Effects of the novel antimigraine agent, frovatriptan, on coronary and cardiac function in dogs

The effects of frovatriptan (VML 251/SB-209509) on coronary artery function were investigated in isolated coronary arteries from beagle dogs. Low concentrations of frovatriptan produced contraction with -logEC50 7.55 +/- 0.08 (n = 11). The maximal observed contraction attained was 56 +/- 7% of the control 5-hydroxytryptamine (5-HT; 10 microM) response. At high concentrations of frovatriptan (>6 microM), reversal of sumatriptan (10 microM)-induced contractions was noted. In arteries precontracted with the thromboxane mimetic, U46619, frovatriptan produced a bell-shaped concentration-response relation with a maximal response at 600 nM. Concentrations of frovatriptan >2 microM produced marked reversal of tone, with full relaxation of precontracted tissues at 200 microM. In anesthetized, open-chest mongrel dogs, intravenous (n = 5) or intracoronary (n = 5) artery administration of frovatriptan (0.0001-1 mg/kg) had no consistent effect on left ventricular end-diastolic pressure, left end-systolic pressure, cardiac contractility, aortic blood flow, systemic peripheral resistance, coronary blood flow, coronary vascular resistance, mean arterial blood pressure, or heart rate when compared with vehicle (n = 3). Intravenous sumatriptan produced minor effects on blood pressure and heart rate. Intracoronary artery administration of sumatriptan (0.0003 mg/kg) produced an increase in systemic peripheral resistance to 120.5 +/- 8.2% compared with vehicle (97.8 +/- 5.4%; p < 0.05). This dose of sumatriptan also produced a significant increase in coronary blood flow and decrease in coronary vascular resistance. Intravenous administration of sumatriptan produced a dose-related reduction in left ventricular diastolic pressure with a reduction to 58.3 +/- 8.3% and 41.7 +/- 25% of control values observed at 0.3 and 1 mg/kg, respectively; however, administration of sumatriptan by an intracoronary route had no effect. In a model of myocardial infarction, comparable doses of sumatriptan (1.0 mg/kg) or frovatriptan (0.1 mg/kg), in terms of their effect on carotid vascular resistance, had no significant effect on infarct size. Frovatriptan had no effect on coronary blood flow after reperfusion; however, sumatriptan produced a significant reduction in coronary blood flow for < or =3 h. These studies show that frovatriptan has the capability of relaxing coronary arteries in vitro, has no overall effect on cardiac function at rest with no effect on coronary hemodynamics after myocardial infarction, and has a profile superior to that of sumatriptan.     

Assessment of digital EEG, quantitative EEG, and EEG brain mapping: report of the American Academy of Neurology and the American Clinical Neurophysiology Society

A. Digital EEG is an established substitute for recording, reviewing, and storing a paper EEG record. It is a clear technical advance over previous paper methods. It is highly recommended. (Class III evidence, Type C recommendation). B. EEG brain mapping and other advanced QEEG techniques should be used only by physicians highly skilled in clinical EEG, and only as an adjunct to and in conjunction with traditional EEG interpretation. These tests may be clinically useful only for patients who have been well selected on the basis of their clinical presentation. C. Certain quantitative EEG techniques are considered established as an addition to digital EEG in: C.1. Epilepsy: For screening for possible epileptic spikes or seizures in long-term EEG monitoring or ambulatory recording to facilitate subsequent expert visual EEG interpretation. (Class I and II evidence, Type A recommendation as a practice guideline). C.2. OR and ICU monitoring: For continuous EEG monitoring by frequency-trending to detect early, acute intracranial complications in the OR or ICU, and for screening for possible epileptic seizures in high-risk ICU patients. (Class II evidence, Type B recommendation as a practice option). D. Certain quantitative EEG techniques are considered possibly useful practice options as an addition to digital EEG in: D.1. Epilepsy: For topographic voltage and dipole analysis in presurgical evaluations. (Class II evidence, Type B recommendation). D.2. Cerebrovascular Disease: Based on Class II and III evidence, QEEG in expert hands may possibly be useful in evaluating certain patients with symptoms of cerebrovascular disease whose neuroimaging and routine EEG studies are not conclusive. (Type B recommendation). D.3. Dementia: Routine EEG has long been an established test used in evaluations of dementia and encephalopathy when the diagnosis remains unresolved after initial clinical evaluation. In occasional clinical evaluations, QEEG frequency analysis may be a useful adjunct to interpretation of the routine EEG when used in expert hands. (Class II and III evidence as a possibly useful test, Type B recommendation). E. On the basis of current clinical literature, opinions of most experts, and proposed rationales for their use, QEEG remains investigational for clinical use in postconcussion syndrome, mild or moderate head injury, learning disability, attention disorders, schizophrenia, depression, alcoholism, and drug abuse. (Class II and III evidence, Type D recommendation). F. On the basis of clinical and scientific evidence, opinions of most experts, and the technical and methodologic shortcomings, QEEG is not recommended for use in civil or criminal judicial proceedings. (Strong Class III evidence, Type E recommendation). G. Because of the very substantial risk of erroneous interpretations, it is unacceptable for any EEG brain mapping or other QEEG techniques to be used clinically by those who are not physicians highly skilled in clinical EEG interpretation. (Strong Class III evidence, Type E recommendation).     

Effects of bryostatin 1, a novel anticancer agent, on intestinal transport and barrier function: role of protein kinase C

BACKGROUND: Bryostatin 1 is a novel chemotherapeutic agent that activates specific members of the protein kinase C (PKC) family in a complex pattern overlapping with, but distinct from, that of tumor-promoting phorbol esters. Phorbol esters profoundly altered epithelial phenotype, abolishing both barrier function and Cl secretion (the latter due to loss of a key transport site, the Na-K-Cl cotransporter). The effects of bryostatin 1 on these parameters are unknown. METHODS: Cl secretion and barrier function of T84 human intestinal epithelia were assessed as cyclic adenosine monophosphate-stimulated short-circuit current and transepithelial resistance, respectively. Na-K-Cl cotransporter function and mRNA expression were assayed by 86Rb uptake and Northern analysis. RESULTS: Bryostatin 1 reduced Cl secretion, Na-K-Cl cotransport, and cotransporter mRNA expression. Unlike phorbol esters, these effects were largely transient. In contrast to phorbol esters, bryostatin 1 did not decrease barrier function. CONCLUSIONS: Bryostatin 1 transiently inhibits Na-K-Cl cotransport and Cl secretion, possibly through a PKC isoform also targeted by phorbol esters. Unlike phorbol esters, bryostatin 1 does not impair barrier function. The data imply that bryostatin 1 and phorbol esters differentially affect a PKC isoform involved in junctional regulation, and that epithelial transport and barrier function may be regulated by distinct PKC isoforms.     

Dopamine and preparatory behavior: I. Effects of pimozide.

The involvement of dopaminergic systems in appetitive and ingestive feeding behaviors was investigated in two experiments. Conditioned preparatory responses to a conditional stimulus (CS+) signaling delivery of a meal were attenuated in rats by doses of 0.4 and 0.6 mg/kg of the dopamine receptor antagonist pimozide. In contrast, animals responded in a normal fashion following the delivery of food. Similarly, in a separate study, the 20-min free-feeding intake of liquid diet by rats that had been deprived of food for 23 hr was unaffected by doses of pimozide as high as 0.6 mg/kg. These findings are consistent with the involvement of dopamine in the production of preparatory behaviors elicited by incentive stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Topographical variation of the human primary cortices: implications for neuroimaging, brain mapping, and neurobiology

The relationships of the "primary" cytoarchitectonic neocortical fields, 17, 41, 3b, and 4 (Brodmann areas), to salient topographic landmarks have been reconstructed from serial histological sections in 20 human cerebral hemispheres (10 brains). Each of these architectonic fields is found to bear a characteristic relationship to a set of enframing anatomic landmarks, in particular, gyri, fissures, and sulci, that can be readily defined by MRI. Two classes of variability were found characteristic, at least to some extent, of each of the fields. Class 1 variability--variability that is not predictable from visible landmarks--was typical of the polar and for the cuneal and lingual extracalcarine distributions of field 17 and the distribution of field 4 upon the paracentral lobule. Class 2 variability--variability that is closely predictable from visible landmarks--is seen in the marked interindividual or interhemispheric variation in size or shape of a field and was found to be prominent for all four fields. Because of the prominence of class 2 variability, direct reference to the landmarks that frame these fields may be expected to be a more reliable basis for functional mapping than reference to a template or stereotactic coordinate-based system of reference to a standard or idealized brain.     

Effects of alcohol and behavior contingencies on human aggression.

Determined the mediating effects of alcohol and behavior contingencies on aggression in male social drinkers. 72 18–35 yr old Ss were randomly assigned to 1 of 6 groups in a 3?×?2 factorial design. To control for alcohol and expectation effects, one third of the Ss received alcoholic beverages, one third received placebo drinks, and another third was not administered any beverages. Aggression was assessed by the intensity and duration of shocks administered to a bogus partner in a modification of the Buss aggression procedure. Half of the Ss were exposed to aversive contingencies correlated with their aggressive responses, and half received random aversive contingencies. The inebriated Ss were significantly more aggressive than the sober Ss. The former Ss displayed an equally aggressive pattern under both contingency conditions, whereas the nonintoxicated Ss displayed a differential response pattern affected by the contingency type. These findings are attributed to the disrupting effect of alcohol on information processing and to the mediating effect of contingencies on the nonintoxicated individuals' aggressive behavior. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Peripeduncular nucleus lesions in the rat: I. Effects on maternal aggression, lactation, and maternal behavior during pre- and postpartum periods.

Bilateral peripeduncular (PPN) lesions made on the 7th postpartum day (L7) with either radiofrequency (RF) current or N-methyl-d,l-aspartic acid (NMDA)/phosphate buffered saline (PBS) reduced maternal aggression (MA) and partially inhibited lactation without producing significant deficits in other items of maternal behavior (MB). RF-PPN lesions did not interfere with prolactin secretion, which suggests that there was deficient oxytocinergic activity. The deficit in MA was not due to interruption of afferent suckling input to the PPN: either thelectomizing females (Day L6) or producing bilateral knifecuts in the mesencephalon (placed caudal to the level of the PPN; Day L7) had no effect on MA, but both procedures impaired lactation. Deficits in MA produced by RF-PPN lesions developed gradually between Days L4 and L7; lesions made either prepartum or on Day L1 did not impair MA or MB. Deficits in lactation first appeared after RF-PPN lesions on Day L1. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of signaled and unsignaled brain stimulation, water, and sucrose reinforcement on running behavior in rats.

34 male Long-Evans hooded rats in 4 groups, reinforced with signaled electrical stimulation of the brain (S-ESB), immediate ESB (I-ESB), water, or sucrose, were run for 20 10-trial sessions in a runway. For 10 sessions the intertrial interval (ITI) was 60 sec, and for 10 sessions the ITI was 5 sec. Both ESB groups ran faster with the shorter ITI, but the ITI effect was significantly smaller for the S-ESB group. The water group showed no significant ITI effect, and the sucrose group ran faster with the longer ITI. All groups showed overnight decrements in running speed. It may be that all reinforcing stimuli have a response-facilitating effect on behavior and that this effect alone can account for both the overnight decrements and the differences in the ITI effect from group to group. (46 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Double-blind, placebo-controlled study of intravenous prostacyclin on hemodynamics in severe Raynaud's phenomenon: the acute vasodilatory effect is not sustained

In 12 patients with severe Raynaud's phenomenon (RP: ischemic ulcers or intractable pain despite use of narcotic analgetics), we studied the acute and long-term hemodynamic effects of epoprostenol on systemic and finger skin circulation. Epoprostenol was infused intravenously (i.v., initial infusion rate of 2 ng/kg/min, with a subsequent increase of 2 ng/kg/min every 30 min to the individually tolerated maximal dose of 8 ng/kg/min) in a triple, 5-h, double-blind, placebo-controlled cross-over study. During epoprostenol infusion, systolic blood pressure (SBP) remained stable, while diastolic BP (DBP) decreased (-8 mm Hg, p < 0.02), with a simultaneous increase in heart rate (HR + 14 beats/min, p < 0.001). Forearm blood flow (FBF) increased and forearm vascular resistance (FVR) decreased during epoprostenol as compared with placebo infusion (p < 0.01). Epoprostenol caused a significant increase in fingertip skin temperature (p < 0.01) as well as in laser Doppler flux (p < 0.02) before and after a standardized cooling test of the hand as compared with placebo. The increase in transcutaneous oxygen tension reached significant difference only during recovery (p < 0.02). No long-term improvement was noted during two additional cooling tests performed 1 and 6 weeks after the completed epoprostenol or placebo triple-infusion cycle. Repeated long-lasting epoprostenol infusion immediately improves the microcirculation, but these effects are not sustained after 1 week.     

The cloning and chromosomal mapping of two novel human opioid-somatostatin-like receptor genes, GPR7 and GPR8, expressed in discrete areas of the brain

Following the cloning of the opioid receptors mu, kappa, and delta, we conducted a search for related receptors. Using oligonucleotides based on the opioid and also the structurally related somatostatin receptors, we amplified genomic DNA using the polymerase chain reaction and isolated fragments of novel G protein-coupled receptor genes. Two of these gene fragments designated clones 12 and 11 were used to isolate the full-length genes. The intronless coding sequences of these genes, named GPR7 and GPR8, shared 70% identity with each other, and each shared significant similarity with the sequences encoding transmembrane regions of the opioid and somatostatin receptors. GPR7 was mapped to chromosome 10q11.2-q21.1 and GPR8 to chromosome 20q13.3. Northern blot analysis using human mRNA demonstrated expression of GPR7 mainly in cerebellum and frontal cortex, while GPR8 was located mainly in the frontal cortex. In situ hybridization revealed expression of GPR7 in the human pituitary. A partial sequence of the mouse orthologue of GPR7 was obtained, and in situ hybridization demonstrated expression in discrete nuclei of brain, namely suprachiasmatic, arcuate, and ventromedial nuclei of hypothalamus. A stable cell line expressing the GPR7 gene was created, but expression levels of the receptor were low. The available pharmacology indicated binding to several opioid drugs such as bremazocine, levorphanol, and beta-FNA, but not to the opioid receptor subtype-selective mu, delta, or kappa agonists.     

Integrative levels, the brain, and the emergence of complex behavior.

The aim of this article is to bring clarity and unification to the question of how certain complex behaviors, such as feeding, learning, language, culture, and neural complexity, are related. Three critical ideas—the organizing principle of integrative levels, the tendency for increased complexity with evolutionary change, and the contextual nature of behavioral events—are central to the discussion. A theoretical framework is presented that synthesizes existing knowledge in a meaningful way. Data are drawn from the behavioral, neuroanatomical, cognitive, and linguistic sciences and integrated within an organized and unified theoretical perspective referred to as developmental dynamic systems theory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of hemodilution on splanchnic perfusion and hepatorenal function. I. Splanchnic perfusion

Perfusion of intestinal organs increases in response to acute normovolemic hemodilution (ANH). However, detailed studies on distribution of regional splanchnic organ perfusion during ANH are lacking. We therefore carried out this study to test the hypothesis that ANH does not cause disturbance of physiologic patterns of regional splanchnic organ blood flow. After governmental permission, 22 anesthetized dogs were instrumented to allow invasive hemodynamic measurements and intracardial injection of radioactive microspheres (diameter 15 micro m) for determination of regional organ perfusion. Measurements were made at baseline (hematocrit 37 +/- 3%) and after ANH with 6% hydroxyethyl starch (mol. wt. 200000 / 0.5) to hct 20 +/- 1%. After completion of the protocol, splanchnic organs were removed and dissected into small samples according to anatomical and functional principles. Regional perfusion was determined based on the microsphere content of each sample. Hepatic, intestinal, and pancreatic blood flow increased with ANH. Hepatic arterial blood flow rose by 86%, whereas portal venous perfusion increased by 28%. Small intestine mucosal perfusion was augmented by 68% while the non-mucosal tissue compartment of the gut wall received 32% more blood flow after ANH which is in proportion to the increase in cardiac index after ANH. This redistribution of intestinal flow might be the basis for the preservation of tissue oxygenation during moderate isovolemic anemia.     

The effect of short peptides isolated from the brain of a hibernating suslik on the rat EEG and behavior

In the Drosophila embryo, at specific choice points along the major motor nerves, subsets of motor axons defasciculate and then steer into their muscle target regions. Here we describe the analysis of beaten path (beat), a gene required for the selective defasciculation of motor axons at these choice points. In beat mutant embryos, motor axons fail to defasciculate and bypass their targets. This phenotype is suppressed by mutations in FasII and conn, two genes encoding cell adhesion molecules expressed on motor axons, suggesting that beat provides an antiadhesive function. beat encodes a novel secreted protein that is expressed by motoneurons during outgrowth. Rescue and ectopic expression experiments support the model that Beat protein is secreted by motor axons where it functions to regulate their selective defasciculation at specific choice points.     

Effects of synthetic human gastrin I on movements on water, electrolytes, and glucose across the human small intestine

The effect of graded doses (0.125, 0.500, 1.00 and 2.00 mug per kg per hr) of intravenous synthetic human gastrin I (SHG) on jejunal transport of water, electrolytes, and glucose from a glucose-saline solution (solution II) was studied in 12 healthy volunteers, using an intestinal perfusion technique with a proximal occluding balloon. SHG when infused at rates of 0.500 mug per kg per hr or greater significantly reduced water and electrolyte absorption; this effect was linearly related to the dose and reached 40 to 60% of basal absorption (and only 10% for glucose) with the highest dose; insorption of sodium and water were significantly decreased by SHG. In a further group of 9 subjects no effect of SHG (2 mug per kg per hr) was found on jejunal absorption from a mannitol-saline solution (solution I) and on ileal absorption from solutions I and II; in 5 additional subjects, SHG did not decrease jejunal transit time of intraluminal fluid. There was no increase in serum thyrocalcitonin during SHG infusion. It is proposed that SHG selectively depresses the glucose-stimulated sodium transport as suggested by the reduction of the rate of net sodium absorption per micromole of glucose absorbed during SHG infusion. Physiological and pathological implications of these findings are discussed, especially in the light of the circulating levels of immunoreactive gastrin achieved during SHG infusion.     

Foci of pathological activity in the human brain and their influence on the spatial-temporal relationships of the EEG

This article discusses the following aspects of the management of the N+ neck: evolution of neck dissection; specificity of staging of the clinically N+ neck; limitations of neck dissection in patients with adverse histologic features; management of bilateral nodal metastases, fixed nodes, and nodes with involvement of skin, nerves or the carotid artery; retropharyngeal nodes; and salvage treatment of the N+ neck following prior irradiation. A summary of the author's own approach is then presented.     

Fluorometric studies on the light chains of skeletal muscle myosin. I. Effects of temperature, ionic strength, divalent metal ions, and nucleotides

Light chains of skeletal muscle myosin were studied through the reactivity of their SH groups with a fluorescent thiol reagent, N-(7-dimethylamino-4-methylcoumarinyl) maleimide (DACM). The experiments were carried out by reacting the reagent with myosin for a short time and measuring the amounts of reacted dye by fluorometry after separating light chains by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The two classes of light chains, alkali light chains and DTNB light chain, were clearly distinguished by their manner of reactivity change, and differences in their environment and in their function were suggested. Although we found that the SH groups of the DTNB light chain were susceptible to very low concentrations of Mg ions (of the order of 10-5 M), we could not observe Ca2+-induced conformational change by our technique. We also estimated the stoichiometry of light chains in skeletal muscle myosin to be 1.37 mol alkali light chain 1, 1.95 mol of DTNB light chain and 0.77 mol of alkali light chain 2 per mole of myosin from the total amounts of our reagent that reacted with each light chain.     

Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties

OBJECTIVES: This study was designed to evaluate how the atrial electrophysiological and antiarrhythmic effects of azimilide compare with those of the specific rapid delayed rectifier (IKr) blocker dofetilide. BACKGROUND: Azimilide, a new class III drug, was initially believed to be a highly selective blocker of the slow delayed rectifier (IKs), but recent studies suggest that azimilide potently blocks IKr. Thus, it has been suggested that azimilide's in vivo effects may simply be due to IKr blockade. METHODS: Dose regimens producing stable effects over time were developed, and two dose levels of azimilide (10 and then 20 mg/kg) or dofetilide (0.08 and then 0.16 mg/kg) were administered to morphine/chloralose-anesthetized dogs during sustained vagal atrial fibrillation (AF). Epicardial mapping was used to measure conduction velocity and AF cycle length. RESULTS: Azimilide terminated AF in 13/14 dogs (93%), while dofetilide terminated AF in 6/12 (50%, P < 0.05). While dofetilide had strong reverse use-dependent effects on atrial ERP (e.g. at lower doses, dofetilide increased ERP by 51 +/- 3% at a basic cycle length, BCL, of 400 ms and by 17 +/- 3% at a BCL of 200 ms), azimilide's effects on ERP were rate-independent (ERP increased at lower dose by 38 +/- 6%, BCL 400 ms; 35 +/- 10%, BCL 200 ms). Neither drug affected conduction. CONCLUSIONS: Azimilide is effective against experimental AF, and increases ERP with a frequency dependence different from the IKr blocker dofetilide, suggesting that azimilide's actions on atrial tissue cannot be attributed exclusively to IKr block, and that effects on other currents (such as IKs) are likely to be important.