Home About us Contact
|
Home About us Contact | ||
|
|
||
Drug Effects (drug + effects)
Selected AbstractsCholinergic modulation of visuospatial responding in central thalamusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Lori A. Newman Abstract Central thalamus has extensive connections with basal ganglia and frontal cortex that are thought to play a critical role in sensory-guided goal-directed behavior. Central thalamic activity is influenced by cholinergic projections from mesopontine nuclei. To elucidate this function we trained rats to respond to lights in a reaction time (RT) task and compared effects of muscarinic (2.4, 7.3, 22 nmol scopolamine) and nicotinic (5.4, 16, 49, 98 nmol mecamylamine) antagonists with the GABAA agonist muscimol (0.1, 0.3, 1.0 nmol) in central thalamus. We compared this with subcutaneous (systemic) effects of mecamylamine (3.2, 9.7, 29 µmol/kg) and scopolamine (0.03, 0.09, 0.26 µmol/kg). Subcutaneous scopolamine increased omissions (failure to respond within a 3-s response window) at the highest dose tested. Subcutaneous mecamylamine increased omissions at the highest dose tested while impairing RT and per cent correct at lower doses. Intrathalamic injections of muscimol and mecamylamine decreased per cent correct at doses that did not affect omissions or RT. Intrathalamic scopolamine increased omissions and RT at doses that had little effect on per cent correct. Anatomical controls indicated that the effects of mecamylamine were localized in central thalamus and those of scopolamine were not. Drug effects did not interact with attention-demanding manipulations of stimulus duration, proximity of stimulus and response locations, or stimulus array size. These results are consistent with the hypothesis that central thalamus mediates decisional processes linking sensory stimuli with actions, downstream from systems that detect sensory signals. They also provide evidence that this function is specifically influenced by nicotinic cholinergic receptors. [source] Verbal memory improved by D -amphetamine: influence of the testing effectHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2010Inge Zeeuws Abstract Objective The improvement of long-term retention of verbal memory after an acute administration of D -amphetamine in recall and recognition tasks has been ascribed to an influence of the drug on memory consolidation. Because recent research has demonstrated that intermediate testing is of overriding importance for retention, we investigated whether D -amphetamine modulates the repeated testing effect in verbal long-term recognition. Method Forty men participated in two double blind placebo controlled studies. In Experiment 1, we manipulated the number of recognition tests and in Experiment 2, we compared repeated with nonrepeated testing of the same items. Results Drug effects were observed on delayed tests only, leaving immediate recognition unaffected. Number of intermediate recognition tests and repeated testing of the same items were not affected by D -amphetamine. Conclusions We conclude that the D -amphetamine memory enhancement is not related to the testing effect. This result supports that D -amphetamine modulates other aspects of the consolidation process, probably related to context effects. Copyright © 2010 John Wiley & Sons, Ltd. [source] Drug effects on salivary glands: dry mouthORAL DISEASES, Issue 4 2003C Scully CBE Objective: To identify drugs associated with the complaint of dry mouth. Materials and Methods: MEDLINE was searched for papers 1980,2002 using keywords, oral, mouth, salivary, drugs, dry mouth and xerostomia, and relevant secondary references were hand-searched. Results: Evidence was forthcoming for a number of xerogenic drugs, especially antimuscarinic agents, some sympathomimetic agents, and agents affecting serotonin and noradrenaline uptake, as well as a miscellany of other drugs such as appetite suppressants, protease inhibitors and cytokines. Conclusion: Dry mouth has a variety of possible causes but drugs , especially those with anticholinergic activity against the M3 muscarinic receptor , are the most common cause of reduced salivation. [source] Effects of atipamezole , a selective ,2 -adrenoceptor antagonist , on cardiac parasympathetic regulation in human subjectsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2004J. Penttilä Summary 1 This double-blind, cross-over, placebo-controlled study on six healthy male volunteers was designed to evaluate the effects of ,2 -adrenoceptor antagonism on cardiac parasympathetic regulation. 2 The subjects received atipamezole intravenously as a three-step infusion, which aimed at steady-state serum concentrations of 10, 30 and 90 ng ml,1 at 50-min intervals. 3 Drug effects were assessed with repeated recordings of blood pressure and electrocardiogram, in which the high-frequency (0.15,0.40 Hz) R-R interval variation is supposed to reflect cardiac parasympathetic efferent neuronal activity. 4 At the end of the three steps of the infusion, the mean (±SD) concentrations of atipamezole were 10.5 (3.9), 26.8 (5.6) and 81.3 (21.1) ng ml,1. 5 Within this concentration range, atipamezole appeared to reduce slightly the high-frequency R-R interval fluctuations, indicating a minor vagolytic effect in the heart. 6 Atipamezole increased systolic and diastolic arterial pressure, on average by 20 and 14 mmHg (maxima at the second step of the infusion), which evidently reflects an overall sympathetic augmentation. [source] Pharmacokinetic,pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010DA Vįsquez-Bahena Background and purpose:, This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats. Experimental approach:, Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg,1 of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg,1 oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI. Results:, A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT0/(1 +MED). LT0 is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 µg·mL,1. Conclusions:, The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics. [source] Motives for substance use among young people seeking mental health treatmentEARLY INTERVENTION IN PSYCHIATRY, Issue 3 2008Leanne Hides Abstract Aims: To explore substance use motives among young people seeking mental health treatment. Methods: Participants consisted of 103 young people seeking mental health treatment, who had used drugs or alcohol in the past year. The young people completed a 42-item substance use motives measure based on the Drinking Motives Measure for their most frequently used substance in the past year. Results: Exploratory factor analysis of the substance use motives scale indicated the young people reported using substances for positive and negative drug effects, to socialize with their peers, and to cope with a negative affect. They did not report using substances for enhancement or conformity motives. Coping motives predicted the presence of a current substance use disorder. Conclusions: The findings support the need for integrated treatment approaches within mental health settings, particularly targeted at young people with co-occurring mental health and substance use problems. [source] Drug classification: science, politics, both or neither?ADDICTION, Issue 7 2010Harold Kalant ABSTRACT Governments currently classify illicit drugs for various purposes: to guide courts in the sentencing of convicted violators of drug control laws, to prioritize targets of prevention measures and to educate the public about relative risks of the various drugs. It has been proposed that classification should be conducted by scientists and drug experts rather than by politicians, so that it will reflect only accurate factual knowledge of drug effects and risks rather than political biases. Although this is an appealing goal, it is inherently impossible because rank-ordering of the drugs inevitably requires value judgements concerning the different types of harm. Such judgements, even by scientists, depend upon subjective personal criteria and not only upon scientific facts. Moreover, classification that is meant to guide the legal system in controlling dangerous drug use can function only if it is in harmony with the values and sentiments of the public. In some respects, politicians may be better attuned to public attitudes and wishes, and to what policies the public will support, than are scientific experts. The problems inherent in such drug classification are illustrated by the examples of cannabis and of salvinorin A. They raise the question as to whether the classification process really serves any socially beneficial purpose. [source] Region-specific changes in gene expression in rat brain after chronic treatment with levetiracetam or phenytoinEPILEPSIA, Issue 9 2010Bjųrnar Hassel Summary Purpose:, It is commonly assumed that antiepileptic drugs (AEDs) act similarly in the various parts of the brain as long as their molecular targets are present. A few experimental studies on metabolic effects of vigabatrin, levetiracetam, valproate, and lamotrigine have shown that these drugs may act differently in different brain regions. We examined effects of chronic treatment with levetiracetam or phenytoin on mRNA levels to detect regional drug effects in a broad, nonbiased manner. Methods:, mRNA levels were monitored in three brain regions with oligonucleotide-based microarrays. Results:, Levetiracetam (150 mg/kg for 90 days) changed the expression of 65 genes in pons/medulla oblongata, two in hippocampus, and one in frontal cortex. Phenytoin (75 mg/kg), in contrast, changed the expression of only three genes in pons/medulla oblongata, but 64 genes in hippocampus, and 327 genes in frontal cortex. Very little overlap between regions or drug treatments was observed with respect to effects on gene expression. Discussion:, We conclude that chronic treatment with levetiracetam or phenytoin causes region-specific and highly differential effects on gene expression in the brain. Regional effects on gene expression could reflect regional differences in molecular targets of AEDs, and they could influence the clinical profiles of AEDs. [source] Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic DrugsEPILEPSIA, Issue 8 2006Wolfgang Löscher Summary:, Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most first-generation AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists. [source] Anticonvulsant Efficacy of Topiramate in Phenytoin-Resistant Kindled RatsEPILEPSIA, Issue 4 2000Elke Reissmüller Summary: Purpose: We evaluated the anticonvulsant efficacy of topiramate (TPM), a structurally novel antiepileptic drug (AED), in amygdala kindled rats that had been preselected with respect to their response to phenytoin (PHT). Methods: Anticonvulsant response was tested by determining the afterdischarge threshold (ADT;i.e., a sensitive measure for drug effects on focal seizure activity). By repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (PHT responders), rats that showed no anticonvulsant response (PHT nonresponders), and rats with variable responses (variable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonresponders. Results: TPM proved to be an effective AED in the kindling model. At 40 mg/kg, significant ADT increases were obtained after both 1 and 4 h after administration. In addition to the effect on focal seizure threshold, seizure severity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonresponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT responders than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders). Conclusions: The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy. [source] Effects of an adapted intravenous amiodarone treatment protocol in horses with atrial fibrillationEQUINE VETERINARY JOURNAL, Issue 4 2007D. de CLERCQ Summary Reason for performing study: Good results have been obtained with a human amiodarone (AD) i.v. protocol in horses with chronic atrial fibrillation (AF) and a pharmacokinetic study is required for a specific i.v. amiodarone treatment protocol for horses. Objectives: To study the efficacy of this pharmacokinetic based i.v. AD protocol in horses with chronic AF. Methods: Six horses with chronic AF were treated with an adapted AD infusion protocol. The protocol consisted of 2 phases with a loading dose followed by a maintenance infusion. In the first phase, horses received an infusion of 6.52 mg AD/kg bwt/h for 1 h followed by 1.1 mg/kg bwt/h for 47 h. In the second phase, horses received a second loading dose of 3.74 mg AD/kg bwt/h for 1 h followed by 1.31 mg/kg bwt/h for 47 h. Clinical signs were monitored, a surface ECG and an intra-atrial electrogram were recorded. AD treatment was discontinued when conversion or any side effects were observed. Results: Three of the 6 horses cardioverted successfully without side effects. The other 3 horses did not convert and showed adverse effects, including diarrhoea. In the latter, there were no important circulatory problems, but the diarrhoea continued for 10,14 days. The third horse had to be subjected to euthanasia because a concomitant Salmonella infection worsened the clinical signs. Conclusion: The applied treatment protocol based upon pharmacokinetic data achieved clinically relevant concentrations of AD and desethylamiodarone. Potential relevance: Intravenous AD has the potential to be an alternative pharmacological treatment for AF in horses, although AD may lead to adverse drug effects, particularly with cumulative dosing. [source] Importance of P-glycoprotein for drug disposition in humansEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2003M. F. Fromm The ATP-binding cassette transporter P-glycoprotein is now recognized as an important determinant for disposition of multiple drugs. The use of P-glycoprotein-expressing cell lines, the generation of P-glycoprotein knockout mice as well as studies in animals and humans contributed to a better understanding on the role of active transport processes for drug disposition. P-glycoprotein is located in tissues with excretory function such as intestine, liver and kidney. Moreover, due to its expression in important blood,tissue barriers (blood,brain and blood,testis barriers), in lymphocytes and in placenta it limits tissue penetration of its substrates. Induction and inhibition of P-glycoprotein have now been identified as important underlying mechanisms of drug interactions in humans. Using selected examples, this review summarizes currently available data on the impact of P-glycoprotein for bioavailability of drugs, drug interactions and drug effects. [source] Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbensEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2009Marcelo T. Marin Abstract Learned associations are hypothesized to develop between drug effects and contextual stimuli during repeated drug administration to produce context-specific sensitization that is expressed only in the drug-associated environment and not in a non-drug-paired environment. The neuroadaptations that mediate such context-specific behavior are largely unknown. We investigated context-specific modulation of cAMP-response element-binding protein (CREB) phosphorylation and that of four upstream kinases in the nucleus accumbens that phosphorylate CREB, including extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase, calcium/calmodulin-dependent kinase (CaMK) II and CaMKIV. Rats received seven once-daily injections of cocaine or saline in one of two distinct environments outside their home cages. Seven days later, test injections of cocaine or saline were administered in either the paired or the non-paired environment. CREB and ERK phosphorylation were assessed with immunohistochemistry, and phosphorylation of the remaining kinases, as well as of CREB and ERK, was assessed by western blotting. Repeated cocaine administration produced context-specific sensitized locomotor responses accompanied by context-specific enhancement of the number of cocaine-induced phosphoCREB-immunoreactive and phosphoERK-immunoreactive nuclei in a minority of neurons. In contrast, CREB and CaMKIV phosphorylation in nucleus accumbens homogenates were decreased by cocaine test injections. We have recently shown that a small number of cocaine-activated accumbens neurons mediate the learned association between cocaine effects and the drug administration environment to produce context-specific sensitization. Context-specific phosphorylation of ERK and CREB in the present study suggests that this signal transduction pathway is selectively activated in the same set of cocaine-activated accumbens neurons that mediate this learned association. [source] Dopamine gene predicts the brain's response to dopaminergic drugEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Michael X Cohen Abstract Dopamine is critical for reward-based decision making, yet dopaminergic drugs can have opposite effects in different individuals. This apparent discrepancy can be accounted for by hypothesizing an ,inverted-U' relationship, whereby the effect of dopamine agents depends on baseline dopamine system functioning. Here, we used functional MRI to test the hypothesis that genetic variation in the expression of dopamine D2 receptors in the human brain predicts opposing dopaminergic drug effects during reversal learning. We scanned 22 subjects while they engaged in a feedback-based reversal learning task. Ten subjects had an allele on the Taq1A DRD2 gene, which is associated with reduced dopamine receptor concentration and decreased neural responses to rewards (A1+ subjects). Subjects were scanned twice, once on placebo and once on cabergoline, a D2 receptor agonist. Consistent with an inverted-U relationship between the DRD2 polymorphism and drug effects, cabergoline increased neural reward responses in the medial orbitofrontal cortex, cingulate cortex and striatum for A1+ subjects but decreased reward responses in these regions for A1, subjects. In contrast, cabergoline decreased task performance and fronto-striatal connectivity in A1+ subjects but had the opposite effect in A1, subjects. Further, the drug effect on functional connectivity predicted the drug effect on feedback-guided learning. Thus, individual variability in how dopaminergic drugs affect the brain reflects genetic disposition. These findings may help to explain the link between genetic disposition and risk for addictive disorders. [source] ORIGINAL ARTICLE: Probability of emergence of antimalarial resistance in different stages of the parasite life cycleEVOLUTIONARY APPLICATIONS (ELECTRONIC), Issue 1 2009Wirichada Pongtavornpinyo Abstract Understanding the evolution of drug resistance in malaria is a central area of study at the intersection of evolution and medicine. Antimalarial drug resistance is a major threat to malaria control and directly related to trends in malaria attributable mortality. Artemisinin combination therapies (ACT) are now recommended worldwide as first line treatment for uncomplicated malaria, and losing them to resistance would be a disaster for malaria control. Understanding the emergence and spread of antimalarial drug resistance in the context of different scenarios of antimalarial drug use is essential for the development of strategies protecting ACTs. In this study, we review the basic mechanisms of resistance emergence and describe several simple equations that can be used to estimate the probabilities of de novo resistance mutations at three stages of the parasite life cycle: sporozoite, hepatic merozoite and asexual blood stages; we discuss the factors that affect parasite survival in a single host in the context of different levels of antimalarial drug use, immunity and parasitaemia. We show that in the absence of drug effects, and despite very different parasite numbers, the probability of resistance emerging at each stage is very low and similar in all stages (for example per-infection probability of 10,10,10,9 if the per-parasite chance of mutation is 10,10 per asexual division). However, under the selective pressure provided by antimalarial treatment and particularly in the presence of hyperparasitaemia, the probability of resistance emerging in the blood stage of the parasite can be approximately five orders of magnitude higher than in the absence of drugs. Detailed models built upon these basic methods should allow us to assess the relative probabilities of resistance emergence in the different phases of the parasite life cycle. [source] Pharmacogenetics and personalised medicineFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2002Werner Kalow ABSTRACT The traditional concern of pharmacogenetics was Mendelian (monogenic) variation, which visibly affected some drug responses. Pharmacogenetics was broadened by the observation that multifactorial genetic influences, in conjunction with environmental factors, usually determine drug responses. Variability of gene expression, a new theme of the science of genetics, also affects pharmacogenetics; for example, enhanced enzyme activity does not necessarily indicate a mutation, but may be the consequence of a drug-induced enhancement of gene expression. Methodological advances permit the conversion of pharmacogenetics into the broad practice of pharmacogenomics; this improves the possibility of identifying genetic causes of common diseases, which means establishing new drug targets, thereby stimulating the search for new drugs. While the main medical effect of pharmacogenetics was an improvement of drug safety, pharmacogenomics is hoped to improve drug efficacy. On the way to personalized medicine, we may stepwise improve the chances of choosing the right drug for a patient by categorizing patients into genetically definable classes that have similar drug effects (as, for example, human races, or any population group carrying a particular set of genes). It is wise to expect that, even after we have reached the goal to establish personalized medicine, we will not have eliminated all uncertainties. [source] The clinical syndrome of Alzheimer's disease: aspects particularly relevant to clinical trialsGENES, BRAIN AND BEHAVIOR, Issue 3 2005R. C. Mohs This paper describes the natural history of the clinical syndrome of Alzheimer's disease (AD) including the cognitive deficit, the neuropsychiatric symptoms, impact on daily functioning, risk factors, medical complications and impact on the use of health-care resources. The clinical presentation of the disease varies greatly from the prodrome through end stage; instruments used to quantify the severity of each aspect of the disease have been developed and are described along with their use in clinical drug trials. Drug treatments for AD are usually developed by first showing a positive effect on the cognitive deficit, with later studies investigating drug effects on other clinical aspects of the disease. [source] Force transducer-based movement detection in fear conditioning in mice: A comparative analysisHIPPOCAMPUS, Issue 1 2002Thomas Fitch Abstract Fear conditioning (FC) allows the dissociation of hippocampal and nonhippocampal behavioral function in rodents, and has become a diagnostic tool in transgenic mouse research employed to investigate mutation-induced changes in brain function. Although the procedural details of the paradigm have been established, quantification of the behavioral output, freezing, remains problematic in mice. Observation-based techniques are time-consuming and may be subject to bias, while movement detection with photocells is imprecise. Here we describe an alternative method for movement detection, based on an electronic force transducer system that allows the quantification of acceleration forces generated by a moving subject. We compare the behavior of two inbred strains of mice (C57BL/6 and DBA/2) whose performance is known to differ in hippocampal tasks, including FC. The comparison is made using multiple techniques: the force transducer approach, and three observation-based methods, a computer-aided event-recording approach, a traditional time-sampling paper/pencil method, and a subjective impression-based scoring system. In addition, we investigate the correlation structures of behavioral elements quantified by event recording, using principal component analyses; we conclude that fear may manifest in multiple forms and in a stimulus- and genotype-dependent manner. We suggest that the force transducer system provides precise quantification of movements in an automated manner and will allow high-throughput screening for mutation and drug effects in mice. However, we also argue that fear responses can be complex, and freezing behavior may not be the only measure of fear or fear-associated memory. Hippocampus 2002;12:4,17. © 2002 Wiley-Liss, Inc. [source] Permutation tests for factorially designed neuroimaging experimentsHUMAN BRAIN MAPPING, Issue 3 2004John Suckling Abstract Permutation methods for analysis of functional neuroimaging data acquired as factorially designed experiments are described and validated. The F ratio was estimated for main effects and interactions at each voxel in standard space. Critical values corresponding to probability thresholds were derived from a null distribution sampled by appropriate permutation of observations. Spatially informed, cluster-level test statistics were generated by applying a preliminary probability threshold to the voxel F maps and then computing the sum of voxel statistics in each of the resulting three-dimensional clusters, i.e., cluster "mass." Using simulations comprising two between- or within-subject factors each with two or three levels, contaminated by Gaussian and non-normal noise, the voxel-wise permutation test was compared to the standard parametric F test and to the performance of the spatially informed statistic using receiver operating characteristic (ROC) curves. Validity of the permutation-testing algorithm and software is endorsed by almost identical performance of parametric and permutation tests of the voxel-level F statistic. Permutation testing of suprathreshold voxel cluster mass, however, was found to provide consistently superior sensitivity to detect simulated signals than either of the voxel-level tests. The methods are also illustrated by application to an experimental dataset designed to investigate effects of antidepressant drug treatment on brain activation by implicit sad facial affect perception in patients with major depression. Antidepressant drug effects in left amygdala and ventral striatum were detected by this software for an interaction between time (within-subject factor) and group (between-subject factor) in a representative two-way factorial design. Hum. Brain Mapping 22:193,205, 2004. © 2004 Wiley-Liss, Inc. [source] Zolpidem and triazolam interact differentially with a delay interval on a digit-enter-and-recall taskHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 2 2001Craig R. Rush Abstract Zolpidem (AMBIEN®), an imidazopyridine, is now the most commonly prescribed hypnotic in the United States. Zolpidem is neuropharmacologically distinct from benzodiazepine hypnotics in that it binds with low affinity to ,5 -containing GABAA -receptor subtypes. Despite its unique benzodiazepine-receptor binding profile, the results of most of the published studies conducted with humans suggest that the absolute magnitude of impairment produced by zolpidem is comparable to that observed with benzodiazepine hypnotics like triazolam. The present study compared the acute effects of zolpidem (0, 7.5, 15 and 22.5,mg) and triazolam (0, 0.1875, 0.375 and 0.5625,mg) in 10 non-drug-abusing humans using a Digit-Enter-and-Recall task with varying delay intervals (0, 10 and 20,s). To more fully characterize the behavioral effects of zolpidem and triazolam, several other performance tasks and subject-rated drug-effect questionnaires were included. Zolpidem and triazolam impaired performance on the Digit-Enter-and-Recall task as a function of dose under all delay intervals. However, the dose-related effects of the drugs interacted differentially with the delay interval such that zolpidem produced significantly less impairment than triazolam following the longest delay (i.e., 20,s). Zolpidem and triazolam produced comparable dose-related impairment on the digit symbol substitution test (DSST), circular lights task, and picture recall/recognition task. Zolpidem and triazolam generally produced qualitatively and quantitatively similar subject-rated drug effects, although some between-drug differences were observed. Consistent with the pharmacokinetics of these drugs, the effects of zolpidem peaked sooner and were shorter in duration than those observed with triazolam. The results of this experiment suggest that zolpidem may have less potential than triazolam to impair recall, which may be due to differences between these compounds in terms of their benzodiazepine-receptor binding profile. The results of the present study are also concordant with previous studies that found that drugs that act at the GABAA -receptor complex can be differentiated based on their interaction with the delay interval on a Digit-Enter-and-Recall task. Copyright © 2001 John Wiley & Sons, Ltd. [source] The effects of cannabis abuse on the symptoms of schizophrenia: Patient perspectivesINTERNATIONAL JOURNAL OF MENTAL HEALTH NURSING, Issue 4 2008William F. Costain ABSTRACT:, This study explored explanatory models used by individuals with schizophrenia in relation to continuing cannabis abuse. Cannabis is known to exacerbate positive symptoms, compound the effects of negative symptoms, and lead to relapse, having a negative effect upon quality of life. If this is so, why would people choose to continue the drug use? Most previous studies exploring this phenomenon have used quantitative methodology where the questions asked have been preset by the researchers and the subjective experience of the patient has been minimized. Qualitative methodology was utilized in this study in order to give voice to the patients' perspectives, and contribute to the knowledge of the frameworks of meanings employed by patients. The majority of participants in this study did not perceive that they had a mental illness and they held strong beliefs regarding the usefulness of cannabis. They gave explanations for their continuing cannabis use that expanded the understanding from previous studies. These included that they sought the drug effects of cannabis use for clarity of voices, control of symptoms, to feel normal, perceived improvement in cognitive function, reduced psychological pain and increased energy. These beliefs may influence a person's adherence with treatment and their future cannabis use. This research has implications for clinical practice as clinicians may lack insight into the importance of the phenomenological beliefs of a person with schizophrenia. This lack of insight by the clinician into the phenomenological beliefs may impact on the development of a therapeutic relationship. [source] A modified Mini Nutritional Assessment without BMI can effectively assess the nutritional status of neuropsychiatric patientsJOURNAL OF CLINICAL NURSING, Issue 13 2009Alan C Tsai Aim and objectives., To determine whether a modified version of the Mini Nutritional Assessment (MNA) without body mass index (BMI) can effectively identify individuals at risk of malnutrition among patients with neuropsychiatric disorders. Background., Neuropsychiatric patients have an additional risk of nutritional disorder due to functional impairments and drug effects. However, their nutritional status is generally neglected. It is important to find a tool that is simple, easy to use and non-invasive. Design., The study involved 105 patients in the acute phase of confirmed neuropsychiatric disorders in an area hospital. All subjects were cognitively able to have effective verbal communication. Method., The study included serum biochemical and anthropometric measurements and an on-site, in-person interview using a structured questionnaire to elicit personal data, health condition and answers to questions in the MNA. Subjects' nutritional statuses were graded with a MNA that adopted population-specific anthropometric cut-off points or one further with the BMI question removed and its assigned score redistributed to other anthropometric questions. Results., Both versions of the modified MNA effectively graded the nutritional status of neuropsychiatric patients and showed good correlations with the major nutritional indicators such as BMI, calf circumference and the length of hospital stay. Conclusions., The MNA can effectively assess the nutritional status of neuropsychiatric patients and enhance timely detection and intervention of their nutritional disorders. A modified MNA without the BMI question can maintain the full functionality of the tool. The version does not require weight and height measurements and thus will enhance the usefulness of the instrument. Relevance to clinical practice., Neuropsychiatric patients are a high-risk group of nutritional disorders. The MNA, especially the one without BMI, has the potential to improve professional efficiency of the primary care workers. [source] Concurrent Detection of Heroin, Fentanyl, and Xylazine in Seven Drug-related Deaths Reported from the Philadelphia Medical Examiner's OfficeJOURNAL OF FORENSIC SCIENCES, Issue 2 2008Stella C. Wong D.O. Abstract:, Recreational drugs, such as cocaine and heroin, are often adulterated with other pharmacological agents to either enhance or diminish the drug effects. Between April 21, 2006 and August 8, 2006, the Philadelphia Medical Examiner's Office detected xylazine (a veterinary sedative) and fentanyl (a synthetic opioid) in specimens taken from seven cases. Initial immunoassay screening was performed on urine and blood for fentanyl, opiate, cocaine, phencyclidine (PCP), and benzodiazepines. All tests reported positive were confirmed by gas chromatography-mass spectrometry. All seven xylazine positive cases tested positive for fentanyl and six cases tested positive for 6-acetylmorphine (a metabolite and definitive marker for heroin). The seventh case was positive for morphine and had a history of heroin abuse. Xylazine was present in urine in all seven cases and blood levels were detected in three cases. The blood concentrations ranged from trace to 130 ng/mL. Fentanyl was present in the blood and urine in each case and blood concentrations ranged from 4.7 to 47 ng/mL. Adulteration of illicit drugs has become an epidemic health concern for drug users. Healthcare professionals need to be aware of this issue, so the patients can be treated in an effective, timely manner. [source] Use of volumetric computerized tomography as a primary outcome measure to evaluate drug efficacy in the prevention of peri-prosthetic osteolysis: A 1-year clinical pilot of etanercept vs. placeboJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2003Edward M. Schwarz Although total hip replacement (THR) is amongst the most successful and beneficial medical procedures to date, long-term outcomes continue to suffer from aseptic loosening secondary to peri-prosthetic osteolysis. Extensive research over the last two decades has elucidated a central mechanism for osteolysis in which wear debris generated from the implant stimulates inflammatory cells to promote osteoclastogenesis and bone resorption. The cytokine tumor necrosis factor alpha (TNF,) has been demonstrated to be central to this process and is considered to be a leading target for intervention. Unfortunately, even though FDA approved TNF antagonists are available (etanercept), currently there are no reliable outcome measures that can be used to evaluate the efficacy of a drug to prevent peri-prosthetic osteolysis. To the end of developing an effective outcome measure, we evaluated the progression of lesion size in 20 patients with established peri-acetabular osteolysis (mean = 29.99 cm3, range = 2.9,92.7 cm3) of an uncemented primary THR over 1-year, using a novel volumetric computer tomography (3D-CT) technique. We also evaluated polyethylene wear, urine N-telopeptides and functional assessments (WOMAC, SF-36 and Harris Hip Score) for comparison. At the time of entry into the study baseline CT scans were obtained and the patients were randomized to etanercept (25 mg s.q., twice/week) and placebo in a double-blinded fashion. CT scans, urine and functional assessments were also obtained at 6 and 12 months. No serious adverse drug related events were reported, but one patient had to have revision surgery before completion of the study due to aseptic loosening. No remarkable differences between the groups were observed. However, the study was not powered to see significant drug effects. 3D-CT data from the 19 patients was used to determine the mean increase in lesion size over 48 weeks, which was 3.19 cm3 (p < 0.0013). Analysis of the urine N-telopeptides and functional assessment data failed to identify a significant correlation with wear or osteolysis. In conclusion, volumetric CT was able to measure progression of osteolysis over the course of a year, thus providing a technology that could be used in therapeutic trials. Using the data from this pilot we provide a model power calculation for such a trial. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] SAFETY OF DEXTROAMPHETAMINE AND COCAINE COMBINATIONS IN COCAINE USERSALCOHOLISM, Issue 2008William Murff Two studies evaluated the safety and abuse liability of d-amphetamine in combination with cocaine in twenty cocaine-using research volunteers maintained in a controlled research laboratory. The first study tested low doses of d-amphetamine (15 mg) administered orally as a 1.5-hr pretreatment before low intranasal doses (48 mg) of cocaine. The study was double-blind, double-dummy, and placebo-controlled. A dose run-up procedure was employed to maximize safety. All drug effects were modest and the main finding of the study was diminished subjective effects of cocaine on a replicate determination of the original cocaine dose. The second study examined higher doses of d-amphetamine (30 mg, p.o.) and cocaine (96 mg, i.n.), alone and in combination, without a gradual dose run-up. Cocaine alone increased subjective mood, cocaine craving, and ratings indicating cocaine abuse potential. Again, replicate administration of cocaine produced lesser subjective effects than the first dose. D-amphetamine alone increased systolic and mean arterial pressures, but produced minimal effects on subjective mood. The combination of d-amphetamine and cocaine never produced effects greater than cocaine alone except for one subject who had an asymptomatic hypertensive episode. The data are interpreted in light of the possible use of stimulants for the treatment of cocaine dependence. [source] Individual Differences in Responses to Ethanol and d-Amphetamine: A Within-Subject StudyALCOHOLISM, Issue 4 2001Louis Holdstock Background: In some individuals, ethanol (EtOH) produces marked stimulant-like subjective effects resembling those of stimulant drugs, like d-amphetamine (AMP). In this study, we examined the neurochemical basis of these individual differences by examining the same subjects' responses to both EtOH and AMP. A positive correlation between subjects' responses to the two drugs may suggest that AMP and EtOH produce their stimulant-like subjective effects by a shared mechanism. Methods: Twenty-seven volunteers (17 male, 10 female), aged 21,35, received beverages or capsules containing EtOH 0.8 g/kg, AMP 10 or 20 mg, or placebo on four separate sessions in random order and under double-blind conditions. Various self-reported and objective drug effects were measured, including measures sensitive to subjective and cognitive stimulant-like effects. Results: EtOH and AMP produced their prototypical subjective and behavioral effects, including increased ratings of stimulant-like subjective effects, increased heart rate and blood pressure, and improved vigilance performance after AMP and increased ratings of sedative-like subjective effects, increased heart rate and blood pressure, and impaired vigilance performance after EtOH. Consistent with previous reports, there was substantial intersubject variability in subjective responses to EtOH: some subjects reported primarily stimulant-like effects, whereas others reported primarily sedative-like effects. To examine the relationship between these responses to EtOH and subjects' responses to AMP, correlations were examined between effects of EtOH and AMP. For all subjects together, there was a significant positive correlation between responses to EtOH and 20 mg AMP on the ARCI A scale (a measure of stimulant-like subjective effects;r= 0.41, p < 0.05). Among only those subjects who reported primarily stimulant-like effects from EtOH, the correlation between EtOH and AMP was 0.64 (p < 0.05). Conclusions: Subjects who experience pronounced stimulant-like effects from EtOH also report greater stimulant effects from AMP, suggesting that these effects may be mediated through similar mechanisms. These correlations between the drugs' effects were not observed on other measures, such as DSST or vigilance task performance or heart rate. This may indicate that these other effects are mediated by separate mechanisms. The study illustrates a novel approach to studying the neurochemical basis of drug effects. [source] Anxiety and Sensitivity to Ethanol and Pentobarbital in Alcohol Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant MiceALCOHOLISM, Issue 12 2000Alison L. Atkins Background: Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice were selectively bred for high and low handling-induced convulsions, respectively, after chronic ethanol treatment. Withdrawal severity is one factor that may contribute to the development of alcoholism and/or substance abuse, and anxiety is another. We sought to explore whether these factors are genetically related. Methods: WSP and WSR mice of two replicate pairs of selected lines were tested for anxiety-related behaviors on the canopy stretched-attend-posture apparatus 20 min after intraperitoneal injection of ethanol (2 g/kg, 20% v/v), pentobarbital (20 mg/kg), or an equivalent volume of saline. Dependent measures of anxiety included number of stretched attend postures (SAP) and time spent in the exposed area of the apparatus. Number of line crossings, which measures overall activity, was also scored. Results: WSP mice given saline exhibited more SAP than WSR mice given saline, which indicated greater baseline anxiety. Ethanol and pentobarbital both reduced SAP and increased time spent in the exposed area of the apparatus, which indicated that both drugs exerted an anxiolytic effect. Despite baseline differences in SAP between selected lines, both anxiolytic drugs reduced SAP to similar levels in WSP and WSR mice. Conclusions: These results support the hypothesis that WSP mice are more sensitive than WSR mice to the anxiety-reducing effects of ethanol and pentobarbital. Some genes that influence this difference are likely to be the same as those that influence ethanol withdrawal severity. Thus, higher basal anxiety and greater genetic sensitivity to anxiolytic drug effects may relate to a greater genetic predisposition to the development of severe alcohol withdrawal signs. [source] Atrial, SA Nodal, and AV Nodal Electrophysiology in Standing Horses: Normal Findings and Electrophysiologic Effects of Quinidine and DiltiazemJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2007Colin C. Schwarzwald Background: Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied. Hypotheses: Standard electrophysiologic methods can be used to study drug effects in horses. Specifically, the effects of diltiazem on atrioventricular (AV) nodal conduction are rate-dependent and allow control of ventricular response rate during rapid atrial pacing in horses undergoing quinidine treatment. Animals: Fourteen healthy horses. Methods: Arterial blood pressure, surface electrocardiogram, and right atrial electrogram were recorded during sinus rhythm and during programmed electrical stimulation at baseline, after administration of quinidine gluconate (10 mg/kg IV over 30 minutes, n = 7; and 12 mg/kg IV over 5 minutes followed by 5 mg/kg/h constant rate infusion for the remaining duration of the study, n = 7), and after coadministration of diltiazem (0.125 mg/kg IV over 2 minutes repeated every 12 minutes to effect). Results: Quinidine significantly prolonged the atrial effective refractory period, shortened the functional refractory period (FRP) of the AV node, and increased the ventricular response rate during atrial pacing. Diltiazem increased the FRP, controlled ventricular rate in a rate-dependent manner, caused dose-dependent suppression of the sinoatrial node and produced a significant, but well tolerated decrease in blood pressure. Effective doses of diltiazem ranged from 0.125 to 1.125 mg/kg. Conclusions and Clinical Importance: Standard electrophysiologic techniques allow characterization of drug effects in standing horses. Diltiazem is effective for ventricular rate control in this pacing model of supraventricular tachycardia. The use of diltiazem for rate control in horses with atrial fibrillation merits further investigation. [source] Anti-inflammatory and tissue-protectant drug effects: results from a randomized placebo-controlled trial of gastritis patients at high risk for gastric cancerALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2001L. A. Fischbach Background: The inflammatory process involving Helicobacter pylori- associated gastritis is thought to lead to epithelial damage and contribute to the development of gastric cancer. Evidence exists from animal and in vitro studies suggesting that tetracyclines have both anti-inflammatory and tissue-protectant effects unrelated to their antimicrobial activity. We attempted to modulate components of H. pylori's inflammatory process by: (i) eliminating the infection; (ii) using tetracycline to alter the host's reaction to the infection without reducing the bacterial load; and (iii) using calcium to counteract the effect of excessive dietary salt. Methods: We conducted a 16-week placebo-controlled clinical trial with 374 H. pylori- associated gastritis patients randomly assigned to one of five groups: (1) triple therapy consisting of metronidazole, amoxicillin and bismuth subsalicylate for 2 weeks, followed by bismuth alone for 14 weeks; (2) calcium carbonate; (3) triple therapy and calcium carbonate; (4) tetracycline; or (5) placebo. Results: Subjects in the tetracycline and triple therapy groups, but not the calcium carbonate only group, showed a reduction in inflammation and epithelial damage vs. those in the placebo group, independent of a change in H. pylori density and other factors. Our results also indicate that epithelial damage may be affected by mechanisms independent of H. pylori density or inflammation. Conclusion: The results are consistent with the hypothesis that tetracycline can decrease inflammation independent of a reduction in the bacterial load. More research is needed to investigate mechanisms leading to epithelial damage which are independent of H. pylori density and inflammation. [source] Gender differences in drug effects: implications for anesthesiologistsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2003H. Pleym Background:, The gender aspect in pharmacokinetics and pharmacodynamics of anesthetics has attracted little attention. Knowledge of previous work is required to decide if gender-based differences in clinical practice is justified, and to determine the need for research. Methods:, Basis for this paper was obtained by Medline searches using the key words ,human' and ,gender' or ,sex,' combined with individual drug names. The reference lists of these papers were further checked for other relevant studies. Results:, Females have 20,30% greater sensitivity to the muscle relaxant effects of vecuronium, pancuronium and rocuronium. When rapid onset of or short duration of action is very important, gender-modified dosing may be considered. Males are more sensitive than females to propofol. It may therefore be necessary to decrease the propofol dose by 30,40% in males compared with females in order to achieve similar recovery times. Females are more sensitive than males to opioid receptor agonists, as shown for morphine as well as for a number of kappa (OP2) receptor agonists. On this basis, males will be expected to require 30,40% higher doses of opioid analgesics than females to achieve similar pain relief. On the other hand, females may experience respiratory depression and other adverse effects more easily if they are given the same doses as males. Conclusion:, These examples illustrate that gender should be taken into account as a factor that may be predictive for the dosage of several anesthetic drugs. Moreover, there is an obvious need for more research in this area in order to further optimize drug treatment in anesthesia. [source] | |||||||||||||||||||||||||||||||||||||