Dataset Information

Evaluation of cytochrome P450-based drug metabolism in hemorrhagic shock rats that were transfused with native and an artificial red blood cell preparation, Hemoglobin-vesicles.

ABSTRACT: Hemoglobin-vesicles (Hb-V) are being developed as red blood cell (RBC) substitutes. In this study, we report on quantitative and qualitative alterations of hepatic cytochrome P450 (CYPs) and the pharmacokinetics of CYP-metabolizing drugs, with a focus on four CYP isoforms (CYP1A2, CYP2C11, CYP2E1 and CYP3A2), after Hb-V resuscitation from a massive hemorrhage. The results of proteome analysis and western blot data indicate that resuscitation with both Hb-V and packed RBC (PRBC) resulted in a decrease in the protein levels of CYPs. Along with a decrease in the protein expression of CYPs, pharmacokinetic studies showed that the elimination of CYP-metabolizing drugs was prolonged in the Hb-V and PRBC resuscitation groups. It is also noteworthy that the CYP-metabolizing drugs in the Hb-V resuscitation group was retained for a longer period compared to the PRBC resuscitation group, and this is attributed to the CYP isoforms having a lower metabolic activity in the Hb-V resuscitation group than that for the PRBC resuscitation group. These findings suggest that resuscitation with Hb-V after a massive hemorrhage has a slight but not clinically significant effect on drug metabolism via CYPs in the liver due to decreased protein levels and the metabolic activity with respect to the CYPs.

SUBMITTER: Tokuno M

PROVIDER: S-EPMC7320716 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Evaluation of cytochrome P450-based drug metabolism in hemorrhagic shock rats that were transfused with native and an artificial red blood cell preparation, Hemoglobin-vesicles.

Tokuno Masahiro M Taguchi Kazuaki K Sakai Hiromi H Ohtsuki Sumio S Yamasaki Keishi K Otagiri Masaki M

Drug metabolism and pharmacokinetics 20200627 5

Hemoglobin-vesicles (Hb-V) are being developed as red blood cell (RBC) substitutes. In this study, we report on quantitative and qualitative alterations of hepatic cytochrome P450 (CYPs) and the pharmacokinetics of CYP-metabolizing drugs, with a focus on four CYP isoforms (CYP1A2, CYP2C11, CYP2E1 and CYP3A2), after Hb-V resuscitation from a massive hemorrhage. The results of proteome analysis and western blot data indicate that resuscitation with both Hb-V and packed RBC (PRBC) resulted in a dec ...[more]

PMID: 32792327

Similar Datasets

Project description:Traumatic brain injury (TBI) is often accompanied by hemorrhage, and treatment of hemorrhagic shock (HS) after TBI is particularly challenging because the two therapeutic treatment strategies for TBI and HS often conflict. Ischemia/reperfusion injury from HS resuscitation can be exaggerated by TBI-induced loss of autoregulation. In HS resuscitation, the goal is to restore lost blood volume, while in the treatment of TBI the priority is focused on maintenance of adequate cerebral perfusion pressure and avoidance of secondary bleeding. In this study, we investigate the responses to resuscitation from severe HS after TBI in rats, using fresh blood, polymerized human hemoglobin (PolyhHb), and lactated Ringer's (LR). Rats were subjected to TBI by pneumatic controlled cortical impact. Shortly after TBI, HS was induced by blood withdrawal to reduce mean arterial pressure (MAP) to 35-40 mmHg for 90 min before resuscitation. Resuscitation fluids were delivered to restore MAP to ~ 65 mmHg and animals were monitored for 120 min. Increased systolic blood pressure variability (SBPV) confirmed TBI-induced loss of autoregulation. MAP after resuscitation was significantly higher in the blood and PolyhHb groups compared to the LR group. Furthermore, blood and PolyhHb restored diastolic pressure, while this remained depressed for the LR group, indicating a loss of vascular tone. Lactate increased in all groups during HS, and only returned to baseline level in the blood reperfused group. The PolyhHb group possessed lower SBPV compared to LR and blood groups. Finally, sympathetic nervous system (SNS) modulation was higher for the LR group and lower for the PolyhHb group compared to the blood group after reperfusion. In conclusion, our results suggest that PolyhHb could be an alternative to blood for resuscitation from HS after TBI when blood is not available, assuming additional testing demonstrate similar favorable results. PolyhHb restored hemodynamics and oxygen delivery, without the logistical constraints of refrigerated blood.

Project description:This is the largest study describing the role of P450 epoxygenase metabolites in septic shock in humans and suggests a novel therapeutic target.ObjectivesOxylipins are oxidative breakdown products of cell membrane fatty acids. Animal models have demonstrated that oxylipins generated by the P450 epoxygenase pathway may be implicated in septic shock pathology. However, these mediators are relatively unexplored in humans with septic shock. We aimed to determine if there were patterns of oxylipins that were associated with 28-day septic shock mortality and organ dysfunction.DesignRetrospective analysis of samples collected during the Vasopressin versus Norepinephrine as Initial Therapy in Septic Shock trial.SettingICUs in the United Kingdom.ParticipantsAdults recruited within 6 hours of onset of septic shock.Main outcomes and measuresOxylipin profiling was performed on 404 serum samples from 152 patients using liquid chromatography-mass spectrometry.ResultsNonsurvivors were found to have higher levels of 14,15-dihydroxyeicosatrienoic acid (DHET) at baseline than survivors (p = 0.02). Patients with 14,15-DHET levels above the lower limit of quantification of the assay were more likely to die than patients with levels below this limit (hazard ratio, 2.3; 95% CI, 1.2-4.5). Patients with measurable 14,15-DHET had higher levels of organ dysfunction and fewer renal failure-free days than those in whom it was unmeasurable. Considering samples collected over the first week of intensive care stay, measurable levels of DHET species were associated with higher daily Sequential Organ Failure Assessment scores that appeared to be accounted for predominantly by the liver component. Measurable 14,15-DHET showed positive correlation with bilirubin (r s = 0.38; p < 0.001) and lactate (r s = 0.27; p = 0.001).Conclusions and relevanceThe P450 epoxygenase-derived DHET species of oxylipins were associated with organ, particularly liver, dysfunction in septic shock and 14,15-DHET was associated with septic shock mortality. These results support further investigation into the role of the P450 epoxygenase-derived oxylipins in sepsis and suggest that this pathway may offer a novel therapeutic strategy in septic shock.

Project description:For the past thirty years, hemoglobin-based oxygen carriers (HBOCs) have been under development as a red blood cell substitute. Side-effects such as vasoconstriction, oxidative injury, and cardiac toxicity have prevented clinical approval of HBOCs. Recently, high molecular weight (MW) polymerized human hemoglobin (PolyhHb) has shown positive results in rats. Studies have demonstrated that high MW PolyhHb increased O2 delivery, with minimal effects on blood pressure, without vasoconstriction, and devoid of toxicity. In this study, we used guinea pigs to evaluate the efficacy and safety of high MW PolyhHb, since like humans guinea pigs cannot produce endogenous ascorbic acid, which limits the capacity of both species to deal with oxidative stress. Hence, this study evaluated the efficacy and safety of resuscitation from severe hemorrhagic shock with high MW PolyhHb, fresh blood, and blood stored for 2 weeks. Animals were randomly assigned to each experimental group, and hemorrhage was induced by the withdrawal of 40% of the blood volume (BV, estimated as 7.5% of body weight) from the carotid artery catheter. Hypovolemic shock was maintained for 50 min. Resuscitation was implemented by infusing 25% of the animal’s BV with the different treatments. Hemodynamics, blood gases, total hemoglobin, and lactate were not different before hemorrhage and during shock between groups. The hematocrit was lower for the PolyhHb group compared to the fresh and stored blood groups after resuscitation. Resuscitation with stored blood had lower blood pressure compared to fresh blood at 2 h. There was no difference in mean arterial pressure between groups at 24 h. Resuscitation with PolyhHb was not different from fresh blood for most parameters. Resuscitation with PolyhHb did not show any remarkable change in liver injury, inflammation, or cardiac damage. Resuscitation with stored blood showed changes in liver function and inflammation, but no kidney injury or systemic inflammation. Resuscitation with stored blood after 24 h displayed sympathetic hyper-activation and signs of cardiac injury. These results suggest that PolyhHb is an effective resuscitation alternative to blood. The decreased toxicities in terms of cardiac injury markers, vital organ function, and inflammation following PolyhHb resuscitation in guinea pigs indicate a favorable safety profile. These results are promising and support future studies with this new generation of PolyhHb as alternative to blood when blood is unavailable.

Project description:Every year more than 500,000 deaths are attributed to trauma worldwide and severe hemorrhage is present in most of them. Transfused platelets have been shown to improve survival in trauma patients, although its mechanism is only partially known. Platelet derived-extracellular vesicles (PEVs) are small vesicles released from platelets upon activation and/or mechanical stimulation and many of the benefits attributed to platelets could be mediated through PEVs. Based on the available literature, we hypothesized that transfusion of human PEVs would promote hemostasis, reduce blood loss and attenuate the progression to hemorrhagic shock following severe trauma. In this study, platelet units from four different donors were centrifuged to separate platelets and PEVs. The pellets were washed to obtain plasma-free platelets to use in the rodent model. The supernatant was subjected to tangential flow filtration for isolation and purification of PEVs. PEVs were assessed by total count and particle size distribution by Nanoparticle Tracking Analysis (NTA) and characterized for cells of origin and expression of EV specific-surface and cytosolic markers by flow cytometry. The coagulation profile from PEVs was assessed by calibrated automated thrombography (CAT) and thromboelastography (TEG). A rat model of uncontrolled hemorrhage was used to compare the therapeutic effects of 8.7?×?108 fresh platelets (FPLT group, n?=?8), 7.8?×?109 PEVs (PEV group, n?=?8) or Vehicle (Control, n?=?16) following severe trauma. The obtained pool of PEVs from 4 donors had a mean size of 101?±?47?nm and expressed the platelet-specific surface marker CD41 and the EV specific markers CD9, CD61, CD63, CD81 and HSP90. All PEV isolates demonstrated a dose-dependent increase in the rate and amount of thrombin generated and overall clot strength. In vivo experiments demonstrated a 24% reduction in abdominal blood loss following liver trauma in the PEVs group when compared with the control group (9.9?±?0.4 vs. 7.5?±?0.5?mL, p?<?0.001>). The PEV group also exhibited improved outcomes in blood pressure, lactate level, base excess and plasma protein concentration compared to the Control group. Fresh platelets failed to improve these endpoints when compared to Controls. Altogether, these results indicate that human PEVs provide pro-hemostatic support following uncontrolled bleeding. As an additional therapeutic effect, PEVs improve the outcome following severe trauma by maintaining hemodynamic stability and attenuating the development of ischemia, base deficit, and cardiovascular shock.

Dataset Information

Evaluation of cytochrome P450-based drug metabolism in hemorrhagic shock rats that were transfused with native and an artificial red blood cell preparation, Hemoglobin-vesicles.

Publications

Evaluation of cytochrome P450-based drug metabolism in hemorrhagic shock rats that were transfused with native and an artificial red blood cell preparation, Hemoglobin-vesicles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets