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Selected Abstracts

Ibudilast: A Non-selective PDE Inhibitor with Multiple Actions on Blood Cells and the Vascular Wall

CARDIOVASCULAR THERAPEUTICS, Issue 3 2001
Yukio Kishi
ABSTRACT Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is widely used in Japan for improving prognosis and relieving symptoms in patients suffering from ischemic stroke or bronchial asthma. These clinical applications are based on the properties of ibudilast that inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory actvity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks. Ibudilast was also reported to significantly attenuate inflammatory cell infiltration in the lumbar spinal cord in an animal model of encephalomyelitis. Future investigations should include effects of ibudilast on inflammatory reactions between endothelium and blood cells, which may initiate the development of atherosclerosis. [source]

Glucagon-like peptide 1(GLP-1) in biology and pathology

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2005
Juris J. Meier
Abstract Post-translational proteolytic processing of the preproglucagon gene in the gut results in the formation of glucagon-like peptide 1 (GLP-1). Owing to its glucose-dependent insulinotropic effect, this hormone was postulated to primarily act as an incretin, i.e. to augment insulin secretion after oral glucose or meal ingestion. In addition, GLP-1 decelerates gastric emptying and suppresses glucagon secretion. Under physiological conditions, GLP-1 acts as a part of the ,ileal brake', meaning that is slows the transition of nutrients into the distal gut. Animal studies suggest a role for GLP-1 in the development and growth of the endocrine pancreas. In light of its multiple actions throughout the body, different therapeutic applications of GLP-1 are possible. Promising results have been obtained with GLP-1 in the treatment of type 2 diabetes, but its potential to reduce appetite and food intake may also allow its use for the treatment of obesity. While rapid in vivo degradation of GLP-1 has yet prevented its broad clinical use, different pharmacological approaches aiming to extend the in vivo half-life of GLP-1 or to inhibit its inactivation are currently being evaluated. Therefore, antidiabetic treatment based on GLP-1 may become available within the next years. This review will summarize the biological effects of GLP-1, characterize its role in human biology and pathology, and discuss potential clinical applications as well as current clinical studies. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2009
Professor K.D. Rainsford
Abstract Objectives Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here. Key findings There is now evidence for symptom - and structure-modifying (radio-logically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15,24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment. Summary The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety. [source]

Pharmacological Mechanisms of Naltrexone and Acamprosate in the Prevention of Relapse in Alcohol Dependence

THE AMERICAN JOURNAL ON ADDICTIONS, Issue 2003
John Littleton M.B.B.S., Ph.D.
Naltrexone and acamprosate may ultimately prove to be useful additions to pharmacotherapy for alcoholism by reducing relapse. Naltrexone is a relatively selective competitive antagonist at mu-opioid receptors, and this activity may explain its anti-relapse action either because endogenous opioids are involved in the positively reinforcing effects of alcohol and/or because these same transmitters are involved in the conditioned anticipation of these effects. In contrast, the pharmacology of acamprosate is still poorly understood. This is not surprising because it is a small flexible molecule with similarities to several neuro-active amino acids and is used in high doses. All these factors suggest that it may have multiple actions. Currently, the best explanation for the effects of acamprosate seems to be that it inhibits the glutamatergic transmitter system involved in both the negative reinforcing effects of alcohol and the conditioned "pseudo-withdrawal" that may be important in cue-induced relapse. [source]