US 2013 0012431A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0012431 A1 Menzaghi et al. (43) Pub. Date: Jan. 10, 2013

(54) METHOD FOR ELEVATING PROLACTIN IN Publication Classification MAMMALS (51) Int. Cl. (75) Inventors: Frederique Menzaghi, Rye, NY (US); A638/07 (2006.01) Michael E. Lewis, West Chester, PA A6M 37/00 (2006.01) (US); Derek T. Chalmers, Riverside, CT A6IP 25/00 (2006.01) (US) A6IP 5/14 (2006.01) A6IP 5/00 (2006.01) (73) Assignee: CARATHERAPEUTICS, INC., A6IP3/10 (2006.01) Shelton, CT (US) (52) U.S. Cl...... 514/4.7: 514/21.9; 514/7.3; 514/17.7; 604/20 (21) Appl. No.: 13/543,128 (22) Filed: Jul. 6, 2012 (57) ABSTRACT Related U.S. Application Data Methods for elevating and stabilizing prolactin levels in a (63) Continuation of application No. 12/300.595, filed on mammal including methods of treating disorders and condi tions associated with reduced serum levels of prolactin are Apr. 22, 2009, now Pat. No. 8,217,000, filed as appli- rovided. Also provided are methods of using certain SVn cation No. PCT/US2007/012285 on May 22, 2007. provided.thetic tetrapeptide provia amides which are peripherallyusing selectiveyn (60) Provisional application No. 60/808,677, filed on May kappa receptor agonists to elevate or stabilize serum 26, 2006. prolactin levels. Patent Application Publication Jan. 10, 2013 Sheet 1 of 7 US 2013/0012431 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 4 6 B 10 12 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 (i-hour infusion) 0.12 mg/kg CR665 (1-hour infusion) ( 0.24 mg/kg CR665 (I-hour infusion) * 0.36 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).

--a-rum------O 2 4 6 8 O 2 Time post-dose (h)

Placebo (1-hour infusion) o 0.24 mg/kg CR665.(1-hour infusion) Patent Application Publication Jan. 10, 2013 Sheet 2 of 7 US 2013/0012431 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) Mate 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)

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 12 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) DO.12 mg/kg CR665 (1-hour infusion) 0.24 mg/kg CRB65 (1-hour infusion) o 0.36 mg/kg CR665 (1-hour infusion) * 0.42 mg/kg CR665 (1-hour infusion) * 0.48 mg/kg CR665 (1-hour intusion) - - - Lower limit of quantification (t.00 mg/mL) Patent Application Publication Jan. 10, 2013 Sheet 3 of 7 US 2013/0012431 A1

Figure 5: Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV . Infusion in Male Subjects (Part A) (Semi logarithmic Scale)

1000

OO

O

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) O.24 mg/kg CR665 (1-hour infusion) o 0.36 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

g s 1000 c S 9. O 1 OO O ac

O - Ot O.05 0.03 Dose0.06 of CR665 (mg/kg)0.12 0.24 0.369.48 Patent Application Publication Jan. 10, 2013 Sheet 4 of 7 US 2013/0012431 A1

Figure 7: Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg CR665 in Female Subjects (Part A) (Linear Scale)

Time post-dose (h)

0.24 mg/kg. CRS65 (1-hour infusion) --- Lower limit of quantification (1.00 ng/ml)

Figure 8: Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg CR665 in Female Subjects (Part A) (Semi logarithmic Scale)

1000 :

1 OO

10

1. Time post-dose (h)

' 0.24 mg/kg CR665 (1-hour infusion) - - - Lower limit of quantification (1.00 ng/ml) Patent Application Publication Jan. 10, 2013 Sheet 5 of 7 US 2013/0012431 A1

Figure9: 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)

S c War. c 9 s 5 o s s S s

6 Time post-dose (h

0.24 mg/kg CR665 (1-hour infusion)(Malel 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 12 Time post-dose (h) 0.03 mg/kg CR665 (5-minute infusion)|Male) o does mg/kg CR665 (5-minute infusion)(Male 0.09 mg/kg CR665 (5-minute infusion) Male 0.05 mg/kg CR665 (5-minute infusion)(Female) - - - Lower limit of quantification (1.00 mg/mL) Patent Application Publication Jan. 10, 2013 Sheet 6 of 7 US 2013/0012431 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)

O 2 4. 6 s o 12 Time post-dose (h) 0.03 mg/kg. CR665 (5-minute infusion)Male O 0.06 mg/kg CR665 (5-minute infusion)(Malel 0.09 mg/kg. CR665 (5-minute infusion)|Male) 0.06 ing/kg CR665 5-minute infusion)EFemale) - - - Lower limit 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 OOO

ob6 Dose of CR665 (mg/kg) Patent Application Publication Jan. 10, 2013 Sheet 7 of 7 US 2013/0012431 A1

Figure 13: Relationship Between AUCo-12 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

50

1OO

50

O 250 500 750 COO AUC(O-int) (ng.h/mL) 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)

O 100. 2O) 300 aCO 500 600 700 800 900 Cmax (ng/ml) OF CR 665 Correlation coefficient=0.565; P-value=0.0040 US 2013/0012431 A1 Jan. 10, 2013

METHOD FOR ELEVATING PROLACTN IN and the use of human milk. Pediatrics 115: 496 506, 2005). MAMMALS According to the American Academy of Pediatrics, in this most current version of their guidance on breastfeeding, CROSS-REFERENCE TO RELATED “Extensive research using improved epidemiologic methods APPLICATIONS and modern laboratory techniques documents diverse and 0001. This application claims priority to and incorporates compelling advantages for infants, mothers, families, and by reference herein U.S. Provisional Application Ser. No. Society from breastfeeding and use of human milk for infant 60/808,677 filed May 26, 2006 and entitled “METHOD FOR feeding. These advantages include health, nutritional, immu ELEVATING PROLACTIN IN MAMMALS nologic, developmental, psychologic, social, economic, and environmental benefits.” Because of the well documented benefits of breastfeeding, insufficient lactation is now viewed BACKGROUND OF THE INVENTION as an important medical problem. 0005. There are numerous risk factors for insufficient lac Field of the Invention tation, including: 0002 The invention relates to the use of peripherally 0006 (i) restarting lactation after termination, e.g., to care selective kappa agonists to elevate serum for a sick infant (Thompson N Relactation in a newborn levels of prolactin for the benefit of a mammal in need of such intensive care setting.J. Hum. Lact. 12: 233-235, 1996) elevation. 0007 (ii) physical abnormality of the breast (Neifert MR et al. Lactation failure due to insufficient glandular develop BACKGROUND ment of the breast. Pediatrics 76:823-828, 1985) 0003 Prolactin is a 198 amino acid polypeptide synthe 0008 (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. J. Principles of Internal Medicine, 16th Ed., p. 2084; also Free Obstet. Gynecol. Neonatal Nurs. 18:309-315, 1989). man ME et al. Prolactin: Structure, function, and regulation 0009 (iv) history of breast surgery (Widdice L The effects of secretion. Physiol. Rev. 80: 1523 1631, 2000). Prolactin is of breast reduction and breast augmentation Surgery on lac also referred to in the art as Galactin, Lactogen, Lactoropin, tation: An annotated bibliography. J. Hum. Lact. 9:161-163, LMTH. LTH, Luteomammotrophic Hormone, Luteotrophic 1993). Hormone, Luteotropin, and Mammotrophin, although these 0010 (v) first time delivery of infant (Dewey K G et al. names are now obsolete. The best studied effects of prolactin Risk factors for suboptimal infant breastfeeding behavior, are on the mammary gland, and include growth and develop delayed onset of lactation, and excess neonatal weight loss. ment of the mammary gland (mammogenesis), synthesis of Pediatrics 112:607-619, 2003). milk (lactogenesis), and maintenance of milk secretion (ga 0011 (vi) premature delivery of infant (Ehrenkranz, RA et lactopoiesis). The endocrine control of lactation involves al. Metoclopramide effect on faltering milk production by multiple complex physiological mechanisms since mammo mothers of premature infants. Pediatrics; 78:614 20, 1986: genesis, lactogenesis, galactopoiesis, and galactokinesis are Feher S D K et al. Increasing breast milk production for all essential for proper lactation. Prolactin is the key hormone premature infants with a relaxation/imagery audiotape. Pedi of lactation and is believed to be the single most important atrics 83:57-60, 1989) galactopoietic hormone. Oxytocin, serotonin, opioid pep 0012 (vii) delivery of more than one infant (Leonard, L. tides, histamine, Substance P, and other physiological Sub Breastfeeding higher order multiples: Enhancing Support stances modulate prolactin release by means of an autocrine/ during the postpartum hospitalization period. J. Hum. Lact. paracrine mechanism at the level of the hypothalamus, 18:386-392, 2002). whereas estrogen and progesterone hormones can act at the 0013 (viii) adoption of infant (Cheales Siebenaler, N. hypothalamic and adenohypophysial levels. Human placental Induced lactation in an adoptive mother. J. Hum. Lact. 15:41 lactogen and growth factors play an essential role in Success 43, 1999). ful lactation during pregnancy, with oxytocin functioning as a 0014 (ix) retention of placental fragments (Neifert, M Ret key galactokinetic hormone. al. Failure of lactogenesis associated with placental retention. 0004 Normal adult serum prolactin levels are about 1025 Am. J. Obstet. Gynecol. 140:477-478, 1981) ng/ml in women and 1020 ng/ml in men. Prolactin is secreted 00.15 (x) use of hormonal birth control (Tankeyoon Met in an episodic manner with a distinct 24 hour pattern. Circu al. Effects of hormonal contraceptives on milk volume and lating prolactin levels are lowest at midday, and a modest infant growth. WHO Special Programme of Research, Devel increase occurs during the afternoon. Prolactin levels opment and Research Training in Human Reproduction Task increase shortly after onset of sleep, peaking in the early force on oral contraceptives. Contraception 30:505-22, 1984) morning. Serum prolactin levels rise Substantially during 0016 (xi) use of certain OTC decongestants (Aljazaf Ket pregnancy (150 200 ng/ml) and decline rapidly within two al. Pseudoephedrine: effects on milk production in women weeks of parturition. Breastfeeding will normally cause pro and estimation of infant exposure via breastmilk. Br. J. Clin. lactin levels to remain elevated, due to Suckling induced acti Pharmacol. 56:18-24, 2003) vation of neural reflexes that that induce prolactin release. 0017 (xii) cigarette smoking (Andersen A N et al: Sup However, inadequate activation of prolactin release will inter pressed prolactin but normal neurophysin levels in cigarette fere with breastfeeding, with a variety of potentially delete Smoking breast feeding women. Clin. Endocrinol. (Oxf) rious psychological and physiological consequences, e.g., a 17:363-8, 1982. failure of mother infant bonding and a failure to transmit 0018 (xiii) prepregnant overweight and obesity (Hilson J maternal protective antibodies to the infant (American Acad A et al. High prepregnant body mass index is associated with emy of Pediatrics, Section on Breastfeeding. Breastfeeding poor lactation outcomes among white, rural women indepen US 2013/0012431 A1 Jan. 10, 2013 dent of psychosocial and demographic correlates. J. Hum. 81, 2000). Hypoprolactinemia of unknown origin has also Lact. 20:18-29, 2004; Rasmussen K M et al. Prepregnant been associated with poor sperm motility in adult men overweight and obesity diminish the prolactin response to (Gonzales G F et al. Hypoprolactinemia as related to seminal suckling in the first week postpartum. Pediatrics 113:465-71, quality and serum testosterone. Arch. Androl. 23:259-65. 2004). 1989), a finding that is supported by the observation that 0019 (xiv) Cesarean delivery (Chapman DJ et al. Identi pharmacological Suppression of prolactin release for several fication of risk factors for delayed onset of lactation. J. Am. weeks in young men decreased Subsequent hCG stimulated Diet. Assoc. 99:450-454, 1999) testosterone secretion (Oseko F et al. Effects of chronic bro 0020 (XV) insulin dependent maternal diabetes (Neu mocriptine induced hypoprolactinemia on plasma testoster bauer, SH et al. Delayed lactogenesis in women with insulin one responses to human chorionic gonadotropin stimulation dependent diabetes mellitus. Am. J. Clin. Nutr. 58:54-60, in normal men. Fertil. Steril. 55:355-357, 1991). Hypopro 1993) lactinemia could also contribute to age related changes in 0021 (xvi) medications to treat labor pain (Riordan Jet al. physiological functions. Serum prolactin concentrations tend The effect of labor pain relief medication on neonatal suck to fall with age, e.g. in older men and estrogen unreplaced ling and breastfeeding duration.J. Hum. Lact. 16:7-12, 2000; postmenopausal women (Maddox P et al. Bioactive and Ransjo Arvidson AB et al. Maternal analgesia during labor immunoactive prolactin levels after TRH stimulation in the disturbs newborn behavior: effects on breastfeeding, tem sera of normal women. Horm. Metab. Res. 24:181-184, 1992; perature, and crying. Birth 28:5-12; 2001). Maddox Petal. Basal prolactin and total lactogenic hormone 0022 (xvii) stress (Chen DC et al. Stress during labor and levels by microbioassay and immunoassay in normal human delivery and early lactation performance. Am. J. Clin. Nutr. sera. Acta Endocrinol. (Copenh.) 125:621-627, 1991). 68:335-344, 1998; Dewey K. Maternal and fetal stress are Remarkably, a comparable quantitative reduction in prolactin associated with impaired lactogenesis in humans. J. Nutr. secretion occurs in critically ill individuals (Van den Berghe 131:3012 S-3015S, 2001) Get al. Thyrotropin and prolactin release in prolonged critical 0023. Signs of insufficient lactation in a human infant illness—dynamics of spontaneous secretion and effects of include: (1) insufficient weight gain in an infant who is receiv growth hormone secretagogues. Clin. Endocrinol. (Oxf) ing food only by breast feeding, even if the infant appears 47:599–612, 1998) as well as in patients with poorly con content; (2) infant latching on poorly; (3) infant Sucking trolled type I diabetes mellitus (Iranmanesh A et al. Attenu inconsistently; (4) inconsistency of let down reflex, and (5) ated pulsatile release of prolactin in men with insulin depen evidence of hunger, indicated by crying soon after feedings. dent diabetes mellitus. J. Clin. Endocrinol. Metab. 71:73-78, 0024 Lactation failure in humans is a common clinical 1990). Hypoprolactinemia is also reported to be a risk factor event with serious emotional sequelae. It has been considered for prolonged lymphopenia and apoptosis associated deple to be a significant problem in 5 to 10% of all lactations. In tion of lymphoid organs in nosocomial sepsis related death in many instances this leads to premature initiation of Supple critically ill children (Felmet K Aetal. Prolonged lymphope ments or total weaning. This is considered to be an inferior nia, lymphoid depletion, and hypoprolactinemia in children child rearing practice and may be harmful to certain infants with nosocomial sepsis and multiple organ failure. J. Immu with an increased risk of gastritis and other disorders. Many mol. 174:3765-72, 2005). The findings reviewed above indi affected women are severely emotionally distressed by their cate that prolactin deficiency may contribute to impaired tes perceived inadequacy, thus affecting the parent child bond. tosterone dependent functioning and age related changes as Failure to thrive in infants is not uncommon if the mother well as vulnerability to illness. refuses to Supplement. 0027. In addition to the apparent roles of prolactin dis 0025. There has therefore been a long need for a medica cussed above, there is evidence that prolactin is important for ment that can promote human lactation, e.g., when there is maintenance of rapid eye movement sleep (REM sleep), insufficient lactation after the birth of the child. For animal which is essential for normal brain function. After observing breeders, the inability of their livestock, e.g., mares, to pro that pregnancy associated sleep enhancement is correlated duce and secrete milk after giving birth can be a significant with the daily Surges of prolactin, investigators found that problem. Should the breeding animals not lactate properly, administration of prolactin to female rats significantly the offspring must then be bottle fed, which is time consum increased REM sleep (Zhang SQetal. Effects of prolactin on ing, labor intensive, and costly; thus, there is a need for a sleep in cyclic rats. Psychiatry Clin. Neurosci. 53:101-3, medicament to safely and effectively promote breeding ani 1999). Consistent with these findings, induction of experi mal lactation. For commercial milk producing animals like mental hypoprolactinemia in male rats was found to decrease cows and goats, there is an economic need to safely and REM sleep (Obál Jr Fetal. Antiserum to prolactin decreases effectively increase their milk production above a normal rapid eye movement sleep (REM sleep) in the male rat. level. Physiol. Behav. 52:1063-1068, 1992). These findings indi 0026. A number of causes of reductions in prolactin levels cate that subjects experiencing insufficient REM sleep could that are associated with insufficient lactation were noted benefit from elevations in prolactin. above. Certain of these causes are also associated with 0028 Based on the findings reviewed above, there is a reduced prolactin levels in non lacting Subjects, e.g., cigarette need for a medicament that can safely and effectively elevate Smoking (FuXe K et al. Neuroendocrine actions of nicotine prolactin level in a variety of subjects with functional hypo and of exposure to cigarette Smoke: medical implications. prolactinemia, particularly including females experiencing Psychoneuroendocrinology 14: 1.9-41, 1989). Other causes insufficient lactation, but also males experiencing insufficient oflow prolactin levels (hypoprolactinemia) include the use of testosterone related functions, and both females and males various therapeutic agents, such as L deprenyl for the treat who are suffering from the effects of severe illness, including ment of migraine (Fanciullacci Met al. Dopamine involve type I diabetes, or who are suffering the effects of insufficient ment in the migraine attack. Funct Neurol. 15 Suppl 3:17.1- REM sleep, e.g., due to insomnia. US 2013/0012431 A1 Jan. 10, 2013

0029. The citation of any reference herein should not be 0039. The invention features methods for treatment and/or construed as an admission that such reference is available as prevention of lactational failure, which can be diagnosed by “Prior Art” to the instant application. various criteria, including: 0040 a) baby is dissatisfied and irritable after breastfeed SUMMARY OF THE INVENTION ing: 0030. In general, the invention provides methods for treat 0041 b) poor infant weight gain in relation to age/length; ing a Subject Suffering from insufficient or inadequate serum 0042 c) lack of breast engorgement/leaking if feeding is prolactin, such as functional hypoprolactinemia and the dis missed; orders disclosed herein and known in the art associated with 0043 d) baby is satisfied by supplemental feeding follow insufficient or inadequate serum prolactin, as well as methods ing breast feeding: for treating a subject in need of elevated or stabilized levels of 0044 e) milk secretion of less than 500 ml/day. prolactin. In one embodiment, a method employs a peripher 0045. These methods involve systemic administration of ally selective kappa opioid receptor agonist compound, compositions that contain one or more compounds that exert optionally in a pharmaceutically acceptable vehicle for local, prolactin elevating, increasing or stabilizing activity via regional or systemic administration, said compound possess kappa receptors, but that do not exhibit a severe or ing prolactin elevating, increasing or stabilizing activity, significant side effect, such as a CNS or diuretic effect at optionally administered without causing a severe or a clini effective dosages. cally significant side effect, such as CNS effects or diuretic 0046. In various embodiments, methods use compositions effects. containing peripherally selective kappa opioid receptor ago 0031. In another embodiment, the invention features a nists that do not, upon systemic administration, evoke severe method of treating functional hypoprolactinemia in a subject or clinically significant diuresis or CNS effects, as defined with a formulation of a peripherally selective kappa opioid herein, particularly at the prolactin elevating dosage. Com receptor agonist, optionally Suitable for incorporation into a positions that contain a peripherally selective kappa opioid controlled drug delivery device. In a particular aspect, a con receptor agonist together with other prolactin elevating com trolled drug delivery device is applied to the skin of a subject. pounds are also provided. In certain embodiments, a controlled drug delivery device is 0047. Typically, compounds intended for use in the com applied to the skin of a subject and optionally further utilizes positions and methods herein possess prolactin elevating, iontophoresis to increase transdermal drug delivery. increasing or stabilizing activity and reduced or tolerable 0032. In certain embodiments, a formulation is a solid or CNS effects, as defined herein, because, without being bound liquid or gel. by any theory, they do not substantially cross the blood brain barrier. A relative or complete absence of substantial crossing 0033. In certain embodiments, a formulation includes a of the blood brain barrier lessens the occurrence of CNS liquid carrier. systemic effects. Kappa opioid receptors agonists that readily 0034. In certain embodiments, a therapeutically effective cross the blood brain barrier could be effective as prolactin dose of a peripherally selective kappa opioid receptoragonist elevating agents, but permeability through the blood brain is selected to produce elevated, increased or stabilized serum barrier can result in severe or intolerable side effects, such as prolactin levels without producing severe or significant diure dysphoria and hallucinations. sis and/or a CNS side effect. 0048 Peripherally selective kappa opioid receptor ago 0035. In certain embodiments, a peripherally selective nists include kappa opioid receptor agonists that do not Sub kappa opioid, receptor agonist produces pharmacologically stantially cross the blood brain barrier as assessed by, assays insignificant or physiologically tolerable levels of said ago described herein or known in the art. The peripherally selec nist in the plasma of an infant consuming the breast milk from tive kappa opioid receptoragonists for use in the methods and or produced by a Subject treated with said agonist. compositions provided herein also include any compound 0036. In certain embodiments, the peripherally selective that by virtue of its interaction, either directly or indirectly, kappa opioid receptor agonist is selected to avoid producing with peripheral kappa opioid receptor receptors ameliorates a severe or a clinically significant side effect in an infant failure of lactation, or elevates, increases or stabilizes levels consuming the breast milk from or produced by a subject of serum prolactin, without exhibiting medically severe or treated with said agonist. significant CNS effects, such as dysphoria and hallucinations, 0037. In certain aspects, the invention features methods of at effective doses. elevating, increasing or stabilizing plasma levels of prolactin 0049. As used herein, the term “peripherally selective.” to a subject in need of elevated, increased or stabilized pro when used in reference to a "kappa opioid receptor agonist' lactin. In one embodiment, a method includes administration refers to a chemical compound having a reduced ability to of a therapeutically effective dose of a peripherally selective cross (traverse) the blood-brain barrier, or that exhibits little kappa opioid receptor agonist to the Subject. In another or substantially no crossing of the blood-brain barrier when embodiment, a method includes administration ofatherapeu not administered to the CNS (brain and spinal cord). As a tically effective dose of a peripherally selective kappa opioid consequence of a reduced ability or inability to cross receptor agonist to the Subject, in combination with a prolac (traverse) the blood-brain barrier, a peripherally selective tin elevating-increasing or -stabilizing dose of a second com kappa opioid receptoragonist typically exhibits fewer or less pound selected from a D2 dopamine receptor antagonist, mu severe (minor or tolerable) side effects in the CNS, such as opioid receptor agonist, or prolactin. dysphoria, hallucinations, or sedation. 0038. In various embodiments a subject is: a person, e.g., 0050. Various measures of the ability of a compound to a human patient, in need of elevated prolactin levels. E.g., the cross (traverse) the blood-brain barrier are known in the art Subject can be: a person in need of stimulation of lactation or and can be used to measure the amount or rate (kinetics) of stabilization of lactation, e.g., a mother. blood-brain barrier crossing (traversal). One non-limiting US 2013/0012431 A1 Jan. 10, 2013 example is to compare the ability of a compound to elicit likely to substantially cross the blood-brain barrier or produce peripheral effects versus the ability of the compound to elicit Severe CNS side effects. BPI values lower than 5 indicate central effects following treatment with a particular com significant or Substantial brain penetration, and, therefore, a pound (e.g., kappa opioid receptor agonist). Peripheral compound that is likely to substantially cross the blood-brain effects can be measured using the mouse writhing test (WT) barrier, which can result in severe side effects (e.g., dyspho and central effects, due to action of kappa opioid receptors ria, hallucinations and sedation) when used clinically. located in the brain and spinal cord, can be measured using the Accordingly, compounds useful in the invention have BPI mouse tail-flick test (TF). values typically greater than 5, or more, for example, BPI 0051. In brief, the mouse writhing test (WT) test (de values of 10, 15, 20, 25, 30, 40, 45, 50, 60, 75, 100, 125, 150, scribed in Bentley et al., Br. J. Phamac., 73:325 (1981)) 175, 200, 225, 250, 275,300, 400, 500, 600, 700, 800, 900, employs conscious male ICR mice (available from Harlan) 1000, 1500, 2000, or more. weighing about 20 to 30 grams. Mice are fasted for about 12 0056 Particular non-limiting compounds of the invention to 16 hours prior to the test and writhing is induced by intra are disclosed in U.S. Pat. No. 5,965,701, are sequences of peritoneal administration of dilute acetic acid (10 ml of 0.6% four D-isomer amino acid residues having a C-terminus aqueous acetic acid/kg body weight). Writhing is scored dur which is a mono ordi-Substituted amide. Representative com ing the 15 minutes following acetic acid administration. pounds, which have an affinity for the kappa opioid receptor Compounds (e.g., kappa opioid receptor agonists) are typi at least 1,000 times their affinity for the mu opioid receptor cally tested at 3 to 4 increasing doses, given by intravenous and an EDso of not greater than about 0.5 mg/kg, include route, and at a unique pretreatment time (e.g., -5 minutes H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, H-D-Phe-D-Phe-D- before acetic acidinjection). This step is used to determine the Nle-D-Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg potency (WT-EDs) as well as a submaximal effective dose NH-4-picolyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr, H-D- (about 80-90% antinociception). In a second step, a submaxi Phe-D-Phe-D-Nle-D-Arg-thiomorpholinyl, H-D-Phe-D- mal effective dose for each specific compound is adminis Phe-D-Nle-D-Arg-NEt, H-D-Phe-D-Phe-D-Nle-D-Arg tered at various pretreatment times (e.g., -5 minutes, -60 NHMe, H-D-Phe-D-Phe-D-Leu-D-Orn-morpholinyl, H-D- minutes, -120 minutes and -180 minutes) prior to the admin Phe-D-Phe-D-Nle-D-Arg-NHhEt, H-D-Phe-D-Phe-D-Nle istration of the acetic acid in order to determine the duration D-Arg-NH-cyclopropyl, H-D-Ala(2Thi)-D-4Cpa-D-Leu-D- of action. Throughout the test, a control group of mice are Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg used which are administered only the vehicle without the piperidinyl, H-D-Phe-D-Phe-D-Leu-D-Orn-NHEt, H-D- compound. The number of writhes are counted over a Phe-D-Phe-D-Leu-D-Lys-morpholinyl, and H-D-Phe-D- 15-minute period, starting from the time of acetic acid injec Phe-D-Nle-D-Arg-piperazinyl. tion, and bioactivity, i.e. antinociception, is expressed as a 0057 Peripherally selective kappa opioid receptor ago percentage, and is calculated as follows: nists of the invention can be , such as those contain 100x(writhes in control group-writhes in treated ing D-amino acids instead of L-amino acids, and which group), writhes in control group optionally can have little to no sequence homology with 0052 Because each submaximal dose likely varies so as known mammalian endogenous opioid peptides, e.g., the not to be directly comparable, results are normalized math , endorphins, and . A peripherally ematically, to provide comparable values. Values higher than selective kappa opioid receptor agonist can comprise a tet 100% indicate greater antinociception than at the beginning rapeptide D-amino acid sequence. Peptides that are encom of the study. Compounds effective at reducing writhing by at passed by the criteria of the invention are any of the known least about 25% at a time of 1 hour are considered to have long mammalian endogenous opioid peptides, e.g., as identified in duration of in vivo action. Akil et al (1984), such as A(1-17), including natu 0053. In addition to using the writhing test to determine rally occurring, processed forms of these peptides, e.g., duration of antinociceptive activity, it is also used to measure (1-13) and dynorphin A (1-8). the in vivo biopotency (short term) of the . This value 0058. The invention, among other things, relates to the use is represented as WT-EDso in milligrams per kg of body of peripherally selective kappa opioid receptoragonists alone weight, a measure of the dosage necessary to reduce the or in conjunction with lactational enhancers, elevators, or number of writhes in the mouse being tested by 50% (as stabilizers for the treatment of lactation failure, or inadequate compared to a control mouse) over a period of 15 minutes. or insufficient lactation in a Subject. 0054 The tail-flick test (TF) is an assay of acute somatic 0059. The invention also relates to the use of peripherally pain, designed to evaluate potency and duration of action of selective kappa opioid agonists, alone or in conjunction with centrally acting (described, for example, in Van lactational enhancers elevators, or stabilizers for the manu derah, et al., J. Pharm. Exper. Therapeutics, 262:190 (1992)). facture of a medicament in treatment of lactation failure or Nociception induced by tail-dip into hot water (52°C.) results in a rapid tail withdrawal, or a “tail-flick. Centrally acting inadequate or insufficient lactation in a subject. compounds are expected to increase, in a dose-related man 0060 Lactational enhancers, elevators, or stabilizers can ner, the latency for tail withdrawal. be chosen from among D2 dopamine receptor antagonists, 0055 “Brain Penetration Index” (BPI) can be used to pro mu opioid receptor agonists, prolactin, or oxytocin, for vide a numerical representation of whethera compound func example. tions centrally or peripherally. BPI is defined as: BPI-TF 0061. The invention further relates to a method for the EDs/WT-EDs; where the EDs values are the doses that treatment of lactation failure, or inadequate or insufficient produce half maximal effect in the mouse writhing test (WT lactation in a Subject, characterized in that a peripherally EDs) and the mouse tail-flick test (TF-EDs), respectively, selective kappa opioid receptor agonist, alone or in conjunc when administered intravenously. A high BPI value reflects tion with a lactational enhancer, elevator, or stabilizer is low brain penetration and, therefore, a compound that is less administered to a female Subject. Non-limiting administra US 2013/0012431 A1 Jan. 10, 2013

tion methods include Subcutaneous, intravenous, intramuscu receptor agonist, formulated together with one or more phar lar, nasal, oral or transdermal administration. maceutically acceptable carrier(s). 0062. The invention moreover relates to a composition 0077. As used herein, the term “formulation refers to a comprising peripherally selective kappa opioid receptorago composition in Solid, e.g., powder, or liquid form, which nist in conjunction with a lactational enhancer, elevators, or includes a peripherally selective kappa opioid receptor ago stabilizers, optionally including a pharmaceutically accept nist. Formulations can provide therapeutic benefits. These able carrier. These and other compositions set forth hereincan formulations may contain a preservative to prevent growth of be used in methods for the treatment of lactation failure, or microorganisms. inadequate or insufficient lactation in a subject, in accordance 0078. By “therapeutically effective” amount is meant a with the invention, as well as a method for the manufacture of tolerable (e.g., does not produce a severe side effect, which these compositions. can be relatively, Substantially, or completely nontoxic) 0063. By lactation failure is here meant both when a amount of an active agent to provide the desired therapeutic female has no or insufficient amount of milk or is at risk for effect. none or insufficient amount of milk. 0079. By “transdermal’ drug delivery is meant adminis 0064. Lactation can be promoted and, therefore, lactation tration of a drug to the skin surface of an individualso that the failure, or inadequate or insufficient lactation in a subject, drug passes through the skin tissue and into the individuals methods are provided in the following situations: blood stream, thereby providing a systemic effect. The term 0065 i) Normalize lactation volumes in women with lac “transdermal' is intended to include “transmucosal” drug tational failure; administration, i.e., administration of a drug to the mucosal 0066 ii) Maintain/enhance, increase lactation in females (e.g., Sublingual, buccal, vaginal, rectal) Surface of an indi of premature babies who are being cared for in a neonatal vidualso that the drug passes through the mucosal tissue and unit; into the individual’s blood stream. 0067 iii) Enhance lactational performance in females 0080. The term “body surface” is used to refer to skin or with twins and triplets; mucosal tissue. 0068 iv) Promote and prolong (frequency or duration) lactation in females with offspring at risk of developing lac I0081. By “predetermined area of skin or mucosal tissue, tose intolerance or other milk allergies if formula milk was which refers to the area of skin or mucosal tissue through used; which a drug enhancer formulation is delivered, is intended a 0069 v) Promote/prolong lactation in females where defined area of intact unbroken living skin or mucosal tissue. adverse hygiene conditions would make the use of formula That area will usually be in the range of about 5 cm to about undesirable; 200 cm, more usually in the range of about 5 cm to about 0070 vi) Enhance, increase or stabilize lactation in 100 cm, typically in the range of about 20 cm to about 60 females where Suckling frequency is diminished during part cm. However, it will be appreciated by those skilled in the art of the day, e.g. working mothers; of drug delivery that the area of skin or mucosal tissue through 0071 vii) To treat females prophylactically if they are at which drug is administered may vary significantly, depending risk for having an insufficient or inadequate amount of milk production. on patch configuration, dose, and the like. 0072 Certain embodiments of the invention involve pep 0082 “Penetration enhancement' or “permeation tides, optionally tetrapeptides containing four D-isomer enhancement as used herein relates to an increase in the amino acid residues, which bind to kappa opioid receptor permeability of the skin or mucosal tissue to a selected phar receptors, which do not substantially cross the blood brain macologically active agent, i.e., so that the rate at which the barrier and enter the brain, which exhibit high affinity for the agent permeates therethrough (i.e., the "flux of the agent kappa opioid receptor versus the mu opioid receptor, which through the body surface) is increased relative to the rate that have high potency and efficacy, and can exhibit a relative long would be obtained in the absence of permeation enhance duration of action in vivo. ment. The enhanced permeation effected through the use of 0073. It is an object herein to provide peripherally selec tive kappa opioid receptor agonists for systemic application Such enhancers can be observed by measuring the rate of that have tolerable, minimal or few if any CNS or diuretic diffusion of drug through animal or human skin using, for effects at dosages that are Sufficient to elevate, increase or example a Franz diffusion apparatus as known in the art and stabilize prolactin and thereby produce a benefit, such as as employed in the Examples herein. increased lactation or prevent significant reductions, or I0083. An “effective amount” or “an effective permeation decreases in lactation, in a subject in need thereof. enhancing amount of a permeation enhancer refers to a 0.074 Mammals are defined herein as all animals, includ nontoxic, nondamaging but sufficient amount of the enhancer ing humans, primates, and ungulates, for which the females of composition to provide the desired increase in skin perme the species have mammary glands and produce milk. ability and, correspondingly, the desired depth of penetration, 0075. As used herein, a “dairy animal' refers to a milk producing animal. In certain embodiments, the dairy animal rate of administration, and amount of drug delivered. produces large Volumes of milk and has a long period of I0084. A genus of peptides has been discovered which lactation, e.g., cows or goats. exhibit high selectivity for the kappa opioid receptor and 0076. The term “pharmaceutically acceptable composi relative long duration of in vivo action and which can exhibit tion” refers to compositions which comprise atherapeutically reduced or Substantially little if any significant brain penetra effective amount of peripherally selective kappa opioid tion. These peptides include sequences in which a sequence US 2013/0012431 A1 Jan. 10, 2013

of four D-isomeramino acids having a C-terminus is either a I0087 Another particular compound useful in the methods mono or disubstituted amide. These compounds have the of the present invention is the compound having the formula: following general formula: HXaa1-Xaa-Xaa-Xaa-Substituted amide wherein Xaa, is (A)D-Phe, (C' Me)D-Phe, D-Tyr, D-Tic or D-Ala(cyclopenty1 or thienyl), with A being H, NO. F. Cl or CH; Xaa, is (A')D-Phe, D-1Nal, D-2Nal, D-Tyror D-Trp. | O | O with A' being A or 3.4C1, Xaa is D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or D-Ala(cyclopentyl) with B being H N N or C" Me, Xaa, is D-Arg, D-Har, D-nArg, D-Lys, D-Lys GE) 1) N ~ /N (Ipr), D-Arg(Et), D-Har(Et), D-Amf(G), D-Dbu, (B)D-Orn AcO G O H O \U/ or D-Orn(Ipr), and with G being Horamidino. Non-limiting amides include ethylamide, morpholinylamide, 4-picolyla mide, piperazineamide, propylamide, cyclopropylamide and diethylamide. AcOC NH GE) 0085. The invention also provides a method of treating a mammal in need of elevated prolactin by increasing levels of H-D-Phe-D-Phe-D-Leu-D-Orn-Morpholinyl, optionally serum prolactin of said mammal, comprising administering excluding or including an acetate counterion. to said mammal an amount of a peripherally selective kappa opioid receptor agonist or a salt thereofor a pro-drug thereof BRIEF DESCRIPTION OF THE FIGURES effective to treat the mammal. In certain embodiments, the method increases or stabilizes levels of serum prolactin to I0088 FIG. 1 is a graph showing the Arithmetic. Mean greater than 25, 50, 75, 100, 125, 150, 175, or 200 ng/ml Changes from Baseline (Pre dose) in Serum Prolactin Con serum in the mammal. In other embodiments the method the centrations Following a 1 hour IV Infusion of CR665 at peripherally selective kappa opioid receptor agonist or salt various dosages in Male Subjects (Part A). thereof or prodrug thereof effective to treat the mammal is a I0089 FIG. 2 is a graph showing the Arithmetic Mean peptide, or ionizes or is metabolized to form a peptide. The Changes from Baseline (Pre dose) in Serum Prolactin Con peptide can comprise a pentapeptide or tetrapeptide, which centrations Following a 1 hour IV Infusion of CR665 in can include a sequence of four D-isomeramino acids having Female Subjects (Part A). a C-terminus that is either a mono- or di-substituted amide. In 0090 FIG. 3 is a graph showing the Arithmetic Mean certain embodiments the peptide has a binding affinity for the Changes from Baseline (Pre dose) in Serum Prolactin Con kappa opioid receptor that is greater than its binding affinity centrations Following a 5 minute IV. Infusion of CR665 in for non-kappa opioid receptors. In particular embodiments Male Subjects (Part B). the peptide has a binding affinity for the kappa opioid receptor 0091 FIG. 4 is a graph showing the Geometric Mean at least 1,000 times greater than its binding affinity for the mu Plasma Concentrations of CR665 Following a 1 hour IV opioid receptor. In some of these particular embodiments the Infusion of CR665 in Male Subjects (Part A) (Linear Scale peptide has a binding affinity for the kappa opioid receptor at 0092 FIG. 5 is a graph showing the Geometric Mean least 1,000 times greater than its binding affinity for the mu Plasma Concentrations of CR665 Following a 1 hour IV opioid receptor and in addition has an EDso for elevating Infusion of CR665 in Male Subjects (Part A) (Semi logarith prolactin of about 0.5 mg/kg or less. mic Scale). I0086 Particular compounds useful in the methods of the I0093. FIG. 6 is a graph showing the Geometric Mean present invention include the compound having the formula: AUC0 or CR665Versus Dose Level Following a 1 hour IV Infusion of CR665 in Male Subjects (Part A). 0094 FIG. 7 is a graph showing the Geometric Mean Plasma Concentrations of CR665Following a 1 hour IV Infu sion of 0.24 mg/kg. CR665 in Female Subjects (Part A) (Lin ear Scale). 0.095 FIG. 8 is a graph showing the Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV N. N Infusion of 0.24 mg/kg. CR665 in Female Subjects (Part A) err^ YS (Semi logarithmic Scale). AcOC O H. O H 2N 0096 FIG. 9 is a graph showing the Arithmetic Mean (SD) Plasma Concentrations of CR665 Following a 1-hour IV Infusion of 0.24 mg/kg. CR665 in Male and Female Sub HN jects (Part A) (Linear Scale). )e. NH 0097 FIG. 10 is a graph showing the Geometric Mean A GE Plasma. Concentrations of CR665 Following a 5-minute IV HN Infusion of CR665 in Male and Female Subjects (Part B) AcOG (Linear Scale). 0.098 FIG. 11 is a graph showing the Geometric Mean H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-picolyl, or a picolyl Plasma Concentrations of CR665 Following a 5-minute IV N-oxide thereof, optionally excluding or including an acetate Infusion of CR665 in Male and Female Subjects (Part B) counterion. (Semi logarithmic Scale). US 2013/0012431 A1 Jan. 10, 2013

0099 FIG. 12 is a graph showing the Geometric Mean kg of body weight to about 100 milligrams/kg of body weight AUCo., a for CR665 Versus Dose Level Following a of said mammal per hour, or per day, or per week or per 5-minute IV Infusion of CR665 in Male Subjects (Part B). month. The prolactin levels can be elevated to greater than 10, 0100 FIG. 13 is a graph showing the Relationship 15, 20, 25, 50, 75, 100, 125, 150, 175, or 200 ng/ml serum Between AUCO 12 h of Changes from Baseline in Serum above the baseline level of serum prolactin. Prolactin and AUCo., ofCR665 over the 0.015 to 0.36 0106. In some embodiments, the method of the invention mg/kg Dose Range in Male Subjects (Part A). for treating insufficient or inadequate lactation in a mammal, 0101 FIG. 14 is a graph showing the Relationship includes administering, separately or in combination an Between Cmax of Changes from Baseline in Serum Prolactin amount of a peripherally selective kappa opioid receptorago and Cmax of CR665 over the 0.015 to 0.36 mg/kg Dose. nist or a salt thereof or a pro-drug thereof, and an amount of Range in Male Subjects (Part A). prolactin effective to treat insufficient or inadequate lactation in the mammal. In other embodiments, the invention provides DETAILED DESCRIPTION a method for treating insufficient or inadequate lactation. The 0102 The nomenclature used to define the peptides is method includes administering an amount of a peripherally specified by Schroder & Lubke, The Peptides, Academic selective kappa opioid receptor agonist or a salt thereof or a Press, 1965, wherein, in accordance with conventional rep pro-drug thereof, to a mammal, separately or in combination, resentation, the N-terminus appears to the left and the C-ter with (1) another prolactin-elevating agent, (2) prolactin, or minus to the right. Where an amino acid residue has isomeric (3) a non-drug therapy, the method effective to treat insuffi forms, it is the L-isomer form of the amino acid that is being cient or inadequate lactation in the mammal. In still other represented herein unless otherwise indicated. embodiments, the invention provides a method for treating 0103) The invention provides methods, compositions, or insufficient or inadequate lactation in a mammal. The method dosage forms that employ and/or contain compounds, such as includes administering separately or in combination 1) a peptides, that are selective for kappa opioid receptor and not peripherally selective kappa opioid receptor agonist or a salt only exhibit a strong affinity for the kappa opioid receptor but thereofora pro-drug thereof, and; 2) another prolactin-elevat exhibit, optionally, long duration of in vivo prolactin elevat ing agent, said administration in an amount effective for ing activity in the absence of a severe or significant side effect, treating insufficient or inadequate lactation in the mammal. such as CNS side effects or diuresis. Exemplary kappa selec 0107. In other embodiments, the invention provides a tive opioid, receptor compounds (e.g., agonists) have a Ki method of for treating a mammal exhibiting insufficient or against a mammalian kappa opioid receptor. Such as a human inadequate milk production or at risk of insufficient or inad kappa opioid receptor, of less than 1000 nM, or less than 100 equate milk production. The method includes administering nM or less than 10 nM, or less than 1 nM, optionally having to said mammal an amount of a peripherally selective kappa a selectivity for kappa opioid receptors over other mamma opioid receptor agonist or salt thereof or prodrug thereof lian opioid receptor Subtypes greater than 100, or greater than effective to treat the mammal. The peripherally selective 1,000 or greater than 10,000 times greater affinity, measur kappa opioid receptor agonist or salt thereof or prodrug able in vitro by the ratio of their IC50 or Ki values against the thereof can include a peptide, or can ionize or metabolize to mammalian, e.g., human mu and delta opioid receptors, form a peptide. The peptide can include a tetrapeptide or a respectively. Kappa opioid receptoragonists can exhibit both pentapeptide. a lack of significant brain penetration and a prolonged dura 0108. In particular embodiments, the prolactin-elevating tion of in vivo activity. Therefore, in addition to the above agent useful in the methods of the present invention can be mentioned kappa opioid receptor affinity and selectivity, administered with a mu opioid receptoragonist selected from compounds also include those that exhibit no significant brain the group consisting of (i) , (ii) , penetration while preserving Substantial activity for measur (iii) , (iv) , (v) , (vi) able or detectable period of time, for example, at least about , (vii) , (viii) , (ix) morphine one hour, at least about two hours, for three hours or longer 6 glucuronide, (X) , (xi) meperidine, (xii) diphe (e.g., 4, 5, 6, 12, 24, 48 hours or clays, or longer). noxylate, (xiii) , (xiv) , (XV) , 0104. In certain embodiments, the method of the invention (xvi) , (xvii) , (xviii) levomethadyl and can be practiced using a peripherally selective kappa opioid (Xviv) propoxyphene. receptor agonist, which when administered peripherally, is 0109. In certain embodiments of the method, the prolac effective to increase or stabilize levels of prolactin without tin-elevating agent can be a peptide having a binding affinity substantially crossing the blood-brain barrier of the subject. for the peripheral kappa opioid receptor that is greater than its In other embodiments, the amount of the peripherally selec binding affinity for non-peripheral kappa opioid receptor. tive kappa opioid receptoragonist administered is an amount Alternatively, the peptide can have a binding affinity for the effective to increase or stabilize levels of prolactin without peripheral kappa opioid receptor that is 10 times greater, 100 causing a severe side effect in the Subject. Alternatively, the times greater, 1,000 times greater, or more than its binding amount of the peripherally selective kappa opioid receptor affinity for a non-peripheral kappa opioid receptor. For agonist administered is an amount effective to increase or instance the peptide can have a binding affinity for the kappa stabilize levels of prolactin with minor or tolerable side opioid receptor which is at least 1,000 times greater than its effects in the subject. Side effects can include a neuropsychi binding affinity for the mu opioid receptor. In certain embodi atric side effect (such as but not limited to dysphoria or ments, the peptide has a binding affinity for the kappa opioid hallucinations), diuresis or sedation. receptor which is at least 1,000 times greater than its binding 0105. In some embodiments, according to the method of affinity for the mu opioid receptor and an EDso for elevating the invention for elevating levels of serum prolactin in a prolactin of about 0.5 mg/kg or less. mammal, the administered dose of the peripherally selective 0110. In a particular embodiment, the invention provides a kappa opioid receptoragonist is between about 1 microgram/ method of treating a mammal in need of elevated or stabilized US 2013/0012431 A1 Jan. 10, 2013 prolactin levels, wherein the method includes administering bilized levels of prolactin, e.g., a person in need of stimulation to said mammal an amount of a peripherally selective kappa of lactation, e.g., a female (mother). The term “mammals' opioid receptoragonist or a salt thereof or a pro-drug thereof, includes humans and all non human mammals, such as non in conjunction with an amount of an additional prolactin human primates, ungulates and ruminants. elevating compound, effective to treat the mammal. The addi tional prolactin elevating compound can include a D2 dopam 0117. As used herein, “effective amount or “sufficient ine receptor antagonist or mu opioid receptor agonist. amount refers to an amount of a compound as described herein that may be therapeutically effective to inhibit, prevent 0111. In one embodiment, the D2 dopamine receptorago or treat a symptom of a particular disease, disorder, condition, nist is selected from the group consisting of (i) domperidone, or side effect. Such diseases, disorders, conditions, and side (ii) metoclopramide, (iii) levosulpiride, (iv) sulpiride, (v) thi effects include those conditions associated with insufficient, ethylperazine, (vi) Ziprasidone, (vii) Zotepine, (viii) cloZap or inadequate circulating levels of prolactin, wherein the ine, (ix) chlorpromazine, (X) acetophenazine, (xi) carphena treatment comprises elevating, increasing, or stabilizing cir Zine (xii) chlorprothixene, (xiii) fluiphenazine, (xiv) loxapine, culating levels of prolactin by contacting cells, tissues or (XV) mesoridazine, (Xvi) molindone, (Xvii) perphenazine, receptors with compounds as set forth herein. Thus, for (Xviii) pimozide, (Xviv) piperacetazine, (XX) prochlorpera example, an "effective amount’, when used in connection zine, (xxi) thioridazine, (xxii) thiothixene, (xxiii) trifluopera with lactational insufficiency or inadequacy, for example, Zine, (XXiv) triflupromazine, (XXV) pipamperone, (XXVi) refers to an amount of a compound required for treatment amperozide, (XXVii) quetiapine, (XXViii) melperone, (XXix) and/or prevention of this condition. An “effective amount', remoxipride, (XXX) haloperidol, (XXXi) rispiridone, (XXXii) when used in connection with functional hypoprolactinemia, olanzepine, (XXXiii)sertindole, and (XXXiv) prochlorperazine. refers to the treatment and/or prevention of one or more 0112. In another embodiment the mu opioid receptorago symptoms, diseases, disorders, and conditions associated nist is selected from the group consisting of (i) morphine, (ii) with circulating levels of prolactin that are undesirably low, hydromorphone, (iii) oxymorphone, (iv) levorphanol, (v) for example, to optimally Sustain a physiological function. methadone, (vi) codeine, (vii) hydrocodone, (viii) oxyc odone, (ix) morphine-6-glucuronide, (X) tramadol, (xi) mep 0118. As used herein, “pharmaceutically acceptable' eridine, (xii) , (xiii) loperamide, (xiv) fentanyl. refers to compounds, materials, compositions, and/or dosage (XV.) Sufentanil, (xvi) alfentanil, (xvii) remifentanil, (xviii) forms which are, within the scope of Sound medical judg levomethadyl, and (Xviv) propoxyphene. ment, Suitable for contact with the tissues of human beings 0113. As used herein, “prolactin elevating activity” refers and animals without severe toxicity, irritation, allergic to the pharmacological activity of a compound if it causes an response, or other complications commensurate with a rea elevation in circulating plasma or serum levels of prolactin in sonable benefit/risk ratio. a subject. A "prolactin increasing activity” refers to a com 0119. As used herein, “in combination with’. “combina pound that causes a measurable or detectable, transient or tion therapy' and “combination products” refer, in certain longer term increase in circulating plasma or serum levels of embodiments, to the concurrent administration to a patient of prolactin in a subject. A “prolactin stabilizing activity” refers a peripherally selective kappa opioid receptor agonist of the to a compound that causes a measurable or detectable, tran invention and either or both of prolactin and a compound with sient or longer term, stabilization in circulating plasma or prolactin elevating, increasing or stabilizing activity but lack serum levels of prolactin in a subject, e.g., prevents or inhibits ing peripherally selective kappa opioid receptoragonist activ a reduction in prolactin levels, maintains a particular level of ity, e.g., a D2 dopamine receptor antagonist, e.g., domperi prolactin for a measurable period of time, prevents or inhibits done. When administered in combination, each component a reduction in prolactin levels below a certain amount (e.g., may be administered at the same time or sequentially in any below 200, 175, 150, 125, 100, 75, 50, 25 ng/ml serum), etc. order at different points in time. Thus, each component may 0114. As used herein, “functional hypoprolactinemia be administered separately but sufficiently closely in time so refers to a condition in which a subject has insufficient or as to provide a desired therapeutic effect. inadequate levels of circulating prolactin required to initiate, maintain or enhance a physiological function, e.g. lactation. 0.120. As used herein, a “D2 dopamine receptor antago The level of circulating prolactin required for a given physi nist” refers to compounds with a binding affinity (K, or K.) ological function will vary, as is known in the art, depending for a mammalian D2 dopamine receptor of less than 10 micro upon the function and the gender and physiological or patho molar, regardless of binding affinity for other receptors. physiological status of the Subject. Thus, for example, a nor Where there is ambiguity or an absence of useful information mal pre pregnancy baseline level of circulating prolactin regarding whether the binding affinity of a compound for a would be insufficient to sustain lactation after delivery. Under mammalian D2 dopamine receptor meets this definition, data these circumstances, the failure of lactation in a post pregnant from in vitro or in vivo functional studies, as are commonly female with this level of prolactin would be characterized as employed by those with skill in the art, can be used to deter a functional hypoprolactinemia, even though the circulating mine whether a compound is a functional antagonist of a level of prolactin would be normal for a non lactating female. mammalian D2 dopamine receptor. 0115. As used herein, “CNS side effect refers to a clini I0121. As used herein, “mu opioid receptoragonist” refers cally significant side effect of a compound in which the Symp to compounds with a binding affinity (K, or K.) for a mam toms are psychiatric or neurological, e.g., visual or auditory malian muopioid receptor of less than 10 micromolar, regard hallucinations, delusions, impaired intellectual functioning, less of binding affinity for other receptors. Where there is or impaired control of Voluntary movements. ambiguity or an absence of useful information regarding 0116. As used herein, the term “subject' is intended to whether the binding affinity of a compound for a mammalian include human and nonhuman mammals. Subjects include a mu opioid receptor meets this definition, data from in vitro or person, e.g., a patient, in need of elevated, increased or sta in vivo functional studies, as are commonly employed by US 2013/0012431 A1 Jan. 10, 2013

those with skill in the art, can be used to determine whether a equacy or insufficiency in lactation associated with insuffi compound is a functional agonist of a mammalian mu opioid cient or inadequate plasma levels of prolactin. The composi receptor. tions should contain an effective amount of a peripherally 0122. As used herein, “dosage unit refers to a physically selective kappa opioid receptoragonist, in a pharmaceutically discrete unit Suited as unitary dosages for a particular indi acceptable carrier. vidual or condition to be treated. Each unit may contain a predetermined quantity of active compound(s) calculated to I0127. The pharmaceutical carrier can be any compatible, produce the desired therapeutic effect(s), optionally in asso non toxic substance suitable to deliver the peripherally selec ciation with a pharmaceutical carrier. The specification for tive kappa opioid receptor agonist to the Subject. Sterile the dosage unit forms may be dictated by (a) the unique water, , fats, waxes, and inert Solids may be used as the characteristics of the active compound(s) and the particular carrier. Pharmaceutically acceptable adjuvants, buffering therapeutic effect(s) to be achieved, and (b) the limitations agents, dispersing agents, and the like, may also be incorpo inherent in the art of compounding Such active compound(s). rated into the pharmaceutical compositions. The concentra 0123. As used herein, “pharmaceutically acceptable salts' tion of peripherally selective kappa opioid receptoragonist or refer to derivatives of compounds wherein the parent com other active agent in the pharmaceutical composition can vary pound is modified by making acid or base salts thereof. widely, i.e., from less than about 0.01% by weight, usually Examples of pharmaceutically acceptable salts include, but being at least about 1% weight to as much as 50% by weight are not limited to, mineral or organic acid salts of basic O. O. residues such as amines; alkali or organic salts of acidic I0128. For oral administration, an active ingredient can be residues such as carboxylic acids; and the like. The pharma administered in Solid dosage forms. Such as capsules, tablets, ceutically acceptable salts include the conventional non toxic and powders, or in liquid dosage forms, such as elixirs, Syr salts or the quaternary ammonium salts of the parent com ups, and Suspensions. Active component(s) can be encapsu pound formed, for example, from non toxic inorganic or lated in gelatin capsules together with inactive ingredients organic acids. For example, Such conventional non toxic salts and powdered carriers, such as glucose, lactose, Sucrose, include those derived from inorganic acids such as hydro mannitol, Starch, cellulose or cellulose derivatives, magne chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric sium Stearate, Stearic acid, sodium saccharin, talcum, magne and the like; and the salts prepared from organic acids such as sium carbonate and the like. Examples of additional inactive acetic, propionic, Succinic, glycolic, Stearic, lactic, malic, ingredients that may be added to provide desirable color, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe taste, stability, buffering capacity, dispersion or other known nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2 acetoxy desirable features are red iron oxide, silica gel, Sodium lauryl benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane sulfate, titanium dioxide, edible white ink and the like. Simi disulfonic, oxalic, isethionic, and the like. These physiologi lar diluents can be used to make compressed tablets. Both cally acceptable salts are prepared by methods known in the tablets and capsules can be manufactured as Sustained release art, e.g., by dissolving the free amine bases with an excess of products to provide for continuous release of medication over the acid in aqueous alcohol, or neutralizing a free carboxylic a period of hours. Compressed tablets can be Sugar coated or acid with an alkali metal base Such as a hydroxide, or with an film coated to mask any unpleasant taste and protect the tablet amine. from the atmosphere, or enteric coated for selective disinte 0.124 Compounds described herein, can be used or pre gration in the gastrointestinal tract. Liquid dosage forms for pared in alternate forms. For example, many amino contain oral administration can contain coloring and flavoring to ing compounds can be used or prepared as an acid addition increase patient acceptance. To facilitate drug stability and salt. Often such salts improve isolation and handling proper absorption, peptides of the invention can be released from a ties of the compound. For example, depending on the capsule after passing through the harsh proteolytic environ reagents, reaction conditions and the like, compounds as ment of the stomach. Methods for enhancing peptide stability described herein can be used or prepared, for example, as and absorption after oral administration are well known in the their hydrochloride or tosylate salts. Isomorphic crystalline art (e.g., Mahato R I. Emerging trends in oral delivery of forms, all chiral and racemic forms, N-oxide, hydrates, Sol peptide and protein drugs. Critical Reviews in Therapeutic Vates, and acid salt hydrates, are also contemplated to be Drug Carrier Systems. 20:153-214, 2003). In addition, oral within the scope of the present invention. delivery of compounds of the invention can be optimized 0.125 Certain acidic or basic compounds of the present through the use of remote controlled capsules as disclosed by invention may exist as Zwitterions. All forms of the com Wilding and Prior in Critical Reviews in Therapeutic Drug pounds, including free acid, free base and Zwitterions, are Carrier Systems 20:405-431 (2003). contemplated to be within the scope of the present invention. I0129. For nasal administration, the peripherally selective It is well known in the art that compounds containing both kappa opioid receptoragonists can beformulated as aerosols. amino and carboxyl groups often exist in equilibrium with The term “aerosol includes any gas-borne Suspended phase their Zwitterionic forms. Thus, any of the compounds of the compounds of the instant invention which is capable of described herein throughout that contain, for example, both being inhaled into the bronchioles or nasal passages. Specifi amino and carboxyl groups, also include reference to their cally, aerosol includes a gas-borne Suspension of droplets of corresponding Zwitterions. the compounds of the instant invention, as may be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Pharmaceutical Compositions Aerosol also includes a dry powder composition of a com 0126. A peripherally selective kappa opioid receptor ago pound of the instant invention Suspended in air or other carrier nist of the invention can be incorporated into a pharmaceuti gas, which may be delivered by insufflation from an inhaler cal composition to ameliorate functional hypoprolactinemia device, for example. See Ganderton & Jones, Drug Delivery in a Subject, e.g., a Subject presenting with a deficiency, inad to the Respiratory Tract, Ellis Horwood (1987); Gonda US 2013/0012431 A1 Jan. 10, 2013

(1990) Critical Reviews in Therapeutic Drug Carrier Systems agents by the combined processes of electromigration and 6:273-313; and Raeburnet al. (1992).J. Pharmacol. Toxicol. electroosmosis. Electrotransport devices generally employ Methods 27:143-159. two electrodes, both of which are positioned in close electri 0130 Parenteral administration of the formulations of the cal contact with some portion of the skin of the body. One present invention includes intravenous, Subcutaneous, intra electrode, called the active or donor electrode, is the electrode muscular and transdermal administrations. from which the therapeutic agent is delivered into the body. 0131 Preparations for parenteral administration include The other electrode, called the counter or return electrode, sterile solutions ready for injection, sterile dry soluble prod serves to close the electrical circuit through the body. In ucts ready to be combined with a solvent just prior to use, conjunction with the patient’s skin, the circuit is completed including hypodermic tablets, sterile Suspensions ready for by connection of the electrodes to a source of electrical injection, sterile dry insoluble products ready to be combined energy, e.g., a battery, and usually to circuitry capable of with a vehicle just prior to use and sterile emulsions. The controlling current passing through the device. Solutions may be either aqueous or nonaqueous, and thereby 0.133 Depending upon the electrical charge of the com formulated for delivery by injection, infusion, or using pound to be delivered transdermally, either the anode or cath implantable pumps. For intravenous, Subcutaneous, and ode may be the active or donor electrode. Thus, if the com intramuscular administration, useful formulations of the pound to be transported is positively charged, e.g., the invention include microcapsule preparations with controlled compound exemplified in Example 1 herein, then the positive release properties (R. Pwar et al. Protein and peptide electrode (the anode) will be the active electrode and the parenteral controlled delivery. Expert Opin Biol Ther: 4(8): negative electrode (the cathode) will serve as the counter 1203-12, 2004) or encapsulation in liposomes, with an exem electrode, completing the circuit. However, if the compound plary form being polyethylene coated liposomes, which are to be delivered is negatively charged, then the cathodic elec known in the art to have an extended circulation time in the trode will be the active electrode and the anodic electrode will vasculature (e.g. Koppal, T. "Drug delivery technologies are be the counter electrode. Electrotransport devices addition right on target'. Drug Discov. Dev. 6, 49-50, 2003). ally require a reservoir or source of the therapeutic agent that 0132 Preparations for transdermal delivery are incorpo is to be delivered into the body. Such drug reservoirs are rated into a device suitable for said delivery, said device connected to the anode or the cathode of the electrotransport utilizing, e.g., iontophoresis (Kalia Y Net al. Iontophoretic device to provide a fixed or renewable source of one or more drug delivery. Adv. Drug Deliv Rev. 56.619-58, 2004) or a desired species or agents. Each electrode assembly is com dermis penetrating surface (Prausnitz M. R. Microneedles for prised of an electrically conductive electrode in ion-transmit transdermal drug delivery. Adv. Drug Deliv Rev. 56:581-7, ting relation with an ionically conductive liquid reservoir 2004), such as are known in the art to be useful for improving which in use is placed in contact with the patient’s skin. Gel the transdermal delivery of drugs. An electrotransport device reservoirs such as those described in Webster (U.S. Pat. No. and methods of operating same are disclosed in U.S. Pat. No. 4.383,529) are one form of reservoir since hydrated gels are 6,718,201. Methods for the use of iontophoresis to promote easier to handle and manufacture than liquid-filled contain transdermal delivery of peptides are disclosed in U.S. Pat. No. ers. Water is one liquid solvent that can be used in such 6,313,092 and U.S. Pat. No. 6,743,432. Herein the terms reservoirs, in part because the salts of the peptide compounds “electrotransport”, “iontophoresis', and “iontophoretic' are of the invention are water soluble and in part because water is used to refer to the delivery through a body Surface (e.g., skin non-irritating to the skin, thereby enabling prolonged contact or mucosa) of one or more pharmaceutically active com between the hydrogel reservoir and the skin. Examples of pounds by means of an applied electromotive force to an reservoirs and sources include a pouch as described in U.S. agent containing reservoir. The compound may be delivered Pat. No. 4,250.878, a pre-formed gel body as disclosed in by electromigration, electroporation, electroosmosis or any U.S. Pat. No. 4,382,529, and a glass or plastic container combination thereof. Electroosmosis has also been referred holding a liquid solution of the drug, as disclosed in the to as electrohydrokinesis, electro convection, and electrically figures of U.S. Pat. No. 4,722,726. For electrotransport, com induced osmosis. In general, electroosmosis of a compound pounds (e.g., peptides) the invention can be formulated with into a tissue results from the migration of solvent in which the flux enhancers such as ionic Surfactants (e.g., U.S. Pat. No. compound is contained, as a result of the application of elec 4,722.726) or cosolvents other than water (e.g., European tromotive force to the therapeutic species reservoir, i.e., Sol Patent Application 278.473). Alternatively the outer layer vent flow induced by electromigration of other ionic species. (i.e., the stratum corneum) of the skin can be mechanically During the electrotransport process, certain modifications or disrupted prior to electrotransport delivery therethrough (e.g., alterations of the skin may occur Such as the formation of U.S. Pat. No. 5,250,023). transiently existing pores in the skin, also referred to as “elec 0.134 Peripherally selective kappa opioid receptor ago troporation.” Any electrically assisted transport of species nists that are well suited for electrotransport can be selected, enhanced by modifications or alterations to the body surface by measuring their electrotransport flux through the body (e.g., formation of pores in the skin) are also included in the Surface (e.g., the skin or mucosa), e.g., as compared to a term “electrotransport’ as used herein. Thus, as used herein, standardized test peptide with known electrotransport flux applied to the compounds of the instant invention, the terms characteristics, e.g. thyrotropin releasing hormone (R. Bur “electrotransport”, “iontophoresis' and “iontophoretic' refer nette et al. J. Pharm. Sci. (1986) 75:738) or vasopressin (Nair to (1) the delivery of charged agents by electromigration, (2) et al. Pharmacol Res. 48:175-82, 2003). Transdermal elec the delivery of uncharged agents by the process of electroos trotransport flux can be determined using a number of in vivo mosis, (3) the delivery of charged or uncharged agents by or in vitro methods well known in the art. In vitro methods electroporation, (4) the delivery of charged agents by the include clamping a piece of skin of an appropriate mammal combined processes of electromigration and electroosmosis, (e.g., human cadaver skin) between the donor and receptor and/or (5) the delivery of a mixture of charged and uncharged compartments of an electrotransport flux cell, with the Stra US 2013/0012431 A1 Jan. 10, 2013 tum corneum side of the skin piece facing the donor compart luose, hydroxypropyl methylcellulose and polyvinylpyrroli ment. A liquid Solution or gel containing the drug to be done. Emulsifying agents include Polysorbate 80 (Tween 80). delivered is placed in contact with the stratum corneum, and A sequestering or chelating agent of metal ions includes electric current is applied to electrodes, one electrode in each EDTA. Pharmaceutical carriers also include ethyl alcohol, compartment. The transdermal flux is calculated by sampling polyethylene glycol and propylene glycol for water miscible the amount of drug in the receptor compartment. Two Suc vehicles and sodium hydroxide, hydrochloric acid, citric acid cessful models used to optimize transdermal electrotransport or lactic acid for pH adjustment. drug delivery are the isolated pigskin flap model (Heit MC et 0.139. Typically a therapeutically effective amount of a al. Transdermaliontophoretic peptide delivery: in vitro and in peripherally selective kappa opioid receptoragonist is at least Vivo studies with luteinizing hormone releasing hormone.J. about 0.01% w/w up to about 50% w/w or more, or more than Pharm. Sci. 82:2403, 1993), and the use of isolated hairless 0.1% w/w of the active compound. The active ingredient may skin from hairless rodents or guinea pigs, for example. See be administered at once, or may be divided into a number of Hadzija BW et al. Effect of freezing on iontophoretic trans Smaller doses to be administered at intervals of time, or as a port through hairless rat skin. J. Pharm. Pharmacol. 44, 387 controlled release formulation. The term “controlled release 390, 1992. Compounds of the invention for transdermal ion formulation' encompasses formulations that allow the con tophoretic delivery can have one, or typically, two charged tinuous delivery of a peripherally selective kappa opioid nitrogens, to facilitate their delivery. receptor agonist to a subject over a period of time, for 0135 The scope of the present invention also includes example, several days to weeks. Such formulations may methods of treating a mammal in need of elevated prolactin administered Subcutaneously or intramuscularly and allow wherein the peripherally selective kappa opioid receptorago for the continual steady state release of a predetermined nist or a salt thereof or a pro-drug thereof is administered amount of compound in the subject over time. The controlled transdermally, for instance and without limitation, by an elec release formulation of peripherally selective kappa opioid trotransport device. The electrotransport device can, in some receptor agonist may be, for example, a formulation of drug embodiments, deliver the peripherally selective kappa opioid containing polymeric microcapsules. Such as those described receptoragonist or a salt thereofora pro-drug thereof through in U.S. Pat. Nos. 4,677,191 and 4,728,721, incorporated a body Surface. herein by reference. The concentration of the pharmaceuti 0136. Other useful transdermal delivery devices employ cally active compound is adjusted so that administration pro high Velocity delivery under pressure to achieve skin penetra vides an effective amount to produce a desired effect. The tion without the use of a needle. Transdermal delivery can be exact dose depends on the age, weight and condition of the improved, as is known in the art, by the use of chemical patient or animal, as is known in the art. For any particular enhancers, sometimes referred to in the art as "permeation Subject, specific dosage regimens can be adjusted over time enhancers', i.e., compounds that are administered along with according to the individual need and the professional judg the drug (or in Some cases used to pretreat the skin, prior to ment of the person administering or Supervising the admin drug administration) in order to increase the permeability of istration of the formulations. Thus, the concentration ranges the stratum corneum, and thereby provide for enhanced pen set forth herein are exemplary only and are not intended to etration of the drug through the skin. Chemical penetration limit the scope or practice of the claimed invention. enhancers are compounds that are innocuous and serve 0140. The unit dose parenteral preparations include pack merely to facilitate diffusion of the drug through the stratum aging in an ampoule or a syringe with a needle. corneum, whether by passive diffusion or an energy driven 0141 All preparations for parenteral administration are process Such as electrotransport. See, for example, Meidan V typically sterile, as is known and practiced in the art. Metal. Enhanced iontophoretic delivery of buspirone hydro 0.142 Illustratively, intravenous infusion of a sterile aque chloride across human skin using chemical enhancers. Int. J. ous buffered solution containing an active compound is an Pharm. 264:73-83, 2003. effective mode of administration. Another embodiment is a 0.137 Pharmaceutically acceptable carriers used in sterile aqueous or oily solution or Suspension containing an parenteral preparations include aqueous vehicles, nonaque active material injected as necessary to produce the desired ous vehicles, antimicrobial agents, isotonic agents, buffers, pharmacological effect. antioxidants, local anesthetics, Suspending and dispersing 0.143 Compositions and methods of the invention can be agents, emulsifying agents, sequestering or chelating agents delivered or administered intravenously, transdermally, intra and other pharmaceutically acceptable Substances. nasally, Subcutaneously, intramuscularly, or orally. Compo 0138 Examples of aqueous vehicles include Sodium sitions can be administered for prophylactic treatment of Chloride Injection, Ringers Injection, Isotonic Dextrose individuals Suffering from, or at risk of a disease or a disorder, Injection, Sterile Water Injection, Dextrose and Lactated e.g., a female experiencing insufficient or inadequate lacta Ringers Injection. Nonacqueous parenteral vehicles include tion. For therapeutic applications, a pharmaceutical compo fixed oils of vegetable origin, cottonseed oil, corn oil, Sesame sition is typically administered to a subject Suffering from a oil and peanut oil. Antimicrobial agents in bacteriostatic or disease or disorder, e.g., a lactational deficiency, in an amount fungistatic concentrations must be added to parenteral prepa sufficient to inhibit, prevent, or ameliorate the disease or rations packaged in multiple dose containers which include disorder. An amount adequate to accomplish this is defined as phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, a “therapeutically effective dose.” methyl and propyl phydroxybenzoic acid esters, thimerosal, 0144. Although not wishing to be bound by any theory, it benzalkonium chloride and benzethonium chloride. Isotonic is believed that peripherally selective kappa opioid receptor agents include sodium chloride and dextrose. Buffers include agonist administered to Subjects stimulates release of the phosphate and citrate. Antioxidants include Sodium bisulfate. anterior pituitary hormone prolactin. The compound is typi Local anesthetics include procaine hydrochloride. Suspend cally administered in an amount Sufficient to stimulate secre ing and dispersing agents include sodium carboxymethylcel tion of prolactin, or stabilize or prevent or inhibit reductions US 2013/0012431 A1 Jan. 10, 2013

or decreases in prolactin, without causing a severe side effect, of drug or at steady state during chronic maternal dosing such as CNS side effects or diuresis. A useful dose range of a (Bennett 1988, 1996). When using this approach to estimate peripherally selective kappa opioid receptor agonist can be daily infant dosage, the AUC is either the AUC from time zero determined by one of skill in the art through routine testing. to infinity after maternal ingestion of a single dose of drug or One skilled in the art recognizes that a dose depends, in part, the AUC within a dosing interval at Steady state during upon physical characteristics of the patient to be treated, e.g., chronic maternal dosing. The Volume of milk ingested by body weight, as well as the route of administration, e.g., infants is commonly estimated as 150 ml/kg/day. The infant intravenous injection or transdermal delivery, and the bio availability and plasma clearance of the compound by that dose (mg/kg) can then be expressed as a percentage of the route of administration, as well as the kappa opioid receptor maternal dose (mg/kg). Compounds of the invention can affinity of the compound. One method of approximating an result in an infant dose of less than 10% of the maternal dose, effective dose is to titrate the dose to achieve a plasma con or less than 1% or less than 0.1% of the maternal dose. Since centration of drug that exceeds the affinity constant (Kdor Ki) compounds of the invention include peptides, they can be of the drug for the kappa opioid receptor, e.g., as determined formulated, e.g., with polymeric microspheres, to protect by a conventional radioreceptor assay as is routinely them from degradation and enhance absorption in the gas employed in the art. One method is to titrate the dose to effect, trointestinal tract (e.g., Mahato RI. Emerging trends in oral e.g., to employ a dose that is found to effectively elevate delivery of peptide and protein drugs. Crit. Rev. Ther: Drug prolactin levels, as measured by an immunoassay selective Carrier Syst. 20:153 214, 2003). Microsphere-encapsulated for prolactin. In this case, although only two samples of peptides, for example typically do not survive the maternal blood, before and after drug administration, are necessary to gastrointestinal environment and release free peptide into the compare the basal prolactin level with the stimulated prolac circulation, such that peptides would be orally bioavailable to tin level, it is typical to measure the stimulated hormonal the offspring through breast milk in significant amounts, levels at timed intervals so that the dosing interval can be which can be readily confirmed by drug assay of infant adjusted to maintain a persistently elevated prolactin level. plasma and/or urine. Serum prolactin concentrations can be assessed by any of several, validated methods as are known in the art, e.g., a 0.148. The utility of the present invention is not limited to prolactin-specific immunoassay, e.g., the IMX prolactinassay promoting, elevating, increasing or stabilizing lactation in (Abbott Laboratories, Abbott Park, Ill.), a microparticle human and non human mammals. Although the prolactin enzyme immunoassay used in conjunction with an Abbott receptor is indeed found in the mammary gland and the ovary, IMx Automated Immunoassay Analyzer. When the desired two of the best characterized sites of prolactin actions in therapeutic effect is to increase lactation, an additional mammals, the receptor is also found in areas of the brain that method of dose titration is to employ a prolactin-elevating are outside the blood brain barrier, and are therefore acces dose that effectively increases the amount of milk that can be sible to circulating prolactin (Freeman ME et al. Prolactin: expressed, for example, to between about 500 to 1000 ml per Structure, function, and regulation of secretion. Physiol. Rev. day for a nursing human mother, with the level of milk expres 80: 1523-1631, 2000). In particular, the prolactin receptor sion selected according to the needs of the nursing infant. The (and/or the mRNA encoding the prolactin receptor) is found needs of the nursing infant can be assessed by methods known in the choroid plexus the area postrema, and the mediobasal to those with skill in the art, and which can include evidence hypothalamus. Prolactin receptors are also present in a wide for adequate lactation: (1) infant is satisfied after breastfeed range of peripheral tissues, including the pituitary gland, ing, (2) infant gains weight appropriately in relation to age/ heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal length, (3) breast engorgement and/or leaking occurs if infant gland, uterus, skeletal muscle, and skin. Accordingly, it is feeding is missed, and (4) milk is secreted in Volumes above contemplated that peripherally selective kappa opioid recep 500 ml/day. The volume of milk ingested by infants is com monly estimated as 150 ml/kg/day. toragonists, as described herein, will be useful in preventing, 0145 The American Academy of Pediatrics has placed an ameliorating or modulating conditions associated with these emphasis on increasing breastfeeding in the United States, regions of the brain and periphery, as well. Thus, for example, and has noted that most drugs likely to be prescribed to the elevated circulating prolactin, caused by a compound of the nursing mother should have no effect on milk Supply or on instant invention, would have access to the mediobasal hypo infant well being (American Academy of Pediatrics, Com thalamus, a region outside the blood-brain barrier that mittee on Drugs. The Transfer of Drugs and Other Chemicals includes the anterior periventricular area, paraventricular Into Human Milk. Pediatrics 108:776-789, 2001). Methods nucleus, and arcuate nucleus (e.g., Merchenthaler I. Neurons of the invention therefore include those that minimize transfer with access to the general circulation in the central nervous of a compound or compounds of the invention into breast milk system of the rat: a retrograde tracing study with fluoro gold. that is fed to an offspring, Such as an infant. The transfer of Neuroscience 44:655-62, 1991). These hypothalamic nuclei drugs into breast milk is most commonly described quantita are critical for neuroendocrine regulation, and contain pro tively using the milk to plasma (M/P) concentration ratio. The lactin receptors, which would thereby be therapeutically accuracy of this value is improved if it is based on the area affected, e.g., in neuroendocrine related disorders, by eleva under the concentration time curves (AUC), of the drug in tions in circulating prolactin caused by a compound of the maternal milk and plasma. instant invention. 0146 The infant daily dose can be estimated with the 0149. A variety of assays may be employed to test whether following equation: the compounds of the invention exhibit high affinity and Estimated Daily Infant Dosage (mg/kg/day)=M/Px selectivity for the kappa opioid receptor, long duration of in average maternal serum concentrationX 150 vivo bioactivity, lack of CNS side effects, and prolactin mL/kg/day elevating activity. Receptor assays are known in the art and 0147 In this case M/P (milk to plasma ratio) is the ratio of kappa opioid receptors from several species have been AUC, to AUC, The average maternal serum concen cloned, as have mu and delta opioid receptors. Kappa opioid tration refers to AUC after maternal ingestion of a single dose receptors as well as mu and delta opioid receptors are classi US 2013/0012431 A1 Jan. 10, 2013 cal, seven transmembrane spanning, G-protein coupled compounds to determine whether such compounds are kappa receptors. Although these cloned receptors readily allow a opioid receptor selective and have high affinity. Such binding particular candidate compound, e.g., a peptide, to be assays can be carried out in a variety of ways as well known to one of skill in the art, and one detailed example of an assay screened, natural sources of mammalian opioid receptors are of this general type is set forth in Young EA et al. H also useful for Screening, as is well known in the art (Dooley Dynorphin A binding and kappa selectivity of CT etal. Selective ligands for the mu, delta, and kappa opioid peptides in rat, guinea pig and monkey brain. Eur: J. Phar receptors identified from a single mixture based tetrapeptide macol. 121:355-65, 1986. positional scanning combinatorial library.J. Biol. Chem. 273: 0153 Various abbreviations used herein are as follows: 18848-56, 1998). Thus, screening against both kappa and mu By D-Nle is meant D-norleucine, and D-Hle represents D-ho opioid receptors, whether of recombinant or natural origin, moleucine. D-Har represents D-homoarginine, and D-nArg may be carried out in order to determine the selectivity of the represents D-norarginine which is one carbon shorter than compound(s) for the kappa over the mu opioid receptor. In D-Arg. By D-Nal is meant the D-isomer of alanine which is general, a mammalian form of the opioid receptor is used for substituted by naphthyl on the B-carbon. Typically, D-2Nal is screening; typically, the species source of the receptors is the employed, i.e. the attachment to naphthalene is at the 2-posi same as the species for which the compound of the invention tion on the ring structure; however, D-1 Nal may also be used. is being assessed, e.g., human placental tissue as a source of The abbreviations D-Cpa and D-Fpa are used to represent, kappa opioid receptors (Porthe Get al. Kappa opiate binding respectively, chloro-D-Phe and fluoro-D-Phe, with D-4Cpa, sites in human placenta. Biochem. Biophys. Res. Commun. D-2Fpa, D-3Fpa and D-4Fpa being typical. D-Npa means nitro-D-Phe, and D-Mpa is used to represent methyl D-Phe. 101: 1-6, 1981) for screening if the contemplated use of the D-34 Cpa means 3,4-dichloro-D-Phe. D-Acp represents screened compounds is for treatment of a human Subject. D-Ala(cyclopentyl). D-Orn represents D-ornithine, and 0150 Binding affinity refers to the strength of interaction D-Dbu represents alpha, gamma-diaminobutyric acid. CML between ligand and receptor. To demonstrate binding affinity represents C" methyl Leu, and CMP and CMO represent for opioid receptors, the compounds of the invention can be CP' Me Phe and C'P' Me Orn. By D-4Amf is meant evaluated using competition binding studies. These studies D-4(NHCH)Phe, and by D-Gmf is meant Amf(amidino) can be performed using cloned kappa and mu opioid recep which represents D-Phe where the 4-position is substituted tors expressed in stable transfected cell lines or naturally with CH-NHC(NH)NH2. Amd represents amidino, and the occurring opioid receptors from a receptor-enriched tissue symbol D-Amf(Amd) is also used. By D-Tic is meant D-1.2. Source, as noted above. In these studies, the test compounds 3,4-tetrahydroisoquinoline-3-carboxylic acid. In Ala(Thi), (unlabeled or cold ligand) are used at increasing concentra Thirepresents the thienyl group, which is typically linked at tions to displace the specific binding of a radiolabeled ligand its 2-position to alanine, although 3-thienyl is an equivalent. that has high affinity and selectivity for the receptor studied. By Ily and Ior are respectively meant isopropyl Lys and Tritiated U-69,593 and DAMGO can be used as ligands in isopropyl Orn where the side chain amino group is alkylated kappa and mu opioid receptor Studies, respectively. Both with isopropyl. ligands are commercially available (NEN-Dupont). DAMGO 0154 By lower alkyl is meant C to C for example, is an acronym for D-Ala, MePhe, Gly-ol-. C-C but including cyclopropyl and cyclobutyl. Me, Et, Pr, The affinity of the radioligands is defined by the concentra Ipr, Bu, Pnand Bzlare used to represent methyl, ethyl, propyl. tion of radioligand that results in half-maximal specific bind isopropyl, butyl, penty1 and benzyl. By Cyp is meant cyclo ing (K) in Saturation studies. The affinity of the test com propyl, and by Cyb is meant cyclobutyl. Although the linkage pound (unlabeled or cold ligand) is determined in is typically to one end of an alkyl chain, the linkage may be competition binding studies by calculating the inhibitory con elsewhere in the chain, e.g. 3-pentyl which may also be stant (K) according to the following formula: referred to as ethylpropyl. 4Nbz, and 4Abz represent 4-ni trobenzyl and 4-aminobenzyl. By 2-, 3- and 4-picolyl (Pic) where ICs-Concentration of the cold ligand that inhibits are meant methylpyridine groups with the attachment being 50% of the specific binding of the radioligand via a methylene in the 2-, 3- or 4-position. F=free radioligand concentration (O155 By Mor is meant morpholinyl, Kaffinity of the radioligand determined in Saturation stud 1CS 0151. When performing these assays under specific con ditions with relatively low concentrations of receptor, the -O) calculated K, for the test compound is a good approximation and by Timo is meant thiomorpholinyl, of its dissociation constant K, which represents the concen tration of ligand necessary to occupy one-half (50%) of the binding sites. A low K, value in the nanomolar and Subnano molar range is considered to identify a high affinity ligand in the opioid field. Exemplary analogs have a K, for kappa -O. opioid receptor of about 10 nanomolar (nM) or less, and AhX is used to represent 4-aminocyclohexyl, and hEt is used typical analogs have a K, of about 1 nM or less. High affinity to represent hydroxyethyl, i.e. —CH2CH2OH. Aeb is used to compounds: (1) enable the use of relatively low doses of drug, represent 4-(2-amino-2-carboxyethyl)benzyl, i.e. which minimizes the likelihood of side effects due to low affinity interactions, and (2) potentially reduce the cost of COOH manufacturing a dose since a correspondingly smaller amount of a higher affinity compound would be required to produce the desired therapeutic effect, assuming equal —ct-( )—cilCOOH absorption, distribution, metabolism, and excretion. 0152 These binding assays employing kappa opioid 0156 By Pip is meant piperidinyl, and by 4-HyP and OxP receptors and mu opioid receptors are straightforward to per are meant 4-hydroxypiperidinyl and 4-oxo-piperidinyl. By form and can be readily carried out with large numbers of Pp.Z is meant piperazinyl. Ecp represents 4-ethylcarbam US 2013/0012431 A1 Jan. 10, 2013

oylpiperazinyl; quaternary ammonium moieties, such as -continued 4-dimethyl piperazinyl (Dmp) or other di-lower alkyl substi tutions, may also be used. Substituted benzyl is typically Abbreviation Definition 4-aminobenzyl, i.e. D-Gmf D-(CH-NHC(NH)NH)- D-Dbu Alpha, gamma-diaminobutyric acid D-Orn D-ornithine D-Ior Isopropyl-D-ornithine —ct-( )-N. Aeb 4-(2-amino-2-carboxyethyl)benzyl Ppz piperazinyl and by 2-Tzl is meant 2-thiazolyl, i.e. Pep 4-phenyl carbamoyl piperazin-1-yl Aao 8-(acetylamino)-3,6-dioxaoct-1-yl Aoo 8-amino-3,6-dioxaoct-1-yl Hoh 6-(L-hydroorotylamino)-hex-1-yl: L-hydroorotic acid is CNHS(O)—COOH Ghx 6-(D-gluconylamino)-hexyl Gao 6-(D-gluconylamino)-3,6-dioxa.oct-1-yl D-4Fpa 4-fluoro-D-phenylalanine 0157 By Dor is meant 6-ornithinyl where the side chain D-4Cpa 4-chloro-D-phenylalanine amino group of L-ornithine is connected by an amide bond to D-34Cpa 3,4-dichloro-D-phenylalanine the C-terminus. D-CML C'methyl-D-Leucine D-Acp D-Ala (cyclopentyl) 0158 D-Phe or substituted D-Phe is an example at the Mor Morpholinyl 1-position. The phenyl ring may be substituted at the 2-, 3 Tmo thiomorpholinyl and/or 4-positions, and commonly Substitutions by chlorine Pip Piperidinyl or fluorine at the 2 or 4-position are particular examples. The 4-HyP 4-hydroxy piperidin-1-yl alpha-carbonatom may also be methylated. Other equivalent OxP 4-oxo-piperidin-1-yl residues which resemble D-Phe may also be used, and these Me Methyl include D-Ala(cyclopentyl), D-Ala(thienyl), D-Tyr and E Ethyl Pr Propyl D-Tic. The 2-position residue can also be D-Phe or substi Bu Butyl tuted D-Phe with such substitutions including a substituent on HEt Hydroxyethyl (i.e., —CH2CH2OH) the 4-position carbon of the phenyl ring or the 3- and 4-posi Cyp Cyclopropyl tions. Alternatively, D-alanine substituted by naphthyl can be BZl Benzyl used, as well as D-Trp and D-Tyr. The 3-position can be D-2Fpa 2-fluoro-D-phenylalanine occupied by a residue such as D-Nle, D-Leu, D-CML, D-Hle, D-Ala.(2Thi) 2-thienyl-D-alanine D-Met or D-Val; however, D-Ala(cyclopentyl) or D-Phe may 4Pic 4-picolyl also be used. D-Arg and D-Har, which may be substituted C'methyl Methyl attached to the alpha carbon of an amino acid with diethyl, are examples for the 4-position; however, D-nArg and other equivalent residues may be used. Such as 0160. In one embodiment, the invention provides a D-Lys or D-Orin (either of which can have its omega-amino method of treating a mammal exhibiting insufficient or inad group alkylated as by isopropyl or have its C-carbon group equate milk production or at risk of insufficient or inadequate methylated). Moreover, D-Dbu, D-4Amf (which is typically milk production; wherein the method includes administering substituted with amidino), and D-His may also be used. to the mammal an amount of a peripherally selective kappa opioid receptor agonist or salt thereof or prodrug thereof Chart of Additional Formula Abbreviations effective to treat the mammal, the peripherally selective kappa opioid receptor agonist or salt thereof or prodrug 0159) thereof being a peptide, or ionizes or is metabolized to form a peptide having the formula:

Abbreviation Definition wherein Xaa, is (A)D-Phe, (C' Me)D-Phe, D-Tyr, D-Tic D-Phe D-phenylalanine or D-Ala(cyclopentyl or thienyl), with Abeing H, NO. F. C. D-Tyr D-tyrosine D-Tic D-1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid or CH; Xaa, is (A')D-Phe, D-1 Nal, D-2Nal, D-Tyror D-Trp, D-Ala D-alanine with A' being A or 3.4C1, Xaa is D-Nle, (B)D-Leu, D-Hle, D-1Na1 D-Alanine Substituted by naphthyl on the beta carbon with D-Met, D-Val, D-Phe or D-Ala(cyclopentyl) with B being H he point of attachment at the 1-position on the naphthyl or C" Me: Xaa, is D-Arg, D-Har, D-nArg, D-Lys, D-Lys ring structure (Ipr), D-Arg(Et), D-Har(Et), D-Amf(G), D-Dbu, (B)D-Orn D-2Na1 D-Alanine Substituted by naphthyl on the beta carbon with or D-Orn(Ipr), with G being Horamidino; and Q is NRR, he point of attachment at the 2-position on the naphthyl morpholinyl, thiomorpholinyl, (C)piperidinyl, piperazinyl, ring structure D-Trp D-tryptophan 4-mono- or 4.4-di-Substituted piperazinyl or delta-ornithinyl, D-Nle D-norleucine with R being lower alkyl, substituted lower alkyl, benzyl, D-Leu D-leucine Substituted benzyl, aminocyclohexyl, 2-thiazolyl 2-picolyl, D-Hle D-homoleucine 3-picolyl or 4-picolyl, R being H or lower alkyl; and C being D-Met D-methionine H. 4-hydroxy or 4-oxo. In a particular embodiment Xaa is D-Wal D-valine D-Phe, Xaa, is D-Nle and Xaa, is D-Arg. In another embodi D-Arg D-arginine ment Q is NHRandR is ethyl, propyl, butyl, cyclopropylor D-Har D-homoarginine D-nArg D-norarginine cyclobutyl. In an alternative embodiment, Q is morpholinyl or D-Lys D-lysine thiomorpholinyl; or Q is NHR and R is 4-picolyl. In another D-Ily sopropyl-D-lysine embodiment, Xaa, is D-Ala(2-thienyl); alternatively, Xaa, is D-Arg (Et2) diethyl-D-arginine D-4FPhe and Xaa, is D-4CIPhe. In still another embodiment, D-Har(Et2) diethyl-D-homoarginine Xaa- is D-Nle or D-Leu and Xaa is D-Ornor D-Amf(Amd). D-Amf D-(NH2CH2)-Phenylalanine In another embodiment, Xaa, is D-Phe, Xaa is D-Leu or D-CML and Xaa, is D-Orn. US 2013/0012431 A1 Jan. 10, 2013

0161 The invention further provides a method of treating duction can be treated by a method according to the present a mammal exhibiting insufficient or inadequate milk produc invention; the method includes administering to the mammal tion or at risk of insufficient or inadequate milk production; an amount of a peripherally selective kappa opioid receptor wherein the method includes administering to the mammalan agonist or salt thereof or prodrug thereof effective to treat the amount of a peripherally selective kappa opioid receptorago mammal, wherein the administration includes intravenous, nist or salt thereof or prodrug thereof effective to treat the Subcutaneous, intramuscular, intranasal, oral, or transdermal mammal, the peripherally selective kappa opioid receptor administration, Such as for instance by an electrotransport agonist or salt thereof or prodrug thereof being a peptide, or device. In one embodiment of the method the electrotransport ionizes or is metabolized to form a peptide having the for device delivers the peripherally selective kappa opioid recep mula: toragonist through a body Surface. 0166 In one particular aspect, the method includes: (a) providing a first electrode; (b) providing a second electrode: wherein Xaa is D-Phe (unsubstituted or substituted by (c) providing a power source electrically connected to said C'P', Me, 2F, 4F or 4C1) or D-Ala(cyclopentyl or thienyl); first and said second electrodes; (d) providing at least one Xaa, is (A')D-Phe, D-1 Nal, D-2Nal or D-Trp, with A' being donor reservoir having the peripherally selective kappa H, 4F, 4C1, 4NO or 3.4C1, Xaa, is D-Nle, D-Leu, D-CML, opioid receptoragonist, wherein said donor reservoir is asso D-Met or D-Acp; Xaa, is D-Arg, D-Arg(Et), D-Lys, D-Ily, ciated with said first or second electrode; and (e) delivering a D-Har, D-Har(Et), D-nArg, D-Orn, D-Ior, D-Dbu, D-Amf therapeutically effective amount of said peripherally selec and D-Amf(Amd); and Q is NR. R. Mor, Tmo, Pip, 4-Hyp, tive kappa opioid receptoragonist through said body Surface. OxP or Ppz, with R being Me, Et, Pr, Bu, hEt, Cyp, Bzl or 0167. The peripherally selective kappa opioid receptor 4-picolyl, and R being H or Et. In one embodiment, Xaa is agonist can administered by any of these methods between D-Phe, Xaa is D-Nle and Xaa, is D-Arg. In another embodi about 1 microgram/kg of body weight to about 100 milli ment, Q is NHRandR is ethyl, propyl, butyl, cyclopropylor grams/kg of body weight of said mammal per hour, day, week cyclobutyl. Alternatively, Q can be morpholinyl or thiomor or month. These methods of the invention delivering the pholinyl. In a further embodiment, Q is NHR and R is peripherally selective kappa opioid receptor agonist admin 4-picolyl. Alternatively, Q is NRR and R is ethyl and R is istered can increase prolactinto levels greater than 10, 15, 20, ethyl. In yet another embodiment, Xaa is D-Phe or D-Ala(2- 25, 50, 75, 100, 125, 150, 175, or 200 ng/ml serum above the thienyl) and Xaa, is D-4ClPhe. In another embodiment, Xaa baseline level of serum prolactin. These methods are particu is D-Nle or D-Leu and Q is morpholinyl. larly advantageous for the treatment of female animal Sub 0162. In a particular embodiment, Xaa is D-Phe, D-4Fpa, jects (particularly a mammal. Such as for instance a primate, D-2Fpa, D-Acp or D-Ala(2Thi); Xaa, is (A)D-Phe, D-1 Nal, ungulate, canine or feline) or human patients, especially preg D-2Nal or D-Trp, with A being 4F or 4Cl: Xaa, is D-Nle, nant females or females that have given birth to an offspring D-Met or D-Leu; Xaa, is D-Arg, D-Har, D-nArg, D-Lys, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 12-24, 24-26, 36-48 D-Orn or D-Amf(Amd); and Q is NHR, Mor, Tmo, Pip or hours, days, weeks, or months. Suitable primates include an Ppz, with R being Et, Pr or 4Pic. ape, gorilla, monkey, macaque, chimpanzee, lemur or oran 0163. In another particular embodiment, the peptide has gutan. Suitable ungulates include a cow, pig, sheep, goat or the formula: horse. 0.168. The invention further provides a method of treating H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, a mammal exhibiting an insufficient or inadequate amount of milk production or at risk of exhibiting an insufficient or H-D-Phe-D-Phe-D-Nle-D-Arg-morpholinyl, inadequate amount of milk production, wherein the method (0164. H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-picolyl, includes administering to the Subject prior to or after child birth an amount of a peripherally selective kappa opioid H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr, receptor agonist in conjunction with a lactation enhancer, such as for instance, oxitocin or a stabilizer effective to treat H-D-Phe-D-Phe-D-Nle-D-Arg-thiomorpholinyl, the mammal. The oxytocin can be administered within one or more hours, days, or weeks following childbirth. In a particu H-D-Phe-D-Phe-D-Nle-D-Arg-Net, lar embodiment, the lactation enhancer or stabilizer is admin istered within one or more hours, days, or weeks following H-D-Phe-D-Phe-D-Nle-D-Arg-NHMe, childbirth. 0169. This invention is further illustrated by the following H-D-Phe-D-Phe-D-Leu-D-Orn-morpholinyl, examples which in no way should be construed as being further limiting. The contents of all cited references (includ H-D-Phe-D-Phe-D-Nle-D-Arg-NHhEt, ing literature references, issued patents, published patent applications, and co pending patent applications) cited H-D-Phe-D-Phe-D-Nle-D-Arg-NH-cyclopropyl, throughout this application are hereby expressly incorporated H-D-Ala(2Thi)-D-4Cpa-D-Leu-D-Arg-morpholinyl, by reference. H-D-Phe-D-Phe-D-Nle-D-Arg-piperidinyl, Examples 0170 The safety, tolerability, pharmacokinetics, and pro H-D-Phe-D-Phe-D-Leu-D-Orn-NHEt, lactin-elevating activity of ascending single intravenous (IV) doses of one of the compounds of the instant invention, H-D-Phe-D-Phe-D-Leu-D-Lys-morpholinyl, or D-phenylalanyl-D-phenylalanyl-D-norleucyl-N-(4-pyridi nylmethyl)-D-argininamide, acetate salt, herein designated H-D-Phe-D-Phe-D-Nle-D-Arg-piperazinyl. as CR665, was assessed in healthy male and surgically sterile 0.165 Mammals exhibiting insufficient or inadequate milk female human subjects following 1-hour or 5-minute infu production or at risk of insufficient or inadequate milk pro sions. CR665, also referenced in the literature as FE 200665, US 2013/0012431 A1 Jan. 10, 2013

is a peripherally selective kappa opioid receptor agonist; see placebo Solution was withdrawn from one or more vials using U.S. Pat. No. 5,965,701; also Riviere P. J.-M. et al. Novel a syringe, and injected into a 60 mL Plastipak polypropylene D-amino acid tetrapeptides demonstrate unprecedented Syringe (Beckton Dickinson S.A., Spain) containing an k-opioid receptor selectivity and antinociception. 30” Int. appropriate volume of sterile NaCl buffer. Res. Conf. (INRC) 1999, Saratoga Springs, N.Y., 0.175 For the 1 hour infusions, the final volume prepared Jul. 10-12, 1999: Wisniewski Ketal. Long acting, selective, was 40 mL, of which 30 mL was infused. The dose calculation peripheral kappa agonists. 26" European Peptide Sympo was as follows: sium, Montpilier, France, Sep. 11-15, 2000; Binder Wet al. and antiinflammatory effects of two novel kappa opioid peptides. Anesthesiology. 94:1034-44, 2001; Riviere Volume of 10 mg/mL CR665 required (mL) = Peripheral kappa-opioid receptor agonists for visceral pain. BrJ Pharmacol. 141:1331-4, 2004). Dose level (mg/kg)x body weight (kg) x 8 (40/3Of 10) Volume of buffer = 40 mL volume of CR665 required (mL) Study Design and Procedures 0171 This clinical study was conducted as a double blind, Table 2 provides some example dilutions, based on a 70 kg placebo controlled, ascending single intravenous (IV) dose, body weight. sequential group study. The results reported herein were obtained with 54 male and female human subjects in fifteen groups as shown in Table X below. This study was double TABLE 2 blind and placebo controlled in order to avoid bias in the CR665 collection and evaluation of data during its conduct. Placebo CR665 dose dose to be infused to be Concentration CR665 NaCl was chosen as the control treatment to assess whether any Dose for a 70 kg prepared of dose solution buffer observed effects were treatment related or simply reflected level person (mg/ solution volume volume the study conditions. In each group, subjects received CR665 (mg/kg) (mg/30 mL) 40 mL) (mg/mL) (mL) (mL) or placebo. Doses were administered as a single constant rate O.O15 1.OS 140 O.04 O.14 39.86 IV infusion over 1 hour (part A) or 5 minutes (part B) on the O.O3 2.10 2.80 O.O7 O.28 39.72 morning of Day 1. Doses were administered in an escalating O.O6 4.20 5.60 O.14 O.S6 39.44 manner following satisfactory review of the safety data and O.12 840 11.20 O.28 1.12 38.88 pharmacokinetic data from the lower dose levels. There was a O.24 16.8O 22:40 O.S6 2.24 37.76 minimum of 6 days between dose escalations to allow suffi cient time for an adequate safety review. Concentration 10 mg/mL 0172 Dose levels were as shown in Table 1: (0176 The dose was administered via a cannula inserted into a suitable vein of the forearm in the non dominant arm of TABLE 1. the subject. The dose was infused over a 1 hour period in the morning between 07:00 and 10:30, using an IMED Gemini Treatments PC 1 infusion pump operating at a constant rate of 0.5 Infusion mL/min (30 mL/h). A total of 30 mL of dosing solution (from Part Group Population Treatment duration 40 mL in the Syringe) was administered, and the Subjects A. A1 Males 0.015 mg/kg placebo. 1 hour remained Supine throughout the infusion. A2 Males 0.03 mg/kg placebo 1 hour 0177. From 24 hours after the start of the infusion, meals A3 Males 0.06 mg/kg placebo 1 hour were provided at appropriate times on each day. Other than A4 Males 0.12 mg/kg placebo 1 hour the fluid restrictions on Day 1, water was freely available at all AS Males 0.24 mg/kg placebo 1 hour A6 Males 0.48 mg/kg placebo 1 hour times. The Volume of fluid consumed up to 24 hours after the A7 Males 0.36 mg/kg placebo 1 hour start of the infusion was recorded as part of the fluid balance A8 Males 0.48 mg/kg placebo 1 hour assessment. Subjects fasted from food and beverages (other A9 Females 0.24 mg/kg placebo 1 hour than water) from 22:00 on Day 1, until the clinical laboratory A10 Females 0.42 mg/kg placebo 1 hour A12 Males 0.42 mg/kg placebo 1 hour samples had been taken on the following day, and for at least B B1 Males 0.03 mg/kg placebo 5 minutes 6 hours prior to the follow up visit. B2 Females 0.06 mg/kg placebo 5 minutes 0178. On arrival at the clinical study center on Day -1, pre B3 Males 0.06 mg/kg placebo 5 minutes dose assessments were performed, including testing a urine B4 Males 0.09 mg/kg/placebo 5 minutes sample for the presence of illicit drugs, administering an alcohol breath test, and the recording of body weight (in 0173 CR665 was prepared according to Good Manufac underclothes). Subjects then commenced a 24 hour urine turing Practice (GMP) standards and provided as bulk supply collection for assessment of creatinine clearance and fluid in, 2 mL glass vials, each containing CR665 Solution (1.1 mL balance. Vitals signs and 12 lead ECG were also assessed, and at a concentration of 10 mg/mL free base in isotonic 0.04M all Subjects received a physical examination. acetate buffer, pH 4.5). Placebo solution (isotonic 0.04M 0179 The condition of each subject was monitored acetate buffer, pH 4.5) for IV administration, of identical throughout the study. In addition, any signs or symptoms appearance, i.e., a clear, colorless solution, was also prepared. were observed and elicited by open questioning, Such as The IV dose solutions were stored at 2°C. to 8° C. “How have you been feeling since you were last asked?” at 0.174. The individual intravenous dose for each subject the following times for each part of the study: Pre dose, 0.5, 1. was prepared from bulk Supplies (2 mL vials containing 1.1 3, 12, 24, 36 and 48 hours after the start of the infusion (up to mL of CR665 or placebo solution). For each dose preparation, 24 hours only for Groups A 1 to A4), and at Follow up an appropriate volume of CR665 solution (10 mg/mL) or aSSeSSment. US 2013/0012431 A1 Jan. 10, 2013

0180 Subjects were also encouraged to spontaneously TABLE 3-continued report adverse events occurring at any other time during the study. Any adverse events and remedial action required were Gamma-glutamyl IUL Haematocrit (PCV) % transferase (GGT) Mean cell volume (MCV) f1. to be recorded for each subject. The nature, time of onset, Sodium mmol/L. Mean cell pg duration and severity were documented, together with the Potassium mmol/L haemoglobin (MCH) Project Physician’s opinion of the relationship to drug admin Chloride mmol/L MCH concentration gdL istration. Calcium mmol/L (MCHC) norganic phosphate mmol/L Platelet count 109 L 0181. The condition of the dosing cannula site for each Glucose mmol/L. Differential WBC 109? Subject was monitored for erythema, pruritus and Swelling at Urea mmol/L. L & 96 the following times: Pre dose, 0.5, 1, 2 and 24 hours after the Bilirubin (total) Imol/L. start of the infusion. Subjects were also encouraged to spon Creatinine Imol/L. taneously report adverse events relating to the infusion site at Total protein g/L any other time during the study. Any adverse events and Albumin g/L observations relating to the infusion site and remedial action required were to be recorded for each subject. The nature, Urinalysis: Units Serology: Units time of onset, duration, and severity were to be documented, Microscopic examination + Hepatitis B surface antigen neg pos together with the Project Physician's opinion of the relation Specific gravity NA (HBSAg) ship to drug administration. bH NA Hepatitis Cantibody' neg pos 0182 Supine and standing blood pressure, supine pulse Protein -- HIV antibodies' neg pos Glucose -- rate and oral body temperature were measured in duplicate at Ketones -- the following times: Day 1: Pre dose, 15 minutes (Part B Blood -- only), 30 minutes, 55 minutes, 1.5, 2, 2.5, 3, 4, 8, 12, 24 and Urobilinogen -- 48 hours after the start of the infusion (up to 24 hours only for Direct bilirubin analyzed only if total bilirubin is elevated Groups AI to A4); and at Follow up visit. Supine vital signs Analyzed at screening only only were measured during the infusion period. Pre dose Neg=Negative blood pressure and pulse rate were measured in triplicate at Pos = Positive approximately 2 minute intervals. The median value was used as the baseline value in the data analysis. All Subsequent 0.184 Blood samples (2.5 mL) were collected for evalua measurements were performed singly, but repeated in dupli tion of serum prolactin at the following times: Pre dose (in cate if outside the relevant clinical reference ranges. If triplicate, with at least a 15 minute interval between each of repeated, the median of the three values were used in the data the triplicate predose samples), 15 minutes, 30 minutes, 45 analysis. Blood pressure and pulse rate were measured using minutes, 1 hour (immediately prior to the end of infusion), 1 automated Critikon DinamapTM PRO 400 monitors. Subjects hour 5 minutes, 1 hour 10 minutes, 1 hour 15 minutes, 1.5, 2, were required to be supine for at least 5 minutes before blood 2.5, 3, 4, 6, 8 and 12 hours after the start of the infusion (18 pressure and pulse rate measurements. Standing blood pres samples). Sure and pulse rate were then measured singly after the Sub 0185. Plasma and urine samples for the analysis of CR665 ject had been sitting for approximately 1 minute and then and N oxide metabolite were prepared by solid phase extrac standing for approximately 2 minutes. Oral body temperature tion. The centrifuged eluates were quantified by liquid chro was measured singly using an Omron digital thermometer. To matography with tandem mass spectrometric detection (LC assess drug effects on cardiovascular function, a 12 lead rest MS/MS). The lower limit of quantification was 1 ng/mL. ing ECG with a 10 second rhythm strip was recorded on a Marquette MAC5000 ECG machine at the following times, 0186. After collection of urine samples, following after the subject has been supine for at least 5 minutes: Day 1: removal of the aliquots for drug assay and/or urinalysis, urine Pre dose, 50 minutes, 2, 4, 8, 24 and 48 hours after the start of was pooled over the following time intervals: 24 to 0 hours the infusion (up to 24 hours only for Groups A1 to A4); and at and 0 to 24 hours after the start of the infusion. A 10 mL the follow up visit. The ECG machine computed the PR, QT aliquot was removed from the each pooled collection for and QTc intervals, QRS duration, and heart rate. The QT determination of urinary creatinine. interval was corrected for heart rate (QTc) using Bazett's 0187. An assessment of fluid balance (made by compari formula. For continuous ECG measurements, continuous car son of volume of fluid consumed and volume of fluid diac Hotter monitoring of each Subject, using Reynolds excreted) was made over the following periods: 24 to 0 hours Tracker II Holier monitors, was performed from 1 hour prior and 0 to 24 hours after the start of the infusion. During these to until 4 hours after the start of the infusion. Blood and urine periods, the volume of fluid consumed and the volume of samples were collected, after at leasta 6 hour fast, for clinical urine excreted was recorded. laboratory evaluations at the following times during the 0188 A full physical examination, including a neurologi study: Predose and 24 hours after the start of the infusion; and cal examination, was performed at the following times: Dis at the follow up visit. charge (Day 2 or 3) and at Follow up visit. 0183 The following evaluations were performed, as 0189 For pharmacokinetic assessments, blood samples shown in Table 3. (1x3 mL) were taken from the contralateral forearm vein(s)at the following times: Pre-dose, 15 minutes, 30 minutes, 45 TABLE 3 minutes, 1 hour (immediately prior to the end of infusion), 1 hour 5 minutes, 1 hour 10 minutes, 1 hour 15 minutes, 1.5, 2, Serum biochemistry: Units Hematology: Units 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after the start of the Aspartate IUL White blood cell count 109 L infusion). An indwelling cannula (Venflon R; BOC Ohmeda aminotransferase (AST) (WBC) AB, Sweden) was used for all blood collection pre-dose and Alanine IUL Red blood cell count 1012 L. up to at least 12 hours after the start of the infusion. Other aminotransferase (ALT) (RBC) wise, samples were collected using Venipuncture. Blood Alkaline phosphatase IUL Haemoglobin gdL samples were collected into pre-chilled 3 mL KEDTA Vacu tainerTM tubes (Becton Dickinson UK, Ltd., Oxford) and, US 2013/0012431 A1 Jan. 10, 2013 after mixing, were placed in a cool box containing crushed 0.195 The following plasma pharmacokinetic parameters ice/water. The samples were centrifuged, within 30 minutes were determined for CR665: of collection, at 1500 g for 10 minutes at approximately 4°C. 0196. C. Maximum plasma concentration For each sample, the separated plasma was transferred into 0.197 t Time of maximum plasma concentration two 5 mL suitably labeled polypropylene, tubes, and stored 0198 t. Terminal half-life-ln(2)/2 immediately at approximately -20°C. Plasma samples were 0199 AUC. Area under the plasma concentration analyzed for CR665 using liquid chromatography with tan time curve from time Zero to time t (time of last quanti dem mass spectrometric detection. fiable plasma concentration) 0200 AUC. Area under the plasma concentration 0190. Urine was collected into standard weight polyethyl time curve from time Zero to infinity calculated as ene containers over the following time intervals: Pre dose AUCo+(C/W) where C is the estimated concen (-24 to 0), 0 to 4, 4 to 8, 8 to 12, 12 to 24 and 24 to 48 hours tration at the last quantifiable concentration curve. after the start of the infusion. During each collection period, 0201 W Terminal-phase rate constant, also known as the containers were stored in a refrigerator at 2 to 8°C. The Kel weight(g) of each collection was recorded prior to removal of (0202 CL Total body clearance Dose/AUC, two Sub samples (each approximately 4 mL) into Suitably 0203 V. Volume of distribution based on terminal labeled polypropylene containers, which were stored within2 phase calculated as hours of collection, at approximately -20°C. Additional ali quots (1x100 mL per collection period) were stored for pos sible future analyses. Any remaining urine from post close 0204 Individual elapsed sampling times were used in the collection intervals was pooled with the rest of the urine pharmacokinetic analysis. C, and t, were obtained collected during the 0 to 24 hour collection period, for analy directly from the experimental observations. For the purpose sis of creatinine clearance. A nominal value for specific grav of calculating AUC, when two consecutive plasma concen ity of 1.018 was used to calculate urine volume. trations below the lower limit of quantification (LLOQ) were encountered after t, all Subsequent values were excluded 0191 The pharmacokinetic analysis was conducted using from the analysis. The exponential rate constant of the termi WinNonlin Enterprise Version 4.0.1. nal-phase, W, was estimated by linear regression of the log 0.192 Pharmacokinetic parameters were determined from concentration-time data associated with the terminal phase of the plasma and urine concentrations of CR665 and the N-ox the plasma concentration-time profile. The number of data ide metabolite using non compartmental procedures. The points included in the regression was determined by visual pharmacokinetic parameters determined are presented in inspection. A minimum of 3 data points in the terminal phase, Table 4 below. excluding C, was required to estimate W. 0205 An assessment of dose-proportionality of the phar TABLE 4 macokinetics of CR665 was also performed. Log-trans formed AUCAUC, and C were derived and a model of Pharmacokinetic Parameters Determined the form: for CR665 and the N-Oxide Metabolite Log(parameter)=Intercept--B'Log(Dose)+Error Parameter Definition where dose is a fixed term was fitted to assess a between AUCo. Area under the plasma concentration-time curve from time Subject estimate of the slope in order to assess dose-propor Zero up to the last quantifiable concentration tionality. A pointestimate of the slope B, with 90% confidence AUCo Area under the plasma concentration-time curve from time intervals, provides a plausible range for which the true slope Zero to infinity % AUC Percentage of AUC that is due to extrapolation from t to occurs. The interpretation of the slope is such that a conclu infinity sion of dose-proportionality for AUCo., AUC, and C of Cmax Maximum observed plasma concentration CR665 will be made if the 90% CI for the slope contains the Cinf Plasma concentration at end of the IV infusion value 1. "max Time of maximum observed plasma concentration 0206. The pharmacodynamic analysis was conducted t Time of last quantifiable plasma concentration using WinNonlin Enterprise Version 4.0.1 (Pharsight Corpo W. Apparent plasma terminal elimination rate constant ration, Mountain View, Calif., USA). The following pharma t1,2 Apparent plasma terminal elimination half-life MRT Intrinsic mean residence time codynamic parameters were calculated from the serum con CL Total plasma clearance (CR665 only) centrations of prolactin: V. Apparent volume of distribution during the terminal phase 0207 Change from baseline (mean of triplicate pre (CR665 only) dose values) at each sampling time V Apparent volume of distribution at steady-state (CR665 only) 0208. Maximum observed change from baseline (C) MR4C Metabolic ratio based on AUC (N-oxide metabolite only) MR. Metabolic ratio based on C (N-oxide metabolite only) 0209 Area under the change from baseline time curve Ae Amount of drug excreted in urine from 0 to 12 hours (AUC) fe Percentage of dose excreted in urine This study was conducted under a MHRA Clinical Trials CLR Renal clearance Authorization (CTA) in accordance with: (1) the relevant articles of the Declaration of Helsinki as adopted by the 18th World Medical Assembly in 1964 and as revised in Tokyo 0193 Dose and body weight normalized values (norm) (1975), Venice (1983), Hong Kong (1989), South Africa were determined for AUCo., AUCo., C. and C. Body (1996) and Scotland (2000); and (2) the ICH Good Clinical weight normalized values norm were determined for V. Practices (GCP) consolidated guidelines adopted in the EU V.SS CL and CL. by CPMP, July 1996, issued as CPMP/ICH/135/95. 0194 The pharmacokinetic analysis was conducted using Drug Safety model independent methods as implemented in WinNonlin software, based on plasma concentrations of CR665 from 0210 All 54 subjects completed the treatment period with those subjects who have received CR665 and have evaluable no severe or serious adverse events. In particular, even at the plasma concentration-time profiles. highest dose levels, there were no signs of the more typical US 2013/0012431 A1 Jan. 10, 2013

CNS symptoms (hallucinations or dysphoria) associated with TABLE 6 intolerable dose levels of previously tested kappa opioid receptor agonists. For the 12-lead ECG evaluations, there Summary of the Pharmacodynamic Parameters of Serum Prolactin were no treatment related trends, significant clinical changes, (Changes from Baseline) Following a 1 hour IV Infusion in Female or abnormalities in the morphology of the 12 lead ECG. Subjects (PartA Similarly, for the clinical laboratory evaluations, there were Dose of (mg/kg no treatment related trends or significant clinical findings in serum biochemistry, hematology, or urinalysis parameters. Placebo O.24 Physical examination of the subjects also revealed no treat females females ment related findings. Parameter (N = 3) (N = 3) 0211. In Parts A and B of the study, there were no treat AUCo-12, 19.7 209 ment or close related trends in mean Supine and standing (ng himL) (23.5) (21.1) systolic and diastolic blood pressure, Supine and standing Cmax 3.67 68.2 pulse rate or oral body temperature. No apparent treatment or (ngmL) (2.27) (14.3) dose related trends in the 12 lead ECG parameters were noted Arithmetic mean (SD) data are presented in Parts A and B. In addition, there were no clinically impor N = Number of subjects studied tant findings in the morphology of the 12 lead ECGs for individual subjects at each dose level of CR665. There was no evidence of prolongation of QTc interval (Bazett's and TABLE 7 Friedericia's corrected) at each dose level of CR665 in male Summary of the Pharmacodynamic Parameters of Serum Prolactin and female Subjects. (Changes from Baseline) Following a 5 minute IV Infusion in Male and 0212 For Parts A and B, there were no clinically important Female Subjects (Part B changes in creatinine clearance, estimated from serum crea tinine, for any subject during the study. The mean creatinine Dose of (mg/kg clearance was generally similar prior to dosing and at 24 hours after dosing for each dose level of CR665 and placebo. males males males males females There were no apparent treatment or dose related trends in Parameter (N = 5) (N = 4) (N = 4) (N = 4) (N = 4) fluid balance (urine excreted-fluid consumed) over the 0 to AUCo-12, -0.876 24.3 74.3 68.5 96.8 24 hour period after the start of the infusion. However, an (ng himL) (34.1) (35.4) (44.2) (13.5) (32.9) increase in the Volume of urine excreted over the first 4 hours Cmax 4.08 33.6 42.O 37.1 32.3 after the start of the infusion was observed at each dose level (ng/mL) (3.63) (14.3) (22.8) (13.3) (14.8) of CR655 compared to placebo in male and female subjects Arithmetic mean (SD) data are presented for Parts A and B of the study. N = Number of subjects studied Pharmacodynamics 0215. In Part A, following 1-hour infusions of 0.015 to 0.48 mg/kg. CR665 in male subjects, there was a rapid and Time Course of Prolactin Elevation by CR665 marked increase in serum prolactin concentrations. At each dose level, maximum serum prolactin concentrations gener 0213. The administration of single IV doses of CR665 ally occurred at 1 hour after the start of the infusion, i.e. at the caused a rapid and marked increase in serum concentrations end of the infusion. There was an apparent dose-related of prolactin across all dose levels in male and female Subjects. increase in mean values for C (maximum changes from Changes from baseline (pre dose) in serum concentrations of baseline in serum prolactin) up to the 0.36 mg/kg dose level. prolactin following 1-hour and 5-minute infusions of placebo Mean C. values were generally similar at the 0.36, 0.42 and and CR665 in male and female subjects are shown in FIGS. 1 0.48 mg/kg dose levels, with maximum serum prolactin lev to 3: els being approximately 5- to 6-fold higher than baseline 0214. The derived pharmacodynamic parameters for (pre-dose) across these dose levels. Mean values for AUCo serum prolactin following 1-hour and 5-minute infusions of h (changes from baseline) increased up to 0.36 mg/kg, and placebo and CR665 in male and female subjects are summa thereafter were generally similar over the 0.36 to 0.48 mg/kg rized in Tables 5 to 7: dose range. Following maximum concentrations of prolactin, TABLE 5 Summary of the Pharmacodynamic Parameters of Serum Prolactin Changes from Baseline) Following a 1 hour IV Infusion in Male Subiects (Part A Dose of (mg/kg

Placebo 0.015 O.O3 O.O6 O.12 O.24 O36 O42 O.48 males males males males males males males males males Parameter (N = 17) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 8) AUCo-12, O.760 30.8 57.4 43.6 89.5 119 140 132 131 (ng himL) (27.5) (87.6) (30.3) (32.2) (38.6) (22.3) (40.0) (51.5) (74.5) Cmax 4.61 22.2 18.8 25.3 39.3 36.3 4S.S. 44.2 47.2 (ng/mL) (3.44) (6.44) (1.47) (6.41) (13.9) (17.3) (16.9) (10.8) (27.4) Arithmetic mean (SD) data are presented N = Number of subjects studied US 2013/0012431 A1 Jan. 10, 2013 20 there was a dose-related decrease to baseline levels. Mean 0220. During the IV infusion of CR665 at dose levels of values had fallen to close to baseline values by 8 hours at the 0.015 to 0.48 mg/kg in male Subjects, plasma concentrations 0.36, 0.42 and 0.48 mg/kg dose levels. increased rapidly, with maximum concentrations generally 0216. In Part A, following 1 hour infusions of 0.24 mg/kg CR665 in female Subjects, maximum serum prolactin con occurring at the end of the 1 hour infusion. Plasma concen centrations occurred at 1 hour after the start of the infusion. trations of CR665 were generally similar at 45 minutes and 1 The mean C. values (change from baseline) in females hour after the start of the infusion for individual subjects at were higher than in male Subjects, with maximum serum each dose level. prolactin levels being approximately 12-fold greater than baseline (pre dose) in females. 0221 Following the end of the IV infusion, plasma con 0217. In Part B, following 5-minute infusions of 0.03 to centrations of CR665 appeared to decline in an essentially 0.09 mg/kg. CR665 in male subjects, maximum serum pro biphasic manner with the start of the elimination phase occur lactin concentrations occurred at 30 minutes after the start of ring between 1.25 and 6.0 hours after the start of the infusion. the infusion, i.e., 25 minutes after the end of the infusion. Mean C. values were generally similar at the 0.03, 0.06 and 0222. The mean apparent elimination half life was rela 0.09 mg/kg dose levels, with maximum serum prolactin lev tively constant in the 0.015 to 0.06 mg/kg dose range, at about els being approximately 4- to 6-fold higher than baseline (pre 0.7 hours, but became longer across the 0.12 to 0.48 mg/kg dose) across these dose levels. In female Subjects, maximum dose range, varying from 1.4 to 1.9 hours, with a trendtoward serum prolactin concentrations occurred at 0.5 to 1 hour after longer halflife values at higher doses. For individual subjects the start of the 5-minute infusion of 0.06 mg/kg. CR665. The across the 0.12 to 0.48 mg/kg dose range, the apparent elimi mean C. value in females was similar to male subjects, with nation half life ranged from 1.2 to 3.0 hours. This apparent maximum serum prolactin levels being approximately 4-fold increase in half life at higher dose levels is consistent with greater than baseline (pre dose) in females. plasma concentrations of CR665 being quantifiable for a Part A longer period of time at the higher dose levels, revealing more of true terminal elimination phase. As a result, statistical Pharmacokinetics of CR665 after a One Hour analysis showed that the elimination half life for CR665 was Intravenous Infusion dose dependent over the entire dose range. 0218. The plasma concentrations of CR665 following a 1 0223 AUCo. and C generally appeared to increase in hour infusion in male subjects are shown in FIGS. 4 and 5. a dose-proportional manner over the dose range of 0.015 to 0219. The pharmacokinetic parameters of CR665 follow 0.48 mg/kg. This observation was confirmed by statistical ing a 1-hour infusion in male Subjects are Summarized in analysis, with the estimates of the slopes (95% CI) from the Table 8. regression analysis for AUC and C being 1.02 (0.978 to TABLE 8 Summary of the Pharmacokinetic Parameters for CR665 Following a 1 hour IV Infusion in Male Subiects (PartA Dose of (mg/kg) males

O.O15 O.O3 O.O6 O.12 O.24 O.36 O42 O.48 Parameter (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 8) AUCo. 3O.O 70.O 129 267 474 808 1080 112O (ng himL) (20.3) (14.2) (30.2) (7.17) (10.4) (8.39) (17.4) (20.5) AUCo. 31.4 72.5 132 270 478 812 1084 112S (ng himL) (21.7) (15.5) (29.8) (7.11) (10.5) (8.37) (17.5) (20.4) Cmax 27.8 65.3 119 231 431 779 943 982 (ng/mL) (15.2) (13.7) (24.8) (5.87) (8.30) (10.1) (13.7) (15.7) tna, 1.00 1.00 0.875 0.750 1.OO 1.OO 1.00 0.875 (h) (0.750-1.02) (1.00-1.00) (0.733-1.35) (0.750-1.00) (1.00-1.00) (0.767-1.00) (0.750-1.00) (0.750-1.00) AUCo. 1979 2349 21 61 2232 1979 2252 2573 2333 (norm) (20.5) (14.6) (30.1) (7.06) (10.2) (8.40) (17.0) (20.5) AUCo. 2O72 2430 22O1 2257 1994 2263 2582 2344 (norm) (22.0) (16.0) (29.7) (7.00) (10.3) (8.38) (17.1) (20.5) Cmax 1837 21.89 1991 1932 1797 2170 2248 2046 (norm) (15.1) (13.8) (24.7) (5.86) (8.12) (10.1) (13.2) (15.9) t1/2 O.691 0.732 O.728 1.65 1.37 1.64 1.78 1.87 (h) (73.2) (50.0) (14.4) (24.0) (17.6) (21.0) (41.8) (36.4) MRT O.S12 O.S10 O.S63 0.723 O.614 O.623 O.618 O649 (h) (43.5) (35.8) (25.7) (23.1) (15.6) (19.8) (17.5) (20.8) CL S60 538 S64 533 629 569 SO4 576 (mL/min) (15.2) (16.0) (17.8) (8.71) (6.47) (11.5) (21.3) (18.6) V. 33.5 34.1 35.5 75.9 74.6 80.6 77.9 93.3 (L) (60.2) (42.2) (7.44) (20.9) (15.7) (13.3) (22.3) (39.1) V 17.2 16.5 19.0 23.1 23.2 21.2 18.7 22.4 (L) (35.4) (31.3) (32.1) (22.3) (18.0) (16.0) (8.42) (20.3) Geometric mean (CV%) data are presented Median (min-max) N = Number of subjects studied (norm) = Normalized for dose and body weight (mg/kg) US 2013/0012431 A1 Jan. 10, 2013

1.06) and 1.02 (0.984 to 1.05). FIG. 6 illustrates the dose TABLE 9-continued proportional increase in AUC for CR665 over the dose range of 0.015 to 0.48 mg/kg. Summary of the Pharmacokinetic Parameters for CR665 Following a 1-hour IV Infusion of 0.24 mg/kg CR665 in Male and Female Subjects 0224. The dose proportionality of the increase in AUC was PartA found to be almost perfectly linear, as shown in FIG. 6, with an R value of 0.98, meaning that, for this data set, 98% of the 0.24 mg/kg variation in systemic exposure to CR665 is due to variation in the administered dose of CR665. The importance of this Males Females observation is that it enables the practitioner to predict, with Parameter (N = 4) (N = 3) a high degree of accuracy, what drug exposures will occur t1/2 1.37 1.16 (h) (17.6) (15.9) with a given dose of drug. In fact, one skilled in the art can use MRT O.614 0.515 this information, together with the calculated pharmacoki (h) (15.6) (12.9) netic parameters of the drug (see Table 6), to accurately CL 629 557 estimate the plasma levels of drug that would result from (mL/min) (6.47) (9.21) V. 74.6 55.7 intravenous infusions of different doses, at what time a steady (L) (15.7) (12.4) state concentration of drug would be achieved, and how to V 23.2 17.2 design individualized dosage regimens to achieve steady state (LS (18.0) (13.1) drug concentrations for a particular patient (Bauer, L. A. Geometric mean (CV%) data are presented Applied Clinical Pharmacokinetics, Chap. 2. “Clinical phar Median (min-max) macokinetic equations and calculations', pp. 26 49, 2001). N = Number of subjects studied Since controlled release formulations (e.g., microspheres) (norm) = Normalized for dose and body weight (mg/kg) and devices (e.g., for electrotransport) are intended to provide 0229. Following administration of 0.24 mg/kg. CR665 in prolonged steady state drug concentrations, the skilled prac female Subjects, maximum plasma concentrations were titioner utilizes this pharmacokinetic information to define obtained at a similar time to those observed in males, i.e., the useful operating characteristics of modes of drug delivery. close to the end of the IN infusion. Thereafter, the disposition 0225 Statistical analysis showed that total plasma clear kinetics of CR655 were similar in male and female subjects, ance of CR665 (CL) was dose-independent; however MRT with a mean terminal elimination half-life of approximately 1.2 to 1.4 hours. At the 0.24 mg/kg dose level, mean values for and the volume of distribution (V and V) were found to be AUCo., AUCo. (norm), C, and C (norm) were gener dose-dependent. This was due to the observed change in the ally similar in male and female subjects. The between-subject elimination rate constant (), which was probably due to the variability for AUCo. and C was low and similar in male fact that the CR665 was quantifiable for a longer period of and female subjects at the 0.24 mg/kg dose level. These time, post-injection, at the higher dose levels, rather than true findings are important because they confirm the predictability dose-dependency in the kinetics of CR665. of the pharmacokinetics of CR665, which assists the skilled 0226 Geometric mean plasma concentrations of CR665 practitioner in the design of alternative dosing regimens that are intended to achieve particular plasma levels of drug over following a 1-hour infusion of 0.24 mg. CR665 in female time. subjects are summarized in FIGS. 7 and 8. 0230. The urinary excretion of CR665 following a 1-hour 0227 Arithmetic mean plasma concentrations of CR665 infusion of 0.24 mg/kg. CR665 in male and female subjects is following a 1-hour infusion of 0.24 mg/kg. CR665 in male and summarized in Table 10. female subjects are summarized in FIG. 9. 0228. The pharmacokinetic parameters of CR665 follow TABLE 10 ing a 1-hour infusion of 0.24 mg/kg. CR665 in male and female subjects are summarized in Table 9. Summary of the Urinary Excretion of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg. CR665 in Male and Female Subiects (Part A TABLE 9 0.24 mg/kg Summary of the Pharmacokinetic Parameters for CR665 Following a Males Females 1-hour IV Infusion of 0.24 mg/kg CR665 in Male and Female Subjects Parameter (N = 4) (N = 3) PartA Aeo-24, 631 446 0.24 mg/kg (Ig) (39.1) (30.0) feo 24, 3.SO 3.02 Males Females (%) (26.2) (23.2) Parameter (N = 4) (N = 3) CLR 0-24, 22.0 16.8 (mL/min) (27.9) (22.7) AUCo. 474 440 (ng himL) (10.4) (10.2) Geometric mean (CV%) data are presented AUCo. 478 442 N = Number of subjects studied (ng himL) (10.5) (10.1) Cmax 431 384 0231. The fraction of the dose excreted in the urine as (ngmL) (8.30) (3.03) tna, 1.OO 0.750 unchanged drug was low in female Subjects, and similar to (h) (1.00-1.00) (0.750-1.00) that seen for male Subjects. AUCo. 1979 1846 Part B (norm) (10.2) (9.71) AUCo. 1994 1855 Extrapolation of Part A PK Data to Design Brief IV (norm) (10.3) (9.65) Infusions of CR665 Cmax 1797 1612 (norm) (8.12) (2.33) 0232 For the Part B studies, five minute infusion dosing protocols were designed using conventional pharmacokinetic US 2013/0012431 A1 Jan. 10, 2013 22 calculations (e.g., Bauer, L. A. Applied Clinical Pharmacoki 0237. In male Subjects, AUCo. and C generally netics, Chap. 2. “Clinical pharmacokinetic equations and cal appeared to increase in a dose-proportional manner over the culations”, pp. 2649, 2001), based on the results obtained in dose range 0.03 to 0.09 mg/kg. This was confirmed by statis the one hour infusion study (Part A). Doses were calculated to tical analysis, with the estimates of the slopes (95% CI) from produce systemic exposures to CR665 similar to those seen in the regression analysis for AUCo. and C being 1.04 the one hour infusion study (0.853 to 1.22)and 1.12 (0.800 to 1.44). FIG. 12 illustrates the 0233 Plasma concentrations of CR665 following a dose-proportional increase in AUC for CR665 over the 5-minute infusion in male and female Subjects are shown in dose range of 0.03 to 0.09 mg/kg in male subjects. FIGS. 10 and 11. 0238. At the 0.06 mg/kg dose level, mean values for 0234. The pharmacokinetic parameters of CR665 follow AUCo., AUCo., (norm), C, and C (norm) were gen ing a 5-minute infusion in male and female Subjects are sum erally similar in male and female Subjects following a marized in Table 11. 5-minute infusion. TABLE 11 Summary of the Pharmacokinetic Parameters for CR665 Following a 5-minute IV Infusion in Male and Female Subiects (Part B Dose of (mg/kg

O.O3 O.O6 O.09 OO6 males males males females Parameter (N = 3) (N = 4) (N = 4) (N = 3) AUCo. 65.9 139 209 12O (ng himL) (12.6) (15.8) (16.2) (9.29) AUCo. 68.4 142 213 122 (ng himL) (11.8) (16.3) (16.4) (8.79) Cmax 233 624 783 52O (ng/mL) (14.5) (32.2) (19.6) (18.8) tna, O.0833 O.0833 O.0833 O.O833 (h) (0.0833-0.100) (0.0833-0.0833) (0.0833-0.0833) (0.0833-0.0833) AUCo. 2192 2327 2318 2013 (norm) (12.3) (16.0) (16.1) (8.92) AUCo. 2273 2372 2369 2044 (norm) (11.6) (16.5) (16.2) (8.43) Cmax 7751 10418 8701 8716 (norm) (14.4) (32.5) (19.8) (18.4) t1/2 1.31 1.00 1.14 O.833 (h) (18.3) (13.0) (23.9) (22.4) MRT O.615 O.SO2 0.537 O419 (h) (448) (26.3) (21.0) (24.2) CL 473 553 575 544 (mL/min) (7.06) (15.5) (14.3) (9.47) V. S3.6 48.0 56.7 39.2 (L) (14.0) (13.4) (33.5) (21.5) V 17.4 16.6 18.5 13.7 (L) (3.13) (24.2) (24.3) (18.8) Geometric mean (CV%) data are presented Median (min-max) N = Number of subjects studied (norm) = Normalized for dose and body weight (mg/kg)

0235. Following the IV infusion of CR665 at dose levels of 0239 Mean values for MRT, CL, V and V were simi 0.03 to 0.09 mg/kg in male Subjects, plasma concentrations lar across the 0.03 to 0.09 mg/kg dose range in male subjects, increased rapidly with maximum concentrations generally which was confirmed by statistical analysis. Mean values for occurring at the end of the 5-minute infusion. Similarly, maxi each parameter were also similar for male and female Subjects mum concentrations of CR665 following administration of 0.06 mg/kg. CR665 in female subjects were also attained at at the 0.06 mg/kg dose level. the end of the 5 minute infusion. Following the end of the IV 0240. In general, low between-subject variability was infusion, plasma concentrations of CR665 appeared to noted for AUC and C in male subjects, with CV '% decline in an essentially biphasic manner, with the start of the values ranging from 11.8 to 16.4% and 19.6% to 32.2%, elimination phase occurring between 1.0 to 2.0 hours after the respectively. Across all doses in male Subjects, the pooled start of the infusion in both male and female subjects. between-subject variability for AUC and C was 15.3% 0236. In male subjects, the mean apparent elimination half and 24.1%, respectively. The between-subject variability for life, about 1.0 to 1.3 hours, was similar across the 0.03 to 0.09 AUCo. and C was also low in female Subjects at the 0.24 mg/kg dose range. Statistical analysis confirmed that the mg/kg dose level, with CV '% values of 8.8% and 18.8%, elimination half life for CR665 was independent of dose. The respectively. disposition kinetics of CR655 were similar in male and female subjects, with the mean terminal elimination half life 0241 The urinary excretion of CR665 following a of CR665 being approximately 0.8 hours in females at the 5-minute infusion in male and female Subjects is Summarized 0.06 mg/kg dose level. in Table 12: US 2013/0012431 A1 Jan. 10, 2013 23

TABLE 12 0242. In male subjects, the fraction of the dose excreted in the urine as unchanged drug was low for all dose levels, with Summary of the Urinary Excretion of CR665 Following a 5-minute IV approximately 3.5% being eliminated up to 24 hours post Infusion in Male and Female Subiects (Part B dose. The fraction of unchanged drug excreted in the urine Dose of (mg/kg was also low in female subjects (3.8%), and similar to male O.09 O.O6 Subjects. males males males females 0243 The amount of CR665 excreted in the urine Parameter (N = 3) (N = 4) (N = 4) (N = 3) increased in a dose proportional manner over the dose range Aeo-24, 70.O 157 262 153 studied in male subjects. This was confirmed by statistical (Ig) (27.3) (25.8) (13.5) (16.9) analysis, with the slopes of the regression not being signifi feo 24, 3.60 3.33 3.56 3.83 (%) (29.6) (27.6) (7.29) (24.0) cantly different from unity. Renal clearance was generally CLR 0-24h 17.1 18.4 2O.S 20.9 low and similar across all dose levels, with dose indepen (mL/min) (22.7) (24.6) (12.0) (17.7) dence being confirmed by statistical analysis. Geometric mean (CV%) data are presented 0244. The results of the statistical analyses to assess the N = Number of subjects studied effect of infusion time on the pharmacokinetic parameters of CR665 in male subjects are presented in Table 13. TABLE 13

Statistical Analysis of the Effect of Infusion Time on the Pharmacokinetic Parameters for CR665 in Male Subjects (Parts A & B)

Geometric least Ratio of Squares means geometric least

5-minute 1-hour squares means 90% CI for the 95% CI for the Parameter infusion infusion 5-minute:1-hour ratio ratio

AUCo. 2286 2238 1.02 O.957 to 1.09 O.944 to 1.11 (norm) AUCo. 2343 2260 1.04 O.971 to 1.11 O.957 to 112 (norm) Cmax 90O2 2003 4.49 3.98 to S.O8 3.87 to S.22 (norm) t1/2 1.28 1.25 1.02 O.804 to 1.29 O.762 to 1.37 (h) MRT iai 0.558 O.6OS O.923 O.817 to 1.04 O.794 to 1.07 (h) CL 538 557 O.964 O.903 to 1.03 0.889 to 1.05 (mL/min)

V 2 61.O 59.1 1.03 O.825 to 1.29 O.784 to 1.36 (L) V 18.1 20.1 O.900 O.804 to 1.01 0.783 to 1.03 (L) feo 24, 3.48 3.46 1.01 O.908 to 1.12 O.887 to 1.15 (%)

(norm) = Normalized for dose and body weight (mg/kg)

0245. In male subjects, the following pharmacokinetic parameters for CR665 were similar following an IV infusion time of 1-hour versus 5-minutes: AUCo., AUC. t. CL, V, V, and feo-2 . Suggesting that the overall Systemic exposure to CR665, based upon AUC and disposition kinet ics, were not affected by the different infusion times. The only parameter, however, for which the statistical analysis con firmed a significant difference was C, which was, as expected, approximately 4.5-fold higher for the 5-minute compared to the 1-hour infusion. 0246 The statistical analyses of the effect of infusion time on the pharmacokinetic parameters of CR665 in female sub jects are presented in Table 14. US 2013/0012431 A1 Jan. 10, 2013 24

TABLE 1.4 Statistical Analysis of the Effect of Infusion Time on the Pharmacokinetic Parameters for CR665 in Female Subiects

Geometric least Ratio of SClareS IIlcallS geometric least 5-minute 1-hour squares means 90% CI for the 95% C for the Parameter infusion infusion 5-minute:1-hour ratio io

AUCo. 2013 1936 1.04 O.918 to 1.18 O.893 o 1.21 (norm) AUCo. 2044 1943 1.OS O928 to 1.19 O.903 (norm) Cmax 8716 1655 5.27 4.17 to 6.66 3.96 (norm) t1/2 O.946 1.OS O.901 O.606 to 134 O554 (h) MRT O430 O498 O864 O.708 to 1.06 0.677 (h) CL 544 573 O.9SO O.837 to 1.08 O.813 (mL/min) V. 45.7 SO.2 O.911 O.628 to 1.32 O.S77 (L) V 14.1 17.0 O.832 O.692 to 1.OO O.664 o 1.04 (L) feo 24, 3.83 2.70 1.42 1.16 to 1.73 (%) (norm) = Normalized for dose and body weight (mg/kg)

0247. In female subjects, the following pharmacokinetic likely cause of the absence of a correlation is the temporal parameters for CR665 were similar following an IV infusion dissociation of pharmacokinetics and pharmacodynamics in time of 1-hour versus 5-minutes: AUC, AUC. t. CL, these subjects: while plasma CR665 concentrations peaked at V, V, and feo, Suggesting that the overall Systemic expo the end of the 5-minute infusion and declined thereafter, sure to CR665, based upon AUC and disposition kinetics, serum prolactin concentrations only began to significantly were not affected by the different infusion times. However, as rise at 10 minutes (5 minutes after the end of the infusion), and would be expected, C, was significantly higher (5.3-fold) continued to rise at 30 minutes, with substantial but declining for the 5-minute compared to the 1-hour infusion. These levels measured at 60 minutes. Under these conditions, a findings reinforce the predictability of the pharmacokinetics correlation between plasma CR665 concentrations and serum of CR665, which aids the skilled practitioner in the design of prolactin concentrations would not be expected. However, drug administration protocols that are designed to achieve a with longer (e.g., 1 hour) infusions of CR665, the plasma particular level of systemic exposure to drug without undue concentration of CR665 may better reflect the concentration experimentation. of CR665 in the pharmacodynamically relevant compartment (i.e., high affinity kappa opioid receptors), and thereby yield Pharmacodynamic the significant linear relationship shown in FIGS. 13 and 14. 0251. Following administration of 0.015 to 0.48 mg/kg Pharmacokinetic Relationship CR665 as a 1-hour infusion in male subjects, AUC and C increased in a dose-proportional manner over the entire 0248. The relationship between pharmacodynamic dose range. The between-subject variability in the pharmaco parameters of serum prolactin (changes from baseline) and kinetics of CR665 was low in male subjects. pharmacokinetic parameters of CR665 following IV infu 0252. In female Subjects, maximum plasma concentra sions of 0.015 to 0.36 mg/kg in male subjects is presented in tions of CR665 occurred at the end of the 1-hour infusion FIGS. 13 and 14. period following a 0.24 mg/kg dose, which was similar to 0249. In Part A, there was a direct linear correlation male subjects. The systemic exposure of CR665, based on between serum concentrations of prolactin (based on AUCo AUC and C, was similar in male and female subjects. 12 h and C) and the plasma concentration of CR665 (based The disposition of CR665 was also similar between genders, on AUC and C) over the 0.015 to 0.36 mg/kg dose range with a mean terminal elimination half-life of 1.2 hours in following a 1-hour infusion in male Subjects, with correlation female subjects. Furthermore, similar between-subject vari coefficients of 0.667 and 0.565 for AUC and C values, ability was observed in male and female subjects. respectively. The AUCo. , and C values for serum pro 0253) The duration of infusion had no effect on the overall lactin appeared to plateau at higher AUCo. and C values systemic exposure to CR665, with AUCo. being similar fol for CR665 associated with dose levels of 0.36 to 0.48 mg/kg, lowing the 1-hour and 5-minute infusions in both male and indicating that the maximum increase in serum prolactin had female Subjects. However, maximum plasma concentrations been achieved by 0.36 mg/kg CR665 administered as a 1-hour of CR665 were notably higher following the 5-minute infu infusion. sion compared to the 1-hour infusion, being approximately 0250 In Part B, there was no apparent correlation between 4.5-fold higher in male subjects and 5.3-fold higher in female serum prolactin concentrations and plasma CR665 concen Subjects. The difference in C was expected because of the trations in male Subjects following a 5-minute infusion. A higher rate of infusion used for the 5-minute infusion (360 US 2013/0012431 A1 Jan. 10, 2013

mL/hour) compared to the 1-hour infusion (30 mL/hour). The 7. The method of claim 2, wherein said peptide has the disposition kinetics of CR665 was similar for the 1-hour and formula: 5-minute infusion, and low between-subject variability was observed for both infusion times. 0254 The apparent volume of distribution at steady state wherein Xaa is D-Phe (unsubstituted or substituted by (V) of CR665 in male subjects ranged from 19 to 23 L over C'P', Me, 2F, 4F or 4CI) or D-Ala(cyclopentyl or thie the 0.12 to 0.48 mg/kg dose range, which is similar to the nyl); Xaa, is (A')D-Phe, D-1 Nal, D-2Nal or D-Trp, with volume of extracellular fluid, and is consistent for a peptide A being H, 4F, 40, 4NO or 3.4C1, Xaa, is D-Nle, with limited ability to penetrate lipid-containing membranes. D-Leu, D-CML, D-Met or D-Acp; Xaa, is D-Arg, This observation reflects another aspect of the present inven D-Arg(Et), D-Lys, D-Ily, D-Har, D-Har(Et), D-nArg, tion: a relatively low volume of distribution. The volume of D-Orn, D-Ior, D-Dbu, D-Amf, and D-Amf(Amd); and Q distribution is a quantitative measure of the extent of distri is NR, R2, Mor, Tmo, Pip, 4-Hyp, OxP or Ppz, with R. bution of drug outside the vasculature; it is the apparent being Me, Et, Pr, Bu, hEt, Cyp, Bzl or 4-picolyl, and R. volume which would contain the entire amount of drug in the being H or Et. body at the same concentration it is present in the blood. In 8. The method of claim 7, wherein Xaa, is D-Phe, Xaa is general, a compound with a low volume of distribution will D-Nle and Xaa, is D-Arg. have physical characteristics that impede transport across 9. The method of claim 7, wherein Q is morpholinyl or biological membranes. Thus, a polar compound with a low thiomorpholinyl. apparent volume of distribution, such as CR665, would not be 10. The method of claim 7, wherein Q is NHR and R is expected to cross the blood-brain barrier as well as lipid 4-picolyl. soluble compounds that typically have a higher apparent Vol 11. The method of claim 7, wherein Xaa is D-Nle or ume of distribution, and a greater propensity to cross the D-Leu and Q is morpholinyl. blood-brain barrier. 12. The method of claim 7, wherein Xaa is D-Phe, 0255 All patents and other references cited herein are D-4Fpa, D-2Fpa, D-Acp or D-Ala(2Thi); Xaa, is (A)D-Phe, hereby incorporated by reference. D-1 Nal, D-2Nal or D-Trp, with A being 4F or 4C1, Xaa is 0256. Other embodiments are within the following claims. D-Nle, D-Met or D-Leu; Xaa, is D-Arg, D-Har, D-nArg, What is claimed is: D-Lys, D-Ornor D-Amf(Amd); and Q is NHR, Mor, Tmo, 1. A method of elevating levels of serum prolactin in a Pip or Ppz, with R being Et, Pr or 4Pic. mammal in need of elevated or stabilized levels of serum 13. The method of claim 2, wherein said peptide has the prolactin, comprising administering to said mammal an formula: H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, H-D-Phe-D- Phe-D-Nle-D-Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D- amount of a peripherally selective kappa opioid receptorago Arg-NH-4-picolyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr. nist, a salt thereof or a pro-drug thereof effective to elevate or H-D-Phe-D-Phe-D-Nle-D-Arg-thiomorpholinyl, H-D-Phe stabilize levels of serum prolactin in the mammal. D-Phe-D-Nle-D-Arg-Net, H-D-Phe-D-Phe-D-Nle-D-Arg 2. The method of claim 1, wherein said peripherally, selec NHMe, H-D-Phe-D-Phe-D-Leu-D-Orn-morpholinyl, H-D- tive kappa opioid receptoragonist, a salt thereofor a pro-drug Phe-D-Phe-D-Nle-D-Arg-NHhEt, H-D-Phe-D-Phe-D-Nle thereof comprises a peptide. D-Arg-NH-cyclopropyl, H-D-Ala(2Thi)-D-4Cpa-D-Leu-D- 3. The method of claim 2, wherein said peptide has a Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg binding affinity for the kappa opioid receptor that is 10 times piperidinyl, H-D-Phe-D-Phe-D-Leu-D-Orn-NHEt, H-D- greater, 100 times greater, 1,000 times greater, or more than Phe-D-Phe-D-Leu-D-Lys-morpholinyl, or H-D-Phe-D-Phe its binding affinity for non-kappa opioid receptors. D-Nle-D-Arg-piperazinyl. 4. The method of claim 2, wherein said peptide has the 14. The method of claim 1, wherein said peripherally selec formula: tive kappa opioid receptor agonist, when administered peripherally, does not substantially cross the blood-brain bar wherein Xaa, is (A)D-Phe, (C' Me)D-Phe, D-Tyr, 1. D-Tic or D-Ala(cyclopentyl or thienyl), with Abeing H. 15. The method of claim 1, wherein said administration NO, F C or CH; Xaa, is (A')D-Phe, D-1 Nal, D-2Nal, comprises intravenous, Subcutaneous, intramuscular, intrana D-Tyr or D-Trp, with A' being A or 3.4C1, Xaa is sal, oral, or transdermal administration. D-Nle, (B) D-Leu, D-Hle, D-Met, D-Val, D-Phe or 16. The method of claim 15, wherein said transdermal D-Ala(cyclopentyl) with B being Hor C''' Me: Xaa, administration is provided by an electrotransport device. is D-Arg, D-Har, D-nArg, D-Lys, D-LyS(Ipr), D-Arg 17. The method of claim 16, wherein said administration (Et), D-Har(Et), D-Amf(G), D-Dbu, (B)D-Orn or comprises: D-Orn(Ipr), with G being Horamidino; and Q is NRR, (a) providing a first electrode; morpholinyl, thiomorpholinyl, (C)piperidinyl, piperazi (b) providing a second electrode: nyl, 4-mono- or 4.4-di-substituted piperazinyl or delta (c) providing a power source electrically connected to said ornithinyl, with R being lower alkyl, substituted lower first and said second electrodes; alkyl, benzyl, Substituted benzyl, aminocyclohexyl, (d) providing at least one donor reservoir having the 2-thiazolyl 2-picolyl, 3-picolyl or 4-picolyl, R being H peripherally selective kappa opioid receptor agonist, or lower alkyl; and C being H, 4-hydroxy or 4-oxo. wherein said donor reservoir is associated with said first 5. The method of claim 4, wherein Q is morpholinyl or or second electrode; and thiomorpholinyl. (e) delivering a therapeutically effective amount of said 6. The method of claim 4, wherein Q is NHR and R is peripherally selective kappa opioid receptor agonist 4-picolyl. through said body Surface. US 2013/0012431 A1 Jan. 10, 2013 26

18. A method of treating a mammal in need of elevated or venting insufficient or inadequate lactation, in a mammal, stabilized prolactin levels, said method comprising adminis comprising administering an amount of a peripherally selec tering to said mammal an amount of a peripherally selective tive kappa opioid receptor agonist or a salt thereof or a pro kappa opioid receptor agonist or a salt thereof or a pro-drug drug thereof, effective to treat or prevent insufficient or inad thereof, and administering, either separately or in combina equate lactation, or to treat reduced sperm motility, age tion with said peripherally selective kappa opioid receptor related disorder, type 1 diabetes, insomnia, or inadequate agonist or a salt thereofor a pro-drug thereof, an amount of an REM sleep in the mammal. additional prolactin elevating compound, effective to treat the 21. The method of claim 20, wherein such amount of a mammal. peripherally selective kappa opioid receptor agonist or a salt 19. The method of claim 18, wherein the prolactin-elevat thereof or a pro-drug thereof is administered to said mammal ing agent is a D2 dopamine receptor antagonist or a mu opioid prior to or after childbirth in conjunction with a lactation receptor agonist. enhancer or stabilizer effective to treat said mammal. 22. The method of claim 21, wherein the lactation enhancer 20. A method for treating reduced sperm motility, an age comprises oxytocin. related disorder, type 1 diabetes, insomnia, or inadequate REM sleep, insufficient or inadequate lactation, or for pre