What exactly does this mean? Also Melcangi is still looking into this? If so that’s amazing.
IDENTIFICATION OF A NOVEL OFF-TARGET FOR THE 5ALPHA-
REDUCTASE INHIBITOR FINASTERIDE
Giatti S.1
, Di Domizio A.2
, Diviccaro S.1
, Falvo E.1
, Caruso D.1
, Contini A.3
, Melcangi
R.C.1
1
Department of Pharmacological and Biomolecular Sciences, UniversitĂ degli Studi di
Milano, Italy
2
SPILLOproject, Paderno Dugnano, Milano, Italy (Website: www.spilloproject.com)
3
Dipartimento Di Scienze Farmaceutiche, UniversitĂ degli Studi di Milano, Italy
PI full address: UniversitĂ degli Studi di Milano, Department of Pharmacological and
Biomolecular Sciences, Neuroendocrinology Unit, Via Balzaretti 9, 20133 Milano, Italy;
silvia.giatti@unimi.it
The 5alpha-reductase inhibitor finasteride is clinically used to reduce dihydrotestosterone
levels in benign prostatic hyperplastic and androgenetic alopecia. Like many
pharmacological agents, this drug is associated to side effects occurring during treatment.
The American Food and Drug Administration Adverse Event Reporting System (FAERS)
described complains associated to physical, psychological, and sexual domains in relation to
finasteride administration [1,5]. These include rash and metabolic abnormalities,
psychological alterations, such as increase in self-harm, slow cognition, changes in
emotional effect, sleep disturbances; in addition, it was also reported decreased or loss of
libido, disorders of ejaculation, erectile dysfunction, testicular atrophy, orgasmic disorders,
and hypogonadism. Since finasteride can pass the blood brain barrier, it is possible that
administration of this compound might alter the steroid metabolism within the nervous
system. In particular, neuroactive steroids are steroidal molecules having a regulatory
function in the nervous system and perturbed levels of these compounds have been described
in many pathological conditions [6].
In agreement with this view, neuroactive steroid levels are altered in an animal model
chronically treated with finasteride. Moreover, also the levels of receptors involved in
neuroactive steroid action in the brain are altered by drug administration [4].
However, steroid metabolism in the brain might not be the only responsible for the side
effects described. Interestingly, in the same animal model, it has been also described an
alteration on gut microbiome composition [3]. Since increasing evidence suggest a
bidirectional communication between the brain and the gut [2], it is possible to hypothesize
that also this alteration can be involved in the symptomatology reported.
In order to identify other pathways altered by finasteride treatment and related to the side
effects described, a multidisciplinary approach was applied to detect off-target proteins of
the drug. A 3D proteome-wide scale in silico screening of a human protein database coupled
to molecular dynamics identified an interesting off-target protein (OTP). Further in vitro and
in vivo experiments strongly suggested that the identified OTP might be a novel finasteride-
interacting protein. Based on the results obtained by our experiments and the evidence
retrieved in the published literature, the novel OTP identified has the potential to participate
in the side effects observed in finasteride users.
I don’t know how to make sense of this. Can anybody more knowledgeable than myself care to shine light on this and it’s implications?
Here is how I interpreted it, others feel free to correct if my take is wrong. BTW, its just an abstract, so not enough context to really learn much.
Sounds like there is a protein (which is likely the result of (epi)genomic changes, i.e. hyper or hypo methylation) that is affected by (increased or decreased) Finasteride. They say “novel”, but I don’t think they mean “never before seen”, because they mention that “evidence retrieved in public literature”. So by “novel” I think they just mean, its never been noted in research that this protein is affected by Finasteride.
Their conclusion is the most important part, they believe there is evidence that this OTP has the ability to cause or play a part in the symptoms of PFS.
Again, Melcangi is killing the PFS research. Leaps and bounds above Khera/Baylor.
The full study (or if anyone can get the presentation slides) will give much more detail.
I still don’t see how fixing one protein is going to fix all the different side effects.
I could see it. I will say no organic type of therapy is going to happen overnight.
I understand there is some fatigue setting in here with the way I go about things. I get it.
I know what im talking about though, I have pretty much backed up everything I have said with studies.
I understood coming here I would be going against the grain.
i’m not claiming to be Mr. Right about everything.
My theory hasn’t changed a whole lot since I came on here, I have just learned more.
Please understand I come from a whole different line of research when it comes to the drug side effects of Accutane.
Im going to have to get back to this,
I am going to show you a very close relationship between retinoic acid, testosterone and androgen signaling.
There’s a protein i’ve mentioned quite a bit now called raldh2.
This is the equivalent of male penis size btw, or could be considered analogous.
Retinoic Acid Is Involved in the Metamorphosis of the Anal Fin into an Intromittent Organ, the Gonopodium, in the Green Swordtail ( Xiphophorus hellerii )
We show that during anal fin metamorphosis of gonopodium outgrowth aldh1a2 is co-expressed with androgen receptors and aldh1a2 gene expression increases in a testosterone concentration-dependent manner, suggesting that RA synthesis might be controlled by androgen signaling.
That Melcangi study sounds great. Makes sense to me seems like my nervous system has been altered more than anything else. Congnition, Visual, Muscle weakness/shakiness, Skin sensitivity.
How do I get involved in a study like that? Id let them study my body all day long