US20050281738A1 - Method and means for detecting inflammatory processes - Google Patents

Method and means for detecting inflammatory processes Download PDF

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US20050281738A1
US20050281738A1 US11/146,065 US14606505A US2005281738A1 US 20050281738 A1 US20050281738 A1 US 20050281738A1 US 14606505 A US14606505 A US 14606505A US 2005281738 A1 US2005281738 A1 US 2005281738A1
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Anders Pettersson
Thomas Lundqvist
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/412—Detecting or monitoring sepsis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Measuring devices for evaluating the respiratory organs
    • A61B5/0813—Measurement of pulmonary parameters by tracers, e.g. radioactive tracers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1206—Administration of radioactive gases, aerosols or breath tests

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  • the present invention relates to a method for determining nitrogen oxide formed in inflammatory processes, to a means for carrying out the method and to a method of manufacture of the means.
  • Nitrogen oxide has important biological functions. It is the structurally simplest mediator in the human body as well as one of the most important weapons of its immune defense. In its later function it is excreted by activated macrophages to kill foreign microorganisms and cells recognized as foreign.
  • nitrogen oxide may be considered an inflammation marker and has been recognized as such in, for instance, inflammatory processes in the gastro-intestinal tract, such as ulcerative colitis and Crohn's disease and celiac disease. In the lung it may assume both roles. It is recognized that levels of nitrogen oxide excretion are raised in asthmatics. Thus it may be considered a marker for asthma which also comprises an important inflammatory component.
  • nitrogen oxide is formed from L-arginine by hydroxylation of one of the guanidino nitrogens in a reaction catalyzed by one of the isoforms of the enzyme nitrogen oxide synthase (NOS).
  • NOS nitrogen oxide synthase
  • Nitrogen oxide may be sampled in situ and measured by, for instance, chemoluminescense (WO 96/17244; WO 97/37587). In situ sampling, for instance in the gastro-intestinal tract and in the urinary tract, often is difficult or at least time-consuming. Samples of exhaled air may contain nitrogen oxide formed in the pulmonary system but also formed elsewhere because of the considerable solubility of NO in water and lipids which makes it freely diffusible in the body. Increased levels of NO in exhaled air thus may be due to inflammation in the pulmonary system as well as elsewhere. This detracts from the potential usefulness of nitrogen oxide as an inflammation marker.
  • a method of the aforementioned kind comprising the per-oral or per-rectal administration of a composition comprising a diagnostically effective amount of arginine terminally labeled with the stable nitrogen isotope 15 N for determination, directly or indirectly, of 15 NO in exhaled air or saliva. It is more preferred for both terminal nitrogen atoms to be labeled. In this specification is understood by ‘terminally labeled’ the labeling of one or both of the terminal guanido nitrogen atoms of L-arginine. Direct determination of 15 NO implies that the compound is measured as such, whereas indirect determination implies that a product into which it has been transformed is measured such as, for instance, 15 N-nitrite or 15 N-nitrate.
  • a method for per-oral administration of a diagnostic composition comprising a diagnostically effective amount of L-arginine terminally labeled with the stable nitrogen isotope 15 N for release in the small intestine and/or in the upper part of the large intestine.
  • a method of the aforementioned kind comprising the per-rectal administration of a composition comprising a diagnostically effective amount of arginine terminally labeled with the stable nitrogen isotope 15 N for release in the lower part of the large intestine.
  • a method of the aforementioned kind comprising the per-oral administration of a diagnostic composition comprising a diagnostically effective amount of L-arginine terminally labeled with the stable nitrogen isotope 15 N for inhalation.
  • Preferred assaying methods for 15 N comprise: IR-spectrometry, laser spectrometry, gas chromatography and mass spectrometry, and their combinations.
  • the determination of 15 N as NO by any of these methods must take into account the fact that atmospheric nitrogen is a mixture of 14 N (99.63%; isotopic abundance) and 15 N (0.37%). In a sample of exhaled air is thus the amount of 15 N in excess of the natural isotopic abundance of 15 N that is representative of labeled nitrogen in arginine.
  • the determination of 15 N as NO by any of these methods must also take into account the purity of the label.
  • NO formed from 15 N 2 -arginine is isotopically quantitatively different from NO formed from unlabeled arginine, the amount of NO formed at or near the site where the labeled arginine is administered can be determined.
  • the site of administration of terminally 15 N-labeled arginine is different from the site of detection of 15 N-labeled NO formed therefrom.
  • terminally labeled 15 N-arginine can be administered orally or rectally to a person suspected to suffer from ulcerative colitis or Crohn's disease, and the intestinally formed 15 N-labeled NO be determined in the exhaled air or, in the form of nitrite or nitrate, in saliva.
  • labeled nitrogen oxide formed from correspondingly terminally labeled 15 N-arginine can be assayed by measurement of one or several of the products to which it is biologically transformed, in particular nitrate. It is known that a substantial amount of nitrogen oxide entering the bloodstream is oxidized to nitrate in which form it is excreted by the kidneys. It is thus within the scope of the invention to determine the formation of labeled nitrogen oxide by measuring labeled 15 NO 3 ⁇ in urine. Another important path for excretion is from the salivary glands.
  • N-labeled arginine can be administered to the lungs in form of a spray or mist for the detection of inflammatory processes in the respiratory system, in particular of asthma, nasal inflammation, and sinusitis.
  • N-labeled arginine can be administered to the circulating blood in form of an injection or infusion for the detection of inflammatory processes in the blood (sepsis) or in tissues in contact with circulating blood.
  • a diagnostic composition for use in diagnosing inflammatory processes comprising a diagnostically effective amount of terminally labeled 15 N-arginine and a pharmaceutically acceptable carrier.
  • Also disclosed is a process for the manufacture of such composition comprising formulating a diagnostically effective amount of terminally labeled 15 N-arginine and a pharmaceutically acceptable carrier into a pharmaceutical composition for per-oral or per-rectal administration.
  • compositions according to the invention for per-oral administration are selected from the group consisting of: enteric delayed release compositions for per-oral administration releasing 15 N-arginine in the small intestine and/or the upper part of the large intestine; nebulizable aqueous solutions of and powders containing terminally labeled 15 N-arginine for administration to the bronchi and the lung.
  • compositions according to the invention for per-rectal administration are selected from enemas, foams, and suppositories.
  • L-[guanido- 15 N 2 ]-arginine is commercially available from ICN Pharmaceuticals, Inc. (Costa Mesa, Calif.) and Tracer Technology, Inc. (Somerville, Mass.). Fully 15 N-labeled arginine can also be used. It can be produced by Corynebacterium herculis or Brevibacterium flavum strains carrying the recombinant DNA pCarg11 or pCarg110 according to the method disclosed in U.S. Pat. No. 5,017,482, which is hereby incorporated by reference, with the proviso that 15 N 3 ammonium sulphate is substituted for ammonium sulphate as the nitrogen source. L-[guanido- 15 N 2 ]-arginine can be used in form of the free base or a pharmaceutically acceptable salt, such as the hydrochloride or aspartate.
  • An enteric tablet for release in the small intestine and the upper large intestine can be prepared according to EP 0 502 092 A1 by substituting a terminally N-labeled arginine for any of the glucocorticoids disclosed therein.
  • a suitable amount of terminally N-labeled arginine, such as L-[guanido- 15 N 2 ]-arginine, is 50 mg, in the form of the free base or a pharmaceutically acceptable salt thereof, such as the hydrochloride.
  • a suitable type of suppository can be made by use of the Salazopyrin® EN, Pharmacia & Upjohn, enema composition in which the active principle sulfasalazine (500 mg) is exchanged for 50 mg L-[guanido- 15 N 2 ]-arginine and 450 mg of suitable neutral constitutents, such as calcium carbonate.
  • Solution for inhalation spray 100 mg L-[guanido- 15 N 2 ]-arginine are dissolved in 10 ml of sterile water. The solution is administered by a nebulizer capable of dispensing measured doses.
  • An enteric tablet of EXAMPLE 2 is administered to the person suspected of inflammation in a fasting state. Breath samples (100 ccm) are taken in 10 min intervals starting at time of administration.
  • a suppository of EXAMPLE 3 is per-rectally administered to the person suspected of inflammation being in a fasting state. Breath samples (100 ccm) are taken in 10 min intervals starting at time of administration.
  • a metered dose (1 ccm) of the solution for inhalation of EXAMPLE 4 is nebulized for inhalation by the patient using of a state-of-the-art nebulizer. Breath samples (100 ccm) are taken in 5 min intervals starting at time of administration.

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Abstract

A method of detecting inflammatory processes comprises (a) administering per-orally or per-rectally a composition comprising a diagnostically effective amount of L-[guanido-15N2]-arginine, L-[guanido-15N]-arginine, their mixtures and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier; (b) collecting a sample of exhaled air, saliva or urine; (c) determining 15NO in the air sample or its transformation products 15N-nitrite and/or 15N-nitrate in the saliva sample or urine. Also disclosed is a corresponding diagnostic composition for use in diagnosing inflammatory processes and a method for its manufacture.

Description

    FIELD OF THE INVENTION
  • The present invention relates to a method for determining nitrogen oxide formed in inflammatory processes, to a means for carrying out the method and to a method of manufacture of the means.
    • BACKGROUND OF THE INVENTION
  • Nitrogen oxide (NO) has important biological functions. It is the structurally simplest mediator in the human body as well as one of the most important weapons of its immune defense. In its later function it is excreted by activated macrophages to kill foreign microorganisms and cells recognized as foreign. In this second capability nitrogen oxide may be considered an inflammation marker and has been recognized as such in, for instance, inflammatory processes in the gastro-intestinal tract, such as ulcerative colitis and Crohn's disease and celiac disease. In the lung it may assume both roles. It is recognized that levels of nitrogen oxide excretion are raised in asthmatics. Thus it may be considered a marker for asthma which also comprises an important inflammatory component.
  • In the body nitrogen oxide is formed from L-arginine by hydroxylation of one of the guanidino nitrogens in a reaction catalyzed by one of the isoforms of the enzyme nitrogen oxide synthase (NOS). In a complex reaction the thus formed hydroxyimino intermediate is oxidatively split into nitrogen oxide and L-citrulline.
  • Nitrogen oxide may be sampled in situ and measured by, for instance, chemoluminescense (WO 96/17244; WO 97/37587). In situ sampling, for instance in the gastro-intestinal tract and in the urinary tract, often is difficult or at least time-consuming. Samples of exhaled air may contain nitrogen oxide formed in the pulmonary system but also formed elsewhere because of the considerable solubility of NO in water and lipids which makes it freely diffusible in the body. Increased levels of NO in exhaled air thus may be due to inflammation in the pulmonary system as well as elsewhere. This detracts from the potential usefulness of nitrogen oxide as an inflammation marker.
    • OBJECTS OF THE INVENTION
  • It is an object of the invention to provide an improved method for determining nitrogen oxide formed in the body.
  • It is another object of the invention to provide a means for carrying out said method.
  • Further objects of the invention will be apparent from the following description of the invention and preferred embodiments thereof, and from the appended claims.
    • SUMMARY OF THE INVENTION
  • According to the present invention is provided a method of the aforementioned kind comprising the per-oral or per-rectal administration of a composition comprising a diagnostically effective amount of arginine terminally labeled with the stable nitrogen isotope 15N for determination, directly or indirectly, of 15NO in exhaled air or saliva. It is more preferred for both terminal nitrogen atoms to be labeled. In this specification is understood by ‘terminally labeled’ the labeling of one or both of the terminal guanido nitrogen atoms of L-arginine. Direct determination of 15NO implies that the compound is measured as such, whereas indirect determination implies that a product into which it has been transformed is measured such as, for instance, 15N-nitrite or 15N-nitrate.
  • According to a first preferred aspect of the invention is provided a method for per-oral administration of a diagnostic composition comprising a diagnostically effective amount of L-arginine terminally labeled with the stable nitrogen isotope 15N for release in the small intestine and/or in the upper part of the large intestine.
  • According to a second preferred aspect of the invention is provided a method of the aforementioned kind comprising the per-rectal administration of a composition comprising a diagnostically effective amount of arginine terminally labeled with the stable nitrogen isotope 15N for release in the lower part of the large intestine.
  • According to a third preferred aspect of the invention is provided a method of the aforementioned kind comprising the per-oral administration of a diagnostic composition comprising a diagnostically effective amount of L-arginine terminally labeled with the stable nitrogen isotope 15N for inhalation.
  • Preferred assaying methods for 15N comprise: IR-spectrometry, laser spectrometry, gas chromatography and mass spectrometry, and their combinations. The determination of 15N as NO by any of these methods must take into account the fact that atmospheric nitrogen is a mixture of 14N (99.63%; isotopic abundance) and 15N (0.37%). In a sample of exhaled air is thus the amount of 15N in excess of the natural isotopic abundance of 15N that is representative of labeled nitrogen in arginine. The determination of 15N as NO by any of these methods must also take into account the purity of the label. The fact that 14N and 15N differ in their mass by 6.6%, in consideration of the natural abundance of 16O oxygen being 99.76%, makes 15N particularly attractive as a marker. It is thus 15N16O which is determined at m/e=31 in the presence of 14N2 (m/e=28), 14N15N (m/e=29), 14N16O (m/e=30) formed from non-labeled L-arginine, 16O2 (m/e=32), 14N18O (m/e=32), 16O17O (m/e=33), 16O18O (m/e=34). Because of the low natural abundance of 17O (0.037%) 14N17O (m/e=31) will be present in minute amounts only, and can be disregarded from.
  • It is advantageous to partially or fully separate the components of a gaseous sample containing 15NO in a gas chromatograph before injecting a sample of the fraction containing nitrogen oxide in the mass spectrometer. Methods for such separation are well known in the art.
  • Since NO formed from 15N2-arginine is isotopically quantitatively different from NO formed from unlabeled arginine, the amount of NO formed at or near the site where the labeled arginine is administered can be determined.
  • Thus, according to a further preferred aspect of the invention, the site of administration of terminally 15N-labeled arginine is different from the site of detection of 15N-labeled NO formed therefrom. For instance, terminally labeled 15N-arginine can be administered orally or rectally to a person suspected to suffer from ulcerative colitis or Crohn's disease, and the intestinally formed 15N-labeled NO be determined in the exhaled air or, in the form of nitrite or nitrate, in saliva.
  • According to still another preferred aspect of the invention labeled nitrogen oxide formed from correspondingly terminally labeled 15N-arginine can be assayed by measurement of one or several of the products to which it is biologically transformed, in particular nitrate. It is known that a substantial amount of nitrogen oxide entering the bloodstream is oxidized to nitrate in which form it is excreted by the kidneys. It is thus within the scope of the invention to determine the formation of labeled nitrogen oxide by measuring labeled 15NO3 − in urine. Another important path for excretion is from the salivary glands. It is thus also within the scope of the invention to determine the formation of labeled nitrogen oxide from correspondingly 15N-labeled L-arginine by measuring 15N-labeled NO3 − in saliva and/or by measuring 15N-labeled NO2 − in saliva to which nitrate is rapidly transformed by the action of certain bacteria colonizing the surface of the tongue.
  • According to still another preferred aspect of the invention 15N-labeled arginine can be administered to the lungs in form of a spray or mist for the detection of inflammatory processes in the respiratory system, in particular of asthma, nasal inflammation, and sinusitis.
  • According to still another preferred aspect of the invention 15N-labeled arginine can be administered to the circulating blood in form of an injection or infusion for the detection of inflammatory processes in the blood (sepsis) or in tissues in contact with circulating blood.
  • According to the present invention is also disclosed a diagnostic composition for use in diagnosing inflammatory processes, comprising a diagnostically effective amount of terminally labeled 15N-arginine and a pharmaceutically acceptable carrier.
  • Also disclosed is a process for the manufacture of such composition comprising formulating a diagnostically effective amount of terminally labeled 15N-arginine and a pharmaceutically acceptable carrier into a pharmaceutical composition for per-oral or per-rectal administration.
  • It is preferred for the compositions according to the invention for per-oral administration to be selected from the group consisting of: enteric delayed release compositions for per-oral administration releasing 15N-arginine in the small intestine and/or the upper part of the large intestine; nebulizable aqueous solutions of and powders containing terminally labeled 15N-arginine for administration to the bronchi and the lung.
  • It is preferred for the compositions according to the invention for per-rectal administration to be selected from enemas, foams, and suppositories.
    • DESCRIPTION OF PREFERRED EMBODIMENTS EXAMPLE 1
  • Terminally N-labeled arginine. L-[guanido-15N2]-arginine is commercially available from ICN Pharmaceuticals, Inc. (Costa Mesa, Calif.) and Tracer Technology, Inc. (Somerville, Mass.). Fully 15N-labeled arginine can also be used. It can be produced by Corynebacterium herculis or Brevibacterium flavum strains carrying the recombinant DNA pCarg11 or pCarg110 according to the method disclosed in U.S. Pat. No. 5,017,482, which is hereby incorporated by reference, with the proviso that 15N3 ammonium sulphate is substituted for ammonium sulphate as the nitrogen source. L-[guanido-15N2]-arginine can be used in form of the free base or a pharmaceutically acceptable salt, such as the hydrochloride or aspartate.
    • EXAMPLE 2
  • Enteric tablet. An enteric tablet for release in the small intestine and the upper large intestine can be prepared according to EP 0 502 092 A1 by substituting a terminally N-labeled arginine for any of the glucocorticoids disclosed therein. A suitable amount of terminally N-labeled arginine, such as L-[guanido-15N2]-arginine, is 50 mg, in the form of the free base or a pharmaceutically acceptable salt thereof, such as the hydrochloride.
    • EXAMPLE 3
  • Suppository. A suitable type of suppository can be made by use of the Salazopyrin® EN, Pharmacia & Upjohn, enema composition in which the active principle sulfasalazine (500 mg) is exchanged for 50 mg L-[guanido-15N2]-arginine and 450 mg of suitable neutral constitutents, such as calcium carbonate.
    • EXAMPLE 4
  • Solution for inhalation spray. 100 mg L-[guanido-15N2]-arginine are dissolved in 10 ml of sterile water. The solution is administered by a nebulizer capable of dispensing measured doses.
    • EXAMPLE 5
  • Determination of inflammatory conditions in the small intestine and the upper part of the large intestine. An enteric tablet of EXAMPLE 2 is administered to the person suspected of inflammation in a fasting state. Breath samples (100 ccm) are taken in 10 min intervals starting at time of administration.
    • EXAMPLE 6
  • Determination of inflamatory conditions in the lower part of the large intestine. A suppository of EXAMPLE 3 is per-rectally administered to the person suspected of inflammation being in a fasting state. Breath samples (100 ccm) are taken in 10 min intervals starting at time of administration.
    • EXAMPLE 7
  • Determination of inflamatory conditions in the lung. A metered dose (1 ccm) of the solution for inhalation of EXAMPLE 4 is nebulized for inhalation by the patient using of a state-of-the-art nebulizer. Breath samples (100 ccm) are taken in 5 min intervals starting at time of administration.
    • EXAMPLE 7
  • Determination of inflammatory conditions in the blood. An intravenous infusion of L-[guanido-15N2]-arginine is administered to a person suspected of sepsis. Breath samples (100 ccm) are taken in 10 min intervals starting at time of administration.
    • EXAMPLE 8
  • Determination of 15NO in gaseous samples. See: D C Macallan et al., Am. J. Physiol. 272 (6, part 2), p. R1888-R1896 (1997).
    • EXAMPLE 9
  • Determination of urinary 15NO3 −. See: P Forte et al., Measurement of Nitric Oxide Synthesis in Humans Using L-[15N2]Arginine. Methods in Enzymology 301 (1999) 92-98. The method is easily modified for measurement of nitrate in saliva.

Claims (22)

1. A method of detecting the existence of an inflammatory process comprising:
administering per-orally or per-rectally to a person a composition comprising a diagnostically effective amount of L-[guanido-15N2]-arginine, L-[guanido15N]-arginine, their mixtures and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier,
collecting a sample of exhaled air, saliva or urine,
determining 15NO in the air sample or its transformation products 15N-nitrite and/or 15N-nitrate in the saliva sample or urine.
2. The method of claim 1, wherein administration is per-oral is for release in the small intestine or in the upper part of the large intestine or both.
3. The method of claim 1, wherein the administration is per-rectal for release in the lower part of the large intestine.
4. (canceled)
5. The method of claim 2, wherein the composition is in form of a tablet, a capsule, or granules.
6. The method of claim 2, wherein the inflammatory process is selected from the group consisting of ulcerative colitis, Crohn's disease and celiac disease.
7. The method of claim 3, wherein the composition is in form of an enema, a suppository or a foam.
8. The method of claim 3, wherein the inflammatory process is ulcerative colitis.
9-10. (canceled)
11. The method of claim 1, wherein determination is by IR-spectrometry, laser spectrometry, mass spectrometry, gas chromatography, and their combinations.
12. (canceled)
13. A diagnostic composition for per-oral administration, including pulmonary administration, and per-rectal administration, for use in diagnosing inflammatory processes, comprising a diagnostically effective amount of L-[guanido-15N2]-arginine, L-[guanido-15N]-arginine, their mixtures, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable per-oral or per-rectal carrier, in a form selected from the group consisting of tablet, capsule, granules, enema, suppository and foam.
14. The composition of claim 13, wherein said amount is from 1 mg to 2,000 mg.
15. A method of manufacture of a diagnostic composition for per-oral administration, including pulmonary administration, and per-rectal administration, for use in diagnosing the existence of an inflammatory process, comprising combining a diagnostically effective amount of L-[guanido-15N2]-arginine, L-[guanido-15N]-arginine, their mixtures, and pharmaceutically acceptable salts thereof, and a suitable pharmaceutically acceptable per-oral or per-rectal carrier into a form selected from the group consisting of tablet, capsule, granules, enema, suppository and foam.
16. The method of claim 15, wherein said amount is from 1 mg to 2,000 mg.
17. The composition of claim 13, wherein the carrier is a peroral carrier and the composition is in form of a tablet, a capsule, or granules.
18. The composition of claim 13, wherein the carrier is a per-rectal carrier and composition is in form of an enema, a suppository or a foam.
19. The method of claim 1, wherein the sample collected is exhaled air or saliva.
20. The method of claim 2, wherein said amount is from 1 mg to 2,000 mg and the sample collected is exhaled air or saliva.
21. The method of claim 20, wherein the composition is in form of a tablet, a capsule, or granules.
22. The method of claim 3, wherein said amount is from 1 mg to 2,000 mg and the sample collected is exhaled air or saliva.
23. The method of claim 22, wherein the composition is in form of an enema, a suppository or a foam.
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RU2303983C1 (en) * 2005-12-27 2007-08-10 Государственное образовательное учреждение высшего профессионального образования "Дальневосточный государственный медицинский университет Федерального агентства по здравоохранению и социальному развитию" METHOD FOR DECREASING EROSIVE-ULCEROUS LESION OF GASTRIC MUCOSA AT THE IMPACT OF ACETYLSALICYLIC ACID (ASA) WITH THE HELP OF A PEPTIDE OF Arg-Tyr-D-Ala-Phe-Gly FORMULA

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