METHOD: Compartmental models were fitted. The final model was determined based on the objective function value and inspection of goodness-of-fit plots. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100 times and resultant changes evaluated.

RESULTS: The absorption kinetics of metformin depend significantly on food status. Under the fasted state, the first-order absorption into the central compartment was preceded by zero-order infusion into the depot compartment, whereas for the fed state, the absorption into the depot was instantaneous followed by first-order absorption from depot into the central compartment. The means of relative mean estimation error (rMEE) ( ME E SAEM ME E FOCEi ) and rRMSE ( RMS E SAEM RMS E FOCEi ) were 0.48 and 0.35, respectively. All parameter estimates given by SAEM appeared to be narrowly distributed and were close to the true value used for simulation. In contrast, the distribution of estimates from FOCEi were skewed and more biased. When initial estimates were perturbed, FOCEi estimates were more biased and imprecise.

METHOD: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (- 15 °C to - 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00-125.00%.

RESULTS: There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92-111.27%), AUC0-∞ (96.94-108.08%) and Cmax (100.11-112.50%) for orphenadrine (n = 25); and AUC0-t (94.29-101.83%), AUC0-∞ (94.77-101.68%) and Cmax (87.12-101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00-125.00%.

CONCLUSION: The test preparation is bioequivalent to the reference preparation and can be used interchangeably.

MATERIALS AND METHODS: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2- period crossover study with a washout period of 7 days. All 28 adult male subjects were required to fast for at least 10 hours prior to drug administration and they were given access to water ad libitum during this period. Thirty minutes prior to dosing, all subjects were served with a standardized high-fat and high-calorie breakfast with a total calorie of 1000 kcal which was in accordance to the EMA Guideline on the Investigation of Bioequivalence. Subsequently, subjects were administered either the test or reference preparation with 240mL of plain water in the first trial period. During the second trial period, they received the alternate preparation. Plasma levels of glibenclamide and metformin were analysed separately using two different high performance liquid chromatography methods.

RESULTS: The 90% confidence interval (CI) for the ratio of the AUC0-t, AUC0-∞, and Cmax of the test preparation over those of the reference preparation were 0.9693-1.0739, 0.9598- 1.0561 and 0.9220 - 1.0642 respectively. Throughout the study period, no serious drug reaction was observed. However, a total of 26 adverse events (AE)/side effects were reported, including 24 that were definitely related to the study drugs, namely giddiness (n=17), while diarrheoa (n=3), headache (n=2) and excessive hunger (n=2) were less commonly reported by the subjects.

MATERIALS AND METHODS: Data from a randomized clinical trial evaluating efficacy of a nonsurgical intervention in women with stress urinary incontinence were used for analyses. The overall score of ICIQ-UI SF ranges from 0 to 21, with greater values indicating increased severity. The ICIQ-LUTSqol ranges from 19 to 76, with greater values indicating increased impact on quality of life. Instruments used in the anchor-based method were the Patient Global Impression of Improvement, patient satisfaction, 1-hour pad test and the incontinence episode frequency. The distribution-based method used an effect size of 0.5 standard deviation. Triangulation of findings was used to converge on a single value of MCID.

RESULTS: At 12-month post-treatment, 106 (88.3%) participants completed the follow-up and were included in the analysis. Anchor-based MCIDs of the ICIQ-UI SF were between 3.4 and 4.4, while the distribution-based MCID was 1.7. Anchor-based MCIDs of the ICIQ-LUTSqol were between 4.8 and 6.9, while the distribution-based MCID was 5.2. Triangulation of findings showed that MCIDs of 4 for ICIQ-UI SF and 6 for ICIQ-LUTSqol were the most appropriate.

METHOD: Four curcumin analogues were synthesized. These analogues and curcumin were evaluated for their BBB permeability in the parallel artificial membrane permeability assay. The transgenic Caenorhabditis elegansGMC101 that expresses human Aβ1-42 was treated with the compounds to evaluate their ability to delay Aβ-induced paralysis. Expression of skn-1mRNA was examined on nematodes treated with selected efficacious compounds. In vitro Aβ aggregation in the presence of the compounds was performed.

KEY FINDINGS: The four analogues showed improved BBB permeability vs curcumin in the PAMPA with the hemi-analogue C4 having the highest permeability coefficient. At 100 μm, analogues C1 and C4 as well as curcumin significantly prolonged the survival of the nematodes protecting against Aβ toxicity. However, only curcumin and C4 showed protection at lower concentrations. skn-1mRNA was significantly elevated in nematodes treated with curcumin and C4 indicating SKN-1/Nrf activation as a possible mode of action.

METHODS: Women with SUI (n = 120) were randomized to either active or sham PMS for 8 weeks (twice/week). Patients answered seven questions on their perception and acceptability, each measured on a 5-point Likert scale. Treatment satisfaction was assessed using two parameters: (i) the single-item question "Overall, please rate how satisfied you are with the treatment" and (ii) Patient Global Impression of Improvement (PGI-I). All adverse events were documented.

MATERIALS AND METHODS: We identified RCTs for SUI interventions published between January 2015 and July 2017. We listed the objective and subjective outcome measures used in eligible trials in the literature search. Using data from our RCT conducted from 2013 to 2016 evaluating pulsed magnetic stimulation for SUI, we analysed the correlation between all measures.

RESULTS: A total of 45 RCTs were included; 28 (62%) involved surgical interventions. The most frequently used objective and subjective measures were the cough stress test and International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF), respectively. In all, 24 different validated questionnaires were administered in the 42 studies that used subjective outcome measure. Analyses of measures used in our trial showed that all measures were significantly correlated with each other except for pelvic floor muscle function. The ICIQ-UI SF showed the highest correlation coefficients (0.587-0.733) with all outcome measures.

METHODS: This study involved 120 female SUI subjects aged ≥21 years old randomized to either active or sham PMS. Treatment involved two PMS sessions per week for 2 months (16 sessions). After 2 months, subjects could opt for 16 additional sessions regardless of initial randomization. The primary response criterion was a 7-point reduction in the total score of the International Consultation on Incontinence Questionnaire-Lower Urinary Tract Symptoms Quality of Life (ICIQ-LUTSqol) questionnaire. Follow-ups were conducted at months 1, 2, 5, 8, and 14.

Objective: To evaluate the efficacy of oral mixed tocotrienols for patients with diabetic peripheral neuropathy.

Design, Setting, and Participants: The Vitamin E in Neuroprotection Study (VENUS) was a parallel, double-blind, placebo-controlled trial that recruited participants from January 30, 2011, to December 7, 2014, with 12 months of follow-up. This trial screened 14 289 patients with diabetes from 6 health clinics and ambulatory care units from 5 public hospitals in Malaysia. A total of 391 patients who reported neuropathic symptoms were further assessed with Total Symptom Score (TSS) and Neuropathy Impairment Score (NIS). Patients 20 years or older with a TSS of 3 or higher and an NIS of 2 or higher were recruited.

Interventions: Patients were randomized to receive 200 mg of mixed tocotrienols twice daily or matching placebo for 12 months. Patients with hyperhomocysteinemia (homocysteine level ≥2.03 mg/L) received oral folic acid, 5 mg once daily, and methylcobalamin, 500 μg thrice daily, in both groups.

Main Outcomes and Measures: The primary outcome was patient-reported neuropathy TSS (lancinating pain, burning pain, paresthesia, and asleep numbness) changes at 12 months. The secondary outcomes were NIS and sensory nerve conduction test result.

Results: Of 391 eligible patients, 300 were recruited (130 [43.3%] male; mean [SD] age, 57.6 [8.9] years; mean [SD] duration of diabetes, 11.4 [7.8] years) and 229 (76.3%) completed the trial. The TSS changes between the tocotrienols and placebo groups at 12 months (-0.30; 95% CI, -1.16 to 0.56; P = .49) were similar. No significant differences in NIS (0.60; 95% CI, -1.37 to 2.65; P = .53) and sensory nerve conduction test assessments were found between both groups. In post hoc subgroup analyses, tocotrienols reduced lancinating pain among patients with hemoglobin A1C levels greater than 8% (P = .03) and normohomocysteinemia (homocysteine level <2.03 mg/L; P = .008) at 1 year. Serious adverse events in both groups were similar, except more infections were observed in the tocotrienols group (6.7% vs 0.7%, P = .04). Results reported were of modified intention-to-treat analyses.

Conclusions and Relevance: Supplementation of oral mixed tocotrienols, 400 mg/d for 1 year, did not improve overall neuropathic symptoms. The preliminary observations on lancinating pain among subsets of patients require further exploration.

METHODS: Women with or without SUI aged ≥21 years old were recruited. Subjects completed the International Consultation of Incontinence-Urinary Incontinence Short Form (ICIQ-UI-SF), International Consultation of Incontinence-Lower Urinary Tract Symptoms Quality of Life (ICIQ-LUTSqol), and EQ-5D questionnaires.

MATERIALS AND METHODS: A cross-sectional survey was conducted involving sexually active women with or without SUI aged at least 21 years old, and their respective partners. Both partners completed the Golombok Rust Inventory of Sexual Satisfaction (GRISS), a 28-item multidimensional measure with separate forms for male and female designed to assess sexual satisfaction of both partners. Spearman rank correlation coefficient was used to analyze bivariate association, whereas multiple regression analysis was used to identify predictors for overall sexual function as measured using GRISS score.

MATERIALS AND METHODS: This randomized, double-blind, sham controlled study was performed in 120 female subjects at least 21 years old with stress urinary incontinence. Treatment involved pulsed magnetic stimulation for 2 sessions per week for 2 months (16 sessions). After 2 months, subjects could opt for 16 additional sessions regardless of initial randomization. The primary response criterion was a 5-point reduction in the ICIQ-UI SF (International Consultation on Incontinence Questionnaire for Urinary Incontinence-Short Form) score. Key secondary response criteria included objective and subjective cure, supplemented by other secondary criteria. Followups were performed at months 1, 2, 5, 8 and 14.

RESULTS: At 2 months 45 of 60 subjects (75%) in the active arm vs 13 of 60 (21.7%) in the sham arm were treatment responders (p <0.001). After 2 months 24 subjects (40%) in the active arm and 41 (68%) in the sham arm elected additional active pulsed magnetic stimulation. At 14 months, subjects who received 32 sessions of active pulsed magnetic stimulation had the highest percentage of treatment responders (18 of 24 or 75.0%), followed by those who received 16 sessions (26 of 36 or 72.2% and 28 of 41 or 68.3%) and those who did not receive any active pulsed magnetic stimulation (4 of 19 or 21.1%) (p <0.001).