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Thursday, 22 August 2019

Bumetanide 5mg for Parkinson’s Disease?



I have been asked twice about off-label therapies for Parkinson’s, both times I mentioned Bumetanide, but having rechecked the literature, there is now plenty of supporting data, enough that a clinical trial has now been put in motion in France.

Parkinson’s disease is all about a lack of dopamine and bumetanide is all about making GABA work as inhibitory. You might wonder why is Peter suggesting people to talk to their doctor about giving their elderly parents a diuretic. Well the lack of dopamine goes on to cause a GABA dysfunction, which is treatable and does improve the symptoms of Parkinson’s.

So, Bumetanide will not cure Parkinson’s, but may reduce its severity.

In the case of the last person who asked me, her mother already takes a diuretic for other reasons, so all she would have to do is to switch drugs to Bumetanide. The doctor was only too happy, when given the evidence, to switch her to Bumetanide - a rare victory for common sense. 

What caught my attention was the dosage of Bumetanide used in the published case histories and the concern about polyuria. Polyuria is too much urination. The dose used was 5mg taken all in one go and that is a lot; you would have to run to the bathroom, which might cause falls in people with poor balance.

Since we recently discovered that Azosemide has the same effect on GABA as Bumetanide, but can have a less urgent effect as a diuretic, it may be that Azosemide is a better choice for Grandma with Parkinson’s.  Incontinence can be a feature of Parkinson’s disease.  The ideal drug will be the new one being developed by Neurochloré for autism.


Standard Parkinson’s Drugs

Since most symptoms of Parkinson’s disease (PD) are caused by a lack of dopamine in the brain, many PD drugs are aimed at either temporarily replenishing dopamine or mimicking the action of dopamine. These types of drugs are called dopaminergic medications. They generally help reduce muscle rigidity, improve speed and coordination of movement and lessen tremor.

L-DOPA, the standard treatment for Parkinson’s is actually also used in some people with autism, in particular people with Angelman Syndrome, although it failed in a clinical trial.


Bumetanide for Parkinson’s?

The clinical trial for Parkinson’s will use the standard rating scale (UPDRS) that is very much centered on motor skills. There is a tiny part on memory.

Cognition is affected in Parkinson’s and this might be another area that improves with Bumetanide; but someone has to bother to measure it.

Nobody has measured the effect of Bumetanide on IQ in those with autism, even though the effect can be substantial.

                                  


Four patients suffering from idiopathic PD at the stage of motor fluctuation were included. All of them gave their written informed consent to receive open-label bumetanide. Bumetanide was progressively titrated up to 3 mg/d (once daily) received for a month. After having verified the good tolerability of the treatment, bumetanide was increased to 5 mg/d (once daily) and received for another month. Bumetanide was added to the patient's usual antiparkinsonian treatment that was maintained stable the month before and unchanged during the study. The patients were assessed before and at 1 and 2 months after the initiation of bumetanide.
At each visit, the patient was asked about any side effects having occurred since the last visit. A Unified Parkinson's Disease Rating Scale (UPDRS)19 was performed before and after 2 months of treatment in a practical OFF stage (the patients came in the afternoon, having not taken antiparkinsonian drugs for 4 hours, and confirmed to be in an OFF stage). At the end of the study, the patient was also asked to give a global impression of change compared with baseline.

Case 3

The patient was a 58-year-old man with a 21-year history of
PD. After early development of disabling motor fluctuation and dyskinesia despite an optimized drug treatment, bilateral subthalamic electrodes were implanted 16 years ago for continuous deep brain stimulation (DBS). He got an excellent control of PD motor symptoms. However, after a year of DBS treatment, he started to develop freezing of gait and dysarthria. Despite many attempts of adjusting the treatment (DBS parameters, changes in drug treatment, and physiotherapy), these symptoms remained disabling and even slowly worsened with time. Motor fluctuation and dyskinesia were well controlled by both DBS (left side: case positive, electrode 2 negative, voltage 3.5 V; right side: case positive, electrode 1 negative, voltage 3 V; for both sides: pulse width 60 microseconds, frequency 100 Hz) and drug treatment. The latter consisted of L-DOPA, 1000 mg/d (5 intakes per day); ropinirole, 2 mg/d; and amantadine, 200 mg/d. The freezing of gait was highly disabling.

At home, the patient could walk a few steps alone with a high risk of falls. Most of the time, he was wheelchair bound. After a few days of bumetanide at a dosage of 5 mg/d, the gait dramatically improved. He was able to walk almost 1000 m without any help.

The voice was unchanged. The UPDRS III in the OFF stage was hardly changed (10% improvement), and the UPDRS II in the worst state improved by 15%. The UPDRS II in the best condition was unchanged (21 to 18). The patient and the caregiver assessed the general improvement at 50%. Despite the polyuria and the fatigue, he has decided to continue the bumetanide treatment.
After a few weeks, the improvement of gait was less dramatic but still noticeable.


GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease 

We report that half striatal cholinergic interneurons are dual transmitter cholinergic and GABAergic interneurons (CGINs) expressing ChAT, GAD65, Lhx7, and Lhx6 mRNAs, labeled with GAD and VGAT, generating monosynaptic dual cholinergic/GABAergic currents and an inhibitory pause response. Dopamine deprivation increases CGINs ongoing activity and abolishes GABAergic inhibition including the cortico-striatal pause because of high [Cl]i levels. Dopamine deprivation also dramatically increases CGINs dendritic arbors and monosynaptic interconnections probability, suggesting the formation of a dense CGINs network. The NKCC1 chloride importer antagonist bumetanide, which reduces [Cl]ilevels, restores GABAergic inhibition, the cortico-striatal pause-rebound response, and attenuates motor effects of dopamine deprivation. Therefore, most of the striatal cholinergic excitatory drive is balanced by a concomitant powerful GABAergic inhibition that is impaired by dopamine deprivation. The attenuation by bumetanide of cardinal features of Parkinson’s disease paves the way to a novel therapeutic strategy based on a restoration of low [Cl]i levels and GABAergic inhibition.



Official Title:
A Randomized Double-blind Placebo-controlled Multicenter Proof-of-concept Trial to Assess the Efficacy and Safety of Bumetanide in Parkinson's Disease
Actual Study Start Date  :
April 26, 2019
Estimated Primary Completion Date  :
September 2020
Estimated Study Completion Date  :
August 2021



Conclusion

There is now a long list of neurological conditions that may respond to bumetanide:-

·        Autism
·        Fragile-X Syndrome
·        Down Syndrome
·        Schizophrenia
·        Huntington’s Disease
·        Parkinson’s Disease

In addition, it is obvious that some epilepsy will respond to Bumetanide. The original epilepsy drug from 150 years ago, KBr, has the same mechanism of action, lowering chloride within neurons.

Perhaps higher doses of Bumetanide need to be trialled in autism, 5mg all at once is far higher than what has been used so far in studies.




2 comments:

  1. Peter,I'm sure you're aware that adults with autism are at greater risk of developing early onset Parkinson's.As early as their forties.

    ReplyDelete
    Replies
    1. Roger, historically not many people with severe autism reached their early forties, so I am not sure how reliable the data is. Some research even suggests autism will protect against Alzheimer’s and other dementia.

      Down Syndrome is associated with early onset Alzheimer’s.

      There is another study just published, this time from Israel, showing the Alzheimer’s drug Donepezil taken with acetylcholine showed a significant improvement in language comprehension in people with autism.

      http://www.xinhuanet.com/english/2019-08/23/c_138330013.htm

      The good news is that the same medications can be used to treat multiple neurological diseases.

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