WO2003053424A1 - Use of a cysteine-containing substance to increase the ventilatory activity and erythropoietin production - Google Patents

Use of a cysteine-containing substance to increase the ventilatory activity and erythropoietin production Download PDF

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Publication number
WO2003053424A1
WO2003053424A1 PCT/CA2002/001900 CA0201900W WO03053424A1 WO 2003053424 A1 WO2003053424 A1 WO 2003053424A1 CA 0201900 W CA0201900 W CA 0201900W WO 03053424 A1 WO03053424 A1 WO 03053424A1
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cysteine
increase
plasma
derivative
concentration
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PCT/CA2002/001900
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French (fr)
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Wulf DRÖGE
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2458781 Canada Inc.
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Priority to AU2002347168A priority Critical patent/AU2002347168A1/en
Priority to EP02782586A priority patent/EP1453498A1/en
Priority to JP2003554182A priority patent/JP2005532989A/en
Priority to CA002469372A priority patent/CA2469372A1/en
Priority to US10/498,393 priority patent/US20050009914A1/en
Publication of WO2003053424A1 publication Critical patent/WO2003053424A1/en
Priority to US13/155,627 priority patent/US20110237672A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention deals with the use of cysteine, a cysteine precursor, or a cysteine derivative or a cysteine-containing substance to improve the oxygen delivery to the tissue by increasing the ventilatory response and the production of the blood-forming hormone erythropoietin (EPO) , especially for the treatment of aging-related or disease-related conditions associated with a decreased oxygen supply to the tissue.
  • EPO blood-forming hormone erythropoietin
  • the oxygen concentration of the tissue plays an important physiological role in all higher organisms.
  • the maintenance of an adequate oxygen supply is mainly ensured by an adequate number of erythrocytes in the blood and by the ventilatory activity.
  • any decrease in arterial oxygen concentration activates the oxygen-sensing arterial chemoreceptors and stimulates in addition the EPO production in liver and kidney cells.
  • the said mechanisms are able to ensure under normal conditions the adequate oxygen supply to the tissue, the oxygen supply decreases in old age, malignant diseases and in cardiorespiratory diseases .
  • the invention solves this problem by providing such an alternative agent based on the use of cysteine or a cysteine derivative to increase the oxygen supply to the tissue, the ventilatory response and the EPO concentration in the plasma.
  • Cysteine its biochemical precursors, cysteine derivatives, and cysteine-containing substances such as cysteine-containing proteins are typically "physiological" agents which play normally a role in the natural metabolism. Accordingly, there are so far no significant side- effects known for the treatment with cysteine or other cysteine derivatives, especially N-acetylcysteine .
  • cysteine By treatment with cysteine, a cysteine derivative, a cysteine precursor, or a cysteine-containing substance, the plasma thiol/disulfide redox status will be shifted to a more reducing condition. This in turn will increase the hypoxic ventilatory activity and the EPO concentration in the plasma of the patients. Ultimately, this treatment improves the oxygen supply to the tissues.
  • thiol group (SH group) of NAC is responsible for the antioxidative shift of the plasma thiol/disulfide redox state, it is reasonable to be expected that the said effects of NAC on the ventialatory activity and the plasma EPO concentration and oxygen supply to the tissue is also provided by other physiological thiol- containing substances, such as cysteine itself, physiological precursor substances of cysteine, other cysteine derivatives, or cysteine-containing polypeptides .
  • cysteine derivative will therefore be used here to describe all substituted cysteine derivatives, physiological cysteine precursors, functional thiol groups, especially N-acetylcysteine as well as cysteine-containing substances, such as cysteine-containing proteins or peptides.
  • the invention is based on the hypothesis that these oxygen sensors are redox sensors which also respond to changes in the plasma thiol/disulfide redox status.
  • N-acetylcysteine NAC
  • thiol 2 disulfide "1 ) a substance which is known to increase the plasma thiol level and/or plasma thiol/disulfide redox status
  • the placebo-controlled double-blind study was performed with healthy, normotonic male non-smoking subjects. The subjects had not taken alcohol, caffeine, or any medication at least during the last 24 hours prior to the study. Also, they had not been engaged in extensive physical exercise for at least 12 hours prior to the study. Twenty- eight subjects were recruited into the study and randomized for the treatment with NAC or placebo. NAC (200 mg capsules) or placebo were administered in three doses of 600 mg per day at 8.00 a.m., 4.00 p.m. and 11.00 p.m.
  • the plasma concentrations of acid soluble thiol (mainly cysteine) and cystine (cysteine disulfide) were determined in the cubital venous blood by a photometric assay and by the amino acid analyzer, respectively.
  • the EPO concentration in serum was determined by the help of a commercial EPO ELISA kit.
  • hypoxic ventilatory response of the subjects was quantitatively determined.
  • the ventilatory activity was determined under two different experimental conditions using an equipment of oxychon-beta.
  • the first measurement the so-called “isocapnic hypoxic ventilatory response” (isocapnic HVR) , was tested under normoxic conditions, i.e., under conditions of normal oxygen concentration and constant carbondioxide concentration.
  • the second measurement the so-called poikilocapnic hypoxic ventilatory response (poikilocapnic HVR) , was determined under normobaric conditions in a hypoxia chamber with a constant Fi0 2 of 12%.
  • ikilocapnic describes study conditions characterized by a variable carbondioxide concentration in the exspiratory air, whereas the term “isocapnic” refers to conditions with a constant carbondioxide concentration.
  • Figure 1 shows the relative change (re as %) in plasma thiol concentration (T) , plasma redox status (RS) , isocapnic hypoxic ventilatory reponse (H) , plasma EPO concentration (E) , and plasma EPO concentration 2 hrs after the 6-hr-exposure to the hypoxia chamber (Eh) .
  • the significance for the differences between N-acetylcysteine- treated group (N) and the placebo-treated control group (P) is indicated by its P-value.
  • Figure 1 shows accordingly that the NAC-treated group had not only a significantly increased plasma thiol concentration (P ⁇ 0.01) and increased plasma thiol/disulfide redox status (thiol 2 disulfide "1 ) (P ⁇ 0.05) but also a significantly increased isocapnic hypoxic ventilatory response as a representative indicator of the ventilatory activity and an increased plasma EPO concentration before and after exposure to the hypoxia chamber (again P ⁇ 0.05) if compared to the placebo-treated group.
  • Figure 2 shows the absolute values of the isocapnic hypoxic ventilatory responses (H) and the plasma EPO concentrations (E) before (time 1) as well as 4 and 5 days, respectively, after start of the treatment (time 2) .
  • Figure 3 shows the correlation between the individual values of the poikilocapnic hypoxic ventilatory responses H (units are min “1 % "1 kg "1 ) at the end of the 6-hr-exposure to the hypoxia chamber 5 days after the start of N-acetylcysteine treatment (black symbols) or placebo treatment (open symbols) and the mean plasma thiol concentration T ( ⁇ M) of the corresponding subjects.
  • the invention deals therefore with the use of cysteine or a cysteine derivative for the preparation of a medication designed to increase the oxygen supply to the tissue, the ventilatory activity, and the plasma EPO concentration.
  • a preferred application of the invention is the use of cysteine or a cysteine derivative for the preparation of a medication for the enhancement of the respiratory activity and the concomitant increase in plasma erythropoietin concentration.
  • the oxygen concentration in the tissue which is determined by both the ventilatory activity and the plasma erythropoietin concentration is abnormally decreased in certain conditions especially in elderly subjects, in cancer patients, or in cardiorespiratory diseases.
  • One of the preferred applications of the invention deals therefore with the use of cysteine or a cysteine derivative in the preparation of a medication for the treatment of conditions with abnormally decreased oxygen supply especially in elderly subjects, malignant diseases, especially in the advanced stages of malignant diseases, and in cardiorespiratory diseases.
  • N-acetylcysteine in the preparation of a medication for the increase in of the oxygen supply to the tissue, ventilatory activity, and plasma EPO concentration is preferred.
  • Cysteine or a cysteine derivative may also be applied in combination with other substances and agents which increase the oxygen supply in the tissue, the respiratory activity or the plasma EPO concentration. Cysteine or one of the cysteine derivatives may be administered either as a powder, as a solution, as a tablet, or as a "slow release tablet".
  • the formulation may also contain conventional additives including substances which improve the taste, stabilizing agents, antioxidants, or similar additives. Cysteine or the cysteine derivative is typically applied orally. However, it may alternatively applied by any other practical method, especially by parenteral or intravenous injection.
  • Cysteine or a cysteine derivative is typically applied for the increase in oxygen supply to the tissue, ventilatory activity and plasma EPO concentration at daily doses between 0.1 g and 20 g, preferentially in daily doses between 0.1 g and 10 g, more preferentially in daily doses between 0.4 g and 3 g.
  • the optimal dosis depends on the plasma thiol concentration and/or the plasma thiol/disulfide redox status of the individual patient and should be chosen accordingly.
  • Another formulation of the invention includes therefore the use of a pharmaceutic composition, containing cysteine or a cysteine derivative for the preparation of a medication for the increase in the oxygen supply to the tissue, ventilatory activity and/or plasma EPO concentration.
  • the invention refers also to the use of cysteine or a cysteine derivative for the increase in the oxygen supply to the tissue, in respiratory activity and plasma EPO concentration, as well as the simul taneous increase in ventilatory activity and plasma EPO concentration, the use of the cysteine derivative, N-acetylcysteine, being preferred.
  • the use of cysteine or a cysteine derivative is furthermore preferred for the treatment of conditions with a decreased oxygen supply, especially in elderly subjects, in malignant diseases, or in cardiorespiratory diseases.
  • the use of a pharmaceutic composition containing cysteine or a cysteine derivative for the increase in the oxygen supply, the ventilatory activity and/or the plasma EPO concentration is also preferred.

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Abstract

The said invention deals with the use of cysteine, a cysteine precursor substance or a cysteine derivative or a cysteine-containing substance to increase the oxygen supply to the tissue by increasing the ventilatory activity and/or by increasing the production of the blood-forming hormone erythropoietin (EPO), especially for the treatment of aging-related or disease-related conditions associated with a decreased oxygen supply to the tissue, especially in elderly subjects, in the treatment of malignant diseases and in cardiorespiratory diseases.

Description

USE OF A CYSTEINE-CONTAINING SUBSTANCE TO INCREASE THE VENTILATORY ACTIVITY AND ERYTHROPOIETIN PRODUCTION
The invention deals with the use of cysteine, a cysteine precursor, or a cysteine derivative or a cysteine-containing substance to improve the oxygen delivery to the tissue by increasing the ventilatory response and the production of the blood-forming hormone erythropoietin (EPO) , especially for the treatment of aging-related or disease-related conditions associated with a decreased oxygen supply to the tissue.
The oxygen concentration of the tissue plays an important physiological role in all higher organisms. The maintenance of an adequate oxygen supply is mainly ensured by an adequate number of erythrocytes in the blood and by the ventilatory activity. In the young healthy organism, any decrease in arterial oxygen concentration (hypoxia) activates the oxygen-sensing arterial chemoreceptors and stimulates in addition the EPO production in liver and kidney cells.
Although the said mechanisms are able to ensure under normal conditions the adequate oxygen supply to the tissue, the oxygen supply decreases in old age, malignant diseases and in cardiorespiratory diseases .
These conditions are presently being treated with synthetic EPO which is typically produced by recombinant DNA technology or with other drugs that increase the ventilatory activity. However, the presently available treatment procedures have substantial disadvantages such as high costs and undesirable side-effects. In addition, the available drugs improve typically either the ventilatory activity or the EPO concentration in the plasma but not both simultaneously.
It is the purpose of this invention to provide an alternative agent for the production of a drug to increase the ventilatory response and EPO concentration, especially in old age and certain disease conditions such as malignant or cardiorespiratory diseases. Preferred is a "physiological" agent which produces little or no side-effects.
The invention solves this problem by providing such an alternative agent based on the use of cysteine or a cysteine derivative to increase the oxygen supply to the tissue, the ventilatory response and the EPO concentration in the plasma.
Cysteine, its biochemical precursors, cysteine derivatives, and cysteine-containing substances such as cysteine-containing proteins are typically "physiological" agents which play normally a role in the natural metabolism. Accordingly, there are so far no significant side- effects known for the treatment with cysteine or other cysteine derivatives, especially N-acetylcysteine .
By treatment with cysteine, a cysteine derivative, a cysteine precursor, or a cysteine-containing substance, the plasma thiol/disulfide redox status will be shifted to a more reducing condition. This in turn will increase the hypoxic ventilatory activity and the EPO concentration in the plasma of the patients. Ultimately, this treatment improves the oxygen supply to the tissues.
These effects of the cysteine derivative N-acetylcysteine (NAC) on the hypoxic ventilatory activity and the plasma EPO concentration, which implicate ultimately the improvement of the oxygen supply to the tissue, was shown in the context of this invention through a placebo- controlled double-blind clinical trial.
Because the thiol group (SH group) of NAC is responsible for the antioxidative shift of the plasma thiol/disulfide redox state, it is reasonable to be expected that the said effects of NAC on the ventialatory activity and the plasma EPO concentration and oxygen supply to the tissue is also provided by other physiological thiol- containing substances, such as cysteine itself, physiological precursor substances of cysteine, other cysteine derivatives, or cysteine-containing polypeptides .
The general term "cysteine derivative" will therefore be used here to describe all substituted cysteine derivatives, physiological cysteine precursors, functional thiol groups, especially N-acetylcysteine as well as cysteine-containing substances, such as cysteine-containing proteins or peptides.
The mechanism of the oxygen sensors which regulate the ventilatory response and the production of EPO is not completely understood (Semenza GL, "Perspectives on oxygen-sensing" ; Cell, 1999; 98; 281- 284) . There are, however, several indications that the production of the superoxide anion radical may serve as a second messenger at least in some oxygen sensors. The superoxide anion, in turn, may activate various redox-sensitive signaling pathways (Acker et al . , "Mechanisms of 02 sensing in the carotid body in comparison with other 02-sensing cells"; NIPS; 1955; 10; 211-216; Acker et al . , "Indications for an NADPH oxidase as a possible p02-sensor in the rat carotid body"; FEBS Lett.; 1989; 256; 75-78; Prabhakar et al . , "Oxygen sensing by the carotid body chemoreceptor" ; J. Appl . Physiol . ; 2000; 88; 2287-2295; Fandrey et al . , "Role of hydrogen peroxide in hypoxia-induced erythropoietin production"; Bioche J.; 1994; 303; 507-510; Huang et al., "Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its α-subunit"; J. Biol. Chem.; 1996; 271; 32253-32259).
Whereas it was previously known that the oxygen sensors are responsive to changes in the oxygen concentration, the invention is based on the hypothesis that these oxygen sensors are redox sensors which also respond to changes in the plasma thiol/disulfide redox status.
In the context of the placebo-controlled double-blind study of two randomly selected groups of subjects, it was shown that the administration of N-acetylcysteine (NAC) , a substance which is known to increase the plasma thiol level and/or plasma thiol/disulfide redox status (thiol2 disulfide"1) , causes unexpectedly an increase in ventilatory activity and plasma erythropietin concentration.
The placebo-controlled double-blind study was performed with healthy, normotonic male non-smoking subjects. The subjects had not taken alcohol, caffeine, or any medication at least during the last 24 hours prior to the study. Also, they had not been engaged in extensive physical exercise for at least 12 hours prior to the study. Twenty- eight subjects were recruited into the study and randomized for the treatment with NAC or placebo. NAC (200 mg capsules) or placebo were administered in three doses of 600 mg per day at 8.00 a.m., 4.00 p.m. and 11.00 p.m.
The plasma concentrations of acid soluble thiol (mainly cysteine) and cystine (cysteine disulfide) were determined in the cubital venous blood by a photometric assay and by the amino acid analyzer, respectively. The plasma thiol/disulfide redox status of the subjects was computed on the basis of these data according to the equation: redox status = thiol2 disulfide"1 (μM) . The EPO concentration in serum was determined by the help of a commercial EPO ELISA kit.
In addition, the hypoxic ventilatory response of the subjects was quantitatively determined. The ventilatory activity was determined under two different experimental conditions using an equipment of oxychon-beta. The first measurement, the so-called "isocapnic hypoxic ventilatory response" (isocapnic HVR) , was tested under normoxic conditions, i.e., under conditions of normal oxygen concentration and constant carbondioxide concentration. The second measurement, the so- called poikilocapnic hypoxic ventilatory response (poikilocapnic HVR) , was determined under normobaric conditions in a hypoxia chamber with a constant Fi02 of 12%.
The term "poikilocapnic" describes study conditions characterized by a variable carbondioxide concentration in the exspiratory air, whereas the term "isocapnic" refers to conditions with a constant carbondioxide concentration.
The results of this study are shown in the following figures:
Figure 1 shows the relative change (re as %) in plasma thiol concentration (T) , plasma redox status (RS) , isocapnic hypoxic ventilatory reponse (H) , plasma EPO concentration (E) , and plasma EPO concentration 2 hrs after the 6-hr-exposure to the hypoxia chamber (Eh) . The significance for the differences between N-acetylcysteine- treated group (N) and the placebo-treated control group (P) is indicated by its P-value.
Figure 1 shows accordingly that the NAC-treated group had not only a significantly increased plasma thiol concentration (P < 0.01) and increased plasma thiol/disulfide redox status (thiol2 disulfide"1) (P < 0.05) but also a significantly increased isocapnic hypoxic ventilatory response as a representative indicator of the ventilatory activity and an increased plasma EPO concentration before and after exposure to the hypoxia chamber (again P < 0.05) if compared to the placebo-treated group.
Figure 2 shows the absolute values of the isocapnic hypoxic ventilatory responses (H) and the plasma EPO concentrations (E) before (time 1) as well as 4 and 5 days, respectively, after start of the treatment (time 2) .
The increase in ventilatory activity (H) and the plasma EPO concentration (E) between time 1 and time 2, which is seen in the N- acetylcysteine-treated group (closed symbols) , is significantly different from that of the placebo-treated control group (open symbols) (P value < 0.01 and < 0.05, respectively).
Figure 3 shows the correlation between the individual values of the poikilocapnic hypoxic ventilatory responses H (units are min"1 %"1 kg"1) at the end of the 6-hr-exposure to the hypoxia chamber 5 days after the start of N-acetylcysteine treatment (black symbols) or placebo treatment (open symbols) and the mean plasma thiol concentration T (μM) of the corresponding subjects.
The high values of the correlation coefficient (r) as well as the small P-values demonstrate the significance of the correlation between the respiratory activity, i.e., the poikilocapnic hypoxic ventilatory response, and the mean plasma thiol concentration of the subject (r = 0.59 and P < 0.01) for the combined treatment groups; r = 0.71 and P < 0.01 for the N-acetylcysteine group. The invention deals therefore with the use of cysteine or a cysteine derivative for the preparation of a medication designed to increase the oxygen supply to the tissue, the ventilatory activity, and the plasma EPO concentration.
A preferred application of the invention is the use of cysteine or a cysteine derivative for the preparation of a medication for the enhancement of the respiratory activity and the concomitant increase in plasma erythropoietin concentration.
The oxygen concentration in the tissue which is determined by both the ventilatory activity and the plasma erythropoietin concentration is abnormally decreased in certain conditions especially in elderly subjects, in cancer patients, or in cardiorespiratory diseases.
One of the preferred applications of the invention deals therefore with the use of cysteine or a cysteine derivative in the preparation of a medication for the treatment of conditions with abnormally decreased oxygen supply especially in elderly subjects, malignant diseases, especially in the advanced stages of malignant diseases, and in cardiorespiratory diseases.
The use of N-acetylcysteine in the preparation of a medication for the increase in of the oxygen supply to the tissue, ventilatory activity, and plasma EPO concentration is preferred.
Cysteine or a cysteine derivative may also be applied in combination with other substances and agents which increase the oxygen supply in the tissue, the respiratory activity or the plasma EPO concentration. Cysteine or one of the cysteine derivatives may be administered either as a powder, as a solution, as a tablet, or as a "slow release tablet". The formulation may also contain conventional additives including substances which improve the taste, stabilizing agents, antioxidants, or similar additives. Cysteine or the cysteine derivative is typically applied orally. However, it may alternatively applied by any other practical method, especially by parenteral or intravenous injection.
Cysteine or a cysteine derivative, especially N-acetylcysteine, is typically applied for the increase in oxygen supply to the tissue, ventilatory activity and plasma EPO concentration at daily doses between 0.1 g and 20 g, preferentially in daily doses between 0.1 g and 10 g, more preferentially in daily doses between 0.4 g and 3 g. However, the optimal dosis depends on the plasma thiol concentration and/or the plasma thiol/disulfide redox status of the individual patient and should be chosen accordingly. Another formulation of the invention includes therefore the use of a pharmaceutic composition, containing cysteine or a cysteine derivative for the preparation of a medication for the increase in the oxygen supply to the tissue, ventilatory activity and/or plasma EPO concentration.
The invention refers also to the use of cysteine or a cysteine derivative for the increase in the oxygen supply to the tissue, in respiratory activity and plasma EPO concentration, as well as the simul taneous increase in ventilatory activity and plasma EPO concentration, the use of the cysteine derivative, N-acetylcysteine, being preferred. The use of cysteine or a cysteine derivative is furthermore preferred for the treatment of conditions with a decreased oxygen supply, especially in elderly subjects, in malignant diseases, or in cardiorespiratory diseases. The use of a pharmaceutic composition containing cysteine or a cysteine derivative for the increase in the oxygen supply, the ventilatory activity and/or the plasma EPO concentration is also preferred.

Claims

Claims
1. Use of cysteine or a cysteine derivative for the preparation of a medication to increase the oxygen supply in the tissue.
2. Use of cysteine or a cysteine derivative for the preparation of a medication to increase the ventilatory activity.
3. Use of cysteine or a cysteine derivative for the preparation of a medication to increase the plasma erythropoietin concentration.
4. Use of cysteine or a cysteine derivative for the preparation of a medication that simulatenously increases the ventilatory activity and the plasma erythropietin concentration.
5. Use of cysteine or a cysteine derivative for the preparation of a medication according to at least one of the claims 1-4 for the treatment of conditions with decreased oxygen supply.
6. Use of cysteine or a cysteine derivative to increase the oxygen supply in the tissue.
7. Use of cysteine or a cysteine derivative to increase the ventilatory activity.
8. Use of cysteine or a cysteine derivative to increase the plasma erythropietin concentration.
9. Use of cysteine or a cysteine derivative to simultaneously increase the ventilatory activity and the plasma erythropietin concentration.
10. Use of cysteine or a cysteine derivative according to at least one of the claims 6-9 for the treatment of conditions with decreased oxygen supply.
11. Use of cysteine or a cysteine derivative according to claims 5-10 in elderly subjects.
12. Use of cysteine or a cysteine derivative according to claims 5-10 in malignant diseases.
13. Use of cysteine or a cysteine derivative according to claims 5-10 in cardiorespiratory diseases.
14. Use according to at least one of the claims 1-13 characterized by the use of the cysteine derivative N-acetylcysteine.
15. Use of a pharmaceutic composition containg cysteine or a cysteine derivative according to at least one of the claims 1-14.
PCT/CA2002/001900 2001-12-11 2002-12-10 Use of a cysteine-containing substance to increase the ventilatory activity and erythropoietin production WO2003053424A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU2002347168A AU2002347168A1 (en) 2001-12-11 2002-12-10 Use of a cysteine-containing substance to increase the ventilatory activity and erythropoietin production
EP02782586A EP1453498A1 (en) 2001-12-11 2002-12-10 Use of a cysteine-containing substance to increase the ventilatory activity and erythropoietin production
JP2003554182A JP2005532989A (en) 2001-12-11 2002-12-10 Use of cysteine-containing substances to increase ventilation activity and erythropoietin production
CA002469372A CA2469372A1 (en) 2001-12-11 2002-12-10 Use of a cysteine-containing substance to increase the ventilatory activity and erythropoietin production
US10/498,393 US20050009914A1 (en) 2001-12-11 2002-12-10 Use of a cysteine-containing substance to increase the ventilatory activity and erythropoientin production
US13/155,627 US20110237672A1 (en) 2001-12-11 2011-06-08 Use of a cysteine-containing substance to increase the ventilatory activity and erythropoietin production

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DE10160796.2 2001-12-11
DE10160796A DE10160796A1 (en) 2001-12-11 2001-12-11 Use of cysteine or its derivative for increasing tissue oxygen supply, respiratory activity and/or plasma erythropoietin levels, e.g. in cancer or cardio-pulmonary disease patients

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR4619M (en) * 1965-02-01 1966-11-28
GB2269748A (en) * 1992-08-04 1994-02-23 British Tech Group Composition for treatment of sickle cell disease
DE4329857A1 (en) * 1993-09-03 1995-03-09 Deutsches Krebsforsch Connection to strengthen the immune system and immune responses
JPH09194361A (en) * 1996-01-19 1997-07-29 Wakunaga Pharmaceut Co Ltd Antitumor agent
WO1998036773A1 (en) * 1997-02-20 1998-08-27 Yale University Therapeutic uses for antioxidants
US5912019A (en) * 1997-02-07 1999-06-15 Musc Foundation For Research Development Compounds for reducing ischemia/reperfusion injury
US6251927B1 (en) * 1999-04-20 2001-06-26 Medinox, Inc. Methods for treatment of sickle cell anemia
WO2001080849A1 (en) * 2000-04-26 2001-11-01 Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Medical Center Method of treating cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4590067A (en) * 1984-10-18 1986-05-20 Peritain, Ltd. Treatment for periodontal disease
SE518784C2 (en) * 2000-12-27 2002-11-19 Nactilus Ab "N-Acetyl-L-Cysteine with Compositions for the Treatment of Neoplasms"

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR4619M (en) * 1965-02-01 1966-11-28
GB2269748A (en) * 1992-08-04 1994-02-23 British Tech Group Composition for treatment of sickle cell disease
DE4329857A1 (en) * 1993-09-03 1995-03-09 Deutsches Krebsforsch Connection to strengthen the immune system and immune responses
JPH09194361A (en) * 1996-01-19 1997-07-29 Wakunaga Pharmaceut Co Ltd Antitumor agent
US5912019A (en) * 1997-02-07 1999-06-15 Musc Foundation For Research Development Compounds for reducing ischemia/reperfusion injury
WO1998036773A1 (en) * 1997-02-20 1998-08-27 Yale University Therapeutic uses for antioxidants
US6251927B1 (en) * 1999-04-20 2001-06-26 Medinox, Inc. Methods for treatment of sickle cell anemia
WO2001080849A1 (en) * 2000-04-26 2001-11-01 Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Medical Center Method of treating cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 199740, Derwent World Patents Index; Class B05, AN 1997-431381, XP002233964 *
HILDEBRANDT WULF ET AL: "Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: Linkage between plasma thiol redox state and O2 chemosensitivity.", BLOOD, vol. 99, no. 5, 1 March 2002 (2002-03-01), March 1, 2002, pages 1552 - 1555, XP002233963, ISSN: 0006-4971 *
SPAPEN H ET AL: "[Acetylcysteine: a promising antioxidant for cardiorespiratory disorders]", NEDERLANDS TIJDSCHRIFT VOOR GENEESKUNDE. NETHERLANDS 2 APR 1994, vol. 138, no. 14, 2 April 1994 (1994-04-02), pages 701 - 705, XP009007345, ISSN: 0028-2162 *

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