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(12) Patent Application Publication (10) Pub. No.: US 2013/0345273 A1 Isaacs Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0345273 A1 Isaacs Et Al US 2013 0345273A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0345273 A1 Isaacs et al. (43) Pub. Date: Dec. 26, 2013 (54) REVERSAL OF DRUG-NDUCED Related U.S. Application Data NEUROMUSCULAR BLOCK USING NOVEL (60) Provisional application No. 61/392,729, filed on Oct. MOLECULAR CONTAINERS 13, 2010, provisional application No. 61/392.722, (75) Inventors: Lyle David Isaacs, Silver Spring, MD filed on Oct. 13, 2010. (US); Da Ma, Carrboro, NC (US); Matthias Eikermann, Cambridge, MA Publication Classification (US) (51) Int. C. (73) Assignees: GENERAL HOSPITAL C07D 487/22 (2006.01) CORPORATION, Boston, MA (US); (52) U.S. C. UNIVERSITY OF MARYLAND, CPC .................................... C07D 487/22 (2013.01) COLLEGE PARK, College Park, MD USPC .......................................................... S14/388 (US) (57) ABSTRACT (21) Appl. No.: 13/878,612 Provided are methods for reversing the effects of agents used for muscular immobilization and/or loss of consciousness (22) PCT Fled: Oct. 13, 2011 and/or loss of pain perception. The method comprises admin istering a composition comprising acyclic CBn-type com (86) PCT NO.: PCT/US11A56140 pounds to an individual in need of reversal of the effects of S371 (c)(1), neuromuscular blocking agents and/oranesthetic agents such (2), (4) Date: Sep. 3, 2013 that the effects of the agent(s) are partially fully reversed. Patent Application Publication Dec. 26, 2013 Sheet 1 of 27 US 2013/0345273 A1 is i.-...-...-.5 Hirnrn'NHH}--HH---H + grea)ar's --- daF-------------EF-E-R sn't N Fo HN-N-N-N- -i- W-N ii-in-i-Isis C O 'erry'sO : n {R Birging N: - Mis?i-Yibr Motor1 R = Me R = CHCHCHSO, Na Citi Stras a weSOs, 5 & if A, feux Figure 1 HS O CC. C.$: Piach CCSt. - CA, s 8 G ------- OR C?. -...------ QR, N - , is it TFA M. N. is N M cer HHRE, sis ge R---R:------------R N.F.-is-it-r OS ba, Ni-- in is Gigi Sia, R site Motor2 Figure 2 Patent Application Publication Dec. 26, 2013 Sheet 4 of 27 US 2013/0345273 A1 Figure 10 CH/SY1OCHH nnnn-nnn-nnnO O HEEOO O orn-Src.H., Cah:17-s-n-O N-N-N-N-N-N-N-NO O O O O-ns-C8H17 Figure 11 Patent Application Publication Dec. 26, 2013 Sheet 8 of 27 US 2013/0345273 A1 A) straaaaaaaaaraaaaraaaaaaaaaraaaaraaaa-araaraaaaraaaaraaaa-ra-aa-ra-rara. ----------. S S s s S & s . 8. ss . stiliš expaxiraxxpaxray. 8. $g S is 88. S8 i. FE sistics Figure 18 Patent Application Publication Dec. 26, 2013 Sheet 9 of 27 US 2013/0345273 A1 Šiš& fisitStSS: Figure 19 Patent Application Publication Dec. 26, 2013 Sheet 10 of 27 US 2013/0345273 A1 E. pºzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzrºzºrº?zº~~'+ sile fastiss Figure 20 Patent Application Publication Dec. 26, 2013 Sheet 11 of 27 US 2013/0345273 A1 Figure 21 Figure 22 Patent Application Publication Dec. 26, 2013 Sheet 12 of 27 US 2013/0345273 A1 s 8s 3 SS s S& w 3. ww.rry g '' ---------------------Terri-rrrrrrrrrrrrrrrrrr. s s ---š.---a-8 is i. 3. SSSSSSSsssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Figure 24 Patent Application Publication Dec. 26, 2013 Sheet 13 of 27 US 2013/0345273 A1 ...A Jull a lull. | la Jall ly ... I lal ill | la - ly ls AM. AJ A it ul. A. in -- I A. -- s re-or- "", 9, 0.18 : 0.16 Š s. E O1a. O. 12 S $ 2 S. 0.1 S. 5 ; 0.08 & : 0.06 $ 0.04 o, O.O2 S O & - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - ------------------------------------------------------------------ Š - - - - - - - - - - - - - - - - - - - - - O 0.2 O4. O6 8.8 1 1.2 note fraction Figure 25 Patent Application Publication Dec. 26, 2013 Sheet 14 of 27 US 2013/0345273 A1 × aggress Figure 27 Patent Application Publication Dec. 26, 2013 Sheet 15 of 27 US 2013/0345273 A1 S is: Kist. E: i:S s Es: § till F.22 E. S. Rotor i, mr. Figure 29 Patent Application Publication Dec. 26, 2013 Sheet 16 of 27 US 2013/0345273 A1 . 4. -- PBS on 154 mg/kg 2 x 308 mg/kg reo 616 mg/kg 8. 924 figkg - 1230 mg/kg . 8. losing day , reer 4 S 8 2 4 8 22 s s Days. Figure 30 tie in Figure 31 Patent Application Publication Dec. 26, 2013 Sheet 17 of 27 US 2013/0345273 A1 S - - w - °, - w, - N R -- --- --- ------ - : E. s s Time (nir Figure 32 8-O- r F3) \ \ 530 - \ S.E -.C - | E: X 8 'S - \ s 39. \ / J - --- Y- --- --- 230– --- - O : 33 EO SO Tisiae (s Figure 33 Patent Application Publication Dec. 26, 2013 Sheet 18 of 27 US 2013/0345273 A1 k -- 2 l tire it is) Figure 34 Patent Application Publication Dec. 26, 2013 Sheet 19 of 27 US 2013/0345273 A1 i 'f S tS. E:'s & s s k to: SSS sists.es www. systsis wW.wiss ps ww. UT Triton o' 25 5 Motor 2, (miki) Figure 35 Patent Application Publication Dec. 26, 2013 Sheet 20 of 27 US 2013/0345273 A1 20 15 1 O 5 O 5 10 15 20 25 30 35 Time (minutes) O 5 1O 15 2O 25 30 35 Time (minutes) Figure 36 Patent Application Publication Dec. 26, 2013 Sheet 21 of 27 US 2013/0345273 A1 18 A Recovery of Single Twitch Height 16 1. I 12 1. - Pacebo g 8 s3Org/kg r as a 60 mg/kg --90 g/kg A.2 --- I ... -------- 1. O 3) a) S. 25. Recovery of Train of Four (TOF) B 2 |-- 15 Pace) -H30 mg/kg : 1 are 60 mg/kg --90 mg/kg O FO 8O GO Figure 37 Patent Application Publication Dec. 26, 2013 Sheet 22 of 27 US 2013/0345273 A1 S Placebo 8 -:------------------------------------------------------------------------------------------- 30 mg/kg 7 ---------------------:------------------------------------------------------------------------------------------------------ 860 mg/kg 6 ----------------------:------------------------------------------------------------------------------------------------------ 90 mg/kg O &mm. Figure 38 Before Motor 30 min after Motorl pCO2 pCO2 pO2 (mmHg) (mm Hg) (mmHg) (mm Hg) Placebo 7.42|0.02 42 6 176L2O (.42|0.04 41 || 3 171 || 2/ Motoril 30 mg/kg 742 - 0.03 42 - 3 185 - 40 742 - 0.03 39 - 2 179 || 42 Motor1 60 mg/kg 7.43 - O.O3 44 – 6 147 | 6 7.43 - 0.02 40 - 6 176 - 76 Motor 1 90 mg/kg- 7.42 + O.O1 43 - 2 176 + 29 7.41 + O.01 41 + 2 187 + 2 Figure 39 Patent Application Publication Dec. 26, 2013 Sheet 23 of 27 US 2013/0345273 A1 450 4) saxxxYN xxxxY saxSas xxx.Yss 35) Sax Yxxx wax Sass s &X. SX ass Wak YasYra 250 - 200 - EL 5 1) 150 - ww. S 1) 5 Placebo -H.30 mg/kg as a 60 mg/kg --90 mgkg xxHR Placebo YHR 30 mg/kg xxxHR 80 mg/kg axHR 90 mg/kg Figure 40 Patent Application Publication Dec. 26, 2013 Sheet 25 of 27 US 2013/0345273 A1 Recovery of twitchheight Figure 42 Patent Application Publication Dec. 26, 2013 Sheet 26 of 27 US 2013/0345273 A1 320 (S Heart rate (bpm) - Y. - 1 > 280 N - 1 9 Y NN - 11 c) Y CD 240 Arterial blood pressure (MAP) n <C 150 I I 11 1 s 1. e N - 1 - 1 1OO NY- 1 1 N- 1 - 1 Respiratory rate (bpm) Wakefulness Ketamine Anesthesia Motor 2 reversal Figure 43 Figure 44 US 2013/0345273 A1 Dec. 26, 2013 REVERSAL OF DRUG-NDUCED lates an inactivates steroidal NMBAs has been used in some NEUROMUSCULAR BLOCK USING NOVEL countries for reversal of rocuronium and vecuronium induced MOLECULAR CONTAINERS neuromuscular block, use of this agent in the U.S. was cur tailed by the Food and Drug Administration because of severe CROSS-REFERENCE TO RELATED allergic reactions and coagulation abnormalities induced by APPLICATIONS it. In addition, benzylisoquinoline-type NMBA compounds, 0001. This application claims priority to U.S. provisional which represent about 30% of the current market volume for NMBA, cannot be reversed by sugammadex. Moreover, it is patent application nos. 61/392.722, filed Oct. 13, 2010, and not possible with any available drug to reverse benzyliso 61/392,729, filed Oct. 13, 2010, the disclosures of which are quinoline-type NMBA (e.g., atracurium or cisatracurium). incorporated herein by reference. Additionally, although the actions of many drugs used in STATEMENT REGARDING FEDERALLY anesthesiology are reversed pharmacologically when no SPONSORED RESEARCH longer desired (e.g., NMBAS, opioids, benzodiazepines), this is not the case for general anesthetic induced loss of con 0002 This invention was made with government support sciousness. Thus, there is an ongoing and unmet need for under grant no. CHE0615049 awarded by the National Sci improvements in reversal of drug-induced neuromuscular ence Foundation. The government has certain rights in the block. invention. BRIEF SUMMARY OF THE INVENTION FIELD OF THE INVENTION 0006. The present invention provides a method for rever 0003. The present invention relates generally to reversal of sal of the effects of agents used for muscular immobilization the effects of agents used to immobilize and anesthetize and/or loss of consciousness and/or loss of pain perception. patients during medical interventions. More particularly, the The method comprises administering a composition compris invention relates to reversal of both, drug-induced neuromus ing a compound of the invention to an individual in need of cular block, and anesthesia by administering novel acyclic reversal of the effects of NMBAs and/oranesthesia such that CBn-type container compounds to individuals in need of the effects of the agent(s) are partially or fully reduced. The Such compositions used in the present invention contain compound (s) having the following structure: BACKGROUND OF THE INVENTION 0004 General anesthesia is a drug-induced, reversible condition comprising five behavioral states: hypnosis (loss of consciousness), amnesia, analgesia, and immobility (no movement in response to pain stimuli), and hemodynamic , , stability with control of the stress response.
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