In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine.

PURPOSE: To investigate the metabolic pathways of triapine in primary cultures of human hepatocytes and human hepatic subcellular fractions; to investigate interactions of triapine with tenofovir and emtricitabine; and to evaluate triapine as a perpetrator of drug interactions. The results will better inform future clinical studies of triapine, a radiation sensitizer currently being studied in a phase III study. METHODS: Triapine was incubated with human hepatocytes and subcellular fractions in the presence of a number of inhibitors of drug metabolizing enzymes. Triapine depletion was monitored by LC-MS/MS. Tenofovir and emtricitabine were co-incubated with triapine in primary cultures of human hepatocytes. Triapine was incubated with a CYP probe cocktail and human liver microsomes, followed by LC-MS/MS monitoring of CYP specific metabolite formation. RESULTS: Triapine was not metabolized by FMO, AO/XO, MAO-A/B, or NAT-1/2, but was metabolized by CYP450s. CYP1A2 accounted for most of the depletion of triapine. Tenofovir and emtricitabine did not alter triapine depletion. Triapine reduced CYP1A2 activity and increased CYP2C19 activity. CONCLUSION: CYP1A2 metabolism is the major metabolic pathway for triapine. Triapine may be evaluated in cancer patients in the setting of HIV with emtricitabine or tenofovir treatment. Confirmatory clinical trials may further define the in vivo triapine metabolic fate and quantify any drug-drug interactions.

Childhood Music Training Induces Change in Micro and Macroscopic Brain Structure: Results from a Longitudinal Study.

Several studies comparing adult musicians and nonmusicians have shown that music training is associated with structural brain differences. It is not been established, however, whether such differences result from pre-existing biological traits, lengthy musical training, or an interaction of the two factors, or if comparable changes can be found in children undergoing music training. As part of an ongoing longitudinal study, we investigated the effects of music training on the developmental trajectory of children's brain structure, over two years, beginning at age 6. We compared these children with children of the same socio-economic background but either involved in sports training or not involved in any systematic after school training. We established at the onset that there were no pre-existing structural differences among the groups. Two years later we observed that children in the music group showed (1) a different rate of cortical thickness maturation between the right and left posterior superior temporal gyrus, and (2) higher fractional anisotropy in the corpus callosum, specifically in the crossing pathways connecting superior frontal, sensory, and motor segments. We conclude that music training induces macro and microstructural brain changes in school-age children, and that those changes are not attributable to pre-existing biological traits.

Improving the oral bioavailability of buprenorphine: an in-vivo proof of concept.

OBJECTIVES: The aim of this study was to improve the oral bioavailability of buprenorphine by inhibiting presystemic metabolism via the oral co-administration of 'Generally Recognized as Safe' compounds, thus providing an orally administered drug product with less variability and comparable or higher exposure compared with the sublingual route. METHODS: The present studies were performed in Sprague Dawley rats following either intravenous or oral administration of buprenorphine/naloxone and oral co-administration of 'Generally Recognized as Safe' compounds referred to as 'adjuvants'. Plasma samples were collected up to 22 h postdosing followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis. KEY FINDINGS: The adjuvants increased Cmax (21 ± 16 ng/ml vs 75 ± 33 ng/ml; 3.6-fold) and AUC(0-22 h) (10.6 ± 8.11 µg min/ml vs 22.9 ± 11.7 µg min/ml; 2.2-fold) values of buprenorphine (control vs adjuvant-treated, respectively). The absolute oral bioavailability of buprenorphine doubled (from 1.24% to 2.68%) in the presence of the adjuvants. CONCLUSIONS: One may suggest that the adjuvant treatment most likely inhibited the presystemic metabolic enzymes, thus decreasing the intestinal 'first-pass effect' on buprenorphine. Additional studies are now required to further explore the concept of inhibiting presystemic metabolism of buprenorphine by adjuvants to potentially increase the oral bioavailability of buprenorphine.

Inhibition of glucuronidation and oxidative metabolism of buprenorphine using GRAS compounds or dietary constituents/supplements: in vitro proof of concept.

The present study investigated the potential of generally recognized as safe (GRAS) compounds or dietary substances to inhibit the presystemic metabolism of buprenorphine and to increase its oral bioavailability. Using IVIVE, buprenorphine extraction ratios in intestine and liver were predicted as 96% and 71%, respectively. In addition, the relative fraction of buprenorphine metabolized by oxidation and glucuronidation in these two organs was estimated using pooled human intestinal and liver microsomes. In both organs, oxidation appeared to be the major metabolic pathway with a 6 and 4 fold higher intrinsic clearance than glucuronidation in intestine and liver, respectively. The oral bioavailability of buprenorphine was predicted to be 1.16%. Inhibition of 75% and 50% of intestinal and hepatic presystemic metabolism would result in an Foral of 49%, which is comparable to the bioavailability of sublingual buprenorphine. In human liver microsomes, chrysin, curcumin, ginger extract, hesperitin, magnolol, quercetin and silybin inhibited ≥50% glucuronidation, whereas chrysin, curcumin, ginger extract, 6-gingerol, pterostilbene, resveratrol and silybin exhibited ≥30% inhibition of oxidation. In human intestinal microsomes, curcumin, ginger extract, α-mangostin, quercetin and silybin inhibited ≥50% glucuronidation while chrysin, ginger extract, α-mangostin, pterostilbene and resveratrol exhibited ≥30% inhibition of oxidation. These results demonstrate the feasibility of our proposed approach of using GRAS or dietary compounds to inhibit the presystemic metabolism of buprenorphine and thus improve its oral bioavailability. An oral buprenorphine formulation containing these inhibitors or their combinations has promising potential to replace sublingual buprenorphine. Copyright © 2016 John Wiley & Sons, Ltd.

Visual phonetic processing localized using speech and nonspeech face gestures in video and point-light displays.

The talking face affords multiple types of information. To isolate cortical sites with responsibility for integrating linguistically relevant visual speech cues, speech and nonspeech face gestures were presented in natural video and point-light displays during fMRI scanning at 3.0T. Participants with normal hearing viewed the stimuli and also viewed localizers for the fusiform face area (FFA), the lateral occipital complex (LOC), and the visual motion (V5/MT) regions of interest (ROIs). The FFA, the LOC, and V5/MT were significantly less activated for speech relative to nonspeech and control stimuli. Distinct activation of the posterior superior temporal sulcus and the adjacent middle temporal gyrus to speech, independent of media, was obtained in group analyses. Individual analyses showed that speech and nonspeech stimuli were associated with adjacent but different activations, with the speech activations more anterior. We suggest that the speech activation area is the temporal visual speech area (TVSA), and that it can be localized with the combination of stimuli used in this study.

Insufficient level of iodine content in household powder salt in Nepal.

Universal salt iodization (USI) is long term strategy for the control of iodine deficiency disorder (IDD) in Nepal. Standardized periodic testing of the iodine content in salt is a critical part of a salt iodisation programme. To achieve programmatic objective, this study was carried out to estimate the iodine content of household salt in Kavre, Lalitpur and Parsa districts of Nepal. Iodometric titration of 1803 salt samples collected from the households through the students of different schools revealed that 289 (16.0%) had less than 15 ppm iodine. Two hundred forty-one powder salt samples without two children logo (14.3% among total powder salt samples) had iodine below 15 ppm. It includes 25.8% of total salt samples from Parsa district of Terai ecological region. Among total, the largest proportion of the population accounting for almost 93.0% used powder salt. In total 1803 salt samples, mean and median iodine concentration were 31.8 ppm (95.0% CI=31.0-32.6) and 29.5 ppm respectively. The mean and median iodine concentration of phoda (dhike) salt were 22.1 ppm (95.0% CI= 19.2-25.1) and 18.9 ppm; powder salt were 32.6 ppm (95.0% CI= 31.7- 33.4) and 30.6 ppm respectively. In the community level, people are still using the non-iodized salt. To eliminate the IDD more efforts are required at program implementation and monitoring level.

Assessment of IDD problem by estimation of urinary iodine among school children.

Iodine deficiency disorder (IDD) is a major micronutrient deficiency problem in Nepal. Urinary iodine estimation has been the gold standard employed for the assessment of iodine status and of IDD. This study was conducted with objective to assess the urinary iodine among the school children of Kavre, Lalitpur and Parsa districts. Attempts were made to relate urinary iodine with salt use and other sociodemographic variables. Altogether 190 urine samples (74 samples from Kavre, 89 from Parsa and 27 from Lalitpur district) were collected from school children aged 5-13 years. The urinary iodine was analyzed by using urinary iodine assay kit (Bioclone Australia Pvt Limited). It was found that 3.2% children had urine iodine concentration below 20 microg/l. Similarly, the percentage of children with urine iodine concentration 21-50 microg/l, 51-99 microg/l, 100-299 microg/l and above 300 microg/l were 14.2%, 10.5%, 43.7% and 28.4% respectively. Iodine deficient population of school children was 39.2% of Kavre, 19.1% of Parsa and 25.9% of Lalitpur. Overall, it was found that 27.9% children had urine iodine level less than the normal WHO levels. The median urine iodine level was 139.0 microg/l of Kavre, 266.7 microg/l of Parsa and 244.4 microg/l of Lalitpur school children. Urinary iodine excretion (UIE) median value among male students was 211.9 microg/l, among female students was 190.2 microg/l and the difference was statistically insignificant (P > 0.05). There was no significant correlation between consumed salt iodine level and urine iodine excretion level (P > 0.05). Short-term iodine supplementation programs should be arranged for iodine deficient children in the study districts. This study shows that IDD continues to be prevalent in the country as a major public health problem, which requires strengthening effective intervention program and other preventive measures.

Retention and effectiveness of HIV/AIDS training of traditional healers in far western Nepal.

OBJECTIVE: To evaluate HIV/AIDS training for traditional healers (THs) in far western Nepal. METHODS: We collected data using a structured questionnaire and assessed THs' knowledge of HIV transmission, misconceptions and preventive measures immediately prior to the initial training conducted from June to December 1999, and then 9-12 months after the training in 2000. We also conducted six focus group discussions (FGD) and assessed THs' performances after the training. We interviewed 12 key informants about their perceptions towards the trained THs. RESULTS: THs significantly improved their knowledge of HIV transmission, misconceptions and preventive measures after the training. The FGD and key informant interview results showed that the trained THs provided culturally acceptable HIV/AIDS education to the local people, distributed condoms and played a role in reducing the HIV/AIDS-related stigma. CONCLUSIONS: THs have a potential to work as key players in HIV/AIDS programmes in Nepal.