This document provides background information on mitochondria and mitochondrial diseases, and discusses supplementation strategies. It describes how mitochondria produce energy in cells and how damage can accumulate over time. Available therapies include supplements like CoQ10, riboflavin, L-carnitine, folinic acid, L-arginine, NAC, and other vitamins/antioxidants. Side effects and considerations for dosing and monitoring are reviewed to safely utilize supplementation for mitochondrial diseases.
Complex eating disorder characterized by obsessive pursuit of thinness through dieting with extreme weight loss and disturbance of body image
Anorexia nervosa is typically characterized by
voluntary restriction of food intake ,distorted body image and fear of gaining weight
constipation in children , pediatric constipation , management of constipation in children , understanding constipation , causes of constipation in children , functional constipation in children , treatment of constipation ,approach to constipation in children ,constipation in infants
Complex eating disorder characterized by obsessive pursuit of thinness through dieting with extreme weight loss and disturbance of body image
Anorexia nervosa is typically characterized by
voluntary restriction of food intake ,distorted body image and fear of gaining weight
constipation in children , pediatric constipation , management of constipation in children , understanding constipation , causes of constipation in children , functional constipation in children , treatment of constipation ,approach to constipation in children ,constipation in infants
Lecture by Prof. Osama Shukir Muhammed Amin FRCP(Edin), FRCP(Glasg), FRCP(Ire), FRCP(Lond), FACP, FAHA, to consolidate information pre-Task Based Learning about Limb Weakness. This lecture addresses upper motor neuron signs, their localization, and rationale for choosing diagnostic investigations. The next lecture will be about lower motor neuron lesions.
Live Counseling and Social Work CEU Webinar: 1-25-2018 at 1pm EST 1.5 CEUs for $10 Register here: https://www.allceus.com/member/cart/index/index?c=30
Objectives
Explore symptoms of cognitive impairment in
Alzheimer’s
Dementias
Review APA Treatment Guidelines for counselors working with persons with Alzheimer’s
Learn how to handle difficult behaviors
An on-demand CEU course can be found here: https://www.allceus.com/member/cart/index/product/id/53/c/
Also see our 2 CEU course on communicating with the cognitively impaired https://www.allceus.com/member/cart/index/product/id/796/c/
Referring to the combination of vitamins and supplements used as therapies in the treatment and management of mitochondrial disease and mitochondrial dysfunction, the "Mito Cocktail" is unique to every patient.
Food, medicine, B-complex vitamins, diseases due to lack of B vitamins, B vitamins as coenzymes, B vitamins in energy metabolism and electron transport chain; ATP production, intracellular and extracellular functions; Importance of B complex vitamins; dietary recommended intakes; toxicity of vitamin B complex; clinical studies of vitamin B complex; dietary guidelines for Americans 2015-2010
Mitochondria , its importance in neurosciencesNitish kumar
mitochondrial role in neurological sciences, its structure, major functions and the neurological diseases caused by improper functioning. complications , manifestations and further control.
Lecture by Prof. Osama Shukir Muhammed Amin FRCP(Edin), FRCP(Glasg), FRCP(Ire), FRCP(Lond), FACP, FAHA, to consolidate information pre-Task Based Learning about Limb Weakness. This lecture addresses upper motor neuron signs, their localization, and rationale for choosing diagnostic investigations. The next lecture will be about lower motor neuron lesions.
Live Counseling and Social Work CEU Webinar: 1-25-2018 at 1pm EST 1.5 CEUs for $10 Register here: https://www.allceus.com/member/cart/index/index?c=30
Objectives
Explore symptoms of cognitive impairment in
Alzheimer’s
Dementias
Review APA Treatment Guidelines for counselors working with persons with Alzheimer’s
Learn how to handle difficult behaviors
An on-demand CEU course can be found here: https://www.allceus.com/member/cart/index/product/id/53/c/
Also see our 2 CEU course on communicating with the cognitively impaired https://www.allceus.com/member/cart/index/product/id/796/c/
Referring to the combination of vitamins and supplements used as therapies in the treatment and management of mitochondrial disease and mitochondrial dysfunction, the "Mito Cocktail" is unique to every patient.
Food, medicine, B-complex vitamins, diseases due to lack of B vitamins, B vitamins as coenzymes, B vitamins in energy metabolism and electron transport chain; ATP production, intracellular and extracellular functions; Importance of B complex vitamins; dietary recommended intakes; toxicity of vitamin B complex; clinical studies of vitamin B complex; dietary guidelines for Americans 2015-2010
Mitochondria , its importance in neurosciencesNitish kumar
mitochondrial role in neurological sciences, its structure, major functions and the neurological diseases caused by improper functioning. complications , manifestations and further control.
A branch of medicine dealing with diseases and metabolic disorders that affect mitochondria. Focusing on diagnosing and treatment of wide range of these diseases. The symptom of these diseases varies from metabolic-induced developmental delay to complex problems that involve many body systems.
cellcycle,cell cycle regulation,phases of cell cycle,cell injury,etiology of cell injury,mechanism of cell injury,apoptosisand necrosis,autophagy,cell death
A well defined presentation on MITOCHONDRIA with all the necessary information including Marker Enzyme as well as the cycles of mithochondria for Undergraduate and post graduate students.
Leukemia, were surviving is regarded as a victory, a disease that still acts as a risk factor among the folks of Hiroshima and Nagasaki, stays as one of the fields to be looked forward for the further research. The above presentation includes the topics to be covered during a presentation on Leukemia. Apt for the students of Pharmacology.
-What are Standards of Care and why does the Mito community need such standards?
-Review the MMS's Standards of Care for Mitochondrial Disease and how they were developed.
-Outline upcoming MMS projects.
What you should know about genetic testing for mitochondrial disordersmitoaction
Amanda Balog, CGC, Senior Genetic Counselor, Mitochondrial and Metabolic Genetics, of GeneDx discusses: "What You Should Know About Genetic Testing for Mitochondrial Disorders."
Richard Frye, MD, PhD, FAAP, FAAN, CPI, will discuss:
*The enteric (gut) microbiome has an important influence on health and disease states in humans.
* The enteric microbiome influences the human host using chemical mediators, some of which can directly affect mitochondrial function
* Short chain fatty acids produced by gut bacteria not only modulate mitochondrial function and cellular regulatory pathways, but can also be used as mitochondrial fuels.
Exercise and nutrition in Mitochondrial Diseasemitoaction
Mark Tarnopolsky, MD, PhD, FRCP,
Depts. of Pediatrics (Neuromuscular + Neurometabolic Disease) and Medicine (Cell Biology/Metabolism, Neurology and Rehabilitation), McMaster University, Hamilton, CANADA
Diagnostic Testing for Mitochondrial Diseasemitoaction
Review traditional diagnostic pathways
Discuss newer testing that has become available in recent years
Review new approaches to attempt to shorten time to diagnosis and increase precision
How to Build Your Mitochondrial Medical Homemitoaction
Topics include:
The importance of a medical home for a mitochondrial disease patient.
Definition of a medical home.
How to establish a medical home.
Why a medical home is an important component of good patient advocacy.
Tips on maintaining a healthy medical home relationship.
Wees will describe theses issues primarily from a pediatric perspective, but she will give adult examples as well.
Wees is a patient advocate with Empowered Medical Advocacy. She assists parents and caregivers each week in navigating toward improved quality of life for their child and their families.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
3. For guidance purposes only 3
Mitochondrial Background
• Each cell contains hundreds to thousands of mitochondria
• Are where energy (ATP) is created in each cell
• Oxidative phosphorylation, pyruvate oxidation, Krebs Cycle (aka TCA cycle, Citric Acid
Cycle), and fatty acid oxidation
• Are prokaryotic in nature (very similar to bacteria)
• Contain their own DNA (mtDNA)
• Produce some of their own proteins
• Replicate on their own during cellular division
• Are inherited solely from the mother
• Ovum contains all fetal mitochondria, sperm does not pass on mitochondria
• This has been challenged recently, but there is no definitive proof sperm contribute
mitochondria or mtDNA to fetal cells
5. For guidance purposes only 5
Mitochondrial Background
• Damage to the mitochondria cannot be reversed
• Unhealthy mitochondria will continue to multiply
• Eventually, as mitochondria are damaged over time, each cell becomes populated
with ineffective or non-functioning mitochondria
• Mitochondrial damage can be inherited
• If mother suffers from a mitochondrial disorder, it will be passed down to children
and may be amplified initially or over time
• Everyone has progressive damage to their mitochondria (and cells)
• Is the reason that we age
• Is more pronounced in those unable to physiologically cope with that damage
6. For guidance purposes only 6
The Krebs Cycle
Image from:
http://uwstudentweb.uwyo.edu/a/ateeter/krebs_cycle.gif
7. For guidance purposes only 7
Electron Transport Chain (ETC)
Image from:
http://www.nature.com/nm/journal/v11/n6/images/nm0605-598-F1.jpg
8. For guidance purposes only 8
Electron Transport Chain (ETC)
• Contained in the inner membrane
• Proton (H+, hydrogen ion) gradient is created in the intermembrane
space and flows into the matrix through ATP Synthase
• Complex I – NADH/Co-Q reductase
• Complex II – Succinate/Co-Q reductase
• Complex III – Co-Q/Cytochrome bc1 reductase
• Complex IV – Cytochrome c oxidase
• ATP Synthase (Complex V) – Processes proton gradient and
creates ATP
10. For guidance purposes only 10
Mitochondrial Location
• All cells contain mitochondria, but some are more reliant
(contain more) than others
• Tissues/sites in decreasing order of vulnerability:
• Brain, skeletal muscle, heart, kidney and liver
• Is the reason why most mitochondrial diseases (mtD) are
neurodegenerative and neuromuscular
11. For guidance purposes only 11
Available Therapies
• Supplementation of nutrients, vitamins and cofactors
• Diet, lifestyle and nutrition
• Exercise, physical therapy
• Speech and cognitive therapies
• Surgery
• For seizures, organ failures, etc
• Assistive devices
• For hearing loss, cardiomyopathies
• Genetic therapy/mitochondrial replacement
• Still highly experimental and speculative
13. For guidance purposes only 13
Supplementation
• Is a combination of vitamins, cofactors and antioxidants
• Formulas vary from patient to patient based on specific
metabolic needs
• Based on blood work, muscle or tissue biopsy, DNA testing
• May need increased dose/extra supplementation during acute
exacerbations of mtD, stress or infection
• Doses may start out the same for all patients initially (depending
on what preference a prescriber has) and adjust as lab values
come back or patient response to certain supplements
• No 2 people, despite having the same genetic mutation, will have the
same dose since response varies
14. For guidance purposes only 14
Supplements
• Most data is anecdotal, not a lot of clinical evidence to support
response of mtD to supplementation
• Not yet proven that these therapies alter the course of mtD
• Parikh, Sumit et al “A Modern Approach to the Treatment of
Mitochondrial Disease”
• Reference for supplement information, implementation and dosing
• Available at http://www.mitoaction.org
• Sumit Parkih, et al “Diagnosis and Management of Mitochondrial
Disease: A Consensus Statement from the Mitochondrial Medicine
Society”
• Most current reference, tries to tie in clinical research and anecdotal
evidence of Mito doctors to generate “consensus statements”
15. For guidance purposes only 15
Coenzyme Q-10
• Is normally created in all mammalian mitochondria
• Integral part of the ETC transfer of electrons from Complex I & II
• Found in all cell and organelle membranes
• Participates in redox reactions (reduction/oxidation – most common type of
biochemical reaction in the body, especially in energy production), acts as an
antioxidant and a pro-oxidant
• Involved in apoptosis (programmed cell death), permeability of mitochondrial
pores, activates uncoupling proteins (acts as a cellular signal)
• Kinetics
• Insoluble in water
• Powder formulations have poor intestinal absorption (max transport in GI tract of
2400mg/day in adults)
• Improved bioavailability when using nano-particles in suspension
• Is FDA approved for the treatment of mtD
Image from:
https://www.truerenu.com/tr/Images/Ingr_Coenzyme-Q10-(CoQ10).jpg
16. For guidance purposes only 16
Coenzyme Q-10
• Ubiquinone: most common, has been available a long time
• Potency may vary greatly between manufacturers
• Oil based gels have higher bioavailability vs. suspensions
• Half-life is 33 hours
• Ubiquinol: more recent, 3-5 times better absorbed
• Half-life of 48 hours
• Idebenone: synthetic version, lower molecular weight
• Proposed to use at lower doses when given SL (sublingually, under the tongue) (0.01-
4mg/kg/day SL vs. 100mg/kg/day PO (by mouth) )
• Possible stimulation of nerve growth factor (NGF), serotonin and dopamine
• May be beneficial in Alzheimer’s, Parkinson’s and Huntington’s Disease, and Friedrich’s ataxia
• All have the side effect of causing wakefulness – take last dose of the day in the
afternoon
• Excess that is not utilized by the body gets stored in fat cells and remains around
for a long time – potentially harmful, needs to be dosed at high doses by a
physician monitoring blood/tissue levels and response.
17. For guidance purposes only 17
Riboflavin (Vitamin B2)
• Is a water-soluble vitamin
• Serves as a flavoprotein precursor (utilized by many proteins in the body)
• Is a key building block for Complex I & II, as well as a cofactor in several other
enzymatic reactions involving fatty acid oxidation and the Krebs Cycle
• Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is caused by a gene
mutation and is an inborn error of metabolism
• Riboflavin supplementation alleviates the symptoms and slows the disease’s progression
• Several non-randomized studies have shown riboflavin to be efficacious in
treating mtD, specifically Complex I & II disease
• Side effect of anorexia, nausea (at high doses), change in urine color
Image from:
http://www.chemistry.wustl.edu/~courses/genchem/LabTutorials/Vitamins/images/Riboflavin.jpg
18. Levocarnitine (L-Carnitine, Carnitine)
• Critical in β-oxidation of fatty acids (FA)
• Helps transport long-chain FAs across the mitochondrial inner membrane
• FAs are then oxidized into Acetyl-CoA and enter the Krebs Cycle
• β-oxidation is critical in tissues such as: heart, skeletal muscle, and liver
• May help prevent CoA depletion and remove excess acyl compounds which
could be toxic
• Some is endogenously produced and the majority comes from diet
• mtD is not due to lack of transport or synthesis of carnitine, rather patients with ETC defects
tend to have a lower free carnitine level (possibly may reflect partial β-oxidation impairment)
• Side effect of body, urine and fecal odor changes – a more “fishy” smell
For guidance purposes only 18
Image from:
http://www.medicinescomplete.com/mc/martindale/2009/images/c541-15-1.gif
19. For guidance purposes only 19
Carnitine’s Role
Image from:
http://www.siteground247.com/~bettergy/index.php?option=com_content&view=article&id=155:acetil-l-carnitina&catid=118:integrazione
20. For guidance purposes only 20
Folinic Acid (Leucovorin)
• Is the reduced form of Folic Acid (Vitamin B9)
• Is a cofactor in multiple metabolic reactions (donates a methyl
group)
• Some case reports state that mtD may lead to cerebral folate
deficiency
• Mechanism behind this is unclear
• Deficiency mostly seen in Kearns-Sayre Syndrome
• Side effect of Folic Acid (and therefore potentially Folinic Acid)
is itchiness
Image from:
http://home.caregroup.org/clinical/altmed/interactions/Images/Nutrients/folicaci.gif
21. L-Arginine
• Arginine use in the body is beneficial for some patients to increase nitric
oxide (NO.) production
• Is a precursor
• Utilized to vasodilate in cardiovascular/cerebrovascular disease
• Not always beneficial in all patients
• May also act as a free-radical scavenger in endothelial cells
• Is not dependent on tissue saturation for effectiveness
• Stroke-like symptoms are present in many mtD syndromes (ex: MELAS)
• Citrulline can be used as well – more expensive
• Oral and IV administration of L-Arginine does show improvement in
clinical symptoms, severity, and frequency of stroke-like episodes
For guidance purposes only
Image from:
http://www.chemsynthesis.com/molimg/1/big/40/40365.gif 21
22. N-Acetylcysteine (NAC)
• Is a medication that is used for several functions:
• Inhaled for cystic fibrosis to loosen mucus in lungs
• Injected for Acetaminophen (Tylenol®) overdoses
• Supplement for kidney disease to help damaged tissue
• In mitochondrial/metabolic therapy it is used in 2 main
functions:
• To act as an anti-oxidant on its own in the body
• To act as a replenishing agent for glutathione, the body’s
natural (and very powerful) anti-oxidant
• NAC is a modified cysteine molecule, which is a part of
glutathione
For guidance purposes only
Image from:
https://upload.wikimedia.org/wikipedia/commons/3/3a/(R)-N-Acetylcysteine_Structural_Formulae.png
http://www.madsci.org/posts/archives/2003-10/1066260582.Bc.1.gif
22
23. N-Acetylcysteine (NAC)
• How it works
• It helps reduce oxidated glutathione back to it reduced state
• Interpretation: when glutathione does its job protecting the body, it
becomes oxidized because it “scavenged” damaging free radicals. This
makes it non-functional. NAC brings it back to its normal state, allowing
glutathione to continue functioning
• Many people have issues making glutathione, or they
cannot make glutathione fast enough to keep up with the
free radicals produced by the body
• Adding NAC helps keep more glutathione “active” in the body
For guidance purposes only 23
24. NAC vs. Glutathione
• While it seems to make sense that replenishing
glutathione would be ideal, its very hard to do
• If administered orally, the body will digest it into amino acids
and absorb it as individual components, destroying its function
• Topical administration works well with getting the medication
into the body, but can be expensive, not very well covered by
insurances and the body needs a constant supply of the
medication since it is always using glutathione (especially in
energy-dependent tissues)
• IV administration is ideal since it makes it into the blood and
distributes well in the body & is a constant administration.
However, this is expensive, and very cumbersome to patients
For guidance purposes only 24
25. NAC vs. Glutathione
• NAC is cheaper and can be administered orally
• Comes in powder or capsules
• Can be swallowed as capsules or opened & mixed with foods/beverages
• Liquid formulations are unstable, exception is the injectable
medication, but it is sealed & under pressure with preservatives
• Smell is pretty powerful – very sulfur-heavy smell (rotten eggs)
• May have a hard time administering to children due to smell, which affects
taste
• Whatever amount of NAC that is not utilized in the body
immediately after taking the medication will remain around
for a while, either waiting to be used for glutathione or as an
antioxidant on its own
• After a while, it is eliminated by the body, and higher doses are fairly
well tolerated
For guidance purposes only 25
26. For guidance purposes only 26
Other Vitamins and Redox Agents
• Thiamine (Vitamin B1): critical in carbohydrate metabolism
• Also used in nucleic acid (DNA base) synthesis indirectly
• Ascorbic Acid (Vitamin C): antioxidant that helps replenish Vitamin E
• Tocopheryl (Vitamin E): antioxidant in the cellular and organelle membranes
• Alpha-Lipoic Acid: antioxidant for cell and mitochondria
• Pyridoxine (Vitamin B6): helps with neuropathy, component of neurotransmitter
synthesis
• Niacin (Vitamin B3): deficiency leads to slow metabolism, intolerance to cold
• Cyanocobalamin (Vitamin B12): RBC (red blood cells) growth and proliferation
27. For guidance purposes only 27
Creatine Monohydrate
• Is present in all cells – either made by the body or from diet
• Undergoes a reaction with ATP to phosphocreatine in the mitochondria
• Source of energy during anaerobic metabolism (when exercising and muscles lack
oxygen)
• Acts as an intracellular buffer for ATP and an energy shuttle for high-energy
phosphates from mitochondria to cytoplasm
• Found in tissues with high energy demands
• Reduced in muscle tissues of patients who have mitochondrial myopathies
• Small studies have shown an increase in high-intensity, isometric, anaerobic and
aerobic power
• No effect on body composition, 2-minute walk, or activity of daily living (ADL) scores
Image from:
http://www.rice.edu/~jenky/images/creatine_reviewPCT01.JPG
28. For guidance purposes only 28
Side Effects
• All of the vitamins cause GI upset
• This is due to the fact that the GI tract is trying to dissolve a massive
amount of concentrated nutrients to absorb them and floods the GI
tract with water
• Leads to nausea, diarrhea and gas
• Steps to mitigate this are:
• Take with food & water
• When starting the medication, if it is an issue, start with 1/4th or 1/2 of the
daily dose for the first week, then increase it over the next couple of weeks
• The body adjusts to this side effect over a 7-10 day period as it gets
used to the daily dose
• Do not get discouraged and stop the medication!
• Talk to you prescriber or pharmacist and go over how you feel with them
29. For guidance purposes only 29
Toxicity/Monitoring
• Overall, very safe and if mistakenly given to wrong child or in overdose, and will
only result in GI distress
• Chronic use of certain vitamins/supplements may lead to toxicity
• CoQ-10: possible pro-oxidant effects and pro-signaling pathways triggered
• Creatine: may elevate SCr (serum creatinine) and crystallize in kidney – is a problem with renal
impairment
• Levocarnitine: possible buildup of toxic metabolites in renal impairment, possible cardiac
rhythm disturbances
• B-complex: neuropathies
• Vitamin E: possible adverse cardiac risks if >400IU/day over an extended period of time
• Drug interactions are mild to non-existent
• Possible erythromycin, warfarin interactions
• Space from any osmotic laxatives (PEG 3350) and bulk-forming laxatives by 1 hour prior, 2 hours
after to maximize absorption.
• Space appropriately from Cholestyramine
30. For guidance purposes only 30
Diet, Lifestyle and Nutrition
• Avoiding mitochondrial toxins
• Certain medications may exacerbate mtD symptoms or are directly toxic to mitochondria
(ETC interference, increase in ROS, impaired protein transport, inhibit mtDNA replication,
or some combination)
• Valproic acid: inhibits FA oxidation, Krebs Cycle and ETC; carnitine depletion
• Anti-retrovirals (HIV medications mostly): impairment of mtDNA replication; lactic
acidosis; carnitine depletion; lipodystrophy
• Statins: CoQ-10 depletion
• ASA: inhibition and uncoupling of ETC
• Aminoglycosides, platinum chemo agents: impaired mtDNA translation
• APAP: oxidative stress (creates ROS compound call NAPQI)
• Metformin: inhibition of ETC, enhanced glycolysis
• Beta-blockers: oxidative stress
• Steroids: unknown
• http://www.mitoaction.org/files/Mito%20Toxins%20Chart.pdf
31. Medication Expectations
• This is not something that will work overnight!
• Allow 1-2 months of taking the medication before making an
assessment if this works for you or not
• Follow up with prescriber for additional blood work or testing
• Keep a diary
• Start a diary 1-2 weeks before therapy – write how you feel or how who
you are caring for feels/behaves
• Track fatigue, pain, thought processes, behavior, etc.
• Track morning, noon and night (if possible)
• Continue while on the medication and review every few weeks or a
month to see how you are doing
• If you decide the medications are not worth the cost based on your
diary, stop the medications and continue the diary
• See how you feel after stopping, you can always restart the medication
For guidance purposes only 31
33. Formulations
• Depending on the pharmacy, there are a myriad of way to
make the compound:
• Suspension
• Powder
• Capsule
• Effervescent packets
• Gummies
For guidance purposes only 33
34. Formulations
• Depending on the dose of supplements per day, some
formulations are preferred over others due to the high
volume of supplements
• Capsules – you may be taking 2-10 capsules a day
• Powder – a calibrated scoop twice a day
• Suspension – 5-10mL twice a day (sometimes less)
• Gummies – usually harder to formulate since a MAXIMUM of
300mg of medication can be added into 1 gummy, typical
formulations may require up to 30 gummies a day to meet daily
dose
• Effervescent packets – may take up to 5 packets a day but can
taste better than other formulations
For guidance purposes only 34
35. Formulations
• All formulations should have the daily dose divided into
at least twice a day administration, and can be up to 4
times a day if necessary
• More frequent dosing leads to better GI absorption of
medications since the GI tract does not become overwhelmed
• Decrease risk of GI upset
• Helps patients who have absorption issues in GI tract
• Decrease compliance of medication because need to remember
frequent dosing and trying to get a child to take a bad-tasting
medication more often may not work well
For guidance purposes only 35
36. Considerations
• Make sure to check where you get your supplements
from
• Not all OTC brands are created the same
• Use brand-name supplements like: Metagenics, Epic4Health,
Solgar, RainbowLight, Pure Encapsulation etc.
• They have a track record of safety and quality because they voluntarily
test what they make
• NO over-the counter supplement is regulated by the FDA,
which means that they DO NOT need to have what they claim
on the label in the medication – if you get CoQ10 600mg
capsules, you may get more or less of the medication
• Contact the manufacturer and ask them what they do for quality control
For guidance purposes only 36
37. Considerations
• Make sure to check where you get your compounds from
• Pharmacies source ingredients from FDA approved wholesalers
which are required to maintain a certain degree of testing and
standards
• Pharmacies get information on the powders they order that has a
sample analysis for contamination and purity, if it fails, the powder is
rejected
• Compounds are NOT FDA-approved, but ingredients should be
sourced from FDA-approved facilities
• Speak with the pharmacy you plan to use and see what their quality
standards are – do they send for testing? Who do they source from?
• If they are PCAB (Pharmacy Compounding Accreditation Board)
Certified, most likely they are following good compounding practices
For guidance purposes only 37
38. Cost
• Using a trusted source for over-the-counter medications may be
more expensive than not, but it is worth the peace of mind
knowing you are paying for something that has quality behind it
• Compounding is even more expensive since there are more
rigorous testing procedures utilized at the wholesaler & pharmacy
level to make the medication
• Pharmacies usually work with insurance companies to cover
medications, though more and more insurances are requiring prior
authorizations (PAs) for compounds or not covering them
• PAs are additional paperwork generated by the pharmacy/doctor which
have to be filled out by the doctor, faxed to the insurance, insurance has to
review them and then make a decision to approve/deny paying for the
medication
• PAs can take anywhere from 2 days to 2 months for processing, depending
on the doctor’s office and the insurance company
For guidance purposes only 38
39. For guidance purposes only 39
Works Cited
• Cassels, Caroline. "Mitochondrial Dysfunction May Play a Role in Autism Spectrum Disorders
Etiology." 15 Apr. 2008. Medscape. Web. 07 Jan. 2010. <http://medscape.com>.
• D'Souza, Gerard, Sarathi Boddapati, and Volkmar Weissig. "Gene Therapy of the Other
Genome: The Challenges of Treating Mitochondrial." Pharmaceutical Research 24.2 (2007):
228-38. Print.
• Mitochondrial Disease Action Committee - MitoAction. Web. 10 July 2010.
<http://www.mitoaction.org>.
• Parikh, Sumit, Russell Saneto, Marni Falk, Irina Anselm, Bruce Cohen, and Richard Haas. "A
Modern Approach to the Treatment of Mitochondrial Disease." Current Treatment Options in
Neurology 11 (2009): 414-30. Print.
• Parikh, Sumit et al. “Diagnosis and Management of Mitochondrial Disease: A Consensus
Statement from the Mitochondrial Medicine Society.” American College of Medical Genetics
and Genomics 17 (2015): 689-701. Print.
• Weissman, Jacqueline et al. "Mitochondrial Disease in Autism Spectrum Disorder Patients: A
Cohort Analysis." PLoS One 3.11 (2008): 1-6. Print.
• Clin Pharmacol Drug Dev. 2014 Jan;3(1):13-7. doi: 10.1002/cpdd.73. Epub 2013 Oct 8.
“Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with
ubiquinol vs. ubiquinone. Web. Feb 7, 2019.
• Food Funct. 2018 Nov 14;9(11):5653-5659. doi: 10.1039/c8fo00971f. “Ubiquinol is superior to
ubiquinone to enhance Ceonzyme Q10 status in older men.” Web. Feb 7, 2019.
41. For guidance purposes only 41
Mitochondrial Background - Genetics
• Some genes for mitochondrial proteins are contained in the nucleus of the cell
• Allows for proteins to be synthesized in the cytosol (main cell body), then delivered to the
mitochondria
• These genes are inherited from mother and father
• The rest of the genes are contained in the mitochondria
• Responsible for subunits of Complex I, Complex III, Complex IV and ATP Synthase
• Each mitochondrion contains 2-10 copies of its DNA
• Are constantly subject to reactive oxygen species (ROS) due to oxidative phosphorylation (main
part of energy cycle) byproducts – leads to mtDNA damage
• Compared to nuclear DNA, there is inadequate repair mechanisms for the mtDNA
• As copies of mtDNA are damaged, more and more proteins are made inaccurately, which shifts
the mitochondrion to an unhealthy state until it is no longer functional (called the threshold
effect)
42. For guidance purposes only 42
Mitochondrial Structure
• Outer membrane (phospholipid
bilayer)
• Contains: transport proteins, lipid
conversion proteins
• Intermembrane space
• Contains: enzymes that use ATP to
phosphorylate other nucleotides
• Inner membrane (phospholipid
bilayer)
• Contains: pores, electron transport
chain (ETC), ATP Synthase, transport
proteins
• Matrix
• Contains: mtDNA, enzymes for the
Krebs Cycle, ribosomes, mtDNA
enzymes, tRNA
Images from:
http://www.eloscense.com/blogoscense/wp-content/uploads/2009/09/MitochondriaSMALL2.jpg
http://supplementalscience.files.wordpress.com/2009/03/mitochondrion.jpg