Current perspectives on pharmacotherapy of Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) is a daunting public health threat that has prompted the scientific community's ongoing efforts to decipher the underlying disease mechanism, and thereafter, target this therapeutically. Although basic research in AD has made remarkable progress over the past two decades, currently available drugs can only improve cognitive symptoms temporarily; no treatment can reverse, stop, or even slow this inexorable neurodegenerative process. Numerous disease-modifying strategies targeting the production and clearance of Aβ, as well as modulation of abnormal aggregation of tau filaments, are currently in clinical trials . AREAS COVERED: this review provides an overview of a wide array of therapeutic approaches under investigation, and the perspectives developed in the last 10 years. EXPERT OPINION: While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease. The scientific community must acknowledge that Alzheimer's disease is a complex multifactorial disorder, and thus a single target or pathogenic pathway is unlikely to be identified. The major aim should be to design ligands with pluripotent pharmacological activities.     

Neurobiological aspects of Alzheimer's disease

INTRODUCTION: The molecular pathogenesis of Alzheimer's disease (AD) includes a variety of risk factors, extracellular deposition of β-amyloid, accumulation of intracellular neurofibrillary tangles, oxidative neuronal damage and inflammatory cascades. Although amyloid-β-containing senile plaques and phospho-tau-containing neurofibrillary tangles are hallmark lesions of AD, neither is specific to nor even a marker of the disease. From a biochemical point of view the most consistent finding is a decreased level of choline acetyltransferase. In recent years, cumulative evidence has been gained on the involvement of neuronal lipoprotein activity, and on the role of cholesterol and other lipids in pathogenesis. Although basic research has made remarkable progress in the past two decades, currently available drugs are only able to improve cognitive symptoms temporarily and no treatment can reverse, stop or even slow this inexorable neurodegenerative process. AREAS COVERED: The various neurobiological events associated with development of AD and the multiple treatment approaches for combating this disorder. EXPERT OPINION: AD is a complex multifactorial disorder and thus a single target or pathogenic pathway is unlikely to be identified. Developing therapeutic interventions demands a greater understanding of the processes and the differential involvement of the various mediators. Effective therapeutics are urgently needed, and it is hoped that anti-amyloid strategies will offer a significant step towards a causal therapy.     

Neoteric pharmacotherapeutic targets in fibromyalgia

INTRODUCTION: Fibromyalgia is a debilitating, chronic pain disorder typically present with allodynia and hyperalgesia. Estimates from the USA suggest that fibromyalgia affects about 5% of women, and is the third most common rheumatic disorder after lower back pain and osteoarthritis. Recent research advances highlighted a role for aberrant central pain processing in fibromyalgia, and consistent with this, the first three drugs (pregabalin, duloxetine and milnacipran) approved by the FDA for fibromyalgia over the past 2 years have a predominantly central mode of action. Despite progress in understanding of fibromyalgia and the long-awaited introduction of three medications for treating it, fibromyalgia continues to pose a significantly unmet medical need, negatively affecting the lives of millions of individuals worldwide in all ethnic groups and all economic classes. AREAS COVERED: Prevailing theories of pathogenesis of fibromyalgia, existing therapies and the potential of current research on novel targets. EXPERT OPINION: Current research on novel sedative-hypnotics, anti-epileptic medications, various reuptake inhibitors, growth hormone agonists, canabinoid agonists, non-opiate analgesics and 5-HT3 antagonists offers hope for the the next generation of therapeutic options for fibromyalgia. With regards to the development of novel pharmacotherapies, there seem to be grounds for increased optimism regarding prospective treatments of the disorder.     

Recent developments for Pseudomonas vaccines

Infections with Pseudomonas aeruginosa are a major health problem for immune-compromised patients and individuals with cystic fibrosis. A vaccine against: P. aeruginosa has long been sought after, but is so far not available. Several vaccine candidates have been assessed in experimental animals and humans, which include sub-cellular fractions, capsule components, purified and recombinant proteins. Unique characteristics of the host and the pathogen have complicated the vaccine development. This review summarizes the current state of vaccine development for this ubiquitous pathogen, in particular to provide mucosal immunity against infections of the respiratory tract in susceptible individuals with cystic fibrosis.     

Hypothyroidism of gene-targeted mice lacking Kcnq1

Thyroid hormones T3/T4 participate in the fine tuning of development and performance. The formation of thyroid hormones requires the accumulation of I(-) by the electrogenic Na(+)/I(-) symporter, which depends on the electrochemical gradient across the cell membrane and thus on K(+) channel activity. The present paper explored whether Kcnq1, a widely expressed voltage-gated K(+) channel, participates in the regulation of thyroid function. To this end, Kcnq1 expression was determined by RT-PCR, confocal microscopy, and thyroid function analyzed in Kcnq1 deficient mice (Kcnq1 ( -/- )) and their wild-type littermates (Kcnq1 ( +/+ )). Moreover, Kcnq1 abundance and current were determined in the thyroid FRTL-5 cell line. Furthermore, mRNA encoding KCNQ1 and the subunits KCNE1-5 were discovered in human thyroid tissue. According to patch-clamp TSH (10?mUnits/ml) induced a voltage-gated K(+) current in FRTL-5 cells, which was inhibited by the Kcnq inhibitor chromanol (10?μM). Despite a tendency of TSH plasma concentrations to be higher in Kcnq1 ( -/- ) than in Kcnq1 ( +/+ ) mice, the T3 and T4 plasma concentrations were significantly smaller in Kcnq1 ( -/- ) than in Kcnq1 ( +/+ ) mice. Moreover, body temperature was significantly lower in Kcnq1 ( -/- ) than in Kcnq1 ( +/+ ) mice. In conclusion, Kcnq1 is required for proper function of thyroid glands.     

Design, synthesis, antimicrobial, anticancer evaluation, and QSAR studies of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones

A series of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones (1–17) was synthesized and tested in vitro for its antimicrobial and anticancer potentials. The biological screening results indicated that compounds having m-chloro substituent on benzaldehyde portion showed antimicrobial potential, whereas compounds having chloro, methoxy, and hydroxyl groups showed anticancer potential. The quantitative structure activity relationship (QSAR) studies indicated the importance of topological parameter, valence first order molecular connectivity index in describing antifungal activity. The developed QSAR models, however, were statistically insignificant with reference to anticancer activity of the synthesized compounds.