US20070031373A1 - Reversal of Adult Onset Disorders with Granulocyte-Colony Stimulating Factors - Google Patents

Reversal of Adult Onset Disorders with Granulocyte-Colony Stimulating Factors Download PDF

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US20070031373A1
US20070031373A1 US11/462,546 US46254606A US2007031373A1 US 20070031373 A1 US20070031373 A1 US 20070031373A1 US 46254606 A US46254606 A US 46254606A US 2007031373 A1 US2007031373 A1 US 2007031373A1
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granulocyte
colony stimulating
effective dose
disease
stem cells
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Carlos Lopez
James Petell
Fred Siegel
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Priority to US13/316,487 priority patent/US20120082642A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/51—Umbilical cord; Umbilical cord blood; Umbilical stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
    • A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

  • a method for treating adult onset neurodegenerative diseases and diabetes by administering an effective dose of Granulocyte-Colony Stimulating Factors.
  • Parkinson's disease is an example of a progressive neurodegenerative disease. It is usually diagnosed in adulthood, usually when the patient is about 55 years of age, and is characterized by tremors, rigidity, and bradykinesia. It is well understood that many of the abnormalities found in these patients are due to the loss of dopamine (DA) neurons in the substantia nigra and the depletion of striatal dopamine levels. More recently, there has been a re-evaluation of the signs and symptoms found in Parkinson's disease patients that has led to the conclusion that Parkinson's disease is a systemic disease with involvement of peripheral nervous tissue. For example, the loss of the sense of smell has been found to be an early sign of Parkinson's disease that is found in most patients.
  • DA dopamine
  • Parkinson's disease a progressive neurodegenerative disease characterized by Parkinson's disease .
  • This symptom of disease is probably due to loss of neurons in the olfactory bulb of the brain.
  • orthostatic hypotension has been shown to be one of the more common signs of Parkinson's disease, probably due to a direct effect on the peripheral nervous system (PNS) of the host.
  • PNS peripheral nervous system
  • Clinical manifestations of Parkinson's disease are not apparent until over 80% of the central or peripheral neurons have degenerated.
  • Most new Parkinson's disease patients are started on dopamine agonists (DA) when first diagnosed, but usually progress to L-DOPA (L-dopamine), the precursor of dopamine in tissue.
  • DA dopamine agonists
  • L-DOPA L-dopamine
  • L-DOPA is used to relieve Parkinsonian motor signs, but has very little effect on PNS signs and symptoms of disease. In fact, its long-term use is usually associated with diminished efficacy and increasingly bothersome side effects.
  • Other examples of chronic degenerative neurological disorders that might be treated in a similar manner include macular degeneration, urinary incontinence, Alzheimer's disease, Multiple Sclerosis and short term memory deficiency. These disorders have in common three characteristics; they are usually diagnosed late in life, there is evidence of familial, but not Mendelian genetic, inheritance of each disease, and patients will have had a period of time as adults before diagnosis of disease when the host appears to function normally without evidence of signs or symptoms of the chronic disease.
  • GDNF Glial-Derived Neurotrophic Factor
  • Granulocyte-Colony Stimulating Factor in normal volunteers and normal donors, usually at a dose of 5 to 10 micrograms per kg per day for 4 to 8 days. The most common toxicities were bone pain, headaches, and fever. While the toxicities were frequent, the severity was generally mild and very few normal donors had to discontinue Granulocyte-Colony Stimulating Factor because of the side effects. Persons treated with Granulocyte-Colony Stimulating Factor were found to have a surge in peripheral blood stem cells 4 to 7 days after initial treatment. The use of Granulocyte-Colony Stimulating Factor for mobilizing peripheral blood stem cells is widespread and appears to be safe and to be capable of generating the stem cells needed for allogenic or autologous transplantation.
  • Granulocyte-Colony Stimulating Factor is capable of mobilizing peripheral hematopoietic stem cells
  • Granulocyte-Colony Stimulating Factor could induce the recruitment of either local or migration of peripheral stem cells to injured neural tissue, differentiate and restore neural function required for the slowly developing lesions found in most chronic diseases.
  • a “self-repair” system has not been described in human studies.
  • Type 1 Diabetes is a major public health problem in the United States affecting 16 million people and accounts for one sixth of all health related expenditures.
  • Type 2 (formerly referred to as noninsulin-dependent diabetes).
  • Type 1 is characterized by beta cell loss and absolute insulin deficiency.
  • Type 2 diabetics Of the patients with diabetes today, approximately 90 to 95% of the inflicted are Type 2 diabetics. It is generally characterized by elevated fasting blood glucose and lack of sensitivity to insulin and impaired insulin secretion.
  • the prevalence of Type 2 diabetes is about 7 percent for persons between 45 to 64 years of age.
  • the microvascular and macrovascular complications of Type 2 diabetes causes significant morbidity and mortality in affected individuals. Diabetic retinopathy, neuropathy, and nephropathy are major causes of functional limitations and disability in this patient population.
  • diabetics may be treated with one, and typically two, of several oral drugs able to lower blood glucose levels which include sulfonylureas, metformin, alpha-glucosidase, troglitazone, and repaglinide. These agents act on one of four mechanisms that alter renal function, liver metabolism, insulin secretion or breakdown of complex carbohydrates. If these drugs are insufficient, insulin treatment may be prescribed alone or together with these oral agents.
  • Parkinson's disease in humans is a systemic disease with symptoms that indicate the PNS is an important target tissue of this disease.
  • this invention directly demonstrated for the first time in humans the potential action of Granulocyte-Colony Stimulating Factors, known to mobilize stem cells into the peripheral blood as well as to cause them to differentiate as a therapy to reverse symptoms of an adult onset neurodegenerative disorder such as Parkinson's disease.
  • Type 2 diabetes was found to be effectively controlled by periodically administering of Granulocyte-Colony Stimulating Factors offering a new approach and a revolutionary treatment for this disease.
  • Granulocyte-Colony Stimulating Factors offering a new approach and a revolutionary treatment for this disease.
  • the administered patient was provided a long term reversal of disease symptoms allowing a more normal lifestyle, a better efficacy for control, an extended period of control without a daily drug requirement, and the potential for reduced side effects for treatment.
  • the present invention is directed to provide a method of treating symptoms associated with a neurodegenerative disease in a human by administering an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof. More preferably, the invention is directed to provide a method for the reversal of symptoms associated with Parkinson's Disease in a human through periodically administering of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof.
  • the invention herein is directed to provide a method of treating symptoms associated with diabetes in humans by administering an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof. More preferably, the invention is directed to provide a method for the extended reduction of blood glucose levels associated with Type 2 diabetes in a human through administering of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof.
  • one or more symptoms of an adult onset neurodegenerative disease are treated by administering to a human an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof.
  • Adult onset neurodegenerative diseases include but are not limited to Parkinson's Disease, macular degeneration, urinary incontinence, age related short term memory loss, and multiple sclerosis. More preferably, one or more symptoms of adult onset Parkinson's disease are reversed by administering an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof is administered to a human with an adult onset neurodegenerative disease by subcutaneous injection, transdermal patch, intravenously, orally or other means.
  • a typical period for administering Granulocyte-Colony Stimulating Factors is from about 1 to 8 days, preferably ranging 3 to 6 days.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof are administered daily to a human for treatment of an adult onset neurodegenerative disease ranging from 0.1 micrograms to 20000 micrograms per kg body weight per day, preferably between 1 to 20 micrograms per kg body weight per day.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof is administered to a human for treatment of an adult onset neurodegenerative disease for about 1 to 8 days and repeated about every 2 to 18 weeks, and more preferably every 4 to 10 weeks.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof is administered into a human for the reversal of one or more symptoms associated with Parkinson's Disease.
  • Symptoms of Parkinson's Disease may be either central nervous system or peripheral nervous system derived and, include but are not limited to, orthostatic hypotension, resting tremor, rigidity, postural instability, micrographia, urinary and gastrointestinal incontinence and lack of sense of smell.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof is administered into a human with an adult onset neurodegenerative disease in combination with stem cells a selected from a group consisting of harvested umbilical cord stem cells, progenitor stem cells or stem cell lines.
  • stem cells a selected from a group consisting of harvested umbilical cord stem cells, progenitor stem cells or stem cell lines.
  • harvested stem cells, progenitor stem cells or stem cell lines are pre-treated with Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof before injection.
  • the level of blood glucose in an adult onset Type 2 diabetic is reduced by treatment with an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof.
  • the blood glucose levels after treatment remain reduced by 2 days longer, more preferably 1 week or longer and most preferably 4 weeks or longer.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof is administered into a human for treatment of diabetes, and preferably Type 2 diabetes, by subcutaneous injection, transdermal patch, intravenously, orally or other means.
  • a typical period for administering is from about 1 to 8 days, more preferably ranging 3 to 6 days.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof administered into a human for treatment of diabetes ranging from 0.1 micrograms to 20000 micrograms per kg body weight per day, preferably between 1 micrograms to 20 micrograms per kg body weight per day.
  • an effective dose of Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or combinations thereof is administered for treatment of Type 2 diabetes for about 1 to 8 days and the treatment is repeated about every 2 to 18 weeks, and preferably every 4 to 10 weeks.
  • Granulocyte-Colony Stimulating Factors is administered at least one weeks before the blood glucose levels rise to levels prior treatment.
  • Granulocyte-Colony Stimulating Factor or its derivatives is effective in improving other brain associated neural diseases that include but are not limited age related memory impairment, Schizophrenia, and Alzheimer's.
  • Granulocyte-Colony Stimulating Factors means Granulocyte-Colony Stimulating Factor or its derivatives, Granulocyte-Macrophage Colony Stimulating Factor or its derivatives, or other biologically or chemically derived compounds or factors that are functional equivalent.
  • “Maintaining” means slowing, interrupting, arresting or stopping the progression of the disease.
  • Reversing means the improvement of one or more symptoms from the diseased state rather than maintaining the current state of disease.
  • Treatment means maintaining the state of the disease or the reversal of a disease symptom.
  • FIG. 1 demonstrates the long term reversal of Parkinson's Disease symptoms using the United Parkinson's Disease Scale to evaluate the condition of the patient administered with Granulocyte-Colony Stimulating Factor over two and one-half years.
  • FIG. 2 demonstrates the reduction of blood glucose levels below the preferred normal limit after Granulocyte-Colony Stimulating Factor was administered to Type 2 diabetic patient.
  • FIG. 3 shows the average time course for blood glucose levels of six treatments with GCSF.
  • the present invention described herein was aimed at performing treatments using Granulocyte-Colony Stimulating Factors administered to patients with neurodegenerative diseases, more preferably Parkinson's disease, to determine whether Granulocyte-Colony Stimulating Factors were able to maintain the state of the diseases, and preferably reverse the symptoms, either partially or completely.
  • neurodegenerative diseases more preferably Parkinson's disease
  • the treatment of the neurodegenerative disease, Parkinson's Disease, with Granulocyte-Colony Stimulating Factors reversed symptoms of both the central nervous system (CNS) and peripheral nervous system (PNS).
  • CNS central nervous system
  • PNS peripheral nervous system
  • Granulocyte-Colony Stimulating Factors delivered in an effective dose was able to reduce blood sugar levels of patients with adult onset Type 2 diabetes for a significant period of time.
  • GCSF Granulocyte-Colony Stimulating Factor
  • human pluripotent granulocyte colony-stimulating factor as well as chemically synthesized polypeptides sharing its biochemical and immunological properties has been previously disclosed (U.S. Pat. Nos. 6,379,661; 6,004,548; 6,830,705; 5,676,941, 6,027,720; 5,994,518; 5,795,968; 5,214,132; 5,218,092; 6,261,550; 4,810,643; 4,810,321).
  • Granulocyte-Colony Stimulating Factor examples include analogs which retained their three-dimensional structures and hybrid molecules maintaining their biological and structural integrity were described by Osslund (U.S. Pat. No. 6,261,550).
  • functional GCSF variants include any proteins, peptides or fragments thereof that are at least 70%, preferably 80% and most preferably at least 90% identity to full-length human GCSF amino acid sequence or its nucleotide sequence.
  • Modifications of GSCF to improve functionality or resident serum clearance include but are not limited to polyethyleneglycol and polyethyleneglycol derivatives thereof, glycosylated forms (LenogastrimTM) (WO 00/44785), norleucine analogs (U.S. Pat. No.
  • GCSF GCSF and albumin fusion protein (AlbugraninTM) (U.S. Pat No. 6,261,250).
  • GCSF or the drug name Filgrastim, is currently being sold as Neupogen® and its polyethylene glycol modified or pegulated form, with the drug name Pegfilgrastim, sold as NeulastaTM.
  • GMCSF Granulocyte-Macrophage Colony Stimulating Factor
  • Examples of closely related functional forms include Granulocyte-Macrophage Colony Stimulating Factor (GMCSF) whose coding DNA sequence and protein including amino acid sequence are known as well as various methods employed to produce recombinant proteins (U.S. Pat. No. 5,641,663).
  • Examples of functional GMCSF variants include any proteins, peptides or fragments thereof that are at least 70%, preferably 80% and most preferably at least 90% identity to full-length human GMCSF amino acid sequence or its nucleotide sequence.
  • Modifications of GSCF to improve functionality or resident serum clearance include but are not limited to polyethyleneglycol and polyethyleneglycol derivatives thereof, glycosylated forms, norleucine analogs, addition of amino acids at either terminus to improve folding, stability or targeting, and fusion proteins, such as GCSF and albumin fusion protein (AlbugraninTM).
  • fusion proteins such as GCSF and albumin fusion protein (AlbugraninTM).
  • An increase in biological or functional activity over the native peptide may reduce the amount of dose and/or the time period required for treatment.
  • Any chemical or biological entity that functions similar to GMCSF can also be employed. Examples of GMCSF, or the drug name Sargramostim, which are currently being sold, include Leukine® or Leucomax® and Leucotropin®.
  • AMD3100 or derivatives thereof (U.S. Pub. No. 2002/0058653, 2003/0130250, U.S. Pat. No. 6,670,354) effective in enhancing or elevating the populations of progenitor and/or stem cells may be used in conjunction with GSCF or GMCSF derivatives or combinations thereof. Treatments with compounds may be administered at the same time or prior to administration of GSCF or GMCSF.
  • oral dosages, and methods thereof, of Granulocyte-Colony Stimulating Factor have been described by Nomura and Kazutoshi (U.S. Pat. No. 5,597,562) that allow for dosage reductions, facilitate dose control, and increase the practical usefulness of the bioactive proteins.
  • Brimelow and Nanette U.S. Pat. No. 6,497,689 have described preferred pH ranges comprising sulfate ions for stabilizations.
  • Granulocyte-Colony Stimulating Factors has been suggested to act as a neuroprotective agent in vitro and may be used for the potential treatment of diseases that result from oxidative stress or apoptosis such as in cerebral ischemia and traumatic brain injury (U.S. Pub. No. 2004/0141946; 2006/0153799).
  • the work was focused on an in vitro model using STAT proteins and GCSF receptor or rat model for cerebral ischemia. It was suggested that GCSF may be used to “treat” broadly ischemic or hypoxic related diseases as well as neurological, psychiatric and neurodegenerative diseases as neuroprotective agent acting to slow, interrupt, arrest or stop the progression of the disease.
  • the work fails to provide insights on how treatment would work in humans as no human study was performed.
  • Type 2 diabetes is an example of a non-neurological disorder that appears to be due to the lack of insulin sensitivity of the target cells or insufficient levels of insulin in response to blood glucose. Although it is unknown what causes Type 2 diabetes, it is clear that the disease is usually first diagnosed as an adult and is usually progressive (in terms of the need for therapy to control blood sugar). Type 2 diabetics will have had a relatively long period of time with normal blood sugar before the fasting blood sugar levels begin to rise and the disease can be diagnosed. Other non-neurological disorders include osteoarthritis and benign prostate hypertrophy.
  • Granulocyte-Colony Stimulating Factors are likely to enhance or be required in the treatment of neurodegenerative diseases by stem cell therapy.
  • a method for the differentiation of stem cells in culture using Granulocyte-Colony Stimulating Factor and other factors, including lipopolysaccharides, to obtain immune system suppressor cells and immune systems stimulator cells was described by Ogle et al (U.S. Pat. No. 6,165,785).
  • a method is useful in differentiating stem cells that are destined to become replacements for damaged cells in neurodegenerative disease and diabetes.
  • injected stimulated stem cells into patients with adult onset Type 2 diabetes and adult onset neurodegenerative diseases, such as Parkinson's Disease, are able to initiate repair or to enhance the effect over Granulocyte-Colony Stimulating Factors alone.
  • the patients provided these stem are also administered Granulocyte-Colony Stimulating Factors for further benefit.
  • patients with the adult onset diseases are injected with stem cells that are not pretreated with Granulocyte-Colony Stimulating Factors but subsequent treatment and provided with an effective dose of Granulocyte-Colony Stimulating Factors to enhance response.
  • the patient was a 61 year-old male with a six year history of Parkinson's Disease. When first diagnosed two years prior, the patient was started on 100 milligrams Amantidine twice daily and 5 milligrams Selegiline twice daily and on increasing doses of Permax, 25 micrograms to 250 micrograms three times daily.
  • Granulocyte-Colony Stimulating Factor (GCSF) was typical of adult onset Parkinson's disease.
  • the patient had blood work performed 7 days before treatment which included CBC, ESR, urine analysis and chemistry screen.
  • CBC CBC
  • ESR urine analysis and chemistry screen.
  • the male patient approximately 67 kg body weight diagnosed with Parkinson's Disease had history of modest hyperlipidemia which was controlled on medications. Physical exam was normal except for some cogwheeling especially on the right.
  • Granulocyte-Colony Stimulating Factor was started at a daily dose of 330 micrograms (1.1 ml) through injection for 5 consecutive days. Patient experienced slight bone pain on second and third days of therapy.
  • GCSF caused reversal of one or more symptoms of Parkinson's Disease upon treatment with the first dose.
  • the reversed symptoms included orthostatic hypotension, resting tremor, rigidity, postural instability, handwriting and urinary and gastrointestinal incontinence.
  • UPDS Unified Parkinson's Disease Scale
  • UPDS evaluates mostly CNS symptoms of Parkinson's Disease four indicators of PNS symptoms were also evaluated included urinary and gastrointestinal incontinence, orthostatic hypotension and loss of smell.
  • the induction of orthostatic hypotension was evaluated by taking blood pressure before and after going from a lying down position to sitting and then standing position and each time taking blood pressure with an automatic apparatus. A drop of 50 mm was associated with developing lightheadedness and orthostatic hypotension. All four indicators were reversed relative to the state prior to GCSF treatment. In fact, the patient was able to exercise without fainting or having to rest (orthostatic hypotension), enjoyed foods and drinks (smell), resolved urinary and gastrointestinal incontinence, and gained sense of smell resulting in a higher quality of life.
  • Example 2 To examine the long term effect of Granulocyte-Colony Stimulating Factor on a patient with adult onset Type 2 diabetes, the patient in Example 2 was monitored for approximately two and one-half years for fasting blood glucose almost every morning. Starting with the first day of therapy with GCSF, every 5 day period was averaged and the mean used to compare blood glucose levels.
  • FIG. 3 shows the analyzed data from blood sugar determinations around six courses of GCSF. Each time after the GCSF is administered the blood sugar dropped well within the normal range after about twenty to thirty days after the start of therapy. In one case drug was not administered until late in the period of follow-up and then the nadir was reached about twenty-five days after the start of that course.
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US12/401,173 US8084421B2 (en) 2005-08-04 2009-03-10 Method of reducing blood glucose levels in type 2 diabetes patients by administering granulocyte-colony stimulating factor
US13/316,487 US20120082642A1 (en) 2005-08-04 2011-12-10 Reversal of Adult Onset Disorders with Granulocyte-Colony Stimulating Factors

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US7365172B2 (en) * 1999-04-26 2008-04-29 Applied Protein Sciences Llc Loop peptide and TGFα for stimulating stem cell proliferation and migration
US20040136998A1 (en) * 2002-10-30 2004-07-15 Bander Neil H. Methods and compositions for treating or preventing insulin-related disorders using binding agents specific for prostate specific membrane antigen
US20040141946A1 (en) * 2002-12-31 2004-07-22 Axaron Bioscience Ag Methods of treating neurological conditions with hematopoietic growth factors

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WO2013096723A1 (fr) * 2011-12-23 2013-06-27 Saref Technologies, Inc. Procédé pour la pousse des cheveux utilisant un facteur de stimulation des colonies de granulocytes

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US20120082642A1 (en) 2012-04-05

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