Force the laboratory to change data? Shocking news about new stroke drug: research fraud expert reveals the truth about "activated protein C"
Force the laboratory to modify data? Top scholar falsifies claims about new stroke drug
Rumor has it that research on a new drug for stroke is suspected to be fraudulent, arousing concern from the scientific community and international food and drug authorities. The important international scientific journal “Science” received an anonymous report alleging that the preclinical research data of the third phase clinical trial of the new stroke drug “3K3A-APC” by Berislav Zlokovic, director of the Institute of Neurogenetics at the University of Southern California, may be falsified, and that the second phase Clinical trial results are over-interpreted. Berislav Zlokovic’s main research areas include pericyte and blood-brain barrier. He has received US$93 million in research funding from the National Institutes of Health.
The “Science” article pointed out that scientists have been trying to develop new drugs to treat stroke for many years to reduce complications related to brain cell death, bleeding and inflammation. Among them, some mechanisms of stroke complications are thought to be related to the destruction of the blood-brain barrier. A small safety study led by Berislav Zlokovic claimed that 3K3A-APC can reduce the severity of brain hemorrhage and prevent cell death after obstructive stroke. However, “Science” successively received anonymous reports alleging that Berislav Zlokovic forced the laboratory team to adjust the data to ensure that the expected results were met, and even manipulated the experimental data to conform to the research hypothesis. As for Berislav Zlokovic himself, he is the co-founder of ZZ Biotech, the biotechnology company that developed 3K3A-APC.
In view of the continuous disclosure of evidence, many neuroscientists who reviewed the paper for Science agreed that all 3K3A-APC clinical trials should be suspended. Wade Smith, a neuroscientist at the University of California, San Francisco, said that the drug must be used immediately after a stroke. Hundreds of patients and their families participating in the trial only have minutes to hours to decide whether to participate in the trial. 3K3A-APC claims that it is beneficial to the brain. The protective effect of bleeding and brain cell death may be suspected of “scientific fraud”.
Is the modified activated protein APC expected to reduce cerebrovascular damage after stroke?
Does 3K3A-APC drug really have the therapeutic potential to repair brain nerve cells and reduce cerebrovascular damage? Hu Chaorong, professor of neurology and deputy dean of the School of Medicine at Taipei Medical University, and consultant physician at the Stroke Center of Taipei Medical University Lishuanghe Hospital, pointed out that 3K3A-APC is a modified activated protein C (APC), and APC is a A protease with anticoagulant and cytoprotective activities that can protect neurons and cerebral vascular endothelial cells from ischemic damage. It is currently approved by the Taiwan Food and Drug Administration in the United States for the treatment of sepsis.
The main function of activated protein C in the human body is to inhibit blood coagulation and indirectly promote fibrinolysis by decomposing specific types of coagulation factors, while reducing thrombin produced when blood vessels are injured. Therefore, activated protein C serves as an indicator to evaluate the prognostic status of sepsis. When activated protein C is used as a drug to treat sepsis, the main adverse side effect is bleeding. However, ZZ Biotech said that transforming activated protein C into 3K3A-APC can reduce the adverse side effects of bleeding.
Dr. Hu Chaorong said that the anticoagulant activity of APC is achieved by hydrolyzing two of the coagulation factors so that blood cannot coagulate, while the cytoprotective activity of APC is initiated by activating the PAR1 receptor (proteolytic activation of protease activated receptor 1). Anti-inflammatory cell message. The anticoagulant activity of the modified 3K3A-APC was significantly reduced (< 10%) while maintaining intact cytoprotective properties. However, a review of the second phase clinical trial of 3K3A-APC (RHAPSODY Trial) found that the placebo group received standard treatment slower than the drug group, and some cases even exceeded the standard treatment time. In the context of “time is brain” Under the concept, the efficacy of the treatment group may be overestimated, and its main treatment indicator is only a smaller bleeding volume, and the indicator of improvement in clinical prognosis seems not clear enough.
Does ischemic stroke damage brain tissue? Why can reoperation be fatal?
“After ischemic stroke, the damage mechanisms to brain tissue include excitatory amino acids, early regulatory gene expression, oxidative stress, neuroinflammation, neurotrophic factors, and angiogenesis, etc. Each mechanism has a corresponding Treatment options, but clinical trials have not yet been successful at this stage!”
Dr. Hu Chaorong pointed out that the current effective treatment for ischemic stroke is to unblock the blocked blood vessels again within a limited time, including intravenous thrombolysis within 4.5 hours after onset or intravascular thrombectomy within 24 hours, which has become the standard treatment. However, intravenous thrombolysis or endovascular thrombectomy will increase the risk of bleeding after cerebral infarction. Some patients will need to undergo blood clot removal and brain decompression surgery, and may even die from the surgery. How to find effective ways to reduce post-treatment complications remains an important research topic in the clinical and neuroscience communities.
The blood-brain barrier is destroyed due to stroke, and the neuroprotective mechanism needs to be studied
As for why the “blood-brain barrier” (BBB) is related to the treatment of cerebral hemorrhage after ischemic stroke? Dr. Hu Chaorong explained that the blood-brain barrier is destroyed during the stroke process, causing the blood in the re-opened blood vessels to overflow and enter the brain tissue of the stroke. This is considered to be one of the main causes of bleeding after cerebral infarction. In addition, cerebrovascular barrier damage is also the main cause of cerebral edema, another major complication of ischemic stroke.
Dr. Hu Chaorong said that among the many treatment mechanisms, “neuroprotection” has the most high hopes, hoping that it can effectively reduce the damage of nerve cells and allow nerve cells to survive longer in ischemic state. However, most clinical trials of neuroprotection are currently based on Ended in failure. Due to a series of complex molecular mechanisms that occur after stroke, it is currently difficult to have a single solution. In particular, it is necessary to provide “precise” drug intervention or treatment at the “right time point”, which is not easy in clinical practice. The current effective treatment methods are still based on “unblocking blood vessels”, that is, thrombolysis, thrombectomy, or a combination of both. Translational research from basic research to clinical practice remains critical in the future.
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