Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques最新文献

Capsaicin, the pungent ingredient of red pepper has become not only a "hot" topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical trials, the 8% capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author's 50 years of experience in this field and on the other hand emphasizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of nociceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor "Transient Receptor Potential Vanilloid 1" (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of "capsaicin-sensitive" tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat threshold are the major obstacles of some TRPV1 antagonists, they could be overcome. The special "multisteric" gating function of the TRPV1 cation channel provides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential analgesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states.

Background: Capsaicin is a specific compound acting on capsaicin-sensitive afferent nerves.

Aim: Capsaicin was used to study the different events of human gastrointestinal physiology, pathology, and clinical pharmacology, and possible therapeutic approaches to enhance gastrointestinal mucosal defense in healthy human subjects and in patients with various different gastrointestinal disorders as well as its use with nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy subjects and in patients.

Materials and methods: The observations were carried out in 198 healthy human subjects and in 178 patients with different gastrointestinal (GI) diseases (gastritis, erosions, ulcer, polyps, cancer, inflammatory bowel diseases, colorectal polyps, cancers), and in 69 patients with chronic (Helicobacter pylori positive and negative) gastritis (before and after eradication treatment). The gastric secretory responses and their chemical composition, gastric emptying, sugar loading test, gastric transmucosal potential difference (GTPD) with application of capsaicin alone, after ethanol alone and with capsaicin, indomethacin-induced gastric mucosal microbleeding without and with capsaicin were studied. The immunohistochemical examinations of the capsaicin receptor (TRVP1), calcitonin gene- related peptide (CGRP), and substance P (SP) were carried out in gastrointestinal tract, and especially in patients with chronic gastritis (with and without Helicobacter infection, before and after classical eradication treatment). Classical molecular pharmacological methods were applied to study the drugs inhibiting the gastric basal acid output.

Results: Capsaicin decreased the gastric basal output, enhanced the "non-parietal" (buffering) component of gastric secretory responses, and gastric emptying, and the release of glucagon. Capsaicin prevented the indomethacin- and ethanol-induced gastric mucosal damage; meanwhile capsaicin itself enhanced (GTPD). Capsaicin prevented the indomethacin-induced gastric mucosal microbleeding. The expression of TRVP1 and CGRP increased in the gastric mucosa of patients with chronic gastritis (independently of the presence of Helicobacter pylori infection), and the successfully carried out eradication treatment. The human first phase examinations (the application of acetylsalicylic acid (ASA), diclqfenac, and naproxen together with capcaicinoids) (given in doses that stimulate capsaicin-sensitive afferent vagal nerves) showed no change in the pharmacokinetic parameters of ASA and diclofenac and the ASA and diclofenac-induced platelet aggregation.

Conclusions: Capsaicin represents a new orally applicable gastroprotective agent in healthy human subjects and in patients with different chemical and Helicobacter pylori-induced mucosal damage and in many other diseases requiring treatment with NSAIDs.

Bradykinin and related kinins may act on two types of receptors designated as B1 and B2. It seems that the B2 receptors are most commonly found in various vascular and non-vascular smooth muscles, whereas B1 receptors are formed in vitro during trauma, and injury, and are found in bone tissues. These bradykinin (BK) receptors are involved in the regulation of various physiological and pathological processes. The mode of kinin actions are based upon the interactions between the kinin and their specific receptors, which can lead to activation of several second-messenger systems. Recently, numerous BK receptor antagonists have been synthesized with prime aim to treat diseases caused by excessive kinin production. These diseases are rheumatoid arthritis (RA), inflammatory diseases of the bowel, asthma, rhinitis and sore throat, allergic reactions, pain, inflammatory skin disorders, endotoxic and anaphylactic shock and coronary heart diseases. On the other hand, BK receptor antagonists could be contraindicated in hypertension, since these drugs may antagonize the antihypertensive therapy and/ or may trigger the hypertensive crisis. It is worth suggesting that the BK receptor agonists might be useful antihypertensive drugs.

Capsaicin is a selective transient receptor potential vanilloid 1 (TRPV1) ion channel agonist and has been demonstrated to reduce nerve conduction of nociceptive C fibers in the trigeminal nerve without affecting conduction in Adelta fibers. This chapter reviews the classification of chronic rhinitis subtypes, the prevalence and epidemiology of nonallergic rhinitis (NAR), postulated pathophysiology and mechanisms of NAR including the role of transient receptor potential (TRP) ion channels and discusses the potential therapeutic benefits of capsaicin in the treatment of chronic rhinitis subtypes, specifically NAR. Evidence supports that hypersensitivity of TRP ion channels on sensory afferent neurons innervating nasal mucosa is responsible for inducing NAR symptoms. These symptoms, characterized as excessive nasal glandular secretion, nasal congestion, and headache, are mediated through neuropeptide release during axonal and parasympathetic reflexes which are initiated by a spectrum of nonspecific irritants that activate TRP channels. Rational approaches to treat the pathophysiology of NAR would be to develop therapies with selective TRPV1 agonist activity like capsaicin that target desensitization of TRP ion channels on sensory afferent nerves.

The capsaicin receptor, transient receptor potential vanilloid type 1 ion channel (TRPV1), has been identified as a polymodal transducer molecule on a sub-set of primary sensory neurons which responds to various stimuli including noxious heat (> -42 degrees C), protons and vanilloids such as capsaicin, the hot ingredient of chilli peppers. Subsequently, TRPV1 has been found indispensable for the development of burning pain and reflex hyperactivity associated with inflammation of peripheral tissues and viscera, respectively. Therefore, TRPV1 is regarded as a major target for the development of novel agents for the control of pain and visceral hyperreflexia in inflammatory conditions. Initial efforts to introduce agents acting on TRPV1 into clinics have been hampered by unexpected side-effects due to wider than expected expression in various tissues, as well as by the complex pharmacology, of TRPV1. However, it is believed that better understanding of the pharmacological properties of TRPV1 and specific targeting of tissues may eventually lead to the development of clinically useful agents. In order to assist better understanding of TRPV1 pharmacology, here we are giving a comprehensive account on the activation and inactivation mechanisms and the structure-function relationship of TRPV1.

Tissue kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, tissue kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and gamma-epithelial Na channel. The tissue kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment tissue kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage.

Laboratory studies support a role of capsaicin as an anti-obesity agent. Intestinal mucosal afferent nerves appear to play a role in controlling adipose tissue distribution between visceral and subcutaneous sites. Activation of the transient receptor potential vanilloid-1 channels by capsaicin prevents adipogenesis. A neurogenic mechanism modulates the regulation of fat metabolism by transient receptor potential vanilloid-1-sensitive sensory nerves. A neural pathway enables the selective activation of the central network that regulates brown adipose tissue sympathetic nerve activity in response to a specific stimulation of gastrointestinal transient receptor potential channels. Dietary capsaicin reduces metabolic dysregulation in obese/diabetic mice by enhancing expression of adiponectin and its receptor. The effects of capsaicin in adipose tissue and liver are related to its dual action on peroxisome proliferator-activated receptor alpha and transient receptor potential vanilloid-1 expression/activation. Local desensitization of the abdominal capsaicin-sensitive fibers attenuates the hypometabolic adaptation to food deprivation. Truncal vagotomy leads to significant reductions in both diet-induced weight gain and visceral abdominal fat deposition. Vagal de-afferentation leads to a more modest, but clinically and statistically significant, reduction in visceral abdominal fat. Thermogenesis and lipid metabolism-related proteins are altered upon capsaicin treatment in white adipose tissue. Capsaicin induces apoptosis and inhibits adipogenesis in preadipocytes and adipocytes. Epidemiologic data show that consumption of foods containing capsaicin is associated with a lower prevalence of obesity. Clinical evidence supports a role of capsaicin as an anti-obesity agent. Both oral and gastrointestinal exposure to capsaicin increase satiety and reduce energy and fat intake; the stronger reduction with oral exposure suggests a sensory effect of capsaicin. Bioactive components containing capsaicin may support weight maintenance after a hypocaloric diet. Capsaicin consumption 1 h before low intensity exercise is a valuable supplement for the treatment of individuals with hyperlipidemia and/or obesity because it improves lipolysis. Capsinoid ingestion increases energy expenditure through the activation of brown adipose tissue in humans. Capsinoid ingestion is associated with an increase in fat oxidation that is nearly significant; and two common genetic variants may be predictors of response. Further clinical research to develop convenient approaches for obese individuals to take advantage of this common dietary ingredient to prevent the onset or curtail the progression of obesity will be instructive and clinically relevant.

Unlabelled: Capsaicin appears to be effective for osteoarthritis pain but it is uncertain whether the effect has a dose response, is consistent across joints, or changes over time.

Methods: Randomized controlled trials of topical capsaicin use in OA were identified from PubMed, EMBASE, and ISI Web of Knowledge. Effect on pain scores, patient global evaluation of treatment effectiveness and application site burning were assessed by standardised mean differences (SMD), using RevMan.

Results: Five double-blind randomized controlled trials and one case-crossover trial of topical capsaicin use were identified. Formulations ranged from 0.025 to 0.075%, and trial durations from 4 to 12 weeks. Trials assessed OA of the knee (n = 3), hand (n = 1), and a mix of joints (n = 2). Capsaicin treatment efficacy (vs. placebo) for change in VAS pain score was moderate, at 0.44 (95% CI 0.25-0.62) over 4 weeks of treatment. There was no heterogeneity between studies, indicating no between-study differences, including effect of OA site or treatment concentration. Two studies reported treatment beyond 4 weeks, with divergent results. One study reported an effect size of -9 mm after 12 weeks, and maximal between-group differences at 4 weeks. A second study reported that between-group differences increased over time, up to 20 weeks. Capsaicin was reported as being safe and well-tolerated, with no systemic toxicity. Mild application site burning affected 35-100% of capsaicin-treated patients with a risk ratio of 4.22 (95% CI 3.25-5.48, n = 5 trials); incidence peaked in week 1, with incidence rates declining over time.

Conclusions: Topical capsaicin treatment four times daily is moderately effective in reducing pain intensity up to 20 weeks regardless of site of application and dose in patients with at least moderate pain and clinical or radiologically defined OA, and is well tolerated.