bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Pharmacology of GW280430A in Humans
Authors: Belmont Matthew R. , Lien Cynthia A. , Tjan Joseph , Bradley Eleanor , Stein Brenna , Patel Sanjay S. , Savarese John J. 
Published: March 2004

Background
An ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans.

Methods
Thirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring.

Results
The ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25-75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 x ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 x ED95 exhibited plasma histamine concentrations indicative of significant histamine release.

Conclusions
GW280430A has a rapid onset and ultrashort duration of action. The recovery rate is rapid, predictable, and independent of dose. Doses at least up to 2.5 x ED95 seem to be free of side effects and seem to be able to provide relaxation within 60-90 s.
Intracarotid Verapamil Decreases both Proximal and Distal Human Cerebrovascular Resistance
Authors: Joshi Shailendra , Meyers Philip M. , Pile-Spellman John , Wang Mei , Sahlein Daniel H. 
Published: March 2004

Background
The authors determined the segmental effects of intracarotid verapamil in human subjects by using a novel method of measuring proximal and distal cerebrovascular resistance. Their hypothesis was that intracarotid verapamil, a calcium channel-blocking drug that augments cerebral blood flow and reverses arterial spasm, would decrease both the proximal-conductance and the distal-arteriolar resistance.

Methods
Coaxial catheters were transfemorally floated into internal carotid and middle cerebral arteries during cerebral angiography. Pressures were recorded in the femoral, internal carotid, and middle cerebral arteries. Hemispheric cerebral blood flow was measured by the intracarotid Xe injection technique. Cerebrovascular resistance was measured for the proximal and distal arteries. Cerebral blood flow and hemodynamic data were recorded during intracarotid infusion of saline and verapamil (1 mg/min) for 5 min. Transcranial Doppler blood flow velocity in the middle cerebral artery was also recorded.

Results
Intracarotid verapamil increased in 133Xe cerebral blood flow from 43 +/- 11 to 59 +/- 11 ml.100 g(-1).min(-1) (P = 0.001; n = 9). The cerebrovascular resistance measured for the proximal and distal arteries decreased from 0.17 +/- 0.95 to 0.12 +/- 0.75 and from 1.63 +/- 0.78 to 1.03 +/- 0.33 mmHg.ml(-1).100 g(-1).min(-1) (P < 0.01), respectively. The calculated proximal-conductive and distal-arteriolar (pial plus parenchymal) resistances showed a similar decrease. Transcranial Doppler measurements (n = 5) underestimated the effects of intracarotid verapamil that were consistent with an increase in middle cerebral artery diameter.

Conclusions
Intracarotid verapamil decreases both the proximal-conductance and the distal-arteriolar resistance. Furthermore, it is feasible to investigate segmental effects of drugs in human subjects by measuring changes in pressure gradients within the cerebral arteries and simultaneous Xe cerebral blood flow measurements.
Mixed-effects Modeling of the Influence of Alfentanil on Propofol Pharmacokinetics
Authors: Mertens Martijn J. , Olofsen Erik , Burm Anton G. L. , Bovill James G. , Vuyk Jaap 
Published: March 2004

Background
The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol.

Methods
The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed.

Results
A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model.

Conclusions
Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.
Nerve Injury Induces a Tonic Bilateral μ-Opioid Receptor–mediated Inhibitory Effect on Mechanical Allodynia in Mice
Authors: Mansikka Heikki , Zhao Chengshui , Sheth Rishi N. , Sora Ichiro , Uhl George , Raja Srinivasa N. 
Published: March 2004

Background
Mice lacking the mu-opioid receptor gene have been used to characterize the role of mu-opioid receptors in nociception and the analgesic actions of opioid agonists. In this study, the authors determined the role of mu-opioid receptors in neuropathic pain behaviors and the effectiveness of mu- and kappa-opioid receptor agonists on this behavior in mice.

Methods
The authors studied the behavioral responses of mu-opioid receptor knockout and wild-type mice to thermal and mechanical stimuli before and after neuropathic pain induced by unilateral ligation and section of the L5 spinal nerve. Response to mechanical stimuli was evaluated by determining the frequency of hind paw withdrawal to repetitive stimulation using a series of von Frey monofilaments. Thermal hyperalgesia was assessed by determining the paw withdrawal latencies to radiant heat and frequency of hind paw withdrawal to cooling stimuli. The effects of systemic morphine, the kappa-opioid agonist U50488H, and naloxone on responses to mechanical and thermal stimuli were also studied in spinal nerve-injured mice.

Results
After spinal nerve injury, wild-type mice developed increased responsiveness to mechanical, heat, and cooling stimuli ipsilateral to nerve injury. mu-Opioid receptor knockout mice not only had more prominent mechanical allodynia in the nerve-injured paw, but also expressed contralateral allodynia to mechanical stimuli. Hyperalgesia to thermal stimuli was similar between mu-opioid knockout and wild-type animals. Morphine decreased mechanical allodynia dose dependently (3-30 mg/kg subcutaneous) in wild-type mice--an effect that was attenuated in the heterozygous mice and absent in the homozygous mu-opioid knockout mice. The kappa-opioid agonist U50488H (3-10 mg/kg subcutaneous) attenuated mechanical allodynia in wild-type, heterozygous, and homozygous mu-opioid mice. Naloxone in wild-type mice resulted in enhanced ipsilateral and contralateral allodynia to mechanical stimuli that resembled the pain behavior observed in mu-opioid receptor knockout mice.

Conclusions
The authors' observations indicate that (1) unilateral nerve injury induces a bilateral tonic activation of endogenous mu-opioid receptor-mediated inhibition that attenuates mechanical allodynia but not thermal hyperalgesia, (2) both mu- and kappa-opioid agonists attenuate neuropathic pain in mice, and (3) the antihyperalgesic actions of morphine are mediated primarily via mu-opioid receptors.
Effects of Alcohol on Verbal Processing: An Event‐Related Potential Study
Authors: Marinkovic Ksenija , Halgren Eric , Maltzman Irving 
Published: March 2004

Abstract:Background:Behavioral studies suggest that alcohol intoxication impairs the speed and accuracy of word recognition and categorization, but alcohol's effects on the brain during verbal cognitive processing are not adequately understood. Using event‐related potentials (ERP) and a word‐recognition paradigm, this study investigated the effects of alcohol intoxication on prelexical, semantic, and mnemonic aspects of verbal processing.Methods:Concurrent measures of ERPs and skin conductance responses were obtained in a word‐repetition priming task and permitted a comparison of the effects of alcohol on the central and autonomic physiologic systems. Social drinkers participated in all four cells of the within‐subjects balanced placebo design, in which the effects of alcohol and information as to the beverage content (expectancy) were manipulated. The average peak blood alcohol level peaked at 0.045%.Results:None of the manipulations affected behavioral performance, and expectancy had no effect on any of the measures. In contrast, alcohol ingestion attenuated the temporoparietal N180, suggesting an impairment in prelexical pattern‐recognition processes. Alcohol significantly increased the amplitude of N450 and the latency of P580, particularly on trials evoking sympathetic arousal as measured with skin conductance responses.Conclusions:Although behavioral measures were unaffected, ERPs showed that a moderately low alcohol dose affected verbal processing during both early, prelexical and late, semantic stages. Alcohol significantly increased the difficulty of semantic access and integration, as reflected in larger N450 amplitude and longer P580 latency. This effect was particularly prominent on arousal‐related trials, suggesting that alcohol impairs processes that modulate cognitive functioning. The lack of an interaction between the factors of repetition and beverage suggests that a moderately low alcohol dose exerts these effects via the semantic and integration systems rather than via memory processes.
Effects of Ethanol Administration and Induction of Anxiety‐Related Affective States on the Acoustic Startle Reflex in Sons of Alcohol‐Dependent Fathers
Authors: Zimmermann Ulrich , Spring Konstanze , Wittchen Hans‐Ulrich , Holsboer Florian 
Published: March 2004

Abstract: Background: The high rate of comorbidity between alcoholism and anxiety disorders suggests some causal link. This study used the startle reflex to investigate whether increased reactivity to stimuli inducing fear or related affective states might be one mechanism by which a family genetic risk promotes the development of alcohol use disorders.Methods: Thirty‐one sons of alcoholics (PH+) were recruited from the participants of a longitudinal epidemiologic survey representative of the Munich area population between 18 and 25 years. Thirty male low‐risk participants without parental alcoholism (PH−) were matched for age and history of psychiatric disorders. The baseline acoustic startle reflex was elicited before and after subjects drank 0.6 g/kg ethanol or placebo in a randomized, double‐blind, placebo‐controlled crossover design. Thereafter, the startle response was investigated while the subjects’ affective state was manipulated by announcement of aversive electric finger stimuli to induce fear potentiation and by presentation of photographic slides previously rated to be pleasant, unpleasant, or neutral in their emotional valence.Results: Plain startle response was lower in PH+ than PH− participants and was equally dampened by alcohol in PH+ and PH− subjects. Threat of finger shocks increased the startle response to the same extent in both groups. This fear potentiation effect was significantly attenuated by alcohol given on the second experimental day but not if alcohol was administered first and placebo on the second day. Pleasant and unpleasant slides decreased and increased startle response, respectively, and this effect was influenced by neither risk group nor alcohol.Conclusions: The acoustic startle reflex seems to be reduced in sons of alcoholics. The nonsignificant results during startle modification do not support the concept of increased reactivity to anxiety‐related environmental stimuli as a mechanism promoting alcohol use disorders in subjects at increased family genetic risk for alcoholism.
Electrical Stimulation of the Anterior Nucleus of the Thalamus for the Treatment of Intractable Epilepsy
Authors: Kerrigan John F. , Litt Brian , Fisher Robert S. , Cranstoun Stephen , French Jacqueline A. , Blum David E. , Dichter Marc , Shetter Andrew , Baltuch Gordon , Jaggi Jurg , Krone Selma , Brodie MaryAnn , Rise Mark , Graves Nina 
Published: March 2004

Summary:  Purpose: Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open‐label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data. Methods: We report an open‐label pilot study of intermittent electrical stimulation of the anterior nucleus of the thalamus in five patients (three men, two women; age range, 24–47 years), with follow‐up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable, programmable devices by using an intermittent, relatively high‐frequency protocol. Stimulation parameters were 100 cycles per second with charge‐balanced alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline. Results: Four of the five patients showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic–clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters. Conclusions: Electrical stimulation of the ANT appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of intractable patients. Further controlled study of deep brain stimulation of the anterior nucleus is warranted.
Daytime Sleepiness in Epilepsy Patients Receiving Topiramate Monotherapy
Authors: Bonanni Enrica , Galli Renato , Maestri Michelangelo , Pizzanelli Chiara , Fabbrini Monica , Manca Maria Laura , Iudice Alfonso , Murri Luigi 
Published: March 2004

Summary:  Purpose: Limited research has focused to date on objective neurophysiological evaluation of daytime sleepiness in patients treated with newer antiepileptic drugs (AEDs), especially when used as monotherapy. This study was aimed at assessing occurrence of daytime sleepiness in newly diagnosed, drug‐naïve patients with partial epilepsy receiving initial topiramate (TPM) monotherapy. Methods: Daytime vigilance was assessed in 14 consecutive, newly diagnosed and never medicated adult patients with focal epilepsy, receiving monotherapy with TPM. At baseline and 2 months after slowly titrated therapy with TPM, 200 mg/day, patients underwent the Multiple Sleep Latency Test (MSLT), visual simple and choice reaction times (VRT), and self‐rated their own degree of sleepiness with the Epworth Sleepiness Scale. A group of 14 age‐ and gender‐matched healthy volunteers served as controls. Results: At baseline, mean daytime sleep latencies on the MSLT were comparable in patients and in controls. Two months after TPM monotherapy, MSLT scores did not significantly change in patients as compared with pretreatment values. Accordingly, subjective daytime sleepiness and VRTs, which were comparable in controls and in untreated patients at baseline, did not change in patients after TPM monotherapy. Conclusions: Study results suggest that an initial short‐course monotherapy with TPM, 200 mg/day, does not impair daytime vigilance in newly diagnosed adult patients with partial seizures.
Controlled serial grinding for high‐resolution three‐dimensional reconstruction
Authors: Chinga G. , JohnSen P. O. , O. DiSerud  
Published: March 2004

SummaryThis work reports an improved preparation procedure for acquiring SEM images for three‐dimensional (3D) reconstruction. The images are acquired consecutively after serial grinding and polishing. Ugelstad beads are used as landmarks for registration purposes and for determining the thickness of the abraded sections. An estimation of the bead sizes necessary for suitable thickness quantification at the corresponding spatial resolution and uncertainty is given. Shape‐based interpolation is used for filling the gaps between the cross‐sections. An indication of the distance between cross‐sections necessary for good interpolation is also given. An example of a 3D reconstructed paper volume is presented. The method is suitable for preparation of fibre and paper as well as other materials.
CD8+ T cells with parasite‐specific cytotoxic activity and a Tc1 profile of cytokine and chemokine secretion develop in experimental visceral leishmaniasis
Authors: Tsagozis Panagiotis , Karagouni Evdokia , Dotsika Eleni 
Published: March 2004

SUMMARY Recently, a prominent role for CD8+ T cells in immunity against pathogens has emerged. The mode of action of CD8+ T cells in murine visceral leishmaniasis and their contribution to the clearance of the parasite has been addressed in the present study. We showed that during the course of experimental infection cytotoxic clones specific for Leishmania infantum antigens developed in the spleen of susceptible BALB/c mice, showed an activated phenotype and became susceptible to apoptotic cell death late in the course of the disease. CD8+ T cells exhibited considerable cytotoxic activity against cells expressing Leishmania antigens. This activity was mediated by both the perforin and the Fas/FasL pathway, as judged from in vitro and in vivo assays. The CD8+ T cells also up‐regulated mRNAs for cytokines (IFN‐γ and TNF‐α) and C‐C chemokines (RANTES and MIP‐1α), which have a major role in immunity against the pathogen. CD8+ T‐cells thus displayed a Tc1 pattern of differentiation. In conclusion, CD8+ T cells appear to play multiple roles in an experimental model of visceral leishmaniasis comprising both cytotoxic activity and secretion of cytokines and chemokines.
The epidemiology of ischaemic colitis
Authors: Higgins P. D. R. , Davis K. J. , Laine L. 
Published: March 2004

SummaryBackground : Ischaemic colitis has been associated with co‐morbid conditions, medications, vascular surgery and advanced age in case reports and case series. Few data exist on the baseline incidence in the general population or on the increased risk imposed by these risk factors.Aim : To systematically review the literature regarding the incidence, prevalence and risk factors for ischaemic colitis.Methods : Searches of bibliographic databases were performed independently by two investigators. Studies were included if they used population‐based samples, disease‐specific population samples or case–control population‐based samples of adults with ischaemic colitis, and reported the incidence, prevalence or risk factors for ischaemic colitis. Eligible articles were reviewed and data were abstracted in a duplicate, independent manner.Results : Four studies were identified that reported the general population incidence and four that reported the disease‐specific population incidence. The incidence of ischaemic colitis in general populations ranged from 4.5 to 44 cases per 100 000 person‐years. The risk was increased two‐ to four‐fold by either prevalent irritable bowel syndrome or chronic obstructive pulmonary disease. The risk was also increased in females and in subjects of 65 years and older.Conclusions : Ischaemic colitis is uncommon in the general population. The effect sizes of the most commonly reported risk factors have not been adequately quantified in population‐based studies.
Hepatitis vaccination in patients with chronic liver disease
Authors: Reiss G. , Keeffe E. B. 
Published: March 2004

SummaryEvidence regarding the outcomes of viral super‐infection in patients with chronic liver disease and practical strategies for hepatitis A and B vaccination of these individuals are reviewed. Patients with acute hepatitis A and chronic hepatitis B have a more severe clinical course and a higher death rate compared with otherwise healthy individuals with hepatitis A, and these differences are most pronounced in older patients and those with histological evidence of chronic hepatitis or cirrhosis, rather than in asymptomatic hepatitis B carriers. Patients with acute hepatitis A super‐infection and chronic hepatitis C have an increased risk of fulminant hepatitis and death. In addition, patients with other chronic liver diseases also appear to be at increased risk for more severe disease with superimposed hepatitis A. Patients with chronic hepatitis B and hepatitis C virus co‐infection have more severe laboratory abnormalities, more severe histological disease, a greater frequency of cirrhosis and complications of cirrhosis, and a higher incidence of hepatocellular carcinoma. Vaccines for both hepatitis A and B are safe and effective if used early in the course of chronic liver disease. Hepatitis A and B vaccination should be part of the routine management of patients with chronic liver disease, preferably as early as possible in the natural course of their disease.