-
British Medical Journal (Clinical... May 1982
Topics: Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Diclofenac; Hepatitis; Humans; Male; Middle Aged; Phenylacetates
PubMed: 6805622
DOI: 10.1136/bmj.284.6329.1605 -
Annals of Hepatology 2014A limited number of medications are typically considered for the management of hepatic encephalopathy occurring as a complication of transjugular intrahepatic... (Review)
Review
A limited number of medications are typically considered for the management of hepatic encephalopathy occurring as a complication of transjugular intrahepatic portosystemic shunt (TIPS) placement. Multiple alternative compounds aimed at disrupting ammoniagenesis are or will soon be available, though their use tends to be limited by a lack of large data sets and of clinical awareness. In this review, we provide a targeted overview of the mechanisms and availability of five anti-ammoniagenic compounds (sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate, L-ornithine L-aspartate, and ornithine phenylacetate) identified as possibly useful alternative therapeutic agents for cirrhotic encephalopathy. Three of these medications have been FDA approved for use in congenital urea cycle disorders only, while two are under active investigation for use in cirrhotic patients. In spite of limitations posed by cost and comorbidities, familiarity with these options may prove beneficial in cases refractory to conventional management.
Topics: Ammonia; Benzoates; Comorbidity; Health Care Costs; Hepatic Encephalopathy; Humans; Hypertension, Portal; Phenylacetates; Phenylbutyrates; Portasystemic Shunt, Transjugular Intrahepatic; Treatment Outcome
PubMed: 24552859
DOI: No ID Found -
Expert Opinion on Therapeutic Targets Feb 2011Nuclear receptor 4A1(NR4A1) (testicular receptor 3 (TR3), nuclear hormone receptor (Nur)77) is a member of the nuclear receptor superfamily of transcription factors and... (Review)
Review
INTRODUCTION
Nuclear receptor 4A1(NR4A1) (testicular receptor 3 (TR3), nuclear hormone receptor (Nur)77) is a member of the nuclear receptor superfamily of transcription factors and is highly expressed in multiple tumor types. RNA interference studies indicate that NR4A1 exhibits growth-promoting, angiogenic and prosurvival activity in most cancers.
AREAS COVERED
Studies on several apoptosis-inducing agents that activate nuclear export of NR4A1, which subsequently forms a mitochondrial NR4A1-bcl-2 complex that induces the intrinsic pathway for apoptosis are discussed. Cytosporone B and related compounds that induce NR4A1-dependent apoptosis in cancer cells through both modulation of nuclear NR4A1 and nuclear export are discussed. A relatively new class of diindolylmethane analogs (C-DIMs) including 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH(3)) (NR4A1 activator) and 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) (NR4A1 deactivator) are discussed in more detail. These anticancer drugs (C-DIMs) act strictly through nuclear NR4A1 and induce apoptosis in cancer cells and tumors.
EXPERT OPINION
It is clear that NR4A1 plays an important pro-oncogenic role in cancer cells and tumors, and there is increasing evidence that this receptor can be targeted by anticancer drugs that induce cell death via NR4A1-dependent and -independent pathways. Since many of these compounds exhibit relatively low toxicity, they represent an important class of mechanism-based anticancer drugs with excellent potential for clinical applications.
Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Nucleus; Humans; Indoles; Mice; Molecular Targeted Therapy; Neoplasms; Nuclear Receptor Subfamily 4, Group A, Member 1; Phenols; Phenylacetates; RNA Interference
PubMed: 21204731
DOI: 10.1517/14728222.2011.547481 -
British Journal of Clinical Pharmacology 19801. The pharmacological effects of the centrally acting antihypertensive drug guanfacine are reviewed. 2. The drug lowers systemic blood pressure in hypertensive rats...
1. The pharmacological effects of the centrally acting antihypertensive drug guanfacine are reviewed. 2. The drug lowers systemic blood pressure in hypertensive rats dose-dependently after oral application of 0.3-5 mg/kg. 3. Evidence is presented that guanfacine produces its antihypertensive action by a specific stimulation of central alpha-adrenoceptors. 4. Certain pharmacological differences between clonidine and guanfacine are discussed.
Topics: Animals; Antihypertensive Agents; Blood Pressure; Cats; Clonidine; Dogs; Dopamine; Dose-Response Relationship, Drug; Guanfacine; Guanidines; Heart Rate; Hypnotics and Sedatives; Phenylacetates; Rabbits; Rats; Receptors, Adrenergic, alpha; Sympathetic Nervous System
PubMed: 6249333
DOI: 10.1111/j.1365-2125.1980.tb04900.x -
Clinical Pharmacokinetics Apr 2022L-Ornithine phenylacetate is an intravenous formulation of the L-ornithine salt of phenylacetic acid under development for the treatment of hepatic encephalopathy. Very...
BACKGROUND AND OBJECTIVE
L-Ornithine phenylacetate is an intravenous formulation of the L-ornithine salt of phenylacetic acid under development for the treatment of hepatic encephalopathy. Very limited clinical data in patients are available, with a phase II study in target patients not designed for dose finding, to support phase III dose selection in a global development program. The objective of the present population pharmacokinetic modeling and simulation was to evaluate dose selection for target patient populations with a low body weight, ethnicity, and hepatic impairment in a global clinical study.
METHODS
A population pharmacokinetic model was developed based on plasma concentrations of L-ornithine, phenylacetic acid, and phenylacetylglutamine data from four clinical trials in healthy subjects and patients with stable cirrhosis or hospitalized adult patients with liver cirrhosis and hepatic encephalopathy. A covariate analysis was conducted to identify source of variability to support dose selection for global clinical development of L-ornithine phenylacetate. Phenylacetylglutamine formation in the pharmacokinetic model also quantified pharmacodynamic effects measured by ammonia removal.
RESULTS
Body weight and hepatic function were significant covariates determining phenylacetic acid exposure. After accounting for body weight, there was no difference between tested Caucasian and Asian populations in phenylacetic acid exposure. Renal dysfunction significantly reduced phenylacetylglutamine excretion. However, renal impairment had no impact on plasma phenylacetic acid and free ammonia levels. Exploratory modeling suggested that L-ornithine might enhance the removal of ammonia.
CONCLUSIONS
With a flat dosing algorithm, special consideration must be given to patients with a small body size (i.e., body weight ≤ 50 kg) and severe hepatic impairment.
Topics: Adult; Ammonia; Clinical Trials as Topic; Hepatic Encephalopathy; Humans; Ornithine; Phenylacetates
PubMed: 34786649
DOI: 10.1007/s40262-021-01075-1 -
British Journal of Clinical Pharmacology 1980The fate of guanfacine has been investigated extensively in animals. Pharmacokinetics and metabolism of [C]-guanfacine were studied in fourteen subjects given 3 mg... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
The fate of guanfacine has been investigated extensively in animals. Pharmacokinetics and metabolism of [C]-guanfacine were studied in fourteen subjects given 3 mg orally (seven subjects) and 2.3 mg intravenously. Plasma levels and urinary excretion of radioactivity were measured by liquid scintillation counting. Parent drug was determined by gas chromatography-mass spectrometry. The analytical results were submitted to pharmacokinetic evaluation using the SAAM 26 programme. Metabolites in urine were identified by high pressure liquid chromatography. Guanfacine was rapidly and completely absorbed. Its absolute bioavailability was close to 100%, no evidence of any first-pass effect being found. Its distribution was characterized by low blood levels, low plasma protein binding and a relatively high affinity to the tissues ( of 300 l). The elimination half-life of the β-phase was 17 hours. The major route of excretion (80% of the dose) was in the urine. About 1/3 to 1/4 of the total clearance of 11 l/h was renal. The principal metabolite was the 3-hydroxy-derivative of guanfacine conjugated as either -glucuronide or -sulphate. The important fraction (30%) of parent drug found in the urine demonstrates a rather moderate biotransformation of guanfacine in man. The results of an additional study after multiple dosing showed that the measured steady-state plasma levels were in agreement with the values predicted from a single dose experiment and proportional to the daily dosage.
Topics: Adult; Aged; Animals; Antihypertensive Agents; Biotransformation; Dogs; Guanfacine; Guanidines; Humans; Kinetics; Male; Metabolic Clearance Rate; Phenylacetates; Protein Binding; Rats; Time Factors; Tissue Distribution
PubMed: 6994775
DOI: 10.1111/j.1365-2125.1980.tb04901.x -
Proceedings of the National Academy of... Aug 2010Aromatic compounds constitute the second most abundant class of organic substrates and environmental pollutants, a substantial part of which (e.g., phenylalanine or...
Aromatic compounds constitute the second most abundant class of organic substrates and environmental pollutants, a substantial part of which (e.g., phenylalanine or styrene) is metabolized by bacteria via phenylacetate. Surprisingly, the bacterial catabolism of phenylalanine and phenylacetate remained an unsolved problem. Although a phenylacetate metabolic gene cluster had been identified, the underlying biochemistry remained largely unknown. Here we elucidate the catabolic pathway functioning in 16% of all bacteria whose genome has been sequenced, including Escherichia coli and Pseudomonas putida. This strategy is exceptional in several aspects. Intermediates are processed as CoA thioesters, and the aromatic ring of phenylacetyl-CoA becomes activated to a ring 1,2-epoxide by a distinct multicomponent oxygenase. The reactive nonaromatic epoxide is isomerized to a seven-member O-heterocyclic enol ether, an oxepin. This isomerization is followed by hydrolytic ring cleavage and beta-oxidation steps, leading to acetyl-CoA and succinyl-CoA. This widespread paradigm differs significantly from the established chemistry of aerobic aromatic catabolism, thus widening our view of how organisms exploit such inert substrates. It provides insight into the natural remediation of man-made environmental contaminants such as styrene. Furthermore, this pathway occurs in various pathogens, where its reactive early intermediates may contribute to virulence.
Topics: Bacteria; Biodegradation, Environmental; Escherichia coli; Genome, Bacterial; Metabolic Networks and Pathways; Multigene Family; Phenylacetates; Phenylalanine; Pseudomonas putida; Styrene
PubMed: 20660314
DOI: 10.1073/pnas.1005399107 -
Clinical Pharmacokinetics Dec 2021Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders,...
BACKGROUND
Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the L-ornithine salt of phenylacetate, is under development for hepatic encephalopathy.
OBJECTIVE
This analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program.
METHODS
Phenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child-Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis.
RESULTS
Phenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child-Pugh C than in Child-Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy.
CONCLUSIONS
Dose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population.
Topics: Ammonia; Glutamine; Humans; Phenylacetates
PubMed: 34125423
DOI: 10.1007/s40262-021-01047-5 -
The New England Journal of Medicine May 2007The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients... (Clinical Trial)
Clinical Trial
BACKGROUND
The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects.
METHODS
We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.
RESULTS
Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes.
CONCLUSIONS
Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.
Topics: Adolescent; Adult; Age Factors; Age of Onset; Amino Acid Metabolism, Inborn Errors; Ammonia; Carbamoyl-Phosphate Synthase I Deficiency Disease; Child; Child, Preschool; Citrullinemia; Female; Humans; Hyperammonemia; Infant; Infant, Newborn; Male; Ornithine Carbamoyltransferase Deficiency Disease; Phenylacetates; Sodium Benzoate; Survival Analysis; Urea
PubMed: 17538087
DOI: 10.1056/NEJMoa066596 -
PeerJ 2022T-37 can infect grapes and other fruit trees and cause root cancer. Given the pollution and damage of chemical agents to the environment, the use of biological control...
BACKGROUND
T-37 can infect grapes and other fruit trees and cause root cancer. Given the pollution and damage of chemical agents to the environment, the use of biological control has become an important area of focus. L2 is a beneficial biocontrol strain isolated and identified in the laboratory, which has a good antibacterial effect on a variety of plant pathogens. The antibacterial metabolites of L2 were separated and purified to obtain a bioactive compound phenylacetic acid (PAA).
METHODS
The potential antibacterial mechanism of PAA against T-37 strain was determined by relative conductivity, leakage of nucleic acids, proteins, and soluble total sugars, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and reactive oxygen species (ROS).
RESULTS
PAA showed good antibacterial activity against strain T-37 with IC of 0.8038 mg/mL. Our data suggested that after treatment with PAA, the relative conductivity, nucleic acid, protein, and total soluble sugar of T-37 were increased significantly compared with the chloramphenicol treatment group and the negative treatment group. The total protein synthesis of T-37 cells was inhibited, the consumption of phosphorus decreased with the increase of incubation time, and the content of ROS was significantly higher than that in the negative treatment group. Meanwhile, the activity of two key enzymes (MDH and SDH) involved in the tricarboxylic acid cycle (TCA cycle) decreased. In addition, T-37 cells were found to be damaged by scanning electron microscopy observation. Our results showed that PAA can destroy cell membrane integrity, damage cell structures, affect cell metabolism, and inhibit protein synthesis to exert an antibacterial effect.
CONCLUSIONS
We concluded that the mechanism of action of the PAA against strain T-37 might be described as PAA exerting antibacterial activity by affecting cell metabolism, inhibiting protein synthesis, and destroying cell membrane integrity and cell ultrastructure. Therefore, PAA has a promising application prospect in the prevention and treatment of root cancer disease caused by .
Topics: Agrobacterium tumefaciens; Bacillus megaterium; Reactive Oxygen Species; Solanum lycopersicum; Anti-Bacterial Agents; Phenylacetates
PubMed: 36389424
DOI: 10.7717/peerj.14304