Originally posted by pivalde
Here we come again to the same discussion we have had several times: Supplement Fig 8 in the paper by Tardiff et al ( included Lindquist) in Feb 2012 telling that metal chelation did not alone explain the positive effect of PBT2. Now we have PBT434, not a hydroxyquinoline but a
8-hydroxyquinazolin-4(3H)-one
, designed to help Parkinson's patient and to have affinity to iron. It is a molecule chemically very close to mitochondrion division inhibitor-1 ( also an quinazolinone ). There are many different quinazolinones. Mdivi-1 has the best quality to prevent mitochondrial division ( see Cassidy-Stone et al 2008 ). However there is some info that mdivi-1 ( and perhaps also other quinazolinones ) does not work in an environment where is a lot of iron (?). In the animal models of Parkinson's disease PBT434 and mdivi-1 work in very similar way.
So IMO PBT434 could have these two qualities: (1) iron chelator and (2) mitochondrion division inhibitor. We know that it is an iron chelator but we do not know if it has any efficacy it self to inhibit mitochondrion division. My strong guess is that PBT434 has both of these qualities and that is why the results in MSA were robust. Now when it looks like iron accumulation activates mitochondrion fission ( Huang XT, Oct 31 2018) so it could be that iron chelation itself could also activate mitochondrion fusion. To me it is self clear or even a must that Prana will soon study how PBT434 helps the energy supply of the nerves and how it does that will be also important when comparing it to the other iron chelators.
Pivalde, I am not disputing anything you say in the above text. Now that we have a trial update of sorts I was just looking at the timing of the PBT434 P1 completion and the completion of the Fair Park 2 deferiprone trial, plus toxicity. Although quite different drugs the DFP trial could give Prana a look at an iron chelator result before the start of the PBT434 P2 trial. That may give Prana some advantage they have never had before. With PBT2 it was always jumping into the human clinical unknown. The euro trial for PBT2 was the first of it's class into human trials. The PBT2 Reach2HD was the first MPAC human trial in HD, and with brain imaging now available for plaques, the IMAGINE trial was the first ever imaging trial of an MPAC for Alzheimer's.
So far there are 2 completed pilot studies of DFP, one 18 patients and one 40 patients. Fairpark2 calls for 338 patients divided about half on the drug and half placebo from memory. Fairpark biomarkers will include:
Magnetic resonance imaging (MRI), i.e. indirect measurements of iron with an R2* sequence
Transcranial ultrasound (i.e. indirect measurements of iron via the hyperechogenicity of substantia nigra)
Dopamine transporter SPECT imaging (123I-FP-CIT, DATscan®
Biochemical biomarkers (in blood and cerebrospinal fluid (CSF)).
Pharmacogenetic markers (i.e. ceruloplasmin genotypes for the disease-modifying effect of iron chelation and COMT genotypes for the symptomatic action of DFP; Grolez et al., 2015).
That is a lot of info compared to previous trials, which was no previous human evidence.
I am just an interested outsider at this point and once again did not dis your MDIVI-1ideas
which I like.
