Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
A combination therapy proposed to be evaluated in this trial, consisting of three already registered compounds with a validated disease mechanism and with known safety profiles, targets key proteins in the dysregulated signal network in stroke, and is expected to synergistically result in post-stroke blood-brain barrier stabilization and neuroprotection. The synergistic mode of action will allow for low doses and is expected to reduce possible side effects while maintaining maximal efficacy
Full description
There is a high need for new drugs & novel approaches for neuroprotection in stroke treatment.
Pre-clinically, three interrelated in silico predicted drug targets and pharmacological principles all belonging to the same signal network were validated at the preclinical level to be causally relevant in stroke and thus hold promise for the first-in-class mechanism-based, curative neuroprotective therapy of an ischemic stroke:
Different representatives of the drug classes of NADPH oxidase inhibitors (NOXi), nitric oxide synthase inhibitors (NOSi), and soluble guanylate cyclase modulators were identified and shown to be highly effective when given alone in different small animal experimentation and in vitro human models. However, since all single target approaches in stroke have so far failed in clinical development during the last decades, and NOS, NOX and sGC all belong to the same disease module, an innovative combined, so-called network pharmacology approach is proposed, i.e., a combination of 3 already registered compounds with a validated disease mechanism: the sGC activator riociguat, the NOS1 inhibitor propylthiouracil, and the NOX inhibitor perphenazine.
Riociguat is an sGC stimulator currently approved and marketed for pulmonary hypertension. Post-reperfusion therapy with riociguat, increased cGMP formation and therefore leads to direct neuroprotection and reduced infarct volume in a stroke animal model. Propylthiouracil is already marketed for the treatment of various subtypes of hyperthyroidism and has been identified as a new member of the class of potent and effective NOS1 inhibitors. Pre-clinically, post-reperfusion treatment with propylthiouracil significantly reduced infarct volume in brain ischemia mice models compared to non-treated animals (pre-clinical in-house data, unpublished). Perphenazine is already marketed as an antiemetic and antipsychotic, has the best NOX inhibitory characteristics compared to other compounds of the same drug class, and significantly reduced infarct size in acute ischemic stroke mice models.
In summary, the combination therapy proposed to be evaluated in this trial, consisting of already registered compounds with a validated disease mechanism and with known safety profiles, targets key proteins in the dysregulated signal network in stroke, and is expected to synergistically result in post-stroke blood-brain barrier stabilization and neuroprotection. The synergistic mode of action will allow for low doses and is expected to reduce possible side effects while maintaining maximal efficacy.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
28 participants in 2 patient groups
Loading...
Central trial contact
Harald Schmidt, MD PhD
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal