RESUMO
Work on the pharmacological effects of high-dose metoclopramide led Beecham scientists to identify the role of 5-HT3 receptors in the emetic response to cytostatic drugs and X-irradiation in animals. Further studies have confirmed and extended knowledge of the novel 5-HT3 antagonist granisetron. Dose-dependent inhibition of the 5-HT-induced Bezold-Jarisch reflex in anaesthetized rats was shown by doses of 0.1-10 micrograms/kg i.v. granisetron. Radioligand binding studies in rat brain revealed a high affinity (Ki 0.26 nM) for 5-HT3 sites and much lower affinities (Ki 1000 - greater than 10,000 nM) for 5-HT1, 5-HT2, 5-HT1A, 5-HT1B/C, 5-HT1C, alpha 1, alpha 2, dopamine D2, benzodiazepine, picrotoxin, beta, histamine H1 or opioid mu, kappa or delta binding sites. Granisetron was effective prophylactically after oral or i.v. doses or by intervention after i.v. doses (0.005-0.5 mg/kg) against cisplatin, cyclophosphamide and doxorubicin or X-irradiation-induced emesis in the conscious ferret in the absence of any side effects. It was concluded therefore, that granisetron is a selective and potent anti-emetic worthy of clinical investigation.
Assuntos
Antineoplásicos/efeitos adversos , Receptores de Serotonina/efeitos dos fármacos , Vômito/induzido quimicamente , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Furões , Granisetron , Frequência Cardíaca/efeitos dos fármacos , Indazóis/metabolismo , Indazóis/uso terapêutico , Masculino , Ensaio Radioligante , Ratos , Ratos Endogâmicos , Antagonistas da Serotonina/uso terapêuticoRESUMO
A number of 5-HT3 receptor antagonists are currently in clinical development as antiemetics. In this paper we focus on two of these antagonists, granisetron and ondansetron, and compare their antimetic activity against cisplatin (10 mg/kg i.v.)- or whole body X-irradiation (200 rads)-induced emesis in the conscious ferret. The results presented here have been discussed in the light of the recently published literature. Our data suggest that in comparison to ondansetron, granisetron is a more potent, longer acting and pharmacologically "cleaner" compound with a more conventional dose-response profile. The possible impact of these features upon the performance of these compounds in the clinic is discussed particularly with respect to dosing regimens and clinical efficacy. Differences appear to be emerging between granisetron and ondansetron in both these respects, although a direct head-to-head clinical comparison has yet to be carried out. This would involve studies monitoring a sufficiently high number of patients receiving severely emetogenic regimes to allow real clinical differences to be detected with the appropriate statistical power.
Assuntos
Antieméticos/uso terapêutico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Antagonistas da Serotonina , Vômito/prevenção & controle , Animais , Cisplatino , Relação Dose-Resposta a Droga , Furões , Granisetron , Ondansetron , Vômito/etiologia , Irradiação Corporal TotalRESUMO
The effects of indomethacin and ibuprofen on gastrointestinal mucosal integrity were studied in conventional and germ-free rats. Only ibuprofen induced significant gastric erosion formation in both conventional and germ-free animals, demonstrating that the presence of micro-organisms is not required in this form of damage. Both indomethacin and ibuprofen caused significant intestinal damage and blood loss in germ-free animals. However, in the conventional counterparts, damage due to indomethacin was enhanced whereas that induced by ibuprofen was not. The results from the present work would suggest that non-steroidal anti-inflammatory drugs such as indomethacin, which are secreted largely in the bile, unlike ibuprofen, may act in concert with bacteria and the constituents of bile to induce, in part, intestinal damage and blood loss.
Assuntos
Mucosa Gástrica/efeitos dos fármacos , Ibuprofeno/toxicidade , Indometacina/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Animais , Feminino , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Hemorragia Gastrointestinal/induzido quimicamente , Vida Livre de Germes , Enteropatias/induzido quimicamente , Enteropatias/patologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Ratos , Úlcera/induzido quimicamente , Úlcera/patologiaRESUMO
The antiemetic activity of granisetron was examined in ferrets aged 10-13 weeks. Emesis was induced by exposure to either whole-body X-irradiation (50 Gy over 10.4 min) or cyclophosphamide (80 mg/kg i.v.) plus doxorubicin (6 mg/kg i.v.). Following exposure to whole-body X-irradiation, the young ferrets vomited with a similar latency to vomit and severity of emesis to that shown by adult animals. Granisetron (0.5 mg/kg i.v.) significantly reduced (P < or = 0.05) the number of vomits and retches and two out of four animals were completely protected. Following injection of cyclophosphamide and doxorubicin, the young ferrets showed a reduced emetic response compared to adult animals. Following a dose of granisetron (0.5 mg/kg i.v.), only one out of four ferrets vomited compared to four out of four in the control group. Further experiments showed that cisplatin (12.5 mg/kg i.v.) was unable to induce vomiting in the young ferret (n = 2). Granisetron (0.5 mg/kg i.v.) was well tolerated by the young ferret and was able to reduce significantly or completely abolish emesis induced by cytostatic treatment. The data support the use of granisetron in pediatric patients and clinical trials are currently underway in this patient population.
Assuntos
Antineoplásicos/efeitos adversos , Granisetron/uso terapêutico , Vômito/induzido quimicamente , Vômito/prevenção & controle , Envelhecimento/fisiologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Furões , Masculino , Vômito/etiologia , Irradiação Corporal Total/efeitos adversosRESUMO
Intravenous infusion over 1 h of 20 mg kg(-1) of alpha-methyldopa produced hypotension in the anaesthetized dog. The magnitude of this effect was, however, inversely correlated with bodyweight. Either rapid intravenous injection of alpha-methyldopa or slow infusion of alpha-methyldopate, was less effective in lowering blood pressure than infusion of free alpha methyldopa in dogs of equivalent bodyweight. Infusion of alpha-methyldopa into a vertebral or internal carotid artery produced hypotensive responses but these were no greater and generally less than those obtained to intravenous infusion. alpha-Methyldopa was therefore capable of producing hypotension in the dog but no evidence was obtained for this being the result of an action within the brain.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Metildopa/farmacologia , Animais , Peso Corporal , Depressão Química , Cães , Feminino , Masculino , Metildopa/análogos & derivados , Fatores de TempoRESUMO
Nabumetone is a novel nonsteroidal antiinflammatory drug (NSAID) with a unique pharmacologic profile. It is nonacidic and demonstrates minimal prostaglandin synthesis inhibition. Because it is nonacidic, nabumetone cannot dissociate in the stomach after oral administration. In contrast, acidic NSAID (active cyclooxygenase inhibitors) can dissociate and concentrate by "ion trapping" in the gastric mucosa, inhibit prostaglandin synthesis and, therefore, cause topically induced erosive mucosal damage. After absorption, nabumetone is converted by first pass metabolism to the active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA), an effective inhibitor of prostaglandin synthesis. 6MNA is hepatically, not renally, cleared and differs from other NSAID because it does not undergo enterohepatic circulation in animals or man. This is thought to contribute to its apparent lack of severe gastrointestinal irritancy. The pharmacologic profile of nabumetone can be summarized in terms of the very large "therapeutic ratio" in comparison with other NSAID.
Assuntos
Butanonas/farmacologia , Administração Tópica , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Gastroenteropatias/induzido quimicamente , Humanos , Injeções Intravenosas , Mucosa Intestinal/efeitos dos fármacos , NabumetonaAssuntos
Dopamina/fisiologia , Coração/efeitos dos fármacos , Metoclopramida/farmacologia , Receptores de Droga , Animais , Pressão Sanguínea/efeitos dos fármacos , Feminino , Isoproterenol/farmacologia , Masculino , Norepinefrina/farmacologia , Fentolamina/farmacologia , Propranolol/farmacologia , Ratos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Artéria Renal/efeitos dos fármacos , Estimulação QuímicaRESUMO
Pre-clinical studies suggest that, whilst NSAIDs have similar anti-inflammatory efficacy, the potential for producing side effects varies widely between members of this class of therapeutic agents. The ways in which NSAIDs produce one of their most serious side effects, gastrointestinal damage, are outlined and consideration is given to ways of minimizing such problems.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Gastroenteropatias/induzido quimicamente , Doenças Reumáticas/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Uso de Medicamentos , Gastroenteropatias/epidemiologia , Gastroenteropatias/mortalidade , Humanos , Equivalência TerapêuticaRESUMO
Two case reports demonstrating the new complete amelioration of the toxicity of alpha-2b recombinant interferon using granisetron i.v. or p.o.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Granisetron/uso terapêutico , Interferon-alfa/efeitos adversos , Neoplasias/psicologia , Antagonistas da Serotonina/uso terapêutico , Vômito/tratamento farmacológico , Atividades Cotidianas , Adulto , Antineoplásicos/administração & dosagem , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Qualidade de Vida , Proteínas Recombinantes , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito/prevenção & controleRESUMO
Repeat oral dosing of nabumetone for 1 month maintains anti-inflammatory efficacy in a carrageenan model of paw oedema yet does not cause gastrointestinal damage. In contrast, ibuprofen or diclofenac, while also retaining anti-inflammatory activity, produced marked gastrointestinal irritancy as evidenced by mucosal damage and blood loss.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Butanonas/administração & dosagem , Diclofenaco/administração & dosagem , Gastroenteropatias/induzido quimicamente , Ibuprofeno/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Peso Corporal/efeitos dos fármacos , Butanonas/toxicidade , Carragenina , Diclofenaco/toxicidade , Edema/induzido quimicamente , Edema/fisiopatologia , Edema/prevenção & controle , Gastroenteropatias/patologia , Hemorragia Gastrointestinal/fisiopatologia , Hemorragia Gastrointestinal/prevenção & controle , Ibuprofeno/toxicidade , Masculino , Nabumetona , Ratos , Ratos EndogâmicosRESUMO
In ferrets, the highly selective 5-HT3 receptor antagonist, granisetron, abolished or reduced emesis induced by cisplatin (10 mg/kg i.v.) or whole body X-irradiation (50 Gy in 10.4 min) in a dose-dependent manner when administered by a variety of routes (intravenous, per os, subcutaneous, intramuscular). Complete protection from vomiting and retching was achieved with 0.5 mg/kg i.v. or p.o. granisetron. Granisetron (0.5 mg/kg i.v.) was also effective when given 6 h before cisplatin, completely protecting 50% of ferrets for a total of 10 h. Following repeat dosing, for either 4 days i.v. or 10 days p.o. before emetic challenge, granisetron (0.5 mg/kg) still retained its antiemetic activity on the 5th or 11th day. Prior treatment with cyclophosphamide (80 mg/kg i.v.) resulted in a significantly shorter time to the onset of vomiting after exposure to X-irradiation. Granisetron, but not saline, abolished vomiting and nausea when given as intervention after this combined emetic regimen. These results show that granisetron has potential flexibility for administration via a variety of different routes and also a long duration of action when used as an antiemetic against a wide range of cytostatic agents.
Assuntos
Granisetron/farmacologia , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Animais , Cisplatino , Relação Dose-Resposta a Droga , Feminino , Furões , Granisetron/administração & dosagem , Masculino , Náusea/induzido quimicamente , Náusea/prevenção & controle , Pré-Medicação , Vômito/induzido quimicamente , Vômito/prevenção & controle , Irradiação Corporal TotalRESUMO
OBJECTIVE: To determine the effects of nabumetone, compared with tiaprofenic acid and etodolac, on anti-inflammatory efficacy and gastrointestinal irritancy in the rat when dosed orally for one month at a high anti-inflammatory dose. METHODS: Carrageenan paw edema was used as a model of inflammation. Gastrointestinal mucosal integrity was assessed by concurrently measuring ulcer formation. mucosal and tissue prostanoid production and plasma haptoglobin. Haemoglobin, present in the cecal contents, was used as a measure of blood loss. RESULTS: Nabumetone, tiaprofenic acid and etodolac inhibited inflammation. Etodolac induced marked gastrointestinal damage and blood loss whereas tiaprofenic acid caused only gastric damage. Nabumetone was found not to alter mucosal integrity. CONCLUSION: Nabumetone proved to be an effective anti-inflammatory agent that was devoid of gastrointestinal irritancy.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Butanonas/efeitos adversos , Sistema Digestório/efeitos dos fármacos , Etodolac/efeitos adversos , Propionatos/efeitos adversos , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Peso Corporal , Butanonas/administração & dosagem , Carragenina , Ceco/química , Etodolac/administração & dosagem , Exsudatos e Transudatos/química , Hemorragia Gastrointestinal/prevenção & controle , Haptoglobinas/análise , Hemoglobinas/análise , Íleo/efeitos dos fármacos , Masculino , Nabumetona , Propionatos/administração & dosagem , Prostaglandinas/análise , Ratos , Ratos Wistar , Fatores de Tempo , Úlcera/etiologiaRESUMO
Many nonsteroidal antiinflammatory drugs have the ability to cause gastrointestinal damage in both animals and man. The aim of the present study was to compare nabumetone, a nonacidic drug, with etodolac on rat gastric mucosal damage and prostanoid synthesis, while concurrently measuring prostanoid production during edema formation in a carrageenan model of paw inflammation. The results showed that both drugs inhibited paw exudate prostaglandin E2 and edema significantly, but they did not inhibit gastric prostanoid production 4 hr after dosing. Gastric damage, however, was observed with etodolac. Additional time-course studies showed that over a 4-hr period, etodolac, unlike nabumetone, markedly inhibited gastric mucosal prostaglandin E2 production, which was associated with gastric erosion formation. Further studies demonstrated that nabumetone did not induce gastrointestinal damage or blood loss when administered to rats in a high antiinflammatory oral dose. In contrast, etodolac produced marked gastrointestinal damage and bleeding, which was evident for up to 48 hr after the dose. It is suggested that nabumetone's favorable gastrointestinal irritancy profile may relate, in part, to its nonacidic nature and to its differential effects on prostanoid production.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Butanonas/farmacologia , Dinoprostona/biossíntese , Etodolac/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , 6-Cetoprostaglandina F1 alfa/biossíntese , Animais , Ceco/química , Depressão Química , Edema/induzido quimicamente , Edema/metabolismo , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/prevenção & controle , Haptoglobinas/análise , Hemoglobinas/análise , Masculino , Nabumetona , Ratos , Ratos WistarRESUMO
We analyzed the effects of the 5-HT3 receptor antagonist granisetron on both acute and delayed phases of cisplatin-induced emesis in the conscious piglet. Animals that received a high dose of cisplatin (5.5 mg/kg i.v.) were observed continuously for 60 h. Seventeen piglets were treated with cisplatin only and acted as controls. In experimental animals, granisetron (administered before cisplatin) was administered either as a single initial injection (7 mg/kg), alone or in combination with dexamethasone (40 mg), or as multiple injections (1 mg/kg) given every 5 h during the first 30 h of the experiment (cumulative dose: 7 mg/kg). Two other groups of piglets were treated with dexamethasone (40 mg) alone or with multiple injections of ondansetron (7 injections at 3.5 mg/kg), respectively. The latency to the first emetic episode was significantly increased in all groups that received a 5-HT3 receptor antagonist, whatever the agent and the protocol of administration. Piglets treated solely with dexamethasone exhibited a latency similar to that of controls. The total number of emetic events during the 60 h was significantly reduced only in the group of piglets treated repeatedly with granisetron and in the group that received an initial dose (7 mg/kg) of granisetron in combination with dexamethasone. We observed that 3 out of 8 piglets treated repeatedly with granisetron did not vomit throughout the experiment. These results demonstrate that granisetron, when administered repeatedly, is efficacious against delayed emesis. They also suggest that serotonin may be involved in the production of the delayed phase of cisplatin-induced emesis.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Granisetron/administração & dosagem , Antagonistas da Serotonina/administração & dosagem , Vômito/prevenção & controle , Animais , Dexametasona/uso terapêutico , Feminino , Masculino , Suínos , Vômito/induzido quimicamenteRESUMO
The antiemetic effect of granisetron, a selective 5-HT3 receptor antagonist, on ouabain-induced emesis was studied using ferrets. In order to clarify the relationship between ouabain-induced emesis and serotonin (5-HT), we examined its effects on 5-HT release from the isolated ileum. Afferent vagal nerve activity was also determined. An intravenous bolus injection of ouabain (0.1-1.0 mg/kg) produced emesis in a dose-dependent manner. Ouabain-induced emesis was inhibited by pretreatment with granisetron. In the isolated ileum, ouabain induced a concentration-dependent increase of 5-HT. This release of 5-HT was suppressed by granisetron. Increases in vagal nerve discharges were observed immediately after the intravenous administration of ouabain (0.1-1.0 mg/kg). These increases were suppressed by granisetron. Taken together, ouabain activates 5-HT release from the mucosa in the gastrointestinal tract. Released 5-HT may activate the vagal afferent nerves, resulting in vomiting. Granisetron inhibited the ouabain-induced elevation of 5-HT and vagal nerve activity. Ouabain may induce emesis as well as negative chronotropic effects by activating the vagus. Our results suggest that ouabain-induced emesis is in part mediated by the 5-HT3 receptors of the peripheral gastrointestinal tract.
Assuntos
Antieméticos/uso terapêutico , Granisetron/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Vômito/prevenção & controle , Abdome/inervação , Animais , Relação Dose-Resposta a Droga , Furões , Íleo/efeitos dos fármacos , Íleo/metabolismo , Técnicas In Vitro , Masculino , Neurônios Aferentes/efeitos dos fármacos , Ouabaína/toxicidade , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina , Serotonina/metabolismo , Nervo Vago/efeitos dos fármacos , Vômito/induzido quimicamenteRESUMO
6MNA, the active metabolite of the non-acidic anti-inflammatory drug nabumetone, was investigated using intravenous administration for effects on (a) carrageenan paw oedema and gastric irritancy compared to either oral nabumetone or both oral and intravenous indomethacin when given acutely and (b) gastrointestinal irritancy when given in repeat dosing studies. An oral dose of nabumetone or intravenous 6MNA produced effective anti-inflammatory activity together with significant inhibition of paw exudate PGE2. An anti-inflammatory oral dose of nabumetone or intravenous 6MNA produced minimal effects on gastric 6-keto-PGF1 alpha production, with an absence of gastric damage, in contrast to indomethacin. In repeat dose studies, 6MNA failed to induce gastrointestinal damage even at doses where general toxicity was evident. These results show that in the rat 6MNA, the active metabolite of nabumetone, is an effective anti-inflammatory drug but, even in very high intravenous doses, does not have the propensity to induce gastrointestinal damage.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Butanonas/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Indometacina/farmacologia , Inflamação/tratamento farmacológico , Ácidos Naftalenoacéticos/farmacologia , 6-Cetoprostaglandina F1 alfa/metabolismo , Administração Oral , Animais , Butanonas/administração & dosagem , Butanonas/metabolismo , Carragenina/administração & dosagem , Carragenina/toxicidade , Dinoprostona/metabolismo , Mucosa Gástrica/metabolismo , Indometacina/administração & dosagem , Inflamação/metabolismo , Injeções Intravenosas , Nabumetona , Ácidos Naftalenoacéticos/administração & dosagem , Ratos , Ratos WistarRESUMO
6MNA, the active metabolite of the nonacidic antiinflammatory drug nabumetone, was investigated using intravenous administration for effects on (1) carrageenan paw edema and gastric irritancy compared with either oral nabumetone or both oral and intravenous indomethacin when given acutely and (2) gastrointestinal irritancy when given in repeat dosing studies. Oral doses of nabumetone or intravenous 6MNA produced effective antiinflammatory activity together with significant inhibition of paw exudate PGE2. Antiinflammatory oral doses of nabumetone or intravenous 6MNA produced minimal effects on gastric 6-keto PGF1 alpha production with an absence of gastric damage, in contrast with indomethacin. In repeat dose studies, 6MNA failed to induce gastrointestinal damage even at doses where general toxicity was evident. These results show that in the rat, 6MNA is an effective antiinflammatory drug but even in very high intravenous doses does not have the propensity to induce gastrointestinal damage.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Butanonas/farmacologia , Sistema Digestório/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Indometacina/farmacologia , Ácidos Naftalenoacéticos/farmacologia , Administração Oral , Animais , Butanonas/administração & dosagem , Carragenina , Sistema Digestório/patologia , Edema/metabolismo , Edema/prevenção & controle , Feminino , Pé , Mucosa Gástrica/metabolismo , Indometacina/administração & dosagem , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Injeções Intravenosas , Masculino , Nabumetona , Ácidos Naftalenoacéticos/administração & dosagem , Prostaglandinas/biossíntese , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
In species which vomit, elevated intestinal serotonin (5-hydroxytryptamine, 5-HT) may stimulate abdominal vagal afferent fibers, which in turn evoke the vomiting reflex. The release of 5-HT from intestinal enterochromaffin (EC) cells is regulated by polymodal mechanisms. The object of this study was to evaluate the involvement of 5-HT autoreceptors in the regulation of 5-HT release from the small intestine. Functional studies were carried out using 5-HT3 receptor agonist and antagonists, and 5-HT4 receptor agonist. Ferret and rat ileal tissue were isolated and 5-HT released into the bathing solution was determined using HPLC with an electrochemical detector (ECD). We previously reported that cisplatin produced a significant increase in cumulative 5-HT release and that ondansetron, a selective 5-HT3 receptor antagonist, did not alter the 5-HT release from the ferret ileum. In this study, a selective 5-HT3 agonist, 2-methyl-5-HT, induced a dose-dependent increase of 5-HT from the rat ileum. This release of 5-HT was significantly reduced by granisetron, a selective 5-HT3 receptor antagonist. Furthermore, a selective 5-HT4 receptor agonist, 5-methoxytryptamine induced a concentration-dependent increase of 5-HT in the rat ileum. These results suggest that both 5-HT3 and 5-HT4 receptors may be involved in intestinal 5-HT release.