OCE-205 in rats and non-human primates: Pharmacokinetic and pharmacodynamic analysis.

Unlabelled: Treatment for complications associated with the hemodynamic consequences of decompensated cirrhosis remains suboptimal. Terlipressin, the latest pharmacological management of hepatorenal syndrome-acute kidney injury (HRS-AKI), targets the vasopressin system but has serious side effects. OCE-205 is a novel peptide designed to target the vasopressin receptor system as a mixed V1a agonist/antagonist, resulting in effective partial agonism without V2 agonism.

OCE-205, a Selective V1a Partial Agonist, Reduces Portal Pressure in Rat Models of Portal Hypertension.

Purpose: Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a receptor partial agonist, intended to have a wider therapeutic window than full vasopressin agonists.

Methods: We aimed to characterize the activity of OCE-205 treatment in two rat models of portal hypertension (PHT).

Partial vasopressin 1a receptor agonism reduces portal hypertension and hyperaldosteronism and induces a powerful diuretic and natriuretic effect in rats with cirrhosis and ascites.

The vasopressin system has emerged as a therapeutic focus for lowering portal hypertension and reducing splanchnic vasodilation in patients with refractory ascites. Clinically available vasopressin agonists are limited by preferential selectivity for V1 receptors that also have steep concentration-response curves with potential risks of excess vasoconstriction and/or complete antidiuretic effects. OCE-205 is a novel, selective, partial V1a receptor agonist with mixed agonist/antagonist activity and no V2 receptor activation at therapeutic doses.

Trace elements in atmospheric wet precipitation in Detroit metropolitan area: Levels and possible sources.

Rain and snow samples were collected in the Detroit metropolitan area and analyzed by inductively coupled plasma-mass spectrometry (ICP-MS). Twenty-two elements were detected in a concentration range from ∼0.03 to ∼1.

Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats.

Unlabelled: Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1 a -AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites.

Native Michigan plants stimulate soil microbial species changes and PAH remediation at a legacy steel mill.

A 1.3-acre phytoremediation site was constructed to mitigate polyaromatic hydrocarbon (PAH) contamination from a former steel mill in Michigan. Soil was amended with 10% (v/v) compost and 5% (v/v) poultry litter.

A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis.

AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC50 = 6 nM vs AMP EC50 = 6 μM) and specificity.

Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist.

Unlabelled: Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, with a prevalence ranging from 10% to 30%. The use of thyroid hormone receptor (TR) agonists for the treatment of NAFLD has not been considered viable because thyroid hormones increase free fatty acid (FFA) flux from the periphery to the liver, induce hepatic lipogenesis, and therefore could potentially cause steatosis. MB07811 is an orally active HepDirect prodrug of MB07344, a liver-targeted TR-beta agonist.

Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs.

Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart.

Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist.

The prodrug [(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811)] of a novel phosphonate-containing thyroid hormone receptor agonist [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxylmethylphosphonic acid (MB07344)] is the first application of the HepDirect liver-targeting approach to a non-nucleotide agent. The disposition of MB07811 was characterized in rat, dog, and monkey to assess its liver specificity, which is essential in limiting the extrahepatic side effects associated with this class of lipid-lowering agents. MB07811 was converted to MB07344 in liver microsomes from all species tested (CL(int) 1.

Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index.

Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRbeta-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index.

Expression of E-cadherin and other paracellular junction genes is decreased in iron-loaded hepatocytes.

Iron overload in the liver may occur in the clinical conditions hemochromatosis and transfusion-dependent thalassemia or by long-term consumption of large amounts of dietary iron. As iron concentrations increase in the liver, cirrhosis develops, and subsequently the normal architecture of the liver deteriorates. The underlying mechanisms whereby iron loading of hepatocytes leads to the pathology of the liver are not understood.

Comparison of anti-hepatitis B virus activities of lamivudine and clevudine by a quantitative assay.

In this study, we used a quantitative assay to measure the concentration-dependent effects of antivirals on extracellular hepatitis B virus (HBV) DNA as well as on different cytoplasmic and nuclear forms of HBV DNA that participate in HBV replication. HBV recombinant baculovirus, which efficiently delivers the HBV genome to HepG2 cells, was used for this study because (i) antivirals can be administered prior to initiation of HBV infection or after HBV infection and (ii) sufficiently high HBV replication levels are achieved that HBV covalently closed circular (CCC) DNA can be easily detected and individual HBV DNA species can be quantitatively analyzed separately from total HBV DNA. The results showed that the levels of HBV replicative intermediate and extracellular DNA decreased in a concentration-dependent fashion following antiviral treatment.

Effects of modulators of protein phosphorylation on heme metabolism in human hepatic cells: induction of delta-aminolevulinic synthase mRNA and protein by okadaic acid.

Effects of modulators of protein phosphorylation on delta-aminolevulinic acid (ALA) synthase and heme oxygenase-1 mRNA were analyzed in the human hepatic cell lines Huh-7 and HepG2 using a quantitative RNase protection assay. Okadaic acid was found to induce ALA synthase mRNA in a concentration-dependent fashion in both Huh-7 and HepG2 cells. The EC(50) for induction of ALA synthase mRNA in Huh-7 cells was 13.

The lipophilic iron compound TMH-ferrocene [(3,5,5-trimethylhexanoyl)ferrocene] increases iron concentrations, neuronal L-ferritin, and heme oxygenase in brains of BALB/c mice.

Mismanagement of intracellular iron is a key pathological feature of many neurodegenerative diseases. Our long-term goal is to use animal models to investigate the mechanisms of iron neurotoxicity and its relationship to neurodegenerative pathologies. The immediate aim of this experiment was to determine regional distribution of iron and cellular distribution of iron storage proteins (L- and H-ferritin) and an oxidative stress marker (heme oxygenase-1) in brains of mice fed the lipophilic iron compound (3,5,5-trimethylhexanoyl) (TMH)-ferrocene.