3,092,548 United States Patent Office Patented June 4, 1963 2 are the various side effects that occur in an appreciable 3,092,548 number of patients, the foremost of which are a blurring METHOD OF TREATING PEPTICULCERS WITH PANTOTHENECACD of vision, drowsiness and a general dry condition mani Albert G. Worton, Columbus, Ohio, assignor to The fested by a retarded salivation, reduction of perspiration Warren-Teed Products Company, Columbus, Ohio, a 5 and diminished urinary output. Other side effects which corporation of Ohio occur in some cases are glaucoma, stimulation of the cen No Drawing. Filed Oct. 27, 1960, Ser. No. 65,256 trol nervous system and in severe cases cardiac and respi 5 Claims. (Ci. 67-55) ratory collapse. These side effects increase to Some de gree with the increase in dosage. Despite the side effects This invention relates to preparation adapted for use O these compounds are fairly selective and highly effective in treating disorders of the gastro-intestinal tract, more in decreasing the volume and acidity of gastric secretion particularly in treating peptic ulcer, both of the duodenal and in reducing gastrointestinal motility. and gastric type, for hyperacidity, hypertropic gastritis, Understandably, the main problem in the past has been splenic flexure syndrome, biliary dyskinesia (postchole to provide a dosage of anticholinergic drug which will cystectomy syndrome) and hiatal hernia or other condi achieve the most beneficial results possible and yet mini tions where anticholinergic effect, either spasmolytic or mize the undesired side effects. One of the objects of antisecretory is indicated or where antiuicerogenic effect this invention is to provide novel compositions containing is indicated. anticholinergics and methods of administering same which Physical and emotional stress are widely known to be will be therapeutically effective even when providing low one of the chief caustive factors of hyperSecretion and 20 total dosages of the anticholinergic, thus minimizing un hypermotility in the gastrointestinal tract. This leads ul desirable side effects. timately to the formation of peptic ulcer in susceptible in An outstanding example of this type of drug are the dividuals, resulting fom failure of the gastro-duodenal scopolamine lower-alkyl salts. A good description of mucosa to withstand the digestive action of the acidic gas these quaternary derivatives of scopolamine (l-hyoscine) tric juice. Research has shown that the effects of local, 25 may be found in U.S. Patent No. 2,753,288 to Visscher. systemic and emotional stress are similar and are inde They are lower alkyl in salts of the tropic acid ester of pendent of the Specific nature of the damaging agent. epoxytropine and may be represented by the following Thus, surgical trauma, rage, fear, anxiety, emotional ten structural formula: sion, frustration, personal confict, physical exertion, burns, infections, etc. can cause the same type of response, name 30 H-H CE (ILOH - ly, an alarm reaction in the organism which is believed to • R.N-CH Hé-o--bH cause the increased utilization of corticoid hormones by H-bH &B, the tissues and a consequent decrease in their blood level. This in turn is thought to cause a discharge of cortcotro pin by the pituitary which stimulates the adrenals to Se 35 X crete more corticoid hormones. However, before the where R is a lower-alkyl group having not more than two adrenal response there is the above-described temporary carbon atoms and X is a member of the group consisting condition of hypocorticism. The overwhelming stress of a halogen having an atomic weight greater than nine along with the secondary adrenal insufficiency (termed 40 teen, sulfate maleate, gluconate, tartirate, citrate, acetate, the shock phase) may produce acute ulcers on the basis phosphate and nitrate. of shock accompanied by hypotension, hemoconcentra Various antiulcerogenic preparations have been pro tion, vascular stasis, capiliary fragility, leading to focal posed to relieve gastroduodenal irritation and to effect a mucosal hemorrhages. This type of ulcer begins to heal curative action on ulcerated conditions. Various pro as soon as the initial injury occurs. teins, fats and other nutrients have been used with some The hypocortical situation comes to an end when the beneficial effects. Naturally occurring pantothenic acid adrenals respond to the corticotropin and Secrete addition is present in these nutrients in extremely small amounts. all corticoid hormone. However, in many cases the adre In addition, synthetically derived pantothenic acid has nals are overstimulated to produce a hypercortical condi been added in very small amounts (vitamin-like quanti tion (termed the counter-shock phase). This condition 50 ties) along with much larger amounts of other vitamins also results when large amounts of corticoid steriods are such as A, D and the remaining B complexes. administered to the organism. This hypercorticism causes Antacids preparations have long been used for tempo (1) an increase in gastric secretion of hydrochloric acid rary reduction of the hydrochloric acid content of the and pepsin in the gastro-intestinal tract and (2) an inhi stomach and upper intestine. bition of fibroblast proliferation and delay of wound heal 55 While these various drugs have been helpful, they all ing due to the inflammatory action. have limitations and the need for other and superior drugs As a result the acute ulcer formed in the shock phase be is apparent. comes deeper, leading to hemorrhage or perforation or Though the presence of hydrochloric acid may be a chronic peptic ulcer. contributing factor in the etiology of ulcers, factors other In the past several types of drug therapy have been 60 than hypersecretion, regardless of the cause, appear to be devised for treatment and cure of peptic ulcer by one involved in the process. Diminished tissue resistance has mechanism or another. One of the most encouraging been felt to be the primary, predisposing factor. has been treatment with an antichlolinergic drug for the Even with the benefit of this knowledge, the cause of purpose of counteracting hypersecretion and hypermotility the diminished tissue resistance has not been satisfactorily in the gastrointestinal tract. 65 explained. It was suggested as long as 20 years ago that The mechanism of action of anticholinergic drugs is the organism simply runs out of something needed to through the inhibition of peripheral distribution of the fight the damaging agent. It has been discovered that parasympathetic (craniosacral autonomic) nerves intesti this something could be pantothenic acid. nal vagus, as well as oculomotor, secretory, bronchial mus It has been experimentally shown that depletion of culature, cardiac, uterus, etc.), resulting in blockade of 70 pantothenic acid is a significant factor in the susceptibility Sastric hypersecretions and intestinal spasticity. to peptic ulcer. The main troubles with the use of anticholinergic drugs It has further been determined that ulcer formation re 3,092,548 3 4. sulting from pantothenic acid deprivation can be pre acid (hereinafter called PA) are utilizable by the body vented by removing either the adrenal cortex or the pitui and are extremely effective in treatment of the effects of tary gland (the source of adenal-stimulating ACTH). gastric hyperacidity and peptic ulcer, which is called the On the other hand, severe ulcers appear rapidly if corti stress disease. Contrary to the indications that PA wouid some is administered to the adrenalectomized or hypo increase the symptoms of gastric disorders, it has been physectomized, pantothenate deficient animal. This dein found not to cause hypermotility even when administered onstrates that pantothenic acid deficiency and adreno in extremely large doses. Accordingly, it is a principal corticoid activity are factors in the etiology of ulcers, but object of this invention to provide methods and compo it does not suggest that pantothenic acid would be effec sitions for administering pantothenic acid in quantiiies tive in treating animal or human ulcers unless the ulcer 10 and preparations effective for the treatment of gastro in cases were due to pantothenic acid deficiency. As yet, testinal disorders. pantothenic acid deficiency in men has been observed It is an object of this invention to provide methods only after experimental induction. However, no ulcers and compositions for administering PA in quantities ef were observed as one of the symptoms. fective as a preventative or treatment of gastric disorders Coenzyme A has been found to be essential in adrenal 15 in individuals experiencing ulcerogenic stimuli such as steriod synthesis and oxidative metabolism. For instance, chronic anxiety states and other stress conditions to com when a subject is deprived of pantothenic acid (the meta bat the increased susceptibility of the gastrointestinal bolic source of coenzyme A), there is a significant de mucosa to anxiety increased adrenal cortical secretions. crease in gastric acid flow presumably due to a decrease Many authorities have observed that corticosteroid in adrenal activity. Hence it is hypothesized that panto 20 treatment (for pulmonary diseases, etc.) increases the in thenic acid deprivation delays and decreases adrenal func cidence of ulcers in humans. Also as previously indi tion in response to stress to accentuate and prolong the cated corticosteroids play a fundamental etiologic role in initial hypocortical condition and thus sensitize the gastro stress ulcer