Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes.

Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours' standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child-Turcotte-Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose-dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%-60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.

In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2.

Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V1) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys8]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg8]-vasopressin (AVP) at V1 and vasopressin-2 (V2) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V1 and V2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [3H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V1) and cyclic adenosine monophosphate (V2). Binding potency at V1 and V2 was AVP>LVP>>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V1 than for V2. Cellular activity potency was also AVP>LVP>>terlipressin. Terlipressin was a partial agonist at V1 and a full agonist at V2; LVP was a full agonist at both V1 and V2. The in vivo response to terlipressin is likely due to the partial V1 agonist activity of terlipressin and full V1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.

Oxidative biomarkers to assess the nanoparticle-induced oxidative stress.

Nanotechnology involves the creation and manipulation of materials at nanoscale levels to create products that exhibit novel properties. Engineered nanomaterials either metals (like carbon and silver) or metal oxides (like zinc oxide, magnesium oxide, and titanium oxide) induce toxicity and oxidative stress by generating free radicals. Various in vitro and in vivo models are available to estimate the oxidative stress induced by the nanoparticles. In this chapter, we describe the methods for the estimation of oxidative stress markers like reactive oxygen species (ROS), DNA damage estimation, and lipid peroxidation products; total antioxidant capacity (TAC) was mentioned.

Cardiovascular risk among university students from developed and developing nations.

BACKGROUND: A key aspect in halting global increase in cardiovascular events is prevention and especially prevention at an early age. Unfortunately, global data regarding cardiovascular risk factors in the young are limited. Therefore the objectives of this study were to identify the most common cardiovascular risk factors among young adults in a university setting in both developed and developing countries. METHODS: Lifestyle and cardiovascular risk factors (smoking status, rates of physical activity, alcohol use, family history, blood pressure, fasting lipid panel, fasting blood glucose) were prospectively evaluated in young adults at three different university settings [University of Michigan (Ann Arbor, USA), University of Kalamoon (Deratiah, Syria), and Kakatiya University (Warangal, India)]. RESULTS: A total of 296 subjects (mean age and standard deviation 22 ± 3 years) were evaluated. Rates of current smoking were markedly higher (p < 0.001) in Syria (43%) compared with the USA (6.2%) and India (1.7%). Subjects in India were significantly (p < 0.001) less likely to engage in physical activity (20.2%) compared with the USA (90.7%) and Syria (68.8%). Fasting blood glucose levels and body mass index were significantly higher (p < 0.001) in Syria as compared to other countries. Significant differences were also noted in LDL, HDL, and triglycerides among the three sites. CONCLUSIONS: Cardiovascular risk factors among young adults in a university setting vary depending on global setting. Based upon the results of this study, targeted interventional programs based on risk findings from individual countries may be a reasonable future strategy to help reduce long term cardiovascular morbidity and mortality.

Predictive models for drugs exhibiting negative food effects based on their biopharmaceutical characteristics.

CONTEXT: A drug is defined to exhibit food effects if its pharmacokinetic parameter, area under the curve (AUC0₋∞) is different when co-administered with food in comparison with its administration on a fasted stomach. Food effects of drugs administered in immediate release dosage forms were classified as positive, negative, and no food effects. OBJECTIVE: In this study, predictive models for negative food effects of drugs that are stable in the gastrointestinal tract and do not complex with Ca²âº are reported. METHODS: An empirical model was developed using five drugs exhibiting negative food effects and seven drugs exhibiting no food effects by multiple regression analysis, based on biopharmaceutical properties generated from in vitro experiments. An oral absorption model was adopted for simulating negative food effects of model compounds using in situ rat intestinal permeability. RESULTS: Analysis of selected model drugs indicated that percent food effects correlated to their dissociation constant, K (K(a) or K(b)) and Caco-2 permeabilities. The obtained predictive equation was: Food effect (%)=(2.60 x 105·P(app))--(2.91 x 105·K)--8.50. Applying the oral absorption model, the predicted food effects matched the trends of published negative food effects when the two experimental pH conditions of fed and fasted state intestinal environment were used. CONCLUSION: A predictive model for negative food effects based on the correlation of food effects with dissociation constant and Caco-2 permeability was established and simulations of food effects using rat intestinal permeability supported the drugs? published negative food effects. Thus, an empirical and a mechanistic model as potential tools for predicting negative food effects are reported.