Ways to increase PDH?

Remy

Administrator
Based on the recent study by Fluge and Mella, it seems likely that part of the energy problem in MECFS comes from insufficient flux through the pyruvate dehydrogenase complex due to a deficiency of an enzyme, pyruvate dehydrogenase.

I think increasing PDH activity can only be a good thing for us in terms of increasing energy and there are several ways to achieve this. I'm hoping to collect a few of them here in this thread for reference and discussion.

https://www.healthrising.org/blog/2016/12/27/chronic-fatigue-syndrome-energy-problems-fluge-mella-study/

1. Dichloroacetate (DCA)
2. Propionyl-l-carnitine
 
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Remy

Administrator
The obvious place to start is DCA (dichloroacetate).

Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate

Pyruvate dehydrogenase complex (PDHC) is a key enzyme in metabolism linking glycolysis to tricarboxylic acid cycle and its activity is tightly regulated by phosphorylation catalyzed by four pyruvate dehydrogenase kinase (PDK) isoforms. PDKs are pharmacological targets for several human diseases including cancer, diabetes, obesity, heart failure, and inherited PDHC deficiency.

We investigated the inhibitory activity of phenylbutyrate toward PDKs and found that PDK isoforms 1-to-3 are inhibited whereas PDK4 is unaffected. Moreover, docking studies revealed putative binding sites of phenylbutyrate on PDK2 and 3 that are located on different sites compared to dichloroacetate (DCA), a previously known PDK inhibitor.

Based on these findings, we showed both in cells and in mice that phenylbutyrate combined to DCA results in greater increase of PDHC activity compared to each drug alone. These results suggest that therapeutic efficacy can be enhanced by combination of drugs increasing PDHC enzyme activity.
@Hip has posted some useful information on dosing as well:

Daily DCA dose recommendations for cancer treatment that I saw here are 10 to 20 mg per kg body weight.

In a study of treatment of congenital lactic acidosis in children, a DCA dose of 12.5 mg per kg body weight was given every 12 hours.

In patients with severe lactic acidosis associated with septic shock, 50 mg of DCA per kg body weight was used; see here.

In a rat study, 5 mg per kg body weight of DCA was used to reduce lactate accumulation in endurance exercising. For humans, that equates to a human dose of 0.8 mg per kg body weight. So for an 80 kg person, the dose would be 64 mg of DCA.

So judging by the cancer doses, typical DCA doses for an 80 kg person would equate to around 800 to 1,600 mg daily. I may try 300 mg of DCA three times daily to start with.
 

Remy

Administrator
Caution is warranted with DCA though as in higher doses, it seems to pretty reliably produce a mostly reversible peripheral neuropathy.

I would think one would want to stay well below the 25 mg/kg dose cited below and perhaps consider the co-administration of thiamine (though it's not clear how well this works, if at all) for prevention.

Neurology. 2006 Feb 14;66(3):324-30.
Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial.
Kaufmann P1, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC.
Author information


Abstract

OBJECTIVE:

To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).
BACKGROUND:

High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS.
METHODS:

The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety.
RESULTS:

During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms.
CONCLUSION:

DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.
 

Remy

Administrator
This study showed that DCA restored mitochondrial respiration in a much lower dose without side effects:

Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration.

In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses
There was no clinically significant change in the QT interval of the electrocardiogram, cardiac rhythm, liver, bone marrow, or renal function.

Dose-limiting toxicity, specifically paresthesia affecting the dorsum of the foot, toes, and fingers (grade II peripheral neuropathy),
consistent with a previously described reversible and dose-dependent, nondemyelinating peripheral neuropathy (26, 28), developed in all five patients taking the highest dose tested (12.5 mg/kg b.i.d.).

Four patients withdrew from the study at that point (weeks 3 to 11), and one accepted a protocol-driven decrease in the dose to 6.25 mg/kg b.i.d., with im- provement of symptoms within 1 to 3 months in all patients. Thus, all patients completing the protocol (n = 16) were taking 3 or 6.25 mg/kg b.i.d., and 6.25 mg/kg b.i.d. was established as the highest tolerated dose, consistent with previous studies in patients with genetic mitochondrial diseases and cancer (23–26).
 

nanobug

Member
I'm going to try DCA, at 333mg/day only due to potential problems with neuropathy. I'm also adding Nicotinamide Riboside at 500mg/day as a precursor to NAD+. NAD+ also appears to inhibit PDK.
 

Remy

Administrator
I'm going to try DCA, at 333mg/day only due to potential problems with neuropathy. I'm also adding Nicotinamide Riboside at 500mg/day as a precursor to NAD+. NAD+ also appears to inhibit PDK.
Let us know how it goes!
 

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