Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sensory neuropeptide, substance P (SP), is present in human airway nerves, beneath and within the epithelium where the condensed localization of neutral endopeptidase (NEP), the major enzyme degrading SP, is observed. To test the hypothesis whether SP stimulates the cough reflex and NEP modifies the cough reflex, we studied the cough response to various stimuli in awake guinea-pigs. Inhibition of NEP with phosphoramidon caused cough, which was inhibited by systemic capsaicin treatment and by aerosols of a specific NK1 receptor antagonist FK 888. Aerosols of FK 888 also inhibited cough induced by bronchoconstricting agents such as acetylcholine and histamine in non-sensitized animals and by ovalbumin antigen in animals sensitized to ovalbumin. The number of coughs induced by histamine aerosols was inhibited by systemic capsaicin treatment and enhanced by pretreatment with a NEP inhibitor phosphoramidon. Likewise, FK 888 inhibited the augmented cough response to aerosolized capsaicin in female guinea-pigs treated with a long-term medication of an angiotensin-converting enzyme inhibitor, cilazapril. In humans, aerosols of SP did not cause cough in normal subjects, whereas it did in patients with common colds. The SP fragment a major metabolite of SP produced by NEP, was less effective compared with SP in these patients, suggesting that damaged epithelium may facilitate the penetration of SP. These findings suggest that SP released from sensory nerves in response to stimuli may mediate cough and NEP may have a role in modulating SP-induced effects.
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PMID:Role of substance P in cough. 923 70

A number of new classes of antihypertensive drugs have become available in the recent years which appear to hold therapeutic potential for better management of hypertension. Losartan, an angiotensin II receptor antagonist, does not produce cough which is classically seen with ACE inhibitors. Fenoldopam, a dopamine D1-receptor agonist, has a rapid and short duration of action and is ideally suited by intravenous infusion for quick control of BP in hypertensive emergencies. Kentaserin, a serotonin (5-HT2A) receptor antagonist, has a long duration of action and can be given once daily. It has the added benefit of having antiplatelet effect. Monatepil, a dual alpha-receptor and calcium channel blocker, has potent antihypertensive effect, lowers serum cholesterol and also has antiatherosclerotic effect. Dual ACE and endopeptidase inhibitor, such as alatriopril, has a "broad spectrum" antihypertensive effect and may be effective in majority of hypertensive patients. Many other classes of antihypertensive drugs are still in the investigative stage, and their therapeutic potentials and safety need to be ascertained in long-term controlled clinical trials.
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PMID:New classes of antihypertensive drugs: therapeutic potentials. 1005 49

Increased sensitivity of cough reflex is a fundamental feature of bronchodilator resistant non-productive cough associated with eosinophilic tracheobronchitis. Our hypothesis is that cough sensitivity is increased by airway allergic reaction characterized by airway eosinophilic inflammation. The aim of this study was to elucidate the hypothesis and clarify the characteristics of the increased cough sensitivity. Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an aerosolized antigen or saline in actively sensitized or non-sensitized (naive) conscious guinea pigs and then bronchoalveolar lavage was performed. The cough response was also measured 1 day before and 1, 2, 3, 5 and 7 days after an aerosolized antigen challenge in sensitized or naive animals. In addition, effect of procaterol (0.1 mg/kg), atropine (1 or 10 mg/kg), phosphoramidon (2.5 mg/kg) given intraperitoneally 30 min before the capsaicin challenge or capsaicin desensitization on the cough response was examined. Furthermore, the thromboxane A2 (TXA2) receptor antagonist S-1452 in a dose of 0.01 or 0.1 mg/kg or vehicle (saline) was given intraperitoneally at 24 and 1 h before the measurement of cough response. Number of coughs caused by capsaicin was extremely increased 24 h after an antigen challenge in sensitized guinea pigs compared with a saline or an antigen challenge in naive animals or a saline challenge in sensitized animals. The increased cough response disappeared at 3-7 days after the antigen challenge. Eosinophils in bronchoalveolar lavage fluid obtained after the measurement of capsaicin-induced coughs, which was performed 24 h after the antigen challenge, were significantly increased in sensitized guinea pigs. The eosinophil count was significantly correlated to the number of capsaicin-induced coughs. Procaterol or atropine did not alter the antigen-induced increase of cough sensitivity, whereas atropine did reduce the cough response in naive animals. Phosphoramidon increased the number of capsaicin-induced coughs in naive guinea pigs but not in sensitized and antigen-challenged animals. Capsaicin desensitization decreased the cough response in both antigen-challenged sensitized guinea pigs and naive animals. S-1452 reduced the antigen-induced increase of cough response in sensitized guinea pigs, but not in naive animals. Airway allergy accompanied with airway eosinophilia induces transient increase in cough sensitivity, which is not mediated by bronchoconstriction. The increased cough sensitivity may result in part from inactivation of neutral endopeptidase and TXA2, one of the inflammatory mediators.
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PMID:Characterization of increased cough sensitivity after antigen challenge in guinea pigs. 1126 Jan 61

Carbocysteine is a mucoactive drug and is being used for both acute and chronic infectious airway diseases. Although carbocysteine can repair the damage of epithelial cells caused by exposure to various agents, the effects of this agent on allergic airway diseases such as asthma and eosinophilic bronchitis with an isolated chronic cough, in both of which epithelial damage may be characteristic, is not clear. We investigated the effects of carbocysteine on antigen-induced cough hypersensitivity to inhaled capsaicin at 48 h and bronchial hyperresponsiveness to inhaled methacholine at 72 h after challenge with an aerosolized antigen in actively sensitized guinea pigs. After measuring bronchial responsiveness, we examined neutral endopeptidase (NEP) activity in the tracheal tissue. Carbocysteine (10, 30, or 100 mg/kg) was given intraperitoneally every 12 h for 3 days after antigen challenge. The number of coughs elicited by an aerosol of capsaicin (10(-4) M) was significantly (p < 0.01) decreased in carbocysteine groups (6.13 +/- 0.59 at 10 mg/kg, 4.88 +/- 0.67 at 30 mg/kg, and 4.50 +/- 0.33 at 100 mg/kg during 3 min measurement) compared with the control group (9.75 +/- 0.53). Furthermore, carbocysteine dose dependently repaired the antigen-induced decrease of NEP activity in the tracheal tissue, but it did not influence the bronchial hyperresponsiveness or bronchoalveolar lavage cell component. These findings suggest that carbocysteine promotes the repair of damaged epithelium by allergic reaction and may be useful in allergic airway diseases accompanied by isolated chronic coughing, especially eosinophilic bronchitis without asthma and tracheobronchitis with cough hypersensitivity.
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PMID:Effects of carbocysteine on antigen-induced increases in cough sensitivity and bronchial responsiveness in guinea pigs. 1135 19

Vasopeptidase inhibitors are a new class of cardiovascular drug that simultaneously inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II. In animal models vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease. Studies in human hypertension show that these agents are effective in decreasing blood pressure regardless of race or age. Experience with omapatrilat, the most clinically advanced of these drugs, has shown it to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. Studies with omapatrilat in congestive heart failure have shown beneficial effects on haemodynamics and symptoms. The vasopeptidase inhibitors appear to have safety profiles similar to ACE inhibitors, though the frequency of side-effects such as angio-oedema and cough remains to be established. Large trials with clinical endpoints, some already in progress, are needed to establish the place of this class of drug beside that of established therapies in conditions such as hypertension, heart failure, ischaemic heart disease, and nephropathy.
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PMID:Vasopeptidase inhibitors. 1194 97

Elevated blood pressure is a risk factor for a variety of cardiovascular disorders, including coronary heart disease, peripheral vascular disease, cardiac failure and cerebrovascular disease. The prevailing view is that an elevated systolic rather than diastolic blood pressure is the major contributor in mortality and morbidity attributed to cardiovascular disorders. Isolated high systolic blood pressure, especially in the elderly, is a major risk factor and should undoubtedly be a target for drug treatment. In the general population, systolic and diastolic blood pressure are highly correlated, and thus it is difficult to dissociate the effects of these two components of the blood pressure and specifically ascribe cardiovascular risk factors to just elevated systolic blood pressure. Therefore, the goal in therapy of an individual with hypertension must be to reduce elevated systolic and diastolic blood pressure in order to reduce mortality and morbidity. ACE and neutral peptidase inhibitors are a new class of drugs that may be beneficial in the treatment of patients with hypertension and heart failure. They may also be useful in the treatment of diabetic patients with hypertension and/or heart failure. Drugs of this class are dual inhibitors of ACE and neutral endopeptidase, and are capable of affecting vascular tone and fluid balance. They are capable of producing vasodilatation by virtue of inhibiting the production of angiotensin II, degradation of natriuretic peptides and bradykinin. They also appear to promote natriuresis and diuresis by amplifying the actions of natriuretic peptidase and reducing aldosterone effects. In addition, they should also attenuate trophogenic actions of the renin angiotensin system and the sympathetic nervous system. Omapatrilat is one drug that appears to be at the advanced stages of clinical development. This drug has been shown to be quite effective in the treatment of hypertension. Evidence also seems to indicate that treatment with omapatrilat results in a higher tendency towards preventing death and worsening heart failure when compared with treatment with a pure ACE inhibitor in patients with advanced heart failure. Overall safety with omapatrilat appears to be good, but like other ACE inhibitors the incidence of cough is higher when compared with placebo. Other common adverse effects noted are headaches, facial flushing/warm sensation, dizziness, nausea and dyspnoea. Of greater concern is the occurrence of angio-oedema, the true incidence of which remains to be fully established as part of the published medical literature.
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PMID:Dual ACE and neutral endopeptidase inhibitors: novel therapy for patients with cardiovascular disorders. 1501 94

Viral infections are major causes of cough. Virus-induced changes in airway sensory nerve function include increased tachykinin expression and, more specifically, expression of tachykinins by Adelta fibers. This change may be mediated by neurotrophins produced in response to viral infection. At the same time, activity of neutral endopeptidase, an enzyme that is important in degrading and inactivating tachykinins, is decreased by airway viral infections. Viral infections can activate eosinophils, releasing proteins that can cause tachykinin release. Moreover, expression of the NK1 receptor is increased by viral infections of the lungs. The expression of M2 muscarinic receptors, which normally decrease the sensitivity of sensory nerves, is decreased by viral infections. So it is possible that viral infections (1) increase expression of tachykinins (by causing neurotrophin expression), (2) increase release of tachykinins (by causing release of eosinophil proteins), (3) decrease degradation of tachykinins (by decreasing neutral endopeptidase activity), (4) increase expression of the NK1 receptor (again mediated by neurotrophins), and (5) increase the sensitivity of airway afferents (by decreasing M2 muscarinic receptor expression). All these changes may potentiate the tachykininergic input into the cough reflex, and may provide new therapeutic targets for controlling virus-induced cough.
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PMID:Pathophysiology of airway viral infections. 1556 71

In this study we investigated the ability of aerosolized substance P to induce either cough or bronchoconstriction in guinea-pigs. We have also examined whether pre-treatment, by the inhaled route, of animals with a combination of the neutral endopeptidase inhibitor, phosphoramidon (10(-3) M), and the diaminopeptidase IV inhibitor, diprotin A (10(-3) M), enhances the airway response to substance P. Moreover, we also assessed whether aerosol pre-treatment of guinea-pigs with either substance P or bradykinin, at 10(-4) M, affects the citric acid-induced cough and/or bronchoconstriction. Challenge of guinea-pigs with substance P only at 10(-3) M resulted in significant bronchconstriction but only a weak and variable cough response (1.1+/-0.6; P>0.05). Pre-treatment of guinea-pigs with both phosphoramidon and diprotin A resulted in a small non-significant increase in the cough response (2.8+/-0.9 vs. 1.1+/-0.6; P>0.05) but significantly enhanced substance P-induced bronchoconstriction (P<0.05). Moreover, exposure of guinea-pigs to substance P (10(-4) M) prior to citric acid challenge (0.6 M) resulted in a significant (P<0.05) enhancement of the citric acid-induced bronchoconstriction but not the citric acid-induced cough (11.7+/-1.8 vs. 12.8+/-1.5; P>0.05). In contrast, exposure of guinea-pigs to bradykinin (10(-4) M) prior to the citric acid challenge resulted in a significant enhancement of the cough response (9.2+/-1.9 vs. 25.8+/-2.5; P<0.05) but not the bronchoconstriction (P>0.05). These data do not support a major peripheral role for substance P in the cough reflex, although bradykinin is able to sensitize the cough reflex. Furthermore, these data suggest that bronchoconstriction, induced by citric acid, is not responsible for the cough associated with this irritant.
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PMID:The role of substance P and bradykinin in the cough reflex and bronchoconstriction in guinea-pigs. 1587 17

Marginal zone B-cell lymphoma of the pulmonary mucosa-associated lymphoid tissue type (pulmonary MALT-MZL), a common kind of primary pulmonary lymphoma, is rare in pulmonary malignant tumors. One patient in our hospital was diagnosed by bronchoscope and the literatures on the subject were reviewed. The patient presented with periodical fever, cough and chest pain, and antibiotic therapy had no use. Chest CT scan showed the consolidation of right middle lobe and left lower lobe with CT angiogram signs, air bronchograms and distended bronchi. Pleural effusion in the left thorax mainly consisted of monocytes. Monoclonal protein was found in the electrophoresis of serum protein. Bronchial stenosis and swollen mucosa were seen with bronchoscope. The tissue section of transbronchial lung biopsy (TBLB) specimens showed diffusedly infiltrated small lymphocytes and a lymphoepithelial lesion. CD20 was positive and CD3, CD5, CD10, CD21, CD23, bcl2, bcl6 were negative in immunohistochemical stain. The clinical manifestations of pulmonary MALT-MZL are nonspecific and misdiagnosis is common, Appropriate invasive biopsy procedures are necessary for early diagnosis. Presentations such as periodical fever, distended bronchi in pulmonary consolidation, monoclonal protein might indicate diagnosis. Treatment includes surgical resection, radiotherapy and chemotherapy. Pulmonary MALT-MZL belongs to inert lymphoma and prognosis is relatively good.
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PMID:[A case of marginal zone B-cell lymphoma of the pulmonary mucosa-associated lymphoid tissue type]. 1765 56

The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists.
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PMID:An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. 1769 38


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