Arzneimittel-Forschung-Drug Research最新文献

Unlabelled: A prospective monocentric open-label and single-arm trial was performed in 19 postmenopausal women with diagnosed vaginal atrophy. The aim was to determine the extent of a systemic exposure to estriol (CAS 50-27-1). Administration of estriol containing pessaries was daily for 21 days. In order to establish a pharmacokinetic profile after single as well as multiple vaginal doses of 0.03 mg estriol blood samples were taken after the first vaginal administration as well as at day 21 after the last administration. Moreover, in order to control for accumulation additional blood samples were taken predose at days 6, 11 and 16.

Results: The initial administration increased the population mean estriol plasma concentration to a maximum of 42.1 pg/ml 1 h after dosing. However, already 12 h after administration the estriol concentration had again dropped below 5 pg/ml (lower limit of quantification) in all patients. Repeated administration did not result in an accumulation of estriol, since 2 h after application of the 21st pessary, the population mean estriol concentration reached a maximum of only 11.9 pg/ml. Moreover, no severe or serious adverse events occurred, and no clinically relevant findings were reported.

Conclusion: Single vaginal application of pessaries containing 0.03 mg estriol resulted in a very low systemic bioavailability, which decreased even more after multiple dosing confirming a favourable safety profile of low dose pessaries administered daily over 21 days.

A series of novel 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indoles (3a-l) were synthesized and their cytotoxicities were analyzed against 3 different human cell lines, including liver (HUH7), breast (MCF7) and colon (HCT116). The Mannich reaction of 3-methylindole (1) with 4-substitutedpiperazines (2) and formaldehyde resulted to the 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H-indoles (3a-l) in 38-69% yields. The investigation of anticancer screening revealed that the tested compounds showed comparable activity to the reference drug 5-fluorouracil and compounds 3g, 3h, 3i and 3k, had lower 50% inhibition (IC50) concentration than reference drug. Moreover, the cytotoxic effect of the most potent compound 3h on HUH7 and MCF7 cells through apoptosis was visualized by Hoechst staining and compared with paclitaxel, which is a mitotic inhibitor acting on microtubules. The morphological features of apoptosis were observed as condensed and fragmented nuclei that are similar to paclitaxel.

In this study, a series of new 5-alkoxy-[1,2,4]triazolo[4,3-a]pyridine derivatives was synthesized and their anticonvulsant activity and neurotoxicity was evaluated with the maximal electroshock and rotarod tests, respectively. The most promising compounds, 3p (5-(4-chlorophenoxy)-[1,2,4]triazolo[4,3-a]pyridine) and 3r (5-(4-bromophenoxy)-[1,2,4]triazolo[4,3-a]pyridine), showed a median effective dose of 13.2 and 15.8 mg/kg and had a protective index value of 4.8 and 6.9, respectively. For exploring the putative mechanism of action, compounds 3n, 3p and 3r were tested in chemically induced models.

For several decades paracetamol has proven its clinical efficacy and safety in the treatment of various acute and chronic pain states. Whereas its pharmacokinetic properties (high oral bioavailability, good penetration into the brain, relative rapid hepatic elimination) are well known, its exact central mode of action remains to be elucidated. According to many international guidelines/recommendations paracetamol is a drug of first choice for relieving mild to moderate pain. It has been successfully combined with opioids for severe pain. Due to its cardiovascular, renal and gastrointestinal safety paracetamol offers several advantages vs. NSAIDs. It should be realized that the maximum daily dose is restricted to 4 g to avoid unnecessary hepatic complications. Keeping this limitation in mind paracetamol still represents a valuable first-line agent in the pharmacological management of pain.

4-Anilinoquinazoline is a privileged scaffold in developing small molecule inhibitors of tyrosine kinases (TK) especially epidermal growth factor receptor (EGFR). 2 series belonging to 3'-substituted-4-anilinoquinazoline scaffold were synthesized and screened in vitro on isolated and a breast cancer cell line. The research aims at exploring the activity of compounds having diverse substituents at 3' position of the aniline moiety. Generally, the meta-substituted-anilinoquinazolines exhibited significant inhibitory activity against isolated enzyme as well as MCF-7 cancer cell line. For instance, compound 10b inhibited >99% of EGFR activities at 10 µM concentration. 6 of the tested compounds exhibited range of anti-proliferative activity below 10 µM potency. In particular, compounds 6e and 10b displayed the highest activity among the tested compounds with IC50 values equal to 8.6 and 4.84 µM, respectively. Structure-based tools were utilized to rationalize EGFR-TK binding of compound 10b since it is the most active compound in the enzyme inhibition test.

Piperine (CAS no: 94-62-2), an alkaloid obtained from Piper nigrum and P. longum is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent anti-hyperglycemic activity of nateglinide (CAS no: 105816-04-4) as evaluated by glucose challenged and alloxan-induced diabetic models, when it was administered with nateglinide. Nateglinide plasma concentrations were also increased, when administered with piperine. The synergistic anti-hyperglycemic activity of nateglinide when administered with piperine can be attributed to increased plasma concentration of nateglinide. The results of this study demonstrate that piperine could be used as a potential bioenhancer along with nateglinide.

The aim of this study was to compare the bioavailability of an oral formulation of the coumarin derivative-vitamine K antagonist acenocoumarol (Acebron™ 4 mg, Test) with the reference formulation (Neo-Sintrom™ 4 mg). We performed a single-dose, double-blind, fasting, 2-period, 2-sequence, crossover study design. Plasma concentrations of acenocoumarol were determined using a validated UPLC-MS/MS method. 24 healthy Chilean volunteers (11 male, 13 female) were enrolled and all of them completed the study. Adverse events were monitored throughout the study. The values of the pharmacokinetic parameters were (mean ± SD): AUC0-24 =1 364.38±499.26 ngxh/mL for the test and 1 328.39±429.20 ngxh/mL for the reference; AUC0-∞ =1 786.00±732.85 ngxh/mL for the test and 1 706.71±599.66 ngxh/mL for the reference; Cmax =180.69±35.11 ng/mL with a Tmax of 1.83±0.95 h for the test and 186.97±38.21 ng/mL with a Tmax of 2.19±0.83 h for the reference. Regarding half life measurements, the mean ± SD of t1/2 were 11.84±4.54 h for the test and 11.08±3.28 h for the reference. The 90% confidence intervals for the test/reference ratio using logarithmic transformed data were 97.89-100.87%, 98.62-101.99% and 98.64-102.38% for Cmax, AUC0-t(24) and AUC0-∞. There were no significant differences in pharmacokinetic parameters between groups.The results obtained in this study lead us to conclude, based on FDA criteria, that the test acenocoumarol formulation (Acebron™, 4 mg tablets) is bioequivalent to the reference product (Neo-Sintrom™, 4 mg tablets).

Glucosamine (CAS 66-84-2) hydrochloride is an amino monosaccharide indicated for the treatment of arthrosis, especially osteoarthritis of the knee joint. This study was conducted to assess and compare the pharmacokinetic (PK) properties, bioavailability of a newly developed dispersible tablet formulation (test) of glucosamine hydrochloride with those of an established branded capsule formulation (reference) in healthy Chinese adult male volunteers.This single-dose, randomized, open-label, 2-period crossover study was conducted in 18 healthy Chinese adult male volunteers under fasting condition. Plasma samples were collected at pre-specified times over a 12-h period following administration in each period and analyzed the plasma glucosamine concentrations by Liquid Chromatography coupled with Tandem Mass Spectrometry (LC/MS/MS) method. The mean (SD) PK parameters of Cmax, Tmax, AUC0-12, and AUC0-∞ after administration of the test and reference formulations were, respectively, as follows: Cmax, 907.01 (444.22) vs. 944.40 (429.89) ng/mL, Tmax, 3.03 (0.95) vs. 3.30 (0.99) hours, AUC0-12, 2891.41 (1352.30) vs. 2889.69 (925.48) ng/mL/h, and AUC0-∞, 3029.90 (1321.36) vs. 3091.87 (870.36) ng/mL/h. The mean (SD) t1/2 was 1.10 (0.52) hours for the test formulation and 1.50 (1.17) hours for the reference formulation. On ANOVA, neither period nor sequence effects were observed for any PK properties. The relative bioavailability of the test formulation was 98.3% assessed by AUC0-12. The 90% CIs of glucosamine for the log-transformed ratios of Cmax, AUC0-12, and AUC0-∞ were 78.4-113.9%, 80.8-108.5% and 80.8-105.8%, respectively, meeting the predetermined criteria for bioequivalence of SFDA.