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Old 20-04-17, 08:48 AM   #1
jasmin
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Default Drug for alzhiemers likely to work with Huntingtons???

Although I am appalled by the 'catchy' headline, I had not heard of these drugs before. As Trazodone (one of the drugs) is available on prescription already and prescribed for depression, I would have thought some Huntington's positive people would already be on it.

If so, wouldn't the association between the medication and slowed progression be picked up the various longitudinal/epidemiological cohort studies that are already ongoing (e.g. HD-enroll?)

I wonder if you can request HD-Buzz to investigate these topics and explain them in plain English?

LINKS:

https://www.mrc.ac.uk/news/browse/mr...ation-in-mice/

http://www.bbc.co.uk/news/health-39641123

the MRC report doesn't mention Huntingtons as being one of the diseases where these drugs could be applied (I trust this more). Shame on the BBC if they have not done their research properly!

I know that the testing has only been performed in human cells and mice - but the fact there may be enough evidence to fund a clinical trial (especially as the drugs are already been tested on humans) is promising. News pieces lie this make me feel hopeful for the future
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Old 20-04-17, 12:39 PM   #2
Allan
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Default Drug for Alzheimer's unlikely to work with Huntington's!

.
Here we go again. Headline news with no backup or supporting evidence given by the news media.

I’ve picked out some bits’n’pieces from the actual research and itemised them for easier [?] reading:

Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice
  • Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is over-activated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions.

  • Thus, in mouse models of neurodegenerative disease, prolonged over-activation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss.

  • Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival.

  • However, the experimental compounds used pre-clinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties.

  • To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs.

  • We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo.

  • Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity.

  • Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival.

  • In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden.

  • These compounds therefore represent potential new disease-modifying treatments for dementia.

  • Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.
Prion infection of mice
  • Tg37 +/? mice were inoculated with 1% brain homogenate of Chandler/RML prions aged 3–4 weeks, as described.

  • Animals were culled when they developed clinical signs of prion disease or lost 20% of body weight from the start of the study. Control mice received 1% normal brain homogenate.
Pharmacological treatment of mice
  • Mice were intraperitoneally injected once daily with 40 mg/kg trazodone hydrochloride or vehicle (sterile saline), or fed powdered diet 5LF2 containing 0.5% dibenzoylmethane ad libitum.

  • Treatment was from 7 weeks post-infection until terminal clinical sign appeared in tg37+/− mice, or from 4 months until 8 months in rTg4510 mice.
  • Sample sizes are based on our previous papers, 12–15 mice are used per group as this gives adequate statistical power to detect changes in longevity and behaviour.

  • Mice were randomly assigned a treatment by cage number, and no mice were excluded from the analysis.

  • Experimenters were blind to the treatment group of the mice when clinical signs were being assessed.
Here’s some more Trazodone stuff:

Use of Trazodone

Amongst other “afflictions” it seems mainly, to have been prescribed as a sedative, relaxant and sleeping pill.

Insomnia (1207 Patients)
Depression (967 Patients)
Sleep Disorder (732 Patients)
Anxiety (162 Patients)
Sleep Disorder Therapy (127 Patients)
Bipolar Disorder (86 Patients)
Ill-Defined Disorder (52 Patients)
Pain (42 Patients)
Fibromyalgia (40 Patients)
Somnolence (39 Patients)
Antidepressant Therapy (34 Patients )
Major Depression (31 Patients)
Suicide Attempt (20 Patients)
Nervousness (17 Patients)
Post-Traumatic Stress Disorder (17 Patients)
Affective Disorder (15 Patients)
Drug Exposure During Pregnancy (13 Patients)
Schizophrenia (13 Patients)
Mental Disorder (12 Patients)
Migraine (12 Patients)
Dementia (12 Patients)
Intentional Overdose (11 Patients)
Feeling Jittery (9 Patients)
Agitation (9 Patients)
Restless Legs Syndrome (8 Patients)
Completed Suicide (7 Patients)
Schizoaffective Disorder (7 Patients)
Bipolar Disorder (7 Patients)
Overdose (7 Patients)
Neuralgia (7 Patients)
Restlessness (6 Patients)
Drug Abuse (6 Patients)
Prophylaxis (6 Patients)
Confusional State (6 Patients)
Crohn's Disease (6 Patients)
Dementia Alzheimer's Type (6 Patients)
Foetal Exposure During Pregnancy (5 Patients)
Panic Disorder (5 Patients)
Sedative Therapy (5 Patients)
Depressive Symptom (5 Patients)
Psychotic Disorder (5 Patients)
Poor Quality Sleep (5 Patients)
Suicidal Ideation (5 Patients)
Schizophrenia, Paranoid Type (5 Patients)
Sedation (5 Patients)
Impaired Gastric Emptying (5 Patients)
Relaxation Therapy (4 Patients)
Anxiety Disorder (4 Patients)
Stress (4 Patients)
Back Pain (4 Patients)
Obsessive-Compulsive Disorder (4 Patients)
Sleep Apnoea Syndrome (4 Patients)
Menopause (4 Patients)
Self Injurious Behaviour (4 Patients)

… and another for comparison:

Neuroprotective Effects of Psychotropic Drugs in Huntington’s Disease [2013]

Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly prescribed to treat Huntington’s disease (HD). In HD preclinical models, while no psychotropic has convincingly affected huntingtin gene, HD modifying gene, or huntingtin protein expression, psychotropic neuroprotective effects include upregulated huntingtin autophagy (lithium), histone acetylation (lithium, valproate, lamotrigine), miR-222 (lithium-plus-valproate), mitochondrial protection (haloperidol, trifluoperazine, imipramine, desipramine, nortriptyline, maprotiline, trazodone, sertraline, venlafaxine, melatonin), neurogenesis (lithium, valproate, fluoxetine, sertraline), and BDNF (lithium, valproate, sertraline) and downregulated AP-1 DNA binding (lithium), p53 (lithium), huntingtin aggregation (antipsychotics, lithium), and apoptosis (trifluoperazine, loxapine, lithium, desipramine, nortriptyline, maprotiline, cyproheptadine, melatonin).

In HD live mouse models, delayed disease onset (nortriptyline, melatonin), striatal preservation (haloperidol, tetrabenazine, lithium, sertraline), memory preservation (imipramine, trazodone, fluoxetine, sertraline, venlafaxine), motor improvement (tetrabenazine, lithium, valproate, imipramine, nortriptyline, trazodone, sertraline, venlafaxine), and extended survival (lithium, valproate, sertraline, melatonin) have been documented. Upregulated CREB binding protein (CBP; valproate, dextromethorphan) and downregulated histone deacetylase (HDAC; valproate) await demonstration in HD models. Most preclinical findings await replication and their limitations are reviewed. The most promising findings involve replicated striatal neuroprotection and phenotypic disease modification in transgenic mice for tetrabenazine and for sertraline. Clinical data consist of an uncontrolled lithium case series (n = 3) suggesting non-progression and a primarily negative double-blind, placebo-controlled clinical trial of lamotrigine.

So, there are 3 indications here for the use of Travadone with hd-individuals:
  • mitochondrial protection [preservation of cells]
  • memory preservation
  • motor improvement

Please note that this drug [and similar] will not offer a cure for hd. It is a pharmaceutical therapy which might alleviate depression and might induce relaxation and have sedative properties.

Follow-up reading: www.drugs.com/trazodone.html

I recently self-trialled Cannabidiol capsules and found them to be a relaxant to several ailments - but very expensive to continue as a regular treatment.

Beware and Be Aware ... that, amongst many other things, mice can't talk and tell you how they feel.

.
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Old 20-04-17, 09:55 PM   #3
charliegirl
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Join Date: Jun 2013
Location: Lancashire
Posts: 113
Default Re: Drug for Alzheimer's unlikely to work with Huntington's!

Quote:
Originally Posted by Allan View Post
.
Here we go again. Headline news with no backup or supporting evidence given by the news media.

I’ve picked out some bits’n’pieces from the actual research and itemised them for easier [?] reading:

Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice
  • Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is over-activated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions.

  • Thus, in mouse models of neurodegenerative disease, prolonged over-activation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss.

  • Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival.

  • However, the experimental compounds used pre-clinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties.

  • To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs.

  • We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo.

  • Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity.

  • Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival.

  • In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden.

  • These compounds therefore represent potential new disease-modifying treatments for dementia.

  • Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.
Prion infection of mice
  • Tg37 +/? mice were inoculated with 1% brain homogenate of Chandler/RML prions aged 3–4 weeks, as described.

  • Animals were culled when they developed clinical signs of prion disease or lost 20% of body weight from the start of the study. Control mice received 1% normal brain homogenate.
Pharmacological treatment of mice
  • Mice were intraperitoneally injected once daily with 40 mg/kg trazodone hydrochloride or vehicle (sterile saline), or fed powdered diet 5LF2 containing 0.5% dibenzoylmethane ad libitum.

  • Treatment was from 7 weeks post-infection until terminal clinical sign appeared in tg37+/− mice, or from 4 months until 8 months in rTg4510 mice.
  • Sample sizes are based on our previous papers, 12–15 mice are used per group as this gives adequate statistical power to detect changes in longevity and behaviour.

  • Mice were randomly assigned a treatment by cage number, and no mice were excluded from the analysis.

  • Experimenters were blind to the treatment group of the mice when clinical signs were being assessed.
Here’s some more Trazodone stuff:

Use of Trazodone

Amongst other “afflictions” it seems mainly, to have been prescribed as a sedative, relaxant and sleeping pill.

Insomnia (1207 Patients)
Depression (967 Patients)
Sleep Disorder (732 Patients)
Anxiety (162 Patients)
Sleep Disorder Therapy (127 Patients)
Bipolar Disorder (86 Patients)
Ill-Defined Disorder (52 Patients)
Pain (42 Patients)
Fibromyalgia (40 Patients)
Somnolence (39 Patients)
Antidepressant Therapy (34 Patients )
Major Depression (31 Patients)
Suicide Attempt (20 Patients)
Nervousness (17 Patients)
Post-Traumatic Stress Disorder (17 Patients)
Affective Disorder (15 Patients)
Drug Exposure During Pregnancy (13 Patients)
Schizophrenia (13 Patients)
Mental Disorder (12 Patients)
Migraine (12 Patients)
Dementia (12 Patients)
Intentional Overdose (11 Patients)
Feeling Jittery (9 Patients)
Agitation (9 Patients)
Restless Legs Syndrome (8 Patients)
Completed Suicide (7 Patients)
Schizoaffective Disorder (7 Patients)
Bipolar Disorder (7 Patients)
Overdose (7 Patients)
Neuralgia (7 Patients)
Restlessness (6 Patients)
Drug Abuse (6 Patients)
Prophylaxis (6 Patients)
Confusional State (6 Patients)
Crohn's Disease (6 Patients)
Dementia Alzheimer's Type (6 Patients)
Foetal Exposure During Pregnancy (5 Patients)
Panic Disorder (5 Patients)
Sedative Therapy (5 Patients)
Depressive Symptom (5 Patients)
Psychotic Disorder (5 Patients)
Poor Quality Sleep (5 Patients)
Suicidal Ideation (5 Patients)
Schizophrenia, Paranoid Type (5 Patients)
Sedation (5 Patients)
Impaired Gastric Emptying (5 Patients)
Relaxation Therapy (4 Patients)
Anxiety Disorder (4 Patients)
Stress (4 Patients)
Back Pain (4 Patients)
Obsessive-Compulsive Disorder (4 Patients)
Sleep Apnoea Syndrome (4 Patients)
Menopause (4 Patients)
Self Injurious Behaviour (4 Patients)

… and another for comparison:

Neuroprotective Effects of Psychotropic Drugs in Huntington’s Disease [2013]

Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly prescribed to treat Huntington’s disease (HD). In HD preclinical models, while no psychotropic has convincingly affected huntingtin gene, HD modifying gene, or huntingtin protein expression, psychotropic neuroprotective effects include upregulated huntingtin autophagy (lithium), histone acetylation (lithium, valproate, lamotrigine), miR-222 (lithium-plus-valproate), mitochondrial protection (haloperidol, trifluoperazine, imipramine, desipramine, nortriptyline, maprotiline, trazodone, sertraline, venlafaxine, melatonin), neurogenesis (lithium, valproate, fluoxetine, sertraline), and BDNF (lithium, valproate, sertraline) and downregulated AP-1 DNA binding (lithium), p53 (lithium), huntingtin aggregation (antipsychotics, lithium), and apoptosis (trifluoperazine, loxapine, lithium, desipramine, nortriptyline, maprotiline, cyproheptadine, melatonin).

In HD live mouse models, delayed disease onset (nortriptyline, melatonin), striatal preservation (haloperidol, tetrabenazine, lithium, sertraline), memory preservation (imipramine, trazodone, fluoxetine, sertraline, venlafaxine), motor improvement (tetrabenazine, lithium, valproate, imipramine, nortriptyline, trazodone, sertraline, venlafaxine), and extended survival (lithium, valproate, sertraline, melatonin) have been documented. Upregulated CREB binding protein (CBP; valproate, dextromethorphan) and downregulated histone deacetylase (HDAC; valproate) await demonstration in HD models. Most preclinical findings await replication and their limitations are reviewed. The most promising findings involve replicated striatal neuroprotection and phenotypic disease modification in transgenic mice for tetrabenazine and for sertraline. Clinical data consist of an uncontrolled lithium case series (n = 3) suggesting non-progression and a primarily negative double-blind, placebo-controlled clinical trial of lamotrigine.

So, there are 3 indications here for the use of Travadone with hd-individuals:
  • mitochondrial protection [preservation of cells]
  • memory preservation
  • motor improvement

Please note that this drug [and similar] will not offer a cure for hd. It is a pharmaceutical therapy which might alleviate depression and might induce relaxation and have sedative properties.

Follow-up reading: www.drugs.com/trazodone.html

I recently self-trialled Cannabidiol capsules and found them to be a relaxant to several ailments - but very expensive to continue as a regular treatment.

Beware and Be Aware ... that, amongst many other things, mice can't talk and tell you how they feel.

.

Hi allan - thanks for that research . It is so annoying that the media hype things up - its cruel really .Its wrong to give false hope . I like the comment bout mice not being able to talk cos they cant tell you how they feel. I am always concerned about medications that increase depression / anxiety/ suicidal thoughts - as these aspects are very real to me and very scary. This must be very common as it is listed frequently. Life is fragile. Thinking about you and your son too, thanks , Charliegirl 🐶 xx
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Old 21-04-17, 12:29 AM   #4
nightowl
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Default Re: Drug for alzhiemers likely to work with Huntingtons???

My husband heard this discussed on radio 4 Today programme with John Humphries. 20/4/17
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Old 21-04-17, 07:20 AM   #5
banda
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Default Re: Drug for alzhiemers likely to work with Huntingtons???

Rightly or wrongly I am afraid I wont allow myself to take any notice of any of this.... just think it is all too late for my hubby or that they wont come to fruition and I wont allow myself to become even minutely excited about the possibility of better drugs then it will be a nice surprise if it ever happens!!
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Old 22-04-17, 11:22 PM   #6
jasmin
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Default Re: Drug for alzhiemers likely to work with Huntingtons???

Thank you all for the replies and the further research.

HDBuzz has been trying to do a lot of damage control this week on this news article about a 'wonder drug' to alleviate all neurodegenerative disorders.

Although getting the facts straight in research terms is proper; it doesn't half suck the hope out of dreaming.

Scientific discovery is a slow, plodding thing. No eureka moments. Any research whose results may be applicable elsewhere is useful and encouraging. I hope to see more in the future - just with better reporting from journalist next time
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