ACTA PHYSIOLOGICA, Issue 4 2004
S. D. Crowley
Abstract The renin,angiotensin system (RAS) modulates a diverse set of physiological processes including development, blood pressure, renal function and inflammation. The principal effector molecule of this system, angiotensin II, mediates most of these actions. The classically recognized functions of the RAS are triggered via the type 1 (AT1) class of angiotensin receptors. Pharmacological blockade of the AT1 receptor lowers blood pressure and slows the progression of cardiovascular and renal diseases. Gene-targeting technology provides an experimental approach for precisely dissecting the physiological functions of the RAS. Here, we review how gene-targeting experiments have elucidated AT1 receptor functions. [source]

The role of autophagy in , -cell lipotoxicity and type 2 diabetes

DIABETES OBESITY & METABOLISM, Issue 2010
G. Las
Autophagy, a ubiquitous catabolic pathway involved in both cell survival and cell death, has been implicated in many age-associated diseases. Recent findings have shown autophagy to be crucial for proper insulin secretion and , -cell viability. Transgenic mice lacking autophagy in their , -cells showed decreased , -cell mass and suppressed glucose-stimulated insulin secretion. Several studies showed that stress can stimulate autophagy in , -cells: the number of autophagosomes is increased in different in vivo models for diabetes, such as db/db mice, mice fed high-fat diet, pdx-1 knockout mice, as well as in in vitro models of glucotoxicity and lipotoxicity. Pharmacological and molecular inhibition of autophagy increases the susceptibility to cell stress, suggesting that autophagy protects against diabetes-relevant stresses. Recent findings, however, question these conclusions. Pancreases of diabetics and , -cells exposed to fatty acids show accumulation of abnormal autophagosome morphology and suppression of lysosomal gene expression suggesting impairment in autophagic turnover. In this review we attempt to give an overview of the data generated by others and by us in view of the possible role of autophagy in diabetes, a role which depending on the conditions, could be beneficial or detrimental in coping with stress. [source]

Reactive species and early manifestation of insulin resistance in type 2 diabetes

DIABETES OBESITY & METABOLISM, Issue 2 2006
L. E. Fridlyand
The early stages of type 2 diabetes mellitus are characterized by the development of insulin resistance (IRe) in muscle cells and adipocytes with the concomitant loss of ,-cell compensation. We have extensively reviewed the literature related to metabolic and signalling pathways of reactive oxygen species (ROS) in regard to the coordinated development of oxidative stress and IRe. We considered the hypothesis that oxidative stress leads to IRe in muscle cells and adipocytes, but found that the data are more consistent with the hypothesis that the cellular mechanisms that protect against oxidative stress per se are capable of creating an ROS-dependent insulin-resistant state. Furthermore, ROS-induced mitochondrial dysfunction can lead to disruptions of lipid metabolism, increasing the intracellular lipid content, and, in addition, contribute to lipid-dependent IRe in myocytes. Together, these two ROS-activated pathways to IRe can contribute to a global state of profound resistance to insulin action. Therapeutic strategies should, therefore, be directed towards reducing insulin resistance without an increase in ROS production or concentration. Pharmacological or other approaches to IRe that result in the activation of mitochondrial biogenesis in particular could be highly beneficial in the prevention or treatment of both insulin resistance and type 2 diabetes. [source]

Dynamics of P2X7 receptor pore dilation: Pharmacological and functional consequences

DRUG DEVELOPMENT RESEARCH, Issue 2-3 2001
I.P. Chessell
Abstract The biophysical and functional properties of the human P2X7 receptor, expressed recombinantly in HEK-293 cells or natively in THP-1 pro-monocytic cells, were investigated in the context of pore dilation and externalisation of mature interleukin 1, (IL1,). In HEK-293 cells, the agonist 2,- and 3,-O-(4-benzoylbenzoyl)-ATP (BzATP) caused concentration-dependent inward currents (EC50 59 ,M) and with prolonged application this agonist caused a gradual increase in inward current culminating in a plateau. This increase in current was associated with pore dilation, determined by intracellular accumulation of YO-PRO-1. BzATP displayed increased potency at the pore-dilated form of the P2X7 receptor (EC50 17 ,M), and positive correlations between apparent receptor density and speed of pore dilation were observed. A monoclonal antibody selectively blocked current mediated by the naïve receptor, while currents through pore-dilated receptors were not significantly affected, which together suggest a conformational change at the level of the receptor during the dilation event. The release of mature IL1, from THP-1 cells was independent of P2X7 -mediated cell lysis, as determined by study of lactate dehydrogenase release. Moreover, using conditions designed to minimise pore dilation (using buffers containing 2 mM Ca2+ and 1 mM Mg2+), BzATP caused significant release of IL1,, but without concomitant YO-PRO-1 accumulation, indicating pore dilation is not required for IL1, release. In addition, short (4-min) incubation of THP-1 cells with BzATP (terminated by enzymatic degradation of BzATP using apyrase) resulted in significant quantities of IL1, release some 60 min later, suggesting commitment of cells to release IL1, can be triggered with only brief receptor ligation. These findings suggest that receptor expression and ligation time are critical factors for selecting multiple functional states of P2X7. Drug Dev. Res. 53:60,65, 2001. © 2001 Wiley-Liss, Inc. [source]

Effects of long-term treatment with dopamine receptor agonists and antagonists on terminal arbor size

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2002
C. L. Parish
Abstract This study demonstrates that pharmacological manipulation of the dopamine (DA) receptors can modulate the size of the axonal tree of substantia nigra pars compacta (SNpc) neurons in mice. Pharmacological blockade or genetic ablation of the D2 receptor (D2R) resulted in sprouting of DA SNpc neurons whereas treatment with a D2 agonist resulted in pruning of the terminal arbor of these neurons. Agents such as cocaine, that indirectly stimulate D2R, also resulted in reduced terminal arbor. Specific D1 agonists or antagonists had no effect on the density of DA terminals in the striatum. We conclude that the D2 receptor has a central role in regulating the size of the terminal arbor of nigrostriatal neurons. These findings have implications relating to the use of dopaminergic agonists in the management of Parkinson's disease and in controlling plasticity following injury, loss or transplantation of DA neurons. [source]

Immune-related mechanisms participating in resistance and susceptibility to glutamate toxicity

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2002
Hadas Schori
Abstract Glutamate is an essential neurotransmitter in the CNS. However, at abnormally high concentrations it becomes cytotoxic. Recent studies in our laboratory showed that glutamate evokes T cell-mediated protective mechanisms. The aim of the present study was to examine the nature of the glutamate receptors and signalling pathways that participate in immune protection against glutamate toxicity. We show, using the mouse visual system, that glutamate-induced toxicity is strain dependent, not only with respect to the amount of neuronal loss it causes, but also in the pathways it activates. In strains that are genetically endowed with the ability to manifest a T cell-dependent neuroprotective response to glutamate insult, neuronal losses due to glutamate toxicity were relatively small, and treatment with NMDA-receptor antagonist worsened the outcome of exposure to glutamate. In contrast, in mice devoid of T cell-dependent endogenous protection, NMDA receptor antagonist reduced the glutamate-induced neuronal loss. In all strains, blockage of the AMPA/KA receptor was beneficial. Pharmacological (with ,2 -adrenoceptor agonist) or molecular intervention (using either mice overexpressing Bcl-2, or DAP-kinase knockout mice) protected retinal ganglion cells from glutamate toxicity but not from the toxicity of NMDA. The results suggest that glutamate-induced neuronal toxicity involves multiple glutamate receptors, the types and relative contributions of which, vary among strains. We suggest that a multifactorial protection, based on an immune mechanism independent of the specific pathway through which glutamate exerts its toxicity, is likely to be a safer, more comprehensive, and hence more effective strategy for neuroprotection. It might suggest that, because of individual differences, the pharmacological use of NMDA-antagonist for neuroprotective purposes might have an adverse effect, even if the affinity is low. [source]

Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2007
Anne Roussin
Abstract Propofol (2,6-diisopropylphenol) is an intravenous short-acting anaesthetic widely used for inducing and maintaining anaesthesia. Propofol is also being increasingly used for sedation. Beside medical use, propofol is abused for recreational purpose, mostly in medical professionals who are not informed of the risk of dependence to this compound. The aim of this review was to provide an overview of molecular, animal and clinical pharmacological data of the literature evidencing the potential for abuse and dependence of propofol. [source]

Olfactory ensheathing cell membrane properties are shaped by connectivity

GLIA, Issue 6 2010
Lorena Rela
Abstract Olfactory ensheathing cells (OECs) have been repeatedly implicated in mediating plasticity, particularly in situ in the olfactory nerve in which they support the extension of olfactory sensory neuron (OSN) axons from the olfactory epithelium to the olfactory bulb (OB). OECs are specialized glia whose processes surround OSN axon fascicles within the olfactory nerve and across the OB surface. Despite their purported importance in promoting axon extension, and following transplants, little is known about either morphology or biophysical properties of OECs in situ. In particular, cell,cell interactions that may influence OEC function are largely unexplored. Here, we studied OEC connectivity and morphology in slice preparations, preserving tissue structure and cell,cell interactions. Our analyses showed that OECs form a matrix of cellular projections surrounding axons, unique among glia, and express high levels of connexin-43. Lucifer Yellow injections revealed selective dye coupling among small subgroups of OECs. Two types of OECs were biophysically distinguished with whole-cell voltage-clamp recordings: (1) with low-input resistance (Ri), linear current profiles, and frequently dye coupled; and (2) with high Ri, nonlinear current profiles, and infrequent dye coupling. Pharmacological blockade of gap junctions changed OEC membrane properties such that linear OECs became nonlinear. Double recordings indicated that the appearance of the nonlinear current profile was associated with the loss of electrical coupling between OECs. We conclude that the diversity of OEC current profiles can be explained by differences in gap-junction connectivity and discuss implications of this diversity for OEC influences on axon growth and excitability. © 2009 Wiley-Liss, Inc. [source]

Heterogeneity of Kir4.1 channel expression in glia revealed by mouse transgenesis

GLIA, Issue 16 2009
Xiaofang Tang
Abstract The weakly inwardly rectifying K+ channel Kir4.1 is found in many glial cells including astrocytes. However, questions remain regarding the relative contribution of Kir4.1 to the resting K+ conductance of mature astrocytes in situ. We employed a bacterial artificial chromosome transgenic approach in mice to visualize Kir4.1 expression in vivo. These mice (Kir4.1-EGFP) express enhanced green fluorescent protein (EGFP) under the transcriptional control of the Kir4.1 promoter. The brains of adult Kir4.1-EGFP transgenic mice showed co-expression of EGFP and Kir4.1 in astrocytes. In addition, weaker expression of EGFP was detected in NG2+ glial cells when compared with EGFP expression in GFAP+ glial cells. Whole-cell voltage clamp recordings of EGFP+ glial cells in the CA1 area of the adult mouse hippocampus indicated astrocytes displaying properties consistent with both the "passive" and "complex" subpopulations. EGFP+ cells with bright fluorescence had the linear current,voltage (I,V) relationships and extensive gap junctional coupling characteristic of passive astrocytes. However, EGFP+ glia with weaker fluorescence displayed properties associated with complex astrocytes including nonlinear I,V relationships and lack of intercellular gap junctional coupling. Pharmacological blockade of inward currents implied that Kir4.1 channels constitute the dominant resting K+ conductance in both glial cell types and are more highly expressed in passive astrocytes. These results suggest differential expression of Kir4.1 in glia and that this channel likely underlies the resting K+ conductance in passive and complex astrocytes. © 2009 Wiley-Liss, Inc. [source]

Migraine Headache Recurrence: Relationship to Clinical, Pharmacological, and Pharmacokinetic Properties of Triptans

HEADACHE, Issue 4 2003
Gilles Géraud MD
Background and Objectives.,Triptan use is associated with headache recurrence, and this has been cited as an important reason for patient dissatisfaction with the treatment. The mechanism by which recurrence occurs is not clear, and the incidence of recurrence varies with the triptan used. In order to explore the pharmacological and physiological interaction of triptans and migraine headache recurrence further, some specific clinical, pharmacological, and pharmacokinetic factors that might influence migraine recurrence were evaluated in a review of the major efficacy data for the drugs in the triptan class. These factors were 5-HT1B and 5-HT1D receptor activities, the pharmacokinetic elimination half-life of each triptan, and the clinical efficacy of each compound, determined by the proportion of patients with headache relief and the therapeutic gain over placebo. Methods.,Clinical data were derived from 31 triptan, placebo-controlled, major efficacy studies used in a previous meta-analysis. The mean recurrence rate, mean headache response, and therapeutic gain were calculated using the results from the individual clinical studies. Mean headache response and therapeutic gain were calculated at the time point used to define recurrence in each study. Data for binding affinity and potency were taken from a direct-comparison in vitro pharmacology study, and the elimination half-life quoted in the data sheet for each triptan was used. Rank correlation with recurrence rate was performed for each of the test parameters. Results.,Mean headache recurrence rates ranged from 17% for frovatriptan 2.5 mg to 40% for rizatriptan. Elimination half-life and recurrence were inversely correlated (r = ,1.0, P = .0016). There was also a significant inverse correlation between 5-HT1B receptor potency and recurrence (r = ,0.68, P = .034), but 5-HT1D receptor potency was not correlated with recurrence (r = ,0.20, P = .54). In addition, the binding affinities for the 5-HT1B and 5-HT1D receptors were not correlated to headache recurrence. Importantly, it also was demonstrated that initial clinical efficacy was not correlated to headache recurrence. The correlation coefficient for headache response was 0.18 (P = .53) and for therapeutic gain, ,0.11 (P = .71). Conclusion.,The incidence of migraine headache recurrence varies between drugs in the triptan class. Migraine recurrence does not appear to be related to initial clinical efficacy, but is influenced by the pharmacological and pharmacokinetic properties of the individual triptans. The triptans with longer half-lives and greater 5-HT1B receptor potency had the lowest rates of headache recurrence. [source]

VSD: A database for schizophrenia candidate genes focusing on variations,

HUMAN MUTATION, Issue 1 2004
Min Zhou
Abstract Schizophrenia is a common mental disease characterized by delusions, hallucinations, and formal thought disorder. It has been demonstrated with genetic evidence that the disease is a polygenic disorder. Pharmacological, neurochemical, and clinical studies have suggested a number of schizophrenia susceptibility loci. In order to systematically search for genes with small effect in the development of schizophrenia, a database called VSD was established to provide variation data for publicly available candidate genes. Most of the genes encode neurotransmitter receptors, neurotransmitter transporters, and the enzymes involved in their metabolism. Other candidate genes extracted from published literature are also included. The variation information has been collected from publicly available mutation and polymorphism databases such as dbSNP, HGVbase, and OMIM, with single nucleotide polymorphism (SNP) being the most abundant form of collected variations. Reference sequences from NCBI's RefSeq database are used as references when positioning variation at transcript and protein levels. The nonsynonymous SNPs (nsSNPs) that lead to amino acid changes in the functional sites or domains of proteins are distinguished since they are more likely to affect protein function and would be target SNPs for association studies. In addition to variation data, gene descriptions, enzyme information, and other biological information for each gene locus are also included. The latest version of VSD contains 23,648 variations assigned to a total of 186 genes. Five-hundred eighty-eight domains and sites annotated in the SWISS-PROT and InterPro databases are found to contain nsSNPs. VSD may be accessed via the World Wide Web (www.chgb.org.cn/vsd.htm) and will be developed as an up-to-date and comprehensive locus-specific resource for identifying susceptibility genes for schizophrenia. Hum Mutat 23:1,7, 2004. © 2003 Wiley-Liss, Inc. [source]

NF-,B inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2009
Nadia Lounnas
Abstract The Bcr-Abl inhibitor imatinib is the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Nevertheless, resistance to imatinib emerges as CML progresses to an acute deadly phase implying that physiopathologically relevant cellular targets should be validated to develop alternative therapeutic strategies. The NF-,B transcription factor that exerts pro-survival actions is found abnormally active in numerous hematologic malignancies. In the present study, using Bcr-Abl-transfected BaF murine cells, LAMA84 human CML cell line and primary CML, we show that NF-,B is active downstream of Bcr-Abl. Pharmacological blockade of NF-,B by the IKK2 inhibitor AS602868 prevented survival of BaF cells expressing either wild-type, M351T or T315I imatinib-resistant mutant forms of Bcr-Abl both in vitro and in vivo using a mouse xenograft model. AS602868 also affected the survival of LAMA84 cells and of an imatinib-resistant variant. Importantly, the IKK2 inhibitor strongly decreased in vitro survival and ability to form hematopoietic colonies of primary imatinib resistant CML cells including T315I cells. Our data strongly support the targeting of NF-,B as a promising new therapeutic opportunity for the treatment of imatinib resistant CML patients in particular in the case of T315I patients. The T315I mutation escapes all currently used Bcr-Abl inhibitors and is likely to become a major clinical problem as it is associated with a poor clinical outcome. © 2009 UICC [source]

,2A -Adrenergic Receptor Signaling Underlies Synergistic Enhancement of Ethanol-Induced Behavioral Impairment by Clonidine

ALCOHOLISM, Issue 3 2009
Tara Summer Bender
Background:, We tested the hypothesis that central ,2A -adrenergic receptor (,2AAR) signaling plays a key role in clonidine-ethanol evoked synergistic behavioral impairment. Methods:, Male Sprague-Dawley rats, with intracisternal and jugular vein cannulae implanted 6 days earlier, were tested for drug-induced behavioral impairment. The latter was assessed as the duration of loss of righting reflex (LORR) and rotorod performance every 15 minutes until the rat recovered to the baseline walk criterion (180 seconds). In a separate cohort, c-Fos expression in locus coeruleus (LC) and cerebellum was determined as a marker of neuronal activity following drug treatment. Results:, Rats that received clonidine (60 ,g/kg, i.v.) followed by ethanol (1 g/kg, i.v.) exhibited synergistic impairment of rotorod performance and LORR. The mixed ,2AAR and I1 -imidazoline receptor agonist clonidine (30, 60, and 90 ,g/kg) synergistically and dose-dependently enhanced behavioral impairment elicited by ethanol (1 g/kg). Possible involvement of I1 -imidazoline receptors was ruled out because selective I1 -agonist rilmenidine (300 ,g/kg, i.v.) did not cause behavioral impairment alone or enhance ethanol-evoked behavioral impairment. Pharmacological blockade of central ,2AAR (RX821002, 0.3 mg i.c.) abolished the synergy between clonidine and ethanol; the behavioral response caused by the drug combination was similar to that caused by ethanol alone. Conversely, involvement of central ,2BAR in the interaction was ruled out because blockade of central ,2BAR (ARC-239) independently evoked a strong sedative effect. Clonidine (60 ,g/kg) or ethanol (1 g/kg) alone increased, but their combination decreased, c-Fos levels in LC, while inconsistent c-Fos responses were observed in cerebellum. Conclusions:, Central ,2AAR, but not I1 -imidazoline or ,2BAR, signaling is implicated in the synergistic enhancement of ethanol-evoked behavioral impairment by clonidine. Although the mechanism of c-Fos response remains to be investigated, this neurochemical response highlights the LC as a neuroanatomical target for clonidine-ethanol behavioral interaction. [source]

Sensitization, Duration, and Pharmacological Blockade of Anxiety-Like Behavior Following Repeated Ethanol Withdrawal in Adolescent and Adult Rats

ALCOHOLISM, Issue 3 2009
Tiffany A. Wills
Background:, Repeated ethanol withdrawal sensitizes anxiety-like behavior in adult rats and causes anxiety-like behavior and decreased seizure thresholds in adolescent rats. Current experiments determined if adolescent rats exhibit sensitized anxiety-like behavior, the duration of this effect, if drug pretreatments blocked these effects, and if these effects differed from those seen in adults. Methods:, Male adolescent rats received three 5-day cycles of 2.5% ethanol diet (ED) separated by two 2-day withdrawal periods, continuous 15 days of 2.5%ED, or a single 5-day cycle of 2.5%ED. Male adult rats received three 5-day cycles of either 2.5% or 3.5%ED. These groups were tested 5 hours into the final withdrawal for social interaction (SI) deficits (an index of anxiety-like behavior). Ethanol intake was monitored throughout and blood concentrations were obtained from separate groups of rats. Additionally, adolescent rats were tested for SI 1, 2, 7, 14, and 18 days and adults 1 and 2 days after the final withdrawal. Some adolescent rats were also pretreated with the CRF1 antagonist CP-154,526, the 5-HT1A agonist buspirone, or the benzodiazepine receptor antagonist flumazenil during the first 2 withdrawals. Results:, SI was reduced in adolescent rats following repeated withdrawals of 2.5%ED while neither a continuous or single cycle ED exposure caused this effect. Adult rats also had reduced SI following repeated withdrawals from both 2.5% and 3.5%ED. This effect was present up to 1 week following the final withdrawal in adolescents but returned to baseline by 1 day in adults. CP-154,526, buspirone, or flumazenil prevented this reduction in SI in adolescent rats. Conclusions:, Adolescent rats exhibit sensitized anxiety-like behavior following repeated withdrawals at ED concentrations similar to those used in adults. However, this effect is longer lasting in adolescent rats. Drugs modulating CRF, 5-HT, or GABA systems during initial withdrawals prevent the development of anxiety-like behavior otherwise manifest during a final withdrawal in adolescent rats. [source]

A Review of Genetic, Biological, Pharmacological, and Clinical Factors That Affect Carbohydrate-Deficient Transferrin Levels

ALCOHOLISM, Issue 9 2004
Michael F. Fleming
Background: Carbohydrate-deficient transferrin (CDT) is an alcohol biomarker recently approved by the U.S. Food and Drug Administration. This test is increasingly being used to detect and monitor alcohol use in a variety of health care, legal, and industrial settings. The goal of this study is to review the genetic, biological, pharmacological, and clinical factors that may affect CDT levels. Methods: A review of the literature identified 95 research articles that met the authors' criteria and reported potential interactions of a variety of factors on percent and total CDT levels. The review established 12 categories of variables that may affect CDT levels. These categories include (1) alcohol use, (2) genetic factors, (3) race, (4) gender, (5) age, (6) liver disease, (7) iron levels, (8) tobacco use, (9) medication such as estrogen and anticonvulsants, (10) metabolic factors such as body mass index and total body water, (11) chronic medical conditions such as rheumatoid arthritis, and (12) surgical patients. Results: There is evidence that %CDT levels are affected by alcohol use, end-stage liver disease, and genetic variants. In addition to these three factors, total CDT levels (CDTect) are also affected by factors that raise transferrin levels such as iron deficiency, chronic illnesses, and menopausal status. Other potential factors such as tobacco and age appear to be confounded by alcohol use. The roles of female gender, low body mass index, chronic inflammatory diseases, and medication on CDT levels require further study. False negatives are associated with female gender, episodic lower level alcohol use, and acute trauma with blood loss. Conclusions: This review suggests that a number of factors are associated with false-positive CDTect and %CDT levels. CDT offers great promise to assist physicians in the care of patients to detect and monitor heavy alcohol use. [source]

Mortality from peptic ulcer bleeding: the impact of comorbidity and the use of drugs that promote bleeding

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2010
K. Åhsberg
Summary Background, Use of drugs promoting peptic ulcer bleed has increased several folds. Aim, To make a time-trend analysis of peptic ulcer bleed patients and evaluate the impact of age, gender, comorbidity and use of drugs promoting peptic ulcer bleed on outcome. Methods, Retrospective review of hospitalizations for peptic ulcer bleed at Lund University Hospital during 1984, 1994 and 2004. Univariate analyses between years and multivariable logistic regression for risk factors of fatal outcome. Results, Incidence decreased from 62.0 to 32.1 per 100 000 inhabitants between 1984 and 2004. Mortality rates were stable. Median age (70,77 years; P = 0.001), number of comorbidities (mean ± s.d.: 0.88 ± 0.96 to 1.16 ± 0.77; P = 0.021), use of aspirin (16,57%; P < 0.001) and warfarin (5,17%; P = 0.02) increased. Pharmacological and endoscopic therapy improved. Age above 65 years (OR: 1.11, 95% CI: 1.02,1.23) and number of comorbidities (OR: 6.00, 95% CI: 2.56,17.4) were independent risk factors for in-hospital mortality. Bleeding promoting drugs did not influence outcome negatively. Aspirin decreased the risk of fatal outcome (OR: 0.12, 95% CI: 0.012,0.67). Conclusions, Incidence of peptic ulcer bleed decreased despite higher prescription rates of bleeding promoting drugs. The in-hospital mortality remained unchanged. The effect of improved therapy against peptic ulcer bleed is probably outweighed by older and more comorbid patients. The decreased risk of fatal outcome in aspirin users warrants further investigations. [source]

Neuropathy as a potential complication of levodopa use in Parkinson's disease: A Pharmacological and Pharmacovigilance point of view,

MOVEMENT DISORDERS, Issue 5 2010
Jean-Louis Montastruc MD
No abstract is available for this article. [source]

Evidence-based medical review update: Pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004

MOVEMENT DISORDERS, Issue 5 2005
Christopher G. Goetz MD
Abstract The objective of this study is to update a previous evidence-based medicine (EBM) review on Parkinson's disease (PD) treatments, adding January 2001 to January 2004 information. The Movement Disorder Society (MDS) Task Force prepared an EBM review of PD treatments covering data up to January 2001. The authors reviewed Level I (randomized clinical trials) reports of pharmacological and surgical interventions for PD, published as full articles in English (January 2001,January 2004). Inclusion criteria and ranking followed the original program and adhered to EBM methodology. For Efficacy Conclusions, treatments were designated Efficacious, Likely Efficacious, Non - Efficacious, or Insufficient Data. Four clinical indications were considered for each intervention: prevention of disease progression; treatment of Parkinsonism, as monotherapy and as adjuncts to levodopa where indicated; prevention of motor complications; treatment of motor complications. Twenty-seven new studies qualified for efficacy review, and others covered new safety issues. Apomorphine, piribedil, unilateral pallidotomy, and subthalamic nucleus stimulation moved upward in efficacy ratings. Rasagiline, was newly rated as Efficacious monotherapy for control of Parkinsonism. New Level I data moved human fetal nigral transplants, as performed to date, from Insufficient Data to Non- efficacious for the treatment of Parkinsonism, motor fluctuations, and dyskinesias. Selegiline was reassigned as Non - efficacious for the prevention of dyskinesias. Other designations did not change. In a field as active in clinical trials as PD, frequent updating of therapy-based reviews is essential. We consider a 3-year period a reasonable time frame for published updates and are working to establish a Web-based mechanism to update the report in an ongoing manner. © 2005 Movement Disorder Society [source]

Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine

PHYTOTHERAPY RESEARCH, Issue 8 2008
Mohsen Imanshahidi
Abstract Barberry (Berberis vulgaris L. family Berberidaceae) is well known in Iran and various parts of this plant including its root, bark, leaf and fruit have been used as folk medicine. The two decades of research has demonstrated different pharmacological and therapeutic effects of B. vulgaris and its isoquinoline alkaloids (particularly berberine). Studies carried out on the chemical composition of the plant show that the most important constituents of this plant are isoquinoline alkaloids such as berberine, berbamine and palmatine. Berberine represents one of the most studied among the naturally occurring protoberberine alkaloids. In addition to B. vulgaris (barberry), berberine is present in many other plants and is used for the treatment of different diseases. This article reviews the traditional uses and pharmacological effects of total extract and the most active ingredient of B. vulgaris (berberine). Copyright © 2008 John Wiley & Sons, Ltd. [source]

Recent advances in the neurobiology of anxiety disorders: Implications for novel therapeutics,

AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 2 2008
Sanjay J. Mathew
Abstract Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. This review focuses on new directions in neurobiological research and implications for the development of novel psychopharmacological treatments. Neuroanatomical and neuroimaging research in anxiety disorders has centered on the role of the amygdala, reciprocal connections between the amygdala and the prefrontal cortex, and, most recently, alterations in interoceptive processing by the anterior insula. Anxiety disorders are characterized by alterations in a diverse range of neurochemical systems, suggesting ample novel targets for drug therapies. Corticotropin-releasing factor (CRF) concentrations are elevated in a subset of anxiety disorders, which suggests the potential utility of CRF receptor antagonists. Pharmacological blockade of the memory-enhancing effects of stress hormones such as glucocorticoids and noradrenaline holds promise as a preventative approach for trauma-related anxiety. The glutamatergic system has been largely overlooked as a potential pharmacological target, although convergent preclinical, neuroimaging, and early clinical findings suggest that glutamate receptor antagonists may have potent anxiolytic effects. Glutamatergic receptor agonists (e.g., D -cycloserine) also have an emerging role in the treatment of anxiety as facilitators of fear extinction during concurrent behavioral interventions. The neuropeptides substance P, neuropeptide Y, oxytocin, orexin, and galanin are each implicated in anxiety pathways, and neuropeptide analogs or antagonists show early promise as anxiolytics in preclinical and/or clinical research. Each of these active areas of research holds promise for expanding and improving evidence-based treatment options for individuals suffering with clinical anxiety. © 2008 Wiley-Liss, Inc. [source]

Pharmacological and Functional Characterization of Novel EP and DP Receptor Agonists: DP1 Receptor Mediates Penile Erection in Multiple Species

THE JOURNAL OF SEXUAL MEDICINE, Issue 2 2008
Nadia Brugger PhD
ABSTRACT Introduction., Despite the widespread use of prostaglandin E1 as an efficacious treatment for male erectile dysfunction for more than two decades, research on prostanoid function in penile physiology has been limited. Aim., To characterize the pharmacological and physiological activity of novel subtype-selective EP and DP receptor agonists. Methods., Radioligand binding and second messenger assays were used to define receptor subtype specificity of the EP and DP agonists. Functional activity was further characterized using isolated human and rabbit penile cavernosal tissue in organ baths. In vivo activity was assessed in rabbits and rats by measuring changes in cavernous pressure after intracavernosal injection of receptor agonists. Main Outcome Measures., Receptor binding and signal transduction, smooth muscle contractile activity, erectile function. Results., In organ bath preparations of human cavernosal tissue contracted with phenylephrine, EP2- and EP4-selective agonists exhibited variable potency in causing relaxation. One of the compounds caused mild contraction, and none of the compounds was as effective as PGE1 (EC50 = 0.23 µM). There was no consistent correlation between the pharmacological profile (receptor binding and second messenger assays) of the EP agonists and their effect on cavernosal tissue tone. In contrast, the DP1-selective agonist AS702224 (EC50 =29 nM) was more effective in relaxing human cavernosal tissue than either PGE1, PGD2 (EC50 = 58 nM), or the DP agonist BW245C (EC50 =59 nM). In rabbit cavernosal tissue, PGE1 and PGD2 caused only contraction, while AS702224 and BW245C caused relaxation. Intracavernosal administration of AS702224 and BW245C also caused penile tumescence in rabbits and rats. For each compound, the erectile response improved with increasing dose and was significantly higher than vehicle alone. Conclusions., These data suggest that AS702224 is a potent DP1-selective agonist that causes penile erection. The DP1 receptor mediates relaxation in human cavernosal tissue, and stimulates pro-erectile responses in rat and rabbit. Thus, rabbits and rats can be useful models for investigating the physiological function of DP1 receptors. Brugger N, Kim NN, Araldi GL, Traish AM, and Palmer SS. Pharmacological and functional characterization of novel EP and DP receptor agonists: DP1 receptor mediates penile erection in multiple species. J Sex Med 2008;5:344,356. [source]

Upregulation of K2P5.1 potassium channels in multiple sclerosis

ANNALS OF NEUROLOGY, Issue 1 2010
Stefan Bittner BSc
Objective Activation of T cells critically depends on potassium channels. We here characterize the impact of K2P5.1 (KCNK5; TASK2), a member of the 2-pore domain family of potassium channels, on T-cell function and demonstrate its putative relevance in a T-cell,mediated autoimmune disorder, multiple sclerosis (MS). Methods Expression of K2P5.1 was investigated on RNA and protein level in different immune cells and in MS patients' biospecimens (peripheral blood mononuclear cells, cerebrospinal fluid cells, brain tissue specimen). Functional consequences of K2P5.1 expression were analyzed using pharmacological modulation, small interfering RNA (siRNA), overexpression, electrophysiological recordings, and computer modeling. Results Human T cells constitutively express K2P5.1. After T-cell activation, a significant and time-dependent upregulation of K2P5.1 channel expression was observed. Pharmacological blockade of K2P5.1 or knockdown with siRNA resulted in reduced T-cell functions, whereas overexpression of K2P5.1 had the opposite effect. Electrophysiological recordings of T cells clearly dissected K2P5.1-mediated effects from other potassium channels. The pathophysiological relevance of these findings was demonstrated by a significant K2P5.1 upregulation in CD4+ and CD8+ T cells in relapsing/remitting MS (RRMS) patients during acute relapses as well as higher levels on CD8+ T cells of clinically isolated syndrome, RRMS, and secondary progressive multiple sclerosis patients during clinically stable disease. T cells in the cerebrospinal fluid from MS patients exhibit significantly elevated K2P5.1 levels. Furthermore, K2P5.1-positive T cells can be found in inflammatory lesions in MS tissue specimens. Interpretation Selective targeting of K2P5.1 may hold therapeutic promise for MS and putatively other T-cell,mediated disorders. ANN NEUROL 2010;68:58,69 [source]

Pharmacological and histological assessment of gut muscle movement in blacklip abalone, Haliotis rubra (Leach)

AQUACULTURE RESEARCH, Issue 5 2003
S Edwards
We examined the basic pharmacology of abalone gut tissues for adrenergic and peptide receptors using ligand binding and by determining the pharmacological effectors of abalone gut motility in a number of gut regions. Contractile responses could not be elicited, even though we could show the existence of ,-adrenergic and peptide receptors. Responses to any muscle contractile agents, including carbachol and potassium chloride, could not be found in blacklip abalone, Haliotis rubra (Leach). Histology confirmed the relative absence of muscular layers in all the tissues of the gut, indicating that previous literature reports of muscular involvement in contractile movement of gut contents did not appear to apply to this species. [source]

Synthesis and Pharmacological Evaluation of N -(Dimethylamino)ethyl Derivatives of Benzo- and Pyridopyridazinones

ARCHIV DER PHARMAZIE, Issue 1 2009
Wanda Pakulska
Abstract New N -(dimethylamino)ethyl derivatives of phthalazinones and pyridopyridazinones 7, 9 were synthesized and assayed as potential analgesic agents in the hot-plate, tail-flick, and writhing tests. Pharmacological assay demonstrated that eight (in ten) of the newly synthesized compounds showed antinociceptive activity. Especially, 2-[2-(dimethylamino)ethyl]-4-phenyl-2H -phthalazin-1-one 7a showed remarkably higher antinociceptive activity in all tests. This is connected with influence on supraspinal, spinal, and peripheral structures. The decreased sensitivity to the pain stimulus in the hot-plate was higher than that of metamizole. [source]

Treatment for Mechanical Valve Thrombosis in the Right Heart: Combined Pharmacological and Mechanical Thrombolysis

ARTIFICIAL ORGANS, Issue 8 2010
Shigeaki Aoyagi
Abstract We report clinical results of combined pharmacological and mechanical thrombolysis for mechanical prosthetic valve thrombosis (PVT) in the right heart. Between January 1992 and December 2008, combined thrombolysis, which consisted of an intravenous infusion of urokinase together with mechanical disruption of thrombus in a prosthetic valve by temporarily increasing the cardiac pacing rate, was performed in three patients with four cases of mechanical PVT in the right heart. The prosthetic valve in all three patients was a bileaflet mechanical valve, and was located in the tricuspid position in two patients and in the pulmonary position in the remaining patient. PVT was diagnosed by echocardiography and cineradiography. Thrombolysis was successful in all four cases in the three patients, and no hemorrhagic complications or clinically symptomatic pulmonary embolisms were observed. Mechanical disruption of thrombus using a pacemaker appears to be an effective adjunctive modality to thrombolysis with fibrinolytic agents for PVT in the right heart. Combined pharmacological and mechanical thrombolysis may improve success rates and reduce the time required for thrombolysis of PVT. [source]

Chronic Pharmacological and Safety Evaluation of HematideÔ, a PEGylated Peptidic Erythropoiesis-Stimulating Agent, in Rodents

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2009
Kathryn W. Woodburn
To support the safety of long-term dosing of chronic renal failure patients, a comprehensive toxicology programme was implemented including rat subchronic and chronic studies. Rats were administered 0, 0.1, 1 and 10 mg/kg of Hematide every 3 weeks for 3 months via subcutaneous injection or for 6 months via intravenous injection. The dosing period was followed by a 6-week follow-up period. The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time- and dose-dependent. The pharmacology profiles were similar regardless of administration route. For example, for male rats at Day 90, subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl for 0.1, 1 and 10 mg Hematide/kg respectively, compared to 2.8, 5.7 and 7.4 g/dl increases for intravenous dosing. Histopathological changes were related to the prolonged severe polycythemia induced in normocythemic animals administered an erythropoiesis-stimulating agent. The findings included extramedullary haematopoiesis in the spleen and liver, bone marrow hypercellularity and organ congestion. Microscopic findings were reversible, demonstrating a return towards control findings within 6 weeks following cessation of dosing. Systemic exposures, based on both area under the curve (AUC) and maximum concentration (Cmax), were substantially greater for intravenous than subcutaneous administration. No Hematide-specific antibodies were detected. In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure. [source]

Calcium sensing and cell signaling processes in the local regulation of osteoclastic bone resorption

BIOLOGICAL REVIEWS, Issue 1 2004
Mone Zaidi
ABSTRACT The skeletal matrix in terrestrial vertebrates undergoes continual cycles of removal and replacement in the processes of bone growth, repair and remodeling. The osteoclast is uniquely important in bone resorption and thus is implicated in the pathogenesis of clinically important bone and joint diseases. Activated osteoclasts form a resorptive hemivacuole with the bone surface into which they release both acid and osteoclastic lysosomal hydrolases. This article reviews cell physiological studies of the local mechanisms that regulate the resorptive process. These used in vitro methods for the isolation, culture and direct study of the properties of neonatal rat osteoclasts. They demonstrated that both local microvascular agents and products of the bone resorptive process such as ambient Ca2+ could complement longer-range systemic regulatory mechanisms such as those that might be exerted through calcitonin (CT). Thus elevated extracellular [Ca2+], or applications of surrogate divalent cation agonists for Ca2+, inhibited bone resorptive activity and produced parallel increases in cytosolic [Ca2+], cell retraction and longer-term inhibition of enzyme release in isolated rat osteoclasts. These changes showed specificity, inactivation, and voltage-dependent properties that implicated a cell surface Ca2+ receptor (CaR) sensitive to millimolar extracellular [Ca2+]. Pharmacological, biophysical and immunochemical evidence implicated a ryanodine-receptor (RyR) type II isoform in this process and localized it to a unique, surface membrane site, with an outward-facing channel-forming domain. Such a surface RyR might function either directly or indirectly in the process of extracellular [Ca2+] sensing and in turn be modulated by cyclic adenosine diphosphate ribose (cADPr) produced by the ADP-ribosyl cyclase, CD38. The review finishes by speculating about possible detailed models for these transduction events and their possible interactions with other systemic mechanisms involved in Ca2+ homeostasis as well as the possible role of the RyR-based signaling mechanisms in longer-term cell regulatory processes. [source]

Pharmacological and pharmacokinetic evaluation of celecoxib prodrugs in rats

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002
Rao N.V.S. Mamidi
Abstract This study demonstrates the utility of an in vitro , in vivo correlative approach in the selection and optimization of a prodrug candidate of celecoxib (CBX), a COX2 inhibitor. As an initial screening step, a comparative single oral dose pharmacokinetic study was conducted in rats for CBX and its three aliphatic acyl water-soluble prodrugs viz., CBX-acetyl (CBX-AC), CBX-propionyl (CBX-PR) and CBX-butyryl (CBX-BU) at high equimolar dose, 100 mg/kg. Only CBX-BU and CBX-PR converted rapidly to CBX and yielded approximately five-fold greater systemic exposure of CBX than CBX alone or CBX-AC. Rank order of systemic exposure of prodrugs in its intact form was CBX-AC >CBX-PR >CBX-BU. Further in vitro hydrolysis studies of CBX prodrugs in intestinal mucosal suspensions and liver homogenates indicated that CBX-BU is rapidly and completely converted to CBX, whereas CBX-PR and CBX-AC require longer incubation period for complete conversion to CBX. There was a very good correlation of the in vitro and in vivo data supporting CBX-BU as the prodrug of choice. Further in vitro pharmacological studies showed that COX2 selective inhibition is improved for CBX-BU as compared to CBX-AC and CBX-PR. Dose proportionality in pharmacokinetic studies of CBX-BU and CBX at equimolar oral doses confirmed that relative oral bioavailability of CBX was improved following CBX-BU administration and there was linearity in pharmacokinetics of CBX over a wide dose range (10,100 mg/kg), whereas CBX in its conventional form showed poor bioavailability and lack of dose linearity in pharmacokinetics. The oral bioavailability of CBX from CBX-BU was dose independent and was in the range 78,96%. At a 50% reduced molar dose, CBX-BU showed an equivalent efficacy to that of CBX in the in vivo carrageenan model. Based on the study, water-soluble CBX-BU prodrug can be considered for clinical development in view of its potential advantages.Copyright © 2002 John Wiley & Sons, Ltd. [source]

Pharmacological and functional characterization of the guinea-pig B2 bradykinin receptor stably expressed in CHO-K1 cell line

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2002
C Robert
In the present study, pharmacological properties of a bradykinin B2 receptor amplified either from guinea-pig ileum or lung and homologous to the previously reported sequence except two amino-acid changes L124,P and N227,Y in the receptor protein were characterized. Tritiated bradykinin ([3H]-BK) specifically bound to the cloned guinea-pig B2 bradykinin receptor stably expressed in Chinese hamster ovary cells (CHO-K1) with a KD value of 0.29±0.07 nM. In competition experiments, bradykinin (BK) affinity constant value was 0.21±0.05 nM while the two specific kinin B1 ligands, des-Arg9 -bradykinin (DBK) and des-Arg9 -Leu8 -bradykinin (DLBK) were unable to compete with [3H]-BK. As the specific peptide antagonist D -Arg-[Hyp3,Thi5,D -Tic7,Oic8]-bradykinin (HOE140), (E)-3-(6-acetamido-3-pyridil)-N-[-N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657) and 1-[[3-[2,4-dimethylquinolin-8-yl)oxymethyl] - 2,4 - dichloro - phenyl]sulfonyl] - 2(S) - [[4-[4-(aminoiminomethyl)-phenylcarbonyl]piperazin-1-yl]carbonyl]pyrrolidine (LF16-0335C) exhibited a high affinity for this receptor with Ki values of 7.34±2.45 nM and 8.54±1.55 nM respectively. BK and kallidin (KD) increased inositol phosphates (IPs) levels with EC50 values of 0.44±0.12 nM and 6.88±0.28 nM, respectively. Neither DLBK nor DBK (0.01 nM to 10 ,M) stimulated or inhibited IPs turnover and as expected HOE140 did not raise IPs production. HOE140 (0.1 ,M) and LF 16-0335c (1 ,M) right shifted the BK response curve with pKB values of 9.2±0.4 and 8.4±0.3, respectively. The results indicate that this cloned guinea-pig receptor displayed typical pharmacological properties of a bradykinin B2 receptor and support the existence of a single B2 receptor in this species. British Journal of Pharmacology (2002) 135, 462,468; doi:10.1038/sj.bjp.0704494 [source]

Pharmacological delayed preconditioning against ischaemia-induced ventricular arrhythmias: effect of an adenosine A1 -receptor agonist

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2001
Renaud Tissier
The goal of this study was to investigate the effects of the delayed pharmacological preconditioning produced by an adenosine A1 -receptor agonist (A1 -DPC) against ventricular arrhythmias induced by ischaemia and reperfusion, compared to those of ischaemia-induced delayed preconditioning (I-DPC). Eighty-nine instrumented conscious rabbits underwent a 2 consecutive days protocol. On day 1, rabbits were randomly divided into four groups: ,Control' (saline, i.v.), ,I-DPC' (six 4-min coronary artery occlusion/4-min reperfusion cycles), ,A1 -DPC100' (N6 -cyclopentyladenosine, 100 ,g kg,1, i.v.), and ,A1 -DPC400' (N6 -cyclopentyladenosine, 400 ,g kg,1, i.v.). On day 2, i.e., 24 h later, the incidence and severity of ventricular arrhythmias during a 30-min coronary artery occlusion and subsequent reperfusion were analysed in all animals, using an arrhythmia score. I-DPC, A1 -DPC100 and A1 -DPC400 significantly reduced the infarct size (34±5, 42±3 and 43±7% of the area at risk, respectively) as compared to Control (55±3% of the area at risk). During both ischaemia and reperfusion, neither the incidence nor the severity of ventricular arrhythmias were altered by A1 -DPC100, A1 -DPC400 or I-DPC as compared to Control. Thus, despite reduction of infarct size induced by delayed preconditioning, A1 -DPC as well as I-DPC failed to exert any anti-arrhythmic effect in the conscious rabbit model of ischaemia-reperfusion. British Journal of Pharmacology (2001) 134, 1532,1538; doi:10.1038/sj.bjp.0704407 [source]