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Antimicrobial Agents and Chemotherapy Apr 2017Lausannevirus belongs to the family within the group of nucleocytoplasmic large DNA viruses (NCLDVs). These giant viruses exhibit unique features, including a large...
Lausannevirus belongs to the family within the group of nucleocytoplasmic large DNA viruses (NCLDVs). These giant viruses exhibit unique features, including a large genome, ranging from 100 kb to 2.5 Mb and including from 150 to more than 2,500 genes, as well as the presence of genes coding for proteins involved in transcription and translation. The large majority of Lausannevirus open reading frames have unknown functions. Interestingly, a bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is encoded in the Lausannevirus genome. The enzyme plays central roles in DNA precursor biosynthesis. DHFR is the pharmacological target of antifolates, such as trimethoprim, pyrimethamine, and proguanil. First, the functionality of Lausannevirus DHFR-TS was demonstrated by the successful complementation of a DHFR-deficient strain with a plasmid expressing the heterologous gene. Additionally, using this heterologous expression system, we demonstrated the susceptibility of Lausannevirus DHFR-TS to proguanil and its resistance to pyrimethamine and trimethoprim. Proguanil may provide a unique and useful treatment if Lausannevirus proves to be a human pathogen. To our knowledge, this is the first time that a DHFR-TS has been described and characterized in an NCLDV.
Topics: DNA Viruses; Enzyme Activation; Folic Acid Antagonists; Humans; Proguanil; Pyrimethamine; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase; Trimethoprim
PubMed: 28137801
DOI: 10.1128/AAC.02573-16 -
Antimicrobial Agents and Chemotherapy Jul 2015The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua...
Population pharmacokinetics, tolerability, and safety of dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine-piperaquine in pregnant and nonpregnant Papua New Guinean women.
The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The area under the plasma PQ concentration-time curve (AUC0-∞) was lower in the pregnant patients (median [interquartile range], 23,721 μg · h/liter [21,481 to 27,951 μg · h/liter] versus 35,644 μg · h/liter [29,546 to 39,541 μg · h/liter]; P < 0.001) in association with a greater clearance relative to bioavailability (73.5 liters/h [69.4 to 78.4] versus 53.8 liters/h [49.7 to 58.2]; P < 0.001), but pregnancy did not influence the pharmacokinetics of DHA. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC0-∞ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.
Topics: Adolescent; Adult; Antimalarials; Area Under Curve; Artemisinins; Biological Availability; Dietary Fats; Drug Combinations; Female; Follow-Up Studies; Food-Drug Interactions; Humans; Infant, Newborn; Malaria, Falciparum; Models, Statistical; Papua New Guinea; Pregnancy; Pregnancy Outcome; Pyrimethamine; Quinolines; Sulfadoxine; Young Adult
PubMed: 25963981
DOI: 10.1128/AAC.00326-15 -
Tropical Medicine & International... Jun 2000We conducted two randomized clinical trials to determine the in vivo efficacy of amodiaquine and sulfadoxine/pyrimethamine in treating Plasmodium falciparum malaria.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
We conducted two randomized clinical trials to determine the in vivo efficacy of amodiaquine and sulfadoxine/pyrimethamine in treating Plasmodium falciparum malaria. Seventy-five patients under the age of 10 years in Kibwezi, Kenya, and 171 patients in Kigoma, Tanzania, were enrolled for treatment. Due to loss of eight patients in Kibwezi and 37 in Kigoma to follow-up, we used best and worst case scenarios for the parasitological response. The in vivo sensitivity of Plasmodium falciparum to amodiaquine was 75% (no loss to follow-up) in Kibwezi and ranged from 85% in the best to 65% in the worst case scenario in Kigoma. The sensitivity to sulfadoxine/pyrimethamine was 70% to 88% in Kibwezi and 65% to 89% in Kigoma. R1 resistance to amodiaquine was 22% in Kibwezi and varied from 6% in the best to 26% for the worst case scenario in Kigoma. The R1 resistance to sulfadoxine/pyrimethamine was 5% to 23% in Kibwezi and 2% to 26% in Kigoma. R2 resistance was 3% for amodiaquine and 7% for sulfadoxine/pyrimethamine in Kibwezi and 9% in Kigoma for each treatment group. There was no statistically significant difference between treatment groups at either study site, except for a slight difference in R1 resistance in the best case scenario, Kibwezi, in favour of S/P. Although both amodiaquine and sulfadoxine/pyrimethamine resistance seems to be increasing, these antimalarials are still effective in parasite clearance.
Topics: Amodiaquine; Animals; Antimalarials; Child; Child, Preschool; Drug Resistance, Microbial; Female; Fever; Humans; Infant; Kenya; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Tanzania; Treatment Outcome
PubMed: 10929148
DOI: 10.1046/j.1365-3156.2000.00570.x -
PloS One Aug 2009Sulfadoxine-pyrimethamine was a common first line drug therapy to treat uncomplicated falciparum malaria, but increasing therapeutic failures associated with the...
Effects of point mutations in Plasmodium falciparum dihydrofolate reductase and dihydropterate synthase genes on clinical outcomes and in vitro susceptibility to sulfadoxine and pyrimethamine.
BACKGROUND
Sulfadoxine-pyrimethamine was a common first line drug therapy to treat uncomplicated falciparum malaria, but increasing therapeutic failures associated with the development of significant levels of resistance worldwide has prompted change to alternative treatment regimes in many national malaria control programs. METHODOLOGY AND FINDING: We conducted an in vivo therapeutic efficacy trial of sulfadoxine-pyrimethamine at two locations in the Peruvian Amazon enrolling 99 patients of which, 86 patients completed the protocol specified 28 day follow up. Our objective was to correlate the presence of polymorphisms in P. falciparum dihydrofolate reductase and dihydropteroate synthase to in vitro parasite susceptibility to sulfadoxine and pyrimethamine and to in vivo treatment outcomes. Inhibitory concentration 50 values of isolates increased with numbers of mutations (single [108N], sextuplet [BR/51I/108N/164L and 437G/581G]) and septuplet (BR/51I/108N/164L and 437G/540E/581G) with geometric means of 76 nM (35-166 nM), 582 nM (49-6890- nM) and 4909 (3575-6741 nM) nM for sulfadoxine and 33 nM (22-51 nM), 81 nM (19-345 nM), and 215 nM (176-262 nM) for pyrimethamine. A single mutation present in the isolate obtained at the time of enrollment from either dihydrofolate reductase (164L) or dihydropteroate synthase (540E) predicted treatment failure as well as any other single gene alone or in combination. Patients with the dihydrofolate reductase 164L mutation were 3.6 times as likely to be treatment failures [failures 85.4% (164L) vs 23.7% (I164); relative risk = 3.61; 95% CI: 2.14 - 6.64] while patients with the dihydropteroate synthase 540E were 2.6 times as likely to fail treatment (96.7% (540E) vs 37.5% (K540); relative risk = 2.58; 95% CI: 1.88 - 3.73). Patients with both dihydrofolate reductase 164L and dihydropteroate synthase 540E mutations were 4.1 times as likely to be treatment failures [96.7% vs 23.7%; RR = 4.08; 95% CI: 2.45 - 7.46] compared to patients having both wild forms (I164 and K540).
CONCLUSIONS
In this part of the Amazon basin, it may be possible to predict treatment failure with sulfadoxine-pyrimethamine equally well by determination of either of the single mutations dihydrofolate reductase 164L or dihydropteroate synthase 540E.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00951106.
Topics: Animals; Antimalarials; Dihydropteroate Synthase; Plasmodium falciparum; Point Mutation; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase
PubMed: 19707564
DOI: 10.1371/journal.pone.0006762 -
Malaria Journal Nov 2017Seasonal malaria chemoprevention (SMC) was recommended in 2012 for young children in the Sahel during the peak malaria transmission season. Children are given a single...
Seasonal malaria chemoprevention (SMC) was recommended in 2012 for young children in the Sahel during the peak malaria transmission season. Children are given a single dose of sulfadoxine/pyrimethamine combined with a 3-day course of amodiaquine, once a month for up to 4 months. Roll-out and scale-up of SMC has been impressive, with 12 million children receiving the intervention in 2016. There is evidence of its overall benefit in routine implementation settings, and a meta-analysis of clinical trial data showed a 75% decrease in clinical malaria compared to placebo. SMC is not free of shortcomings. Its target zone includes many hard-to-reach areas, both because of poor infrastructure and because of political instability. Treatment adherence to a 3-day course of preventive treatment has not been fully documented, and could prove challenging. As SMC is scaled up, integration into a broader, community-based paradigm which includes other preventive and curative activities may prove beneficial, both for health systems and for recipients.
Topics: Africa South of the Sahara; Amodiaquine; Antimalarials; Chemoprevention; Child, Preschool; Drug Combinations; Humans; Infant; Malaria; Pyrimethamine; Seasons; Sulfadoxine
PubMed: 29183327
DOI: 10.1186/s12936-017-2132-1 -
Molecules (Basel, Switzerland) Nov 2021In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for...
In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.
Topics: Crystallography, X-Ray; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Pyrimethamine; Pyrimidines; Tetrahydrofolate Dehydrogenase; Trimethoprim
PubMed: 34771128
DOI: 10.3390/molecules26216721 -
The Lancet. Infectious Diseases Jan 2011After the launch of the National Malaria Control Programme in 1953, the number of malaria cases reported in India fell to an all-time low of 0·1 million in 1965.... (Review)
Review
After the launch of the National Malaria Control Programme in 1953, the number of malaria cases reported in India fell to an all-time low of 0·1 million in 1965. However, the initial success could not be maintained and a resurgence of malaria began in the late 1960s. Resistance of Plasmodium falciparum to chloroquine was first reported in 1973 and increases in antimalarial resistance, along with rapid urbanisation and labour migration, complicated the challenge that India's large geographical area and population size already pose for malaria control. Although several institutions have done drug-resistance monitoring in India, a complete analysis of countrywide data across institutions does not exist. We did a systematic review of P falciparum malaria drug-efficacy studies in India to summarise drug-resistance data and describe changes over the past 30 years to inform future policy. Continued use of chloroquine for treatment of P falciparum malaria in India will likely be ineffective. Resistance to sulfa-pyrimethamine should be closely monitored to protect the effectiveness of treatment with artesunate plus sulfadoxine-pyrimethamine, which is the new first-line treatment for P falciparum malaria. Strategies to reduce the emergence and spread of future drug resistance need to be proactive and supported by intensive monitoring.
Topics: Antimalarials; Artemisinins; Artesunate; Chloroquine; Drug Combinations; Drug Resistance; Geography; Humans; India; Malaria, Falciparum; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Time Factors; Treatment Outcome
PubMed: 21183147
DOI: 10.1016/S1473-3099(10)70214-0 -
Japanese Journal of Infectious Diseases 2012Malaria is a protozoan disease transmitted by the bite of the Anopheles mosquito. Among five species that can infect humans, Plasmodium falciparum is responsible for the... (Review)
Review
Malaria is a protozoan disease transmitted by the bite of the Anopheles mosquito. Among five species that can infect humans, Plasmodium falciparum is responsible for the most severe human malaria. Resistance of P. falciparum to chloroquine and pyrimethamine/sulfadoxine, conventionally used antimalarial drugs, is already widely distributed in many endemic areas. As a result, artemisinin-based combination therapies have been rapidly and widely adopted as first-line antimalarial treatments since the mid-2000s. Recent population and evolutionary genetic analyses have proven that the geographic origins of parasite lineages resistant to the conventional drugs are considerably limited. Almost all resistance emerged from either Southeast Asia or South America. The Greater Mekong subregion in Southeast Asia is probably the most alarming source of resistance, from which P. falciparum resistant to chloroquine and pyrimethamine/sulfadoxine dispersed to Africa. The emergence of artemisinin resistance has also recently been confirmed in the Greater Mekong. The WHO Global Malaria Programme has recently launched a "Global Plan for Artemisinin Resistance Containment," which aims to prevent the spread of artemisinin resistance while also stopping the emergence of novel resistance. However, an inadequate understanding of a mechanism of artemisinin resistance and the lack of reliable genetic markers to monitor artemisinin resistance make it difficult to survey the spread of resistance. Elucidation of such markers would substantially contribute to the design of an effective policy for the containment of artemisinin resistance.
Topics: Africa; Antimalarials; Artemisinins; Asia, Southeastern; Biological Evolution; Chloroquine; Drug Combinations; Drug Resistance; Gene Flow; Humans; Plasmodium falciparum; Pyrimethamine; South America; Sulfadoxine
PubMed: 23183197
DOI: 10.7883/yoken.65.465 -
Antiviral Research Jan 2019Rabies virus transmits from animals to humans and causes encephalitis. Every year more than 15 million people receive a post exposure prophylaxis (PEP) treatment that is...
Rabies virus transmits from animals to humans and causes encephalitis. Every year more than 15 million people receive a post exposure prophylaxis (PEP) treatment that is highly effective in the prevention of rabies disease. However, when clinical symptoms appear, for example in people who did not receive PEP, rabies is almost invariably fatal. Due to the limited access to PEP in some target populations, mostly in Asia and in Africa, rabies causes at least 59,000 deaths a year. PEP is not effective after the onset of symptoms and attempts to develop a treatment for clinical rabies have been unsuccessful. After screening a library of 385 FDA-approved drugs, we found that pyrimethamine inhibits rabies infection in vitro through the inhibition of adenosine synthesis. In addition, this compound shows a synergistic interaction with ribavirin. Unfortunately, in rabies infected-mice, pyrimethamine showed no efficacy. One possible explanation may be that the antiviral effect is negated by the observed interference of pyrimethamine with the innate immune response.
Topics: Adenosine; Animals; Antiviral Agents; Drug Synergism; Mice; Mice, Inbred BALB C; Pyrimethamine; Rabies virus; Ribavirin; Small Molecule Libraries; Virus Replication
PubMed: 30367894
DOI: 10.1016/j.antiviral.2018.10.016 -
Archives of Disease in Childhood Jan 1986Toxoplasma was the cause of encephalitis in a 4 year old boy. He recovered completely after treatment with pyrimethamine and sulphadimidine. Toxoplasma encephalitis has...
Toxoplasma was the cause of encephalitis in a 4 year old boy. He recovered completely after treatment with pyrimethamine and sulphadimidine. Toxoplasma encephalitis has a high mortality, and active treatment is recommended.
Topics: Child, Preschool; Drug Therapy, Combination; Encephalitis; Humans; Male; Pyrimethamine; Sulfamethazine; Toxoplasmosis
PubMed: 3954425
DOI: 10.1136/adc.61.1.84