Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
  • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
  • G01N2333/575—Hormones
  • G01N2333/61—Growth hormones [GH] (Somatotropin)

Definitions

• the present invention provides a method for diagnosing the etiology of short stature in children.
• Stimulated growth hormone GH secretion using a variety of provocative agents including 1-dopa, clonidine, arginine and insulin have been assessed in slowly or poorly growing children in an attempt to determine the etiology of short stature.
• provocative agents whose action is mediated by growth hormone releasing hormone (GHRH) cannot differentiate hypothalamic defects from pituitary defects in the GH neuroendocrine axis.
• GHRH growth hormone- releasing hormone
• patents 5,065,747 issued November 19, 1991, and 4,844,096 issued July 4, 1989 describe methods for reducing the variability in GH levels by administering somatostatin prior to provocative testing or prior to determining the etiology of growth hormone deficiency.
• the present invention provides a new and more effective way to use stimulated GH secretion as a reliable and effective tool for diagnosing GH secretory deficits in short- statured children.
• the present invention provides a diagnostic procedure for determining whether short stature in a child is due to a deficiency in growth hormone releasing hormone (GHRH) or GHRP-6 or a peptite which causes release of growth hormone (GH) by the same cellular mechanism.
• GHRH growth hormone releasing hormone
• GHRP-6 growth hormone releasing hormone
• the diagnostic procedure of the present invention is carried out by establishing baseline levels of growth hormone in the blood of the child having short stature, then administering sequentially a growth hormone releasing compound, GHRP-6, or a peptide which causes growth hormone release by the same cellular mechanism as GHRP-6, or the combination of GHRH and GHRP-6 and then measuring the changes, if any, in the levels of growth hormone in the blood of the short-statured child resulting from the three different administrations.
• GHRP-6 growth hormone releasing compound
• GHRH growth hormone releasing compound
• GHRP-6 a growth hormone releasing compound which causes growth hormone release by the same cellular mechanism as GHRP-6
• the growth hormone releasing compound can be administered either first or second, generally on different days, i.e., before or after the GHRP-6 or peptide which acts similarly at a cellular level.
• the quantities of each agent to be administered is any quantity known to be effective in causing an increase in growth hormone levels, i.e., an amount which will stimulate release of growth hormone.
• GHRH may not be the only endogenous agent that provides stimulation for GH secretion.
• a xenobiotic hexapeptide, GHRP-6 which has different binding characteristics from GHRH (E.E. Codd et al., Neuropharmacology 1989; ,28 . , 1139-1144 and A.D. Blake, et al., J. Endocrinol. 1991; 129. 11-19) and utilizes a different somatotroph second messenger system (K. Cheng et al., Endocrinol.
• GHRP-6 is effective in some, but not all, short-statured children to whom it is administered (C.Y. Bowers et al. , J. Clin. Endocrinol. Metab. 1991; 1 _, 292-298 and V.
• GHRP-6 is a hexapeptide having the following structure: His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 .
• GHRP-6 in practicing the present invention, GHRP-6, as well as all other synthetic peptides in the same class of drugs that release GH by the same cellular mechanism as GHRP-6 referred to hereinafter as GHRP-6 or analogs thereof, will be used as diagnostic agents in children for differential diagnosis of growth hormone (GH) deficiency of various etiologies.
• Responses to GHRP-6 or analogs thereof will be compared with those resulting from administration of the endogenous GH releasing hormone (GHRH) and from co-administration of GHRH and GHRP-6 to better understand the cause of growth deficits in short statured children.
• GHRH endogenous GH releasing hormone
• GHRP-6 acts as a functional analog for a yet undefined GHRH co- factor or co-secretagogue
• hyposensitivity to a provocative GHRH challenge could represent deficiency of that endogenous co-secretagogue (represented by GHRP-6) rather than down- regulation of pituitary receptor or deficits in GH synthesis and/or release.
• Such a child could have normal GHRH concentrations/secretion and a normal pituitary, but display poor GH secretion in the absence of the endogenous GHRP-6 analog.
• this child would respond normally to a challenge dose of GHRP-6 because his/her complement of GHRH would be available.
• the present invention provides a new clinical application for GHRP-6 and other synthetic GH secretagogues that function by the same mechanism as GHRP-6.
• the invention is important because it not only provides a reliable method for identifying children with low GH secretory capability, but also helps diagnose the etiology of GH deficiency and perhaps provide a key to appropriate treatment.
• children who are shorter than other children of a comparable age who have been identified as in need potentially of growth hormone or some agent that would stimulate growth hormone production would be monitored for the purpose of establishing a baseline level of growth hormone in the blood.
• the child is administered GHRH at a dose ranging from 100 ng/kg body weight to 100 mg/kg body weight.
• the GHRH peptide is administered and blood samples are monitored over a period of 120 minutes to determine whether the exogenous GHRH increased growth hormone levels.
• the child is administered GHRP-6 or an analog thereof at a dose of 100 ng/kg body weight to 1 mg/kg body weight for one day. Blood samples are measured for any change in growth hormone levels.
• Additional administration of peptides may be made but a day of rest, i.e., a day during which neither peptide type is administered should intervene administration days.
• the dosage amount can be varied to determine optimal dosages.
• the changes, if any, in growth hormone levels to either or both of GHRH or GHRP-6 or analog thereof will provide an insight to the etiology of the short stature condition of the child.
• any growth hormone releasing compound can be utilized in the diagnostic procedure of the present invention.
• GHRH is the preferred growth hormone releasing compound for use in the claimed invention.
• the growth hormone releasing compounds which may be used in practicing the present invention are any such compounds known to induce growth hormone (GH) secretion and include growth hormone releasing hormone (GHRH) (1-44) and analogs GHRH (1-40) and GHRH (1-29) thereof.
• GHRH growth hormone releasing hormone
• GHRH growth hormone releasing hormone
• GHRH growth hormone releasing hormone
• U.S. Patent 4,622,312 provides an excellent description of GHRH and analog thereof, which can be used in the presently claimed invention.
• Reissue patent RE33,699 provides a summary of patents which teach growth hormone releasing compounds.
• GHRP-6 and analogs thereof means GHRP-6 and any peptide compound that releases GH by the same cellular mechanism.
• the pentapeptide Tyr-D-Trp- Gly-Phe-Met-NH 2 (K. Cheng et al. , Endocrinol. 1989; 124. 2791-2798) is a useful analog in the release of GH.
• Other compounds considered analogs of GHRP-6 for purposes of the present invention have been reported. For example, C.Y.
• the growth hormone levels in the blood of the child can be measured by any well known procedures, e.g., using an immunoradiometric assay as described by C.Y. Bowers et al., J. Clin Endocrinol. Metab 1990; 7J), 975-982 or any other contemporary, scientifically accepted method.
• the appropriate replacement therapy can ensue whereby either a growth hormone releasing compound or a GHRP-6 or analog thereof or a combination of both GH secretagogues is administered to the child.

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• General Physics & Mathematics (AREA)
• Endocrinology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Investigating Or Analysing Biological Materials (AREA)

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Citations (2)

• 1993
  • 1993-06-22 WO PCT/US1993/005955 patent/WO1994000759A1/fr not_active Application Discontinuation
  • 1993-06-22 EP EP93916678A patent/EP0650597A4/fr not_active Withdrawn
  • 1993-06-22 CA CA 2139326 patent/CA2139326A1/fr not_active Abandoned

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