An attempt to enhance solubility of metoclopramide base by Solid dispersion strategy and its application on development of Transdermal device

Chemotherapy induced nausea and vomiting (CINV) is an issue, which usually occurs in cancer patient. Despite high bioavailability of oral and intravenous administration, these have some drawbacks. The oral route causes hepatic first pass metabolism and intravenous route is invasive in nature. Hence, antiemetic drug by means of transdermal route is necessary to administer in such cases. The aim of the present investigation is to develop suitable Transdermal Therapeutic System (TTS) with an objective to enhance solubility and skin permeability properties of metoclopramide base. Preformulation study begins with an approach to enhance solubility of 40 metoclopramide base by solid dispersion technique. transdermal films were prepared with 41 the solid dispersion as well as with pure drug. Phase solubility study at various temperatures reveals binding constants (Ka, 95-350 M-1 for PVP K30; 56-81 M-1 for HPßCD). Spontaneity of solubilization was justified by AL type linear profiles. The films showed satisfactory diffusion (%), permeation rate and flux after 8 h study. The transdermal patches as prepared were analyzed under FTIR, DSC and SEM. Both solubility and permeability rate in this investigation have been enhanced. So, it can be affirmed that this route would effectively enhance bioavailability

Metoclopramida inhibe la agregación plaquetaria inducida por ADP / Metoclopramide inhibit of the platelets aggregation induced by ADP

La metoclopramida reduce la presión arterial en sujetos normotensos e hipertenso durante estímulos presores moderados a severos pretratados con Labetalol, igualmente tiene efecto hipotensor en hipertensos durante urgencia hipertensiva y en anillos de aorta de rata ha mostrado un efecto antidrenérgico alfa 1. En el presente trabajo se reporta la inhibición de la agregación plaquetaria inducida por ADP en presencia de metoclopramida, hallazgo este que puede ser de importancia clínico-terapéutica en pacientes con preeclampsia en donde coexiste hipertensión arterial y actividad proagregante plaquetaria aumentada así como también niveles plasmáticos de serotonina elevados

Analysis of neurogenic contractions induced by ML-1035 and other benzamides in the guinea-pig non-stimulated isolated ileum.

4-Amino-5-chloro-substituted benzamides have been shown to increase gastric motility in-vivo and enhance field-stimulated and peristaltic contractions in-vitro. The present experiments examined the contractile response to a series of benzamides in the guinea-pig non-stimulated ileum. Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine (% acetylcholine response = 12 +/- 2, 19 +/- 3, 26 +/- 2, 51 +/- 3, n = 13, 8, 17, and 21, with EC50 values of 0.85, 1.8, 5.7, and 14.2 microM for cisapride, zacopride, metoclopramide, and ML-1035 (4-amino-5-chloro-2-((2-methylsulphinyl)-ethoxy)-N- (2-(diethylamino)-ethyl)-benzamide hydrochloride), respectively). ML-1035 contractions were completely blocked by atropine and tetrodotoxin, while ganglionic blockade with hexamethonium was ineffective. Metoclopramide has been reported to sensitize postjunctional muscarinic receptors, however, ML-1035 did not enhance acetylcholine-induced contractions. Tropisetron (ICS 205-930, 1 microM), caused a parallel rightward shift in the concentration-response curve for both ML-1035 and zacopride (EC50 = 14.2 +/- 1.3 and 1.8 +/- 0.8 microM in the absence, and 26 +/- 2.7 and 6.9 +/- 2.3 microM in the presence of tropisetron for ML-1035 and zacopride, respectively) with apparent pKB values of 5.9 and 6.0 for the respective compounds. 5-Hydroxytryptaminergic receptor desensitization by 2-methyl-5-hydroxytryptamine (5-HT3) and 5-methoxytryptamine (5-HT4), attenuated the response to ML-1035.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurally mediated effects of metoclopramide on pigeon oesophageal muscle.

The effects induced by metoclopramide (MCP) were examined in transverse muscular strips from pigeon oesophagus. MCP (0.1 nM-10 microM) induced a concentration-dependent excitatory effect on the EMG activity, characterized mainly by an increase in the spike burst frequency. Such an excitatory effect was fully antagonized by tetrodotoxin and partially antagonized by atropine, by naloxone and by desensitization of the preparation to 5-hydroxytryptamine (5-HT). The atropine-resistant excitatory component was not modified by guanethidine. The combination of naloxone and atropine was more effective than a single antagonist in blocking the response to MCP. The combination of naloxone and 5-HT desensitization failed to further reduce the MCP-induced excitatory effect. The present results indicate that the excitatory effects of MCP are mediated via neural elements. MCP activates both cholinergic and non-cholinergic, non-adrenergic excitatory neurons. Furthermore, results suggest that serotoninergic and opioid neural pathways might be involved in the excitatory effects of MCP.

Emesis and defecations induced by the 5-hydroxytryptamine (5-HT3) receptor antagonist zacopride in the ferret.

Three antiemetic compounds (zacopride, batanopride, granisetron [BRL43694]) were evaluated for the production of gastrointestinal side effects in the conscious ferret after i.v. or p.o. administration. Zacopride evoked multiple emetic and defecatory responses at clinically relevant doses (0.003-0.3 mg/kg) and in a dose-dependent manner. The oral route was the more potent one for eliciting emesis (ED50 0.033 mg/kg). At 0.3 mg/kg p.o., zacopride reliably evoked an 80 to 100% incidence of emesis and a 40 to 80% incidence of defecation. In contrast, batanopride and BRL43694 i.v. evoked a small (10%) incidence of these side effects, but only at 0.1 to 10 mg/kg doses. When given p.o. (0.00003-10 mg/kg), these latter compounds never evoked emesis and significantly reduced (P less than .05) the incidence of defecation below that of vehicle. Responses to zacopride (0.3 mg/kg p.o.) were challenged by i.p. pretreatment with the 5-hydroxytryptamine receptor agonist 2-methyl serotonin, the 5-hydroxytryptamine receptor antagonist BRL43694, the quaternary atropine derivative glycopyrrolate, the dopamine receptor antagonist domperidone or selective abdominal vagotomies. All compounds and either bilateral or dorsal vagotomy significantly reduced the incidence of emesis, but did not abolish it. Latency to first emesis was delayed by BRL43694, domperidone or dorsal vagotomy. The data suggest that the emetic response to p.o. zacopride is mediated in part by 5-hydroxytryptamine receptors residing on either enteric neurons or vagal afferents. However, the underlying pharmacology of the response may also include activation of cholinergic and dopaminergic pathways.

Substituted benzamides. 1. Potential nondopaminergic antagonists of chemotherapy-induced nausea and emesis.

A series of new substituted benzamides has been synthesized and evaluated for dopamine antagonist activity and for antagonism of cisplatin-induced emesis in the dog and in the ferret. It was found that modification of the 2-methoxy substituent of metoclopramide was detrimental to dopaminergic D2 antagonism but not necessarily to antagonism of cisplatin-induced emesis. A number of analogues having a beta-keto, beta-hydroxy, beta-methoxy, beta-imino, or beta-unsaturated alkyloxy substituent instead of methoxy have shown equal or superior protection from emesis to that of metoclopramide. At the same time these compounds were found to be free of dopaminergic D2 antagonism in both in vitro ([3H]spiperone binding) and in vivo tests (rat catalepsy, antagonism of apomorphine-induced stereotypy in the rat, and apomorphine-induced emesis in the dog).

Analgesic effect of metoclopramide and its mechanism.

Metoclopramide produced a significant analgesic effect when tested by both acetic acid induced writhing and hot plate test. This effect was reduced by naloxone suggesting opioid involvement. Further, bromocriptine which inhibits the release of PRL attenuated the effect of metoclopramide indicating that this drug could act by releasing PRL. The unaltered analgesic effect of metoclopramide by yohimbine reveals that alpha-2 adrenoceptors may not be involved in this action.

Increased dopaminergic activity inhibits basal and metoclopramide-stimulated prolactin and thyrotropin secretion.

The influence of physiological to pharmacological doses of dopamine (DA) on basal and metoclopramide (MTC)-stimulated PRL and TSH secretion was studied in 11 regularly menstruating women between days 3 and 8 of the cycle. In groups of 6, the women received 5-h infusions of either 5% glucose or DA in a solution of 5% glucose at a rate of 12-16 ml/h, adjusted according to weight. Infusion rates of DA were 0.04 microgram/kg . min (low), 0.4 microgram/kg . min (medium), and 4.0 micrograms/kg . min (high). After 3 h of infusion, 10 mg MTC were given iv. Blood samples were collected every 15 min from 1 h before to 2 h after the infusion, for a total of 8 h, for measurements of PRL and TSH. The mean serum PRL concentrations declined significantly (P less than 0.05) during DA infusions to nadir values of 62 +/- 5% (+/- SEM; low), 43 +/- 3% (medium), and 43 +/- 6% (high) of the basal levels, whereas basal TSH levels declined significantly, to 64 +/- 5% of basal levels (P less than 0.05), during both the medium and high dose DA infusions. On paired comparisons, the hormone responses to MTC were lower (P less than 0.05) during the infusion of high dose DA (PRL, 2286 +/- 495% vs. 891 +/- 328%; TSH, 100 +/- 43% vs. 60 +/- 15%), but were not changed when MTC was given during the low and medium doses of DA. A rebound phenomenon was found for PRL (P less than 0.05) after the medium and high doses of DA and for TSH (P less than 0.05) after the high dose. These results indicate that doses of DA considered physiological inhibit PRL and TSH secretion and larger doses inhibit their responses to the DA antagonist MTC.

An analysis of the hypothalamic sites at which substituted benzamide drugs act to facilitate gastric emptying in the guinea-pig.

An analysis of the hypothalamic sites at which the substituted benzamides, metoclopramide and clebopride, act to facilitate gastric emptying was undertaken in the guinea-pig. Standard stereotaxic techniques for intracerebral injection via chronically indwelling intracerebral guides were combined with measurement of gastric emptying by fluoroscopic following of the passage of barium sulphate spheroids from the stomach. Injections were made at 7 different locations within the hypothalamus at Ant. 8.0, 8.9 and 9.6, Lat. +/- 1.0, +/- 1.6, +/- 2.2 (relative to the stereotaxic frame) and at 7.0, 8.0 and 9.0 mm below guide tips in the cortex. The most sensitive sites for gastric facilitation by the substituted benzamides were located at Ant. 8.9, Lat. +/- 1.6, Vert. -8.0, -9.0, the "perifornical area". As the distance of the injection site from the area of the fornix increased, so the facilitatory gastric action diminished, with marked delays or loss in response occurring when injection sites were moved 1 mm above, 0.6 mm lateral, 0.4 mm medial, 0.9 mm posterior or 0.7 mm anterior. The facilitatory gastric actions of metoclopramide and clebopride in the perifornical area of the hypothalamus were not mimicked by haloperidol, domperidone or sulpiride. Atropine, injected into the hypothalamus, markedly reduced gastric emptying; hexamethonium was less effective, and phentolamine, propranolol and methysergide were inactive. Atropine (but not hexamethonium, phentolamine, propranolol or methysergide), injected into the hypothalamus, dose-dependently antagonised the facilitatory gastric action of metoclopramide injected at the same site. Carbachol (but not serotonin, noradrenaline, dopamine or apomorphine), injected into the perifornical area, caused marked facilitation of gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of various pharmacological agents on the metoclopramide-induced increase in cholinergic-mediated contractions of rat isolated forestomach.

In longitudinal muscle strips of rat forestomach, metoclopramide (Mcp) increased the height of cholinergic-mediated contractions evoked by electrical field stimulation, probably by facilitating the release of neuronal acetylcholine. This response to Mcp was not prevented by drugs which blocked the synthesis of prostanoids or the actions of nicotine, morphine, noradrenaline, histamine and substance P. An involvement of dopamine in the mechanism of the response to Mcp was also excluded. Tachyphylaxis with 5-hydroxytryptamine (5HT) increased the electrically-evoked contractions and prevented the response to Mcp. Of the 5HT antagonists tested, only high concentrations of methysergide or phenylbiguanide reduced the ability of Mcp to increase the cholinergic-mediated contractions. These experiments are discussed in relation to the possibility that Mcp may increase neuronal ACh release in the gut by affecting 5HT synthesis or by acting on 5HT receptors.

Dopaminergic inhibition of metoclopramide-induced aldosterone secretion in man. Dissociation of responses to dopamine and bromocriptine.

This study was designed to investigate the role of dopaminergic mechanisms in the control of aldosterone secretion in man. Five normal male subjects in metabolic balance at 150 meq sodium/d and 60 meq potassium/d constant intake received the specific dopamine antagonist, metoclopramide, 10 mg i.v. on 2 consecutive d. On the 1st d, the subjects received an infusion of 5% glucose solution (vehicle) from 60 min before to 60 min after metoclopramide administration; on the 2nd d, an infusion of dopamine 4 mug/kg per min was substituted for vehicle. Metoclopramide in the presence of vehicle increased plasma aldosterone concentrations from 2.4+/-1.1 to a maximum of 17.2+/-2.8 ng/100 ml (P < 0.01) and serum prolactin concentrations from 7.5+/-5.0 to a maximum of 82.2+/-8.7 ng/ml (P < 0.01). Dopamine 4 mug/kg per min did not alter basal plasma aldosterone concentrations, but blunted the aldosterone responses to metoclopramide significantly; in the presence of dopamine, plasma aldosterone concentrations increased from 3.1+/-0.5 to 6.2+/-1.4 ng/100 ml (P < 0.05) in response to metoclopramide. The incremental aldosterone responses to metoclopramide were significantly lower in the presence of dopamine than with vehicle. Dopamine 4 mug/kg per min suppressed basal prolactin to <3 ng/ml and inhibited the prolactin responses to metoclopramide; serum prolactin concentrations increased to a maximum of 8.5+/-2.3 ng/ml with metoclopramide in the presence of dopamine. The subjects were studied in the same manner except that dopamine 2 mug/kg per min was administered instead of the 4-mug/kg per min dose. Dopamine 2 mug/kg per min attenuated the aldosterone and prolactin responses to metoclopramide, but was less effective than the 4-mug/kg per min dose of dopamine. Metoclopramide 10 mg i.v. was administered to five additional subjects after pretreatment with the dopamine agonist, bromocriptine, 2.5 mg or placebo at 6 p.m., midnight, and 6 a.m. before study. Bromocriptine suppressed basal serum prolactin levels and completely inhibited the prolactin responses to metoclopramide. In contrast, bromocriptine did not alter basal plasma aldosterone concentrations or the aldosterone responses to metoclopramide. Plasma renin activity, plasma cortisol, and serum potassium concentrations were unchanged by metoclopramide, dopamine, or bromocriptine. The results of this study suggest that the aldosterone response to metoclopramide is mediated by metoclopramide's antagonist activity at the dopamine receptor level. The results further suggest dissociation of the responses to the dopamine agonists, dopamine and bromocriptine, and indicate that a new type of dopamine receptor may inhibit aldosterone secretion.

Pathogenesis of diabetic gastroparesis: a pharmacologic study.

The motor function of the antrum was studied in 7 normal subjects, 4 patients with diabetes without GI symptoms, and 7 patients with diabetic gastroparesis. Both the number of antral contractions and the cumulative antral activity (percent of time during which the antrum contracted) in patients with diabetic gastroparesis were significantly lower than in normal subjects and diabetic patients without gastroparesis (P less than 0.01). Interdigestive motor complexes were observed in all normal subjects, but they were not present in any patients with diabetic gastroparesis. Intravenous metoclopramide did not affect the rate of antral contractions (P less than 0.1), but it increased the cumulative antral activity (P less than 0.001) in normal subjects and diabetics without gastroparesis. Metoclopramide, however, did not alter the rate of antral contractions (P less than 0.09) or the total cumulative antral activity (P less than 0.09) in diabetic patients with gastroparesis. Furthermore, in normal subjects, the action of metoclopramide was blocked by atropine sulfate (P less than 0.003). Bethanechol caused a slight increase in the number of antral contractions (P less than 0.05) and cumulative antral activity (P less than 0.01) in normal subjects. This cholinergic drug caused a marked increase in the rate of antral contractions and the cumulative antral activity in diabetic patients with gastroparesis. Antral contractions and cumulative antral activity were restored by bethanechol to normal values. These findings suggest a variable degree of gastric neuropathy in individual patients with diabetic gastroparesis with functionally intact antral muscles as assessed by their pharmacologic response to cholinergic stimulation.

Pharmacological analysis of the effects of metoclopramide on the transmurally stimulated guinea-pig ileum.

The effects of metoclopramide (Mcp), a benzamide derivative, have been quantitatively analyzed on the responses of the isolated guinea-pig ileum to transmural stimulation. Mcp (0.03 microgram ml-1 upwards) increased these responses but this effect which was calcium-dependent was not concentration-dependent (up to 30 micrograms ml-1). Mcp antagonized the inhibitor effects of noradrenaline, dopamine, procaïne, adenosine triphosphate, bufexamac and hydrocortisone on the ileal responses, but not those of tetrodotoxin and verapamil.

Atropine suppression of basal and metoclopramide-induced human pancreatic polypeptide secretion in man.

The administration of metoclopramide (MET) increased human pancreatic polypeptide (hPP) levels in 17 of 18 male and female control subjects. In all the control subjects, the increase was from a mean (+/- SD) basal level of 96 +/- 60 pg/ml, to a peak of 221 +/- 170 pg/ml. The peak occurred at 30 min, and levels had decreased by 60 min in all subjects. Atropine pretreatment in five male control subjects significantly decreased basal hPP levels and completely abolished the response to MET. It thus likely that the hPP increase consequent to MET administration is related to the latter's cholinergic properties.

Pharmacological analysis of the effects of metoclopramide on the guinea pig isolated stomach.

A pharmacological analysis has been made of the effects of metoclopramide on the contractile activity of isolated longitudinal muscle strips prepared from the guinea pig stomach. Metoclopramide produced up to 3-fold increases in the amplitude of the spontaneous contractions exhibited by such a preparation. This phenomenon was antagonized by hyoscine but not by tetrodotoxin nor by hexamethonium. The contractile response to transmural stimulation was also enhanced by metoclopramide, as was the response to extrinsic acetylcholine. Neural inhibitory systems were not affected by metoclopramide. The apparent sensitization to extrinsic acetylcholine was, however, prevented by tetrodotoxin and hexamethonium, implying that this effect depends upon ganglionic stimulation by acetylcholine. These results suggest that metoclopramide may act by increasing the amount of acetylcholine released at the postgangionic cholinergic nerve ending.