Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-11
2002-12-03
Fan, Jane (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S395000, C546S273700, C548S307100
Reexamination Certificate
active
06489346
ABSTRACT:
TECHNICAL FIELD
The present invention relates to pharmaceutical preparations comprising substituted benzimidazole proton pump inhibitors.
BACKGROUND OF THE INVENTION
Omeprazole is a substituted benzimidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, that inhibits gastric acid secretion. Omeprazole belongs to a class of antisecretory compounds called proton pump inhibitors (“PPIs”) that do not exhibit anti-cholinergic or H
2
histamine antagonist properties. Drugs of this class suppress gastric acid secretion by the specific inhibition of the H
+
, K
+
-ATPase enzyme system (proton pump) at the secretory surface of the gastric parietal cell.
Typically, omeprazole, lansoprazole and other proton pump inhibitors are formulated in an enteric-coated solid dosage form (as either a delayed-release capsule or tablet) or as an intravenous solution (or as a product for reconstitution), and are prescribed for short-term treatment of active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive systematic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These conditions are caused by an imbalance between acid and pepsin production, called aggressive factors, and mucous, bicarbonate, and prostaglandin production, called defensive factors. These above-listed conditions commonly arise in healthy or critically ill patients, and may be accompanied by significant upper gastrointestinal bleeding.
H
2
-antagonists, antacids, and sucralfate are commonly administered to minimize the pain and the complications related to these conditions. These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the aforementioned conditions and/or produce adverse side effects, such as mental confusion, constipation, diarrhea, and thrombocytopenia. H
2
-antagonists, such as ranitidine and cimetidine, are relatively costly modes of therapy, particularly in NPO patients, which frequently require the use of automated infusion pumps for continuous intravenous infusion of the drug.
Patients with significant physiologic stress are at risk for stress-related gastric mucosal damage and subsequent upper gastrointestinal bleeding (Marrone and Silen, Pathogenesis, Diagnosis and Treatment of Acute Gastric Mucosa Lesions, Clin Gastroenterol 13: 635-650 (1984)). Risk factors that have been clearly associated with the development of stress-related mucosal damage are mechanical ventilation, coagulopathy, extensive burns, head injury, and organ transplant (Zinner et al., The Prevention of Gastrointestinal Tract Bleeding in Patients in an Intensive Care Unit, Surg. Gynecol. Obstet., 153: 214-220 (1981); Larson et al., Gastric Response to Severe Head Injury, Am. J. Surg. 147: 97-105 (1984); Czaja et al., Acute Gastroduodenal Disease After Thermal Injury: An Endoscopic Evaluation of Incidence and Natural History, N Engl. J. Med, 291: 925-929 (1974); Skillman et al., Respiratory Failure, Hypotension, Sepsis and Jaundice: A Clinical Syndrome Associated with Lethal Hemorrhage From Acute Stress Ulceration, Am. J. Surg., 117: 523-530 (1969); and Cook et al., Risk Factors for Gastrointestinal Bleeding in Critically Ill Patients, N. Engl. J. Med., 330:377-381 (1994)). One or more of these factors are often found in critically ill, intensive care unit patients. A recent cohort study challenges other risk factors previously identified such as acid-base disorders, multiple trauma, significant hypertension, major surgery, multiple operative procedures, acute renal failure, sepsis, and coma (Cook et al., Risk Factors for Gastrointestinal Bleeding in Critically Ill Patients, N. Engl. J. Med., 330:377-381 (1994)). Regardless of the risk type, stress-related mucosal damage results in significant morbidity and mortality. Clinically significant bleeding occurs in at least twenty percent of patients with one or more risk factors who are left untreated (Martin et al., Continuous Intravenous cimetidine Decreases Stress-related Upper Gastrointestinal Hemorrhage Without Promoting Pneumonia, Crit. Care Med., 21: 19-39 ('1993)). Of those who bleed, approximately ten percent require surgery (usually gastrectomy) with a reported mortality of thirty percent to fifty percent (Czaja et al., Acute Gastroduodenal Disease After Thermal Injury: An Endoscopic Evaluation of Incidence and Natural History, N Engl. J. Med, 291: 925-929 (1974); Peura and Johnson, Cimetidine for Prevention and Treatment of Gastroduodenal Mucosal Lesions in Patients in an Intensive Care Unit, Ann Intern Med., 103: 173-177 (1985)). Those who do not need surgery often require multiple transfusions and prolonged hospitalization. Prevention of stress-related upper gastrointestinal bleeding is an important clinical goal.
In addition to general supportive care, the use of drugs to prevent stress-related mucosal damage and related complications is considered by many to be the standard of care (AMA Drug Evaluations). However, general consensus is lacking about which drugs to use in this setting (Martin et al., Continuous Intravenous Cimetidine Decreases Stress-related Upper Gastrointestinal Hemorrhage Without Promoting Pneumonia, Crit. Care Med., 21: 19-39 (1993); Gafter et al., Thrombocytopenia Associated With Hypersensitivity to Ranitidine: Possible Cross-reactivity with Cimetidine, Am. J. Gastroenterol, 64: 560-562 (1989) Martin et al., Stress Ulcers and Organ Failure in Intubated Patients in Surgical Intensive Care Units, Ann Surg., 215: 332-337 (1992)). In two recent meta-analyses (Cook et al., Stress Ulcer Prophylaxis in the Critically Ill: A Meta-analysis, Am. J. Med., 91: 519-527 (1991); Tryba, Stress Ulcer Prophylaxis—Quo Vadis? Intens. Care Med. 20: 311-313 (1994)) Antacids, sucralfate, and H
2
-antagonists were all found to be superior to placebo and similar to one another in preventing upper gastrointestinal bleeding. Yet, prophylactic agents are withdrawn in fifteen to twenty percent of patients in which they are employed because of failure to prevent bleeding or control pH (Ostro et al., Control of Gastric pH With Cimetidire Boluses Versus Primed Infusions, Gastroenterology, 89: 532-537 (1985) Siepler, A Dosage Alternative for H-2 Receptor Antagonists, Continuous-Infusion, Clin. Ther., 8 (Suppl A): 24-33 (1986); Ballesteros et al., Bolus or Intravenous Infusion of Ranitidine: Effects on Gastric pH and Acid Secretion: A Comparison of Relative Cost and Efficacy, Ann. Intern. Med., 112:334-339 (1990)), or because of adverse effects (Gafter et al., Thrombocytopenia Associated With Hypersensitivity to Ranitidine: Possible Cross-reactivity With Cimetidine, Am. J. Gastroenterol, 64: 560-562 (1989); Sax, Clinically Important Adverse Effects and Drug Interactions With H2-Receptor Antagonists: An Update, Pharmacotherapy 7(6 pt 2): 110S-115S (1987); Vial et al., Side Effects of Ranitidine, Drug Saf, 6:94-117(1991); Cantu and Korek, Central Nervous System Reactions to Histamine-2 Receptor Blockers, Ann. Intern Med., 114: 1027-1034 (1991); and Spychal and Wickham, Thrombocytopenia Associated With Ranitidine, Br. Med. J., 291: 1687 (1985)). In addition, the characteristics of an ideal agent for the prophylaxis of stress gastritis were analyzed by Smythe and Zarowitz, Changing Perspectives of Stress Gastritis Prophylaxis, Ann Pharmacother, 28: 1073-1084 (1994) who concluded that none of the agents-currently in use fulfill their criteria.
Stress ulcer prophylaxis has become routine therapy in intensive care units in most hospitals (Fabian et al., Pneumonia and Stress Ulceration in Severely Injured Patients, Arch. Surg., 128: 185-191 (1993); Cook et al., Stress Ulcer Prophylaxis in the Critically Ill: A Meta-Analysis, Am. J. Med., 91: 519-527 (1991)). Controversy remains regarding pharmacologic intervention to prevent stress-related bleeding in critical care patients. It has been suggested that the incidence and risk of gastrointestinal bleeding has de
Fan Jane
Mahoney Joseph A.
Mayer Brown Rowe & Maw
Stiebel Thomas R.
The Curators of the University of Missouri
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