Vigabatrin, a GABA Transaminase Inhibitor, Reversibly Eliminates Tinnitus in an Animal Model

[Danny Boy]

A wide variety of drugs have been tested as potential tinnitus therapeutics, with generally negative, and a few mixed, results (Dobie 1999). Reports of successful tinnitus treatment using drugs of unknown specificity and unknown mechanisms of action (Jastreboff et al. 1997) may be therapeutically informative but cannot be used to advance the neuroscience of tinnitus. Both basic science and clinical research indicate that the GABA neurotransmitter system is a reasonable focus for tinnitus research. The GABA analog gabapentin has been tested in both an animal model (Bauer and Brozoski 2001) and a controlled clinical trial (Bauer and Brozoski 2006), with partial success. Unfortunately, although gabapentin is a GABA analog, its mechanism of action is still uncertain (Lanneau et al. 2001). Vigabatrin is a specific GABA agonist with a well-characterized mechanism of action: suicide blockade of GABA transaminase (GABA-T) (French 1999; Guberman 1996; Richens 1991). That central GABA levels are elevated by vigabatrin has been well documented in animal (Behar and Boehm 1994; de Graaf et al. 2006) and human (Mattson et al. 1995; Petroff and Rothman 1998) studies. More importantly, the present research demonstrated that vigabatrin treatment effectively eliminated the psychophysical evidence of chronic tinnitus in an animal model.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538419/

 

[Atlantis]

A wide variety of drugs have been tested as potential tinnitus therapeutics, with generally negative, and a few mixed, results (Dobie 1999). Reports of successful tinnitus treatment using drugs of unknown specificity and unknown mechanisms of action (Jastreboff et al. 1997) may be therapeutically informative but cannot be used to advance the neuroscience of tinnitus. Both basic science and clinical research indicate that the GABA neurotransmitter system is a reasonable focus for tinnitus research. The GABA analog gabapentin has been tested in both an animal model (Bauer and Brozoski 2001) and a controlled clinical trial (Bauer and Brozoski 2006), with partial success. Unfortunately, although gabapentin is a GABA analog, its mechanism of action is still uncertain (Lanneau et al. 2001). Vigabatrin is a specific GABA agonist with a well-characterized mechanism of action: suicide blockade of GABA transaminase (GABA-T) (French 1999; Guberman 1996; Richens 1991). That central GABA levels are elevated by vigabatrin has been well documented in animal (Behar and Boehm 1994; de Graaf et al. 2006) and human (Mattson et al. 1995; Petroff and Rothman 1998) studies. More importantly, the present research demonstrated that vigabatrin treatment effectively eliminated the psychophysical evidence of chronic tinnitus in an animal model.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538419/

Where can you get this?

 

[Danny Boy]

Where can you get this?

Prescription only.

 

[Atlantis]

Prescription only.

The article you posted is from 2007, how come nobody has reported success for tinnitus?

 

[Danny Boy]

The article you posted is from 2007, how come nobody has reported success for tinnitus?

I've never heard it mentioned on tinnitus talk.

 

[Joan A.]

It can cause blindness, irreversibly

 

[Atlantis]

It can cause blindness, irreversibly

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759040/

Potential patients can be counseled that with long-term vigabatrin therapy, they are at a 40% risk for peripheral visual field loss, which usually is not severe or symptomatic, but it is likely to be irreversible. It is helpful to illustrate typical vigabatrin-related visual field losses with patients—the normal boundaries of peripheral vision with two eyes can be illustrated by having the patient and examiner extend their arms out and then moving them horizontally together until the limits of peripheral vision are demonstrated (generally at 140 degrees of separation). Average ranges of vigabatrin-related field loss can be demonstrated by moving the arms forward horizontally until they are 100 to 60 degrees apart. Patients can be reassured that visual loss equivalent to blindness is highly unlikely: the U.S. disability standard specifies that less than 20 degrees of total visual field is equivalent to blindness. However, they should be counseled that this degree of field loss may interfere with or prohibit driving privileges, in some cases.

 

[Joan A.]

Vigabatrin (Sabril®) and tiagabine (Gabitril®), two drugs that act on different aspects of GABAergic neurotransmission, have been studied in an animal model of noise-induced tinnitus. Vigabatrin is used as an anticonvulsant and to treat infantile spasms. It irreversibly inhibits GABA transaminase (GABA-T), the enzyme that catabolizes GABA, thereby increasing GABA levels (115–117). Vigabatrin also induces tonic release of GABA by causing the GABA transporter to operate in reverse (118). Tiagabine is used to treat seizures and panic disorders (119–121) and acts by inhibiting the uptake of GABA via the GAT-1 transporter, thereby increasing the availability of GABA at its receptor (122, 123).

It has been proposed that tinnitus arises from loss of inhibition in the CNS as a result of cochlear deafferentation caused by noise, aging or ototoxic drugs (72, 124–126). To test this hypothesis, noise-exposed rats with behavioral evidence of tinnitus were treated with vigabatrin or tiagabine. Tiagabine did not suppress noise-induced tinnitus; however, vigabatrin suppressed noise-induced tinnitus, and the tinnitus reappeared when treatment was discontinued (73). We are unaware of any clinical trials in which vigabatrin has been used to treat tinnitus; however, given the positive animal data, vigabatrin is a potential drug candidate for a clinical study in tinnitus. However, it is known that the drug can cause irreversible visual disturbances, limiting it use in humans (127).

Source; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136369/

 

[Atlantis]

It's ironic, what could possibly help us causes visual loss. Can join the Blind Forum then instead...

 

[Joan A.]

@Atlantis

i was not ironic with you. Like you and others suffers, somtimes i search something related to pain or epilepsy, because seems that tinnitus pathways in the brain are used but the same conditions. Anyway i tried vigabatrin (and many others) in 2010 for 1 month without success. The more effective AEDs for tinnitus seemed the Tegretol and for others the Gabapentin in combination with klonopin.

Unfortunately for us, we are not considered "suffers" and the research is poor. Damn.

Best wishes

 

[Jahhsoul]

I tried Carbamazepine 200 mg 1 month after the origin of my T. I think it didint affect my T, just the perception in first days right after the ingestion.

 

[Joan A.]

I tried Carbamazepine 200 mg 1 month after the origin of my T. I think it didint affect my T, just the perception in first days right after the ingestion.

Hi Jan

For how long did you took it?

 

[Jahhsoul]

Hi Jan

For how long did you took it?

1 month, 200 mg each night.

 

[Joan A.]

1 month, 200 mg each night.

i don't want bother but if it gave benefit (reducing volume) why stop it?

 

[Jahhsoul]

The main reason is AM-101 xD

Maybe I continue it after the trial if I dont get any benefits. In addition I started to take Carbamazepine at the same time than Rivotril (Benzo), so I cannot be sure what of those drugs gave me the that reduction, and I dont even know if that reduction was real or subjetive

 

[undecided]

I've used Sabril (vigabatrin) as a benzo enhancer. 1g seemed to do the trick.
On its own, doesn't do much at all. It's not even a decent downer, too weak. Totally useless for tinnitus.
Not really surprising, in order for it to work, you must find a way to artificially increase GABA availability. Only benzos can do that fast enough.
I should note that I never had any vision problems during or after its use.

 

[Joan A.]

The main reason is AM-101 xD

Maybe I continue it after the trial if I dont get any benefits. In addition I started to take Carbamazepine at the same time than Rivotril (Benzo), so I cannot be sure what of those drugs gave me the that reduction, and I dont even know if that reduction was real or subjetive

I hope the best for you and for your information, the tegretol reduce the blood level of clonazepam. I would go for the first. THe second can be effective but with quick addiction, tolerance and so less effective.

"CarBAMazepine may reduce the blood levels and effects of clonazePAM. You may need a dose adjustment if you have been taking clonazePAM and are starting treatment with carBAMazepine. Let your doctor know if clonazePAM becomes less effective or is no longer controlling your symptoms. In addition, using thesemedications together may increase side effects such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience some impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with these medications. Avoid driving or operating hazardous machinery until you know how the medications affect you. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor."

Source: http://www.drugs.com/interactions-check.php?drug_list=703-0,497-234

 

[Jahhsoul]

@Joan A. Thanks for the information. My doctor said I could take these 2 drugs at same time. I have to say the dose of Rivotril was just 0.5mg per night. No effects on driving. 1 or 2 days per week I drank alcohol with no problems associated.

 

[Lyrica]

Would it be possible to inject Vigabatrin straight into the auditory cortex were the tinnitus is generated in order to selectively destroy GABA transaminase in that area?


(ofcourse i wouldn't inject it myself )

 

[gintas]

I tried Carbamazepine 200 mg 1 month after the origin of my T. I think it didint affect my T, just the perception in first days right after the ingestion.

how is you experience about carbamazepine now ? you still using it ? seems i have benefit from it . but not sure

 

[Jahhsoul]

@gintas I stopped it because of a clinical trial. But I think I wouldnt have continue the tratment.

I took Carba with Benzos so I cannot say anything clear. Maybe I try it again later.

It reduces your T or the annoyance of it?

 

[gintas]

@gintas I stopped it because of a clinical trial. But I think I wouldnt have continue the tratment.

I took Carba with Benzos so I cannot say anything clear. Maybe I try it again later.

It reduces your T or the annoyance of it?

reduces T. but i am not sure i using it along with Trobalt

 

[Jahhsoul]

reduces T. but i am not sure i using it along with Trobalt

I woul never do that. You can use benzos and anit-epiletic but 2 different antiepileptics is a really bad idea I think.

 

[linearb]

I know someone on another forum who was successfully using Sabril to reduce their T for a while.

Getting rid of T but slowly going blind seems like a bad tradeoff to me...

 

[Nucleo]

Getting rid of T but slowly going blind seems like a bad tradeoff to me...

Pretty bad deal indeed.

 

[linearb]

Pretty bad deal indeed.

the thing which kept me from ever trying it is

The Marketing Authorisation Holders survey (involving 335 vigabatrin recipients aged >14 years) indicated that 31% of patients [95% confidence interval (CI) 26 to 36%] had a visual field defect attributable to vigabatrin, compared with a 0% incidence of visual field defects (upper 95% CI 3%) in an unexposed control group. Other studies in adults have given similar overall prevalences, with a total of 169 of 528 patients diagnosed with vigabatrin-associated field defects (32%, 95% CI 28 to 36%). Male gender seems to be associated with an increase in the relative risk of visual field loss of approximately 2-fold. The pattern of defect is typically a bilateral, absolute concentric constriction of the visual field, the severity of which varies from mild to severe. Data gathered so far suggest that the cumulative incidence increases rapidly during the first 2 years of treatment and within the first 2 kg of vigabatrin intake, stabilising at 3 years and after a total vigabatrin dose of 3 kg.

That is a huge correlation, and as a male, it sounds like I'd have a better than 50% chance of encountering some degree of visual field loss within a relatively short time of starting the drug.

Newer studies have linked the visual damage to a taurine deficiency, which has led some prescribers to encourage people to take supplemental taurine. It may be that taurine used regularly and in some correct protocol could greatly minimize the risks... but the data is not there yet.

It also seems pretty clear that the reason this works is similar to why benzos can be effective; Sabril is a very narrow target drug, as far as I know the only pharmacokinetic action documented is the breakdown of the enzyme that metabolizes GABA. So, if Sabril works for someone, there are probably other things which will have a similar effect. I sort of shudder to ever say "benzos are safer than X", but in the case of Sabril this is probably correct; benzos only tend to cause severe and irreversible neurological problems after very extended use, or incorrect withdrawal.

 

[undecided]

I have taken lots of Sabril (1000mg per pop) only to prolong and potentate the effect of benzodiazepines.
While I was aware of its potentially unsafe side-effect profile, I was quite careless with it since it did what I intended it to do.

Never had any eye problems while on it. Nowadays, 6+ months since I last used it, I still have no visual field issues or any other problem with my vision.
That's my experience, anyway.

Sabril on its own is quite useless, which makes sense to me, considering its mechanism of action.
Paraphrasing @linearb 's explanation, it simply helps to retain a constant amount of GABA in the brain, for a longer period of time. So if you somehow manage to increase GABA levels (say, through benzo use), Sabril really kicks in.
If GABA levels stay normal, you're not gonna feel much (that might depend on dosage though).

I originally found out about Sabril through @Viking, who mentioned he had a bit of benefit through it.
I don't think think he's around the forum anymore to elaborate...

 

[Lyrica]

Benzo's don't increase GABA levels. They simply bind to the GABA-A receptor and cause it to open further in response to GABA molecules binding to it.

Vigabatrin does increase GABA concentrations and extend it's duration of action.

Visual field defects seem to be light dependent. So maby taking your dose at night should theoretically reduce the risk of retinal damage.

 

[undecided]

Benzo's don't increase GABA levels. They simply bind to the GABA-A receptor and cause it to open further in response to GABA molecules binding to it.

Yes, I suppose I expressed my thought incorrectly, I should have written 'stimulate' instead of 'increase'.
Anyway, glad we sorted this out, also quite interesting that I'm having a conversation with an anxiolytic medical product

 

[Lyrica]

Haha yes. Lyrica can also reduce tinnitus temporarily