Handbook of experimental pharmacology
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Handb Exp Pharmacol · Jan 2012
ReviewPrimary prevention of ischaemic cardiovascular disorders with antiplatelet agents.
In those who have already survived myocardial infarction (MI) or stroke, or have had a transient ischaemic episode (TIA), daily low dose aspirin (ASA) reduces the risk of recurrences by an amount that greatly exceeds the risk of serious bleeding (secondary prevention). ASA is therefore recommended for these people. However, in primary prevention-reducing risk in those so far free of clinically manifest episodes-the benefit is of the same order as the bleeding hazard, (which is much the same in both primary and secondary prevention contexts). ⋯ These results alter the balance in primary prevention between benefit and hazard as it appears for arterial events alone, tipping it towards the use of ASA. Consequently, new guidelines on advice and decisions on ASA in primary prevention are now needed. Low dose ASA, eg. 75 mg daily is as effective as higher doses for all the vascular and cancer benefits established in the meta-analyses, and it causes less serious bleeding than higher doses.
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Understanding the role of ontogeny in the disposition and actions of medicines is the most fundamental prerequisite for safe and effective pharmacotherapeutics in the pediatric population. The maturational process represents a continuum of growth, differentiation, and development, which extends from the very small preterm newborn infant through childhood, adolescence, and to young adulthood. Developmental changes in physiology and, consequently, in pharmacology influence the efficacy, toxicity, and dosing regimen of medicines. ⋯ These developmental components that result in critical windows of development of immature organ systems that may lead to permanent effects later in life interact in a complex, nonlinear fashion. The ontogeny of these physiologic processes provides the key to understanding the added dimension of development that defines the essential differences between children and adults. A basic understanding of the developmental dynamics in pediatric pharmacology is also essential to delineating the future directions and priority areas of pediatric drug research and development.
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Handb Exp Pharmacol · Jan 2011
ReviewThe role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation.
Bile formation is an important function of the liver. Bile salts are a major constituent of bile and are secreted by hepatocytes into bile and delivered into the small intestine, where they assist in fat digestion. In the small intestine, bile salts are almost quantitatively reclaimed and transported back via the portal circulation to the liver. ⋯ The substrates of BSEP are practically restricted to bile salts and their metabolites. It is, however, subject to inhibition by endogenous metabolites or by drugs. A sustained inhibition will lead to acquired cholestasis, which can end in liver injury.
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Caffeine, an antagonist of adenosine A(1), A(2A) and A(2B) receptors, is known as an adjuvant analgesic in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen in humans. In preclinical studies, caffeine produces intrinsic antinociceptive effects in several rodent models, and augments the actions of NSAIDs and acetaminophen. Antagonism of adenosine A(2A) and A(2B) receptors, as well as inhibition of cyclooxygenase activity at some sites, may explain intrinsic antinociceptive and adjuvant actions. ⋯ Low doses of caffeine given systemically inhibit antinociception by several analgesics (acetaminophen, amitriptyline, oxcarbazepine, cizolirtine), probably reflecting block of a component of action involving adenosine A(1) receptors. Clinical studies have demonstrated adjuvant analgesia, as well as some intrinsic analgesia, in the treatment of headache conditions, but not in the treatment of postoperative pain. Caffeine clearly exhibits complex effects on pain transmission; knowledge of such effects is important for understanding adjuvant analgesia as well as considering situations in which dietary caffeine intake may have an impact on analgesic regimens.