Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2000-05-24
2002-07-30
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S439000, C424S441000, C424S048000, C424S049000, C424S653000, C514S900000, C514S901000, C514S902000
Reexamination Certificate
active
06426085
ABSTRACT:
BACKGROUND OF THE INVENTION
Until recently, excessive gastric acidity and mental stress were thought to be major pathophysiological reasons for occurrence of peptic ulcers. In the early 1980, Marshall and Warren (Warren, Lancet, 1:1273-1275, 1983 and Marshall et al., Lancet, 2:1311-1315, 1984) first reported an unidentified curved bacilli in the stomach of patients with gastritis and peptic ulcers. These bacilli, which later were identified as a gram negative spiral bacterium and named
Helicobacter pylori
(Goodwin et al., Int. J. Syst. Bacteriol. 39:397-405, 1989), have been demonstrated to be associated with gastritis and peptic ulcers (Buck et al., J. Infect. Dis. 153:664-669, 1986 and Graham, Gastroenterology 96:615-625, 1989), and are thought to be transmitted by person-to-person contact.
Recent clinical investigations have shown a definitive presence of
H. Pylori
in the dental plaque (Nguyen et al., Journal of Clinical Microbiology 31(4):783-787, 1993; Desai et al., Scandinavian Journal of Gastroenterology 26:1205-1208, 1991; and Lambert et al., Lancet 341(8850):957, 1993), and have also shown that standard oral hygiene practice does not help reduce
H. Pylori
presence in the oral cavity (Nguyen et al., Journal of Clinical Microbiology 31(4):783-787, 1993). As a result of these recent discoveries associating bacterial infection in the causation of peptic ulcer disease, questions regarding the previously established paradigms of ulcer treatment and healing processes have been raised.
H
2
receptor blockers which suppress acid secretion, such as cimetidine (Tagamet®) and ranitidine (Zantac®), have been used to treat and heal duodenal ulcers (Jones et al., Gut. 28:1120-1127, 1987; McIsaac et al., Aliment. Pharmacol. Therap. 1:369-381, 1987; and Boyed et al., Amsterdam:Excerpta Medica, 14-42, 1984). Recently, however, a number of clinical investigations have demonstrated that 70-80% of healed duodenal ulcers reoccur within the next year (Goodwin et al., Int. J. Syst. Bacteriol 39:397-407, 1989), and that these drugs do not reverse the tendency for ulcers to form (Wormsley, British Medical Journal 293: 1501, 1986; Gudman et al., British Medical Journal i:1095-1097, 1978; and Bardhan et al., British Medical Journal 84:621-623, 1982).
For many years, bismuth compounds have been used for treating ulcers. Clinical investigations comparing the efficacy of CBS (also known as tripotassium dicitrato bismuthate (TDB)) with placebo (Lambert, Scandinavian Journal of Gastroenterology 26(Supplement 185):13-21, 1991), cimetidine (Bianchi, et al., Lancet 2:698, 1984), and ranitidine (Bianchi et al., Gut. 2:565, 1984; Lee et al., Lancet 1:1299-1301, 1985; and Dobrilla et al., Gut. 29:181-187, 1988) in initial healing and relapse rates of duodenal ulcers, have shown significantly lower relapse rates in patients treated with CBS. The therapeutic efficacy of CBS (and other bismuth compounds), in healing duodenal ulcers and lowering relapse rates, is attributed to its specific antibacterial activity against
H. Pylori
(McNutty et al., Antimicrobial Agents Chemotherapy 28:837-838, 1985; Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511, 1986; and Goodwin et al., J. of Antimicrobial Agents Chemotherapy 17:309-314, 1986). The minimum inhibitory concentration (MIC) for CBS against
H. Pylori
is reported to be 8 mg/L (Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511) and the range is 4-32 mg/L (Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511).
In addition to its bacteriocidal activity, CBS has been demonstrated to enhance mucus glycoprotein secretion, strengthen viscoelastic gel properties of mucus, cause increased concentration of epithelial growth factor (EGF) in ulcer tissue, and stimulate prostaglandin synthesis in the gastric antral mucosa (Lee, Scandinavian Journal of Gastroenterology 26(Supplement 185):1-6, 1991). These gastroprotective properties of CBS may contribute to the initial healing of duodenal ulcers and the observed lower rates of relapse by returning the gastric mucosal cells to normal physiologic function. The gastroprotective effects of CBS in prevention of gastric lesions induced by various ulcerogenic agents and the mechanism of ulcer healing have been demonstrated in animal studies (Konturek et al., Digestion 37(Supplement 2):8-15, 1987 and Konturek et al., Scandinavian Journal of Gastroenterology 21(Supplement 122):6-10, 1986).
Because of the finding that bismuth is an effective antibacterial agent against
H. Pylori
, concomitant dosages of bismuth-containing compounds with other anti-ulcer drugs have been increasingly applied in many clinical cases for treatment of peptic ulcers. The most commonly used regiments include double or triple therapy with bismuth; meanwhile, some recent reports regarding quadruple therapy (wherein a proton pump inhibitor is added to triple therapy) have shown eradication rates of over 90%, but also cause severe side effects such as vomiting and diarrhea.
Additionally, while antibacterial therapy (bismuth and amoxycillin or doxycycline) was shown to be effective in eliminating
H. Pylori
from the gastric mucosa of duodenal ulcer patients, this therapy had no effect on the
H. Pylori
colonies in their dental plaque (Desai et al., Scandinavian Journal of Gastroenterology 26:1205-1208, 1991, Nguyen et al., Journal of Clinical Microbiology 31(4):783-787, 1993). The continued presence of
H. Pylori
in the dental plaque raises the question of whether the relapse of duodenal ulcers is inevitable (Desai et al., Scandinavian Journal of Gastroenterology 2:1205-1208, 1991 and Abraham et al., Indian Journal of Gastroenterology 2(4):265-6, Editorial, 1990).
Triple therapy, consisting of an antibiotic (amoxicillin, tetracycline or erythromycin), metronidazole, and bismuth compounds, has been reported to result in more than a 95% eradication rate for
H. Pylori
, and reduced ulcer relapse rate to less than 10% during a 12-month follow-up period (Graham et al., Gastroenterology 102:493-496, 1992 and Borody et al., Gastroenterology 102:A 44, 1992). It is interesting to note that metronidazole as a single agent has only 5% eradication rate for
H. Pylori
, but as a component of triple therapy, it increases the eradication rate to as high as 95%. When metronidazole-resistant strains of
H. Pylori
are encountered (about 25% of the
H. Pylori
strains are resistant), the eradication rate falls to about 50% (Logan et al., Lancet M. 1249-1252, 1991).
One possible explanation for this observed clinical efficacy of metronidazole in combination therapy is that metronidazole is actively secreted in the saliva (Mustofa et al., International Journal of Clinical Pharmacology, Therapy, and Toxicology 29(12):474-478, 1991) where it might be exerting its antimicrobial action against dental plaque-bound
H. Pylori
colonies. The typical steady state saliva represent 10 to 20 times the MIC for
H. Pylori
. Another antibiotic, Clarithromycin, a new-generation macrolide, which has shown a 40 to 60% cure rate as a single agent, is also secreted in the saliva. Therefore, it is reasonable to believe that in order to achieve nearly complete eradication of
H. Pylori
, and prevent peptic ulcer relapse, eradication of this organism from the oral cavity is essential. Colloidal bismuth subcitrate (CBS), the most effective single agent against
H. Pylori
, is however not absorbed significantly from the GI, and therefore, produces no salivary concentrations. But as a single agent, it is about 6 to 8 times more effective in eradicating
H. Pylori
than metronidazole. The present invention therefore is related to development of a therapeutic modality to effectively eradicate
H. Pylori
reservoir from the oral site, as well as the gastric mucosal wall.
Furthermore, recent clinical studies have implicated this insidious organism in gastric cancer (Parsonnet, Gastroenterology Clinics of America,
Helicobacter pylori
Infection, Dooley C P, Cohen, H. Guest Editors, Volume 22, No. 1, pp. 89-104, March 1993). A progression of gastric pathology from gastritis and
Brinks Hofer Gilson & Lione
Josman Laboratories Inc.
Kishore Gollamudi S.
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