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

The bladder is an organ rich in vanilloid targets: dense unmyelinated c-fibers partially responsible for bladder sensation and response to noxious stimuli. Drugs such as capsaicin and resiniferatoxin (RTX) interact with the VR1 vanilloid receptor subtype to initially excite then subsequently desensitize the c-fibers. This chapter examines the literature describing the use of vanilloid receptor agonists in the treatment of the following urological disorders: neurogenic bladder (NGB), overactive bladder (OAB), and interstitial cystitis/painful bladder syndrome (IC/PBS). Review of the literature was performed using Pubmed and the following key words "capsaicin," "resiniferatoxin (RTX)," and "neurogenic bladder," "overactive bladder (OAB)," and "interstitial cystitis," "painful bladder syndrome." Articles focusing on randomized trials comparing intravesical administration of a vanilloid receptor agonist to placebo and those in English were reviewed. We conclude that capsaicin and RTX do appear to provide some acceptable treatment results in patients with neurogenic bladder, though larger studies are needed to confirm this. Although efficacy has been shown in some studies, currently the use of vanilloids cannot be recommended for routine use in patients with OAB as the need for catheterization may cause the risk to outweigh the benefit of treatment. Similarly, for the treatment of BPS, vanilloid receptor agonists lack strong evidence for efficacy or tolerability; larger studies are needed to define their role. Understanding how vanilloids are able to impact these disorders, however, may help further elucidate their underlying pathophysiological processes.

The TRPV1 receptor is known to play a role in nociceptive transmission in multiple organ systems, usually in response to the pain of inflammation. TRPV1 antagonism has so far shown limited benefit in antinociception. Capsaicin, a TRPV1 agonist, has been shown to induce a refractory period in the nerve terminal expressing TRPV1 and even, in sufficient dosing, to create long-term nerve terminal defunctionalization. This has led to research into topical capsaicin as a treatment for multiple painful conditions. The majority of work has focused on musculoskeletal pain and neuropathic pain and has revealed that although low-dose topical capsaicin has limited effectiveness as an analgesic, high-dose capsaicin, when tolerated, has the potential for long-term analgesia in certain types of neuropathic pain.

Capsaicin, one of the major pungent ingredients found in red peppers, has been recently demonstrated to induce apoptosis in many types of malignant cell lines including colon adenocarcinoma, pancreatic cancer, hepatocellular carcinoma, prostate cancer, breast cancer, and many others. The mechanism whereby capsaicin induces apoptosis in cancer cells is not completely elucidated but involves intracellular calcium increase, reactive oxygen species generation, disruption of mitochondrial membrane transition potential, and activation of transcription factors such as NFkappaB and STATS. Recently, a role for the AMP-dependent kinase (AMPK) and autophagy pathways in capsaicin-triggered cell death has been proposed. In addition, capsaicin shows antitumor activity in vivo by reducing the growth of many tumors induced in mice. In this chapter, we report the last advances performed in the antitumor activity of capsaicin and review the main signaling pathways involved.

Neurogenic pain and pruritus are the common chief complaints at dermatology office visits. Unfortunately, they are also notoriously difficult conditions to treat. Topical capsaicin used as a single therapy or as an adjuvant offers a low-risk option for patients who do not achieve control on other therapies. This chapter presents the evidence behind topical capsaicin use in dermatologic conditions characterized by neurogenic pain or pruritus, including postherpetic neuralgia, notalgia paresthetica, brachioradial pruritus, lichen simplex chronicus, prurigo nodularis, pruritus ani, pruritus of hemodialysis, aquagenic pruritus, apocrine chromhidrosis, lipodermatosclerosis, alopecia areata, and psoriasis. It presents the most common capsaicin formulations, dosages, and durations of treatment for each condition. Additionally, the chapter addresses various adverse effects and limitations in the use of topical capsaicin in dermatology.

The function of TRPV1 in the peripheral nervous system is increasingly being investigated for its anti-inflammatory and antinociceptive properties in an effort to find a novel target to fight pain that is nonaddictive. However, in recent years, it was discovered that TRPV1 is also associated with a wide array of functions and behaviors in the central nervous system, such as fear, anxiety, stress, thermoregulation, pain, and, more recently, synaptic plasticity, the cellular mechanism that allows the brain to adapt to its environment. This suggests a new role for brain TRPV1 in areas such as learning and memory, reward and addiction, and development. This wide array of functional aspects of TRPV1 in the central nervous system (CNS) is in part due to its multimodal form of activation and highlights the potential pharmacological implications of TRPV1 in the brain. As humans also express a TRPV1 homologue, it is likely that animal research will be translational to humans and therefore worthy of exploration. This review outlines the basic expression patterns of TRPV1 in the CNS along with what is known regarding its signaling mechanisms and its role in the aforementioned brain functions. As TRPV1 involvement in synaptic plasticity has never been fully reviewed elsewhere, it will be a focus of this review. The chapter concludes with some of the potential pharmaceutical implications of further TRPV1 research.

A large variety of antihypertensive drugs, such as angiotensin converting enzyme inhibitors, diuretics, and others, are prescribed to hypertensive patients, with good control of the condition. In addition, all individuals are generally believed to be salt sensitive and, thus, severe restriction of salt intake is recommended to all. Nevertheless, the physiological defense mechanisms in the kidney against excess salt intake have not been well clarified. The present review article demonstrated that the renal (tissue) kallikrein-kinin system (KKS) is ideally situated within the nephrons of the kidney, where it functions to inhibit the reabsorption of NaCl through the activation of bradykinin (BK)-B2 receptors localized along the epithelial cells of the collecting ducts (CD). Kinins generated in the CD are immediately inactivated by two kidney-specific kinin-inactivating enzymes (kininases), carboxypeptidase Y-like exopeptidase (CPY), and neutral endopeptidase (NEP). Our work demonstrated that ebelactone B and poststatin are selective inhibitors of these kininases. The reduced secretion of the urinary kallikrein is linked to the development of salt-sensitive hypertension, whereas potassium ions and ATP-sensitive potassium channel blockers ameliorate salt-sensitive hypertension by accelerating the release of renal kallikrein. On the other hand, ebelactone B and poststatin prolong the life of kinins in the CD after excess salt intake, thereby leading to the augmentation of natriuresis and diuresis, and the ensuing suppression of salt-sensitive hypertension. In conclusion, accelerators of the renal kallikrein release and selective renal kininase inhibitors are both novel types of antihypertensive agents that may be useful for treatment of salt-sensitive hypertension.

Diabetic retinopathy (DR) is a major microvascular complication associated with type 1 and type 2 diabetes mellitus, which can lead to visual impairment and blindness. Current treatment strategies for DR are mostly limited to laser therapies, steroids, and anti-VEGF agents, which are often associated with unwanted side effects leading to further complications. Recent evidence suggests that kinins play a primary role in the development of DR through enhanced vascular permeability, leukocytes infiltration, and other inflammatory mechanisms. These deleterious effects are mediated by kinin B1 and B2 receptors, which are expressed in diabetic human and rodent retina. Importantly, kinin B1 receptor is virtually absent in sane tissue, yet it is induced and upregulated in diabetic retina. These peptides belong to the kallikrein-kinin system (KKS), which contains two separate and independent pathways of regulated serine proteases, namely plasma kallikrein (PK) and tissue kallikrein (TK) that are involved in the biosynthesis of bradykinin (BK) and kallidin (Lys-BK), respectively. Hence, ocular inhibition of kallikreins or antagonism of kinin receptors offers new therapeutic avenues in the treatment and management of DR. Herein, we present an overview of the principal features and known inflammatory mechanisms associated with DR along with the current therapeutic approaches and put special emphasis on the KKS as a new and promising therapeutic target due to its link with key pathways directly associated with the development of DR.

This chapter reviews the scientific and clinical evidence supporting the use of topical formulations containing the pungent principle of chili peppers--capsaicin, for the treatment of peripheral neuropathic pain. Given the limitations of current oral and parenteral therapies for the management of pain arising from various forms of nerve injury, alternate therapeutic approaches that are not associated with systemic adverse events that limit quality of life, impair function, or threaten respiratory depression are critically needed. Moreover, neuropathic conditions can be complicated by progressive changes in the central and peripheral nervous system, leading to persistent reorganization of pain pathways and chronic neuropathic pain. Recent advances in the use of high-dose topical capsaicin preparations hold promise in managing a wide range of painful conditions associated with peripheral neuropathies and may in fact help reduce suffering by reversing progressive changes in the nervous system associated with chronic neuropathic pain conditions.