Animal, fungal and marine sources of CGP and increased CGP concentrations for disease management and for the treatment of non-neurological and / or neurological conditions

Abstract

Described herein are improvements in the analysis, regulation of IGF-1 function, and its application in disease management of non-neurological and / or neurological conditions. More specifically, methods for the clinical application of cyclic glycine-proline (cGP) and / or the cGP / IGF-1 molar ratio as plasma biomarkers for the prediction of risk and reversal of non-neurological and / or neurological conditions with IGF-1 dysfunction, and the use of GP-containing animal, marine or fungal-based materials, such as hydrolyzed bovine and marine collagen, mushroom and seaweed concentrates / extracts, together with plant-based cGPMAX™, to treat the same. The methods indirectly use cGP and the cGP / IGF-1 molar ratio, together with means to regulate and normalize the cGP and cGP / IGF-1 molar ratio (and thus active IGF-1 concentration), to more accurately measure IGF-1 function in vivo, and specific treatment methods for individuals with lower cGP levels, or reduced cGP levels, relative to a standard set of baseline data. Supplementation with cGPMAX™ formulated with bovine collagen effectively improved sensory function in patients with diabetic neuropathy.

Description

[Technical field]

[0001] Technical Field Described herein are improvements in the analysis, regulation of IGF-1 function and its application in disease management of non-neurological and / or neurological conditions. More particularly, methods for the clinical application of cyclic glycine-proline (cGP) biomarker for predicting risk and reversing non-neurological and / or neurological conditions with IGF-1 dysfunction and the use of cGP-containing animal, marine and / or fungal based materials, such as hydrolyzed bovine and marine collagen, mushroom and seaweed concentrates / extracts, together with cGP encapsulated in softgel capsules, for the treatment thereof. [Background technology]

[0002] Background technology Insulin-like growth factor-1 (IGF-1) is a protein produced as an endocrine hormone. It is the primary mediator (effector) of the effects of growth hormone and stimulates somatic growth of nearly all cells in the body. In addition to its growth effects, IGF-1 can also regulate neuronal and cellular DNA synthesis.

[0003] It is also a neurotrophic factor and has an important role in various neuronal functions, such as cognitive function. IGF-1 is produced throughout life, but is lowest in infants (especially newborns), increases in adulthood, and decreases with age. Measurement of IGF-1 function is a biomarker of cognitive decline with age and can then be used to know whether and when interventions such as drug treatments may be useful. IGF-1 levels are low in infants. However, IGF-1 function plays an important role during infant brain development and affects brain function later in life.

[0004] However, plasma IGF-1 concentrations have historically been poor biomarkers of IGF-1 function because direct measurements of IGF-1 provide inconsistent results that cannot be used with any degree of confidence. For example, a historical use may be testing for IGF-1 in the blood as a screening test for growth hormone deficiency and abnormal growth patterns, but the results are primarily induction of total IGF-1, not a specific measure of active IGF-1.

[0005] It is understood that the inconsistent results of direct IGF-1 measurement may be due to the fact that most IGF-1 is inactive in vivo. What is important is that it is the active part. In plasma, more than 95% of IGF-1 binds to IGF-binding protein-3 (IGFBP-3), and once bound, IGF-binding protein-3 prevents the activation of IGF-1 functional receptor. Therefore, when IGF-1 is measured directly, there is no distinction between active and inactive forms, and therefore the actual amount of activity of IGF-1 in vivo is not known, and the active part is the biomarker of interest.

[0006] The IGF-1 / IGFBP-3 ratio can be used as a surrogate for unbound bioactive IGF-1, but in practice this ratio also does not provide a clear indication since most IGFBP-3 does not bind to IGF-1.

[0007] As can be seen, alternative measures of IGF-1 may be useful as a means to track IGF-1 function and therefore use this measure as a biomarker of patient health. For example, cyclic glycine-proline (cGP), a metabolite of IGF-1, is neuroprotective via improving / normalizing the bioavailability of IGF-1 in plasma.

[0008] In response to understanding IGF-1 levels, it may be desirable to modulate or support the patient's natural immunity and repair the system by increasing the IGF-1 active portion thereof.

[0009] Furthermore, since IGF-1 is closely associated with a variety of animal functions, one of which is age-related neurodegenerative functions, methods to both measure the associated changes and to treat, ameliorate, or accelerate the cure of various associated conditions would be useful.

[0010] The human body has the ability to protect itself from injury and disease, for example, our hormone system becomes more active. However, our ability to help recovery is not always effective in achieving better recovery, especially in the elderly, due to the gradual decline of hormones with age. Stroke occurs in young and elderly populations. Younger stroke patients can recover quickly and better, while older patients may recover slower and less well. IGF-1 function is also important for stroke recovery. Therefore, a reliable biomarker of IGF-1 function in stroke can be used for the prognosis of stroke or other neurological conditions, and furthermore, a method for predicting the ability of stroke recovery can help in designing the clinical management of individual patients. However, as mentioned above, plasma IGF-1 or IGF-1 / IGFBP-3 ratio is not a reliable biomarker. Therefore, it has been found that the use of cyclic glycine-proline (cGP) as a biomarker of IGF-1 function to aid the spontaneous recovery of stroke patients and the treatment method thereof is useful.

[0011] The important function of IGF-1 in blood circulation is to maintain vascular remodeling, which is the process of endothelial cell production, and to form capillary networks. The function of capillaries is to deliver nutrients to tissues (cells) and remove metabolic waste from tissues (cells) to maintain physiological function. Research results have established evidence that cGP improves vascular remodeling by regulating the function of IGF-1 in vascular diseases such as hypertension, stroke and cognitive impairment.

[0012] The health benefits of cGP are well known and it has been identified in natural plants including blackcurrant, and blackcurrant anthocyanin (BCA) concentrates / extracts encapsulated in gelatin hard shells have been utilized for therapeutic effects.

[0013] As an age-related condition, Parkinson's disease (PD) is the second most common neurodegenerative condition. IGF-1 is a neurotrophic factor that plays a key role in maintaining neuronal survival and brain function. IGF-1 resistance, characterized by increased IGF-1 in circulation and / or brain tissue, as well as impaired IGF-1 function, has been reported to be associated with neurological impairment and cognitive decline in PD and Alzheimer's disease (AD) patients. As mentioned above, changes in serum IGF-1 concentration have been used as a biomarker of IGF-1 dysfunction to monitor the prognosis and treatment response of PD, although this remains controversial. High consumption of berries has been reported to be associated with a lower risk of PD, although the mechanism underlying this putative benefit remains unclear.

[0014] However, the concentration of cGP in plants is relatively low and increases after being encapsulated in gelatin softgel / hardshell.Although gelatin softgel / hardshell is an additional source of cGP, the clinical application of blackcurrant extract encapsulated in gelatin may be sufficient to support and manage general health, but not for aging-related health problems.Nevertheless, it would be useful to obtain cGP from other sources at higher cGP concentrations to ensure effective bioavailability.

[0015] Further aspects and advantages of the improvements in the analysis, modulation of IGF-1 function and disease management of non-neurological and / or neurological conditions resulting from impaired IGF-1 function resulting from increased concentrations of cGP-derived sources will become apparent from the ensuing description, which is given by way of example only. Summary of the Invention [Means for solving the problem]

[0016] overview Described herein is a method for the clinical application of cGP plasma biomarkers for predicting risk and reversing non-neurological and / or neurological conditions with IGF-1 dysfunction and the use of enrichment / extraction of cGP-containing animal, marine and / or fungal based materials, such as hydrolyzed bovine collagen, to treat the same. The method indirectly uses cGP and the cGP / IGF-1 ratio together with a means to adjust the cGP and cGP / IGF-1 ratio (and thus active IGF-1 concentration) to more accurately measure IGF-1 function in vivo and specific treatment methods for individuals with lower cGP levels or reduced cGP levels relative to a standard set of baseline data.

[0017] In a first aspect, there is provided a method of treating a non-neurological and / or neurological condition associated with IGF-1 dysfunction in an animal, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in a biological sample; c) comparing the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in the biological sample with a standard to determine whether the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in the set of results corresponds to a relative standard for estimating the IGF-1 function of the individual; and d) administering to the animal a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine, seaweed, and / or fungal-based materials: Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal Includes.

[0018] In a second aspect, there is provided a method of predicting risk of age-related non-neurological and / or neurological conditions in an animal using cyclic glycine proline (cGP) as a plasma biomarker with altered IGF-1 function and biomarker-guided intervention, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples at a first set age of the animal, or at an early stage of a neurological condition, or prior to treatment of the animal with a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal based material; c) re-measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples at further set age intervals in the animals or at further stages of non-neurological and / or neurological conditions or after treatment of the animals with a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal based materials; d) comparing the measured cGP concentration and / or the ratio of the cGP concentration to the total measured amount of IGF-1 in biological samples at set age intervals with those at a first set age, or at the early stage of a non-neurological and / or neurological condition with IGF-1 dysfunction, or before treatment of the animal with a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal based material, to ascertain whether there is a change in the measured cGP concentration and / or the ratio of the cGP concentration to the total measured amount of IGF-1 in a series of outcomes, thereby determining whether the animal is at increased risk of developing a non-neurological and / or neurological condition from cognitive decline relative to a standard set of baseline data, and using said measured ratios to select an individual patient for cGP treatment and an appropriate dosage for cGP treatment in said patient. Includes.

[0019] In a third aspect, there is provided a method for predicting the capacity of spontaneous recovery in an animal having a non-neurological and / or neurological condition with impaired IGF-1 function using cyclic glycine-proline (cGP) as a plasma biomarker of IGF-1 function, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) plasma biomarker and activity concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples at baseline from the onset (<72 h) of the non-neurological and / or neurological condition; and c) re-measuring the concentration of cyclic glycine-proline (cGP) plasma biomarker and the activity concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples at further intervals during recovery of the animals; d) assessing the animals' functional recovery from baseline and at further set intervals. Including, The baseline concentration of CGP from a series of data predicts short-term outcome of recovery of the animal's non-neurological and / or neurological condition, such that the higher the baseline cGP concentration, the more favorable the animal's prognosis based on an assessment of functional recovery.

[0020] In a fourth aspect, Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in animals The present invention provides the use of a concentrate / extract of cGP derived from animal, marine and / or fungal based materials in the manufacture of a medicament formulated for the treatment of chronic obstructive pulmonary disease.

[0021] In a fifth aspect, there is provided the use of a concentrate / extract of cGP derived from animal, marine and / or fungal based material in the manufacture of a medicament formulated for oral administration to ameliorate and / or treat the effects of a non-neurological and / or neurological condition in a patient in need thereof.

[0022] In a sixth aspect, Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing (normal / physiological) concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing or normalizing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in animals In accordance with the present invention, functional properties are provided that include a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine and / or fungal based materials, formulated to be administered to an animal for the treatment of chronic inflammatory bowel disease.

[0023] In a seventh aspect, there is provided a method for ameliorating the effects of hypertension and / or stroke; and / or treating hypertension and / or stroke; and / or reducing symptoms associated with hypertension and / or stroke in a patient in need thereof, the method comprising administering a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine and / or fungal based material.

[0024] In an eighth aspect, there is provided a method for ameliorating and / or treating the effects of Parkinson's disease or symptoms associated with Parkinson's disease, or complications associated with cognitive impairment, in a patient in need thereof, the method comprising administering a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine and / or fungal based material.

[0025] In a ninth aspect, there is provided a method of treating a non-neurological and / or neurological condition associated with IGF-1 dysfunction in an animal, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in a biological sample; c) comparing the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in the biological sample with a standard to determine whether the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in the set of results corresponds to a relative standard for estimating the IGF-1 function of the individual; and d) administering to the animal a therapeutically effective amount of a concentrate / extract of cGP-containing animal, marine and / or fungal-based material to: Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal Includes.

[0026] In a tenth aspect, there is provided a method of predicting risk of age-related non-neurological and / or neurological conditions in an animal using cyclic glycine proline (cGP) as a plasma biomarker with altered IGF-1 function, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples at a first set age of the animal or at the early stage of a non-neurological and / or neurological condition or prior to treatment of the animal with a therapeutically effective amount of a concentrate / extract of cGP-containing animal, marine and / or fungal based material; c) re-measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples after further set age intervals or further stages of non-neurological and / or neurological conditions of the animals or treatment with a therapeutically effective amount of a concentrate / extract of cGP-containing animal, marine and / or fungal based material; d) comparing the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in the biological samples at set age intervals to a first set age, or to an early stage of the non-neurological and / or neurological condition, or to before treatment of the animal with a therapeutically effective amount of the cGP-containing animal-, marine- and / or fungal-based material concentrate / extract, to ascertain whether there is a change in the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in a series of outcomes, thereby determining whether the animal is at increased risk of developing a non-neurological and / or neurological condition from cognitive decline relative to a standard set of baseline data, and using said measured ratios to select an appropriate individual patient for cGP-containing animal-, marine- and / or fungal-based material treatment and a suitable dosage for the cGP-containing animal-, marine- and / or fungal-based material treatment in said patient. Includes.

[0027] In an eleventh aspect, Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in animals The present invention provides the use of a concentrate / extract of cGP-containing animal, marine and / or fungal based material in the manufacture of a medicament formulated for the treatment of chronic obstructive pulmonary disease (COPD) and / or chronic obstructive pulmonary disease (COPD).

[0028] In a twelfth aspect, there is provided the use of cGP-containing animal, marine and / or fungal based material in the manufacture of a medicament formulated for oral administration to ameliorate and / or treat the effects of a non-neurological and / or neurological condition in a patient in need thereof.

[0029] In a thirteenth aspect, Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing (normal / physiological) concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing or normalizing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in animals In accordance with the present invention, there is provided an extract comprising a concentrate / extract of cGP-containing animal, marine and / or fungal-based material in a therapeutically effective amount formulated to be administered to an animal for the treatment of the disease.

[0030] In a fourteenth aspect, there is provided a method for ameliorating the effects of hypertension and / or stroke; and / or treating hypertension and / or stroke; and / or reducing symptoms associated with hypertension and / or stroke in a patient in need thereof, the method comprising administering a therapeutically effective amount of a concentrate / extract of cGP-containing animal, marine and / or fungal based material.

[0031] In a fifteenth aspect, there is provided a method for ameliorating and / or treating the effects of Parkinson's disease or symptoms associated with Parkinson's disease, or complications associated with cognitive impairment, in a patient in need thereof, the method comprising administering a therapeutically effective amount of a concentrate / extract of cGP-containing animal, marine and / or fungal-based material.

[0032] In a sixteenth aspect, there is provided a method for ameliorating and / or treating the effects of metabolic disorders and associated complications, such as peripheral neuropathy, renal insufficiency, retinopathy, and other complications due to poor capillary function associated with type 2 diabetes.

[0033] In a seventeenth aspect, a method of ameliorating and / or treating the effects of cancer, including terminal cancer, is provided.

[0034] In an eighteenth aspect, there is provided a softgel or hard shell capsule that is used to encapsulate a cGP extraction material for administration of the cGP extraction material and that increases the cGP concentration of the extraction material contained therein over time.

[0035] The above advantages may vary. In relation to the biomarker, cGP as described is a stable metabolite of IGF-1 and, based on the inventors' work, is easily measured in biological samples taken from animals. cGP is less variable than IGF-1 in distinguishing active from inactive forms and is therefore more reliable than measuring total IGF-1. In relation to the described methods of measuring changes in cGP and / or addressing neurological conditions, the advantage of clinical application of cyclic glycine-proline (cGP) as a reliable biomarker allows for selection of patients suitable for treatment and individual dosing regimens. Increased cGP indicates risk of a neurological condition and decreased cGP indicates the stage of the neurological condition. Advantageously, patients suitable for treatment can be selected based on their cGP levels and changes in cGP levels can be easily monitored for adjusted or individualized treatment regimens. Advantageously, high concentrations of cGP in collagen from animal and marine tissues have been found to be several thousand times higher than their counterparts in plant-based materials. Supplementation with higher concentration products of animal, marine and / or fungal origin is highly advantageous when adjusting dosing regimens as it allows for faster effective treatment of non-neurological and / or neurological conditions, and the products improve or support the management of acute conditions such as traumatic brain injury (TBI), stroke and other types of injuries as they help the body reach effective concentrations faster.

[0036] The use of cGP from animal, marine and / or fungal materials in such a measurable and known manner is not known or accomplished in the art. cGP extracted from these sources has not been used in a known and measurable manner, but is now possible and described herein. Experimental results show new or at least alternative uses of cGP extracts that can provide significant and measurable benefits to patients and potentially do not interfere with existing art treatments or cause undesirable side effects. Furthermore, in the context of natural products and related bioactive compounds in general, the methods and uses described herein provide a unique way of knowing when it is appropriate to intervene in a treatment and further provide a way to measure the success or failure of a treatment. This insight into timing and efficacy is what many pharmaceuticals aim for and is not commonly observed in natural products containing bioactive compounds.

[0037] A further advantage which the inventors have unexpectedly discovered is that the softgel capsule used to encapsulate the cGP extract material increases the cGP concentration of the extract material contained therein over time.

[0038] BRIEF DESCRIPTION OF THE DRAWINGS Further aspects of the present method relating to the clinical application of the cyclic glycine-proline (cGP) plasma biomarker for predicting the risk of and reversing the reversal of non-neurological and neurological conditions associated with IGF-1 dysfunction and the use of cGP-containing animal, marine and / or fungal based materials, such as concentrates / extracts of hydrolyzed bovine collagen powder, for treating the same will become apparent from the following description, given by way of example only, and with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0039] [Figure 1] The relative concentrations of cGP (ng / mg) in animals, fungi, seaweed and marine products are shown; [Diagram 2] demonstrate that urinary cGP concentrations are significantly increased 3 hours after oral consumption of 100 mg of bovine collagen powder; [Diagram 3]Pearson correlation analysis suggests a strong positive correlation between urinary and plasma cGP concentrations (r=0.78, p<0.001); [Figure 4] Figure 1 shows improved sensibility after oral supplementation with a new formulation of cGPMAX™ blended with bovine collagen. Repeated measures analysis of variance suggested that sensibility decreased after 3 and 6 months of cGPMAX™ supplementation (p=0.0007). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Detailed Description As mentioned above, methods are described herein relating to the clinical application of cyclic glycine-proline (cGP) plasma biomarker for predicting risk and reversing non-neurological and neurological conditions and the use of cGP-containing animal, marine and / or fungal based materials, such as bovine collagen concentrates / extracts, together with cGP encapsulated in softgel capsules to treat the same. The methods use the ratio of cGP and cGP / IGF-IGFBP3 together with a means to adjust the ratio of cGP and cGP / IGF-1 (and thus active IGF-1 concentration) to more accurately measure IGF-1 indirectly in vivo and provide specific treatment methods for individuals with lower cGP levels or reduced cGP levels relative to a standard set of baseline data.

[0041] For purposes of this specification, the terms "about" or "approximately" and grammatical variations thereof mean an amount, level, degree, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by up to 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of the referenced quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0042] The term "substantially" or grammatical variations thereof refers to at least about 50%, such as 75%, 85%, 95% or 98%.

[0043] The term "comprises" and its grammatical variations shall be understood to have an inclusive meaning, i.e., to include not only the listed components to which it directly refers, but also other components or elements not specified.

[0044] The term extract should be understood as the extraction of cGP from the source material, and the extract and / or concentrate may be a source or carrier of cGP when suitably extracted from animal, marine and / or fungal sources.

[0045] In a first aspect, there is provided a method of treating a non-neurological and / or neurological condition associated with IGF-1 dysfunction in an animal, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in a biological sample; c) comparing the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in the biological sample with a standard to determine whether the measured cGP concentration and / or the ratio of the measured cGP concentration to the measured total amount of IGF-1 in the set of results corresponds to a relative standard for estimating the IGF-1 function of the individual; and d) administering to the animal a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine, seaweed, and / or fungal-based materials: Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal Includes.

[0046] In a second aspect, there is provided a method for predicting risk of age-related non-neurological and / or neurological conditions in an animal using cyclic glycine proline (cGP) as a plasma biomarker with altered IGF-1 function, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples at a first set age of the animal, or at an early stage of a neurological condition, or prior to treatment of the animal with a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal based material; c) re-measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples after further set age intervals of the animals or further stages of non-neurological and / or neurological conditions or treatment of the animals with a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal-based materials; and d) comparing the measured cGP concentration and / or the ratio of the cGP concentration to the total measured amount of IGF-1 in biological samples at set age intervals with those at a first set age, or at the early stage of a non-neurological and / or neurological condition with IGF-1 dysfunction, or before treatment of the animal with a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal based material, to ascertain whether there is a change in the measured cGP concentration and / or the ratio of the cGP concentration to the total measured amount of IGF-1 in a series of outcomes, thereby determining whether the animal is at increased risk of developing a non-neurological and / or neurological condition from cognitive decline relative to a standard set of baseline data, and using said measured ratios to select an individual patient for cGP treatment and an appropriate dosage for cGP treatment in said patient. Includes.

[0047] In a third aspect, there is provided a method of predicting spontaneous recovery in an animal having a non-neurological and / or neurological condition with impaired IGF-1 function using cyclic glycine-proline (cGP) as a plasma biomarker of IGF-1 function, the method comprising: a) obtaining a biological specimen from an animal; b) measuring the concentration of cyclic glycine-proline (cGP) plasma biomarker and active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples from the animals at baseline from onset of the non-neurological and / or neurological condition (<72 h in an acute condition); c) re-measuring the concentration of cyclic glycine-proline (cGP) plasma biomarker and the activity concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in biological samples at further intervals during recovery of the animals; d) assessing the animals' functional recovery from baseline and at further set intervals. Including, The baseline concentration of CGP from a series of data predicts short-term outcome of recovery of the animal's non-neurological and / or neurological condition, such that the higher the baseline cGP concentration, the more favorable the animal's prognosis based on an assessment of functional recovery.

[0048] Cyclic glycine-proline (cGP) is a stable fragment naturally formed by unbound bioactive IGF-1. cGP competes with IGF-1 for binding to IGFBP-3 in a concentration-dependent manner. The inventors have found that cGP is a measurable and reliable plasma biomarker that strongly correlates with the amount of active IGF-1 as a result of the concentration-dependence of inactivation described above. Thus, instead of relying on direct IGF-1 measurements, which are variable, the presence or absence of active IGF-1 function can be measured by measuring cGP concentrations.

[0049] The inventors' work has shown that higher concentrations of cGP liberate more IGF-1 from IGFBP-3 via the concentration-dependence described above, thus resulting in increased bioavailable IGF-1.

[0050] In addition to direct cGP measurement, the inventors have determined that the relative concentration of cGP and IGF-1 (i.e., the cGP / IGF-1 molar ratio) can also represent the amount of bioavailable IGF-1 in patients, and therefore potentially serve as a suitable biomarker for IGF-1-related cognitive function.It has also been found that increased cGP indicates the risk of neurological conditions, and decreased cGP correlates with the stage of neurological conditions.Therefore, it is assumed that treatment with cGP extract can prevent or delay the onset of cognitive decline.

[0051] The term "biomarker" as used herein refers to the molar ratio of cGP or cGP to total IGF-1 that can be traced in an animal as a means of examining the health and function of the animal. Health and function can include, but is not limited to, the detection of a "normal" or "healthy" state for an animal relative to a historical standard measurement for either the animal or the population. Health and function can also include the detection of a non-normal or non-healthy animal state that may be related to a condition, disease or abnormal condition. As can be understood, terms such as "normal" or "healthy" are subjective terms, but in the context of this specification, the term is a relative measure of the described biomarker compound or ratio compared to either the historical details for the animal and / or the variation relative to a population referred to as a baseline or standard.

[0052] As mentioned above, the standard can be based on a set of data collected for an individual animal. For example, data on the average cGP and molar ratio of cGP to total IGF-1 can be collected for an animal over a period of time, e.g., 1 week to 6 months to 2 years. Variations in biomarker concentrations or ratios can be observed and analyzed to find a "typical" value for the animal, and that data and the extent of any deviations can be used to understand normal or standard values ​​versus typical variations, thus identifying if non-normal or atypical changes have occurred.

[0053] A standard may alternatively, or in conjunction with individual animal data, be based on a set of data collected on a population. A population may be, for example, a sex group, a group defined by age, a group defined by a symptom, condition or disease state, etc.

[0054] cGP and / or IGF-1 may be measured in a biological specimen taken from an animal. For the purposes of this specification, the terms "biological specimen", "body sample" or "sample" may be used interchangeably and collectively refer to a specimen taken or extracted from a patient, stored and later analyzed. Sample extraction techniques may be, for example, by swab, venipuncture, stick, biopsy, fraction, urination, stool sample, etc. In selected embodiments, the biological specimen may be: cerebrospinal fluid (CSF), plasma, urine, breast milk, any other biological specimen (tears and any other body function) and combinations thereof.

[0055] cGP and / or total IGF-1 in a biological sample can be measured by a technique selected from: ELISA, HPLC, mass spectrometry, and combinations thereof. Other analytical techniques in the art can also be used and reference to such techniques should not be understood as limiting.

[0056] In a fourth aspect, Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in animals The present invention provides the use of a concentrate / extract of cGP derived from animal, marine and / or fungal based materials in the manufacture of a medicament formulated for the treatment of chronic obstructive pulmonary disease.

[0057] In a fifth aspect, there is provided the use of a concentrate / extract of cGP derived from animal, marine and / or fungal based material in the manufacture of a medicament formulated for oral administration to ameliorate and / or treat the effects of a non-neurological and / or neurological condition in a patient in need thereof.

[0058] In a sixth aspect, Preventing a decrease in the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing (normal / physiological) concentration of cGP and / or the ratio of cGP to total measured IGF-1 in the animal; and / or Increasing or normalizing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in animals In accordance with the present invention, there is provided a concentrate / extract comprising a therapeutically effective amount of cGP derived from animal, marine and / or fungal based materials, which is formulated to be administered to an animal for the treatment of chronic inflammation.

[0059] In a seventh aspect, there is provided a method for ameliorating the effects of hypertension and / or stroke; and / or treating hypertension and / or stroke; and / or reducing symptoms associated with hypertension and / or stroke in a patient in need thereof, the method comprising administering a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine and / or fungal based material.

[0060] The inventors have found that when a concentrate / extract of cGP is applied to patients with hypertension (high blood pressure), their blood pressure is reduced to acceptable baseline levels.

[0061] Non-neurological conditions or diseases for treatment and predicting recovery may be selected from, but are not limited to, hypertension, acute brain injury (e.g., concussion), weight change in obese women, and postnatal development.

[0062] In an eighth aspect, there is provided a method for ameliorating and / or treating the effects of Parkinson's disease or symptoms associated with Parkinson's disease, or complications associated with cognitive impairment, in a patient in need thereof, the method comprising administering a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine and / or fungal based material.

[0063] The neurological condition or disease for treatment may be selected from, but is not limited to, cerebrovascular accident (CVA) or stroke, mild cognitive impairment (MCI), Alzheimer's disease, vascular dementia, hypertension and its associated cerebral complications, Parkinson's disease and / or any other aging-related condition or IGF-1 deficiency-related condition.

[0064] Stroke is an exemplary neurological condition in which insufficient blood flow to the brain typically leads to cell death, causing parts of the brain to fail to function properly. The inventors have identified that cGP concentrations and the ratio of cGP to total IGF-1 are altered in stroke patients through the biomarkers described above, and the extent to which cGP or the ratio is reduced is a strong indicator of patient recovery and outcome. Less reduction is associated with faster recovery and potentially fewer ongoing problems. Although the exact mechanism for this has not been proven, lower cGP levels or the ratio of cGP to total IGF-1 corresponds to less active IGF-1, as IGF-1 is associated with growth, and therefore corresponds to slower growth of neural pathways and thus slower recovery. Based on this discovery, the inventors show that administration of concentrated cGP extracts from animal, marine and / or fungal-based materials can increase cGP levels and / or the ratio of cGP to total IGF-1, thus ameliorating the effects of stroke, treating stroke, or at least reducing symptoms associated with stroke and / or other neurological conditions.

[0065] A further example of a neurological condition evaluated by the inventors is Parkinson's disease (PD), the second most common neurodegenerative condition. As mentioned above, insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays an important role in neuronal survival and brain function. IGF-1 resistance, characterized as an increase in circulating IGF-1 with impaired IGF-1 function, plays a role in the disease progression of idiopathic PD, cognitive impairment and PD pathology. Therefore, changes in plasma concentrations of IGF-1 have also been evaluated by the inventors as a biomarker for monitoring IGF-1 function to predict the prognosis and treatment response of PD and other conditions such as metabolic disorders and cancer.

[0066] For purposes herein, the terms "amelioration," "treatment," or "reduction of symptoms" refer to a decrease in the measured effect of at least one sign or symptom associated with a neurological condition by at least 1, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10% compared to that measured in a patient without administration of blackcurrant extract.

[0067] Administration may halt a decrease in cGP concentration or a decrease in the molar ratio of cGP to total IGF-1 as a result of a non-normal condition, such as that caused by a disease or condition or resulting from symptoms associated with a disease or condition. The term "halt a decrease" as used refers to the cGP concentration and / or the ratio of cGP to total IGF-1 remaining within at least 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10% of the concentration or ratio measured prior to administration.

[0068] Administration may increase cGP concentration and / or the molar ratio of cGP to IGF-1 by at least 1, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10% over what would be measured in patients without cGP extract administration. The inventors unexpectedly found that there may be a 25% increase in cGP in cerebrospinal fluid (CSF) after cGP extract supplementation. Without being bound by theory, this suggests effective uptake by the brain after oral administration, an important finding for the treatment of any brain disease. Furthermore, cGP extract may increase the formation of cGP in human plasma. To the best of the inventors' knowledge, there are no other studies that have shown effective brain uptake of at least 25% of cGP in CSF. Furthermore, clinical trials are ongoing to confirm the effectiveness and uptake of supplementation with high concentrations of cGP products and how these supplements help to reach effective concentrations faster. Additionally, elucidation of the mechanism may provide important scientific evidence to further support cGP extract as an intervention in normalizing IGF-1 function.

[0069] The animals referred to in the above embodiments may be humans. The animals may alternatively be non-human animals. References to animals may be used interchangeably herein with the words "subject" or "patient," and reference to one or the other should not be understood as limiting.

[0070] In one embodiment, the animal to which the cGP extract is administered may be a healthy animal that does not exhibit any abnormal cGP and / or ratio of cGP to total IGF-1. In this embodiment, the extract may be administered proactively as a means to prevent or avoid alterations in cGP or the ratio of cGP to total IGF-1 that may then be associated with a disease, condition, or symptoms of a disease or condition. Alternatively, the animal may have a pre-existing condition, pathology, and / or symptoms associated with a condition or pathology.

[0071] As mentioned above, terms such as "normal", "healthy" and "healthy" are subjective terms, but in the context of this specification, the terms are relative measures of the described biomarker compounds or ratios compared to either historical details about the animal and / or variations relative to a population referred to as a baseline or standard. The baseline of an individual may vary between age, sex, and any other medical conditions that may be related to IGF-1 function. It has been found that the change in cGP and / or the ratio of cGP to total IGF-1 from the baseline of an individual is more important information in guiding treatment and cGP dosing regimens. An exemplary study conducted by the inventors showed that plasma cGP levels in healthy women are 3.5ng / mg, while in elderly people aged 50-70 years, it is 8-10ng / ml and in PD patients is 12ng-15ng / ml due to the decline in IGF-1 function in the elderly and IGF-1 resistance in PD patients. The increase in cGP concentration is an endogenous response to maintain IGF-1 function. When this response loses its effectiveness, patients develop symptoms, such as dementia in PD patients.

[0072] The described medicament may be formulated for oral administration in one embodiment. Oral administration is a non-invasive and convenient means of administering bioactive compounds, and this method has been well studied for oral supplements. In addition, a method for marketing the described method for regulatory approval may be useful. Despite the reference to oral administration, the medicament may be formulated for parenteral administration, for example, non-limiting examples being injections, sublingual wafers, or suppositories. Overcoming the blood-brain barrier (BBB) ​​has been extensively described in the art for many bioactive compounds, and thus there is some digression as to whether oral or parenteral methods are preferred, or whether the BBB allows for transfer. The inventor has found that oral administration of cGP extract crosses the blood-brain barrier and therefore may be a useful means of administration.

[0073] The concentrate / extract itself can be a dry powder in one embodiment. The processed powder can be micronized to a diameter in the micron range and can have a particle size of less than 1000, or 100, or 10, or 1 micron. The medicine containing the extract can be formulated as a pill, tablet, capsule, liquid, powder, micronized powder, gel, liquid-filled softgel, and combinations of these forms. Extracts in the art can be coarse powders with particle sizes greater than 1000 microns. Such extracts can be difficult to solubilize in an aqueous environment, and thus micronized forms of the described extracts can be useful, because they are easier to solubilize and therefore more rapidly and more completely ingested and transferred to the animal's bloodstream.

[0074] As stated above, the dose is a therapeutically effective amount. In one embodiment, a therapeutically effective dose of concentrated cGP may provide a daily dose of at least 10,000-100,000 ng (10-100 μg). It has been discovered that the high concentration of cGP in collagen from animal and marine tissues can be several thousand times that of the plant-based equivalent. The blend of ingredients as a formulation provides an effective daily dose for the purpose of maintaining health, preventing disease or treating neurological or non-neurological conditions. The clinical application of plant-based cGP has some limitations due to the low concentration of cGP. For example, this is limiting for the health management of people with IGF-1 dysfunction, who require increased demand and uptake of cGP concentration in the body. Thus, the initial period of cGP supplementation from plant sources will usually take several weeks or months to see an accumulation of cGP to an effective level. This is the limitation of plant-sourced cGP in its clinical application in disease management, especially in acute conditions.

[0075] Advantageously, supplementation with higher concentrations of cGP products of animal, marine and / or fungal origin will help the body reach therapeutically effective concentrations more quickly, which is important for or in supporting the management of acute conditions such as traumatic brain injury (TBI), stroke, other types of injury, and complications of metabolic disorders such as diabetic peripheral neuropathy (Example 3), and cancer.

[0076] As should be understood, the dosages used may vary depending on factors such as the individual animal's metabolism, the species of the animal, the weight of the animal, the age of the animal, medical condition, health status and other factors, and therefore these dosages should not be viewed as limiting. Other types of organic-based materials, including concentrates of cGP, and / or combinations thereof, could conceivably be used in the present invention.

[0077] Ingredients with high concentrations of cGP can be derived from any animal, marine and / or fungal source, including any organism (not limited to bovine), marine and bone collagen types 1-7, and the like.

[0078] Health claims for collagen are mainly limited to skin, hair and nails. The basement membrane (BM) is part of the structure of blood vessels, especially those in the brain. Collagen is the biological and structural component of BM. Experimental mutations in collagen result in BM dysfunction, which has been demonstrated in studies in animal models of stroke, other cerebrovascular diseases and several developmental neurological conditions. However, these known studies are limited to examining collagen mutations and their association with pathological changes in tissues, and therefore the inventor's invention is not relevant to health claims and disease management of collagen, including neurological and vascular conditions. Furthermore, there is no association or teaching or suggestion of cGP and collagen in the art.

[0079] The hydrolysis process cleaves collagen / gelatin proteins to form linear peptides with hydrolyzed proline-glycine repeats. Cyclization of these linear peptides produces cGP. Apart from replacing tissues with collagen / gelatin, the inventors advocate the use of collagen or gelatin as a viable source of native cGP to normalize IGF-1 function.

[0080] In some embodiments, the extract may be hydrolyzed bovine collagen powder, collagen marine skin powder, hydrolyzed fish skin powder, and bone collagen.

[0081] The described process may be produced using body parts selected from: skin, protein, bone, muscle, tendon, etc. and / or combinations thereof. In one embodiment, the extract may be produced by steeping and other novel extraction methods of animal, marine and / or fungal materials and then dried to form a concentrated powder which may then be micronized. The micronized powder may optionally be encapsulated if a capsule form is desired or otherwise processed into a final form. In another embodiment, the extract concentrate and / or liquid product may be the source of the cGP extract product.

[0082] The blend may include cyclic glycine-proline (cGP) in a concentration that provides a daily dose of at least 10,000 ng or more, and / or at least the amount of cGP necessary to provide a health benefit.

[0083] Without being bound by theory, it is understood that these extracts, either in combination or separately, may be responsible for the observed in vivo effects on IGF-1 binding and thus the observed increase in cGP concentration and / or cGP to total IGF-1 ratio. However, the extract may contain other compounds other than cGP from animal, marine and / or fungal sources, and there may be other bioactive compounds or synergistic effects from the extract that are not purely attributable to these compounds. As a result, specific reference to these compounds is not intended to exclude the bioactivity of other compounds that may be present in the extract.

[0084] The above advantages may vary. In relation to biomarkers, the described cGP is a stable metabolite of IGF-1 and, based on the inventors' work, is easily measured in biological samples taken from animals. cGP is formed from the unbound active form of IGF-1 and is therefore more reliable than measuring total IGF-1. In relation to the described methods of increasing cGP and / or addressing neurological conditions, the use of cGP concentrates / extracts from animal, marine and / or fungal sources in such a measurable and known manner is not known or has not been perfected in the art. Thus, animal products have much higher cGP concentrations than plant-derived cGP such as blackcurrant. It has been advantageously found that oral administration of bovine collagen can further increase cGP concentrations in the human system (urine) of participants who have been using cGPMax™ for a long period of time. The disadvantage of low concentrations of cGP in plant-based products is that consumers often experience a longer "build-up" period to notice improvement, making them less suitable for treating patients with acute and / or severe conditions. Thus, the significantly higher cGP concentration of animal, marine and fungal derived products can increase cGP concentration to effective levels much faster than plant-based products. Considering that plant-based cGPMax is mainly used to support the health of normal people, other sources with higher cGP concentrations are suitable to support the health of people with medical conditions that have IGF-1 deficiency, and new products from animal, marine, plant and fungal derivatives can be developed for stroke recovery and other medication conditions that have systemic and cerebrovascular conditions due to IGF-1 deficiency. Therefore, any newly developed products can also be suitable for acute conditions with increased demand for cGP in their system, such as traumatic brain injury and onset.

[0085] The inventors have also found that collagen and gelatin (heated forms of collagen) are rich in the glycine-hydroxyproline amino acid sequence and, unexpectedly, degradation of collagen / gelatin can form significant amounts of cGP. The main component of the softgel capsules used to encapsulate the blackcurrant concentrate containing cGP is gelatin.

[0086] Preliminary studies have shown that the formation of cGP by gelatin degradation may depend on lower pH and higher temperature. For example, blackcurrant concentrate has a low pH of 2.5, which can degrade gelatin and form cGP, especially in hot environments. The inventors have observed an increase in cGP concentration (0.1ng / mg to 10ng / mg) in blackcurrant concentrate after encapsulation in softgel capsules. It is a significant finding that pH and temperature ranges can increase cGP levels during storage of the extract to improve efficacy. This same phenomenon may be applicable to any cGP extract encapsulated in softgel capsules, regardless of whether it is sourced from plant, animal, marine and / or fungal origin. Blackcurrant concentrate incubated with collagen for 2 weeks at 35°C also increases cGP concentration from 40ng / mg to 120ng / mg compared to the blended sample incubated for 2 weeks at 4°C. This phenomenon may also be applicable to other ingredients from plant, animal, marine and fungal origins.

[0087] cGP extract has not been used in a known and measurable way, but it is currently possible and as described herein. Further testing of the effectiveness of cGP with collagen blends in cognitive and metabolic disorders in elderly people may indicate new or at least alternative uses of cGP extract that can provide significant and measurable benefits to patients and potentially do not interfere with existing state of the art treatments or cause undesirable side effects.

[0088] In connection with the described methods of measuring changes in cGP and / or treating neurological conditions, the advantage of clinical application of cyclic glycine-proline (cGP) as a reliable plasma biomarker allows the selection of patients suitable for treatment and individualized dosing regimens. An increase in cGP indicates the risk of a neurological condition, while a decrease in cGP indicates the stage of a neurological condition. Advantageously, patients suitable for treatment can be selected based on their cGP levels, and changes in cGP levels can be easily monitored for an adjusted or personalized treatment regimen. Adjustment of the dosing regimen of cGP extract allows for effective treatment of neurological conditions, thus improving long-term recovery (more than 3 months) and preventing long-term complications (cognitive impairment) associated with neurological and peripheral neurological conditions. A further advantage is that cGP levels can be monitored simply by measuring urine samples, due to the ease of analysis, which is important for future large-scale clinical trials of cGP extract.

[0089] Furthermore, in the context of natural products and related bioactive compounds in general, the methods and uses described herein provide a unique way to know the right time to intervene in a treatment, and further provide a way to measure the success or failure of a treatment. This insight into timing and efficacy is what many pharmaceuticals strive for and is not commonly observed in natural products that contain bioactive compounds.

[0090] The above-described embodiments may also be broadly described as consisting of the parts, elements and features individually or collectively referenced or indicated in the specification of this application, and any or all combinations of two or more of said parts, elements or features.

[0091] Furthermore, where specific integers that have known equivalents in the art to which the embodiments pertain are referenced herein, such known equivalents are deemed to be incorporated herein as if individually set forth. EXAMPLES

[0092] Example of working example The above-mentioned methods relating to increased concentrations of the cyclic glycine-proline (cGP) biomarker for predicting risk of and ameliorating non-neurological and neurological conditions, and cGP-containing animal, marine and / or fungal-based materials, such as concentrates / extracts of cGP, for treating the same, are described with reference to specific examples.

[0093] Example 1 Identification of cGP concentrations in animal, fungal and marine sources The present inventors have previously identified the presence of cGP in natural plants, including blackcurrant. However, the cGP concentration is low (approximately 0.1-1 ng / mg). Clinical application of plant cGP alone is insufficient to support and manage general health, especially aging health. A source with increased concentrations of cGP would be more beneficial for its clinical application in disease management. In particular, the management of acute conditions such as traumatic brain injury (TBI), stroke, and other types of injury, where supplementation with high concentrations of cGP products helps the body reach effective concentrations more quickly.

[0094] Using a novel processing / extraction method, the inventors have identified high concentrations of cGP in collagen from animal and marine tissues. The extract is produced by soaking and then drying to form a concentrated powder, which is then micronized. The micronized powder can be optionally blended with other cGP-containing ingredients, or encapsulated if a capsule form is desired, or otherwise processed into the final formulation.

[0095] The concentrations of cGP in animal and marine sources are shown in Figure 1. The cGP concentrations are 1300-4400 ng / mg, which is several thousand times higher than the corresponding plant-based products. As previously mentioned, this high concentration of cGP is important in managing or supporting the management of acute conditions such as traumatic brain injury (TBI), stroke, and other types of injuries.

[0096] To generate a vegetarian or vegan version of cGPMAX™, the inventors have identified cGP-enriched ingredients sourced from mushrooms and seaweeds. Some examples are listed in Table 1. Health claims for brain function, such as for the Turkey tail mushroom, are widely asserted, but no association exists with either cGP or IGF-1.

[0097] Example 2 Pharmacokinetics of oral administration of bovine collagen powder Clinical trials have been completed by the inventors to determine whether supplementation with bovine collagen powder is 1) orally bioavailable, 2) whether supplementation with a >40-fold concentration of cGP from bovine collagen can result in a further increase in cGP concentrations in humans, and 3) whether higher doses of cGP will help the body reach effective concentrations more quickly than supplementation with a plant-based product.

[0098] All study participants had been taking cGPMax™ regularly for more than one year as part of their dietary intake. The concentration of cGP in cGPMax™ is a minimum of 10,000 ng / day (10 μg / day). The concentration of cGP varies based on the needs of the clinical application and can be manipulated via formulation.

[0099] To determine whether bovine collagen supplementation would further increase cGP concentrations in the body, an open-label pharmacokinetic study was conducted. Bovine collagen powder was dissolved in warm water. Urine samples were collected before and 3 hours after oral administration of a single dose of 100 mg. Differences between the two time points were analyzed using a paired t-test.

[0100] FIG. 2 shows that urinary cGP concentrations are significantly increased 3 hours after oral consumption of 100 mg bovine collagen powder.

[0101] Protein binding plays an important role in the pharmacokinetics of cGP and cGP analogs. The "effective" dose of cGP (or cGP analogs) was determined by the amount of cGP required to saturate the protein binding sites. This can be achieved by administration of higher doses for shorter periods (as shown in Figure 2) or lower doses of cGP for longer periods.

[0102] Compared to plant-based cGP products, animal collagen can provide effective doses of cGP in a shorter period of time. Collagen is orally bioavailable, and administration of 440 μg cGP (100 mg bovine collagen powder) further increased cGP concentrations in participants 3 hours after a single dose, thus suggesting a rapid increase in cGP levels with collagen.

[0103] Urinary cGP concentrations are highly correlated with those in circulation that have been assessed in stroke patients. Pearson correlation analysis suggests a strong positive correlation between urinary and plasma cGP concentrations (r=0.78, p<0.001, FIG. 3).

[0104] The high correlation between urinary and plasma cGP concentrations also supports that cGP is primarily excreted via the kidney. Excessive amounts of cGP in the circulation will leave the circulation via the kidney. Pharmaceutically developed cGP analogs are used in the high μg to low mg dose range.

[0105] In comparison, the cGP concentration provided by collagen supplementation is still lower than that of pharmaceutical synthetic analogues.Therefore, collagen-based cGP is safe for long-term supplementation.Therefore, the absorption and tissue utilization of cGP in natural foods may be favorable compared to synthetic analogues.

[0106] Collagen contains many proline and glycine sequences. Although collagen has a variety of cyclized prolines, there is no teaching or suggestion in the art that collagen contains cGP, and it is only suggested that collagen's health benefits are mainly contributed to skin and joints. The inventors were the first to identify the presence of cGP in collagen. A large amount of experimental and clinical research results by the inventors have shown a correlation between clinical outcomes and endogenous cGP concentrations, which is supported by the effectiveness of cGP treatment in experimental studies. Such high concentrations of cGP found in collagen are an important mechanism for the health claims of collagen and other cGP-derived sources. Thus, this discovery may extend previous claims in the art that collagen is beneficial from skin and joint health to cerebral and systemic vascular conditions, neurological disorders, metabolic disorders, etc.

[0107] Furthermore, the inventors have noted that fungi contain a variety of cyclic proline-containing peptides, which may contribute to fungal health claims. However, there are currently no literature reports on the presence of cGP in fungi. Further ongoing testing may identify the presence of cGP in various fungi, which may be a contributing factor to fungal health claims. For example, the inventors have identified high cGP concentrations in extracts of Coriolus versicolor (18 ng / mg) and several other mushrooms (Table 1).

[0108] Example 4 Supplementation with cGPMAX™ improved peripheral neuropathy in patients with type 2 diabetes. The inventors investigated the efficacy of cGPMAX™, reformulated with hydrolyzed collagen, for peripheral neurological conditions. Type 2 diabetes mellitus (T2DM) is the leading cause of peripheral neuropathy, a progressive neurological condition that occurs in 25-50% of T2DM patients.

[0109] The early stages of diabetic peripheral neuropathy (DPN) often manifest as sensory changes that progress to loss of sensation, numbness, pain, or burning in the extremities, distal weakness, or atrophy, which can result in impaired balance and gait. Without treatment, peripheral neuropathy has a poor prognosis and is the leading cause of limb amputation. The 5-year survival rate for limb amputation is about 2 years or less, compared to colon, breast, and prostate cancer.

[0110] An open-label study was conducted in patients with a >5-year clinical diagnosis of T2DM. Participants were scheduled for three clinic visits at various time points: before supplementation, 3 months, and 6 months after supplementation. Eighteen T2DM patients completed follow-up. Daily supplementation with cGPMAX™ provided 20-40 μg of natural cGP. Peripheral neuropathy was assessed in both feet.

[0111] Sensory function for pressure, vibration and temperature was scored as follows: 1=normal; 2=reduced sensation; and 3=absent sensation using the Semmes-Weinstein monofilament test, vibration perception threshold test and cold / ward detection thresholds test, respectively. A total score >22 indicated abnormal sensory function, with higher scores indicating more severe impairment. The total scores for pressure, temperature and vibration sensation were used for statistical analysis by repeated measures analysis of variance.

[0112] All participants experienced improvement in their DNP symptoms, with the majority reporting significant improvement after 2 months (or sooner) of supplementation.

[0113] Repeated measures analysis of variance showed significant differences between time points (p=0.0006, f[1.3, 22.25]=13.54, n=18). Compared to baseline (before supplementation), cGPMAX™ supplementation showed a significant reduction in total DNP scores (p=0.003) at 3 and 6 months (p=0.0007), as best shown in Figure 4.

[0114] This clinical outcome is the first evidence supporting the efficacy of cGPMAX™ in a peripheral neurological condition.

[0115] Summary / Conclusion · Animal, marine and fungal products have cGP concentrations that are much higher than those of cGP extracts derived from plants such as blackcurrant; · Oral administration of bovine collagen can further increase cGP concentrations in the human system (urine) of participants who were using the plant-based cGPMAX™ for a long period of time; · The significantly higher cGP concentrations of animal, marine and fungal derived products can increase cGP concentrations to effective levels much faster than plant-based sourced cGP. Given that plant-based cGPMax™ formulations are primarily used to support the health of normal people, new products from animal, marine and fungal derivatives can be developed to improve stroke recovery and other medication conditions with systemic and cerebrovascular conditions; · cGPMax™ formulated with collagen provided a higher dose of cGP (20-40 μg / day). Supplementation with 20-40 μg / day cGPMAX™ for 6 months improved sensory function in T2DM patients with peripheral neuropathy; The newly developed product may also be suitable for acute conditions where there is an increased need for cGP in the system, such as traumatic brain injury and chronic conditions.

[0116] Example 4 Increased cGP concentration by chemical degradation of collagen / gelatin. The inventors have also found that collagen and gelatin (heated forms of collagen) are rich in the glycine-hydroxyproline amino acid sequence and, unexpectedly, degradation of collagen / gelatin results in the formation of significant amounts of cGP. The main component of the softgel capsules used to encapsulate the blackcurrant concentrate containing cGP is gelatin.

[0117] Preliminary studies have shown that the formation of cGP by gelatin degradation may depend on lower pH and higher temperature. Without being bound by theory, blackcurrant concentrate (a plant-based extract containing cGP for experimental purposes) has a low pH of 2.5, which degrades gelatin and forms cGP, especially in hot environments.

[0118] The inventors have observed an increase in cGP concentration (0.1 ng / mg to 10 ng / mg) in blackcurrant concentrate after it has been encapsulated in softgel capsules. It is a significant discovery that the pH and temperature ranges can increase the cGP levels during storage of the extract, improving efficacy.

[0119] A stability study in which a mixture of blackcurrant concentrate and collagen was stored together at 35° C for 2 weeks increased the cGP concentration to 110 ng / mg compared to 40 ng / mg stored for 2 weeks at 4° C. The laboratory report of this stability study is available.

[0120] Empty softgels (containing no blackcurrant concentrate) or unencapsulated blackcurrant were evaluated separately.

[0121] The total amount of cGP in the softgel alone was 26ng / mg and the blackcurrant concentrate was 0.1ng / mg, giving a total amount of cGP of 7030ng / capsule. However, analysis of the entire capsule (softgel and encapsulated blackcurrant concentrate together) increased the total amount of cGP from 7030ng cGP to 11000ng. Reports from an independent testing laboratory also confirmed this cGP concentration.

[0122] This data suggests that the interaction of blackcurrant concentrate with the gelatin softgels was important to increase cGP from its initial level, and low pH, high temperature and / or other ingredients may have contributed to the active degradation of gelatin in the softgels. Further experimental testing is being conducted.

[0123] It should be understood that the clinical applications of the cyclic glycine-proline (cGP) biomarker for predicting risk of and reversing amelioration of neurological and / or non-neurological conditions having IGF-1 dysfunction, and method aspects relating to the use of cGP-containing animal, marine and / or fungal based materials, such as hydrolyzed bovine and marine collagen, mushroom and seaweed concentrates / extracts, together with cGP encapsulated in softgel capsules, for treating the same, are described by way of example only, and modifications and additions may be made without departing from the scope of the claims herein.

Claims

1. 1. A method of treating a non-neurological and / or neurological condition associated with IGF-1 dysfunction in an animal, comprising: a) obtaining a biological specimen from said animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in said biological sample; c) comparing the measured cGP concentration and / or the molar ratio of the cGP concentration to the measured total amount of IGF-1 in the biological sample with a standard to determine whether the measured cGP concentration and / or the ratio of the cGP concentration to the measured total amount of IGF-1 in a set of results corresponds to the relative standard for estimating IGF-1 function in the individual; and d) administering to said animal a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal based materials: Preventing a decrease in the concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in an animal; and / or maintaining the existing concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in an animal. A method comprising:

2. 1. A method for predicting risk of age-related non-neurological and / or neurological conditions in an animal using cyclic glycine proline (cGP) as a plasma biomarker with altered IGF-1 function, comprising: a) obtaining a biological specimen from said animal; b) measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in said biological sample at a first set age of said animal or at an early stage of said non-neurological and / or neurological condition or prior to treatment of said animal with a therapeutically effective amount of a concentrate / extract of cGP from animal, marine and / or fungal based material; c) re-measuring the concentration of cyclic glycine-proline (cGP) as a plasma biomarker for active concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in said biological sample at further set age intervals of said animal or at further stages of said non-neurological and / or neurological condition or after treatment of said animal with said therapeutically effective amount of a concentrate / extract of cGP from said animal, marine and / or fungal based material; and d) comparing the measured cGP concentration and / or the molar ratio of the measured cGP concentration to the measured total amount of IGF-1 in the biological sample at the set age interval with that at the first set age, or at the early stage of the non-neurological and / or neurological condition having IGF-1 dysfunction, or before the treatment of the animal with the therapeutically effective amount of the concentrate / extract of the cGP from animal, marine and / or fungal based material, to ascertain whether there is a change in the measured cGP concentration and / or the molar ratio of the measured cGP concentration to the measured total amount of IGF-1 in a series of results, thereby determining whether the animal is at increased risk of developing a non-neurological and / or neurological condition from cognitive decline relative to a standard set of baseline data, and using said measured ratios to select an individual patient for cGP treatment and a suitable dosage of cGP treatment in said patient. A method comprising:

3. 1. A method for predicting spontaneous recovery in an animal having a non-neurological and / or neurological condition with impaired IGF-1 function using cyclic glycine-proline (cGP) and the cGP / IGF-1 molar ratio as plasma biomarkers of IGF-1 function, comprising: a) obtaining a biological specimen from said animal; b) measuring the concentration of cyclic glycine-proline (cGP) plasma biomarker and activity concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in said biological sample at baseline in said animal from onset of said non-neurological and / or neurological condition (<72 h in acute conditions); c) re-measuring the concentration of the cyclic glycine-proline (cGP) plasma biomarker and the activity concentration-dependent insulin-like growth factor 1 (IGF-1) bioavailability in said biological samples at further intervals during recovery of said animals; d) assessing the animal's functional recovery from the baseline and at further set intervals. Including, The method wherein the baseline concentration of CGP from a series of data predicts short-term outcome of recovery of a non-neurological and / or neurological condition of the animal, such that the higher the baseline CGP concentration, the more favorable the prognosis for the animal based on the assessment of functional recovery.

4. Preventing a decrease in the concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in an animal; and / or maintaining the existing concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in the animal; and / or Increasing the concentration of cGP and / or the ratio of cGP to total measured IGF-1 in an animal Use of a concentrate / extract of cGP derived from animal, marine and / or fungal based materials in the manufacture of a medicament formulated for the treatment of chronic rheumatoid arthritis.

5. Use of a concentrate / extract of cGP derived from animal, marine and / or fungal based materials in the manufacture of a medicament formulated for oral administration to ameliorate and / or treat the effects of non-neurological and / or neurological conditions in a patient in need thereof.

6. Preventing a decrease in the concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in an animal; and / or Maintaining the existing (normal / physiological) concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in the animal; and / or Increasing or normalizing the concentration of cGP and / or the molar ratio of cGP to total measured IGF-1 in an animal. The present invention relates to a concentrate / extract comprising a therapeutically effective amount of cGP derived from animal, marine and / or fungal based materials, which is formulated to be administered to an animal for the treatment of chronic inflammatory diseases.

7. A method for ameliorating the effects of hypertension and / or stroke; and / or treating hypertension and / or stroke; and / or reducing symptoms associated with hypertension and / or stroke in a patient in need thereof, said method comprising administering a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine and / or fungal based materials.

8. A method for ameliorating and / or treating the effects of Parkinson's disease or symptoms associated with Parkinson's disease, or complications associated with cognitive impairment, in a patient in need thereof, said method comprising administering a therapeutically effective amount of a concentrate / extract of cGP derived from animal, marine and / or fungal based material.

9. 4. The method according to any one of claims 1 to 3, wherein the non-neurological and / or neurological condition or disease is cerebrovascular accident or stroke, mild cognitive impairment (MCI), Alzheimer's disease, vascular dementia, Rett's syndrome, concussion, hypertension and its associated cerebral complications, Parkinson's disease and / or any other ageing-related condition or IGF-1 deficiency-related condition.

10. The method of any one of claims 1 to 3, wherein the administration stops the decrease in cGP levels as a result of the disease or condition.

11. The method of any one of claims 1 to 3, wherein administration increases cGP concentrations by at least 1% relative to those that would be measured in said patient without administration of the cGP extract.

12. The method of any one of claims 1 to 3, wherein the animal is a human.

13. The method of any one of claims 1 to 3, wherein the animal is healthy.

14. The method of any one of claims 1 to 3, wherein the animal has a pre-existing condition or pathology.

15. The method of any one of claims 1 to 3, wherein the standard or baseline is based on a set of data collected for the patient.

16. The method of any one of claims 1 to 3, wherein the standard or baseline is based on a set of data collected on a population.

17. The method of any one of claims 1 to 3, wherein the medicament is formulated for oral administration.

18. The method of any one of claims 1 to 3, wherein the medicament is formulated for parenteral administration.

19. The method of any one of claims 1 to 3, wherein the medicament is formulated as a pill, tablet, capsule, liquid, powder, micronized powder, gel, liquid filled softgel and / or combinations thereof.

20. 20. The method of claim 19, wherein the particle size of the micronized powder is substantially between 1 and 1000 microns.

21. The method of any one of claims 1 to 3, wherein the medicament is administered to provide a therapeutically effective dose of at least 10,000 to 100,000 ng (10 to 100 µg) of concentrated cGP as a daily dose.

22. The method according to any one of claims 1 to 3, wherein there is at least a 25% increase in cGP in the cerebrospinal fluid (CSF) after cGP extract supplementation.

23. 7. The concentrate / extract of any one of claims 4 to 6, wherein the concentrate / extract having a high concentration of cGP is derived from any animal, marine and / or fungal source, including any organism selected from any of bovine, marine and bone collagen sources.

24. The concentrate / extract according to any one of claims 4 to 6, wherein the hydrolysis process of the extract cleaves collagen / gelatin proteins to form linear peptides with hydrolyzed proline-glycine repeat sequences, and cyclization of these linear peptides results in the production of cGP to normalize IGF-1 function.

25. 24. The concentrate / extract of claim 23, wherein the concentrate / extract is hydrolyzed bovine collagen powder, collagen marine skin powder, hydrolyzed fish skin powder and / or bone collagen.

26. 7. The concentrate / extract according to any one of claims 4 to 6, wherein said concentrate / extract is processed and produced using body parts selected from skin, protein, bone, muscle, tendon etc. and / or combinations thereof.

27. 27. The concentrate / extract of claim 26, wherein the concentrate / extract is produced by steeping animal, marine and / or fungal material and then drying to form a concentrated powder which is then micronized.

28. 28. The concentrate / extract of claim 27, wherein the micronized powder is encapsulated in a softgel and / or a hard shell.

29. 7. The extract of any one of claims 4 to 6, wherein the concentrate / extract blend comprises cyclic glycine-proline (cGP) in a concentration providing a daily dose of at least 10,000 ng or more.

30. The concentrate / extract according to any one of claims 4 to 6, which, in combination or separately, is due to the observed in vivo effect on IGF-1 binding and the observed increase in cGP concentration and / or cGP to total IGF-1 ratio.

31. The concentrate / extract according to any one of claims 4 to 6, wherein the concentrate / extract contains other bioactive compounds other than cGP.

32. 7. The concentrate / extract according to any one of claims 4 to 6, wherein collagen and gelatin (heated form of collagen) are rich in glycine-hydroxyproline amino acid sequence and said degradation of collagen / gelatin forms significant amount of cGP.

33. 33. The concentrate / extract of claim 32, wherein the formation of cGP by gelatinolysis is dependent on lower pH and higher temperature.

34. 34. A concentrate / extract as claimed in claim 32 or claim 33, wherein the increase in cGP concentration after capsulisation in a softgel capsule is between 0.1 ng / mg and 10 ng / mg.

35. A concentrate / extract according to any one of claims 32 to 34, wherein the concentrate incubated with collagen at 35°C for 2 weeks increases the cGP concentration from 40 ng / mg to 120 ng / mg.

36. A softgel or hard shell capsule used to encapsulate a cGP extract material for administration of the cGP extract material, thereby increasing the cGP concentration of said extract material contained therein over time.

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