Ketonep Mechanism of Action

Pharmacological Classification: Renal Nutrition Therapy (Nutrition Therapy in chronic kidney disease).
Pharmacology: Alpha Ketoanalogue + Essential Amino Acids (Ketonep) tablet is an oral nutritional formulation, which contains all essential nutritional salts, which help in reduction of Nitrogen supply and provide calcium, used in reduction of kidney disease. It contains all amino acids essential for uremic patients, five out of them are keto or hydroxyanalogue in the form of calcium salts. Therefore, it allows reduction in the nitrogen supply and provides calcium. In combination with very low protein diet, it helps in delaying the progression of kidney disease.
Alpha ketoanalogues of valine, leucine, isoleucine, methionine, phenylalanine, and (in one instance) tryptophan, and histidine, along with the remaining essential amino acids, were administered orally to 10 patients with severe chronic uremia fed a diet low in protein but adequate in calories. Ketoacid dosage varied from 6 to 14 g daily, as sodium or calcium salts. Net nitrogen intake calculated as intake minus urinary protein nitrogen averaged 1.8 g/day. The urea space was either estimated or measured with [14C] urea and daily changes in the body urea pool were calculated. Urea appearance was measured as the sum of urea excretion and the change in urea pool. If these ketoacids were converted to amino acids and utilized for protein synthesis, a fall in urea nitrogen appearance should occur. In five subjects, ketoacids were given for 15-18 days and then withdrawn. Urea nitrogen appearance increased 1.55 g/day on withdrawing ketoacids, and corrected nitrogen balance decreased by 1.73 g/day. In two other subjects ketoacid administration was followed, on two occasions each, by a period of administration of nine essential amino acids. In three of these four instances, urea appearance rose significantly with amino acids. In four patients studied at high blood urea levels, ketoacid treatment was relatively ineffective; two of these improved enough clinically to be managed as an outpatient for short intervals, despite virtual anuria. No accumulation of ketoacids in plasma or urine could be detected, and no toxicity was identified.
Alpha-ketoanalogues of the essential amino acids might be useful in the treatment of uremia. This proposal was based on several earlier observations: (a) urea is continually degraded to ammonia and carbon dioxide by intestinal urease in normal subjects (2, 3) as well as in patients with uremia (3-7); (b) uremic patients respond favorably to restriction of dietary protein (8-10); (c) urea or ammonia can be utilized for protein synthesis (1, 11-18), particularly when dietary protein is restricted (1, 11, 12, 15, 17); and (d) alpha-ketoanalogues of most of the essential amino acids can promote growth in rats fed diets devoid of the corresponding amino acids (19-26). Thus, urea nitrogen might be reutilized for conversion of ketoacids to essential amino acids lowering blood urea concentration and promoting protein synthesis simultaneously. Because of the scarcity of these ketoacids this proposal has not been tested, but Richards and his associates (27, 28), as well as other workers (29-30), have shown that two ketoacids, the analogues of valine and phenylalanine, can replace valine or phenylalanine in the diet of normal (27, 29, 30) as well as uremic (27, 29, 30) as well as uremic (27) individuals, though not with complete efficiency. The present study was undertaken to evaluate the efficacy, safety, and feasibility of administering these ketoacids as supportive therapy in the management of severe chronic uremia. Seven potentially useful ketoanalogues are known, but because of difficulties in obtaining two of them, most of these studies were conducted using only five, the analogues of valine, leucine, isoleucine, methionine, and phenylalanine. Apparently, only two (the analogues of valine and phenylalanine) have previously been administered to human subjects.
Histidine is a heterocyclic amino acid which is essential for infant growth and which may be essential for some other groups, such as patients with uremia. Histidine and histidine hydrochloride are used as dietary supplements.
Histidine, like glycine, is sometimes used in the conjunction with antacid in the treatment of gastric hyperacidity. Threonine is an aliphatic amino acid which is an essential constituent of the diet. It is used as a dietary supplement. Threonine has been investigated for the treatment of various spastic disorders. Tryptophan is an essential amino acid which has also been used in the management of depression. It has however, been associated with an outbreak of the eosinophilia myalgia syndrome. Essential constituent of the diet, Tryptophan and DL-tryptophan have been used as dietary supplements. Tryptophan is readily absorbed from the gastro-intestinal tract. Tryptophan is extensively bound to plasma albumin. It is metabolized in the liver by tryptophan pyrrolase. Metabolites include hydroxytryptophan, which is then converted to serotonin, and kynurenine derivatives. Some tryptophan is converted to nicotinic acid and nicotinamide. Pyridoxine and ascorbic acid are cofactors in the decarboxylation and hydroxylation respectively of tryptophan and hydroxylation respectively of tryptophan; pyridoxine apparently prevents the accumulation of the kynurenine metabolites.