Exacerbation of Airway Hyperreactivity by (±)Salbutamol in Sensitized Guinea Pigs

Hoshiko, Ken-ichiro; Morley, John E.

doi:10.1254/jjp.63.159

Cited by 50 publications

(24 citation statements)

References 19 publications

(15 reference statements)

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“…Although, Ssalbutamol induced a weak relaxation of equine isolated bronchi pre-contracted by histamine, it induced an increase in airway smooth muscle responsiveness to the cumulative dose response to this spasmogen in both normal and RAO bronchi. In agreement with these findings, racemic salbutamol induced an exaggerated conctractile response to histamine in airway tissues obtained from sensitized from guinea pigs [21]. It has been speculated that the pro-inflammatory and pro-constrictory activity of S-isomer, are mediated by the activation of transcriptional nuclear factor κB (NF-κB) as has been demonstrated in human isolated airways [23],.…”

Section: Discussionsupporting

confidence: 66%

“…In line with these results, it has been documented that detrimental effects of the racemic mixture of β 2 -agonists are strictly related to the S-isomers [2,6,21,22]. Although, Ssalbutamol induced a weak relaxation of equine isolated bronchi pre-contracted by histamine, it induced an increase in airway smooth muscle responsiveness to the cumulative dose response to this spasmogen in both normal and RAO bronchi.…”

Section: Discussionmentioning

confidence: 54%

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Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi

Matera¹,

Calzetta²,

Rogliani³

et al. 2011

Pulmonary Pharmacology & Therapeutics

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 54%

Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi

Matera¹,

Calzetta²,

Rogliani³

et al. 2011

Pulmonary Pharmacology & Therapeutics

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“…(S) -Albuterol was originally thought to be pharmacologically inert, but has since been found to induce exaggerated airway reactivity and exacerbate asthmatic conditions [7, 8]. (S) -Albuterol increases intracellular calcium and airway hyperresponsiveness to spasmogens [9, 10]. (S) -Albuterol is metabolized more slowly than levalbuterol [11, 12], so that, depending on the frequency and intervals of repeated dosing, the levels of (S) -albuterol in tissues in vivo may exceed those of levalbuterol, and thereby may contribute to the cumulative adverse effects of (S) -albuterol.…”

Section: Introductionmentioning

confidence: 99%

Levalbuterol Inhibits Human Airway Smooth Muscle Cell Proliferation: Therapeutic Implications in the Management of Asthma

Ibe¹,

Portugal²,

Raj³

2006

Int Arch Allergy Immunol

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Background: Racemic albuterol is a mixture of (R)- and (S)-enantiomers of albuterol. Its pharmacological activity and clinical efficacy reside in the (R)-enantiomer (levalbuterol), but the (S)-enantiomer exacerbates airway reactivity in nonclinical models. The role of albuterols in airway smooth muscle cell (SMC) proliferation is not well understood. Methods: The effect of levalbuterol on human bronchial SMC growth was compared with the effects of racemic albuterol and (S)-albuterol. Cells were fed albuterols and ³H-thymidine in 5% FBS and incubated for 24 h. The effect of (S)-albuterol on levalbuterol actions was also studied and so were the effects of cAMP/PKA, PI-3 kinase, NK-ĸB, and retinoblastoma (Rb) proteins on albuterols and human bronchial SMC proliferation. Results: Levalbuterol inhibited cell proliferation at low concentrations. The growth-inhibitory effect of levalbuterol occurs via activation of the cAMP/PKA pathway. Addition of (S)-albuterol to levalbuterol decreased the growth-inhibitory effect of levalbuterol, and (S)-albuterol attenuated levalbuterol-induced cAMP release by 65%. Levalbuterol inhibited NF-ĸB and Rb protein expressions. ICI-118551 abrogated the inhibitory properties of levalbuterol. The PAF receptor antagonist CV-3988 inhibited (S)-albuterol-induced cell growth, with no effect on levalbuterol. Conclusions: Levalbuterol inhibits cell growth by activating the cAMP/PKA pathway and inhibiting PI-3 kinase, NF-ĸB and Rb protein expression, and (S)-albuterol induces cell growth by activating PAF-receptor-mediated cell signaling.

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“…The dose was therefore doubled which resulted in detectable plasma concentrations. Blood samples were collected before and at 5,8,11,15,30,45,60,90,120,180 and 240 min after the salbutamol aerosol was instilled. Urine was not collected in this set of experiments.…”

Section: Subjectsmentioning

confidence: 99%

“…Racemic R,S-salbutamol is taken for the relief of reversible bronchoconstriction and the therapeutic activity is associated with the R-enantiomer [2±4]. S-salbutamol has been demonstrated to cause increased airway responsiveness to carbachol in vitro and in vivo (in guinea-pigs) [5,6]. Previously it has been shown that metabolism occurs in both airways and the gastrointestinal tract by stereoselective sulphate conjugation [7].…”

mentioning

confidence: 99%

Colony-stimulating factor therapy and febrile neutropenia induced by chemotherapy: need for economical studies

Urban¹,

Lebeau²

1999

Eur Respir J

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Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use.Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng . mL -1 . The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached.In conclusion, the clinical consequences of increasing plasma concentrations of Ssalbutamol need to be further assessed. Eur Respir J 1999; 13: 1230±1235. Many drugs are formulated as racemic mixtures and it has become clear that the enantiomers may differ in their pharmacokinetic and pharmacodynamic properties. There are numerous examples of enantioselective differences [1], and single enantiomers have taken the place of racemic drugs in several areas of medicine. Salbutamol (albuterol) is a sympathomimetic drug, with potent b 2 -adrenoceptor stimulating properties. Racemic R,S-salbutamol is taken for the relief of reversible bronchoconstriction and the therapeutic activity is associated with the R-enantiomer [2±4]. S-salbutamol has been demonstrated to cause increased airway responsiveness to carbachol in vitro and in vivo (in guinea-pigs) [5,6]. Previously it has been shown that metabolism occurs in both airways and the gastrointestinal tract by stereoselective sulphate conjugation [7]. The rate by which the bronchodilating R-enantiomer is sulphated greatly exceeds that of the S-enantiomer in vitro [8]. Unchanged R-and S-salbutamol is excreted in urine [9]. Stereoselective elimination has been reported after administration of the racemate by oral [3, 10], intravenous or rectal routes [9], findings that were also supported by in vitro experiments [11,12]. These observations indicate a more efficient removal of the active bronchodilating R-enantiomer, exposing the body to higher concentrations of the S-enantiomer. Repeated dosing could then lead to a greater ratio of S:R salbutamol in the blood over time. Assuming that adverse effects are associated with S-salbutamol in humans, the clinical implication of stereoselective d...

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Exacerbation of Airway Hyperreactivity by (±)Salbutamol in Sensitized Guinea Pigs

Cited by 50 publications

References 19 publications

Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi

Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi

Levalbuterol Inhibits Human Airway Smooth Muscle Cell Proliferation: Therapeutic Implications in the Management of Asthma

Colony-stimulating factor therapy and febrile neutropenia induced by chemotherapy: need for economical studies

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