scholarly journals The effect of Point Mutations in Dihydrofolate reductase genes and Multidrug resistance gene 1-86 on treatment of falciparum malaria in Sudan

2009 ◽  
Vol 4 (02) ◽  
pp. 061-069 ◽  
Author(s):  
Rahma Udu Yusuf ◽  
Sabah Ahmed Omar ◽  
Raphael Muchangi Ngure
Keyword(s):  
Drug Resistance ◽  
Falciparum Malaria ◽  
Dihydrofolate Reductase ◽  
Antimalarial Drugs ◽  
Multi Drug Resistance ◽  
Dot Blot ◽  
Open Label ◽  
Multidrug Resistance Gene ◽  
Pcr Rflp ◽  
Mdr 1

Background: One of the major problems to the treatment of malaria is the emergence and spread of parasite resistant to antimalarial drugs. Due to increased chloroquine (CQ) resistance, the antifolate combinations are becoming important in the chemotherapy of falciparum malaria. However, resistance to antifolate exists and they are still effective in the above combinations. This study aimed at determining the prevalence of antimalarial drug resistance markers in P. falciparum isolates, involving the detection of mutations at the mdr 1- 86 which associates with amodiaquine resistance, and dhfr mutations associated with SP resistances. Methods: The dot-blot/ probe hybridization, which is more sensitive and specific; it detects parasitaemia of less than 100 parasites/µl of blood, and can identify a minority parasite genotype down to 1% in a mixture, was adopted to determine multi-drug resistance (mdr1-86) to show the correlation of Amodiaquine (AQ) resistance and PCR/ RFLP adopted to determine dihydrofolate reductase (dhfr) baseline resistance to Sulphadoxine- Pyrimethamine (SP) resistance in Nubian region of southern Sudan. A randomized open label trial of Artesunate (AS) + SP and AS+ SP was carried out in children less than 5 years. Molecular analysis of filter paper preserved blood samples collected was carried out to provide a baseline estimate of allele prevalences. Results: Baseline of the allele prevalence of the mdr1 86 locus in the AS+ AQ was successful for 80 isolates: 71(8.11%) carried parasites harbouring the mdr1-86 Tyr resistance allele, while 7 (89.19%) carried mdr1-86 Asn sensitivity allele and 2 (2.7%) were of mixed infection, having both resistance and wild type allele. Overall, the prevalence of the dhfr point mutation, codon 51, 59 and 108: 82.5% (132/160) carried mutations at dhfr (N51I, C59R or S108N), but triple mutants were rare (3.1%) in the AS + SP arm. Conclusion: The research provides the evidence that mutations present in dhfr and mdr1 86 has a significant effect on the type of treatment following SP and AQ chemotherapy. SP resistance may spread rapidly, and AS + AQ is likely to be a better option, provided AQ use is restricted to the combination. The significance of the study shows that definitely combination of drugs improves SP therapy at the study site. Keywords: Antimalarial drugs, P. falciparum, dhfr, mdr-1, dot-blot hybridisation technique, PCR/RFLP

scholarly journals Canine multi-drug resistance-1 mutation prevalence: A South African perspective

2014 ◽  
Vol 85 (1) ◽  
Author(s):  
Lérica Le Roux-Pullen ◽  
Henriëtte Van der Zwan
Keyword(s):  
Drug Resistance ◽  
South African ◽  
Gene Mutation ◽  
Macrocyclic Lactone ◽  
Multi Drug Resistance ◽  
Prevalence Data ◽  
Geographical Regions ◽  
African Perspective ◽  
Mdr 1

The multi-drug resistance (mdr-1) gene mutation is a phenomenon well known to current veterinary practitioners. The mutation causes a predisposition for, amongst other phenomena, macrocyclic lactone-induced neurotoxicosis in affected canines, a condition that can be fatal. Various herding dog breeds can be heterozygous or homozygous for the mutation, and prevalence differs only slightly in dog populations between geographical regions. This report provides prevalence data of the canine mdr-1 mutation in 306 South African dogs.

Multi-Drug Resistance (MDR-1) in Newly Diagnosed AIDS-Lymphoma

1999 ◽  
Vol 21 (1) ◽  
pp. A32
Author(s):  
Anil Tulpule ◽  
Andy Sherrod ◽  
Maria Norilyn Sanchez ◽  
Byron M. Espina ◽  
Dharshika Dharmapala ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multi Drug Resistance ◽  
Newly Diagnosed ◽  
Mdr 1

scholarly journals Selection of pfcrt K76 and pfmdr1 N86 Coding Alleles after Uncomplicated Malaria Treatment by Artemether-Lumefantrine in Mali

2021 ◽  
Vol 22 (11) ◽  
pp. 6057
Author(s):  
Hamma Maiga ◽  
Anastasia Grivoyannis ◽  
Issaka Sagara ◽  
Karim Traore ◽  
Oumar B. Traore ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Falciparum Malaria ◽  
Recurrent Infection ◽  
Plasmodium Falciparum Malaria ◽  
Chloroquine Resistance ◽  
Multi Drug Resistance ◽  
Chloroquine Resistance Transporter ◽  
Malaria Transmission Season ◽  
Parasite Populations ◽  
Selection Of

Background: Artemether-lumefantrine is a highly effective artemisinin-based combination therapy that was adopted in Mali as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study was designed to measure the efficacy of artemether-lumefantrine and to assess the selection of the P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multi-drug resistance 1 (pfmdr1) genotypes that have been associated with drug resistance. Methods: A 28-day follow-up efficacy trial of artemether-lumefantrine was conducted in patients aged 6 months and older suffering from uncomplicated falciparum malaria in four different Malian areas during the 2009 malaria transmission season. The polymorphic genetic markers MSP2, MSP1, and Ca1 were used to distinguish between recrudescence and reinfection. Reinfection and recrudescence were then grouped as recurrent infections and analyzed together by PCR-restriction fragment length polymorphism (RFLP) to identify candidate markers for artemether-lumefantrine tolerance in the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multi-drug resistance 1 (pfmdr1) gene. Results: Clinical outcomes in 326 patients (96.7%) were analyzed and the 28-day uncorrected adequate clinical and parasitological response (ACPR) rate was 73.9%. The total PCR-corrected 28-day ACPR was 97.2%. The pfcrt 76T and pfmdr1 86Y population prevalence decreased from 49.3% and 11.0% at baseline (n = 337) to 38.8% and 0% in patients with recurrent infection (n = 85); p = 0.001), respectively. Conclusion: Parasite populations exposed to artemether-lumefantrine in this study were selected toward chloroquine-sensitivity and showed a promising trend that may warrant future targeted reintroduction of chloroquine or/and amodiaquine.

scholarly journals Targeted cytotoxic bombesin analog AN-215 effectively inhibits experimental human breast cancers with a low induction of multi-drug resistance proteins

2005 ◽  
Vol 12 (4) ◽  
pp. 999-1009 ◽  
Author(s):  
Jörg B Engel ◽  
Andrew V Schally ◽  
Gabor Halmos ◽  
Benjamin Baker ◽  
Attila Nagy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Multi Drug Resistance ◽  
Breast Cancers ◽  
Human Breast ◽  
Resistance Protein ◽  
Grp Receptors ◽  
Mdr 1

The cytotoxic analog of bombesin (BN)/gastrin releasing peptide (GRP) AN-215 consisting of 2-pyrrolinodoxorubicin (AN-201), a superactive derivative of doxorubicin linked to a bombesin analog carrier, displays a high affinity to BN/GRP receptors and can be targeted to tumors that express these receptors. We evaluated the antitumor effect and the toxicity of AN-215 in 5 human breast cancer cell lines xenografted into nude mice. In addition, we measured the mRNA expression of multi drug resistance protein 1 (MDR-1), multi drug resistance related protein 1 (MRP-1) and breast cancer resistance protein (BCRP) by real-time PCR analysis after treatment with AN-215. All five cell lines expressed BN/GRP receptors, and AN-215 significantly (P<0.05) inhibited tumor growth in all models, while its cytotoxic radical AN-201 had no significant effect in four models. In MX-1 tumors, AN-201 had a significantly weaker antitumor effect than AN-215. The effect of AN-215 was nullified by a blockade of BN/GRP receptors with a bombesin antagonist. Low or no induction of MDR-1, MRP-1 and BCRP occurred after treatment with AN-215. In conclusion, targeted chemotherapy with the cytotoxic BN/GRP analog AN-215 strongly inhibits breast cancers that express BN/GRP receptors and might provide a new treatment modality for mammary carcinoma.

scholarly journals Efficacy of Three Antimalarial Regimens for Uncomplicated Plasmodium Falciparum Malaria in Cambodia, 2009 – 2011: A Randomized Control Trial

2021 ◽  
Author(s):  
Dysoley Lek ◽  
Agus Rachmat ◽  
Dustin Harrison ◽  
Geoffrey Chin ◽  
Suwanna Chaoratanakawee ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Copy Number ◽  
Controlled Trial ◽  
Artemisinin Resistance ◽  
Uncomplicated Falciparum Malaria ◽  
Multi Drug Resistance ◽  
Directly Observed Therapy ◽  
Open Label ◽  
Northern Border

Abstract Background: Antimalarial resistance remains an important public health challenge in Cambodia. The effectiveness of three therapies for uncomplicated Falciparum malaria were evaluated in Oddar Meanchey province in Northern Cambodia from 2009 – 2011.Methods: In this randomized, open-label, parallel group controlled trial, 211 subjects at least 5 years old with uncomplicated Falciparum malaria were treated with directly observed therapy. Over 3 days, 63 received artesunate-mefloquine (AS/MQ), 77 received dihydroartemisinin-piperaquine (DHA/PPQ), and 71 received atovaquone-proguanil (ATQ/PG). Subjects were followed for 42 days or until recurrent parasitemia. Genotyping of msp1, msp2, and glurp among individual parasite isolates distinguished recrudescence from reinfection. Pfmdr1 copy number was measured by real-time PCR and half-maximal parasite inhibitory concentrations (IC50) was measured in vitro by 48-hour isotopic hypoxanthine incorporation assay.Results: The primary outcome of per-protocol PCR-adjusted efficacy at 42 days was analyzed for 190 (90.0%) of the enrolled subjects. PCR-adjusted efficacy (95% confidence interval) at 42 days was 80.6% (70.8 – 90.5%) for AS/MQ, 97.2% (93.3 – 100%) for DHA/PPQ, and 92.9% (86.1 – 99.6%) for ATQ/PG. On day 3, 59.3% remained parasitemic. At baseline, 46.9% had microscopic P. falciparum gametocytemia. Both recurrences in the DHA/PPQ arm lost Pfmdr1 copy number amplification at recrudescence. All four recurrences in the ATQ/PG arm were wild-type for cytochrome bc1. One subject withdrew from the ATQ/PG arm due to drug allergy.Conclusions: This previously unpublished study was conducted at the epicenter of substantial multi-drug resistance that emerged soon thereafter. Occurring early in the national transition from AS/MQ to DHA/PPQ, both DHA/PPQ and ATQ/PG had acceptable efficacy against uncomplicated falciparum malaria. However, efficacy of AS/MQ was only 80% with apparent mefloquine resistance based on elevated Pfmdr1 copy number and IC50. By 2009, there was already significant evidence of artemisinin resistance not previously reported at the Northern Cambodia-Thai border. This study suggests the basis for early development of significant DHA/PPQ failures within 3 years of introduction. Artemisinin resistance likely occurred on the Northern border concurrently with that reported along the Western border in Pailin.Trial Registration: This legacy trial was conducted prior to International Committee of Medical Journal Editors’ requirements for preregistration on ClinicalTrials.gov. The full protocol has been provided.

scholarly journals Prevalence of pfk13 and pfmdr1 polymorphisms in Bounkiling, Southern Senegal

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0249357
Author(s):  
Ambroise Ahouidi ◽  
Rafael Oliveira ◽  
Lis Lobo ◽  
Cyrille Diedhiou ◽  
Souleymane Mboup ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Pcr Amplification ◽  
Parasite Clearance ◽  
Dried Blood Spots ◽  
Multi Drug Resistance ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Multidrug Resistance Gene ◽  
Filter Papers

Background Delayed Plasmodium falciparum parasite clearance has been associated with Single Nucleotide Polymorphisms (SNPs) in the kelch protein propeller domain (coded by pfk13 gene). SNPs in the Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) are associated with multi-drug resistance including the combination artemether-lumefantrine. To our knowledge, this is the first work providing information on the prevalence of k13-propeller and pfmdr1 mutations from Sédhiou, a region in the south of Senegal. Methods 147 dried blood spots on filter papers were collected from symptomatic patients attending a hospital located in Bounkiling City, Sédhiou Region, Southern Senegal. All samples were collected between 2015–2017 during the malaria transmission season. Specific regions of the gene pfk13 and pfmdr1 were analyzed using PCR amplification and Sanger sequencing. Results The majority of parasites (92.9%) harboured the pfk13 wild type sequence and 6 samples harboured synonymous changes. Regarding pfmdr1, wild-type alleles represented the majority except at codon 184. Overall, prevalence of 86Y was 11.9%, 184F was 56.3% and 1246Y was 1.5%. The mutant allele 184F decreased from 73.7% in 2015 to 40.7% in 2017. The prevalence of haplotype NFD decreased from 71.4% in 2015 to 20.8% in 2017. Conclusions This study provides the first description of pfk13 and pfmdr1 genes variations in Bounkiling, a city in the Sédhiou Region of Senegal, contributing to closing the gap of information on anti-malaria drug resistance molecular markers in southern Senegal.

Multi-drug resistance gene-1 (MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by C0 or C2 measurements

2007 ◽  
Vol 21 (2) ◽  
pp. 252-257 ◽  
Author(s):  
Salim Fredericks ◽  
AnaMaria Jorga ◽  
Iain A.M. MacPhee ◽  
Sandrine Reboux ◽  
Elizabeth Shiferaw ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Gene ◽  
Multi Drug Resistance ◽  
Drug Resistance Gene ◽  
Mdr 1
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