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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 -
The Cochrane Database of Systematic... Jul 2021Intermittent preventive treatment could help prevent malaria in infants (IPTi) living in areas of moderate to high malaria transmission in sub-Saharan Africa. The World... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intermittent preventive treatment could help prevent malaria in infants (IPTi) living in areas of moderate to high malaria transmission in sub-Saharan Africa. The World Health Organization (WHO) policy recommended IPTi in 2010, but its adoption in countries has been limited.
OBJECTIVES
To evaluate the effects of intermittent preventive treatment (IPT) with antimalarial drugs to prevent malaria in infants living in malaria-endemic areas.
SEARCH METHODS
We searched the following sources up to 3 December 2018: the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library), MEDLINE (PubMed), Embase (OVID), LILACS (Bireme), and reference lists of articles. We also searched the metaRegister of Controlled Trials (mRCT) and the WHO International Clinical Trials Registry Platform (ICTRP) portal for ongoing trials up to 3 December 2018.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) that compared IPT to placebo or no intervention in infants (defined as young children aged between 1 to 12 months) in malaria-endemic areas.
DATA COLLECTION AND ANALYSIS
The primary outcome was clinical malaria (fever plus asexual parasitaemia). Two review authors independently assessed trials for inclusion, evaluated the risk of bias, and extracted data. We summarized dichotomous outcomes and count data using risk ratios (RR) and rate ratios respectively, and presented all measures with 95% confidence intervals (CIs). We extracted protective efficacy values and their 95% CIs; when an included trial did not report this data, we calculated these values from the RR or rate ratio with its 95% CI. Where appropriate, we combined data in meta-analyses and assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS
We included 12 trials that enrolled 19,098 infants; all were conducted in sub-Saharan Africa. Three trials were cluster-RCTs. IPTi with sulfadoxine-pyrimethamine (SP) was evaluated in 10 trials from 1999 to 2013 (n = 15,256). Trials evaluating ACTs included dihydroartemisinin-piperaquine (1 trial, 147 participants; year 2013), amodiaquine-artesunate (1 study, 684 participants; year 2008), and SP-artesunate (1 trial, 676 participants; year 2008). The earlier studies evaluated IPTi with SP, and were conducted in Tanzania (in 1999 and 2006), Mozambique (2004), Ghana (2004 to 2005), Gabon (2005), Kenya (2008), and Mali (2009). One trial evaluated IPTi with amodiaquine in Tanzania (2000). Later studies included three conducted in Kenya (2008), Tanzania (2008), and Uganda (2013), evaluating IPTi in multiple trial arms that included artemisinin-based combination therapy (ACT). Although the effect size varied over time and between drugs, overall IPTi impacts on the incidence of clinical malaria overall, with a 30% reduction (rate ratio 0.70, 0.62 to 0.80; 10 studies, 10,602 participants). The effect of SP appeared to attenuate over time, with trials conducted after 2009 showing little or no effect of the intervention. IPTi with SP probably resulted in fewer episodes of clinical malaria (rate ratio 0.78, 0.69 to 0.88; 8 trials, 8774 participants, moderate-certainty evidence), anaemia (rate ratio 0.82, 0.68 to 0.98; 6 trials, 7438 participants, moderate-certainty evidence), parasitaemia (rate ratio 0.66, 0.56 to 0.79; 1 trial, 1200 participants, moderate-certainty evidence), and fewer hospital admissions (rate ratio 0.85, 0.78 to 0.93; 7 trials, 7486 participants, moderate-certainty evidence). IPTi with SP probably made little or no difference to all-cause mortality (risk ratio 0.93, 0.74 to 1.15; 9 trials, 14,588 participants, moderate-certainty evidence). Since 2009, IPTi trials have evaluated ACTs and indicate impact on clinical malaria and parasitaemia. A small trial of DHAP in 2013 shows substantive effects on clinical malaria (RR 0.42, 0.33 to 0.54; 1 trial, 147 participants, moderate-certainty evidence) and parasitaemia (moderate-certainty evidence).
AUTHORS' CONCLUSIONS
In areas of sub-Saharan Africa, giving antimalarial drugs known to be effective against the malaria parasite at the time to infants as IPT probably reduces the risk of clinical malaria, anaemia, and hospital admission. Evidence from SP studies over a 19-year period shows declining efficacy, which may be due to increasing drug resistance. Combinations with ACTs appear promising as suitable alternatives for IPTi.
Topics: Africa South of the Sahara; Amodiaquine; Antimalarials; Artemisinins; Bias; Confidence Intervals; Disease Eradication; Drug Combinations; Endemic Diseases; Hospitalization; Humans; Infant; Malaria; Parasitemia; Pyrimethamine; Quinolines; Randomized Controlled Trials as Topic; Sulfadoxine
PubMed: 34273901
DOI: 10.1002/14651858.CD011525.pub3 -
Malaria Journal Feb 2021In Tanzania, the uptake of optimal doses (≥ 3) of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria (IPTp-SP) during pregnancy has remained...
Predictors for the uptake of optimal doses of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy in Tanzania: further analysis of the data of the 2015-2016 Tanzania demographic and health survey and malaria indicator survey.
BACKGROUND
In Tanzania, the uptake of optimal doses (≥ 3) of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria (IPTp-SP) during pregnancy has remained below the recommended target of 80%. Therefore, this study aimed to investigate the predictors for the uptake of optimal IPTp-SP among pregnant women in Tanzania.
METHODS
This study used data from the 2015-16 Tanzania demographic and health survey and malaria indicator survey (TDHS-MIS). The study had a total of 4111 women aged 15 to 49 who had live births 2 years preceding the survey. The outcome variable was uptake of three or more doses of IPTp-SP, and the independent variables were age, marital status, education level, place of residence, wealth index, occupation, geographic zone, parity, the timing of first antenatal care (ANC), number of ANC visits and type of the health facility for ANC visits. Predictors for the optimal uptake of IPTp-SP were assessed using univariate and multivariable logistic regression.
RESULTS
A total of 327 (8%) women had optimal uptake of IPTp-SP doses. Among the assessed predictors, the following were significantly associated with optimal uptake of IPTp-SP doses; education level [primary (AOR: 2.2, 95% CI 1.26-3.67); secondary or higher education (AOR: 2.1, 95% CI 1.08-4.22)], attended ANC at the first trimester (AOR: 2.4, 95% CI 1.20-4.96), attended ≥ 4 ANC visits (AOR: 1.9, 95% CI 1.34-2.83), attended government health facilities (AOR: 1.5, 95% CI 1.07-1.97) and geographic zone [Central (AOR: 5, 95% CI 2.08-11.95); Southern Highlands (AOR: 2.8, 95% CI 1.15-7.02); Southwest Highlands (AOR: 2.7, 95% CI 1.03-7.29); Lake (AOR: 3.5, 95% CI 1.51-8.14); Eastern (AOR: 1.5, 95% CI 1.88-11.07)].
CONCLUSIONS
The uptake of optimal IPTp-SP doses is still low in Tanzania. The optimal uptake of IPTp-SP was associated with attending ANC in the first trimester, attending more than four ANC visits, attending government health facility for ANC, having primary, secondary, or higher education level, and geographic zone. Therefore, there is a need for health education and behavior change interventions with an emphasis on the optimal use of IPTp-SP doses.
Topics: Adolescent; Adult; Antimalarials; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Combinations; Female; Health Facilities; Humans; Malaria, Falciparum; Middle Aged; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Prenatal Care; Pyrimethamine; Sulfadoxine; Tanzania; Young Adult
PubMed: 33549094
DOI: 10.1186/s12936-021-03616-2 -
Naunyn-Schmiedeberg's Archives of... Sep 2017The study was intended to investigate the effect of concomitant administration of antimalarial drug (pyrimethamine or arteether) on pharmacokinetic and post coitus... (Comparative Study)
Comparative Study
The study was intended to investigate the effect of concomitant administration of antimalarial drug (pyrimethamine or arteether) on pharmacokinetic and post coitus contraceptive efficacy of ormeloxifene in female Sprague-Dawley rats. A serial sampling technique coupled with LC-MS/MS detection was utilized for quantification of ormeloxifene in plasma samples collected from female rats treated with ormeloxifene only and ormeloxifene with pyrimethamine or arteether. Coitus-proven female rats were utilized to investigate the effect of pyrimethamine or arteether coadministration on contraceptive efficacy of ormeloxifene by investigating the presence or absence of implantations and status of corpora lutea on day 10 post coitum. None of the sperm-positive rats treated with ormeloxifene with or without coadministration of pyrimethamine or arteether showed any sign of pregnancy, confirming that concomitant administration of antimalarial drugs (pyrimethamine or arteether) did not affect the pharmacodynamic profile of ormeloxifene. Although there was no sign of pharmacodynamic interaction, the volume of distribution of ormeloxifene increased significantly on cotreatment with pyrimethamine. However, coadministration of arteether did not affect any of the pharmacokinetic parameters of ormeloxifene. The compiled results of preliminary study in female rats support that pyrimethamine or arteether can be prescribed with ormeloxifene.
Topics: Animals; Antimalarials; Artemisinins; Benzopyrans; Chromatography, Liquid; Contraceptives, Postcoital; Drug Interactions; Female; Male; Pregnancy; Pyrimethamine; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tissue Distribution
PubMed: 28689253
DOI: 10.1007/s00210-017-1401-4 -
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 -
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 -
The Lancet. Infectious Diseases May 2019
Topics: Humans; Pregnancy; Africa; Drug Combinations; Malaria; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Pregnancy Complications, Parasitic
PubMed: 30922819
DOI: 10.1016/S1473-3099(18)30796-5 -
Future Medicinal Chemistry Aug 2021STAT3 is a pro-oncogenic transcription factor. Pyrimethamine (PYM) is a STAT3 inhibitor that suppresses the proliferation of some cancer cells through downregulation of...
STAT3 is a pro-oncogenic transcription factor. Pyrimethamine (PYM) is a STAT3 inhibitor that suppresses the proliferation of some cancer cells through downregulation of STAT3 target proteins. We have used structure-based tools to design novel PYM-based compounds. Intracellular target validation studies revealed that representative compounds and downregulate STAT3 downstream proteins and inhibit STAT3 DNA binding domain (DBD). Relative to PYM, a cohort of these compounds are >100-fold more cytotoxic to cancer cells with constitutively active (high pSTAT3) and basal (low pSTAT3) STAT3 signaling, suggesting that STAT3 DBD inhibition is deleterious to the proliferation of cancer cells with low and high pSTAT3 levels. These are promising leads for further preclinical evaluation as therapeutic agents for STAT3-dependent cancers.
Topics: Binding Sites; Cell Line; Cell Proliferation; DNA; Down-Regulation; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Protein Domains; Pyrimethamine; S Phase Cell Cycle Checkpoints; STAT3 Transcription Factor; Signal Transduction; Structure-Activity Relationship
PubMed: 34180263
DOI: 10.4155/fmc-2021-0088 -
Journal of Chromatographic Science Oct 2021A simple, accurate and precise RP-HPLC method was developed for the simultaneous determination of chloroquine, pyrimethamine and cetirizine hydrochloride concentrations...
A simple, accurate and precise RP-HPLC method was developed for the simultaneous determination of chloroquine, pyrimethamine and cetirizine hydrochloride concentrations in bulk drug and human serum. The assay was performed using a mobile phase of methanol: water (70:30) at pH of 2.8 ± 0.05 on the Purospher C-18 column with UV detection at 230 nm and rosuvastatin used as an internal standard. The retention times observed for chloroquine, pyrimethamine and cetirizine hydrochloride were 3.5, 2.5 and 5.5 minutes, respectively. The method was found to be specific for the assayed drugs showing a linear response in the concentration range of 1-100 μg mL-1 with coefficients of determination values of (r = 0.999). The method was developed and validated according to ICH guidelines. The method was used to monitor the serum samples and was found to be sensitive for therapeutic purposes, showing the potential to be a useful tool for routine analysis in laboratories.
Topics: Cetirizine; Chloroquine; Chromatography, High Pressure Liquid; Humans; Pyrimethamine; Reproducibility of Results
PubMed: 33621328
DOI: 10.1093/chromsci/bmab018 -
Medecine Et Sante Tropicales Aug 2016Until 2006, the Mauritanian Ministry of Health recommended chloroquine and sulfadoxine-pyrimethamine for first- and second-line treatment of uncomplicated malaria,...
BACKGROUND
Until 2006, the Mauritanian Ministry of Health recommended chloroquine and sulfadoxine-pyrimethamine for first- and second-line treatment of uncomplicated malaria, respectively. This study assessed the clinical efficacy of sulfadoxine-pyrimethamine in Kobeni as first-line treatment.
MATERIALS AND METHODS
This study included 55 patients with Plasmodium falciparum infections, who were treated with sulfadoxine-pyrimethamine and followed up for 28 days. Isolates were genotyped to distinguish between recrudescence and reinfection. Treatment success rates and survival were analysed per protocol to evaluate drug efficacy.
RESULTS
After inclusion, 2 patients were excluded for protocol violations, and 3 patients were lost to follow-up. Of the remaining 50 patients (per protocol population), 43 (86%) had adequate clinical and parasitological responses. Of the 7 patients with treatment failure, 5 (10%) were early failures, while 2 (4%) had initially responded and had late clinical failure on day 7, associated with recrudescence. With the exception of one adult weighing 91 kg, all treatment failures occurred in children aged from 7 to 12 years.
CONCLUSIONS
Sulfadoxine-pyrimethamine monotherapy was moderately effective but insufficiently reliable in view of the relatively high rate of early treatment failure. The high prevalence of chloroquine resistance found in earlier studies and the results of the present study on sulfadoxine-pyrimethamine justify the change in national policy and systematic use of artemisinin-based combination therapy for first-line treatment of P. falciparum malaria in Mauritania.
Topics: Adolescent; Adult; Antimalarials; Child; Child, Preschool; Drug Combinations; Female; Humans; Malaria, Falciparum; Male; Mauritania; Middle Aged; Pyrimethamine; Sulfadoxine; Treatment Failure; Young Adult
PubMed: 27694087
DOI: 10.1684/mst.2016.0578