Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke

Ranjan, Amaresh K.; Briyal, Seema; Gulati, Anil

doi:10.1038/s41598-020-69673-w

Cited by 23 publications

(33 citation statements)

References 59 publications

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“…We assessed the mitochondrial DNA using mitochondrial DNA specific TaqMan probe and primers for MT-ATP8 gene, which is present in mitochondrial genome as a single copy and is absent in nuclear genome. We performed in situ PCR in kidney tissues and carried out fluorescence confocal microscopy to detect the FAM labeled TaqMan probe as described in our previous studies ( Ranjan et al, 2012 ; AK Ranjan and Hardikar, 2015 ; Ranjan et al, 2020 ). We observed that CQ had significantly higher mitochondrial DNA fluorescence than vehicle, which could be due to less ROS generation in CQ than vehicle ( Figure 8 ).…”

Section: Discussionmentioning

confidence: 99%

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

et al. 2021

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Background: Centhaquine (CQ) (Lyfaquin®) is in late stage clinical development as a safe and effective first-in-class resuscitative agent for hemorrhagic shock patients (NCT02408731, NCT04056065, and NCT04045327). Acute kidney injury (AKI) is known to be associated with hemorrhagic shock. Hence, effect of CQ on protection of kidneys from damage due to hemorrhagic shock was investigated.Methods: To assess effect of CQ on AKI in shock, we created a rat model with hemorrhagic shock and AKI. Renal arteries were clamped and de-clamped to induce AKI like ischemia/reperfusion model and hemorrhage was carried out by withdrawing blood for 30 min. Rats were resuscitated with CQ (0.02 mg/kg) for 10 min. MAP, heart rate (HR), and renal blood flow (RBF) were monitored for 120 min.Results: CQ produced a significant improvement in RBF compared to vehicle (p< 0.003) even though MAP and HR was similar in CQ and vehicle groups. Blood lactate level was lower (p = 0.0064) in CQ than vehicle at 120 min post-resuscitation. Histopathological analysis of tissues indicated greater renal damage in vehicle than CQ. Western blots showed higher HIF-1α (p = 0.0152) and lower NGAL (p = 0.01626) levels in CQ vs vehicle. Immunofluorescence in the kidney cortex and medulla showed significantly higher (p< 0.045) expression of HIF-1α and lower expression of Bax (p< 0.044) in CQ. Expression of PHD 3 (p< 0.0001) was higher, while the expression of Cytochrome C (p = 0.01429) was lower in the cortex of CQ than vehicle.Conclusion: Results show CQ (Lyfaquin®) increased renal blood flow, augmented hypoxia response, decreased tissue damage and apoptosis following hemorrhagic shock induced AKI, and may be explored to prevent/treat AKI.Translational Statement: Centhaquine (CQ) is safe for human use and currently in late stage clinical development as a first-in-class resuscitative agent to treat hemorrhagic shock. In the current study, we have explored a novel role of CQ in protection from hemorrhagic shock induced AKI, indicating its potential to treat/prevent AKI.

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Section: Discussionmentioning

confidence: 99%

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

et al. 2021

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“…Intravenous sovateltide resulted in higher neuronal progenitor cell (NPC) differentiation and better mitochondrial morphology and biogenesis in the brain of stroked rats [ 41 , 42 ]. Exposure of cultured NPCs to hypoxia also showed higher NPC differentiation and maturation with sovateltide [ 41 , 42 ]. ET B receptors are vital for the development of neural crest-derived epidermal melanocytes and enteric neurons [ 19 , 27 , 28 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation of ET B receptors by sovateltide facilitated restoration of cerebral blood flow and improvement in neurological and motor function in a rat model of cerebral ischemia [ 24 , 25 , 29 , 30 ]. Sovateltide-treated animals showed strong evidence of neural tissue repair and regeneration, including decreased infarct volume and oxidative stress, increased pro-angiogenic, pro-survival and anti-apoptotic markers; and increased numbers of proliferating cells [ 24 , 25 , 29 , 30 , 41 , 42 ]. The SONAR trial administered a selective ET A receptor antagonist (leaving ET B receptors unblocked) in patients with type 2 diabetes mellitus with chronic kidney disease [ 51 ], who have a significantly greater risk of cardiovascular accidents [ 52 ], providing indirect supporting evidence of a reduced number of nonfatal strokes in these patients.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke

et al. 2021

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Background 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). Objective 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. Methods 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. Results 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 impro...

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“…Sovateltide (an ET B receptor agonist) injected intravenously showed higher neuronal progenitor cells (NPCs) differentiation along with better mitochondrial morphology and biogenesis in the brain stroked rats. Exposure of cultured NPCs to hypoxia also showed higher NPC differentiation and maturation with sovateltide [46, 47]. ET B receptors are vital for the development of neural crest-derived epidermal melanocytes and enteric neurons [19, 27, 28, 48, 49].…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation of ET B receptors by sovateltide facilitated restoration of cerebral blood flow and improvement in neurological and motor function after stroke [24, 25, 29, 30]. Sovateltide treated animals showed strong evidence of neural tissue repair and regeneration including decrease in infarct volume and oxidative stress, increased pro-angiogenic, pro-survival and antiapoptotic markers as well as number of proliferating cells [24, 25, 29, 30, 46, 47]. A safe and maximum tolerated dose of sovateltide was determined in the clinical phase I trial (CTRI/2016/11/007509) in healthy human volunteers [5].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke

Gulati

Agrawal

Vibha

et al. 2020

Preprint

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Background: Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). Objective: To determine safety, tolerability and efficacy of sovateltide as an adjuvant to standard of care (SOC) in acute cerebral ischemic stroke patients. Methods: A prospective, multi-centric, randomized, double-blind, controlled study to compare efficacy of sovateltide in patients with acute cerebral ischemic stroke was conducted in 40 patients, of which 36 completed 90-day follow-up. Patients who had stroke within the last 24 hours with a radiologic confirmation of ischemic stroke were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. All patients in both groups received SOC for stroke. Patients randomized in the sovateltide group received three doses of sovateltide (each dose 0.3 μg/kg) administered as an IV bolus over 1 minute at an interval of 3 hours ± 1 hour on day 1, day 3 and day 6 (total dose of 0.9 μg/kg/day). Patients randomized in the placebo group received equal volume of saline. Efficacy was evaluated by neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scales. Quality of Life was measured by EuroQoL (EQ-5D) and stroke specific quality-of-life (SS-QoL). Results: Patients received saline (n=18; 11 male and 7 female) or sovateltide (n=18; 15 male and 3 female) within 24 hours of onset of stroke. Number of patients receiving investigational drug within 20 hours of onset of stroke were 14/18 in saline and 10/18 in sovateltide cohorts. The baseline characteristics and SOC in both cohorts was similar. Sovateltide treatment resulted in a significantly quicker recovery as measured by improvements in neurological outcomes in mRS and BI scales on day 6 compared to day 1 (p<0.0001). Moreover, sovateltide increased the frequency of favorable outcomes in all scales at 3 months. An improvement of ≥2 points in mRS was observed in 60% and 40% patients in sovateltide and saline groups, respectively (p=0.0519; odds ratio 5.25). BI improvement of ≥40 points was 64% and 36% in sovateltide and saline groups, respectively (p=0.0112; odds ratio 12.44). An improvement of ≥6 points was seen in NIHSS in 56% of patients in sovateltide vs 43% in saline groups (p=0.2714; odds ratio 2.275). Number of patients with complete recovery achieving NIHSS score of 0 and BI of 100 were significantly more (p<0.05) in sovateltide group compared to saline group. Sovateltide treatment resulted in improved Quality of Life as measured by EuroQoL and SS-QoL (stroke specific quality-of-life) on day 90. Sovateltide was well tolerated and all patients received complete treatment with no incidence of drug related adverse event reported. Hemodynamic, biochemical or hematological parameters were not affected with sovateltide. Conclusion: Sovateltide was safe, well tolerated, and resulted in quicker recovery and improved neurological outcome in acute cerebral ischemic stroke patients 90 days post-treatment.

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Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke

Cited by 23 publications

References 59 publications

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke

Efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke

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