Sleep-Predominant Lowering of Ambulatory Blood Pressure by Bedtime Inhalation of a Novel Muscarinic M3 Receptor Antagonist: A New “Bronchoantihypertensive” Strategy Targeting the Lung in Hypertension with Chronic Obstructive Pulmonary Disease

Kario, Kazuomi; Uno, Hideyuki; Shimada, Kazuyuki

doi:10.1291/hypres.31.817

Cited by 4 publications

(2 citation statements)

References 20 publications

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“…Similar considerations may result in a long-acting antihistamine (Fig. 3D) (40), b2-agonist for asthma (41), and M3 antagonist for chronic obstructive pulmonary disease (COPD) (42) and hypertensive COPD (43 In Vivo Assessment of Elastase Inhibitors. In vitro testing suggested that X0 was the most effective tripeptide mimetic of the three inhibitors and that when derivatized and linked to SP-B1-25 as SP-B1-25-X2 should be more effective than SP-B1-25-X1.…”

Section: Discussionmentioning

confidence: 85%

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Guarnieri

Spencer²,

Lucey³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastaseinduced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with <0.6% residual elastase activity, provided no protection from elastase-induced emphysema. Covalently combining an endogenous peptide from the target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy.lung cancer | resistant infections | tuberculosis | asthma I nhalation is an important means of systemically delivering drugs that require immediate onset of action because the lungs provide a facile conduit to the bloodstream (1). Conversely, rapid lung clearance of small molecules causes a significant challenge for the development of pulmonary therapeutics. Rodent models of elastase-induced emphysema, for example, highlight the challenges for the development of effective drugs for pulmonary diseases. Potent in vitro human neutrophil elastase (HNE) inhibitors are cleared from the animals' lungs in minutes and may even exacerbate HNEinduced emphysema (2), whereas one intratracheally instilled dose of elastase causes maximum lung damage after 4 wk (3). The combination of long-term chronic pulmonary damage that characterizes the progression of emphysema with the rapid lung clearance (4) and potential nephrotoxicity (5) of small molecule drugs indicates that there is a profound need for new ways of producing pulmonary therapeutics with long lung residence time pharmacodynamics.Because emphysema is a chronic disease, any treatment will likely be administered over the course of the patient's life, and thus long-acting agents may induce an immune response that would negate the therapeutic effect. The ability of the treatment to access all regions of the vast lung surface area must also be considered. One way to slow the clearance of a small molecule inhibitor from the lung is to attach it to a larger polymer (6). For instance, the covalent linkage of a hydrophilic polymer to a peptidyl carbamate inhibitor increases the half-life by 100-fold in the lungs of hamsters and pro...

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Section: Discussionmentioning

confidence: 85%

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Guarnieri

Spencer²,

Lucey³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The results suggest that several mechanisms underlying pulmonary and cardiovascular diseases interact with each other, as impaired pulmonary function is associated with an (8), is superior to manual measurements at corresponding times. Measurements of BP and HR in an office, and even ambulatory around-the-clock profiles at half-hourly or hourly intervals for a few days, can lead to unwarranted treatment for the rest of the patient's life or to no treatment for people who need it, thus placing them at high risk.…”

Section: Impaired Cardiovascular Function Predicts Mortality From Resmentioning

confidence: 94%

Impaired Cardiovascular Function Predicts Mortality from Respiratory Disorders in the Elderly

Otsuka¹,

Hotta²,

Takasugi³

et al. 2008

Hypertens Res

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Chronic cardiovascular disease and chronic respiratory disorders are two conditions commonly encountered in clinical practice. Pulmonary and cardiovascular functions contribute jointly to a better quality of life, and when either one of these functions is impaired, the risk of disorders associated with the other function increases. Several prospective populationbased studies showed that impaired pulmonary function is associated with an elevated risk of cardiovascular disease (1-3). A study of a population in Saskatchewan, Canada, showed that the prevalence of cardiovascular disease and the incidence of hospitalization related to cardiovascular disease are higher among patients with chronic obstructive pulmonary disease (COPD) (4). We asked, in turn, whether or not impaired cardiovascular function may be predictive of outcomes related to respiratory disorders.We were able to address this question because we had been conducting, since 2000, a community-based study called the Longitudinal Investigation of Longevity and Aging in Hokkaido County (LILAC) to evaluate this population's neurocardiological function. Our goal in the present in LILAC was to prevent cardiovascular events, including stroke and myocardial ischemic events, in order to stop the decline in cognitive function of the elderly in that community. Impaired cardiovascular function, assessed by a 1-h record of ambulatory ECG and brachial-ankle pulse wave velocity (baPWV), predicted mortality from respiratory disorders in this elderly population. It was a surprising outcome, beyond our expectations from the LILAC study, even though our multivariate Cox model had already shown that all-cause and cardiovascular mortality could be predicted by cognitive function (5), carotid intima-media thickness (IMT) (6), and fractal detrended fluctuation analysis of heart rate (HR) variability (7), beyond the prediction provided by age.We examined 298 subjects (119 men and 179 women) older than 75 years (average age: 79.6 years). Blood pressure (BP) was measured at the beginning of the study in a sitting position. The baPWV was measured between the right arm and each ankle in a supine position, using an ABI/Form instrument (Nippon Colin, Komaki, Japan). Measurements were taken in duplicate after a rest period of at least 5 min. Only baPWV measurements from participants with normal ankle-brachial pressure index (ABI) values (> 0.90) were considered. The maximal value among the four readings was used for analysis. An echocardiogram and a conventional ECG record were also obtained. In addition, we analyzed the first 1-h record of the ambulatory ECG obtained during the routine medical examination conducted each year in July.The Japanese version of the Mini-Mental State Examination (MMSE) and the Hasegawa Dementia Scale Revised (HDSR) were used to assess overall cognitive function, including verbal orientation, memory, and constructional ability (Kohs block test). The "Up and Go" test measured, in s, the time it took the subject to stand up from a chair, walk a distance of 3 ...

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Chronic kidney disease and premature ageing

et al. 2014

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Chronic kidney disease (CKD) shares many phenotypic similarities with other chronic diseases, including heart failure, chronic obstructive pulmonary disease, HIV infection and rheumatoid arthritis. The most apparent similarity is premature ageing, involving accelerated vascular disease and muscle wasting. We propose that in addition to a sedentary lifestyle and psychosocial and socioeconomic determinants, four major disease-induced mechanisms underlie premature ageing in CKD: an increase in allostatic load, activation of the 'stress resistance response', activation of age-promoting mechanisms and impairment of anti-ageing pathways. The most effective current interventions to modulate premature ageing-treatment of the underlying disease, optimal nutrition, correction of the internal environment and exercise training-reduce systemic inflammation and oxidative stress and induce muscle anabolism. Deeper mechanistic insight into the phenomena of premature ageing as well as early diagnosis of CKD might improve the application and efficacy of these interventions and provide novel leads to combat muscle wasting and vascular impairment in chronic diseases.

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Sleep-Predominant Lowering of Ambulatory Blood Pressure by Bedtime Inhalation of a Novel Muscarinic M3 Receptor Antagonist: A New “Bronchoantihypertensive” Strategy Targeting the Lung in Hypertension with Chronic Obstructive Pulmonary Disease

Cited by 4 publications

References 20 publications

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Impaired Cardiovascular Function Predicts Mortality from Respiratory Disorders in the Elderly

Chronic kidney disease and premature ageing

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