The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels.
Though ...mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials.
In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed.
Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008).
Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.
Tobacco use causes 7 million deaths per year; most national guidelines require people who use tobacco to opt in to care by affirming they are willing to quit. Use of medications and counseling is low ...even in advanced economy countries.
To evaluate the efficacy of opt-out care vs opt-in care for people who use tobacco.
In Changing the Default (CTD), a Bayesian adaptive population-based randomization trial, eligible patients were randomized into study groups, treated according to group assignment, and debriefed and consented for participation at 1-month follow-up. A total of 1000 adult patients were treated at a tertiary care hospital in Kansas City. Patients were randomized from September 2016 to September 2020; final follow-up was in March 2021.
At bedside, counselors screened for eligibility, conducted baseline assessment, randomized patients to study group, and provided opt-out care or opt-in care. Counselors and medical staff provided opt-out patients with inpatient nicotine replacement therapy, prescriptions for postdischarge medications, a 2-week medication starter kit, treatment planning, and 4 outpatient counseling calls. Patients could opt out of any or all elements of care. Opt-in patients willing to quit were offered each element of treatment described previously. Opt-in patients who were unwilling to quit received motivational counseling.
The main outcomes were biochemically verified abstinence and treatment uptake at 1 month after randomization.
Of a total of 1000 eligible adult patients who were randomized, most consented and enrolled (270 78% of opt-in patients; 469 73% of opt-out patients). Adaptive randomization assigned 345 (64%) to the opt-out group and 645 (36%) to the opt-in group. The mean (SD) age at enrollment was 51.70 (14.56) for opt-out patients and 51.21 (14.80) for opt-out patients. Of 270 opt-in patients, 123 (45.56%) were female, and of 469 opt-out patients, 226 (48.19%) were female. Verified quit rates for the opt-out group vs the opt-in group were 22% vs 16% at month 1 and 19% vs 18% at 6 months. The Bayesian posterior probability that opt-out care was better than opt-in care was 0.97 at 1 month and 0.59 at 6 months. Treatment use for the opt-out group vs the opt-in group was 60% vs 34% for postdischarge cessation medication (bayesian posterior probability of 1.0), and 89% vs 37% for completing at least 1 postdischarge counseling call (bayesian posterior probability of 1.0). The incremental cost-effectiveness ratio was $678.60, representing the cost of each additional quit in the opt-out group.
In this randomized clinical trial, opt-out care doubled treatment engagement and increased quit attempts, while enhancing patients' sense of agency and alliance with practitioners. Stronger and longer treatment could increase cessation.
ClinicalTrials.gov Identifier: NCT02721082.
The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in ...pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.
High concentrations of electrophilic lipid alkenals formed during oxidative stress are implicated in cytotoxicity and disease. However, low concentrations of alkenals are required to induce ...antioxidative stress responses. An established clearance pathway for lipid alkenals includes conjugation to glutathione (GSH) via Michael addition, which is catalyzed mainly by glutathione transferase isoform A4 (GSTA4-4). Based on the ability of GSTs to catalyze hydrolysis or
-Michael addition of GSH conjugates, and the antioxidant function of low concentrations of lipid alkenals, we hypothesize that GSTA4-4 contributes a homeostatic role in lipid metabolism. Enzymatic kinetic parameters for
-Michael addition with trans-2-Nonenal (NE) reveal the chemical competence of GSTA4-4 in this putative role. The forward GSTA4-4-catalyzed Michael addition occurs with the rapid exchange of the C2 proton of NE in D
O as observed by NMR. The isotope exchange was completely dependent on the presence of GSH. The overall commitment to catalysis, or the ratio of first order k
for 'forward' Michael addition to the first order k
for H/D exchange is remarkably low, approximately 3:1. This behavior is consistent with the possibility that GSTA4-4 is a regulatory enzyme that contributes to steady-state levels of lipid alkenals, rather than a strict 'one way' detoxication enzyme.
Drug-combination nanoparticles (DcNP) allow the formulation of multiple HIV drugs in one injectable. In nonhuman primates (NHP), all drugs in DcNP have demonstrated long-acting pharmacokinetics (PK) ...in the blood and lymph nodes, rendering it suitable for a Targeted Long-acting Antiretroviral Therapy (TLC-ART). To support the translation of TLC-ART into the clinic, the objective is to present a physiologically based PK (PBPK) model tool to control mechanisms affecting the rather complex DcNP-drug PK. Two species contribute simultaneously to the drug PK: drugs that dissociate from DcNP (Part 1) and drugs retained in DcNP (Part 2, presented separately). Here, we describe the PBPK modeling of the nanoparticle-free drugs. The free-drug model was built on subcutaneous injections of suspended lopinavir, ritonavir, and tenofovir in NHP, and validated by external experiments. A novelty was the design of a lymphatic network as part of a whole-body PBPK system which included major lymphatic regions: the cervical, axillary, hilar, mesenteric, and inguinal nodes. This detailed/regionalized description of the lymphatic system and mononuclear cells represents an unprecedented level of prediction that renders the free-drug model extendible to other small-drug molecules targeting the lymphatic system at both the regional and cellular levels.
•A novel LC-MS/MS method was developed for quantification of meta-iodobenzylguanidine (mIBG)•The method consists of a reproducible and simple extraction with a 5 min run time.•Method validation was ...performed with mouse plasma and liver homogenate.•The method quantifies mIBG selectively, accurately, and precisely in plasma and tissue matrices.
meta-iodobenzylguanidine (mIBG) is a radiopharmaceutical used for the diagnosis and treatment of neuroendocrine cancers. Previous quantification of mIBG in biodistribution and pharmacokinetic studies mainly relied on the use of radiolabeled mIBG, which involves the handling of highly radioactive materials. The goal of this study was to develop a nonradioactive analytical method for quantifying mIBG in mouse plasma and tissue homogenates using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Samples were prepared for analysis using a protein precipitation method. Mass spectrometry analysis was performed using 4-hydroxyphenformin as the internal standard, and the mass-to-charge transitions were 276.1 → 217.0 for mIBG and 222.1 → 121.0 for 4-hydroxyphenformin. The quantification limit of mIBG was 0.98 ng/mL, and the method was linear up to 500 ng/mL. The accuracy, inter-day and intra-day precision were 96–112%, 5.5–14.4%, and 3.7–14.1%, respectively, suggesting that the method was accurate and precise in quantifying mIBG at multiple concentrations in mouse plasma and liver homogenates. The extraction recovery was 96–106% and the matrix effect was 95–110%, indicating that the method was reproducible in quantifying mIBG with minimal impact from the biological matrices. In summary, we have developed and validated a fast, high-throughput quantification method of non-radiolabeled mIBG using LC-MS/MS. This method is reproducible, accurate, and precise, and can be used to quantify mIBG in plasma and tissue matrices to determine the pharmacokinetics and biodistribution of mIBG in preclinical animal models.
Drug-combination nanoparticles (DcNPs) administered subcutaneously represent a potential long-acting lymphatic-targeting treatment for HIV infection. The DcNP containing lopinavir (LPV)-ritonavir ...(RTV)-tenofovir (TFV), Targeted-Long-Acting-Antiretroviral-Therapy product candidate 101 (TLC-ART 101), has shown to provide long-acting lymphocyte-targeting performance in nonhuman primates. To extend the TLC-ART platform, we replaced TLC-ART 101 LPV with second-generation protease inhibitor, atazanavir (ATV). Pharmacokinetics of the ATV-RTV-TFV DcNP was assessed in macaques, in comparison to the equivalent free drug formulation and to the TLC-ART 101. After single subcutaneous administration of the DcNP formulation, ATV, RTV, and TFV concentrations were sustained in plasma for up to 14 days, and in peripheral blood mononuclear cells for 8 to 14 days, compared with 1 to 2 days in those macaques treated with free drug combination. By 1 week, lymph node mononuclear cells showed significant levels for all 3 drugs from DcNPs, whereas the free controls were undetectable. Compared with TLC-ART 101, the ATV-RTV-TFV DcNP exhibited similar lymphocyte-targeted long-acting features for all 3 drugs and similar pharmacokinetics for RTV and TFV, whereas some pharmacokinetic differences were observed for ATV versus LPV. The present study demonstrated the flexibility of the TLC-ART's DcNP platform to include different antiretroviral combinations that produce targeted long-acting effects on both plasma and cells.
The combination of ampicillin plus ceftaroline has been suggested to be more reliably synergistic against
than ampicillin plus ceftriaxone using time-kill methods. The purpose of this study was to ...determine if this trend persists in a two-compartment model of simulated endocardial vegetations (SEV) using clinically relevant pharmacokinetic exposures of these antimicrobials. Three clinically derived
strains were included in the study. The MICs of study antimicrobials were determined by broth microdilution. Simulations of ampicillin (2 g every 4 h q4h; maximum concentration of drug in serum
, 72.4 mg/liter; half-life
, 1.9 h), ceftaroline-fosamil (600 mg q8h;
, 21.3 mg/liter;
, 2.66 h), ceftriaxone (
, 257 mg/liter;
, 8 h), and ampicillin plus ceftaroline and ampicillin plus ceftriaxone were evaluated against 3 strains of
isolated from patients with endocarditis in an
PK/PD SEV model over 72 h, with a starting inoculum of ∼9 log
CFU/g. All strains were susceptible to ampicillin (MIC, ≤2 mg/liter). Ceftaroline MICs varied from 2 to 16 mg/liter. All strains had ceftriaxone MICs of 256 mg/liter. W04 and W151 exhibited high-level aminoglycoside resistance but W07 did not. Ampicillin plus ceftaroline resulted in significantly greater reductions in CFU per gram by 72 h than ampicillin for all strains (
≤ 0.025) than ampicillin plus ceftriaxone for W04 (
= 0.019) but not W07 or W151 (
≥ 0.15). A 4-fold increase in ampicillin MIC was observed for W07 at 72 h, but this was prevented by the addition of ceftaroline or ceftriaxone. The combination of ampicillin plus ceftaroline appears to be at least as efficacious as ampicillin plus ceftriaxone and may lead to improved activity against some strains of
, but these differences may be small and the clinical significance should not be overestimated.
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Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory ...depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a−/−/1b−/−, and Abcb1a−/−/1b−/−/Abcg2−/− mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a−/−/1b−/− and Abcb1a−/−/1b−/−/Abcg2−/− mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a−/−/1b−/− and Abcb1a−/−/1b−/−/Abcg2−/− mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2. In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a−/−/1b−/− or Abcb1a−/−/1b−/−/Abcg2−/− mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC–MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on fetal exposure to norbuprenorphine, but plays a significant role in restricting its brain distribution. The differential impacts of P-gp on norbuprenorphine distribution into the brain and fetus are likely, at least in part, due to the differences in amounts of P-gp protein expressed in the blood-brain and blood-placental barriers. BCRP is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine. Finally, fetal AUCs of the metabolite norbuprenorphine-β-d-glucuronide were 3–7 times greater than maternal plasma AUCs, while the maternal brain AUCs were <50% of maternal plasma AUCs, suggesting that a reversible pool of conjugated metabolite in the fetus may contribute to the high fetal exposure to norbuprenorphine.
Background
Risky alcohol consumption is on the rise among older adults. Biomarkers such as phosphatidylethanol (PEth) have been used to evaluate the correspondence between an objective, ...laboratory‐based biomarker and self‐report of alcohol consumption. This study examined the relationship between PEth, self‐report of alcohol consumption, and health indices in a sample of community‐dwelling older to middle‐age adults (aged 35 to 89) with healthy and risky levels of alcohol consumption.
Methods
Self‐reports of alcohol consumption were collected using the Alcohol Use Disorders Identification Test (AUDIT) and Form 30. In addition, indices of health along with a blood sample to determine PEth values were collected (N = 183).
Results
PEth was correlated with age, AUDIT‐C, AUDIT total, alcohol consumption, mood, and liver function measures but not with medical comorbidity or body mass index (J Gerontol B Psychol Sci Soc Sci 73, 2018, 633). Alcohol consumption over the past 30 days measured with Form 30 was the strongest predictor of PEth levels for both middle‐age and older adults, with age a small contributing predictor. General alcohol consumption patterns for amount of alcohol consumed over a 30‐day period revealed middle‐age adults consumed larger amounts of alcohol compared with older adults, but older adults consumed alcohol on more days than middle‐age adults. Middle‐age participants evidenced higher PEth levels than older adults at comparable drinking rates.
Conclusions
Overall, findings suggest a strong relationship between alcohol consumption and PEth levels with age a small but contributing factor to predicting PEth levels.
Unhealthy alcohol consumption is on the rise in older adults. A sample of middle age and older adults (age 35–89 years) found middle age adults consumed more drinks over thirty days (Form ‐30), whereas older adults consumed alcohol over more days (Form‐30). Alcoholic drinks consumed over 30 days was a strong predictor of phosphatidylethinol (PEth) (above left) with age a contributing factor (above right).
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