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1.
Nat Commun ; 11(1): 4813, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968076

RESUMO

Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deleting the homologous gene in P. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Testes Genéticos/métodos , Heme/genética , Heme/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Inativação de Genes , Humanos , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Toxoplasma/efeitos dos fármacos , Toxoplasma/genética
2.
Nat Commun ; 11(1): 3922, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764664

RESUMO

The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is also essential for the survival of the malaria parasite, yet its natural function remains unresolved. We identify host-derived peptides of 4-11 residues, varying in both charge and composition, as the substrates of PfCRT in vitro and in situ, and show that PfCRT does not mediate the non-specific transport of other metabolites and/or ions. We find that drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Our results indicate that PfCRT transports peptides from the lumen of the parasite's digestive vacuole to the cytosol, thereby providing a source of amino acids for parasite metabolism and preventing osmotic stress of this organelle. The resolution of PfCRT's native substrates will aid the development of drugs that target PfCRT and/or restore the efficacy of existing antimalarials.


Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Animais , Transporte Biológico Ativo , Resistência a Medicamentos/genética , Feminino , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/fisiologia , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Modelos Biológicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Oligopeptídeos/metabolismo , Oócitos/metabolismo , Plasmodium falciparum/genética , Transporte Proteico , Proteínas de Protozoários/genética , Xenopus laevis
3.
Nat Commun ; 11(1): 4015, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782246

RESUMO

Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.


Assuntos
Antimaláricos/farmacologia , Eritrócitos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Eritrócitos/parasitologia , Interações Hospedeiro-Parasita , Humanos , Concentração Inibidora 50 , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Fosforilação/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Plasmodium falciparum/fisiologia , Análise Serial de Proteínas , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
ACS Infect Dis ; 6(9): 2524-2531, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32786284

RESUMO

The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 µM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 µM and 13.31 ± 1.24 µM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 µM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.


Assuntos
Antivirais/farmacologia , Artemisininas/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Animais , Antimaláricos/farmacologia , Chlorocebus aethiops , Descoberta de Drogas , Reposicionamento de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Pandemias , Células Vero
5.
Life Sci ; 258: 118205, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777300

RESUMO

AIMS: Coronavirus disease 2019 (COVID-19) has appeared in Wuhan, China but the fast transmission has led to its widespread prevalence in various countries, which has made it a global concern. Another concern is the lack of definitive treatment for this disease. The researchers tried different treatment options which are not specific. The current study aims to identify potential small molecule inhibitors against the main protease protein of SARS-CoV-2 by the computational approach. MAIN METHODS: In this study, a virtual screening procedure employing docking of the two different datasets from the ZINC database, including 1615 FDA approved drugs and 4266 world approved drugs were used to identify new potential small molecule inhibitors for the newly released crystal structure of main protease protein of SARS-CoV-2. In the following to validate the docking result, molecular dynamics simulations were applied on selected ligands to identify the behavior and stability of them in the binding pocket of the main protease in 150 nanoseconds (ns). Furthermore, binding energy using the MMPBSA approach was also calculated. KEY FINDINGS: The result indicates that simeprevir (Hepatitis C virus NS3/4A protease inhibitor) and pyronaridine (antimalarial agent) could fit well to the binding pocket of the main protease and because of some other beneficial features including broad-spectrum antiviral properties and ADME profile, they might be a promising drug candidate for repurposing to the treatment of COVID-19. SIGNIFICANCE: Simeprevir and pyronaridine were selected by the combination of virtual screening and molecular dynamics simulation approaches as a potential candidate for treatment of COVID-19.


Assuntos
Antimaláricos/farmacologia , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Naftiridinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Simeprevir/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Inibidores de Proteases/farmacologia , Serina Proteases , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
6.
PLoS One ; 15(8): e0235401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817665

RESUMO

BACKGROUND: Current malaria control and elimination strategies rely mainly on efficacious antimalarial drugs. However, drug resistance is a major threat facing malaria control programs. Determination of drug resistance molecular markers is useful in the monitoring and surveillance of malaria drug efficacy. This study aimed to determine the mutations and haplotypes frequencies of different genes linked with antimalarial drug resistance in certain areas in Sudan. METHODS: A total of 226 dried blood spots (DBS) of microscopically diagnosed P. falciparum isolates were collected from Khartoum and three other areas in Sudan during 2015-2017. Plasmodium falciparum confirmation and multiplicity of infection was assessed using the Sanger's 101 SNPs-barcode and speciation was confirmed using regions of the parasite mitochondria. Molecular genotyping of drug resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, exonuclease, Pfk13, parasite genetic background (PGB) (Pfarps10, ferredoxin, Pfcrt, Pfmdr2)) was also performed. All genotypes were generated by selective regions amplicon sequencing of the parasite genome using the Illumina MiSeq platform at the Wellcome Sanger Institute, UK then genotypes were translated into drug resistance haplotypes and species determination. FINDINGS: In total 225 samples were confirmed to be P. falciparum. A higher proportion of multiplicity of infection was observed in Gezira (P<0.001) based on the Sanger 101 SNPs -barcode. The overall frequency of mutant haplotype Pfcrt 72-76 CVIET was 71.8%. For Pfmdr1, N86Y was detected in 53.6%, Y184F was observed in 88.1% and D1246Y was detected in 1.5% of the samples. The most frequently observed haplotype was YFD 47.4%. For Pfdhfr (codons 51, 59,108,164), the ICNI haplotype was the most frequent (80.7%) while for Pfdhps (codons 436, 437, 540, 581, 613) the (SGEAA) was most frequent haplotype (41%). The Quadruple mutation (dhfr N51I, S108N + dhps A437G, K540E) was the highest frequent combined mutation (33.9%). In Pfkelch13 gene, 18 non-synonymous mutations were detected, 7 of them were detected in other African countries. The most frequent Pfk13 mutation was E433D detected in four samples. All of the Pfk13 mutant alleles have not been reported to belong to mutations associated with delayed parasite clearance in Southeast Asia. PGB mutations were detected only in Pfcrt N326S\I (46.3%) and Pfcrt I356T (8.2%). The exonuclease mutation was not detected. There was no significant variation in mutant haplotypes between study areas. CONCLUSIONS: There was high frequency of mutations in Pfcrt, Pfdhfr and Pfdhps in this study. These mutations are associated with chloroquine and sulfadoxine-pyrimethamine (SP) resistance. Many SNPs in Pfk13 not linked with delayed parasite clearance were observed. The exonuclease E415G mutation which is linked with piperaquine resistance was not reported.


Assuntos
Resistência a Medicamentos/genética , Malária/parasitologia , Mutação , Plasmodium falciparum/genética , Adolescente , Antimaláricos/farmacologia , Criança , Cloroquina/farmacologia , Feminino , Humanos , Malária/epidemiologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Pirimetamina/farmacologia , Sudão , Sulfadoxina/farmacologia , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Adulto Jovem
7.
PLoS Med ; 17(8): e1003203, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822347

RESUMO

BACKGROUND: Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria. METHODS AND FINDINGS: We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites. In a pilot study, participants were inoculated (Day 0) with approximately 2,800 viable P. falciparum ART-R parasites. In a comparative study, participants were randomised to receive approximately 2,800 viable P. falciparum ART-R (Day 0) or artemisinin-sensitive (ART-S) parasites (Day 1). In both studies, participants were administered a single approximately 2 mg/kg oral dose of artesunate (AS; Day 9). Primary outcomes were safety, ART-R parasite infectivity, and parasite clearance. In the pilot study, 2 participants were enrolled between April 27, 2017, and September 12, 2017, and included in final analyses (males n = 2 [100%], mean age = 26 years [range, 23-28 years]). In the comparative study, 25 participants were enrolled between October 26, 2017, and October 18, 2018, of whom 22 were inoculated and included in final analyses (ART-R infected participants: males n = 7 [53.8%], median age = 22 years [range, 18-40 years]; ART-S infected participants: males n = 5 [55.6%], median age = 28 years [range, 22-35 years]). In both studies, all participants inoculated with ART-R parasites became parasitaemic. A total of 36 adverse events were reported in the pilot study and 277 in the comparative study. Common adverse events in both studies included headache, pyrexia, myalgia, nausea, and chills; none were serious. Seven participants experienced transient severe falls in white cell counts and/or elevations in liver transaminase levels which were considered related to malaria. Additionally, 2 participants developed ventricular extrasystoles that were attributed to unmasking of a predisposition to benign fever-induced tachyarrhythmia. In the comparative study, parasite clearance half-life after AS was significantly longer for ART-R infected participants (n = 13, 6.5 hours; 95% confidence interval [CI] 6.3-6.7 hours) compared with ART-S infected participants (n = 9, 3.2 hours; 95% CI 3.0-3.3 hours; p < 0.001). The main limitation of this study was that the ART-R and ART-S parasite strains did not share the same genetic background. CONCLUSIONS: We developed the first (to our knowledge) human model of ART-R malaria. The delayed clearance profile of ART-R parasites after AS aligns with field study observations. Although based on a relatively small sample size, results indicate that this model can be safely used to assess new drugs against ART-R P. falciparum. TRIAL REGISTRATION: The studies were registered with the Australian New Zealand Clinical Trials Registry: ACTRN12617000244303 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372357) and ACTRN12617001394336 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373637).


Assuntos
Anti-Infecciosos/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/sangue , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/metabolismo , Adolescente , Adulto , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/farmacologia , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Artemisininas/efeitos adversos , Artemisininas/farmacologia , Artesunato/efeitos adversos , Artesunato/farmacologia , Artesunato/uso terapêutico , Austrália/epidemiologia , Feminino , Cefaleia/induzido quimicamente , Voluntários Saudáveis , Humanos , Malária Falciparum/epidemiologia , Masculino , Náusea/induzido quimicamente , Parasitos/metabolismo , Projetos Piloto , Adulto Jovem
8.
PLoS One ; 15(8): e0237791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822392

RESUMO

Artemisinin-based combination therapies (ACTs) have been recommended by the World Health Organization (WHO) as first-line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria since 2005 in Democratic Republic of Congo (DRC) and a regular surveillance of the ACT efficacy is required to ensure the treatment effectiveness. Mutations in the propeller domain of the pfk13 gene were identified as molecular markers of artemisinin resistance (ART-R). This study investigated the pfk13-propeller gene polymorphism in clinical isolates of P. falciparum collected in the DRC. In 2017, ten geographical sites across DRC were selected for a cross-sectional study that was conducted first in Kinshasa from January to March, then in the nine other sites from September to December. Dried blood samples were collected from patients attending health centers for fever where diagnosis of Malaria was first made by rapid diagnostic test (RDT) available on site (SD Bioline malaria Ag Pf or CareStart Malaria Pf) or by thick blood smear and then confirmed by a P. falciparum real-time PCR assay. A pfk13-propeller segment containing a fragment that codes for amino acids at positions 427-595 was amplified by conventional PCR before sequencing. In total, 1070 patients were enrolled in the study. Real-time PCR performed confirmed the initial diagnosis of P. falciparum infection in 806 samples (75.3%; 95% CI: 72.6%- 77.9%). Of the 717 successfully sequenced P. falciparum isolates, 710 (99.0%; 95% CI: 97.9% - 99.6) were wild-type genotypes and 7 (1.0%; 95% CI: 0.4% - 2.1%) carried non-synonymous (NS) mutations in pfk13-propeller including 2 mutations (A578S and V534A) previously detected and 2 other (M472I and A569T) not yet detected in the DRC. Mutations associated with ART-R in Southeast Asia were not observed in DRC. However, the presence of other mutations in pfk13-propeller gene calls for further investigations to assess their implication in drug resistance.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Adolescente , Adulto , Idoso , Antimaláricos/farmacologia , Artemisininas/farmacologia , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Resistência a Medicamentos , Feminino , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Adulto Jovem
9.
PLoS Negl Trop Dis ; 14(8): e0008506, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745103

RESUMO

Plasmodium vivax has become the predominant malaria parasite and a major challenge for malaria elimination in the Greater Mekong Subregion (GMS). Yet, our knowledge about the evolution of P. vivax populations in the GMS is fragmental. We performed whole genome sequencing on 23 P. vivax samples from the China-Myanmar border (CMB) and used 21 high-coverage samples to compare to over 200 samples from the rest of the GMS. Using genome-wide single nucleotide polymorphisms (SNPs), we analyzed population differentiation, genetic structure, migration and potential selection using an array of methods. The CMB parasites displayed a higher proportion of monoclonal infections, and 52% shared over 90% of their genomes in identity-by-descent segments with at least one other sample from the CMB, suggesting preferential expansion of certain parasite strains in this region, likely resulting from the P. vivax outbreaks occurring during this study period. Principal component, admixture, fixation index and phylogenetic analyses all identified that parasites from the CMB were genetically distinct from parasites from eastern parts of the GMS (Cambodia, Laos, Vietnam, and Thailand), whereas the eastern GMS parasite populations were largely undifferentiated. Such a genetic differentiation pattern of the P. vivax populations from the GMS parasite was largely explainable through geographic distance. Using the genome-wide SNPs, we narrowed down to a set of 36 SNPs for differentiating parasites from different areas of the GMS. Genome-wide scans to determine selection in the genome with two statistical methods identified genes potentially under drug selection, including genes associated with antifolate resistance and genes linked to chloroquine resistance in Plasmodium falciparum.


Assuntos
Malária Vivax/epidemiologia , Malária Vivax/parasitologia , Plasmodium vivax/genética , Polimorfismo de Nucleotídeo Único , Antimaláricos/farmacologia , China , Surtos de Doenças , Resistência a Medicamentos/genética , Antagonistas do Ácido Fólico/farmacologia , Genômica , Humanos , Mianmar , Filogenia , Plasmodium vivax/efeitos dos fármacos
10.
Mikrobiyol Bul ; 54(3): 463-478, 2020 Jul.
Artigo em Turco | MEDLINE | ID: mdl-32755521

RESUMO

Malaria still remains to be a public health threat and one of the most important infectious diseases to get attention from World Health Organization. No domestic malaria cases have been reported on the island of Cyprus since 1948, as a result of successful elimination process. All of the malaria cases detected in recent years are imported cases. As known, hundreds of medicines are obtained from plants and traditional medicine are used in endemic places of malaria. The cause of malaria - Plasmodium parasites, are developing resistance to antimalarial drugs. Hence, research on plant extracts and essential oils have gained great interest in recent years to obtain new and safe agents/substances. In our study, it was aimed to investigate the in vivo antimalarial activities of essential oils obtained from Origanum dubium, Origanum majorana, Salvia fruticosa and Laurus nobilis plants which grows in Northern Cyprus against Plasmodium berghei - the rodent malaria agent. Plants were collected in appropriate seasons and were dried to obtain and analyze essential oils via Clevenger Apparatus system. L929 mouse fibroblast cell line and MTT [3-(4.5-dimethylthiazole-2-yl) -2.5-diphenyltetrazolium bromide] kit were used to determine the cytotoxic activities of the essential oils obtained. In our study, total of 36 mice (Balb/c) of 6 groups (6 mice in each group) were formed: chloroquine group (CG) (50 mg/kg) as malaria reference group, untreated control group (UTCG), O.dubium (OD) (20 mg/kg), O.majorana (OM) (20 mg/kg), S.fruticosa (SF) (20 mg/kg) and L.nobilis (LN) (20 mg/kg). The essential oils were given to mice infected with P.berghei strain orally on 0, 1, 2 and 3rd days (4 times in total). Blood was taken from the tail end of each mouse 24 hours after the last treatment and blood collection was continued every two days until the mice died. Withdrawn blood taken from the mice were prepared as a thin smear and stained with Giemsa. Then, parasitemia percentages in each smear were calculated. As a result of the cytotoxicity tests, cytotoxic activity was not found at 100 µg/ml (20 mg/kg) in all oils except OD essential oil. While the mice receiving chloroquine continued their lives with the disappearance of the parasite on the 6thday, the mice in the UTCG died on the 9th day. The parasitemia rate reached 35% in the OM group on the 23rd day, in the OD group on the 21st day and in the other groups (SF and LN) on the 14th day and the mice have died. In our study, the difference between the life span in all groups was found statistically significant (p≤ 0.001). As a result, the essential oils O.majorana (14 days increase according to UTCG) an endemic plant of Cyprus and O.dubium (12 days increase according to UTCG) which had an antimalarial effect, decreased parasitemia and increased the life span of mice more than two times, indicated that they could be a source for the acquisition of new antimalarial molecules.


Assuntos
Antimaláricos , Malária , Óleos Voláteis , Origanum , Extratos Vegetais , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Chipre , Células Alimentadoras , Malária/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Origanum/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Plasmodium berghei/efeitos dos fármacos
11.
Artigo em Inglês | MEDLINE | ID: mdl-32660993

RESUMO

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 µM) and hypnozoites (IC50, 29.24 µM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.


Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Ivermectina/farmacologia , Fígado/efeitos dos fármacos , Malária/tratamento farmacológico , Plasmodium cynomolgi/efeitos dos fármacos , Animais , Antimaláricos/sangue , Antimaláricos/farmacocinética , Disponibilidade Biológica , Cloroquina/sangue , Cloroquina/farmacocinética , Esquema de Medicação , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/parasitologia , Ivermectina/sangue , Ivermectina/farmacocinética , Fígado/parasitologia , Macaca mulatta , Malária/parasitologia , Masculino , Parasitemia/tratamento farmacológico , Plasmodium cynomolgi/crescimento & desenvolvimento , Plasmodium cynomolgi/patogenicidade , Cultura Primária de Células , Esquizontes/efeitos dos fármacos , Esquizontes/crescimento & desenvolvimento
12.
Rev Saude Publica ; 54: 68, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32638884

RESUMO

Chloroquine (CQ) and its analog hydroxychloroquine (HCQ) were recently included in several clinical trials as potential prophylactic and therapeutic options for SARS-COV-2 infection/covid-19. However, drug effectiveness in preventing, treating, or slowing the progression of the disease is still unknown. Despite some initial promising in vitro results, rigorous pre-clinical animal studies and randomized clinical trials have not been performed yet. On the other hand, while the potential effectiveness of CQ/HCQ is, at best, hypothetical, their side effects are factual and most worrisome, particularly when considering vulnerable groups of patients being treated with these drugs. in this comment, we briefly explain the possible mechanisms of action of CQ/HCQ for treating other diseases, possible actions against covid-19, and their potent side effects, in order to reinforce the necessity of evaluating the benefit-risk balance when widely prescribing these drugs for SARS-COV-2 infection/covid-19. We conclude by strongly recommending against their indiscriminate use.


Assuntos
Antimaláricos/farmacologia , Betacoronavirus , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/farmacologia , Pneumonia Viral/tratamento farmacológico , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Betacoronavirus/efeitos dos fármacos , Cloroquina/efeitos adversos , Cloroquina/farmacocinética , Contraindicações de Medicamentos , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacocinética , Pandemias , Medição de Risco
13.
Cell Signal ; 73: 109706, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32629149

RESUMO

Chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) have been thrust into our everyday vernacular because some believe, based on very limited basic and clinical data, that they might be helpful in preventing and/or lessening the severity of the pandemic coronavirus disease 2019 (COVID-19). However, lacking is a temperance in enthusiasm for their possible use as well as sufficient perspective on their effects and side-effects. CQ and HCQ have well-known properties of being diprotic weak bases that preferentially accumulate in acidic organelles (endolysosomes and Golgi apparatus) and neutralize luminal pH of acidic organelles. These primary actions of CQ and HCQ are responsible for their anti-malarial effects; malaria parasites rely on acidic digestive vacuoles for survival. Similarly, de-acidification of endolysosomes and Golgi by CQ and HCQ may block severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) integration into host cells because SARS-CoV-2 may require an acidic environment for its entry and for its ability to bud and infect bystander cells. Further, de-acidification of endolysosomes and Golgi may underly the immunosuppressive effects of these two drugs. However, modern cell biology studies have shown clearly that de-acidification results in profound changes in the structure, function and cellular positioning of endolysosomes and Golgi, in signaling between these organelles and other subcellular organelles, and in fundamental cellular functions. Thus, studying the possible therapeutic effects of CQ and HCQ against COVID-19 must occur concurrent with studies of the extent to which these drugs affect organellar and cell biology. When comprehensively examined, a better understanding of the Janus sword actions of these and other drugs might yield better decisions and better outcomes.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Cloroquina/farmacologia , Endossomos/efeitos dos fármacos , Complexo de Golgi/efeitos dos fármacos , Hidroxicloroquina/farmacologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/enzimologia , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Citocinas/metabolismo , Endocitose/efeitos dos fármacos , Endossomos/metabolismo , Complexo de Golgi/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Hidroxicloroquina/uso terapêutico , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Malária/tratamento farmacológico , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico
14.
BMJ Open ; 10(6): e039978, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: covidwho-592392

RESUMO

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus , Imunização Passiva/métodos , Imunossupressores/farmacologia , Pandemias , Plasma/imunologia , Pneumonia Viral , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto/classificação , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Ensaios Clínicos como Assunto/estatística & dados numéricos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Estudos Transversais , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Sistema de Registros/estatística & dados numéricos , Terapias em Estudo/métodos , Terapias em Estudo/estatística & dados numéricos
15.
Adv Rheumatol ; 60(1): 32, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: covidwho-591986

RESUMO

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Assuntos
Antimaláricos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Erupção por Droga/etiologia , Interações Medicamentosas , Feminino , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Humanos , Lipídeos/sangue , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Gravidez , Insuficiência Renal/prevenção & controle , Doenças Retinianas/induzido quimicamente , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
16.
Biochem Pharmacol ; 178: 114114, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32579957

RESUMO

The coronavirus disease 2019 (COVID-19), elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a pandemic public health emergency of global concern. Other than the profound severe pulmonary damage, SARS-CoV-2 infection also leads to a series of cardiovascular abnormalities, including myocardial injury, myocarditis and pericarditis, arrhythmia and cardiac arrest, cardiomyopathy, heart failure, cardiogenic shock, and coagulation abnormalities. Meanwhile, COVID-19 patients with preexisting cardiovascular diseases are often at a much higher risk of increased morbidity and mortality. Up-to-date, a number of mechanisms have been postulated for COVID-19-associated cardiovascular damage including SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) activation, cytokine storm, hypoxemia, stress and cardiotoxicity of antiviral drugs. In this context, special attention should be given towards COVID-19 patients with concurrent cardiovascular diseases, and special cardiovascular attention is warranted for treatment of COVID-19.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antivirais/farmacologia , Betacoronavirus/fisiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/metabolismo , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Internalização do Vírus/efeitos dos fármacos
17.
Int J Risk Saf Med ; 31(3): 111-116, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474476

RESUMO

The emerging COVID-19 pandemic poses a threat to the global health care system. Given the lack of antiviral therapies or vaccines for the disease, the antimalarial drug hydroxychloroquine (HCQ) obtained much attention as a treatment for COVID-19. However, there are limited and uncertain clinical data to support the beneficial effect of this drug in COVID-19 treatment. HCQ has several side effects and warnings, including blindness, heart failure, and renal toxicity, even with recommended doses. For severe cases of COVID-19 or in patients with preexisting conditions, administering such a drug could be fatal, particularly when taken at high doses or in combination with other antibiotics. However, further well-designed studies that would address the optimal dose, duration of treatment, possible side effects, and long-term usage outcomes are needed to make the final decision. In this paper, we aim to discuss the risk of using HCQ in treating COVID-19 patients, including its possible side effects.


Assuntos
Antimaláricos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Betacoronavirus , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacologia , Pandemias
18.
BMJ Open ; 10(6): e039978, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518212

RESUMO

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO's International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers. MAIN OUTCOMES: Trial intervention, sponsorship, critical design elements and specified outcomes RESULTS: Overall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020. CONCLUSIONS: While accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus , Imunização Passiva/métodos , Imunossupressores/farmacologia , Pandemias , Plasma/imunologia , Pneumonia Viral , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto/classificação , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Ensaios Clínicos como Assunto/estatística & dados numéricos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Estudos Transversais , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Sistema de Registros/estatística & dados numéricos , Terapias em Estudo/métodos , Terapias em Estudo/estatística & dados numéricos
19.
Heart Rhythm ; 17(9): 1445-1451, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32479900

RESUMO

BACKGROUND: Early during the current coronavirus disease 19 (COVID-19) pandemic, hydroxychloroquine (HCQ) received a significant amount of attention as a potential antiviral treatment, such that it became one of the most commonly prescribed medications for COVID-19 patients. However, not only has the effectiveness of HCQ remained questionable, but mainly based on preclinical and a few small clinical studies, HCQ is known to be potentially arrhythmogenic, especially as a result of QT prolongation. OBJECTIVE: The purpose of this study was to investigate the arrhythmic effects of HCQ, as the heightened risk is especially relevant to COVID-19 patients, who are at higher risk for cardiac complications and arrhythmias at baseline. METHODS: An optical mapping technique utilizing voltage-sensitive fluorescent dyes was used to determine the arrhythmic effects of HCQ in ex vivo guinea pig and rabbit hearts perfused with the upper therapeutic serum dose of HCQ (1000 ng/mL). RESULTS: HCQ markedly increased action potential dispersion, resulted in development of repolarization alternans, and initiated polymorphic ventricular tachycardia. CONCLUSION: The study results further highlight the proarrhythmic effects of HCQ.


Assuntos
Antimaláricos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hidroxicloroquina/farmacologia , Animais , Estimulação Cardíaca Artificial , Infecções por Coronavirus/tratamento farmacológico , Cobaias , Coração/diagnóstico por imagem , Coelhos , Técnicas de Cultura de Tecidos , Imagens com Corantes Sensíveis à Voltagem
20.
PLoS Comput Biol ; 16(6): e1007945, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555701

RESUMO

The spread of drug resistance of Plasmodium falciparum and Plasmodium vivax parasites is a challenge towards malaria elimination. P. falciparum has shown an early and severe drug resistance in comparison to P. vivax in various countries. In fact, P. vivax differs in its life cycle and treatment in various factors: development and duration of sexual parasite forms differ, symptoms severity are unequal, relapses present only in P. vivax cases and the Artemisinin-based combination therapy (ACT) is only mandatory in P. falciparum cases. We compared the spread of drug resistance for both species through two compartmental models using ordinary differential equations. The model structure describes how sensitive and resistant parasite strains infect a human population treated with antimalarials. We found that an early transmission,i.e., before treatment and low effectiveness of drug coverage, supports the prevalence of sensitive parasites delaying the emergence of resistant P. vivax. These results imply that earlier attention of both symptomatic cases and reservoirs of P. vivax are essential in controlling transmission but also accelerate the spread of drug resistance.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária Vivax/transmissão , Plasmodium vivax/efeitos dos fármacos , Humanos , Malária Vivax/psicologia
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