Application of the antitussive agents oxelaidin and butamirate as anti-glioma agents

Glioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM. In this study, high-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on GBM cell lines, LN229, U87 and T98G. Cough suppressants, oxelaidin and butamirate inhibited GBM growth. A Ras family GTPase, Ras-related associated with diabetes (RRAD), contributes to activation of STAT3, which is essential for survival and growth of many cancer types. Interestingly, oxelaidin and butamirate did not affect proliferation in RRAD negative GBM cells. Docking simulation analyses revealed selective interactions between oxelaidin and RRAD. The mechanism by which butamirate and oxelaidin inhibits GBM cell growth involves the suppression of STAT3 transcriptional activity, leading to down-regulation of cyclin D1 and survivin. In addition, components of RRAD-associated signaling cascades, including p-EGFR, p-Akt, and p-STAT3, were inhibited upon oxelaidin treatment. Intraperitoneal administration of oxelaidin or butamirate markedly suppressed tumor growth in a glioblastoma xenograft mouse model without significant adverse effects. Our collective findings indicate that oxelaidin and butamirate exert anti-tumor effects in glioblastoma, supporting its utility as a novel therapeutic candidate for glioblastoma.

Derivation of New Surveillance System for Influenza-like Illness Using Claims Data 2014-2018 in Korea (Preprint)

BACKGROUND Influenza is an important public health concern. A national surveillance system that easily and rapidly detects influenza epidemics is lacking. OBJECTIVE We assumed that the rate of influenza-like illness (ILI) related-claims is similar to the current ILI surveillance system. METHODS We used the Health Insurance Review and Assessment Service-National Patient Samples (HIRA-NPS), 2014-2018. We defined ILI-related claims as outpatient claims that contain both antipyretic and antitussive agents and calculated the weekly rate of ILI-related claims. We compared ILI-related claims and weekly ILI rates from clinical sentinel surveillance data. RESULTS We observed a strong correlation between the two surveillance systems each season. The absolute thresholds for the four-years were 84.64 and 86.19 cases claims per 1,000 claims for claims data and 12.27 and 16.82 per 1,000 patients for sentinel data (Figure 5). Both the claims and sentinel data surpassed the epidemic thresholds each season. The peak epidemic in the claims data was reached one to two weeks later than in the sentinel data. The epidemic patterns were more similar in the 2016-2017 and 2017-2018 seasons than the 2014-2015 and 2015-2016 seasons. CONCLUSIONS Based on hospital reports, ILI-related claims rates were similar to the ILI surveillance system. ILI claims data can be loaded to a drug utilization review system in Korea to make an influenza surveillance system.

Diagnoses and Management of Adult Cough: an Indian Environmental Medical Association (EMA) Position Paper (Preprint)

BACKGROUND Cough is a common yet distressing symptom that results in significant health care costs from outpatient visits and related consultations. OBJECTIVE Understanding the pathobiology of cough in recent times has undergone an evolution with Cough hypersensitivity syndrome (CHS) being suggested in most cases of dry cough. In case of productive cough however ancillary mechanisms including impaired Mucociliary clearance in addition to hypermucosecretory bronchospastic conditions of Smoker’s cough, asthma-COPD overlap syndrome, AECB, allergic bronchopulmonary aspergillosis need to be critically addressed while optimizing patient care with symptomatic therapy in such cases while avoiding its misuse in most of the situations METHODS In this review, evidence-based graded recommendations on use of Pro- & Antitussives as a Position Paper were developed based on the Level and Quality of Scientific evidence as per Agency of Health Care and Quality Systems (AHRQ) and Clinical insights, offered by a multidisciplinary EMA panel in India. RESULTS Management of acute or chronic cough involves addressing common issues of environmental exposures and patient concerns before instituting supportive therapy with antitussives or bronchodilatory cough formulations containing mucoactives, anti-inflammatory or Beta-2 agonist agents CONCLUSIONS The analyses provides a real world approach on the management of acute or chronic cough in various clinical conditions including with Pro- or antitussive agents

Evidence-Based Acute Bronchitis Therapy

Acute bronchitis is a disease characterized by inflammation of the large airways within the lung accompanied by a cough lasting from 1 to 3 weeks. The inflammation occurs as a result of an airway infection or environmental trigger, with viral infections accounting for an estimated 89% to 95% of cases. Symptomatic treatment of cough is primarily required for patients, though in most cases the condition is self-limiting. Therapy consists of both nonpharmacological and pharmacological options to include antibiotics and antivirals, antitussive agents, protussive agents, and beta-2-agonists. This article reviews the treatment options for acute bronchitis and recommends criteria for use.

Suppression of the cough reflex by inhibition of ERK1/2 activation in the caudal nucleus tractus solitarii of the rabbit

The caudal nucleus tractus solitarii (cNTS), the predominant site of termination of cough-related afferents, has been shown to be a site of action of some centrally acting antitussive agents. A role of ERK1/2 has been suggested in acute central processing of nociceptive inputs. Because pain and cough share similar features, we investigated whether ERK1/2 activation could also be involved in the central transduction of tussive inputs. For this purpose, we undertook the present research on pentobarbital sodium-anesthetized, spontaneously breathing rabbits by using microinjections (30–50 nl) of an inhibitor of ERK1/2 activation (U0126) into the cNTS. Bilateral microinjections of 25 mM U0126 caused rapid and reversible reductions in the cough responses induced by both mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. In particular, the cough number and peak abdominal activity decreased. Bilateral microinjections of 50 mM U0126 completely suppressed the cough reflex without affecting the Breuer-Hering inflation reflex, the pulmonary chemoreflex, and the sneeze reflex. These U0126-induced effects were, to a large extent, reversible. Bilateral microinjections of 50 mM U0124, the inactive analog of U0126, at the same cNTS sites had no effect. This is the first study that provides evidence that ERK1/2 activation within the cNTS is required for the mediation of cough reflex responses in the anesthetized rabbit. These results suggest a role for ERK1/2 in the observed effects via nontranscriptional mechanisms, given the short time involved. They also may provide hints for the development of novel antitussive strategies.

Depression of cough reflex by microinjections of antitussive agents into caudal ventral respiratory group of the rabbit

We have previously shown that the caudal nucleus tractus solitarii is a site of action of some antitussive drugs and that the caudal ventral respiratory group (cVRG) region has a crucial role in determining both the expiratory and inspiratory components of the cough motor pattern. These findings led us to suggest that the cVRG region, and possibly other neural substrates involved in cough regulation, may be sites of action of antitussive drugs. To address this issue, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30–50 nl) of some antitussive drugs into the cVRG of pentobarbital-anesthetized, spontaneously breathing rabbits. [d-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and baclofen at the lower concentrations (0.5 mM and 0.1 mM, respectively) decreased cough number, peak abdominal activity, and peak tracheal pressure and increased cough-related total cycle duration (Tt). At the higher concentrations (5 mM and 1 mM, respectively), both drugs abolished the cough reflex. DAMGO and baclofen also affected baseline respiratory activity. Both drugs reduced peak abdominal activity, while only DAMGO increased Tt, owing to increases in expiratory time. The neurokinin-1 (NK1) receptor antagonist CP-99,994 (10 mM) decreased cough number, peak abdominal activity, and peak tracheal pressure, without affecting baseline respiration. The NK2 receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the cVRG is a site of action of some antitussive agents and support the hypothesis that several neural substrates involved in cough regulation may share this characteristic.

Modulation of the cough reflex by antitussive agents within the caudal aspect of the nucleus tractus solitarii in the rabbit

We have previously shown that ionotropic glutamate receptors in the caudal portion of the nucleus tractus solitarii (NTS), especially in the commissural NTS, play a prominent role in the mediation of tracheobronchial cough and that substance P potentiates this reflex. This NTS region could be a site of action of some centrally acting antitussive agents and a component of a drug-sensitive gating mechanism of cough. To address these issues, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30–50 nl) of centrally acting antitussive drugs into the caudal NTS of pentobarbitone-anesthetized, spontaneously breathing rabbits. [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and baclofen decreased baseline respiratory frequency because of increases in the inspiratory time only at the higher concentration employed (5 mM and 1 mM, respectively). DAMGO (0.5 mM) and baclofen (0.1 mM) significantly decreased cough number, peak abdominal activity, peak tracheal pressure, and increased cough-related total cycle duration. At the higher concentrations, these agents suppressed the cough reflex. The effects of these two drugs were counteracted by specific antagonists (10 mM naloxone and 25 mM CGP-35348, respectively). The neurokinin-1 (NK1) receptor antagonist CP-99,994 (10 mM) abolished cough responses, whereas the NK2 receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the caudal NTS is a site of action of some centrally acting drugs and a likely component of a neural system involved in cough regulation. A crucial role of substance P release in the mediation of reflex cough is also suggested.