Arzneimittel-Forschung-Drug Research最新文献

To discover new bioactive lead compounds for medicinal purposes, herein, sulfone biscompounds bearing dihydrothiazoles (3-9, 14, 15), acrylamide (11), thiazolidinones (12, 13, 20), thiophenes (16, 17) and benzothiophene (19) were prepared and tested for their anticancer activity. The structures of the products were confirmed from elemental analysis as well as spectral data. All the synthesized compounds showed remarkable anticancer activity against human breast cancer cell line especially, compound (3) with IC50 value 23.02 µM which was better than that of Doxorubicin by three folds. In order to elucidate the mechanism of action of their cytotoxic activity molecular docking on the active sites of farnesyl transferase and arginine methyl transferase was performed for all synthesized compounds and good results were obtained.

The immunomodulatory effects of lactic acid bacteria have been demonstrated previously. In this study, a Lactobacillus plantarum strain was selected and enriched with selenium nanoparticles for use as a new immunomodulating agent in a breast cancer murine model. 30 female inbred BALB/c mice were equally divided into a test group and a control group. For 2 weeks prior to tumor induction, each mouse received a daily oral administration of 2.5×108 CFU/ml of L. plantarum enriched with selenium nanoparticles (SeNPs), and then 1×106 4T1 cells were injected subcutaneously. After tumor induction, daily SeNP administration was repeated for 3 cycles of 7 days on/3 days off. Immunological parameters such as levels of cytokines, NK cell activity, tumor growth, and mouse survival were evaluated. The production of the pro-inflammatory cytokines IFN-γ, TNF-α, and IL-2 in spleen cell cultures was increased in test mice administered SeNP-enriched L. plantarum. The test mice also showed significant increases in NK cell activity. The tumor volumes of treated mice were decreased and their survival rate notably increased when compared to mice that received L. plantarum alone or control mice. Administration of SeNP-enriched L. plantarum can induce an efficient immune response through the elevation of the pro-inflammatory cytokines IFN-γ, TNF-α and IL-2 levels and increased NK cell activity. Therefore, this treatment may result in better cancer prognosis.

Olanzapine is a widely used agent for the treatment of schizophrenia.The aim of this study was to evaluate bioequivalence of two 10-mg tablet formulations of olanzapine following single oral dose in adult male volunteers.This was a randomized, single-dose, open-label, crossover bioequivalence study. Plasma samples were collected before dosing and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0, 72.0, 96.0, 120.0 and 144.0 h after dosing. Plasma concentrations of olanzapine were determined by using a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Statistical analysis of the pharmacokinetic parameters Cmax, AUC0-144, and AUC0-∞ was conducted to determine bioequivalence. Adverse events were monitored, recorded and evaluated by investigators throughout the study.24 healthy male Chinese volunteers between the ages of 18-40 years with a body mass index (BMI) between 19 and 24 kg/m2 were enrolled in the study. The mean (SD) Cmax, AUC0-144, and AUC0-∞ values after administration of the test and reference formulations, respectively, were as follows: 18.91 (5.320) vs. 18.44 (4.758) ng/mL, 582.9 (118.23) vs. 587.3 (127.12) ng/mL · h, and 615.4 (131.39) vs. 615.8 (137.45) ng/mL · h. The 90% CIs for the ratios of AUC0-144 and Cmax were 96.9% to 102.4% and 93.7% to 110.2%, respectively. The relative bioavailability of the test formulation to reference formulation was 100.1%. Both formulations were generally well tolerated and no serious AEs were reported in the study.The 90% CIs for the ratios of mean Cmax, AUC0-144, and AUC0-∞ met the regulatory criteria for bioequivalence.

The study was aimed at determination of pharmacokinetic parameters of a previously synthesized salicylidine-sulfamethoxazole-Zn(II) monohydrate in normal humans. This new derivative of sulfamethoxazole was reported to be more active and less toxic than the parent drug by our group. 10 volunteers received a 200 mg dose of the drug orally. Blood samples were collected just before and after 0.16, 0.33, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0 and 8.0 h of administration of the drug. The plasma samples were analyzed for sulfamethoxazole by a new validated high performance liquid chromatography method having a suitable limit of quantification. The dose of each drug was well tolerated without any adverse effect. The maximum plasma sulfamethoxazole concentration was 280 μg L - 1 at a tmax 1.30 h. This suggests a rapid onset effect of the complex as compared with the parent drug. The plasma half-life, clearance, and volume of distribution of sulfamethoxazole from salicylidine-sulfamethoxazole-Zn(II) monohydrate were 1.64 h, 0.24 L h - 1 and 0.57 L kg - 1 respectively. The elimination of sulfamethoxazole followed the first order kinetics with R2>0.984. The larger value of volume of distribution and clearance for the new derivative, as compared to that of the parent drug, show that the new derivative may exhibit prolonged antimicrobial effect with rapid clearance.

Unlabelled: OBEJCTIVE: To compare the bioavailability of two 50-mg lamotrigine dispersible tablet formulations (Epilepax®, Ivax-TEVA Argentina Laboratories, Argentina, as a test formulation, and Lamictal®, GlaxoSmithKline, UK, as a reference formulation) in 24 healthy male volunteers.

Material and methods: This study was a randomized, 2-period, 2-sequence crossover design that was open for subjects and investigators, but blind for the bioanalytical lab. Serum samples were obtained over a 120-h interval. A 9-day wash-out period was allowed between treatments. The concentrations of lamotrigine were analyzed by high-performance liquid chromatography followed by ultraviolet-visible detection. Lamotrigine time-concentrations curves were obtained and the following pharmacokinetic parameters were calculated: AUC0-t, AUC0-inf and Cmax. Bioequivalence was declared if the 90% confidence interval (CI) of the mean test/reference ratios for AUC0-t, AUC0-inf and Cmax were within 80.00-125.00%.

Results: The geometric mean and respective 90% CI of test/reference percent ratios were 100.83% (92.53-107.88%) for AUC0-t, 99.91% (93.79-108.40%) for AUC0-inf, and 95.62% (90.91-100.57%) for Cmax. No serious adverse events were observed. 1 patient reported a mild rash following the administration of each formulation.

Conclusion: This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in this sample of fasting healthy volunteers. These results suggest that bioequivalence studies evaluating 50-mg doses of Lamotrigine are feasible and recommended, since such doses may minimize the risk of severe rash or Stevens-Johnson Syndrome. This study was registered at the Argentinean Clinical Trials National Registry (www.anmat.gov.ar), No 1666/2008.

In the fermentation of milk by certain lactic acid bacteria, casein is degraded into bioactive tripeptides shown to lower blood pressure in experimental animal models and in mildly hypertensive humans. This effect is suggested to result mainly in inhibition of angiotensin converting enzyme 1 (ACE-1).Due to the complexity of renin-angiotensin system (RAS), several other enzymes than ACE-1 can participate in the production of vasoactive components. Therefore, in the present study we investigated effects of tripeptides isoleucine-proline-proline (IPP), valine-proline-proline (VPP) and leucine-proline-proline (LPP) on some endothelial enzymes that are important in RAS or otherwise have a role in the endothelial function. The enzymes investigated were renin, chymase, neutral endopeptidase (NEP), prolyl oligopeptidase (POP), cathepsin G, endothelin converting enzyme 1 (ECE-1), and cyclooxygenase 1 and 2 (COX -1 and COX-2).The tripeptides inhibited prolyl oligopeptidase (POP) dose-dependently. IPP was the most potent inhibitor (IC50 486±95 µM). Contrary, cathepsin G was activated by IPP, VPP and LPP as well as the amino acids proline and isoleucine. The other investigated enzymes were not affected. Inhibition of POP and activation of cathepsin G do not explain the blood pressure lowering effects of the tripeptides. Thus the inhibition of ACE-1 remains the most plausible mechanism of the antihypertensive effects of the tripeptides.

Background: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase developed for the management of hyperuricemia in patients with gout.

Objective: To investigate the pharmacokinetics and also evaluate the effects of gender and food on the pharmacokinetics of febuxostat in healthy Chinese volunteers.

Methods: A phase I, 3-period study was performed in healthy Chinese male and female subjects. Subjects either received single 40 mg, multiple 40 mg and single 80 mg doses of febuxostat under fasted conditions, or received single 80 mg doses under fed condition. Plasma concentrations of febuxostat were collected and determined at 14 time points over 48 h.

Results: After 40 mg and 80 mg single dose administration of febuxostat, the C max were 2.308±0.812 and 4.559±1.246 μg/mL, the T max were 1.6±0.6 and 2.1±1.0 h, the t 1/2 were 6.8±1.7 and 6.7±1.9 h, and the AUC0-∞ were 7.704±1.723 and 16.34±3.87 μg∙h/mL, respectively. In the multiple-dose study at 40 mg dose for 6 consecutive days, the mean (SD) steady-state pharmacokinetic parameters on day 8 were similar to those following a single dose of febuxostat on day 1. In addition, food caused a decrease of 33% for C max and a delay of 0.3 h for T max. Gender had no significant effect on the pharmacokinetics of febuxostat. Febuxostat was well tolerated over the investigated dose range.

Conclusion: Compared with the previous study, the pharmacokinetics of febuxostat appeared to be different between Chinese and other races.

Metronidazole is a BCS (Biopharmaceutics Classification System) class 1 drug, traditionally considered the choice drug in the infections treatment caused by protozoa and anaerobic microorganisms. This study aimed to evaluate bioequivalence between 2 different marketed 250 mg metronidazole immediate release tablets. A randomized, open-label, 2×2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a 7-day washout period. The formulations were administered as single oral dose and blood was sampled over 48 h. Metronidazole plasma concentrations were determined by a liquid chromatography mass spectrometry (LC-MS/MS) method. The plasma concentration vs. time profile was generated for each volunteer and the pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC0-∞, ke, and t1/2 were calculated using a noncompartmental model. Bioequivalence between pharmaceutical formulations was determined by calculating 90% CIs (Confidence Intervall) for the ratios of Cmax, AUC0-t, and AUC0-∞ values for test and reference using log-transformed data. 22 healthy volunteers (11 men, 11 women; mean (SD) age, 28 (6.5) years [range, 21-45 years]; mean (SD) weight, 66 (9.3) kg [range, 51-81 kg]; mean (SD) height, 169 (6.5) cm [range, 156-186 cm]) were enrolled in and completed the study. The 90% CIs for Cmax (0.92-1.06), AUC0-t (0.97-1.02), and AUC0-∞ (0.97-1.03) values for the test and reference products fitted in the interval of 0.80-1.25 proposed by most regulatory agencies, including the Brazilian agency ANVISA. No clinically significant adverse effects were reported. After pharmacokinetics analysis, it concluded that test 250 mg metronidazole formulation is bioequivalent to the reference product according to the Brazilian agency requirements.