Effects of Theophylline on Diaphragmatic Strength and Fatigue in Patients with Chronic Obstructive Pulmonary Disease

Murciano, D; Aubier, Michel; Lecocguic, Y; Parienté, R

doi:10.1056/nejm198408093110601

Cited by 259 publications

(75 citation statements)

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“…Among them, dose-dependent bronchodilatation leads to improvement of ventilatory patterns and reduces trapped air. In patients with chronic obstructive pulmonary disease, theophylline was shown to improve oxygenation as well as the forced expiratory volume in one second [15,22]. Similar effects can be expected in subjects acutely exposed to hypobaric hypoxia [23].…”

Section: Discussionsupporting

confidence: 51%

“…The multiple pharmacological effects of theophylline (a phosphodiesterase inhibitor) are well characterized, and comprise a decrease in cerebral blood flow [8], suppression of microvascular permeability in the brain and lungs [9], a bronchodilating effect [10], central respiratory stimulation [11], a decrease in pulmonary arterial pressure [12], inhibition of inflammatory mediators [13], a reduction in periodic breathing [14], improved diaphragmatic contractility [15], and induction of mild diuresis.…”

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confidence: 99%

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Theophylline improves acute mountain sickness

et al. 2000

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A randomized two-part study was conducted in order to determine the efficacy of theophylline in the treatment of acute mountain sickness during fast ascent to altitudes >2,500 m.Fourteen healthy male subjects participated in a randomized single-blind placebocontrolled crossover study carried out in a decompression chamber (simulated altitude 4,500 m). A second randomized single-blind, placebo-controlled study was conducted at a high-altitude research laboratory (3,454 m) and included 21 healthy male subjects. The study medication was either 375 mg oral slow-release theophylline (250 mg if <70 kg) or a matched placebo tablet taken twice daily. The acute mountain sickness score (AMSS) was assessed three times a day, beginning 18 h prior to altitude exposure and continuing for 18 h after altitude exposure. In addition, measurements of respiratory frequency, pulse rate, oxygen saturation and arterial blood gas levels were performed.Acute mountain sickness was significantly reduced by theophylline during the decompression chamber study (mean SD 1.2 0.9) with placebo versus 3.6 0.8 with theophylline; p=0.03). During the high-altitude study, subjects with theophylline showed a significantly lower AMSS on arrival and after 18 h at altitude (0.6 versus 2.3, p=0.03). Oxygenation was improved in both parts of the study.In conclusion, oral slow-release theophylline improves acute mountain sickness. Eur Respir J 2000; 15: 123±127. This study was supported, in part, by Byk Gulden, Constance, Germany.Acute mountain sickness (AMS) is a frequent medical disorder in travellers who rapidly ascend to altitudes >2,500 m [1]. When altitudes >4,000 m are reached within hours, only few do not have at least mild symptoms. The symptoms of mild AMS include headache, dizziness, fatigue, gastrointestinal symptoms and sleep disturbance. During prolonged stay at high altitude, symptoms improve usually within 24±48 h.The pathogenesis of AMS is not fully understood, but it is generally agreed that the main underlying cause is hypoxia, which initiates the pathogenetic processes leading to AMS. Hypoxia is thought to cause water retention or a shift of water from intracellular to extracellular compartments [2], increase microvascular permeability [3] and increase cerebral blood flow [4]. All of these factors may contribute to AMS, although the role of enhanced cerebral blood flow remains controversial [5].AMS is normally best prevented by ascending slowly to high altitude. However, when rapid ascent is necessary (i.e. during rescue operations or passive transportation to high altitude), medical prophylaxis may be indicated. Acetazolamide at a dose of 250 mg twice daily and dexamethasone at doses of >4 mg twice daily have been reported effective in the preventive treatment of AMS [6,7].The effects of theophylline on AMS have not been studied, although its pharmacological profile would seem to predispose this substance to the treatment of AMS. The multiple pharmacological effects of theophylline (a phosphodiesterase inhibitor) are well cha...

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Section: Discussionsupporting

confidence: 51%

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Theophylline improves acute mountain sickness

et al. 2000

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“…3,8,9,14 The mechanism for this is unknown, but extracellular calcium may be necessary for aminophylline to have a potentiating effect on diaphragmatic contractility. 14 In the present study, we showed that inhaled aminophylline significantly increased contractility in fatigued diaphragm (groups 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7] Among these drugs, aminophylline IV, a methylxanthine methyltransferase compound, has been widely used to increase contractility of fatigued diaphragm in healthy subjects 8 and in patients with chronic obstructive pulmonary disease (COPD). 9 Early studies [10][11][12] suggested the efficacy of an inhaled form of methylxanthine, but, according to a MEDLINE search (key terms: aminophylline, methylxanthine, inhalation, and diaphragmatic fatigue; years: , this modality has not been used to treat diaphragmatic fatigue.…”

Section: Introductionmentioning

confidence: 99%

Treatment of diaphragmatic fatigue with inhaled aminophylline therapy in an experimental canine model: an open-label, dose-ranging, pharmacologic study

Fujii

2003

Current Therapeutic Research

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Background: Diaphragmatic fatigue may contribute to the development of respiratory failure. Although aminophylline administered IV has been widely used to treat diaphragmatic fatigue, to date it has not been used in aerosol formulation for this purpose.Objective: The aim of this study was to assess the efficacy of inhaled aminophylline on contractility of fatigued diaphragm in an experimental canine model.Methods: This open-label, dose-ranging, pharmacologic study was conducted at the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba (Ibaraki, Japan). Diaphragmatic fatigue was induced in healthy, male, mongrel dogs by intermittent supramaximal bilateral electrophrenic stimulation at a low frequency (20 Hz) applied for 30 minutes. Immediately after the end of the fatigue-producing period, group 1 received inhaled vehicle only, group 2 received inhaled aminophylline 12.5 mg/mL, group 3 received inhaled aminophylline 25 mg/mL, and group 4 was infused with verapamil 0.1 mg/kg·min during inhalation of aminophylline 25 mg/mL. Diaphragmatic contractility was assessed using transdiaphragmatic pressure (Pdi).Results: Twenty-eight dogs were used in the study (7 dogs were assigned to each treatment group). When fatigue was established, Pdi at low-frequency stimulation decreased significantly from baseline in all groups (all P Ͻ 0.05), and no significant change in Pdi was found at high-frequency stimulation. In groups 2 and 3, during aminophylline inhalation, Pdi at 20-Hz stimulation increased significantly from fatigued values (both P Ͻ 0.05). Pdi increased significantly more in group 3 than in group 2 (P Ͻ 0.05). In group 4, infusion of verapamil offset the increase in Pdi seen with aerosolized aminophylline in fatigued diaphragm. The integrated electrical activity of the diaphragm did not change significantly in any group.Conclusions: Inhaled aminophylline significantly improved contractility of fatigued diaphragm in a dose-related manner in this experimental canine model CURRENT THERAPEUTIC RESEARCH(P Ͻ 0.05). Its potent effect may be caused by transmembrane calcium movement. (Curr Ther Res Clin Exp. 2003;64:725-732)

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“…These are: MV modes that help the diaphragm contribute to respiration in an active way; various exercise methods, prevention of catabolic processes and pharmacotherapy [5]. Studies on both humans and animals have show that the application of prophylactic theophylline in pharmacotherapy practices prevents diaphragmatic weakness and reverses diaphragmatic fatigue [6][7][8][9][10][11][12][13][14][15][16][17]. However, in most of these studies, the effect of theophylline on the contraction strength of diaphragmatic muscles has been evaluated, but the effect on diaphragmatic atrophy was never mentioned.…”

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The Effect of Theophylline on the Prevention of Mechanical Ventilation-Induced Diaphragm Atrophy in Rats

Aydin¹,

Teke²,

Toy³

et al. 2014

Adv Clin Exp Med

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Background. Movement disorders and atrophy occur in the diaphragm, the most important muscle of respiration, because of mechanical ventilation (MV). Objectives. In this animal model, we aimed to evaluate the effect of intravenous theophylline administration on the prevention of mechanical ventilation-induced diaphragmatic atrophy. Material and Methods. In our study, 30 healthy male Sprague-dawley rats were used. They were divided into 3 equal groups. Group 1: the control group (no MV); group 2: the placebo group that received MV; Group 3: the theophylline group composed of rats that received both MV and theophylline therapy. In all 3 groups, the diaphragmatic atrophy was evaluated histopathologically. Results. In the histopathological examination, no macroscopic thickening and microscopic atrophy were observed in the diaphragm in the control group. In the placebo group (group 2), macroscopically definite thickening was observed in all rats, and microscopically, heavy (+++) atrophy was observed. In the theophylline group (group 3), there was no atrophy in one rat. In 8 rats, light (+), and in 1 rat medium (++) atrophy was observed. Conclusions. In our study, it was shown that atrophy occurred in the diaphragms of rats after MV, and the atrophy was decreased after theophylline administration (Adv Clin Exp Med 2014, 23, 1, 33-38).

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Effects of Theophylline on Diaphragmatic Strength and Fatigue in Patients with Chronic Obstructive Pulmonary Disease

Cited by 259 publications

References 20 publications

Theophylline improves acute mountain sickness

Theophylline improves acute mountain sickness

Treatment of diaphragmatic fatigue with inhaled aminophylline therapy in an experimental canine model: an open-label, dose-ranging, pharmacologic study

The Effect of Theophylline on the Prevention of Mechanical Ventilation-Induced Diaphragm Atrophy in Rats

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