11

Lyme DiseaseLyme DiseaseAn Integrative ApproachAn Integrative Approach

Robert LaCava, MDRobert LaCava, MD

Constantine A. Kotsanis, MDConstantine A. Kotsanis, MD

ReferencesReferences

www.cdc.gov The Great ImposterThe Great Imposter ILADSILADS Emedicine.comEmedicine.com Uptodate.comUptodate.com

33

The Discovery of Insulin The Discovery of Insulin (1920)(1920)

A Canadian Medical MiracleA Canadian Medical Miracleof the 20of the 20thth Century Century

Frederick Grant Banting, MD (1891 – 1941) Charles Herbert Best, MD (1899-1978) John James Richards Macleod, MD (1876-1935) James Bertram Collip, MD (1892-1965)

44

History of InsulinHistory of Insulin Potentiation Therapy (IPT) Potentiation Therapy (IPT)

Donato Perez Garcia, Sr., M.D. (1896 – 1971) a.k.a. “Donato 1” (the inventor)

Surgeon Lieutenant in the Mexican Army Donato Perez Garcia Bellon, M.D. (1930 – 2000) a.k.a. “Donato 2” Donato Perez Garcia, Jr., M.D. a.k.a. “Donato 3” Steven G. Ayre, M.D. (Introduced IPT to USA in 1970s)

55

Insulin Potentiation Insulin Potentiation Therapy (IPT)Therapy (IPT)

IPT is a pharmaceutical-based protocol using insulin as a biologic response modifier of

the endogenous mechanisms of any disease.

In IPT, insulin is used to selectively target diseased cells with lowered doses of pharmaceuticals, enhancing drug effects on diseased cells and, at the same time, effectively reducing dose-related pharmaceutical side effects on host normal

tissues.

66

InsulinInsulin A peptide hormone, produced by beta cells of the pancreas and regulates carbohydrate and

fat metabolism

Human insulin is composed of 51 aaStored in the body as a hexamerThe active form is a monomer

77

Insulin-Like Growth Factor 1Insulin-Like Growth Factor 1(IGF-1)(IGF-1)

Also known as somatomedin C A hormone similar in molecular structure as insulin Important in childhood growth Has anabolic effect in adults Consists of 70 aa Primarily produced by the liver Production is stimulated by GH One of the most potent activators of AKT signaling

pathway Potent inhibitor of programmed cell death

88

Exocrine

AutocrineParacrine

Endocrine

Some “New” Terminology…Some “New” Terminology…Modes of Cellular SecretionModes of Cellular Secretion

99

The combination of insulin and IGF-I operates autonomously at the cellular level within diseased cells, and this operation is free from any higher level of integrated control…

(Cont’d)…

The Mechanisms of DiseaseThe Mechanisms of Disease

1010

The two work together in an autocrine and/or paracrine manner and in a complementary fashion, with IGF-I being the major anabolic hormone responsible for mediating messages about growth of the disease, while insulin regulates and provides the fuel for these processes.

Zapf J., Froesch E.R. Insulin-like growth factors/somatomedins: structure, secretion, biological actions and physiological role. Hormone Res 24:121-130, 1986.

The Mechanisms of DiseaseThe Mechanisms of Disease

1111

How does How does it work?it work?

How could this be?How could this be?

1212

Insulin receptors are widely distributed in mammalian organisms with their being from 100 to 100,000 receptors per cell in different tissues. Rarely are there any cells having no receptors at all.

Rosen OM. After insulin binds. Science 273:1452-1457, 1987

1313

Supraphysiologic concentrations of insulin can replace the IGF-I requirement in defined media through cross-reaction with the IGF-I receptor.Goustin et al. Growth factors and cancer. Cancer Res 46:1015-1029, 1986.

1414

- Increased

Intracellular

Dose Intensity

MEMBRANE EFFECTS

- Altered Cell

Membrane

Permeability

METABOLICEFFECTS

Schema of IPT Mechanisms

Low-Dose

AntimicrobialsInsulin

ReceptorsIGF

ReceptorsX10X 6

Exogenous InsulinExogenous Insulin

Synergy

Ligand effect is a function of receptor concentration

−Increased

Sensitivity to

Antimicrobials

−Increased

drug potency

1515

Problem Areas in Full Dose Problem Areas in Full Dose Antimicrobial TherapyAntimicrobial Therapy

1) An adequate intracellular dose intensity requirs the systemic administratoin of high doses of drugs

2) Lack of antimicrobial specificity for drugs

3) Drug resistance

4) 1) + 2) + 3) = Widespread dose-related drug side effects

1616

What would be the Elements of an What would be the Elements of an Ideal Solution to this Antimicrobial Ideal Solution to this Antimicrobial

DilemmaDilemma??

1) To develop a mechanism that bypasses microbe drug resistance.

2) To deliver lowered doses of drug more specifically into this diseased cell population.

3) To maintain and /or enhance pharmaceutical cell-killing effectiveness in any disease.

4) To reduce or avoid drug side effects in normal cells.

1717

Antimicrobial TherapyAntimicrobial Therapy

I - Membrane Effect

II - Metabolic Effect

1818

IPT & Antimicrobial TherapyIPT & Antimicrobial Therapy

I - Membrane Effect

- Increased cell membrane permeability

- - Increased intracellular dose intensity

- - Lowered total dose of drugs- - Reduced dose-related side effects

- - Shorten treatment cycle intervals

1919

Stearic acid Stearic acid Oleic acid - saturated - - monounsaturated -- saturated - - monounsaturated -

Tristearin Triolein m.p. 68 deg. Cm.p. 68 deg. C m.p. 5 deg. C m.p. 5 deg. C

Mechanisms of Membrane Effects

1) Insulin activation of delta-9 desaturase

At 37 deg. C Membrane fluidity/permeability

2020

Mechanisms of Membrane Effects (cont’d)

2)2) Drug adsorption onto glucose molecules with transmembrane transport then occurring via the insulin-activated glucose transport protein

3)3) Adsorption of drug molecules onto insulin with the resulting chimeric drug-insulin complex being internalized into the cell by a process of receptor-mediated endocytosis

2121

IPT & Antimicrobial TherapyIPT & Antimicrobial Therapy

II - Metabolic Effect

- Increased sensitivity to antimicrobial drugs- Drugs become more potent- Microbial drug resistance is eliminated or greatly reduced

2222

- Increased

Intracellular

Dose Intensity

MEMBRANE EFFECTS

- Altered Cell

Membrane

Permeability

METABOLICEFFECTS

Schema of IPT Mechanisms

Low-Dose

AntimicrobialsInsulin

ReceptorsIGF

ReceptorsX10X 6

Exogenous InsulinExogenous Insulin

Synergy

Ligand effect is a function of receptor concentration

−Increased

Sensitivity to

Antimicrobials

−Reduction or .

elimination of

microbial drug

resistance

2323

IPT & Drug TherapyIPT & Drug Therapy

“Smart Bomb” effect: Excess of insulin-sensitive receptors on human diseased cells causes predominance of insulin effect in diseased cells, sparing normal host tissues = INCREASED SAFETY

Synergy of insulin’s membrane and metabolic effects enhances antimicrobial drug action in diseased cells = INCREASED EFFICACY

2424

Insulin Potentiation Insulin Potentiation TherapyTherapy

A Renaissance in Chronic Disease States

Lyme Disease Lyme Disease An Integrative ApproachAn Integrative Approach

Robert LaCava, MDRobert LaCava, MD

Lecture GoalsLecture Goals

• Present a broader concept of IPT for Present a broader concept of IPT for

Lyme Disease and Mold IllnessLyme Disease and Mold Illness

• Present integrative approaches to treat Present integrative approaches to treat

Lyme DiseaseLyme Disease

Thanks toThanks to

Donato Perez Garcia, M.D.Donato Perez Garcia, M.D. Steven G. Ayre, M.D.Steven G. Ayre, M.D. Joe Burrascano, M.D.Joe Burrascano, M.D.

Sean Devlin, D.O. Sean Devlin, D.O. Constantine A. Kotsanis, M.D. Constantine A. Kotsanis, M.D.

ILADS General InformationILADS General Information

Basic FactsBasic Facts“Nature’s Dirty Needle”Ixodes pacificus (Western Black Legged Tick)

So tiny it can be missed.

Only 16% recall a tick bite. Painless.

Spirochetes are long and slender gram negative bacteria that are tightly coiled looking like telephone cords

• A spirochete that causes Lyme disease. Inappropriate name for this disorder – which is more exactly a type of multiple microbial inflammatory disorder (MMID) involving several different infection agents including Borrelia burgdorferi, babesios, bordetellosis, HHV-6, parasites, ehrlichiosis, etc.

• Lyme disease was first recognized in U.S. and published in the N.E.J.M. in 1975 by Dr. Allan Steere following a mysterious outbreak of possible juvenile rheumatoid arthritis, near the community of Lyme, Connecticut.

Facts & StatisticsFacts & Statistics

• Fastest growing vector-borne infectious disease in the USA• CDC estimates are over 200,000 new cases per year!• In the USA, rate of new cases exceeds that of HIV/AIDS

• Anyone can get it – affects all ages, both genders, and even our pets

• Present worldwide. • Lyme has been reported in all 50 states

• Ticks can survive down to 17 degrees below zero! (may still get tick bites in wintertime)

• There are more new strains of Borrelia identified• In many areas, lawns have higher tick concentrations than the

surrounding woods

Three Phases of Lyme DiseaseThree Phases of Lyme Disease

• Early localized• Early disseminated disease• Chronic Lyme disease – late

• ill with Lyme for one or more years

Why The Concern?Why The Concern?Illness Can Vary From Mild To SevereIllness Can Vary From Mild To Severe

• Early Lyme, if promptly recognized and appropriately treated, can be cured

• Untreated Lyme may progress, causing a very severe illness and disability

• Can be latent for months to years, and later result in catastrophic, permanent damage

• Deaths have been reported• Most symptoms are non-specific• Mild symptoms often are dismissed• The Great Imitator

• Osteoarthritis, Rheumatoid arthritis, 1 degree & 2 degree A-V block, Epilepsy, MS, ACS, Atrial fibrillation, Atrial flutter, Dementia, Meningitis, Wasting Syndrome, Cancers, Auto-immune syndrome, Parkinson’s disease, Depression, Adrenal fatigue, Thyroid disorders, Personality disorders

Why The Concern? - Why The Concern? - continuedcontinued

Illness Can Vary From Mild To SevereIllness Can Vary From Mild To Severe

• More medical errors from incorrect diagnosis and unnecessary or dangerous treatments

• Fibromyalgia, MS/CFS, depression, ALS (Lou Gehrig’s disease), malingering, Munchausen’s syndrome

• Often, patients see literally dozens of doctors and undergo an encyclopedia of tests, Lyme is missed, and they still have no diagnosis; interpretation of possible negative testing is of great concern

• Even negative testing needs to be interpreted. • When medical doctors cannot find a cause for the complaints, they

refer patients to a psychiatrist (blame the patient for his/her illness!)• Can be transmitted from mother to child; trans-placentally• Transmitted as a blood borne pathogen

• Probably sexually transmitted according to UK doctors.

Diagnosing Lyme – the SymptomsDiagnosing Lyme – the SymptomsA difficult taskA difficult task

• Headaches, photophobia, stiff neck• Fatigue, intolerance of exercise• Aches in and around joints• Numbness, tingles, sense of vibration• Poor coordination, imbalance, light-headed, need to sit or lie

down, especially in afternoon• Forgetful, confused, speech errors, ADD-like• Sleep disturbance• Intolerance of stress, alcohol, sleep deprivation (any of these will

make all symptoms worse)• Subtle onset of nonspecific “viral-like” symptoms often obscure

the diagnosis

The RashThe Rash

• Erythema migrans with central clearing and necrotic center

• Typical “Bullseye” rash occurs in only 1/3 to 1/2 cases

• Expands over time, painless, raised, may be warm RINGWORM

• Scaly center• Reference. Looks like a SPIDER BITE

Blood TestingBlood Testing• LYME (Borrelia burgdorferi)

• Serologic tests (ELISA, Western Blot)• PCR – also poorly sensitive - <30%

• CD57 (Natural Killer Cells)• Low counts seen in Chronic Lyme when the infection has been

active > 1 year• Can be a screening test• Predicts a relapse if low when antibiotics end

• Even a spinal tap serology will miss over 90% of cases!• Blood test may miss up to 1/2 of cases!!!• CO-INFECTIONS• Situation is worse – pick up 30% at best!!!• Conclusion: LYME IS A CLINICAL DIAGNOSIS

Serologic TestingSerologic Testing• A two-tiered strategy recommends

• ELISA – IFA may substitute• Western Blot

• ELISA testing usually derives from the whole organism. B. burgdorferi antigen are similar to others. Therefore cross-reaction is not uncommon.

• I find ELISA test of very little value and tend to go immediately to Western Blot testing or immunblot.

• Western Blot are antigen specific and can detect either lgM or lgG antibodies

• PCR (polymerase chain reaction) tests for the DNA of the Lyme disease spirochete

• Western Blot, ELISA, PCR can all be profound on either blood test or lumbar puncture

Selective Approaches to Selective Approaches to Lyme Disease TestingLyme Disease Testing

• DOT – Blot studies • Epitope studies• Selective studies of 31 band, lgC and lgM equivocal

colorimentiuric variants• New lab – selective culture – of Joe Barrascano –

Philadelphia, Advanced Laboratories IGC (10 day turn around)

• VISEC6, ELISA CCG • Comparable sensitivity to the lg ELISA with improved specificity

• Point System for making a clinical diagnosis by Joe Barrascano

Problem of Antibiotic Therapy in Problem of Antibiotic Therapy in MMID (“Lyme”)MMID (“Lyme”)

• An adequate intracellular dose internally requires the systemic administration of very high doses of drugs

• Lack of absolute specificity of drugs administered in MMID.• Need of drugs to cross the blood brain barrier to deal with

certain neurologic effects.• Systemic toxicity (i.e. hepatic) to large doses of

immunologic agents• Combination of the above leads to widespread potential

drug side effects.

What would be the elements of an What would be the elements of an ideal solution to this antibiotic ideal solution to this antibiotic

dosing dilemma?dosing dilemma?

• Develop a method to differentiate the infected cell population for the normal cell population

• To deliver lowered dosage of drugs more specifically to the infected cells

• To reduce or avoid antibiotic therapy side effects to normal cells.

Treatment For Chronic LymeTreatment For Chronic Lyme

• Antibiotics used in cycles• Oxidative therapy• Silver hydrosol treatment• Detoxification• Immune modulation• Anti Inflammatory Regimens

TreatmentTreatmentMore Than Antibiotics!More Than Antibiotics!

• Enforced rest• NO caffeine• NO alcohol• NO smoking at all• Low-carb• High quality protein diet• Daily vitamins and other nutritional support• Maintain hydration• Exercise program• Never any steroids!

Integrative ApproachesIntegrative Approaches• Detox: very important!

• Must keep these patients well hydrated• Encourage active detox with FIR (saunas and mats)• Oral treatment with zeolite, chlorella, fulvic acid and bentonite clay• Patients encouraged to exercise 30-60 minutes at least 5 days a week

• Intermittent fasting with juicing• Ionic foot baths• Deep tissue therapy/lymphatic massage• Meditation (TM, Audio assisted)• Biofeedback• Skin brushing• Homeopathic detox

Integrative ApproachesIntegrative Approaches

• Bowel irrigation/colonics with ozone• IV chelation• Glutathione IV• Metabolic and Immune Support:

• IV Myers Cocktail• IV Vit C and Freamine• Vit D3, zinc, selenium po• Mushroom extract: turkey tail, chaga, Maitake, Reishi and Cordyceps • Low dose Cortef and adrenal cortical extract

• These treatment regimens represent a group of options that are ‘outside of the box’ and have been show to help our patients who have been failed by traditional therapy.

Integrative ApproachesIntegrative Approaches• Oxidative therapy:

• There are many styles and approaches. Ones we use include Major Autohemotherapy (IM), Prolozone (Joint and soft tissue) utilizing ozone, IV H202 is also used in tandem with the ozone treatments

• Silver hydrosol:• Given IV and orally. • Patient have been treated for as long as 9 months

Homeopathic Approaches Homeopathic Approaches To LymeTo Lyme

• Syphilinum 9c/30c• Lachesis matus• Ledum palustre• Rhus Tox/Apis Mellificia

• Check modalities for joint pain first

• Anti-metal helps• Plumbum metallicum, mercurius solubilis

• Belladona

Herbal Approach To LymeHerbal Approach To Lyme

• Byron White Formulation• Aa Baab; A-Bart; A Lyme• Samento

Insulin Potentiation TherapyInsulin Potentiation Therapy

• IPT: • Using the insulin receptors as gateways to target

intracellular organism with antibiotics and nutraceuticals• IV Abx used include ceftriaxone (500-1000mgs) and

Doxycycline (Vibramycin, 100-200mgs)• IM/IV Abx used is Penicillin G (8-12 million units)• Flush meds with 5-10cc’s of DMSO in patients with CNS

and joint symptoms

• IPT is the only therapy that crosses the blood brain barrier

Schema of IPT Mechanisms

Exogenus Insulin

Low Dose AntibioticInsulin

Receptors

x4

MEMBRANE EFFECTS

- Altered cell membrane permeability

- Increased intracellular dose intensity

Infected CellInfected Cell

Ligand effect is a function of receptor

concentration

Mechanism of Membrane Mechanism of Membrane Effects of InsulinEffects of Insulin

• Insulin activation of dela-9 desacturase at 37 degrees Celsius – membrane fluidity and permeability increased

• Drug absorption into glucose molecules with transmembrane transport then occurring via the insulin activated glucose transport protein

• Absorption of drug molecules onto insulin with the resulting chimeric drug insulin complex being internalized into the cell by a process of receptor-mediated endocytosis

IPT and MMID (“Lyme”) IPT and MMID (“Lyme”) Membrane EffectMembrane Effect

• Increased cell membrane permeability• Increased intercellular dose intensity• Lowered total dose of drugs concentrate• Reduced dose related side effects• Shortened time course of cycle intervals

IPT and MMID (“Lyme”)IPT and MMID (“Lyme”)

• IPT targets the affected, inflammatory area for therapy – kind of a “smart bomb” effect

• IPT allows specificity of therapy with different agents• IPT allows the introduction of multiple antibiotics in

very low dosages to the area for specific killing effect to microbes

Lyme Disease Lyme Disease Left UntreatedLeft Untreated

TEST RESULTS MARCH 2011

RESULTS JUNE 2013

Lyme IgM Western Blot 18 kDa.**23-25 kDa. 28 kDa. 30 kDa.**31 kDa.**34 kDa.**39 kDa.**41 kDa. 45 kDa. 58 kDa. 66 kDa.**83-93 kDa.

NEGATIVE-------+-+--

NEGATIVE----INDINDIND++-++-IND

Lyme IgG Western Blot18 kDa.**23-25 kDa. 28 kDa. 30 kDa.**31 kDa.**34 kDa.**39 kDa.**41 kDa. 45 kDa. 58 kDa. 66 kDa.**83-93 kDa.

NEGATIVE----INDIND-+---IND

POSITIVE----+++IND++-+--

Abs. CD8-CD57+ Lymphs 24 8

Protocols To Integrative Treatment For Protocols To Integrative Treatment For Lyme & MoldLyme & Mold

• CASE STUDY # 1• C.E. a 35 year old female.

• History of seizures and severe pain (Sept 2011). • Came to us for possible Lyme disease. • Chief complaints: seizures & severe pain (due to Lyme disease)

• Diagnosis• Original diagnosis before IMO: seizure disorder• Diagnosis/treatment for at IMO: probable Lyme disease, severe

arthritis• Tests Taken• Tests taken: Western Blot, Salivary cortisol, • High levels of Trichothecene Mycotoxins (systemic yeast infestation)

Protocols To Integrative Treatment Protocols To Integrative Treatment For Lyme & MoldFor Lyme & Mold

• Original Mission • Relieve pain

• Methods• IPT• Treated with mixed antibiotics; rocephin, doxycycline,

tygacil, clindamycin• Supplements: daily vitamins – thyroid & adrenal support• Medications: thyroid, adrenals, roxithromycin

•  

Protocols To Integrative Treatment Protocols To Integrative Treatment For Lyme & MoldFor Lyme & Mold

• Results• Complete resolution in 6 weeks

• No further ambulation

• No further joint or lumbar pain

• No further seizures• Excellent improvement in sleep (5 = GREAT)*• Excellent improvement in appetite (5 = GREAT)*• Overall feeling on a scale of 1 (Poor) – 5 (Great) = 5

GREAT* 

Protocols To Integrative Treatment Protocols To Integrative Treatment For Lyme & MoldFor Lyme & Mold

• CASE STUDY # 2• J.S. 30 year old female.

• History: 2-3 years of severe pain• Chief complains: constant muscle/joint pain, exhaustion, inability to

concentrate

• Diagnosis• Original diagnosis before coming to us: Fibromyalgia/CFIDS• Diagnosis/treatment with us: Mold

• Tests taken• ELISA, CBC with differential platelet (high RDW), Tricothecene (+),

Protocols To Integrative Treatment Protocols To Integrative Treatment For Lyme & MoldFor Lyme & Mold

•  Original Mission• Relieve pain

• Methods• IPT for anti fungals

•  • Results

• Complete relief of pain and brain fog• Mycotoxin count down to 0• Note. Patient went back to work environment and mycotoxins

rose again

Protocols To Integrative Treatment Protocols To Integrative Treatment For Lyme & MoldFor Lyme & Mold

• CASE STUDY # 3• S.S. 37 year old female.

• History: illness since 1995 (17+yrs), diagnosed mold exposure 10/2012, Lyme disease 10/2012, orthoscopic surgery (both knees),

• Reason she came: treatment for mycotoxins• Chief complaint(s): digestive, joint pain/stiffness/swelling, mental cognition

• Diagnosis• Original diagnosis before coming to us: mycotoxins, Lyme disease, food

sensitivities• Diagnosis/treatment with us: As well as above; Mold, thyroid

• Tests taken• ELISA – Ochrathoxin (+), Allergies, Western Blot (+),

Protocols To Integrative Treatment Protocols To Integrative Treatment For Lyme & MoldFor Lyme & Mold

• Original Mission• Treatment of Lyme & mycotoxicosis

• Methods• IPT for Lyme and mycotoxins

•  • Results

• Complete resolution of fatigue, joint pain and brain fog• Ochratoxin levels went down 50%• CD8 –CD57+ levels went up 49L/uL (36 to 85)

ConclusionConclusion

• IPT is a unique therapy for targeting inflamed and IPT is a unique therapy for targeting inflamed and infected areasinfected areas

• IPT is a unique drug delivery system to get to specific IPT is a unique drug delivery system to get to specific placesplaces

• IPT is the only therapy that crosses the blood brain IPT is the only therapy that crosses the blood brain barrierbarrier

Bibliography/ReferencesBibliography/References• Cullen J.K., Yee D., Sly W.S. et alCullen J.K., Yee D., Sly W.S. et al

• Insulin-like growth factor receptor expression and function in human breast cancer. Cancer res 50:48-53, 1990

• Papa V., Pezzino V., Constantino A., et alPapa V., Pezzino V., Constantino A., et al • Elevated insulin receptor control in human breast cancer. J Clin Invest 86:1503-1510,

1990

• Rosen O.MRosen O.M. . • After insulin binds. Science 273: 1452-1457, 1987

• Alabaster O., Vonderhaar B.K., Shafie S.MAlabaster O., Vonderhaar B.K., Shafie S.M• Metabloic modification by insulin enhanced cytotoxicity in MCF-7 human breast

cancer cells. Eun J Cancer Clin Oncology 17:1097-1103, 1981

• Burrascano Joseph JBurrascano Joseph J• Adrenal topic in Lyme disease. Managing Lyme disease, 18th edition, October 2008

• www.cdc.govwww.cdc.gov• The Great ImposterThe Great Imposter• ILADSILADS• Emedicine.comEmedicine.com• Uptodate.comUptodate.com