US005389664A United States Patent [19] [11] Patent Number: 5,389,664 Baile et a1. [45] Date of Patent: Feb. 14, 1995

[54] ALLEVIATING STOMACH ULCERS IN 5,223,515 6/1993 Mikura et a1...... 514/338 SWINE FOREIGN PATENT DOCUMENTS [75] Inventors: Clifton A. Baile, Chesterfield; 5 12 Pa _ _ _ Frances 9- Bwmomo, 919119099401 3333350 423$? 552% 142.82. . L- McLaughlin, Chesterfield; Billy D. 1234058 6/1971 United Kingdom . Vineyard, St. Louis, all of Mo. _ _ OTHER PUBLICATIONS [73] Ass1gnee: Monsanto Company, St. Loms, Mo. _ v , _ _ Adelstein et a1. “Subsntuted Potential Inhibitors of [21] APPI- N0-= 223,377 H+/K+ ATPase” 31 J. Med. Chem. 1215-20 (1988). [22] Filed: Apr. 5, 1994 stapleton et a1. “Sucralfate in the Prevention of Porcine ' Experimental Peptic Ulceration”, Amer. J. Med. 21-22 Related US. Application Data (1289)‘ . , _ _ SmIth and Kasson, J. Anim. 801., vol. 68, No. 12, pp. COntlIlUZ-UOI! Of S61‘. NO. 910,863, Jul. 8, 1992, aban med' Smith and Kasson J. Anim. Sci, V01. 69, NO. 2, pp. [51] Int. C1.6 ...... A61K 31/415; A61K 31/47; 571-577 (1991). A61K 37/00; A61K 31/445 Tksukimi et a1., Gastroenterology, vol. 104, No. 4(2), [52] US. Cl...... 514/394; 514/9; 1992, p. A181. 514/11; 514/314; 514/338; 514/395; 514/396; Joseph Alper “Ulcers as an Infectious Disease”, Sci 514/806; 514/866 ence, vol. 260, pp. 159-160 (1993). [58] Field Of Search ...... 514/314, 338, 9, l1, Silen, “Experimental Models of Gastric Ulceration and 514/394, 395, 306, 366, 396 Injury”, pp. G395-G402, American Physiol. Soc. - (1988). [56] 1 References Cited Glaven, S. B., and Sandor Szabo, “Experimetnal Gas U-s- PATENT DOCUMENTS tric Mucosal Injury” The FASEB Journal, pp. 825-832

4,045,563 8/ 1977 Berntsson et a1...... 424/263 ' (1992). 4,045,564 8/1977 Berntsson et a1. . 424/263 . . . . . 4,182,766 1/1980 Krasso et a1...... 424/263 pn’f'a'l" Exam"_’e’_Mananne _M- cmtms 4,255,431 3/1981 Junggren et a1. .. 424/263 48mm’ Exammer-jK- Weddmgwn 4,359,465 11/1982 Ruwart ...... 514/314 Attorney, Agent, 0rF1rm—-Ge0rge R- Beck; Gary M 4,472,409 9/1984 Senn-Bil?nger 424/263 Pond 4,628,098 12/1986 Nohara et a1. 546/271 4,689,333 8/1987 Nohara 61; a1 514/338 [571 ABSTRACI 4,758,579 7/ 1988 K0111 8! a1 514/ 333 Alleviation of stomach ulcers in swine which are being 4,361,868 8/1989 ------530/399 administered exogenous somatotropin, by administering 4,873,337 10/1989 $111 6? a1...... 546/271 to the Swine a compound Selected from 5,013,743 5/1991 Iwahi et_a1...... 514/338 h 1 lalk 1 uh. I thi b . .daz 1 d 5,039,806 8/1991 Bradstraim et a1 546/271 eter9°¥° 3’ y (8 my °r . 0) can?‘ ° es an 5,045,321 9/1991 Makino et a1 ...... 424/475 [benzlmldamlYKsul?nYl °r thwhlkyllan?mes 5,185,347 2/1993 Katano et a1 514/322 5,215,974 6/1993 Alminger et a1 ...... 514/80 19 Claims, N0 Drawings 5,389,664 1 2 (6%) and Stafac® antibacterial growth promotant ALLEVIATING STOMACH ULCERS IN SWINE (0.011%) have been found ineffective or not statistically effective. This is a continuation of application Ser. No. It is believed that at the rates of PST administration 07/910,863, ?led on Jul. 8, 1992, now abandoned. 5 generally envisioned for commercialization, the propor In swine that are being administered a porcine so tion of swine that may die from the effects of PST matotropin (PST), e.g., to increase their growth rate, aggravated ulceration is rarely greater than a few per feed-to-meat conversion efficiency, leanness and/or cent and normally less than one percent. However, to sow milk, the somatotropin may contribute to stomach more fully permit realization of the great potential of ulcers which, in severe cases, can cause death. See somatotropins for improving economics of the swine Smith and Kasson, J. Anim. Sci. 68:4109-16 (1990) and industry and providing higher quality (leaner) pork 69:571-77 (1991). These authors indicate that the mech products, it is an object of this invention to provide anism by which somatotropin causes such ulcers is un methods and articles of manufacture useful for alleviat known. The dif?culty of understanding this mechanism ing ulcers in swine being administered PST. Details of has been increased by the failure of various commonly the practice and utility of this invention in achieving used anti-ulcer products to alleviate ulcers in swine to that objective and others will be apparent from the which a somatotropin is being administered. following disclosure. For example, histamine H2 receptor antagonists such as Tagamet® cimetidine (SmithKline Beecham), Zan SUMMARY OF THE INVENTION tac ® ranitidine (Glaxo), Pepcid ® famotidine (Merck) 20 and Axid ® nizatidine (Lilly) are widely used in treat This invention provides a method for alleviating ul ing stomach ulcers in humans. However, a histamine cers, and decreasing concomitant mortality in swine H2 receptor antagonist (ranitidine) has been found to which are being administered exogenous somatotropin, have little effect for alleviating ulcers in PST-treated which comprises administering a benzimidazole com swine when 150 mg/day of the ranitidine is adminis 25 pound selected from heterocyclylalkyl(sul?nyl or thio) tered by 3>bismuth subcitrate 30 Also provided by the invention are articles of manu (Gist-Brocades). These form a complex with protein facture that are useful in practicing the method of this aceous exudate (albumin) at the ulcer site and thus pres invention, which articles comprise a porcine somatotro ent a film barrier against diffusion of hydrogen ions to pin and a benzimidazole compound selected from stomach epithelial tissue. However, the addition of 1 or heterocyclylalkyl(sulf1nyl or thio)benzimida.zoles and 4 gm sucralfate/ 3 kg of a ?nely ground pelleted diet fed 35 [benzimidazolyl(sulfmyl or thio)alkyl]anilines, said arti to PST-treated 58-67 kg swine has been ineffective or cles being adapted for contemporaneous injection of the inconclusive for alleviating stomach ulcers, and the somatotropin and benzimidazole compound to effect administration of 500 mg/day of De-Nol was likewise prolonged release into the circulatory system of the ineffective. swine of somatotropin in an amount effective to in Various E-type prostaglandins have unequivocally crease the growth rate, feed efficiency, leanness or sow demonstrated an ability to alleviate ulcers in humans. milk of the swine, and of the benzimidazole compound However, the synthetic prostaglandin E1 methyl ester, in an amount effective to alleviate stomach ulcers in the Cytotec ® misoprostol (Searle), has been found to have swine. very little effect in alleviating ulcer development in PRIOR ART PST-treated hogs using 2Xdaily oral gavages of miso 45 prostal totaling either 400 or 800 pg/day. Free-radical Heterocyclylalkyl(sul?nyl or thio)benzimidazoles are scavengers have been found to alleviate stomach ulcers known to be useful for alleviating stomach ulcers in in hogs not being treated with PST. For example, Vita mammals that are not being administered exogenous min U has been found effective against diet-induced somatotropin. See U.S. Pat. Nos. 4,045,563 and ulceration in hogs. Tamas, et al., Oesophagogastric Ulcer 50 4,045,564 (Berntsson, et al; issued Aug. 30, 1977); in Swine and Vitamin U, III-IV, 34 Acta. Veterinaria 4,182,766 (Krassé, et al., issued Jan. 8, 1980); 4,255,431 Hungarica 81-100 (1986). However, Vitamin U has (J unggren, et al; issued Mar. 10, 1981); 4,472,409 (Senn been found not signi?cantly effective against stomach Bilfmger; issued Sep. 18, 1984); 4,628,098 (Nohara, et al; ulcers in PST-treated hogs when included in feed at 800 issued Dec. 9, 1986); 4,758,579 (Kohl, et al; issued Jul. ppm. Other free-radical scavengers, e. g., Vitamin E 55 19, 1988); 4,873,337 (Sih, et al; issued Oct. 10, 1989); (100 IU/kg plus 0.25 ppm selenium), and other possible 5,039,806 (Bradstram, et al; issued Aug. 13, 1991); and in-feed ulcer alleviators, e.g., wheat midds (5%), San 5,045,321 (Makino, et al; issued Sep. 3, 1991), the disclo toquin ® feed preservative (Monsanto) (0.75 gm/day), sures of which are incorporated herein by reference. oat hulls (9%) and cysteine (800 ppm), have been found However, one of the most widely used compounds of similarly ineffective or not statistically effective against that class, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2 stomach ulcers in PST-treated hogs. pyridyl)methylsul?nyl]benzimidazole (Prilosec ® ome Still other recognized stomach ulcer treatments have prazole; Merck) has been found ineffective for alleviat been found ineffective or not statistically effective in ing swine stomach ulcers induced by bile duct ligation. PST-treated hogs. For example, Vitamin K in the form Stapleton, et al., Sucralfate in the Prevention of Porcine of menadione (6 mg/day), a clotting time-associated 65 Experimental Peptic Ulceration, 86 (Suppl. 6A) Amer. J. drug, and alfalfa (9% in feed; high in Vitamins E and K) Med. 21-22 (1989). Various pyridylalkylthioben have been found ineffective, and feed additives that zimidazoles, their oral or parenteral administration, and slow down the gastric emptying rate, such as tallow their biological (e.g., anti-in?ammatory) activities are 5,389,664 3 4 disclosed in British 1,234,058, which was published Jun. zolyl, thiazolinyl, quinolyl, or piperidyl, each of which 3, 1971. can be further unsubstituted or have 1, 2 or 3 ring sub [Benzimidazolylsulfmylalky?anilines are also known stituents (alike or different) which do not unacceptably to be useful for alleviating stomach ulcers in mammals interfere with performance of the benzimidazole com that are not being administered exogenous somatotro pound for use in this invention. These substituents (alike pin. See, e.g., Adelstein, et al., Substituted 2-[(2-Ben or different) can be chosen from chloro, bromo, ?uoro, zimidazobsul?nyl)methyl]anilines as Potential Inhibitors iodo, alkyl and ?uorinated alkyl groups, wherein each of H+/K+ATPase, 31 J. Med. Chem. 1215-20 (1988) alkyl can be straight-chain or branched and contain one, and European Patent Appln. published Dec. 10, 1986 two, three or four (preferably one) carbon atom(s). under No. 204,215, the disclosures of which are incor Also as shown in that prior art, the alkyl radical link porated herein by reference. ing the heterocyclyl radical and the sulfur atom in the DETAILED DESCRIPTION sul?nyl or thio radical can be straight-chain or branched and can contain one, two, three or four (pref This invention is useful with any swine to which a erably one) carbon atom(s). Used illustratively herein somatotropin is being administered. These swine may 15 are the following benzimidazoles: include sows to which the somatotropin is being admin istered to enhance milk production. However, the in timoprazole—2-[2-pyridylmethylsul?nyl]ben vention is most commonly used with growing swine zimidazole; _ (e.g., ?nishing hogs) which may be barrows, gilts or thio analog of timoprazole*—2-[2-pyridylmethylthio] boars. These hogs usually have a body weight between 20 benzimidazole; about 20 and about 150 kg. omeprazole 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2 The somatotropins with which this invention is useful pyridyl)methylsul?nyl]benzimidazole; and include any compound having somatotropin-like activ lansoprazole-2-[[3-methyl-4-( 2,2,2 tri?uoroethoxy ity in swine. These include compounds equivalent to or )-2-pyridyl) ]methylsul?nyl ]benzimidazole. ‘sometimes referred to as timoprazole sul?de or reduced timoprazole. otherwise providing biological activity approximating 25 Most preferred for use in this invention are the 2-[2 the effects of native porcine somatotropin. Examples pyridylmethyl(sulfmyl or thio)]benzimidazoles, includ are disclosed in US. Pat. Nos. 4,861,868 (Krivi; issued ing especially timoprazole, its thio analog, and the 5 Aug. 29, 1989) and 5,104,806 (Souza; issued Apr. 14, methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl 1992), European Patent Appln. published Feb. 28, 1990 sul?nyl]benzimidazoles, including omeprazole. Nor under No. 355,460 (Cady, et al.), European Patent 30 Appln. published Jun. 20, 1984 under No. 111,389 (See mally, timoprazole provides excellent results and, espe burg, et al.), European Patent Appln. published Apr. 4, cially in some modes of administration such as injection 1984 under No. 104,920 (Movva, et a1.) and European of pellets, its thio analog provides even better results, Patent Appln. published Jun. 5, 1991 under No. 429,788 e.g., in terms of prolongation and steadiness of release (Wang, et al.), the disclosures of which are incorporated from the injected pellet(s). Methods for preparing such herein by reference. Administration of a growth hor benzimidazoles are well known; some are described in mone releasing factor or other somatotropin secreta the patents and patent applications cited in the preced gogue that simulates administration of exogenous so ing description of prior art. Various 2-[2-pyridylmethy1 matotropin by stimulating the release of additional en thio]benzimidazoles useful in this invention, their prepa dogenous somatotropin should be considered equiva ration and a method for their conversion to the corre lent for purposes of this invention. sponding 2-[2-pyridylmethylsul?nyl]benzimidazoles, The PST can be administered by daily injection or also useful in this invention, are disclosed in European other parenteral methods, and is desirably administered Patent Appln. published Aug. 3, 1988 under No. by injection or implantation of a delivery system from 302,720 and/or the aforementioned British Patent which the PST is released into the circulatory system of 45 1,234,058, the disclosures of which are incorporated the swine for a period of at least about 1, and preferably herein by reference. Many similarly useful structural at least about 3 weeks. A period of PST release for up to variations of these compounds and methods for their about 6 weeks, or even longer, is desirable. The admin preparation will be apparent to those skilled in the art. istration may be at any rate (constant or variable) and in Alternatively, the benzimidazole compound used in any amount effective to increase the growth rate, feed this invention can be any [benzimidazolyl(sul?nyl or to-meat conversion efficiency (“feed efficiency”), lean thio)alky1]aniline which is effective for alleviating stom ness or milk production of the swine. This is usually at ach ulcers in swine, and especially those of the pars an average rate of at least about 1, and preferably at esophagea. Typically these benzimidazoles are effective least about 2 mg/day. For economic reasons and other for inhibiting activity of the acid secretory enzyme wise, the daily dose is usually not greater than about 20, 55 H+/K+ATPase. Preferred among these benzimida more commonly not greater than about 10, and most zoles are 2-[(2-benzimidazolyl sulfmyl or thio)methyl desirably not greater than about 5 mg/day. ]anilines which can be further unsubstituted or have The benzimidazole compound used in this invention additional substituents (alike or different) chosen from can be any heterocyclylalkyl(sul?nyl or thio)ben chloro, bromo, ?uoro, iodo, alkyl and ?uorinated alkyl zimidazole which is effective for alleviating stomach 60 groups, each containing 1, 2, 3 or 4 carbon atoms, ulcers in swine, and especially those of the pars eso provided such substituents do not unacceptably inter phagea which, in swine, is particularly susceptible to fere with performance of the benzimidazole compound gastric ulcers. Typically these benzimidazoles are effec for use in this invention. Speci?c illustrations of these tive for inhibiting H+/K+ATPase enzyme activity in benzimidazoles compounds are: parietal cells in swine stomachs. 65 2-[(2-benzimidazolylthio)methyl]-N-methylaniline; As shown in the aforementioned prior art, the hetero 2-[(2-benzimidazolylsul?nyl)methyl]-N-methylaniline; cyclyl radical in such benzimidazole compounds can be 2-[(2-benzimidazolylthio)methyl]-4-methylaniline; and pyridyl, imidazolyl, imidazolinyl, benzimidazolyl, thia 2-[(2-benzimidazolylsul?nyl)methyl]-4-methylaniline. 5,389,664 5 6 The benzimidazole compound can be administered reground feed (18% protein with 0.25% supplemental orally, e.g., in feed or water, or parenterally, e.g., by lysine) available ad libitum. After 6 days, stomachs from injection together with or separately from the somato all hogs were recovered and scored for ulceration ac tropin. Desirably the somatotropin and benzimidazole cording to the following system. are administered simultaneously or contemporaneously, 5 i.e., by injecting or implanting doses of each from which Ulcer Scoring they will be concurrently released into the circulatory Each stomach is removed by severing the esophagus system of the swine over a prolonged (preferably sub and duodenum 5 cm away from their connections with stantially similar) period of time. Such prolonged re the stomach. The stomach is cut from the pylorus along lease may be accomplished from an implanted osmotic the greater curvature to within 5 cm of the esophageal pump containing a flowable formulation of the benz opening. The stomach is emptied, its inner surface is imidazole compound, or injected pellet(s) made by gently cleaned without abrading the esophageal area, compacting the dry particulate benzimidazole in a quan and the stomach is then spread open with its inner sur tity enough to provide the required average daily dose face facing upward. The severity of any ulcer present is for the desired length of time. The rate and amount of 15 rated by evaluating together the size and depth of the administration of the benzimidazole compound are lesion, as follows. A lesion which encompasses essen those e?‘ectivc to signi?cantly alleviate (i.e., prevent or tially all of the esophageal area of the stomach is desig reduce the severity of) stomach ulcers in the swine, nated total. If a substantial proportion of the area of particularly those of the pars esophagea. These will epithelial tissue remains, the lesion is designated partial. depend on the potency of the speci?c benzimidazole 20 The depth of the ulcer is designated mild, moderate or compound being employed, the ulcer susceptibility of severe. Mild ulcers are those in which the surface epi the breed or other characteristics of the swine in the thelial layer is slightly reddened. An erosion with a environment in which the swine are being treated and depth of approximately 0.25 mm is designated moder maintained. Although the rate and amount of adminis ate. A very deep erosion (e.g., several mm) which re tration can vary widely, they will most commonly be at 25 sults in complete loss of the epithelial layer in the ulcer least about 1 (preferably at least about 5) mg/day, and ated area is designated severe. After the size (area) and will usually be not greater than about 50 (preferably not depth of the ulcer are determined, the severity of the greater than about 25 mg/day. ulcer is scored numerically as follows: The following speci?c examples are illustrative only and do not imply any limitations on the scope of this 30 _ _ invention Partial and Mild - 1 Total and Moderate - 7 ' Total and Mild - 3 Partial and Severe - 8 EXAMPLES 1_4 Pamal and Moderate - 5 Total and Severe - 10

Several benzimidazole compounds were tested as . . alleviators of stomach ulcers in swine being adminis- 35 ?esults of the ulcer Scoring for Groups 1-6 are m Table tered a PST. 60 cross-bred barrows weighing about ' TABLE I 20 mg/d pST Group 3 Group 4 Group 5 Group 6 40 mg 20 mg 40 mg 400 mg Group 1 Group 2 omeprazole omeprazole timoprazole timoprazole Control 20 mg/d pST once daily twice daily once daily once daily Number of Hogs 1o 101 10 10 10 10 Ulcer Score 0.10 8.00 2.40 1.60 0.50 0.00 lOne hog died on day 5. The cause was undetermined. However, an ulcer was not present.

90—l00 kg were randomly assigned to the following These results show that omeprazole and, to an even groups of 10 hogs each: greater extent, timoprazole are highly effective for alle Group l—Control (administered neither PST nor viating stomach ulcers in PST-treated swine. benzimidazole). 50 Groups 2 thru 6—Injected with a high dose (20 Comparative Examples A & B mg/day) of PST by daily injection for 6 days to In the study which included Examples 1-4, 2 addi aggravate ulcer development for this study of ulcer tional groups of 10 hogs, each being administered the inhibition effects. same PST in the same manner and the same amount (20 Group 3 (Example l)--Additionally administered 40 55 mg/day), were administered during the same 6 day mg/ day omeprazole by single oral gavage. period either 150 mg/day of ranitidine (50 mg injected Group 4 (Example 2)—Additionally administered 40 3>

effects. Group 2 (Example 5)—40 mg/day timoprazole by 15 twice-daily injection of 20 mg. These results show that timoprazole and its thio ana Group 3 (Example 6)-—1O mg/day timoprazole by log are highly effective for alleviating stomach ulcers in twice-daily injection of 5 mg. PST-treated swine. Group 4 (Example 7)—10 mg/day timoprazole by While speci?c embodiments of the invention have steady infusion from an implanted Alzet pump. been described, it will be apparent to those skilled in the All hogs had ?nely ground, pelleted and reground art that various modi?cations thereof can be made with feed (18% protein with 0.25% supplemental lysine) out departing from the true spirit and scope of the in available at libitum. After 7 days, stomachs from all vention. Accordingly, it is intended that the following surviving hogs were scored for ulceration according to claims cover all such modi?cations within the full in the system described in Examples l-4, with the results 25 ventive concept. shown in Table II. We claim: 1. A method for alleviating stomach ulcers in swine TABLE II which comprises: 20 mg/d pST administering to swine a compound, effective to alle Group 2 Group 3 Group 4 Group 1 20 mg 5 mg 10 mg/d viate pars esophageal ulcers in swine being admin no timoprazole timoprazole timoprazole istered exogenous porcine somatotropin, in an timoprazole twice daily twice daily (Alzet) amount which is effective to alleviate said ulcers, Number of 101 101 1o1 101 wherein said Hogs compound being a benzimidazole compound ef Ulcer Score 7.80‘ 1.104 2.70“ 4.301’ 35 fective for inhibiting H+/K+ ATPase activity in lOne hog within each of the 4 treatments died within a 2~day period (days 3-4). parietal cells in swine stomachs which is selected from heterocyclylalkyl(sul?nyl or thio)ben zimidazoles and [benzimidazolyl(sul?nyl or thio) EXAMPLES 8-1 1 alkyl]anilines. Several different administrations of timoprazole or its 4-0 2. A method of claim 1 in which the benzimidazole thio analog were tested for alleviation of stomach ulcers compound is a 2-[2-pyridylmethyl(sul?nyl or thio)]ben in swine being administered by daily injection a PST of zimidazole. the kind employed in Examples l-4. 80 cross-bred bar 3. A method of claim 2 in which the benzimidazole rows weighing about 90-100 kg were randomly as compound is 2-[2-pyridylmethylthio]benzimidazole. signed to the following 8 groups of 10 hogs each: 45 4. A method of claim 2 in which the benzimidazole Group l——Control (administered neither PST nor a compound is 2-[2-pyridylmethylsul?nyl]benzimidazole. benzimidazole) . 5. A method of claim 2 in which the benzimidazole Group 2—Injected for 28 days with 20 mg/day PST. compound is 5~methoxy-2-[(4-methoxy-3,S-dimethyl Group 3 (Example 8)—Injected with 20 mg PST/day 2-pyridyl)methylsul?nyl]benzimidazole. and 40 mg timoprazole/day for 28 days. 50 6. A method of claim 1 in which the benzimidazole Group 4 (Example 9)—-Injected with 20 mg PST/ day compound is administered by injection contemporane for 6 days and then, for 22 days, 20 mg PST/day ously with the somatotropin. and 40 mg timoprazole/day. 7. The method of claim 1 wherein: Group 5 (Example 10)-—Injected with 20 mg the effective amount comprises an amount of the PST/day for 6 days and then, for 22 days, 3 mg 55 benzimidazole compound effective for releasing a PST/day and 10 mg timoprazole/day. daily dose between about 1 and about 50 milligrams Group 6—Injected with 20 mg PST/day for 6 days per day. and then 3 mg PST/day for 22 days. 8. The method of claim 7 wherein: Group 7--Administered neither PST nor a benzimid the daily dose comprises between about 5 and about azole for 22 days; then injected with 20 mg 50 milligrams per day. PST/ day for 6 days. 9. The method of claim 7 wherein: Group 8 (Example ll)—Administered neither PST the daily dose comprises between about 5 and about nor a benzimidazole for 22 days and then, for 6 25 milligrams per day. days, 20 mg PST/day and 40 mg/day of 2-[2 10. The method of claim 1 wherein: pyridylmethylthio1benzimidazole. 65 the exogenous somatotropin is being administered in All hogs had ?nely ground, pelleted and reground an amount effective for aggravating ulcer develop feed (18% protein with 0.25% supplemental lysine) ment in the pars esophagea. available ad libitum. After 29 days, stomachs from all 11. The method of claim 1 wherein: 5,389,664 10 the exogenous somatotropin is being administered at the administered exogenous somatotropin is released an average rate from about 1 to about 20 milligrams in the swine for a period of at least 1 week. per day. 16. The method of claim 11 wherein: 12. The method of claim 11 wherein: the administered exogenous somatotropin is released the exogenous somatotropin is being administered at in the swine for a period of at least 3 weeks. an average rate from about 1 to about 10 milligrams 17. The method of claim 11 wherein: per day. the administered exogenous somatotropin is released 13. The method of claim 11 wherein: in the swine for a period of more than 6 weeks. the exogenous somatotropin is being administered at 18. The method of claim 1 wherein: 1O an average rate from about 1 to about 5 milligrams the exogenous somatotropin and the benzimidazole per day. compound are concurrently released into the swine over a period of time. 14. The method of claim 11 wherein: 19. The method of claim 18 wherein: the exogenous somatotropin is being administered at the period of time for release of each of the exoge an average rate from about 2 to about 5 milligrams 15 nous somatotropin and the benzimidazole com per day. pound is substantially similar. 15. The method of claim ‘11 wherein: * * * *

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