A Randomized Controlled Trial of Thai Medicinal Plant-4 Cream versus Diclofenac Gel in the Management of Symptomatic Osteoarthritis of the Knee.

Background: Osteoarthritis of the knee is a common degenerative musculoskeletal condition. Thai Medicinal Plant-4 (TMP-4) cream is made up of Garcinia mangostana peel, Sesamum indicum seeds, Glycine max (L.) Merr. seeds, and Centella asiatica leaves, all of which have anti-inflammatory and analgesic properties. The present study aimed at determining the efficacy and safety of TMP-4 cream versus diclofenac gel in the treatment of symptomatic osteoarthritis of the knee. Methods: A randomized-controlled trial was conducted to assess knee pain on a scale of 100 mm Visual Analog Scale (VAS) and other key metrics, including VAS knee stiffness, a modified 10-step stair climb test, a timed up and go test, the Knee Injury and Osteoarthritis Outcome Score, and safety outcomes, following administration of either TMP-4 cream or diclofenac gel for 4 weeks. Results: A total of 199 patients with moderate knee pain intensity were randomly assigned to either TMP-4 cream or diclofenac gel (allocation ratio 1 : 1). The mean changes of VAS knee pain in the TMP-4 cream and diclofenac gel groups were -31.68 ± 14.18 mm and -31.09 ± 12.41 mm, respectively, (mean difference = -0.58, 95% confidence interval = -4.37-3.20, P=0.761). The upper limit of 95% confidence interval for the comparison between TMP-4 cream and diclofenac gel was within the predefined margin of 7 mm for noninferiority. The safety was comparable between the two interventions. Conclusions: TMP-4 cream was noninferior to diclofenac gel in relieving osteoarthritic knee pain and may be considered as an alternative therapeutic option in the treatment of symptomatic osteoarthritis of the knee.

Clinical Efficacy and Safety of Thai Herbal Formulation-6 in the Treatment of Symptomatic Osteoarthritis of the Knee: A Randomized-Controlled Trial.

BACKGROUND: Osteoarthritis of the knee is the most common form of arthritis. Identifying effective and safe herbal formulations that are locally available is viewed as a priority for sustainable development in a region. This study aimed to evaluate the efficacy and safety of Thai herbal formulation-6 (THF-6) in comparison with oral diclofenac in patients with moderate-to-severe osteoarthritis of the knee. METHODS: This randomized, double-blind, active-controlled, noninferiority trial randomly assigned patients with osteoarthritis of the knee to receive either THF-6 or diclofenac for four weeks. The primary outcome measure was the change from baseline in knee pain as measured by a 100 mm visual analog scale (VAS). Secondary outcome measures included knee stiffness, a stair climb test, the Knee Injury and Osteoarthritis Outcome Score, and safety parameters. Outcomes were assessed on a biweekly basis. Modified intention-to-treat (MITT) and perprotocol (PP) analyses were applied. RESULTS: A total of 200 patients were enrolled of whom 175 (87.5%) were included in the MITT analysis and 153 (76.5%) in the PP analysis. The mean change in VAS pain did not differ between the two groups, and the upper limit of the two-sided 95% confidence interval (CI) for comparison between the two groups was within the prespecified margin of 10 mm for noninferiority (MITT analysis: mean difference = 0.86, 95% CI = -4.39 to 6.10, p=0.748; PP analysis: mean difference = 1.98, 95% CI = -3.61 to 7.56, p=0.486). Significant improvement was observed in all the efficacy parameters in both groups. Dyspepsia was the most common adverse event: 23 patients in the THF-6 group and 28 in the diclofenac group (p=0.417). CONCLUSIONS: THF-6 offers an alternative to oral diclofenac for the short-term treatment of osteoarthritis of the knee. It was shown to be noninferior to oral diclofenac in relieving knee pain. This trial is registered with ChiCTR-IPR-15007213.

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.

Analgesic, anti-inflammatory, and chondroprotective activities of Cryptolepis buchanani extract: in vitro and in vivo studies.

Cryptolepis buchanani Roem. & Schult. is widely used in folk medicine in Southeast Asia for treating muscle tension and arthritis. This study aimed to investigate an analgesic activity of the methanol extract of C. buchanani (CBE) in acetic acid-induced writhing response in mice, and to examine its anti-inflammatory activity in ethyl phenylpropiolate- (EPP-) induced ear edema and carrageenan-induced paw edema in rats. Its effects on cartilage degradation induced by interleukin-1ß (IL-1ß) in porcine cartilage explant culture were also determined. This study demonstrated that CBE significantly reduced acetic acid-induced writhing response. It also inhibited edema formation in both EPP-induced ear edema and carrageenan-induced paw edema models. In cartilage explant culture, CBE significantly reduced the sulfated glycosaminoglycan and hyaluronan released into culture media while it reserved the uronic acid and collagen within the cartilage tissues. It also suppressed the matrix metalloproteinase-2 activity with no effect on cell viability. In conclusion, CBE shows analgesic, anti-inflammatory, and chondroprotective effects in this preliminary study. Therefore, CBE may be useful as an alternative treatment for osteoarthritis.

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.

Influence of fructooligosaccharide on pharmacokinetics of isoflavones in postmenopausal women.

The objective of the present paper was to determine the influence of fructooligosaccharide (FOS) on the pharmacokinetics of isoflavones in healthy postmenopausal women. The study was a fixed-sequence, two-phase, crossover study. Twelve subjects received a single oral dose of 300 mL of a soy beverage. Blood samples were collected before the dose and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 32 h after the administration of the soy beverage. After a washout period of at least 1 week, subjects were assigned to receive oral doses of FOS, 5 g each time, twice a day (after breakfast and dinner) for 14 days, followed by a single oral dose of the same soy beverage on the next day. Blood samples were then collected at the same time points mentioned previously. Plasma isoflavone concentrations were determined by HPLC. Continuous oral administrations of FOS followed by a single oral administration of soy beverage caused significant increases in C(max), AUC(0-32), and AUC(0-∞) of genistein and AUC(0-32) of daidzein, comparing to those obtained following a single oral dose of soy beverage alone. Other pharmacokinetic parameters (T(max) and t(1/2) of both aglycones and AUC(0-∞) of daidzein) between both regimens were not significantly different.

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.

Effects of vitamin d plus calcium supplements on pharmacokinetics of isoflavones in thai postmenopausal women.

The objective of this study was to determine the effects of vitamin D(3) plus calcium supplements (D(3)-calcium) on pharmacokinetics of isoflavones in Thai postmenopausal women. This study was an open-labeled, randomized three-phase crossover study. Twelve healthy subjects were randomized to receive one of the following regimens: (a) a single dose of isoflavones, (b) a single dose of isoflavones, and D(3)-calcium, or (c) continuous D(3)-calcium for 7 days followed by a single dose of isoflavones on the 8th day. After a washout period, subjects were switched to receive the 2 remaining regimens according to their randomized sequences. Blood samples were collected before dose and at specific time points until 32 hours after isoflavone administration. Plasma was treated with ß-glucuronidase/sulfatase to hydrolyze glucuronide and sulfate conjugates of daidzein and genistein. Plasma concentrations of daidzein and genistein were determined by high performance liquid chromatography. The estimated pharmacokinetic parameters of isoflavones were time to maximal plasma concentration (T(max)), maximal plasma concentration (C(max)), half-life (t(1/2)) and area under the plasma concentration-time curve (AUC). T(max) of daidzein and genistein after regimen B was significantly longer than that of regimen A. Other pharmacokinetic parameters of daidzein and genistein obtained following the three regimens were not significantly different.

Effects of taurine on anxiety-like and locomotor behavior of mice.

Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. We have previously reported that chronic supplementation of taurine in drinking water to mice increases brain excitability, mainly through alterations in the inhibitory GABAergic system. In this study we investigated the effects of chronic versus acute taurine treatment on anxiety-like and locomotor behaviors using two behavioral tests: elevated plus-maze and open-field. These two test conditions generated different levels of anxiety, and both anxiolytic and anxiogenic effects of taurine could be assessed. We used two paradigms for taurine treatment: Acute injection versus chronic supplementation. In the open field test, taurine supplementation increased whereas taurine injection suppressed locomotor activity. We found that taurine supplementation induced an increase in the total distance traveled, the overall movement speed, the time the animals spent mobile, the number of line crossings, and the time the animals entered the center zone. In the elevated arm maze, taurine injection suppressed anxiety whereas taurine supplementation was anxiogenic. The major findings of this are two folds: First these results suggest that taurine might play a role in the modulation of anxiety and locomotor activity. Second, taurine when injected acutely had opposite effects than when administered chronically.

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.

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.

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.

Electroacupuncture versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial.

BACKGROUND: The purpose of this study was to compare the efficacy of electroacupuncture (EA), diclofenac and their combination in symptomatic treatment of osteoarthritis (OA) of the knee. METHODS: This study was a randomized, single-blind, placebo controlled trial. The 193 out-patients with OA of the knee were randomized into four groups: placebo, diclofenac, EA and combined (diclofenac plus EA). Paracetamol tablets were prescribed as a rescue analgesic during the study. The patients were evaluated after a run-in period of one week (week 0) and again at the end of the study (week 4). The clinical assessments included the amount of paracetamol taken/week, visual analog scale (VAS), Western Ontario and McMaster Universities (WOMAC) OA Index, Lequesne's functional index, 50 feet-walk time, and the orthopedist's and patient's opinion of change. RESULTS: One hundred and eighty six patients completed the study. The improvement of symptoms (reduction in mean changes) in most outcome parameters was greatest in the EA group. The proportions of responders and patients with an overall opinion of "much better" were also greatest in the EA group. The improvement in VAS was significantly different between the EA and placebo group as well as the EA and diclofenac group. The improvement in Lequesne's functional index also differed significantly between the EA and placebo group. In addition, there was a significant improvement in WOMAC pain index between the combined and placebo group. CONCLUSION: EA is significantly more effective than placebo and diclofenac in the symptomatic treatment of OA of the knee in some circumstances. However, the combination of EA and diclofenac treatment was no more effective than EA treatment alone.