US 2009020251 8A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0202518 A1 Wang (43) Pub. Date: Aug. 13, 2009

(54) TREATMENT OF SEPSIS AND Related U.S. Application Data NFLAMMATION WITH ALPHA2A (60) Provisional application No. 60/680,999, filed on May ADRENERGIC ANTAGONSTS 13, 2005. (75) Inventor: Ping Wang, Roslyn, NY (US) Publication Classification (51) Int. Cl. Correspondence Address: A 6LX 39/395 (2006.01) AMSTER, ROTHSTEIN & EBENSTEIN LLP A6II 3/478 (2006.01) 90 PARKAVENUE A6IPI/00 (2006.01) NEW YORK, NY 10016 (US) (52) U.S. Cl...... 424/130.1: 514/397 (73) Assignee: The Feinstein Institute of Medical (57) ABSTRACT Research Provided are methods for treating a mammal undergoing sepsis, or at risk for sepsis. Also provided are methods of (21) Appl. No.: 11/920,309 preventing or treating a physiological effect of sepsis in a mammal. Additionally provided are methods of inhibiting an (22) PCT Fled: May 11, 2006 inflammatory response in a mammal. Further provided is the use of an O-adrenergic antagonist for the manufacture of a (86) PCT NO.: PCT/US06/18717 medicament for preventing or treating a physiologic effect of Sepsis in a mammal, and the use of an O-adrenergic antago S371 (c)(1), nist for the treatment of a mammal having sepsis or at risk for (2), (4) Date: Dec. 15, 2008 SepS1S. Patent Application Publication Aug. 13, 2009 US 2009/0202518A1

F.G. 1

100 S80 S2 CS 60 A4 a Sy 40 * P-0.05 vs. Vehicle, n=20/group- 520 -O- Vehicle CM) O -O- BRL-44408 maleate

0 1 2 3 4 5 6 7 8 9 10 Days after CLP US 2009/02025 18 A1 Aug. 13, 2009

TREATMENT OF SEPSIS AND mal with an O-adrenergic antagonist Such that a physiologic NFLAMMATION WITH ALPHA2A effect of the sepsis is prevented or reduced. ADRENERGIC ANTAGONSTS 0010. The invention is also directed to methods of inhib iting an inflammatory response in a mammal, where the CROSS-REFERENCE TO RELATED inflammatory response is mediated by a proinflammatory APPLICATION cytokine. The methods comprise treating the mammal with an 0001. This application claims the benefit of U.S. Provi C2-adrenergic antagonist Sufficient to inhibit the inflamma sional Patent Application Ser. No. 60/680,999, filed May 13, tory response. 2005. 0011 Additionally, the invention is directed to the use of an O-adrenergic antagonist for the manufacture of a medi STATEMENT REGARDING FEDERALLY cament for preventing or treating a physiologic effect of sep SPONSORED RESEARCH ORDEVELOPMENT sis in a mammal. 0012. In further embodiments, the invention is directed to 0002 The U.S. Government has a paid-up license in this the use of an O-adrenergic antagonist for the treatment of a invention and the right in limited circumstances to require the mammal having sepsis or at risk for sepsis. patent owner to license others on reasonable terms as pro vided for by the terms of GMO53008, awarded by the BRIEF DESCRIPTION OF THE DRAWING National Institutes of Health. 0013 FIG. 1 is a graph of experimental results showing BACKGROUND OF THE INVENTION increased Survival of rats undergoing sepsis when treated 0003 (1) Field of the Invention The present invention with the C2-adrenergic antagonist BRL-44408 maleate. generally relates to treatments of sepsis and inflammation. More specifically, the invention is directed to the use of C DETAILED DESCRIPTION OF THE INVENTION adrenergic antagonists to treat sepsis and inflammatory dis 0014. The present invention is based in part on the inven CaSCS. tor's discovery that treating a mammal with an O-adrener 0004 (2) Description of the Related Art gic antagonist can prevent or reduce physiologic effects of 0005. Despite advances in the management of trauma vic sepsis and inflammation. See Example. tims, the incidence of sepsis and septic shock has increased 0015 Thus, in some embodiments, the present invention is significantly over the past two decades. It has been estimated directed to methods of treating a mammal undergoing sepsis. that in the United States alone, more than 750,000 patients The methods comprise treating the mammal with an O develop sepsis and septic shock each year with an overall adrenergic antagonist Such that a physiologic effect of the mortality rate of 28.6%. Severe sepsis is a common, expen sepsis is prevented or reduced. sive, and frequently fatal condition, with as many deaths 0016. These methods are expected to be effective with any annually as those from acute myocardial infarction. Sepsis is C-adrenergic antagonist now known or later discovered. the 3rd leading cause of death overall in the United States. A Nonlimiting examples of C-adrenergic antagonists that are recent report indicates that the average costs per septic patient encompassed within these embodiments are BRL-44408 are at least S22, 100, with annual total costs of more than S16 maleate, RX821002, rauwolscine, idazoxan, piribedil, ati billion nationally. Activated protein C(APC) is the only FDA pamezole, dihydroergotamine, phentolamine, phenoxyben approved specific treatment for sepsis, but its use is limited to Zamine, tolazoline, ARC 239, efaroxan, RS 79948, spiroX non-Surgical adult patients with severe sepsis. APC cannot be atrine, and yohimbine. The selection of C2-adrenergic used in trauma victims and Surgical patients who develop antagonist can be made by the skilled artisan without undue sepsis, due to its adverse effects on coagulation. Thus, there is experimentation, taking into account, e.g., the selectivity and a great need for an effective novel therapy for sepsis, espe side effects of the compound and the sensitivity or hypersen cially Surgical sepsis. The market potential for sepsis treat sitivity of the mammal to the compound. In some preferred ment is estimated at S10-25 billion annually in the United embodiments, the C2-adrenergic antagonist is BRL-44408 States alone. maleate. The C2-adrenergic antagonist can also be an anti body or an aptamer, which can be made by routine methods SUMMARY OF THE INVENTION well known in the art. 0006. Accordingly, the inventor has discovered that treat 0017 For all embodiments of the present invention, the ing a mammal with an C2-adrenergic antagonist can prevent C2-adrenergic antagonist, or a salt thereof, is preferably or reduce physiologic effects of sepsis and inflammation. formulated in a pharmaceutical composition. These compo 0007 Thus, in some embodiments, the invention is sitions can be formulated without undue experimentation for directed to methods of treating a mammal undergoing sepsis. administration to a mammal, including humans, as appropri The methods comprise treating the mammal with an O ate for the particular application. Additionally, proper dos adrenergic antagonist Such that a physiologic effect of the ages of the compositions can be determined without undue sepsis is prevented or reduced. experimentation using standard dose-response protocols. 0008. In other embodiments, the invention is directed to 0018. Accordingly, the compositions designed for oral, methods of treating a mammal at risk for sepsis. The methods lingual, Sublingual, buccaland intrabuccal administration can comprise treating the mammal with an O-adrenergic be made without undue experimentation by means well antagonist Sufficient to prevent or reduce a physiologic effect known in the art, for example with an inert diluent or with an of the sepsis. edible carrier. The compositions may be enclosed in gelatin 0009. The present invention is additionally directed to capsules or compressed into tablets. For the purpose of oral methods of preventing or treating a physiologic effect of therapeutic administration, the pharmaceutical compositions sepsis in a mammal. The methods comprise treating the mam of the present invention may be incorporated with excipients US 2009/02025 18 A1 Aug. 13, 2009

and used in the form of tablets, troches, capsules, elixirs, peripheral vascular resistance and/or regional blood perfu Suspensions, syrups, wafers, chewing gums and the like. sion), renal function, hepatic function, gut absorptive func 0019 Tablets, pills, capsules, troches and the like may also tion, adrenal function, insulin responsiveness, altered cytok contain binders, recipients, disintegrating agent, lubricants, ine (e.g., IL-10, TNF-C. IL-1B and/or IL-6) release, and Sweetening agents, and flavoring agents. Some examples of physiological effects of altered cytokine release (e.g., inflam binders include microcrystalline cellulose, gum tragacanth or mation). To evaluate the prevention or reduction of physi gelatin. Examples of excipients include starch or lactose. ologic effects of sepsis, it is preferred that physiologic effects Some examples of disintegrating agents include alginic acid, that are easily measured are compared before and after treat corn starch and the like. Examples of lubricants include mag ment. Examples of these effects are elevation of serum nesium Stearate or potassium Stearate. An example of a TNF-A levels, elevation of serum ALT levels, elevation of glidant is colloidal silicon dioxide. Some examples of Sweet serum AST levels, elevation of serum lactate, and elevation of ening agents include Sucrose, saccharin and the like. serum creatinine. In preferred embodiments, the measured Examples of flavoring agents include peppermint, methyl physiological effect of the sepsis is elevation of serum TNF-A salicylate, orange flavoring and the like. Materials used in levels. Determination of shock, or its direct effects (e.g., preparing these various compositions should be pharmaceu hemoconcentration, peripheral vascular resistance, etc.) is tically pure and nontoxic in the amounts used. also easily measured and can be utilized. 0020. The compositions of the present invention can easily 0025. These methods can also comprise treating the mam be administered parenterally such as for example, by intrave mal with a second treatment that can reduce a physiological nous, intramuscular, intrathecal or Subcutaneous injection. effect of the sepsis. Examples of such treatments include Parenteral administration can be accomplished by incorpo administration of adrenomedullin, adrenomedullin binding rating the compositions of the present invention into a solu protein, activated protein C, or milk fat globule epidermal tion or Suspension. Such solutions or Suspensions may also growth factor-factor VIII. The latter treatment is described in include sterile diluents such as water for injection, saline U.S. Provisional Patent Application 60/680,628, titled MILK Solution, fixed oils, polyethylene glycols, glycerine, propy FAT GLOBULE EPIDERMAL GROWTH FACTOR VIII lene glycol or other synthetic solvents. Parenteral formula tions may also include antibacterial agents such as for AND SEPSIS, filed May 13, 2005. example, benzyl alcohol or methyl parabens, antioxidants 0026. In other embodiments, the invention is directed to Such as for example, ascorbic acid or Sodium bisulfite and methods of treating a mammal at risk for sepsis. The methods chelating agents such as EDTA. Buffers such as acetates, comprise treating the mammal with an O-adrenergic citrates orphosphates and agents for the adjustment oftonic antagonist sufficient to prevent or reduce a physiologic effect ity Such as sodium chloride or dextrose may also be added. of the sepsis. As with the methods described above, these The parenteral preparation can be enclosed in ampules, dis embodiments are not limited to any particular C2-adrenergic posable Syringes or multiple dose vials made of glass or antagonists. Examples of useful C-adrenergic antagonists are BRL-44408 maleate, RX821002, rauwolscine, idazoxan, plastic. piribedil, atipamezole, dihydroergotamine, phentolamine, 0021 Rectal administration includes administering the pharmaceutical compositions into the rectum or large intes phenoxybenzamine, tolazoline, ARC 239, efaroxan, RS tine. This can be accomplished using Suppositories or 79948, spiroxatrine, and yohimbine. In some preferred enemas. Suppository formulations can easily be made by embodiments, the C2-adrenergic antagonist is BRL-44408 methods known in the art. For example, Suppository formu maleate. The C2-adrenergic antagonist can also be an anti lations can be prepared by heating glycerinto about 120° C. body or an aptamer, as discussed above. dissolving the composition in the glycerin, mixing the heated 0027. These methods can also comprise treating the mam glycerin after which purified water may be added, and pour mal with a second treatment that can reduce a physiological ing the hot mixture into a Suppository mold. effect of the sepsis. Examples of such treatments include 0022 Transdermal administration includes percutaneous administration of adrenomedullin, adrenomedullin binding absorption of the composition through the skin. Transdermal protein, activated protein C, or milk fat globule epidermal formulations include patches (such as the well-known nico growth factor-factor VIII. tine patch), ointments, creams, gels, Salves and the like. 0028. The methods of the present invention prevent or 0023 The present invention includes nasally administer reduce any physiologic effect of sepsis, including shock and ing to the mammal atherapeutically effective amount of the TNF-C levels. composition. As used herein, nasally administering or nasal 0029. The present invention is also directed to methods of administration includes administering the composition to the preventing or treating a physiologic effect of sepsis in a mam mucous membranes of the nasal passage or nasal cavity of the mal. The methods comprise treating the mammal with an patient. As used herein, pharmaceutical compositions for C2-adrenergic antagonist Such that a physiologic effect of nasal administration of a composition include therapeutically the sepsis is prevented or reduced. effective amounts of the composition prepared by well 0030. As with the methods described above, these known methods to be administered, for example, as a nasal embodiments are not limited to any particular C2-adrenergic spray, nasal drop, Suspension, gel, ointment, cream or pow antagonists. Examples of useful C-adrenergic antagonists der. Administration of the composition may also take place are BRL-44408 maleate, RX821002, rauwolscine, idazoxan, using a nasal tampon or nasal Sponge. piribedil, atipamezole, dihydroergotamine, phentolamine, 0024. The methods of the present invention prevent or phenoxybenzamine, tolazoline, ARC 239, efaroxan, RS reduce any physiologic effect of sepsis, including shock 79948, spiroxatrine, and yohimbine. In some preferred (which in turn affects endothelial cell function, smooth embodiments, the C2-adrenergic antagonist is BRL-44408 muscle contractility, cardiac output, stroke Volume, systemic maleate. The C2-adrenergic antagonist can also be an anti oxygen delivery, lactic acidosis, hemoconcentration, total body or an aptamer, as discussed above. US 2009/02025 18 A1 Aug. 13, 2009

0031. These methods can also comprise treating the mam diabetes, ankylosing spondylitis, Berger's disease, Type I mal with a second treatment that can reduce a physiological diabetes, ankylosing spondylitis, Berger's disease, Retier's effect of the sepsis. Examples of such treatments include syndrome, or Hodgkins disease. Preferably, the condition is administration of adrenomedullin, adrenomedullin binding appendicitis, peptic, gastric and duodenal ulcers, peritonitis, protein, activated protein C, or milk fat globule epidermal pancreatitis, ulcerative, pseudomembranous, acute and growth factor-factor VIII. ischemic colitis, hepatitis, Crohn's disease, asthma, allergy, 0032. The methods of the present invention prevent or anaphylactic shock, organischemia, reperfusion injury, organ reduce any physiologic effect of sepsis, including shock and necrosis, hay fever, sepsis, septicemia, endotoxic shock, TNF-C levels. cachexia, septic abortion, disseminated bacteremia, burns, 0033 Since O-adrenergic antagonists reduce TNF-C. Alzheimer's disease, coeliac disease, congestive heart failure, levels, treatment with C2-adrenergic antagonists are effec adult respiratory distress syndrome, cerebral infarction, cere tive to reduce inflammatory responses mediated by proin bral embolism, spinal cord injury, paralysis, allograft rejec flammatory cytokines, since Such responses generally are tion and graft-Versus-host disease. In the most preferred mediated in large part by TNF-C. Thus, the invention is also embodiments, the condition is septic shock. directed to methods of inhibiting an inflammatory response in 0037. The present invention is also directed to the use of an a mammal, where the inflammatory response is mediated by C-adrenergic antagonist for the manufacture of a medica a proinflammatory cytokine. These methods comprise treat ment for preventing or treating a physiologic effect of sepsis ing the mammal with an O-adrenergic antagonist Sufficient in a mammal. As with the methods described above, these to inhibit the inflammatory response. embodiments are not limited to any particular C2-adrenergic 0034. As with the methods described above, these antagonists. Examples of useful C-adrenergic antagonists embodiments are not limited to any particular C2-adrenergic are BRL-44408 maleate, RX821002, rauwolscine, idazoxan, antagonists. Examples of useful C-adrenergic antagonists piribedil, atipamezole, dihydroergotamine, phentolamine, are BRL-44408 maleate, RX821002, rauwolscine, idazoxan, phenoxybenzamine, tolazoline, ARC 239, efaroxan, RS piribedil, atipamezole, dihydroergotamine, phentolamine, 79948, spiroxatrine, and yohimbine. In some preferred phenoxybenzamine, tolazoline, ARC 239, efaroxan, RS embodiments, the C-adrenergic antagonist is BRL-44408 79948, spiroXatrine, and yohimbine. In some preferred maleate. The C2-adrenergic antagonist can also be an anti embodiments, the C2-adrenergic antagonist is BRL-44408 body or an aptamer, as discussed above. maleate. The C2-adrenergic antagonist can also be an anti 0038. In related embodiments, the invention is addition body or an aptamer, as discussed above. ally directed to the use of an O-adrenergic antagonist for the 0035. In preferred embodiments, the proinflammatory treatment of a mammal having sepsis or at risk for sepsis. 0039. As with the methods described above, these cytokine is TNF-C. embodiments are not limited to any particular C-adrenergic 0036. In other preferred embodiments, the mammal is suf antagonists. Examples of useful C-adrenergic antagonists fering from, or at risk for, a condition mediated by an inflam are BRL-44408 maleate, RX821002, rauwolscine, idazoxan, matory cytokine cascade. Nonlimiting examples of such con piribedil, atipamezole, dihydroergotamine, phentolamine, ditions include appendicitis, peptic, gastric and duodenal phenoxybenzamine, tolazoline, ARC 239, efaroxan, RS ulcers, peritonitis, pancreatitis, ulcerative, pseudomembra 79948, spiroxatrine, and yohimbine. In some preferred nous, acute and ischemic colitis, diverticulitis, epiglottitis, embodiments, the C2-adrenergic antagonist is BRL-44408 achalasia, cholangitis, cholecystitis, hepatitis, Crohn's dis maleate. The O-adrenergic antagonist can also be an anti ease, enteritis, Whipple's disease, asthma, allergy, anaphylac body or an aptamer, as discussed above. tic shock, immune complex disease, organ ischemia, reper 0040. In preferred embodiments, the proinflammatory fusion injury, organ necrosis, hay fever, sepsis, septicemia, cytokine is TNF-C. endotoxic shock, cachexia, hyperpyrexia, eosinophilic granu 0041 Preferred embodiments of the invention are loma, granulomatosis, sarcoidosis, septic abortion, epid described in the following example. Other embodiments idymitis, vaginitis, prostatitis, urethritis, bronchitis, emphy within the scope of the claims herein will be apparent to one Sema, rhinitis, cystic fibrosis, pneumonitis, skilled in the art from consideration of the specification or pneumoultramicroscopicsilicovolcanoconiosis, alvealitis, practice of the invention as disclosed herein. It is intended that bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, res the specification, together with the example, be considered piratory syncytial virus infection, herpes infection, HIV exemplary only, with the scope and spirit of the invention infection, hepatitis B virus infection, hepatitis C virus infec being indicated by the claims, which follow the example. tion, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, Example 1 demmatomyositis, Sunburn, urticaria, warts, wheals, Vasuli tis, angiitis, endocarditis, arteritis, atherosclerosis, throm 0042. The nervous system regulates the inflammatory bophlebitis, pericarditis, myocarditis, myocardial ischemia, response in real time. Our previous studies have shown that periarteritis nodosa, rheumatic fever, Alzheimer's disease, the sympathetic neurotransmitter, norepinephrine (NE), coeliac disease, congestive heart failure, adult respiratory increases TNF-C. release via activation of C2-adrenoceptor distress syndrome, meningitis, encephalitis, multiple Sclero (C-AR) on Kupffer cells (KCs). In cultured KCs, NE sis, cerebral infarction, cerebral embolism, Guillame-Barre increases the release of TNF-C. by 3.4-fold and a specific syndrome, neuritis, neuralgia, spinal cord injury, paralysis, antagonist for C-AR, BRL-44408 maleate, reduces TNF-C. uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Pag secretion by 51%. However, it remains unknown whether in et's disease, gout, periodontal disease, rheumatoid arthritis, Vivo administration of C-AR antagonists in Sepsis is ben synovitis, myasthenia gravis, thryoiditis, systemic lupus eficial. erythematosus, Goodpasture's syndrome, Behcets's Syn 0043 Sepsis was induced in male rats by cecalligation and drome, allograft rejection, graft-Versus-host disease, Type I puncture (CLP). The CLP model of sepsis has been used US 2009/02025 18 A1 Aug. 13, 2009

extensively as a reliable model of the pathophysiologic and 6. The method of claim 1, wherein the physiological effect immunologic alterations in human sepsis. of the sepsis is elevation of serum TNF-C. levels. 0044 BRL-44408 maleate (2.5 mg/kg BW) was adminis 7. The method of claim 1, wherein the physiological effect tered intravenously at the time of CLP. Twenty hours after of the sepsis is shock. CLP, the rats were sacrificed and blood and liver samples 8. The method of claim 1, further comprising treating the were collected. Serum levels of TNF-C, liver enzymes (i.e., mammal with a second treatment that can reduce a physi AST and ALT), lactate and creatinine were measured. Gene ological effect of the sepsis. expression of TNF-C. in the liver was analyzed. In additional 9. The method of claim 8, wherein the second treatment is groups of animals, the necrotic cecum was excised at 20 h administration of adrenomedullin, adrenomedullin binding post-CLP and the 10-day survival was recorded. The results protein, activated protein C, or milk fat globule epidermal (means-SE) are shown in Table 1. growth factor-factor VIII. 10-25. (canceled) TABLE 1. 26. A method of inhibiting an inflammatory response in a Sham CLP CLP mammal, wherein the inflammatory response is mediated by Control Vehicle BRL-44408 maleate a proinflammatory cytokine, the method comprising treating the mammal with an O-adrenergic antagonist Sufficient to TNF-C. (pg/ml) 65.8 8.2 16O2S2* 91.8 + 8.1" inhibit the inflammatory response. TNF-Of G3PDH O2 O.O1 1.4 - 0.3* 0.5 + 0.1" (mRNA) 27. The method of claim 26, wherein the C-adrenergic ALT (IU/L) 8.5 - 3.1 40.94.4* 20.5 + 4.5" antagonist is BRL-44408 maleate, RX821002, rauwolscine, AST (IU/L) 13.6 2.1 55.7 7.7% 20.9 +5.3" idazoxan, piribedil, atipamezole, dihydroergotamine, phen Lactate (mg/dl) 10.8 - 0.9 32.6 2.1* 20.6+ 1.9" tolamine, phenoxybenzamine, tolazoline, ARC 239, efar Creatinine (mg/dl) O.80.2 2.3 0.48 1.1 + 0.2* oxan, RS 79948, spiroxatrine, or yohimbine. One-way ANOVA: 28. The method of claim 26, wherein the C-adrenergic *P & .05 vs. Sham; antagonist is BRL-44408 maleate. "P< .05 vs. Vehicle, n = 6/group 29. The method of claim 26, wherein the C-adrenergic 0045. Our results indicate that BRL-44408 maleate antagonist is an antibody or an aptamer. administration decreased the expression of TNF-C., attenu 30. The method of claim 26, wherein the proinflammatory ated tissue injury (Table 1), and reduced mortality (FIG. 1) in cytokine is TNF-C. septic animals. Thus, modulation of the sympathetic nervous 31. The method of claim 26, wherein the mammal is Suf system by blocking C-adrenergic receptors appears to be a fering from, or at risk for, a condition mediated by an inflam novel treatment for inflammatory conditions such as sepsis. matory cytokine cascade. 0046. In view of the above, it will be seen that the several 32. The method of claim 31, wherein the condition is advantages of the invention are achieved and other advan appendicitis, peptic, gastric and duodenal ulcers, peritonitis, tages attained. pancreatitis, ulcerative, pseudomembranous, acute and 0047. As various changes could be made in the above ischemic colitis, diverticulitis, epiglottitis, achalasia, cholan methods and compositions without departing from the scope gitis, cholecystitis, hepatitis, Crohn's disease, enteritis, of the invention, it is intended that all matter contained in the Whipple's disease, asthma, allergy, anaphylactic shock, above description and shown in the accompanying drawings immune complex disease, organischemia, reperfusion injury, shall be interpreted as illustrative and not in a limiting sense. organ necrosis, hay fever, sepsis, septicemia, endotoxic 0048 All references cited in this specification are hereby shock, cachexia, hyperpyrexia, eosinophilic granuloma, incorporated by reference. The discussion of the references granulomatosis, sarcoidosis, septic abortion, epididymitis, herein is intended merely to Summarize the assertions made vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhini by the authors and no admission is made that any reference tis, cystic fibrosis, pneumonitis, pneumoultramicroscopicsili constitutes prior art. Applicants reserve the right to challenge covolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, the accuracy and pertinence of the cited references. pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus 1. A method of treating or preventing a physiological effect infection, hepatitis C virus infection, disseminated bacter of sepsis in a mammal undergoing sepsis or a mammal at risk emia, Dengue fever, candidiasis, malaria, filariasis, amebia for sepsis, the method comprising treating the mammal with sis, hydatid cysts, burns, dermatitis, dermatomyositis, Sun an O-adrenergic antagonist such that a physiologic effect of burn, urticaria, warts, wheals, Vasulitis, angiitis, endocarditis, the sepsis is prevented or reduced. arteritis, atherosclerosis, thrombophlebitis, pericarditis, 2. The method of claim 1, wherein the C2-adrenergic myocarditis, myocardial ischemia, periarteritis nodosa, rheu antagonist is BRL-44408 maleate, RX821002, rauwolscine, matic fever, Alzheimer's disease, coeliac disease, congestive idazoxan, piribedil, atipamezole, dihydroergotamine, phen heart failure, adult respiratory distress syndrome, meningitis, tolamine, phenoxybenzamine, tolazoline, ARC 239, efar encephalitis, multiple Sclerosis, cerebral infarction, cerebral oxan, RS 79948, spiroxatrine, or yohimbine. embolism, Guillame-Barre syndrome, neuritis, neuralgia, 3. The method of claim 1, wherein the C2-adrenergic spinal cord injury, paralysis, uveitis, arthritides, arthralgias, antagonist is BRL-44408 maleate. osteomyelitis, fasciitis, Paget's disease, gout, periodontal dis 4. The method of claim 1, wherein the C2-adrenergic ease, rheumatoid arthritis, synovitis, myasthenia gravis, thry antagonist is an antibody or an aptamer. oiditis, Systemic lupus erythematosus, Goodpasture's Syn 5. The method of claim 1, wherein the physiologic effect of drome, Behcets's syndrome, allograft rejection, graft-Versus the sepsis is elevation of serum TNF-C. levels, elevation of host disease, Type I diabetes, ankylosing spondylitis, serum ALT levels, elevation of serum AST levels, elevation of Berger's disease, Type I diabetes, ankylosing spondylitis, serum lactate, and elevation of serum creatinine. Berger's disease, Retier's syndrome, or Hodgkin's disease. US 2009/02025 18 A1 Aug. 13, 2009

33. The method of claim 31, wherein the condition is adult respiratory distress syndrome, cerebral infarction, cere appendicitis, peptic, gastric and duodenal ulcers, peritonitis, bral embolism, spinal cord injury, paralysis, allograft rejec pancreatitis, ulcerative, pseudomembranous, acute and tion or graft-Versus-host disease. ischemic colitis, hepatitis, Crohn's disease, asthma, allergy, 34. The method of claim 31, wherein the condition is septic anaphylactic shock, organischemia, reperfusion injury, organ shock. necrosis, hay fever, sepsis, septicemia, endotoxic shock, 35-42. (canceled) cachexia, septic abortion, disseminated bacteremia, burns, Alzheimer's disease, coeliac disease, congestive heart failure,