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University of Kentucky UKnowledge Veterinary Science Faculty Patents Veterinary Science 7-11-2006 Long Acting, Reversible Veterinary Sedative and Analgesic and Method of Use Thomas Tobin University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/gluck_patents Part of the Veterinary Medicine Commons Recommended Citation Tobin, Thomas, "Long Acting, Reversible Veterinary Sedative and Analgesic and Method of Use" (2006). Veterinary Science Faculty Patents. 14. https://uknowledge.uky.edu/gluck_patents/14 This Patent is brought to you for free and open access by the Veterinary Science at UKnowledge. It has been accepted for inclusion in Veterinary Science Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. US007074834B2 (12) United States Patent (10) Patent N0.: US 7,074,834 B2 Tobin (45) Date of Patent: Jul. 11, 2006 (54) LONG ACTING, REVERSIBLE VETERINARY 4,742,054 A 5/1988 Naftchi SEDATIVE AND ANALGESIC AND METHOD 4,950,648 A 8/1990 Raddatz et a1. OF USE 5,635,204 A * 6/1997 GevirtZ et a1. ............ .. 424/449 5,942,241 A 8/1999 Chasin et a1. (75) Inventor: Thomas Tobin, Lexington, KY (US) 5,958,933 A 9/1999 Naftchi (73) Assignee: University of Kentucky Foundation, OTHER PUBLICATIONS Lexington, KY (US) MEDLINE AN 20000025586, Veveris et al, Brit. J. Pharmacol, 128 (5), 1089-97, Nov. 1999, abstract.* ( * ) Notice: Subject to any disclaimer, the term of this Veterinary Pharmacology and Therapeutics, Adams, pp. patent is extended or adjusted under 35 160-161,1995.* U.S.C. 154(b) by 0 days. GuanabenZ (Wytensin), Prescription Drug Referene from Health Square.com, May 18, 2001. (21) Appl. No.: 09/865,175 (22) Filed: May 24, 2001 * cited by examiner Primary Examiner4Christopher S. F. LoW (65) Prior Publication Data Assistant ExamineriAmy LeWis US 2002/0091161 A1 Jul. 11, 2002 (74) Attorney, Agent, or F irmiKing & Schickli, PLLC Related US. Application Data (57) ABSTRACT (60) Provisional application No. 60/206,625, ?led on May 24, 2000. Aveterinary composition comprising a guanidine derivative, (51) Int. Cl. e.g., guanabenZ or guanabenZ acetate is provided Which A61K 31/155 (2006.01) produces a rapid acting and long lasting sedative and anal (52) US. Cl. ..................................... .. 514/634; 514/398 gesic effect in a subject animal that is selectively reversible. (58) Field of Classi?cation Search .............. .. 514/634, The use of guanabenz in the horse provides for a safe, 514/398, 183, 315, 462, 452 effective, long lasting and rapidly reversible sedative and See application ?le for complete search history. analgesic Which can be used on the standing animal. Meth ods of use of the compositions of the invention are also (56) References Cited provided. U.S. PATENT DOCUMENTS 4,060,640 A 11/1977 Kodama et a1. 15 Claims, 2 Drawing Sheets U.S. Patent Jul. 11,2006 Sheet 1 of2 US 7,074,834 B2 120 SJ 551330 A 100 1 E 1 <5 2, 80 I 1:: so i 8 ,9 . I EL 40 4 Q Guanabenz-1D0 mg.|v 2D 0 Guanabenz w/ Yohimbine (60 mg, iv) ! u ‘t x x 1 1 W T’ O 1 2 3 4 5 5 7 Time (h) Fig. 1 (.0 O O N-\ HWRL control(%latency) O c Guanabenz-wo mg, iv 01 O Time3 4 (h)5 Fig. 2 U.S. Patent Jul. 11,2006 Sheet 2 0f 2 US 7,074,834 B2 Fig. 3 ab. o Urrne glucose Blood glucose Guanabenz-10O mg, iv oEomQw$3.2mcosozuoa$5mZEEEnO2E:20:95mmOQEO m mmwmw ,1“mu4wwm.wM,inhun US 7,074,834 B2 1 2 LONG ACTING, REVERSIBLE VETERINARY e.g., a single intravenous administration of 300 mg of SEDATIVE AND ANALGESIC AND METHOD xylaZine in an adult horse produces moderate sedation and OF USE analgesia lasting from betWeen about 30 to about 60 min utes. Therefore, there exists a need in the art for a long acting This application claims the bene?t of priority in US. sedative and analgesic Which can produce profound sedation Provisional Application Ser. No. 60/206,625, ?led on May and analgesia for longer periods of time folloWing a single 24, 2000. administration of the active. Upon administration of the alpha-2-agonists, horses typi FIELD OF INVENTION cally assume a Wide stance With the head extended and loWered (ptosis). In male horses, some relaxation of the The present invention relates to the ?eld of veterinary penis may occur and the loWer lip becomes ?accid. Muscle medicine and to compositions and methods of use for rapid relaxation and ataxia may be severe, particularly When large acting reversible sedatives, tranquilizers and analgesics in doses are administered. The effects of alpha-2-adreno recep animals. In particular, the present invention relates to a rapid tor agonists can be speci?cally antagoniZed (reversed) by the acting reversible sedative and analgesic having 0t adrenergic administration of and alpha-2-adreno receptor antagonist agonist activity that is adapted for use in the standing (Hubbell J. A. E. and Muir W. W. Standing Chemical animal. Restraint p. 1874192 in Equine Internal Medicine by Reed S. M and Bayly W. M, 1997) BACKGROUND OF THE INVENTION Central alpha-2-adrenergic agonist cross the blood-brain 20 barrier and stimulate alpha-2-adrenergic receptors in the Veterinary medicine and especially in large animal prac vasomotor region of the brainstem. Stimulation Of these tice, e.g., equine and bovine medicine and surgery, has receptors decreases sympathetic tone, brain turnover of incorporated various diagnostic, therapeutic and surgical norepinephrine and central sympathetic out?oW and activity procedures into the daily routine of the large animal prac of the preganglionic sympathetic nerves. The net effect is a titioner. Many of these procedures are greatly facilitated and 25 reduction in norepinephrine release. Central alpha-2-adren can be accomplished in the standing animal if the animal ergic agonist may also stimulate the peripheral alpha-2 remains clam, motionless, and virtually pain free. An addi adrenergic receptors that mediate vasoconstriction. The tional consideration is that it may also be bene?cial to calm usual physiologic effect is a decrease in peripheral resistance the animal, e.g., the coW or horse, before bringing it into and sloWing of the heart rate; hoWever, output is either proximity of expensive equipment or to minimiZe the poten 30 unchanged or mildly decreased. Preservation of cardiovas tial for human injury. cular re?exes prevents postural hypertension. Commonly used are sedatives Which have a calming In human medicine, a variety of guanidine derivatives effect and tranquiliZers Which are a class of drugs used in the have been used clinically as anti-hypertensive agents, treatment of anxiety states. The goal of sedative and tran including clonidine, guanabenZ, guanacline, guanadrel, gua quiliZer administration is to eliminate fear, produce a calm 35 naZodine, guanethidine, guanfacine and guanochlor, guan ing effect, reduce resistance to manipulation, and, to the oxabenZ and guanoxan. extent there is an analgesic effect of the drug, to ideally GuanabenZ (l-[2,6-dichlorobenZylidine-amino]-3-guani eliminate pain. Generally, users or user facilities of such dine) is an anti-hypertensive drug Whose mechanism of sedatives, tranquiliZers and analgesics are veterinary hospi action is an agonistic stimulatory effect of the central alpha-2 tals, veterinarians Working under ?eld conditions, animal 40 adrenergic receptors in the cardiovascular regulatory centers control facilities, humane societies, Zoos, researchers and in the brainstem and spinal cord. Its therapeutic effects in the like. humans include a reduction in sympathetic tone (a reduction Classically, sedatives are a distinct groups of drugs based in heart rate and cardiac output), an increase in parasympa on their central nervous system (CNS) site of action. Seda thetic tone (a reduction in heart rate and cardiac output) and tives are classically considered as agents that act at the 45 vasodilation (a relaxation of capacitance vessels and reduc cortical level and, if given in suf?cient quantities, Will tion in total peripheral resistance). GuanabenZ is currently produce CNS depression to the point of hypnosis (arti?cial marketed in human medicine in the general class of medi sleep). TranquiliZers act at the sub-cortical levels, particu cines called antihypertensives. It is used to treat high blood larly at the reticular activating system, effectively ?ltering pressure (hypertension). GuanabenZ acetate is available on afferent and efferent nervous system activity. Increasing 50 the market as 4 and 8 mg tablets to be taken orally, e.g., as doses of tranquiliZers produce greater degrees of calming WYTENSIN® (Wyeth-Ayerst, Alexandria, Va.) but do not produce hypnosis. In practical use in animals, Certain uses of guanabenZ have been previously disclosed drugs acting at different levels of the CNS have been used in the art. For example, US. Pat. No. 4,060,640, to Kodama to obtain the same result, thus the distinction often has et al., describes guanabenZ, and its related compounds, as become blurred and the term sedative-tranquiliZer has 55 being central nervous system depressants that reduce hyper evolved. excitability and induce sedation, overcoming psychic Alpha-2-adreno receptor agonists produce sedation, depression in humans. muscle relaxation and analgesia When administered intrave US. Pat. No. 5,958,933 to Naftchi discloses guanabenZ, nously or intramuscularly. Alpha-2-adreno receptor agonists as part of a drug combination, as being a neurologically are used to provide standing chemical restraint for various 60 active compound that When administered in an appropriate procedures, to provide analgesia, and to act as sedatives dosage amount is suf?cient to restore neurological function prior to anesthesia.
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    Br. J. Pharmac. (1987), 91, 457-466 Difference in the potency ofa2-adrenoceptor agonists and antagonists between the pithed rabbit and rat J.M. Bulloch, 'J.R. Docherty, 2N.A. Flavahan, J.C. McGrath & C.E. McKean Institute ofPhysiology, University ofGlasgow, Glasgow G12 8QQ, Scotland 1 The subtypes ofa-adrenoceptors which mediate pressor responses to sympathomimetic agonists or to nerve stimulation in pithed rabbits have been classified according to the effects of 'selective' antagonists and a comparison has been made, for the xt2-subtype, with corresponding responses in the rat. 2 In the rabbit the dose-response curve for phenylephrine was shifted to the right in parallel by prazosin (1 mg kg-') and was unaffected by rauwolscine (1 mg kg '). The dose-response curve for noradrenaline was shifted to the right by prazosin (I mg kg -') and was shifted to a smaller extent by rauwolscine (1 mg kg -') or imiloxan (1Omg kg-'). After rauwolscine, prazosin produced a rightward shift larger than when given alone. After prazosin, rauwolscine produced a rightward shift larger than when given alone. 3 The responses to pressor nerve stimulation at low frequencies (< 1 Hz) could be reduced by prazosin, rauwolscine or imiloxan but those at a higher frequency could be reduced only by prazosin. 4 These results indicate that the responses to noradrenaline or to nerve stimulation are mediated by both a,- and a2-adrenoceptors. Low doses or frequencies have a proportionately greater component which is M2 5 Responses to noradrenaline after prazosin (1 mg kg -'), were sufficiently sensitive to rauwolscine to be considered as predominantly a2.
  • Un Novedoso Enfoque Para El Diseño De Fármacos Antimicrobianos Asistido Por Computadora

    Un Novedoso Enfoque Para El Diseño De Fármacos Antimicrobianos Asistido Por Computadora

    TOMOCOMD-CARDD: Un Novedoso Enfoque para el Diseño de Fármacos Antimicrobianos Asistido por Computadora Autora: Yasnay Valdés Rodríguez. Tutores: Prof. Dr. Yovani Marrero Ponce. Prof. MSc. Ricardo Medina Marrero. 2005-2006 La ignorancia afirma o niega rotundamente; la ciencia duda… Voltaire (1694-1778) Quiero dedicar este trabajo a todas aquellas personas que me aprecian y desean lo mejor para mi, especialmente a mis padres. A mi padre Dedico este trabajo con mucho amor, por hacerme comprender que siempre se puede llegar mas lejos, y que no hay nada imposible, solamente hay que luchar... A mi madre Por su infinita bondad, por su sacrificio inigualable. A mis familiares Por todo su apoyo y ayuda que me han mostrado incondicionalmente. A mi hermano Por ser mi fuente de inspiración. A la humanidad “...porque si supiera que el mundo se acaba mañana, yo, hoy todavía, plantaría un árbol” Quiero agradecer a todas aquellas personas que me han ayudado a realizar este sueño: A mis padres por todo el sacrificio realizado, y aún parecerles poco, los amo mucho. A mi madre por estar siempre a mi lado en los buenos y malos momentos ayudándome a levantarme en cualquier recaída. A mi padre por guiarme en la vida y brindarme sus consejos siempre útiles, por darme fuerza y vitalidad. A mi mayor tesoro, mi hermano, que me alumbra de esperanza día a día. A mis tías y primos que me ayudaron mucho, aún estando lejos. A mi novio que me apoyo en todas mis decisiones y con paciencia supo ayudarme. A mis tutores y cotutores que siempre me dieron la mano; especialmente a Yovani por su paciencia, a quien debo gran parte de mi formación como profesional por sus exigencias.