Hibernation-Based Approaches in the Treatment of Hemorrhagic Shock

Wolf, Andrea; Lusczek, Elizabeth R.; Beilman, Gregory J.

doi:10.1097/shk.0000000000001094

Cited by 14 publications

(12 citation statements)

References 110 publications

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“…Organ protection during traumatic HS can in principle be caused by various mechanisms including therapeutic strategies addressing damage-associated molecular patterns (18), immunomodulation (19), coagulation (20), oxidative stress (21), hibernation programs (22), endothelial dysfunction and barrier sealing (2), and others.…”

Section: Introductionmentioning

confidence: 99%

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

et al. 2020

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Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products

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Section: Introductionmentioning

confidence: 99%

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

et al. 2020

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“…Agents that could decrease metabolic activity to reduce oxygen demand were studied. Histone deacetylase inhibitors such as valproic acid and suberoylanilide hydroxamic acid 14,15 , hydrogen sulfide and its donor sodium sulfide 16,17 , mitochondria targeted hydrogen sulfide donor AP39 18 , formulation consisting of d-beta-hydroxybutyrate and melatonin 19 and other hibernation based approaches have been tried 20 but none has shown any promise clinically. Hemoglobin-based blood substitutes were prepared as resuscitative agents.…”

Section: Introductionmentioning

confidence: 99%

A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin^®) as a resuscitative agent in hypovolemic shock patients

Gulati

Choudhuri

Gupta

et al. 2020

Preprint

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Centhaquine is a novel, first-in-class resuscitative agent for the treatment of hypovolemic shock. Efficacy of centhaquine for the treatment of hypovolemic shock as an adjuvant to standard of care (SOC) was evaluated in a prospective, multi-center, randomized, double-blind, placebo-controlled Phase 3 study. Key inclusion criteria were; systolic blood pressure of ≤90 mm Hg, blood lactate levels of ≥2 mmol/L and patients receiving SOC in a hospital or ICU setting. Patients were randomized in a 2:1 ratio either to the centhaquine group receiving centhaquine dose of 0.01 mg/kg by IV infusion along with SOC or to the control group receiving SOC plus saline. Primary endpoints of the study were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), change in blood lactate levels and change in base deficit. Mortality through day 28 was the key secondary endpoint. A total of 197 patients were screened, of which 105 patients met the eligibility criteria and were included in the study. Out of 105 patients, 71 patients were randomized to centhaquine group and 34 patients to control group. Demographics and baseline characteristics of patients in both groups was comparable. Hemoglobin level was 9.38 ± 0.71 g/dL and 8.73 ± 0.55 g/dL in control and centhaquine groups, respectively at the time of inclusion in the study. At 24 hours of resuscitation, SBP of more than 110 mmHg was in 59.38% patients of control and 81.82% patients of centhaquine group (P=0.00842). Similarly, at 24 hours of resuscitation, DBP of more than 70 mmHg was in 50.00% patients in control group and 78.46% patients in centhaquine group (P=0.002175). The number of patients with blood lactate levels of 1.5 mmol/L or less were 46.88% in the group with standard treatment compared to 69.35% in centhaquine group (P=0.0168). The number of patients with base-deficit of less than minus 2 were 46.88% in standard treatment group compared to 68.25% in those receiving centhaquine (P=0.0217). Centhaquine treatment significantly reduced 28-day all-cause mortality. In the control group, the mortality rate was 11.76% compared to 2.94% in the centhaquine group (odds ratio: 4.4; 95% CI 0.9651 to 23.74 and P=0.037). No drug related adverse event was reported. Centhaquine (Lyfaquin®) is a highly efficacious resuscitative agent for the treatment of hypovolemic shock as an adjuvant to SOC. The study protocol (PMZ-2010/CT-3.1/2018) was approved by the Drug Controller General of India (DCGI), Ministry of Health and Family Welfare, Government of India and Institutional Ethics Committee of all the 14 Institutions.

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“…While a number of synthetic peptides display nanomolar From a translational perspective, peptide-based probes provide an ideal tool for studying the cardioprotective effects of the δOR, given their low brain penetration. While numerous enkephalin-like peptides have been synthesized that interact with excellent potency and selectivity for δORs and µORs [13], a majority of studies [14] investigating δOR involvement in ischemia have utilized the synthetic peptide d-Ala 2 , d-Leu 5 -enkephalin (DADLE, Figure 1) [15,16], because DADLE possesses improved proteolytic stability and improved selectivity for δORs over µORs relative to Leu 5 -enkephalin [6,17]. However, DADLE's discovery in 1977 [18], predated identification of β-arrestin as a modulator of opioid signaling [14,[19][20][21], With the use of contemporary cellular assays it is now apparent that DADLE pharmacologically signals similarly to Leu 5 -enkephalin, though it recruits β-arrestin 2 (arrestin 3) slightly more efficaciously.…”

Section: Introductionmentioning

confidence: 99%

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

Cassell

Sharma

et al. 2019

Molecules

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As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu 5 -enkephalin and the more metabolically stable synthetic peptide (d-Ala 2 , d-Leu 5 )-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR's protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe 4 position of Leu 5 -enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe 4 of Leu 5 -enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe 4 may be combined with other modifications to Leu 5 -enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.

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Hibernation-Based Approaches in the Treatment of Hemorrhagic Shock

Cited by 14 publications

References 110 publications

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin^®) as a resuscitative agent in hypovolemic shock patients

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

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Hibernation-Based Approaches in the Treatment of Hemorrhagic Shock

Cited by 14 publications

References 110 publications

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin®) as a resuscitative agent in hypovolemic shock patients

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

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A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin^®) as a resuscitative agent in hypovolemic shock patients