Microbial transformation of artemisinin and its derivatives / 中国中药杂志

Microbial transformation is an efficient enzymatic approach for the structural modification of exogenous compounds to obtain derivatives. Compared with traditional chemical synthesis, the microbial transformation has in fact the undoubtable advantages of strong region-and stereo-selectivity, and a low environmental and economic impact on the production process, which can achieve the reactions challenging to chemical synthesis. Because microbes are equipped with a broad-spectrum of enzymes and therefore can metabolize various substrates, they are not only a significant route for obtaining novel active derivatives, but also an effective tool for mimicking mammal metabolism in vitro. Artemisinin, a sesquiterpene with a peroxy-bridged structure serving as the main active functional group, is a famous antimalarial agent discovered from Artemisia annua L. Some sesquiterpenoids, such as dihydroartemisinin, artemether, and arteether, have been developed on the basis of artemisinin, which have been successfully marketed and become the first-line antimalarial drugs recommended by WHO. As revealed by pharmacological studies, artemisinin and its derivatives have exhibited extensive biological activities, including antimalarial, antitumor, antiviral, anti-inflammatory, and immunomodulatory. As an efficient approach for structural modification, microbial transformation of artemisinin and its derivatives is an increasingly popular strategy that attracts considerable attention recently, and numerous novel derivatives have been discovered. Herein, this paper reviewed the microbial transformation of artemisinin and its artemisinin, including microbial strains, culture conditions, product isolation and yield, and biological activities, and summarized the advances in microbial transformation in obtaining active derivatives of artemisinin and the simulation of in vivo metabolism of drugs.

Electrocardiographic effect of artemisinin-piperaquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine treatment in falciparum malaria patients

Abstract INTRODUCTION: Artemisinin-based combination therapy (ACT), such as artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine (DP), and artemether-lumefantrine (AL), is the first-line treatment for malaria in many malaria-endemic areas. However, we lack a detailed evaluation of the cardiotoxicity of these ACTs. This study aimed to analyze the electrocardiographic effects of these three ACTs in malaria patients. METHODS: We analyzed the clinical data of 89 hospitalized patients with falciparum malaria who had received oral doses of three different ACTs. According to the ACTs administered, these patients were divided into three treatment groups: 27 treated with AP (Artequick), 31 with DP (Artekin), and 31 with AL (Coartem). Electrocardiograms and other indicators were recorded before and after the treatment. The QT interval was calculated using Fridericia's formula (QTcF) and Bazett's formula (QTcB). RESULTS: Both QTcF and QTcB interval prolongation occurred in all three groups. The incidence of such prolongation between the three groups was not significantly different. The incidence of both moderate and severe prolongation was not significantly different between the three groups. The ΔQTcF and ΔQTcB of the three groups were not significantly different. The intra-group comparison showed significant prolongation of QTcF after AL treatment. CONCLUSIONS: Clinically recommended doses of DP, AL, and AP may cause QT prolongation in some malaria patients but do not cause torsades de pointes ventricular tachycardia or other arrhythmias.

Ameliorative effect of vitamin E on biochemical and ultrastructural changes in artemether-induced renal toxicity in rats / Efecto paliativo de la vitamina E sobre los cambios bioquímicos y ultraestructurales en la toxicidad renal inducida por arteméter en ratas

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.

Vitamin C administration attenuated artemether induced hepatic injury in rats / La aAdministración de vitamina C atenúa la lesión hepática inducida por artemeter en ratas

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.

Study of erythrocytes as a novel drug carrier for the delivery of artemether

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.

Artemeter-Lumefantrine therapeutic efficacy, safety and plasma levels in patients with uncomplicated falciparum malaria from the Colombian Pacific region / Eficacia terapéutica, seguridad y niveles plasmáticos del Artemeter-Lumefantrine en pacientes con malaria falciparum no complicada de la región del Pacifico Colombiano

Introduction: In Colombia, the published studies for the treatment of uncomplicated Plasmodium falciparum malaria with Artemether-Lumefantrine are scarce. The aim of the study was to evaluate the therapeutic efficacy and safety profile of this combination. Methods: A clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28‑day World Health Organization validated protocol. Patients received supervised antimalarial treatment and the primary efficacy endpoint was the clinical and parasitological response. Safety was assessed through adverse events surveillance and plasmatic levels of antimalarial drugs were measured. Results: 88 patients were included. Adequate clinical and parasitological response rate of 100% on day 28 was achieved in 84 patients, diagnosed by thick blood smear examination. There were four parasitological therapeutic failures (5%) detected by polymerase chain reaction. Discusion: Therapeutic efficacy similar to previous studies was established with a slight increase in therapeutic failure. The serum levels of the antimalarials were adequate and the few cases of therapeutic failure were not related. Conclusion: Treatment of uncomplicated P. falciparum malaria with Artemeter-Lumefantrine was effective and safe in the study population. All patients reached adequate plasma concentrations of the drugs; therapeutic failures were not associated with low blood levels of the drug clinical trial.

Introducción: Son escasos los estudios en Colombia sobre eficacia del tratamiento para Plasmodium falciparum con la combinación Artemeter-Lumefantrina. El objetivo de este estudio fue evaluar la eficacia terapéutica y el perfil de seguridad de este tratamiento combinado. Métodos: Se realizó un ensayo clínico en adultos con malaria por P. falciparum no complicada, utilizando el esquema de 28 días recomendado por la Organización Mundial de la Salud (OMS). Los pacientes recibieron el tratamiento supervisado y el desenlace primario evaluado fue la respuesta clínica y parasitológica. La seguridad fue evaluada a través de vigilancia de efectos adversos y medición de niveles plasmáticos del medicamento. Resultados: Se incluyeron 88 pacientes. La tasa de curación clínica y parasitológica fue del 100% en 84 pacientes que tuvieron examen de gota gruesa al día 28. Hubo cuatro (5%) fallas parasitológicas detectada por reacción en cadena de polimerasa. Discusión: La eficacia terapéutica fue similar a la reportada en estudios previos con un ligero aumento de falla terapéutica. Los niveles plasmáticos de los antimalaricos fueron adecuados y no relacionados con la falla terapéutica. Conclusión: El tratamiento de malaria por P. falciparum no complicada con Artemeter-Lumefantrina fue efectiva y segura en la población estudiada. Todos los pacientes alcanzaron niveles en plasma adecuados y no se encontró asociación de falla terapéutica con bajos niveles en sangre.

The Neurotoxic Effects of Artemether on the Cytoarchitecture of the Trapezoid Nuclei of Adult Male Wistar Rats (Rattus novegicus) / Efectos Neurotóxicos del Artemeter sobre la Citoarquitectura del Núcleo Trapezoide en Ratas Machos Adultas Wistar (Rattus novegicus)

In Man, artemether is given at 160mg/kg/bodyweight for three days in the treatment of malarial. This study investigated the effects of corresponding 1.23/mg/kg/bodyweight of artemether for a period of seven days on the trapezoid nuclei and the behavioural functions on day 7 after drug administration in rats. This study observed no gross or morphological differences between the two groups of animals (control and experimental groups) on day 7 at the completion of experimental procedure. A significant statistical increase in average body weight was observed in the control groups C1 (which received only standard diet and water) and C2 (which received 1.23mg/kg/bodyweight of normal saline intramuscularly in addition to standard diet and water) from 140- + 19.65g on day 1 to 146 + 19.90g on Day 1 and 151 + 12.0g on Day 1 to 156.2 + 12.2g on Day 7 respectively. There was a non-statistically significant apparent reduction in body weight in the experimental group E, (which received intramuscular injection of 1.23mg/kg/bodyweight of artemether) from 160 + 9.0g on Day 1 to 157.4 + 8.0g on Day 7. The assessment of brainstem nuclei showed patchychromatic appearance of neurons of the trapezoid nuclei in the experimental group as against the normal vesicular appearance of neurons of the trapezoid nuclei in the Control Group C. The rats in the control groups CI and C2 displayed normal balance and co-ordination, while rats in the experimental group E, showed abnormalities of balance and co-ordination. Using t-test analysis technique at 95% confidence interval i.e t < 0.05 and P - value = 2.26, no significant difference was observed between the average brain weight in the control groups C1 and C2 and the experimental group E.

En el Hombre, el artemeter es dado en el tratamiento de la malaria en dosis de 160 mg/kg de peso, por tres días. Este estudio abordó los efectos de un tratamiento con artemeter, durante 7 días (en dosis de 1,23 mg/kg de peso) sobre el núcleo trapezoide de ratas y las funciones de conducta, en el día 7 después de la administración de la droga. No se observaron ni macro ni diferencias morfológicas entre dos grupos de animales (grupos control y experimental) en el día 7 de la completación del procedimiento. Un incremento estadísticamente significativo en el promedio del peso del cuerpo fue encontrado en el grupo control C1 (el que recibió solamente una dieta standard y agua) y C2 (que recibió 1,23 mg/kg de peso de solución salina intramuscular agregada a la dieta y al agua) que fue desde 140± 19,65 g y 146 ± 19,9 g en el día 1, respectivamente y de 151 ± 12 g y de 156,2 ± 12,2 g en el día 7, respectivamente. No hubo una reducción aparente estadísticamente significativa en el peso del cuerpo del grupo experimental (el cual recibió inyección intramuscular de 1,23 mg/kg de peso de artemeter), la que fue desde 160 ± 9 g en el día 1 y de 157,4 ± 8, en el día 7. La evaluación de núcleos del tronco encefálico mostró apariencia cromática irregular de las neuronas del núcleo trapezoide en el grupo experimental contrariamente a la apariencia vesicular normal de las neuronas de este núcleo en el grupo control. Las ratas de los grupos controles C1 y C2 presentaron un normal balanceo y coordinación, mientras que las ratas del grupo experimental, mostraron anormalidades de balanceo y coordinación. Usando el test t con 95% de intervalo de confianza, p 0,05 y con un valor p=2,26, no se observaron diferencias estadísticamente significativas entre el promedio de los grupos C1 y C2 y del grupo experimental.

Study on improvement of output of semi-synthesis of artemether

Beta-Artemether (12beta-O-menthyldihyroartemisinin), a potent antimalarial drug has been synthetised from dihydroartemisinin using nonpolar waterimmiscible solvents and boron trifluorid etherate as a catalyst. Using this methods we always obtain a mixture of beta and alpha artemether with the ratio from 3/1 to 4/1 and the yield of beta-artemether is about 60%. Using polar waterimmiscible solvents in place of nonpolar waterimmiscible solvents in the synthesis can improve the ratio of beta/alpha artemether to 20/1 and the yield of beta-artemether increase to about 70% beta-artemether.