- Email: [email protected]
342 H1-receptor antagonist (H1RA) concentrations are higher in skin than in serum following IV dosing
VOLUME NUMBER
Abstracts
87 1. PART 2
341 lHEIIL-RxEPxxANIlAccNI~ _(ClM-DB.SJEEME~~
ui.RAl
343
t
OFlIiEI$ZINE w m ITS. . . . SW. M.D. and K.J. Sincns. Ph.D. Winnipeg, Canada. Inchronicurticariatreatmant,theefficacy ellhmaabysinultaneuls OfanqRAneybe administrationofanIi$?A,dueinparttoa @annacokinetic effect, with the KpA decreasclearanceoftheH+?Aandixreasingse.nmland coxe&rations.Westudiedthe tissue?RA effect of mation of the w CIM on thenewf4RACEI,whichhasdoarmerrtedefficacy inchronicurticaria and is excret& 60-70% UncfiangedbythereMlXUte. cm, lOng,wasgivenIvto5 rabbits, 2 weeksbeforecIM; after CIM, lOOmg/kgbidforl week:and2weeksafterCIMwasdisamtinued. Blood sanples were obtained at -0.1, 0.1, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 ard 24h after CEl'. Ser&CEl~c&ce&rationsweremaasur&byBPLC. Sta&ard @annacokinetic and statistical data analyseswereperform3d. (*pco.o5) RESULTS: WithCIW FostClM CET PreCIM 1.49.3 4.1+1.9* 1.25.2 ts 8259+1506* 5906+1005 ADC 61922887 7.4kl.3 5.2+0.2* 7.OiG.7 Cl [t$r) A~~:~,~~.'~'~~,~;~~.~(LFg)] Co-administrationo~ ClMwithCEI significantly irrcreasea CEI serum concentrations (AX) andt+. and decreased Cl, nrobablydueto tran&nti&ainnantofhepatiC~funCtio;lbyCIM, txltalsodue to amqxtitionbetween CIMandCET for renal clearanCeof CEI.
342
3-m -= %M’ -?lIQmINsKINmiaNINL?.muMFo~Iv
ARE
F.E.R. Sm. &,D.. X. Chen. Fh.D.. T. as-d K.J. Simms. Ph.D. Winnipag, Cenada. Wahvr&hesized#atthelacrb&weenthe admini&ticm ofIi$?Aandthe&effedcnwheal arKI flare ~ionmightbedue todelayed distribitionofthe~RAintotheskin.Wa testedthis~islyadsinister~lOmg hydroxyzina (Ii), 10 mg cetirizine (C) or 10 ng die (D) IVtorakbits. Blood samples were obtained at -0.1, 0.08, 0.25, 0.5, 1,2,3, 4,6,8, turl I.2 hours after dceirq. At these times &inbic@eswereobtainedfruatheshavedback usinga3wAarFunch.Skinsaupleswere blottedfreeofblocd,[email protected] lOMKOHfor24hoursbeforeH, CorD
w.
serum (SC) and skin measlnred~ingHFlc tima.H, CandDSKCw
quantitation. H, CorD (SK) axcenbxticnswere
andplottedversus significantly higher than SC (p-0.01) fmn 0.25h-12h. 6h-12h and O.O8h-12h rescectivelv. SKC ware greater than SC (2-lo-fold-for H, i.5lo-fold for C and 20-50-fold for D). In previous mwimrmsqpreksion of studies in rat&its, histamine-induced wheals in the skin was 90%, 98% and 60% for H, C and D respectively. Intheratbitxdel,thereisnodelayinH, CorDentryintotheskinfollowinglS'doeing. Ihedistrilxtionintoskindiffersaaxmqstthe HpAstudied. SKC/SCratioedonotrelate to pobancyintheskin.melagbetween~RA a&ninistrationandtheeffectonwhealandflare sKpressioncannotbaexplainedonthebasi.sof delayed HpA penetratian into the skin. An alternative qz&anationnnrstthereforebe scught at the xceptor level.
225
AWARIWAbMoDELF0RSlVDYOF'DiEEFFECTOF IlEPATICDY~~fHD~ GWJII~OFItS-E IILFW HYDROXYZINE (H) AND m Ph.D., F E R Sinrnx. M.D Winnipeg, Canada. H is &&zntlv used f&- oruritus relief. H elimination*is i&red sig&ficantly in patients with BD (J Clin Fhannacol 29;809-815, 1989). lhe active matabolite of H, CET, is only 30-40% matabolized by the liver, the rest baiq excreteduxhaqad.Wehypothesizedthatthe eliminationof CETmightbeless affectedby HD thantheeliminationof H. Wedevelqedan anima1mode1inwhichtostudyihisprob1em.H 10 mg, or CETlOq, were given Ivto 5 rabbits, 2weekabefcrre,and3daysaftercq(0.5mL/ kg) was injected intraperitcneally to induce BD. SerumHandCEIwWXmeasllred byI-IPrcandHDwas -usingM (SGCW) andALT (SGIT). FSSULTS: (.EO.O5) Before BD AfterHD 1.49.7 2.6fl.7 H tJi 04 HAUC (nghr/mL) 840+_325 1393+274* 47.8515.2 26.9+4.9* H Cl (ml&in/kg) 20.5k4.6 32qt_312 AD (U/L) 501+203* 35.8kl5.5 ALT W/L) 1.6fl.5 3.2+0.7* CET t'i w CEIADC (rqhr/mL) 6007+1019 11572+4030* CET. Cl (mL/min/kg) 7.221.6 3.9+1.0* 8.43.0 434+442 Asc (U/L) 19.43.7 516f425* ALT (U/L) CU&ndu&HD&reasedHa.ndCETt~ard ADZ and decreased H and CEI Cl significantly. Linear correlations of ADT and ASC with phanracokinetic results were not possible duet0 thewiderangeofADTandASIvalues.CEI elimination, like H elimination, appears to be impaired in HD.
344 ORALMPADJUNCTIVE P
FOR
We evaluated the potential benefit of (oral cromolyn sodium) as a Gastrocrom' corticosteroid-sparing agent in the treatment of corticosteroid-dependent idiopathic anaph laxis (CSD-IA). Gastrocrom was ah inistered prospectively evaluated case serie?to z patients with CSD-IA. These patients had been followed long-term (average duration 5 years) by our allergy service and each had a well established minimum maintenance dose of prednisone (range from 60 mg od to 10 mg god) below which his or her 8 isease activity could not be controlled. These patients were treated with a standard dose of Gastrocrom 200 mg qid for at least 4 weeks and were maintained on their prior regimen of antihistamines and/or oral adrenergic agents while attempting a reduction-in their corticosteroid dose. After 3-6 therapy 1 patient months of Gastrocrom discontinued the use of prednisone, 2 patients tolerated a greater than 50% reduction in prednisone dosage, 1 patient achieved a small reductiqn in prednisone WIzr, and thytients failed to. respond. apparent efficacy of Gastrocroo?n as a corticosteroid-sparing ;I:;: in 3 out of 6 ,patients studied we suggest a trial of Gastrocrom for pkients with idio athic anaphylaxis who have a well extab f ished requirement for chronic prednisone therapy to control disease activity.
Abstracts
87 1. PART 2
341 lHEIIL-RxEPxxANIlAccNI~ _(ClM-DB.SJEEME~~
ui.RAl
343
t
OFlIiEI$ZINE w m ITS. . . . SW. M.D. and K.J. Sincns. Ph.D. Winnipeg, Canada. Inchronicurticariatreatmant,theefficacy ellhmaabysinultaneuls OfanqRAneybe administrationofanIi$?A,dueinparttoa @annacokinetic effect, with the KpA decreasclearanceoftheH+?Aandixreasingse.nmland coxe&rations.Westudiedthe tissue?RA effect of mation of the w CIM on thenewf4RACEI,whichhasdoarmerrtedefficacy inchronicurticaria and is excret& 60-70% UncfiangedbythereMlXUte. cm, lOng,wasgivenIvto5 rabbits, 2 weeksbeforecIM; after CIM, lOOmg/kgbidforl week:and2weeksafterCIMwasdisamtinued. Blood sanples were obtained at -0.1, 0.1, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 ard 24h after CEl'. Ser&CEl~c&ce&rationsweremaasur&byBPLC. Sta&ard @annacokinetic and statistical data analyseswereperform3d. (*pco.o5) RESULTS: WithCIW FostClM CET PreCIM 1.49.3 4.1+1.9* 1.25.2 ts 8259+1506* 5906+1005 ADC 61922887 7.4kl.3 5.2+0.2* 7.OiG.7 Cl [t$r) A~~:~,~~.'~'~~,~;~~.~(LFg)] Co-administrationo~ ClMwithCEI significantly irrcreasea CEI serum concentrations (AX) andt+. and decreased Cl, nrobablydueto tran&nti&ainnantofhepatiC~funCtio;lbyCIM, txltalsodue to amqxtitionbetween CIMandCET for renal clearanCeof CEI.
342
3-m -= %M’ -?lIQmINsKINmiaNINL?.muMFo~Iv
ARE
F.E.R. Sm. &,D.. X. Chen. Fh.D.. T. as-d K.J. Simms. Ph.D. Winnipag, Cenada. Wahvr&hesized#atthelacrb&weenthe admini&ticm ofIi$?Aandthe&effedcnwheal arKI flare ~ionmightbedue todelayed distribitionofthe~RAintotheskin.Wa testedthis~islyadsinister~lOmg hydroxyzina (Ii), 10 mg cetirizine (C) or 10 ng die (D) IVtorakbits. Blood samples were obtained at -0.1, 0.08, 0.25, 0.5, 1,2,3, 4,6,8, turl I.2 hours after dceirq. At these times &inbic@eswereobtainedfruatheshavedback usinga3wAarFunch.Skinsaupleswere blottedfreeofblocd,[email protected] lOMKOHfor24hoursbeforeH, CorD
w.
serum (SC) and skin measlnred~ingHFlc tima.H, CandDSKCw
quantitation. H, CorD (SK) axcenbxticnswere
andplottedversus significantly higher than SC (p-0.01) fmn 0.25h-12h. 6h-12h and O.O8h-12h rescectivelv. SKC ware greater than SC (2-lo-fold-for H, i.5lo-fold for C and 20-50-fold for D). In previous mwimrmsqpreksion of studies in rat&its, histamine-induced wheals in the skin was 90%, 98% and 60% for H, C and D respectively. Intheratbitxdel,thereisnodelayinH, CorDentryintotheskinfollowinglS'doeing. Ihedistrilxtionintoskindiffersaaxmqstthe HpAstudied. SKC/SCratioedonotrelate to pobancyintheskin.melagbetween~RA a&ninistrationandtheeffectonwhealandflare sKpressioncannotbaexplainedonthebasi.sof delayed HpA penetratian into the skin. An alternative qz&anationnnrstthereforebe scught at the xceptor level.
225
AWARIWAbMoDELF0RSlVDYOF'DiEEFFECTOF IlEPATICDY~~fHD~ GWJII~OFItS-E IILFW HYDROXYZINE (H) AND m Ph.D., F E R Sinrnx. M.D Winnipeg, Canada. H is &&zntlv used f&- oruritus relief. H elimination*is i&red sig&ficantly in patients with BD (J Clin Fhannacol 29;809-815, 1989). lhe active matabolite of H, CET, is only 30-40% matabolized by the liver, the rest baiq excreteduxhaqad.Wehypothesizedthatthe eliminationof CETmightbeless affectedby HD thantheeliminationof H. Wedevelqedan anima1mode1inwhichtostudyihisprob1em.H 10 mg, or CETlOq, were given Ivto 5 rabbits, 2weekabefcrre,and3daysaftercq(0.5mL/ kg) was injected intraperitcneally to induce BD. SerumHandCEIwWXmeasllred byI-IPrcandHDwas -usingM (SGCW) andALT (SGIT). FSSULTS: (.EO.O5) Before BD AfterHD 1.49.7 2.6fl.7 H tJi 04 HAUC (nghr/mL) 840+_325 1393+274* 47.8515.2 26.9+4.9* H Cl (ml&in/kg) 20.5k4.6 32qt_312 AD (U/L) 501+203* 35.8kl5.5 ALT W/L) 1.6fl.5 3.2+0.7* CET t'i w CEIADC (rqhr/mL) 6007+1019 11572+4030* CET. Cl (mL/min/kg) 7.221.6 3.9+1.0* 8.43.0 434+442 Asc (U/L) 19.43.7 516f425* ALT (U/L) CU&ndu&HD&reasedHa.ndCETt~ard ADZ and decreased H and CEI Cl significantly. Linear correlations of ADT and ASC with phanracokinetic results were not possible duet0 thewiderangeofADTandASIvalues.CEI elimination, like H elimination, appears to be impaired in HD.
344 ORALMPADJUNCTIVE P
FOR
We evaluated the potential benefit of (oral cromolyn sodium) as a Gastrocrom' corticosteroid-sparing agent in the treatment of corticosteroid-dependent idiopathic anaph laxis (CSD-IA). Gastrocrom was ah inistered prospectively evaluated case serie?to z patients with CSD-IA. These patients had been followed long-term (average duration 5 years) by our allergy service and each had a well established minimum maintenance dose of prednisone (range from 60 mg od to 10 mg god) below which his or her 8 isease activity could not be controlled. These patients were treated with a standard dose of Gastrocrom 200 mg qid for at least 4 weeks and were maintained on their prior regimen of antihistamines and/or oral adrenergic agents while attempting a reduction-in their corticosteroid dose. After 3-6 therapy 1 patient months of Gastrocrom discontinued the use of prednisone, 2 patients tolerated a greater than 50% reduction in prednisone dosage, 1 patient achieved a small reductiqn in prednisone WIzr, and thytients failed to. respond. apparent efficacy of Gastrocroo?n as a corticosteroid-sparing ;I:;: in 3 out of 6 ,patients studied we suggest a trial of Gastrocrom for pkients with idio athic anaphylaxis who have a well extab f ished requirement for chronic prednisone therapy to control disease activity.