Effects of the antimigraine compound zolmitriptan ('Zomig') on psychomotor performance alone and in combination with diazepam in healthy volunteers

Zolmitriptan (Zomig^TM) is a 5HT_1B/1D agonist which has the ability to cross the intact blood-brain barrier to access central as well as peripheral receptors. Because of the potential for central nervous system side effects, this randomized, double-blind, placebo-controlled, 6-period crossover study evaluated the effects of 2.5 and 5 mg doses of zolmitriptan on psychomotor performance and investigated any pharmacodynamic or pharmacokinetic interaction with diazepam. Twelve healthy volunteers received the following "treatments" as single doses: zolmitriptan 2.5 mg, zolmitriptan 5 mg, diazepam 10 mg, zolmitriptan 2.5 mg+diazepam 10 mg, zolmitriptan 5 mg+diazepam 10 mg and placebo. Pre-dose and at 1, 4, 8, and 24 h post-dose, the following validated battery of psychomotor tests was performed: Bond-Lader visual analogue scales (calmness, contentedness, and alertness factors), critical flicker fusion test, choice reaction time (recognition, motor, and total reaction times), finger-tapping test, number cancellation test and digit symbol substitution test. Plasma concentrations of zolmitriptan, its active metabolite, and diazepam and its active metabolites were measured at the same timepoints. Zolmitriptan 2.5 and 5 mg had no effect on psychomotor function when given alone. In contrast, diazepam 10 mg had profound effects, consistent with its sedative properties, but there was no synergism on concomitant administration of either dose of zolmitriptan. Plasma concentrations of zolmitriptan, diazepam, and their respective active metabolites were similar when the two drugs were given alone or in combination.     

Experimental models of brain injury

General categories of experimental brain injury models are reviewed regarding their clinical significance, and two new models are presented that use different methodology to produce injury. This report describes and characterizes the pathophysiologic changes produced by a novel fluid percussion (FP) method and a controlled cortical impact (CI) technique, both developed at the General Motors Research Laboratories (GMRL). The new models are compared to prior experimental brain injury techniques in relation to ongoing physical and analytical modeling used in automotive safety research by GMRL. Experimental results from our laboratory indicate that although the FP technique, currently the most widely used method for producing brain injury, is useful for producing graded injury responses systemically and centrally, it is not well-suited for detailed biomechanical analyses. This conclusion is based on high-speed cineradiographic studies where the physiologic saline in the FP cannula was substituted with a radiopaque contrast medium (Conray 1:1 dilution/saline). High speed x-ray movies (1000 fps) were taken of the fluid percussion pulse (1.5-3.4 atm/20 msec) in sagittal, dorsal, and frontal planes of orientation. When viewed together, the cineradiography revealed a complex, dynamic interaction between the injected fluid and the skull/cranial contents. Rapid lateral and anterior/posterior epidural fluid flow suggest that the pathology and dysfunction following FP brain injury reflects diffuse mechanical loading of the brain. Because fluid is used to transfer mechanical energy to brain tissue, and because fluid flow characteristics (i.e., direction, velocity, and displacement) are dependent on the brain geometry and species used, accurate analytical and biomechanical analyses of the resultant injury would be difficult at best. In contrast, the cortical impact model of experimental brain injury uses a known impact interface and a measurable, controllable impact velocity and cortical compression. These controlled variables enable the amount of deformation and the change in deformation over time to be accurately determined. In addition, the CI model produces graded, reproducible cortical contusion, prolonged functional coma, and extensive axonal injury, unlike the FP technique. The quantifiable nature of the single mechanical input used to produce the injury allows correlations to be made between the amount of deformation and the resultant pathology and functional changes.(ABSTRACT TRUNCATED AT 400 WORDS)     

A study of galactose intolerance in human and rat liver in vivo by 31P magnetic resonance spectroscopy.

An oral load of 20 mg/kg galactose produces significant changes in the 31P magnetic resonance spectrum of the liver of a galactosemic patient. The peak at 5.2 ppm (which includes inorganic phosphate and galactose-1-phosphate) increased on two occasions to about twice its original size 60 min after galactose administration. An oral load of 10 mg/kg galactose given to a second patient produced no discernible changes at 30 min. We have also used an animal model of galactose intolerance, in which galactose metabolism in rats was blocked by the acute administration of ethanol. Studies in vivo and in vitro showed that the increase in the peak at 5.2 ppm was largely due to galactose-1-phosphate. We have shown in this preliminary study that small amounts of galactose can produce significant elevation of hepatic galactose-1-phosphate, which can be detected by 31P magnetic resonance spectroscopy.     

Physiologic, histopathologic, and cineradiographic characterization of a new fluid-percussion model of experimental brain injury in the rat

The fluid-percussion technique produces experimental brain injury by rapid injection of a fluid volume into the closed cranial cavity. The experiments reported here characterize a new, more controlled technique for fluid-percussion brain injury in the rat and systematically examine systemic physiologic, histopathologic, and electroencephalographic responses in the rat at two levels of injury severity. The new technique was developed to permit independent variation of the fluid pressure pulse parameters and, thus, more accurately define the brain loading conditions associated with fluid-percussion injury. The new technique produced changes in mean arterial blood pressure similar to previous techniques; however, bradycardia was not observed. Significant increases in heart rate were produced by both injury levels and were more prolonged at the high level of injury severity. Both magnitudes of injury produced significant decreases in EEG amplitude immediately postinjury, but high severity injury produced a greater decrease in delta frequency band (1-4 Hz) activity than did low severity injury. Both levels produced hemorrhage at the site of injury, thalamus, corpus callosum, hippocampus, and fimbria hippocampus similar to previous techniques. Higher levels of injury produced more extensive cerebral hemorrhage and greater spinal involvement. In a separate group of animals, cineradiographic images were made at coronal, sagittal, and dorsal orientations during the fluid pressure pulse. Intracranial fluid movement was characterized by rapid radial movement within the epidural space. The data suggest that the distributed nature of fluid-percussion induces pathology, and dysfunction may reflect a diffuse mechanical loading of the brain surface. The model appears to give repeatable effects useful in the study of closed head injury.     

Copper vapor laser fragmentation of gallstones: in vitro measurements of wall heat transmission

Laser fragmentation is a promising new modality in management of retained CBD stones. Recent reports demonstrate the feasibility of lasers for this, but few studies have evaluated their safety (e.g., thermal injury may occur at greater than 43 degrees C). This study was conducted to measure heat transmission from lased bilirubinate and mixed stones to a simulated CBD wall. Four welded thermocouples were passed to the inside wall of 6-mm polyvinyl tubing 90 degrees apart to surround the lumen stone. The thermocouples were interfaced to a computer and temperatures were recorded every 270 msec. The tubing was submerged in a 37 degrees C water bath for all lasing work. A copper vapor laser (wavelength, 510 nm; 5.6 W; 5 kHz; pulse length, 30 ns) was attached to a 650-micron quartz fiber. A stone was "impacted" in the tubing and the laser fiber was pushed against the stone while making multiple passes to fragment it. Thirty mixed gallstones (mean size, 6.9 X 5.1 mm) and 20 bilirubinate gallstones (mean size, 7.1 X 5.2 mm) were fragmented during the study. Maximum temperature (Tmax), duration of Tmax (TmaxD), interval to stone piercing (TiP), and interval to fragmentation (TiF) were measured and comparisons were carried out with the SPSS statistical package using the t test procedure. The Tmax generated during fragmentation of bilirubinate stones (43.4 +/- 1.7 degrees C) was significantly less (P less than 0.002) than the Tmax for mixed stones (54.0 +/- 2.7 degrees C) but both Tmax values represented potentially injurious temperature levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reflux gastritis in the intact stomach.

Gastric biopsy specimens from patients who have undergone gastric surgery frequently exhibit foveolar hyperplasia, oedema, vasodilatation and congestion, and a paucity of inflammatory cells as consequences of entero-gastric reflux. Similar, albeit generally milder, changes were found in 47 of 316 (15%) non-surgical patients undergoing endoscopy for dyspeptic symptoms. To relate these changes to bile reflux or other potential gastric irritants the total bile acid concentration was measured in samples of fasting gastric juice, and the use of a symptom questionnaire ascertained the patients' cigarette consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and alcohol intake. When patients with reflux gastritis were compared with normal controls (n = 91), significant increases in associated peptic ulceration and NSAID use were found in the group with reflux, but no increases in bile acid concentrations. Indeed, only one patient had evidence of duodenogastric reflux. It is concluded that most cases of "reflux gastritis" in the intact stomach are not due to reflux of bile. Our findings indicate an important pathogenic role for long term NSAID use, in what might be usefully termed type C or "chemical" gastritis.     

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.