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April 2014 Teleconference

April 2014 Teleconference
Written By:  Alyssa Davi

April 8th, 2014

April’s teleconference was a review of drugs with known mitochondrial toxicity

It is increasingly accepted that children with autism are under stress at a cellular level.  The question then becomes how to treat this mitochondrial dysfunction and protect cells from future injury.  One direct way to reduce stress and toxicity to cells is by eliminating exposure to medications and chemicals with known mitochondrial toxicity whenever possible. 

Due to the fact that a large number of autistic children will become aging adults over the next several decades, and the natural process of aging and age-related diseases will begin, it is going to be increasingly important for physicians and families to recognize what medications should be avoided in autistic people with mitochondrial dysfunction in order to reduce unnecessary and adverse mitochondrial reactions and toxicity.

Mitochondrial Pharmacogenetics is the study of how mitochondria react to drugs/chemicals based on a person’s genes.  It is an important area of research because short term exposure, as well as long term exposure, to some medications can injure mitochondria.  Therefore, it is important to be aware of what research already exists regarding mitochondrial drug toxicity and this information is especially important information for all physicians treating children with autism and their families. 

In a 2009 MitoAction teleconference  with Dr. James Dykens, Director of Investigative Cellular Toxicity at Pfizer Drug Safety Research &  Development and co-author of the 2008 book, Drug Induced Mitochondrial Dysfunction,  he discusses the relationship of mitochondrial function to overall health and discusses the effects of potential drug-induced mitochondrial toxicity.

To read a summary of this webcast please visit this link:

http://www.mitoaction.org/blog/may-mito-meeting-drug-toxicity-mitochondria

An audio podcast of this lecture is also available through MitoAction titled Drug Toxicity and Mitochondria and dated May 1, 2009.

http://www.mitoaction.org/podcasts/drug-toxicity-and-mitochondria

And follow this link to view Dr. Dykens’ slides that accompanied this teleconference:

http://www.mitoaction.org/files/Dykens%20for%20Mitoaction.pdf

In Drug Induced Mitochondrial Dysfunction (DIMD) it states, “Drugs with even modest effects on mitochondrial pathways, when given over long periods of time, may actually display profound mitochondrial toxicity in tissues with high ATP demand.” (DIMD; page 476)  Per Dr. Bruce Cohen, a pediatric neurologist from Akron Children’s hospital, “Organs with high energy demands are especially vulnerable to mitochondrial injury; these include but are not limited to, the brain, muscle, nerve, cochlear, kidney, liver and the pancreas. (http://www.orlive.com/akronchildrens/mitochondrial)

Therefore, part of a good management plan for children and adults with known mitochondrial dysfunction includes limiting exposure to medications with known mitochondrial toxicity whenever possible.

What do we know about drug safety testing?

A study completed by a British Medical Journal found that less than half of all drug trials funded by the U.S. National Institute of Health were published within 30 months of being finished.  Previous studies have found that one quarter to one half of drug studies went unpublished.  This is due to several reasons; one, results could hurt sales of a drug, two, researchers feared the release of results that contradict their original hypothesis, and three, some journals are uninterested in publishing negative results. This is concerning, as not releasing this information regarding drug safety could put patients at risk for adverse reactions. 

What is known about the way mitochondria are injured by medications?

In the book Drug Induced Mitochondrial Dysfunction, they state “Mitochondria are often the target of drug-induced toxicity.  This can occur through several mechanisms, such as inhibition of the oxidative phosphorylation complexes, uncoupling of the electron transport from ATP synthesis, redox cycling of the xenobiotic, inhibition of the Krebs Cycle, inhibition of B-fatty acid oxidation, irreversible opening of the mitochondrial permeability transition pore, inhibition of transporters within the mitochondrial membranes and impairment of either mtDNA synthesis or mtDNA-encoded protein synthesis.”  (DIMD; page 398)

In Drug Induced Mitochondrial Dysfunction, it states that mitochondrial protein synthesis is more closely related to bacterial endosymbiont than cytoplasmic protein synthesis.  “As a result, antibiotics that bind to the bacterial ribosome and target bacterial protein synthesis may also bind to the mitochondrial ribosome and inhibit mitochondrial protein synthesis” (DIMD; page 465)Of interest, is the fact that “toxicity caused by inhibition of mitochondrial protein synthesis is not immediately observed.  Mitochondria turn over slowly in many tissues.  Depending on the degree of inhibition, time is required for the amount of mitochondrial machinery and the ability to synthesize ATP fall below a pathogenic threshold value.” (DIMD; page 465)  This delayed reaction can make connecting the adverse symptoms to an environmental exposure (like a medication or chemical) very difficult as it happens slowly, over time, as mitochondrial function falls below a critical threshold and the individual then becomes symptomatic. 

“Classes of antibiotics that bind to the bacterial ribosome and inhibit bacterial protein synthesis include chloramphenicol, tetracyclines, aminoglycosides, macrolides, lincosamides, and most recently oxazolidinones.”   And in other studies, linezolid inhibited mitochondrial translation.  “A number of in vivo studies have shown that the activity and amount of Complex I, III, and IV, which contain mitochondrial encoded subunits are significantly reduced in linezolid-treated cultured human cells, in cells and tissues from treated patients and in treated rats.”  (DIMD; page 467) 

Fluoroquinolones, a broad spectrum antibiotic, still frequently prescribed for urinary tract infections, upper respiratory infections, and pneumonia as well as ear infections received the FDA’s strongest alert warning, a “black box warning”, for increased risk of tendinitis and tendon rupture when taking this medication.  Cipro (also within this call of antibiotics) also received a “black box warning” from the FDA but is still being used for some pediatric patients.  In 2011, a second black box warning was added to this fluoroquinolones stating there is a risk of fluoroquinolone-associated Myasthenia Gravis Exacerbation but it is still being prescribed today.  Fluoroquinolones have been found to reduce glutathione (GSH) and increase reactive oxygen species (ROS).  “The order of quinolone potency in depleting GSH was trovafloxacin, grepafloxacin, ciprofloxacin, gatifloxacin, clinafloxacin, levofloxacin.”  (DIMD; page 107) Anecdotal regressions have been seen in autistic children when taking Cipro (floxacin) for ear infections and debilitating CNS and muscle symptoms, as well as tendon injury, from fluoroquinolones have been reported.

Another mechanism of drug-induced mitochondrial injury seems to be the formation of “megamitochondria”.  This is when multiple mitochondria fuse together.   It is hypothesized that this may occur when a cell is exposed to a prolonged period of oxidative stress and that this aberrant mitochondrial function takes place “as an adaptive change because mitochondria form less reactive oxygen species (ROS) and maintain ATP production in this state.” (DIMD; page 108)

What medications are known to cause mitochondrial injury?

In a webcast lecture called, The Mitochondrial Toxicity of Prescription Pharmacopoeia given by Dr. Bruce H. Cohen, Director of Pediatric Neurology at Akron Children’s Hospital, he discusses medications with known mitochondrial toxicity.  Dr. Cohen states that there are hundreds of medications known to inhibit mitochondrial complex I function.

To listen to this excellent audio-cast please visit this link:

http://www.orlive.com/akronchildrens/mitochondrial

In June of 2010, Dr. Katherine Sims, a pediatric neurologist and researcher from Boston's Massachusetts General Hospital, presented an audio-conference through MitoAction and she identified many drugs that have known mitochondrial toxicity.  To listen to this podcast please visit this link:

http://www.mitoaction.org/blog/medication-exposures-mitochondrial-toxicity

This is a combined table of those medications discussed by Dr. Cohen, Dr. Simms and those discussed in Drug Induced Mitochondrial Dysfunction which are known to impair mitochondrial function.  Many of these drugs are still prescribed and used in adults and children.

Table 1-

Reported Drugs with Mitochondrial Toxicity

Pharmacologic Category

Medication

Adverse Reaction

Symptoms

1.  Anticonvulsants

Valproate (Depakote, Valproic Acid)

sequesters and depletes carnitine; decreases fatty acid oxidation; Krebs cycle, Electron Transport Chain (ETC) activity and oxidative phosphorylation; Complex IV inhibition

Hepatopathy

 

Dantrolene

inhibits Complex I

 

 

Phenytoin

inhibits Complex I

 

2.  Psychotropics

 

 

 

    a.  antidepressants

Amitriptyline (Elavil)

causes autonomic dysfunction

 

 

Amoxapine

 

 

 

Fluoxetine (Prozac)

inhibits OXPHOS  (Cohen) Interferes with the lipid bilayer of the inner mitochondrial membrane (particularly at high dose) (103)

 

 

Citalopram (Cipramil)

 

 

    b.  antipsychotics

Chlorpromazine (Thorazine)

inhibits brain and liver mitochondrial respiration

 

 

Haloperidol (Haldol), Fluphenazine (Prolixin)

depletes glutathione and inhibits mitochondrial respiration in brain and Complex I activity

 

 

Resperidone (Risperdol)

 

 

    c.  Barbituates

Phenobarbital

reduces mitochondrial protein synthesis; decrease number and size of mitochondria

 

 

Secobarbital (Seconal)

inhibits Complex I

 

 

Butalbital (Fiorinal)

 

 

 

Amobarbital (Amytal)

 

 

 

Pentobarbital (Nembutal)

 

 

    d.  Anxiety Medications- Benzodiazepines-

Alprazolam (Xanax)

inhibit adenosine nucleotide translocase

 

 

Diazepam (Valium, Diastat)

inhibit adenosine nucleotide translocase

 

3.  Cholesterol medications

Statins          Cerivastatin    Fluvastatin   Atrovastatin  Simvastatin    Lovastatin                   

reduce endogenous Coenzyme Q10,   inhibits Complex III, induces mitochondrial permeability transition (MPT)

myopathy

 

Bile acids- Cholestyramine

inhibits ETC

 

 

Ciprofibrate

inhibits Complex I

 

 

Fenofibrate

inhibits Complex I

 

 

Clofibrate

inhibits Complex I

 

4.  Analgesics/anti-inflammatory

ASA (Aspirin, Acetylsalicylic Acid)

inhibits ETC and uncouples oxidative-phosphorylation

Reye Syndrome (hepatic failure)

 

Acetaminophen (Tylenol)

increases oxidative stress

Hepatopathy

 

Ibuprofen (Advil and Motrin)

 inhibits fatty acid oxidation and beta oxidation of medium and short chain fatty acids

 

 

Naproxen (Aleve)

 

 

 

Indomethacin (Indocin)

 

 

 

Diclofenac

 

 

5.  Antibiotics

Tetracycline

Inhibits beta-oxidation; inhibits mitochondrial protein synthesis and fatty acid oxidation

 

 

Fluoroquinolones- Trovafloxacin, Grepafloxacin, Ciprofloxacin, Gatifloxacin, Clinafloxacin, Levofloxacin

depletes glutathione and increases reactive oxygen species

 

 

Minocycline

Inhibits beta-oxidation; inhibits mitochondrial protein synthesis

 

 

Chloramphenicol

inhibits mitochondrial protein synthesis

 

 

Aminoglycosides       streptomycin gentamycin     neomycin       kanamycin

impairs mtDNA translation

hearing loss; cardiac toxicity and renal toxicity

 

Linezolid (Zyvox)

inhibit mitochondrial translation- DIMD

lactic acidosis; optic and peripheral neuropathy

 

Antimycin

inhibits Complex III

 

 

Cephaloidine

inhibits Complex IV

 

 

Macrolide- erythromycin

inhibits translation

rapid vision loss in people with Leber Hereditary Optic Neuropathy ( LHON) 11778 mutation

6.  Anti-arrhythmic

Amiodarone

inhibits beta-oxidation

 

7.  Steroids

 

reduce transmembrane mitochondrial potential

reports of deterioration in people with Kearns-Sayre Syndrome

8.  Anti-viral

Interferon

impairs mtDNA transcription

 

9.  Anti-retrovirals

Zidovudine

impairs mtDNA replication which causes mtDNA depletion, decreases Complex I and Complex IV activity

carnitine deficiency; lactic acidosis; lipodystrophy; neuropathy; myopathy; hypatic dysfunction

10.  Cancer medications

Doxorubicine (Adriamycin)

 

 

 

Cis-platinum

impairs mtDNA transcription

hearing loss; cardiac toxicity, renal toxicity

 

Tamoxifen

depletes ATP, inhibits Complex III, IV, V

 

 

Cyclophosphamide

inhibits Complex II

 

11.  Pain medication

Capsaisin

Inhibits Complex I

 

12.  Anti-fungal medication

Ketoconazole

Inhibits Complex II

 

13.  Diabetes Medication

Biguanides (Metformin)

inhibits oxidative-phosphorylation; enhances glycolysis; inhibits Complex I

 

14.  Anesthesia

 

 

 

    a.  General

Halothane (Fluothane)

inhibits Complex I

 

 

Isoflurane

inhibits Complex III

 

 

Sevoflurane

inhibits Complex III

 

 

Propofal

inhibits mitochondrial function

 
 

Nitrous Oxide

inhibits cis-acotinase and iron-containing electron electron enzymes; affecting energy production

 

    b.  Local

Bupivacaine (Marcaine)

uncouples oxidation and phosphorylation; inhibits Complex I

increased risk of heart rhythm disturbances; uncouples heart cell mitochondria

 

Lidocaine (Xylocaine)

inhibits Complex I

 

    

Sources:

   

1.  Cohen, BH (August 11, 2011) The Mitochondrial Toxicity of Prescription Pharmacopoeia, webcast, Akron Children's Hospital: http://www.orlive.com/akronchildrens/mitochondrial

2.  Sims, K (June 4, 2010) Table of Reported Drugs with Mitochondrial Toxicity, audiocast, MitoAction: http://www.mitoaction.org/blog/medication-exposures-mitochondrial-toxicity

3.  Dykens, JA, Will, Yvonne. Drug-Induced Mitochondrial Dysfunction. New Jersey: Wiley; 2008.

In 2012, Barry Smeltzer published an article in Autism Science Digest called, Environmental Agents, Pharmaceuticals, and Mitochondrial Dysfunction.  Below is a link to this article and relevant tables.

http://www.healingprovisions.net/PDF/ASD05_Smeltzer.pdf

 

Table 2-

Medications documented to induce mitochondrial damage

Condition or drug class*

Medications*

Alcoholism

Disulfiram (Antabuse®)

Analgesics (for pain), nonsteroidal anti-inflammatory drugs (NSAID s)

Aspirin, acetaminophen (Tylenol), diclofenac (Voltaren®, Voltarol®, Diclon®, Dicloflex®, Difen, and Cataflam®), fenoprofen (Nalfon®),Indomethacin (Indocin®, Indocid®, Indochron E-R®, Indocin-SR®), Naproxen (Aleve®, Naprosyn®)

Anesthetics

Bupivacaine, lidocaine, propofol

Angina

Perhexiline, amiodarone (Cordarone®), diethylaminoethoxyhexesterol (DEAEH)

Antiarrhythmic (regulating heartbeat)

Amiodarone (Cordarone®)

Antibiotics

Tetracycline, antimycin A

Antidepressants

Amitriptyline (Lentizol), amoxapine (Asendis), citalopram (Cipramil), fluoxetine (Prozac, Symbyax, Sarafem, Fontex, Foxetin,

Ladose, Fluctin, Prodep, Fludac, Oxetin, Seronil, Lovan)

Antipsychotics

Chlorpromazine, fluphenazine, haloperidol, risperidone, quetiapine, clozapine, olanzapine

Anxiety

Alprazolam (Xanax®), diazepam (Valium, Diastat)

Barbiturates

Amobarbital (Amytal®), aprobarbital, butabarbital, butalbital (Fiorinal®), hexobarbital (Sombulex®), methylphenobarbital (Mebaral®),

pentobarbital (Nembutal®), phenobarbital (Luminal®), primidone, propofol, secobarbital (Seconal®, Talbutal®), thiobarbital

Cholesterol

Statins: atorvastatin (Lipitor®, Torvast®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®), pitavastatin (Livalo®, Pitava®),

pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®), simvastatin (Zocor®, Lipex®)

Bile acids: cholestyramine (Questran®), clofibrate (Atromid-S®), ciprofibrate (Modalim®), colestipol (Colestid®), colesevelam (Welchol®)

Cancer (chemotherapy)

Mitomycin C, profiromycin, adriamycin (also called doxorubicin and hydroxydaunorubicin and included in chemotherapeutic

regimens ABVD, CHOP, and FAC)

Dementia

Tacrine (Cognex®), Galantamine (Reminyl®)

Diabetes

Metformin (Fortamet®, Glucophage®, Glucophage XR, Riomet1), troglitazone, rosiglitazone, buformin

HIV/AID S

Atripla, Combivir®, Emtriva®, Epivir® (abacavir sulfate), Epzicom, Hivid® (ddC, zalcitabine), Retrovir® (AZT, ZDV, zidovudine),

Trizivir®, Truvada®, Videx® (ddI, didanosine), Videx® EC, Viread®, Zerit® (d4T, stavudine), Ziagen®, Racivir®

Epilepsy/seizure

Valproic acid (Depacon®, Depakene®, Depakene syrup, Depakote®, Depakote ER, Depakote sprinkle, divalproex sodium)

Mood stabilizers

Lithium

Parkinson’s disease

Tolcapone (Tasmarm, Entacapone) (COMTanm, also in the combination drug Stalevom)

Source: Adapted from Table 5 in Neustadt J, Pieczenik SR. Medication-induced mitochondrial damage and disease.

Mol Nutr Food Res. 2008 Jul;52(7):780-8.

 

Table 3-

Organ systems affected by medication-induced mitochondrial toxicity

Cardiovascular toxicity

Hepatic (LIVER) toxicity

Renal (KIDNEY) toxicity

Nucleoside reverse transcriptase

Isoniazid

Doxorubicin (DO X)

inhibitors (NRTI s)

Valproic acid

Cysplatin

Zidovudine (AZT )

Tamoxifen

Gentamicin

Bupivacaine

Flutamide

Cyclosporin A

Lidocaine

Lamivudine

Ifosfamide

Thiazohdinediones (TZD )

Zidovudine (AZT )

Statins

Doxorubicin (DO X)

Zalcitabine

Tenofovir

Sorafenib

Phenoformin

 

Daunorubicin

Metformin

 

Epirubicin

Nefazodone

 

Idarubicin

Abacavir

 

Celecoxib

Didanosine

 

Diclofenac

Nevirapine

 

Ibuprofen

Tenofovir

 

Indomethacin

Stavudine

 

Mefenamic acid

Ketoconazole

 

Meloxicam

Divalproex Sodium

 

Naproxen

 

 

Piroxicam

 

 

Sulindac

 

 

Atenolol

 

 

Pioglitazone

 

 

Rosiglitazone

 

 

Source: Dykens JA, Will Y. The significance of mitochondrial toxicity testing in drug development. Drug Discov Today.  2007 Sep;12(17-18):777-85. Epub 2007 Aug 22.

Table 4-

Mitochondrial Impairment of Drugs Receiving Black Box Warnings

 

Hepatotoxicity                                              Cardiovascular

Antivirals

Antibiotics

Anthracyclines

Anti-Cancer

Abacavir

Isoniazid

Daunorubicin

Arsenic Trioxide

Didanosine

Ketoconazole (oral)

Doxorubicin

Cetuximab

Emtricitabine

Streptozocin

Epirubicin

Denileukin diftitox

Entecavir

Trovafloxacin

Idarubicin

Mitoxantrone

Emtricitabine

 

 

Tamoxifen

Lamivudine

CNS

NSAIDs

 

Nevirapine

Dantrolene

Celecoxib

Beta-Blocker

Telbivudine

Divalproex Sodium

Diclofenac

Atenolol

Tenofovir

Felbamate

Diflunisal

 

Tipranavir

Naltrexone

Etodolac

Antiarhythmic

Stavudine

Nefazodone

Fenoprofen

Amiodarone (oral)

Zalcitabine

ValproicAcid

and Alper’s

Ibuprofen

Disopyramide

Zidovudine

 

Indomethacin

Dofetilide

 

Hypertension

Ketoprofen

Ibutilide

Anti-Cancer

Bosentan

Mefenamic acid

 

Flutamide

 

Meloxicam

CNS

Dacarbazine

 

Naproxen

Amphetamines

Gemtuzumab

 

Nabumetone

Atomoxetin

Methotrexate

 

Oxaprozin

Droperidol

Pentostatin

 

Piroxicam

Methamphetamine

Tamoxifen

 

Salsalate

Pergolide

 

 

Sulindac

 

 

 

Thioridazine

Diabetes

Elevated serum liver enzymes (AST, ALT) reflect hepatocyte death.

Tolmetin

Pioglitazone

 

Rosiglitazone

 

 

Anaesthetic

 

Lactic acidosis reflects mitochondrial impairment.

Bupivacaine

 

 

 

 

 

 

 

Source: Dr. James Dykens, Director of Investigative Cellular Toxicity at Pfizer Drug Safety Research &  Development

http://www.mitoaction.org/files/Dykens%20for%20Mitoaction.pdf

The kidneys and liver are organs with high susceptibility to mitochondrial injury.  In Drug Induced Mitochondrial Dysfunction, the authors state, “More than 1000 drugs are known to be hepatotoxic (liver toxic).” (DIMD; page 144)  “Drug Induced Liver Injury (DILI) is a major problem for the pharmaceutical industry, because it is a frequent cause of the failure of drug molecules to get approved for human use, and a frequent cause for court litigations and/or drug withdrawal after marketing.” (DIMD; page 145) 

According to the National Institute of Health, acetaminophen overdose is one of the most common poisonings worldwide and a frequent cause of drug induced liver injury.  There are over 600 over-the-counter medications (not requiring a prescription) available for sale today that contain acetaminophen.  As a response, the manufacturers of Tylenol (which is acetaminophen and a commonly used over-the-counter medication in children), recently added a warning on their caps: "Contains acetaminophen. Always read the label." Anecdotally, there are a group of parents who have children diagnosed with autism who believe overuse of acetaminophen or use of acetaminophen with the administration of vaccines may have played some role in the development of their child’s autistic symptoms. 

What research has been done on the adverse effects of anesthesia and sedation on mitochondrial function?

Many medications have been identified that can be problematic for people with mitochondrial disease during sedation and anesthesia.   See Table 1 above.  Anecdotally, there have been many reports of severe regressions in autistic children following inhalational anesthesias.  This topic is outside the scope of this article, but to read more about anesthesia risks, protocols and precautions for people with mitochondrial disease visit this link:

http://www.mitoaction.org/autism/december-2011-teleconference

Conclusion:

Some over the counter medications and prescription medications have risks of mitochondrial toxicity in susceptible individuals.  It is important to weigh the pros and cons of any medication (before taking it) under the guidance of a knowledgeable physician.  However, in a child with known mitochondrial dysfunction, if the medication adversely affects mitochondria, this need is increased, as developmental regressions and worsening of neurological symptoms can occur.

Mitochondrial drug toxicity is a serious health concern that has significant medical consequences for a cohort of susceptible people.  “The study of mitochondrial pharmacogenetics is just beginning, but with increased recognition that mitochondria play a pathogenic role in many neurodegenerative disorders, these efforts will lead to better, less toxic drugs with “greater specificity”. (DIMD; page 136)

Please join us on July 8th, 2014 for our next teleconference when we will continue this discussion and discuss toxins in our environment that have known mitochondrial toxicity

To participate in this resource-share by telephone, please call 1-866-414-2828 and enter code 017921# at the prompt.