Dose Of Domperidone Research Articles

Small Dose of Domperidone Potentiated the Effects of TRH and Serotonin on Prolactin Release in Ovariectomized, Estrogen-Treated Rats

A transient antagonism of the dopaminergic action by using a dopamine antagonist, domperidone, plus a dopamine agonist, CB154, has been shown to potentiate the effect of thyrotropin-releasing hormone (TRH) on prolactin (PRL) secretion. In order to test whether the serotonin (5-HT)-induced PRL secretion can also be enhanced in a similar way, we used 5-HT instead of TRH in our first experiment. We found that the dose of domperidone used (10 micrograms/rat) seems to be excessive since it induced a marked and substantial increase in PRL release and the use of CB154 further masked the action of 5-HT. We used a smaller dose of domperidone (1 microgram/rat) without the CB154 and found that it induced a moderate amount of PRL release which lasted for over 1 h. Given TRH (1 microgram/rat) or 5-HT (0.3 mg/rat) 1 h later resulted in a significant increase in plasma PRL which was much higher than that induced by TRH or 5-HT alone. The potentiating effect of domperidone was even more significant for the 5-HT- than the TRH-stimulated PRL secretion. Pretreatment with 5-HT or vasoactive intestinal polypeptide (10 micrograms/rat) were without any effect in potentiating the action of TRH. In conclusion, antagonizing the dopamine action appears to enhance the stimulatory effect of TRH and 5-HT on PRL secretion.

Gastric emptying and gastrointestinal symptoms in patients with atrophic gastritis and the effects of domperidone.

The relationship of gastric emptying of liquid to the extent of fundal gastritis and gastrointestinal symptoms was investigated in a total of 37 subjects comprising healthy controls with no gastrointestinal symptoms and patients with constant gastrointestinal symptoms for at least 1 year. Gastric emptying was measured by the acetaminophen absorption method, and the extent of fundal gastritis was determined by the endoscopic Congo-red test developed at this hospital. Gastric emptying was significantly slower in patients with gastrointestinal symptoms than in healthy subjects. It was also significantly slower in patients with than in those without severe fundal gastritis. Gastrointestinal symptoms were significantly more frequent in patients with delayed gastric emptying. The acute effect of oral administration of domperidone on gastric emptying was examined. A single dose of domperidone (20 mg) significantly increased the rate of gastric emptying.

In-vivo evaluation of dopamine receptor-mediated inhibition of gonadotrophin secretion from the pituitary gland of the goldfish, Carassius auratus.

Dopamine acts directly on the pituitary to modulate gonadotrophin (GtH) secretion in goldfish (Carassius auratus). In the light of this important role for dopamine in the regulation of goldfish reproduction, this investigation was designed to evaluate the receptor specificity of this dopamine inhibition and to describe the use of domperidone, a specific dopamine D2-receptor antagonist, in the manipulation of pituitary function in goldfish. To investigate the specificity of dopamine inhibition of GtH secretion, selected dopamine receptor antagonists were injected i.p. to block dopamine receptors thereby increasing GtH secretion as reflected by increased serum concentrations of GtH. Serum GtH levels were significantly increased by the active stereoisomer (-)-sulpiride in a dose-related fashion; (+)-sulpiride had no effect. Comparison of dopamine antagonists at low doses indicated that only domperidone and pimozide caused significant increases in serum concentrations of GtH. Dopamine antagonists potentiated the action of a gonadotrophin-releasing hormone analogue (GnRH-A) with an order of potency of domperidone = pimozide greater than metoclopramide = fluphenazine. [3H]Domperidone, injected i.p. with unlabelled domperidone, entered the blood and achieved maximum concentrations 12 h after injection, but did not accumulate in the brain in appreciable amounts. Gonadal 3H radioactivity was usually equal to or in excess of blood radioactivity, while [3H]domperidone was highly concentrated in the pituitary in a time-dependent fashion, with maximal accumulation occurring 24 h after injection. The time-course of pituitary accumulation of [3H]domperidone correlated well with the temporal increase in serum GtH levels in response to i.p. injected domperidone or domperidone plus an analogue of LHRH. Domperidone increased serum concentrations of GtH in a dose-related fashion; an analogue of salmon GnRH (sGnRH-A) increased the sensitivity and magnitude of the serum GtH response to domperidone. Serum concentrations of GtH were increased by sGnRH-A in a dose-related fashion; a low dose of domperidone substantially increased the sensitivity of the serum GtH response to sGnRH-A. These results indicate that dopamine inhibits GtH secretion from the goldfish pituitary by acting through a specific mechanism mediated by a dopamine D2 receptor. Domperidone increased serum concentrations of GtH, potentiated the action of gonadotrophin-releasing hormones and did not pass into the brain after i.p. injection into goldfish. The data also suggest that dopamine and GnRH, although acting through different receptors, influence the effect of each other on GtH release.

Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis.

The involvement of 5-hydroxytryptamine (5-HT) 5-HT3 receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT3 receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT3 receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT3 receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.

Identification of dopamine receptor subtypes in the hypotensive action of SK&F 85174 in anesthetized rats.

1 We have performed experiments to determine the effect of SK&F 85174 on blood pressure in anaesthetized rats and identify dopamine receptor subtype(s) involved in its action. 2 SK&F 85174 decreased blood pressure in a dose-related manner. There were no significant changes in heart rate. The hypotensive action was short-lasting and was significantly antagonized by the selective DA1-receptor antagonist. SCH 23390 (100 micrograms/kg). This dose of SCH 23390 did not alter the hypotension produced by the DA2-receptor agonist, quinpirole. 3 The DA2-receptor antagonist, domperidone (25 micrograms/kg), did not significantly alter the hypotension produced by lower doses of SK&F 85174, but antagonized the hypotensive action of the highest dose of SK&F 85174 by about 35%. This dose of domperidone antagonized the hypotension produced by quinpirole by 85% without affecting the hypotensive action of the DA1-receptor agonist, fenoldopam. 4 These results show that at lower doses of SK&F 85174, the hypotension is due primarily to DA1-receptor activation, whereas DA2-receptor activation may also contribute to the blood pressure decrease produced by higher doses of SK&F 85174.

Effects of domperidone and thyrotropin-releasing hormone on secretion of luteinizing hormone and prolactin during the luteal phase and following induction of luteal regression in sheep

Effects of domperidone, a peripheral dopamine receptor antagonist, on secretion of LH and prolactin were studied during the luteal phase and following administration of PGF 2α. Since hyperprolactinemia has been reported to inhibit secretion of LH in ewes, effects of thyrotropin-releasing hormone (TRH) also were examined. Ewes 8–10 days post-estrus were assigned to be treated with: 1) vehicle (n=5); 2) 0.3 mg domperidone (n=6); 3) 1.0 mg domperidone (n=6); 4) 3 μg TRH (n=6); or 5) 10μg TRH (n=6) every 4 hours for 60 hr. Luteal regression was induced with PGF 2α at 12 hr after initiation of treatments. During the luteal phase, pulses of LH were more frequent (P<.05) and the amplitudes of these were higher (P<.05) in ewes treated with domperidone or TRH than in control ewes. These changes in LH occured even though each treatment elevated markedly concentrations of prolactin in plasma. After induction of luteal regression, mean of LH and frequency of LH discharges were similar in all groups. However, in ewes treated with the 1.0 mg/4 hr dose of domperidone the pulse amplitude was greater than in the other groups (2.3 vs 1.1 ng/ml). Dose-response relationships and the magnitude of the prolactin release following domperidone or TRH varied with time. Treatments did not affect the timing of the LH surge or the increase in progesterone associated with the subsequent cycle. Based on these data we conclude that: 1) endogenous hypothalamic dopamine mediates some of the inhibitory effects of progesterone on secretion of LH and prolactin; 2) dopamine limits the extent of the usual follicular phase increase in prolactin; 3) acute hyperprolactinemia does not inhibit the secretion of LH; and 4) administration of TRH can increase the frequency and amplitude of LH pulse frequency and amplitude in sheep in the luteal phase of LH in sheep.

Increased serum prolactin but normal TSH during prolonged domperidone treatment in children.

The influence of the dopamine receptor blocking agent domperidone on prolactin and TSH secretion was studied in 16 infants, aged 10-360 days, who were treated for gastroesophageal reflux. The pretreatment serum prolactin levels were not statistically different from the levels in age-matched controls and showed the well-known inverse relationship with age. During treatment with domperidone a significant increase in prolactin level was observed on days 1, 4 and 21-28, the mean values on these three days not being statistically different. No correlation could be found between the serum prolactin levels and the corresponding plasma domperidone levels. One infant of this series and three not included in this series developed reversible breast hypertrophy with galactorrhoea in three of them: in none of them was the prolactin level, corrected for age, above 1 SD of the mean. All had received relatively high doses of domperidone. In 13 patients domperidone did not influence TSH secretion.

Action of dopamine on the exocrine pancreatic secretion of the intact dog.

The effects of dopamine and domperidone, a dopamine antagonist, have been studied on the exocrine secretion of the dog pancreas. The purpose of this study was to see if dopamine acted on enzyme secretion and if its action was merely 'pharmacological' or had a physiological role. Conscious Beagle dogs, fitted with Thomas cannulae were studied following infusions of dopamine 125-1000 micrograms kg-1 h-1. During dopamine infusion, a secretory peak lasting 10 min was observed. This was followed by a stable plateau which was approximately 1/3 of the peak. The pattern of water, bicarbonate and protein secretion was similar. The maximum effect was obtained with 500 micrograms kg-1 h-1 dopamine. The stimulatory action of dopamine was blocked by domperidone, without any detected effect on the central nervous system, but not by propranolol or phenoxybenzamine. Domperidone 10 micrograms kg-1 almost completely suppressed the secretory response to the maximally effective dose of dopamine. This inhibition was not competitive. Atropine decreased the secretory response to dopamine. The protein response was not observed when dopamine was infused against a background infusion of secretin. This suggests that the effect of dopamine on protein secretion could be due to a wash-out phenomenon. The maximally effective dose of domperidone, 10 micrograms kg-1, did not modify the pancreatic response to a solid meal. Thus, in the non-anaesthetized dog, the effect of dopamine on water and bicarbonate secretion has been confirmed. It is concluded that dopamine had no detectable action on protein secretion and that the physiological role of dopamine with respect to pancreatic secretion is still questionable.

Further evidence that central neurotensin inhibits pituitary prolactin secretion by stimulating dopamine release from the hypothalamus.

Intracerebroventricular (icv) injection of neurotensin (NT) (2 micrograms/rat) suppressed prolactin (PRL) release induced by L-5-hydroxytryptophan (1 mg/100 g body wt, iv), prostaglandin E2(1 microgram/rat, icv), and FK33-824 (10 micrograms/100 g body wt, iv), a Met5-enkephalin analog, in urethane-anesthetized or conscious rats. In contrast, NT did not suppress elevated plasma PRL levels sustained by a large dose of domperidone (10 micrograms/100 g body wt, iv), a peripheral dopamine antagonist. In in vitro experiments, NT (10(-5) M) stimulated dopamine release from perifused rat hypothalamic fragments. These results suggest that central NT inhibits PRL secretion by stimulating dopamine release from the hypothalamus into hypophysical portal blood in the rat.

Domperidone-induced increase in lower oesophageal sphincter pressure does not affect azygos blood flow in patients with cirrhosis.

An increase in lower oesophageal sphincter pressure induced by domperidone has previously been reported to decrease superior portosystemic collateral flow in patients with portal hypertension owing to cirrhosis. Although a 10-mg intravenous dose of domperidone was effective in increasing lower oesophageal sphincter tone in a group of six patients with cirrhosis, the same dose failed to affect azygos blood flow in a matched group of six patients. The results do not support the hypothesis that an increase in lower oesophageal sphincter tone can decrease flow through oesophageal varices in patients with cirrhosis.

Simultaneous catalepsy and apomorphine-induced stereotypic behavior in mice

Intraventricular administration of haloperidol or chlorpromazine produces catalepsy and blocks apomorphine-induced stereotypic behavior. Low intraventricular doses of domperidone, sulpiride and spiperone, equally cataleptogenic as haloperidol or chlorpromazine, augment rather than diminish stereotypic behavior produced by subsequent apomorphine treatment. The resultant stereotypic behavior continues even while the animal is in a rigid cataleptic posture and is marked by persistent gnawing and licking. Prior to the induction of catalepsy and after recovery from it, mice display the entire range of typical apomorphine-induced behavior including sniffing, climbing, gnawing, and licking. This animal model may be related to the clinical observation of the coexistence of tardive dyskinesia and drug-induced Parkinsonism in individual patients.

Effect of domperidone on apomorphine inhibition of the copulatory response and exploratory behaviour in the female rat.

The effects of domperidone, a peripheral dopamine receptor blocker which poorly crosses the blood-brain barrier, on copulatory and exploratory behaviour were studied in apomorphine (oestrogen + progesterone) treated ovariectomized rats. The dose of domperidone (1.0 mg/kg) which clearly prevented the inhibitory action of apomorphine on the lordotic response did not influence the effect of apomorphine in an exploratory test situation. This finding indicates that peripherally (intraperitoneally) administered domperidone influences dopaminergic mechanisms implicated in the copulatory behaviour of the female rat, but not dopaminergic mechanisms involved in exploratory behaviour. The possibility that domperidone reaches the brain region responsible for the lordotic behaviour, e.g. the hypothalamus, is discussed.

A pilot study of high-dose domperidone as an antiemetic in patients treated with cisplatin

A dose-finding multicenter study was undertaken to evaluate the antiemetic efficacy of domperidone, an antidopaminergic drug, which has been proposed as a suitable alternative to high-dose metoclopramide in the control of cisplatin-induced nausea and vomiting. Forty-five patients were treated with different increasing high doses of domperidone (30, 60, 120 or 150 mg) administered by i.v. infusion over 20 min every 2 hr for a total of four doses for each patient, starting 30 min before chemotherapy. The number of episodes of emesis, the duration of nausea and vomiting and side-effects were recorded. Results do not suggest any specific difference in protective effect between the regimens tested. Moreover, occurrence of serious side-effects indicated that the safety of high-dose domperidone is doubtful.

Central inhibitory action of TRH on prolactin secretion in the rat.

Intravenous (iv) injection of FK33-824 [( D-Ala2, MePhe4, Met-(O)5-ol]-enkephalin, 8 and 16 nmole/100 g body wt), a potent Met5-enkephalin analog, and domperidone (1.2, 2.4, and 24 nmole/100 g body wt), a dopamine antagonist, resulted in a dose-related increase in plasma prolactin (PRL) levels in urethane-anesthetized male rats. PRL release induced by FK33-824 (16 nmole/100 g body wt, iv) was inhibited by intraventricular (icv) injection of TRH (0.6 nmole/rat). DN-1417 (gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide citrate, 0.6 nmole/rat, icv), a TRH analog, also blunted PRL release induced by FK33-824. PRL release induced by a smaller dose of domperidone (1.2 nmole/100 g body wt, iv) was blunted by TRH and DN-1417, whereas both peptides failed to suppress elevated PRL levels induced by larger doses of domperidone. These results suggest that TRH not only stimulates PRL secretion by acting directly at the pituitary, but has an inhibitory action on PRL release through activation of the central dopaminergic mechanism.

Studies on the central and peripheral dopaminergic control of PRL secretion in man: failure to demonstrate the existence of a dopamine-mediated prolactin-inhibiting factor.

The existence of a putative central prolactin-inhibiting factor (PIF) distinct from dopamine (DA) but dependent on DA mechanisms for release has been suggested from recent animal studies. We investigated the possibility of the existence of such a PIF in man by combining the use of monoiodotyrosine (MIT), an inhibitor of central DA synthesis, domperidone, a DA receptor antagonist that does not enter the blood-brain barrier and DA itself. 6 normal volunteers underwent three sets of studies: (1) PRL stimulation test to 400 micrograms TRH i.v., 1 g MIT orally or 5 mg domperidone i.v., (2) peripheral DA receptor blockade study in which either domperidone, MIT or TRH was administered at 120 min during a 240-min domperidone infusion (50 micrograms/min) which was preceded by a 5-mg bolus dose of domperidone i.v. and, (3) DA infusion study in which MIT was administered at 120 min during a 240-min infusion of DA in a dose (0.5 microgram/kg X min) known to elevate peripheral DA concentration to levels reported for pituitary portal plasma. In the PRL stimulation tests, the mean +/- SE peak response was significantly greater (p less than 0.002) with domperidone (3,900 +/- 840 mIU/l) than with MIT (1,880 +/- 400 mIU/l) or TRH (2,094 +/- 450 mIU/l). In the peripheral DA receptor blockade study the initial domperidone-induced PRL response was not sustained during the domperidone infusion. Neither a second dose of domperidone nor MIT administration at 120 min resulted in a significant release of PRL.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolactin has a direct effect on adrenal androgen secretion.

The role of PRL in the secretion of androgens by the adrenal glands was investigated in vivo and in vitro. In women with hyperprolactinemia whose pituitary-adrenal function was normal, there was significant correlation between serum PRL and dehydroepiandrosterone sulfate [(DHEA-S) gamma = 0.48, P less than 0.05, n = 34] and DHEA (gamma = 0.50, P less than 0.05, n = 34), but not with androstenedione. Long term administration of sulpiride to normal women increased both serum PRL and DHEA-S, whereas acute elevation of PRL after a single iv dose of domperidone had no influence on the serum DHEA-S levels. Monolayer cultures of human adrenal cells were used in order to study the direct effect of PRL on adrenal androgen secretion. The daily secretion of DHEA-S, DHEA, androstenedione, and cortisol was determined. In the absence of ACTH, PRL had no effect on steroid secretion in a 7-day culture period. In the presence of ACTH, there was a daily increase in the secretion of steroids. PRL, when added in combination with ACTH, potentiated the effect of ACTH on DHEA-S and DHEA but not on androstenedione and cortisol secretion on the seventh day in culture. These results indicate that PRL has a direct synergistic effect with ACTH on adrenal cells to increase adrenal androgen release. Increases in DHEA-S and DHEA but not androstenedione in vitro and correlation between serum PRL and DHEA-S and DHEA but not androstenedione in women with hyperprolactinemia suggest that the synergistic effect of PRL on adrenal androgen secretion may result from partial inhibition of adrenal 3 beta-hydroxysteroid dehydrogenase.

Evidence that prolactin does not affect the induction of sexual behaviour by oestradiol and progesterone in ovariectomized rats.

Injection of 2.5 mg of the dopamine receptor antagonist domperidone raised serum prolactin concentrations within 3 h and high prolactin levels were maintained for 12 h in ovariectomized rats pretreated with 2 micrograms oestradiol benzoate (OB). This dose of domperidone stimulated the display of sexual behaviour in ovariectomized OB-treated rats within 3 h of administration. The behavioural effect of domperidone, but not its effect on serum prolactin concentrations, was blocked by adrenalectomy. Daily treatment with domperidone had no inhibitory effect on the subsequent induction of sexual behaviour by OB and progesterone in ovariectomized rats. A slight facilitation of the behaviour was noticed in OB-treated rats given daily domperidone injections, but this effect was cancelled by adrenalectomy. The results suggest that an acute increase in serum prolactin levels has no effect on the induction of sexual behaviour by OB in itself, but can stimulate the secretion of an adrenal product, perhaps progesterone, which facilitates the behaviour. Similarly, constant high levels of prolactin by themselves have no effect on the subsequent induction of sexual behaviour by OB and progesterone.

A comparison of domperidone and haloperidol effects on different dopaminergic neurons in the rat brain

Domperidone, a dopamine (DA) receptor antagonist with reportedly preferential actions outside of the blood-brain barrier, and haloperidol, a centrally active DA antagonist, were compared with respect to their abilities to increase the activity of dopaminergic neurons in the rat brain. The activity of nigrostriatal, mesolimbic, tuberohypophyseal and tuberoinfundibular dopamine nerves was estimated by measuring the in vivo rate of DA synthesis (dihydroxyphenylalanine accumulation following administration of an inhibitor of aromatic L-amino acid decarboxylase) in the striatum, olfactory tubercle, posterior pituitary and median eminence, respectively. In an initial study, the rates of DA synthesis in striatum, olfactory tubercle, and posterior pituitary were determined at 2, 8, and 16 h after subcutaneous administration of 0.25, 2.5, or 25 mg/kg domperidone. At the lowest dose of domperidone, DA synthesis was increased only in the posterior pituitary at 8 and 16 h; at the intermediate dose, DA synthesis increased in the posterior pituitary at 8 and 16 h and in the olfactory tubercle at 8 h. Only at 8 h after the highest dose of domperidone was DA synthesis increased in the striatum. When 2.5 mg/kg of doperidone or haloperidol were administered, DA synthesis in posterior pituitary and median eminence was increased in a similar fashion (in the latter region only at 16 h). In contrast, domperidone promoted only modest and delayed increases in DA synthesis in the olfactory tubercle and had no effect in the striatum. These results indicate that systemically administered domperidone preferentially increases DA synthesis in neurons terminating outside the blood-brain barrier, but after a pronounced delay, high doses of the drug can also activate DA neurons which project to the forebrain.

Elevation of circulating prolactin concentrations may not cause striatal dopamine receptor supersensitivity

Neuroleptic drugs, on repeated administration, increase plasma prolactin levels and induce behavioural and biochemical changes suggesting supersensitivity of striatal dopamine receptors. It has been suggested that the increase in plasma prolactin is responsible for the change in striatal dopamine receptors. We now find that repeated administration of haloperidol (5 mg/kg i.p.) for 21 days, followed by a 3 day drug-washout period, caused a 12-fold increase in circulating prolactin concentration in samples taken 1 h after the last injection. Haloperidol treated animals also exhibited an exaggerated stereotyped response to apomorphine 0.0625–0.5 mg/kg s.c.) and an increase in striatal dopamine receptor numbers labelled by [ 3H]spiperone. Administration of the same dose of domperidone or sulpiride (5 mg/kg i.p., 21 days), compounds which penetrate poorly into brain, also elevated plasma prolactin levels, but failed to alter cerebral dopamine function. Our findings indicate that neuroleptic-induced elevations in plasma prolactin levels are not responsible for the induction of cerebral dopaminergic supersensitivity.

Influence of dopamine on rumino-reticular motility and rumination in sheep.

The effects of intracerebroventricular (i.c.v.) and intravenous (i.v.) administration of dopamine and its antagonists (domperidone and metoclopramide) on forestomach motility were investigated in four sheep fitted with Nichrome electrodes and strain gauges implanted on the reticulum and the caudo-dorsal sac of the rumen. Infused by the i.c.v. route at a rate of 2 micrograms . kg-1 . min-1, dopamine inhibited the phasic contractions of the reticulo-rumen. A similar effect was obtained following i.v. administration of doses which were 10 times higher, but the effect was associated with an increased tone of the rumen wall. Prior i.v. administration of domperidone (0.5 micrograms . kg-1) blocked these effects and a selective blockade of the dopamine-induced inhibition of phasic contractions was obtained with higher dose of domperidone (2.5 micrograms . kg-1) administered centrally. When dopamine was infused alone ventricularly or intravenously after metoclopramide (40 micrograms . kg-1), it induced a transient (6-8 min) period of rumination, which could be blocked by a prior i.c.v. administration of tolazoline. It was concluded that dopamine acts on rumino-reticular motility in sheep through specific dopamine receptors (i) centrally by inhibiting the frequency of reticular contraction and (ii) peripherally by increasing the muscular tone of the rumen, and its effects on rumination involved alpha 2 adrenergic receptors located in the central nervous system.