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Single-isomer R-salbutamol is not superior to the racemate ragarding bronchial hyperreactivity
Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Twenty-six patients with mild to moderate asthma were enrolled in a doubleblind, randomised, cross-over study. Bronchial response to provocation, given as isocapnic hyperventilation with cold air (IHCA), was measured before and after one week's medication with single isomer R-salbutamol and racemic R/S-salbutamol, respectively. Doses of 0.63 mg R-salbutamol or 1.25 mg R/S-salbutamol were inhaled by nebuliser three times daily dming medication-weeks. Impulse oscillometry (IOS) as well as forced expiratory volume dming one second (FEV1) were methods used to identify bronchial response to provocation. Two patients withdrew from the investigation due to side-effects, one from Rthe other from R,S-salbutamol.

The aim of this study was to investigate the effects from medication with R,S- and R-salbutamol on bronchial response to provocation.

Intra-individual differences of < 2% between days in baseline values, measured as total airway resistance (R5) by IOS and ≤ 1% measured as FEV1. indicated comparable resting bronchial conditions. After a week's medication no significant differences in airway responsiveness to provocation could be demonstrated irrespective of the medication used.

Neither regular medication with inhaled corticosteroids up to 800 mg/day nor any increase in ahway inflammation, was found to influence the results.

Plasmaconcentrations of R-salbutamol were intra-individually lower after R- than after R,S-salbutamol. Considerable amounts of S-salbutamol were retrieved in plasma after medication with pure R-salbutamol.

We conclude that we were unable to demonstrate favourable effects of R-salbutamol over R,S-salbutamol regarding response to provocation with cold air after medication of one week's duration.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-81908OAI: oai:DiVA.org:liu-81908DiVA: diva2:556419
Available from: 2012-09-25 Created: 2012-09-25 Last updated: 2012-09-25Bibliographically approved
In thesis
1. A study on pharmacokinetic and pharmacodynamic effects of salbutamol-isomers
Open this publication in new window or tab >>A study on pharmacokinetic and pharmacodynamic effects of salbutamol-isomers
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Astma är en kronisk inflammatorisk luftvägssjukdom som förekommer i hög - och enligt rapporter ökande - frekvens världen över. Defmitionen av astma inkluderar varierande luftvägsobstruktion och ökad bronkiell reaktivhet gentemot olika stimuli. Medicinering mot astma består vanligtvis av bronkvidgande beta-receptor-agonister som ofta kombineras med inflammationshärmnande medel såsom kortikosteroider.

Salbutamol. en beta-receptor-agonist har två isomerer. R-salbutamol och S-salbutamol, och används ofta som racemat. Bronk-vidgning åstadkommes enbart av R-isomeren medan S-salbutamol har misstänkis öka bronkiell hyperreakiivitet. Salbutamol genomgår stereoselektiv metabolisering. som gynnar R-enantiomeren. Detta medför att S-enantiomeren kvarstannar längre i kroppen och att S/R-kvoten i plasma överstiger ett.

Farmakokinetiska studier genomfördes på 22 friska frivilliga försökspersoner. Resultatet av stereoselektiv metabolisering sågs mera uttalat efter nedsväljning av salbutan10lracemat än efter inhalation eller endotrakeal tillförsel av preparatet. Upprepade inhalationer ledde till ökande S/R-kvoter i plasma. Båda isomererna återfanns i högre halter i plasma från icke kortisonbehandlade astmapatienter än från friska personer efter nedsväljning av racerniskt salbutamol. Efter en veckas kortisonbehandling (budesonid) åtföljt av salbutamolracemat. låg astmapatienternas plasmakoncentrationer lägre än tidigare och liknade dem hos friska icke-kortisonbehandlade personer.

Femton patienter med astma utvaldes slumpmässigt i ett crossover försök antingen till behandling med racerniskt salhutamol (tre doser tmder sex timmar) eller till att vara utan behandling. Fyra tinm1ar efter inhalation var tolv av fjorton patienter fortfarande bronkvidgade och också skyddade mot effeki av hyperventilatorisk bronkprovokation. Två patienter visade tecken till ökat svar på provokation trots vidgade bronker jämfört med en dag utan behandling. Plasmahalter av isomerer gav ingen förklaring till dessa skilmader i svar på provokation. Tjugotvå patienter med astma ingick i en annan randomiserad crossover studie avseende behandling med inhalationer av racemiski salhutamol och ren R-salbutamol. Sex tinm1ar efter sista dos av endera läkemedlet hade bronkvidgningen upphört hos alla patienter. R-salbutamol visade sig inte vara överlägset salbutamolracemat som skydd mot bronkiell provokation - tvärtom tyckies den kraftigaste hyperreaktiviteten föreligga efter medicinering med rent R-salbutamol. Plasma från blodprover tagna efter medicinering med ren R-salbutamol imlehöll avsevärda mängder av s-isomeren och tenderade att imlehålla lägre halt av R-isomeren än efter tillförsel av sammla mängd R-salbutamol som racemat. Man kunde spåra ett samband mellan detta och ökad bronkiell reaktivitet.

Sammanfattning: Avsevärda inter-individuella skillnader föreligger gällande stereoselektiv metabolisering av salhutamol och farmakodynanuska konsekvenser av medicinering. De här redovisade studierna visar på behovet av fortsatta tmdersökningar.

Abstract [en]

Asthma is a common chronic inflammatory airway disease with reported increasing incidence over the world. Definition of asthma includes variable obstruction of the airways and increase in bronchial responsiveness to various stimuli. Drug treatment for asthma traditionally consists of bronchodilatory beta-receptor-agonists, often in combination with anti-inflammatory remedies such as corticosteroids.

Salbutamol, a beta-receptor-agonist, has two stereo-isomers, R-salbutamol and Ssalbutamol, and is mostly given as a racemate. The ability for bronchodilation rests in the R-isomer, whereas the S-isomer has been suspected to increase bronchial hyperresponsiveness. Salbutamol m1dergoes stereo-selective metabolism favouring the Renantiomer. This leaves the S-enantiomer to rest for longer time in the body, and gives SiR-ratios in plasma exceeding one.

Pharmacokinetic stndies were performed in twenty-two healthy volunteers. Stereoselective metabolism was more pronounced after oral delivery than after inhalation or endotracheal deposition of the racemate. Repeated inhalations gave rise to increasing SiR-ratios in plasma. Higher plasma-levels of both isomers were obtained in non-cortisone-treated patients with asthma compared to healthy volunteers after ingestion of racemic salbutamol. Following cortisone-treatment (budesonide) for one week the plasma-levels of asthmatic patients were lowered and resembled those of non-treated volunteers.

Fifteen patients with asthma were randomly assigned to three repeated inhalations of racemic salbutamol over six hours or to "'non-treatment" in a crossover fashion. Twelve out of fomteen patients were still bronchodilated and also protected against the impact of a hyperventilation challenge four hours after inhalations. Two patients showed signs of increased response to provocation in spite of dilatation, compared to a non-treatment day. Plasma-levels of isomers did not explain these differences in response. Twenty-four patients with asthma were randomly assigned to one week's inhalation medication with either racemate or pure R-salbutamol in another crossover study. Six hours after the last inhaled dose, bronchodilation had faded away in all patients. R-salbutamol did not prove superior to racemate in protecting against a hyperventilation-challenge - on the contrary the most intensive hyper-responsiveness was seen after medication with the R-enantiomer. Plasma-levels drawn after medication with the pme R-isomer held considerable amounts of the S-isomer and tended to hold lower levels of the R-isomer than when equal amounts or R-salbutamol was given as racemate. A connection could be traced between this and increased hyper-responsiveness.

Conclusion: Considerable inter-individual variations in stereoselective metabolism of salbutamol and in pharmacodynamic consequences of medication were found. These studies point at the necessity for further investigations.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 51 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 766
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27525 (URN)12181 (Local ID)91-7373-523-X (ISBN)12181 (Archive number)12181 (OAI)
Public defence
2003-01-17, Berzeliussalen, Hälsouniversitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-25Bibliographically approved

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