logging in or signing up Препараты для терапии бронхообструкции Arkhipov Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 142 Category: Entertainment License: All Rights Reserved Like it (0) Dislike it (0) Added: June 15, 2009 This Presentation is Public Favorites: 0 Presentation Description No description available. Comments Posting comment... Premium member Presentation Transcript ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? 15 ???? 2009 ?. ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ??? : ??? Barnes and Adcock, 2003 GRE ??? ????? (????????, ?????????, ????????) GR ???? ???? ??????? ??? ?? ???????? ???????????? : ??????? ??? ?? ???????? ???????????? ????????? ??????????????? ????????? ?????? ?????????????? ?????? ??? ???????? ??? : ????????? ??????????????? ????????? ?????? ?????????????? ?????? ??? ???????? ??? Woolley KL Am. J. Respir. Crit. Care Med. 1996; 154:237-243. John M Am. J. Respir. Crit. Care Med. 1998; 157:256-262. Williams CM, J. Allergy Clin. Immunol. 2000; 105:847-859. Nelson DJ Am. J. Respir. Crit. Care Med. 1995; 151:475-481. Barnes PJ Am. J. Respir. Crit. Care Med. 1996; 154:S21-S27. Kai H Am. J. Physiol. 1996; 271:L484-L488. ?????? ??? : ?????? ??? Laitinen LA, et al. J Allergy Clin Immunol. 1992;90:32-42. ????????????? ???????? : ????????????? ???????? Busse et al., JACI 1998 ? PEF ???., ?/??? ?????? ??????? 800 ??? 400 ??? 200 ??? 100 ??? ??????? n=92-98 ? ?????? ?????? ????????? ?????????? : ????????? ?????????? Toogood et al: JACI 1982 -10 0 10 20 30 40 1600 -200 -150 -100 -50 0 50 100 150 ????????? ???, ?/??? ????????? ????? ???????????, ??-3 ???????? ????, ??? ????????????? ?????????? ? ??????? : ????????????? ?????????? ? ??????? ????????? ???? ???-???????? ????????? ????? ????????? ?? ????? ?????????????????? ? ?? ????????????? ??? ?????? ????????? ????? ??????????? 1 ??? ? ????? ??? ????????? ??. ????: ????-????? : ????: ????-????? Holt S et al. BMJ 2001;323:1–8 Masoli M. et al. Eur Respir J 2004; 23: 552–558. ?????????? ?????????(8 ???????????? – 2324 ???????) (1435 ???????) ????? ?? ?????????? ???? ? ?????????? ???? ? 895 ??????? ?? ?????? 12 ???. ???????. : ????? ?? ?????????? ???? ? ?????????? ???? ? 895 ??????? ?? ?????? 12 ???. ???????. Malmstrom, K et al. Ann Intern Med 1999;130,487-495 ????????????? ???? ????????????? ??? : ????????????? ???? ????????????? ??? * - ???????? ????? ????????? 1 ??? ? ???? ??? ????????? ?? ?????????? ????????? ?? ?????? ????????, ??? ?????????? ?????????????? : ?????????? ????????? ?? ?????? ????????, ??? ?????????? ?????????????? Pedersen S. et al. J. Allergy Clin. Immunol. 1995; 95:29–33. Alving, K., et al. Am. J. Respir. Crit. Care Med. 1995; 151:A129. 0 100 200 400 600 800 ???? ??????????, ??? 100 80 60 40 20 0 % ?? max ??????????: ???? - ????? : ??????????: ???? - ????? Powell H and Gibson PG. MJA 2003; 178: 223–225 ??????? ?????????????? ??? ? ????????????? ???? : ??????? ?????????????? ??? ? ????????????? ???? ????? ?????? Foresi : ?????? Foresi Foresi ?, Catena E. CHEST 2000; 117:440–446 ????????? 800 ???/??? ????????? 200 ???/??? ????????? 200 ???/??? + 800 ??? ????????? 800 -1 0 6 ?????? ???? ??????? ??? ?????????? : ???? ??????? ??? ?????????? Foresi ?, Catena E. CHEST 2000; 117:440–446 ?????? ?????????????? ???????? ????, ???????? ??????? ?? ?????? ? 6 ???., ??????? ???? ?????? ?? ?? ?? 56% : ?????? ?????????????? ???????? ????, ???????? ??????? ?? ?????? ? 6 ???., ??????? ???? ?????? ?? ?? ?? 56% ????? ???????? ??? ? ??? ????????????? ?????????? Suissa S et al. NEJM 2000;343:332-6 0 50 100 150 200 250 1 2 3 4 5 6 7 ????? ???????? SABA ? ???. ?????????? ?? ?? ?? 10 000 ??????? ? ??? Suissa S et al:AJRCCM 1994:159:604-10 ??????????? ??????? ??? : ??????????? ??????? ??? Horvath G Eur Respir J 2006; 27:172–187 ??????????? ??????? ??? : ??????????? ??????? ??? Kumar SD Am J Respir Crit Care Med 2000; 161:918–921 Mak JCW, Am J Physiol Lung Cell Mol Physiol 1995; 12:L41-L46. ?????????? ?????? ???? ß-???????????????? ? ??????? ?????????? ??? ?????? 1 ??? ????? ???????? ? ???. ???????? ???????? ??????? : ???????? ???????? ??????? 1 - Rodrigo G. Chest 1999; 121:1977–1987 2 - Rowe BH. Cochrane Systematic Reviews 2001, DOI: 10.1002/14651858 3 - Ellul-Micallef R. Br J Clin Pharmacol 1983; 15: 419-422. 4 - Le Merre C et al. Am J Respir Crit Care Med 1997; 155:A352. 5 - Rodrigo G. Chest, 2006; Vol. 130, #5 ?????????: ?????????? ? ???????? : ?????????: ?????????? ? ???????? ? ????? ? ???????? ???? ????????? ?? ????? 1% ?? ???????? ????. ? ??????? ??????? ???????? ???????? ?? ????? 0,3% ?? ???? ???????? ???????. ???????????? ?????????? ? ????? ????????????? ? 300 ??? ??????, ??? ? ????? ?? ???????, ?????????? ????????. J Allergy Clin Immunol 2007;120:798-802. ?????????: ?????????? ? ?????????? : ?????????: ?????????? ? ?????????? ???? ?????????? ? 5,5 ???. ?????????? ??????. ?????????? ?????? ? ???????????? ???, ???????? FDA ????????? ????????? ????? ??? ?????????? ?. ?????????? ???????????? ? ?????????? ? ?????????? American College of Allergy, Asthma and Immunology (ACAAI). FDA: www.fda.gov ????????????? ??????? ??? : ????????????? ??????? ??? ???????: ????????? ?????? ???????? ??????? ??? ???????? ???????????? ?????? ??????????? ?????????: ????????? ??????? ????????????? ?-? ??????? ????????? ???????? ?????????? ????? (????) ?????????? ????? ?????? ??????????? (????) ?????????????, ?????????? ?????? ???????? ???????? ???????? ??????????? ????????? ??????. ?????????? ????????????? ???: ????-?????? : ????????????? ???: ????-?????? Powell H and Gibson PG. MJA 2003; 178: 223–225 ???? ?????? ???????- ?????????????? ???????? ????????????? ??????? Slide 27: Graeme P Currie and Brian J Lipworth. BMJ 2006;332;1439-1441 Slide 28: Graeme P Currie and Brian J Lipworth. BMJ 2006;332;1439-1441 Slide 29: Consensus Development Conference: Osteoporosis. Am J Med 1993 Slide 30: Laryngoscope, 114:1566–1569, 2004 ?????????? ????????? ??????????? ???????????? ?????????? ??????????? ????????? ????????? ???????? ??????? – ??????? ??? ????????? : ????????? ???????? ??????? – ??????? ??? ????????? Miller-Larsson et al, 1999 Miller-Larsson et al, 1998 ???????? ????? ??????? ??? : ??????? ??? AstraZeneca, data on file ?????????? : ?????????? Bundschuh DS et al. Am J Resp Crit Care Med. 2001;16? O O H O O O O H C-21 O O H O O O OH H C-21 ?????????? ???????? ??????????-?? ???. ?????????? * 12 ???. ?????????? * 1212 * - ?????????? ????????????? = 100 ?????????: ?????????? ? ????? : ?????????: ?????????? ? ????? FDA: www.fda.gov 1 2 4 5 6 7 8 9 3 0 10 11 12 ??????? 13 14 15 16+ ?????????? ??? (HFA) ??? ??? ????????? ?? ?????????? ??? ???????????? ??? ??? (HFA) ????????? ????????? ?????????? ?? ??????????/?????????? ?? ????????? ?? 3 ???? ??????? ????????? ?????? ? 2-? ??? ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ?????????????? : ?????????????? Slide 37: NOVITAS-MMDCCLX Slide 38: ??????? ???????, ?????????? ?? ????? ? ????????? Slide 39: ??????? ???????, ?????????? ?? ????? ? ????????? Slide 40: ß ? as ??? ?????????????? Slide 41: ß ? ??? ?????????????? as ??? ???? PKA 1 ???. ?????? ß2-?????????????????? : 1 ???. ?????? ß2-?????????????????? ?? ????????? ? ??????? ??? ??????? ? ??????? ???1 ????? ???????. ?????????: ???????????? ????? ?? ????????? SABA (?? FEV1) ?? 17.8% [95% CI, 27.2% - 8.5%]; ??????? ??? ?????? «????-?????» SABA ?? 34.8% [CI, 45.7% -24%]; PC20 ?? 26% [CI, 37% - 11%]; ß2-????????? ??????????: ???????????????? ????????? ?? 18.3% [CI, 31.6% -5.1%], ?????????? ?? 23.1% [CI, 39.4% - 6.8%], ????? ?? ????????????? in vitro ?? 32.7% [CI, 56.5% -9.0%]. Shelley R. Salpeter et al. Ann Intern Med.2004; 140: 802-813 Slide 43: as ?????????????? ß-??????? ßARK1=GRK2 ? ß Pi PKA PKG GRKs Slide 44: Mark Boterman, 2006 ????????? ß2-???????????????? : ????????? ß2-???????????????? ???????? ???????????? ???? ???????; ????????? ?????? ????????????, ????????????? ? TNF-a ??????? ???????? ? ????????????; ???????????? ???????????? ?????? ?????? ? ???????????, ????????? ????????? ?????????; ??????? ????????????? ??????????? ???????; ???????? ???????? ????? ? ???????? ????????????? ???????; ????????? ???????? ???????; Barnes P. Effect of beta agonists on inflammatory cells. J. Allergy Clin. Immunol., 1999, 104 (2), 10-17. Slide 46: Tamura G. New Engl J Med, 2005; 352:15 ?????? ??????????? ? ??????? 37 ???, ??? ???????????? ?????????? ? ?????????? ? 30 ???. ??????????????? : ??????????????? ???? - ?????? : ???? - ?????? Kemp JP, et al. J Allergy Clin Immunol 1997;99(Suppl. 2):S329 0 10 20 30 40 50 NS * ** *** ??????? FORM 6 ???*2 FORM 12 ???*2 FORM 24 ???*2 ? ??? (L/min) 12 ????? ????? ?????????? ?????????????? ? ß2-????????????????? ???????? ? ??????? : ?????????????? ? ß2-????????????????? ???????? ? ??????? Lipworth BJ. Thorax 2001;56:506–507 Aziz I ?t al. Eur J Clin Pharmacol 1998;54:377–81. Lipworth BJ et al. Am J Med 1989;86:653–7. Slide 50: X-C Lewell Berlin 1999 ?????????? ?????????? Slide 51: X-C Lewell Berlin 1999 Slide 56: Hanania NA et al. Am J Respir Crit Care Med Vol 165. pp 1353–1358, 2002 ß2-????????????????? ??????????? ????????: ?????? ? ????????? ???????? : ß2-????????????????? ??????????? ????????: ?????? ? ????????? ???????? Källström et al 1994 ?????????? (?????, ???????) ?????????? ?????????? (????????) 100 50 0 –10 –9 –8 –7 –6 –5 ???????????? ?? (%) Log (????/?) ??????- ??????? ????????????? ?????????? ?????????? LABA : ????????????? ?????????? ?????????? LABA Am J Respir Crit Care Med Vol 165. pp 1353–1358, 2002 M. Molimard, E. Naline, Y. Zhang. Eur Respir J 1998; 11: 583–588. In vitro - ? ?????? ?? ????????????? ???????, ?????????? (? ??????? ?? ?? ???????????) ????? ????????? ? ???????? ??????????? SABA. «Down»-????????? ß2-?????????? : «Down»-????????? ß2-?????????? Giannini ? ?? al. Chest 2001;119;1671-1675 ?????????? ? ???????, ???????????? ? ???????? ???????????? : ?????????? ? ???????, ???????????? ? ???????? ???????????? Bateman ED et al. Respiratory Research 2006, 7:13 ?????????? ?????????? ? ?????????????? ß2-AR : ????? ??????????????? ?????? ??????? ????????? ??????? Pauwels RA 1997 Pearlman DS, 1992; D’Alonzo GE, 1994 ?????????? ????????: Ramage L, 1994; Nelson JA, 1998 ?????????: Giannini D, 1996 ?????????? ???????????: Cheung D, 1992 ?????????? ?????????? ? ?????????????? ß2-AR ?????????? ?? ?????????? ????????? ?? ?????????? ?????, ? ??????? «????» ? ?????????????????? ????????? , ?????? ?????? ? ?????? : ?????????? ?? ?????????? ????????? ?? ?????????? ?????, ? ??????? «????» ? ?????????????????? ????????? , ?????? ?????? ? ?????? Borgström L, et al (1996), Palmqvist M, et al (1997), Tötterman KJ, et al (1998), Löfdahl C-G, Svedmyr N (1989) Rosenborg J, et al (2000) 0 6 12 ????????- ??????? ???????? ? ?????? ???????? ????????? ?????? ????? (????) ?????????? SABA ??????? ?? ??????????? ??????? ??????? ????: : ??????? ????: J. Malolepszy et al. Eur Respir J 2001; 18: 928–934 Ostrom NK (2003 ?) ?????????? ? ???? 228 ???/???. ?? ?????????? ?? ???????????? ?? ???????????? ? ??????? ???? Ankerst J (2003 ? ) ?????????? ? ???? 54 ??? ?? 4 ???? – ?? ???????? ????????? ????????????? ???????? ? ??????? ?? ?+ ?????/? ??? 20 ????????? ?? 3 ????: ?????????? 110 ?? ?????????? 90 ?? ?????????????? ß-???????????????? : ?????????????? ß-???????????????? ???????????????? ß-?????????? ????? ß-??????? 0 ~1-2 ???? ~5 ????? ?????? ? ?????? ?????? (Chong LK, 2003; Nishikawa DM, 1996; Nogami M, 1993) ??????? ? ?????? (Bengtsson B, 1982 ? 1984; Schafers MA, 2001) ?????????? vs ?????????? : ?????????? vs ?????????? Kips JC Am J Respir Crit Care Med Vol 164. pp 923–932, 2001 ????????? ???????????? : ????????? ???????????? ????????? 12 ?????? ? ???? – ??? ?????????? : ????????? 12 ?????? ? ???? – ??? ?????????? Sears MR et al. Eur Respir J 2009; 33: 21-32 ??? ??????????? ???????????? ??????????? 68 000 ??????? 49906 ???????, ?????????? ?????????? 8 ????????? ??????? (0,34 ?? 1000 ??? ??????) 18098 ???????, ?????????? ??????? 2 ????????? ?????? (0,22 ?? 1000 ??? ??????) ???????? ????????????? ?? ??????? ????????? ????????????? ??????? : ????????? ????????????? ??????? Sears MR et al. Eur Respir J 2009; 33: 21-32 ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. : ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. Castle W et al. BMJ 1993; 306: 1034–1037. Nelson HS et al. Chest 2006;129;15-26 Salpeter SR et al. Ann Intern Med. 2006;144:904-912. Bateman, E. et. al. Ann Intern Med 2008;149:33-42 ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. : ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. Castle W et al. BMJ 1993; 306: 1034–1037. Nelson HS et al. Chest 2006;129;15-26 Salpeter SR et al. Ann Intern Med. 2006;144:904-912. Bateman, E. et. al. Ann Intern Med 2008;149:33-42 Novartis database (5 970 ???????): ?????????? ? ??????????? ?????????? ????????? ? 2 ???? ????, ??? ??? ?????? ???????. RELIEF study (18 124 ???????): ?????????? ?? ???????? ??????????, ?? ?? 14% ??????? ???? ?????????? ??. AstraZeneca databases (50 426 ? 68 004 ???????): ?????????? ?? ?????? ?? ?????????? ?? ??. 1960-?: ß2-?????????????????????????? ???????? ??????????? ?????????? ?? ?? : 1960-?: ß2-?????????????????????????? ???????? ??????????? ?????????? ?? ?? ??????? ? ????????? ??????? ß2-?????????????????? ????????? ???????? ?????????? ? ??????? ?? 1990-?: ß2-???????????????????????????? ???????? ??????? ?????????? ?? ?? : 1990-?: ß2-???????????????????????????? ???????? ??????? ?????????? ?? ?? LABA + ???? : LABA + ???? P.J. Barnes. Eur Respir J 2002; 19: 182–191 LABA + ???? : LABA + ???? Barnes PJ Eur Respir J 2007; 29: 587–595 ??????????????? ???????? ????? ??????????, ??? ??? ??????????, ??????????? ?? ??????????? : ??????????????? ???????? ????? ??????????, ??? ??? ??????????, ??????????? ?? ??????????? ????? ???????? : ???? ß2-??????? ? ???????? ????? ???? ????????? ?????????: ??? ?????????? ????????? - 18%. ??? ??????? ????????? - 65%. ??? ????????? ????????? – ?? 74%. ????? ????????????????? ?????? ? ??????? ? ?????????????? ?? ?? ?????? ?????? ?? ????????? 150 ???? ? ????. ????? 60% ??????? ??????? ???????????? ???. ????? ???????? Cerveri I et al. Eur Respir J. 1997 Dec;10(12):2761-5. ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ???????? ?????? ??????? : ???????? ?????? ??????? ???????????? ??????? ??????? ?????????????: a-AR (???????????), ß-AR (?????????) ?????????????????: ?-??????????????? (???????????) ????????? ?????????? (????????, ???????????, ????????) ?????????????: NO Slide 79: H-ACh R M1 a,ß-Adr R ???????????? ????? ????????????? ????? ???????????????? ?????, eg. n. vagus M2 M3 ????????? ?1 ? ?3 ?????????????????. ??? ?????? ??? ???????? ???????. ????????? M2 – ????????????????. ??? ???????? ???????? ???????. ?-???????????? : ?-???????????? ??????????? ?????????? ???????? ??????? ???????? ???????????????? ?????????? ? - ???????????????? : ???????????????? ?????????? ? - ???????????????? ??????? ????????????? : ??????? ????????????? Disse B et al. Life Sci 1999; 64:457-464 ???????????????? ???????? ???????????? ? ??????????? : ???????????????? ???????? ???????????? ? ??????????? van Noord JA et al. Thorax 2000; 55: 289-94 ???1 (?) ???? ????? ????????? 1.5 1.6 1.1 1.3 1.2 1.4 ???? ????? ????????? 1.5 1.6 1.1 1.3 1.2 1.4 92-? ???? 1-? ???? 0 5 -1 1 2 3 4 6 0 5 -1 1 2 3 4 6 ?????????? ??????????? ???1 (?) ????????????? : ????????????? ???????? ???????? ????? : ???????? ???????? ????? ???????????? ??????? ??????? ?????????????: ß-AR (?) ?????????????????: ?-??????????????? (?) ????????? ?????????? (????????, ???????????, ????????) ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ?????????? : ?????????? ?????????? (Xolair): ??????????? ????????????? 14 ???????????? 3143 ??????? : ?????????? (Xolair): ??????????? ????????????? 14 ???????????? 3143 ??????? ???????? ????????? ??????? ??????? ????????????? IgE ? ??????? ?? 90%. ?????????? ?????????? ?????????? ???????????? ????? ?? 50%. ????????? 50% ???????, ?????????? ?????????? ???????? ??????????? ??????? ???? ??? ? ??????? ?? 119 ???/???. ?? ????????? ? ??????? ? ???????, ?????????? ?????????? ? 2,5 ???? ???? ????????? ???????? ??? ??? ?????? ??????. ??????? ????????????? ?????????? ??????? ???????????? ???????????? ??????. Boulet LP Am J Respir CritCare Med 1997;155(6):1835– 40. Busse W J Allergy Clin Immunol 2001;108(2):184– 90. Walker SThe Cochrane Library 2007, Issue 1 ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ?????????????????? ????????? : ?????????????????? ????????? ??????????? ? ??????????? ???????? ????????????? ????????????? ?????????????? ?????????? I ???? (??T1-?????????), ? ???????? ?????????? ?????????? 5-?????????????? ????????? : ????????? ?? ????????????? ???????? LABA ????????? ????????????? ??????? (? ?.?. ????????? ?????) ????? ??????????????? ???????? ??????? ??????????? ????????????? ??????? ????, ??????? ??????????? ???????????? ????????? ? ????? ?????????????? ????????????????????? ?????????? ???????????? ???????? ??????????????? ? ??????????? ?? ????????, ??????????? ????, ?????? ????????????? ?????????? (???????????, ??????????????? ????????, ???? ? ?.?.), ????????????? ??????????? ? ??????? ?????????? ? ??????????????? ????????? : ?????????? ? ??????????????? ????????? ????????????? ??????? ?????? ?????? ?????????? (??? ?? ? ????) ß2-????????????????? ??? ?????? ?????? ???????????????? ??????????? : ??????????? GSK159802 ? ??????????? ?????????? / ??????????? ?????? (???+??????????) ?????????? ??????????????? 4 (??????????) ?????????? ????????? (CAT-213 ???????? ? ????????????? ?????????) ????????? ??????? TNF-a ?????????????? ???????? ? ????????????? IL-5 ? IL-4 ??????????? ???????????? ?????? ????????? : ??????????? ???????????? ?????? ????????? 14,9 ??? 80 ???????????? > 5 000 ????????? 897 ??? $ 20% ?????? ?? ????????? FDA Slide 95: 1981 1982 1983 1984 1985 2000 ???????????? (????????????????) ????????? : ???????????? (????????????????) ????????? ?????????? ?.?. ? ?????. ????????? ??????????? 2008; ?4: ?. 18-21 You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.
Препараты для терапии бронхообструкции Arkhipov Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 142 Category: Entertainment License: All Rights Reserved Like it (0) Dislike it (0) Added: June 15, 2009 This Presentation is Public Favorites: 0 Presentation Description No description available. Comments Posting comment... Premium member Presentation Transcript ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? 15 ???? 2009 ?. ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ??? : ??? Barnes and Adcock, 2003 GRE ??? ????? (????????, ?????????, ????????) GR ???? ???? ??????? ??? ?? ???????? ???????????? : ??????? ??? ?? ???????? ???????????? ????????? ??????????????? ????????? ?????? ?????????????? ?????? ??? ???????? ??? : ????????? ??????????????? ????????? ?????? ?????????????? ?????? ??? ???????? ??? Woolley KL Am. J. Respir. Crit. Care Med. 1996; 154:237-243. John M Am. J. Respir. Crit. Care Med. 1998; 157:256-262. Williams CM, J. Allergy Clin. Immunol. 2000; 105:847-859. Nelson DJ Am. J. Respir. Crit. Care Med. 1995; 151:475-481. Barnes PJ Am. J. Respir. Crit. Care Med. 1996; 154:S21-S27. Kai H Am. J. Physiol. 1996; 271:L484-L488. ?????? ??? : ?????? ??? Laitinen LA, et al. J Allergy Clin Immunol. 1992;90:32-42. ????????????? ???????? : ????????????? ???????? Busse et al., JACI 1998 ? PEF ???., ?/??? ?????? ??????? 800 ??? 400 ??? 200 ??? 100 ??? ??????? n=92-98 ? ?????? ?????? ????????? ?????????? : ????????? ?????????? Toogood et al: JACI 1982 -10 0 10 20 30 40 1600 -200 -150 -100 -50 0 50 100 150 ????????? ???, ?/??? ????????? ????? ???????????, ??-3 ???????? ????, ??? ????????????? ?????????? ? ??????? : ????????????? ?????????? ? ??????? ????????? ???? ???-???????? ????????? ????? ????????? ?? ????? ?????????????????? ? ?? ????????????? ??? ?????? ????????? ????? ??????????? 1 ??? ? ????? ??? ????????? ??. ????: ????-????? : ????: ????-????? Holt S et al. BMJ 2001;323:1–8 Masoli M. et al. Eur Respir J 2004; 23: 552–558. ?????????? ?????????(8 ???????????? – 2324 ???????) (1435 ???????) ????? ?? ?????????? ???? ? ?????????? ???? ? 895 ??????? ?? ?????? 12 ???. ???????. : ????? ?? ?????????? ???? ? ?????????? ???? ? 895 ??????? ?? ?????? 12 ???. ???????. Malmstrom, K et al. Ann Intern Med 1999;130,487-495 ????????????? ???? ????????????? ??? : ????????????? ???? ????????????? ??? * - ???????? ????? ????????? 1 ??? ? ???? ??? ????????? ?? ?????????? ????????? ?? ?????? ????????, ??? ?????????? ?????????????? : ?????????? ????????? ?? ?????? ????????, ??? ?????????? ?????????????? Pedersen S. et al. J. Allergy Clin. Immunol. 1995; 95:29–33. Alving, K., et al. Am. J. Respir. Crit. Care Med. 1995; 151:A129. 0 100 200 400 600 800 ???? ??????????, ??? 100 80 60 40 20 0 % ?? max ??????????: ???? - ????? : ??????????: ???? - ????? Powell H and Gibson PG. MJA 2003; 178: 223–225 ??????? ?????????????? ??? ? ????????????? ???? : ??????? ?????????????? ??? ? ????????????? ???? ????? ?????? Foresi : ?????? Foresi Foresi ?, Catena E. CHEST 2000; 117:440–446 ????????? 800 ???/??? ????????? 200 ???/??? ????????? 200 ???/??? + 800 ??? ????????? 800 -1 0 6 ?????? ???? ??????? ??? ?????????? : ???? ??????? ??? ?????????? Foresi ?, Catena E. CHEST 2000; 117:440–446 ?????? ?????????????? ???????? ????, ???????? ??????? ?? ?????? ? 6 ???., ??????? ???? ?????? ?? ?? ?? 56% : ?????? ?????????????? ???????? ????, ???????? ??????? ?? ?????? ? 6 ???., ??????? ???? ?????? ?? ?? ?? 56% ????? ???????? ??? ? ??? ????????????? ?????????? Suissa S et al. NEJM 2000;343:332-6 0 50 100 150 200 250 1 2 3 4 5 6 7 ????? ???????? SABA ? ???. ?????????? ?? ?? ?? 10 000 ??????? ? ??? Suissa S et al:AJRCCM 1994:159:604-10 ??????????? ??????? ??? : ??????????? ??????? ??? Horvath G Eur Respir J 2006; 27:172–187 ??????????? ??????? ??? : ??????????? ??????? ??? Kumar SD Am J Respir Crit Care Med 2000; 161:918–921 Mak JCW, Am J Physiol Lung Cell Mol Physiol 1995; 12:L41-L46. ?????????? ?????? ???? ß-???????????????? ? ??????? ?????????? ??? ?????? 1 ??? ????? ???????? ? ???. ???????? ???????? ??????? : ???????? ???????? ??????? 1 - Rodrigo G. Chest 1999; 121:1977–1987 2 - Rowe BH. Cochrane Systematic Reviews 2001, DOI: 10.1002/14651858 3 - Ellul-Micallef R. Br J Clin Pharmacol 1983; 15: 419-422. 4 - Le Merre C et al. Am J Respir Crit Care Med 1997; 155:A352. 5 - Rodrigo G. Chest, 2006; Vol. 130, #5 ?????????: ?????????? ? ???????? : ?????????: ?????????? ? ???????? ? ????? ? ???????? ???? ????????? ?? ????? 1% ?? ???????? ????. ? ??????? ??????? ???????? ???????? ?? ????? 0,3% ?? ???? ???????? ???????. ???????????? ?????????? ? ????? ????????????? ? 300 ??? ??????, ??? ? ????? ?? ???????, ?????????? ????????. J Allergy Clin Immunol 2007;120:798-802. ?????????: ?????????? ? ?????????? : ?????????: ?????????? ? ?????????? ???? ?????????? ? 5,5 ???. ?????????? ??????. ?????????? ?????? ? ???????????? ???, ???????? FDA ????????? ????????? ????? ??? ?????????? ?. ?????????? ???????????? ? ?????????? ? ?????????? American College of Allergy, Asthma and Immunology (ACAAI). FDA: www.fda.gov ????????????? ??????? ??? : ????????????? ??????? ??? ???????: ????????? ?????? ???????? ??????? ??? ???????? ???????????? ?????? ??????????? ?????????: ????????? ??????? ????????????? ?-? ??????? ????????? ???????? ?????????? ????? (????) ?????????? ????? ?????? ??????????? (????) ?????????????, ?????????? ?????? ???????? ???????? ???????? ??????????? ????????? ??????. ?????????? ????????????? ???: ????-?????? : ????????????? ???: ????-?????? Powell H and Gibson PG. MJA 2003; 178: 223–225 ???? ?????? ???????- ?????????????? ???????? ????????????? ??????? Slide 27: Graeme P Currie and Brian J Lipworth. BMJ 2006;332;1439-1441 Slide 28: Graeme P Currie and Brian J Lipworth. BMJ 2006;332;1439-1441 Slide 29: Consensus Development Conference: Osteoporosis. Am J Med 1993 Slide 30: Laryngoscope, 114:1566–1569, 2004 ?????????? ????????? ??????????? ???????????? ?????????? ??????????? ????????? ????????? ???????? ??????? – ??????? ??? ????????? : ????????? ???????? ??????? – ??????? ??? ????????? Miller-Larsson et al, 1999 Miller-Larsson et al, 1998 ???????? ????? ??????? ??? : ??????? ??? AstraZeneca, data on file ?????????? : ?????????? Bundschuh DS et al. Am J Resp Crit Care Med. 2001;16? O O H O O O O H C-21 O O H O O O OH H C-21 ?????????? ???????? ??????????-?? ???. ?????????? * 12 ???. ?????????? * 1212 * - ?????????? ????????????? = 100 ?????????: ?????????? ? ????? : ?????????: ?????????? ? ????? FDA: www.fda.gov 1 2 4 5 6 7 8 9 3 0 10 11 12 ??????? 13 14 15 16+ ?????????? ??? (HFA) ??? ??? ????????? ?? ?????????? ??? ???????????? ??? ??? (HFA) ????????? ????????? ?????????? ?? ??????????/?????????? ?? ????????? ?? 3 ???? ??????? ????????? ?????? ? 2-? ??? ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ?????????????? : ?????????????? Slide 37: NOVITAS-MMDCCLX Slide 38: ??????? ???????, ?????????? ?? ????? ? ????????? Slide 39: ??????? ???????, ?????????? ?? ????? ? ????????? Slide 40: ß ? as ??? ?????????????? Slide 41: ß ? ??? ?????????????? as ??? ???? PKA 1 ???. ?????? ß2-?????????????????? : 1 ???. ?????? ß2-?????????????????? ?? ????????? ? ??????? ??? ??????? ? ??????? ???1 ????? ???????. ?????????: ???????????? ????? ?? ????????? SABA (?? FEV1) ?? 17.8% [95% CI, 27.2% - 8.5%]; ??????? ??? ?????? «????-?????» SABA ?? 34.8% [CI, 45.7% -24%]; PC20 ?? 26% [CI, 37% - 11%]; ß2-????????? ??????????: ???????????????? ????????? ?? 18.3% [CI, 31.6% -5.1%], ?????????? ?? 23.1% [CI, 39.4% - 6.8%], ????? ?? ????????????? in vitro ?? 32.7% [CI, 56.5% -9.0%]. Shelley R. Salpeter et al. Ann Intern Med.2004; 140: 802-813 Slide 43: as ?????????????? ß-??????? ßARK1=GRK2 ? ß Pi PKA PKG GRKs Slide 44: Mark Boterman, 2006 ????????? ß2-???????????????? : ????????? ß2-???????????????? ???????? ???????????? ???? ???????; ????????? ?????? ????????????, ????????????? ? TNF-a ??????? ???????? ? ????????????; ???????????? ???????????? ?????? ?????? ? ???????????, ????????? ????????? ?????????; ??????? ????????????? ??????????? ???????; ???????? ???????? ????? ? ???????? ????????????? ???????; ????????? ???????? ???????; Barnes P. Effect of beta agonists on inflammatory cells. J. Allergy Clin. Immunol., 1999, 104 (2), 10-17. Slide 46: Tamura G. New Engl J Med, 2005; 352:15 ?????? ??????????? ? ??????? 37 ???, ??? ???????????? ?????????? ? ?????????? ? 30 ???. ??????????????? : ??????????????? ???? - ?????? : ???? - ?????? Kemp JP, et al. J Allergy Clin Immunol 1997;99(Suppl. 2):S329 0 10 20 30 40 50 NS * ** *** ??????? FORM 6 ???*2 FORM 12 ???*2 FORM 24 ???*2 ? ??? (L/min) 12 ????? ????? ?????????? ?????????????? ? ß2-????????????????? ???????? ? ??????? : ?????????????? ? ß2-????????????????? ???????? ? ??????? Lipworth BJ. Thorax 2001;56:506–507 Aziz I ?t al. Eur J Clin Pharmacol 1998;54:377–81. Lipworth BJ et al. Am J Med 1989;86:653–7. Slide 50: X-C Lewell Berlin 1999 ?????????? ?????????? Slide 51: X-C Lewell Berlin 1999 Slide 56: Hanania NA et al. Am J Respir Crit Care Med Vol 165. pp 1353–1358, 2002 ß2-????????????????? ??????????? ????????: ?????? ? ????????? ???????? : ß2-????????????????? ??????????? ????????: ?????? ? ????????? ???????? Källström et al 1994 ?????????? (?????, ???????) ?????????? ?????????? (????????) 100 50 0 –10 –9 –8 –7 –6 –5 ???????????? ?? (%) Log (????/?) ??????- ??????? ????????????? ?????????? ?????????? LABA : ????????????? ?????????? ?????????? LABA Am J Respir Crit Care Med Vol 165. pp 1353–1358, 2002 M. Molimard, E. Naline, Y. Zhang. Eur Respir J 1998; 11: 583–588. In vitro - ? ?????? ?? ????????????? ???????, ?????????? (? ??????? ?? ?? ???????????) ????? ????????? ? ???????? ??????????? SABA. «Down»-????????? ß2-?????????? : «Down»-????????? ß2-?????????? Giannini ? ?? al. Chest 2001;119;1671-1675 ?????????? ? ???????, ???????????? ? ???????? ???????????? : ?????????? ? ???????, ???????????? ? ???????? ???????????? Bateman ED et al. Respiratory Research 2006, 7:13 ?????????? ?????????? ? ?????????????? ß2-AR : ????? ??????????????? ?????? ??????? ????????? ??????? Pauwels RA 1997 Pearlman DS, 1992; D’Alonzo GE, 1994 ?????????? ????????: Ramage L, 1994; Nelson JA, 1998 ?????????: Giannini D, 1996 ?????????? ???????????: Cheung D, 1992 ?????????? ?????????? ? ?????????????? ß2-AR ?????????? ?? ?????????? ????????? ?? ?????????? ?????, ? ??????? «????» ? ?????????????????? ????????? , ?????? ?????? ? ?????? : ?????????? ?? ?????????? ????????? ?? ?????????? ?????, ? ??????? «????» ? ?????????????????? ????????? , ?????? ?????? ? ?????? Borgström L, et al (1996), Palmqvist M, et al (1997), Tötterman KJ, et al (1998), Löfdahl C-G, Svedmyr N (1989) Rosenborg J, et al (2000) 0 6 12 ????????- ??????? ???????? ? ?????? ???????? ????????? ?????? ????? (????) ?????????? SABA ??????? ?? ??????????? ??????? ??????? ????: : ??????? ????: J. Malolepszy et al. Eur Respir J 2001; 18: 928–934 Ostrom NK (2003 ?) ?????????? ? ???? 228 ???/???. ?? ?????????? ?? ???????????? ?? ???????????? ? ??????? ???? Ankerst J (2003 ? ) ?????????? ? ???? 54 ??? ?? 4 ???? – ?? ???????? ????????? ????????????? ???????? ? ??????? ?? ?+ ?????/? ??? 20 ????????? ?? 3 ????: ?????????? 110 ?? ?????????? 90 ?? ?????????????? ß-???????????????? : ?????????????? ß-???????????????? ???????????????? ß-?????????? ????? ß-??????? 0 ~1-2 ???? ~5 ????? ?????? ? ?????? ?????? (Chong LK, 2003; Nishikawa DM, 1996; Nogami M, 1993) ??????? ? ?????? (Bengtsson B, 1982 ? 1984; Schafers MA, 2001) ?????????? vs ?????????? : ?????????? vs ?????????? Kips JC Am J Respir Crit Care Med Vol 164. pp 923–932, 2001 ????????? ???????????? : ????????? ???????????? ????????? 12 ?????? ? ???? – ??? ?????????? : ????????? 12 ?????? ? ???? – ??? ?????????? Sears MR et al. Eur Respir J 2009; 33: 21-32 ??? ??????????? ???????????? ??????????? 68 000 ??????? 49906 ???????, ?????????? ?????????? 8 ????????? ??????? (0,34 ?? 1000 ??? ??????) 18098 ???????, ?????????? ??????? 2 ????????? ?????? (0,22 ?? 1000 ??? ??????) ???????? ????????????? ?? ??????? ????????? ????????????? ??????? : ????????? ????????????? ??????? Sears MR et al. Eur Respir J 2009; 33: 21-32 ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. : ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. Castle W et al. BMJ 1993; 306: 1034–1037. Nelson HS et al. Chest 2006;129;15-26 Salpeter SR et al. Ann Intern Med. 2006;144:904-912. Bateman, E. et. al. Ann Intern Med 2008;149:33-42 ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. : ?????????? ???? ?????????? ?????? ??? ??????? ?????? ??? ?????? ???????????, ?????? ??? ????. Castle W et al. BMJ 1993; 306: 1034–1037. Nelson HS et al. Chest 2006;129;15-26 Salpeter SR et al. Ann Intern Med. 2006;144:904-912. Bateman, E. et. al. Ann Intern Med 2008;149:33-42 Novartis database (5 970 ???????): ?????????? ? ??????????? ?????????? ????????? ? 2 ???? ????, ??? ??? ?????? ???????. RELIEF study (18 124 ???????): ?????????? ?? ???????? ??????????, ?? ?? 14% ??????? ???? ?????????? ??. AstraZeneca databases (50 426 ? 68 004 ???????): ?????????? ?? ?????? ?? ?????????? ?? ??. 1960-?: ß2-?????????????????????????? ???????? ??????????? ?????????? ?? ?? : 1960-?: ß2-?????????????????????????? ???????? ??????????? ?????????? ?? ?? ??????? ? ????????? ??????? ß2-?????????????????? ????????? ???????? ?????????? ? ??????? ?? 1990-?: ß2-???????????????????????????? ???????? ??????? ?????????? ?? ?? : 1990-?: ß2-???????????????????????????? ???????? ??????? ?????????? ?? ?? LABA + ???? : LABA + ???? P.J. Barnes. Eur Respir J 2002; 19: 182–191 LABA + ???? : LABA + ???? Barnes PJ Eur Respir J 2007; 29: 587–595 ??????????????? ???????? ????? ??????????, ??? ??? ??????????, ??????????? ?? ??????????? : ??????????????? ???????? ????? ??????????, ??? ??? ??????????, ??????????? ?? ??????????? ????? ???????? : ???? ß2-??????? ? ???????? ????? ???? ????????? ?????????: ??? ?????????? ????????? - 18%. ??? ??????? ????????? - 65%. ??? ????????? ????????? – ?? 74%. ????? ????????????????? ?????? ? ??????? ? ?????????????? ?? ?? ?????? ?????? ?? ????????? 150 ???? ? ????. ????? 60% ??????? ??????? ???????????? ???. ????? ???????? Cerveri I et al. Eur Respir J. 1997 Dec;10(12):2761-5. ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ???????? ?????? ??????? : ???????? ?????? ??????? ???????????? ??????? ??????? ?????????????: a-AR (???????????), ß-AR (?????????) ?????????????????: ?-??????????????? (???????????) ????????? ?????????? (????????, ???????????, ????????) ?????????????: NO Slide 79: H-ACh R M1 a,ß-Adr R ???????????? ????? ????????????? ????? ???????????????? ?????, eg. n. vagus M2 M3 ????????? ?1 ? ?3 ?????????????????. ??? ?????? ??? ???????? ???????. ????????? M2 – ????????????????. ??? ???????? ???????? ???????. ?-???????????? : ?-???????????? ??????????? ?????????? ???????? ??????? ???????? ???????????????? ?????????? ? - ???????????????? : ???????????????? ?????????? ? - ???????????????? ??????? ????????????? : ??????? ????????????? Disse B et al. Life Sci 1999; 64:457-464 ???????????????? ???????? ???????????? ? ??????????? : ???????????????? ???????? ???????????? ? ??????????? van Noord JA et al. Thorax 2000; 55: 289-94 ???1 (?) ???? ????? ????????? 1.5 1.6 1.1 1.3 1.2 1.4 ???? ????? ????????? 1.5 1.6 1.1 1.3 1.2 1.4 92-? ???? 1-? ???? 0 5 -1 1 2 3 4 6 0 5 -1 1 2 3 4 6 ?????????? ??????????? ???1 (?) ????????????? : ????????????? ???????? ???????? ????? : ???????? ???????? ????? ???????????? ??????? ??????? ?????????????: ß-AR (?) ?????????????????: ?-??????????????? (?) ????????? ?????????? (????????, ???????????, ????????) ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ?????????? : ?????????? ?????????? (Xolair): ??????????? ????????????? 14 ???????????? 3143 ??????? : ?????????? (Xolair): ??????????? ????????????? 14 ???????????? 3143 ??????? ???????? ????????? ??????? ??????? ????????????? IgE ? ??????? ?? 90%. ?????????? ?????????? ?????????? ???????????? ????? ?? 50%. ????????? 50% ???????, ?????????? ?????????? ???????? ??????????? ??????? ???? ??? ? ??????? ?? 119 ???/???. ?? ????????? ? ??????? ? ???????, ?????????? ?????????? ? 2,5 ???? ???? ????????? ???????? ??? ??? ?????? ??????. ??????? ????????????? ?????????? ??????? ???????????? ???????????? ??????. Boulet LP Am J Respir CritCare Med 1997;155(6):1835– 40. Busse W J Allergy Clin Immunol 2001;108(2):184– 90. Walker SThe Cochrane Library 2007, Issue 1 ????????? ??? ??????? ???????????????? : ????????? ??? ??????? ???????????????? ????????????? ??? ?2-????????????????? ?-???????????? ????-IgE ????????? ?????? ???????? ?????????????????? ????????? : ?????????????????? ????????? ??????????? ? ??????????? ???????? ????????????? ????????????? ?????????????? ?????????? I ???? (??T1-?????????), ? ???????? ?????????? ?????????? 5-?????????????? ????????? : ????????? ?? ????????????? ???????? LABA ????????? ????????????? ??????? (? ?.?. ????????? ?????) ????? ??????????????? ???????? ??????? ??????????? ????????????? ??????? ????, ??????? ??????????? ???????????? ????????? ? ????? ?????????????? ????????????????????? ?????????? ???????????? ???????? ??????????????? ? ??????????? ?? ????????, ??????????? ????, ?????? ????????????? ?????????? (???????????, ??????????????? ????????, ???? ? ?.?.), ????????????? ??????????? ? ??????? ?????????? ? ??????????????? ????????? : ?????????? ? ??????????????? ????????? ????????????? ??????? ?????? ?????? ?????????? (??? ?? ? ????) ß2-????????????????? ??? ?????? ?????? ???????????????? ??????????? : ??????????? GSK159802 ? ??????????? ?????????? / ??????????? ?????? (???+??????????) ?????????? ??????????????? 4 (??????????) ?????????? ????????? (CAT-213 ???????? ? ????????????? ?????????) ????????? ??????? TNF-a ?????????????? ???????? ? ????????????? IL-5 ? IL-4 ??????????? ???????????? ?????? ????????? : ??????????? ???????????? ?????? ????????? 14,9 ??? 80 ???????????? > 5 000 ????????? 897 ??? $ 20% ?????? ?? ????????? FDA Slide 95: 1981 1982 1983 1984 1985 2000 ???????????? (????????????????) ????????? : ???????????? (????????????????) ????????? ?????????? ?.?. ? ?????. ????????? ??????????? 2008; ?4: ?. 18-21