The effects of clonazepam and vigabatrin in hyperekplexia

Hyperekplexia is an autosomal dominant disorder caused by a point mutation in the al subunit of the glycine receptor, characterized by excessive startle responses followed by temporary generalized stiffness. Clonazepam, effective in open case studies, potentiates, through unknown mechanisms, the neurotransmitter gamma-aminobutyric acid (GABA). Vigabatrin increases GABA by inhibition of the GABA catabolic enzyme GABA-transaminase. Effects of clonazepam (1 mg for 1 day) and vigabatrin (1000 mg per day for 5 days) were investigated in a double-blind placebo-controlled cross-over study in 4 patients with hyperekplexia. The pharmacodynamic parameters were startle reflexes, studied 3 times during the day. At each time, 2 trains of IO auditive stimuli (113 dB) were given at intervals of 10 and 60 s. Startle movements were quantified with summed areas of EMG-bursts of the orbicularis oculi, sternocleidomastoid, biceps and thenar muscles. The degrees of stiffness and drowsiness were quantified with visual analogue scores (VAS) IO times during the day, by both the patient and the observer. Clonazepam, but not vigabatrin, reduced startle activity significantly in both paradigms. The degree of stiffness and drowsiness was not significantly influenced by either drug. (C) 1997 Elsevier Sciences B.V

The effect of duodenal distension upon antro-pyloric motility and liquid gastric emptying in pigs

Article first published online: 21 JAN 2008Background: This study has investigated first the role of the antrum and pylorus in the retardation of gastric emptying during distension of the duodenum, and second whether ascending duodenal intramural nerves contribute to control of both antro-pyloric motility and liquid gastric emptying in response to distension of the duodenum. Methods: Studies were performed on 18 pigs. In six the duodenum was transected 1–2 cm distal to the pylorus, to intempt intramural nerves, in six the pylorus was excised and a further six pigs without any transection or resection acted as controls. Motility of the antrum, pylorus and duodenum was recorded by a sleeve/side hole manometric catheter. Gastric emptying was measured by drainage of the duodenum through a cannula. Results: In control animals distension of the duodenum inhibited antro-pyloric pressure waves (APPW), from 1.52 waves/min at minimum distension to 0.25/min at maximum distension (P = 0.0007), stimulated isolated pyloric pressure waves (IPPW), from 0.56/min to 1.80/min (P = 0.034) and slowed emptying of a 1000 mL load of 5% dextrose over 30 min from 788 mL to 251 mL (P = 0.0001). Duodenum transected animals did not show the duodenal distension-induced stimulation of IPPW (maximum distension: 0.93/min), but both the distension-induced inhibition of APPW (maximum distension: 0.85/min) and slowing of emptying (maximum distension: 52 mL emptied) were unaltered. Similarly in pylorus-excised animals, duodenal distension inhibited APPW (maximum distension: 0.47/min) and slowed liquid emptying (maximum distension: 267 mL), effects which did not differ from control animals. Retardation of gastric emptying by duodenal distension may be due in part to inhibition of antral contractions. Conclusions: Under the conditions of this experiment, increased pyloric resistance to flow does not play a major role in the slowing of emptying by duodenal distension, but the stimulation of the pylorus by duodenal distension depends on duodenal intramural neural pathways. Duodenal distension-induced feedback control of emptying is mediated primarily via pathways other than ascending intraduodenal nerves.P. J. Treacy, G. G. Jamieson and J. Den

Effects of posture on gastric emptying, transpyloric flow, and hunger after a glucose drink in healthy humans

The original publication can be found at www.springerlink.comPrevious studies suggest that posture has relatively little effect on gastric emptying of high-nutrient liquids; these studies have, however, only assessed overall rates of gastric emptying, whereas gastric emptying is known to be predominantly a pulsatile phenomenon. In healthy subjects perceptions of appetite, such as hunger, are inversely related to antral area and content; hence, changes in intragastric meal distribution induced by posture may affect appetite. Gastric emptying is a major determinant of postprandial glycemia. The aims of this study were to evaluate the effects of posture on patterns of transpyloric flow (TF), gastric emptying (GE), antral area (AA), hunger, and the glycemic response to oral glucose. Eight healthy young subjects (five males, three females; mean age, 24.0 ± 2.4 years; BMI, 21.2 ± 0.6 kg/m2) were studied twice in random order, once in the sitting position and once in the lying (supine) position. After consuming 600 ml water with 75 g glucose, labeled with 20 MBq 99mTc-sulfur colloid, subjects had simultaneous measurements of (i) TF during consumption of the drink by Doppler ultrasonography, (ii) GE with scintigraphy, (iii) AA at t = −5 and t = 30 min by ultrasonography, and (iv) perceptions of appetite with a visual analogue scale. During drink ingestion TF was greater in the sitting, compared with the lying, position (586 ± 170 vs. 177 ± 65 [cm/sec]×sec; P < 0.05). Posture affected intragastric distribution; more of the drink was retained in the distal stomach in the sitting position (e.g., at 30 min: sitting, 29 ± 3%, vs. lying, 12 ± 3%; P < 0.0001) but had no effect on the overall rate of GE or the blood glucose response. AA at t = 30 min (P<0.005) was greater in the sitting position; there was an inverse relationship between hunger and AA at 30 min (r = −0.53, P < 0.05). We conclude that posture influences initial TF and intragastric distribution, but not the overall rate of GE of, or the glycemic response to, a large-volume nutrient liquid. The increases in AA and content in the sitting position are associated with a reduction in hunger.Karen L. Jones, Deirdre O’Donovan, Michael Horowitz, Antonietta Russo, Yong Lei, Trygve Hauske

Sample collection, biobanking, and analysis

Pediatric pharmacokinetic studies require sampling of biofluids from neonates and children. Limitations on sampling frequency and sample volume complicate the design of these studies. In addition, strict guidelines, designed to guarantee patient safety, are in place. This chapter describes the practical implications of sample collection and their storage, with special focus on the selection of the appropriate type of biofluid and withdrawal technique. In addition, we describe appropriate measures for storage of these specimens, for example, in the context of biobanking, and the requirements on drug assay methods that they pose. Pharmacokinetic studies in children are possible, but they require careful selection of an appropriate sampling method, specimen volume, and assay method. The checklist provided could help prospective researchers with the design of an appropriate study protocol and infrastructur

New management approaches for gastroparesis

Copyright © 2005 Nature Publishing GroupManagement of patients with gastroparesis is challenging. Although the syndrome has multiple causes and knowledge of the pathophysiology and natural history is far from complete, a number of common management principles can be applied. The relatively poor correlation between uppergastrointestinal symptoms and disordered gastric emptying represents a major difficulty in the therapeutic approach, and evidence to support the efficacy of current management strategies is often suboptimal, especially in relation to long-term therapy. In this review, the common causes and pathophysiology of gastroparesis are summarized, the diagnostic approach considered, and the evidence to support medical and surgical therapies reviewed. These therapies include currently available prokinetic drugs, novel medical therapies, and the promising technique of gastric electrical stimulation.Christopher K Rayner and Michael Horowit