Administration Of Domperidone Research Articles

Preliminary Reports on Plasma Prolactin and TSH Responses to Domperidone and TRH Administration in Patients Affected by Simple Thyroid Goiter Associated with Benign Breast Disease

Preliminary Reports on Plasma Prolactin and TSH Responses to Domperidone and TRH Administration in Patients Affected by Simple Thyroid Goiter Associated with Benign Breast Disease

Modulatory role for prolactin in the elevation of striatal dopamine receptor density induced by chronic treatment with dopamine receptor antagonists

The chronic administration of haloperidol (HAL), domperidone (DOM), or sulpiride (SUL) increased the density of striatal dopamine (DA) receptors in intact but not in hypophysectomized (Hypox) male rats. This effect was independent of changes in body weights of the rats and of the drugs' abilities to produce cataleptic behavior. All treatments of intact rats increased serum rat prolactin (rPRL) concentrations, while Hypox rats had rPRL levels equivalent to zero. At the doses used in these studies, the striatal DA receptor densities were increased only if the rPRL levels were also increased. Chronic cysteamine (CYS) treatment decreased body weight gain, acutely decreased cataleptic behavior to HAL, decreased serum rPRL levels, and prevented the increase in serum rPRL levels due to HAL administration. While CYS itself did not alter striatal DA receptor density, it prevented the increase in density associated with the chronic administration of HAL (1 mg/kg). Since CYS decreased rPRL levels, these results lend further support to the hypothesis that rPRL (and prolactin in general) is a pituitary hormone with modulatory action on the increase in striatal DA receptor density.

Effect of domperidone on acetyl salicylic acid and acetaminophen absorption in rabbits

Interactions between acetyl salicylic acid (ASA) and acetaminophen (AC) with domperidone were investigated by oral administration of ASA (50 mg/kg) or AC (100 mg/kg) alone or in combination with domperidone (1 mg/kg) to rabbits. Plasma samples were collected before and 5, 10, 15, 20, 25, 30 and 45 min and 1, 2, 3, 4, 6, 10, 24 and 30 h after ASA administration. Similarly, plasma samples were collected before and 0.25, 0.5, 0.75, 1.25, 2, 3, 4.5 and 6.0 h after AC administration. Assays of ASA and AC in plasma were performed using HPLC methods. Domperidone had no significant effect on the maximum plasma concentration (C max), the time taken to reach C max (T max), the area under the curve (AUC) to infinity and the elimination half-life ( t 1 2 ) of ASA and AC. However, domperidone significantly increased the plasma AC concentrations at 1.25 and 2.0 h in comparison with the control. Also. domperidone consistently demonstrated an increase in AUCs up to 6 h and to infinity for AC after domperidone administration in all of 5 rabbits. It was concluded that domperidone (1 mg/kg) does not significantly affect ASA and AC absorption in rabbits.

Persistence of a defective tuberoinfundibular dopaminergic function in rats after long-term removal of oestrogen treatment. An in vivo study.

The function of the tuberoinfundibular dopaminergic (TIDA) neurons of 49 rats bearing oestradiol-valerate (EV)-induced prolactin (Prl) secreting tumours (prolactinomas) was evaluated in vivo, 7 months after discontinuation of EV-treatment, with neuroactive drugs acting via stimulation or inhibition of DA neurotransmission. Based on the size and morphologic appearance of the pituitary and on determination of plasma Prl levels, rats previously treated with EV could be divided into those bearing macro- (31/49) and those bearing micro-prolactinomas (18/49). Administration of the indirect DA agonist drug nomifensine (10 mg/kg iv) lowered plasma Prl levels in control rats, but failed to do so in rats bearing either macro- or microprolactinomas. Administration of the DA receptor antagonist domperidone (50 micrograms/kg ip) or the synthetic enkephalin analogue FK 33-824 (1 mg/kg ip) failed to induce a rise in plasma Prl in rats with macro-, but induced a clear-cut rise in plasma Prl in those with microprolactinomas. Prl unresponsiveness to all three neuroactive drugs indicates that long time after EV withdrawal TIDA neuronal function is still highly impaired in rats bearing EV-induced macroprolactinomas. The impairment of TIDA neuronal function would be of lesser extent in rats bearing microprolactinomas as revealed by a defective response to only one of the three applied neuroendocrine probes.

Effects of domperidone therapy on symptoms and upper gastrointestinal motility in infants with gastroesophageal reflux

We evaluated the effect of domperidone, a novel prokinetic agent, on symptoms and esophageal and gastric motility in 15 infants (six boys), mean age 7.9 months, with moderate to severe gastroesophageal reflux (GER) and upper gastrointestinal motility disturbances. Patients received domperidone orally for 6 weeks and underwent weekly assessment of five GER-associated symptoms, weight change, and side effects. Mean total symptom scores significantly improved after treatment (P less than 0.01). Vomiting, "spitting," and coughing each improved significantly. Postprandial reflux time (defined as esophageal pH less than 4.0) and percent peristaltic esophageal contractions improved significantly (p less than 0.05). Gastric fundic contractions, present in only four infants before treatment, occurred in nine after domperidone administration. Although mean gastric emptying of isotope-labeled formula was not improved, it improved greater than or equal to 10% over baseline in nine patients. Peristaltic amplitude, lower esophageal sphincter pressure, and esophageal acid clearance time were unchanged. Side effects were minimal. We conclude that domperidone is a useful and safe agent for treatment of gastroesophageal reflex in infants because it addresses the motility abnormalities inherent in the pathophysiology of the disorder.

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)

Lack of effect of domperidone on gastrin release: evidence for a peripheral activity of the drug.

The effect of intravenous administration of domperidone, a dopamine receptor antagonist with peripheral activity, on basal and submaximal pentagastrin-stimulated gastric acid secretion and gastrin release has been evaluated in healthy volunteers. No significant changes were observed in the parameters studied. The lack of effect on gastrin release appears to confirm that domperidone is unable to penetrate the blood brain barrier in appreciable amounts in adults.

Increased forearm vascular resistance after dopamine blockade.

The peripheral haemodynamic effects of a 40 mg intravenous injection of domperidone (a dopamine antagonist) have been studied in 10 normal subjects. In four subjects domperidone was infused directly into the brachial artery and the effects on forearm blood flow were measured. When administered systemically, domperidone significantly decreased forearm blood flow by 9% (P less than 0.01) and significantly increased calculated forearm vascular resistance by 11% (P less than 0.01). The drug produced no measurable changes in forearm blood flow at any dose when infused directly into the brachial artery. A further study was carried out into the effects of a systemic injection of domperidone on peripheral sympathetic tone. Reduction of sympathetic tone in the forearm was achieved by passively raising the legs of eight recumbent subjects. Before domperidone administration, passive leg elevation significantly increased forearm blood flow by 39% and decreased forearm vascular resistance by 13%. After drug administration the absolute values of vascular resistance increased and the changes between the supine and elevated position values when compared with those of the corresponding values prior to drug administration were significantly lower. These results suggest that the role of domperidone in increasing peripheral vascular tone is unlikely to be mediated by a direct local effect on peripheral resistance vessels. Any effect the drug may have is suggested to be mediated via a central control mechanism.

Plasma growth hormone responses to sulpiride in patients with acromegaly.

The role of endogenous dopamine (DA) on plasma GH secretion was studied in 12 patients with active acromegaly. After intramuscular administration of 100 mg sulpiride, 3 out of 12 patients showed distinct increases in their plasma GH (cases 1-3: sulpiride-responders). The GH increases far exceeded the ranges of physiological fluctuation in two cases studied (case 1 & 3). After domperidone administration, case 3 showed a quite similar GH increase as after sulpiride. Plasma GH responses to TRH and sulpiride were still observed in case 2 even after the basal GH levels were normalized by the transsphenoidal hypophysectomy. The three sulpiride-responders showed so-called paradoxical GH decreases following the administration of L-dopa (500 mg, p.o.) or DA (5 micrograms/kg/min over 90 min, i.v.). However, the basal plasma PRL levels and the responses to sulpiride in these 3 cases were not homogeneous. These results indicate that endogenous DA has a tonic inhibitory effect on GH secretion in some cases of acromegaly, and that tumorous somatotrophs rather than elevated GH levels are the critical factor for such inhibition. Further, the sensitivities of somatotrophs and lactotrophs to DA appeared to be heterogeneous in acromegalic patients.

Cholinergic independent dopaminergic regulation of motilin release in man.

This study investigated the dopaminergic control of motilin secretion in normal volunteers. Dopamine infusion caused a significant decline of plasma motilin levels, but had no effect on human pancreatic polypeptide (hpp) secretion. Dopamine antagonism with domperidone resulted in a significant elevation of motilin 10 and 20 min after the drug administration, and a significant elevation of hpp at 20 and 30 min. Atropine suppressed the basal levels of motilin and hpp but did not alter the increment of motilin levels after domperidone administration, while atropine suppressed domperidone induced secretory response of hpp. These results suggest that dopaminergic mechanisms exert a tonic inhibitory effect on motilin secretion in normal subjects.

Mechanisms regulating hormone release and the duration of dioestrus in the lactating rat.

Lactation in rats nursing seven pups was associated with a period of dioestrus lasting for 3 weeks, reduced LH secretion, hyperprolactinaemia and increased serum progesterone levels. Removal of the litter resulted in increased LH secretion, a prompt return of oestrus and termination of the prolactin-dependent luteal phase. Administration of domperidone (2.5 mg/day), a dopamine receptor antagonist, to rats deprived of their litters on day 1 or 9 post partum maintained hyperprolactinaemia and delayed the reappearance of oestrus. Administration of bromocriptine (0.5 mg/day), a dopamine receptor agonist, to lactating rats with suckling pups suppressed prolactin secretion and advanced oestrus, females in the middle of lactation being considerably more sensitive to prolactin suppression than those in the early post-partum period. Cross-fostering experiments revealed that the greater sensitivity to bromocriptine of mothers in late lactation was due to their lactational age rather than to the age of the offspring. Similarly, the length of lactational dioestrus was not affected either by giving newborn pups to females in the middle of lactation or by giving 9-day-old pups to newly parturient females.

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.

Evidence for dopaminergic modulation of pancreatic polypeptide secretion in man

This study examines the role of dopaminergic mechanisms in the regulation of human pancreatic polypeptide (hPP) secretion in 11 normal male volunteers. Administration of domperidone (20 mg iv), an extracerebral inhibitor of dopamine receptors, resulted in a hPP rise (p<0.05) within 10 min and a peak response (p<0.01) at 15 min after drug administration. Administration of the dopaminergic agonist, bromocriptine, 2.5 mg tid for 4 days eliminated hPP responses to isometric handgrip exercise in these 11 volunteers. These results suggest that dopaminergic mechanisms may exert a tonic inhibitory effect on hPP secretion in normal subjects.

Effect of domperidone, an extracerebral inhibitor of dopamine receptors, on thyrotropin, prolactin, renin, aldosterone, and 18-hydroxycorticosterone secretion in man.

This study investigates the dopaminergic mechanisms involved in the control of corticosteroid secretion in normal subjects. TSH, PRL, PRA, aldosterone, and 18-hydroxycorticosterone (18-OHB) were measured before and after the administration of domperidone (10 mg, iv) to eight healthy males. Domperidone, a selective peripheral dopamine antagonist, stimulated TSH and PRL secretion. Plasma concentrations of aldosterone, 18-OHB, cortisol, and PRA were not altered by domperidone. This is in contrast to previous observations of aldosterone, 18-OHB, and PRA responses to metoclopramide, a dopamine antagonist which readily crosses the blood-brain barrier. Domperidone may fail to stimulate aldosterone, 18-OHB, and renin secretion because it does not cross the blood-brain barrier or does not function as an antagonist for adrenal dopamine receptors modulating 18-OHB and aldosterone secretion.

Defective central nervous system dopaminergic function in rats with estrogen-induced pituitary tumors, as assessed by plasma prolactin concentrations.

Mature cycling female rats were each injected at 3-week intervals with 2 mg estradiol valerate (EV) in sesame oil. Controls received an equivalent volume of sesame oil. The administration of EV induced, at first, hyperplasia and then, 10 weeks after the first EV injection, adenomatous changes in the pituitary gland. Concurrently, there was a striking rise in plasma PRL concentrations, which reached values of about 2 μg/ml at 25 weeks. Acute administration of nomifensine (NOM), an indirectly acting dopamine (DA) agonist, to EV-injected rats suppressed baseline PRL levels at 1 week but failed to significantly decrease PRL levels at 4, 7, 10, and 25 weeks. Unlike NOM, bromocriptine, a direct DA agonist, strikingly reduced baseline PRL levels in EV-injected rats 1,10, and 25 weeks after the first EV injection. The administration of domperidone (DOM), a potent blocker of DA receptors, inconsistently increased plasma PRL at 1 week and was ineffective at the following time intervals. Since both NOM and DOM are d...

On the role of dopamine receptors in the central regulation of human TSH.

The effects of acute administration of haloperidol (4 mg im) and pimozide (4 mg orally) on TSH and Prl secretion were studied in normal and hypothyroid man. The TRH-induced TSH secretion before and after pre-medication with pimozide and domperidone, a peripheral dopamine (DA) blocker, was also evaluated in a group of normal subjects. Haloperidol and pimozide induced a marked increment in serum Prl; mean Prl levels were still significantly elevated 12 h following pimozide administration. A small but significant TSH increase was observed following haloperidol and pimozide in normal as well as hypothyroid subjects. Both domperidone and pimozide significantly enhanced TRH-induced TSH release. In another experiment 3 women with primary thyroid failure received an infusion of DA (4 micrograms/kg/min for 4 h) with and without domperidone administration. TSH and Prl levels were suppressed by DA, but the effect was completely abolished by domperidone. The results suggest that psychotrophic drugs, such as haloperidol and pimozide, can, like substituted benzamides, stimulate TSH release in man. Since domperidone and DA do not cross the blood-brain-barrier and domperidone significantly enhanced the TSH response to TRH, the data also support the hypothesis that human TSH is regulated by DA at the hypothalamus (median eminence) and/or pituitary level.

Evidence for central selective dopamine receptor stimulation in the mediation of nomifensine-induced hyperalgesia and the effects of opiate antagonists

The hyperalgesic effects of nomifensine were studied using a modified tail immersion test in mice. Intracerebroventricular injection of the peripherally acting dopamine antagonist domperidone totally antagonized nomifensine-induced hyperalgesia but this blockade was not evident after peripheral administration of domperidone suggesting mediation of hyperalgesia at a central location. The dopamine antagonist cis-flupenthixol and also bromocriptine shifted the nomifensine-induced hyperalgesia dose-response curve to the right, whereas sulpiride had no antagonistic effect. These results are discussed in relation to the D-1 and D-2 classification of dopamine receptors, and their putative agonists and antagonists. Naloxone produced a blockade of nomifensine-induced hyperatgesia, but another opiate antagonist MR 1452, though inherently hyperalgesic, did not modify the hyperalgesia produced by nomifensine. These findings do not rule out the participation of an opiate receptor in the mechanism of opiate antagonist blockade of nomifensine-induced hyperalgesia. However, they may suggest that MR 1452-induced hyperalgesia depends on a different mechanism from that of induced by nomifensine since they were not synergistic.

Tests of Prolactin Secretion in the Diagnosis of Hyperprolactinemic States: Nomifensine and Domperidone

Forty-one subjects with hyperprolactinemia underwent testing on separate occasions with nomifensine, an indirectly acting dopamine agonist, and domperidone, a dopamine receptor-blocking agent. Nomifensine (200 mg orally) did not significantly modify plasma levels of prolactin (PRL) in 17 subjects in whom the existence of a pituitary tumor had been established at surgery (12 subjects) or was highly probable (5 subjects). Of the remaining 24 patients with hyperprolactinemia of uncertain etiology, 6 had PRL responsiveness to nomifensine (decrease of baseline PRL levels greater than or equal to 30%) and 18 had PRL unresponsiveness to the drug. The administration of domperidone (4-mg bolus injected intravenously) showed in 36 of the 41 patients the existence of a homogeneity between PRL responsiveness to nomifensine and PRL responsiveness to domperidone. In only five patients was failure of nomifensine to lower plasma PRL levels associated with an increase in plasma PRL levels after domperidone administration (at least doubling of baseline PRL levels). The combined application of nomifensine and domperidone tests holds promise of being a useful method for distinguishing among hyperprolactinemic subjects those with a prolactinoma.

Evidence of sex difference in dopaminergic modulation of serum TSH secretion in primary hypothyroidism.

We have demonstrated the sex difference with respect to the dopaminergic modulation of serum TSH secretion in patients with primary hypothyroidism. Ten patients, 4 men and 6 women, with hypothyroidism were given 10 mg of Domperidone (Domp) iv, a very potent and specific dopamine receptor blocking agent, which could not readily cross the blood brain barrier. There was a significant rise in the TSH level after Domp iv in female patients with primary hypothyroidism, from basal values at zero time at 74.4 +/- 33.8 (M +/- SE) microU/ml to 171.2 +/- 94.9 at 30 min (p less than 0.001), 159.6 +/- 100.5 at 60 min (p less than 0.001). In contrast, no significant change in serum TSH values after Domp iv occurred in male patients with primary hypothyroidism, from basal values at zero time of 181.1 +/- 39.9 microU/ml to 171.4 +/- 31.1 at 30 min, 180.7 +/- 33.2 at 60 min and 172.7 /+- 31.0 at 90 min. After thyroid hormone therapy, max delta TSH values and the change from basal to peak values were significantly related to basal TSH values in female patients with primary hypothyroidism (r = +0.93, p less than 0.001), while max delta TSH in male patients was inversely related to basal TSH values within the limited concentrations (r - =0.78, p less than 0.02). It was conjectured from our results that maximum TSH responses to intravenous administration of domperidone in male and female hypothyroid patients were observed in respectively different basal TSH values, that is, less than 100 microU/ml in males and more than 100 microU/ml in females. Our findings provided evidence of sex difference in dopaminergic modulation of TSH secretion in primary hypothyroidism.

On the pharmacokinetics of domperidone in animals and man. I. Plasma levels of domperidone in rats and dogs. Age related absorption and passage through the blood brain barrier in rats.

Domperidone, a novel gastrokinetic and antinauseant lacking central side-effects, was administered intravenously to male Wistar rats and orally to fasted rats of either sex and to 1- and 6-day old neonates at doses of 2.5 mg 14C-labelled drug/kg. The biphasic absorption of domperidone in fasted rats was extremely rapid suggesting a partial absorption from the stomach. The metabolism of domperidone was sex- and age-related: it was slower in the female rat and in the neonates. The elimination system for the metabolites was still immature in the 1-day old pups. The distribution of domperidone (and related metabolites) to the rat brain was limited, brain concentrations being lower than corresponding plasma levels in all cases. In 1-day old neonates, the blood-brain barrier was less obstructive to the passage of domperidone than in older rats. In Beagle dogs, domperidone pharmacokinetics were described by a two-compartment model with half-lives of distribution and elimination of 6 minutes and 2.45 hours respectively. The time-courses of the drug plasma levels were similar for single and repeated (once daily for 11 months) doses of 2.5, 10 and 40 mg/kg, indicating that chronic administration of domperidone, even at high dose levels, did not alter its pharmacokinetics. AUC-values increased proportionally with the dose pointing to linear pharmacokinetics over a wide dose range.