Ictal speech and language dysfunction in adult epilepsy: Clinical study of 95 seizures.

PURPOSE: To analyze the semiological characteristics of the language and speech disorders arising during epileptic seizures, and to describe the patterns of language and speech disorders that can predict laterality of the epileptic focus. METHOD: This study retrospectively analyzed 95 consecutive videos of seizures with language and/or speech disorders in 44 patients admitted for diagnostic video-EEG monitoring. Laterality of the epileptic focus was defined according to electro-clinical correlation studies and structural and functional neuroimaging findings. Language and speech disorders were analyzed by a neurologist and a speech therapist blinded to these data. RESULTS: Language and/or speech disorders were subdivided into eight dynamic patterns: pure anterior aphasia; anterior aphasia and vocal; anterior aphasia and "arthria"; pure posterior aphasia; posterior aphasia and vocal; pure vocal; vocal and arthria; and pure arthria. The epileptic focus was in the left hemisphere in more than 4/5 of seizures presenting with pure anterior aphasia or pure posterior aphasia patterns, while discharges originated in the right hemisphere in almost 2/3 of seizures presenting with a pure vocal pattern. No laterality value was found for the other patterns. CONCLUSION: Classification of the language and speech disorders arising during epileptic seizures into dynamic patterns may be useful for the optimal analysis of anatomo-electro-clinical correlations. In addition, our research has led to the development of standardized tests for analyses of language and speech disorders arising during seizures that can be conducted during video-EEG sessions.

GABA spectra and remote distractor effect in progressive supranuclear palsy: A pilot study.

Disturbances of the gamma-aminobutyric-acid (GABA) system have been suspected of contributing to the pathophysiology of progressive supranuclear palsy (PSP). The ability to rapidly resolve competitive action decisions, such as shifting the gaze to one particular stimulus rather than another, can be predicted by the concentration of GABA in the region of the frontal cortex relevant to eye movements. For this reason, our study measured GABA levels in seven PSP patients and eight healthy controls, using proton magnetic resonance spectroscopy, and assessed the relationship of these measurements to the remote distractor effect (RDE), an eye-movement paradigm investigating competitive action decisions. No significant differences were found in either frontal-eye-field GABA levels or RDE between PSP patients and controls.

Thrombolysis in Stroke Patients with Isolated Aphasia.

BACKGROUND: Data about evolution of aphasia following stroke are rare and controversial especially following fibrinolysis. The aim of this study was to describe the early clinical patterns of isolated aphasia in consecutive stroke patients with or without thrombolysis. METHODS: Clinical and radiological data of consecutive stroke patients were routinely entered in prospective registry. Patients were considered aphasic when NIHSS (National Institutes of Health Stroke Scale) item 9 >0. 'Isolated aphasia' was defined by aphasic patients without motor limb deficit. We created a 'composite language score' obtained by summing the NIHSS items 1b, 1c and 9, which reflects language-processing ability. Recovery of functions was evaluated as measured by global NIHSS, composite language score and language screening test (LAST) at baseline, H24 and day 7 (D7). 'Mild deficit' was defined as global NIHSS <5. RESULTS: A total of 100 consecutive patients met study criteria for isolated aphasia. Twenty-five underwent thrombolysis and 75 did not. There was no difference between the 2 groups concerning demographic characteristics, involved territories and presence of arterial occlusion, initial median NIHSS, composite language and LAST scores at entrance. Evolution was significantly better in thrombolysed patient for the 3 testings: NIHSS, composite language score and LAST at D7 (respective p = 0.0002; p = 0.01 and p = 0.004). Similar results were found when we focused on the subgroups of patients with initial 'mild' deficits (p = 0.01; p = 0.0003 and p = 0.007). No symptomatic hemorrhagic transformation occurred following thrombolysis. CONCLUSION: These data strongly suggest that thrombolysis is safe and effective in patients with 'isolated aphasia,' even if the global NIHSS score is <5.

Hypnosis and movement disorders: State of the art and perspectives.

INTRODUCTION: Hypnosis might represent an interesting complementary therapeutic approach to movement disorders, as it takes into account not only symptoms, but also well-being, and empowers patients to take a more active role in their treatment. METHODS: Our review of the literature on the use of hypnosis to treat movement disorders was done by systematically searching the PubMed database for reports published between 1984 and November 2015. The following variables were extracted from each selected paper: study design; sample size; type of movement disorder; hypnotic procedure; treatment duration; and efficacy. RESULTS: Thirteen papers were selected for detailed analysis. Most concerned tremor in Parkinson's disease and tics in Gilles de la Tourette syndrome. Although promising, the data were insufficient to allow conclusions to be drawn on the efficacy of hypnosis in movement disorders or to recommend its use in this setting. CONCLUSION: Well-designed studies taking into account some specific methodological challenges are needed to determine the possible therapeutic utility of hypnosis in movement disorders. In addition to the potential benefits for such patients, hypnosis might also be useful for studying the neuroanatomical and functional underpinnings of normal and abnormal movements.

'The Move', an innovative simulation-based medical education program using roleplay to teach neurological semiology: Students' and teachers' perceptions.

INTRODUCTION: Neurological disorders are frequently being managed by general practitioners. It is therefore critical that future physicians become comfortable with neurological examination and physical diagnosis. Graduating medical students often consider neurological examination as one of the clinical skills they are least comfortable with, and they even tend to be neurophobic. One way to improve the learning of neurological semiology is to design innovative learner-friendly educational methods, including simulation training. METHODS: The feasibility of mime-based roleplaying was tested by a simulation training program in neurological semiology called 'The Move'. The program was proposed to third-year medical students at Pierre and Marie Curie University in Paris during their neurology rotation. Students were trained to roleplay patients by miming various neurological syndromes (pyramidal, vestibular, cerebellar, parkinsonian) as well as distal axonopathy, chorea and tonic-clonic seizures. Using an anonymous self-administered questionnaire, the students' and teachers' emotional experience and views on the impact of the program were then investigated. RESULTS: A total of 223/365 students (61%) chose to participate in the study. Both students and teachers felt their participation was pleasant. Students stated that The Move increased their motivation to learn neurological semiology (78%), and improved both their understanding of the subject (77%) and their long-term memorization of the teaching content (86%). Although only a minority thought The Move was likely to improve their performance on their final medical examination (32%), a clear majority (77%) thought it would be useful for their future clinical practice. Both students (87%) and teachers (95%) thought The Move should be included in the medical curriculum. CONCLUSION: Mime-based roleplaying simulation may be a valuable tool for training medical students in neurological semiology, and may also help them to overcome neurophobia.

[LAST-Q: Adaptation and normalisation in Quebec of the Language Screening Test]. / LAST-Q: adaptation et normalisation franco-québécoises du Language Screening Test.

The goal of the present study was to adapt and to establish normative data for the recently developed Language Screening Test (LAST; Flamand-Roze et al., 2011) in the French-Canadian population according to age and level of education. After an adaptation process, 100 French-Canadian speakers were evaluated with the LAST-Q. As expected, a perfect score of 15/15 was obtained for all high level education participants, and a score of 14/15 was obtained for all participants with a lowest level of education or aged 80 years or more. Thanks to this adaptation, LAST-Q can be used in acute patients in stroke unit in Quebec.

[Language and swallowing disorders in acute stroke patients: tools and early management]. / Troubles du langage et de la déglutition à la phase aiguë des accidents vasculaires cérébraux : outils d'évaluation et intérêt d'une prise en charge précoce.

INTRODUCTION: The contribution of stroke units to improve morbidity, mortality and recovery in stroke victims is clearly demonstrated. However, acute management of language disorders in these specialized units is controversial and little standardization is seen for the management of swallowing disorders. STATE OF THE ART: The recently validated French scale for rapid screening for language disorders (LAST) in acute stroke patients should enable optimal detection and early management. A standardized protocol should be used to screen for and manage swallowing disorders. This protocol should include daily evaluations, individually tailored rehabilitation sessions, adaptation of food textures, patient education for adequate eating position, team training, and information for families. PERSPECTIVES AND CONCLUSIONS: These protocols imply co-operation and coordination between the medical and allied profession teams and the daily presence of a speech and language therapist. This presence is crucial for patients in stroke units to achieve the full benefits of the management scheme proposed in this paper.

Aphasia in border-zone infarcts has a specific initial pattern and good long-term prognosis.

BACKGROUND: While border-zone infarcts (BZI) account for about 10% of strokes, studies on related aphasia are infrequent. The aim of this work was to redefine specifically their early clinical pattern and evolution. METHODS: We prospectively studied consecutive patients referred to our stroke unit within a 2-year period. Cases of aphasia in right-handed patients associated with a MRI confirmed left-sided hemispheric BZI were included. These patients had a standardized language examination in the first 48 h, at discharge from stroke unit and between 6 and 18 months later. RESULTS: Eight patients were included. Three had anterior (MCA/ACA), two posterior (MCA/PCA), two both anterior and posterior, and one bilateral BZI. All our patients initially presented transcortical mixed aphasia, characterized by comprehension and naming difficulties associated with preserved repetition. In all patients, aphasia rapidly improved. It fully recovered within a few days in three patients. Initial improvement was marked, although incomplete in the five remaining patients: their aphasias specifically evolved according to the stroke location toward transcortical motor aphasia for the three patients with anterior BZI and transcortical sensory aphasia for the two patients with posterior BZI. All patients made a full language recovery within 18 months after stroke. CONCLUSIONS: We report a specific aphasic pattern associated with hemispheric BZI, including an excellent long-term outcome. These findings appear relevant to (i) clinically suspect BZI and (ii) plan rehabilitation and inform the patient and his family of likelihood of full language recovery.

[Congenital hypogonadotropic hypogonadism]. / Hypogonadisme hypogonadotrope congénital.

Congenital hypogonadotropic hypogonadism is defined by reduced steroid hormone synthesis and secretion due to low LH and FSH secretion. It is a rare disease with an unknown prevalence (about 1/5000). It results from a fetal defect in GnRH neuron migration, a defect of pituitary development or from a functional defect of the hypothalamopituitary axis between GnRH neurons and gonadotropic cells. The diagnosis should be considered at birth in males with micropenis, during adolescence in case of delayed puberty or absent puberty, and during adulthood in case of infertility. It may be restricted to the gonadotropic axis, combined with other endocrine system defects or be part of a complex syndrome. Several gene defects have now been described. Molecular studies should be performed to confirm the diagnosis and to help provide appropriate genetic counseling. Treatment to induce puberty should be provided at adolescence, followed by hormonal substitution treatment during adulthood. Specific infertility treatment may also be proposed but patients with the dominant form of gonadotropic deficiency should be informed of the risk of transmission.

PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine.

Dietary proteins are mostly absorbed as di- and tripeptides by the intestinal proton-dependent transporter PepT1. We have examined the effects of leptin on PepT1 function in rat jejunum and in monolayers of the human enterocyte-like 2 cell Caco-2. Leptin is produced by the stomach and secreted in the gut lumen. We show here that PepT1 and leptin receptors are expressed in Caco-2 and rat intestinal mucosal cells. Apical (but not basolateral) leptin increased Caco-2 cell transport of cephalexin (CFX) and glycylsarcosine (Gly-Sar), an effect that was associated with increased Gly-Sar uptake, increased membrane PepT1 protein, decreased intracellular PepT1 content, and no change in PepT1 mRNA levels. The maximal velocity (Vmax) for Gly-Sar transport was significantly increased by leptin, whereas the apparent Michaelis-Menten constant (Km) did not change. Furthermore, leptin-stimulated Gly-Sar transport was completely suppressed by colchicine, which disrupts cellular translocation of proteins to plasma membranes. Intrajejunal leptin also induced a rapid twofold increase in plasma CFX after jejunal perfusion with CFX in the rat, indicating enhanced intestinal absorption of CFX. These data revealed an unexpected action of gastric leptin in controlling ingestion of dietary proteins.

Structure-activity studies including a Psi(CH(2)-NH) scan of peptide YY (PYY) active site, PYY(22-36), for interaction with rat intestinal PYY receptors: development of analogues with potent in vivo activity in the intestine.

Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.

Effect of alpha 2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat.

1. The purpose of the present study was to analyze the effects of the alpha 2-adrenoceptor agonists clonidine, guanabenz, detomidine and medetomidine on pepsin secretion in conscious rats provided with gastric chronic fistula and to compare this with acid secretion. 2. Basal interdigestive gastric secretion, which is mainly neurally driven in the rat, and the secretion directly stimulated by the two main stimulants of chief cells, cholecystokinin octapeptide (CCK8) and methacholine, were studied. 3. Basal secretion of pepsin and acid was inhibited by all four drugs with comparable EC50S. 4. CCK-stimulated pepsin and acid secretion was less sensitive than basal pepsin and acid secretion to alpha 2-adrenoceptor inhibition. 5. Methacholine-stimulated pepsin and acid secretion was not changed by clonidine and guanabenz; methacholine-stimulated acid was even marginally increased by clonidine. 6. These results do not favour the presence of alpha 2-receptors on chief cells in the rat stomach. They rather suggest that pepsin inhibition by alpha 2-adrenoceptor agonists is indirect and due to central or peripheral inhibition of the discharge of nerve fibres activating pepsin secretion.

In vivo activities of peptide and pseudo-peptide analogs of the C-terminal octapeptide of cholecystokinin on pancreatic secretion in the rat.

Most studies measuring the agonist and antagonist activities of CCK analogs and derivatives on the exocrine pancreas have been done with in vitro models. However, extrapolation to the in vivo situation may be sometimes hazardous, due to the catabolism of the peptides by circulating and tissue peptidases, and to their eventual interaction with various endogenous factors. The present experiments were organized to measure the efficacy and potency on pancreatic secretion of the rat in vivo of a series of CCK 8 analogs whose binding and activity had been previously measured on guinea-pig and rat isolated acini. The molecules tested were derivatives of Boc-(Nle 28-Nle 31)-CCK 26-33 (1), and comprised 2-phenylethylester derivatives, des-Phe derivatives, and a series of pseudo-peptides with a "reduced" bond CH2-NH replacing the peptide bond in position 28-29 to 32-33. They were perfused in anaesthetized rats, and the outputs of sodium, bicarbonate and total protein were measured. All of the derivatives studied had in vivo the same efficacy as (1) on the output of protein, and were 10 to 500 times less potent. For most compounds, the relative order of potencies measured in vivo was similar to that measured in vitro on amylase secretion by rat acini. However, the derivatives with reduced bonds in positions 28-29 and 29-30 were respectively 3 and 2 times less potent in vivo, relative to (1), while derivatives with reduced bonds in positions 30-31, 31-32 and 32-33 were 1.5 to 2.5 times more potent in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of pepsin secretion by regulatory peptides in the rat stomach: comparison with acid secretion.

Previous studies of the control of pepsin secretion by neurohumoral agents showed some discrepancies between in vitro (isolated cells) and in vivo experiments. In the present work, the effects on pepsin secretion of CCK, pentagastrin, secretin, VIP, neurotensin, histamine, and methacholine were reinvestigated in conscious gastric fistula rats, in comparison to acid secretion. ED50's and doses inducing maximal responses were measured to directly compare the potency and efficacy of these substances. Methacholine was the most efficient (maximal response = 4.5 x basal level, ED50 = 1.3 mumol/kg.h) and CCK the most potent (ED50 = 1.9 nmol/kg.h) stimulant, whereas secretin was a potent (ED50 regulators of pepsin secretion in the rat. Pentagastrin and histamine did not stimulate pepsin output, as found by others with isolated chief cells in vitro. Neurotensin and large doses of VIP marginally inhibited pepsin secretion.

Endogenous opioid peptides in the control of food intake in cats.

In this report, we investigated the role of exogenous and endogenous enkephalins on food intake in the cat, using, respectively, exogenous [D-Ala2-Met5]-enkephalin (DAME) and acetorphan (Ac) in order to inhibit the degradation of endogenous enkephalins. In addition, the selective peripheral antagonist naltrexone methylbromide (NTxMB) and the nonselective antagonist naloxone (Nx) were used in an attempt to discriminate central and peripheral opioid receptors. In 18-hours food-deprived animals, Ac (5 mg/kg IV) increased milk intake during sham feeding (+18%, p less than 0.05), but did not modify it in feeding conditions. Nx (1 mg/kg SC) reduced milk intake in sham-feeding experiments (-67%, p less than 0.01) more than in milk-feeding conditions (-30%, p less than 0.01). NTxMB (1 mg/kg SC) did not modify milk intake in sham-feeding but decreased it in feeding experiments. In nonfasted animals, Ac did not modify food intake. IV infusion of DAME (50 micrograms/kg) resulted in a reduction of daily food intake (-32%, p less than 0.01). Nx (1 mg/kg SC) decreased the earlier 30 min intake followed by reduction of daily intake (-30%, p less than 0.01). NTxMB (1 and 4 mg/kg SC) increased the 30-min intake dose dependently, without significant change in daily intake. In conclusion, Ac increases food intake in sham-feeding conditions, suggesting that endogenous enkephalins are likely to be involved in the stimulation of food intake. The effects of Nx and NTxMB furthermore suggest both a central activation, and a peripheral inhibition of food intake by opiates when food is allowed to proceed normally through the digestive tract.

Effect of rGRF on exocrine pancreatic secretion of the rat in vivo.

Human and rat GRFs have been reported to stimulate cAMP production and amylase release by guinea pig acinar cells in vitro, with different potencies. Previous reports indicated that hGRF had no effect on pancreatic secretion of the rat in vivo. In the present experiments, dose-response studies were made with rGRF, VIP and secretin on the pancreatic secretion of anaesthetized rats. All three peptides stimulated pancreatic secretion. rGRF induced a slight water and electrolyte secretion, with an efficacy about ten times smaller than secretin, and a potency about thirty times smaller. rGRF stimulated total protein output with the same efficacy as secretin and VIP, and with the same potency as VIP, that is about 100 times smaller than secretin. rGRF increased the concentration of total protein, but not that of bicarbonate in pancreatic juice. Maximal doses of VIP and rGRF did not show any additive effect. It is concluded that large doses of rGRF are able to stimulate the rat acinar cells in vivo, presumably through an interaction with VIP receptors.

Antisecretory effect of peptide YY through neural receptors in the rat jejunum in vitro.

Basal short circuit current (Isc) was measured in stripped rat jejunum after addition of neural antagonists and of peptide YY (PYY). Basal Isc was slightly (by 10-21%) but significantly inhibited by tetrodotoxin, hexamethonium, idazoxan, and the sigma antagonist BMY 14,802. PYY (10(-7) M) reduced basal Isc by approximately 54%. This inhibition was unchanged by hexamethonium but reduced by 44-68% in the presence of tetrodotoxin, idazoxan, haloperidol, BMY 14,802, and atropine. The Y2 agonist pYY(3-36) was more potent than the Y1 agonist (Leu31,Pro34)PYY. In conclusion, PYY reduces basal Isc in rat jejunum in part through a neural mechanism involving muscarinic receptors, alpha2 adrenoceptors, and sigma receptors and, in part, through a direct effect on enterocytes. The PYY effect seems mainly carried out through Y2-receptor activation.

Inhibitory effects of peptide YY on basal and VIP-stimulated short-circuit current in the rat jejunum: influence of technical conditions on observed results.

The interaction of PYY and VIP was studied in stripped and intact rat jejunum preparations mounted in Ussing chambers. PYY decreased basal Isc in intact as well as in stripped jejunum. Stripping was necessary to evidence a stimulation of basal Isc by VIP. When PYY and VIP were administered at the same time in the serosal bath, their effects seemed additive; VIP stimulation took over when VIP was present in ten times larger amounts than PYY, while PYY inhibition predominated at isomolar concentrations (10(-7) M) of both peptides. However, when PYY was administered three to six minutes before isomolar amounts of VIP, the VIP stimulation developed without being notably hampered. At this time, however, the amount of radioimmunoassayable PYY in the serosal compartment represented still 60% of the added amount. In conclusion, the experimental conditions can significantly change the results: stripping the longitudinal muscle/myenteric plexus impairs the effect of PYY and VIP in a different fashion, while the timing and order of administration of the peptides may change the apparent interaction between VIP stimulation and PYY inhibition.

Neural mechanism of the antisecretory effect of peptide YY in the rat colon in vivo.

The purpose of this work was to determine the mechanism of the antisecretory effect of peptide YY in the rat colon and whether this effect is physiological. In this prospect, doses of exogenous peptide YY producing physiological and supraphysiological plasma levels were intravenously infused in rats provided with colonic and jejunal ligated loops in vivo, under secretory stimulation by vasoactive intestinal peptide. Peptide YY decreased the secretory effect of VIP in a dose-related fashion. The effect of peptide YY was blocked or strongly decreased by tetrodotoxin, hexamethonium, idazoxan, haloperidol, and the sigma antagonist BMY 14, 802 in both the colon and jejunum. We conclude that peptide YY decreases water and electrolyte secretion in the colonic mucosa by a complex neural mechanism involving at least two neurons connected through a nicotinic synapse, alpha-2 adrenoceptors and sigma receptors, and that this effect can occur with physiological doses of peptide YY.

External pancreatic secretion in the rat: supramaximal inhibition induced by the cholecystokinin octapeptide [CCK(26-33)] and analogs altered on the 28-29 bond.

Supramaximal doses of cholecystokinin induce in vitro submaximal biological responses, desensitization and residual stimulation. In vivo, supramaximal inhibition and oedematous pancreatitis have been reported. The aim of this study was to analyze the in vivo response of the pancreatic secretion of the rat to a wide range of doses of CCK8 and analogs prepared by alterations of the Met(28)-Gly(29) bond, a modification that may lead to potent agonists. We used Boc-[Nle28-Nle31]-CCK(26-33) (1) and derivatives of (1) with the 28-29 peptide bond replaced by CH2-NH (2), CO-CH2 (3), CH2-CH2 (4), NH-CO (5). On infusions, the ED50's (pmol/kg.min) for protein output were 4 for CCK8 and (1), 11 for (3), 40 for (2) and (4), and 860 for (5). The relative order of the in vivo potencies was near to the one determined in vitro on isolated rat acini. On bolus injections, the maximal response was observed with 300 pmol/kg of CCK8, and peaked 10-15 min after the injection. With higher doses of CCK8, the secretory peak was smaller, and was delayed relative to the moment of the injection. Supramaximal doses of CCK analogs induced the same pattern of response; however, the peak injection delay was in some cases smaller than after CCK8. Determination of the plasma CCK levels indicated that the time of peak effect after supramaximal doses of CCK8 was delayed relative to the time of effective maximal plasma CCK levels. This suggests a slow dissociation of CCK8 from one of its pancreatic binding sites in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)