Study of Possible Effects of the Drugs Propylthiouracil, Riociguat and Perphenazine on Circulation of Healthy Volunteers

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This trial is part of the Horizon 2020 project, REPO-TRIAL, on in-silico, mechanism-based drug repurposing in high unmet-medical-need indications. This project aims to identify causal, rather than symptomatic disease mechanisms for highly precise and effective interventions. Here a signalling module...

This trial is part of the Horizon 2020 project, REPO-TRIAL, on in-silico, mechanism-based drug repurposing in high unmet-medical-need indications. This project aims to identify causal, rather than symptomatic disease mechanisms for highly precise and effective interventions. Here a signalling module comprised of reactive oxygen species (ROS) formation and cyclic GMP signalling has been identified to be involved in post-stroke blood-brain-barrier disruption and neuronal death. It can be targeted by repurposing three drugs, which inhibit overshooting nitric oxide (NO) and ROS formation, respectively, and stimulate compromised neuroprotective cyclic GMP formation. It is possible that two of the drugs (riociguat, perphenazine) may cause a drop and one drug an elevation of blood pressure (propylthiouracil) leading to an overall drop in blood pressure. On top of that, the three drugs may synergise on blood pressure in a previously not recognised manner. These potential safety concerns, expressed in a scientific advice meeting by the Federal Institute for Drugs and Medical Devices (BfArM), shall be tested in the present phase I safety trial. Ischemic stroke is the leading cause of acquired disability in adulthood (WHO report). As of 2020, only one approved pharmacological treatment option, intravenous thrombolysis (rtPA), is available. However, intravenous thrombolysis is used only for a fraction of stroke patients given its strict inclusion criteria, broad exclusion criteria, and the risk of lethal iatrogenic intracranial bleeding. While mechanical recanalization therapy has improved patient outcomes, it is also limited by (i) relatively narrow time windows for effective treatment, (ii) being available to patients with large vessel occlusions only, and (iii) by requiring a dedicated infrastructure to treat these patients. Given these limitations there is a need for new approaches to stroke management. The ideal intervention would (i) be directly neuroprotective, (ii) reduce the brain infarct volume, (iii) improve functional neurological outcomes, (iv) increase survival, (v) be safe, i.e. bear no risk to cause secondary bleeding, (vi) be broadly applicable, and (vii) logistically compatible with recanalization. NO synthase, NOS1, is overactivated, NADPH oxidases, NOX4 and NOX5 get induced and overactivated, NO and NOX-derived reactive non-steroidal anti-inflammatory drug oxygens species (ROS) toxify each other; one target being sGC, which is oxidatively damaged to no longer contain haeme and no longer respond to NO to form neuroprotective cyclic GMP (cGMP). Consequently, inhibiting NOS1 and NOX4/5, and reactivating haeme-free apo-sGC synergistically results in post-stroke blood-brain-barrier stabilisation and neuroprotection. The NOX4/5-NOS1-sGC signalling network is required for vascular endothelial maintenance and dysregulated after an ischemic stroke. After an ischemic event, NOX4/5 and NOS enzymes are over-activated and lead to an excessive release of ROS in vivo. Such ROS can damage multiple cellular structures, including soluble guanylate cyclase (sGC), which no longer responds to nitric oxide (NO) to form neuroprotective cyclic GMP (cGMP). Consequently, pre-clinical pharmacological inhibition of NOX4/5, NOS1, and restoration of sGC activity lead to reduced infarct volumes in vivo, especially when administered in combination. The three agents used in the described pre-clinical experiments, perphenazine, propylthiouracil, and riociguat, are approved medicines used for non-stroke-related indications. Perphenazine, a typical antipsychotic, and propylthiouracil, a thyroid peroxidase inhibitor used for the treatment of hyperthyroidism, have previously been identified as off-target inhibitors of NOX4 and NOS, respectively. Riociguat, approved for treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), is a first-in-class sGC stimulator. Given the pre-clinical evidence for a signalling-network-based combination therapy consisting of perphenazine, propylthiouracil, and riociguat, the investigators hypothesize that combined use of these substances as an add-on treatment to the current standard of care will reduce infarct volume and improve neurological function in patients with ischemic stroke.

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