Theophylline and its metabolites produce a stimulating cholinergic effect on the small intestine and a nonadrenergic noncholinergic relaxing effect on the colon: a comparative study in the rabbit intestine

Psarra, Theophano A.; Batzias, Georgios; Peeters, Theo; Papadopoulou, Maria S.

doi:10.1111/j.1365-2885.2007.00904.x

Cited by 4 publications

(8 citation statements)

References 48 publications

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“…For theophylline, the most frequently DDI-related proteins are CYP1A2, CYP3A, cholinergic receptors, and adrenergic receptors. Experiments showed that theophylline (or its metabolites) could stimulate cholinergic effect [28]. Beta-adrenergic blockers may also interfere the effects of theophylline if they are taken together [29].…”

Section: Resultsmentioning

confidence: 99%

Characterization of the mechanism of drug-drug interactions from PubMed using MeSH terms

et al. 2017

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Identifying drug-drug interaction (DDI) is an important topic for the development of safe pharmaceutical drugs and for the optimization of multidrug regimens for complex diseases such as cancer and HIV. There have been about 150,000 publications on DDIs in PubMed, which is a great resource for DDI studies. In this paper, we introduced an automatic computational method for the systematic analysis of the mechanism of DDIs using MeSH (Medical Subject Headings) terms from PubMed literature. MeSH term is a controlled vocabulary thesaurus developed by the National Library of Medicine for indexing and annotating articles. Our method can effectively identify DDI-relevant MeSH terms such as drugs, proteins and phenomena with high accuracy. The connections among these MeSH terms were investigated by using co-occurrence heatmaps and social network analysis. Our approach can be used to visualize relationships of DDI terms, which has the potential to help users better understand DDIs. As the volume of PubMed records increases, our method for automatic analysis of DDIs from the PubMed database will become more accurate.

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Section: Resultsmentioning

confidence: 99%

Characterization of the mechanism of drug-drug interactions from PubMed using MeSH terms

et al. 2017

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“…Theophylline and other PDE inhibitors not only decrease airway inflammation but also improve pulmonary function [15] by acting directly on bronchial tone to induce bronchodilation. In clinical use, theophylline has also been found to be effective on visceral smooth muscle spasm-induced symptoms [16-18]. However, neither the potency, nor the efficacy of drotaverine has been tested in respect of airway smooth muscle relaxation.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Airway Smooth Muscle Relaxant Effect of Drotaverine

Patai

Guttman

Mikus³

2018

Pharmacology

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Background: Drotaverine, a type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, blocks the degradation of 3’,5’-cyclic adenosine monophosphate. However, published receptor binding data showed that drotaverin also binds to the L-type voltage-operated calcium channel (L-VOCC). Based on these molecular mechanisms of action, a direct and indirect (by blocking the constrictor response) relaxant effect on airway smooth muscle can be predicted, which has not yet been assessed. Summary: Accordingly, drotaverine and reference agents were tested both on the histamine-, methacholine-, or KCl-induced contraction response and on precontracted guinea pig tracheal preparations. It was found that drotaverine not only relaxed the precontracted tracheal preparations but also decreased mediator-induced contraction. These effects of drotaverine were concentration dependent, with a significantly higher potency on the KCl-induced response, than on either the histamine or methacholine induced one. A similar result was noted for nifedipine. The PDE inhibitor, theophylline, also relaxed the precontracted preparations but was ineffective on the mediator-induced contraction in a physiologically relevant concentration range. Moreover, theophylline did not show selectivity and was the least potent relaxant among the 3 tested molecules. Key Message: These results show that drotaverine is a more potent airway smooth muscle relaxant molecule than theophylline. This enhanced potency on relaxation and inhibition of the constrictor response, at least partly, may be explained by the combined L-VOCC blocking and PDE inhibitory potential of drotaverine.

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“…Pharmacology and rabbit [21,22], but also the guinea pig antrum [23], the rabbit fundus, antrum and pylorus [21], the rabbit distal [24] and ascending [25] colon, as well as the colon [26] and taenia coli [27] in the guinea pig. Conversely, a contractile effect of theophylline was also described on the stimulated guinea pig ileum [28][29][30], and more recently in the rabbit small intestine [25].…”

Section: Fundamental and Clinicalmentioning

confidence: 99%

“…Besides the relaxing effect of theophylline on the respiratory tissues in several animal species [9–14], man included [15–17], which underlies the clinical bronchodilator properties of the drug, a relaxing effect has been also demonstrated on gastrointestinal smooth muscle tissues. In particular, in vitro and in vivo studies have shown that theophylline relaxes the lower oesophageal sphincter (LOS) in man [18], opossum [19,20] and rabbit [21,22], but also the guinea pig antrum [23], the rabbit fundus, antrum and pylorus [21], the rabbit distal [24] and ascending [25] colon, as well as the colon [26] and taenia coli [27] in the guinea pig. Conversely, a contractile effect of theophylline was also described on the stimulated guinea pig ileum [28–30], and more recently in the rabbit small intestine [25].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, in vitro and in vivo studies have shown that theophylline relaxes the lower oesophageal sphincter (LOS) in man [18], opossum [19,20] and rabbit [21,22], but also the guinea pig antrum [23], the rabbit fundus, antrum and pylorus [21], the rabbit distal [24] and ascending [25] colon, as well as the colon [26] and taenia coli [27] in the guinea pig. Conversely, a contractile effect of theophylline was also described on the stimulated guinea pig ileum [28–30], and more recently in the rabbit small intestine [25]. Information about the effects of theophylline’s metabolites, 1‐methylxanthine (1‐MX), 3‐methylxanthine (3‐MX), 1,3‐dimethyluric acid (1,3‐DMU) and 1‐methyluric acid (1‐MU), derives from the authors’ previous studies, where it was shown that the effects of the metabolites on the regions of the rabbit upper gastrointestinal tract are either weaker or opposite to those of theophylline [21], while all four metabolites were found to mimic the contractile effect of theophylline on the small intestinal regions, their efficacy and potency being comparable and in some cases higher than that of the parent drug [25].…”

Section: Introductionmentioning

confidence: 99%

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The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites

Psarra

Batzias

Peeters

et al. 2010

Fundamemntal Clinical Pharma

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This study investigates the effect of theophylline along the rabbit gastrointestinal tract in comparison with the pharmacodynamic effect produced by the combined application of its three major metabolites. At concentrations up to 10(-3) m, theophylline relaxed, in a declining order from the lower oesophageal sphincter (LOS) to pylorus, all regions of the upper gastrointestinal tract, but only the ascending colon from the intestinal regions studied. At concentrations higher than 10(-3) m, instead of relaxing, theophylline strongly contracted the antrum and pylorus. In all three small intestinal regions, at concentrations up to 10(-3) m, theophylline produced a weak contraction, which at higher concentrations became very strong, and at 10(-2) m was comparable to that produced by a supramaximal dose of acetylcholine. The additive relaxing effect resulting from the combined application of the theophylline's metabolites was, from oesophagus to pylorus, weaker than that produced by theophylline, while on the ascending colon it was comparable to that of the parent drug. In contrast, the additive contractile effect of the metabolites on the three small intestinal regions was four to five times higher the one produced by theophylline. In conclusion, this study shows that the additive effect of the combined application of theophylline's major metabolites on the rabbit gastrointestinal tract plays a major role in the final response of the intestine, and a minor one in the final responses of the gastric regions, while both the parent drug and the metabolites contribute to the final responses of the oesophagus and LOS.

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Theophylline and its metabolites produce a stimulating cholinergic effect on the small intestine and a nonadrenergic noncholinergic relaxing effect on the colon: a comparative study in the rabbit intestine

Cited by 4 publications

References 48 publications

Characterization of the mechanism of drug-drug interactions from PubMed using MeSH terms

Characterization of the mechanism of drug-drug interactions from PubMed using MeSH terms

Assessment of the Airway Smooth Muscle Relaxant Effect of Drotaverine

The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites

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