ATC Group: A16AX Various alimentary tract and metabolism products

Anethole trithione is a bile secretion-stimulating drug that restores salivation and relieves the discomfort of dry mouth in chemotherapy-induced xerostomia. In addition, this agent has exhibited chemopreventive properties. The mechanism of action to these activities have yet to be formally elucidated.

Eliglustat is a potent and specific inhibitor of glucosylceramide synthase, and acts as a substrate reduction therapy (SRT) for GD1.

Elivaldogene autotemcel is indicated for the treatment of early cerebral adrenoleukodystrophy in patients less than 18 years of age, with an ABCD1 genetic mutation. Elivaldogene autotemcel adds functional copies of the ABCD1 cDNA into patients' HSCs through transduction of autologous CD34+ cells with Lenti-D LVV. Following successful engraftment with genetically modified cells, the expression of ALDP is expected to be life-long.

Patients with MoCD Type A have mutations in the Molybdenum Cofactor Synthesis 1 (MOCS1) gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP. Substrate replacement therapy with fosdenopterin provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulphite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulphites.

Givosiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of aminolevulinic acid synthase 1 (ALAS1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference, resulting in a reduction of induced liver ALAS1 mRNA towards normal. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), the key causal factors of attacks and other disease manifestations of AHP.

Glycerol phenylbutyrate is a nitrogen-binding medicinal product. Urea cycle disorders (UCDs) are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH3, NH4+). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Glycerol phenylbutyrate is indicated for use as adjunctive therapy for chronic management of patients with urea cycle disorders (UCDs).

Lonafarnib is a disease modifying agent that prevents farnesylation, thereby reducing the accumulation of aberrant progerin and progerin-like proteins in the cell’s inner nuclear membrane. This results in maintaining cell integrity and normal function.

Lumasiran is a double-stranded small interfering ribonucleic acid (siRNA) that reduces levels of glycolate oxidase (GO). Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. This results in reduction of urinary and plasma oxalate levels, the underlying cause of disease manifestations in patients with primary hyperoxaluria type 1 (PH1).

Migalastat is a pharmacological chaperone that is designed to selectively and reversibly bind with high affinity to the active sites of certain mutant forms of α-Gal A, the genotypes of which are referred to as amenable mutations. Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum and facilitates their proper trafficking to lysosomes.

Miglustat is an inhibitor of glucosylceramide synthase, the enzyme responsible for the first step in the synthesis of most glycolipids, and a pharmacokinetic enzyme stabiliser of cipaglucosidase alfa. Miglustat is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease and for the treatment of progressive neurological manifestations in patients with Niemann-Pick type C disease. Also, miglustat must be used in combination with cipaglucosidase alfa for long-term enzyme replacement therapy in adults with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency).

Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate.

Sapropterin is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan. The rationale for administration of sapropterin in patients with BH4-responsive PKU is to enhance the activity of the defective phenylalanine hydroxylase and thereby increase or restore the oxidative metabolism of phenylalanine. The rationale for administration of sapropterin in patients with BH4 Deficiency is to replace the deficient levels of BH4, thereby restoring the activity of phenylalanine hydroxylase.

Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine which is then excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore provides an alternate vehicle for waste nitrogen excretion.

Teduglutide is an analogue of GLP-2. The naturally occurring human glucagon-like peptide-2 (GLP-2) is a peptide secreted by L cells of the intestine which is known to increase intestinal and portal blood flow, inhibit gastric acid secretion, and decrease intestinal motility. In several nonclinical studies, teduglutide has been shown to preserve mucosal integrity by promoting repair and normal growth of the intestine through an increase of villus height and crypt depth.

Both the prodrug (telotristat ethyl) and its active metabolite (telotristat) are inhibitors of L-tryptophan hydroxylases (TPH1 and TPH2, the rate limiting steps in serotonin biosynthesis). Serotonin plays a critical role in regulating several major physiological processes, including secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-secreted in patients with carcinoid syndrome. Through inhibition of peripheral TPH1, telotristat reduces the production of serotonin, thus alleviating symptoms associated with carcinoid syndrome.

Trientine is a copper-chelating agent whose principal mechanism of action is to eliminate absorbed copper from the body by forming a stable complex that is then eliminated through urinary excretion. Trientine may also chelate copper in the intestinal tract and so inhibit copper absorption.

Uridine triacetate is an acetylated form of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation. It is indicated in patients with hereditary orotic aciduria who cannot synthesize adequate quantities of uridine due to a genetic defect in uridine nucleotide synthesis.

The active moiety in zinc acetate is zinc cation, which blocks the intestinal absorption of copper from the diet and the reabsorption of endogenously secreted copper.