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.
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 3HAVP 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.
The aim of the present study was to evaluate the oxidative stress and anti-oxidant status in rat serum following intra-tracheal instillation of multi wall carbon nanotubes (MWCNT). The lungs of rats ...were intra-tracheally instilled with (single dose of) Phosphate-buffered saline (PBS)+1% of Tween 80 (Solvent Control) or MWCNT or carbonyl Iron (negative control) or quartz particles (positive control) at a dose of 0.2, 1 and 5mg/kg body weight. Following exposure, the blood samples were collected at 1, 7, 30 and 90days of post instillation of nanoparticles and different parameters were estimated to assess the oxidative stress induced by the instillation of MWCNT. Exposure of MWCNT to rats produced a significant (p<0.05) dose dependent reduction of blood total anti-oxidant capacity, glutathione, superoxide dismutase, catalase activity and increased lipid peroxidation product, (Malondialdehyde) levels than PBS+1% Tween 80 control group. This reduction in the total anti-oxidant capacity in nanotubes exposed rats indicates the reduction in anti-oxidant deference mechanisms due to the instillation of MWCNT. These results indicate that, exposure of multi wall carbon nanotubes induces oxidative stress by reducing the total anti-oxidant capacity in rats. The findings suggest possible occupational health hazard in chronic exposures.
This study evaluated the ability of the multi wall carbon nanotubes (MWCNT) to induce extra pulmonary toxicities in rats following intra-tracheal (IT) instillation of two MWCNT. Two carbon ...nanoparticles were instilled into the lungs of rats (0.2, 1, and 5 mg/kg b.w.) and at different post-exposure intervals, blood and organs like liver, kidney, etc. were collected. The histopathological examination of liver tissues revealed a dose-dependent periportal lymphocytic infiltration, ballooning, foamy degeneration, and necrosis at all post-instillation periods. However, examination of kidney revealed the tubular necrosis and interstitial nephritis with 5 mg/kg dose at 1 month of post-instillation of both MWCNT. These liver and kidney toxicities were further confirmed by the elevated levels of respective tissue damage biomarkers. These results suggest the extra pulmonary toxicities of these carbon nanoparticles might be due to the translocation into the liver and kidney.
Cyclophosphamide, an alkylating agent widely used as anticancer agent, biotransformed in vivo to unstable phosphoramidic mustard and acrolein, where the latter metabolite has been found responsible ...for hemorrhagic cystitis and renal toxicity. Being one of the most popular strategies to avoid these deleterious effects, prodrug design has been attempted, which can, in addition, enable selective drug targeting. Our efforts to design, synthesize and evaluate the enzymatically activated prodrug phosphorodiamidic mustard as potential candidate for selective chemotherapy in antibody-directed enzyme prodrug therapy or prodrug monotherapy strategies are described. We propose an improved synthesis of prodrug 14, consisting of a galactose moiety, a spacer and a cytotoxic drug and its cytotoxicity has been investigated. The prodrug 14 has been found to be nontoxic (in vitro) which could be a valuable candidate for further development.
To screen for inhibitory effects of diosmin on cytochrome P(450)-mediated metabolism of metronidazole in healthy volunteers.
Before/after non-blinded investigation conducted in healthy male ...volunteers.
After an overnight fast, metronidazole (two 400-mg tablets) was administered to 12 volunteers, either alone or after a 9-day pretreatment period with a once-daily dose of diosmin 500-mg tablets under direct observation. Serum concentrations of metronidazole up to 48 h postdose and urinary concentrations of metronidazole and its two major metabolites up to 24 h postdose were measured using reversed-phase high-performance liquid chromatography.
Metronicazole plasma AUC((0- infinity )) and C(max) were significantly higher after diosmin pretreatment by (mean) 27% and 24%, respectively. However, time to reach peak concentration (t(max)) was not affected significantly. Urinary excretion of acid and hydroxy metabolites in urine was decreased significantly, while excretion of unchanged metronidazole was increased.
Diosmin pretreatment significantly altered the metabolism of metronidazole, as demonstrated by changes in plasma pharmacokinetics as well as by urinary recovery of both parent drug and its major metabolites. This may be caused by the inhibition of cytochrome P(450) enzymes.
Apparently two forms of β-galactosidase (β-GAL) in cells or tissue sections can be detected by enzyme histochemical staining (X-GAL). Using a sensitive and specific HPLC method we have determined the ...pH dependent activity of β-GAL in cell lines of lung carcinoma (A549), colon carcinoma (Caco2-TC7), promyelocytic leukemia (HL60), hepatoma (HepG2) and human liver homogenates. The HPLC method has been validated and the influence of pH and substrate concentration was studied. There was a good linear correlation between HPLC and quantitative enzyme histochemistry (pH 4.5:
r=0.985; pH 6.0:
r=0.967). Both, pH 4.5 β-GAL and pH 6 β-GAL could be demonstrated in all biological material tested and pH 6 β-GAL activity was always lower (25–50%) than pH 4.5 activity. In Caco2-TC7 cells both activities increased by a factor of 10 from day 3 to day 17 after seeding. In addition, since the β-GAL activity decreased with increase in pH both in human liver homogenates (independent of the age of the donor) as well as in tumor cell lysates in a similar fashion we believe that the activity at pH 6 can hardly be considered as an exclusive ‘senescence marker’. In addition, the more sensitive HPLC method could demonstrate activity in cells that showed negative reaction with X-GAL.
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 Ca2+ 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 (Ka or Kb) and Caco-2 permeabilities. The obtained predictive equation was: Food effect (%) = (2.60 × 105·Papp) − (2.91 × 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.
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.
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