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Pharmacological Strategies (pharmacological + strategy)
Selected AbstractsNew Pharmacological Strategies for the Treatment of Atrial FibrillationANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 3 2009Alexander Burashnikov Ph.D. Atrial fibrillation (AF) is a growing clinical problem, increasing in prevalence as the population of the United States and countries around the world ages. Intensive research aimed at improving prevention, diagnosis, and treatment of AF is ongoing. Although the use and efficacy of catheter ablation-based approaches in AF treatment have increased significantly in the last decade, pharmacological agents remain the first-line therapy for rhythm management of AF. Currently available anti-AF agents are generally only moderately effective and associated with extracardiac toxicity and/or a risk for development of life-threatening ventricular arrhythmias. Included among current investigational strategies for improving the effectiveness and safety of anti-AF drugs is the development of (1) Agents that produce atrial-specific or predominant inhibition of IKur, IK-ACh, or INa; (2) "Upstream therapies" that effect nonion channel targets that reduce atrial structural remodeling, hypertrophy, dilatation, inflammation, oxidative injury, etc; (3) Derivatives of "old" anti-AF drugs with an improved safety pharmacological profile; and (4) Gap junction therapy aimed at improving conduction without affecting sodium channels. This review focuses on new pharmacological approaches under investigation for the treatment of AF. [source] Postural induced-tremor in psychiatryPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 6 2008Beatriz Arbaizar md Postural tremor is the most common movement disorder in psychiatry, and often a difficult problem for clinicians. It can be classified as physiological, essential, drug-induced, and postural tremor in Parkinson's disease. Drugs used in psychiatry that can produce postural tremor, include lithium, valproic acid, lamotrigine, antidepressants, and neuroleptics. Clinical characteristics of postural tremor induced by each of these drugs are described. Pharmacological strategies for therapy in disabling drug-induced tremor include beta-blockers, primidone, gabapentin, topiramate, and benzodiazepines; their utility, doses and side-effects are also discussed. [source] Therapeutics for alcoholism: what's the future?DRUG AND ALCOHOL REVIEW, Issue 1 2007ANDREW J. LAWRENCE Abstract As with other addictions, human alcoholism is characterised as a chronically relapsing condition. Consequently, the therapeutic goal is the development of clinically effective, safe drugs that promote high adherence rates and prevent relapse. These products can then be used in conjunction with psychosocial approaches. In this review, preclinical studies are highlighted that indicate the mechanism of action of currently used anti-craving medications or demonstrate the potential of novel pharmacological agents for the treatment of alcohol use disorders. While current pharmacological strategies are far from ideal, there are a number of candidate molecules that may ultimately be developed into therapeutic agents. In addition, prescribing clinicians should also consider strategies such as combinations of various drugs to aid in the regulation of aberrant alcohol consumption. [source] Hippocampal structure and the action of cholinomimetic drugsDRUG DEVELOPMENT RESEARCH, Issue 3 2002John G. Csernansky Abstract Cholinomimetic drugs have become the clinical standard for the treatment of patients with dementia of the Alzheimer type (DAT). However, uncertainty remains as to the proportion of patients that respond to such drugs, and how one might predict the capacity for response before treatment is begun. The thesis of the present review is that the neuroanatomical integrity of the hippocampus determines, at least in part, the capacity of DAT patients to respond to cholinomimetic drugs. Neuroimaging studies suggest that volume losses and other neuroanatomical deformities of the hippocampus are common in patients with even mild DAT. Moreover, more severe neuroanatomical deformities of the hippocampus are associated with more severe dementia symptoms and more rapid clinical decline. Animal research, including studies of cholinergic antagonists, glutamatergic antagonists, hippocampal lesions, and animals with mutant amyloid precursor protein genes, demonstrate that behavioral abnormalities similar to those found in DAT patients, especially those related to memory, are associated with hippocampal pathology. Cholinomimetic drugs, in particular, the cholinesterase inhibitors, have been shown to reverse some but not all of these behavioral abnormalities. More research is needed in DAT patients to determine whether an analysis of hippocampal structure or function can reliably predict the outcome of treatment with cholinomimetic drugs. Further work in animals is also needed to determine the limitations of cholinomimetic drugs for reversing various types of cognitive deficits, and to develop and test other pharmacological strategies for the treatment of DAT. Drug Dev. Res. 56:531,540, 2002. © 2002 Wiley-Liss, Inc. [source] ,-Amyloid immunization approaches for Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 2 2002Bruno P. Imbimbo Abstract Alzheimer's disease (AD) represents the third leading cause of death in the U.S. and the leading cause of dementia in the elderly population. Until recently, there was little hope of efficiently combating this devastating disease. The deposition of ,-amyloid (A,) is the major pathological hallmark of AD brains. Genetic, biochemical, and pharmacological evidence support the hypothesis that A, plays a key role in the development of the disease. Thus, in the last 5 years a number of pharmacological strategies have been developed to interfere with the A, cascade. The most revolutionary of these approaches was proposed in 1999 by scientists at Elan Pharmaceuticals, which immunized against A, transgenic mice with spontaneously developing A, pathology. The immunization was achieved by subcutaneous injections of a preaggregated form of the synthetic human 42-amino acid A, emulsified with Freund's adjuvant, an immune stimulant. The vaccination caused a near complete inhibition of A, plaque formation in younger animals and a marked reduction of the A, burden in older animals. The effects on A, plaques were accompanied by a reduction of A,-associated astrogliosis and neuritic dystrophy. These results were later confirmed by other groups with similar vaccination protocols, which also demonstrated that the A, immunization of transgenic animals normalize or reduce the cognitive impairment associated with A, pathology. Interestingly, effective removal of brain A, plaques was also obtained by peripherally administering A, antibodies. The mechanism with which the vaccine increases A, clearance is not fully understood. Centrally, the vaccine appears to activate A, phagocytosis by microglial monocytes. Peripherally, serum A, antibodies bind and sequester A,, thus altering its equilibrium between CNS and plasma. The dramatic results obtained in animal models of AD raised unprecedented hopes for both a preventive and a curative intervention for this devastating disorder. A vaccine preparation for human use (AN-1792) composed of preaggregated human A,42 peptide and a highly purified saponin derivative (QS-21) was developed by Elan Pharmaceuticals and Wyeth Ayerst and tested in AD patients. Unfortunately, a Phase IIa study aimed at evaluating the safety and immunological activity of AN-1792 in 360 AD patients was discontinued because 15 subjects receiving the vaccine developed serious signs of CNS inflammation. Both central activation of cytotoxic T cells and autoimmune reactions were proposed as potential mechanisms of toxicity. Other therapeutic A, vaccination strategies are being pursued, including immuno-conjugates and monoclonal antibodies. The future of these and other A, immunization approaches depend on a clear understanding of the mechanism of A, clearance and additional insight into the role of inflammation in the AD brain. Drug Dev. Res. 56:150,162, 2002. © 2002 Wiley-Liss, Inc. [source] Headache attributed to spontaneous low CSF pressure: report of three cases responsive to corticosteroidsEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2004S. Gentile The therapy of headache attributed to spontaneous low CSF pressure (previously defined as spontaneous intracranial hypotension) is still a matter of debate. Epidural blood patch is considered the most effective treatment. However, pharmacological strategies may be considered before blood patch. We report three patients with headache attributed to spontaneous low CSF pressure that were successfully treated with oral prednisone. Additional studies may be useful to prove the effectiveness of corticosteroids in this syndrome. [source] New pharmacological strategies against metastatic spreadFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2008G.Y. Perret Abstract Although metastatic spread is the most frequent cause of death in cancer patients, there are very few drugs specifically targeting this process. Bases for a new antimetastatic drug discovery strategy are weak because a great number of unknowns characterize the complete understanding of the metastatic cascade mechanisms. Moreover, the current experimental models are too simplistic and do not account for the complexity of the phenomenon. Some targets have been identified but too few are validated. Among them, the metastasis suppressor genes seem to be the most promising. In spite of this, during recent years, a dozen of molecules, which fulfil the definition of a specific metastatic drug that inhibits the metastases without altering the growth of the primary tumour (which can be eradicated by surgery), have been identified and assessed for the proof of the concept. The continuation of this effort would benefit in terms of efficiency, if the objectives were defined more precisely. It is particularly important to distinguish molecules that prevent spread of the metastatic cells of the early-stage primary tumour from the ones which induce a regression of the established metastases or to inhibit the transition from disseminated occult tumour cells to dormant micrometastasis. This second goal is a priori more relevant in the current clinical setting where the detection of early metastatic spread is very difficult, and therefore would call for greater effort on the part of the scientific community. [source] Neutrophil apoptosis: A target for enhancing the resolution of inflammationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2009János G. Filep Abstract Neutrophils are essential for host defense and their programmed cell death and removal are critical for the optimal expression as well as for efficient resolution of inflammation. Delayed neutrophil apoptosis or impaired clearance of apoptotic neutrophils by macrophages contributes to the progression of chronic inflammation. Under most conditions, neutrophils are exposed to multiple factors and their fate would ultimately depend on the balance between pro-survival and pro-apoptotic signals. Life or death decisions are tightly controlled by a complex network of intracellular signaling pathways. Accumulating data indicate that receptors, such as the formyl peptide receptor 2/lipoxin receptor or ,2 -integrins can generate contrasting cues in neutrophils in a ligand-specific manner and suggest a hierarchy among these signals. In this article, we review recent advances on how pro-apoptosis and pro-survival signals interact to determine the fate of neutrophils and the inflammatory response, and highlight novel pharmacological strategies that could be used to enhance the resolution of inflammation by redirecting neutrophils to apoptosis. J. Cell. Biochem. 108: 1039,1046, 2009. © 2009 Wiley-Liss, Inc. [source] Phosphodiesterase-linked inhibition of nonmicturition activity in the isolated bladderBJU INTERNATIONAL, Issue 9 2004J.I. Gillespie Over the past few months Gillespie has published several papers in the BJU International investigating the overactive bladder and BOO, using novel models and theories. This next paper continues these concepts and shows that the mechanisms influencing the frequency of agonist-induced phasic activity in the isolated bladder model is slowed by cAMP. These findings will have important implications in future pharmacological strategies in the overactive bladder. OBJECTIVE To explore the influence of intracellular cAMP on phasic activity in the isolated bladder (phasic rises in intravesical pressure associated with waves of contraction and local stretches that can be activated by muscarinic or nicotinic agonists), as it has been argued that this activity underlies nonmicturition contractions, and that it contributes to the generation and modulation of afferent nerve activity. MATERIALS AND METHODS Isolated whole bladders from female guinea pigs (270,300 g) were cannulated via the urethra and suspended in a chamber containing oxygenated Tyrode solution at 33,35 °C. Bladder pressure was recorded and pharmacological agents added to the solution bathing the abluminal surface of the bladder. RESULTS Forskolin (1,3 µmol/L), an activator of adenyl cyclase, reduced the frequency and amplitude of the phasic activity induced by the muscarinic agonist arecaidine (300 nmol/L). There were similar changes in frequency and amplitude in bladders exposed to the nonspecific phosphodiesterase (PDE) inhibitor iso-butyl-methyl-xanthene (IBMX). The actions of specific PDE inhibitors were explored to assess which isoenzymes might be responsible for regulating phasic activity. ENHA (PDE-2), zaprinast (PDE-5, -6, -8, -9 and -11) and siguazodan (PDE-3) had no effect. Zardavarine (PDE-3, -4) and Ro 20-1724 (PDE-4) reduced both the frequency and amplitude of the phasic activity. Nerve-mediated rises in intravesical pressure were also inhibited by Ro 20-1724, and the inhibition was more pronounced at 6.5 Hz than at 30 Hz stimulation. Ro 20-1724 inhibited nerve-mediated fluctuations induced by prolonged (200 s) stimulation at 6.5 Hz. CONCLUSION The mechanisms influencing the frequency of agonist-induced phasic activity in the isolated bladder are slowed by cAMP. Degradation of intracellular cAMP in the cells responsible for phasic activity appears to involve primarily PDE-4. The importance of these observations in relation to the overall physiological regulation of the bladder are discussed, and the possible importance of these findings in the development of pharmacological strategies to modulated bladder activity reviewed. [source] Effects of ,-aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesityFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2010Karima Begriche Abstract ,-Aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this ,-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts caused by the absence of, or low leptin expression on lipid homeostasis and body weight in humans and animals and (ii) recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, at least in some individuals. [source] | ||||||||||