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(12) Patent Application Publication (10) Pub. No.: US 2014/0221277 A1 Menzaghi Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0221277 A1 Menzaghi Et Al US 20140221277A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0221277 A1 Menzaghi et al. (43) Pub. Date: Aug. 7, 2014 (54) METHOD FOR ELEVATING PROLACTIN IN tion No. 12/300,595, filed on Apr. 22, 2009, now Pat. MAMMALS No. 8,217,000, filed as application No. PCT/US2007/ 012285 on May 22, 2007. (71)71) ApplicantsApplicants: MStFrederi Le.g.,M hi, RVe, S. SterNY E.(US) ); (60) Provisional application No. 60/808,677, filed on May (US); Derek T. Chalmers, Riverside, CT 26, 2006. (US) Publication Classification (72) Inventors: Frederique Menzaghi, Rye, NY (US); (51) Int. Cl. Michael E. Lewis, West Chester, PA A638/07 (2006.01) (US); Derek T. Chalmers, Riverside, CT A6II 45/06 (2006.01) (US) (52) U.S. Cl. CPC ................. A61 K38/07 (2013.01); A61K 45/06 (73) Assignee: CARATHERAPEUTICS, INC., (2013.01) SHELTON, CT (US) USPC ............................. 514/4.7: 514/7.3; 514/11.5 (21) Appl. No.: 14/087,142 (57) ABSTRACT Methods for elevating and stabilizing prolactin levels in a (22) Filed: Nov. 22, 2013 mammal including methods of treating disorders and condi tions associated with reduced serum levels of prolactin are O O provided. Also provided are methods of using certain Syn Related U.S. Application Data thetic tetrapeptide amides which are peripherally selective (63) Continuation of application No. 13/543,128, filed on kappa opioid receptor agonists to elevate or stabilize serum Jul. 6, 2012, now abandoned, Continuation of applica prolactin levels. Patent Application Publication Aug. 7, 2014 Sheet 1 of 7 US 2014/0221277 A1 Figure 1: Arithmetic Mean Changes from Baseline (Pre dose) in Serum Prolactin Concentrations Following a 1 hour IV Infusion in Male Subjects (Part A) O 2 A. 6, B 10 2 Time post-dose (h) Placebo (1-hour infusion) o 0.015 mg/kg CR665 (1-hour infusion) 0.03 mg/kg CR665 (1-hour infusion) (0.06 mg/kg. CR665 (1-hour infusion) 0.12 mg/kg CR665 (3-hour infusion) o 0.24 mg/kg. CR665 (1-hour infusion) to.36 mg/kg CR665 (1-hour infusion) 0.42 mg/kg CR665 (1-hour infusion) * 0.48 mg/kg CR665 (1-hour infusion) Figure 2: Arithmetic Mean Changes from Baseline (Pre dose) in Serum Prolactin Concentrations Following a 1 hour IV Infusion in Female Subjects (Part A). O 2 A 6 8 - to 2 Time post-dose (h) Placebo (1-hour infusion) O 0.24 mg/kg CR665 (1-hour infusion) Patent Application Publication Aug. 7, 2014 Sheet 2 of 7 US 2014/0221277 A1 Figure 3: Arithmetic Mean Changes from Baseline (Pre dose) in Serum Prolactin Concentrations Following a 5 minute IV Infusion in Male Subjects (Part B) Time post-dose (h) Placebo (5-minute infusion)(Male o 0.03 mg/kg CR665 (5-minute infusion),Male 0.06 mg/kg CR665 (5-minute infusion)(Malel do.09 mg/kg CR665 (5-minute infusion) Male) 0.06 mg/kg CR665 (5-minute infusion) (Femalel Figure 4: Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV Infusion in Male Subjects (Part A) (Linear Scale) o 2 4. 6 8 10 2 Time post-dose (h) 0.015 mg/kg CFR665 (i-hour infusion) O 0.03 mg/kg CR665 (1-hour infusion) is 0.06 mg/kg CR665 1-hour infusion) 0.12 mg/kg CR665 (1-hour infusion) 0.24 mg/kg CR565 (i-hour infusion) o 0.36 mg/kg CR665 (1-hour infusion) * 0.42 mg/kg CR665 (1-hour infusion) * 0.48 mg/kg CR665 (t-hour intusion) - - - Lower limit of quantification (1.00 mg/mL) Patent Application Publication Aug. 7, 2014 Sheet 3 of 7 US 2014/0221277 A1 Figure 5: Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV . Infusion in Male Subjects (Part A) (Semi logarithmic Scale) 110OO OOO Time post-dose (h) 0.015 mg/kg CR665 (1-hour infusion) O 0.03 mg/kg CR665 (1-hour infusion) 0.06 mg/kg CR665 (1-hour infusion) 0.12 mg/kg CR665 (1-hour infusion) 0.24 mg/kg CR665 (1-hour infusion) 8 O.36 mg/kg CR665 (1-hour infusion) 0.42 mg/kg CR665 (1-hour infusion) * 0.48 mg/kg CR665 (I-hour infusion) - - - Lower limit of quantification (1.00 ng/ml) Figure 6: Geometric Mean AUCo. for CR665 Versus Dose Level. Following a 1 hour IV Infusion in Male Subjects (Part A) logarithmic Scale OOOO OOO 0.05 0.03 0.06 0,12 0.24 0.369.48 Dose of CR665 (mg/kg) O4 Patent Application Publication Aug. 7, 2014 Sheet 4 of 7 US 2014/0221277 A1 Figure 7: Geometric Meari Plasma Concentrations of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg CR665 in Female Subjects (Part A) (Linear Scale) s S. 8 S U cus S 8 scretire"r-s-s-p-...-s:-...--si-...-------------------------...--- - -w- - - - - - 4. 6 8 O 12 Time post-dose (h) 0.24 mg/kg. Ca565 i-hour infusion) --- Lower limit of quantification (1.00 nglml) Figure 8: Geometric Mean Plasma Concentrations of CR665 Following a hour IV Infusion of 0.24 mg/kg CR665 in Female Subjects (Part A) (Semi logarithmic Scale) 1OOO iScy loo - , 5t 100 5 10 i 1. sI l N l 1 tic-casses, lesses essess- -----als - r Time post-dose (h) 0.24 mg/kg CR665 (1-hour infusion) - - - Lower limit of quantification (1.00 ng/mL) Patent Application Publication Aug. 7, 2014 Sheet 5 of 7 US 2014/0221277 A1 Figure 9: Arithmetic Mean (SD) Plasma Concentrations of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg CR665 in Male and Female Subjects (Part A) (Linear Scale) so . Nm sh9 SC d d s s S V S 10 Time post-dose (h 0.24 mg/kg gR665 (1-hour infusion)(Male o 0.24 mg/kg CR665 (1-hour infusion) Female) Figure 10: Geometric Mean Plasma Concentrations of CR665 Following a 5-minute IV Infusion in Male and Female Subjects (Part B) (Linear Scale) o 2 4. 6 8 10 2 Time post-dose (h) 0.03 mg/kg CR665 (5-minute infusion)(Male) o 0.06 mg/kg CR665 (5-minute infusion),Male 0.09 mg/kg CR665 (5-minute infusion) Mae E.O.05 mg/kg CR665 (5-minute infusion)(Female - - - Lower limit of quantification (1.00 mg/ml) Patent Application Publication Aug. 7, 2014 Sheet 6 of 7 US 2014/0221277 A1 Figure 11: Geometric Mean Plasma Concentrations of CR665 Following a 5-minute IV infusion in Male and Female Subjects (Part B) (Semi logarithmic Scale) - - t r -r 6 8 O 12 Time post-dose (h) 0.03 mg/kg CR665 (5-minute infusion)Male C 0.06 mg/kg CR665 (5-minute infusion)(Male) 0.09 mg/kg. CR665 (5-minute infusion) Male) 0.06 mg/kg CR665 (5-minute infusion)(Female) - - - lower lirit of quantification (1.00 ng/ml) Figure 12: Geometric Mean AUCo. for CR665 Versus Dose Level Following a 5 minute IV Infusion in Male Subjects (Part B) Logarithmic scale 1000 0.06 Dose of CR665 (mg/kg) Patent Application Publication Aug. 7, 2014 Sheet 7 of 7 US 2014/0221277 A1 Figure 13: Relationship Between AUCo-2, of Changes from Baseline in Serum Prolactin and AUCo. of CR665 over the 0.015 to 0.36 mg/kg Dose Range in Male Subjects (Part A) 200 a 0 250 so 75o 1OOO AUC(O-int) (ng.html) OF CR665 Correlation coefficient=0.667; P-value=0.0004 Figure 14: Relationship Between Cmax of Changes from Baseline in Serum Prolactin and Cmax of CR665 over the 0.015 to 0.36 mg/kg Dose Range in Male Subjects (Part A) 80 60 40 O --- O 20 e e d 0. | --- --- O 100. 2O) 300 400 500 600 FOO 800 900 Cmax (ng/mL) OF CR665 Correlation coefficient=0.565; P-value=0.0040 US 2014/022 1277 A1 Aug. 7, 2014 METHOD FOR ELEVATING PROLACTN IN most current version of their guidance on breastfeeding, MAMMALS “Extensive research using improved epidemiologic methods and modern laboratory techniques documents diverse and CROSS-REFERENCE TO RELATED compelling advantages for infants, mothers, families, and APPLICATIONS Society from breastfeeding and use of human milk for infant feeding. These advantages include health, nutritional, immu 0001. This application claims priority to and incorporates nologic, developmental, psychologic, social, economic, and by reference herein U.S. Provisional Application Ser. No. environmental benefits.” Because of the well documented 60/808,677 filed May 26, 2006 and entitled “METHOD FOR benefits of breastfeeding, insufficient lactation is now viewed ELEVATING PROLACTIN IN MAMMALS as an important medical problem. 0007. There are numerous risk factors for insufficient lac BACKGROUND OF THE INVENTION tation, including: 0002 1. Field of the Invention 0008 (i) restarting lactation after termination, e.g., to care 0003. The invention relates to the use of peripherally for a sick infant (Thompson N Relactation in a newborn selective kappa opioid receptor agonists to elevate serum intensive care setting.J. Hum. Lact. 12: 233-235, 1996) levels of prolactin for the benefit of a mammal in need of such 0009 (ii) physical abnormality of the breast (Neifert MR elevation. et al. Lactation failure due to insufficient glandular develop 0004 2. Background ment of the breast. Pediatrics 76:823-828, 1985) 0005 Prolactin is a 198 amino acid polypeptide synthe 0010 (iii) absence of breast enlargement during preg sized in pituitary lactotrophs, which constitute about 20 per nancy (Moon J et al. Breast engorgement: contributing vari cent of adenohypophysial cells (for review, see Harrison's ables and variables amenable to nursing intervention.
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