Peter H. Jones

Chapter 19 Agents for the Treatment of Peptic Ulcer Disease

Publisher Summary In recent times, the introduction of new, effective drugs for peptic ulcer disease therapy has increased dramatically. However, different drugs are not equally effective in all patients and some patients remain refractory to the treatment. In addition, the high relapse rates after successful treatment remain a significant problem and challenge for the future, while it seems clear that peptic activity as well as acid are contributing factors, current reasoning incorporates additional factors, into the etiology of the disease. Bicarbonate secretion, quality and quantity of mucus production and release, blood flow, cell junctions, and ion pumps are some functions thought to enhance mucosal protection that is key to the prevention of this disease. Thus, no single element may account for mucosal protection as all may be potential contributing factors. Researchers have provided insight into mucosal protective mechanisms. These studies led to the introduction of the term “cytoprotection” generally accepted to mean protection of the gastric mucosa by prostaglandins (PGs) at doses lower than those required to inhibit acid secretion. Preclinical and clinical efforts continue with a large number of synthetic PG analogs. The development, chemistry, and status of most of these compounds have been discussed in this chapter. The mechanism of the gastric anti-secretory effect of E-type PGs has been established with the identification and characterization of a PG receptor on the cell membrane of canine parietal cells.

Alpha chain unsaturated derivatives of misoprostol

Misoprostol, a 15-deoxy-16-hydroxy-16-methyl analog of PGE1, is an effective agent for the treatment of peptic ulcer disease. Efforts to impede metabolic degradation of the alpha chain of misoprostol led to the discovery of a second clinical candidate in this series. Enisoprost, a delta 4Z derivative of misoprostol, is more potent as a gastric antisecretory agent and longer acting than misoprostol. These findings prompted further work to determine the effects that two double bonds in the alpha chain might have on the activity profile of misoprostol. The most promising structure in this series was a 1:1 mixture of 3E,5Z and 3Z,5Z dienes which was about three times more potent than misoprostol in inhibiting gastric secretion in dogs, while the separation of the diarrheogenic effect was significantly improved. Chromatographic separation of the mixture was very difficult, but small amounts of each isomer were obtained by HPLC, and preliminary antisecretory studies indicated that most of the activity resided in the 3E,5Z isomer. A stereospecific synthesis of the 3E,5Z isomer was carried out to provide sufficient quantities for complete pharmacological assessment. The 3E,5Z diene was about three times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.

Chapter 18. Recent Advances in the Treatment of Inflammatory Bowel Disease

Publisher Summary This chapter discusses the recent advances in the treatment of inflammatory bowel disease. Crohns disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD). The etiology of IBD is not known. Active current areas of research into the etiology of IBD are focusing on Mycobacterium paratuberculosis as an initiator in CD and pathogenic E. coli involvement in UC. There has been a major growth in the study and characterization of a number of soluble mediators implicated in the inflammatory response associated with IBD. The role of platelet activating factor (PAF), as a mediator of the inflammatory response in IBD, is currently under investigation. Recent data indicates that kinins and specifically bradykinin may be involved in the inflammation observed in IBD. A more recent theory suggests the etiology of UC involves a defect in mucin synthesis and/or degradation. For most physicians corticosteroids are the first therapeutic approach for IBD. 5-aminosalicylic acid (5-ASA) is clearly effective in UC. But, its mechanism of action is not confirmed. The role of immunosuppressive therapy in IBD has been controversial since its inception. Disodium chromoglycate has been reported to be active clinically in the treatment of UC. The role of inflammatory mediators in IBD has prompted the introduction of a number of new agents designed to control their action. However, it is clear that a need still exists for more therapeutically efficacious agents for the treatment of IBD, including CD and UC.