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NEUROPHARMACOLOGICAL COMPARISON BETWEEN DOMPERIDONE and METOCLOPRAMIDE Abstract-Domperidone, a New Gastrokinetic with Potent

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NEUROPHARMACOLOGICAL COMPARISON BETWEEN DOMPERIDONE and METOCLOPRAMIDE Abstract-Domperidone, a New Gastrokinetic with Potent In in vitro binding assays, domperidone In in vitro experiments on the isolated was found to be a potent and specific guinea-pig stomach, domperidone selectively dopamine antagonist, but ex vivo and in vivo NEUROPHARMACOLOGICAL COMPARISON BETWEEN DOMPERIDONE AND METOCLOPRAMIDE A. WAUQUIER, C.J.E. NIEMEGEERS and P.A.J. JANSSEN Department of Pharmacology, Janssen Pharmaceutica , B-2340 Beerse, Belgium Accepted October 17, 1980 Abstract-Domperidone, a new gastrokinetic with potent antiemetic properties is devoid of central effects, up to high dose levels. To assess the CNS activity of domperidone and metoclopramide, the inhibition of intracranial self-stimulation (ICS) in two different situations, and the influence on EEG in dogs were studied. The dissociation between the antiemetic and central effects of both compounds were evaluated in dogs given a stereotypogenic dose of apomorphine. A significant and dose related inhibition of ICS (conditioned situation) was obtained with 0.8 and 1.6 mg/kg i.v. domperidone and with 0.125, 0.25 and 0.50 mg/kg i.v. metoclopramide. The ED50 values were 0.79 mg/kg and 0.25 mg/kg respectively. The effect was most pronounced 4 hr after administration with domperidone and 15 min after administration with metoclopramide. In the EEG studies, no specific structure-related effects were found but the total potency was increased with domperidone 0.8 and 1.6 mg/kg i.v. and with metoclopramide 0.063, 0.125, 0.25 and 0.50 mg/kg i.v. This increase was due to a decrease in fast frequencies, an increase of slower frequencies and a slight increase of the amplitude. Sleep-like patterns were not observed with either compound. In the apomorphine-test in dogs, the ratio between the i.v. ED50 values for antagonism of stereotypy and of emesis was 180 (1.8/0.01) for domperidone and 2.67 (0.64/0.24) for metoclopramide. Thus, central effects and antiemetic effects are concomitant with metoclopramide, whereas with domperidone, extremely large doses are required to obtain central effects. Domperidone, 5-chloro-1-{1-[3-(2, 3 inhibited the relaxation induced by intra dihydro-2-oxo-1-H-benzimidazol-1-yl) arterial dopamine (3). The latter experiment propyl]-4-piperidinyl}-1,3 dihydro-2H suggests that dopamine is involved in the benzimidazol-2-one, is a new gastrokinetic local feedback control of gastric motility with potent antiemetic properties. Domperi and that the gastrokinetic effect of dom done is reportedly effective for functional peridone can be explained by its interference gastrointestinal disorders, such as dyspepsia, with dopamine receptors, at the level of the gastroesophageal reflux, nausea and vomiting stomach. (1-2). binding experiments showed that domperi For the EEG experiments, dogs were done did not reach the dopamine receptors in implanted with cortical (surface) and sub the rat striatum (4). cortical (depth) electrodes. Surface electrodes Given intracerebrally, domperidone acted were stainless steel screws (one in the as a potent dopamine antagonist (5), but bone of the skull in the frontal region, a given systemically, extremely large doses second in the temporal region and a third in were required to observe central effects the occipital region). Depth electrodes (1). All these studies suggested that consisted of a stainless steel needle (0.5 domperidone cannot readily cross the blood mm diameter, insulated except for 1 /2 mm brain barrier. of the tip) and an insulated stainless steel In the present experiments, domperidone wire (0.2 mm diameter). The wire was and metoclopramide were studied in the dog inserted into the needle such as to protrude in a number of tests indicative for central 1 /2 mm beneath the tip of the needle. Depth activity: intracranial self-stimulation, electro electrodes were implanted in the caudate encephalography and apomorphine-induced nucleus, basolateral amygdala, dorsal hip stereotypy. The difference between the pocampus and oral pontine reticular antiemetic ED50 and the antistereotypic formation. Coordinates of the depth electrodes ED50, measured in the same dogs given a were determined according to the stereo high dose of apomorphine was used as a taxic atlas of Dua-Sharma et al. (7) and measure of dissociation between peripheral corrected for individual skull dimensions. and central activity of both compounds. For the self-stimulation experiments, depth electrodes were placed in the lateral preoptic MATERIALSAND METHODS region, nucleus accumbens, lateral hypo Subjects: The subjects were 15 adult thalamus both brain sites and in some dogs male inbred Labrador dogs (self-stimulation an additional electrode was placed either in experiments), 7 adult male inbred Beagle the substantia nigra, basolateral amygdala or dogs (electroencephalography) and 6 adult the posterior hypothalamus (8). inbred Beagle dogs of both sexes (stereotypy After surgery, the dogs were placed in a and emesis). recovery room and treated daily with Dicas Surgery: For the intracranial self-stimu trepton 1500, i.m., for at least 5 days. After lation experiments and EEG, dogs were two weeks of recovery, the dogs were implanted as described previously (6). In regularly transferred to the experimental short: the dogs were premedicated with 5 ml room in order to adapt to the environment. Hypnorm"' s.c., followed by 5 ml Nembutal The experiments were begun at the earliest i.v. (pentobarbital natrium, 60 mg/ml). The 1 month after surgery. Intracranial self-stimulation (ICS): After animals were positioned in a stereotaxic recovery, dogs were trained to press a lever, apparatus (David Kopf Instruments), im which triggered electrical brain-stimulation, mediately intubated, connected to a respirator through a swivel-device which permitted (Bird, Mark 4) and artificially ventilated with the aid of a nitrous oxide oxygen blender the animal to move freely in a 0.9 x 1.15 m cage, without twisting the electrode leads. (N20: 75%, 02: 25%) (Bird). The electrical stimulation consisted of a 500 msec train of biphasic square wave pulses at (a) Hypnorm: 10 mg fluanisone (R 2028) and 0.315 mg fentanyl dihydrogen citrate and 0.2 mg a rate of 300 pulses per second, each pulse fentanyl base (R 4263) per ml. had a duration of 1 msec and an intensity of less than 0.5 mA. After establishing self frontal-occipital and temporal-occipital for stimulation, the dogs were further trained the cortical electrodes. according to one of the following procedures: Recordings were taken for 5-min periods: a) free situation: the dogs were allowed to 60 min and 30 min before injection and at press a lever in the cage described above, for 0-5, 5-10, 10-15, 30-45, 45-50 and 60-65 n times 10-min periods, n being the number min after injection. Three additional 5-min of electrodes tested in a dog; an interval of periods were taken 4 hr after injection of the 3 min without brain-stimulation, separated two highest doses of domperidone and each period (9); b) conditioning situation: metoclopramide. the dogs were partially restrained in a Power spectral analysis of 4 channels was 'pavlo vstand' and allowed to press a lever done on-line with the aid of a PDP 11/E10 for brain-stimulation according to the fol minicomputer system (Digital Equipment lowing procedure: each session consisted of Corporation) (10). In short, the EEG-signal 20 trials of 20 sec during which brain (7 channels) is digitized in the analogue to a stimulation was available upon a tone of digital converter and processed by the 1,000 Hz (conditioned stimulus or CS) computer. Digitizing, at a rate of 5 msec, spaced with an interval of 30 sec, during allowed a frequency pass band of 0 to 100 Hz. which lever-pressing had no programmed A Fast-Fourier program transforms an consequences (6). epoch of 1024 sample points (5.12 sec) to After stabilization of lever pressing be the amplitude-frequency domain. To reduce haviour, experimental sessions were held on the results obtained by the Fast-Fourier Monday, Wednesday and Friday. At least two transformation, the power of each harmonic sessions separated each drug treatment. In is computed and accumulated in 7 defined procedure a) dogs were given domperidone, frequency bands (resolution ±0.2 Hz) : 0.5 either subcutaneously, orally or intravenously 3.5 Hz (delta), 3.5-7.5 Hz (theta), 7.5-9.5 Hz and metoclopramide intravenously (see Table (alpha 1), 9.5-13.5 Hz (alpha 2), 13.5 2). In procedure b) dogs were given i.v. 17.5 Hz (beta 1), 17.5-25 Hz (beta 2), 25-40 either domperidone or metoclopramide (see Hz (beta 3). The total signal (4.6 min) was Fig. 1). These dogs were injected only once divided into 9 periods consisting of 6 per week (on Wednesdays) according to subsequent epochs (each epoch lasting the following sequence: 1 st dose of 5.12 sec). Six medians of the corresponding domperidone, 1st dose of metoclopramide, epochs of each of the 9 periods were 2nd dose of domperidone, 2nd dose of calculated, i.e. the median of the 1st, the metoclopramide, etc. Sessions were run median of the 2nd, ..., the median of the 1 5 min and 4 hr after drug injections. last (6th) epoch of each period. This Electroencephalography (EEG): The dogs technique was introduced to eliminate were kept unrestrained in a shielded cage extremely high and low values, caused by and the electrodes were connected to a movement artifacts or by the variety of the mingograph. The EEG was recorded on a signal. Finally, the mean power, standard 12-channel Elema-Schbnander at a paper deviation and standard error of the 6 medians speed of 1 5 mm/sec. Filters and time constant were computed for each of the 7 defined was set at respectively, 70 Hz and 0.3 sec.
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