Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2001-10-09
2004-05-25
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S009200, C424S001810
Reexamination Certificate
active
06740305
ABSTRACT:
BACKGROUND OF THE INVENTION
Gastric emptying plays a major role in many diseases that impair the highly coordinated physiological response to the presence of food and digestive fluids in the stomach. The most common pathophysiological causes for gastric emptying dysregulation are acid-peptic related diseases; gastritis; metabolic, endocrine or neurological disorders; obstructions; adverse responses to drugs and surgery; exercise and a variety of rare or idiopathic conditions. These disorders are significant in terms of morbidity, and their incidence will increase with the aging population and the expected presentation of more cases of diabetes, obesity, gastric surgery, and chronic liver disease.
Improved diagnostic approachs are needed for the assessment of gastric emptying disorders. New medications make gastric disorders more treatable than in the past, but empirical trials of these drugs are expensive, and a high degree of placebo effect exists in the population. The gold standard diagnostic method for gastric emptying is scintigraphy, assessed as liquid or solid emptying. This method is of limited availability at the patient bedside or in a physician's office. It is also expensive and, furthermore, includes the use of radioactively labeled foods and imaging technology not suitable for follow-up testing or for all patient candidates (e.g., fertile women, pregnant women and children). For drug development or in other research settings where consistency is important, scintigraphy is problematic because medical centers have not converged on a single, uniform protocol. For these reasons, other non-invasive techniques such as ultrasonography, electrogastrography, magnetic resonance imaging and tomography of swallowed radiopaque markers have been proposed or are being developed as validated alternatives to nuclear medicine methodologies, but these are equally problematic and logistically complex procedures for delivery at the point of patient care.
Recently, breath tests with stable isotopes have been developed to reliably assess gastric emptying by tracking the absorption and disposition of metabolizable foods that have been tagged with non-radioactive
13
C. Applicable to both the emptying of liquid and solid foods, the principal advantage of breath test technology in general is that no radiation is required and specific implementations of emptying test protocols can be performed without biological hazard and without complex equipment at the point of patient care. In practice, however, currently available diagnostic methods still involve inconveniently slow breath test protocols or expensive breath test substrates (labeled algae formulations) that may limit general clinical use.
For example, the use of octanoic acid is controversial in the medical literature and the results are highly setting dependent. The pure acid is oily, difficult to dispense in unit doses, and has a strong and disagreeable taste. The octanoic acid sodium salt is a dry powder, thus easier to divide into unit doses, and has a more acceptable taste. However, with either the free octanoic acid or its sodium salt, the test takes up to four hours and requires multiple breath samples because the pharmacokinetic modeling analysis requires several hours of post emptying data. In addition, if octanoic acid or its salt is used for Ad gastric emptying, the substrate material partitions out of the solid phase in a test meal, which can affect consistency of results. Octanoic acid is a surfactant and does not adsorb strongly to protein in the test meal. More importantly, this material is absorbed from the small intestine by a complex route and is then transported to and metabolized in various other sites within the body beyond the enterocytes and the splanchnic bed, e.g. heart, muscle and kidney. Because, in effect, gastric emptying is not the rate-limiting step in the delivery of labeled CO
2
to the breath during the post-absorptive fate of octanoate, the use of this and related substrates in a breath test is prone to misinterpretation attributable to confounding metabolic factors.
Therefore, there is a need for new breath test substrates that are inexpensive to manufacture and deliver compared with alternatives in radiology and nuclear medicine, perform well in liquid or solid phase emptying trials, are rapidly metabolized to allow for a faster trial completion and can be applied under a variety of physiological and metabolic conditions.
SUMMARY OF THE INVENTION
The invention is directed to the use of various linear and cyclic acyl aminoacid peptidomimetics as gastric emptying probes. The physical and biochemical properties of the probes described herein render them more suitable in methods of measuring gastric emptying time than those compositions known in the prior art. The linear and cyclic acyl aminoacid peptidomimetics useful in the method of the invention are preferably selected from the group consisting of:
where
R2=H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl tert-butyl, isopentyl, isohexyl, phenyl, phenylmethyl; and
R3=H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl tert-butyl, isopentyl, isohexyl, phenyl, phenylmethyl,
R4=H, formyl, acetyl, benzoyl, benzyloxycarbonyl, t-butoxycarbonyl, butyryl, ethoxycarbonyl, hippuryl, isopropyloxycarbonyl, methoxyacetyl, methoxycarbonyl, pivaloyl, proplonyl;
R5=H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl tert-butyl, isopentyl, isohexyl, phenyl, phenylmethyl; and
R6=H, If R5≠H; CH2-OH, CH2-SH, CH2-CH2-OH, CH2-CH2-S—CH3, CH2-COOR2, CH2-CH2-COOR2, CH2-CH2-CH2-COOR3, CH2-H2-CON—R3, CH2-CH2-CH2-NH2, or CH2-CH2-CH2-CH2-NH2 and
where:
R2=H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl tert-butyl, isopentyl, isohexyl, phenyl, phenylmethyl; and
R3=H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl tert-butyl, isopentyl, isohexyl, phenyl, phenylmethyl,
W=CH2, CH-alkyl, CH-aryl, CH2CH2, CH2-CH-alkyl, CH2-CH-aryl
X=N, O, S
Y=N, N—CH
3
; and
Z=N, O, S.
Three requisite properties differentiate the compounds of this invention from other substances in the current practice of breath tests for gastric emptying:
1) Their adsorptive and bulk-phase behavior as aminoacids and as polyfunctional, nitrogen containing derivatives in contrast to fatty acids, permits them to bind tightly, both ionically and electrostatically, to polar and non-polar constituents of foods, in particular with protein. These properties, commonly understood to be the hallmark of amphiphilic molecules, insure that the compounds of this invention will remain tightly crosslinked to the solid phase of foods during the emptying process from the stomach and, therefore, not partition into the liquid phase thereby causing measurement error;
2) The facility for rapid absorption by and rapid transport through the mucosa of the small intestine is a further requisite property embodied in the compounds of this invention. Acyl aminoacids and their peptidomimetic derivatives are essential nutrients whose rapid absorption has been a focus of the evolution of the digestive system of carnivore mammals, including humans. Since fatty acids are not normal dietary constituents, the mechanisms for their absorption into and through the mucosa are more complex, require assistance by enzymes and emulsifiers, and are more susceptible to interindividual variations in transport capacity;
3) Enterally administered free amino acids, acyl aminoacids and their peptidomimetic derivatives are preponderantly metabolized locally at the level of the enterocyte and in the splanchnic bed, so that the time span between their complete absorption into the mucosa and their conversion into the oxidation end-product, CO
2
, which is the parameter measured by breath tests, is demonstrably shorter than that of fatty acids. In contrast, the oxidative fate of fatty acids, such as octanoate, comprises several more, time depen
Cawthorn Christian
Côté France
Hartley Michael G.
Renault Ogilvy
Xanthus Life Scienes, Inc.
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