Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving urea or urease
Reexamination Certificate
2000-01-03
2004-01-13
Gitomer, Ralph (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving urea or urease
C435S034000
Reexamination Certificate
active
06677129
ABSTRACT:
BACKGROUND
1. Field of Invention
The present invention relates generally to health care diagnostics and specifically to an improved method for oral sampling in a human subject for rapid detection of the presence of infection, the specific embodiment being the detection of the urease activity associated with
Helicobacter pylori
infection in the human.
Helicobacter pylori
(
H. pylori
) is a common pathogen in humans and specifically causes disease of the stomach. In industrialized countries, infection can be present in half of all persons older than 50 years. First identified in 1983
, H. pylori
is now known to cause chronic gastritis or inflammation of the stomach, as well as gastric and duodenal ulcers. It is also associated with gastric malignancy (Thomas, E., et al., “The role of the oral cavity in
Helicobacter pylori
infection,”
Am. J. Gastroenterol
., 1997 December; 92(12): 2148-2154). This and other publications cited are incorporated by reference herein.
Combinations of antibiotics and bismuth and/or gastric acid blocking agents are used to treat
H. pylori
infection in the stomach. Bismuth salicylate inhibits the urease activity of
H. pylori
(Prewett, E., et al., “Comparison of one-day oral dosing with three bismuth compounds for the suppression of
Helicobacter pylori
assessed by the 13C-urea breath test,”
Aliment. Pharmacol. Ther
., 1992 February; 6(1): 97-102).
The scientific literature states that the mode of transmission of
H. pylori
between humans is unknown.
H. pylori
has been identified in the mouths of humans in some instances, involving isolation from the dental plaque, saliva and gingival pockets. However, studies of the prevalence of oral colonization by
H. pylori
have shown variable results with most known infected persons having negative oral results (Thomas et al., 1997, supra).
In some instances an association has been observed between
H. pylori
detectable in the mouth and presence of the organism in the stomach (Mapstone, N., et al., “Identification of
Helicobacter pylori
DNA in the mouths and stomachs of patients with gastritis using PCR,”
J. Clin. Pathol
., 1993; 46: 540-543). In some cases the strain of
H. pylori
in saliva is found to match that in the stomach (Ferguson, D., et al., “Isolation of
Helicobacter pylori
from saliva,”
J. Clin Microbiol
., 1993 October; 31(10): 2802-2804). In lieu of oral colonization, it has been suggested that reflux of gastric contents (gastroesophageal reflux) into the oral area may be the factor accounting for occasional recovery of
H. pylori
organisms from the mouth (Madinier, I., et al., “Oral carriage of
Helicobacter pylori
: a review,”
J. Periodontol
., 1997 January; 68(1): 2-6).
H. pylori
has been suggested to be associated with health disorders beyond gastric inflammatory conditions (Wisniewski, R., and Peura, D., “
Helicobacter pylori
: behond peptic ulcer disease,”
Gastroenterologist
, 1997 December; 5(4): 295-305; “The germ theory of heart disease,” Newsday, Mar. 3, 1998; Markus, H., and Mendall, M., “
Helicobacter pylori
infection: a risk factor for ischemic cerebrovascular disease and carotid atheroma,”
J. Neurol. Neurosurg. Psychiatry
, 1998 January; 64(1): 104-107).
Detection of
H. pylori
in oral fluid samples derived from the pharynx, as an indicator of current infection status has not been described in humans until the present invention. In one study, tissue biopsies of the larynx, which lies below the pharynx and is not contacted during sampling of the pharynx, were found to contain urease activity in only a minority of subjects with chronic laryngitis (Borkowski, G., et al., “A possible role of
Helicobacter pylori
infection in the etiology of chronic laryngitis,”
Eur Arch Otorhinolaryngol
, 1997; 254: 481-482).
Some research suggests that conditions of the pharynx or throat area may be involved in diseases of the gastrointestinal tract (Zavadiak, H., “The relationship of duodenal peptic ulcer and gastroduodenitis to a chronic staphlococcal infection,”
Lik Sprava
, 1993 May; 5-6: 65-69; Minocha, A., et al., “Is a history of tonsillectomy associated with a decreased risk of
Helicobacter pylori
infection?”,
J. Clin. Gastroenterol
., 1997 December; 25(4): 580-582). These studies suggest associations between changes in the lymphatic tissues and subsequent gastrointestinal disease, but not pharyngeal sampling for diagnostic purposes.
In a canine study, multiple tissue biopsies were obtained following experimental
H. pylori
infection.
H. pylori
was found in a pharynx biopsy of only one of several experimentally infected, gnotobiotic canine test subjects (Radin, M., et al., “
Helicobacter pylori
gastric infection in gnotobiotic beagle dogs,”
Infect. Immun
., 1990 August; 58(8): 2606-2612). Canines are not naturally affected by
H. pylori
infection and these and other non-humans do not serve as a reservoir of
H. pylori
, however.
H. pylori
produces abundant urease, more than other currently known bacteria. The high urease activity of
H. pylori
allows it to survive in an acid environment, by production of ammonia from urea and thereby signicantly elevating the pH of the environment of the organisms. The unique ability of
H. pylori
to produce abundant urease has been utilized to identify presence of the organism in solid tissue specimens placed into small test volumes containing urease substrate. In an initially acid pH environment of greater than approximately 2.5, the urease activity of
H. pylori
in a solid tissue specimen can metabolize urea to raise the pH (U.S. Pat. No. 4,923,801, Marshall and Guerrant, 1990). This and other patents cited are incorporated by reference herein. When present in significant quantities,
H. pylori
organisms have sufficient preformed urease to raise the pH in the absence of additional bacterial growth.
The urease activity of common, non-
H. pylori
bacteria is destroyed by acid environments. A relatively stronger acid environment is required to destroy the urease of
H. pylori
. Increased acidity stimulates the urease activity of
H. pylori
(Miederer, S., Grubel, P., “Profound increase of
Helicobacter pylori
urease activity in gastric antral mucosa at low pH,”
Dig. Dis. Sci
., 1996 May; 41(5): 944-949).
The rapid urease test has a high sensitivity for detection of urease activity and is considered a reliable method for assessment of
H. pylori
infection in solid tissue specimens. One rapid form of the urease test utilizes a gel into which the tissue sample is placed (CLOtest; U.S. Pat. No. 4,748,113, Marshall, May 1998). The gel acts as a support for the tissue specimen and reagents and contains the urease substrate and pH indicator. This test requires up to 24 hours for completion. Methods of applying urea and a pH indicator to gastric mucosa during endoscopic procedures, to rapidly detect tissue colonized by
H. pylori
are also in use (Thillainayagam, A., et al., “Diagnostic efficiency of an ultrarapid endoscopy room test for
Helicobacter pylori,” Gut
, 1991 May; 32(5): 467-469; Iseki, K., et al., “
Helicobacter pylori
infection in patients with early gastric cancer by the endoscopic phenol red test,”
Gut
, 1998; 42: 20-23).
A test-strip form of the rapid urease test which provides visual results on solid tissue specimens within an hour or more at room temperature has been developed (Yousfi, M., et al., “Comparison of Agar Gel (CLOtest) or Reagent strip (PyloriTek) rapid urease tests for detection of
Helicobacter pylori
infection,”
Am. J. Gastroenterol
., 1997 June; 92(6): 997-999; Elitsur, Y., et al., “Prospective comparison of rapid urease tests (PyloriTek, CLOtest) for the diagnosis of
Helicobacter pylori
infection in symptomatic children: a pediatric multicenter study,”
Am. J. Gastroenterol
., 1998 February; 93(2): 217-219; U.S. Pat. No. 5,314,804, Boguslaski and Carrico, May 1994; U.S. Pat. No. 5,420,016, Boguslaski and Carrico, May 1995). This test strip was developed for detection of urease activity in solid tissue specimens obtained from the stomach.
2. Discussion of Prior Art
Confirmatio
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