Handbook of experimental pharmacology
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A series of government actions have evolved since the 1990s to facilitate the development of medicinal products for pediatric use using a combination of incentives and mandates. The initiatives have been successful in stimulating activity and interest in products developed for pediatric use. The initiatives continue to evolve as experience accumulates and regulatory agencies develop robust cooperative programs. A multidimensional program is necessary to achieve the necessary goal of aligning pediatric therapeutics with adult therapeutics and providing children the most favorable opportunity to benefit and minimize risk to vulnerable populations.
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For more than a half century, tobacco manufacturers have conducted sophisticated internal research to evaluate nicotine delivery, and modified their products to ensure availability of nicotine to smokers and to optimize its effects. Tobacco has proven to be a particularly effective vehicle for nicotine, enabling manipulation of smoke chemistry and of mechanisms of delivery, and providing sensory cues that critically inform patterns of smoking behavior as well as reinforce the impact of nicotine. ⋯ A review of internal documents indicates important historical differences, as well as significant differences between commercial brands, underscoring the effectiveness of methods adopted by manufacturers to control nicotine dosing and target the needs of specific populations of smokers through commercial product development. Although the focus of the current review is on the manipulation of nicotine dosing characteristics, the evidence indicates that product design facilitates tobacco addiction through diverse addiction-potentiating mechanisms.
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Neuropathic pain syndromes, i.e., pain after a lesion or disease of the peripheral or central nervous system, are clinically characterized by spontaneous pain (ongoing, paroxysms) and evoked types of pain (hyperalgesia, allodynia). A variety of distinct pathophysiological mechanisms in the peripheral and central nervous system operate in concert: In some patients the nerve lesion triggers molecular changes in nociceptive neurons that become abnormally sensitive and develop pathological spontaneous activity (upregulation of sodium channels and receptors, e.g., vanilloid TRPV1 receptors, menthol-sensitive TRPM8 receptors, or alpha-receptors). These phenomena may lead to spontaneous pain, shooting pain sensations, as well as heat hyperalgesia, cold hyperalgesia, and sympathetically maintained pain. ⋯ Therefore, a new hypothetical concept was proposed in which pain is analyzed on the basis of underlying mechanisms. The increased knowledge of pain-generating mechanisms and their translation into symptoms and signs may in the future allow a dissection of the mechanisms that operate in each patient. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs acting against those particular mechanisms, it should ultimately be possible to design optimal treatments for the individual patient.
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Migraine is a neurovascular disorder which affects one fifth of the general population. Disability due to migraine is severe and involves patients from infancy through senescence and it is aggravated by the fact there is no complete cure. ⋯ These novel antagonists block the receptor for the sensory neuropeptide calcitonin gene-related peptide (CGRP), which upon release from peripheral terminals of trigeminal perivascular neurons dilates cranial arterial vessels. Whether neurogenic vasodilatation is the major contributing factor to generate the pain and the associated symptoms of the migraine attack or whether other sites of action of CGRP receptor antagonists are responsible for the antimigraine effect of these compounds is the subject of current and intense research.