Thunbergia laurifolia Exhibits Antifibrotic Effects in Human Hepatic Stellate Cells.

Leaves of Thunbergia laurifolia (TL) have been reported to have antioxidation, anti-inflammatory, detoxifying, and hepatoprotective effects. However, studies relating to antifibrotic activity have not been reported. Currently, there is no standard treatment for hepatic fibrosis. This study aimed to investigate the antifibrotic activity of TL in human hepatic stellate LX-2 cells. Results from cell viability and cell death assays showed that the extract at high concentrations was toxic to LX-2 cells. TL extract reversed the transformation of LX-2 cells to myofibroblast-like characteristics in response to stimulation by transforming growth factor-beta 1. This action may be associated with the effect of TL in suppressing α-SMA and collagen-I production observed by immunofluorescence study and western blot analysis. Additionally, TL extract significantly decreased MMP-9 activity which is consistent with the reduction of MMP-9, MMP-2, and TIMP-1 gene expression. The effect of TL in suppressing fibrosis may be associated with its ability to inhibit the activation of p38 MAPK and Erk1/2 kinases as examined by western blot analysis. Our study provides convincing evidence that TL possesses antifibrotic activity which may be through the suppression of TGF-ß1-mediated production of MMPs, collagen-1, and α-SMA in hepatic stellate cells.

Effects of the Chinese Herbal Formulation (Liu Wei Di Huang Wan) on the Pharmacokinetics of Isoflavones in Postmenopausal Women.

A combination of soy isoflavones and Liu Wei Di Huang Wan (LWDHW) is potentially effective for postmenopausal women with intolerable vasomotor episodes who are not suitable candidates for hormonal therapy. The objective of this open-label, three-phase, crossover study was to determine the influence of both single and multiple oral doses of LWDHW on isoflavone pharmacokinetics in healthy postmenopausal women. Eleven subjects were assigned to receive the following regimens in a fixed sequence with washout periods of at least one week: Phase A, a single oral dose of soy milk; Phase B, a single oral dose of soy milk coadministered with LWDHW; and Phase C, multiple oral doses of LWDHW for 14 days followed by a single oral dose of soy milk. Blood samples were collected and mixed with ß-glucuronidase/sulfatase to hydrolyze isoflavone conjugates to their respective aglycones (i.e., daidzein and genistein) and were determined using high performance liquid chromatography. The pharmacokinetic parameters analyzed were maximal plasma concentration (C max), time to reach peak concentration (T max), area under the plasma concentration-time curve (AUC), and half-life (t 1/2). The results found no statistically significant differences in pharmacokinetic parameters of daidzein and genistein among the three regimens.

Effect of synbiotic fermented milk on oral bioavailability of isoflavones in postmenopausal women.

The purpose of this study was to investigate the effect of synbiotic fermented milk, containing Lactobacillus paracasei and inulin, on oral bioavailability and pharmacokinetics of isoflavones in healthy postmenopausal women. The study was a one-group pre-post treatment study. Twelve subjects were assigned to consume a single oral dose of 375 mL of soy beverage. Blood samples were collected immediately before and at various time points until 32 hours after the administration of the soy beverage. After a washout period, subjects were requested to consume 180 mL of synbiotic fermented milk after breakfast and dinner for 14 days, followed by a single oral dose of 375 mL of soy beverage on the next day. Collection of blood samples after the administration of the soy beverage were performed at the same time points as the former phase. Plasma isoflavone concentrations were measured by using high-performance liquid chromatography (HPLC) technique. In conclusion, this study highlighted that continuous consumption of synbiotic fermented milk followed by a single oral administration of soy beverage significantly enhanced oral bioavailability of isoflavones compared with a single oral dose of soy beverage alone.

Pharmacokinetics of Caffeine following a Single Administration of Coffee Enema versus Oral Coffee Consumption in Healthy Male Subjects.

The objective of this study was to determine the pharmacokinetics of caffeine after single administration of a coffee enema versus coffee consumed orally in healthy male subjects. The study design was an open-label, randomized two-phase crossover study. Eleven healthy subjects were randomly assigned either to receive 500 mL of coffee enema for 10 minutes or to consume 180 mL of ready-to-drink coffee beverage. After a washout period of at least 10 days, all the subjects were switched to receive the alternate coffee procedure. Blood samples were collected immediately before and at specific time points until 12 hours after coffee administration in each phase. The mean caffeine content in both the coffee solution prepared for the coffee enema and the ready-to-drink coffee beverage was not statistically different. The C max and AUC of caffeine obtained from the coffee enema were about 3.5 times significantly less than those of the coffee consumed orally, despite having slightly but statistically faster T max. The t 1/2 of caffeine obtained following both coffee procedures did not statistically differ. In summary, the relative bioavailability of caffeine obtained from the coffee enema was about 3.5 times significantly less than those of the coffee consumed orally.

Bioequivalence study of donepezil hydrochloride tablets in healthy male volunteers.

The objective of this study was to investigate the bioequivalence of two formulations of 5 mg donepezil HCL tablets: Tonizep as the test and Aricept as the reference. The two products were administered as a single oral dose according to a randomized two-phase crossover with a 3-week washout period in 20 healthy Thai Male volunteers. After drug administration, serial blood samples were collected over a period of 216 hours. Plasma donepezil concentrations were measured by high performance liquid chromatography with UV detection. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The logarithmically transformed data of AUC(0-∞) and C(max) were analyzed for 90% confidence intervals (CI) using ANOVA. The mean (90% CI) values for the ratio of AUC(0-∞) and C(max) values of the test product over those of the reference product were 1.08 (1.02-1.14) and 1.08 (0.99-1.17), respectively (within the bioequivalence range of 0.8-1.25). The median T(max) for the test product was similar to that of the reference product (2.0 hr), and the 90% CI for the T(max) difference between the two preparations was -0.19 to 0.29 hr and within the bioequivalence range of ± 20% of the T(max) of the reference formulation. Our study demonstrated the bioequivalence of the two preparations.

Bioequivalence study of modified-release gliclazide tablets in healthy volunteers.

This study was aimed to investigate bioequivalence of modified-release 30 mg gliclazide tablets in 18 healthy Thai volunteers. A test product, Glycon MR (Siam Bheasach, TH), was compared with a reference product, Diamicron MR (Servier, France). The study was performed under a single-dose, two-treatment, two-period, and two-sequence crossover design in fasted and fed conditions with a washout period of 2 weeks. Blood samples were collected for 72 h after drug administration. Drug plasma concentrations were determined by HPLC with a UV detector. Analysis of pharmacokinetic characteristics was based on a non-compartmental model. The logarithmically transformed data of C(max) and AUCs were analyzed for 90% confidence intervals using ANOVA. The test product gave slightly higher C(max) in both conditions and shorter T(max) in the fed condition. However, there is no significant difference in pharmacokinetic characteristics between both products under fasted and fed conditions. Effect of food was not significantly observed. The 90% confidence intervals were within the acceptance criteria of 0.80-1.25 regardless of the food effect, indicating bioequivalence between the two products on the rate and extent of gliclazide MR absorption without regard to meals.

Pharmacokinetics of ganoderic acids a and f after oral administration of ling zhi preparation in healthy male volunteers.

The objectives of this paper were to evaluate the pharmacokinetics of ganoderic acids A and F after a single oral dose of the water extract of MG2-strain Ling Zhi (MG2FB-WE) and to assess the influence of food on the pharmacokinetics in 12 healthy male volunteers. This study was a single-dose, open-label, randomized, two-phase crossover study with at least 2 wk washout period. Each subject was randomly assigned to receive a single oral dose of 3,000 mg of MG2FB-WE in granular formulation dissolved in 200 mL of warm water, either under a fasting condition, or immediately after a standard breakfast (fed condition). Blood samples were collected immediately before and at specific time points until 8 h after MG2FB-WE administration. Plasma ganoderic acids A and F concentrations were determined by using liquid chromatography-mass spectrometry (LC-MS) technique. In conclusion, the pharmacokinetic profile of both ganoderic acids under a fasting condition was characterized by rapid absorption from the gastrointestinal tract (T(max) at approximately 30 min) and a short elimination half-life (<40 min). Food significantly decreased C(max) and delayed T(max), but did not affect the extent of ganoderic acid A absorption. However, concomitant food intake markedly impeded both rate and extent of ganoderic acid F absorption.

Pharmacokinetics and bioequivalence study of the two 20-mg quinapril hydrochloride tablet formulations in healthy Thai male volunteers.

OBJECTIVE: To determine the pharmacokinetics and bioequivalence of two 20-mg quinapril hydrochloride tablet preparations; Quinaril (The Biolab Ltd, Bangkok, Thailand) as the test and Accupril as the reference. MATERIAL AND METHOD: The present study was a single dose, randomized two-period crossover design conducted in 24 healthy volunteers under fasting conditions with a 7-day washout period. Serial plasma concentrations of quinapril and its active metabolite quinaprilat up to 24 h after dosing were determined by HPLC with UV detection. The pharmacokinetic parameters were analyzed by noncompartmental analysis and the ANOVA was carried out using logarithmically transformed data of the AUC and C as well as untransformed T(max). RESULTS: There were no significant differences between the two preparations regarding the T(max) of quinapril and quinaprilat and their median T(max) were 0.5 h and 1.4 - 1.5 h, respectively. The half-life of quinapril (1.2 h) was faster than quinaprilat (1.8-1.9 h) although the volume of distribution (Vd/F) of quinapril (1.1 L/kg) was larger than quinaprilat (0.3 L/kg), however, its clearance rate (CL/F) was faster when compared to quinaprilat (20-26 ml/min/kg vs. 1.7 ml/min/kg). The mean (90% CI) for the ratios Reference/Test of quinapril were 0.99 (0.89-1.10), 0.99 (0.90-1.09) and 1.01 (0.90-1.14), respectively for AUC(0-24), AUC(0-infinity) and C(max). Similarly, the corresponding values for quinaprilat were 0.95 (0.90-1.01), 0.95 (0.90-1.01) and 1.03 (1.00-1.07), respectively. These values were within the bioequivalence range of 0.80 - 1.25, thus, demonstrated the bioequivalence of the two preparations. CONCLUSION: The results of the present study indicated that the two quinapril HCL preparations are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.

Effect of doses on the bioavailability of phenytoin from a prompt-release and an extended-release preparation: single dose study.

OBJECTIVE: To determine the effect of doses on the bioavailability of a prompt-release and an extended-release phenytoin capsule after given as single doses. MATERIAL AND METHOD: Eight healthy male volunteers were given single oral doses of 100, 200, and 300 mg of a prompt-release preparation (Ditoin) and an extended-release phenytoin (Dilantin Kapseals) preparation in a crossover design with a two weeks washout period after an overnight fast. Serial blood samples were collected over 72 h post-dose. Plasma phenytoin concentrations were determined by HPLC and pharmacokinetic parameters were analyzed by non-compartmental model. RESULTS: Rate of phenytoin absorption from the prompt-release preparation was more prolonged after the 300mg dose (T(max) 4.5 h) than those of the 100- and 200-mg doses (T(max) 3.5 and 3 h, respectively). Similarly, the T(max) of the 200- and the 300-mg extended-release preparation (5.5 and 4 h) were more prolonged than the 100-mg dose (3 h). Bioequivalence analysis showed that the C(max) of all doses of the prompt-release preparation were higher than those values of the extended-release preparation with the mean C(max) ratio (90% CI) of 1.32 (1.24-1.40), 1.26 (1.14-1.40), and 1.29 (1.10-1.51) for the 100-, 200- and 300-mg doses, respectively. The extent of absorption (AUC(0-infinity)) of 100-mg phenytoin was bioequivalent between the two preparations [mean AUC ratio (90% CI) of 1.15 (1.11-1.18)], however, for higher doses, the prompt-release products produced higher bioavailability than the extended-release products [mean AUC ratio (90% CI) of 1.19 (1.07-1.33) and 1.17 (0.98-1.38), respectively for the 200- and 300-mg doses]. The difference in the bioavailability did not affect the elimination of phenytoin and their half-lives were comparable (11-13 h). CONCLUSION: The bioavailability of phenytoin from both preparations increased proportionally over the dose range of 100-300-mg, however, the bioavailability of the prompt-release preparation was higher than the corresponding doses of the extended-release product.

Efficacy and safety of gentamicin by interval and intravenous dosage adjustment based on the gestational age in Thai neonates.

OBJECTIVE: To determine the pharmacological efficacy and safety of the gentamicin regimen that adjusts intravenous dose and interval based on the gestational age (GA) in Thai neonates. MATERIAL AND METHOD: Neonates aged < or = 7 days, who had received gentamicin for clinically suspected or high risk of sepsis and had no contraindication to gentamicin usage were enrolled. They were stratified into four groups by GA as < or = 29, 30-33, 34-37 and > or = 38 weeks gestation. Gentamicin administration in each group was 5, 4.5, 4 and 4 mg/kg/dose every 48, 36, 36 and 24 hours respectively according to Neofax regimen. Peak serum gentamicin concentration (SGC), trough SGC and serum creatinine (Cr) were obtained. RESULTS: Forty-nine neonates were enrolled. Forty-four (89.7%) had peak SGC within the desirable range (5-12 mg/L). Three neonates had slightly high peak SGC. Their peak SGCs were 13.0, 12.21 and 12.20 mg/L. Two neonates had slightly low peak SGC. Their peak SGCs were 4.91 and 4.4 mg/L. All neonates had trough SGC below 2 mg/L. None had significant rising of serum Cr during the present study period. CONCLUSION: This gentamicin regimen yielded good pharmacological efficacy and safety in Thai neonates, who were in the first week of life and had no renal function impairment.

Pharmacokinetic study of the combination of tacrolimus and fluconazole in renal transplant patients.

BACKGROUND: It was hypothesized that fluconazole in combination with tacrolimus can be used safely with an imitated area under curve (AUC) compared to tacrolimus. At every time point, this combination was presumed to correlate well with pre-intervention AUC, thus the dosage could be significantly reduced. MATERIAL AND METHOD: There were two groups of patients. Group I (n = 15) included patients who received tacrolimus at 0.1-0.3 mg/kg/day within one week after transplantation. These patients were studied for tacrolimus whole blood concentrations. The tacrolimus dosage was then reduced by 40% and given in combination with fluconazole at 100-200 mg/day for one week, tacrolimus whole blood concentrations were studied again. Group II (n = 8) included patients who had been transplanted for more than 3 months and had received a stable dosage of tacrolimus in combination with fluconazole for at least one month. RESULTS: In group I, before fluconazole combination, trough levels correlated well with AUC0-12. After fluconazole combination, trough levels still correlated well with AUC0-12. The after/before fluconazole-combination ratio of AUC0-12 and maximum tacrolimus concentration (Cmax) was 1.08 (90%CI; 0.98-1.19) and 1.17 (90%CI; 1.00-1.36), respectively. Correspondingly, the oral bioavailability, which was the after/ before fluconazole combination ratio of AUC0-12/dose and absorption rate (Cmax/dose/body weight), was significantly increased [2.08 (90%CI; 1.80-2.40) and 2.24 (90%CI; 1.99-2.51), respectively]. Tacrolimus clearance after the fluconazole combination was significantly reduced, compared with before the combination (14.74 vs 38.79 L/h, p = 0.001). Mean tacrolimus dosage in this group could be reduced from 10.7 mg/day before fluconazole combination to 5.7 mg/day after it and to 3.7 mg/day at 3 months after transplantation (p = 0.001). In group II, trough levels correlated well with AUC0-12 and the mean tacrolimus dosage in this group was only 2.9 mg/day. CONCLUSION: This present study showed a good correlation between tacrolimus trough levels and AUC, which occurred in monotherapy or in patients who received fluconazole. The tacrolimus trough levels could be trusted in monitoring patients who received a tacrolimus-based immunosuppressive regimen. The combination to fluconazole was ascertained and it was safe to reduce the dose of tacrolimus.

Pharmacokinetics of isoflavones, daidzein and genistein, after ingestion of soy beverage compared with soy extract capsules in postmenopausal Thai women.

BACKGROUND: Isoflavones from soybeans may provide some beneficial impacts on postmenopausal health. The purpose of this study was to compare the pharmacokinetics and bioavailability of plasma isoflavones (daidzein and genistein) after a single dose of orally administered soy beverage and soy extract capsules in postmenopausal Thai women. METHODS: We conducted a randomized two-phase crossover pharmacokinetic study in 12 postmenopausal Thai women. In the first phase, each subject randomly received either 2 soy extract capsules (containing daidzin : genistin = 7.79 : 22.57 mg), or soy beverage prepared from 15 g of soy flour (containing daidzin : genistin = 9.27 : 10.51 mg). In the second phase, the subjects received an alternative preparation in the same manner after a washout period of at least 1 week. Blood samples were collected immediately before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24 and 32 h after administration of the soy preparation in each phase. Plasma daidzein and genistein concentrations were determined by using high performance liquid chromatography (HPLC). The pharmacokinetic parameters of daidzein and genistein, i.e. maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the plasma concentration-time curve (AUC) and half-life (t1/2), were estimated using the TopFit version 2.0 software with noncompartmental model analysis. RESULTS: There were no significant differences in the mean values of Cmax/dose, AUC0-32/dose, AUC0- proportional, variant/dose, Tmax, and t1/2 of genistein between both preparations. For pharmacokinetic parameters of daidzein, the mean values of Cmax/dose, Tmax, and t1/2 did not significantly differ between both preparations. Nonetheless, the mean AUC0-32/dose and AUC0- proportional, variant/dose after administration of soy extract capsules were slightly (but significantly, p < 0.05) higher than those of soy beverage. CONCLUSION: The bioavailability of daidzein, which was adjusted for the administered dose (AUC/dose), following a single oral administration of soy beverage was slightly (but significantly) less than that of soy extract capsules, whereas, the bioavailability adjusted for administered dose of genistein from both soy preparations were comparable. The other pharmacokinetic parameters of daidzein and genistein, including Cmax adjusted for the dose, Tmax and t1/2, were not different between both soy preparations.

Chinese herbal recipe versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial [ISRCTN70292892].

BACKGROUND: Duhuo Jisheng Wan (DJW) is perhaps the best known and most widely used Chinese herbal recipe for arthralgia, but the clinical study to verify its efficacy is lacking. The purpose of this study was to compare the efficacy of DJW versus diclofenac in symptomatic treatment of osteoarthritis (OA) of the knee. METHODS: This study was a randomized, double-blind, double-dummy, controlled trial. The 200 patients suffering from OA of the knee, were randomized into the DJW and diclofenac group. The patients were evaluated after a run-in period of one week (week 0) and then weekly during 4 weeks of treatment. The clinical assessments included visual analog scale (VAS) score that assessed pain and stiffness, Lequesne's functional index, time for climbing up 10 steps, as well as physician's and patients' overall opinions on improvement. RESULTS: Ninety four patients in each group completed the study. In the first few weeks of treatment, the mean changes in some variables (VAS, which assessed walking pain, standing pain and stiffness, as well as Lequesne's functional index) of the DJW group were significantly lower than those of the diclofenac group. Afterwards, these mean changes became no different throughout the study. Most of the physician's and patients' overall opinions on improvement at each time point did not significantly differ between the two groups. Approximately 30% of patients in both groups experienced mild adverse events. CONCLUSION: DJW demonstrates clinically comparable efficacy to diclofenac after 4 weeks of treatment. However, the slow onset of action as well as approximately equal rate of adverse events to diclofenac might limit its alternative role in treatment of OA of the knee.

A bioequivalence study of the cefuroxime axetil in healthy volunteers.

UNLABELLED: The bioequivalence of 250-mg cefuroxime axetil was evaluated; Furoxime (by the Siam Bheasach Company, Thailand) as the test and Zinnat (GlaxoWellcome) as the reference. The two products were administered as a single dose according to a two-way crossover design, 1-week washout period to 12 healthy Thai male volunteers. Thereafter, serial blood samples were collected over a period of 15 hours. Plasma cefuroxime concentrations were measured by HPLC. The pharmacokinetic parameters were analyzed by noncompartmental analysis. RESULTS: The Tmax [median (range, h)] of Furoxime and Zinnat were 1.5 (1.0-3.0) and 1.75 (1.0-3.5), respectively. The Tmax of Furoxime was faster than Zinnat with the mean (90% CI) of difference in Tmax of -0.5 [(-1.01)-0.01] h. Bioequivalence analysis showed that the AUC(0-infinity) and the Cmax of the two products were not significantly different. The point estimator (90% CI) for the ratio [Furoxime/Zinnat] of log transformed data of the AUC(0-infinity) and Cmax were 1.03 (0.98-1.20) and 1.09 (1.02-1.24), respectively and were within the bioequivalence range of 0.80-1.25.

Bioequivalence study of generic acyclovir compared with the brand name acyclovir.

UNLABELLED: The bioequivalence study of 200-mg generic acyclovir was conducted in healthy males. The reference Zovirax and the test Zevin were administered as a single oral dose after an overnight fast in a two-period, crossover design separated by 1 week. Serial blood samples were collected over a period of 24 hours. Plasma acyclovir concentrations were determined by HPLC and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The t 1/2 for the test (4.5 +/- 2.4 h) and Zoviraxl (3.9 +/- 2.6 h) were comparable. The analysis of variance was carried out and the median Tmax (1.50 h) for the test was not statistically difference from Zovirax. The mean (90% CI) of the AUC0-infinity and the Cmax ratios for (Test/reference) were 0.95 (0.83-1.09) and 0.95 (0.83-1.10), respectively. These values fell within the bioequivalence criteria of 0.80-1.25, thus it was concluded that Zevin and Zovirax were bioequivalence.