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Malaria Journal Mar 2022Malaria in Mali remains a primary cause of morbidity and mortality, with women at high risk during pregnancy for placental malaria (PM). Risk for PM and its association...
Risk factors for placental malaria, sulfadoxine-pyrimethamine doses, and birth outcomes in a rural to urban prospective cohort study on the Bandiagara Escarpment and Bamako, Mali.
BACKGROUND
Malaria in Mali remains a primary cause of morbidity and mortality, with women at high risk during pregnancy for placental malaria (PM). Risk for PM and its association with birth outcomes was evaluated in a rural to urban longitudinal cohort on the Bandiagara Escarpment and the District of Bamako.
METHODS
Placental samples (N = 317) were collected from 249 mothers who were participants in a prospective cohort study directed by BIS in the years 2011 to 2019. A placental pathologist and research assistant evaluated the samples by histology in blinded fashion to assess PM infection stage and parasite density. Generalized estimating equations (GEE) were used to model the odds of PM infection.
RESULTS
In a multivariable model, pregnancies in Bamako, beyond secondary education, births in the rainy season (instead of the hot dry season), and births to women who had ≥ 3 doses of sulfadoxine-pyrimethamine (SP) instead of no doses were associated with reduced odds of experiencing PM (active and past infections combined). Births in later years of the study were strongly associated with reduced odds of PM. Maternal age, which was positively associated with offspring year of birth, was significant as a predictor of PM only if offspring year of birth was omitted from the model. Gravidity was positively associated with both maternal age and offspring year of birth such that if either variable was included in the model, then gravidity was no longer significant. However, if maternal age or year of offspring birth were not adjusted for, then the odds of PM were nearly two-fold higher in primigravida compared to multigravida. Birth outcomes improved (+ 285 g birth weight, + 2 cm birth length, + 75 g placental weight) for women who had ≥ 3 doses of SP compared to no doses, but no difference was detected in birth weight or length for women who had 2 instead of ≥ 3 SP doses. However, at 2 instead of ≥ 3 doses placentas were 36 g lighter and the odds of low birth weight (< 2500 g) were 14% higher. Severe parasite densities (> 10% erythrocytes infected) were significantly associated with decreases in birth weight, birth length, and placental weight, as were chronic PM infections. The women who received no SP during pregnancy (7% of the study total) were younger and lacked primary school education. The women who received ≥ 3 doses of SP came from more affluent families.
CONCLUSIONS
Women who received no doses of SP during pregnancy experienced the most disadvantageous birth outcomes in both Bamako and on the Bandiagara Escarpment. Such women tended to be younger and to have had no primary school education. Targeting such women for antenatal care, which is the setting in which SP is most commonly administered in Mali, will have a more positive impact on public health than focusing on the increment from two to three doses of SP, although that increment is also desirable.
Topics: Cohort Studies; Drug Combinations; Female; Gravidity; Humans; Malaria; Mali; Placenta; Pregnancy; Prospective Studies; Pyrimethamine; Risk Factors; Sulfadoxine
PubMed: 35361195
DOI: 10.1186/s12936-022-04125-6 -
Acta Parasitologica Sep 2019Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the...
Pravastatin and Simvastatin Pretreatment in Combination with Pyrimethamine and Sulfadiazine Reduces Infection Process of Toxoplasma gondii Tachyzoites (RH Strain) in HeLa Cells.
PURPOSE
Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite's apicoplast.
METHODS
To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (10) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 10) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine.
RESULTS
Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control.
CONCLUSION
Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects.
Topics: Antiprotozoal Agents; Cell Survival; Drug Synergism; HeLa Cells; Humans; Life Cycle Stages; Pravastatin; Pyrimethamine; Simvastatin; Sulfadiazine; Toxoplasma; Toxoplasmosis
PubMed: 31286354
DOI: 10.2478/s11686-019-00076-2 -
Acta Parasitologica Mar 2022The problem of resistance to antiparasitic drugs, associated with their side effects, suggest exploring other alternatives, including medicinal plants. Dracocephalum...
BACKGROUND
The problem of resistance to antiparasitic drugs, associated with their side effects, suggest exploring other alternatives, including medicinal plants. Dracocephalum kotschyi (D. kotschyi), for example, from Lamiaceae family, is a plant widely used in Iran and in many countries, and to which interesting pharmacological properties have been attributed. This study aimed to investigate in vitro and in vivo anti-Toxoplasma activities of D. kotschyi extract in experimental models of acute toxoplasmosis.
METHODS
Anti-Toxoplasma activity of the extracts in vitro was performed on Vero Cell, using the MTT test. Vero cell were infected with (3 × 10 tachyzoites/well) following treatment with Dichloromethane (F1), dichloromethane: methanol (F2), methanol (F3), methanol: water (F4), and deionized water (F5) extracts of D. kotschyi, and pyrimethamine and sulfadiazine (positive control). MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was used to measure cell viability. Effects of extracts on tachyzoites viability were evaluated by trypan blue exclusion method, followed by light microscopy. For in vivo test, 18 groups of 8-10-week-old Inbred Balb/c mice weighing 18-20 g, were intraperitoneally infected with 2 × 10 tachyzoites and then treated with sterile PBS (negative control), pyrimethamine (25 mg/kg) and sulfadiazine (500 mg/kg) as positive controls, and F1 to F5 extracts (at doses 50, 100 and 200 mg/kg).
RESULTS
The 50% Inhibitory Concentration of F1 extract, F2 extract, Sulfadiazine (Positive control) and Pyrimethamine (Positive control) were 8.77 µg, 7.1 µg 391.18 µg, and 84.20 µg, respectively, while the selectivity indices were 15.667, 30.197, 1.552 and 4.064, respectively. In vivo anti-Toxoplasma activity test showed that Methanol: water (F-4) 50 extract was more active than the positive control.
CONCLUSIONS
Indeed, the extract allowed a survival rate of 10% of the mice, compared to 0% for all the other groups. D. kotschyi has the potential to be valorized in the management of toxoplasmosis.
Topics: Animals; Lamiaceae; Mice; Models, Theoretical; Plant Extracts; Toxoplasma; Toxoplasmosis
PubMed: 34800216
DOI: 10.1007/s11686-021-00491-4 -
Malaria Journal Dec 2022Despite significant progress in eliminating malaria from the state of Odisha, India, the disease is still considered endemic. Artesunate plus sulfadoxine-pyrimethamine...
BACKGROUND
Despite significant progress in eliminating malaria from the state of Odisha, India, the disease is still considered endemic. Artesunate plus sulfadoxine-pyrimethamine (AS + SP) has been introduced since 2010 as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study aimed to investigate the prevalence of mutations associated with resistance to chloroquine (CQ), sulfadoxine-pyrimethamine (SP), and artesunate (ART) in P. falciparum parasites circulating in the state.
METHODS
A total of 239 isolates of P. falciparum mono infection were collected during July 2018-November 2020 from the four different geographical regions of the state. Genomic DNA was extracted from 200 µL of venous blood and amplified using nested polymerase chain reaction. Mutations on gene associated with CQ (Pfcrt and Pfmdr1) were assessed by PCR amplification and restriction fragment length polymorphism, artemisinin (Pfk13) gene by DNA sequencing and SP (Pfdhfr and Pfdhps) genes by allele-specific polymerase chain reaction (AsPCR).
RESULTS
The point mutation in Pfcrt (K76T) was detected 2.1%, in Pfmdr1 (N86Y) 3.4%, and no mutations were found in Pfkelch13 propeller domain. Prevalence of Pfdhfr, Pfdhps and Pfhdfr-Pfdhps (two locus) gene mutations were 50.43%, 47.05% and 49.79% respectively. The single, double, triple and quadruple point mutations in Pfdhfr gene was 11.2%, 8.2%, 17.2% and 3.4% while, in Pfdhps gene was 10.9%,19.5%, 9.5% and 2.7% respectively. Of the total 13 haplotypes found in Pfdhfr, 8 were detected for the first time in the state and of the total 26 haplotypes found in Pfdhps, 7 were detected for the fisrt time in the state. The linked quintuple mutation Pfdhfr (N51I-C59R-S108N)-Pfdhps (A437G-K540E) responsible for clinical failure (RIII level of resistance) of SP resistance and A16V-S108T mutation in Pfdhfr responsible for cycloguanil was absent.
CONCLUSION
The study has demonstrated a low prevalence of CQ resistance alleles in the study area. Despite the absence of the Pfkelch13 mutations, high prevalence of Pfdhfr and Pfdhps point mutations undermine the efficacy of SP partner drug, thereby threatening the P. falciparum malaria treatment policy. Therefore, continuous molecular and in vivo monitoring of ACT efficacy is warranted in Odisha.
Topics: Humans; Antimalarials; Artesunate; Chloroquine; Drug Combinations; Drug Resistance; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine; Sulfadoxine; India
PubMed: 36566182
DOI: 10.1186/s12936-022-04403-3 -
Ocular Immunology and Inflammation 2020: To evaluate the effectiveness of treatments for ocular toxoplasmosis (OT).: A review of charts was conducted from patients who experienced an active episode of OT...
: To evaluate the effectiveness of treatments for ocular toxoplasmosis (OT).: A review of charts was conducted from patients who experienced an active episode of OT treated at the Federal University of São Paulo and associated sites. OT charts were reviewed to determine treatment effectiveness based on clinical judgment, taking clinical course and outcome into consideration in addition to change in best-corrected visual acuity. Treatment emergent adverse events (TEAEs) were used to assess safety.: Overall, 451/1200 patient charts met the inclusion criteria. The most commonly prescribed treatment was trimethoprim + sulfamethoxazole (52.3%) followed by pyrimethamine + sulfadiazine (28%). Treatment was successful in 96.9% of patients. Irrespective of the treatment, active lesions were resolved in 63.9% of patients within 6 weeks. Vision improved in 56.3% of patients. The incidence of TEAEs was low (10%).: All treatments were effective for active episodes of OT, with few side effects.
Topics: Adult; Anti-Bacterial Agents; Eye Infections, Parasitic; Female; Follow-Up Studies; Humans; Male; Middle Aged; Retrospective Studies; Toxoplasmosis, Ocular; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 30806556
DOI: 10.1080/09273948.2019.1569242 -
Food and Waterborne Parasitology Sep 2019Congenital toxoplasmosis (CT), the result of a primary infection of pregnant women with which was transmitted to the fetus, may result in mild to deep injuries... (Review)
Review
Congenital toxoplasmosis (CT), the result of a primary infection of pregnant women with which was transmitted to the fetus, may result in mild to deep injuries occurring in the newborn or later in its development or in adolescence. The visual and cognitive impairment that can result imposes substantial economic costs on the individual and society. Numerous observational studies favor the conclusion that, with preventive measures currently available, it is possible to reduce the incidence of infections in pregnant women, the incidence of fetal infection by preventing transplacental transmission, and the gravity of injury in infected newborns. Treatment of infected newborns can also reduce the severity of consequences and the frequency of their occurrence later in life. Prevention programs, however, are applied in only a few countries; in most countries implementation of a national prevention program has not been considered or has been thought to be too expensive. This article lists the methods of prevention of CT and describes existing national prevention programs in France and Austria. It analyzes the economic costs and benefits of maternal screening for CT prevention and mitigation for society and for health systems. The economic feasibility of implementing national screening in low-prevalence, high-cost countries is illustrated with the example of the United States. New diagnostic tools are discussed and the implication of lower costs is considered, for countries with well-established screening programs as well as those with inadequate prenatal care networks.
PubMed: 32095628
DOI: 10.1016/j.fawpar.2019.e00058 -
PloS One 2022The amplification of GTP cyclohydrolase 1 (pfgch1) in Plasmodium falciparum has been linked to the upregulation of the pfdhfr and pfdhps genes associated with resistance...
BACKGROUND
The amplification of GTP cyclohydrolase 1 (pfgch1) in Plasmodium falciparum has been linked to the upregulation of the pfdhfr and pfdhps genes associated with resistance to the antimalarial drug sulfadoxine-pyrimethamine. During the 1990s and 2000s, sulfadoxine-pyrimethamine was withdrawn from use as first-line treatment in southeast Asia due to clinical drug resistance. This study assessed the temporal and geographic changes in the prevalence of pfdhfr and pfdhps gene mutations and pfgch1 amplification a decade after sulfadoxine-pyrimethamine had no longer been widely used.
METHODS
A total of 536 P. falciparum isolates collected from clinical trials in Thailand, Cambodia, and Lao PDR between 2008 and 2018 were assayed. Single nucleotide polymorphisms of the pfdhfr and pfdhps genes were analyzed using nested PCR and Sanger sequencing. Gene copy number variations of pfgch1 were investigated using real-time polymerase chain reaction assay.
RESULTS
Sequences of the pfdhfr and pfdhps genes were obtained from 96% (517/536) and 91% (486/536) of the samples, respectively. There were 59 distinct haplotypes, including single to octuple mutations. The two major haplotypes observed included IRNI-AGEAA (25%) and IRNL-SGKGA (19%). The sextuple mutation IRNL-SGKGA increased markedly over time in several study sites, including Pailin, Preah Vihear, Ratanakiri, and Ubon Ratchathani, whereas IRNI-AGEAA decreased over time in Preah Vihear, Champasak, and Ubon Ratchathani. Octuple mutations were first observed in west Cambodia in 2011 and subsequently in northeast Cambodia, as well as in southern Laos by 2018. Amplification of the pfgch1 gene increased over time across the region, particularly in northeast Thailand close to the border with Laos and Cambodia.
CONCLUSION
Despite the fact that SP therapy was discontinued in Thailand, Cambodia, and Laos decades ago, parasites retained the pfdhfr and pfdhps mutations. Numerous haplotypes were found to be prevalent among the parasites. Frequent monitoring of pfdhfr and pfdhps in these areas is required due to the relatively rapid evolution of mutation patterns.
Topics: Humans; Plasmodium falciparum; Folic Acid Antagonists; Dihydropteroate Synthase; Malaria, Falciparum; DNA Copy Number Variations; Tetrahydrofolate Dehydrogenase; Thailand; Sulfadoxine; Pyrimethamine; Antimalarials; Drug Resistance; Sulfanilamide; Drug Combinations
PubMed: 36525403
DOI: 10.1371/journal.pone.0278928 -
Acta Tropica Mar 2021Pyrimethamine was first introduced for the treatment of malaria in Asia and Africa during the early 1980s, replacing chloroquine, and has become the first line of drugs... (Review)
Review
Pyrimethamine was first introduced for the treatment of malaria in Asia and Africa during the early 1980s, replacing chloroquine, and has become the first line of drugs in many countries. In recent years, development of pyrimethamine resistance in Plasmodium vivax has become a barrier to effective malaria control strategies. Here, we describe the use of meta-barcoded deep amplicon sequencing technology to assess the evolutionary origin of pyrimethamine resistance by analysing the flanking region of dihydrofolate reductase (dhfr) locus. The genetic modelling suggests that 58R and 173L single mutants and 58R/117N double mutants are present on a single lineage; suggesting a single origin of these mutations. The triple mutants (57L/58R/117N, 58R/61M/117N and 58R/117N/173L) share the lineage of 58R/117N, suggesting a common origin. In contrast, the 117N mutant is present on two separate lineages suggesting that there are multiple origins of this mutation. We characterised the allele frequency of the P. vivax dhfr locus. Our results support the view that the single mutation of 117N and double mutations of 58R/117N arise commonly, whereas the single mutation of 173L and triple mutations of 57L/58R/117N, 58R/61M/117N and 58R/117N/173L are less common. Our work will help to inform mitigation strategies for pyrimethamine resistance in P. vivax.
Topics: Antimalarials; Drug Resistance; Humans; Malaria, Vivax; Mutation; Phylogeny; Plasmodium vivax; Pyrimethamine; Tetrahydrofolate Dehydrogenase
PubMed: 33406444
DOI: 10.1016/j.actatropica.2020.105821 -
Molecular Biology and Evolution Jan 2021We studied five chemically distinct but related 1,3,5-triazine antifolates with regard to their effects on growth of a set of mutants in dihydrofolate reductase. The...
We studied five chemically distinct but related 1,3,5-triazine antifolates with regard to their effects on growth of a set of mutants in dihydrofolate reductase. The mutants comprise a combinatorially complete data set of all 16 possible combinations of four amino acid replacements associated with resistance to pyrimethamine in the malaria parasite Plasmodium falciparum. Pyrimethamine was a mainstay medication for malaria for many years, and it is still in use in intermittent treatment during pregnancy or as a partner drug in artemisinin combination therapy. Our goal was to investigate the extent to which the alleles yield similar adaptive topographies and patterns of epistasis across chemically related drugs. We find that the adaptive topographies are indeed similar with the same or closely related alleles being fixed in computer simulations of stepwise evolution. For all but one of the drugs the topography features at least one suboptimal fitness peak. Our data are consistent with earlier results indicating that third order and higher epistatic interactions appear to contribute only modestly to the overall adaptive topography, and they are largely conserved. In regard to drug development, our data suggest that higher-order interactions are likely to be of little value as an advisory tool in the choice of lead compounds.
Topics: Adaptation, Biological; Alleles; Drug Resistance; Epistasis, Genetic; Evolution, Molecular; Folic Acid Antagonists; Genetic Fitness; Plasmodium falciparum; Pyrimethamine; Saccharomyces cerevisiae; Tetrahydrofolate Dehydrogenase
PubMed: 32745183
DOI: 10.1093/molbev/msaa196 -
Malaria Journal Nov 2019Malaria in pregnancy (MiP) contributes to devastating maternal and neonatal outcomes. Coverage of intermittent preventive treatment during pregnancy (IPTp) remains... (Review)
Review
Malaria in pregnancy (MiP) contributes to devastating maternal and neonatal outcomes. Coverage of intermittent preventive treatment during pregnancy (IPTp) remains alarmingly low. Data was compiled from MiP programme reviews and performed a literature search on access to and determinants of IPTp. National malaria control and reproductive health (RH) policies may be discordant. Integration may improve coverage. Medication stock-outs are a persistent problem. Quality improvement programmes are often not standardized. Capacity building varies across countries. Community engagement efforts primarily focus on promotion of services. The majority of challenges can be addressed at country level to improve IPTp coverage.
Topics: Adolescent; Adult; Antimalarials; Capacity Building; Communicable Disease Control; Community Participation; Female; Health Policy; Humans; Malaria; Patient Acceptance of Health Care; Pregnancy; Pregnancy Complications, Parasitic; Quality Improvement; Reproductive Health; Young Adult
PubMed: 31752868
DOI: 10.1186/s12936-019-3004-7