Phenylbutyric acid sodium salt

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The aromatic fatty acid known as 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid is the precursor of the salt known as sodium phenylbutyrate. Because the compound’s metabolites provide an alternate route to the urea cycle, it is used in the treatment of conditions related to the urea cycle. This allows for the excretion of excess nitrogen.

Research into the use of sodium phenylbutyrate as an anti-cancer drug and in protein misfolding illnesses such as cystic fibrosis has been prompted, respectively, by the fact that sodium phenylbutyrate is both an inhibitor of histone deacetylase and a chemical chaperone.

Structure and possessed characteristics

The chemical structure of sodium phenylbutyrate consists of an aromatic ring connected to butyric acid. It is a sodium salt of an aromatic fatty acid. The sodium salt of 4-phenylbutyric acid is known by its chemical name, which is phenylbutyrate of sodium. It grows crystals that are water-soluble and off-white in color.

Medical uses

The tablet or powder form of sodium phenylbutyrate, which may be given orally or by nasogastric intubation, has a flavor that is very salty and unpleasant. It is used to treat urea cycle disorders, which are genetic diseases in which nitrogen waste builds up in the blood plasma as ammonia glutamine (a state called hyperammonemia). This occurs as a result of deficiencies in the enzymes carbamoyl phosphate synthetase I, ornithine transcarbamylase, or argininosuccinic acid synthetase. If it is not managed, it will cause mental retardation as well as an early death. Children who are born with urea cycle problems often live longer than 12 months with the help of dialysis, amino acid supplements, and a diet that limits the amount of protein they consume. Sodium phenylbutyrate metabolites enable the kidneys to eliminate excess nitrogen in lieu of urea. Patients could need ongoing care throughout the rest of their lives. In the 1990s, researchers were the ones who first developed the therapy, and the United States eventually gave its stamp of approval. In April of 1996, the Food and Drug Administration (FDA) was established.

Negative consequences

Amenorrhea and other forms of menstruation disruption may have negative effects on about one-fourth of all women. Only four percent of patients report experiencing a decrease of appetite. Three percent of patients report having an unpleasant body odor as a result of the metabolization of phenylbutyrate, and the same percentage report having an unpleasant taste. In addition to a variety of other documented side effects, gastrointestinal problems and largely moderate signs of neurotoxicity are found in less than two percent of individuals. Other adverse effects include: Because the therapy with sodium phenylbutyrate might imitate maternal phenylketonuria owing to the synthesis of phenylalanine, administration while pregnant is not indicated because it could possibly cause brain damage to the fetal developing brain.


Disorders of the urea cycle

Because of some fortuitous discoveries, Dr. Saul Brusilow, Mark Batshaw, and their colleagues at the Johns Hopkins School of Medicine in the early 1980s found that the administration of sodium phenylbutyrate led to an alternative pathway for the disposal of nitrogen. This discovery was made possible by some serendipitous discoveries. They had studied ketoacid therapy for another inborn error of metabolism, citrullinemia, in the late 1970s, and they observed that treatment with arginine led to an increase of nitrogen in the urine and a drop in ammonia in the blood. This was discovered after they had studied ketoacid therapy for citrullinemia in the late 1970s. When the researchers told Norman Radin about their discovery, he recalled reading an article in 1914 about using sodium benzoate to decrease the amount of urea that is excreted. Because sodium phenylacetate was utilized in another publication published in 1919, the researchers decided to treat five patients with hyperammonemia using benzoate and phenylacetate and then publish their findings in the journal Science. The researchers reported their findings on the use of benzoate and arginine for the treatment of urea cycle disorders in the NEJM in 1982 and 1984 respectively. Since sodium phenylbutyrate does not have the odor of phenylacetate, its use began to become more widespread in the early 1990s.

Chemical buffering agent

A point mutation in the Cystic Fibrosis Transmembrane Conductance Regulator protein, also known as F508-CFTR, is what causes the protein to be unstable and misfold in cystic fibrosis patients. As a result, the protein is unable to reach the cell membrane because it is stuck in the endoplasmic reticulum. The absence of CFTR in the cell membrane is what causes the disruption in chloride transport that is characteristic of cystic fibrosis and its associated symptoms. It is possible for sodium phenylbutyrate to perform the role of a chemical chaperone. In this capacity, it is able to stabilize the mutant CFTR in the endoplasmic reticulum and make it possible for it to reach the cell surface.

Inhibitor of the histone deacetylase enzyme

Because of its activity as an inhibitor of histone deacetylase, sodium phenylbutyrate is currently being researched for use as a potential differentiation-inducing agent in malignant glioma and acute myeloid leukemia. Additionally, sodium phenylbutyrate is being investigated for use in the treatment of certain sickle-cell disorders as an alternative to hydroxycarbamide due to the fact that it induces expression of fetal hemoglobin to replace missing adult hemoglob There has been no published evidence to far that supports the use of the substance in the clinical treatment of cancer, and it continues to be under examination on a limited scale despite the fact that small-scale research is now being conducted. An further potential therapy for Huntington’s disease is sodium phenylbutyrate, which is now the subject of research as a potential therapeutic agent.


Phenylbutyrate has been linked to extended lifespans in Drosophila studies.

Dr. Curt Freed and Wenbo Zhou of the University of Colorado demonstrated that the administration of phenylbutyrate halted the progression of Parkinson’s disease in mice. They did this by activating a gene known as DJ-1, which has the ability to prevent the death of dopaminergic neurons in the midbrain. They want to begin testing phenylbutyrate on human subjects for the treatment of Parkinson’s disease beginning in July of 2011.


The removal of nitrogen by the action of phenylbutyrate metabolites

One example of a prodrug is phenylbutyrate. In the human body, it is first converted to phenylbutyryl-CoA, and then it is metabolized by mitochondrial beta-oxidation, primarily in the liver and kidneys, to produce the active form, phenylacetate. [18] Phenylacetate then conjugates with glutamine to produce phenylacetylglutamine, which is then eliminated with the urine. Because it has the same quantity of nitrogen as urea, it may be used as an alternative to urea for getting rid of nitrogen in the body.

If Pure PBA is given orally in the form of a pill or powder weighing 5 grams, the drug may be detected in the blood within 15 minutes and reaches its maximum concentration in the circulation within an hour. Within half an hour, it is converted into phenylacetate via the metabolic process.

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