Herpesan Mechanism of Action

Pharmacology: The active ingredient present in Herpesan Gel namely Carbenoxolone Sodium is derived from glycyrrhizic acid. Carbenoxolone Sodium is steroidal in structure and steroid-like activity has been demonstrated with regard to both anti-inflammatory and mineralocorticoid activity.
Glycyrrhizic acid has significant anti-viral activity against a range of viruses including Herpes Simplex Type I, Vaccinia and Influenza Types A and B. Herpes Simplex Type I virus is irreversibly inactivated by glycyrrhizic acid.
In keeping with its steroid-like structure, Carbenoxolone Sodium has significant anti-inflammatory actions and suppresses rat paw oedema caused by formaldehyde and tuberculin. Carbenoxolone Sodium has about one third the potency of hydrocortisone in these studies. Other steroid-like activities include mineralocorticoid effects as a consequence of both direct aldosterone like activity of Carbenoxolone Sodium and its ability to potentiate endogenous aldosterone activity.
The efficacy of Carbenoxolone Sodium in ulcer healing is most likely related to increased mucous secretion with consequent cyto-protection. Peskar has demonstrated that Carbenoxolone Sodium inhibits the prostaglandin degrading enzymes 15-hydroxy-prostaglandin-dehydrogenase and delta ¹³-prostaglandin reductase.
Pharmacodynamics: Smooth muscle: Carbenoxolone does not modify the action of a variety of spasmogens active on smooth muscle including acetylcholine, nicotine, histamine, 5-hydroxytryptamine or barium and does not influence gastrointestinal motility.
Cardiovascular system: The elevation of blood pressure produced by prolonged dosage with Carbenoxolone is exerted indirectly through sodium retention associated with mineralocorticoid activity.
Pharmacokinetics: Absorption following topical application to the oral mucous membrane: In clinical use for the treatment of gastric ulcer Carbenoxolone has been used in doses up to 300 mg/day. A 5 g tube of Herpesan Gel contains 100 mg Carbenoxolone. Topical application of Herpesan Gel is likely to involve the use of about 250 mg per application equivalent to 20 mg Carbenoxolone per day. It would be expected that absorption of Carbenoxolone following topical application would be much smaller than that following oral dosing. Rinsing the mouth with 30 ml of an aqueous solution containing 0.067% Carbenoxolone three times daily for one month did not produce detectable plasma Carbenoxolone levels.
After a single 200 mg oral dose, plasma carbenoxolone levels reach 30 μg/ml. Reference is made in the documentation provided to a study in which topical application of a carbenoxolone containing gel three times daily for one month produced a plasma carbenoxolone level of 5.3 μg/ml at the end of the treatment period. However this statement is uncorroborated by an original literature reference.
Metabolism and elimination: In rats given an oral dose of ¹⁴C Carbenoxolone labelled in the succinate moiety, a substantial proportion of the label is rapidly excreted as carbon dioxide. Since it would be expected that because of its place in intermediary metabolism, free succinate would rapidly appear as exhaled carbon dioxide, this finding indicates that in the rat, carbenoxolone is readily hydrolysed at the ester linkage to succinate and glycyrrhetic acid. Such hydrolysis could not be detected after incubation of carbenoxolone with blood or with liver homogenate but carbenoxolone could be hydrolysed by incubation with rat stomach or faecal contents.
It was therefore suggested that hydrolysis can take place within the gastrointestinal tract prior to absorption and that the gut microbial flora in this species are likely to be responsible for this metabolism. In rats, triturated glycyrrhetic acid was converted by the liver to the 30-glucuronide, the 3-0-glucuronide and to the 3-0-hydrogen sulphate and these metabolites were excreted into the bile.
By contrast, in man after oral administration of ¹⁴C succinate labelled carbenoxolone, a much smaller proportion of the label (12-20%) appeared in exhaled carbon dioxide with the overwhelming majority (70-80%) appearing in the faeces. No appreciable hydrolysis was found in stomach contents even when these were buffered to pH 8. Only inconsequential amounts (0.2-1.0%) of label was excreted in the urine. It was established using TLC that the form present in faeces was carbenoxolone itself with only traces of glycyrrhetic acid detected. In human patients with T -tube drainage, one major metabolite, the 30-glucuronide was detected in bile with only traces of other metabolites including glycyrrhetic acid 3-sulphate. It is concluded that metabolism in man differs substantially from that in the rat with little hydrolysis of carbenoxolone itself within the gastrointestinal tract and with a single major glucuronide metabolite being excreted in bile and reconverted to carbenoxolone in the small intestine.