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Journal of Cardiovascular Pharmacology Dec 2017Clopidogrel is one of the most frequently prescribed drugs worldwide; however, the presence of clopidogrel resistance and high susceptibility to genetic variations and... (Review)
Review
Clopidogrel is one of the most frequently prescribed drugs worldwide; however, the presence of clopidogrel resistance and high susceptibility to genetic variations and drug interactions are facilitating the development of other antiplatelet drugs. To overcome clopidogrel resistance, several promising clopidogrel analogues have been developed in China, such as vicagrel (and its deuterated analogues), PLD-301, and W1. These novel chemical analogues are all characterized by much faster and more efficient bioconversion to clopidogrel thiolactone (or 2-oxo-clopidogrel, the precursor of clopidogrel active metabolite) in the intestine than clopidogrel itself through bypassing the first-step P450-mediated oxidation of clopidogrel in the liver. Of them, metabolic conversion of vicagrel and PLD-301 to 2-oxo-clopidogrel is catalyzed by intestinal carboxylesterase 2 and alkaline phosphatase, respectively. In this review article, we summarized all evidence on highly efficient bioconversion to their shared precursor of clopidogrel active metabolite and the mechanisms underlying such a pronounced improvement. These drugs in the pipeline would be promising antiplatelet drugs that could be superior to clopidogrel in future patient care.
Topics: Acute Coronary Syndrome; China; Clopidogrel; Drug Discovery; Drug Resistance; Humans; Phenylacetates; Platelet Aggregation Inhibitors; Prodrugs; Thiophenes; Ticlopidine
PubMed: 28817486
DOI: 10.1097/FJC.0000000000000529 -
Molecular and Cellular Endocrinology Dec 2017Thyroid hormones (THs) play key roles in modulating the overall metabolism of the body, protein synthesis, fat metabolism, neuronal and bone growth, and cardiovascular... (Review)
Review
Thyroid hormones (THs) play key roles in modulating the overall metabolism of the body, protein synthesis, fat metabolism, neuronal and bone growth, and cardiovascular as well as renal functions. In this review, we discuss on the thyroid hormone synthesis and activation, thyroid hormone receptors (TRs) and mechanism of action, applications of thyroid hormone analogues, particularly the compounds that are selective ligands for TRβ receptors, or enzyme inhibitors for the treatment of thyroidal disorders with a specific focus on thyroid peroxidase and iodothyronine deiodinases. We also discuss on the development of small-molecule deiodinase mimetics and their mechanism of deiodination, as these compounds have the potential to regulate the thyroid hormone levels.
Topics: Animals; Biomimetic Materials; Enzyme Inhibitors; Humans; Iodide Peroxidase; Molecular Mimicry; Organophosphonates; Phenyl Ethers; Phenylacetates; Receptors, Thyroid Hormone; Thyroxine
PubMed: 28408161
DOI: 10.1016/j.mce.2017.04.006 -
Journal of Labelled Compounds &... May 2024Fast and straightforward incorporation of radionuclides into pharmaceutically relevant molecules is one of the main barriers to preclinical and clinical tracer research....
Fast and straightforward incorporation of radionuclides into pharmaceutically relevant molecules is one of the main barriers to preclinical and clinical tracer research. Late-stage direct incorporation of cyclotron-produced [C]CO to afford carbon-11-labeled radiopharmaceuticals has the potential to provide ready-to-inject positron emission tomography agents in less than an hour. The present work describes photocatalyzed carboxylation of alkylbenzene derivatives to afford C-phenylacetic acids. Reaction conditions and scope are investigated followed by application of this methodology to the preparative radiosynthesis of [C]fenoprofen, a nonsteroidal anti-inflammatory drug.
Topics: Carbon Radioisotopes; Phenylacetates; Catalysis; Radiopharmaceuticals; Radiochemistry; Photochemical Processes; Chemistry Techniques, Synthetic
PubMed: 37941130
DOI: 10.1002/jlcr.4073 -
Molecular Genetics and Metabolism Mar 2018Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury...
PURPOSE OF STUDY
Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.
METHODS USED
Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery.
SUMMARY OF RESULTS
Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years.
CONCLUSION
Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.
Topics: Ammonia; Drug Combinations; Female; Glutamine; Humans; Hyperammonemia; Infant, Newborn; Male; Mutation; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Phenylacetates; Pregnancy; Prenatal Care; Prenatal Diagnosis; Sodium Benzoate; Treatment Outcome; Urea
PubMed: 29396029
DOI: 10.1016/j.ymgme.2018.01.004 -
American Journal of Health-system... Jul 2014Current literature on the safety and efficacy of various intermediate- and long-acting preparations of methylphenidate and dexmethylphenidate for pediatric... (Review)
Review
PURPOSE
Current literature on the safety and efficacy of various intermediate- and long-acting preparations of methylphenidate and dexmethylphenidate for pediatric attention-deficit/hyperactivity disorder (ADHD) is reviewed.
SUMMARY
The efficacy of methylphenidate in controlling ADHD symptoms is firmly established. Given the drug's relatively short half-life in pediatric patients (about 2.5 hours), a number of intermediate- and long-acting products have been developed; these extended-release methylphenidate products provide the same efficacy as immediate-release (IR) formulations, with the convenience of less frequent dosing. Intermediate-acting methylphenidate preparations have effects lasting as long as 8 hours, but peak concentrations are not attained for up to 5 hours, and many patients may require twice-daily dosing. Long-acting methylphenidate products developed to address these challenges include a controlled-release tablet and bimodal-delivery capsules containing mixtures of IR and extended-release beads (durations of effect, 8-12 hours). Options for patients with difficulty swallowing tablets or capsules include a once-daily transdermal delivery system and a once-daily liquid formulation. Dexmethylphenidate (the more pharmacologically active d-isomer of racemic methylphenidate) can provide efficacy comparable to that of IR methylphenidate at half the dose; an extended-release form of dexmethylphenidate can provide less fluctuation in peak and trough concentrations than the IR form. Methylphenidate and dexmethylphenidate products in capsule form can be opened and sprinkled on applesauce.
CONCLUSION
The various formulations of IR and intermediate- and extended-release methylphenidate and dexmethylphenidate can be useful options in satisfying patients' individual needs in the management of ADHD. All are equally efficacious in controlling ADHD symptoms.
Topics: Attention Deficit Disorder with Hyperactivity; Capsules; Central Nervous System Stimulants; Child; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Humans; Methylphenidate; Tablets
PubMed: 24973373
DOI: 10.2146/ajhp130638 -
Current Opinion in Rheumatology Mar 2015To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States. (Review)
Review
PURPOSE OF REVIEW
To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States.
RECENT FINDINGS
A new xanthine oxidase inhibitor, Topiloric (Fujiyakuhin Co., Ltd. Japan) Uriadec (Sanwa Kagaku Kenkyusho Co., Ltd. Japan), has been developed and labelled in Japan. An inhibitor of purine nucleoside phosphorylase, Ulodesine, is in development in combination with allopurinol. The rest of the medications in the pipeline for hyperuricemia are targeting renal transporters of uric acid, mainly URAT1 and OAT4, acting as uricosuric agents. Most of them, such as lesinurad and arhalofenate, are being tested in trials in combination with allopurinol and febuxostat. The most potent RDEA3170 is being tested in monotherapy, but also associated with febuxostat. Recently, medications showing dual activity, inhibiting both xanthine oxidoreductase and URAT1, have been communicated or started exploratory clinical trials. There is no report of medications targeting other transporters such as Glut9 or ABCG2.
SUMMARY
There are a number of medications in the pipeline targeting hyperuricemia, mostly uricosurics in combination with xanthine oxidase inhibitors, but some targeting both xanthine oxidoreductase and URAT1. Increasing the number of available medications will ensure proper control of hyperuricemia to target serum urate levels in the near future for most, if not all, patients with hyperuricemia.
Topics: Acetamides; Drug Design; Gout; Gout Suppressants; Humans; Hyperuricemia; Imino Furanoses; Molecular Targeted Therapy; Phenylacetates; Pyrimidinones; Thioglycolates; Triazoles; Uricosuric Agents
PubMed: 25603039
DOI: 10.1097/BOR.0000000000000146 -
Food and Chemical Toxicology : An... Jan 2022The existing information supports the use of this material as described in this safety assessment. Phenethyl phenylacetate was evaluated for genotoxicity, repeated dose...
The existing information supports the use of this material as described in this safety assessment. Phenethyl phenylacetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that phenethyl phenylacetate is not genotoxic. Data provide a calculated MOE >100 for the repeated dose toxicity endpoint. Data on read-across analog benzyl benzoate (CAS # 120-51-4) provide an MOE >100 for the developmental toxicity endpoint. The fertility and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to phenethyl phenylacetate is below the TTC (0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from analog benzyl phenylacetate (CAS # 102-16-9) show that there are no safety concerns for phenethyl phenylacetate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra; phenethyl phenylacetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; phenethyl phenylacetate was found not to be PBT as per the IFRA Environmental Standards and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.
Topics: Academies and Institutes; Acetates; Animals; Dermatitis, Photoallergic; Dermatitis, Phototoxic; Endpoint Determination; Environmental Exposure; Europe; Fertility; Humans; Mutagenicity Tests; North America; Odorants; Perfume; Phenols; Phenylacetates; Registries; Reproduction; Respiratory System; Risk Assessment; Safety; Skin; Toxicity Tests
PubMed: 34843869
DOI: 10.1016/j.fct.2021.112711 -
The Lancet. Oncology Jun 2018
Topics: Administration, Intravenous; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Evidence-Based Medicine; Glutamine; Humans; Neoplasms; Neurotoxicity Syndromes; Patient Safety; Phenylacetates; Quackery; Risk Assessment; Treatment Outcome
PubMed: 29893248
DOI: 10.1016/S1470-2045(18)30338-3 -
Bioorganic & Medicinal Chemistry Letters Feb 2022In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had...
In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had relatively high affinity for the GABA receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD = 5.2 mg/kg in rabbits), comparable duration of the loss of righting reflex (LORR), and significant shorter recovery time (time to walk) than propanidid. Furthermore, compound 10 (TI = 18.1) showed higher safety profile than propanidid (TI = 14.7) in rabbits. Above results suggested that compound 10 may have predictable and rapid recovery profile in anesthesia.
Topics: Animals; Drug Design; Guinea Pigs; Hypnotics and Sedatives; Male; Mice; Phenylacetates; Piperazines; Rabbits; Rats, Sprague-Dawley; Receptors, GABA-A; Rats
PubMed: 34896213
DOI: 10.1016/j.bmcl.2021.128497 -
Molecular Medicine Reports Dec 2018Drug‑induced liver injury (DILI) is a common hepatic disease. The identification of biomarkers for DILI prediction is critical for rational drug use. The aim of the...
Drug‑induced liver injury (DILI) is a common hepatic disease. The identification of biomarkers for DILI prediction is critical for rational drug use. The aim of the present study was to investigate liver injury caused by binaprofen and identify proteins that may serve as early biomarkers to predict DILI. For in vivo DILI assays, zebrafish were exposed to acetaminophen (APAP) and binaprofen for 12‑96 h before lethal concentration 50 (LC50), histopathological analysis, conventional and non‑conventional biomarker measurements were conducted. In vitro assays were performed in cultured liver cells; after 6‑24 h treatment with APAP and binaprofen the same measurements were conducted as aforementioned. The in vivo assays indicated that the LC50 of APAP was 5.2 mM, whereas the LC50 of binaprofen was 1.2 mM; 12‑48 h post‑treatment, liver cells exhibited mild to moderate vacuolization in a time‑ and concentration‑dependent manner in response to both drugs. During this time, conventional and non‑conventional biomarkers were also altered in a time‑ and concentration‑dependent manner; however, alterations in the levels of non‑conventional biomarkers occurred at an earlier time point compared with conventional biomarkers. The in vitro assays indicated that the half maximal inhibitory concentration (IC50) of APAP was 16.2 mM, whereas the IC50 of binaprofen was 5.3 mM; 12‑48 h post‑treatment, cultured liver cells exhibited mild to moderate swelling in a time‑ and concentration‑dependent manner. Alterations in the levels of conventional and non‑conventional biomarkers were similar to those observed in the in vivo assays. As a non‑steroidal anti‑inflammatory drug, binaprofen exhibited expected levels of liver toxicity in in vitro and in vivo assays, which were similar to APAP. Total bile acid and argininosuccinate lyase were identified as early biomarkers, which could accurately predict onset of binaprofen‑induced liver injury.
Topics: Animals; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; Immunohistochemistry; Liver Function Tests; Male; Phenylacetates; ROC Curve; Zebrafish
PubMed: 30320395
DOI: 10.3892/mmr.2018.9549