irl-1620 and Brain-Ischemia

Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, has been previously shown to increase cerebral blood flow, have anti-apoptotic activity and produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509).. Our objective was to determine the safety, tolerability and efficacy of sovateltide as an addition to standard of care (SOC) in patients with acute cerebral ischemic stroke.. A prospective, multicentric, randomized, double-blind, placebo-controlled study was conducted to compare the safety (primary objective) and efficacy (secondary objective) of sovateltide in patients with acute cerebral ischemic stroke. Adult males or females aged 18-70 years who had experienced a radiologically confirmed ischemic stroke within the last 24 h were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. Patients randomized to the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized to the placebo group received an equal volume of saline. Every patient in both groups received SOC for stroke. Efficacy was evaluated using neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scores from day 1 through day 90. Quality of life was measured using the EuroQoL-5 Dimensions (EQ-5D) and Stroke-Specific Quality of Life (SSQoL) at 60 and 90 days of follow-up.. A total of 40 patients with acute cerebral ischemic stroke were enrolled in this study, of whom 36 completed the 90-day follow-up. Patients received saline (n = 18; 11 male and 7 female) or sovateltide (n = 18; 15 male and 3 female) within 24 h of onset of stroke. The number of patients receiving investigational drug within 20 h of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts was similar. Sovateltide was well-tolerated, and all patients received complete treatment with no incidence of drug-related adverse events. Hemodynamic, biochemical or hematological parameters were not affected by sovateltide. Sovateltide treatment resulted in improved mRS and BI scores on day 6 compared with day 1 (p < 0.0001), an effect not seen in the saline group. Sovateltide increased the frequency of favorable outcomes at 3 months. An improvement of ≥ 2 points on the mRS was observed in 60 and 40% of patients in the sovateltide and saline groups, respectively (p = 0.0519; odds ratio [OR] 5.25). An improvement on the BI of ≥ 40 points was seen in 64 and 36% of the sovateltide and saline groups, respectively (p = 0.0112; OR 12.44). An improvement of ≥6 points on the NIHSS was seen in 56% of patients in the sovateltide group versus 43% in the saline group (p = 0.2714; OR 2.275). The number of patients with complete recovery (defined as an NIHSS score of 0 and a BI of 100) was significantly greater (p < 0.05) in the sovateltide group than in the saline group. An assessment of complete recovery using an mRS score of 0 did not show a statistically significant difference between the treatment groups. Sovateltide treatment resulted in improved quality of life as measured by the EQ-5D and SSQoL on day 90.. Sovateltide was safe and well-tolerated and resulted in improved neurological outcomes in patients with acute cerebral ischemic stroke 90 days post-treatment.. The study is registered at CTRI/2017/11/010654 and NCT04046484.

Topics: Brain Ischemia; Double-Blind Method; Endothelins; Female; Humans; Injections, Intravenous; Ischemic Stroke; Male; Middle Aged; Peptide Fragments; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic; Receptor, Endothelin B; Treatment Outcome

Manipulation of the central endothelin (ET) system via either ETA antagonists or ETB agonists following experimental cerebral ischemia has been shown to be beneficial in previous experimental studies. In order to further explore the involvement of these receptors in cerebral ischemia, we determined changes in binding affinity (Kd) and density (Bmax) of ETA and ETB receptors in the rat brain at 24 h and 1 week following middle cerebral artery occlusion (MCAO). Rats subject to MCAO exhibited significant neurological and motor function deficit as well as large infarct volumes (126.41±40.12 and 152.82±21.67 mm(3) on days 1 and 7, respectively). Bmax increased (P<0.01) and Kd decreased (P<0.01) for ETA receptors in the infarcted right cerebral hemisphere compared to sham 24 h post MCAO. However, after 7 days of MCAO, Bmax of ETA receptors was similar, while Kd in the infarcted hemisphere increased (P<0.05) compared to sham. Binding characteristics for brain ETB receptors were not altered 24 h post MCAO. However, 7days following MCAO, there was a significant decrease (P<0.001) in Kd values and an increase (P<0.001) in Bmax values for ETB receptors in the ischemic cerebral hemisphere. The initial increase in ETA receptors is damaging and may be aggravating cerebral ischemia due to its vasoconstrictive actions. On the other hand, since ETB receptors have been shown to enhance brain angiogenesis, it is possible that an increase in binding characteristics of these receptors is part of a natural defense mechanism to repair the ischemic brain.

Topics: Animals; Brain Ischemia; Endothelins; Infarction, Middle Cerebral Artery; Iodine Radioisotopes; Male; Peptide Fragments; Radioligand Assay; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors

We have earlier shown that stimulation of endothelin B receptors by IRL-1620 provides significant neuroprotection at 24h following cerebral ischemia. However, the effect of IRL-1620 is not known in the subacute phase of cerebral ischemia, where development of cerebral edema further contributes towards brain damage. This study was designed to determine the effect of IRL-1620 on neurological functions, infarct volume, oxidative stress, and endothelin receptors following permanent middle cerebral artery occlusion for 7 days. Rats received three intravenous injections of either vehicle or IRL-1620 [Suc-[Glu9,Ala11,15]-Endothelin-1(8-12)] at 2, 4, and 6h post occlusion. Treatment with IRL-1620 reduced infarct volume (54.06 ± 14.12 mm(3) vs. 177.06 ± 13.21 mm(3)), prevented cerebral edema and significantly improved all neurological and motor function parameters when compared to the vehicle-treated group. Vehicle-treated middle cerebral artery occluded rats demonstrated high levels of malondialdehyde and low levels of reduced glutathione and superoxide dismutase; these effects were reversed in IRL-1620 treated rats. No change in expression of endothelin A receptor was observed 7 days after induction of cerebral ischemia in vehicle or IRL-1620 treated rats. Rats receiving IRL-1620 demonstrated an upregulation of endothelin B receptor only in the infarcted hemisphere 7 days following occlusion. All effects of IRL-1620 were blocked by endothelin B receptor antagonist, BQ788. Results of the present study demonstrate that IRL-1620, administered on day 1, provides significant neuroprotection till 7 days after the induction of cerebral ischemia in rats. Selective endothelin B receptor activation may prove to be a novel therapeutic target in the treatment of cerebral ischemia.

Topics: Animals; Brain; Brain Ischemia; Endothelins; Glutathione; Malondialdehyde; Motor Activity; Muscle Strength; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Rats; Receptor, Endothelin B; Superoxide Dismutase; Up-Regulation