WO2013177005A1 - Traitements de syndrome métabolique et de maladie chronique - Google Patents

Traitements de syndrome métabolique et de maladie chronique Download PDF

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WO2013177005A1
WO2013177005A1 PCT/US2013/041734 US2013041734W WO2013177005A1 WO 2013177005 A1 WO2013177005 A1 WO 2013177005A1 US 2013041734 W US2013041734 W US 2013041734W WO 2013177005 A1 WO2013177005 A1 WO 2013177005A1
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patient
insulin
blood
glucose
normal
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PCT/US2013/041734
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Albert Fay Hill
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Albert Fay Hill
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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
    • A61K38/22—Hormones
    • A61K38/28—Insulins

Definitions

  • a treatment is needed that will not just palliate but cure many if not ali of these diseases, a treatment that can be applied after the appearance of the disease, is non-invasive, essentiaify non-toxic, of brief duration, inexpensive, familiar to clinicians, and simple to apply, one whose effectiveness can be easily demonstrated, and that can be quickly made available worldwide.
  • Metabolic Syndrome is found in many disease situations from cancer to cardiovascular disease to cataracts to Parkinson's disease to sepsis and autoimmune disorders.
  • Provided herein is a treatment for metabolic syndrome and its associated diseases based in the inventor's discovery of the relationship between Metabolic Syndrome, chronic inflammation and the immune system cascade.
  • inflammation occurs because, while the body was stiSi fighting or recovering from a prior antigenic challenge, a second infection occurred.
  • the body can only deal with one antigenic challenge at a time.
  • the cytokine and endocrine response to the first challenge is suppressive to the clone(s ⁇ of lymphocytes selected by the second challenge. Only the innate immune system can respond to the second challenge, and it is inadequate.
  • the secondary challenge is from a virulent pathogen, the result can be a fulminant infection, sometimes fatal, if it is a weak pathogen, the result will be a chronic infection, if the secondary challenge is vigorous and happens while the response to the first is moving into the adaptive phase, autoimmunity will occur in the first infection,
  • Chronic inflammations and autoimmune diseases interfere with the adaptive response the body normally makes to antigenic challenges.
  • the result is that a person with either chronic inflammation or autoimmunity is unable to deal effectively with further challenges and will develop stiil more chronic inflammations, autoimmune diseases or be unable to deal with a serious challenge such as H1 1 influenza.
  • immune suppressants can reduce symptoms but not cure the disease.
  • insulin is a powerful stimulant to lymphocytes and can awaken ceils rendered inert by the cytokine/endocrine mix. Selected lymphocytes are activated and secrete cytokines to terminate the innate phase and re-start the adaptive phase. Pathogens are destroyed, tumors eliminated and inflammations disappear,
  • Sepsis, cancer, and other conditions such as chronic diseases and the accompanying metabolic syndrome are due to the failure of the adaptive immune system to activate so as to fully destroy a pathogen or tumor.
  • diseases can be cured by stimulating anergic lymphocytes to activate and perform their normal functions. This is done by an infusion of insulin to maintain blood levels mimicking those occurring during the adaptive immune phase of a primary infection.
  • a method of stimulating adaptive immune cascade activity in a patient in need thereof comprising administering insulin in a pharmaceuticaify acceptable carrier to said patient via continuous intravenous infusion in amounts sufficient to maintain the patient's blood insulin level at about 15 to about 25 ⁇ /mi above their normal fasting pre-treatment level for a period of time sufficient to stimulate adaptive immune cascade activity in said patient,
  • Hormonal mix supporting chronic infection causes insulin resistance, rising levels of insulin, and metabolic syndrome.
  • Anergic lymphocytes are activated, destroy tumor, initiate healing.
  • Patient is in beginning of adaptive response to a first microbial infection.
  • Brain is deceived by shower of innate supporting cytokines from second infection into returning to endocrine support of innate phase, suppression of adaptive. Adaptive response to first infection stops, sinks back into innate phase.
  • lymphocytes specific to antigen are inadequate to dear the body of microbes bu continue to bind to infected cells, release anti-bodies and cytokines to attract innate cells.
  • First infection becomes autoimmune. Lymphocytes support continuing attack by innate ceils.
  • Anergic lymphocytes are activated in autoimmune disease and chronic inflammation, destroy pathogens, downregu!ate innate responses, initiate healing in both.
  • innate cells ⁇ e.g., neutrophils, monocytes ⁇ try vainly to sto first challenge, become harmful to organs.
  • Anergic lymphocytes are activated, destroy pathogens, down -regulate innate response, initiate healing.
  • Figure 1 diagrams mechanisms of chronic inflammation, metabolic syndrome and future antigenic challenges.
  • FIG. 3 diagrams mechanisms of chronic inflammation's interference with immune cascades and its resultant contribution to cancer.
  • FIG. 4 diagrams mechanisms of stalled immune cascades and their effect on autoimmune diseases.
  • a method of stimulating adaptive immune cascade activity in a patient in need thereof comprising administering insulin in a pharmaceutically acceptable carrier to said patient via continuous intravenous infusion in amounts sufficient to maintain the patient's blood insulin level at about 15 to about 25 ⁇ /mi greater than the patient's pre-treatment fasting blood insulin level for a period of time sufficient to stimulate adaptive immune cascade activity in said patient.
  • the patient can be a human or other mammal.
  • Insulin is administered at the rate of between about 0.10 U/kg/hr and about 0.15 U/kg/hr or more to accompfish this result in typical adult humans in need of the present treatment.
  • Administration of insulin can be initiated at about 0.10 U/kg/hr and increased as necessary to achieve the desired insulin b!ood levels.
  • the patient's insulin blood levels are monitored at least about every three to four hours, and the rate of insulin administration adjusted as required to maintain the patient's blood insulin levels within the desired range.
  • the insulin can be regular, human-made, insulin including commercially available brands such as Regular !fetin II ® , Humuiin ® R, and Novolin ® R.
  • the immune response comprises a cascade of phases, an innate immune phase, followed by an adaptive immune phase, followed by a hea!ing phase. Each phase comprises its own cascade of events, all as more fuiiy described below.
  • a patient in need of stimulation of adaptive immune cascade activity is a patient in which the adaptive immune cascade has not been substantially activated, or has stalled and faiied to proceed to heaiing phase.
  • the immune system comprises an innate immune phase, an adaptive (also known as acquired) immune phase, and a heaiing phase.
  • Each phase comprises a cascade of events, i.e., a series molecular, biochemical, and/or physiological processes occurring in a succession of stages each of which is closely related to or depends on the output of the previous stage.
  • the normal progression of an immune cascade can become stalled or inhibited when one or more processes required for norma! activity of the cascade faii to adequately occur.
  • To "stimulate adaptive immune cascade activity" as used herein means to cause the adaptive immune system to normally progress, activating immune cells that eliminate or prevent pathogenic growth.
  • Patients in need of stimulation of adaptive immune cascade activity have an initial blood insulin level less than normal, e.g., about 25 pU/mi or less.
  • the patient's "initial" blood insulin level is defined as the patient's fasting blood insulin level immediately prior to treatment using the methods hereof.
  • Patients generally have a final (after-treatment ⁇ blood insulin level greater than about 25 ⁇ /mi, and in embodiments, e.g., in obese patients, greater than or equal to about 40 ⁇ /mi. or higher.)
  • CD4 cells are T-heSper lymphocytes, which lead the attack against infections.
  • CDS cells are typically cytotoxic T-!ymphocytes, which carry a CDS marker.
  • Normal healthy humans typically have a CD4:CDS ratio of between about 1.5 to about 2 to 1. Lower ratios indicate that the adaptive immune phase is insufficiently active, Higher-than-normal CD4:CD8 ratios indicate that the adaptive immune system is activated. Patients in need of stimulation of adaptive immune cascade activity often have a !ower-than-normal initial CD4:CDS ratio.
  • the “initial” CD4:CDS ratio is the CD4:CD8 ratio prior to administration of insulin in the present methods.
  • some patients in need of stimulation of adaptive immune activity ⁇ e.g., patients with autoimmune diseases such as active lupus and multiple sclerosis ⁇ can have a norma! or slightly higher-than-normal initial CD4:CD8 ratio, such as 2:1, 3:1, 4:1 or 5:1], indicating partially-activated adaptive immune cascades in which further activation is still needed for production of effective cytotoxic T-!ymphocyte activity to ameliorate the patient's condition.
  • Patients having chronic inflammation can have initial CD4:CDS ratios of about 2 to 3 to 1.
  • the methods provided herein are considered to have been successful when the patient has a final CD4:CDS ratio that is both higher than norma! and that is higher than the patient's initial CD4:CDS ratio prior to treatment.
  • the "final" CD4:CD8 ratio is the CD4:CDS ratio after completion of the treatment method hereof.
  • CD4:CDS ratios much higher than normal have been achieved by the methods hereof, e.g., greater than or equal to: about 10:1, about 15:1, about 30: 1, 45:1 and up to 70:1 or higher. The higher the ratio the more activation of the adaptive immune system has been achieved.
  • the patient's final CD4:CD8 ratios are measured at the completion of the insulin administration, and in embodiments the patient's initial CD4:CDS ratios are measured prior to beginning insuiin administration,
  • the patient is not typically considered to be in need of stimulation of adaptive immune activity by the administration of insulin unless the patient's insulin blood levels are less than about 25 ⁇ /ml. In obese patients insulin levels iess than about 30 are considered to indicate need of stimulation of adaptive immune activity by the administration of insulin. In embodiments, prior to beginning administration of insulin the patient's insulin blood level is tested,
  • the method comprises continuous intravenous infusion of insulin, so as to "damp” (maintain) the patient's blood insulin level at about 15 to about 25 pU/rnl above the patient ' s pre-treatment normal blood insulin ievei.
  • the rate of insulin administration can be varied in order to lamp the patient's biood insu!in levels within the desired range.
  • blood insulin ievei refers to the level of insulin measured in a fasting patient's blood or serum.
  • plasma insulin level is used synonymously with the term “biood insulin level.”
  • continuous with respect to the infusion of insulin means that insulin administration is kept up without interruption except for (1] possible brief interruptions if a patient's blood insulin ievei exceeds the desired range, such interruptions lasting onfy long enough for the patient's insulin ievei to return to the desired range; and/or ⁇ 2 ⁇ longer interruptions required if a patient develops a dangerously-high fever, these fonger interruptions lasting only long enough for the patient's fever to return to non-dangerous ieveis.
  • administration of insulin in the present method is not interrupted for the purpose of correcting the patient's blood glucose levels, if the patient's glucose ieveis drop below normal, additional glucose is administered,
  • Maintaining the patient's insuiin ieveis about 15 to about 25 ⁇ /ml above the patient's pre- treatment norma! blood insulin level typically results in the onset of a fever within several hours, e.g., about four to about twelve hours.
  • the method hereof is performed for at least a period of time sufficient to produce a fever and possibly other fiu-Sike symptoms, such as aching muscles and unusuai tiredness, in the patient.
  • a "fever” is a temperature above the normal temperature of the patient. In humans the norma! temperature is considered to be 9S.6 , F, however different individuals may have lower or higher norma! temperatures. Temperatures about 3 , F above the patient's norma! temperature ⁇ e.g., about 101,5 °F to about 102 a F in an aduft human whose normal temperature is about 98,6 °F) are generally considered indicative of a fever.
  • insulin administration can be continued without interruption until the patient's fever returns to normal, and thereafter for at least about four to about eight hours, insulin administration can be performed for a total of about 48 to about 96 hours to ensure that the patient's adaptive immune cascade has been activated, in the event that insulin administration has been interrupted due to a dangerousiy-high fever,, insulin administration is resumed when the patient's temperature drops to nondangerous levels.
  • the insulin administration can be continued until the cumulative time during which insulin administration has been performed reaches about 48 to about 96 hours.
  • the patient's glucose blood levels are periodically monitored, in embodiments by testing glucose blood levels once an hour, while insulin is being administered, Sufficient glucose is administered to maintain norma! blood glucose levels in the patient, e.g., between about 80 mg/d! and about 120 mg/di in humans.
  • Glucose can be administered enterai!y or parenteraily in the form of medical glucose preparations known to the art.
  • Supplementary glucose can also be administered in the form of food such as candy bars and other sugar-containing foods.
  • Glucose is administered in a dosage high enough to maintain normaf to high blood glucose levels but not so high as to cause severe hyperglycemia or diabetic coma.
  • gfucose is maintained at levels slightly above normal, e.g. , more than about 120 mg/di u to typical post-meal levels of about 260, if the patient's renal , liver function and blood sugar levels are norma!, glucose administration can be started with 5% glucose (dextrose) in a physiologically acceptable soiution with minimal sodium.
  • the glucose infusion can be maintained as long as necessary, typically at a rate of about 5 grams per hour per unit of insulin being administered.
  • Glucose is generally continuously administered to avoid hypoglycemia; mild hyperglycemia is not considered harmful.
  • the patient's potassium levels are also periodically monitored, in embodiments, by testing potassium levels in the patient's blood as is known to the art.
  • potassium levels are tested every six hours or less, !f the patient's blood (serum J potassium levels fall below normal, which in humans is about 3,5 to about 5,5 mEq/L (1 mEq/L potassium equals 39 mg/Lj, potassium in a pharmaceutically acceptable carrier is administered enteraliy or parenteraily by methods known to the art to adjust the patient's blood potassium levels to the desired range
  • mild hyperkalemia about 5.1 to about 6.0 mEq/L in humansj is maintained in the patient, as described in US Patent No, 6/143, 717, and administration of potassium is begun when the patient's blood potassium level fails to less than about 5.1 mEq/L Potassium can be administered in an amount of between about 10 mEq and about 300 mEq per 75 kilograms of body weight per day to keep the patient's potassium levels within the desired range,
  • Insulin, potassium and glucose are controlled separately, A single solution containing all three components would make such control difficult. Thus, it is recommended that separate intravenous solutions be administered, e.g. , in a piggyback arrangement as is known to the art.
  • the patient in need of treatment by the present method suffers from metabolic syndrome, a condition known to the art.
  • metabolic syndrome a condition known to the art.
  • the term “suffers from” as used herein carries its ordinary meaning in the art, i.e., that the patient has been diagnosed with the condition; or if the condition is undiagnosed, has symptoms indicative of the condition.
  • the term “metabolic syndrome” is a name for a group of risk factors that occur together and increase the risk for coronary artery disease, stroke,, and type 2 diabetes. Metabolic syndrome is typically characterized by the risk factors of having extra weight around the middle and upper parts of the body (central obesity, sometimes described as an "apple-shaped" body ⁇ , and insulin resistance, in which the body cannot use insuiin effectively.
  • Metabolic Syndrome features insuiin resistance, dyslipidemia, elevated blood glucose, high blood pressure, and frequently obesity, it is associated with a chronic inflammation, autoimmune disease, tumor or a wound that will not heal,
  • Metabolic syndrome may be caused by or accompanied by excess biood clotting and low levels of inflammation throughout the body. Diagnostic criteria differ, but the World Health
  • metabolic syndrome when one of the following: diabetes meifitus, impaired glucose tolerance, impaired fasting glucose and insulin resistance, is present and two of the following criteria are present: blood pressure 140/90 mmHg, dyslipidemia: triglycerides (TG): >1,695 mmol/L and high-density lipoprotein cholesterol (HDL-C) ⁇ 0.9 mmo!/L in a male) and ⁇ 1,0 mmol/L in a female, central obesity with waist:hip ratio > 0,90 in a male and > 0.85 in a female, or body mass index > 30 kg/m2, and microalbuminuria with urinary albumin excretion ratio ⁇ 20 pg/min or albumin reatinine ratio ⁇ 30 mg/g.
  • TG triglycerides
  • HDL-C high-density lipoprotein cholesterol
  • Metabolic syndrome as used herein applies to the condition as diagnosed by any criteria known in the art. Metabolic syndrome is thought to be a precursor to, and present in a wide range of diseases, including type 2 diabetes, cardiovascular disease, stroke, cancer, polycystic ovary syndrome, fatty liver disease, gout, and asthma.
  • Metabolic Syndrome represents an attempt by the body to transfer nutrients from the reservoir of peripheral tissues to those stressed tissues. Insensitivity to insulin causes peripheral tissues to lose amino acids, lipids, glucose and sons into the blood, in time the patient may develop on- Insu!in-Dependent Diabetes Me!iitus. The stressed tissues access the nutrients by means of the growth hormone/IGF- 1 system, In short, where there is a chronic inflammation, autoimmunity, healing wound or cancer, there is metabolic syndrome,
  • Metabolic Syndrome develops most often when a person is challenged by pathogens and selected lymphocytes fail to activate completely and destroy the offending pathogen and, instead becoming anergic.
  • Antigenic competition The most common reason that lymphocytes become anergic is antigenic competition. If a patient is challenged by a new infection while still fighting a previous one, the patient cannot mount a strong acquired defense against the second infection.
  • infection #2 is severe and occurs while the response to infection #1 is moving into the acquired phase, so many cytokines will be released by damaged tissues in the second infection that there will be an interruption in the cascade in the first Infection. Insulin secretion is disrupted; CD4 and CDS ceils do not fully develop while antigen-specific Th-17 cells continue to summon PMNs and monocytes to the area. Levels of SL-2 drop and those of TGF and IL-10 do not rise high enough to stop Th-17 cells. Pathogens survive to continue tissue destruction. The result is autoimmunity in the first infection, chronic inflammation in the second and Metabolic Syndrome.
  • lymphocytes selected by antigen in the chronic infection, autoimmune disease or cancer means the lymphocytes will run their normal course of down-regulating innate ceils, destroying pathogens, transforming into T-regs, and becoming memory cells or becoming apoptotic. Such activation of iymphocytes cannot be achieved with cytokines, whose actions are not fully understood and whose use is dangerous.
  • Chronic inflammation e.g., as a low level of inflammation through the body, is often present in metabolic syndrome and suppresses the adaptive immune system so that these diseases can develop.
  • a high- sensitivity cardiac reactive protein (HSCRP) test which is measured in mg/L (with a range of ⁇ 1.0 mg/L being a low relative risk for "cardiovascular disease events" to >3.0 mg/L being a high relative risk), can identify chronic inflammation.
  • An inflammatory marker test for inter!eukin 6 (!L-6) is also useful with the HSC P test to identify chronic inflammation and can also predict enhanced risk of developing type two diabetes. Testing of CRP, IL-6, tumor necrosis factor (T F) and interSeukin 1 ⁇ (III ⁇ ) and/or InterSeukin 8 ⁇ ILS ⁇ is also used to diagnose chronic inflammation,
  • Chronic inflammation indicates the adaptive immune cascade is not properly activated, and the innate immune system is giving signals to the brain to keep the innate system active and suppress the adaptive immune cascade.
  • Chronic inflammation is associated with allergy (inflammatory cytokines induce autoimmune reactions); Alzheimer's (chronic inflammation destroys brain ceils); anemia (inflammatory cytokines attack erythropoietin production); aortic .
  • valve stenosis chronic inflammation damages heart valves
  • arthritis cells of the innate immune system stimulated by inflammatory cytokines destroy joint cartilage and synovial fluid
  • cancer chronic inflammation suppresses adaptive immunity and permits cancers to develop
  • congestive heart failure chronic inflammation contributes to heart muscle wasting
  • fibromyalgia inflammatory cytokines are elevated
  • fibrosis inflammatory cytokines attack traumatized tissue
  • heart attack chronic inflammation contributes to coronary atherosclerosis ⁇ ; kidney failure (inflammatory cytokines restrict circulation and damage nephrons); lupus (inflammatory cytokines induce an autoimmune attack); pancreatitis inflammatory cytokines induce pancreatic cell injury); psoriasis (inflammatory cytokines induce dermatitis); stroke (chronic inflammation promoted thromboembolic events); and surgical complications (inflammatory cytokines prevent healing), !n all these there is no adaptive immune response to end the pathogenic challenge.
  • the patient in need of treatment by the present method suffers from at least one chronic infection, which is typically a "secondary infection," i.e., an infection by a microorganism ⁇ e.g., virus, bacteria, or fungus) that follows an initial infection by another microorganism.
  • secondary infections are often chronic. Stimulation of adaptive immune cascade activity by the methods hereof allows antibodies and/or T-ceils specific to the microorganisms causing the second infection to be produced so as to resolve the secondary infection,
  • the patient suffers from one or more tumors, or the patient may suffer from a healing wound, e.g., as a result of accidental trauma or surgery, and has subsequently contracted an infection by a microorganism.
  • a healing wound e.g., as a result of accidental trauma or surgery
  • Such patients are typically in the healing phase of the immune response.
  • the adaptive immune cascade is suppressed, and patients are especially susceptible to infection.
  • Tumors which the body- treats like healing wounds, can be shrunk by the methods hereof by stimulation of the adaptive immune cascade to activate tumor-specific immune ceils.
  • Chronic infections are also ameliorated or completely cleared by adaptive immune cell attack on the pathogen causin the infection as a result of the methods described herein.
  • the patient in need of treatment by the present methods suffers from an autoimmune disease.
  • Many autoimmune diseases involve the presence of pathogens.
  • Autoimmune diseases include: Active chronic hepatitis (HYBsAg negative); Acute disseminated encephalomyelitis ⁇ ADEM); Acute hemorrhagic leukoencephalitis ⁇ Hurst's disease); Agammaglobulinemia, primary; Allergic asthma; Allergic asthma; Aiiergic eczema; Aiiergic rhinitis; Alopecia areata; Ankylosing spondylitis'; Anti- GBfvl/anti-TBM disease; Antiphosphoiipid antibody syndrome ⁇ APS ⁇ ; Arteriosclerosis; Atherosclerosis; Autism; Autoimmune Addison's disease; Autoimmune aplastic anemia; Autoimmune atrophic gastritis; Autoimmune dysautonomia; Autoimmune hemolytic anemia; Autoimm
  • Dermatomyositis Oevic's disease ⁇ neuromyelitis optical; Diabetes, type 1; Discoid lupus; Discoid lupus erythematosus; DressSer's syndrome; Eosinophilic fasciitis; Erythema nodosum; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibrosing alveolitis; Food allergies;
  • hemoglobinuria ⁇ PNH Pars planitis ⁇ peripheral uveitis); Parsonnage-Tu rner syndrome; Pemphigoid; Pemphigus vulgaris; Pernicious anemia; Phacogenic uveitis; POEMS syndrome; Polyarteritis nodosa; Polymyalgia rheumatics; Polymyositis; Postmyocardiai infarction syndrome; Postpericardiotomy syndrome; Premature menopause; Primary biliary cirrhosis; Primary myxedema; Progesterone dermatitis; Psoriasis; Psoriatic arthritis; Pulmonary fibrosis, idiopathic; Pure red ceSi aplasia; Pyoderma gangrenosum; Raynaud's disease; Reflex sympathetic dystrophy; Reiter's syndrome; Relapsing polychondritis; Restless leg syndrome; Rheumatic fever; Rheumatoid arthritis
  • a method of stimulating immune cascade activity in a patient in need thereof comprises: determining that said patient's initial blood insulin level is less than about 25 ⁇ /mi, e.g., using commercially available ELISA kits in real time.
  • the method also comprises determining the patient's initial CD4:CD8 ratio, then administering insulin to the patient via continuous intravenous infusion at a rate sufficient to move potassium into the cells, especially, the lymphocytes.
  • a lymphocyte kills another ceil, the lymphocyte loses Its surface charge and injects perforin into the cell it is kiiling.
  • the rate of insuiin infusion herein is typically about 0,10 to about 0.15 U/kg/hr
  • the insulin is administered so as to raise the patient's blood insulin level to about three times norma! levels and stimulate adaptive immune cascade activity in the patient.
  • the method also comprises periodically monitoring the patient's blood insulin, glucose and potassium le els and adjusting said rate of insulin administration to maintain the desired blood insulin level.
  • Glucose is also administered in amounts sufficient to maintain the patient's blood glucose levels within norma! range; and potassium is administered to maintain mild hyperkalemia in the patient as shown by potassium blood levels between about 5,1 to about 6,0 mEq L.
  • Insulin administration can be interrupted in the event said patient develops a dangerously high fever and resumed when the patient's temperature drops to a non-dangerous level. Administration of insulin is continued for at least about four to about eight hours after the patient's fever returns to normal.
  • the method can also include measuring the patient's final CD4:CDS ratio after administration of the insulin, wherein the patient's final CD4:CD8 ratio is both greater than the patient's initial CD4:CDS ratio and greater than or equal to about 3 :1.
  • a system for stimulating adaptive immune cascade activity in a patient in need thereof comprising: (a) insulin in a suitable pharmaceutical carrier for intravenous infusion in an amount sufficient to stimulate adaptive immune cascade activity in said patient when administered to said patient by intravenous infusion over a period of at least about 48 to about 96 hours; (bj at least one biood insulin test apparatus; and ⁇ c ⁇ instructions for administering the insulin for the purpose of stimulating adaptive immune cascade activity in a patient in need thereof.
  • the system can be scaled for a singie patient or can be scaled for a clinic accommodating multiple patients for treatment using the methods hereof.
  • Insulin, glucose and potassium can be supplied in convenient dosage forms in quantities required for performing the method for single patients.
  • Test apparatuses such as test kits, can be packaged for singie patients, or laboratory-sized test equipment can be provided to accommodate a number of patients.
  • Apparatuses for administering insulin intravenously, and for administering glucose and potassium are known to the art and commercially available for each patient to be treated by the systems hereof. Quantities of equipment and pharmaceutical preparations are readily calculated by those skilled in the art to provide for adequate and complete performance of the methods hereof.
  • Blood insulin test apparatuses are known to the art, e.g., the insulin ELISA kit of Dako
  • insulin preparations are available commercially through medical suppliers, as described above.
  • the insulin is provided in standard size ⁇ e.g., 11) intravenous bags. Quantities and convenient packaging for the reagents used in the method are readily calcuiated and procured by those skilled in the art.
  • a total amount of insulin required for a single patient is between about 350 and about 2100 Units, depending on duration of the insuiin infusion and the patient's weight, in embodiments at least about 2100 Units of insuiin per patient is provided. If patients are overweight and require even higher amounts of insulin, the system can comprise such further amounts, as can be readily estimated by one skilled in the art. Analogs of regular insulin having the effects described herein for regular insulin can also be used in the methods hereof.
  • Apparatuses for administering insulin via continuous intravenous infusion are also known to the art and commercially available through medical equipment suppliers. Standard intravenous drip apparatuses can be used, e.g, the Alans UK Ltd. intravenous infusion pump.
  • the system provided herein can also comprise at least one blood glucose test apparatus (glucose monitor).
  • glucose monitors are widely commercially available, e.g., the One Touch 3 glucose monitors of LifeScan, Inc., Wayne, PA.
  • the system can a!so comprise pharmaceutical acceptable glucose suitable for enteral administration, such as candy, or for parenteral administration, inducting intravenous administration, in an amount sufficient to maintain the patient's biood glucose at norma! ieveis during administration of said insuiin over a period of at least about 48 to about 96 hours.
  • glucose is widely commercial iy available, e.g., Hospira 5% dextrose solution, Hospira, !nc, ; Lake Forest, !L.
  • the glucose is provided in an amount sufficient to maintain the patient's blood glucose at normal levels during administration of said insulin over a period of at least about 48 to about 96 hours,
  • a totai amount of glucose required for a single patient is between about 150 and about 6000 g, depending on duration of the insulin infusion and the patient's weight.
  • at !east about 6000 g of glucose per patient is provided, if patients are overweight and require even higher amounts of glucose, the system can comprise such further amounts, as can be readily estimated by one skilled in the art.
  • Apparatuses for administration of glucose are known to the art and widely commercially available, and include standard intravenous infusion equipment.
  • glucose administration can be done via piggyback components attached to the insulin infusion equipment.
  • Apparatuses for administering glucose are known to the art.
  • administration of potassium can be piggybacked onto the insulin infusion apparatus using standard intravenous components.
  • the system hereof can afso comprise at least one blood potassium level test
  • Blood potassium test apparatuses are known to the art, e.g., Medica Corporation's EasyElectrolytes test device or the Quantofix ® potassium test kit of Sigma-Aldrich. St, Louis, MO.
  • the system can also include pharmaceutically acceptable potassium preparations providing potassium in an amount sufficient to maintain the patient's biood potassium at normal levels during administration of said insuiin over a period of at least about 48 hours.
  • Potassium is provided for each patient in an amount sufficient to maintain the patient's blood potassium at normal (3.5 mEq/L to 5,0 mEq/L ⁇ to mifdly hyperka!emic levels (5.1 mEq/mf to 6.1 mEq/m! ⁇ during the administration of the potassium over a period of at least about 48 to 96 hours.
  • a total amount of potassium required for a singie patient is between about 120 and about 200 mEq, depending on duration of the insulin infusion and the patient's weight.
  • At least about 2000 mEq of potassum per patient is provided. If patients are overweight and require even higher amounts of potassium, the system can comprise such further amounts, as can be readily estimated by one skilled in the art.
  • the potassium can be provided in a suitable pharmaceutical carrier in standard dosage forms including intravenous dosage forms.
  • Apparatuses for administering potassium are widely known and commercially available.
  • administration of potassium can be piggybacked onto the insulin infusion apparatus using standard intravenous components.
  • the system hereof can also comprise at least one thermometer for taking the patient's temperature.
  • the system hereof can further comprise at least one CD4:CDS ratio test apparatus.
  • test apparatuses are known to the art and commercially available, e.g., flow eytometers from Partec GmbH of Munster, Germany, Becton Dickinson of California, Coulter Corporation, Florida, Guava Technologies, California.
  • metabolic syndrome is used to herein to denote any of the conditions known to the art and listed herein as being associated with metabolic syndrome.
  • metabolic syndrome is usually the result of a chronic inflammation [Jackson, Michael J. et aL] .
  • lymphocytes present the pathogen's antigen in conjunction with the host's major histocompatibility complex (fvlHC) for recognition by lymphocytes [Bogen], Once activated by antigens, lymphocytes begin a rapid process of proliferation and differentiation. Differentiating lymphocytes express receptors for insulin-like growth factor (IGF-1), which contributes to their maturation. lnterleukin-17 (11-17 ⁇ is secreted by T-helper-17 ⁇ Th-17 ⁇ cells and promotes neutrophil maturation and chemotaxis [Louten et a!. ⁇ .
  • IGF-1 insulin-like growth factor
  • these cells constitute a link between T-eeil activity and the accumulation of neutrophils locally in organs [Sergejeva and Linden]; !L-27 also has an effect on ceils of the monocyte lineage, which can play a significant role in pathogenic conditions [Sergejeva and Linden], Since they are lymphocytes that bind specifically to antigen, Th-17 cells serve as sentinels, releasing chemokines to attract cells of the innate system and cytokines to notify the brain what kind of challenge it is f acing in an infection and what kind of response is needed: basophil, neutrophil, eosinophil and/or monocyte.
  • St has long been noted that cells of the innate immune system have a regulatory role in the developing adaptive immune phase [Fearon and Locksley], But it has not so commonly been recognized that by the secretion of cytokines, newly-selected lymphocytes exert n early and powerful control over the innate immune system from the beginning of the cascade, lnterleukin-1 (IL-l), interfeukin-6 (!L-6) and Tumor Necrosis Factor alpha ⁇ TNFct ⁇ are secreted by lymphocytes and antigen-presenting cells SAPCs; [Hirsc and Kroemerl and contribute to chemotaxis and activity of polymorphonuclear leukocytes.
  • IL-1 lnterleukin-1
  • !L-6 interfeukin-6
  • Tumor Necrosis Factor alpha ⁇ TNFct ⁇ are secreted by lymphocytes and antigen-presenting cells SAPCs; [Hirsc and Kroemerl and contribute to chemotaxis and activity
  • cytokines are also swept through the body to various organs, including the liver and brain [DinareSlo and oidawer, p.17], interferon gamma (INFy) is secreted by lymphocytes and other cells and increases the antigenicity of host tissues [Shah et al.], preparing them for an attack by cytotoxi T-ceSis (CTLs ⁇ .
  • CTLs ⁇ cytotoxi T-ceSis
  • Th-17 cells develop more quickly than Th-1 and Th-2 ceils, and summon monocytes and PMNs to the scene. But as Th-1 and Th-2 cells multiply, they release IL-2 which stimulates the growth of other T helper cells and cytotoxic T lymphocytes (CTLS). As the proliferation advances, they come to outnumber Th-17 ceils and inactivate, kiil or transform them into iTreg ceSis. As IL-2 increases, numbers of Th-17 cells [Ad!er] and PMNs decline, and monocytes transform into macrophages.
  • CTL-2 cytotoxic T lymphocytes
  • TGFp insulin-like Growth Factor- 1 ⁇ IGF-2 ⁇ supports maturation of developing lymphocytes [Johnson], but in the healing phase participates in the downregulation of adaptive immunity, !n these events, enormous energy and utilization of materials are required. That is achieved by changes in the endocrine profile,
  • Cytokines secreted by APCs and lymphocytes and damaged tissues induce an endocrine response including rising levels of Cortisol [Hirsch and Kroemer, lO ff], glucagon, catecholami es and growth hormone [Dinarelio and Moidawer; Berczi and Nagy, p. 100],
  • This endocrine mix causes insulin resistance and catabo!ism in peripheral tissues. They release ions, lipids, glucose and amino acids into the metabolic pool from which they can be acquired by proliferating cells of the [Beisei],
  • the endocrine system supports the function of the innate immune cells and the expansion of lymphocyte clones.
  • this endocrine profile is immunosuppressive, exerting multiple inhibitory effects at the levels of both APCs and T cells [Hirsch and Kroemer, p, 3], However, since the antigen-selected clones of lymphocytes had already been activated before the mix developed, those clones (T helpers 1 and 2 (Th-1 and Th-2), Cytotoxic T Lymphocytes (CTLs) and B cells ⁇ are not suppressed but continue their proliferation and maturation, permitting the development of the adaptive immune phase,
  • the second part of the cascade is the adaptive (acquired) immune phase. It features the efficient attack on the pathogen by lymphocytes specific to that pathogen. While lymphocytes proliferate and mature during the innate immune phase, the adaptive immune phase may be defined as the period during which lymphocytes become the predominant immune cells and act to clear pathogens from the body. Receptors for IGF-2 vanish and do not reappear for 48 hours [Segretin, ef al. ⁇ . T helper 1 cells release into the environment cytokines ⁇ e.g. lnterieukin-2, IL-12J that activate selected CTLs to eliminate host ceils that have been invaded by pathogens. T-he!per 2 cells secrete cytokines (IL4, !L-5) to activate B ceils. They transform into plasma ceils and release antibodies that bind to pathogens, making it easier for macrophages to engu!f and destroy them,
  • cytokines e.g., Snterieukin-10 (11-20) and interieukin-2 ⁇ IL-2 ⁇ , released by helper T-ee!is also powerfully downregufate the innate immune response [Shah ef ai. p, 289], thus preventing further damage to the host [Dinarelio and Moida er], Levels of SL-1 and TNFa decline and inflammation recedes as lymphocytes swiftly destroy infected cells and circulating microorganisms.
  • IL-2 released by Th-1 CD4+ cells to activate CTLs has a suppressive effect on Th-17 ceils. Reduced levels of iL-17 slow the appearance of neutrophils and monocytes [Hammerich, ef ai. ⁇ .
  • insulin receptors appear on proliferating lymphocytesfKrug et a!.; Helderman and Strom, 1977; Brown et at.; Berczi and agy p, 72], While naive lymphocytes have few detectable receptors for insulin, once activated they produce 6000 [Helderman and Strom, 197S].
  • the endocrine mix of the adaptive immune phase supports the full activation of antigen-selected and cytokine- stimuiated lym hocytes.
  • the selected c!one(s) are able to acquire from the metabolic poo! the nutrients they need to proliferate and perform their function of eliminating targeted antigens.
  • the rising levels of insulin and the cytokines released by lymphocytes also stimulate macrophages and natural killer ⁇ MK ⁇ cells to act aggressively [Costa Rosa, et al], but are anti-inflammatory.
  • the endocrine profile in this second phase is also immunosuppressive.
  • Glucocorticoids continue to be high, suppressing proliferation of clones stimulated by any secondary infection, it is believed that lucocorticoids working synergisticaily with cytokines are mostly responsible for the immunosuppression.
  • insulin is high ⁇ >40 ⁇ .tU/ml ⁇ when a new cascade begins, it can add to the suppression of newly stimulated T lymphocytes [fV!ito, N. et a!.; offler], This contributes to Antigenic Competition which will be discussed later.
  • Cells of the adaptive immune phase are elegantly specific and highly efficient killers as well as potent regulators of the immune cascade. But they are also more vulnerable to negative interference than cells of the innate immune phase. They In order to function properly, they must ⁇ 1 ⁇ bind tightly to antigen presented in the fv HC, ⁇ 2) receive stimulation from cytokine(s), and ⁇ 3 ⁇ be stimulated by insulin, Lack of any one of these will cause functional inactivation [Rudd
  • the third, healing phase features deletion of lymphocytes that could cause autoimmunity, transformation of some activated lymphocytes into memory ceils, and restoration of damaged or destroyed tissue, Natural T-regu!atory cells (nT-regsj from the spleen appear in the circulation, causing apoptosis of armed lymphocytes.
  • Some CD4+ Th-1 cells transform into induced T-regs (iT-regs) and join in the suppression of activated lymphocytes [Chen and Oppenheim].
  • TGF- ⁇ 5 ⁇ potently anti-immuneJYansforming Growth Factor- ⁇
  • CDS cells also participate in the suppression of immunity, but their action is still not well understood Nelson].
  • the endocrine mix changes a third time. Insulin sinks to normal or even lower levels while counter-regulatory hormones and glucocorticoids continue to produce insulin resistance in peripheral tissues. The fiver and other tissues produce high levels of Insulin-like Growth Factor- i f IGF-1). Dividing ceils of damaged tissues produce receptors for this hormone and are therefore able to access the nutrients.
  • the endocrine mix is immunosuppressive and catafooiic, or at least anti- anabolic, and stimulates insulin resistance
  • the effect is to preserve nutrients for repair of the wound and deny them to immune ceils, thereby further downregu- fating the immune response.
  • Physiological concentrations of !GF-1 have a profoundly suppressive effect on fyrrtphocytes[Himt and Eardley].
  • IGF-1 causes systemic production of Transforming Growth Factor-p " fTGFp) to increase substantial !y.
  • Insulin rises in the adaptive immune phase for onfy two to three days, to a tightly controlled level ⁇ 30 ⁇ 5 ⁇ /mi) [Rayfiefd, et a!. ⁇ in the blood and exerts its effects only on lymphocytes already antigen-selected and cytokine-stimuiated. Insulin below this level fails to stimulate lymphocytes and above 40 ⁇ /mi becomes suppressive [Hunt and Eardley]. [0086] Even after so brief a description of the three endocrine mixes secreted during an immune cascade, it can be seen that hormones have a powerful effect on immunity.
  • lymphocytes selected to meet the second challenge cannot activate because of the immunosuppressive endocrine mix.
  • the response to infection #1 will usually continue, with selected lymphocytes for infection #1 activating and efficiently destroying the invading pathogens, although healing may be delayed.
  • the endocrine mix from infection #1 is so suppressive that lymphocytes selected by Infection #2 cannot fully activate.
  • Cortisol wilf be immunosuppressive to lymphocytes of infection #2 [Roitt, p. 169].
  • Infection #1 Even after Infection #1 has fully resolved, the brain is still receiving messages from damaged tissues of Infection #2 that the body is host to an infection, it continues to support the innate immune phase with the endocrine mix described above for the innate phase, featuring glucocorticoids, glucagon, growth hormone, catecholamines and low insulin and thyroid. That is the endocrine mix that characterizes metabolic syndrome.
  • insulin levels will rise as the body tries to deal with hyperglycemia. Lymphocytes are not activated by the slow rise of insulin levels as they respond to this slow rise of insu- iin by producing fewer insulin receptors [ offler (2991)3, in some cases, the chronic inflammation will resolve ove time. In others, such as periodontal disease, sinusitis, irritable bowel syndrome, chronic fatigue syndrome, and neuropathies [Oldstone, p. ix], it may continue for years.
  • Healthy young persons can also be victims of inappropriate inflammations. For example, if a young adult is fighting one infection and is exposed to H1N1 influenza, he will be unable to deal effectively with the flu. The virus will multiply, sometimes with fatal results. Or if the f!u was Infection #1, and another infection was secondary, the latter can become virulent or chronic, depending on the kind of microorganism involved.
  • Autoinfiammatory and autoimmune diseases are different. Autoimmune diseases are transferable to a healthy animal by transplanting T-ce!Ss or antibodies from a sick animal [Kodama; Koarada; George],
  • autoinfiammatory disease is the result of the immune cascade being stalled in the Innate Phase and unable to enter the Adaptive Phase as seen in Infection #2 of antigenic competition. There are no lymphocytes present to restrain the innate response or to destroy remaining pathogens. Autoimmunity is defined as the cascade being stalled in the Adaptive Phase and unable to enter the Healing Phase, The question is how to move both cascades ahead in the normal way, ending with the appearance of T-regs.
  • oitt et ai state that "the erosion of cartilage and bone in rheumatoid arthritis is mediated by macrophages and fibroblasts, which become stimulated by cytokines from activated T-ceSis and immune complexes generated by a vigorous immunological reaction within the synovial tissue . . . . ' * and go on to say that "it is difficult to identify a role for the T-cei! as a pathogenic agent as distinct from a T-helper function in the organ specific disorder.” [Roitt].
  • mice which also lack CD-8T-celis stifl develop colitis even with accelerated kinetics [Nelson], As Dinarello and Moldawer have said, "[Tjhere is now growing recognition that persistent activation of the innate immune system occurs in a variety of autoimmune diseases including rheumatoid arthritis. This prolonged activation leads to the conditional complaints, metabolic abnormalities, and destruction and remodeling of tissues experienced by patients with chronic and uncontrolled progressive disease.” [Dinarello and Moldawer p, 16], So, if the second infection is significant and occurs at an inopportune time, it can disrupt the normal response to the first infection, causing it to degenerate into a chronic, autoimmune reaction,
  • T helper ceils will reactivate, and secrete !L-2 and other lymprtokines to downregulate the innate attack, stimulate lymphocytes to destroy pathogens and produce T-regs to shut down the entire immune reaction and let healing proceed.
  • the method provided herein to terminate a harmful infection that develops during recovery from a wound is to enlist the assistance of lymphocytes that have been rendered anergic by lack of insulin stimulation. This can be done by infusion of insulin during and after surgery, providing exogenously the materials needed by the lymphocytes while the body devotes endogenous resources to healing.
  • lymphocytes are cbemotacttcally attracted to a tumor and infiltrate it. But then the high levels of TGFp produced by the tumor transform some T-celis into T-regs and cause anergy in the others. But when the energy of selected clones is overcome and the adaptive system is restarted, a povverfu! immune response will quickly destroy the tumor.
  • the treatment disclosed herein can rouse such inert,, anergic lymphocytes.
  • the present investigator developed the model of immunity disciosed herein while working in the fie!d of oncology. Seeking the reason the immune system did not destroy tumors, he noted that the endocrine and metabolic environment of the body during an infection was different from that during recovery from a wound. In addition, the endocrine mi when the patient is host to a tumor is identical to that when the patient is recovering from an infection, injury or surgery. He concluded that the brain was "deceived” by growth factors produced by the tumor into "thinking" there was a wound to heal, and the brain therefore commanded the hormonal mix that caused peripheral tissues to be cannibalized of nutrients which were provided to the tumor/wound [Homburger].
  • a chronic inflammation means the immune cascade is stuck in the innate phase and cannot enter the adaptive phase
  • an autoimmune disease means the cascade is stuck in the adaptive phase
  • a tumor means the cascade is stuck in the healing phase, producing another version of metabolic syndrome.
  • Sepsis occurs when the body cannot produce a robust adaptive response to a potent microbial challenge. Most commonly, it happens when the body is in the recovery mode, as after surgery, when immune suppression is greatest.
  • the endocrine mix is powerfully immunosuppressive because the body is devoting metabolic resources to healing. Insulin is low.
  • DCs dendritic cells
  • macrophages are phagocytosed by dendritic cells (DCs) and macrophages and presented to selected lymphocytes, which bind poorly, and begin inadequate differentiation and proliferation [Louten, Sergejeva].
  • IGF-1 ordinarily secreted in high amounts during healing phase, falls as SL-1, TNFa, fFN, TGFp and IL-6 levels rise.
  • !L-6 even rises as high as 7,500 times normal. This mix of cytokines produces greater numbers of Th-17 cells which secrete !L-17, summoning ever more PMNs and monocytes. Since lymphocytes specific to the pathogen are anergic and release no 11-2 and 11-10, T-regs do not develop. Without that restraint the innate system goes wild.
  • irnmunoenhancement is an effective treatment. Insulin will provide anergic lymphocytes the stimulus they need to attack the pathogens and release 11-10 and il-2 to restrain the innate phase. CTLs will attack infected cells and plasma cells will release antibodies to bind to humoral pathogens, insulin also stimulates phagocytosis by macrophages fWeeker]. Obesity
  • the body can mount only one adaptive response at a time, it must be remembered that when a person is vaccinated the body goes through a full blown immune response, from the innate phase through the adaptive phase and even into recover/.
  • the antigen must be phagocy- tosed by dendritic cells, and presented to lymphocytes. T and B cells must perform their work and then become memory cells or undergo apoptosis.
  • a vaccination is not as challenging as the response to an infection, but it still leaves the patient vulnerable to a new pathogen. As we have seen above, the result will vary with the pathogen. But the person who becomes victim to an infection while the body is dealing with the vaccination will be left with a chronic inflammation or autoimmune disease.
  • the chronic disease can be effectively dealt with by restarting the immune process, as described in the treatment section be!ow.
  • the problem can be avoided if it is recognized that during the period folio - ing a vaccination the patient is vulnerable to infections. Children should not be permitted to go to school or play with others for a few days. Adults should not go to work or be in a crowd.
  • Metabolic syndrome is a neuroendocrine response that is not only immunosuppressive but also has its own harmful side effects such as Cushing-!ike hypercortisoiism [Anagnostis], Such diseases can be cured by stimulating anergic lymphocytes to activate and perform their normal functions of downregulating the action of polymorphonuclear ieukocytes and monocytes, destroying pathogens and then promoting healing. . This is done by an infusion of insulin to maintain biood levels mimicking those occurring during the adaptive phase of the immune response to a primary infection.
  • a naive, i.e., unseiected, lymphocyte can sense that the level of insulin is too high and, when stimulated by antigen, reduce the number of receptors it will present in order to protect against overstimulation. Lymphocytes must learn to do this because insulin levels are subject to many spikes, as after meals. If the rise in the hormone is acute the newly-selected cells produce so few receptors they cannot activate and perform their killing. But If the rise has been chronic, the lymphocytes have had time to adjust, present the appropriate number of receptors, and mount a defense against antigenic challenges. Thus, obese patients or others with a form of metabolic syndrome can still mount at least a weak adaptive response to a new antigenic challenge. The response is strong enough to preserve life in most infectious challenges but may leave the patient with another chronic inflammation. The response is not normal because, as explained previously, metabolic syndrome causes production of an immunosu pressive mix of cytokines and hormones.
  • anergic lymphocytes cannot activate. However, no surge of Cortisol accompanies the additional increment of insulin infused in this treatment. Lymphocytes that have downregu!ated the number of receptors they present can respond to the signal, activate, attack the pathogen causing the chroni inflammation, release cytokines to downregu!ate the harmful innate response, and carry forward the cascade into the healing phase.
  • the treatment for those with pre-existing hyperinsuiinemia is the same as for cancer patients who have hypoinsuiinemia.
  • insulin, potassium and glucose are administered intravenously, with insulin maintained at about 15 to about 25 ⁇ /m! above the patients normal pre- treatment fasting blood insulin level for about 24 to about 48 hours or longer, e.g., about 96 hours, to be maximally effective, if insulin is not administered by infusion, the liver will be able to counter what is being done by extracting and dismantling the insulin. Usually insulin is administered at this level will bring blood insulin to the target level. The same dose will increase plasma levels of insulin by 15- 25 iU/m! in obese subjects and activate anergic lymphocytes.
  • Glucose and potassium can be adjusted to avoid hypokalemia and hypoglycemia.
  • individuals vary in their sensitivities to insulin and the physician may have to make adjustments in the dose being infused; but the amount recommended here, when infused, has been shown to move potassium from plasma into the ceils. This enables the enzymatic reactions necessar for final activation. The same dose raises insulin by the same increment in patients suffering from hypennsuiinemia,
  • glucose administration should be increased, if a patient's potassium blood level fails below about 4 mEq/L, the dose being administered must be increased to bring the level to at least about 5 mEq/L, and in embodiments at least about 6 mEq/L
  • insulin infused at about 0,1 U/kg/hr will bring blood insulin levels to the target level.
  • a rule of thumb is to administer about 5 grams of glucose per unit of insulin being infused.
  • insulin can be increased to 0,15 U/kg/hr. insulin levels can be checked before breakfast lunch and dinner. Glucose can be checked every one to two hours. If the patient becomes hypoglycemic, glucose administration is increased; but the insulin dose is not altered. The patient will become feverish and develop mild flu-like symptoms. This is a sign that the immune cascade has re-started. Of course, in case of septic patients, they will al eady be febrile since the body is in the innate phase of the immune response. However, their insulin level will be low and this treatment will move them from the innate to the adaptive phase.
  • a fever is a sign that the immune response has begun, if the fever should rise to a dangerous SeveS, it is because the tumor is being destroyed and the patient's liver cannot extract and destroy the toxins rapidly enough. Treatment is suspended until the fever has declined, then resumed.
  • the method should be supervised by an internist skilled administering insulin or an experienced endocrinologist.
  • Insulin plasma levels to be maintained during insulin infusion should be high enough to stimulate the adaptive immune system but not so high as to interfere with lymphocyte functionality, in gen- era! blood insulin levels insulin levels 15-25 mU/mi above the patient's norma! pre -treatment insulin !eve!s should be maintained during the treatment.
  • the treatment method is to administer insulin at 0,1 U/kg/hr, which can be increased to 0.15 U/kg/hr if no fever develops within 12 hours, for a period of 48 to 96 hours in order to raise and maintain the patient's p!asma insulin levels 15-25 ⁇ /mi above the patient's normal pre- treatment plasma insulin level.
  • Patients who develop an infection after receiving a vaccination which turns into a chronic inflammatory condition are among those who will benefit from receiving the treatment as soon as possible.
  • patients who wish to receive a vaccination such as many e!deriy patients, who already have an infection or chronic inflammatory condition should be treated by the method hereof before receiving the vaccination.
  • Patients who should not be treated by this method are patients with acute infectious diseases and fasting p!asma insulin levels of 25 pU/mS or more and less than about 40 ⁇ /mi. Such insulin levels indicate the patient is probably already mounting a norma! adaptive immune response and the treatment could incapacitate the lymphocytes involved in this norma! response. However, if the patient also has a history, or strong signs of metabolic syndrome, and fasting insu!in levels of about 35 or greater ⁇ /ml, then the patient can benefit from the treatment method hereof.
  • Persons who should not be treated by these methods include those who have received a transplant; persons with advanced brain tumors that are like!y to swell; persons with unduly large tumor burdens as tumor disintegration might produce dangerously high !eve!s of toxins; persons with kidneys unable to process the fluids; persons with insulin a!!ergy; and persons with fasting insu!in !eveis at or above target !eve!,
  • Example 1 Need for continuous insulin infusion [00137] FDA and i B permissions were received for human tests. Volunteer patients protested against hospitalization, and it was reluctantly agreed to let them be treated as out-patients. They received one shot of long-lasting insulin in the morning and g!ucose and potassium pills to take during the day. They all responded with flu-like symptoms and a rise in the CD4/CD8 ratio from sub-normal to as high as 71/1. Analysis of the data showed that only occasionally for short periods did insulin levels in the biood rise to targeted levels. A patient would be given a certain dose of insulin one morning and his biood ievei would rise to 24. The next day after receiving the same dose, his b!ood level would drop to 12. It was hypothesized that the body was resisting our treatment, trying to hold levels at the lower-than- normaf levels common for cancer patients.
  • This example indicates that intravenous infusion of the cocktail of glucose, insulin and potassium 24 hours a day ensured effective treatment. Insulin infusion for at feast about 24 hours, and up to about 48 to about 96 hours or more can be required depending on the patient's response.
  • [00140] infusion is begun at 8:00 am of insulin at 0.1 U/kg/hr (4.5 U/hr), glucose at 22 g hr, and potassium at 2 mEq/hr. She sleeps most of the morning but is awakened at 12:00 pm for lunch. She feels feverish and says she hopes she does not have the flu. It is explained to her that it is more likely that the immune system is actively attacking her tumors. She nods stoically. Her temperature at 2:00 pm is 100.5 C 'F, She sleeps most of the afternoon, awakens at 4:30 pm complaining that she is "burning up," aches ail over, particularly in the upper legs, and is finding it harder to breathe.
  • Pre-prandial tests show insulin at 32 ⁇ /mi, glucose at 135 mg di, and potassium at 5.6 mEq/L.
  • the tumors on her mastectomy scar are swollen and tender and she agrees to aspiration.
  • Microscopic examination shows them filled with a clear liquid and many lymphocytes and macrophages. She watches television with her husband and falls asieep by 9:00 pm. She awakens at 4:00 am when more biood is drawn and says she is very hot. Her temperature is 102 °F, Her gown is sweaty,
  • Her temperature is 100.2 °F.
  • Her temperature has fallen to 99.5 °F and her breathing has improved.
  • Her CD4/CD8 ratio is 42/1 and her b!ood insu!in is 30 ⁇ /mi.
  • a 23-year-oid white man presents with Type I Diabetes ten weeks after a bout with coxsackie B4 virus. He is admitted to the hospitai for treatment. Tests show 10-20% of his beta cells remain. Fasting insulin level is 3 ⁇ /rni, glucose is 215 mg di and K+ and temperature are normal His CD4/CDS ratio is 4/1.
  • Treatment is begun at S:00 am. Regular insulin is infused at 0.1 U/kg hr, glucose at 2 grams per hour and potassium at 2 mEq per hour. He walks up and down the hallway, pushing his pumps ahead of him, then watches TV. At 12:00 pm, his insulin is 25 ⁇ /mi, K+ normal and glucose 250 mg/d!.
  • Administered glucose is reduced to 1 gram per hour. His temperature is 99.2 °F. He eats a normal funch. At 4:00 pm he complains that he feels hot and sick. His temperature is 101.2 °F. At 6:00 pm, insulin is 30 ⁇ /mi, glucose 142 mg di, his temperature is 101,5 °F and his CD4/CDS ratio is 14/1. He has no appetite but accepts some soup, reads, watches TV, and sleeps.
  • Tests prior to treatment show normal temperature, fasting insulin level of 6 ?U/ml, glucose of 115 mg/di, and normal potassium. His CD4/CDS ratio is 3/1.
  • a catheter is inserted in his left arm and treatment begun at 8:00 am. He receives 0.1 U/kg regular insulin, 2 mEq + and 2 grams of glucose per hour. At noon he is found to have a giucose level of 75 rng/dl, his glucose is raised to 4 grams per hour and he is urged to eat a candy bar. There are no side effects. He eats a light lunch at 1:00, fed by his wife, watches TV, then dozes for an hour.
  • Pre-dinner insulin fevel at 6:00 pm is 26 ?U/ml, g!ucose 116 mg dl, normal K+ and temperature 99.9 oF. He eats a normal dinner, watches TV, visits with wife, daughter and grandchiidren, complains that he feeis hot and that his tremor is worse,
  • Dendritic cells and resident macrophages phagocytose pathogens.
  • Dendritic cells macrophages present antigen combined with Major Histocompatibility Complex (MHC), secrete il-l, il-6, !L-S. IL-23, il-15, tumor necrosis factor, ehemokines.
  • MHC Major Histocompatibility Complex
  • CD4 lymphocytes bind to antigen presented by antigen presenting cells (APCs).
  • Th-17 cells differentiate in presence of TGFp and IL-6 or ll- ⁇ and SL-23.
  • Th-1 cells produce IL-2, growth factor for lymphocytes, T-regulatory ceils and natural killer i ) ceils; down-regulate Th-17 and innate cells,
  • CDSs bind to antigen, begin proliferation and differe tiation.
  • Cytokines bind to receptors in the brain.
  • Catecholamines enhance giycogenoiysis , increase giuconeogenesis
  • Glucagon increases production, release of giucose.
  • Th-17s reach maximum expansion. As levels of Transforming Growth Factor beta (TGFp) rise, Th- 17s begin transformation into Th-ls or induced T regulatory cells (iTregs).
  • TGFp Transforming Growth Factor beta
  • CD4 cells are expanding rapidly , differentiating into Th-1 or Th-2, in proportions corresponding to magnitude of humoral or intracellular challenge.
  • CDS cells differentiate into CTLs. Natural Killer ceils, Natural Killer T cells expand, differentiate. B cells become plasma cells, manufacture antibodies.
  • Lymphocyte clones reach point of maximum expansion, differentiation under influence of IL-2. Th-17 cells continue decline due to rising levels of IL-2, fL-4, IFNQHammerich et a!,],
  • Brain receives signal from rising levels of 11-2, that lymphocyte compartment is at maximum, commands change in endocrine mix.
  • lymphocyte compartment is optimal
  • Insulin rises to three times normal.
  • Cortisol remains high, producing insulin resistance, increasing giuconeogenesis.
  • Glucagon rises to five times normal, producing giuconeogenesis.
  • Mi continues suppression of lymphocytes not antigen-selected and cytokine stimulated.
  • Selected lymphocytes present 6,000 insulin receptors, receive last essential stimulus, begin attack on pathogens.
  • IL-15 produced by non-iymphoid cells, supports parallel attack by NK cells
  • IL-10 produced in rising amounts by T-regs, inhibits synthesis of SL-1, !F QTNF GM-CSF further decreasing innate attack.
  • Monocytes become macrophages, are stimulated by insulin to aggressively phagocytose pathogens. Remaining PfvlNs die,
  • Cytotoxic T lymphocytes ⁇ CTLs ⁇ destroy cells infected with pathogens.
  • Antibodies released by plasma ceils bind to humoral pathogens, facilitate destruction by macrophages.
  • Th-17 cells transform into T-regs, secrete IL-10.
  • CD4 T-regs and CDS T-regs expand, provoke apoptosis among armed lymphocytes. .. Fever, C-reactive protein (C P), erythrocyte sedimentation rate ⁇ ES ) fail
  • iGF-1 receptors reappear.
  • Glucagon, Cortisol remain high, continuing insulin resistance, stimulating gSuconeogenesis, Systemic TGFP rises, further suppressing immunity, supporting repletion of tissues, Mixture is profoundly immunosuppressive and catabolic of periphera! tissues. Effect is to cannibalize peripheral tissues for use in replacing damaged ceils.
  • Th-17s transform into iT-regs, produce IL-10.
  • nT-regs appear in increasing numbers, produce TGFp.
  • iGF-1 binds to, inactivates T cells, 8 cells, NK cells.
  • T regs inhibit CD-4, CD-S, T and B lymphocytes, and T cells, dendritic cells (DCs), macrophages.
  • DCs dendritic cells
  • Macrophages debride damaged tissues, release angiogenic factors, assist repair of tissues, Damaged tissues access nutrients, proliferate, begin recovery.
  • lymphocytes become memory cells.

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Abstract

Un syndrome métabolique survient dans des états de maladie comprenant le cancer, une maladie cardiovasculaire, la maladie de Parkinson, une septicémie et des troubles auto-immuns. Une inflammation chronique du syndrome métabolique survient lorsqu'une seconde infection survient lors d'un premier défi antigénique. Le corps peut traiter uniquement un défi antigénique à la fois. La réponse cytokine et endocrine au premier défi élimine le ou les clones de lymphocyte sélectionnés par le second défi de telle sorte que seul le système immunitaire inné répond au second défi, et elle est inadéquate. Une infection secondaire virulente peut entraîner la mort. Un défi secondaire faible entraîne une infection chronique. Un défi secondaire vigoureux, alors que la réponse au premier défi entre dans la phase immunitaire adaptative, peut entraîner une auto-immunité, l'insuline est un puissant stimulant des lymphocytes et réveille les lymphocytes sélectionnés rendus inertes par le mélange cytokine/endocrine, qui sécrètent des cytokines pour terminer la phase innée et redémarrer la phase adaptative. Les agents pathogènes sont détruits, les tumeurs sont éliminées et les inflammations disparaissent.
PCT/US2013/041734 2012-05-21 2013-05-18 Traitements de syndrome métabolique et de maladie chronique WO2013177005A1 (fr)

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