-
1.
[Evaluation of drug-drug interactions between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets].
Mai, JJ, Zhang, H, Peng, YY, Yang, X, Mao, L, Luo, L, Xie, HM, Zhang, YJ, Li, XJ, Ding, YH
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology. 2020;(10):838-843
Abstract
Objective: To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers. Methods: A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software. Results: (1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C(max) and AUC(0-tau) geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C(max) GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C(max) GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC(0-t) GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C(max) and AUC(0-t) were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C(max) and AUC(0-72) GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion: Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.
-
2.
Nutrimetabolomics reveals food-specific compounds in urine of adults consuming a DASH-style diet.
Reisdorph, NA, Hendricks, AE, Tang, M, Doenges, KA, Reisdorph, RM, Tooker, BC, Quinn, K, Borengasser, SJ, Nkrumah-Elie, Y, Frank, DN, et al
Scientific reports. 2020;(1):1157
Abstract
Although health benefits of the Dietary Approaches to Stop Hypertension (DASH) diet are established, it is not understood which food compounds result in these benefits. We used metabolomics to identify unique compounds from individual foods of a DASH-style diet and determined if these Food-Specific Compounds (FSC) are detectable in urine from participants in a DASH-style dietary study. We also examined relationships between urinary compounds and blood pressure (BP). Nineteen subjects were randomized into 6-week controlled DASH-style diet interventions. Mass spectrometry-based metabolomics was performed on 24-hour urine samples collected before and after each intervention and on 12 representative DASH-style foods. Between 66-969 compounds were catalogued as FSC; for example, 4-hydroxydiphenylamine was found to be unique to apple. Overall, 13-190 of these FSC were detected in urine, demonstrating that these unmetabolized food compounds can be discovered in urine using metabolomics. Although linear mixed effects models showed no FSC from the 12 profiled foods were significantly associated with BP, other endogenous and food-related compounds were associated with BP (N = 16) and changes in BP over time (N = 6). Overall, this proof of principle study demonstrates that metabolomics can be used to catalog FSC, which can be detected in participant urine following a dietary intervention.
-
3.
TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101.
Premoli, I, Rossini, PG, Goldberg, PY, Posadas, K, Green, L, Yogo, N, Pimstone, S, Abela, E, Beatch, GN, Richardson, MP
Annals of clinical and translational neurology. 2019;(11):2164-2174
Abstract
OBJECTIVE Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. METHODS TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2-, 4-, and 6-hours post drug intake in a double-blind, placebo-controlled, randomized, two-period crossover study of 20 healthy male volunteers. RESULTS Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15-55 msec after TMS) and at late (150-250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration. INTERPRETATION Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early-stage clinical trials.
-
4.
Vitamin C intervention may lower the levels of persistent organic pollutants in blood of healthy women - A pilot study.
Guo, W, Huen, K, Park, JS, Petreas, M, Crispo Smith, S, Block, G, Holland, N
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2016;:197-204
Abstract
Emerging evidence suggests that exposure to endocrine-disrupting chemicals including persistent organic pollutants (POPs) such as organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) has a long term impact on human health. The goal of this pilot study was to test whether antioxidant intervention by vitamin C supplementation may be a remedial approach to decrease body burden of POPs in humans. Using solid phase extraction coupled with a triple quadrupole mass spectrometer and a gas chromatography high resolution mass spectrometry, we measured 18 PCBs, 7 OCPs, and 5 PBDEs in the blood of 15 healthy California women (8 were obese/overweight and 7 had normal weight) before and after 2 months of vitamin C supplementation (1000 mg/day). We observed higher PBDE levels than PCBs and OCPs, but only PCB and OCP levels were strongly and positively correlated with participant's BMI and age. We also found statistically significant decreases in 6 PCBs (PCB-74, PCB-118, PCB-138, PCB-153, PCB-180, and PCB-187), and 2 OCPs (4,4'-DDE, and 4,4'-DDT), but not PBDEs after vitamin C supplementation. Pending confirmation of this pilot finding in a larger study of both sexes, vitamin C intervention may have important public health implications in protecting health by reducing body burdens of POPs.
-
5.
Rapid slowing of the atrial fibrillatory rate after administration of AZD7009 predicts conversion of atrial fibrillation.
Aunes, M, Egstrup, K, Frison, L, Berggren, A, Stridh, M, Sörnmo, L, Edvardsson, N
Journal of electrocardiology. 2014;(3):316-23
Abstract
BACKGROUND Effects on the atrial fibrillatory rate (AFR) were studied during infusion with the combined potassium and sodium channel blocker AZD7009. METHODS AND RESULTS Patients with persistent atrial fibrillation (AF) were randomized to AZD7009 or placebo. Thirty-five patients converted to sinus rhythm (SR) and were matched to 35 non-converters. The mean AFR before conversion was 231 fibrillations per minute (fpm), having decreased by 41%; in non-converters, it was 296 fpm at the end of infusion, having decreased by 26%. The rate of decrease was greater in converters at 5 min, -88 vs. -66 fpm (p=0.02), and at 10 min, -133 vs. -111 fpm (p=0.048). The AFR-SD and the exponential decay decreased. A small left atrial area was the only baseline predictor of conversion to SR. CONCLUSIONS AZD7009 produced a significantly more rapid decrease of the AFR in converters than in non-converters, but the AFR at baseline was not predictive of conversion.
-
6.
Lack of a pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation.
Iwamoto, M, Kassahun, K, Troyer, MD, Hanley, WD, Lu, P, Rhoton, A, Petry, AS, Ghosh, K, Mangin, E, DeNoia, EP, et al
Journal of clinical pharmacology. 2008;(2):209-14
Abstract
Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration = 33 nM in 50% human serum). In vitro characterization of raltegravir inhibition potential was assessed against a panel of cytochrome P450 (CYP) enzymes. An open-label, 2-period study was conducted to assess the effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP 3A4 probe substrate: period 1, 2.0 mg of midazolam; period 2, 400 mg of raltegravir every 12 hours for 14 days with 2.0 mg of midazolam on day 14. There was no meaningful in vitro effect of raltegravir on inhibition of a panel of CYP enzymes and induction of CYP 3A4. In the presence of raltegravir, midazolam area under the curve extrapolated to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)) geometric mean ratios were similar (geometric mean ratios and 90% confidence intervals: 0.92 [0.82, 1.03] (P = .208) and 1.03 [0.87, 1.22] (P = .751), respectively). No substantial differences were observed in T(max) (P = .750) or apparent half-life (P = .533) of midazolam. Plasma levels of midazolam were not substantially affected by raltegravir, which implies that raltegravir is not a clinically important inducer or inhibitor of CYP 3A4 and that raltegravir would not be expected to affect the pharmacokinetics of other drugs metabolized by CYP 3A4 to a clinically meaningful extent.
-
7.
Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study.
Markowitz, M, Nguyen, BY, Gotuzzo, E, Mendo, F, Ratanasuwan, W, Kovacs, C, Prada, G, Morales-Ramirez, JO, Crumpacker, CS, Isaacs, RD, et al
Journal of acquired immune deficiency syndromes (1999). 2007;(2):125-33
Abstract
BACKGROUND Raltegravir is an HIV-1 integrase strand-transfer inhibitor with potent in vitro activity. This study explored the antiretroviral activity and safety of raltegravir in treatment-naive patients with plasma HIV-1 RNA levels > or = 5000 copies/mL and CD4 T-cell counts > or = 100 cells/mm. METHODS Multicenter, double-blind, randomized, controlled study of raltegravir at doses of 100, 200, 400, and 600 mg twice daily versus efavirenz at a dose of 600 mg/d, all in combination with tenofovir at a dose of 300 mg/d and lamivudine at a dose of 300 mg/d (clinicaltrials.gov identifier: NCT00100048). RESULTS In the 198 patients treated (160 on raltegravir and 38 on efavirenz), the mean HIV-1 RNA level ranged from 4.6 to 4.8 log10 copies/mL at baseline. At weeks 2, 4, and 8, the proportion of patients achieving an HIV-1 RNA level <50 copies/mL was greater in each of the raltegravir treatment groups than in the efavirenz group. By week 24, all treatment groups appeared similar, with plasma HIV-1 RNA levels <400 copies/mL in 85% to 98% of patients and <50 copies/mL in 85% to 95% of patients. These reductions were maintained through week 48 in 85% to 98% of patients and in 83% to 88% of patients, respectively. Five (3%) patients on raltegravir and 1 (3%) on efavirenz experienced virologic failure before week 48. Drug-related clinical adverse events were less common with raltegravir than with efavirenz. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides. CONCLUSIONS Raltegravir at all doses studied was generally well tolerated in combination with tenofovir and lamivudine. Raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate.
-
8.
Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase.
Murray, JM, Emery, S, Kelleher, AD, Law, M, Chen, J, Hazuda, DJ, Nguyen, BY, Teppler, H, Cooper, DA
AIDS (London, England). 2007;(17):2315-21
Abstract
OBJECTIVE Raltegravir (MK-0518) belongs to the new class of HIV integrase inhibitors. To date, there have been no reports investigating the potential for differential effects on viral dynamics with integrase inhibitors relative to current antiretroviral drugs. METHODS Patients in this phase II study (P004) were antiretroviral treatment naive. Part 1 of this study compared monotherapy with raltegravir (100 mg, 200 mg, 400 mg, or 600 mg twice daily) with placebo over 10 days. In part 2, patients were enrolled for 48 weeks of combination therapy, with randomization to one of the four dosages of raltegravir or to efavirenz, in addition to tenofovir and lamivudine. Mathematical models were used to investigate processes underlying viral dynamics. RESULTS From day 15 through to day 57, individuals in the raltegravir arm were significantly more likely to have HIV RNA < 50 copies/ml (P < or = 0.047). Plasma viral loads were 70% lower at initiation of second-phase decay for individuals taking raltegravir than for those taking efavirenz (P < 0.0001). This challenges the current hypothesis that second-phase virus originates from infected long-lived cells, as an integrase inhibitor should not impact on viral production from this cell population. Mathematical modeling supported two hypotheses as consistent with these observations: (i) that second-phase virus arises from cells newly infected by long-lived infected cells and (2) that it arises from activation of latently infected cells with full-length unintegrated HIV DNA. CONCLUSIONS These observations challenge the current understanding of HIV-1 turnover and compartmentalization. They also indicate the promise of this new integrase inhibitor raltegravir.