Apparently a 1960s chemotherapy drug has the ability to prevent SOD1 aggregation and can break apart previous aggregates, all without interfering with the function of the normal protein. This should be quite interesting to see if that improves the proteomic breakdown and recycling of the misfolded protein which we know is ubiquitin-tagged for breakdown.

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ENV
= Le meilleur vin, avec les meilleurs amis. =

Use my rule of thumbs and common sense when looking for new drugs.

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Don't just ask what scientists can do to speed up the solution for ALS or when they will do it, instead ask yourself what you can do right now to solve ALS asap.

I'm enjoying it, but there's more urgent projects to be started than research funds available. I suspect that idiots constantly are applying for them.

The rule of thumbs is simple, just ensure that the drug candidate heals ulcers, but be extra cautious if it causes them.

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Don't just ask what scientists can do to speed up the solution for ALS or when they will do it, instead ask yourself what you can do right now to solve ALS asap.

Possible method of ameliorating some of the toxicity of Cisplatin?

D-Methionine Protects against Cisplatin-induced Neurotoxicity in Cortical Networks.

Abstract

Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer.

Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus. D-Methionine (D-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatin-induced side effects in animals without antitumor interference.

In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of D-Met.

Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons.

Cisplatin at 0.10 - 0.25mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5mM caused irreversible loss of neuronal activity, accompanied by cell death.

Pretreatment with D-Met, at a concentration of 1.0mM, prevented the cisplatin-induced excitation at 0.10 - 0.25mM, caused sustained excitation without occurrence of cell death at 0.5mM, and delayed cell death at 0.75mM cisplatin.

L-Methionine, the optical isomer, showed lower potency and less efficacy than D-Met, was less protective against 0.1mM cisplatin, and proved ineffective at a concentration of 0.5mM cisplatin.

Pre-exposure time of D-Met was associated with the protective effects at 0.1 and 0.5mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that D-Met protects central nervous system tissue from acute cisplatin toxicity.

http://www.ncbi.nlm.nih.gov/pubmed/22732230

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Interaction of Cisplatin with Human Superoxide Dismutase

cis-Diamminedichloroplatinum(II) (cisplatin) is able to interact with human superoxide dismutase (hSOD1) in the disulfide oxidized apo form with a dissociation constant of 37 ± 3 μM through binding cysteine 111 (Cys111) located at the edge of the subunit interface. It also binds to Cu2–Zn2 and Zn2–Zn2 forms of hSOD1.

Cisplatin inhibits aggregation of demetalated oxidized hSOD1, and it is further able to dissolve and monomerize oxidized hSOD1 oligomers in vitro and in cell, thus indicating its potential as a leading compound for amyotrophic lateral sclerosis.

http://pubs.acs.org/doi/abs/10.1021/ja211591n

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

did you find a retailler for cp ethypharm

you re great spider
see you!

This paper was from 1993 so I don't know how relevant?

New cisplatin analogues in development. A review.

The mechanism of the cytotoxic activity of platinum complexes has also been studied intensely. Recently synthesised analogues have been designed to interact with DNA in a manner different from cisplatin and carboplatin, with the desire of finding new structures with a superior or wider spectrum of antitumor efficacy. Most recently, water soluble platinum complexes that retain antitumour activity, but that can be effectively absorbed after oral administration, have been synthesised with the goal of improving patient quality of life.

Nine platinum analogues are currently in clinical trials around the world (ormaplatin [tetraplatin], oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 [NK-121], 254-S, JM-216 and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) [LNDDP]). Some of these analogues only represent attempts to reduce cisplatin toxicity and/or allow administration without forced hydration and diuresis, which carboplatin already does. Others are 'third generation' complexes shown to have limited or no cross-resistance with cisplatin in preclinical studies. They are being tested clinically with particular attention to this highly desirable property.(ABSTRACT TRUNCATED AT 400 WORDS)

http://www.ncbi.nlm.nih.gov/pubmed/7693428

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Spider,
there may be a different root to the same end without toxic side effects and maybe easier to obtain

Have a look at:

http://www.als.net/forum/yaf_postsm352512_Potential-therapeutics-against-SOD1-misfolding-and-aggregation.aspx#352512

I'm thinking of Orotic acid - Target SOD1 Cys111 same target as Cisplatin and if you read the literature that I posted it may be a better substance?

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Spider,
Taken from the document link you posted:

Orotic acid has a low acute toxicity. In repeated doses orotic acid induces fatty
livers in the rat, but not in other species tested.

Several studies have shown that repeated dosing of orotic acid to rats and some other species promotes the formation of tumours initiated by various known carcinogenic substances.

The usual concentration to promote tumours has been 1 % in the diet, but also 0.5 and 0.2 % in the diet has been shown to have promoting effect, while 0.1 % in the diet did not have effect within the time span tested (up to 20 weeks).

A No Observed Adverse Effect Level for this effect can thus be determined to be 50 mg/kg bw/day, while the Lowest Observed Effect Level is 100 mg/kg bw/day.

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Orotic acid - Target SOD1 Cys111

Based on the experimental results, we propose a mechanism of SOD aggregation that can be used to explain various observations made in the clinical and model studies of SOD-mediated ALS.

In addition, we have computationally identified orotic acid as a potential binding ligand to the cysteine 111 crevice of SOD with the ability to inhibit the aggregation according to our proposed aggregation mechanism.


Under oxidative aggregation condition, 0.1 mM orotate blocks the aggregation of both WT and pathogenic mutant SOD.

http://www.als.net/forum/yaf_postsm352481_Genetic-defects-in-ALS-and-relevance-to-PALS.aspx#352481

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again