| 1. |
- DeWitt, Douglas S., et al.
(författare)
-
Pre-clinical testing of therapies for traumatic brain injury
- 2018
-
Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:23, s. 2737-2754
-
Tidskriftsartikel (refereegranskat)abstract
- Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients.
|
|
| 2. |
- Nyberg, Joakim, 1978-, et al.
(författare)
-
RETRACTED: Population Kinetics of 0.9% Saline Distribution in Hemorrhaged Awake and Isoflurane-anesthetized Volunteers
- 2019
-
Ingår i: Anesthesiology. - : Ovid Technologies (Wolters Kluwer Health). - 0003-3022 .- 1528-1175. ; 131:3, s. 501-511
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Population-based, pharmacokinetic modeling can be used to describe variability in fluid distribution and dilution between individuals and across populations. The authors hypothesized that dilution produced by crystalloid infusion after hemorrhage would be larger in anesthetized than in awake subjects and that population kinetic modeling would identify differences in covariates. Methods: Twelve healthy volunteers, seven females and five males, mean age 28 +/- 4.3 yr, underwent a randomized crossover study. Each subject participated in two separate sessions, separated by four weeks, in which they were assigned to an awake or an anesthetized arm. After a baseline period, hemorrhage (7 ml/kg during 20 min) was induced, immediately followed by a 25 ml/kg infusion during 20 min of 0.9% saline. Hemoglobin concentrations, sampled every 5 min for 60 min then every 10 min for an additional 120 min, were used for population kinetic modeling. Covariates, including body weight, sex, and study arm (awake or anesthetized), were tested in the model building. The change in dilution was studied by analyzing area under the curve and maximum plasma dilution. Results: Anesthetized subjects had larger plasma dilution than awake subjects. The analysis showed that females increased area under the curve and maximum plasma dilution by 17% (with 95% CI, 1.08 to 1.38 and 1.07 to 1.39) compared with men, and study arm (anesthetized increased area under the curve by 99% [0.88 to 2.45] and maximum plasma dilution by 35% [0.71 to 1.63]) impacted the plasma dilution whereas a 10-kg increase of body weight resulted in a small change (less than1% [0.93 to 1.20]) in area under the curve and maximum plasma dilution. Mean arterial pressure was lower in subjects while anesthetized (P < 0.001). Conclusions: In awake and anesthetized subjects subjected to controlled hemorrhage, plasma dilution increased with anesthesia, female sex, and lower body weight. Neither study arm nor body weight impact on area under the curve or maximum plasma dilution were statistically significant and therefore no effect can be established.
|
|
