Photodegradation, toxicity and density functional theory study of pharmaceutical metoclopramide and its photoproducts.

Pharmaceuticals as ubiquitous organic pollutants in the aquatic environment represent substances whose knowledge of environmental fate is still limited. One such compound is metoclopramide, whose direct and indirect photolysis and toxicological assessment have been studied for the first time in this study. Experiments were performed under solar radiation, showing metoclopramide as a compound that can easily degrade in different water matrices. The effect of pH-values showed the faster degradation at pH = 7, while the highly alkaline conditions at pH = 11 slowed photolysis. The highest value of quantum yield of metoclopramide photodegradation (ϕ = 43.55·10-4) was obtained at pH = 7. Various organic and inorganic substances (NO3-, Fe(III), HA, Cl-, Br-, HCO3-, SO42-), commonly present in natural water, inhibited the degradation by absorbing light. In all experiments, kinetics followed pseudo-first-order reaction with r2 greater than 0.98. The structures of the photolytic degradation products were tentatively identified, and degradation photoproducts were proposed. The hydroxylation of the aromatic ring and the amino group's dealkylation were two major photoproduct formation mechanisms. Calculated thermochemical quantities are in agreement with the experimentally observed stability of different photoproducts. Reactive sites in metoclopramide were studied with conceptual density functional theory and regions most susceptible to •OH attack were characterized. Metoclopramide and its degradation products were neither genotoxic for bacteria Salmonella typhimurium in the SOS/umuC assay nor acutely toxic for bacteria Vibrio fischeri.

Pregnancy outcome following in-utero exposure to ondansetron: A prospective comparative observational study.

The objective of the study was to evaluate the rate of major congenital anomalies after first trimester exposure to ondansetron for nausea and vomiting of pregnancy (NVP). The design is a prospective, comparative, observational cohort study, performed at the Israeli Teratology Information Service between 2010 and 2014. Follow-up was obtained for 195 ondansetron-exposed, 110 metoclopramide-exposed, and 778 pregnancies with non-teratogenic exposure (NTE). The overall rate of major anomalies did not significantly differ between the groups [4/200 = 2.0 % (ondansetron), 1/109 = 0.9 % (metoclopramide), and 13/731 = 1.8 % (NTE)]. All the anomalies in both the ondansetron and metoclopramide groups, and 6/13 anomalies in the NTE group, were cardiac septal defects most of which spontaneously resolved. Both ondansetron (adjHR = 0.29, 95 % CI 0.10-0.80) and metoclopramide (adjHR = 0.27, 95 % CI 0.08-0.86) were associated with lower miscarriage rate compared to NTE. Based on the present study, ondansetron during pregnancy is not associated with an increased risk for overall major anomalies, nor for clinically important cardiac defects. It may be a reasonable alternative for women with severe NVP who do not respond to first line medications.

The effect of anti-emetic drugs on rat embryonic heart activity.

Nausea and vomiting of pregnancy (NVP) is the most common medical complaint during pregnancy affecting up to 70% of pregnant women worldwide. Some antiemetic medications (AEM) (droperidol, domperidone, granisetron, metoclopramide and trifluoperazine) used to treat NVP have the unwanted side effect of hERG blockade. The hERG potassium channel is essential for normal heart rhythm in both the adult human and the human and rat embryo. Animal studies show hERG blockade in the embryo causes bradycardia and arrhythmia leading to cardiovascular malformations and other birth defects. Whole rat embryo in vitro culture was used to determine the effect of the above listed AEM and meclizine on the heart rate of Gestational day 13 rat embryos. These embryos are similar in size and heart development to 5-6-week human embryo. The results showed that all of the AEMs caused a concentration-dependent bradycardia. Droperidol had the lowest margin of safety.

Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels.

BACKGROUND: Metoclopramide and domperidone are prokinetic and antiemetic substances often used in clinical practice. Although domperidone has a more favorable side effect profile and is considered the first-line agent, severe cardiac side effects were reported during the administration of both substances. Cardiac Na channels are common targets of therapeutics inducing cardiotoxicity. Therefore, the aim of this study was to investigate whether the differential cardiotoxicities of metoclopramide and domperidone correlate with the block of Na channels. METHODS: Effects of metoclopramide and domperidone on the human α-subunit Nav1.5 expressed in human embryonic kidney 293 cells and on Na currents in neonatal rat cardiomyocytes were investigated by means of whole-cell patch clamp recordings. RESULTS: Tonic block of resting Nav1.5 channels was more potent for domperidone (IC50 85 ± 25 µM; 95% confidence interval [CI], 36-134) compared with metoclopramide (IC50 458 ± 28 µM; 95% CI, 403-513). Both agents induced use-dependent block at 10 and 1 Hz, stabilized fast and slow inactivation, and delayed recovery from inactivation. However, metoclopramide induced considerably smaller effects compared with domperidone. Na currents in rat cardiomyocytes displayed tonic and use-dependent block by both substances, and in this system, domperidone (IC50 312 ± 15 µM; 95% CI, 22-602) and metoclopramide (IC50 250 ± 30 µM; 95% CI, 191-309) induced a similar degree of tonic block. CONCLUSIONS: Our data demonstrate that the clinically relevant cardiotoxicity of domperidone and metoclopramide corresponds to a rather potent and local anesthetic-like inhibition of cardiac Na channels including Nav1.5. These data suggest that Nav1.5 might be a hitherto unrecognized molecular mechanism of some cardiovascular side effects, for example, malignant arrhythmias of prokinetic and antiemetic agents.

Abortifacient effect of metoclopramide in female albino rats.

BACKGROUND: Metoclopramide a dopamine receptor antagonist is commonly used to treat nausea and vomiting. Long term use can cause parkinsonism, galactorrhoea and gynaecomastia. As it is lipid soluble, it enters the brain, easily crosses the placental barrier and can affect the fetus. Hence, the present study is designed to assess the risk of metoclopramide in pregnant albino rats. OBJECTIVES: To study the abortifacient effect of metoclopramide in pregnant albino rats. METHODS: Eighteen pregnant rats were divided into three groups of six rats each. The abortifacient activities of metoclopramide were studied in the doses of 1 mg/kg and 3 mg/kg intramuscularly. The treatments were started on the 6th day of pregnancy and continued till the 15th day. Rats were laparotomised on 19th day of pregnancy for evaluation of abortifacient action. In both the horns of the uterus, number of implantation sites, resorption sites, dead and live fetuses were observed. RESULTS: The mean percentage of aborted fetus was 17.22 +/= 21.13 33.88 +/= 37.73 after 1mg/kg and 85.21 +/=18.93 after 3mg/kg of metoclopramide. The abortifacient effect of higher dose was significantly larger compared to both control group and low dose group, but there was no significant difference between the mean percentage of abortion in control group and the low dose group of metoclopramide. CONCLUSION: Metoclopramide at 3mg/kg intra muscular has abortifacient effects in female albino rats.

Investigation of developmental toxicity and teratogenicity of antiemetics on rat embryos cultured in vitro.

In this study, we aimed to investigate and compare the direct toxic and teratogenic effects of dimenhydrinate, metoclopramide and trimethobenzamide HCl, antiemetic drugs on embryonic growth and development in cultured rat embryos. Embryos were explanted on day 9.5 of gestation and cultured. Whole rat serum was used as a culture medium for the control group while different concentrations of dimenhydrinate (2.5-20 µg/ml), metoclopramide (10-50 µg/ml) and trimethobenzamide HCl (25-100 µg/ml) were added to serum for the experimental groups. Effects of antiemetics on embryonic developmental parameters were compared, and embryos were evaluated for the presence of any malformations. Also, the total DNA was extracted from the cells to determine the fragmentation of nuclear DNA of embryonic cells. Compared with the control embryos, the antiemetics significantly decreased all growth and developmental parameters dose dependently. There was no difference regarding the fragmentation of nuclear DNA of the all used agents and controls. Amongst the agents, trimethobenzamide HCl was found to have more toxic and teratogenic potential, and metoclopramide appears to be the least toxic antiemetic and therefore could be more safely used and might be preferred for the treatment of nausea and vomiting in pregnancy.

Cell membrane lytic action of metoclopramide and its relation to tardive dyskinesia.

The long-term use of many antipsychotic medications carries a risk of tardive dyskinesia in a small proportion of patients. Although metoclopramide is an antipsychotic at high doses, this drug is more commonly used at low daily doses to accelerate stomach movement of food. Because prolonged use of metoclopramide has also been associated with tardive dyskinesia, this drug is convenient to study to examine the possible basis of tardive dyskinesia. Previous work proposed that antipsychotics accumulated in the melanin granules of the human substantia nigra, ultimately building up to high concentrations that could disrupt cell membranes of nigral neurons. While previous work demonstrated the accumulation of metoclopramide in postmortem human nigral tissue, it remained to be tested whether high concentrations of metoclopramide would actually disrupt cell membranes. Therefore, the present work examined whether metoclopramide could disrupt cell membranes, using human erythrocytes directly exposed to various concentrations of metoclopramide in vitro. It was found that metoclopramide caused disruption of the red cells starting at a threshold of 1 mM, which would result in ~280 µmoles of metoclopramide per kilogram of dry red cell membranes. However, the nonspecific adsorption of metoclopramide to human substantia nigra is ~23 µmol/kg of dry solids (measured at the clinical spinal fluid concentration of metoclopramide). Therefore, the membrane-lytic concentration of metoclopramide is only about 12 times higher than that after a single exposure of the drug to the nigral tissue. Hence, metoclopramide accumulation in the substantia nigra over a matter of months may lead to nigral neuron damage.

[Effects of metoclopramide-induced hyperprolactinemia on the murine corneal]. / Efeito da hiperprolactinemia induzida pela metoclopramida na córnea de camundongas.

PURPOSE: To evaluate the morphological changes in murine cornea upon metoclopramide-induced hyperprolactinemia during the proestrous phase or pregnancy. METHODS: Forty adult mice were divided into two groups: (control) CTR1 and (treated with metoclopramide (MET1). After fifty days, half of the mice were sacrificed. The remaining animals were mated, and then labeled as pregnant controls (CTR2). Part of these animals were treated with metoclopramide and constituted the metoclopramide-treated pregnant (MET2) group. The groups CTR2 and MET2 were sacrificed on the 6th day of pregnancy. The hormonal levels were assessed by chemioluminescence and radioimmunoassay methods and the cornea was removed for the histomorphometric study. RESULTS: The epithelial, stromal, endothelial and total thickness in the experimental group was: MET1 and MET2 were higher than one in the control group: CTR1 and CTR2. There was a significant reduction of the hormonal level in the animals that received metoclopramide as compared to controls (CTR1: estradiol = 156.6 +/- 42.2 pg/ml; progesterone = 39.4 +/- 5.1 ng/ml; prolactin = 130.4 +/- 26.2 ng/ml; MET1: estradiol = 108.0 +/- 33.1 pg/ml; progesterone = 28.0 +/- 6.4 ng/ml; prolactin = 551.5 +/- 23.3 ng/ml; CTR2: estradiol = 354.0 +/- 56.0 pg/ml; progesterone = 251.0 +/- 56.0 ng/ml; prolactin = 423.2 +/- 28.1 ng/ml; MET2: estradiol = 293.0 +/- 43.0 pg/ml; progesterone = 184.0 +/- 33.0 ng/ml; prolactin = 823.1 +/- 51.1 ng/ml). CONCLUSION: The metoclopramide-induced hyperprolactinemia may increase corneal layers, mainly in pregnant mice. Possibly, this effect is related to reduction in estrogen and progesterone production.

Efeito da hiperprolactinemia induzida pela metoclopramida na córnea de camundongas / Effects of metoclopramide-induced hyperprolactinemia on the murine corneal

OBJETIVO: Avaliar as alterações morfológicas promovidas pela hiperprolactinemia induzida pela metoclopramida na córnea de camundongas durante a fase de proestro e na gestação. MÉTODOS: Quarenta camundongas adultas foram divididas, aleatoriamente, em dois grupos, a saber: controle (CTR1) e metoclopramida (MET1). Após 50 dias metade dos animais de cada grupo foram sacrificados. O restante dos animais foi acasalado, constituindo dois grupos: controle prenhe (CTR2) e o metoclopramida prenhe (MET2), que foi sacrificado no 6° dia de gestação. Após decapitação dos animais coletou-se sangue para dosagens de estradiol, progesterona e prolactina, em seguida removidos os globos oculares para estudo histomorfométrico da córnea. RESULTADOS: As espessuras do epitélio, estroma, endotélio e a espessura total das córneas dos grupos experimentais: MET1 e MET2 mostraram-se mais espessados quando comparados com os grupos controles: CTR1 e CTR2, respectivamente. Houve redução dos níveis hormonais do estrogênio e da progesterona nos animais que receberam metoclopramida em comparação com os respectivos controles (CTR1: estradiol = 156,6±42,2 pg/ml; progesterona = 39,4±5,1 ng/ml; prolactina = 130,4±26,2 ng/ml; MET1: estradiol = 108,0±33,1 pg/ml; progesterona = 28,0±6,4 ng/ml; prolactina = 551,5± 23,3 ng/ml; CTR2: estradiol = 354,0±56,0 pg/ml; progesterona = 251,0± 56,0 ng/ml; prolactina = 423,2±28,1 ng/ml; MET2: estradiol = 293,0± 43,0 pg/ml; progesterona = 184,0±33,0 ng/ml; prolactina = 823,1±51,1 ng/ml). CONCLUSÃO: A hiperprolactinemia induzida pela metoclopramida produziu espessamento da córnea, sobretudo, em camundongas prenhes. Possivelmente este efeito está relacionado com a redução da produção hormonal de estrogênio e de progesterona.

PURPOSE: To evaluate the morphological changes in murine cornea upon metoclopramide-induced hyperprolactinemia during the proestrous phase or pregnancy. METHODS: Forty adult mice were divided into two groups: (control) CTR1 and (treated with metoclopramide (MET1). After fifty days, half of the mice were sacrificed. The remaining animals were mated, and then labeled as pregnant controls (CTR2). Part of these animals were treated with metoclopramide and constituted the metoclopramide-treated pregnant (MET2) group. The groups CTR2 and MET2 were sacrificed on the 6th day of pregnancy. The hormonal levels were assessed by chemioluminescence and radioimmunoassay methods and the cornea was removed for the histomorphometric study. RESULTS: The epithelial, stromal, endothelial and total thickness in the experimental group was: MET1 and MET2 were higher than one in the control group: CTR1 and CTR2. There was a significant reduction of the hormonal level in the animals that received metoclopramide as compared to controls (CTR1: estradiol = 156.6±42.2 pg/ml; progesterone = 39.4±5.1 ng/ml; prolactin = 130.4±26.2 ng/ml; MET1: estradiol = 108.0±33.1 pg/ml; progesterone = 28.0±6.4 ng/ml; prolactin = 551.5±23.3 ng/ml; CTR2: estradiol = 354.0±56.0 pg/ml; progesterone = 251.0±56.0 ng/ml; prolactin = 423.2±28.1 ng/ml; MET2: estradiol = 293.0±43.0 pg/ml; progesterone = 184.0±33.0 ng/ml; prolactin = 823.1±51.1 ng/ml). CONCLUSION: The metoclopramide-induced hyperprolactinemia may increase corneal layers, mainly in pregnant mice. Possibly, this effect is related to reduction in estrogen and progesterone production.

Metoclopramide-induced hyperprolactinaemia caused marked decline in pinopodes and pregnancy rates in mice.

BACKGROUND: The impact of hyperprolactinaemia on endometrial function, along with embryo implantation, has been the subject of discussion. This article examines whether experimental hyperprolactinaemia can affect mouse ovarian function, endometrial pinopodes and embryo implantation. METHODS: For pinopode analysis, 60 female mice were randomly divided into two groups: control (vehicle) and experimental [metoclopramide (MCP) 200 microg per day]. Injections were given subcutaneously for 50 days, and then, normally cycling females were housed with male mice for copulation during proestrus. The animals were killed on the fifth day following coitus when the antimesometrium portions of the uterine horns were removed for endometrial analysis. Blood was collected for prolactin (PRL) determination. In the second experiment, 60 female mice were used to evaluate the ovarian function by measuring estrogen and progesterone levels and counting luteal bodies and oocytes in the oviduct and uterus during estrus. RESULTS: The highest pregnancy rates and the largest population of pinopodes were both found in the vehicle group (P<0.01). Estrogen and progesterone levels in MCP-treated mice were lower than those in control mice (P<0.05). Also, the number of implantations was significantly lower in the MCP-treated group compared with the vehicle group after embryo transfer (P<0.001). CONCLUSION: PRL seems to have suppressive effects on ovarian function and the number of pinopodes; conceivably, hyperprolactinaemia has a negative effect on mouse embryo implantation.

Comparison of the effects of metoclopramide and domperidone on HERG channels.

Torsades de pointes (TdP) is a potentially fatal form of ventricular arrhythmia that occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings). A likely mechanism for QT prolongation and TdP is blockade of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by HERG (human ether-a-go-go-related gene). The gastroprokinetic agent cisapride is a potent blocker of HERG currents and serious cardiac arrhythmias and deaths from TdP and ventricular fibrillation have been reported in patients taking cisapride. The aim of the present study was to compare the effects of the gastroprokinetic agents domperidone and metoclopramide on HERG channels transiently expressed in human embryonic kidney (HEK 293) cells using the whole-cell configuration of the patch-clamp technique. Both domperidone and metoclopramide concentration-dependently blocked HERG currents, and the following values were calculated for IC(50) (the concentrations causing half-maximal inhibition) and n (the Hill coefficient): 57.0 nmol/l and 0.99 for domperidone, 5.4 micromol/l and 0.95 for metoclopramide. The observation that the extent of block of HERG currents by domperidone increased at more positive membrane potentials whereas block of HERG currents by metoclopramide displayed a smaller degree of voltage dependency seems to indicate that domperidone and metoclopramide have distinct binding sites on HERG channels. In conclusion, the potency for block of HERG currents is about 100-fold lower for metoclopramide when compared to domperidone.

The expression of androgen receptors in the epithelial cells of the rat prostate lateral lobe in experimental hyperprolactinaemia: a morphological and immunohistochemical study.

The effect of hyperprolactinaemia on the prostate has still not been fully elucidated. The aim of the study was to estimate the influence of hyperprolactinaemia on expression of the androgen receptor (AR) in rat epithelial cells of the prostate lateral lobe and on the morphology of these cells. Studies were performed on sexually mature male Wistar rats. To provoke hyperprolactinaemia rats received i.p. metoclopramid (MCP). For light and electron microscopy the lateral lobes were obtained routinely. The intensity of the immunohistochemical reaction of AR (expression of AR) in the epithelial cells of the prostate lateral lobe was assessed by optical density measurements with the help of computer image analysis. Ultrastructural observations of the epithelial cells of the lateral lobe were carried out by means of transmission and scanning electron microscopes. The results showed a more than twofold increase in prolactin (PRL) concentration in the serum, but a twofold decrease in testosterone (T). The intensity of the immunohistochemical reaction of AR in the epithelial cells of the lateral lobe in the experimental group was higher than in the control group. We noted changes in the morphology of the epithelial cells of the prostate lateral lobe in the experimental group.

A simple method to investigate the inhibitory effects of drugs on gastric emptying in the mouse in vivo.

INTRODUCTION: The aim was to develop a simple method to study modification of gastric motility in the mouse in vivo. METHODS: Mice were fed a hydrated diet in which the fluid content of standard laboratory chow was increased by adding water. Gastric emptying was assessed at specified times following a 1-h treatment period with orally administered pharmacological agents. RESULTS: We demonstrated consistent and progressive gastric emptying over a 4-h period, stomach content being decreased from 7.52+/-0.90 at time zero to 2.80+/-0.25 mg/g body weight after 4 h. Results demonstrated typical effects of inhibitory agents (atropine and morphine) and showed inhibitory effects of three potassium channel opening agents, pinacidil, cromakalim, and SDZ PCO400: the residue remaining in the stomach was increased by 3.66+/-0.84, 6.56+/-1.35, and 5.68+/-1.33 mg/g body weight respectively 1 h after treatment with 10 mg/kg of these agents, compared to vehicle controls. DISCUSSION: The inhibitory activity observed correlated well with previous studies on the effects of potassium channel opening agents on mouse gastrointestinal motility in vivo and in vitro. The present model may thus be of value in the pharmacological investigation of gastrointestinal motility owing to cost and convenience advantages, together with the possibility of its application to studies using transgenic animals.

Pharmacokinetics and central nervous system toxicity of declopramide (3-chloroprocainamide) in rats and mice.

Declopramide (3-chloroprocainamide) has been identified in previous studies as a representative of a new class of chemosensitizers. In this study, the toxicity and pharmacokinetics of declopramide have been investigated and compared with a structural analog, metoclopramide (MCA). Declopramide has not induced central nervous system (CNS)-related side effects in rats at doses up to 200 mg/kg, whereas MCA does at 12.5 mg/kg. In addition, declopramide did not bind to dopamine D2 receptors in subcellular preparations at doses up to 100 microM, whereas MCA showed affinity at 1 microM. Declopramide bound with affinity to 5-hydroxytryptamine3 receptors which are important in controlling vomiting. In contrast to MCA, declopramide has a rapid clearance from serum, a lower tissue concentration (about 15-fold lower than MCA) and a lower oral bioavailability (about 6-fold lower than MCA). However, declopramide was shown in vitro to possess a higher tumor cell absorption rate. One of the main metabolites of declopramide was identified as N-acetyl declopramide. Taken together, these data suggest that the clinical development of declopramide as a sensitizer of radio- and chemotherapies is an improvement over MCA, because it can be administered in a high dose and is devoid of CNS side effects.

Neutral metoclopramide sensitizes cytotoxicity induced by ionizing radiation in SCID mice xenografted with a human brain astrocytoma.

A formulation of metoclopramide (MCA) conformationally altered by neutralization of pH (nMCA, Neu-Sensamide) has been shown to have the same efficacy of enhancing the cytotoxicity of a single dose of 1 Gy radiation as acidic formulations (e.g., Primperan, Sensamide) in a human lung adenocarcinoma (H2981) xenografted into SCID mice. In the present study, 2 x 1 Gy radiation was combined with 2 x 2 mg nMCA/kg body weight injected 2 hr before radiation treatment for evaluation of radiosensitization in SCID mice xenografted with a human brain astrocytoma (T24). Given in this treatment schedule, nMCA alone at 2 mg/kg showed no cytotoxic effect on tumor growth in vivo. When combined with 2 x 1 Gy of radiation, however, the cytotoxicity was significantly increased as measured by tumor growth delay over the radiation-only-treated group. Furthermore, nMCA was absorbed into brains of mice and rats as efficiently as acidic MCA (aMCA) when analyzed 45 min after i.m. injection by high-performance liquid chromatography.

Pharmacokinetics, toxicity, side effects, receptor affinities and in vitro radiosensitizing effects of the novel metoclopramide formulations, sensamide and neu-sensamide.

Metoclopramide is a drug which has experienced worldwide use in the clinic for over 30 years as an antiemetic. Recently, it has also been shown to possess radio- and chemosensitizing properties in both animal tumour models and humans at the higher dose of 2 mg/kg. Two new metoclopramide formulations are being clinically developed and they differ mainly in whether the pH of their formulations are acidic (pH 2.5-3.5) or neutral (pH 6.5-7.0). Here we report that intramuscular administration of neutral metoclopramide is about 100% bioavailable, safer and with reduced side effects compared to acidic metoclopramide delivered by intramuscular injection to rats within the dose range of 3.5 to 14 mg/kg. The intramuscular administration of metoclopramide was also about 100% bioavailable compared to the intravenous route of administration. Furthermore, neutral metoclopramide had significantly decreased affinity for dopamine D2 receptors and increased affinity for 5-hydroxytryptamine, receptors, but the radiosensitizing potency was the same, when compared to equimolar concentrations of acidic metoclopramide. Taken together these data support the continued development of neutral metoclopramide for high dose intramuscular administration of metoclopramide for future clinical use as both an antiemetic and radiosensitizer.

Gastric motility and mucosal ulcerogenic responses induced by prokinetic drugs in rats under prostaglandin-deficient conditions.

The present study was performed to examine whether gastric prokinetic drugs may induce damage in the rat stomach under normal and prostaglandin (PG)-deficient conditions. Male SD rats fasted for 18 hr were administered subcutaneously with three different prokinetic drugs such as metoclopramide (3-60 mg/kg), ondansetron (0.3-3 mg/kg), and cisapride (3-30 mg/kg). Half the number of these animals were pretreated with indomethacin (5 mg/kg) subcutaneously for induction of PG deficiency in the stomach. Administration of these drugs increased gastric motor activity in a dose-dependent manner and expedited gastric emptying at lower doses than those affecting gastric motility; the potency of the hypermotility effect was in the following order: metoclopramide = ondansetron > cisapride. None of these drugs alone caused gross damage in the stomach, although whitish rough areas were observed in the gastric mucosa along the folds. In the rats pretreated with indomethacin, however, both metoclopramide and ondansetron provoked multiple hemorrhagic lesions in the gastric mucosa. Indomethacin at this dose showed over 90% inhibition of cyclooxygenase activity without causing any damage in the stomach, and this PG-deficient effect was not affected by coadministration with the prokinetic drugs. The mucosal ulcerogenic responses induced by metoclopramide in the presence of indomethacin were significantly inhibited by prior administration of atropine (1 mg/kg) or PGE2 (300 micrograms/kg) at doses that inhibited gastric hypermotility induced by metoclopramide. These results suggest that: (1) gastric prokinetic drugs induce damage in rat stomachs under PG-deficient conditions at the doses that enhance gastric motility and emptying but not at the doses that expedite gastric emptying only, and (2) gastric hypermotility has the potential to cause gross damage in the stomach, supporting the importance of gastric motility as a pathogenic element of gastric lesions.

Toxicity, antitumor and chemosensitizing effects of 3-chloroprocainamide.

3-Chloroprocainamide (3-CPA), an analog of metoclopramide (MCA), dose-dependently inhibited tumor growth in scid mice xenografted with a human brain astrocytoma (T24) when given intramuscularly to mice every third day for 14-20 days. 3-CPA was shown to have the same efficacy on tumor growth inhibition as neutral metoclopramide (neutral MCA) at the doses of 10-40 mg/kg when evaluated by tumor doubling time, tumor growth time for tumor volumes to reach 1000 mm3 and area under growth curve. 3-CPA at the dose of 3 x 40 mg/kg was also shown to enhance the cytotoxicity induced by a single dose of cisplatin at 7.5 mg/kg. A dose of < or = 160 mg/kg of 3-CPA did not show any notable extrapyramidal symptoms which was observed for neutral MCA treated mice at the dose of 20 mg/kg. The lethal response dose of 3-CPA for scid mice was 320 mg/kg which is 4 times higher than that determined for neutral MCA (80 mg/kg). These results support 3-CPA as a good candidate drug representing a new generation of benzamides for further clinical development as a cancer therapy drug.