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An increasing number of patients complain to medical institutions about a cough that persists for more than 8 weeks, namely chronic cough. The cough observed in patients with chronic cough is not responsive to conventional antitussive agents such as dihydrocodeine and dextromethorphan, and this is a major clinical problem. The most common pathology of chronic cough in Japan is dry cough. Two causes of dry cough are increased sensitivity of cough receptors (cough hypersensitivity) and increased contraction of bronchial smooth muscle. Among these, the mechanisms of cough hypersensitivity are diverse, and understanding these mechanisms is important for the diagnosis and treatment of chronic cough. In this paper I will review the regulatory mechanisms of cough hypersensitivity, especially the regulation of Aδ fiber excitability by C fibers. Furthermore, the central mechanisms involved cough reflex are discussed in relation to central acting antitussives.

Peritoneal lavage was developed as a simple method to evacuate the ascitic fluid associated with pancreatitis. Although a number of studies demonstrated its efficacy in improvement of clinical manifestations, a meta-analysis of randomized control studies could not reveal its effectiveness on mortality or morbidity in severe acute pancreatitis. However, it has been well established that the ascitic fluid with pancreatitis is extremely toxic and to induce organ damage due to apoptotic cell death. Particularly, we have recently found that the ascitic fluid with pancreatitis can induce bacterial translocation due to the increase of gut permeability. Therapeutic strategy of peritoneal lavage, i.e. evacuation of toxic substances from peritoneal cavity, should be reevaluated to achieve further improvement of treatment result of severe acute pancreatitis.

Nasal allergy is the most common type I allergic disease. During allergic reaction, chemical mediators may be released from residual cell, and thus, attract additional inflammatory cells. One mediator implicated in this response is bradykinin (BK), a potent proinflammatory nonapeptide. This study was designed to investigate the effects of BK on nasal mucosa, and to determine the role of angiotensin-converting enzyme (ACE) in BK-induced nasal responses. BK nasal provocation (100 micrograms) was studied in 7 normal volunteers and 7 patients with perennial allergic rhinitis. After provoking of BK response, nasal secretions and saline lavage fluids were collected for analysis of total protein (a protein secretion marker), albumin (a vascular permeability marker), and lysozyme (a serous cell marker). In addition, after administering of Captopril 50 mg, a specific ACE inhibitor, the same protocol was performed. In both groups, BK induced plasma exudation and serous gland secretion. Premedication with captopril did not alter BK-induced responses in normal individuals. In allergic patients, captopril enhanced BK-induced vascular permeability, but not glandular secretion. These results indicate that allergic subjects have nasal hyperresponsiveness to BK, and that ACE predominantly modulates the vascular permeability of allergic nasal mucosa. It seems likely that BK may contribute to the expression of nasal allergic symptoms, and that inhibition of ACE may lead to increased nasal responsiveness.

From the screening of a number of new pyrazole derivatives, the title compound, PZ-177, was selected as the most significant derivative for analgestic and anti-edematous actions, in this paper, we report the anti-edematous activity of PZ-177 as assessed by detailed analysis. PZ-177 showed a markedly inhibitory effect against rat paw edema induced by various phlogists (carragenin, dextran, egg albumin, serotonin, formalin and bradykinin). It also inhibited edema induced by anti-rat rabbit serum. The activity of PZ-177 was more potent than that of mepirizole and the same as that of phenylbutazone. Though this agent has a central depressive effect, it is considered that the action has actually little influence on anti-edematous effect, as carrageenin-induced edema was inhibited in spinal rats. On the other hand, the anti-edematous effect of PZ-177 was reduced significantly in adrenalectomized rats. It is therefore suggested that the potent anti-edematous action of PZ-177 is exerted partially by a direct action at the inflamed site and mediated partially by stimulation of the hypophysis-adrenal system.

Using the model of knee pain reaction induced by intra-articular injection of endogenous pain substances, especially bradykinin (BK) in rats, the mechanism of the analgesic effect of sodium hyaluronate (SPH) was investigated. The simultaneous administration of prostaglandin E2 with BK or hyaluronidase digestion of endogenous hyaluronic acid (HA) in our experiments brought remarkable hyperalgesia on BK-induced knee pain. These results suggest that higher sensitivity to the pain reaction is induced in a diseased joint (higher prostaglandin content, lower concentration and molecular size of HA in synovial fluid) than in a normal one. SPH definitely decreased BK-induced pain, and its analgesic effect was observed for a longer period, depending on its dose in pre-treatment and the degree of its distribution in synovial tissues. As the analgesic effect of SPH was observed in the hyaluronidase-treated joint as well, it is suggested that the increasing viscosity of synovial fluid caused by increasing HA concentration can decrease the pain even without normalizing molecular size of HA in the joint. HA oligomer and other compounds with similar viscosity or with similar polyanionic character as SPH showed no analgesic effect. From these results, it seems that the characteristic steric configurations of higher molecular HA are needed for the manifestation of the analgesic effect. SPH seems to show its analgesic effect by covering pain receptors in synovial tissues and holding endogenous pain substances in its molecule.