Jaswant Singh Gidda

Effects of LY267108, an erythromycin analogue derivative, on lower esophageal sphincter function in the cat

BACKGROUND/AIMS Erythromycin (EM-A) and some of its analogues stimulate gastrointestinal smooth muscle contractions. Because gastroesophageal reflux disease (GERD) in humans is in part caused by a reduction in lower esophageal sphincter (LES) pressure, the aim of this study was to investigate the effect of LY267108 (an EM-A analogue with no significant antimicrobial activity) on LES function. METHODS In ketamine-anesthetized cats, LES pressure was recorded using a Dent sleeve. RESULTS In cats, LY267108 increased LES pressure, as did motilin and EM-A. Neither LY267108, EM-A, nor motilin altered LES relaxation in response to a swallow. LY267108 increased LES pressure in cats in which the basal LES pressure was lowered experimentally by perfusing the distal esophagus with HCl (0.1 N for 3 days) or following isoproterenol (3.0 micrograms/kg intravenously). In summary, LY267108 increases LES pressure in normal cats, did not affect the relaxation of the LES in response to a swallow, and increases LES pressure in animals with an experimentally induced decrease in LES pressure. CONCLUSIONS The results suggest that LY267108 may be useful in treating GERD because of its ability to increase LES pressure and thus present a barrier for gastroesophageal reflux.

Syntheses and antifungal activities of novel 3-amido bearing pseudomycin analogues.

As a result of our core SAR effort, we discovered a large number of 3-amido pseudomycin B (PSB) analogues (e.g., 4e LY448212 and 5b LY448731) that retain good in vitro and in vivo (IP) activities against Candida and Cryptococcus without inherent tail vein irritation. Several dimethylamino termini bearing 3-amides (e.g., 5b) also exhibited improved potency against Aspergillus in vitro. When evaluated in a two-week rat toxicology study, it was found that all animals receiving 4e (up to 75 mg/kg) were found to be normal. On the basis of these observations, we are convinced that it is possible to broaden the antifungal spectrum and improve the safety profile of pseudomycin analogues at the same time.

Pharmacological profile of LY301317, a potent and selective 5-HT1A agonist

LY301317 ((4r)‐(−)‐4‐(dipropylamino)‐6‐(5‐oxazolinyl)‐1,3,4,5‐tetrahydrobenz[c,d]indole) has high affinity for the 5‐HT1A receptor and weak affinity for the 5‐HT1D and histamine‐H1 receptors. No significant affinity was found for the other amine receptors studied. In rats, LY301317 produced potent in vivo effects that are characteristic of compounds with agonist activity at the 5‐HT1A receptor, such as an increase in serum corticosterone concentration, a reduction in 5‐HIAA concentration in brain tissue, induction of flat body posture and lower lip retraction (components of a serotonin syndrome), and a decrease of core body temperature. In pigeons trained to discriminate 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT) from saline, full generalization to LY301317 was observed. LY301317 increased punished responding in both the pigeon and rat conflict tests for anxiolytic activity. LY301317 reduced immobility in the rat forced swim model used to indicate potential antidepressant activity. In pigeons, LY301317 blocked emesis induced by a chemical (ditolyguanidine), by a 5‐HT3 agonist (m‐(chlorophenyl)‐biguanide), and by an oncolytic agent (cisplatin), as well as vomiting induced by conditioning to environmental stimuli (a model of anticipatory nausea and vomiting). In addition, LY301317 blocked cisplatin‐ and ipecac‐induced vomiting in the dog and motion‐induced emesis in the cat. It was concluded that LY301317 is an orally active, potent, and selective agonist for the 5‐HT1A receptor with potential clinical utility as an anxiolytic, an antidepressant, and a broad‐spectrum antiemetic. Drug Dev. Res. 40:17–34, 1997.

Effect of Zatosetron on Ipecac‐Induced Emesis in Dogs and Healthy Men

Serotonin receptor (5‐HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5‐HT3 receptor antagonists also have antiemetic activity in ipecac‐induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5‐HT3 receptor antagonist, on ipecac‐induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5‐hydroxyindoleacetic acid (5‐HIAA) excretion in healthy men. In separate randomized, placebo‐controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac‐induced emesis in both groups. In dogs, zatosetron inhibited ipecac‐induced emesis in a dose‐dependent manner with a 100‐μg/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5‐HIAA/creatinine ratio (mg/g) or 5‐HIAA excretion rate (μg/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac‐induced emesis in healthy men, as has been shown previously with other 5‐HT3 receptor antagonists in chemotherapy‐induced emesis in cancer patients. We did not observe the increase of urinary 5‐HIAA in our study with ipecac‐induced emesis, however, as has been described previously in cisplatin‐induced emesis. Our study indicates that ipecac‐induced emesis may be a useful model for testing 5‐HT3 receptor antagonists for antiemetic activity in dogs and healthy men.