5-HT3 Receptor Blocker Research Articles

Ligand-gated ion channels opened by 5-HT in molluscan neurones.

1. 5-Hydroxytryptamine (5-HT) activated a fast (70 ms to half maximum) and desensitizing inward current through non-selective channels conducting predominantly monovalent cations in neurons of Helix aspersa. 2. alpha-Methyl-5-HT was equipotent with 5-HT in activating this current, but the known selective agonists at vertebrate 5-HT3 receptors, 2-methyl-5-HT and arylbiguanides were ineffective (< 100 microM). 5-Methoxytryptamine which is inactive on vertebrate 5-HT3 receptors was a very weak agonist. 3. The responses were antagonized by the specific vertebrate 5-HT3 receptor blocker MDL-72222 (IC50 = 1 microM), but were only weakly affected by ondansetron (10 microM). The 5-HT2-type antagonist, ketanserin (< 5 microM) had no effect. The responses were also antagonized by the non-specific antagonists (+)-tubocurarine and strychnine. 4. Unitary currents through channels non-selective for monovalent cations, and with a conductance of 2pS, could be activated repeatedly by 5-HT or alpha-methyl-5-HT in outside-out patches from neurones exhibiting the fast 5-HT-activated current (I[5-HT]fast), even in the presence of 500 microM GDP-[beta S] in the recording pipette. This strongly supports direct-gating of these channels by 5-HT. The properties of these unitary currents resembled those of I[5-HT]fast. 5. The pharmacological properties of this molluscan 5-HT-operated, ligand-gated channel differed sufficiently from known vertebrate 5-HT3-type receptors to suggest that it represents a new class of 5-HT receptor.

Prevention and treatment of postoperative nausea and vomiting with 5-HT3-receptor blockers

Since there continues to be a high incidence of postoperative nausea and vomiting associated with many types of surgery, and the standard antiemetics often do not achieve satisfactory results, there have been attempts to use the 5-HT3 antagonists. This group of substances is relatively new, but has already been used successfully as an antiemetic during chemotherapy. To date, results are on hand for four different 5-HT3 receptor blockers: ondansetron, tropisetron, granisetron and dolasetron. Applied intravenously, all four have been effective both in prophylaxis and also as therapy for postoperative emesis. Except for ondansetron, there is so far no definitely clear knowledge about the lowest possible effective dosage. The entire group is well tolerated: only occasional and minor side effects have been reported. Even though not all the hopes originally set in the 5-HT3 group of antagonists have been fulfilled, progress has nevertheless been achieved. Especially noteworthy points are a positive cost-effectiveness relationship of these drugs and their appropriate use in case of the proper indications.

Endocrine tumors of the gastrointestinal tract: systemic treatment

Neuroendocrine gut and pancreatic tumors are neoplasms that present distinct features from other malignant tumors. Firstly, in most patients, tumor growth is rather slow, and even in advanced metastatic disease, there is very little impairment of the general well-being of the individual, e.g. appetite and weight. Secondly, these tumors are known to produce specific peptide hormones which may be factors in some clinical conditions e.g. carcinoid, Zollinger-Ellison and hypoglycemic syndromes. These conditions can be critical to the patients and can occasionally be lethal. Therefore, the treatment of neuroendocrine tumors must control the clinical symptoms related to hormone over-production and prevent further tumor growth. These two features are not always in parallel. Systemic treatment of neuroendocrine tumors mainly consists of chemotherapy, interferon and somatostatin analog administration. Chemotherapy has been used for at least 30 years; the most effective combination has proved to be streptozotocin with 5-fluorouracil or adriamycin. This combination produces biochemical responses in up to 60% of patients with endocrine pancreatic tumors; the results in carcinoid patients are very poor and response rates are < or = 10%. Alpha-interferon (IFN-alpha) produces biochemical responses in approximately 50% of patients with malignant carcinoid tumors, significant reductions in tumor size in 15% and a further 39% of patients have disease stabilization with no further tumor growth. Somatostatin analogs have only been used clinically within the last 10 years, but produce symptomatic improvement in 70% of cases, biochemical responses in 40-60%, but rarely produce any significant reduction in tumor size. These analogs are particularly useful to control severe clinical symptoms and are the first-line therapy for the management of carcinoid patients both peri- and intra-operatively. Patients with endocrine pancreatic tumors, particularly those with glucagon and vasointestinal peptide-producing tumors, benefit most from this type of treatment. Recently, a combination of IFN-alpha and a somatostatin analog has showed an additive effect of these two drugs. The side effects of streptozotocin and 5-fluorouracil are mainly nausea and vomiting which can be controlled with 5-HT3 receptor blocker therapy. Another significant adverse reaction is impaired renal function. The adverse reactions to IFN-alpha are mainly flu-like symptoms, fatigue, mild impairment of liver and bone marrow function and autoimmune reactions in 15% cases. Somatostatin analog treatment causes a low frequency of adverse reactions, those which do occur include gall stone formation and steatorrhea. Future systemic treatment should be based on increased knowledge of the tumor biology, particularly growth-regulatory mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Galanin Interacts with Serotonin in Stimulating Prolactin Secretion in the Rat

Abstract The interaction of galanin (GAL) with serotonin (5-HT) in the regulation of prolactin (PAL) secretion was investigated in urethaneanesthetized male rats. Intracerebroventricular administration of 5-HT (1 and 10 mu g) and GAL (1 mu g) caused an increase in plasma PRL levels, but co-administration of GAL did not show any additive effect on 5-HT-induced PRL secretion. Pretreatment with methysergide (0.25 mg/kg), a nonselective 5-HT1 and 5-HT2 receptor antagonist, partially inhibited the PRL increase induced by GAL. On the other hand, neither ketanserin (0.25 mg/kg), a selective 5-HT2 receptor antagonist, nor ICS 205-930 (0.25 mg/kg), a selective 5-HT3 receptor blocker, had any effect on GAL-induced increase in PRL secretion. Parachlorophenylalanine (300 mg/kg), a 5-HT synthesis inhibitor, however, caused a marked enhancement of PRL release induced by GAL, which was partially inhibited by a 5-HT neurotoxin, 5, 6-dihydroxytryptamine. Parachlorophenylalanine also caused a potentiation of 5-HT-induced PRL release, possibly by sensitizing 5-HT receptors. These findings suggest that 5-HT receptors are, at least partly, involved in GAL-induced PRL release in the rat.

Development and Optimization of Mouth Dissolving Film of Granisetron using 32 Factorial Design and Response Surface Methodology

Granisetron is a highly selective serotonin (5-HT3) receptor blocker which prevents the vomiting reflex induced by serotonin during cancer chemotherapy. The objective of present research work was development and optimization of mouth dissolving film of granisetron hydrochloride. Solvent casting method was used for preparation of mouth dissolving film. Various film forming polymers like PVP K-30, PVA, maltodextrin, HPMC E5 LV and lycoat RS 720 along with and plasticizer like Propylene glycol, Poly ethylene glycol 400 and glycerin were used for selection of suitable polymer plasticizer combination. Film prepared using lycoat RS 720 and PEG-400 was found satisfactory and further factorial design and desirability function was used for optimization. Regression equation and counter plots were executed to dependent variables i.e., tensile strength, % elongation, elastic modulus and % drug release in 1 minutes to independent variables. Results of experimental design revealed that the independent factors lycoat RS 720 and PEG-400 significantly influenced the mechanical properties and % drug release from the film which was ultimately reflected in this formulation of optimized batch. All experimental design formulations were evaluated for weight variation, thickness, drug content, % moisture loss, pH, folding endurance and stability study at 40˚ ± 2˚ C/75 ± 5% RH. From the result of optimized batch it can be concluded that an optimized formulation was stable with suitable packaging and the high % drug release of film in simulated saliva indicate that it can be used for drug delivery system of granisetron hydrochloride having first pass metabolism