RESUMEN
Abstract Tuberculosis treatment consists of a drug combination, where isoniazid is the core drug and alcoholism is a factor highly related to poor patient compliance with the therapy. CYP2E1 is an enzyme involved both in the metabolism of ethanol and in the formation of hepatotoxic compounds during the metabolism of isoniazid. The shared metabolism pathway accounts for the possibility of pharmacokinetic interaction in cases of concomitant alcohol use during tuberculosis treatment. The aim of this study was to evaluate the effect of repeated exposure of Wistar rats (males, 250 g, n=6) to ethanol on the pharmacokinetics of a single dose of isoniazid in combination with pyrazinamide and rifampicin (100 mg/kg, 350 mg/kg and 100 mg/kg, respectively). An animal group received the combination of drugs and ethanol and was compared to a control group, which received the combination of drugs without exposure to ethanol. The plasma concentrations of isoniazid were determined by a UHPLC/UV bioanalytical method that was previously validated. Biochemical markers of liver function were measured to assess potential damage. A lower elimination half-life of isoniazid was observed in the ethanol group than in the control group (t1/2 0.91 h versus 1.34 h). There was no evidence of hepatotoxicity through the biomarker enzymes evaluated. The results allow us to infer that although there are no biochemical changes related to liver damage, there is a slight influence of ethanol exposure on the pharmacokinetic profile of isoniazid. This change may have a relevant impact on the efficacy of isoniazid in the outcome of tuberculosis treatment.
Asunto(s)
Animales , Masculino , Ratas , Farmacocinética , Etanol/efectos adversos , Isoniazida/análisis , Tuberculosis/patología , Biomarcadores/análisis , Citocromo P-450 CYP2E1/farmacologíaRESUMEN
The objectives of this study were to extract and purify Bixin from the seeds of Bixa orellana and to evaluate its hypoglycemic activity in vivo, as well as, to conduct an in silico study of selectivity on peroxisome proliferator-activated receptors via molecular docking and molecular dynamics simulations. Oral administration of Bixin (10 mg/kg) significantly reduced their glucose level that was alloxan-induced diabetic rats. Bixin showed in silico selectivity on peroxisome proliferator-activated receptors (PPARs), particularly by the peroxisome proliferator-activated receptor gamma (PPARγ), which supports the hypoglycemic activity of Bixin. From the results obtained, it can be inferred that Bixin presents hypoglycemic characteristics, which was confirmed by the results obtained from the in vivo and in silico tests. Bixin may act by other pathways to control blood glucose and thus it is possible that it presents a different toxicity profile than troglitazone, rosiglitazone and pioglitazone. However, more studies on the activity and toxicity of Bixin are needed to evaluate for further clinical use. Communicated by Ramaswamy H. Sarma.
Asunto(s)
Diabetes Mellitus Experimental , Tiazolidinedionas , Aloxano , Animales , Carotenoides , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Simulación del Acoplamiento Molecular , PPAR gamma , RatasRESUMEN
The incorporation of doxorubicin (DOX) in a microemulsion (DOX-ME) has shown beneficial consequences by reducing the cardiotoxic effects of DOX. The aim of this study was to determine the distribution of DOX-ME in Ehrlich solid tumor (EST) and the heart, and compare it with that of free DOX. The distribution study was conducted with female Swiss mice with EST (n = 7 per group; 20-25 g). Animals received a single dose (10 mg/kg, i.p.) of DOX or DOX-ME 7 days after tumor inoculation. Fifteen minutes after administration, the animals were sacrificed, and the tumor and heart tissues were taken for immediate analysis by ultra-performance liquid chromatography. No difference was observed in DOX concentration in tumor tissue between DOX and DOX-ME administration. However, the most remarkable result in this study was the statistically significant reduction in DOX concentration in heart tissue of animals given DOX-ME. Mean DOX concentration in heart tissue was 0.92 ± 0.54 ng mg(-1) for DOX-ME and 1.85 ± 0.34 ng mg(-1) for free DOX. In conclusion, DOX-ME provides a better tissue distribution profile, with a lower drug concentration in heart tissue but still comparable tumor drug concentration, which indicates that antitumor activity would not be compromised.
Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Materiales Biocompatibles , Doxorrubicina/farmacocinética , Emulsiones , Animales , Cromatografía Liquida , Femenino , Ratones , Distribución TisularRESUMEN
Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission.
Asunto(s)
Antimaláricos/efectos adversos , Antimaláricos/uso terapéutico , Profármacos/efectos adversos , Profármacos/uso terapéutico , Aedes/parasitología , Animales , Antimaláricos/farmacología , Línea Celular , Cloroquina/efectos adversos , Cloroquina/farmacología , Cloroquina/uso terapéutico , Dipéptidos/efectos adversos , Dipéptidos/farmacología , Dipéptidos/uso terapéutico , Glucosafosfato Deshidrogenasa/metabolismo , Hemólisis/efectos de los fármacos , Células Hep G2 , Humanos , Malaria Vivax/tratamiento farmacológico , Masculino , Plasmodium gallinaceum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Primaquina/efectos adversos , Primaquina/análogos & derivados , Primaquina/farmacología , Primaquina/uso terapéutico , Profármacos/farmacología , Ratas , Ratas WistarRESUMEN
The combination of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) is used in the treatment of tuberculosis. Although this treatment is effective in most clinical cases, the side-effects and the development of mycobacterium resistance have hindered its success. There is evidence that the combination of INH, RMP and ciprofloxacin (CIPRO) is useful in the treatment of tuberculosis. However, the influence of this drug combination on the hepatotoxicity of INH is unknown. In this study, the safety of combined INH, RMP and CIPRO was evaluated. Male albino rabbits (n = 20) were divided into four groups and subjected to multiple oral doses for 7 days according to the following treatments: water (group 1); 50 mg/kg INH (group 2); 50 mg/kg INH + 100 mg/kg RMP (group 3) and 50 mg/kg INH + 100 mg/kg RMP + 50 mg/kg CIPRO (group 4). Blood samples were taken before and after treatments for the determination of ALT, AST, ALP and bilirubin to assess hepatotoxicity. For pharmacokinetic analysis, serial blood samples were collected over 24 h on day 7 of treatment. Plasma concentrations of INH and acetylisoniazid (AcINH) were determined by HPLC. Biochemical parameters did not show any statistically significant differences between the groups that received the drug combinations. The pharmacokinetic profile of INH was also similar for both groups of combinations. These findings allow us to infer that the inclusion of CIPRO did not increase the risk of hepatotoxicity when compared with the classic combination of INH and RMP.
Asunto(s)
Antibióticos Antituberculosos/administración & dosificación , Ciprofloxacina/administración & dosificación , Isoniazida/administración & dosificación , Rifampin/administración & dosificación , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Antibióticos Antituberculosos/sangre , Antibióticos Antituberculosos/farmacocinética , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Ciprofloxacina/farmacocinética , Combinación de Medicamentos , Isoniazida/sangre , Isoniazida/farmacocinética , Masculino , Conejos , Rifampin/farmacocinéticaRESUMEN
Gastrotoxicity is a major problem for long-term therapy with non-steroidal anti-inflammatory drugs (NSAIDs). DICCIC (1-(2,6-dichlorophenyl)indolin-2-one) is a new diclofenac prodrug, which has proven anti-inflammatory activity without gastroulcerogenic effect. The aim of this work was to compare the pharmacokinetic profiles of diclofenac from DICCIC (7.6 mg/kg equivalent to 8.1 mg/kg diclofenac) and diclofenac (8.1 mg/kg) administration in Wistar rats weighing 250-300 g (n=20). The doses were calculated by interspecific allometric scaling based on the 2 mg/kg from diary human dose of diclofenac. Blood samples were collected in heparinized tubes via the femoral artery through the implanted catheter. The plasma was separated and quantitation was made in a HPLC system with a UV-Vis detector. The confidence limits of the bioanalytical method were appropriate for its application in a preclinical pharmacokinetic study. The AUC of diclofenac from DICCIC (53.7± 5.8 ug/mL.min) was significantly less (Mann Whitney test, p<0.05) than that of diclofenac from diclofenac administration (885.9 ± 124,8 ug/mL.min). Terminal half-life of diclofenac from DICCIC (50.1 ± 17.2 min) was significantly less (Mann Whitney test, p<0.05) than that of diclofenac from diclofenac administration (247.4 ± 100.9 min). Still the parameters clearance and distribution volume were calculated for diclofenac from diclofenac, whose results were 9.2 ±1.2 mL/min.kg and 3.3 ±1.2 L/kg, respectively. The results of DICCIC from DICCIC administration were 108.9 ± 19.6 mL/min.kg and 7.8 ± 2.4 L/kg for clearance and distribution volume, respectively. The pharmacokinetic profile demonstrated that there was an increase in diclofenac elimination and a lower exposure to diclofenac with administration of DICCIC compared to diclofenac.