RESUMO
Artemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardiotoxicity. To achieve this, we prepared polymeric nanocapsules (NCs) from different biodegradable polyesters, namely poly(D,L-lactide) (PLA), poly-ε-caprolactone (PCL), and surface-modified NCs, using a monomethoxi-polyethylene glycol-block-poly(D,L-lactide) (PEG5kDa-PLA45kDa) polymer. Using this approach, we were able to encapsulate high yields of ATM (>85%, 0−4 mg/mL) within the oily core of the NCs. The PCL-NCs exhibited the highest percentage of ATM loading as well as a slow release rate. Atomic force microscopy showed nanometric and spherical particles with a narrow size dispersion. We used the PCL NCs loaded with ATM for biological evaluation following IV administration. As with free-ATM, the ATM-PCL-NCs formulation exhibited potent antimalarial efficacy using either the "Four-day test" protocol (ATM total at the end of the 4 daily doses: 40 and 80 mg/kg) in Swiss mice infected with P. berghei or a single low dose (20 mg/kg) of ATM in mice with higher parasitemia (15%). In healthy rats, IV administration of single doses of free-ATM (40 or 80 mg/kg) prolonged cardiac QT and QTc intervals and induced both bradycardia and hypotension. Repeated IV administration of free-ATM (four IV doses at 20 mg/kg every 12 h for 48 h) also prolonged the QT and QTc intervals but, paradoxically, induced tachycardia and hypertension. Remarkably, the incorporation of ATM in ATM-PCL-NCs reduced all adverse effects. In conclusion, the encapsulation of ATM in biodegradable polyester NCs reduces its cardiovascular toxicity without affecting its antimalarial efficacy.
RESUMO
Glioblastomas are tumors that present a high mortality rate. Artemether (ART) is a lactone with antitumor properties, demonstrating low bioavailability and water solubility. In the present study, we developed lipid-core nanocapsules (LNC) containing pequi oil (Caryocar brasiliense Cambess) as the oily core for ART-loaded LNCs (LNCART) and evaluated their effect on human glioblastoma cells (U-87 MG). LNCs were developed by interfacial deposition of a preformed polymer, followed by physicochemical characterization. LNCART revealed a diameter of 0.216 µm, polydispersity index of 0.161, zeta potential of -12.0 mV, and a pH of 5.53. Furthermore, mitochondrial viability, proliferation, total antioxidant status, and antioxidant enzyme activity were evaluated. ART reduced cell viability after 24 h and proliferation after 48 h of treatment at concentrations equal to or above 40 µg . mL-1. LNCART, at 1.25 µg . mL-1, reduced these parameters after 24 h of treatment. Furthermore, superoxide dismutase (SOD) activity was elevated, while glutathione reductase (GR) activity was reduced. These findings suggest that ART loaded into LNC may be a promising alternative to improve its pharmacological action and possible application as a therapeutic agent for glioblastoma.
Assuntos
Glioblastoma , Nanocápsulas , Humanos , Nanocápsulas/química , Antioxidantes/farmacologia , Artemeter , Sobrevivência Celular , Glioblastoma/tratamento farmacológico , Lipídeos/química , PolímerosRESUMO
BACKGROUND Cerebral malaria is a lethal complication of Plasmodium falciparum infections in need of better therapies. Previous work in murine experimental cerebral malaria (ECM) indicated that the combination of artemether plus intraperitoneal whole blood improved vascular integrity and increased survival compared to artemether alone. However, the effects of blood or plasma transfusion administered via the intravenous route have not previously been evaluated in ECM. OBJECTIVES To evaluate the effects of intravenous whole blood compared to intravenous plasma on hematological parameters, vascular integrity, and survival in artemether-treated ECM. METHODS Mice with late-stage ECM received artemether alone or in combination with whole blood or plasma administered via the jugular vein. The outcome measures were hematocrit and platelets; plasma angiopoietin 1, angiopoietin 2, and haptoglobin; blood-brain barrier permeability; and survival. FINDINGS Survival increased from 54% with artemether alone to 90% with the combination of artemether and intravenous whole blood. Intravenous plasma lowered survival to 18%. Intravenous transfusion provided fast and pronounced recoveries of hematocrit, platelets, angiopoietins levels and blood brain barrier integrity. MAIN CONCLUSIONS The outcome of artemether-treated ECM was improved by intravenous whole blood but worsened by intravenous plasma. Compared to prior studies of transfusion via the intraperitoneal route, intravenous administration was more efficacious.
RESUMO
Artemether (ART) and lumefantrine (LUM) are the gold standard antimalarial drugs used for the treatment of malaria in children and pregnant women. Typically, ART and LUM are delivered orally in the form of a combined tablet, however, the appropriateness of this route of administration for these drugs is questionable due to the poor absorption and therefore bioavailability observed unless administered alongside lipid-rich foods. Transdermal drug delivery in the form of a patch-type system has been identified as a viable alternative to the conventional tablet-based therapy. A novel, surfactant-based ART-LUM formulation (S3AL), developed for transdermal delivery, may eliminate the shortcomings associated with oral delivery; namely poor drug absorption which is caused by the inherently low solubility of ART and LUM. Moreover, by successfully delivering these antimalarials transdermally, first-pass metabolism will be avoided leading to enhanced drug bioavailability in both cases. The S3AL formulation contained ART and LUM at equal concentrations (2.5% w/w of each) as well as Procetyl® AWS (30% w/w), oleic acid (10% w/w), 1-methyl-2-pyrrolidone (10% w/w), and water (45% w/w). The addition of LUM to the formulation changed the system from a striae structure to a dark field structure when visualized by a polarized light microscope. Additionally, this system possessed higher viscosity and superior skin bioadhesion, as evidenced by mechanical characterization, when compared to a similar formulation containing ART alone. S3AL was also proven to be biocompatible to human keratinocyte cells. Finally,in vitrostudies demonstrated the propensity of S3AL for successful delivery via the transdermal route, with 2279 ± 295 µg cm-2of ART and 94 ± 13 µg cm-2of LUM having permeated across dermatomed porcine skin after 24 h, highlighting its potential as a new candidate for the treatment of malaria.
Assuntos
Antimaláricos , Combinação Arteméter e Lumefantrina , Tensoativos/química , Administração Cutânea , Animais , Antimaláricos/administração & dosagem , Antimaláricos/química , Antimaláricos/farmacocinética , Combinação Arteméter e Lumefantrina/administração & dosagem , Combinação Arteméter e Lumefantrina/química , Combinação Arteméter e Lumefantrina/farmacocinética , Humanos , Pele/metabolismo , Solubilidade , SuínosRESUMO
The worldwide presence of Leishmania parasites increases in the poorest regions. Current leishmaniasis treatments are unsatisfactory due to resistance development, side effects and cost. Herein, we describe the in vitro activity of artemisinin (ART), artemether (ATM), artesunate (ATS) and dihydroartemisinin (DHA) against Leishmania amazonensis. Selected compounds were assayed in the animal model of cutaneous leishmaniasis in BALB/c mice. On intracellular amastigotes, similar activity (pâ¯>â¯0.05) was observed for ART, ATM and ATS (IC50â¯=â¯15.0-19.2⯵M), which were inferior (pâ¯<â¯0.05) respect to reference endoperoxide ascaridole (IC50â¯=â¯11.5⯱â¯1.0⯵M) and superior (pâ¯<â¯0.05) compared with reference drug Glucantime® (IC50â¯=â¯30.1⯱â¯9.0⯵M). In contrast, DHA (IC50â¯=â¯38.5⯱â¯4.7⯵M) showed higher IC50 values (pâ¯<â¯0.05) than other artemisinins and ascaridole, but similar (pâ¯>â¯0.05) than Glucantime®; while deoxyartemisinin caused smaller inhibition (IC50â¯=â¯88.9⯱â¯5.2⯵M). Selectivity indexes of >13, 6, 11 and 1 were obtained for ART, ATM, ATS and DHA, respectively. In addition, the potential effect of ART and ATS was also demonstrated in the murine model, causing a significant reduction (pâ¯<â¯0.05) of the lesion size and parasite load regarding untreated animals and treated with vehicle. Effects of both artemisinins were comparable (pâ¯>â¯0.05) with Glucantime® and ascaridole-treated mice. In particular, artemisinin is recommended to further studies, which could be an advantage over the ascaridole endoperoxide and could be useful in endemic areas of parasite resistance to antimonials.
Assuntos
Artemisininas/farmacologia , Leishmania mexicana/efeitos dos fármacos , Carga Parasitária , Tripanossomicidas/farmacologia , Animais , Artemeter/farmacologia , Artesunato/farmacologia , Modelos Animais de Doenças , Feminino , Camundongos/parasitologia , Camundongos Endogâmicos BALB CRESUMO
Artemether (ART) was combined with triglyceride of docosahexaenoic acid (DHA) as the lipid-core in nanoemulsions (NE), nanostructured lipid carriers (NLC), and PEG-PLA nanocapsules (NC) formulations, and their effects on human breast cancer cells were evaluated. ART has been extensively used for malaria and has also therapeutic potential against different tumor cells in a repositioning strategy. The concentration-dependent cytotoxicity in vitro was determined in tumor lineages, MDA-MB-231 and MCF-7, and non-tumor MCF-10A cells for free-ART/DHA combination and its formulations. The cells were monitored for viability, effects on cell migration and clonogenicity, cell death mechanism, and qualitative and quantitative cell uptake of nanocarriers. The lipid-nanocarriers showed mean sizes over the range of 110 and 280 nm with monodisperse populations and zeta potential values ranging from -21 to -67 mV. The ART encapsulation efficiencies varied from 57 to 83 %. ART/DHA co-loaded in three different lipid nanocarriers reduced the MDA-MB-231 and MCF-7 viability in a dose-dependent manner with enhanced selectivity toward tumor cell lines. They also reduced clonogenicity and the ability of cells to migrate showing antimetastatic potential in both cell lines and triggered apoptosis in MCF-7 cells. Confocal microscopy and flow cytometry analysis showed that NC, NLC, and NE were rapidly internalized by cells, with higher interaction displayed by NE with MCF-7 cells compared to NC and NLC that was correlated with the strongest NE-fluorescence in cells. Therefore, this study not only demonstrated the value of this new combination of ART/DHA as a new strategy for breast cancer therapy but also showed enhanced cytotoxicity and potential metastatic activity of lipid-based formulations against human breast cancer cells that indicate great potential for pre-clinical and clinical translation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Artemeter/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Portadores de Fármacos , Nanocápsulas , Triglicerídeos/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Apoptose/efeitos dos fármacos , Artemeter/química , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/química , Composição de Medicamentos , Emulsões , Feminino , Humanos , Células MCF-7 , Metástase NeoplásicaRESUMO
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/toxicidadeRESUMO
This experiment was designed to study the administration of normal doses of one of recent antimalarial drug and coadministration of vitamin E on the kidney tissue. A total twenty-four adult male albino rats were used and divided into four groups: the first one served as a control, the second received artemether orally for three days consecutively. The rats of the third and fourth groups received the same dose of artemether concomitantly with 50 and 100 mg/kg vitamin E orally daily for 2 weeks. After the last dose, the rats were sacrificed and the kidney tissues with blood samples obtained and processed for light, electron microscopic and biochemical analysis. Histologically, artemether treated kidneys showed atrophied glomeruli with widened urinary space and kidney tubules were degenerated with disturbed contour and some vacuoles inside it. Ultrastructurally, the glomeruli of this group showed hypertrophic endothelial cells, irregularity of its basement membrane, disrupted foot processes and filtration slits. The kidney tubule cells showed loss of basal infoldings, cytoplasmic vacuolation, polymorphic damaged swollen mitochondria a loss of its microvilli towards its capillary lumen. Artemether plus vitamin E of the rat kidney groups showed improvement of morphological changes compared to the changes seen in artemether alone. These data were confirmed by biochemical findings with marked improvement of blood urea and creatinine levels and increase of anti-oxidant enzyme activities of glutathione peroxidase and superoxide dismutase in the vitamin E treated groups. The results of this study revealed that vitamins E can improve the adverse changes of artemether of rat renal tissue.
Este proyecto fue diseñado para estudiar la administración de dosis normales de uno de los medicamentos antipalúdicos y de la administración de vitamina E en el tejido renal. Se utilizaron 24 ratas albinas machos adultas divididas en cuatro grupos: el primero sirvió como control, el segundo recibió arteméter por vía oral durante tres días consecutivos. Las ratas del tercer y cuarto grupos recibieron la misma dosis de arteméter concomitantemente con 50 y 100 mg / kg de vitamina E por vía oral diariamente durante 2 semanas. Después de la última dosis, las ratas fueron sacrificadas y se obtuvo el tejido renal de cada muestra los cuales fueron procesados para análisis con microscopías de luz y electrónica, además de exámenes bioquímicos. Histológicamente, los riñones tratados con arteméter mostraron atrofia glomerular con espacio urinario ensanchado y túbulos renales degenerados con contorno alterado y algunas vacuolas en su interior. Ultraestructuralmente, los glomérulos de este grupo mostraron células endoteliales hipertróficas, irregularidad de su membrana basal, procesos alterados del pie y hendiduras de filtración. Las células del túbulo renal mostraron pérdida de inflexiones basales, vacuolación citoplasmática, mitocondrias dañadas y pérdida de sus microvellosidades hacia la luz capilar. Arteméter más vitamina E en los grupos de riñón de rata mostraron una mejora de los cambios morfológicos, en comparación con los cambios observados en arteméter solamente. Estos datos fueron confirmados por hallazgos bioquímicos con una marcada mejoría de los niveles de urea y creatinina en sangre y un aumento de las actividades enzimáticas antioxidantes de la glutatión peroxidasa y la superóxido dismutasa en los grupos tratados con vitamina E. Los resultados de este estudio revelaron que la vitamina E puede mejorar los cambios adversos del arteméter del tejido renal de la rata.
Assuntos
Animais , Masculino , Ratos , Vitamina E/farmacologia , Injúria Renal Aguda/induzido quimicamente , Artemeter/toxicidade , Vitamina E/administração & dosagem , Microscopia Eletrônica , Biomarcadores/análise , Ratos Wistar , Rim/efeitos dos fármacos , Rim/patologia , Rim/ultraestrutura , Antimaláricos/toxicidadeRESUMO
This research was designed to investigate the potential protective effect of vitamin C supplementation against hepatocyte ultrastructural alterations induced by artemether (antimalarial drug) administration. Twenty-four adult male albino rats were used in this study and were divided into four groups (n=6). Group I served as a control and rats in group II administrated artemether (4 mg/kg B.W) orally for three consecutive days. Group III administered artemether plus a low dose of vitamin C (2.86 mg/kg/l water) while group IV received artemether plusa high dose of vitamin C (8.56 mg/kg). At the end of the experimental period (14 days), the harvested liver tissues were examined by transmission electron microscopy (TEM), and blood samples were assayed for biomarkers of liver injury and oxidative stress. Artemether significantly (p<0.05) augmented biomarkers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and oxidative stress such as superoxide dismutase (SOD), Glutathione Peroxidase (GPX), and caused degeneration and damage of the rough endoplasmic reticulum and disrupted mitochondria. The blood sinusoids were also damaged with distortion of their canaliculi. Administration of vitamin C showed improvement of liver biomarkers, and liver parenchyma, especially in a high dose of vitamin C.We concludes that vitamin C is a partial protective agent against artemether-induced liver injury.
Esta investigación fue diseñada para investigar el posible efecto protector de la vitamina C contra las alteraciones ultraestructurales de los hepatocitos, inducidas por la administración de arteméter (medicamento antipalúdico). En el estudio se utilizaron 24 ratas albinas macho adultas y se dividieron en cuatro grupos (n = 6). El grupo I fue designado como control y las ratas en el grupo II se adminstró Arteméter (4 mg / kg de peso corporal) por vía oral durante tres días consecutivos. En el grupo III se administró arteméter, además de una dosis baja de vitamina C (2,86 mg / kg / l de agua) mientras que el grupo IV recibió arteméter más una dosis alta de vitamina C (8,56 mg / kg). Al final del período experimental (14 días), los tejidos hepáticos recolectados se examinaron por microscopía electrónica de transmisión (MET), y las muestras de sangre se analizaron en busca de biomarcadores de daño hepático y estrés oxidativo. El arteméter aumentó significativamente (p <0,05) los biomarcadores de daño hepático como alanina aminotransferasa (ALT), aspartato aminotransferasa (AST) y estrés oxidativo como superóxido dismutasa (SOD), glutatión peroxidasa (GPX) y causó degeneración y daño de la retículo endoplásmico rugoso y mitocondrias alteradas. Los sinusoides sanguíneos también fueron dañados con la distorsión de sus canalículos. La administración de vitamina C mostró una mejoría de los biomarcadores hepáticos y el parénquima hepático, especialmente en una dosis alta de vitamina C. Concluimos que la vitamina C es un agente protector parcial contra la lesión hepática inducida por arteméter.
Assuntos
Animais , Ratos , Ácido Ascórbico/administração & dosagem , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Artemeter/toxicidade , Ácido Ascórbico/farmacologia , Superóxido Dismutase/análise , Biomarcadores , Ratos Sprague-Dawley , Estresse Oxidativo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/ultraestrutura , Microscopia Eletrônica de Transmissão , Modelos Animais de Doenças , Medicamentos Hepatoprotetores , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glutationa Peroxidase/análiseRESUMO
Malaria is a worldwide health issue, with 216 million cases reported in 2016. Due to the widespread resistance of Plasmodium falciparum to conventional drugs, the first line treatment recommended by World Health Organization for uncomplicated malaria is artemisinin-based combined therapy (ACT), which combines two drugs with different mechanisms of action. The association of artemether and lumefantrine is the most common ACT used in the clinical practice. However, there have been reports of clinical artemisinin and derivatives partial resistance, which is defined as delayed parasite clearance. In this context, the monitoring of drug concentration in biological matrices is essential to evaluate treatment response, the need of dose adjustment and the occurrence of dose dependent adverse effects. Furthermore, it is also important for pharmacokinetic studies and in the development of generic and similar drugs. Determination of antimalarial drugs in biological matrices requires a sample pre-treatment, which involves drug extraction from the matrix and analyte concentration. The most used techniques are protein precipitation (PP), liquid-liquid extraction (LLE) and solid phase extraction (SPE). Subsequently, a liquid chromatography step is usually applied to separate interferences that could be extracted along with the analyte. Finally, the analytes are detected employing techniques that must be selective and sensitive, since the analyte might be present in trace levels. The most used approach for detection is tandem mass spectrometry (MS-MS), but ultraviolet (UV) is also employed in several studies. In this article, a review of the scientific peer-review literature dealing with validated quantitative analysis of artemether and/or lumefantrine in biological matrices, from 2000 to 2018, is presented.
Assuntos
Antimaláricos/análise , Combinação Arteméter e Lumefantrina/análise , Técnicas de Química Analítica/métodos , Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Combinação Arteméter e Lumefantrina/administração & dosagem , Combinação Arteméter e Lumefantrina/farmacocinética , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Humanos , Malária Falciparum/tratamento farmacológico , Sensibilidade e EspecificidadeRESUMO
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 JovemRESUMO
According to the most recent World Health Organization statistics, malaria infected approximately 219 million people in 2017, with an estimate of 435,000 deaths (World Health Organization, 2018). Communities isolated from cities are the most deprived of access to the necessary hospital facilities. Herein we report the development of a transdermal bioadhesive containing artemether (ART), an alternative, potentially lifesaving, treatment regimen for malaria in low-resource settings. Bioadhesives were prepared from an aqueous blend of hydroxyethylcellulose (4.5% w/w), ART, propoxylated-ethoxylated-cetyl-alcohol, polysorbate 80, propyleneglycol, glycerine, mineral oil, and oleic acid. In this study, the average pore size of bioadhesive 5.5b was 52.6 ± 15.31 µm. Differential scanning calorimetry and thermogravimetric analyses confirm the thermal stability of ART bioadhesives at room temperature. Tensile tests indicated good mechanical properties for bioadhesive 5.5b, when compared to 5.5a, where 5.5b showed elastic modulus 0.19 MPa, elongation at break 204%, tensile stress 0.31 MPa, tensile strength at break 0.23 MPa. Bioadhesion assays suggested that formulations containing surfactants had higher detachment forces. Permeation studies demonstrated that the best outcome was achieved with a bioadhesive containing 25 mg ART (5.5b) that after 24 h released 6971 ± 125 µg, which represents approximately 28% of drug permeation. Data reported presents a promising candidate for a new antimalarial transdermal formulation.
Assuntos
Antimaláricos/farmacocinética , Artemeter/farmacocinética , Malária Falciparum/tratamento farmacológico , Pele/metabolismo , Adesivo Transdérmico , Administração Cutânea , Animais , Antimaláricos/administração & dosagem , Antimaláricos/química , Artemeter/administração & dosagem , Artemeter/química , Artemisia annua/química , Criança , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Humanos , Malária Falciparum/parasitologia , Permeabilidade , SuínosRESUMO
Abstract Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated malaria. Currently, there appears to be a downward trend in the efficacy of ACT in some parts of sub-Saharan Africa because some patients have been positive for Plasmodium parasite 3 days after artemether-lumefantrine treatment. We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.
Assuntos
Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Malária Falciparum/tratamento farmacológico , Combinação Arteméter e Lumefantrina/uso terapêutico , Antimaláricos/uso terapêutico , Falha de Tratamento , Combinação Arteméter e Lumefantrina/efeitos adversos , Pessoa de Meia-Idade , Antimaláricos/efeitos adversosRESUMO
Resealed erythrocytes have been explored in various dimensions of drug delivery, owing to their high biocompatibility and inability to initiate immune response. The present research was designed to evaluate the drug delivery potential of erythrocytes by loading a hydrophobic anti-malarial drug, Artemether. Three different loading techniques were applied to achieve maximum optimized drug loading. A HPLC method was validated for drug quantification in erythrocytes. The relatively high loading was achieved using hypotonic treatment was 31.39% as compared to other two methods. These, drug loaded erythrocytes were characterized for membrane integrity via ESR showing higher ESR values for drug loaded cells as compared to normal cells. Moreover, microscopic evaluation was done to observe morphological changes in erythrocytes after successful loading which showed swollen cells with slight rough surface as compared to smooth surface of normal cells. Drug release was studied for 8 h which showed more than 80% release within 3-7 h from erythrocytes treated with different hypotonic methods. Overall, the study revealed a potential application of erythrocytes in delivery of hydrophobic drugs using hypotonic treatment as compared to other methods.
Assuntos
Eritrócitos/classificação , Liberação Controlada de Fármacos , Artemeter/administração & dosagem , Preparações Farmacêuticas/administração & dosagem , Cromatografia Líquida de Alta Pressão/métodosRESUMO
BACKGROUND: There is general international agreement that the importance of vivax malaria has been neglected, and there is a need for new treatment approaches in an effort to progress towards control and elimination in Latin America. This open label randomized clinical trial evaluated the efficacy and safety of three treatment regimens using either one of two fixed dose artemisinin-based combinations or chloroquine in combination with a short course of primaquine (7-9 days: total dose 3-4.2 mg/kg) in Brazil. The primary objective was establishing whether cure rates above 90% could be achieved in each arm. RESULTS: A total of 264 patients were followed up to day 63. The cure rate of all three treatment arms was greater than 90% at 28 and 42 days. Cure rates were below 90% in all three treatment groups at day 63, although the 95% confidence interval included 90% for all three treatments. Most of the adverse events were mild in all treatment arms. Only one of the three serious adverse events was related to the treatment and significant drops in haemoglobin were rare. CONCLUSION: This study demonstrated the efficacy and safety of all three regimens that were tested with 42-day cure rates that meet World Health Organization criteria. The efficacy and safety of artemisinin-based combination therapy regimens in this population offers the opportunity to treat all species of malaria with the same regimen, simplifying protocols for malaria control programmes and potentially contributing to elimination of both vivax and falciparum malaria. Trial registration RBR-79s56s.
Assuntos
Artemisininas/uso terapêutico , Cloroquina/uso terapêutico , Malária Vivax/tratamento farmacológico , Plasmodium vivax/efeitos dos fármacos , Primaquina/uso terapêutico , Adulto , Idoso , Brasil , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Artemether (ATM) cardiotoxicity, its short half-life and low oral bioavailability are the major limiting factors for its use to treat malaria. The purposes of this work were to study free-ATM and ATM-loaded poly-ε-caprolactone nanocapules (ATM-NC) cardiotoxicity and oral efficacy on Plasmodium berghei-infected mice. ATM-NC was obtained by interfacial polymer deposition and ATM was associated with polymeric NC oily core. For cardiotoxicity evaluation, male black C57BL6 uninfected or P. berghei-infected mice received, by oral route twice daily/4 days, vehicle (sorbitol/carboxymethylcellulose), blank-NC, free-ATM or ATM-NC at doses 40, 80 or 120 mg kg-1. Electrocardiogram (ECG) lead II signal was obtained before and after treatment. For ATM efficacy evaluation, female P. berghei-infected mice were treated the same way. ATM-NC improved antimalarial in vivo efficacy and reduced mice mortality. Free-ATM induced significantly QT and QTc intervals prolongation. ATM-NC (120 mg kg-1) given to uninfected mice reduced QT and QTc intervals prolongation 34 and 30%, respectively, compared with free-ATM. ATM-NC given to infected mice also reduced QT and QTc intervals prolongation, 28 and 27%, respectively. For the first time, the study showed a nanocarrier reducing cardiotoxicity of ATM given by oral route and it was more effective against P. berghei than free-ATM as monotherapy.
Assuntos
Antimaláricos/administração & dosagem , Artemeter/administração & dosagem , Cardiotoxicidade/prevenção & controle , Nanocápsulas/química , Plasmodium berghei/efeitos dos fármacos , Administração Oral , Animais , Antimaláricos/toxicidade , Artemeter/toxicidade , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Malária/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as an increased parasite clearance time, manifesting as a positive thick-blood smear on day 3 after treatment (D3 positivity). Recently, mutations in the propeller domain of the P. falciparumkelch13 gene (K13 propeller) have been associated with ART resistance. In this study, we surveyed AL effectiveness at D3 and molecular markers of drug resistance among 187 uncomplicated P. falciparum cases in 4 regions of Colombia from June 2014 to July 2015. We found that 3.2% (4/125) of patients showed D3 positivity, 100% (163/163) of isolates carried wild-type K13 propeller alleles, 12.9% (23/178) of isolates had multiple copies of the multidrug resistance 1 gene (mdr1), and 75.8% (113/149) of isolates harbored the double mutant NFSDD mdr1 haplotype (the underlining indicates mutant alleles). These data suggest that ART resistance is not currently suspected in Colombia but that monitoring for lumefantrine resistance and AL failures should continue.
Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Adolescente , Adulto , Combinação Arteméter e Lumefantrina , Colômbia , Combinação de Medicamentos , Resistência a Medicamentos , Feminino , Humanos , Masculino , Plasmodium falciparum/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
The emerging resistance to artemisinin derivatives that has been reported in South-East Asia led us to assess the efficacy of artemether-lumefantrine as the first line therapy for uncomplicated Plasmodium falciparum infections in Suriname. This drug assessment was performed according to the recommendations of the World Health Organization in 2011. The decreasing number of malaria cases in Suriname, which are currently limited to migrating populations and gold miners, precludes any conclusions on artemether efficacy because adequate numbers of patients with 28-day follow-up data are difficult to obtain. Therefore, a comparison of day 3 parasitaemia in a 2011 study and in a 2005/2006 study was used to detect the emergence of resistance to artemether. The prevalence of day 3 parasitaemia was assessed in a study in 2011 and was compared to that in a study in 2005/2006. The same protocol was used in both studies and artemether-lumefantrine was the study drug. Of 48 evaluable patients in 2011, 15 (31%) still had parasitaemia on day 3 compared to one (2%) out of 45 evaluable patients in 2005/2006. Overall, 11 evaluable patients in the 2011 study who were followed up until day 28 had negative slides and similar findings were obtained in all 38 evaluable patients in the 2005/2006 study. The significantly increased incidence of parasite persistence on day 3 may be an indication of emerging resistance to artemether.
Assuntos
Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Adulto Jovem , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Resistência a Medicamentos , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Malária Falciparum/parasitologia , Parasitemia , Plasmodium falciparum/efeitos dos fármacos , Combinação de Medicamentos , Incidência , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Parasitemia/epidemiologia , Suriname/epidemiologiaRESUMO
Artemisinin-based combination therapy-resistant malaria is rare in Sub-Saharan Africa. The World Health Organization identifies monitoring and surveillance using day-3 parasitaemia post-treatment as the standard test for identifying suspected artemisinin resistance. We report three cases of early treatment failure due to possible artemisinin-based combination therapy-resistant Plasmodium falciparum malaria. All cases showed adequate clinical and parasitological responses to quinine. This study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa.