Efficacy of domperidone in infants and children with gastroesophageal reflux.

This study sought to define the therapeutic efficacy of domperidone in infants and children with gastroesophageal reflux. A double-blind, placebo-controlled trial was performed in seventeen children (ages 5 months to 11.3 years) with moderate to severe gastroesophageal reflux who had not responded to standard nonpharmacological therapy. Subjective and objective measures (weight gain, esophageal pH probe study, radionuclide gastric emptying scan) of gastroesophageal reflux were evaluated. Therapy with domperidone for 4 weeks was effective only in reducing the total number of reflux episodes in the two-hour postprandial period (p less than 0.01); however, it did not result in symptomatic improvement or significant improvement in other measures of gastroesophageal reflux or gastric emptying. After therapy for 8 weeks symptomatic improvement was reported in some patients who had denied improvement after 4 weeks of therapy, suggesting that more than 4 weeks of therapy may be required for some patients to obtain a clinical response. Mild self-limited diarrhea was reported by six patients (four domperidone, two placebo). We conclude that domperidone is tolerated by most infants and children with gastroesophageal reflux; however, 4 weeks of therapy was only minimally effective in producing objective improvement of gastroesophageal reflux and did not result in symptomatic improvement. Further studies of longer duration are needed to resolve the question raised by this study: that domperidone may be beneficial for patients with gastroesophageal reflux when given for more than four weeks.

Transcoronary platelet activation and consumption in coronary artery disease: studies at rest.

The platelet count(PC), plasma platelet factor 4 (PF4) and plasma beta-thromboglobulin(beta TG) have been measured in blood obtained from a peripheral vein, the aortic root and the coronary sinus in 7 patients with normal coronary arteries, 9 patients with lesser degrees of coronary artery disease(CAD) and in 13 patients with severe CAD under resting conditions. In each patient group values obtained in the peripheral venous blood were similar to those obtained in normal subjects. In each group values obtained in blood from the coronary sinus were similar to those obtained in blood from the coronary aortic root and in most instances these were similar to values obtained in peripheral venous blood. for example, in the 13 subjects with hemodynamically significant 3-vessel or 2-vessel CAD the mean values in blood from a peripheral vein, the aorta and the coronary sinus respectively were: PC-194, 205, and 208 x 10(9)/1; PF4-3.3, 3.7, and 3.5 ng/ml; and beta TG-15.5, 23.0 and 18.6 ng/ml. These findings provide no support for the occurrence of continuous platelet activation or platelet consumption in the coronary vessels or elsewhere in patients with stable CAD, under resting conditions, regardless of its severity.

Selective inhibition of responses of feline dorsal horn neurones to noxious cutaneous stimuli by tizanidine (DS103-282) and noradrenaline: involvement of alpha 2-adrenoceptors.

The effects of tizanidine (DS103-282) were compared with those of noradrenaline and other adrenoceptor agonists on responses of laminae IV and V neurones in the lumbar dorsal horn to noxious and innocuous cutaneous stimuli in the anaesthetized cat. Tizanidine, noradrenaline and the alpha 2-receptor agonist, clonidine, depressed spontaneous activity and responses to noxious, but not those to innocuous, stimuli when administered iontophoretically, either near the recording site in laminae IV-V, or into laminae II-III, i.e. 300-900 microns dorsal to the recording site. Iontophoretic ejection of dopamine, the beta-agonist isoprenaline and the alpha 1-agonists phenylephrine and amidephrine had no effect at either site, or only relatively weak and sometimes non-selective depressant actions on neuronal responses to cutaneous stimuli. The preferential depressant actions of tizanidine, noradrenaline and clonidine were antagonized by the selective alpha 2-antagonist RX781094 administered iontophoretically at the same site as the agonists, and by intravenously administered yohimbine. In contrast, the alpha 1-antagonists, prazosin and WB4101, the beta-antagonist, sotalol and opiate antagonist, naloxone did not alter the depressant actions of these agonists on laminae IV and V neurones. These findings indicate that the selective inhibitory effect of tizanidine and noradrenaline on responses of laminae IV and V neurones to noxious peripheral stimuli are mediated at alpha 2-adrenoceptors situated in either laminae IV and V or laminae II-III. The possible physiological relevance of these receptors is discussed.

Excitatory and inhibitory responses of Purkinje cells, in the rat cerebellum in vivo, induced by excitatory amino acids.

Responses of rat cerebellar Purkinje cells to iontophoretically administered excitatory amino acids have been studied in vivo. Responses to N-methyl-D-aspartate (NMDA) were either biphasic (excitation followed by inhibition) or purely inhibitory and were antagonized by the selective NMDA-receptor antagonist, 2-amino-5-phosphonovalerate. Quisqualate and kainate either excited or induced biphasic responses, in these neurones, which were only reduced by amino acid antagonists that acted at non-NMDA receptors. The excitatory amino acid-induced inhibitions were also antagonized by the selective gamma-aminobutyric acid (GABA) antagonist, picrotoxin, suggesting that they were indirectly mediated via GABAergic inhibitory interneurones, which could be excited via NMDA and non-NMDA receptors.

Tizanidine (DS103-282), a centrally acting muscle relaxant, selectively depresses excitation of feline dorsal horn neurones to noxious peripheral stimuli by an action at alpha 2-adrenoceptors.

The effects of microiontophoretic ejection of tizanidine were compared with those of adrenoceptor agonists on responses of single laminae IV and V neurones to noxious and innocuous cutaneous stimuli. Tizanidine, noradrenaline and clonidine depressed neuronal responses to noxious but not innocuous stimuli. Spontaneous activity was also depressed by these three substances. By contrast, beta- and alpha 1-adrenoceptor agonists had no consistent effect on neuronal responses to cutaneous stimuli. The selective actions of tizanidine, noradrenaline and clonidine were reversibly antagonized by the alpha 2-adrenoceptor antagonist RX781094 but not by WB4101 (alpha 1 antagonist). The binding of an alpha 2-adrenoceptor ligand to rat brain membranes was preferentially displaced by tizanidine. These results indicate an interaction of tizanidine with central alpha 2-adrenoceptors.

Platelet activation caused by cardiac catheter blood collection, and its prevention.

The study of platelet changes occurring across the coronary circulation is important in the investigation of the platelet's role in ischemic heart disease. It requires blood sampling through cardiac catheters. This could activate platelets and alter the results of tests of platelet activation and reactivity. This study was designed to examine this problem and to devise satisfactory methods for obtaining blood for platelet studies through long catheters. Blood collected through catheters introduced with a guide-wire had a much higher plasma heparin neutralising activity (HNA), platelet factor 4(PF4) and beta-thromboglobulin (beta TG) than peripheral venous blood, and lower platelet count(PC). Blood collected through catheters introduced via a sheath, and kept filled with anticoagulant/antiplatelet solution until blood sampling, gave results similar to peripheral venous blood for the PC, platelet aggregate ratio, platelet fluorescent granule count, and for plasma HNA, PF4 and beta TG. It is concluded that platelets are activated during blood collection through cardiac catheters; however, with appropriate precautions, blood which is satisfactory for platelet studies can be obtained.

Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis.

Intraepithelial eosinophils in esophageal biopsy specimens were noted to be an indicator of prolonged acid reflux. The presence of even a few intraepithelial eosinophils correlated with abnormal acid clearance determined by overnight intraesophageal pH probe study. This new marker also appeared to be an early lesion, as evidence by its presence in children under age 2 yr, and in biopsy specimens from the proximal esophagus where traditional histometric features (basal zone thickening and papillary lengthening) were lacking. Furthermore, when intraepithelial eosinophils were seen in the proximal 75% of the esophagus, they served to identify more severe disease by correlation with greater abnormalities in the pH probe study. Although this new marker is a histologic indication of prolonged acid reflux and may be appreciated in routine endoscopic biopsy specimens in children, it has been observed in patients over 18 yr of age and may be applicable to the adult population.