Effects of isoflavone interventions on bone mineral density in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials.

Isoflavones have a structure similar to 17ß-estradiol, so they may be useful to postmenopausal women in preventing bone loss related to estrogen deficiency. The present study integrated the findings from 63 randomized controlled trials and found that isoflavone interventions may have benefits in the prevention and treatment of menopause-related osteoporosis. PURPOSE: This study aimed to determine the efficacy of isoflavone interventions on bone density outcomes and the safety of isoflavone interventions in postmenopausal women by means of systematic review and meta-analysis. METHODS: A systematic search was performed on three databases (PubMed, Scopus, and Cochrane Library). Included studies were limited to randomized controlled trials (RCTs) assessing the effects of isoflavone intervention on bone mineral density (BMD) in postmenopausal women. Mean difference (MD) in BMD or relative risk for adverse outcomes was used as a summary effect measure; pooled-effect estimates were calculated using a random-effects model. RESULTS: A total of 63 RCTs, involving 6427 postmenopausal women, were included in the meta-analysis. Statistically significant differences in BMD at the last follow-up visit between the two groups (isoflavones vs. control) were found at the lumbar spine (MD = 21.34 mg/cm2, 95% CI = 8.21 to 34.47 mg/cm2, p = 0.001), the femoral neck (MD = 28.88 mg/cm2, 95% CI = 15.05 to 42.71 mg/cm2, p < 0.0001), and the distal radius (MD = 19.27 mg/cm2, 95% CI = 5.65 to 32.89 mg/cm2, p = 0.006). The positive effects in improved BMD were primarily associated with two formulations, i.e., genistein 54 mg/day and ipriflavone 600 mg/day. Isoflavone interventions were generally safe and well tolerated. CONCLUSION: Isoflavone interventions, genistein (54 mg/day) and ipriflavone (600 mg/day) in particular, have beneficial effects on BMD outcomes and are safe in postmenopausal women. They may be considered as a complementary or alternative option in the prevention and treatment of menopause-related osteoporosis.

Impact of CYP1A2 genetic polymorphisms on pharmacokinetics of antipsychotic drugs: a systematic review and meta-analysis.

OBJECTIVE: To determine the impact of CYP1A2 genetic polymorphisms on the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs in humans by means of systematic review and meta-analysis. METHOD: A systematic search was conducted in PubMed and Scopus databases as of June 26, 2018. Studies reporting the pharmacokinetic parameters of CYP1A2-metabolized antipsychotic drugs in individuals who were genotyped for CYP1A2 genetic polymorphisms were retrieved. Pharmacokinetic parameters of individuals who have mutant alleles of a CYP1A2 genetic polymorphism were compared with the wild-type individuals. Pooled-effect estimates, presented as standardized mean difference, were calculated by means of the fixed-effect or random-effects model, as appropriate. RESULTS: Ten studies involving 872 clozapine users, seven studies involving 712 olanzapine users, and two studies involving 141 haloperidol users were included. All but one study reported no associations between any CYP1A2 genetic polymorphisms and the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs. The pooled-effect estimates through meta-analyses of seven studies demonstrated no significant associations between the -163C>A or -2467delT polymorphism and clozapine or olanzapine concentrations in the blood. CONCLUSIONS: This study suggests that CYP1A2 genetic polymorphisms have no significant impact on the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs. CYP1A2 genotyping may have no clinical implications for personalized dosing of CYP1A2-metabolized antipsychotic drugs.

Antioxidant effects after coffee enema or oral coffee consumption in healthy Thai male volunteers.

We designed an open-label, randomized two-phase crossover study to investigate the antioxidant effects after single and multiple doses of a coffee enema versus coffee consumed orally. Eleven healthy subjects were randomly assigned to either receive a coffee enema (3 times weekly for 6 visits) or consume ready-to-drink coffee (2 times daily for 11 days). After a washout period, subjects were switched to receive the alternate coffee procedure. Blood samples were collected at specific time points for the determination of serum levels of glutathione (GSH), malondialdehyde (MDA) and trolox equivalent antioxidant capacity (TEAC). The findings showed that either single or multiple administrations of the coffee enema or orally consumed coffee doses seemed not to produce any beneficial effects to enhance serum GSH levels or to decrease serum MDA levels over the study period of 12 days. In contrast, mean serum TEAC levels at day 12 after the coffee enema and at days 6 and 12 after oral coffee consumption were significantly reduced from their corresponding baseline values. Thus, no beneficial effects with respect to an enhancement of serum GSH and TEAC levels or a decrease in serum MDA concentrations were demonstrated after coffee enema or orally consumed ready-to-drink coffee.

Raised chondroitin sulfate epitopes and hyaluronan in serum from rheumatoid arthritis and osteoarthritis patients.

OBJECTIVES: Serum hyaluronan (HA) and chondroitin sulfate (CS) epitopes WF6 and 3B3 (+) were determined to investigate disease association in patients with osteoarthritis (OA), rheumatoid arthritis (RA) and healthy controls. METHODS: Specific assays for HA and CS epitopes WF6 and 3B3 (+) were established and applied to a cross-sectional study of serum samples from patients (96 OA, 57 RA and 50 healthy controls). RESULTS: Both CS epitopes were increased in serum of many OA and RA patients and average levels were significantly above in healthy controls. In contrast serum HA was increased in RA, but only in few OA patients. CONCLUSIONS: CS epitopes WF6 and 3B3 (+) are raised in serum of patients with both OA and RA and were thus distinct from serum HA. The results suggest that OA may be detected systemically as well as RA. The range of levels of CS epitopes detected in OA and RA was wide and correlation with any aspect of disease activity is yet to be determined.

Bioequivalence study of generic amlodipine in healthy Thai male volunteers.

SUBJECTS, MATERIAL AND METHODS: To determine the bioequivalence of 10 mg generic amlodipine in healthy male volunteers, the reference and the test formulations were administered as a single oral dose after overnight fasting in a crossover study separated by 2-week washout interval. After dosing, serial blood samples were collected for a period of 144 h. Plasma amlodipine concentrations were determined by LC-MS/MS and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The mean elimination half-life (t1/2) for the test (40 h) and the reference (44 h) were within the values previously reported. The rate of absorption reflected by tmax had a difference of -0.33 h, with a 90% CI of (-1.52)-0.85 (acceptable range +/- 1.3). Although the tmax of the test (5 h) was faster than the reference (6 h), the mean (90% CI) of the AUC(0-infinity) and Cmax ratios Test/Reference were 0.91 (0.87-0.97) and 1.01 (0.93-1.09), respectively. These values were within the range of 0.80-1.25, thus, the study demonstrated the bioequivalence of the 2 formulations.

Pharmacokinetics and bioequivalence testing of generic fluconazole preparations in healthy thai volunteers.

AIM: To determine the bioequivalence of two oral formulations of generic fluconazole in twelve healthy Thai volunteers. SUBJECTS, MATERIALS AND METHODS: The test preparation was Flucozole (Siam Bheasach, Thailand) and the reference was Diflucan (Pfizer Inc.). The two products were administered as 200 mg single oral doses in a two-period crossover design with a two-week washout period. After drug administration, serial blood samples were collected over a period of 72 hours. Serum fluconazole concentrations were determined by HPLC, and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The time to reach the maximal concentration (Tmax, hour) of Flucozole (1.18 +/- 0.56) was statistically faster than that of Diflulan (1.59 +/- 0.54). The 90% confidence intervals of the AUC(0 - infinity) ratio and the Cmax, ratio muT/muR for Flucozole/Diflucan were 0.97 - 1.20 and 1.01 - 1.26, respectively. These values were within the acceptable bioequivalence intervals of 0.80 - 1.25 and 0.7 - 1.43 for the ratio of the average AUC(0 - infinity) and Cmax, respectively. CONCLUSION: Thus, our study demonstrated the bioequivalence of Flucozole and Diflucan with respect to the rate (Cmax) and extent of absorption (AUC(0 - infinity).

Pharmacokinetics and bioavailability studies of generic ondansetron, and the innovator preparation, in healthy Thai male volunteers.

The pharmacokinetics and bioequivalence of two oral formulations of ondansetron were evaluated; Zetron (Biolab Pharmaceutical, Bangkok, Thailand), as the test formulation and Zofran (Glaxo Wellcome Operations, Greenford, UK), as the reference formulation. The two products were administered as a single oral dose of 8 mg according to a randomized two-way crossover design to 12 healthy Thai male volunteers. The washout period between treatment was 1 week. Ondansetron plasma concentrations were measured using HPLC. The oral bioavailability of ondansetron averaged 67 per cent and the elimination half-life after oral administration was 5.6 hours. The means and parametric 90 per cent CI of the ratios of Cmax and AUC 0-alpha [mu Zetron (Test)/mu Zofran (Reference)] were 0.95 (0.84-1.07) and 0.94 (0.80-1.10), respectively. These values were well within the bioequivalence range of 0.8-1.25 as established by the US-FDA. The mean difference of Tmax (Test-Reference) was approximately 20 per cent. Thus, our study demonstrated bioequivalence of the two products (Zetron and Zofran) regarding the rate and extent of absorption.

The comparative bioavailability of a generic and the innovator fluconazole preparations in healthy Thai volunteers.

We studied the pharmacokinetics and compared the oral bioavailability of the "generic" (Biozole, Biolab Company, Thailand) and the "innovator" (Diflucan, Pfizer Incorporation, U.S.A.) fluconazole preparations in 12 healthy Thai volunteers. A 200 mg single oral dose of each preparation was given to the subjects in a randomized double-blind 2-period crossover design with 2 weeks washout period. Blood samples were collected just before and at 0.5, 1, 2, 2.5, 3, 4, 24, 48, 56 and 72 hours after drug administration. Serum fluconazole concentrations were determined by using high performance liquid chromatography. Individual concentration-time profiles and the pharmacokinetic parameters were analyzed by the noncompartmental pharmacokinetic method [TOPFIT, a pharmacokinetic data analysis program]. The pharmacokinetic parameters (Tmax, Cmax, Vd, Cl) of fluconazole in Thai healthy volunteers were comparable to those values observed in Caucasian subjects. The relative bioavailability of the generic Biozole was 102.38 +/- 9.79 per cent of Diflucan. The means and 90 per cent confidence intervals (90% CI) of the [Biozole/Diflucan] ratio of AUC0-72, AUC0-inf and Cmax were 1.02 (0.98-1.06), 0.99 (0.95-1.03) and 1.13 (1.03-1.25), respectively. These values were well within the acceptable bioequivalence ranges of 0.8-1.25 proposed by the US FDA. The means and 90 per cent CI of Tmax differences [Biozole-Diflucan] were -0.46 [(-1.03)-(0.12)]. This value was outside the stipulated bioequivalence range of +/- 0.41 h (+/- 20% of the Tmax of the reference formulation). Nevertheless, the Tmax difference was not expected to be related to the differences in safety and efficacy of the drug. Hence, Biozole and Diflucan were bioequivalent with respect to the extent of absorption (AUC), and the Cmax, and could be used interchangeably.

Comparative studies of quality and bioavailability of methotrexate in Thai patients with rheumatoid arthritis.

The bioavailability of the two generic methotrexate oral preparations (Emtrexate, Pharmachemie Company, Holland and Methotrexate Remedica, Remedica, Cyprus as the test preparations), were compared to the innovator (Methotrexate Lederle, Lederle, U.S.A. as the reference) in 10 patients with rheumatoid arthritis. A single 7.5 mg oral dose of each preparation was given to the subjects in a randomized, double-blind, three-period crossover design with a 1 week washout period. Serum methotrexate concentrations were determined by using Fluorescence Polarization Immunoassay (Abbott TDx). No significant differences in pharmacokinetic parameters (AUC, Cmax, and Tmax) were observed between the test and reference preparations. The mean and 90 per cent CI of the ratio Emtrexate/Methotrexate Lederle and Methotrexate Remedica/Methotrexate Lederle of the Cmax, AUC0-8, and AUC0-alpha were 0.93 (0.87-1.00), 0.9 (0.82-0.98), 0.88 (0.79-0.99) and 0.97 (0.93-1.02), 0.95 (0.90-0.99), 0.94 (0.86-1.02), respectively. These values were well within the acceptable bioequivalence range of 0.8-1.25. The mean and 90 per cent CI of Tmax difference between Emtrexate-Methotrexate Lederle and Methotrexate Remedica-Methotrexate Lederle also overlapped the stipulated bioequivalence range of the Tmax differences of +/- 0.25 hour. Thus, Emtrexate and Methotrexate Remedica were considered bioequivalent to the reference Methotrexate Lederle regarding the rate of absorption and the extent of absorption.