US5162373A
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US
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Methods and improved formulations for the determination and treatment of malignant disease in patients
Assignee: The University of Texas System
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Filing: 1989-08-28
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Granted: 1992-11-10
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Expires: 2009-08-28
Abstract
Abstract Disclosed are total parenteral nutrition formulations which include essential amino acids in combination with either arginine or ornithine, for use in detection of recurrent malignant disease in patients. Such formulations stimulate tumor-specific polyamine production to a greater extent than non-tumor related polyamine production. Additionally, such formulations were found to specifically promote an increase in red block cell putrescine levels of tumor-bearing rats. Nontumor-bearing rats were not found to be similarly reactive to these formulations. Methods for making and administering these formulations as well as their use in preventing DFMO-induced toxicity are also disclosed. The present invention also comprises formulations for use in the rejuvination of compromised mucosal surfaces. The ornithine-containing formulations are also useful in preventing the onset of gut atrophy attendant to long term parenteral administration. The present formulations also prove a prophylactic function in preventing the onset of secondary infections by promoting mucosal cell growth in opportunitized tissues of persons with compromised mucosal surfaces. The formulations contain ornithine in a final concentration of between about 0.60% and 1.00% by weight. Such formulations have been found shown to stimulate the growth of intestinal mucosal villi of the small intestine. The formulation may be provided in the form of a complete parenteral formulation or as a standard parenteral formulation additive to be used in conjunction with a standard TPN formulation. Methods for making and administering these formulations as well as their use in preventing gut atrophy and averting secondary infection are also disclosed.
Inventors
- 👤 Jaffer Ajani
- 👤 Bruce Grossie, Jr.
- 👤 Kenji Nishioka
- 👤 David M. Ota
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-27 22:13
CPC Classifications
A; A61; A61K; A61K38/00; A61K38/01
Claims Analysis
Total Claims: 33
Claim 1
Independent Claim
25 words
A formulation comprising a growth promoting concentration of ornithine of at least 0.5% in a pharmaceutically acceptable diluent containing methionine suitable for preventing gut atrophy.
Claim 2
Dependent Claim
25 words
A formulation comprising a growth promoting concentration of ornithine of at least 0.5% in a pharmaceutically acceptable diluent containing methionine suitable for preventing gut atrophy.
Claim 3
Dependent Claim
21 words
The formulation of claim 1 wherein the pharmaceutically acceptable diluent is selected from the group consisting of: glucose; TRAVESOL®; and water.
Claim 4
Dependent Claim
12 words
The formulation of claim 1 wherein the pharmaceutically acceptable diluent is TRAVESOL®.
Claim 5
Dependent Claim
24 words
The formulation of claim 1 further defined as comprising ornithine in a concentration range of between 0.55% and 2.0% by weight of the formulation.
Claim 6
Dependent Claim
26 words
The formulation additive of claim 1 defined further as comprising ornithine in a concentration range of between about 2% and 10% by weight of the additive.
Claim 7
Dependent Claim
21 words
The formulation of claim 1 defined further as comprising ornithine in a concentration range of between about 0.60% and 1% ornithine.
Claim 8
Dependent Claim
16 words
The formulation of claim 1 defined further as comprising ornithine in a concentration of about 0.65%.
Claim 9
Dependent Claim
51 words
A formulation comprising a pharmaceutically acceptable amount at least 0.5% of ornithine and a mixture of the following amino acids: leucine methionine; phenylalanine; lysine; valine; isoleucine; threonine; tryptophan; and histidine, together in a pharmaceutically acceptable diluent, wherein said formulation includes less than 1% arginine and is suitable for preventing gut atrophy.
Claim 10
Dependent Claim
51 words
A formulation comprising a pharmaceutically acceptable amount at least 0.5% of ornithine and a mixture of the following amino acids: leucine methionine; phenylalanine; lysine; valine; isoleucine; threonine; tryptophan; and histidine, together in a pharmaceutically acceptable diluent, wherein said formulation includes less than 1% arginine and is suitable for preventing gut atrophy.
Claim 11
Dependent Claim
18 words
The formulation of claim 8, further defined as comprising less than 0.10% by weight final concentration of arginine.
Claim 12
Dependent Claim
76 words
The formulation of claim 8, wherein the pharmaceutically acceptable amount of amino acids comprise the following weight range of the respective amino acids for every 100 milliliters of the formulation: 250 to 1400 mg leucine; 200 to 1400 mg isoleucine; 200 to 1250 mg valine; 100 to 900 mg phenylalanine; 50 to 850 mg methionine; 150 to 750 mg lysine; 85 to 500 mg histidine; 100 to 550 mg threonine; and 50 to 200 mg tryptophan.
Claim 13
Dependent Claim
38 words
A method of preventing intestinal epithelial atrophy in a patient comprising: (a) identifying a patient requiring non-oral nutritional support; and (b) administering to the patient the formulation defined in claim 8, wherein the mode of administration is parenteral.
Claim 14
Dependent Claim
62 words
A method for treating compromised mucosal surfaces in a patient comprising the steps of: (a) identifying a patient having a compromised mucosal epithelial cell surface; (b) administering to the patient a therapeutically effective amount of the formulation defined in claim 1 or 8; and (c) repeating the formulation administration for a period of at least 8 days, wherein the administration is parenteral.
Claim 15
Dependent Claim
59 words
A method for enhancing intestinal mucosal villi growth in a patient comprising: (a) identifying a patient having a compromised mucosal epithelial surface: (b) administering to the patient a therapeutically effective amount of the formulation defined in claim 1 or 9; and (c) repeating the formulation administration for a period of at least 8 days, wherein the administration is parenteral.
Claim 16
Dependent Claim
75 words
A method of formulating a feeding solution from the additive of claim 1 comprising: mixing a volume of the additive of claim 1 with a volume of pharmaceutically acceptable diluent; and stirring the mixture sufficiently so as to achieve a homogenous solution, wherein the ratio of the additive to the pharmaceutically acceptable diluent is 1:9 (v/v) so as to provide a final concentration of ornithine of between 0.55% and 2.0% by weight of the formulation.
Claim 17
Dependent Claim
11 words
The method of claim 12, wherein the patient is a human.
Claim 18
Dependent Claim
11 words
The method of claim 13, wherein the patient is a human.
Claim 19
Independent Claim
14 words
The method of claims 11, 12, or 13 wherein the patient is a human.
Claim 20
Dependent Claim
90 words
A method of preparing the formulation of claim 1 comprising: (a) measuring a quantity of ornithine; (b) mixing the ornithine with a volume of a pharmaceutically acceptable diluent to form a solution; (c) stirring the solution sufficiently so as to form a homogenous formulation; and (d) adding a sufficient additional volume of pharmaceutically acceptable diluent having methionine so as to constitute an ornithine concentration of between about 0.55% and about 2% by weight of the formulation and a final arginine concentration of less than 1% by weight of the formulation.
Claim 21
Dependent Claim
13 words
The method of claim 18 wherein the pharmaceutically acceptable diluent is 10% TRAVESOL®.
Claim 22
Independent Claim
64 words
A method for enhancing villi growth of the small intestine in a patient comprising administering to the patient a parenteral formulation including ornithine in a 10% TRAVESOL® diluent, wherein the ornithine is included in a final concentration of at least 0.55% by weight of the formulation, and wherein the arginine is included in a concentration of less than 1.0% by weight of the formulation.
Claim 23
Independent Claim
64 words
A method for enhancing villi growth of the small intestine in a patient comprising administering to the patient a parenteral formulation including ornithine in a 10% TRAVESOL® diluent, wherein the ornithine is included in a final concentration of at least 0.55% by weight of the formulation, and wherein the arginine is included in a concentration of less than 1.0% by weight of the formulation.
Claim 24
Independent Claim
95 words
A method for treating intestinal mucosal surface atrophy in a cancer bearing patient comprising the steps of: (a) identifying a patient with cancer requiring non-oral nutritional support; and (b) administering a parenteral formulation to the patient, the parenteral formulation including a pharmaceutically acceptable amount of ornithine and a mixture of amino acids selected from the group consisting of: leucine; methionine; phenylalanine; lysine; valine; isoleucine; threonine; tryptophan; and histidine, together in a pharmaceutically acceptable diluent, wherein the final concentration of ornithine is at least 0.55% by weight of the formulation and wherein the administering is parenteral.
Claim 25
Independent Claim
95 words
A method for treating intestinal mucosal surface atrophy in a cancer bearing patient comprising the steps of: (a) identifying a patient with cancer requiring non-oral nutritional support; and (b) administering a parenteral formulation to the patient, the parenteral formulation including a pharmaceutically acceptable amount of ornithine and a mixture of amino acids selected from the group consisting of: leucine; methionine; phenylalanine; lysine; valine; isoleucine; threonine; tryptophan; and histidine, together in a pharmaceutically acceptable diluent, wherein the final concentration of ornithine is at least 0.55% by weight of the formulation and wherein the administering is parenteral.
Claim 26
Dependent Claim
21 words
The method of claim 21 wherein the formulation is defined further as comprising less than 1% arginine by weight final concentration.
Claim 27
Dependent Claim
21 words
The method of claim 21 wherein the pharmaceutically acceptable diluent is selected from the group consisting of: TRAVESOL®; and glucose solution.
Claim 28
Independent Claim
96 words
A method for treating mucosal surface atrophy in a non-cancer bearing patient comprising the steps of: (a) identifying a patient having intestinal mucosal surface atrophy; and (b) administering a parenteral formulation to the patient, the parenteral formulation including a pharmaceutically acceptable amount of ornithine, arginine, and a mixture of amino acids selected from the group consisting of: leucine; methionine; phenylalanine; lysine; valine; isoleucine; threonine; tryptophan; and histidine, together in a pharmaceutically acceptable diluent, wherein the final concentration of ornithine is at least 0.55% by weight of the formulation and wherein administration of the formulation is parenteral.
Claim 29
Independent Claim
96 words
A method for treating mucosal surface atrophy in a non-cancer bearing patient comprising the steps of: (a) identifying a patient having intestinal mucosal surface atrophy; and (b) administering a parenteral formulation to the patient, the parenteral formulation including a pharmaceutically acceptable amount of ornithine, arginine, and a mixture of amino acids selected from the group consisting of: leucine; methionine; phenylalanine; lysine; valine; isoleucine; threonine; tryptophan; and histidine, together in a pharmaceutically acceptable diluent, wherein the final concentration of ornithine is at least 0.55% by weight of the formulation and wherein administration of the formulation is parenteral.
Claim 30
Dependent Claim
15 words
The method of claim 21, 22, or 24, wherein the pharmaceutically acceptable diluent is TRAVESOL®.
Claim 31
Dependent Claim
13 words
The method of claim 21, or 24 wherein the patient is a human.
Claim 32
Dependent Claim
59 words
The method of claim 21 or 24 wherein the pharmaceutically acceptable amount of amino acids comprise the following weight range of respective amino acids for every 100 milliliters of the formulation: 250-1400 mg leucine; 200-1400 mg isoleucine; 200-1250 mg valine; 100-900 mg phenylalanine; 50-850 mg methionine; 150-750 mg lysine; 85-500 mg histidine; 100-550 mg threonine; and 50-200 mg tryptophan.
Claim 33
Dependent Claim
20 words
The method of claim 21, or 24 wherein the administering is over a time period of at least 5-8 days.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1995-11-10 | 1996-05-11 | 1996-11-10 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1999-11-10 | 2000-05-11 | 2000-11-10 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2003-11-10 | 2004-05-11 | 2004-11-10 | $7700.00 | Window Closed / Lapsed |