Pharmacokinetics, safety and tolerability of three dosage regimens of buccal adhesive testosterone tablets in healthy men suppressed with leuprorelin.

We used a randomised, double-blind, crossover design to evaluate the pharmacokinetics, safety and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to </=5.38 nmol/l with leuprorelin acetate, took BATT (10, 20 or 30 mg) daily for 10 days. There was a 4-day washout between treatments. Substantial testosterone absorption occurred from BATT, and mean serum testosterone, free testosterone and dihydrotestosterone (DHT) concentrations over 24 h showed circadian variation. Steady state was reached by day 5. Average 24-h concentrations for the three BATT doses were within the normal range for eugonadal men: testosterone 11.67-14.57 nmol/l, free testosterone 0.026-0.33 nmol/l and DHT 1.66-2.03 nmol/l. On all three doses, peak testosterone and free testosterone was reached 8-9 h after tablet application; DHT peaked about 1-2 h later, and declined more slowly. Hormone concentrations increased with BATT dose, but increases were less than dose-proportional. There was no evidence of testosterone accumulation. BATT was well tolerated

Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial

Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and health care resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE. We conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were assigned randomly to groups that received placebo or OP (10, 15, or 20 g/d, based on the severity of liver disease), plus each institution’s standard of care (eg, lactulose to achieve 2–3 bowel movements with or without rifaximin, in accordance with guidelines). The primary end point was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stages 3/4 or improvement to HEST stages 0/1 from baseline stage 2, in the intent-to-treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory). Median times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P = .129). Analyses of central laboratory–confirmed increases in levels of ammonia at baseline (n = 201) showed clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and in 29% in the placebo group (P = .552). In a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE. ClinicalTrials.gov no: NCT01966419. [Display omitted

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 similar to 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Overt hepatic encephalopathy (OHE) is characterized by severe liver impairment and signs of neurocognitive dysfunction commonly associated with hyperammonemia. Ornithine phenylacetate (OP), a potent ammonia scavenger, has an acceptable safety profile in patients with decompensated cirrhosis and gastrointestinal bleeding, and lowers plasma ammonia levels. WHAT QUESTION DID THIS STUDY ADDRESS? What are the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of OP and its metabolites in patients hospitalized due to OHE with cirrhosis and hyperammonemia? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? PK/PD analysis results are consistent with the putative mechanism of action of OP. Mean plasma levels of OP analytes reach steady state in approximately 48-72 hours, regardless of dose, and appear to increase as liver function declines. OP treatment significantly reduces plasma ammonia and improves clinical OHE stage, supporting the proposed central role of ammonia in HE. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? OP treatment may be beneficial as a first-line treatment for patients with OHE; however, additional studies are warranted

Clinical and molecular features of the hereditary mixed polyposis syndrome.

BACKGROUND and AIMS: Various inherited syndromes predispose to the development of colonic juvenile polyps and colorectal cancer, with potential importance for sporadic tumorigenesis. This study describes features of a possibly new syndrome of atypical juvenile polyps and other colonic tumors and compares these features with those of known gastrointestinal tumor syndromes. METHODS: A large family, St. Mark's family 96, with a tendency to develop colonic polyps of mixed histological types is described. Genetic linkage to known polyposis syndromes has been tested. RESULTS: Adenomatous and hyperplastic polyps occur in affected members of the family, although the characteristic lesion is an atypical juvenile polyp. Some affected individuals have developed polyps of more than one type, and individual polyps may contain features of more than one histological type. Polyps can undergo malignant change. Typically, fewer than 15 polyps are found at colonoscopy and there is no extracolonic disease associated with the development of polyps. The family's polyps seem to be inherited in an autosomal-dominant fashion, but the disease is probably unlinked to candidate loci with importance in colorectal tumorigenesis, such as APC, hMSH2, and hMLH1. CONCLUSIONS: We term this family's disease hereditary mixed polyposis syndrome (HMPS). Although mutations in the putative HMPS gene may be responsible for syndromes such as juvenile and Peutz-Jeghers polyposes, HMPS may also be a distinct disease

Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor

©2003 – 2008 Society of Petroleum EngineersM. M. Hossain and M. M. Amr