mİtokondrİal dİsfonksİyonlarda ft yaklaŞimi · •metabolic syndrome 1. stafstromce, rho jm....
TRANSCRIPT
MİTOKONDRİALDİSFONKSİYONLARDA
FT YAKLAŞIMI
Doç. Dr. Mehmet Mahir Atasoy
MALTEPE ÜNİVERSİTESİ TIP FAKÜLTESİ
Girişimsel Radyoloji & Meme Radyolojisi
Fonksiyonel Tıp Kliniği
eicindeMalnioctnu Fro fteuitts Ineh T81
©20
ENERJİ HAYATTIR
Canlı mı yoksa ölümü
olduğunuzu mitokondrialzarlarınızın arasındaki elektriksel
potansiyel farkı belirler.
E
nerg
yD
IS-O
RD
ER Maximum İyilik Hali
Biyokimyasal Disfonksiyonlar
Semptomatik Disfonksiyonlar
Hastalıkların teşhisi
Irreversible Dejenerasyon
Engellilik (Disabilite)
Ölüm
ENERJİ YOLAKLARI
Brain 22%
Heart 9%
Pancreas*
Muscle 22%
Liver 21%
Adipose 4%
Eye*
Ear*
Kidney 8%
Bowel*
KULLANILAN ENERJİ ORANLARI
Nerves*Immune &
Other*
McClave SA, Snider HL. Dissecting the energy needs of the body. Curr Opin Clin Nutr Metab Care. (2001) 4(2):143-7
Ağırlığın %7 si
enerjinin %60
ını kullanıyor.
MİTOKONDRİAL DANSİTE
Elsie, J Comp Physiol B (1985)156:3-11
TissueMitochondrial
volume density(Hücre
volümündeki %)
Mitochondrial memb. surface area
(m2)/cm3 doku
Heart 42 34
Kidney 38 22
Liver 27 11
Skeletal Muscle 8 12
Lung 6 2
Brain 5 5
Beyin Mitos >5x Kalp Mitos
PRİMER MİTOKONDRİAL HASTALIKLAR
• Mitochondrial encephalomyopathy and lactic acidosis with stroke-like-episodes (MELAS)
• Leber hereditary optic neuropathy
• Leigh syndrome
• Maternally inherited diabetes and deafness
• Mitochondrial complex III deficiency
• Myoclonic epilepsy with ragged-red fibers
• Neuropathy, ataxia, and retinitis pigmentosa
• Non-syndromic deafness
• Palmoplantar keratoderma with deafness
• Progressive external ophthalmoplegia
MİTOKONDRİAL HASTALIKLAR
herhangi bir yaşta
herhangi bir organ bulgusu ile
herhangi bir şikayet ile kendini
gösterebilir.
Genelde birden tetiklenme
hikayesi verirler.
Munnich A, Rotig A, Chretien D, et al. Clinical presentation of mitochondrial disorders in childhood. J Inherit Metab Dis. 1996;19:521–527
MİTOKONDRİPATİ DÜŞÜNDÜRENLER
• Visual loss and blindness• Ptosis• Ophthalmoplegia*• Optic atrophy• Hearing loss and deafness• Acquired strabismus• Retinitis pigmentosa
• Kidneys• Renal tubular dysfunction• Wasting• Nephrotic Syndrome
• Heart• Tachycardia• Cardiac conduction defects (heart blocks)• Cardiomyopathy• WPW syndrome
• Ears & Eyes • Endocrine glands• Diabetes• “HYPOGLYCEMIA”• Hypothyroidism• Growth Hormone Deficiency• Parathyroid failure (low calcium)
• Liver• Hypoglycemia (low blood sugar)• Liver failure
• Systemic• Failure to gain weight• IUGR• Microcephaly• Fatigue• Short stature• Respiratory problems• Sleep Apnea• Delayed Waking from Anesthesia
• Brain• Developmental delays• Dementia & Parkinson's• Depression• Neuro-psychiatric disturbances• Migraines• Autistic Features/Mental retardation• Headaches• Seizures• Atypical cerebral palsy• Strokes
• Nerves• Weakness (may be intermittent)• Absent reflexes• Fainting• Neuropathic pain• Dysautonomia –• temperature instability
• Muscles• Exercise Intolerance out of proportion to weakness• Exercise-induced Myalgia• Muscle Wasting• Weakness• Cramping• Hypotonia• Unexplained Rhabdomyolysis
• GI• Exocrine pancreatic failure• Pseudo-obstruction• Gastroesophogeal reflux• Dysmotility• Diarrhea or constipation• Gastrointestinal problems• Irritable bowel syndrome• Vomiting/Peristalsis
MİTOKONDRİPATİ DÜŞÜNDÜRENLER
metabolik bir hastalık olarak
KANSER 2.0KANSERDEN KORUNMA YOLLARI
NÖROMUSKULER HASTALIKLARDA MITOKONDRİ SAĞLIĞI ÇOK ÖNEMLİ
1. CBC, Ferritin2. Rutin biyokimya, A1C, Insulin, KC fonk.3. Ammonia4. Lactate, & Lactate:Pyruvate Ratio5. Creatine Kinase6. Quantitative Plasma Amino Acids7. Quantitative Urine Organic Acids8. Plasma Acyl-carnitine Profile9. CoQ10,10. Ox Stress markers, Anti-Ox capacity11. Genomic/Metabolomic Evaluation
MİTOKONDİRAL FONKSİYON DEĞERLENDİRMELERİ
1) CBC-FERRİTİN
• Low hemoglobin: Hypochromic Anemia
• Low hemoglobin affects O2 availability
• It also affects Cytochrome enzymes in the electron transport chain (ETC) because Fe is a cofactor in the cytochrome enzymes
• Low WBC, Neutrophils, and Platelets
• Seen in High Ox Stress States
• Low Ferritin- think ETC cytochrome function
• Yorgunluk şikayteti olanlarda Ferritin >75
2) TEMEL BİYOKİMYA
1. Sodyum (Na)/Potasium (K) – think pump
2. Karbon Dioxide (CO2) – if low then organic acid evaluation
3. Anyon Gap
4. Glukoz/ Insulin/ HgbA1C /Lipids
5. Kalsiyum
6. RBC Mg, Zn, Cu
7. Albumin (Alb), Alkaline Phosphatase (ALP), Bilirubin (Bil) Total
2) TEMEL BİYOKİMYA
8. Aspartate Transaminase (AST),Alanine Transaminase (ALT)
9. GGT: Marker of GSH recycling, oxidative stress exposures, POP accumulation, DMII risk
10. Blood Urea Nitrogen
(BUN)
11. T otal Protein
12. Creatinine (Cr)
13. RBC-Magnesium
Lipoic
Acid
Magnesium
Inter Memb Space
ATP-MG++ COMPLEX
3) Amonyum
• Amonyum yüksekliği oksidatif strese bağlı oluşur ve mito. Disfonksiyonaneden olabilir.
• Amonyum seviyeleri ürik asit hastalıkları ve ve organik asid hastalıklarında yükselir.
Rama Rao KV1, Jayakumar AR, Norenberg MD. Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes. Neurochem Int. 2005 Jul;47(1-2):31-8.
NH
H
H
NH3
4) LAKTAT /PİRUVAT ORANI
• Yüksek L/P
• Inherited disorders of the respiratory chaincomplex
• Respiratory chain defects usually result in L:P ratios >20.
• Tricarboxylic acid cycle disorders
• IF acutely ill – may have false High Ratio
• Düşük L/P
• inherited disorder of pyruvate metabolism
• Defects of the pyruvate dehydrogenase complex result in L:P ratios <10.
• The L/P ratio is characteristically normal in well patients.
LAKATİK ASİDOZA NEDEN OLAN DURUMLAR
Serum laktik
asit düzeyi çok
değerli değil.
Mitokondrial
disfonksiyon
değerlendirme
sinde sabah ilk
idrardaki laktat
düzeyi daha
değerli.
Erroneous Elevations
1. Difficulty with specimen collection
2. Use of a tourniquet
3. Delayed specimen Handling
Systemic Disease
1. Hypoxia
2. Hypotension
3. Shock
4. Sepsis
5. Cardiac failure
6. Renal failure
7. Short Bowel Syndrome (d-lactate)
Cerebral Disease (CSF lactate)
1. Prolonged Seizures
2. Meningitis/ encephalitis
3. Cerebral Ischemia
4. Malignancy
5. Other metabolic diseasesMitochondrial Medicine Society
Metabolic Disease
1. Amino acid disorders
2. Organic acidemias
3. Urea cycle defects
4. Pyruvate metabolism defects
5. Kreb cycle defects
6. Mitochondrial OXPHOS disorders
7. Fatty acid oxidation disorder
8. Disorders of liver-glycogen metabolism
9.Disorders of liver-gluconeogenesis
10.Biotinidase deficiency
11.Thiamine deficiency
Toxin Exposures
1. Carbon Monoxide
2. Methanol
Physiological
1. Anaerobic Exercise
5) KREATİN KİNAZ (CK)
• An enzyme primarily found in the brain, skeletal muscles, and heart
• These tissues all also have very high mitochondrial content
• Indicator of Rhabdomyolysis
• Often mildly elevated with muscle involvement
6) KANTİTATİF PLAZMA AMİNOASİTLERİ
• Global Elevation → Catabolism
• Elevated Alanine*** >450 abnl.
• Alanine/lysine <3:1 normal
• Alanine/Phenylalanine+Tyrosine <4.1normal
• Elevated Glycine
• Elevated Sarcosine
• Elevated Tyrosine
• Elevated Proline
TCA YA GİREN AMİNO ASİTLER
7) İDRARDA ORGANİK ASİTLER
• TCA cycle intermediates elevated ***
• Elevated Ethylmalonate**
• 3-methylglutaconate, 3-methylglutarate**
• Dicarboxylic acids**
• Adipate – product of oxidative rancidity
• Suberate – ox rancidity
• MCTs and Fasting cause false positives
** These commonly occur, but are rarely diagnostic of a particular condition & sarcopenia (low Cr) may cause ratios to be falsely high
Organic Acids Urine Test
ORGANİK ASİTLER
Laboratory Evaluations In Integrative and Functional Medicine - Bralley & Lord
Laboratory Evaluations In Integrative and Functional Medicine - Bralley & Lord
LAKTAT VE SİTRAT YÜKSEK İSE AMONYUM SİKLUSU İÇİN ARJİNİN VE COQ10 AKLA GELİR.
CİDDİ YORGUNLUK VE BAŞAĞRISI
bHB. Succinate, Fum, Mal, HMG yüksek;
CoQ10…. eksik
8) PLAZMA ACETYL-CARNİTİNE
• Düşük Serbest Carnitine
• Yüksek Acyl/Serbest Carnitine oranı
Kalén A, Appelkvist EL, Dallner G. Age-related changes in the lipid compositions of rat and human tissues.Lipids. 1989 Jul;24(7):579-84.
Koenzim Q10 i kullanalım kullandıralım
• 420 patients with New York Heart Association Class III or IV congestive
heart failure.
• Randomized Placebo & CoQ10 (100 mg TID)
• 17 Centers in Denmark, Sweden, Austria, Slovakia, Poland, Hungary, India,
Malaysia, and Australia.
Mortensen, S. A., Rosenfeldt, F., Kumar, A., Dolliner, P., Filipiak, K. J., Pella, D., … Littarru, G. P. (2014). The Effect of Coenzyme Q10 on Morbidity and Mortality in Chronic Heart Failure. JACC: Heart Failure, 2(6), 641-649. doi:10.1016/j.jchf.2014.06.008
Q-SYMBIO TRİAL
• At 3 months - Trend to reduced NT-proBNP
• At 2 yrs.- MACE (major adverse cardiovascular event) reached by
• 14% (29 patients) in CoQ10 vs.
• 25% (55 patients) in Placebo.
• CoQ10 – all P< 0.05• Lower cardiovascular mortality
• Lower Hospitalizations
• Improved NYHA class
• ALL CAUSE MORTALITY
• Fewer adverse events than Placebo!European Society of Cardiology (ESC). "First drug to significantly improve heart failure mortality in over a decade.” ScienceDaily,25 May 2013.
9) COQ10 ÖZET
• Antioxidant, electron shuttle
• Used with
• Hypertension• Heart Failure• Hyperlipidemia
• Depression• Fatigue• Athletic performance
• Exercise Recovery• Neurodegenerative conditions
• AD, PD, HD
• Dose 30-1200 mg
• Absorption highly variable among
preparations
• Ubiquinone interconverts with
Ubiquinol – as long as it is absorbed,
the form is inconsequential.
10) OXİDATİVE STRESS
MARKIRLARI
Ho E, Karimi Galougahi K, Liu CC, Bhindi R, Figtree GA. Biological markers of oxidative stress: Applications to cardiovascular research and practice. Redox Biol. 2013 Oct 8;1:483-91. doi: 10.1016/j.redox.2013.07.006.
DEĞERLENDİRMELER
• Damaged DNA -- 8-OH Deoxyguanosine
• Damaged Fats -- Lipid Peroxides, oxidized LDL, Isoprostane F2
• Damaged Sugars -- HgbA1c, AGEs
• Damaged Proteins -- 3-Nitrotyrosine
• Total Antioxidant Capacity (TAC)
• Micronutrient Deficiency -- serum, RBC, urine(see Functional Nutrition PFC-MVP Biomarkers in your IFM Toolkit)
11. MİTO DNA TESTLERİ
• Mitochondrial DNA (mtDNA)
• Standard mtDNA analysis
• PCR for common point mutations (3243A>G, 8344A>G, 8993T>G or C)
• PCR or Southern blotting for large rearrangements
• Full mtDNA sequencing
• Nuclear DNA testing
• Single gene (MNGIE)
• Small Panel (few-several genes: e.g. COX deficiency, mtDNA depletion)
• Mito-exome (1,100 genes)
• Exome (22,000 genes)
• Genome (all of the DNA)
MİTOKONDRİAL DİSFONKSİYONGÖSTERGELERİ ÖZETİ
• Lactate/Pyruvate
• >20 in Resp. Chain D/O
• <10 Pyruvate DH defect
• Low Magnesium
• Amino Acids
• Elevated Alanine & Proline
• Elevated Glycine
• Elevated Sarcosine
• Elevated Tyrosine
• Ox Stress Markers
• Red ragged fibers on microscopy
• Organic Acid (urine)
• TCA cycle intermediates
• Ethylmalonate, Adipate, Suberate,
• 3-methylglutaconate, 3-methylglutarate
• Dicarboxylic acids
• Acylcarnitines
• Low free carnitine
• Elevated acyl:free carnitine ratio
• Low CoQ10
• Nuclear or Mito DNA variants with metaboliccorrelates
RH Haas et al., The in-depth evaluation of suspected mitochondrial disease, Mol Genet Metab. 2008May;94(1):16-37.
MİTOKONDRİALDİSFONKSİYON DESTEKLERİ
1) Modifiable Lifestyle Factors (MLF):
• Sleep/O2, Exercise, Diet, Stress, Relationships
2) Metabolic Support – precursors, substrates
3) Membrane Support - Lipids & Methylation
4) Oxidative Stress Mitigation
5) Detox Interventions & Inflammation reduction
UYKU PNESİ : DÜŞÜK O2
Lavie L, Oxidative stress in obstructive sleep apnea and intermittent hypoxia Sleep Medicine Reviews (2014), http://dx.doi.org/10.1016/j.smrv.2014.07.003
EGZERSİZ
Oxidative Medicine and Cellular Longevity Volume 2015, Article ID 917085, http://dx.doi.org/10.1155/2015/917085
EGZERSİZ & MİTOKONDRİ BİYOGENEZİ
1. Skeletal muscle mitochondria: a major player in exercise, health and disease. Biochim Biophys Acta. 2014Apr;1840(4):1276-84.2. Image: Wiggs MP. Can endurance exercise preconditioning prevention disuse muscle atrophy? Frontiers in Physiology. 2015;6:63. doi:10.3389/fphys.2015.00063.
THE KETOGENİC DİET (KD)
KETOJENİK & IF
• Reduces inflammation (NF-kB)
• Reduces ROS production
• Reduces apoptosis
• Enhances mitochondrial biogenesis
• Enhances ATP production
• Increases insulin sensitivity
• Increases leptin sensitivity
NÖROLOJİK HASTALIKLARDA KETOJENİK BESLENME
• Drug-resistant epilepsy: proven long-term anticonvulsant effects; neuroplasticity
• Alzheimer’s disease: overcomes impaired glucose metabolism; protects against β-amyloid
• Parkinson’s disease: increased mitochondrial efficiency; overcomes complex I defects
• Brain tumors & other cancers
• Autism spectrum disorders
• Migraines
• Metabolic syndrome
1. Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012 Apr 9;3:59. doi: 10.3389/fphar.2012.00059.2. Akram M. A focused review of the role of ketone bodies in health and disease. J Med Food. 2013 Nov;16(11):965-7. doi: 10.1089/jmf.2012.2592.
BARSAK MİKROBİYATASI KETOJENİK DİYETİN ANTİ-NÖBET ETKİLERİNDE ÇOK ÖNEMLİ
• Changes in the gut microbiota are required for the anti-seizure effects of the KD
• KD microbiota regulate amino acid γ-glutamylation and hippocampal GABA/glutamate
Olson CA, Vuong HE, Yano JM, et al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell. 2018 Jun 14;173(7):1728-1741.e13. doi: 10.1016/j.cell.2018.04.027.
MİTOKONDRİALDİSFONKSİYON DESTEKLERİ
1) Modifiable Lifestyle Factors (MLF):
• Sleep/O2, Exercise, Diet, Stress, Relationships
2) Metabolic Support – precursors, substrates
3) Membrane Support - Lipids & Methylation
4) Oxidative Stress Mitigation
5) Detox Interventions & Inflammation reduction
2) METABOLİK TEDAVİ
1o Metabolic Treatment
• B vitamins (B1, B2, B3, B5, B6, B12, Folate, Biotin)
• Fe, Mg (Mineral Cofactors in ATP production)
• CoQ10
• Carnitine
2o Metabolic Treatment
• Creatine
• AA Rebalance
• SAM-e
KREATİN
• Creatine + Phosphate = phosphocreatine
• Source of high energy phosphate
• Released during anaerobic metabolism• Intracellular buffer for ATP
• Energy shuttle for high-energy-phosphates from mitochondria →cytoplasm
AMİNO ASİT REPLASMANI
Bralley JA, Lord RS. Treatment of chronic fatigue syndrome with specific amino acid supplementation. J App Nutr.1994;46:74–78
MİTOKONDRİAL DİSFONKSİYONDESTEKLERİ
1) Modifiable Lifestyle Factors (MLF):
• Sleep/O2, Exercise, Diet, Stress, Relationships
2) Metabolic Support – precursors, substrates
3) Membrane Support - Lipids & Methylation
4) Oxidative Stress Mitigation
5) Detox Interventions & Inflammation reduction
3) LİPİD SUPPORT/REPLACEMENT
1o Oral Lipid Support*• If fecal fat, GI symptoms, dry skin, consider supporting
Pancreatic Lipase, Bile Acids• Phosphatidyl Choline (PC) 1 – 10 gm / day• Fish oil (EPA/DHA)• Flax Oil (aLA)• Evening Primrose Oil/Borage oil (GLA)
2o IV Lipid Replacement
LİPİDS İN THE MİTO MEMBRANE
Phosphatidyl Choline
Phosphatidyl-Ethanolamine
Phospatidic Acid
Phosphatidyl-Serine
Cardiolipin
MİTOKONDRİAL DİSFONKSİYONDESTEKLERİ
1) Modifiable Lifestyle Factors (MLF):
• Sleep/O2, Exercise, Diet, Stress, Relationships
2) Metabolic Support – precursors, substrates
3) Membrane Support - Lipids & Methylation
4) Oxidative Stress tedavisi
5) Detox Interventions & Inflammation reduction
4) OKSİDATİF STRES TEDAVİSİ
1o Oxidative Stress Treatments• Direct Anti-oxidants: Vitamin-C, Vitamin-A, Vitamin E• ALA, CoQ10• NAC (critical factor for GSH)• Se, Cu, Mn (cofactors for antioxidant enzymes)
2o Oxidative Stress TreatmentsAnti-Oxidant Induction agents
• Sulforaphane-Glucosinolate/ Cruciferous• Resveratrol/Red Wine• Curcumin/Turmeric• EGCG/Green Tea• Pterostilbine/Blueberries
MİTOKONDRİAL DİSFONKSİYONDESTEKLERİ
1) Modifiable Lifestyle Factors (MLF):
• Sleep/O2, Exercise, Diet, Stress, Relationships
2) Metabolic Support – precursors, substrates
3) Membrane Support - Lipids & Methylation
4) Oxidative Stress tedavisi
5) Detox & Inflamasyon tedavileri
5) DETOX
1o - Detox Enzyme Inducers & substrates• Sulphoraphane-Glucosinolate, Quercitin• Silymarin (Milk Thistle)
• NAC – substrate for GSH• TMG – Choline rescue to protect PC in membranes• SAMe - Supports production of GSH from HCY
• Direct Glutathione (GSH):• S-acetyl-GSH, Liposomal-GSH
• Intra-Nasal GSH
• Intravenous GSH
• Nebulized GSH
COQ10
COQ10 – MORTALİTE
CoQ10
• Levels >0.73 umol/l have lowest risk of sudden cardiac death
• A level of >1.7 is ideal
• UTL – no evidence of human deleterious effects. Mouse extrapolated UTL of 500-1200 mg/d
Molyneaux, J Am Coll Cardiol. 2008;52(18):1435-1441. doi:10.1016/j.jacc.2008.07.044
HEPATİC MİTOCHONDRİA
• The liver is one of the richest organs in terms of number and density of mitochondria.
• Each liver cell contains 1000–2000 mitochondria, 20% of the cell volume.
• Most chronic liver diseases are associated with the accumulation of damaged mitochondria.
• Liver mitochondria have unique features since they are the hubthat integrates hepatic metabolism of carbohydrates, lipids, andproteins.
ASPARTATE
AST
(LIVER FUNCTIONS)
GSH İS A POTENTİAL ENERGY DRAİN VİA “LİVER ENZYMES” ALT, AST, LDH
NASH
Düşük SAMe düşük mitokondrial GSH a neden
oluyor.
PC:PE oranı da düşer ve membran akışkanlığı
azalır.
(PC:PE = PhosphatidylCholine:PhosphatidylEthanolamine)
Caballero F, Fernández A, Matías N, et al. Specific Contribution of Methionine and Choline in Nutritional Nonalcoholic Steatohepatitis: IMPACT ON MITOCHONDRIAL S-ADENOSYL-l-METHIONINE AND GLUTATHIONE. The Journal of Biological Chemistry. 2010;285(24):18528-18536.doi:10.1074/jbc.M109.099333.
ATP
Adenine
Ribose
Phosphate groups (high potential energy)
S-ADENOSYLMETHİONİNE(SAME)
folic acid
N-formylfolic acid
N-methylfolic acid +B12
homocysteine
SAHomocysteine
methionine
ONE-CARBON METABOLISM
N
N N
N
CH2 O
OH HO
O
..H3C S.. CH2CH2 CH COOH
NH2
NH2 ATP!!!!!O. O O
P.O P O P OH
O O O
N
N N
N
O
OH HO
NH2
CH3
S-adenosylmethionine+ ..
CH2 S CH2 CH2 CH COOH
NH2
TMG
ATP
Methylation is dependent upon
Mitochondrial Function
SAM E- METHYL (-CH3) VERİCİ
•Phosphatidyl Choline
•CoQ10
• Epinephrine
•Melatonin
• Sarcosine
•Carnitine
•Creatine
•Creatine Phosphate
•Methyl-RNA
•Methyl -DNA
•Methyl B12
•Methoxy-estrogens
•Methoxy-catechols
•Methoxy-Proteins
• Spermidine,Polyamines
•Methylthioadenosine
SAME &ALCOHOLİC LİVERCİRRHOSİS:
A RANDOMİZED, PLACEBO-CONTROLLED, DOUBLE-BLİND, MULTİCENTER CLİNİCAL TRİAL
123 patients with alcoholic cirrhosis were randomly
assigned to receive either 1200 mg of SAMe or a placebo daily
for two years.
Mato Jm, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999Jun;30(6):1081-9.
SAME İN ALCOHOLİC LİVER CİRRHOSİS: DEATH AND LİVER TRANSPLANT PREVENTİON
For patients with Childs class A & B at beginning of study, rate of combined liver transplant or death was..
• 29% for placebo vs.• 12% for SAMe ( p=0.025).
Mato Jm, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999 Jun;30(6):1081-9.
ERKEN DÖNEMDE SAME TEDAVİSİ• Discussion: “…to have a beneficial effect, [SAM-e] treatment
should be maintained for a period longer than 1 year. During the first 12 months of treatment there were no differences between survival curves”
• “Conclusions: The present results indicate that long-term treatment with [SAM-e] may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.”
Mato Jm, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999 Jun;30(6):1081-9.
SAME ÖZET –
• Tükenmişlik durumlarında da antidepresanlar kadar
etkili
• Ağrı giderilmesinde etkili
• Sirozlu hastalarda etkili
• Hafızaya destek
• NASH de destek
• Glutatyon üretimine destek
• Lipid peroksidasyonunu azaltır.
• SOD aktivitesini azaltır
• Hepatit C de faydalı??
Am J Clin Nutr 2002;76(suppl):1172S–6S.BMC MS Disorders, 2004, SAMe vs. celecoxib for tx of OA, 2004,5:6
• Transports fatty acids into mitochondrial matrix for oxidation
• Increase Complex IV activity
• Conditions:• DM, sepsis, renal disease, cardiomyopathy
• Dose up to 2 grams
• RCT on centenarians• Vs. Placebo Improvements in:
• Physical fatigue
• Mental fatigue
• Fatigue severity
• Lower total fat mass
• Increased muscle mass
• Improved cognitive function
L KARNİTİN
SİLYMARİN (MİLK THİSTLE) & T2DPROTEİNURİA
• Human Diabetic Nephropathy study• RDBPCT placebo vs. Silymarin 420 mg
• UACR (urinary albumin/creatinine ratio)
• Improvement sig higher in SLY group• TNF-alpha and MDA also improved
• Silymarin is mitochondrial protectant
Fallahzadeh MK, et al. Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: a randomized, double-blind, placebo-controlled trial. Am J Kidney Dis. 2012 Dec;60(6):896-903. doi:10.1053/j.ajkd.2012.06.005
Federico A, Dallio M, Loguercio C. Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules. 2017 Jan 24;22(2). pii: E191. doi:10.3390/molecules22020191.
KAS KAYBI VE YAŞLANMA
Petersen CM, et al. Skeletal Muscle Mitochondria and Aging: A Review Journal of Aging Research. 2012 Article ID 194821
D3 (20,000 IU QOD x 10-12 wks.) augments muscle mitochondrial maximal oxidative phosphorylation after exercise in symptomatic,
vitamin D deficient individuals.
All patients reported improvement in fatigue after cholecalciferol therapy
Sinha A, Hollingsworth KG, Ball S, Cheetham T. Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle. J Clin Endocrinol Metab. 2013 Mar;98(3):E509-13. doi: 10.1210/jc.2012-3592.
ALA DOZLARI VE ENDİKASYONLARI
• Human uses: Liver disease, Amanita Poisoning, Radiation exposure, Neurodegenerative Dz, DM, Neuropathy, Insulin Resistance, Metabolic Syndrome, Hyper TG, PCOS
• 60 to 2400 mg in divided doses
• Doses >200 mg immediate release can cause hypoglycemia – Extended release formulations preferred
Image: Golbidi S, Badran M, Laher I. Diabetes and Alpha Lipoic Acid. Frontiers in Pharmacology. 2011;2:69.doi:10.3389/fphar.2011.00069.
• Coenzyme Q10*: 30-500 mg/day
• NAC: 1-4 gm/day divided
• Glutathione
• Probiotics
• SAM-e: 200-2400 mg/d divided
• Sulphoraphane to up-regulate AhR and increase GPX and Glutathione Synthase
• Thiamine (B1) 150-300mg/d
(Cofactor for Pyruvate DH)
• Riboflavin (B2)* 10-400 mg/d (Flavin
precursor for Complex I and II)
• Niacin (B3) and NAD
• Pyridoxine (B6)
• Folate, 5-MTHF, leukovorin*
• Peds: 0.5-2.5 mg/kg/d DDX2
• Adult: 2.5-25 mg QD DDX2
• Methyl-B12, 200-5k mg/d +biotin,
pantothenic acid (B5)
• Biotin – FA Oxidation 1-8 mg/d
* Parikh et al. Curr Treat Options Neurol. 2009 November ; 11(6):414–430.
MİTOKONDRİOPATİDE DESTEKLER
• Creatine*• Enhances muscle phosphocreatine• Adult: 10g/day divided• Pediatric: 0.1g/kg/d divided
• Carnitine• 500-2000 mg/day divided
• Alpha-Lipoic Acid*• 60-2400 mg/d divided
• Arginine-AKG• 600-4000 mg/d divided
• Magnesium• Optimized for absorption to bowel
tolerance
• Arginine*• Acute Stroke: 500mg/kg IV per day for 1-3
days, Maint: 150-300 mg/kg divided x3
• Anti-Ox enzyme inducers• SGS, EGCG, Resveratrol, Curcumin,
Pterostilbene
• Antioxidants• Vitamin E 400-800/d
• Vitamin C 2-4 gm/d
• K2 – MK-7• 45-300 mcg/d divided
• Bypass complex III with vitamin C
* Parikh et al. Curr Treat Options Neurol. 2009 November ; 11(6):414–430.
MİTOKONDRİOPATİDE DESTEKLER
Membrane Phospholipids• Phosphatidylcholine• Phosphatidylethanolamine• Doses 500-8000 mg/d
• Lipid Replacement Therapy repairs inner mitochondrial membranes• Combination products have shown 35% decrease in fatigue
and 26% increase in mitochondrial activity
Agadjanyan M, J Chronic Fatigue Syndr. 2003;11(3):23-26.
MİTOKONDRİOPATİDE DESTEKLER
MİTOKONDİRPATİLERDE PEDİATRİK DOZLAR
Compound Dose (mg/kg/d) Rationale
Coenzyme Q10 3 - 15By-pass Complex I defect,
Augment Complex
II/ anti-oxidant
Creatine monohydrate 100 (max 7g/d) Alternative energysource/neuroprotection
Riboflavin 2.5 – 5 Bypass Complex I defect
Alpha-lipoic acid 3.5 – 10 Anti-oxidant, AMPK upregulation
Vitamin E 5 – 10 Anti-oxidant
Vitamin C 5 – 10 Anti-oxidant
L-carnitine 15 – 50 Free fatty Acidtransport/neuroprotection
Thiamine 2.5 – 5 Enhance pyruvate entry intomitochondria
fonksiyoneltipegitimi.com
@fonksiyoneltipegitimi