Drugs linked to mitochondrial toxicity (eg: tetracycline, minocycline, metformin)

[Tunguska]

In researching this to find a link for this thread, I just learned that Dr. Jay Cohen passed away in Dec 2015. I am shocked and had no idea. I consulted with him in 2010 when I had a neurotoxic reaction to Levaquin and he was a very kind man and smart doctor.

I either missed or forgot about that too (well I hope I didn't just forget). That's quite a loss.

 

[Hip]

http://www.myquinstory.info/fda-makes-label-changes-to-the-fluoroquinolones/

I thought that the Citizen Petition had led to official changes in the FDA label of FQ antibiotics re: mitochondrial toxicity but apparently this has not gone through yet. I believe that it will one day.

From your above link, it says:

the FDA has denied Dr. Bennet’s Citizen Petition on mitochondrial toxicity. In a statement outlining the reason for the petition denial that FDA stated "The literature discussed in the Review, which is based primarily on animal data and in vitro data, provides insufficient support for the proposition that levofloxacin causes mitochondrial toxicity, and that this toxicity results in levofloxacin-induced peripheral neuropathy."

I don't think FDA are denying the damaging effects that fluoroquinolones can have, but they are saying at present there is not enough evidence to state with certainty that the damage comes from mitochondrial toxicity. But the evidence may well become available with new studies (or alternatively, new studies might find that fluoroquinolones cause damage by mechanisms other than mitochondrial toxicity).

I would put fluoroquinolones in the "potentially may cause mitochondrial toxicity" category at the moment, until new studies come in. I wonder why they are not included in the mitochondrial toxicity list from www.mitoaction.org?

 

[Gingergrrl]

I would put fluoroquinolones in the "potentially may cause mitochondrial toxicity" category at the moment, until new studies come in.

I found a lot of links that stated different things re: FQ's and Mito toxicity and debated which ones to post. Some state that it causes Mito toxicity and some leave it in the maybe category. I lack the science background to know if Mito toxicity is the mechanism but there is something seriously wrong with an antibiotic that almost tore the tendon in my right arm after taking seven pills. Another black box warning that advocates are fighting for is that FQ's are causing retinal detachment in the eyes (thank God this part did not happen to me!).

 

[Learner1]

How do you know?

Because all my symptoms and lab work point to it, and I have responded well to mitochondria targeted therapies.

 

[Learner1]

From your above link, it says:


I don't think FDA are denying the damaging effects that fluoroquinolones can have, but they are saying at present there is not enough evidence to state with certainty that the damage comes from mitochondrial toxicity. But the evidence may well become available with new studies (or alternatively, new studies might find that fluoroquinolones cause damage by mechanisms other than mitochondrial toxicity).

I would put fluoroquinolones in the "potentially may cause mitochondrial toxicity" category at the moment, until new studies come in. I wonder why they are not included in the mitochondrial toxicity list from www.mitoaction.org?

Because the mitoaction list is not comprehensive and it's out of date. At the UMDF Conference, it was made quite clear to the clinicians that 75% of the many drugs tested by the researchers were in some way toxic to mitochondria.

As for fluoroquinolones, this article discusses the topic, with several links to research:
http://www.hormonesmatter.com/fluoroquinolone-time-bomb-mitochondria-damage/

 

[mariovitali]

Because all my symptoms and lab work point to it, and I have responded well to mitochondria targeted therapies.

What kind of therapy are you taking / have tried?

 

[Learner1]

What kind of therapy are you taking / have tried?

NT Factor, phospatidyl choline, CoQ10, l-carnitine, acetyl-l-carnitine, d-ribose, NADH, manganese, 5-MTHF, B12, magnesium, B6, and B2.

 

[mariovitali]

NT Factor, phospatidyl choline, CoQ10, l-carnitine, acetyl-l-carnitine, d-ribose, NADH, manganese, 5-MTHF, B12, magnesium, B6, and B2.

OK Thanks.

Have you ever performed a Fibroscan? It checks for any Liver fibrosis.

 

[Learner1]

No, I looked it up, though. It says "Liver biopsies are useful for distinguishing between viruses affecting the liver and other causes of chronic liver disease, whereas transient elastography can only test the stiffness and steatosis." I'm not sure it would be useful for me - I've had CT scans and regular labs measuring liver markers.

Also, today's post over on Health Rising has a good discussion of mitochondria.

https://www.healthrising.org/blog/2...-fibromyalgia-chronic-fatigue-syndrome-mecfs/

Fixing peroxynitrite damage and giving mitochondria the ingredients they need are critical. I'm doing a combo of Martin Pall's, Sarah Myhill's, and Garth Nicolson's programs, but my treatment is based on lab work suggesting the needed components of my protocol.

 

[mariovitali]

@Learner1

There are many cases where Liver Disease goes unnoticed and Liver Enzymes appear to be normal.

Since you are looking at the Mitochondrial aspect, have a look at this patent :


https://www.google.ch/patents/US20140031432

and also this post might be of interest :


http://algogenomics.blogspot.com/2017/05/results-from-classification-analysis.html

 

[Learner1]

Interesting angle. I do take a good dose of vitamin K daily and eat lots of dark leafy greens, as I agree vitamin K is important for a lot of reasons, including inflection fighting and bone health. This adds to its usefulness.

I've had abnormal liver numbers, mostly AST, ALT, and serum ferritin. As a cancer survivor, my doctors were quite concerned. I'm not at risk for fatty liver disease or cirrhosis.

But, I have had, and been treated for, significant arsenic, cadmium, and lead toxicity, which I expect is the case with many PWME, from the reactions to methylating nutrients I read about on this site. Cort alluded to this too in the peroxynitrite article and in the comments after.

Even though I'd been tested for the metals and chelated previously to remove mercury and platinum, it wasn't until I started using PolyMVA (forgot it on my previous list, sorry) that they started coming out of me, and were measurable on a blood test.

PolyMVA is an alpha lipoic acid polymer which can get into the mitochondria and pull toxins out, which then need to be moved through Phase 1, 2, and 3 detox, which happens mainly in the liver.

At the United Mitochondrial Disease Conference, they showed slides of mitochondria filled with arsenic - they'd fed rats arsenic to see what would happen and took pictures of their mitochondria to prove the point.

Using the PolyMVA initially made me sicker as the metals came out of me, but my doctor beefed up my detox nutrients, and over time, the toxins havegone away, and my liver numbers have improved.

They're still higher than normal, but we believe its because I have a chlamydia pneumoniae infection active in my liver, which is my current project.

I was worried about my liver, but the radiologist and I looked at the CT images, and he said it looked fantastic. I could do a biopsy, but I'm doing a lot of nutrient supplementation, which I believe is helping.

As for my mitochondria, I don't have primary mitochondrial disease, which is genetic, like the MELAS, Leigh syndrome, etc in your article.

I do have some SNPs which make BH4 recycling difficult, make me prone to peroxynitrite damage, and make me unable to easily replenish mitochondrial membranes, sort of a perfect storm...

Removing toxicity has greatly increased my energy over the past year and improved my liver function, but as we all know, this is a complex disease, and there are other challenges to face.

 

[mariovitali]

@Learner1

Hmm, yes all makes sense to me apart from the CT scan you mentioned. You see, i am not sure as to whether Liver Fibrosis can be identified with a CT Scan.

From what i've read so far (but may be i missed it!) it seems that Fibroscan and Liver Biopsy are used For Liver Fibrosis assessment. The problem with Fibroscan is that it gets more accurate as the extension of damage increases (so it may miss fibrosis in the early stages).

If you could check with a Hepatologist what i said about getting for Liver Fibrosis a *definite* assessment it would be great, especially since your Liver enzymes are still elevated. Are you taking any antibiotics by the way? If yes which kind?

 

[Learner1]

I was on rifampin and azythromycin and am currently doing ozone and other immunomodulating therapies.

My enzymes are ok now, and my liver seems to be doing its job. Serum ferritin is still a little high, but nothing like it was, and we have some good ideas why.

But, I appreciate knowing about FibroScan...its always good to know what tools are available. Tell me, though, if it showed fibrosis, etc. what treatment is there? It makes sense to me to keep feeding the body good nutritional building blocks to try to repair, which I'm already doing... does "modern" medicine have a better answer?

Thanks much for expanding my thinking...

 

[mariovitali]

No problem @Learner1

Regarding Rifampin, this is Rifampicin. From Wikipedia for Rifampicin :

The most serious adverse effect is hepatotoxicity, and patients receiving it often undergo baseline and frequent liver function tests to detect early liver damage.

The more common side effects include fever, gastrointestinal disturbances, rashes, and immunological reactions. Taking rifampicin usually causes certain bodily fluids, such as urine, sweat, and tears, to become orange-red in color, a benign side effect that nonetheless can be frightening if it is not expected. This may also be used to monitor effective absorption of the drug (if drug color is not seen in the urine, the patient may wish to move the drug dose farther in time from food or milk intake). The discolorization of sweat and tears is not directly noticeable, but sweat may stain light clothing orange, and tears may permanently stain soft contact lenses. Since rifampicin may be excreted in breast milk, breast feeding should be avoided while it is being taken.

Other adverse effects include:

• Liver toxicity — hepatitis, liver failure in severe cases
• Respiratory — breathlessness
• Cutaneous — flushing, pruritus, rash, hyperpigmentation,[27] redness and watering of eyes
• Abdominal — nausea, vomiting, abdominal cramps, diarrhea
• Flu-like symptoms — chills, fever, headache, arthralgia, and malaise. Rifampicin has good penetration into the brain, and this may directly explain some malaise and dysphoria in a minority of users.
• Allergic reaction — rashes, itching, swelling of the tongue or throat, severe dizziness, and trouble breathing[28]

Now i am not suggesting that Rifampicin has caused you Liver Damage! It's just that i always feel that one should be on the safe side. I do read a lot of References saying that one may have Liver Damage while tests may be ok.

I would like to have a definite answer from a Hepatologist -make them three- as to what is the most precise test to *definitely* rule out any Liver Damage.

 

[Learner1]

Yes, I know. My liver has been better AFTER the rifampin. I'm getting copious liver support nutrients, but I agree, and neither my doctor nor I are keen on using antibiotics, but I have a very entrenched infection.

You are very wise to warn people about the risk of damage.

And, I went to a liver doctor who told me that my supplements were causing all of my problems and to stop taking them, that the liver doesn't get infections, and hard sold me on a colonoscopy as he owns the machine! Some help that was, and a total waste of money...

 

[Chocolove]

Mitochondrial Disorders: Medicines to Avoid
Prescriber Update 38(2): 29-30
June 2017

Medicines can affect many of the different functions within the mitochondria.

The mitochondrial respiratory chain (MRC) is composed of five enzyme complexes: I-V and uses cytochrome c and coenzyme Q10, which act as electron carriers. Pharmacotherapy induced MRC dysfunction may result from the direct inhibition of one or more of the enzyme complexes or uncoupling of oxidative phosphorylation. As the enzyme complexes are susceptible to free radical-induced oxidative damage, medicines that cause oxidative stress may also result in MRC toxicity. The replication of mtDNA and protein synthesis may also be affected by medicines 2,4.

High quality evidence of the effects of medicines in people with mitochondrial disease is sparse. Much of the available information is derived from in vitro or animal studies. Additionally, due to the great diversity in mitochondrial disease manifestations, conflicting outcomes can be reported in different patients for the same medicine. Consensus appears to be lacking on which medicines should be completely avoided and which may be used with close monitoring1–5. A summary of the available data is provided in Table 1.

Table 1: Medicines to avoid in patients with mitochondrial disease1-5*...
Medicine .... Proposed mechanism .... Adverse effects related to mitochondrial toxicity
...

Sertraline... Inhibits MRC I and V, inhibits oxidative phosphorylation ... Hepatotoxicity
...

http://www.medsafe.govt.nz/profs/PUArticles/June2017/MitochondrialDisordersMedicinestoAvoid.htm

 

[Learner1]

Here are some other articles on drugs and mitochondrial toxicity:

https://www.ncbi.nlm.nih.gov/pubmed/?term=Nadanaciva S[Author]&cauthor=true&cauthor_uid=21718246

http://www.sciencedirect.com/science/article/pii/S0168827810010664

 

[Chocolove]

Interesting article that...@learner1....Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

More than a 1000 drugs of the modern pharmacopoeia can induce liver injury with different clinical presentations [1,2]. In the most severe cases, drug-induced liver injury (DILI) can require liver transplantation or lead to the death of the patient [3]....

Importantly, drug-induced mitochondrial dysfunction can be due to the drug itself and/or to reactive metabolites generated through cytochrome P450-mediated metabolism [5,6,8].

Mitochondrial dysfunction is a generic term, which includes alteration of different metabolic pathways and damage to mitochondrial components.

In addition, these mitochondrial disturbances can have a variety of deleterious consequences, such as oxidative stress, energy shortage, accumulation of triglycerides (steatosis), and cell death.

 

[Chocolove]

Biochim Biophys Acta. Author manuscript; available in PMC 2012 Jun 4.

Published in final edited form as:
Biochim Biophys Acta. 2012 Feb; 1822(2): 185–195.
Published online 2011 Oct 17. doi: 10.1016/j.bbadis.2011.10.008
PMCID: PMC3366688
NIHMSID: NIHMS374044
Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis
Ana P. Gomes,a,b Filipe V. Duarte,a Patricia Nunes,a Basil P. Hubbard,b João S. Teodoro,a Ana T. Varela,a John G.

Here, we demonstrate that BBR supplementation increases skeletal muscle mitochondrial biogenesis and improves mitochondrial function in a rodent model of diet induced obesity. Furthermore, we show that these effects are SIRT1-dependent. These effects are associated with significant reductions in adiposity and improvements in overall insulin sensitivity...

3.3. Mitochondrial function is rescued by BBR
Mitochondria play an important role in the development of insulin resistance and hyperglycemia [8,44]. Boosting mitochondrial activity provides, at least in part, a potential mechanism by which several therapeutic agents act [19–21].

In order to address whether the beneficial effects of Berberine (BBR) are related to its ability to alter mitochondrial function, we evaluated the function of isolated mitochondria. As reported before, high fat diet (HFD) feeding induced mitochondrial dysfunction in skeletal muscle (Fig. 2A–E). This was demonstrated by decreased oxygen consumption (State 3), and decreased maximal oxygen consumption in the presence of FCCP (vFCCP), which is dependent only on the oxidative efficiency of the electron transport chain (Fig. 2A).

These defects in mitochondrial respiration were rescued by treatment with BBR. In accordance with decreased mitochondrial function, mitochondrial ATP content was also decreased by HFD feeding and this was rescued by BBR (Fig. 2E). The changes in mitochondrial function induced by HFD feeding, seem to be the result of impairments in the mitochondrial ATPase (Fig. 2D) and electron transport chain (ETC) complexes like Succinate dehydrogenase (SDH) (Fig. 2B) and Cytochrome c Oxidase (COX) (Fig. 2C).

BBR supplementation was able to revert mitochondrial dysfunction induced by HFD by restoring ATPase and ETC activities (Fig. 2B–D).

Although BBR has previously been shown to negatively impact hepatic mitochondrial function in in vitro assays or in cells exposed to concentrations higher than the one used in our study [27,30,45,46], we also observed an improvement in the function of hepatic mitochondria isolated from animals treated with BBR (data not shown). This suggests a dose-dependent, indirect but positive action of BBR on mitochondria....

3.4. BBR rescues mitochondrial function in a SIRT1-dependent manner...

...Here, we show for the first time, that the beneficial effects of BBR are accompanied by an increase in mitochondrial function and biogenesis in skeletal muscle. Our results also confirm these findings in a cell-based model.

It is important to note that short term treatments with BBR were previously reported to inhibit ETC complex I [27], decrease ATP content in hepatocytes [29] and cause mitochondrial fragmentation, depolarization, and oxidative stress in K1735-M2 cells when used at concentrations 2–5 times higher than the concentrations used in this study [54]. Moreover, when BBR is incubated with isolated liver mitochondria, mitochondrial respiration is inhibited and mitochondrial permeability transition is induced [55].

...Therefore, while our findings demonstrate improved mitochondrial function by BBR, they do not rule out the possibility of toxic effects of BBR on mitochondria under different conditions or at higher concentrations.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366688/

 

[Chocolove]

Nutrients. 2015 Sep 22;7(9):8152-69. doi: 10.3390/nu7095385.
Rutin Increases Muscle Mitochondrial Biogenesis with AMPK Activation in High-Fat Diet-Induced Obese Rats.
Seo S1, Lee MS2, Chang E3, Shin Y4, Oh S5, Kim IH6, Kim Y7.
Author information
Abstract
Decreased mitochondrial number and dysfunction in skeletal muscle are associated with obesity and the progression of obesity-associated metabolic disorders. The specific aim of the current study was to investigate the effects of rutin on mitochondrial biogenesis in skeletal muscle of high-fat diet-induced obese rats.

Supplementation with rutin reduced body weight and adipose tissue mass, despite equivalent energy intake (p < 0.05).

Rutin significantly increased mitochondrial size and mitochondrial DNA (mtDNA) content as well as gene expression related to mitochondrial biogenesis, such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor-1 (NRF-1), transcription factor A (Tfam), and nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, sirtulin1 (SIRT1) in skeletal muscle (p < 0.05). Moreover, rutin consumption increased muscle adenosine monophosphate-activated protein kinase (AMPK) activity by 40% (p < 0.05). Taken together, these results suggested at least partial involvement of muscle mitochondria and AMPK activation in the rutin-mediated beneficial effect on obesity.

KEYWORDS:
AMPK activity; mitochondria; obesity; rutin; skeletal muscle

PMID: 26402699
PMCID: PMC4586580
DOI: 10.3390/nu7095385
Free PMC Article