USOO5889038A United States Patent (19) 11 Patent Number: 5,889,038 Lencer et al. (45) Date of Patent: Mar. 30, 1999 54 METHODS AND PRODUCTS FOR Smith, P., et al., “Gastrointestinal Infections in AIDS”, TREATING DARRHEAAND SCOURS: USE Annals of Internal Medicine, 1992, 116:1:63-77. OF CLOTRIMAZOLE AND RELATED Tzipori et al., “The Journal of Infectious Diseases' 1995; AROMATIC COMPOUNDS 171:1069–71 by The University of Chicago. Verdon et al., “The Journal of Infectious Diseases' 1995; 75 Inventors: Wayne I. Lencer, Jamaica Plain; Carlo 171:1069–71 by The University of Chicago. Brugnara, Newton Highlands; Seth White et al., “The Journal of Infectious Diseases' 1995; Alper, Jamaica Plain, all of Mass. 171:1069–71 by The University of Chicago. A. Plattenberg, A. Stoehr, H.J. Stellbrink, H. Albrecht, W. 73 Assignee: Children’s Hospital, Boston, Mass. Meigel “A preparation from bovine colostrum in the treat ment of HIV-positive patients with chronic diarrhea Clin. 21 Appl. No.: 621,169 Investig.(1993) 71:42-45. 22 Filed: Mar 20, 1996 Glendon D. Sinks, et al., “Effects of lasalocid infection and growth in young dairy calves' JAVMA, Vol. No. 12, 51) Int. Cl. .......................... A61K 31/47; A61K 31/44; 1947–1951 (1992). A61K 31/415; A61K 31/40; A61K 31/405; J.A. Rump et al., “Treatment of diarrhoea in human immu A61K 31/38; A61K 31/34 nodeficiency virus-infected patients with immunoglobulins 52 U.S. Cl. .......................... 514/396; 514/312; 514/314; from bovine colostrum” Clin. Investig. (1992) 75:588-594. 514/332; 514/335; 514/339; 514/340; 514/341; R. Fayer “Activity of Sulfadimethoxine against cryptospo 514/343; 514/397; 514/398; 514/399; 514/414; ridiosis in dairy calves”. J. Parasitol., 78(3), 1992, pp. 514/415; 514/438: 514/444; 514/471; 514/473; 534-537. 514/867 A.J. Roussel Jr., et al., “Effect of ketoprofen on Escherichia 58 Field of Search ..................................... 514/312, 314, coli heat-stable enterotoxin-induced diarrhea in calves' 514/332, 335, 339, 340, 341, 343, 396, Am. J. Vet. Res., vol. 54, No. 12, Dec. 1993,(2088–2090). 397, 398, 399, 414, 415, 438, 444, 471, Hadya S. Nagesha, et al., “A variant serotype G3 rotavirus 473, 867 in piglets”, Journal of Medical Virology 38:79–85 (1992). 56) References Cited H.W. Moon, DVM, PhD “Mechanisms in the pathogenesis of diarrhea: a review”, Journal of the American Veterinary U.S. PATENT DOCUMENTS Medical Association, v. 172, 443-448 (1978). 3,655,882 4/1972 Wright et al............................ 424/147 Travis C. McGuire, DVM, PhD, et al., “Failure of colostral 3,965,112 6/1976 White et al. ......................... 260/309.6 immunoglobulin transfer in calves dying from infectious 3,984,539 10/1976 Khouw et al. ............................ 424/87 disease”, Journal Amer. Veterinary Medical Assoc. 169(7), 712-718 (1976). FOREIGN PATENT DOCUMENTS Denis Archambault, DVM, PhD, et al., “Immune response A-39340/89 8/1990 Australia ..................... A61K 39/395 of pregnant heiferS and cows to bovine rotavirus inoculation A-52547/90 11/1990 Australia ....................... A61K 37/02 and passive protection to rotavirus infection in newborn FR 2 715 O68 calves fed colostral antibodies or colostral lymphocytes', A1 1/1994 France. Am. J. Vet. Res., vol. 49, No. 7, 1084–1091 (1988). DE 4130689 A1 3/1993 Germany. Dale L. Haggard, DVM, MS, “Bovine enteric colibacillo 62-163662 7/1987 Japan. sis’, Vet. Clinc. Of N. Am.: Food Animal Practice vol. 1, No. WO91/15199 10/1991 WIPO. 3, 495-508 (1985). WO96/08242 3/1996 WIPO. F. Birki, et al., “Reduction of rotavirus-, coronavirus-and WO97/04244 3/1997 WIPO. E. coli-associated calf-diarrheas in a large-size dairy herd by means of dam Vaccination with a triple-vaccine”, J. Vet. OTHER PUBLICATIONS Med. B33.241–252 (1986). Rufo, P., et al., “The Antifungal Antibiotic, Clotimazole, Inhibits Cl Secretion by Polarized . J. Clin. Invest., (List continued on next page.) 1996, 98:9:2066-2075. Rufo, P., et al., “Inhibition of K' Transport and C Secretion Primary Examiner Kimberly Jordan in T84 Cells by Clotrimazole (CLT)”, J. General Physiol Attorney, Agent, or Firm Wolf, Greenfield & Saks, P.C. ogy, 1995, 106:38a, Abstract. 57 ABSTRACT Mentzer, D., et al., “Parenterale Ernährung bei Gewichtsy erlust und chronischer Diarrhoe . " Aids-Forschung A method and product for treating and preventing diarrhea AIFO-5th German Aids Congress, 1994, 9:11:621 (#333) and Scours is provided. The method involves treating a Abstract. Subject who has diarrhea, or Scours, or is at risk of getting Peters, M., et al., “Die akute und chronische Diarrhó', Med. diarrhea or Scours with an aromatic compound of the inven Munatschr. Pharm., 1994, 17:12:358-366. tion. The products of the invention are a veterinary prepa Brugnara C., et al., “Inhibition of CA2+-dependent K+ ration of the aromatic compound of the invention and an Transport and Cell Dehydration in Sickle . J. Clin. anti-Scours agent, and a pharmaceutical preparation of the Invest., 1993, 92:1:520–526. aromatic compound of the invention and an anti-diarrheal Simon, D., et al., “Treatment Options for AIDS-Related agent. Espohageal and Diarrheal Disorders”, The American J. of Gastroenterology, 1992, 87:3:274–281. 29 Claims, 2 Drawing Sheets 5,889,038 Page 2 OTHER PUBLICATIONS Carlo Brugnara et al., “Inhibition of Ca"-dependent K" “Bovine rota-coronavirus-Escherichia coli antibody transport and cell dehydration in Sickle erythrocytes by (Bovine Origin) first defense”, Immucell Corp. Product clotrimazole and other imidazole derivatives', J. Clin. Instruction Sheet (1990). Invest., vol. 92, 520–526 (1993). D. Waltner-Toews, S.W., et al., “A field of evaluate the Brugnara et al., “Ion channels and genetic diseases, Society efficacy of a combined rotavirus-coronavirus/Escherichia of General Physiologists 48th Annual Symposium pp. 1-3 coli vaccine in dairy cattle', Can. J. Comp. Med 49:1-9 (1985). (1994). B. Kaiser, et al., “Protection against acute, ascending pyelo Carlo Brugnara, et al., “Oral administration of clotrimazole nephritis caused by Escherichia coli in rats, using isolated and blockage of human erythrocyte Ca'-Activated K' capsular antigen conjugated to bovine Serum Albumin', Channel: the imidazole ring is not required for inhibitory Infection and Immunity, v. 39 pp. 142-146 (1983). activity”, JPET 273:266–272, (1995). I. Hajer, BVSC, PhD, et al., “Antigens of bovine coronavirus strain LY-138 and their diagnostic properties”, Am. J. Vet. Mana Vajanaphanich, et al., “Long-term uncoupling of Res., vol.39, pp. 441–444 (1978). chloride secretion from intracellular calcium levels by Ins(3, Harald Brissow, et al., “Cross-neutralizing antibodies 4,5,6)P.", Nature vol. 371, 711–714 (1994). induced by Single Serotype vaccination of cows with rotavi rus”, J. Gen. Virol. 69, 1647–1658 (1988). Carlo Brugnara, et al., “Therapy with oral clotrimazole R.C. Heel, R.N., et al., “Miconazole: a preliminary review of induces inhibition of the gardos channel and reduction of its therapeutic efficacy in Systemic fungal infections, Drugs erythrocyte dehydration in patients with Sickle cell disease”, 19:7–30 (1980). J. Clin. Invest. vol. 97, No. 5, 1227–1234 (1996). W. Ritter, et al., “Pharmacokinetic fundamentals of vaginal treatment with clotrimazole”, Chemotherapy 28 (Suppl. E. Lohrmann et al., “A new class of inhibitors of cAMP 1):37–42 (1982). mediated CI secretion in rabbit colon, acting by the cAM Wolfgang Ritter, PhD., “Pharmacokinetic fundamentals of P-Activated K' conductance”, Pflügers Arch-Eur. J. vaginal treatment with clotrimazole”, Am. J. Obstet. Physiol. 429:517-530 (1995). Gynecol. Aug. 1, 1985 (945-947). Ilko G. Iliev, et al., “Potassium channels in epithelial cells”, B. Duhm et al., “The pharmacokinetics of clotrimazole 'C', Cellular and Molecular Biology Research, vol.39, No. 6, pp. Postgraduate Medical Journal 50 (Jul. Suppl.) 13-16 (1974). 601–611, (1993). Lucia DeFranceschi et al., “Treatment with oral clotrimazole blocks Ca"-activated K transport and reverses erythrocyte Kiertisin Dharmsathaphorn, et al., "Vasoactive intestinal dehydration in transgenic SAD mice’, J. Clin. Invest. Vol. polypeptide-induced chloride Secretion by a colonic epithe 93, 1670–1676 (1994). lial cell line”, J. Clin. Invest., vol. 75,462-471 (1985). U.S. Patent Mar. 30, 1999 Sheet 1 of 2 5,889,038 BaCl CHARYBDOTOXN 5~ |º=<;:orovavo NBIA §Njalº NITOHOvaHyoS, ?NITOHOva?vo iT c+l/\\, U.S. Patent Mar. 30, 1999 Sheet 2 of 2 5,889,038 O w O CY) 2 & o ll Z (N > c5 H Y CC CD { O CC w C H GN O S. t O cy) 2 S. I (NO > H O O O O 2 OO CO S. OCN (3AWIONOW/9XIV Lon WLOL 9%) Xnl--3 qugs 5,889,038 1 2 METHODS AND PRODUCTS FOR diarrhea in AIDS patients include administration of antibi TREATING DARRHEAAND SCOURS: USE otics and administration of immunoglobulins or an immu OF CLOTRIMAZOLE AND RELATED noglobulin enriched fraction of bovine colostrum. AROMATIC COMPOUNDS Colostrum, which is the first milk produced by mammals after birthing is enriched with antibodies. BACKGROUND OF THE INVENTION Acute diarrhea or Scours, is a main cause of death in many Acute and chronic diarrheaS represent a major medical newborn barn animals Such as calves and pigs. Scours is problem in many areas of the world. Diarrhea is both a often caused by ETEC with a K99 pilus antigen. Infection Significant factor in malnutrition and the leading cause of with the ETEC causes hypersecretion of fluid and electro death (5,000,000 deaths/year) in children less than five years lytes. HyperSecretion in turn causes dehydration and pH old. Secretory diarrheaS are also a dangerous condition in imbalance which may result in death of the newborn calf or patients of acquired immunodeficiency Syndrome (AIDS) pig.