1. Thiorphan and acetorphan inhibit gastric secretion by a central, non-opioid mechanism in the rat
J Chariot, A Tsocas, C Rozé, M Chicau-Chovet, M Dubrasquet, J M Lecomte Eur J Pharmacol . 1988 Sep 23;154(3):247-54. doi: 10.1016/0014-2999(88)90198-7.
Thiorphan and its prodrug, acetorphan, are two inhibitors of enkephalinase (EC 3.4.24.11), a membrane-bound peptidase which plays an important role in the metabolic degradation of enkephalins. Since exogenous opioids have been reported to both stimulate and inhibit gastric secretion, the effects of thiorphan and acetorphan were studied in conscious rats equipped with chronic gastric fistulas. While i.v. thiorphan had no effect, both i.c.v. thiorphan and i.v. acetorphan potently inhibited the basal gastric acid output and the acid output stimulated by pentagastrin. Conversely, neither drug affected the histamine- or methacholine-induced stimulation of acid secretion. Neither thiorphan or acetorphan had any effect on the acid secretion stimulated by a combination of pentagastrin and acetylcholine in vagotomized rats. The results strongly suggest that both drugs inhibit gastric secretion through an effect at the level of the central nervous system, which decreases the vagal drive to the stomach. However, the effects of thiorphan and acetorphan were not prevented by naloxone. This is at variance with most of the effects of these drugs reported to date, including the inhibition of gastric secretion in cats. Furthermore, these effects were observed at doses which could inhibit other enzymes apart from enkephalinase. This suggests that the antisecretory action in rats is related to the protection of some non-opioid peptide(s) from degradation. In conclusion, both peptidase inhibitors inhibit gastric secretion of the rat through a central mechanism involving unknown, non-opioid peptide(s).
2. Functional diarrhea
Jan Tack Gastroenterol Clin North Am . 2012 Sep;41(3):629-37. doi: 10.1016/j.gtc.2012.06.007.
Chronic diarrhea is a frequent and challenging problem in clinical medicine. In a considerable subgroup of these, no underlying cause is identified and this is referred to as functional diarrhea. A consensus definition for functional diarrhea is based on loose stool consistency and chronicity and absence of coexisting irritable bowel syndrome. Underlying pathophysiology includes rapid intestinal transit, which may be worsened by stress or be triggered by a preceding infectious gastroenteritis. Diagnostic work-up aims at exclusion of underlying organic disease. Treatment starts with dietary adjustments, aiming at decreasing nutrients that enhance transit and stool and at identifying precipitating food items.
3. Angiotensin receptor-neprilysin inhibitior (thiorphan/irbesartan) decreased ischemia-reperfusion induced ventricular arrhythmias in rat; in vivo study
Amany H Hasanin, Takwa Mohammed Abdulsalam, Reham Hussein Mohamed, Ahmed El Sayed Badawy Eur J Pharmacol . 2020 Sep 5;882:173295. doi: 10.1016/j.ejphar.2020.173295.
Ventricular arrhythmias are considered as a major risk of sudden cardiac death. This study was designed to investigate the potential effects of angiotensin receptor neprilysin inhibitor; thiorphan/irbesartan (TH/IRB) combination therapy on myocardial ischemic-reperfusion (I/R)-induced arrhythmia. Fifty male Wistar rats were divided into 5 groups; (I, II): Sham, I/R both received DMSO intraperitoneally before the procedure. (III, IV, V): TH/IRB + IR (0.1/5 mg/kg, 0.1/10 mg/kg and 0.1/15 mg/kg). The drugs were injected intraperitoneally 15 min before I/R induction. Electrocardiograms changes, mean arterial blood pressure, incidence of ventricular tachycardia (VT), incidence of ventricular fibrillation (VF) and arrhythmia score were assessed. Cardiac levels of creatinine kinase-MB (CK-MB), Malondialdehyde (MDA), superoxide dismutase (SOD), endothelin-1 (ET-1), ATP content, and Na+/K+-ATPase pump activity were measured. TH (0.1 mg/kg) in combination with IRB (5, 10 and 15 mg/kg) produced significant decrease in QTc interval duration, ST height, incidence of VT and VF, duration of VT + VF, and arrhythmia score compared to I/R group. All treated groups showed significant decrease in the cardiac levels of: CK-MB, MDA and ET-1 and significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to I/R. TH/IRB + IR (0.1/10 mg/kg) group produced significant decrease in CK-MB, MDA and ET-1 and a significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to other treated groups. In conclusion, angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) decreased arrhythmia score and decreased cardiac damage. These could be explained in part by its ability to decrease oxidative stress and ET-1, increase ATP, and Na+/K+-ATPase pump activity in this rat model of I/R-induced arrhythmia.
