Toxicity of theophylline depends on plasma concentration by single and also repeated dosing in rats

Onodera, Kenji; Shibata, Mitsuhiko; Kojima, Jun; Wachi, Masayuki; Sogawa, Norio; Furuta, Hiroaki; Kamei, Junzo

doi:10.1006/phrs.2001.0831

Cited by 9 publications

(5 citation statements)

References 21 publications

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“…Compared with healthy control subjects, theophylline largely normalized haemodynamic responses to hypoglycaemia in diabetic patients. The doses of 100 mg kg −1 for compound 1a and 50 mg kg −1 for 2a, as well as appropriate equivalent doses of nitrates 1 and 2, used in our studies were selected on the basis of a literature survey (Warszawski et al 1978;Selvig 1981;Blake et al 1988;Nadai et al 1992;Zeruesenay et al 1992;Bruguerolle & Dubus 1999;Park et al 1999;Onodera et al 2001). The doses were then reduced on the basis of the observed effect, with assessment of their efficacy.…”

Section: Tablementioning

confidence: 99%

Synthesis, pharmacological activity and nitric oxide generation by nitrate derivatives of theophylline

Korzycka

Górska

2008

Journal of Pharmacy and Pharmacology

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Nitrates of theophylline derivatives - potential nitric oxide (NO) donors - were synthesized by esterification of 7-hydroxyalkyl theophylline derivatives with fuming nitric acid. The nitrates obtained were tested in-vitro in reactions with sulfydryl compounds at appropriately adjusted pH and temperature. Under the applied conditions, the synthesized compounds underwent decomposition to release NO, quantified using a polarographic method using a selective isolated (ISO-NO) sensor. The effects of dyphylline and proxyphylline and their new synthesized nitrates on arterial blood pressure (BP) were measured in spontaneously hypertensive (SH) rats. BP was measured in conscious SH rats using the tail-cuff method. Both short- and long-term administration of the xanthines tested significantly decreased systolic, diastolic and mean BP. The hypotensive effect of a single dose of nitrate dyphylline on mean BP was greater than that of the parent compound (P = 0.000012; P=0.000472 at 30 and 60 min post-dose, respectively), whereas proxyphylline and its nitrate derivative had similar activity. In rats treated with the tested compounds for 9 days twice daily, the decrease in BP persisted for at least 16 h after the last dose. Proxyphylline produced the most marked decrease in diastolic and mean BP. Among the xanthines examined, proxyphylline nitrate had the strongest hypotensive effect when administered in a single dose to animals pretreated with the same compound for 9 days. These results indicate that insertion of a nitrate group weakly modifies the hypotensive action of the studied xanthines in SH rats.

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Section: Tablementioning

confidence: 99%

Synthesis, pharmacological activity and nitric oxide generation by nitrate derivatives of theophylline

Korzycka

Górska

2008

Journal of Pharmacy and Pharmacology

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“…), 4 theophylline (25 mg/kg, i.p. ), 34 sildenafil (5 mg/kg, i.p. ), 35 lead acetate (100 mg/kg, i.p.)…”

Section: Treatment Schedulesmentioning

confidence: 99%

Protection by sildenafil and theophylline of lead acetate-induced oxidative stress in rat submandibular gland and saliva

et al. 2003

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The role of oxidative stress in lead toxicity has been proposed in many organs, however, no study has been performed in the salivary glands, which are important parts of the gastrointestinal tract with a high implication in health of the whole body. Recently, it has been proposed that increasing the levels of cGMP and cAMP in the cells may protect from the neurotoxicity of lead. The objective of this study was to determine the ability of lead acetate to produce oxidative stress in rat submandibular as the main salivary gland of the body and to study the role of pretreatment by specific phosphodiesterase inhibitors in the prevention of oxidative stress. Lead acetate (100 mg/kg), alone or in combination with theophylline (25 mg/kg) and sildenafil (5 mg/kg), was administered intraperitoneally to rats. After 2 hours and under general anaesthesia, the submandibular gland ducts were cannulated intraorally using microcannula, and pure saliva was collected for 30 min using pilocarpine (8 mg/kg) as a secretagogue. The submandibular glands were then isolated free under surgery. Oxidative stress in the gland and pure saliva were evaluated measuring lipid peroxidation (thiobarbituric acid reactive substances assay), total thiol groups content and total antioxidant capacity (the ferric reducing ability assay). Results showed significant oxidative stress in the gland and secretions as indicated by increased lipid peroxidation, decreased total antioxidant capacity and thiol group levels. The use of cAMP and cGMP phosodiesterase inhibitors, theophylline and sildenafil, prevented leadinduced increased lipid peroxidation and also protected from decreased thiol groups content and total antioxidant power of the gland and secretions. The same trend of effects was observed in gland and saliva. It is concluded that lead toxicity is mediated through oxidative stress in salivary glands, while increasing intracellular cAMP and cGMP levels may prevent lead-induced oxidative stress.

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“…Attempts to reveal mechanisms of the arrhythmogenic action of aminophylline/theophylline have been performed previously, using various animal models. In rats, aminophylline induced tachycardia and elevated blood pressure and potential cardiac ischemia ( Shamsuzzaman et al, 2016 ), which may be related to theophylline-induced myocardial fibrosis found as a long-term concentration-/dose-dependent side effect in a notable portion of rats ( Onodera et al, 2001 ). In a canine model, aminophylline significantly enhanced AV nodal and His–Purkinje conduction; this effect was potentiated in combined therapy with metaproterenol ( Komadina et al, 1992 ).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, this does not explain the origin of AF associated with aminophylline treatment. Effects of theophylline/aminophylline on cardiac electrophysiology were studied mostly in animal models ( Komadina et al, 1992 ; Onodera et al, 2001 ; Shamsuzzaman et al, 2016 ). However, a conclusive explanation of their proarrhythmic action has not been provided, and data from human cardiomyocytes (CMs) embedded in cardiac syncytia have been missing completely.…”

Section: Introductionmentioning

confidence: 99%

Aminophylline Induces Two Types of Arrhythmic Events in Human Pluripotent Stem Cell–Derived Cardiomyocytes

et al. 2022

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Cardiac side effects of some pulmonary drugs are observed in clinical practice. Aminophylline, a methylxanthine bronchodilator with documented proarrhythmic action, may serve as an example. Data on the action of aminophylline on cardiac cell electrophysiology and contractility are not available. Hence, this study was focused on the analysis of changes in the beat rate and contraction force of human pluripotent stem cell–derived cardiomyocytes (hPSC-CMs) and HL-1 cardiomyocytes in the presence of increasing concentrations of aminophylline (10 µM–10 mM in hPSC-CM and 8–512 µM in HL-1 cardiomyocytes). Basic biomedical parameters, namely, the beat rate (BR) and contraction force, were assessed in hPSC-CMs using an atomic force microscope (AFM). The beat rate changes under aminophylline were also examined on the HL-1 cardiac muscle cell line via a multielectrode array (MEA). Additionally, calcium imaging was used to evaluate the effect of aminophylline on intracellular Ca2+ dynamics in HL-1 cardiomyocytes. The BR was significantly increased after the application of aminophylline both in hPSC-CMs (with 10 mM aminophylline) and in HL-1 cardiomyocytes (with 256 and 512 µM aminophylline) in comparison with controls. A significant increase in the contraction force was also observed in hPSC-CMs with 10 µM aminophylline (a similar trend was visible at higher concentrations as well). We demonstrated that all aminophylline concentrations significantly increased the frequency of rhythm irregularities (extreme interbeat intervals) both in hPSC-CMs and HL-1 cells. The occurrence of the calcium sparks in HL-1 cardiomyocytes was significantly increased with the presence of 512 µM aminophylline. We conclude that the observed aberrant cardiomyocyte response to aminophylline suggests an arrhythmogenic potential of the drug. The acquired data represent a missing link between the arrhythmic events related to the aminophylline/theophylline treatment in clinical practice and describe cellular mechanisms of methylxanthine arrhythmogenesis. An AFM combined with hPSC-CMs may serve as a robust platform for direct drug effect screening.

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Toxicity of theophylline depends on plasma concentration by single and also repeated dosing in rats

Cited by 9 publications

References 21 publications

Synthesis, pharmacological activity and nitric oxide generation by nitrate derivatives of theophylline

Synthesis, pharmacological activity and nitric oxide generation by nitrate derivatives of theophylline

Protection by sildenafil and theophylline of lead acetate-induced oxidative stress in rat submandibular gland and saliva

Aminophylline Induces Two Types of Arrhythmic Events in Human Pluripotent Stem Cell–Derived Cardiomyocytes

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