scholarly journals Efficacy and Safety of Viable Selective Germline Genome Edited Pigs Skin Xenotransplants in Patients with Thermal Burns

2022 ◽  
Author(s):  
lijin zou ◽  
youlai zhang ◽  
ying he ◽  
Hui Yu ◽  
Fan Yang ◽  
...  
Keyword(s):  
Barrier Function ◽  
Standard Of Care ◽  
Immunosuppressive Drug ◽  
Skin Grafts ◽  
Efficacy And Safety ◽  
Safety Issues ◽  
Thermal Burns ◽  
Long Duration ◽  
Skin Xenograft

Background: Rapid closure of open wound, either temporarily or perpetually, is recognized as the standard of care in patients with thermal burns. Human cadaveric allograft and simple genetically modified porcine xenografts are not able to provide enough durable time for extensively burned patients. A selective germline genome edited pig (SGGEP) skin xenograft, Xeno X skin, would be a valuable candidate to the clinical options. Methods: In an ongoing investigator-initiated clinical trial in patients with thermal burns, the efficacy and safety of cryopreserved Xeno X skin grafts of SGGEP for burned patients were evaluated. Each patient received surgical grafting with a skin xenotransplant and wild type pig extracellular matrix (wpECM) in a side-by-side manner for in-situ comparison. The primary outcome measures of xeno-skin grafts included Xeno X skin safety and tolerability, as well as the quality and duration of temporary barrier function yielded by Xeno X skin grafts (as determined by Baux score). Seven parameters included in the analysis were vascularization, pigmentation, thickness, relief, pliability, surface area and the overall opinion, with each calculated on an independent 0-10 scale. Results: A total of 16 burned patients completed the trial. All the patients tolerated Xeno X skin grafts well and no advent events were observed. In all cases, Xeno X skin grafts were vascularized and fully adherent, they also exhibited better overall outcomes than those of wpECM. Xeno X skin grafts survived for at least 25 days without a need of any immunosuppressive drug, well consistent with our earlier preclinical studies in non- human primates. Conclusion: Xeno X skin grafts of SGGEP did not incur any signs of local and systemic safety issues, and in the meanwhile provided a high quality and long duration of temporary barrier function for burned patients. This is a major milestone in the xenotransplant field, indicating that genome-edited organ xenotransplant has become a clinical reality.

31 A phase 3 open-label, controlled, randomized trial evaluating the efficacy and safety of a bioengineered allogeneic cellularized construct in patients with deep partial-thickness thermal burns

2021 ◽  
Vol 42 (Supplement_1) ◽  
pp. S25-S26
Author(s):  
Angela L F Gibson ◽  
James H Holmes ◽  
Jeffrey W Shupp ◽  
David Smith ◽  
Victor Joe ◽  
...  
Keyword(s):  
Donor Site ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Thermal Burns ◽  
Treatment Site ◽  
Severe Burns ◽  
Donor Site Pain ◽  
The Difference ◽  
Percent Area ◽  
Site Pain

Abstract Introduction Autograft (AG) is the standard of care for treatment of severe burns. While AG provides effective wound closure (WC), the procedure creates a donor site wound prone to pain and scarring. In a phase 1b trial, no deep partial-thickness (DPT) wound treated with a bioengineered allogeneic cellularized construct (BACC) required AG by Day 28 and WC at the BACC site was achieved in 93% of patients by Month (M) 3. This phase 3 study (NCT03005106) evaluated the efficacy and safety of this BACC in patients with DPT burns. Methods Enrolled patients were aged ≥18 years with 3–49% TBSA thermal burns on the torso or extremities. In each patient, two DPT areas (≤2,000 cm2 total) deemed comparable following excision were randomized to treatment with either cryopreserved BACC or AG. Coprimary endpoints were 1) the difference in percent area of BACC treatment site and AG treatment site autografted at M3 and 2) the proportion of patients achieving durable WC of the BACC treatment site without AG at M3. Ranked secondary endpoints were: 1) the difference between BACC and AG donor sites in average donor site pain intensity through Day 14; 2) the difference between BACC and AG donor site cosmesis at M3; and 3) the difference between BACC and AG treatment site cosmesis at M12. Safety assessments were performed in all patients through M12. Results Seventy-one patients were enrolled. By M3, there was a 96% reduction in mean percent area of BACC treatment sites that required AG, compared with AG treatment sites (4.3% vs 102.1%, respectively; P<.0001). BACC treatment resulted in durable WC at M3 without AG in 92% (95% CI: 85.6, 98.8; 59/64) of patients for whom data was available. By M3, mean donor site Patient and Observer Scar Assessment Scale (POSAS) observer total score (±SD) was significantly lower (more like normal skin) for BACC donor sites compared with AG donor sites (6.3 ± 1.71 vs 16.3 ± 7.71; P<.0001). At M12, mean POSAS observer total score (±SD) was 15.6 (± 8.34) for BACC treatment sites compared with 16.3 (± 9.41) for AG treatment sites (P=.4268). The most common BACC-related adverse event (AE) was pruritus, which occurred in 11 (15%) patients. All BACC-related AEs were mild or moderate in severity. Conclusions This phase 3 study achieved both coprimary endpoints, including significant autograft sparing and durable WC in DPT burns. Both donor site pain and donor site cosmesis were favorable outcomes of significantly reduced use of AG in BACC-treated patients. M12 POSAS for BACC did not differ significantly from AG. This BACC may offer a new treatment for severe burns to reduce or eliminate the need for AG. Applicability of Research to Practice This BACC has shown clinical benefit in patients with DPT thermal burns, potentially mitigating donor site morbidity. External Funding Stratatech, a Mallinckrodt Company; Funding and technical support for the Phase 3 clinical study were provided by the Biomedical Advanced Research and Development Authority (BARDA), under the Assistant Secretary for Preparedness and Response, within the U.S. Department of Health and Human Services, under Project BioShield Contract No. HHSO100201500027C.

scholarly journals Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

2021 ◽  
Vol 13 ◽  
pp. 175883592110311
Author(s):  
Chiun Hsu ◽  
Lorenza Rimassa ◽  
Hui-Chuan Sun ◽  
Arndt Vogel ◽  
Ahmed O. Kaseb
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Healthcare Providers ◽  
Safety Data ◽  
Standard Of Care ◽  
Antiangiogenic Agents ◽  
Efficacy And Safety ◽  
First Line

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

scholarly journals Pharmacogenetics in drug development

2005 ◽  
Vol 360 (1460) ◽  
pp. 1579-1588 ◽  
Author(s):  
Alun D McCarthy ◽  
James L Kennedy ◽  
Lefkos T Middleton
Keyword(s):  
Pharmaceutical Companies ◽  
Efficacy And Safety ◽  
Plasma Drug ◽  
Dose Selection ◽  
Drug Discovery And Development ◽  
Safety Issues ◽  
Drug Choice ◽  
Probability Of Success ◽  
Safety Studies ◽  
Appropriate Therapy

Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx—the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success—the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines.

Improved defibrillator waveform safety factor with biphasic waveforms

1983 ◽  
Vol 245 (1) ◽  
pp. H60-H65 ◽  
Author(s):  
J. L. Jones ◽  
R. E. Jones
Keyword(s):  
Safety Factor ◽  
Voltage Gradient ◽  
Excitation Threshold ◽  
Efficacy And Safety ◽  
Myocardial Cells ◽  
Safety Factors ◽  
Adult Type ◽  
Intracellular Microelectrodes ◽  
Cultured Myocardial Cells

Excitation thresholds and arrhythmias were studied in "adult-type" cultured chick embryo myocardial cells after electric field stimulation with biphasic, truncated, and rectified underdamped RLC (resistance-inductance-capacitance) type waveforms, to test the hypothesis that the negative phase of biphasic waveforms ameliorates membrane dysfunction induced by the initial positive portion. Photocell mechanograms and intracellular microelectrodes monitored extrasystoles and depolarization-induced arrhythmias. Rectifying or truncating biphasic waveforms did not alter the excitation threshold. However, shock intensities producing specific postshock arrhythmias or a specific severity of postshock prolonged depolarization differed significantly when biphasic waveforms were truncated or rectified. The voltage gradient producing a specific dysfunction was 12-14% lower for the truncated version than for the biphasic; that for the rectified version was 17-27% lower than for the biphasic version (although both contained the same energy). Safety factor, the ratio between shock intensity producing specific dysfunction and that producing excitation, was determined for each waveform. Biphasic waveforms had larger safety factors than truncated or rectified waveforms. Since safety factor, as measured in cultured myocardial cells, closely corresponds with in situ defibrillating effectiveness (14), the significantly higher safety factors of biphasic waveforms suggest that carefully shaped biphasic waveforms might improve the efficacy and safety of cardiac defibrillation procedures.

scholarly journals Efficacy and Safety of Topical Timolol Eye Drops in the Treatment of Myopic Regression after Laser In Situ Keratomileusis: A Systematic Review and Meta-Analysis

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaochen Wang ◽  
Guiqiu Zhao ◽  
Jing Lin ◽  
Nan Jiang ◽  
Qian Wang ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Treated Group ◽  
Laser In Situ Keratomileusis ◽  
Control Group ◽  
Eye Drops ◽  
Efficacy And Safety ◽  
China National Knowledge Infrastructure ◽  
Knowledge Infrastructure ◽  
Significant Difference

Aims. The aim of this study was to assess the efficacy and safety of timolol in the treatment of myopic regression after laser in situ keratomileusis (LASIK).Methods. We searched MEDLINE, CENTRAL, EMBASE, China National Knowledge Infrastructure (CNKI), and Chinese Biological Medicine (CBM) from the inception to July 2015 for relevant randomized controlled trials that examined timolol therapy for myopic regression. The methodological quality of the studies included was assessed using the Revman 5.3 software.Results. We included six clinical trials involving 483 eyes in this review, including 246 eyes in treated group and 237 eyes in controlled group. We observed statistically significant improvements on the postoperative SE in the 3 months. However, the change of CCT was not statistically different between the control group and the experimental group. There were fewer cases of IOP, UDVA, and CDVA in treated group having significant difference from the controlled group.Conclusions. Topical timolol could be an effective treatment for reduction of myopic regression especially the spherical errors after myopic LASIK. Further RCTs with larger sample sizes for these trials are warranted to determine the efficacy and limitation for myopic regression after LASIK.

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