No abstract

Detrusor specimens were obtained from 5 patients affected by interstitial cystitis (IC) and 5 patients with bladder carcinoma (controls). Muscle strips were prepared for in vitro pharmacological studies. In all detrusor strips taken from IC patients, an important portion of the electrically-induced contraction was atropine-resistant. In contrast, atropine-resistance was never observed in control detrusors. H1 and H2 antagonists did not affect noncholinergic contractile response which, conversely, was abolished following desensitization to alpha, beta methylene ATP (APCPP). Detrusor muscle from patients affected by IC exhibited an increase in sensitivity to APCPP and a decrease in sensitivity to acetylcholine with respect to control detrusor. Taken together these results are consistent with the presence of a purinergic neurotransmission in parasympathetic nerve terminals of the urinary bladder affected by IC, probably as a consequence of alterations in the innervation and/or electrical coupling between smooth muscle cells. The sensitivity of IC detrusor muscle to histamine was much lower than that of control detrusor, suggesting a desensitization of histamine receptors present in the bladder wall of IC patients.

BackgroundAnamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM.MethodsFluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response.ResultsANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs.ConclusionANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.

Background Constipation and L-dopa-induced gastric dysmotility are common gastrointestinal (GI) symptoms in Parkinson’s disease (PD). We investigate the novel ghrelin agonist, HM01 influence on GI motor dysfunctions in 6-hydroxydopamine (6-OHDA) rats. Methods HM01 pharmacological profiles were determined in vitro and in vivo in rats. We assessed changes in fecal output and water content, and gastric emptying (GE) in 6-OHDA rats treated or not with orogastric (og) HM01 and L-dopa/carbidopa (LD/CD, 20/2 mg kg−1). Fos immunoreactivity (ir) cells in specific brain and lumbosacral spinal cord were quantified. Key results HM01 displayed a high binding affinity to ghrelin receptor (Ki: 1.42 ± 0.36 nM), 4.3±1.0 h half-life and high brain/plasma ratio. 6-OHDA rats had reduced daily fecal output (22%) and water intake (23%) compared to controls. HM01 (3 and 10 mg kg−1) similarly reversed the decreased 4-h fecal weight and water content in 6-OHDA rats. Basal GE was not modified in 6-OHDA rats, however, LD/CD (once or daily for 8 days) delayed GE in 6-OHDA and control rats that was prevented by HM01 (3 mg kg−1 acute or daily before LD/CD). HM01 increased Fos-ir cell number in the area postrema, arcuate nucleus, nucleus tractus solitarius and lumbosacral intermediolateral column of 6-OHDA rats where 6-OHDA had a lowering effect compared to controls. Conclusions & Inferences 6-OHDA rats display constipation- and adipsia-like features of PD and L-dopa-inhibited GE. The new orally active ghrelin agonist, HM01 crosses the blood brain barrier and alleviates these alterations suggesting a potential benefit for PD with GI disorders.

Palonosetron is the only 5-HT 3 receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT 3 receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT 3 crosstalk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dosedependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT 3 receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.