Assessment of dose–effect and therapeutic time window in preclinical studies of rhEGF and GHRP-6 coadministration for stroke therapy

Subirós, Nelvys; Pérez-Saad, Héctor; Berlanga, Jorge; Aldana, Lizet; García-Illera, Gerardo; Gibson, Claire L.; Garcia-del-Barco, D.

doi:10.1179/1743132815y.0000000089

Cited by 5 publications

(5 citation statements)

References 46 publications

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“…In this study, the positive and significant correlation between time to treatment and mRS suggests that earlier intervention with EGF+GHRP6 may decrease disability 6 months after the onset of symptoms. This finding is also consistent with our pre-clinical studies ( 19 ). Although the immediate intervention is likely to enhance the therapeutic effects, we anticipate that components of this combination therapy will also target later secondary events, promoting survival of the neurovascular unit and activating endogenous neuroprotective pathways, which would predict a longer-lasting effect ( 56 , 57 ).…”

Section: Discussionsupporting

confidence: 94%

“…The EGF+GHRP6 combined therapy for stroke was designed to activate a cascade of endogenous neuroprotection mechanisms, including regeneration of adult neural stem cells and repair in the penumbra zone ( 26 – 31 , 57 , 71 , 72 ). The activation of these pathways could explain the clinical (neurological, functional, and survival) outcomes evidenced in this study, which had been previously demonstrated in stroke animal models ( 17 – 19 ). The events induced by both active agents in this combined therapy have a scope that transcends beyond the acute phase of brain infarction ( 57 , 71 , 73 , 74 ).…”

Section: Discussionsupporting

confidence: 72%

“…Molecules that trigger cytoprotective effects can be considered candidates for combined therapies (8). Particularly, a combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) has demonstrated benefit in preclinical contexts by activating pleiotropic endogenous mechanisms of survival and brain protection (15)(16)(17)(18)(19). Both molecules cross the blood-brain barrier (20)(21)(22)(23), and their receptors are widely distributed in brain tissues (24,25).…”

Section: Introductionmentioning

confidence: 99%

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Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Hernández-Bernal,

Estenoz-García,

Gutiérrez-Ronquillo

et al. 2024

Front. Neurol.

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ObjectiveThis study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.MethodsA multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18–80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.ResultsThe study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8–11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06–1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03–1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.ConclusionEGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.Clinical Trial RegistrationRPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Hernández-Bernal,

Estenoz-García,

Gutiérrez-Ronquillo

et al. 2024

Front. Neurol.

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“…Fortunately, synthetic ghrelin analogs offer prolonged stability, significant plasma release for up to 24 h, oral bioavailability and the ability to co-bind CD36, which may be useful to diminish Aβ-driven microglial inflammation (Bulgarelli et al, 2009;Muller et al, 2015;Berlanga-Acosta et al, 2017). To further enhance efficacy, the combination of ghrelin agonists with other growth factors, such as EGF (Barco et al, 2011, del Barco et al, 2011 Barco-Herrera et al, 2013;Subiros et al, 2016), GH (Wu et al, 2009b;Zhou et al, 2017), insulin (Granado et al, 2011) and GLP-1 (Duarte et al, 2018), or DAG, to prevent AGencouraged glucose intolerance and hypoinsulinemia (Gauna et al, 2004;Kiewiet et al, 2009), may be profitable. On the other hand, due to the possible development of ghrelin resistance in AD and reports of gastrointestinal complications in some PD patients, clinical studies are warranted to monitor the longterm effectiveness of AG.…”

Section: Resultsmentioning

confidence: 99%

Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

Reich

Hölscher

2020

Front. Neurosci.

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Much thought has been given to the impact of Amyloid Beta, Tau and Alpha-Synuclein in the development of Alzheimer's disease (AD) and Parkinson's disease (PD), yet the clinical failures of the recent decades indicate that there are further pathological mechanisms at work. Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impaired neurogenesis and, of course, widespread axonal, synaptic and neuronal degeneration that leads to cognitive and motor impediments. Interestingly, the acylated form of the hormone ghrelin has shown the potential to ameliorate the latter pathologic changes, although some studies indicate a few complications that need to be considered in the long-term administration of the hormone. As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone's therapeutic benefits for the treatment of AD and PD.

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“…56 Garcia del Barco and coworkers in our group have opened unprecedented avenues, by combining GHRP-6 and EGF as a therapeutic approach to ameliorate the damages of multiple sclerosis, 57 peripheral axonal pathology, 58 and brain ischemia in animal models. 59 , 60 They have demonstrated that in all these experimental substrates the combined action of GHRP-6 and EGF is associated with a better outcome in both clinical and pathological fields.…”

Section: Pharmacological Repositioning Of Ghrpmentioning

confidence: 99%

Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects

Berlanga‐Acosta

Abreu-Cruz

Herrera

et al. 2017

Clin Med Insights Cardiol

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Background:Growth hormone-releasing peptides (GHRPs) constitute a group of small synthetic peptides that stimulate the growth hormone secretion and the downstream axis activity. Mounting evidences since the early 1980s delineated unexpected pharmacological cardioprotective and cytoprotective properties for the GHRPs. However, despite intense basic pharmacological research, alternatives to prevent cell and tissue demise before lethal insults have remained as an empty niche in the clinical armamentarium. Here, we have rigorously reviewed the investigational development of GHRPs and their clinical niching perspectives.Methodology:PubMed/MEDLINE databases, including original research and review articles, were explored. The search design was date escalated from 1980 and included articles in English only.Results and Conclusions:GHRPs bind to two different receptors (GHS-R1a and CD36), which redundantly or independently exert relevant biological effects. GHRPs’ binding to CD36 activates prosurvival pathways such as PI-3K/AKT1, thus reducing cellular death. Furthermore, GHRPs decrease reactive oxygen species (ROS) spillover, enhance the antioxidant defenses, and reduce inflammation. These cytoprotective abilities have been revealed in cardiac, neuronal, gastrointestinal, and hepatic cells, representing a comprehensive spectrum of protection of parenchymal organs. Antifibrotic effects have been attributed to some of the GHRPs by counteracting fibrogenic cytokines. In addition, GHRP family members have shown a potent myotropic effect by promoting anabolia and inhibiting catabolia. Finally, GHRPs exhibit a broad safety profile in preclinical and clinical settings. Despite these fragmented lines incite to envision multiple pharmacological uses for GHRPs, especially as a myocardial reperfusion damage-attenuating candidate, this family of “drugable” peptides awaits for a definitive clinical niche.

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Assessment of dose–effect and therapeutic time window in preclinical studies of rhEGF and GHRP-6 coadministration for stroke therapy

Cited by 5 publications

References 46 publications

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects

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