT in Ghana.
Topics: Amodiaquine; Antimalarials; Child; Child, Preschool; Drug Resistance; Ghana; Humans; Infant; Infant, Newborn; Lumefantrine; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Genetic; Quinolines
PubMed: 32669113
DOI: 10.1186/s12936-020-03320-7 -
Annals of Parasitology 2020The purpose of this study was to update efficacy data of Artesunate-Amodiaquine (AS+AQ) and Artemether-Lumefantrine (AL) used as first-line malaria treatment in Côte... (Randomized Controlled Trial)
Randomized Controlled Trial
The purpose of this study was to update efficacy data of Artesunate-Amodiaquine (AS+AQ) and Artemether-Lumefantrine (AL) used as first-line malaria treatment in Côte d'Ivoire since 2005. This was an open-label, randomized trial conducted in patients older than 6 months with uncomplicated P. falciparum malaria at six sentinel sites. The WHO 2009 protocol on surveillance of anti-malaria drug efficacy was used with primary outcomes as ACPR corrected by PCR at day 42. Secondary endpoints were parasite and fever clearance times and safety. From January to July 2016, 712 patients were included in the trial. 353 and 359 patients were randomly assigned respectively to the AS+AQ and AL arm. Day 42 PCR-adjusted ACPR in the per-protocol analysis was 99.4% and 98.8% in AS+AQ and AL arm respectively. Delayed parasite clearance was observed in six patients at Abidjan and Yamousssoukro sites. Both ACTs were well tolerated. Both ACTs remain efficacious for uncomplicated P. falciparum malaria treatment in Côte d'Ivoire. But regarding delayed parasite clearance observed in this study, a close monitoring and supervision for ACT resistance are essential for future malaria treatment and control strategies in Côte d'Ivoire.
Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Cote d'Ivoire; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria; Malaria, Falciparum; Treatment Outcome
PubMed: 33789028
DOI: 10.17420/ap6604.299 -
Evidence-based Complementary and... 2021Multivisceral, neurological, hepatic, and renal damage has been witnessed following the use of artemisinin-based combination therapy (ACT) and herbal medicine. These...
INTRODUCTION
Multivisceral, neurological, hepatic, and renal damage has been witnessed following the use of artemisinin-based combination therapy (ACT) and herbal medicine. These multiple organ damages make us think of muscle damage. The objective was to study the myotoxicity of the combination of ACTs with medicinal plants.
MATERIALS AND METHODS
Muscle cells (RD cells) were brought into contact with preparations of antimalarial drugs and/or antimalarial herbs. The following drugs were used: artesunate 100 mg/amodiaquine 270 mg (ASAQ) and artemether 80 mg/lumefantrine 480 mg (AL); plant (PSA) and plant (PEP) at 10 g/ml. After 5 days of incubation, the cells were counted by using a hemocytometer with trypan blue solution.
RESULTS
Artesunate/amodiaquine caused a significant drop in the number of muscle cells, compared to the control, between D2 and D4 ( < 0.001). There was also a significant difference between the control and artemether/lumefantrine between D2 ( < 0.01) and D4 ( < 0.001) and between the control and the plant, on D2 ( < 0.001), D4 ( < 0.001), and D5 ( < 0.05). In tubes treated with ASAQ and , cell mortality was over 30%. Finally, statistically significant cell destruction in the tubes treated with the combination of antimalarial drugs and traditional plants compared to those of the control was observed from D2 ( < 0.001).
CONCLUSION
Artemisinin-based combination therapy remains effective and well tolerated. But its combination with medicinal plants induced myotoxic effects. This toxicity would appear to be of the additive type. Further studies should be able to better elucidate the mechanism of this toxicity.
PubMed: 34306158
DOI: 10.1155/2021/8861574 -
PloS One 2020Drug resistance remains a concern for malaria control and elimination. The effect of interventions on its prevalence needs to be monitored to pre-empt further selection....
BACKGROUND
Drug resistance remains a concern for malaria control and elimination. The effect of interventions on its prevalence needs to be monitored to pre-empt further selection. We assessed the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs: sulfadoxine-pyrimethamine (SP), chloroquine (CQ) and artemisinin combination therapy (ACTs) after the scale-up of a vector control activity that reduced transmission.
METHODS
A total of 400 P. falciparum isolates from children under five years were genotyped for seventeen single nucleotide polymorphisms (SNPs) in pfcrt, pfmdr1, pfdhfr, pfdhps and pfk13 genes using polymerase chain reaction (PCR) and high resolution melting (HRM) analysis. These included 80 isolates, each randomly selected from cross-sectional surveys of asymptomatic infections across 2010 (baseline), 2011, 2012, 2013 (midline: post-IRS) and 2014 (endline: post-IRS) during the peak transmission season, when IRS intervention was rolled out in Bunkpurugu Yunyoo (BY) District, Ghana. The proportions of isolates with drug resistant alleles were assessed over this period.
RESULTS
There were significant decreases in the prevalence of pfdhfr- I51R59N108 haplotype from 2010 to 2014, while the decline in pfdhfr/pfdhps- I51R59N108G437 during the same period was not significant. The prevalence of lumefantrine (LM), mefloquine (MQ) and amodiaquine (AQ) resistance-associated haplotypes pfmdr1-N86F184D1246 and pfmdr1-Y86Y184Y1246 showed decreasing trends (z = -2.86, P = 0.004 and z = -2.71, P = 0.007, respectively). Each of pfcrt-T76 and pfmdr1-Y86 mutant alleles also showed a declining trend in the asymptomatic reservoir, after the IRS rollout in 2014 (z = -2.87, P = 0.004 and z = -2.65, P = 0.008, respectively). Similarly, Pyrimethamine resistance mediating polymorphisms pfdhfr-N108, pfdhfr-I51 and pfdhfr-R59 also declined (z = -2.03, P = 0.042, z = -3.54, P<0.001 and z = -4.63, P<0.001, respectively), but not the sulphadoxine resistance mediating pfdhps-G437 and pfdhps-F436 (z = -0.36, P = 0.715 and z = 0.41, P = 0.684, respectively). No mutant pfk13-Y580 were detected during the study period.
CONCLUSION
The study demonstrated declining trends in the prevalence of drug resistant mutations in asymptomatic P. falciparum infections following transmission reduction after an enhanced IRS intervention in Northern Ghana.
Topics: Amodiaquine; Antimalarials; Biomarkers, Pharmacological; Carrier State; Child, Preschool; Chloroquine; DNA, Protozoan; Drug Combinations; Drug Resistance; Female; Genotype; Ghana; Humans; Infant; Malaria; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Protozoan Proteins; Pyrimethamine; Sulfadoxine
PubMed: 33284800
DOI: 10.1371/journal.pone.0233478 -
Malaria Journal Sep 2018Malaria is a major health problem in sub-Saharan Africa where over 90% of the world's malaria cases occur. Artemisinin-based combination therapy (ACT) is recommended by...
BACKGROUND
Malaria is a major health problem in sub-Saharan Africa where over 90% of the world's malaria cases occur. Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization as first-line and second-line treatments for uncomplicated falciparum malaria. However, there are a growing number of reports of sub-standard and falsified anti-malarial medicines in sub-Saharan Africa.
METHODS
A cross-sectional study was conducted in Embu County, Kenya on the quality of anti-malarial medicines available in public and private facilities. Sampling of anti-malarial medicines from public and private hospitals, health centers and pharmacies was conducted between May and June 2014. Quality control tests were performed at the Drug Analysis and Research Unit, University of Nairobi, using ultraviolet spectrophotometry and high-performance liquid chromatography. A test for microbial load was also conducted for suspension formulations.
RESULTS
A total of 39 samples were collected from public and private facilities across the Embu County. A visual inspection of the medicines showed no signs of sub-standard or falsification. All ACT passed identification, assay and dissolution tests. Of 11 suspension samples collected, none failed the microbial load test although one sample had 50 colony forming units (cfu). No oral artemisinin monotherapy medicines were encountered during the survey. Amodiaquine and chloroquine monotherapy products accounted for 5% of the collected samples, despite their ban in Kenya. Two herbal anti-malarial formulations were collected during the survey. Sulfadoxine/pyrimethamine (SP) was also found to be available use for malaria treatment, not in accordance with malaria treatment guidelines.
CONCLUSION
All the anti-malarial drugs analysed in this study passed the quality control tests. This is encouraging given the high malaria burden in Kenya. Regulatory actions are required to counter SP and herbal products for malaria treatment.
Topics: Antimalarials; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Health Facilities; Humans; Kenya; Pharmaceutical Preparations; Pharmacies; Spectrophotometry
PubMed: 30219080
DOI: 10.1186/s12936-018-2482-3