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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 1 November 2007 (01.11.2007) PCT WO 2007/123699 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (21) International Application Number: CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, PCT/US2007/007935 FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, (22) International Filing Date: 29 March 2007 (29.03.2007) IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, (25) Filing Language: English MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (26) Publication Language: English RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (30) Priority Data: 60/787,552 30 March 2006 (30.03.2006) US (84) Designated States (unless otherwise indicated, for every 60/841,739 1 September 2006 (01.09.2006) US kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, DANA-FARBER CANCER INSTITUTE, INC. ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [US/US]; 44 Binney Street, Boston, MA 021 15 (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (72) Inventors; and PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (75) Inventors/Applicants (for US only): FISHER, David, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). E. [US/US]; 44 Binney Street, Cambridge, MA 021 15 (US). D'ORAZIO, John [US/US]; University of Kentuck Published: College of Medicine, Pediatrics (Hematology-Oncology), — with international search report The Markers, Cancer Center, and The Graduate Center for — before the expiration of the time limit for amending the Toxicol, ogy, Combs Research Building, 800 Rose Street, claims and to be republished in the event of receipt of Lexington, KY 40536-0096 (US). KHALED, Mehdi amendments [US/US]; 44 Binney Street, Cambridge, MA 021 15 (US). (74) Agent: VINCENT, Matthew, P.; Fish & Neave IP Group, For two-letter codes and other abbreviations, refer to the "G uid Ropes & Gray LLP, One International Place, Boston, MA ance Notes on Codes and Abbreviations" appearing at the beg in 021 10-2624 (US). ning of each regular issue of the PCT Gazette. (54) Title: METHODS AND COMPOSITIONS FOR MODULATING MELANOGENESIS BY USING A MCLR AGONIST (57) Abstract: The present invention provides compositions comprising an MClR agonist and methods using these compositions for inducing or inhibiting UV- independent pigmentation of human skin and/or for enhancing UV- dependent pigmentation of human skin. METHODS AND COMPOSITIONS FOR MODULATING MELANOGENESIS BY USING A MClR AGONIST RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 5 60/787,552, filed on March 30, 2006; and to U.S. Provisional Application No. 60/841,739, filed on September 1, 2006, the entire contents of which applications are incorporated herein by reference. BACKGROUND O F THE INVENTION Melanocytes (pigment cells) are cells located in the basal layer of the 10 epidermis and in the hair bulb. Melanin pigment is deposited in melanocyte-specific organelles called melanosomes that are then transferred from the melanocyte to surrounding keratinocytes so that the pigment becomes widely dispersed through the epidermis (outer layer) of the skin or the hair shaft. Melanin is a dark pigment that protects against ultraviolet radiation and provides color in the skin, eyes and hair of 15 humans and other animals. When skin is exposed to ultraviolet radiation, such as that contained in sunlight, melanocytes increase their synthesis of melanin. Melanin is deposited in melanosomes, which are vesicles found within the melanocytes. The melanosomes are extruded from the melanocytes and carried to the surface of the skin by 20 keratinocytes, which internalize the melanin containing melanosomes. The end result is that the visible layers of the skin exhibit a brown color typically known as a "tan." Solar radiation is a major environmental mutagen, and adaptive tanning is widely recognized as an important defensive mechanism against UV-mediated 25 injury (Gilchrest et al. 1996 Photochem Photobiol 63:1). Fair-skinned individuals have the highest incidence of melanoma and also tend to exhibit minimal adaptive tanning (Sturm 1998 Mutat Res 422:69). Skin "fairness" in humans is largely the result of sequence variants in McIr, the melanocyte receptor for Melanocyte- Stimulating Hormone or melanotropin (MSH), Mountjoy et al. 1992 Science 30 257:1248). hi mankind, more than 60 non-conservative natural variants o McIr have been reported (see Table 1). Population studies demonstrate that several alleles are associated with red hair and fair skin (the RHC phenotype) (Box et al, 1997 Hum. MoI. Genet. 6:1891; Healy et al, 2000 Lancet 355:1072; Smith et al, 1998 Invest. Dermatol. 111:1 19; Valverde et al, 1995 Nat. Genet. 11:328). The strong RHC alleles (designated R) show odds ratios for red hair ranging from 50 to 120. These are the frequent Rl 51C, Rl 6OW and D294H variants and the rare D84E and R142H alleles. The weaker RHC alleles V60L, V92M, R163Q, designated r, have odd ratios for red hair ranging roughly from 2 to 6. The R variants R142H, Rl 51C, Rl 60W and D294H together with the r allele V60L are present in 30 % of the North European population, and account collectively for over 60% of all cases of red hair (Healy et al, 2001 Hum. MoI. Genet. 10:2397). Table 1. Reported Non-conservative Natural Variants of McIr Variant Codon substitution R160W CGG-TGG R160Q CGG-CAG R162P CGG- CCG R163Q CGA- CAA A164R GCC-CGC A 17 1D GCC-GAC V173del 520_523delGTC V174I GTC-ATC F179ins nt537_538iπsC F196L TTC- CTC R213W CGG—TGG P230L CCG- CTG P256S CCC-TCC H260P CAT-CCT T272M ACG-ATG K278E AAG—GAG N279S AAC-GGC N279K || AAC—AAA 1287M ATC—ATG D294H JfGAC-CAC Y298H J TAC- CAC A299T ! GCC—ACC A299V J GCC—GTC T308M ACG—ATG C315R TGC—CGC Though other signaling pathways may play a role in pigmentation (Van Raamsdonk et al. 2004 Nat Genet 36:961), variant McJr receptors typically generate weak or absent ligand-induced cAMP second messenger responses (Valverde et al. 1995 Nat Genet 11:328). MSH is produced as a component of the pro- opiomelanocortin (POMC) precursor, POMC in the pituitary and skin, where its expression is induced by UV exposure (Tsatmali et al. 2000 Pigment Cell Res 13 Suppl 8:125). Although deficient tanning in McJr variant individuals is consistent with a critical role for MSH in this response, other studies have suggested that melanocyte DNA damage responses mediate UV-induced pigmentation (Eller et al. 1994 Nature 372:413; and Corre et al. 2004 J Biol Chem 279:51226) and a genetically controlled system has been lacking, in which to determine the precise role of MSH-McJr in this response. Additionally, it was previously unknown whether the pigmentation machinery remains "available" for dark (eumelanin) pigmentation in these individuals. The data presented herein utilize a mouse model of the fair-skinned phenotype to confirm an essential role for McJr in UV-induced pigmentation, as well as UV-induced MSH production by epidermal keratinocytes. Furthermore, a topical cAMP agonist is seen to robustly rescue eumelanin production on this genetic background thereby affording major UV protection. These results were extended to human skin, and the data presented herein also demonstrates a synergistic effect on skin pigmentation by the topical administration of a combination of cAMP agonists. Increasing skin pigmentation would be desirable both to increase melanin protection from ultraviolet radiation without exposing the skin to UV light, to correct hypopigmentation disorders, and for cosmetic purposes to achieve a "safe" tan or to darken hair color. Conversely, decreasing pigmentation by providing inhibitors of this pathway could be desirable to treat disorders such as melasma, chloasma, post-inflammatory hyperpigmentation, solar lentigines, and the like. SUMMARY OF THE INVENTION One aspect of the invention provides a composition for inducing UV- independent pigmentation of human skin and/or for enhancing UV-dependent pigmentation of human skin, comprising an McIr agonist, formulated to penetrate the human skin to the stratum basale, and provided in an amount sufficient to cause macroscopically observable pigmentation when applied to human skin. In certain embodiments, the composition comprises micro- or nanoparticles of an McIr agonist and a bioadhesive coating or matrix, wherein (i) said particles penetrate the human skin and release the McIr agonist to contact melanocytes in the skin in an amount sufficient to cause macroscopically observable pigmentation when applied to human skin, and (ii) said composition leaves no visible residue on the skin one hour after administration. In certain embodiments, the McIr agonist is formulated as a composition comprising a liposome preparation, an organogel, a humectant, a non-ionic surfactant or chitosan to enhance penetration of the stratum corneum. Another aspect of the invention provides a dermatological or cosmetological composition for an external topical administration to human skin, comprising together with pharmaceutically and/or cosmetologically acceptable excipients: at least one UVA-stabilizing and/or UVB-stabilizing screening agent, and an McIr agonist, formulated to penetrate the human skin to the stratum basale, and provided in an amount sufficient to cause macroscopically observable pigmentation when applied to human skin.
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    Supplementary material BMJ Open Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to September 16, 2019> # Searches Results 1 exp Hypertension/ 247434 2 hypertens*.tw,kf. 420857 3 ((high* or elevat* or greater* or control*) adj4 (blood or systolic or diastolic) adj4 68657 pressure*).tw,kf. 4 1 or 2 or 3 501365 5 Sex Characteristics/ 52287 6 Sex/ 7632 7 Sex ratio/ 9049 8 Sex Factors/ 254781 9 ((sex* or gender* or man or men or male* or woman or women or female*) adj3 336361 (difference* or different or characteristic* or ratio* or factor* or imbalanc* or issue* or specific* or disparit* or dependen* or dimorphism* or gap or gaps or influenc* or discrepan* or distribut* or composition*)).tw,kf. 10 or/5-9 559186 11 4 and 10 24653 12 exp Antihypertensive Agents/ 254343 13 (antihypertensiv* or anti-hypertensiv* or ((anti?hyperten* or anti-hyperten*) adj5 52111 (therap* or treat* or effective*))).tw,kf. 14 Calcium Channel Blockers/ 36287 15 (calcium adj2 (channel* or exogenous*) adj2 (block* or inhibitor* or 20534 antagonist*)).tw,kf. 16 (agatoxin or amlodipine or anipamil or aranidipine or atagabalin or azelnidipine or 86627 azidodiltiazem or azidopamil or azidopine or belfosdil or benidipine or bepridil or brinazarone or calciseptine or caroverine or cilnidipine or clentiazem or clevidipine or columbianadin or conotoxin or cronidipine or darodipine or deacetyl n nordiltiazem or deacetyl n o dinordiltiazem or deacetyl o nordiltiazem or deacetyldiltiazem or dealkylnorverapamil or dealkylverapamil
  • Bradycardic Effects of AQ-A 39 (Falipamil) in Situ and in Isolated, Blood-Perfused Dog Hearts Comparison with Alinidine and Verapamil

    Bradycardic Effects of AQ-A 39 (Falipamil) in Situ and in Isolated, Blood-Perfused Dog Hearts Comparison with Alinidine and Verapamil

    Bradycardic Effects of AQ-A 39 (Falipamil) in Situ and in Isolated, Blood-Perfused Dog Hearts Comparison with Alinidine and Verapamil Yasuhiro OGIWARA, M.D., Yasuyuki FURUKAWA, M.D., Kunio AKAHANE, M.D., Masayuki HANIUDA, M.D., and Shigetoshi CHIBA, M.D. SUMMARY The cardiovascular effects of a specific bradycardic agent, AQ-A 39, were investigated in intact donor dogs and isolated and cross-perfused dog heart preparations. Intravenous administration of AQ-A 39 (10- 1000ƒÊg/kg) to the donor dog caused a dose-dependent heart rate de- crease in the donor dog and a decreased atrial rate in the isolated atrium perfused by the donor's blood. The arterial blood pressure of the donor dog and contractile force of the atrial preparation were unchanged or slightly decreased. The direct injection of AQ-A 39 (1-300ƒÊg) into the sinus node artery of the isolated atrium caused dose-dependent negative chronotropic and slight, transient positive inotropic responses. Alinidine and verapamil caused marked negative chronotropic and inotropic re- sponses. The negative chronotropic effect of AQ-A 39 was not modified by atropine. However, it was enhanced slightly but significantly by pro- pranolol, indicating that AQ-A 39-induced bradycardia was antagonized partly by beta-adrenoceptor function. These results confirmed that AQ-A 39 selectively reduced sinus rate by a direct action on the sinus node. Furthermore, the potency of the bradycardic action, compared with the decrease in contractility, was greater than for alinidine or verapamil. AQ-A 39 (300ƒÊg) tended to depress norepinephrine (NE)-induced posi- tive chronotropic but not inotropic effects in isolated atria.