14 replies to this topic

[Bateau]

Found a cool 2013 study that reviewed the literature for medications that could be used as atypical treatments to treat the underlying causes of Alzheimer's instead of simply minimizing the symptoms like all the current medications do, aside from Memantine.

 

Was hoping that we could extend this discussion here further.

 

 

...The only approved medications for Alzheimer's Disease [AD] are symptomatic and there are no currently available disease modifying treatments. Hence, a disease modifying treatment is desperately needed... Developing novel compounds for any indication is a time, effort, and money consuming endeavor and most treatments never make it to market. Other research and development strategies are needed, especially for the treatment of AD. We provide a review of the current literature in assessing possibilities of repurposing medications currently used for non-AD indications. Many different compounds from many different pharmacological classes have already been studied in an AD context. We provide a "pragmatic drug repurposing score" for each of these compounds based on type of studies conducted, number of possible mechanisms of action, efficacy in AD and other neurodegenerative disease studies, tolerability profile, and their ability to cross the blood brain barrier. The current data suggest several compounds worthy of further study as treatments for AD. Compounds with the highest scores include lithium (+12), minocycline (+11), exenatide (+10), valproic acid (+9), methylene blue (+9), nimodipine (+9), and nicotine (+9).

→ source (external link)

 

 

Basically want to talk about which of these looks the most promising currently. IIRC nicotine is looking less promising nowadays. Certain meds like minocycline, exenatide and nimodipine are practically never discussed on these forums, although apparently further discussion is warranted.

 

Hoping to do a basic theoretical benefit/risk assessment and talk about which medications might be the most promising as add-on therapy to traditional therapy (Acetylcholinesterase Inhibitor's, Memantine, lifestyle change)

Edited by Bateau, 24 April 2015 - 10:05 PM.

[Bateau]

 

Another tetracycline derivative, minocycline has also been investigated as a potential treatment for several neurodegenerative disorders including AD, Parkinson's disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) [56-58]. Minocycline is an antibiotic used to treat a variety of ailments including acne vulgaris and several sexually transmitted diseases. In vitro and animal models have demonstrated neuroprotection against a-beta oligomer- associated neurotoxicity and attenuated cognitive and behavioral impairments through anti-inflammatory and anti- apoptotic mechanisms [57-69]. It may also inhibit tau phosphorylation in some populations and reduce some tau iso-forms [58, 61, 62, 66]. Long-term use of minocycline is generally well-tolerated in these populations [57]

 

Valproic acid (VPA) is a commonly used antiepileptic drug (AED) and mood stabilizer used for the treatment of bipolar disorder. VPA demonstrates multiple MOAs that may be useful for the treatment of AD. The five major path- ways VPA may ameliorate AD pathology is by decreasing cytokine production, reducing a-beta, decreasing tau phosphorylation, anti-apoptotic effects, and decreased aberrant network activity [90]. A-beta load is reduced by activation of microglial phagocytosis as well as upregulation of neprilysin expression, which degrades amyloid [90-92]. Tau phosphorylation is likely reduced by VPA's ability to reduce cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 beta (GSK-3beta), which are known to be actively involved in abnormal tau hyperphosphorylation [93]. VPA demonstrates anti-apoptotic effects by decreasing the expression of apoptotic proteins (i.e., caspases-3, ␣9, and ␣12) and increasing the expression of anti-apoptotic proteins (i.e., bcl- 2) [94]. Despite these promising studies, a randomized con- trolled double-blinded trial of VPA in moderate AD was unsuccessful in slowing cognitive, neuropsychiatric, or functional decline and treatment was associated with significant adverse effects [95].

 

Lithium is a naturally occurring salt used for the treat- ment of bipolar and other affective disorders. It has several properties that make it attractive as a potential treatment of multiple neurodegenerative disorders, including AD. Must studies have focused on its ability to inhibit GSK-3beta, one of the kinases principally responsible for tau hyperphosphorylation. Lithium also has several neuroprotective and anti-apoptotic features [118, 119]. Clinical trials of lithium have had mixed results. A single-blind study of AD subjects failed to demonstrate amelioration of cognitive symptoms and biomarkers, whereas a trial of aMCI subjects demonstrated some cognitive improvement and decrease in CSF p- tau levels [120, 121]. Lithium can exhibit toxicity that can vary widely depending on the individual and serum concentration, thus tolerability has been questioned. A study of AD patients given microdoses of daily lithium demonstrated good tolerability with attenuation of cognitive decline [122].

 

GLP-1 analogs increase insulin secretion in addition to decreasing glucagon secretion in DM II patients, making it of interest for regulating insulin and glucose in relation to AD. Two GLP-1 analogs approved for treatment of DM II, liraglutide and exenatide, have been studied in AD. Attractive properties of liraglutide include its neuroprotective and long term potentiation enhancement capabilities in addition to antiinflammatory activity and reduction of a-beta and plaque levels [177-180]. Liraglutide may also promote neurogenesis [181]. A randomized controlled trial of liraglutide in AD patients is currently in process [182].
Exenatide is similar to liraglutide, but is a shorter acting GLP-1 analog [177]. Its potential for an AD treatment stems from its neuroprotective, anti-oxidant, and its p-tau and a- beta reducing abilities [183-188]. Like liraglutide, exenatide may also have neurotrophic properties [185].

 

CCBs are antihypertensive agents that block various cal- cium channels, preventing the influx of calcium into the cell. Hypertension is a risk factor for dementia in general and AD in particular and increase of intracellular calcium is often one of the initial signs of neuronal cell death in neurodegenera- tive diseases. An in vitro study has suggested that blockade of specific calcium channels are necessary for CCBs neuroprotective effects from a-beta associated neurotoxicity (e.g., P/Q- and N-type calcium channels) [201]. CCBs can further be divided into dihydropyridine and non-dihydropyridine classes.
Most of the CCBs studied in AD are of the dihydropyridine class. Some of the physiologic effects observed with these compounds include improvement of regional cerebral blood flow (nilvadipine), reduced a-beta levels (nilvadipine, nitrendipine), antiinflammatory effects (nimodipine), and neuroprotection (isradipine, nimodipine) [202-206]. Several dihydropyridine CCBs have demonstrated the ability to lessen cognitive decline. Although correcting hypertension is likely beneficial in itself, clinical efficacy has occurred regardless of baseline hypertension status [207]. Treatment effects may also depend on BBB permeability as nilvadipine, a highly liphophilic and BBB permeable CCB, prevented cognitive decline in MCI patients whereas amlodipine, which has low lipophilicity and BBB penetration, did not demonstrate this benefit [208]. CCBs in general are also well tolerated [207]. A Cochrane review of the subject concluded that nimodipine may offer some benefit in the treatment of dementia caused by AD, vascular disease, or a combination of the two conditions [209].

 

Methylene blue (MB) is used to treat carbon monoxide poisoning. Its use has been investigated in several neurodegenerative disorders including AD, PD, and tauopathies. MB's beneficial properties include antioxidant and neuroprotective activity, inhibition of tau aggregation and a-beta oligomerization, and increases proteasome activity [80, 229- 239]. One study has not replicated improvement of tau hyperphosphorylation or neurodegeneration with MB treatment [240]. Although data are unpublished, a clinical trial of MB in AD subjects failed to meet its primary outcome [241]. MB is currently in phase 3 clinical trials in AD.

 

Nicotine replacement therapy is used for smoking cessation and has symptomatic benefit in cognitive impairment due to its effect on nicotinic receptors [242]. However, nicotine may also affect the pathophysiology of AD by reducing a-beta levels [243-245], though other studies have not replicated this finding or have found that nicotine may even exacerbate tau phosphorylation [246, 247]. Nicotine may also improve demyelination and hence be of use in multiple sclerosis [248].

 

Edited by Bateau, 24 April 2015 - 10:15 PM.

[axonopathy]

Minocycline is a very interesting molecule because its neuroprotective via so many disparate mechanisms of action (e.g., antioxidant, inhibition of inflammatory glial activiation, direct inhibition of apoptosis and necrosis, potent ant-inflammatory).

 

However, I took minocycline for a year and developed drug-induced lupus (an autoimmune reaction to one's own cellular components which can cause demylination) with elevated transaminases (liver impairment). So be careful! Just because something looks good in preclinical/clinical settings doesn't mean its worth the risks of bodily harm. It's hard to fully appreciate the gravity of these tradeoffs until something goes wrong. 

[Bateau]

Minocycline is a very interesting molecule because its neuroprotective via so many disparate mechanisms of action (e.g., antioxidant, inhibition of inflammatory glial activiation, direct inhibition of apoptosis and necrosis, potent ant-inflammatory).

 

However, I took minocycline for a year and developed drug-induced lupus (an autoimmune reaction to one's own cellular components which can cause demylination) with elevated transaminases (liver impairment). So be careful! Just because something looks good in preclinical/clinical settings doesn't mean its worth the risks of bodily harm. It's hard to fully appreciate the gravity of these tradeoffs until something goes wrong. 

Thanks for your response!

 

Very sorry to hear about the experience with minocycline. Do you mind sharing why you took it for such an extended period of time? Did the lupus and elevated transaminases stop after you stopped taking mino?

 

Currently Calcium Channel Blockers look very promising as many people who are of the age to have Alzheimer's shoul be on a medication to lower blood pressure anyways, and certain CCB's like Nimodipine and Nitrendipine already have clinical evidence showing that they slow the progression of cognitive decline.

Another really cool study about the same subject. Different researchers/authors, many of the same results though.

Edited by Bateau, 26 April 2015 - 08:41 PM.

[axonopathy]

Both the lupus and elevated transaminases resolved after I discontinued the minocycline.

 

Are calcium blockers promising for the treatment of Alzheimer's because they reduce hypertension/improve cardiovascular system or because of the effect of calcium channel blockade in the CNS?

[xks201]

What is a good source of minocycline? 

[Bateau]

Are calcium blockers promising for the treatment of Alzheimer's because they reduce hypertension/improve cardiovascular system or because of the effect of calcium channel blockade in the CNS?

 

I believe the current theory is that there is no singular benefit behind CCB's and dementia. They are anti-inflammatory and anti-apoptotic, and reduce Amyloid-beta formation. I do believe that the blood pressure lowering is thought to be the main benefit for vascular dementia (for which other classes of meds to lower blood pressure should be effective), while the main benefit for Alzheimer's is the calcium blockade in the CNS, while for mixed dementia, all the combined effects seem to be whats slowing the progression.

 

Clarification: Many blood pressure lowering meds seem to be effective for Vascular dementia, while CCB's (and maybe meds effecting Angiotensin II) show unique promise for all forms of dementia (Alzheimer's, Vascular, Mixed etc.)
 

[Bateau]

This shit just gets more and more confusing. Everything was pointing to CCB's being the best option, and then this study pops up showing that they were the only blood pressure lowering meds that didn't prevent cognitive decline

http://www.ncbi.nlm....PMC3885216/#R26

 

Sometimes i hate science....

 

Edit: Just rechecked the study and they didn't assess the efficacy of any of the CCB's that have shown promise for Dementia (they tested : amlodipine, bepridil, felodipine, diltiazem, isradipine, mibefradil, nicardipine, nifedipine, nisoldipine, and verapami; never tested Nimodipine or Nitrendipine)

 

 

Edited by Bateau, 27 April 2015 - 03:31 PM.

[mag1]

Large UK for minocycline in AD.
http://www.kcl.ac.uk...ase-(MADE).aspx

A family member is currently afflicted with very severe Alzheimer's dementia, we have tried some odd treatments.

For example, a few years ago it was reported that monophosphoryl lipid A (MPL) cured mice of Alzheimer's.

http://www.scienceda...30115143852.htm

 

 

Interestingly, Cervarix, the widely used vaccine given to American girls to prevent cervical cancer (caused by an STD) also contains MPL. Other treatments are in development that also use MPL. Her doctor agreed to administer the vaccine, though our loved is not at risk of contracting an STD. The complete set of doses of the vaccine likely have not helped. However, this could be because the mice received weekly doses over several months.

 

The implications of possibly influencing the rate of dementia with this vaccine among the female population has received very little scrutiny. It can not be certain giving the vaccine in this way will prevent rather than cause dementia.

Such counter-intuitive results are not unknown to medical science. Without scientific study, we will likely have no idea. It is disturbing that such technologies are introduced without a greater understanding of what the long term consequences will be. Perhaps one consequence in the distant future will be that more women will have to be dementia caregivers for their male loved ones.

We have also been giving our loved one Keppra for quite some time based on a body of scientific evidence. However, the recent positive human clinical trial with Keppra has encouraged us to reduce the dose to 125 mg twice a day. The dose found to be effective in the study (reversed AD activity in early Ad patients).

 

http://www.scienceda...50311124200.htm

 

 

Part of the problem with these off label treatments is there is no money to be made. The drugs are often generic by the time the alternative uses are found. For example, it is becoming increasingly plausible that 3-Bromopyruavte is a cure for cancer. However, this widely used fungicide simply might not have enough real world patentable protection, in order to be developed. The original research was published in 2001. The FDA authorized immediate enrollment of a phase 1 clinical almost 2 years ago.

 

http://www.longecity...e-6#entry727962
 

 

 

 

 

 

 

Edited by mag1, 16 May 2015 - 05:59 AM.

[Bateau]

So after reviewing the literature on antihypertensives and Alzheimers, it seemed pretty clear that certain Calcium Channel Blockers (CCB's) and agents that effects the Renin-Angiotensin-Aldosterone System (RAAS) have the most benefits. Of the RAAS agents, (Renin inhibitors, ACE inhibitors and Angiotensin Receptor Blockers), Angiotensin Receptor Blockers (ARB's) look the most promising, due to them inhibiting the negative effectis of Angiotensin II, but not inhibiting the positive effects of ACE and Angiotensin II, and ARB's have significant epidemiological evidence suggesting delaying the progression of dementia.

 

Of the CCB's, only a few seem to have an effect. Nilvadipine is currently is going through Stage III trials for Alzheimer's and looks the most promising, but Nitrendipine, Nicardipine, and Nimodipine also seem promising.

 

Of the ARB's, Losartan and Valsartan seem the most promising to me. Both have been proven to be effective cognitive enhancers, and both inhibit the most destructive stage of aBeta on the brain, soluble aBeta 1-42 oligomerization. Telmisartan, which many people consider due to its penetration of the blood-brain-barrier and PPAR-gamma activation, looked initially promising, but has no effect or even accelerates the production of aBeta, and also doesn't have proof of cognitive enhancement.

 

TL;DR: Use of Nilvadipine and Losartan/Valsartan for patients with high-blood pressure and Alzheimer's/dementia seems very warranted, even with nilvadipines lack of acceptance by the FDA.

 

[axonopathy]

So after reviewing the literature on antihypertensives and Alzheimers, it seemed pretty clear that certain Calcium Channel Blockers (CCB's) and agents that effects the Renin-Angiotensin-Aldosterone System (RAAS) have the most benefits. Of the RAAS agents, (Renin inhibitors, ACE inhibitors and Angiotensin Receptor Blockers), Angiotensin Receptor Blockers (ARB's) look the most promising, due to them inhibiting the negative effectis of Angiotensin II, but not inhibiting the positive effects of ACE and Angiotensin II, and ARB's have significant epidemiological evidence suggesting delaying the progression of dementia.

 

Of the CCB's, only a few seem to have an effect. Nilvadipine is currently is going through Stage III trials for Alzheimer's and looks the most promising, but Nitrendipine, Nicardipine, and Nimodipine also seem promising.

 

Of the ARB's, Losartan and Valsartan seem the most promising to me. Both have been proven to be effective cognitive enhancers, and both inhibit the most destructive stage of aBeta on the brain, soluble aBeta 1-42 oligomerization. Telmisartan, which many people consider due to its penetration of the blood-brain-barrier and PPAR-gamma activation, looked initially promising, but has no effect or even accelerates the production of aBeta, and also doesn't have proof of cognitive enhancement.

 

TL;DR: Use of Nilvadipine and Losartan/Valsartan for patients with high-blood pressure and Alzheimer's/dementia seems very warranted, even with nilvadipines lack of acceptance by the FDA.

 

I'm confused. Is the neuroprotective effect of antihypertensives due to improving cerebral blood flow? Or are the alternate mechanisms you mentioned more important, e.g., inhibition of amyloid beta? 

[Bateau]

 

I'm confused. Is the neuroprotective effect of antihypertensives due to improving cerebral blood flow? Or are the alternate mechanisms you mentioned more important, e.g., inhibition of amyloid beta? 

 

 

There are multiple mechanisms in place here.

 

For the Calcium Channel Blockers, blockade of L-type calcium channels can lead to direct protection of neurotoxicity. Also the improved cerebral blood flow probably plays a factor. Nilvadipine in particular has lots of promise, particularly for Alzhiemers due to the disease modification of Amyloid Beta and Tau metabolism. See this and particularly this. According to Archer (see this fascinating video), Nilvadipine also has cognitive enhancing aspects in normal, healthy subjects. It has unique aspects when it comes to CCBs with its Amyloid & Tau inhibiting properties, accumulation in brain, and cognitive enhancement in healthy subjects.

 

For the angiotensin receptor blockers, it gets a little more complex. Using ARBs uncouples the feedback mechanism for Angiotensin II, causing huge amounts to be produced, but preventing the hypertensive effects. In the brain Angiotensin II causes neurogenesis and has neuroprotective and cognitive enhancing abilities. Also the increase in Angiotenisin II may cause more Angoitensin to be converted to Angiotensin IV, which should share similar effects to taking Dihexa (Angiotensin IV analog), and may explain the cognitive enhancing effects of losartan in particular, which has lots of evidence for enhancing cognition, even in healthy normo-tensive subjects

 

Apart from that, Losartan and Valsartan carry additional benefit with their modification of soluble amyloid 1-42 oligomers (This Study), which is currently considered the most destructive part of amyloid pathology, it causes the most damage and correlates better with levels of dementia than deposited amyloid plaques.

 

Long story short, the antihypertensive effects do play a part, but its a small part. The anti-hypertensives I've mentioned are considered uniquely promising for the additional effects they have.

[resveratrol_guy]

 

 

I'm confused. Is the neuroprotective effect of antihypertensives due to improving cerebral blood flow? Or are the alternate mechanisms you mentioned more important, e.g., inhibition of amyloid beta? 

 

 

There are multiple mechanisms in place here.

 

For the Calcium Channel Blockers, blockade of L-type calcium channels can lead to direct protection of neurotoxicity. Also the improved cerebral blood flow probably plays a factor. Nilvadipine in particular has lots of promise, particularly for Alzhiemers due to the disease modification of Amyloid Beta and Tau metabolism. See this and particularly this. According to Archer (see this fascinating video), Nilvadipine also has cognitive enhancing aspects in normal, healthy subjects. It has unique aspects when it comes to CCBs with its Amyloid & Tau inhibiting properties, accumulation in brain, and cognitive enhancement in healthy subjects.

 

For the angiotensin receptor blockers, it gets a little more complex. Using ARBs uncouples the feedback mechanism for Angiotensin II, causing huge amounts to be produced, but preventing the hypertensive effects. In the brain Angiotensin II causes neurogenesis and has neuroprotective and cognitive enhancing abilities. Also the increase in Angiotenisin II may cause more Angoitensin to be converted to Angiotensin IV, which should share similar effects to taking Dihexa (Angiotensin IV analog), and may explain the cognitive enhancing effects of losartan in particular, which has lots of evidence for enhancing cognition, even in healthy normo-tensive subjects

 

Apart from that, Losartan and Valsartan carry additional benefit with their modification of soluble amyloid 1-42 oligomers (This Study), which is currently considered the most destructive part of amyloid pathology, it causes the most damage and correlates better with levels of dementia than deposited amyloid plaques.

 

Long story short, the antihypertensive effects do play a part, but its a small part. The anti-hypertensives I've mentioned are considered uniquely promising for the additional effects they have.

 

 

Thanks for this excellent contribution regarding Nilvadipine. I think it deserves its own thread, which I've created here.

[Mian Ali Ismail]

Can Exenatide be given to nondiabetic patients and is it safe ?

 

[jack black]

This shit just gets more and more confusing. Everything was pointing to CCB's being the best option, and then this study pops up showing that they were the only blood pressure lowering meds that didn't prevent cognitive decline

http://www.ncbi.nlm....PMC3885216/#R26

 

Sometimes i hate science....

 

Edit: Just rechecked the study and they didn't assess the efficacy of any of the CCB's that have shown promise for Dementia (they tested : amlodipine, bepridil, felodipine, diltiazem, isradipine, mibefradil, nicardipine, nifedipine, nisoldipine, and verapami; never tested Nimodipine or Nitrendipine)

 

my read of that study is different. CCB decreased risk of AD, but it was not statistically significant. diuretics seemed the best bang in this study.