Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-08-03
2003-04-15
Travers, Russell (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001730, C424S439000, C424S001650, C424S009100, C424S001810, C600S532000, C600S534000
Reexamination Certificate
active
06548043
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a standard test meal kit that is used in the diagnosis of gastrointestinal disorders characterized by changes in the rate of gastric emptying. The kit contains at least a test meal in the form of a dry mix and a tracer. The test meal dry mix is both meat-free and algae-free, and thus is more palatable than the prior art test meals. The tracer may be combined with the test meal dry mix, or preferable, is provided separate. The kit components may also include a container for mixing and cooking the test meal, a breath collection device, including multiple evacuated tubes, juice or water for reconstituting the test meal, a stirring implement, a temperature indicator, sample labels and a cooking device such as a portable convection oven or microwave.
The test meal is standardized in several respects, including caloric content, volume, carbohydrate, fat and protein proportions, method of preparation and method of administration. The test meal is packed in a stable dry mix form, which can be easily shipped and stored indefinitely at room temperature. The test meal is used with a non-radioactive tracer molecule, such as
13
C-sodium octanoate, which may be provided separate from the dry mix, thus minimizing concerns about stability and FDA regulation. The test meal is reconstituted on site with liquid and tracer, cooked, cooled, administered to a patient, and followed by an appropriate diagnostic measurement, such as the
13
CO
2
breath test.
2. Background of the Invention
Delayed gastric emptying affects tens of millions of patients who are diagnosed with various functional gastrointestinal disorders, including gastroesophageal reflux disease (GERD), non-ulcer dyspepsia (NUD), and diabetic gastroparesis, which affects half of all diabetes patients. The non-specific nature of delayed gastric emptying disorders often requires the rate of gastric emptying to be measured objectively. Measurement of gastric motility is achieved by monitoring the progression of a labeled test solid or liquid meal through the stomach. The rate of appearance of the label reveals information about the mechanics of gastric emptying.
The rate of gastric emptying can be influenced by many factors, including decreased fundic tone, decreased antral peristalsis, alterations in the gastric pacemaker, antropyloroduodenal incoordination, pyloric spasm, and intestinal dysmotility. Gastric emptying is also affected by a number of variables in test procedure, such as meal volume and temperature, the caloric density and nutritional content of the test meal, patient position and stress levels, patient gender and age, the technique of incorporating the label into the meal, and the method used for data acquisition and processing. In order to adequately study delayed gastric emptying, it is important that variations such as these should be minimized or otherwise accounted for.
The established diagnostic tool for monitoring solid and liquid phase gastric emptying is scintigraphic measurement of gamma emission from a radiolabeled test meal. The gamma emission from the radiolabel is visualized with a gamma camera held over the patient's abdomen and its progress from the stomach measured. This technique can be used to measure both solid and liquid phases of digestion, although the emptying of solids is generally of greater diagnostic significance.
Scintigraphy, however, is extremely costly and is limited by the availability of gamma cameras at clinical sites. More importantly, there are significant risks to the patient and the clinician associated with exposure to the radioactive tracer used in the scintigraphy. Further, the time required for the test is considerable, during which the patient must remain motionless under the gamma counter.
The expense and inconvenience of the scintigraphy test led to the creation of a simplified breath test. The breath test employs the metabolic reaction of 1-
13
C-octanoic acid as a tracer of gastric activity, and is alternatively known as the “Octanoate Breath Test” or “OBT.” Specifically, the
13
C-octanoate breath test employs the stable isotope
13
C, and gastric emptying is measured indirectly by monitoring the appearance of
13
CO
2
in breath subsequent to ingestion and metabolism of the
13
C-octanoate.
Octanoic acid is a naturally occurring eight-carbon fatty acid typically found in butter as an ester. It is a liquid at room temperature that is not water soluble. Generally, this and other medium chain fatty acids are efficiently absorbed by the small intestine and transported to the liver. In the liver, octanoic acid freely enters the mitochondria where it is oxidized to produce CO
2
. Exhaled CO
2
is collected at regular intervals using a breath collection device and
13
CO
2
content is measured with a mass spectrometer.
In the proposed invention, the Gastric Motility Breath Test (GMBT), the test meal is labeled with
13
C-sodium octanoate, a water soluble solid. The test meal is administered after an overnight fast and breath samples are collected at 15 minute intervals over one to several hours. Mathematical analysis of the
13
CO
2
appearance in breath reveals estimates of gastric emptying parameters. The first parameter is the lag time (T
lag
). T
lag
corresponds to the trituration phase in which particles are selectively retained in the stomach until they become small enough to allow passage through the pylorus. T
lag
increases with delayed gastric emptying. The second parameter is the half emptying time (T
½
). T
½
is the time at which half of the meal has passed through the stomach. T
½
increases when gastric emptying is delayed. The resulting curve reflects the sum influence of gastric emptying, digestion, absorption, and metabolism. The metabolic processing of octanoate is rapid and reproducible. Therefore, delays in emptying are due to differences in gastric motility.
The advantages of the breath test are that 1) there is no radioactivity exposure for the patient or clinician; 2) the test can be administered anywhere without need for specialized shielding equipment or disposal procedures; 3) there is no requirement for specialized training of personnel to handle the radioactivity; 4) increased convenience for the patient; and 5) it does not require access to expensive imaging equipment.
The original scintigraphy method required clinicians to mix radiolabeled tracer into scrambled eggs or chicken liver and cook the meal on site. Like the original scintigraphy method, the breath test is also administered with a scrambled egg or liver pate test meal. However, there are problems associated with using egg or liver for any type of gastric emptying test.
Specifically, there can be difficulty with uniform incorporation of the isotope into the egg or liver. To obtain radioactive liver,
99m
Tc-SC is injected into the wing vein of a live chicken. The label is taken up by hepatic Kupffer cells resulting in an intracellular trapped label. Because this process is cumbersome, many centers switched to adding label to scrambled eggs.
For the egg-based tests, the yolk and egg white are first separated because the label is only readily solubilized in the yolk. The label is added to the yolk, which is then beaten. The egg white is added back and again beaten, followed by cooking. Alternatively, the labeled yolk is cooked entirely separately from the egg white, and the two components are mixed and digested together.
A second problem is that meal homogeneity is difficult to maintain. Eggs, for example, vary in caloric content, size and composition. In addition, improper and non-standardized cooking conditions can affect the outcome of the test and prevent the intra-clinic comparison of test results. Further, palatability was less than desirable, especially with the liver based test.
U.S. Pat. No. 4,985,232 teaches a standardized test meal combining radiolabel with freeze dried beef. The freeze dried beef was an attempt to offer a uniform delivery system that could be used in a standa
Bolt Daniel L.
Goodman Keith J.
Wagner David A.
Jenken & Gilchrist
Metabolic Solutions, Inc.
Sharareh S
Travers Russell
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