scholarly journals Decreased prevalence of the Plasmodium falciparum Pfcrt K76T and Pfmdr1 and N86Y mutations post-chloroquine treatment withdrawal in Katete District, Eastern Zambia

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Mwenda C. Mulenga ◽  
Lungowe Sitali ◽  
Ilinca I. Ciubotariu ◽  
Moonga B. Hawela ◽  
Busiku Hamainza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Complete Recovery ◽  
The Body ◽  
Chloroquine Resistance ◽  
Treatment Withdrawal ◽  
Combination Regimen ◽  
Drug Pressure ◽  
Length Polymorphisms ◽  
Chloroquine Treatment ◽  
First Choice

Abstract Background In 2002, Zambia withdrew chloroquine as first-line treatment for Plasmodium falciparum malaria due to increased treatment failure and worldwide spread of chloroquine resistance. The artemisinin combination regimen, artemether–lumefantrine, replaced chloroquine (CQ) as first choice malaria treatment. The present study determined the prevalence of CQ resistance molecular markers in the Pfcrt and Pfmdr1 genes in Eastern Zambia at 9 and 13 years after the removal of drug pressure. Methods Samples collected from Katete District during the drug therapeutic efficacy assessments conducted in 2012 and 2016 were assayed by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) to determine the prevalence of genetic mutations, K76T on the Pfcrt gene and N86Y on the Pfmdr1 gene. A total of 204 P. falciparum-positive DBS samples collected at these two time points were further analysed. Results Among the samples analysed for Pfcrt K76T and Pfmdr1 N86Y in the present study, 112 (82.4%) P. falciparum-infected samples collected in 2012 were successfully amplified for Pfcrt and 94 (69.1%) for Pfmdr1, while 69 (65.7%) and 72 (68.6%) samples from 2016 were successfully amplified for Pfcrt and Pfmdr1, respectively. In 2012, the prevalence of Pfcrt 76K (sensitive) was 97.3%, 76T (resistant) was 1.8%, and 0.8% had both 76K and 76T codons (mixed). Similarly in 2012, the prevalence of Pfmdr1 86N (sensitive) was 97.9% and 86Y (resistant) was 2.1%. In the 2016 samples, the prevalence of the respective samples was 100% Pfcrt 76K and Pfmdr1 86N. Conclusion This study shows that there was a complete recovery of chloroquine-sensitive parasites by 2016 in Katete District, Eastern Zambia, 13 years following the withdrawal of CQ in the country. These findings add to the body of evidence for a fitness cost in CQ-resistant P. falciparum in Zambia and elsewhere. Further studies are recommended to monitor resistance countrywide and explore the feasibility of integration of the former best anti-malarial in combination therapy in the future.

scholarly journals Decreased Prevalence of the Plasmodium Falciparum Pfcrt K76T and Pfmdr1 N86Y Mutations Post- Chloroquine Treatment Withdrawal in Katete District, Eastern Zambia

2021 ◽  
Author(s):  
Mulenga Chilumba Mwenda ◽  
Lungowe Sitali ◽  
Ilinca Ciubotariu ◽  
Moonga B Hawela ◽  
Busiku Hamainza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Complete Recovery ◽  
The Body ◽  
Chloroquine Resistance ◽  
Treatment Withdrawal ◽  
Combination Regimen ◽  
Drug Pressure ◽  
Length Polymorphisms ◽  
Chloroquine Treatment ◽  
First Choice

Abstract Background: In 2002, Zambia withdrew chloroquine as first line treatment for Plasmodium falciparum malaria due to increased treatment failure and world-wide spread of chloroquine resistance. The artemisinin combination regimen artemether-lumefantrine replaced chloroquine as first choice malaria treatment. The present study determined the prevalence of chloroquine resistance molecular markers in the malaria parasite Pfcrt and Pfmdr1 genes in Eastern Zambia at nine and thirteen years after the removal of drug pressure.Methods: We assayed by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) the prevalence of the genetic mutations, K76T on the Pfcrt gene and N86Y on the Pfmdr1 gene in samples collected from Katete District during drug therapeutic efficacy assessments conducted in 2012 and 2016.Results: A total of 204 P. falciparum positive samples from 2012 and 2016 were further analysed for Pfcrt K76T and Pfmdr1 N86Y. 112 P. falciparum infected samples collected in 2012 were successfully amplified for Pfcrt and Pfmdr1, while 69 (65.7%) and 72 (68.6%) samples from 2016 were successfully amplified for Pfcrt and Pfmdr1. In 2012, the prevalence of Pfcrt 76K was 97.3%, 76T was 1.8%, and 0.8% had both 76K and 76T codons. The prevalence of Pfmdr1 86N was 97.9% and 86Y was 2.1%. In the 2016 samples, the prevalence of the respective parasite genotypes was 100% Pfcrt 76K and Pfmdr1 86N.Conclusion: This study shows that there was a complete recovery of chloroquine-sensitive parasites by 2016 in Katete District, thirteen years following the withdrawal of CQ. These findings add to the body of evidence for a fitness cost in chloroquine-resistant P. falciparum in Zambia and elsewhere. Further studies are recommended to explore the feasibility of integration of the former best antimalarial in combination therapy in the future.

scholarly journals Double Mutation in thepfmdr1Gene Is Associated with Emergence of Chloroquine-Resistant Plasmodium falciparum Malaria in Eastern India

2014 ◽  
Vol 58 (10) ◽  
pp. 5909-5915 ◽  
Author(s):  
Sabyasachi Das ◽  
Santanu Kar Mahapatra ◽  
Satyajit Tripathy ◽  
Sourav Chattopadhyay ◽  
Sandeep Kumar Dash ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Treatment Failure ◽  
Early Treatment ◽  
Chloroquine Resistance ◽  
Major Public Health Problem ◽  
Early Treatment Failure ◽  
Double Mutation ◽  
Chloroquine Treatment ◽  
Late Treatment

ABSTRACTMalaria is a major public health problem in tropical and subtropical countries, including India. This study elucidates the cause of chloroquine treatment failure (forPlasmodium falciparuminfection) before the introduction of artemisinin combination therapy. One hundred twenty-six patients were randomized to chloroquine treatment, and the therapeutic efficacy was monitored from days 1 to 28. Anin vitrosusceptibility test was performed with all isolates. Parasitic DNA was isolated, followed by PCR and restriction digestion of different codons of thepfcrtgene (codons 72 to 76) and thepfmdr1gene (N86Y, Y184F, S1034C, N1042D, and D1246Y). Finally, sequencing was done to confirm the mutations. Forty-three (34.13%) early treatment failure cases and 16 (12.69%) late treatment failure cases were observed after chloroquine treatment.In vitrochloroquine resistance was found in 103 isolates (81.75%). Twenty-six (60.47%) early treatment failure cases and 6 (37.5%) late treatment failure cases were associated with the CVMNK-YYSNYallele (the underlined amino acids are those that were mutated). Moreover, the CVIEK-YYSNYallele was found in 8 early treatment failure (18.60%) and 2 late treatment failure (12.5%) cases. The presence of the wild-typepfcrt(CVMNK) andpfmdr1(YYSNY) double mutant allele in chloroquine-nonresponsive cases was quite uncommon.In vivochloroquine treatment failure andin vitrochloroquine resistance were strongly correlated with the CVMNK-YYSNYand CVIEK-YYSNYhaplotypes (P< 0.01).

scholarly journals Cross sectional study to determine chloroquine resistance among Plasmodium falciparum clinical isolates from Khartoum, Sudan

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 208 ◽  
Author(s):  
Walaa Salah Abdulla Mohammed ◽  
Kyakonye Yasin ◽  
N.S. Mahgoub ◽  
Muzamil Mahdi Abdel Hamid
Keyword(s):  
Plasmodium Falciparum ◽  
Cross Sectional Study ◽  
Food Vacuole ◽  
Chloroquine Resistance ◽  
World Health ◽  
Cross Sectional ◽  
Field Isolates ◽  
Drug Of Choice ◽  
Chloroquine Treatment ◽  
Health Organization

Background:  Malaria continues to present a global health threat; the World Health Organization (WHO) reported 214 million cases of malaria by the year 2015 with a death rate of 438000. Sudan is endemic to malaria with over 95% of malaria cases due to Plasmodium falciparum. Chloroquine is a well-established drug in the treatment of P. falciparum malaria although its use has declined since its introduction as the drug of choice in treatment of malaria in Sudan. The mechanism of resistance has been attributed to mutations in P. falciparum Chloroquine resistance transporter gene coding for a key food vacuole proteins. In current study we aimed at verifying the genetic cause of resistance to Chloroquine in field isolates of P. falciparum. Methods: Twenty P. falciparum cases were diagnosed from East Nile hospital in Khartoum and recruited in the investigation. Nested PCR was conducted to isolate mutation region in the PfCRT gene and the amplicons were sequenced using Sanger sequencing technique (Macrogen, Soule Korea). Results: 16/20 (80%) of the field isolates contained base pair mutation of codon 76 in the pfcrt gene thus being resistant to chloroquine treatment and only 4/20 (20%) did not contain such mutation. Conclusions: High treatment failures associated with Chloroquine treatment is evident of the high prevalence of mutant strains of P. falciparum field isolates thus suggesting the reduced relevance of Chloroquine as a treatment choice in the management of P. falciparum malaria.

scholarly journals Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?

Parasitology ◽  
2011 ◽  
Vol 138 (12) ◽  
pp. 1459-1468 ◽  
Author(s):  
COLIN J. SUTHERLAND ◽  
HAMZA BABIKER ◽  
MARGARET J. MACKINNON ◽  
LISA RANFORD-CARTWRIGHT ◽  
BADRIA BABIKER EL SAYED
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Selective Pressure ◽  
Severe Disease ◽  
Preventive Therapy ◽  
Combination Regimen ◽  
First Line ◽  
Drug Pressure ◽  
Paediatric Malaria ◽  
Parasite Populations

SUMMARYArtemisinin-based combination therapy is exerting novel selective pressure upon populations of Plasmodium falciparum across Africa. Levels of resistance to non-artemisinin partner drugs differ among parasite populations, and so the artemisinins are not uniformly protected from developing resistance, already present in South East Asia. Here, we consider strategies for prolonging the period of high level efficacy of combination therapy for two particular endemicities common in Africa. Under high intensity transmission, two alternating first-line combinations, ideally with antagonistic selective effects on the parasite genome, are advocated for paediatric malaria cases. This leaves second-line and other therapies for adult cases, and for intermittent preventive therapy. The drug portfolio would be selected to protect the ‘premier’ combination regimen from selection for resistance, while maximising impact on severe disease and mortality in children. In endemic areas subject to low, seasonal transmission of Plasmodium falciparum, such a strategy may deliver little benefit, as children represent a minority of cases. Nevertheless, the deployment of other drug-based interventions in low transmission and highly seasonal areas, such as mass drug administration aimed to interrupt malaria transmission, or intermittent preventive therapy, does provide an opportunity to diversify drug pressure. We thus propose an integrated approach to drug deployment, which minimises direct selective pressure on parasite populations from any one drug component. This approach is suitable for qualitatively and quantitatively different burdens of malaria, and should be supported by a programme of routine surveillance for emerging resistance.

scholarly journals The impact of HIV-associated immunosuppression on the Plasmodium falciparum chloroquine resistance transporter gene (PfCRT) of HIV patients in Akure, Nigeria

2020 ◽  
Vol 44 (1) ◽  
Author(s):  
Iyabo Adepeju Simon-Oke ◽  
Adeola Olanireti Ade-Alao ◽  
Foluso Ologundudu
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Prevalence ◽  
Cd4 Count ◽  
Chloroquine Resistance ◽  
Hiv Care ◽  
Transporter Gene ◽  
Hiv Patients ◽  
Chloroquine Resistance Transporter ◽  
Hiv Test ◽  
Low Prevalence

Abstract Background The study evaluated the prevalence of malaria and Plasmodium falciparum chloroquine resistance transporter gene (PfCRT) in HIV patients attending Specialist Hospital, Akure. This study was carried out between April and June 2019. Three hundred and seventeen (317) patients attending the antiretroviral clinic (ART) were involved, out of which 89 (28.08%) were males and 228 (71.92%) were females. HIV test was done using the Unigold® HIV test kit, malaria test was done using thick and thin blood smear, CD4 test was done using the Partec® CD4 counter and PCR was used to detect the presence of plasmodium falciparum mutant gene. The data obtained from this analysis was subjected to Pearson’s Chi-square test. Results The overall result showed low prevalence of malaria (23.03%) in the sampled patients. Highest malaria prevalence (31.0%) was recorded in HIV patients with CD4 count between 200–500 cells/μl of blood, with the males recording 24.7% malaria prevalence. The age group 20–29 years recorded the highest prevalence of 27.3%. A higher prevalence 91.1% of PfCRT gene in HIV-positive and (40.0%) in HIV-negative patients was recorded with 100% prevalence in patients with CD4 count ≤ 200. This shows that the low prevalence of malaria recorded in this study could be credited to good health-seeking attitude of HIV patients and the upscale of HIV care and treatment centres. Conclusion The high prevalence of PfCRT gene shows that treatment of malaria with chloroquine is still being practised despite the availability of artemisinin-based combination therapy (ACTs) as the recommended regimen for malaria treatment.

scholarly journals Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Alena Pecinova ◽  
Zdenek Drahota ◽  
Jana Kovalcikova ◽  
Nikola Kovarova ◽  
Petr Pecina ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Respiratory Chain ◽  
Reactive Oxygen Species Production ◽  
Reactive Oxygen ◽  
Epidemiological Studies ◽  
The Body ◽  
Oxygen Species ◽  
Brown Adipose ◽  
First Choice ◽  
Species Production

Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10−2–10−1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.

Role of pfmdr1 mutations on chloroquine resistance in Plasmodium falciparum isolates with pfcrt K76T from Papua New Guinea

Acta Tropica ◽  
2006 ◽  
Vol 98 (2) ◽  
pp. 137-144 ◽  
Author(s):  
Toshihiro Mita ◽  
Akira Kaneko ◽  
Francis Hombhanje ◽  
Ilomo Hwaihwanje ◽  
Nobuyuki Takahashi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Papua New Guinea ◽  
New Guinea ◽  
Chloroquine Resistance
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