Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 128
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Regul Toxicol Pharmacol ; 129: 105114, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35007669

RESUMO

Artemisinin-hydroxychloroquine sulfate tablets (AH) are considered a relatively inexpensive and novel combination therapy for treating all forms of malaria, especially aminoquinoline drugs-resistant strains of P.falciparum. We aim to carry out acute and subacute oral toxicity studies in rats to acquire preclinical data on the safety of AH. Acute toxicity was evaluated in Sprague-Dawley (SD) rats at a single dose of 1980, 2970, 4450, 6670, and 10000 mg/kg. A 14-days subacute toxicity was assessed in SD rats at doses of 0, 146, 219, 328, and 429 mg/kg. The median lethal dose (LD50) of acute oral administration of AH in rats is found to be 3119 mg/kg, and toxic symptoms include decreased spontaneous activity, dyspnea, bristling, soft feces, spasticity, and convulsion. Repeated doses of AH have toxic effects on the nervous system, skin, blood system, liver, kidney, and spleen in rats. The main toxic reactions include epilation, emaciation, mental irritability, decreased body weight gain and food consumption, changes in the hematological and biochemical parameters, especially pathological lesions in the liver, kidney, and spleen. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of AH are considered to be 219 mg/kg and 328 mg/kg, respectively.


Assuntos
Antimaláricos/toxicidade , Artemisininas/toxicidade , Hidroxicloroquina/toxicidade , Administração Oral , Animais , Antimaláricos/administração & dosagem , Antimaláricos/farmacologia , Artemisininas/administração & dosagem , Artemisininas/farmacologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/farmacologia , Dose Letal Mediana , Masculino , Nível de Efeito Adverso não Observado , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
2.
Eur J Med Chem ; 215: 113295, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33636536

RESUMO

For the first time, eight novel artemisinin-piperazine-furane ether hybrids (5a-h) were efficiently synthesized and investigated for their in vitro cytotoxic activity against some human cancer and benign cells. The absolute configuration of hybrid 5c was determined by X-ray crystallographic analysis. Hybrids 5a-h exhibited more pronounced growth-inhibiting action on hepatocarcinoma cell lines than their parent dihydroartemisinin (DHA) and the reference cytosine arabinoside (ARA). The hybrid 5a showed the best cytotoxic activity against human hepatocarcinoma cells SMMC-7721 (IC50 = 0.26 ± 0.03 µM) after 24 h. Furthermore, hybrid 5a also showed good cytotoxic activity against human breast cancer cells MCF-7 and low cytotoxicity against human breast benign cells MCF-10A in vitro. We found the cytotoxicity of hybrid 5a did not change when tumour cells absorb iron sulfate (FeSO4); thus, we conclude the anti-tumour mechanism induced by iron ions (Fe2+) is unclear.


Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Furanos/farmacologia , Piperazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Artemisininas/síntese química , Artemisininas/toxicidade , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/toxicidade , Humanos , Células MCF-7 , Piperazinas/síntese química , Piperazinas/toxicidade
3.
Arch Toxicol ; 95(7): 2485-2495, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34021777

RESUMO

The majority of drug candidates fails the approval phase due to unwanted toxicities and side effects. Establishment of an effective toxicity prediction platform is of utmost importance, to increase the efficiency of the drug discovery process. For this purpose, we developed a toxicity prediction platform with machine-learning strategies. Cardiotoxicity prediction was performed by establishing a model with five parameters (arrhythmia, cardiac failure, heart block, hypertension, myocardial infarction) and additional toxicity predictions such as hepatotoxicity, reproductive toxicity, mutagenicity, and tumorigenicity are performed by using Data Warrior and Pro-Tox-II software. As a case study, we selected artemisinin derivatives to evaluate the platform and to provide a list of safe artemisinin derivatives. Artemisinin from Artemisia annua was described first as an anti-malarial compound and later its anticancer properties were discovered. Here, random forest feature selection algorithm was used for the establishment of cardiotoxicity models. High AUC scores above 0.830 were achieved for all five cardiotoxicity indications. Using a chemical library of 374 artemisinin derivatives as a case study, 7 compounds (deoxydihydro-artemisinin, 3-hydroxy-deoxy-dihydroartemisinin, 3-desoxy-dihydroartemisinin, dihydroartemisinin-furano acetate-d3, deoxyartemisinin, artemisinin G, artemisinin B) passed the toxicity filtering process for hepatotoxicity, mutagenicity, tumorigenicity, and reproductive toxicity in addition to cardiotoxicity. Experimental validation with the cardiomyocyte cell line AC16 supported the findings from the in silico cardiotoxicity model predictions. Transcriptomic profiling of AC16 cells upon artemisinin B treatment revealed a similar gene expression profile as that of the control compound, dexrazoxane. In vivo experiments with a Zebrafish model further substantiated the in silico and in vitro data, as only slight cardiotoxicity in picomolar range was observed. In conclusion, our machine-learning approach combined with in vitro and in vivo experimentation represents a suitable method to predict cardiotoxicity of drug candidates.


Assuntos
Artemisininas , Cardiotoxicidade , Animais , Artemisininas/toxicidade , Aprendizado de Máquina , Software , Peixe-Zebra
4.
Sci Total Environ ; 756: 143851, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33257061

RESUMO

Artemisinin extracted from Artemisia annua L. plants has a range of properties that qualifies it to treat several diseases, such as malaria and cancer. However, it has short half-life, which requires making continuous use of it, which has motivated the association of artemisinin (ART) with polymeric nanoparticles to increase its therapeutic efficiency. However, the ecotoxicological safety of this association has been questioned, given the scarcity of studies in this area. Thus, in this work the toxicity of Poly (ε-Caprolactone) nanocapsules added with ART (ART-NANO) in zebrafish (Danio rerio), embryos and adults was studied. Different endpoints were analyzed in organisms exposed to ART-NANO, including those predictive of embryotoxicity and histopatoxicity. Embryotoxicity was analyzed based on Organization for Economic Co-operation and Development (OECD) test guideline (236) for fish embryo acute toxicity applied to zebrafish (Danio rerio) at 96 hpf under five nominal logarithmic concentrations (0.125 to 2.0 mg/ L). Our results demonstrate, mainly, that fertilized eggs presented increased coagulation, lack of heart rate, vitelline sac displacement and lack of somite formation. On the other hand, adult individuals (exposed to the same concentrations and evaluated after 24 and 96 h of exposure) have shown increased pericarditis. Therefore, the treatment based on ART, poly (ε-caprolactone) nanocapsules and on their combination at different concentrations have shown toxic effects on zebrafish embryos and adult individuals.


Assuntos
Artemisininas , Nanocápsulas , Poluentes Químicos da Água , Adulto , Animais , Artemisininas/toxicidade , Caproatos , Embrião não Mamífero , Humanos , Lactonas , Poluentes Químicos da Água/toxicidade , Peixe-Zebra
5.
Toxicol Appl Pharmacol ; 402: 115127, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32622917

RESUMO

Pregnant women are one of the most susceptible and vulnerable groups to malaria, the most important parasitic disease worldwide. Artemisinin-based combination therapies (ACTs) are recommended for the treatment of uncomplicated malaria in all population groups including pregnant women. However, due to the embryotoxicity observed in animal studies, ACTs have long been contraindicated during the first trimester in pregnant women. Despite the safety concerns raised in pre-clinical studies, recent findings on ACTs's use in pregnant women appear to be reassuring regarding safety and have prompted a revision of malaria treatment guidelines for first trimester of pregnancy. To contribute to the risk-benefit assessment of ACTs, we conducted a systematic literature review of animal studies published between 2007 and 2019, which evaluated the embryotoxic effects of artemisinin and its derivatives among pregnant mammals. Eighteen experimental studies fitted the inclusion criteria. These studies confirmed and further characterized the severe embryolethal and embryotoxic dose-dependent effects of artemisinin and its derivatives when administered during the organogenesis period in rats, rabbits and monkeys. Timing of administration and dosage of the drug were found to be key factors in the appearance of embryo damage. Overall, the translation of the findings of artemisinin derivatives use in animal studies to pregnant women remains disturbing. Thus, a policy change in the use of ACTs during the first trimester in pregnant women for the treatment of uncomplicated malaria does not seem pertinent and if implemented, it should be accompanied by solid pharmacovigilance systems, which are challenging to establish in malaria endemic countries.


Assuntos
Anormalidades Induzidas por Medicamentos , Antimaláricos/toxicidade , Artemisininas/toxicidade , Malária/prevenção & controle , Complicações Parasitárias na Gravidez/prevenção & controle , Animais , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Humanos , Gravidez
6.
Int. j. morphol ; 38(2): 278-288, abr. 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1056435

RESUMO

This experiment was designed to study the effects of oral administration of artemether which is the most rapid-acting class of antimalarial drugs and the possible protective effect of vitamin E taken with it on the liver of albino rats. A total of twenty-four adult male albino rats were used in this study and were divided into four groups. Group one served as a control and rats in group two exposed to oral intake of artemether daily for fifteen days. The third and fourth groups treated with artemether plus low and high doses of vitamin E respectively. At the end of the experiment, the rats were sacrificed, and the livers were obtained and processed for histological, biochemical and statistical studies. Histological study of the hepatocytes of rats exposed to artemether showed nearly complete disintegration of most cellular contents except few numbers of mitochondria and rough endoplasmic reticulum. Also, the cytoplasm of these cells had few lysosomes, many vacuoles and irregular nuclei with abnormal distribution of chromatin and were shown. The hepatic sinusoids were dilated and filled with blood and vacuoles and bile ductules were abnormal in its structure. Treatment with low and high doses of vitamin E in concomitant with artemether ameliorated the hepatic histopathological lesions and its parenchyma attained nearly normal structure. As far as biochemical changes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rats treated with artemether were significantly elevated as compared to the control. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were significantly increased in the liver in rats treated with artemether. However, vitamin E ameliorated the rise in ALT and AST with decreased MDA concentration and levels of SOD as compared to the corresponding artemether group values. Results of the present suggest that artemether has a harmful and stressful effect on hepatic tissue and the treatment with vitamin E may alleviate this toxicity.


Este experimento fue diseñado para estudiar los efectos de la administración oral de arteméter, la clase de medicamentos antipalúdicos de acción rápida, y el posible efecto protector de la vitamina E en el hígado de ratas albinas. Se utilizaron un total de 24 ratas albinas machos adultas y se dividieron en cuatro grupos. El grupo uno sirvió como control y las ratas en el grupo dos recibieron la dosis oral de arteméter diariamente durante 15 días. Los grupos tres y cuatro fueron tratados con arteméter, más dosis bajas y altas de vitamina E, respectivamente. Al final del experimento, se sacrificaron las ratas y se obtuvieron y procesaron los hígados para estudios histológicos, bioquímicos y estadísticos. El estudio histológico de los hepatocitos de ratas expuestas a arteméter mostró una desintegración casi completa de la mayoría de los contenidos celulares, excepto algunos mitocondrias y retículo endoplásmico rugoso. Además, el citoplasma de estas células tenía pocos lisosomas, muchas vacuolas y núcleos irregulares con distribución anormal de cromatina. Los sinusoides hepáticos estaban dilatados y llenos de sangre y vacuolas, y los conductos biliares tenían una estructura anormal. El tratamiento con dosis bajas y altas de vitamina E en forma concomitante con arteméter mejoró las lesiones histopatológicas hepáticas y su parénquima alcanzó una estructura casi normal. En cuanto a los cambios bioquímicos, la alanina aminotransferasa (ALT) y la aspartato aminotransferasa (AST) en ratas tratadas con arteméter se elevaron significativamente en comparación con el control. Los niveles de superóxido dismutasa (SOD) y malondialdehído (MDA) aumentaron significativamente en el hígado en ratas tratadas con arteméter. Sin embargo, la vitamina E mejoró el aumento de ALT y AST con una disminución de la concentración de MDA y los niveles de SOD en comparación con los valores correspondientes del grupo de arteméter. Los resultados del presente estudio sugieren que el arteméter tiene un efecto dañino y estresante sobre el tejido hepático y el tratamiento con vitamina E puede aliviar esta toxicidad.


Assuntos
Animais , Masculino , Ratos , Vitamina E/farmacologia , Artemisininas/toxicidade , Doença Hepática Crônica Induzida por Substâncias e Drogas/enzimologia , Aspartato Aminotransferases/análise , Vitamina E/administração & dosagem , Microscopia Eletrônica de Transmissão , Alanina Transaminase/análise , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Antimaláricos/toxicidade
7.
Regul Toxicol Pharmacol ; 109: 104486, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31580888

RESUMO

Artemisinin-piperaquine tablet (trade name Artequick, ATQ), is a novel combination therapy for the treatment of malaria and especially for resistant P.falciparum malaria. The aim of our study was to assess the potential sub-acute toxicity profile of ATQ by oral administration route in rhesus monkeys. Monkeys were administrated once daily with doses of ATQ (39.1, 78.2, 156.4 mg/kg) for 21 days and then followed-up a 56-day recovery period. The administration of ATQ at high dose produced significant changes in the clinical signs primarily involved in gastrointestinal and nervous systems. Body weight loss, significant decrease in food consumption and body temperature were observed in monkeys at high dose. Various hematological and biochemical parameters changes, and significant pathological lesions (adrenal gland, thymus and femur epiphyseal) were observed in the middle and high dose group at the end of the treatment period. However, the toxic effects of ATQ were reversed and delayed adverse drug reaction did not occur during the recovery period. Based on the results of this study, the no-observed-adverse-effect level for ATQ was considered to be 39.1 mg/kg in rhesus monkeys.


Assuntos
Antimaláricos/toxicidade , Artemisininas/toxicidade , Trato Gastrointestinal/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Quinolinas/toxicidade , Administração Oral , Animais , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Macaca mulatta , Masculino , Nível de Efeito Adverso não Observado , Quinolinas/administração & dosagem , Comprimidos , Testes de Toxicidade Subaguda , Perda de Peso/efeitos dos fármacos
8.
Drug Chem Toxicol ; 42(6): 608-614, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29681192

RESUMO

Artemisinin is a substance extracted from the Chinese plant Artemisia annua L. widely used in natural medicine for the treatment of various diseases. Artemether is a substance synthesized from artemisinin, and both drugs are commonly administered in the treatment of malaria. Although considered effective antimalarial drugs, very little is known about the genotoxic, cytotoxic and mutagenic effects of these drugs. Therefore, in the present study, we evaluated the genotoxic, mutagenic and cytotoxic effects of artemisinin (12.5, 25 and 50 µg/mL) and artemether (7.46; 14.92 and 29.84 µg/mL) in cultured human lymphocytes using the comet assay, the micronucleus test and the cytotoxicity assay for detection of necrosis and apoptosis by acridine orange/ethidium bromide staining. Our results showed a significant increase (p < 0.05) in the rate of DNA damage measured by comet assay and in the micronucleus frequency after treatment with both drugs. It was also observed that only artemisinin induced a statistically significant increase (p < 0.05) in the number of lymphocytes with death by necrosis 48 h after treatment. The results demonstrated that these two drugs induce mutagenic, genotoxic and cytotoxic effects in cultured human lymphocytes. Our data indicate the need for caution in the use of such drugs, since genotoxic/mutagenic effects may increase the risk of carcinogenesis.


Assuntos
Antimaláricos/toxicidade , Artemeter/toxicidade , Artemisininas/toxicidade , Linfócitos/efeitos dos fármacos , Adulto , Antimaláricos/administração & dosagem , Apoptose/efeitos dos fármacos , Artemeter/administração & dosagem , Artemisininas/administração & dosagem , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Linfócitos/patologia , Masculino , Testes para Micronúcleos , Testes de Mutagenicidade , Mutagênicos/administração & dosagem , Mutagênicos/toxicidade , Necrose/induzido quimicamente , Adulto Jovem
9.
Ecotoxicol Environ Saf ; 158: 108-113, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-29665557

RESUMO

The anti-malarial drug artemisinin is extracted from the leaves of Artemisia annua L. Due to toxicity to some microorganisms, the release of artemisinin from this medicinal plant in commercial cultivation might produce a potential risk for phosphorus (P) solubilizing bacteria (PSB). Therefore, the growth, P mobilization, and proton and organic acid efflux by two PSB isolates, Bacillus subtilis and Pseudomonas fluorescens, obtained from the soil without growing A. annua L. in history in the region for growing A. annua L., Chongqing, China, were studied through soil and solution incubations with different nominal concentrations of artemisinin (0, 2.5, 5.0, and 10.0 mg/kg or mg/L). Addition of artemisinin into soil and culture solutions decreased significantly the number of PSB except P. fluorescens at a low artemisinin concentration (2.5 mg/L) in culture solution which remained unchanged in comparison with the control (without artemisinin). This suggests high artemisinin inhibited the cell division or led to the death of PSB, and the different species responded differently to artemisinin. Compared with original soil, PSB inoculation significantly increased Olsen P, whilst the addition of artemisinin decreased this P form in soil. There was a positive correlation between the number of PSB and Olsen P content in soils (r2 = 0.824, n = 8), indicating the involvement of PSB in P mobilization of insoluble minerals. Oxalate and acetate were commonly found in the bacterial culture solutions, which accounted for 73.6-84.4% of all organic acids in the culture medium without artemisinin. Malate was detected in the culture solution of B. subtilis, and citrate and succinate in P. fluorescens. The percentage of tricalcium phosphate solubilization (PTPS) positively correlated to the concentrations of protons and all organic acids (r2proton=0.901, n=8, P<0.01; r2organic acids=0.923, n=8, P<0.01). The concentrations of protons, organic acids and soluble inorganic P in culture solutions, and PTPS were decreased simultaneously as nominal artemisinin concentrations increased. For these decreases it implies the metabolic inhibition and the death of PSB caused by artemisinin could be the main reasons for the less efflux of protons and organic acids, presumably resulting in the decreased ability of PSB to mobilize inorganic P. Therefore, artemisinin released from A. annua L. in commercial and continual cultivation could adversely affect the community structure and inorganic P mobilization of PSB in soils.


Assuntos
Antimaláricos/toxicidade , Artemisininas/toxicidade , Bacillus subtilis/efeitos dos fármacos , Fósforo/análise , Pseudomonas fluorescens/efeitos dos fármacos , Bacillus subtilis/metabolismo , Bactérias/metabolismo , Fósforo/metabolismo , Pseudomonas fluorescens/metabolismo , Solo , Microbiologia do Solo
10.
Toxicol Appl Pharmacol ; 341: 8-15, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29309768

RESUMO

Dihydroartemisinin (DHA), the main active metabolite of artemisinin, has been used to treat malaria and has anticancer activities. Previous work has shown that DHA has negative impacts on embryos in rodents and primates. However, whether DHA has adverse effects on oocyte maturation is unknown. In the present study, we evaluated the toxic effects and possible mechanisms of DHA on porcine oocyte maturation. The results showed that exposure to DHA inhibited porcine oocyte polar body extrusion, and blocked cell cycle progression. Meanwhile, early embryo development after parthenogenetic activation was also impaired. DHA disturbed spindle morphology and actin assembly in porcine oocytes by reducing phosphorylation levels of MAPK. Moreover, the ROS content was increased and the mitochondrial membrane potential decreased in oocytes treated with DHA. DHA also increased the levels of intracellular and mitochondrial calcium. Furthermore, Annexin V-FITC staining showed that early apoptosis occurred in DHA-treated oocytes. The mRNA levels of apoptosis-related genes BAX and CASP3 were increased, and the anti-apoptotic gene BCL2 was decreased in oocytes exposed to DHA. Taken together, these results indicate that DHA exposure impairs porcine oocyte maturation in vitro via mechanisms involved in cytoskeleton dynamics, oxidative stress, calcium homeostasis, and apoptosis.


Assuntos
Artemisininas/toxicidade , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Oogênese/efeitos dos fármacos , Oogênese/fisiologia , Animais , Antimaláricos/toxicidade , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células Cultivadas , Feminino , Espécies Reativas de Oxigênio/metabolismo , Suínos
11.
Environ Toxicol Pharmacol ; 57: 86-94, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29227908

RESUMO

Artemisinin-based drugs are documented to possess anticancer potential that is selectively effective to cancer cells. However, this selectivity is disputable in different studies and the mechanism is still unclear. To clarify this discrepancy, this study employed five assays to evaluate the cytotoxic effects of artemisinin and artesunate on normal human bronchial epithelial (HBE) cells and lung adenocarcinoma A549 cells. The results of five cytotoxic assays coherently showed that artemisinin and artesunate caused dose-dependent cytotoxicity in both HBE and A549 cells with a slight selectivity to A549 cells. Further, both HBE cells and A549 cells demonstrated elevated levels of intracellular reactive oxygen species (ROS) and increased DNA damage. Since artemisinin and artesunate exerted significant cytotoxic effect on both normal cells and cancer cells via the same pathway of ROS-mediated DNA damage, the side effects of artemisinin and artesunate on normal cell cannot be ignored when developing their antitumor effects.


Assuntos
Artemisininas/toxicidade , Brônquios/citologia , Células Epiteliais/efeitos dos fármacos , Células A549 , Artesunato , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Células Epiteliais/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Birth Defects Res ; 110(7): 553-578, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29193867

RESUMO

BACKGROUND: Combination medicines including an artemisinin are the mainstay of antimalarial therapy. Artemisinins are potent embryotoxicants in animal species due to their trioxane moiety. METHODS: As part of its development, the new synthetic trioxolane antimalarial artefenomel (OZ439) was tested in rat whole embryo culture and in rat embryo-fetal toxicity studies with dosing throughout organogenesis or with a single dose on Gestational Day (GD) 12. The single-dose studies included groups treated with artesunate to allow a direct comparison of the embryotoxicity of the two antimalarials and included toxicokinetics hematology and histological examination of embryos. In addition, the distribution of artefenomel-related material in plasma was determined after the administration of 14 C-artefenomel. RESULTS: Artefenomel and artesunate showed similar patterns of embryotoxicity including cardiovascular defects and resorption with a steep dose-response. They both also caused a depletion of circulating embryonic erythroblasts both in vitro and in vivo and decreases in maternal reticulocyte count. However, artefenomel was ∼250-fold less potent than the active metabolite of artesunate (dihydroartemisinin) as an embryotoxicant in vitro. The safety margin (based on AUC) for artefenomel administered on GD 12 was approximately 100-fold greater than that for artesunate. Also, unlike artesunate, artefenomel was not a selective developmental toxicant. CONCLUSIONS: The lesser embryotoxicity of artefenomel is likely linked to its original design which included two blocking side groups that had been introduced to lower the reactivity with ferrous iron. Our data support the hypothesis that artefenomel's improved safety margin is linked to a lower potential for inhibiting heme biosynthesis in embryonic erythroblasts.


Assuntos
Adamantano/análogos & derivados , Antimaláricos/toxicidade , Artesunato/toxicidade , Embrião de Mamíferos/efeitos dos fármacos , Peróxidos/toxicidade , Adamantano/farmacocinética , Adamantano/toxicidade , Animais , Artemisininas/toxicidade , Benzoxazinas/toxicidade , Relação Dose-Resposta a Droga , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Idade Gestacional , Heme/biossíntese , Técnicas de Cultura de Órgãos , Organogênese/efeitos dos fármacos , Peróxidos/farmacocinética , Ftalimidas/toxicidade , Ratos
13.
J Pharm Pharmacol ; 69(11): 1437-1446, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28809448

RESUMO

OBJECTIVES: To evaluate the in-vivo efficacy of solid SMEDDS containing combination of artemether and lumefantrine. METHODS: Formulation development of solid SMEDDS containing combination of artemether and lumefantrine was carried out using spray drying technique. These S-SMEDDS were evaluated for reduction in parasitemia and mortality as well as subacute toxicity in mice. Haematology, biochemical parameters and histopathology were performed for evaluating safety of formulation. Pharmacokinetic characterization of both drugs was performed after oral administration in rats. KEY FINDINGS: Optimized solid SMEDDS containing low, medium and high dose were more effective in reducing parasitemia and mortality of mice as compared to marketed tablets containing high dose of these drugs. Single oral administration of solid SMEDDS containing high-dose combination could maintain plasma concentration of lumefantrine above the minimum effective concentration for ≈4 days. CONCLUSIONS: Solid SMEDDS containing low-, medium- and high-dose combination of artemether and lumefantrine are more effective than marketed tablets.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Sistemas de Liberação de Medicamentos , Etanolaminas/administração & dosagem , Fluorenos/administração & dosagem , Administração Oral , Animais , Antimaláricos/farmacocinética , Antimaláricos/toxicidade , Combinação Arteméter e Lumefantrina , Artemisininas/farmacocinética , Artemisininas/toxicidade , Química Farmacêutica , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Composição de Medicamentos , Emulsões , Etanolaminas/farmacocinética , Etanolaminas/toxicidade , Feminino , Fluorenos/farmacocinética , Fluorenos/toxicidade , Masculino , Camundongos , Ratos , Ratos Wistar , Comprimidos
14.
Biochim Biophys Acta Mol Cell Res ; 1864(7): 1285-1294, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28454894

RESUMO

The molecular action of artemisinins (ARTs) is not well understood. To determine the molecular and cellular basis that might underlie their differential effects observed in anti-malarial and anti-cancer studies, we utilized the yeast Saccharomyces cerevisiae to examine their toxicity profiles and properties. Previously we reported that while both low levels (2-8µM) of artemisinin (ART) and dihydroartemisinin (DHA) partly depolarize the mitochondrial membranes, inhibiting yeast growth on non-fermentable media, only DHA at moderate levels (such as 40µM) potently represses yeast growth on fermentable media via a heme-mediated pathway. Here we show that the lack of toxicity of ART even at high levels (200-400µM) on fermentable medium is due to the presence of Sod1. While we expected this normally Sod1-supressed action to be heme-mediated like DHA, surprisingly, this toxicity of ART is due to further depolarization of the mitochondrial membrane. We also found that for DHA, the Sod1-suppressible anti-mitochondrial action is hidden by its heme-mediated cytotoxicity, and becomes readily noticeable only when the heme-mediated action is compromised and Sod1 is inactivated. Based on these findings, we propose that depending on the cell type and particular compound, ARTs work via one or more of the three types of activities: a Sod1-independent, partial mitochondria-depolarizing action; a Sod1-suppressible, more severe mitochondria-depolarizing action; and a heme-mediated general cytotoxicity. These action properties may underlie the disparities seen in the efficacy and toxicity of various ARTs, and additionally suggest it is important for researchers to clearly detail the particular compound when reporting on the effects of ARTs.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/metabolismo , Superóxido Dismutase-1/metabolismo , Antimaláricos/toxicidade , Artemisininas/toxicidade , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Superóxido Dismutase-1/genética
15.
PLoS One ; 12(2): e0171840, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28182780

RESUMO

Dihydroartemisinin (DHA) and artesunate (ARS), two artemisinin derivatives, have efficacious anticancer activities against human hepatocarcinoma (HCC) cells. This study aims to study the anticancer action of the combination treatment of DHA/ARS and farnesylthiosalicylic acid (FTS), a Ras inhibitor, in HCC cells (Huh-7 and HepG2 cell lines). FTS pretreatment significantly enhanced DHA/ARS-induced phosphatidylserine (PS) externalization, Bak/Bax activation, mitochondrial membrane depolarization, cytochrome c release, and caspase-8 and -9 activations, characteristics of the extrinsic and intrinsic apoptosis. Pretreatment with Z-IETD-FMK (caspase-8 inhibitor) potently prevented the cytotoxicity of the combination treatment of DHA/ARS and FTS, and pretreatment with Z-VAD-FMK (pan-caspase inhibitor) significantly inhibited the loss of ΔΨm induced by DHA/ARS treatment or the combination treatment of DHA/ARS and FTS in HCC cells. Furthermore, silencing Bak/Bax modestly but significantly inhibited the cytotoxicity of the combination treatment of DHA/ARS and FTS. Interestingly, pretreatment with an antioxidant N-Acetyle-Cysteine (NAC) significantly prevented the cytotoxicity of the combination treatment of DHA and FTS instead of the combination treatment of ARS and FTS, suggesting that reactive oxygen species (ROS) played a key role in the anticancer action of the combination treatment of DHA and FTS. Similar to FTS, DHA/ARS also significantly prevented Ras activation. Collectively, our data demonstrate that FTS potently sensitizes Huh-7 and HepG2 cells to artemisinin derivatives via accelerating the extrinsic and intrinsic apoptotic pathways.


Assuntos
Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Carcinoma Hepatocelular/metabolismo , Farneseno Álcool/análogos & derivados , Neoplasias Hepáticas/metabolismo , Salicilatos/farmacologia , Acetilcisteína/farmacologia , Antineoplásicos/farmacologia , Artemisininas/toxicidade , Sinergismo Farmacológico , Farneseno Álcool/farmacologia , Células Hep G2 , Humanos
16.
Birth Defects Res B Dev Reprod Toxicol ; 107(6): 243-257, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28032463

RESUMO

The combination of artemether plus lumefantrine is a type of artemisinin-based combination therapy (ACT) recommended by the World Health Organization for uncomplicated falciparum malaria except in the first trimester of pregnancy. The first trimester restriction was based on the marked embryotoxicity in animals (including embryo death and cardiac and skeletal malformations) of artemisinins such as artesunate, dihydroartemisinin, and artemether. Before recommending ACTs for use in the first trimester, the World Health Organization has requested that all information relevant to the assessment of risk of ACTs to the embryo be made available to the public. This report describes the results of embryo-fetal development studies of artemether alone, lumefantrine alone, and the combination in rats and rabbits as well as toxicokinetic studies of lumefantrine in pregnant rabbits. The developmental no-effect levels for lumefantrine were 300 mg/kg/day in rats (based on a 25% decrease in litter size at 1000 mg/kg/day) and 1000 mg/kg/day in rabbits. The calculated safety margins based on human equivalent dose and plasma Cmax and AUC values were in the range of 2.5- to 17-fold. The developmental no-effect levels for artemether were 3 mg/kg/day in rats and 25 mg/kg/day in rabbits. Lumefantrine caused no teratogenicity and was not a potent embryotoxin in rats and rabbits. Expected artemisinin-like findings were seen with artemether alone and with artemether/lumefantrine combined except that no malformations were observed. There were no findings in pregnant rats and rabbits that would cause increased concern for the use of artemether-lumefantrine in the first trimester compared to other ACTs.


Assuntos
Antimaláricos/toxicidade , Artemisininas/toxicidade , Etanolaminas/toxicidade , Fluorenos/toxicidade , Testes de Toxicidade , Animais , Artemeter , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Lumefantrina , Malária Falciparum/tratamento farmacológico , Masculino , Exposição Materna/efeitos adversos , Gravidez , Coelhos , Ratos , Ratos Sprague-Dawley , Toxicocinética
17.
Drug Des Devel Ther ; 10: 3837-3850, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27920499

RESUMO

Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C-8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Nanopartículas/química , Análise de Variância , Animais , Antimaláricos/toxicidade , Artemeter , Artemisininas/toxicidade , Disponibilidade Biológica , Química Farmacêutica , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Derivados da Hipromelose/química , Dose Letal Mediana , Malária Vivax/tratamento farmacológico , Malária Vivax/parasitologia , Masculino , Camundongos , Tamanho da Partícula , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Povidona/química , Solubilidade , Comprimidos
18.
PLoS One ; 11(10): e0164838, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27736969

RESUMO

Artesunate (ART) has anti-cancer activities for a variety of solid tumors. The aim of this study was to investigate the anti-metastatic effect of ART on cervical cancer cells. In vivo anti-metastatic effect of ART was investigated in mice with the lung metastasis model by the subcutaneous injection of ART. The interaction of HOTAIR and COX-2 was measured by RNA immunoprecipitation and RNA pull-down assay. The effect of ART on metastasis of CaSki and Hela cells was evaluated by invasion and migration assay. We found that ART inhibited cervical cancer metastasis and HOTAIR expression. HOTAIR overexpression partially abolished the anti-metastatic effect of ART on cervical cancer cells. In addition, HOTAIR can interact with COX-2 to positively regulate COX-2 expression and catalytic activity. Finally, overexpression of COX-2 reversed the effect of HOTAIR knockdown on Hela cell migration and invasion. Taken together, our data revealed that ART may elicit anti-metastatic effect against cervical cancer by inhibition of HOTAIR expression, which resulted in the decrease of COX-2 expression.


Assuntos
Antineoplásicos/toxicidade , Artemisininas/toxicidade , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Artemisininas/química , Artemisininas/uso terapêutico , Artesunato , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/química , Dinoprostona/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Imunoprecipitação , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Ligação Proteica , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Transplante Heterólogo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
19.
Int J Pharm ; 513(1-2): 504-517, 2016 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-27596113

RESUMO

Patients with cerebral malaria (CM) are unable to take oral medication due to impaired consciousness and vomiting thus necessitating parenteral therapy. Quinine, artemether, and artesunate which are currently used for parenteral malaria therapy have their own drawbacks. The World Health Organization (WHO) has now banned monotherapy and recommends artemisinin-based combination therapy for malaria treatment. However, presently there is no intravenous formulation available for combination therapy of malaria. Artemether-Lumefantrine (ARM-LFN) is a WHO approved combination for oral malaria therapy. However, the low aqueous solubility of ARM and LFN hinders their intravenous delivery. The objective of this study was to formulate ARM-LFN nanostructured lipid carriers (NLC) for intravenous therapy of CM. ARM-LFN NLC were prepared by microemulsion template technique and characterized for size, drug content, entrapment efficiency, drug release, crystallinity, morphology, amenability to autoclaving, compatibility with infusion fluids, stability, antimalarial efficacy in mice, and toxicity in rats. The ARM-LFN NLC showed sustained drug release, amenability to autoclaving, compatibility with infusion fluids, good stability, complete parasite clearance and reversal of CM symptoms with 100% survival in Plasmodium berghei-infected mice, and safety in rats. The biocompatible ARM-LFN NLC fabricated by an industrially feasible technique offer a promising solution for intravenous therapy of CM.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Portadores de Fármacos/administração & dosagem , Etanolaminas/administração & dosagem , Fluorenos/administração & dosagem , Malária Cerebral/tratamento farmacológico , Nanoestruturas/administração & dosagem , Administração Intravenosa , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Antimaláricos/toxicidade , Combinação Arteméter e Lumefantrina , Artemisininas/química , Artemisininas/uso terapêutico , Artemisininas/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Portadores de Fármacos/toxicidade , Combinação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões , Etanolaminas/química , Etanolaminas/uso terapêutico , Etanolaminas/toxicidade , Feminino , Fluorenos/química , Fluorenos/uso terapêutico , Fluorenos/toxicidade , Lipídeos/química , Malária Cerebral/parasitologia , Masculino , Camundongos Endogâmicos C57BL , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Nanoestruturas/toxicidade , Plasmodium berghei/isolamento & purificação , Ratos Wistar
20.
Eur J Med Chem ; 122: 635-646, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27448920

RESUMO

In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction of acid anhydrides, or acid chlorides with artemisinin derived alcohol. In vitro antiplasmodial activity assessments were conducted against intraerythrocytic NF54 and Dd2 Plasmodium falciparum strains. Cytotoxicities were assessed, using normal human fetal lung fibroblast (WI-38) and Chinese hamster ovarian (CHO) mammalian cell lines, while anticancer activities were tested by using panels with three cell lines, consisting of renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells. Most compounds were found active against the breast cancer cell line. Since antiplasmodial activities for most compounds were found comparable only to that of artesunate, this study did not yield any esters with significantly improved antimalarial efficacies, nor did it deliver any promising antitumor hits. However, from the outcomes of this study, compounds with good safety profiles and increased thermal stabilities, compared to the clinically used artemisinins, were identified. The benzoate derivative 11 was found to have antimalarial activity, comparable to that of dihydroartemisinin and was it subsequently identified as a candidate for further investigation in the urgent search for new, safe and effective antimalarial drugs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Artemisininas/síntese química , Artemisininas/farmacologia , Desenho de Fármacos , Animais , Antineoplásicos/química , Antiprotozoários/química , Antiprotozoários/toxicidade , Artemisininas/química , Artemisininas/toxicidade , Células CHO , Linhagem Celular Tumoral , Técnicas de Química Sintética , Cricetinae , Cricetulus , Ésteres , Humanos , Plasmodium falciparum/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...