Sodium Phenylacetate

Valproic acid has been reported to induce hyperammonemia via inhibition of N-acetylglutamate, a cofactor for carbamyl phosphate synthetase. Concomitant use of valproic acid with sodium phenylacetate and sodium benzoate may exacerbate urea cycle disorders and antagonize plasma ammonia lowering effects of the ammonia detoxicant.

Some anti-infective agents (e.g., penicillin) may compete with phenylacetylglutamine and hippurate for active renal tubular secretion, affecting drug disposition.

Probenecid inhibits renal transport of organic compounds (including aminohippuric acid), and may affect renal excretion of phenylacetylglutamine and hippurate.

Sodium phenylacetate (NaPA) has been shown to synergize with retinoic acid (RA) in inducing the differentiation of human neuroblastoma cells. Our studies indicated that NaPA can impact on the RA differentiation program by upregulating nuclear retinoic acid receptor-beta (RAR beta) expression. /Investigators/ have found that NaPA does not alter the half-life of RAR beta mRNA; thus, increased stability of mRNA levels does not contribute to NaPA induction. In contrast, NaPA was able to specifically activate a reporter gene construct (delta SV beta RE-CAT) which contains a retinoic acid response element (RARE beta) that is located in the RAR beta promoter. Activation of delta SV beta RE-CAT by NaPA also occurred in neuroblastoma cells cotransfected with a nuclear retinoic acid receptor expression vector, demonstrating the independence of this activation on cellular RAR levels. Taken together, our findings suggest that induction of RAR beta by NaPA is regulated at the level of transcription and mediated through the retinoic acid response element, RARE beta. This effect may account, at least in part, for the strong synergy between NaPA and RA in promoting neuroblastoma differentiation.

For more Interactions (Complete) data for Sodium phenylacetate (6 total), please visit the HSDB record page.

IDENTIFICATION AND USE: Sodium phenylacetate is pale yellow in aqueous solution. It is used as a precursor in production of penicillin G; intermediate for producing heavy metal salts which act as fungicides. Used with sodium benzoate for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. HUMAN STUDIES: Sodium phenylacetate and sodium benzoate decrease ammonia concentrations by serving as alternatives to urea for the excretion of waste nitrogen. Phenylacetate is conjugated with glutamine in the liver and kidneys to form phenylacetylglutamine, and benzoate is conjugated with glycine to form hippuric acid; phenylacetylglutamine and hippuric acid subsequently are excreted in urine. Overdosage has been reported during sodium phenylacetate and sodium benzoate treatment. Causes of death in these patients included cardiorespiratory failure/arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1 patient), respiratory failure (1 patient), intractable hypotension and probable sepsis (1 patient), and unknown (1 patient). Additionally, other signs of intoxication may include obtundation (in the absence of hyperammonemia), hyperventilation, a severe compensated metabolic acidosis, perhaps with a respiratory component, large anion gap, hypernatremia and hyperosmolarity, progressive encephalopathy, cardiovascular collapse. Adverse effects occurring in 6% or more of patients receiving sodium phenylacetate and sodium benzoate include vomiting, hyperglycemia, hypokalemia, seizures, and mental impairment. Adverse neurotoxic effects (principally somnolence, fatigue, lightheadedness) have been reported in cancer patients receiving iv phenylacetate (250-300 mg/kg daily for 14 days, repeated at 4-week intervals). Less frequently, headache, dysgeusia, hypoacusis, disorientation, impaire

/SIGNS AND SYMPTOMS/ Overdosage has been reported during sodium phenylacetate and sodium benzoate treatment in urea cycle-deficient patients. All patients in the uncontrolled open-label study were to be treated at the same dose of sodium phenylacetate and sodium benzoate. However, some patients received more than the dose level specified in the protocol. In 16 of the 64 deaths, the patient received a known overdose of sodium phenylacetate and sodium benzoate. Causes of death in these patients included cardiorespiratory failure/arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1 patient), respiratory failure (1 patient), intractable hypotension and probable sepsis (1 patient), and unknown (1 patient). Additionally, other signs of intoxication may include obtundation (in the absence of hyperammonemia), hyperventilation, a severe compensated metabolic acidosis, perhaps with a respiratory component, large anion gap, hypernatremia and hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death.

/SIGNS AND SYMPTOMS/ Adverse effects occurring in 6% or more of patients receiving sodium phenylacetate and sodium benzoate include vomiting, hyperglycemia, hypokalemia, seizures, and mental impairment.

/SIGNS AND SYMPTOMS/ Adverse neurotoxic effects (principally somnolence, fatigue, lightheadedness) have been reported in cancer patients receiving iv phenylacetate (250-300 mg/kg daily for 14 days, repeated at 4-week intervals). Less frequently, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of existing neuropathy were reported. Acute onset of these effects (which were mainly mild) occurred upon initiation of such therapy and were reversible upon discontinuance of the drug.

/CASE REPORTS/ ... We report three patients with hyperammonaemia who received inappropriate doses of intravenous sodium benzoate and sodium phenylacetate that resulted in severe complications. Ambiguous medical prescriptions and inadequate cross-checking of drug dosage by physicians, nurses and pharmacists were the main causes of these incidents. All the patients presented with alteration in mental status, Kussmaul respiration and a partially compensated metabolic acidosis with an increased anion gap. Two patients developed cerebral oedema and hypotension and died. The third survived after haemodialysis. Plasma levels of benzoate and phenylacetate were excessively high. The possible mechanisms of toxicity, management and safety measures are discussed.

For more Human Toxicity Excerpts (Complete) data for Sodium phenylacetate (8 total), please visit the HSDB record page.

Sodium phenylacetate's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC). Sodium phenylacete (Phenylacetic acid, its esters, and its salts) is on the US DEA (Drug Enforcement Administration) list of surveillance chemicals used in clandestine drug manufacture(2).

/ALTERNATIVE and IN VITRO TESTS/ Multiform glioblastomas represent the most aggressive brain tumors. Here, the cooperative effects of sodium phenylacetate (NaPa) and/or tamoxifen (TAM) on CNS1 and 9L glioblastoma cell lines in vitro and in an experimental animal tumor model were investigated. The drug effects on cell cycle and apoptosis were investigated by flow cytometry. CNS1 cells were implanted subcutaneously in nude mice to form tumors which were then treated with NaPa, TAM or NaPa/TAM. A significant inhibitory effect of NaPa on the two glioma cell lines (LD50 of 10 mM) was observed. 10(-5) M of TAM inhibited approximately 35% of 9L cell growth, and 90% of CNS1 cell growth. When a combination of both drugs included 10(-9) M of TAM, inhibition of about 50% of 9L cell growth and 75% of CNS1 cell growth occurred. The NaPa/TAM combined treatment increased the number of G0/G1 arrested cells and apoptotic cells as compared to treatments with NaPa or TAM alone. Inhibition of CNS1 tumor growth were observed after a two week treatment with NaPa (32 mg/kg/day) or TAM (6 mg/kg/day). These results showed a synergistic effect between these two drugs on tumor cell proliferation, caused by cell cycle arrest in the G0/G1 phase and by induction of apoptosis.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Organic acids and related compounds/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist respirations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Activated charcoal is not effective ... . Do not attempt to neutralize, because of exothermic reaction. Cover skin burns with dry, sterile dressings after decontamination ... . /Organic acids and related compounds/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Early intubation, at the first sign of upper airway obstruction, may be necessary. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary. Start IV administration of D5W TKO. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Organic acids and related compounds/

LD50 Mouse ip 2710 mg/kg

LD50 Mouse iv 1500 mg/kg

Chemical: Benzeneacetic acid, sodium salt

Status: Cease Manufacture Update: 14-09-2017 https://echa.europa.eu/registration-dossier/-/registered-dossier/20502

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sodium phenylacetate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Phenylacetic acid, its esters and its salts (DEA Code Number: 8791) is a DEA monitored importation and exportation substance /Phenylacetic acid/

Used as an intermediate for penicillin g and certain fungicides; Also used in the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle (with sodium benzoate); [HSDB]

Antimetabolites, Antineoplastic

Precursor in production of penicillin G; intermediate for producing heavy metal salts which act as fungicides.

Used with sodium benzoate for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.

MEDICATION

Sodium phenylacetate formulations: Parenteral for injection concentrate, for iv use only, 100 mg/mL (of sodium phenylacetate) and 100 mg/mL (of sodium benzoate), Ammonul 10%/10%, Ucyclyd.

Grade: 50% solution; dry salt.