Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-Like Effect in Stroke: Rationale, Design, and Protocol for a Prospective Randomized Controlled Trial

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Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-Like Effect in Stroke: Rationale, Design, and Protocol for a Prospective Randomized Controlled Trial

Shuyu Lv^1,2, Wenbo Zhao³, Gary B. Rajah^4,5, Chaitu Dandu⁴, Lipeng Cai², Zhe Cheng², Honglian Duan², Qingqing Dai², Xiaokun Geng^1,2,3,4* and Yuchuan Ding^4,6

• ¹Luhe Institute of Neuroscience, Capital Medical University, Beijing, China
• ²Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
• ³China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
• ⁴Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
• ⁵Department of Neurosurgery, Munson Medical Center, Traverse City, MI, United States
• ⁶Department of Research and Development Center, John D. Dingell VA Medical Center, Detroit, MI, United States

Background: Following an acute ischemic stroke (AIS), rapidly initiated reperfusion therapies [i. e., intravenous thrombolysis (IVT) and endovascular treatment (EVT)] demonstrate robust clinical efficacy. However, only a subset of these patients can benefit from these therapies due to their short treatment windows and potential complications. In addition, many patients despite successful reperfusion still have unfavorable outcomes. Thus, neuroprotection strategies are urgently needed for AIS patients. Chlorpromazine and promethazine (C+P) have been employed in clinical practice for antipsychotic and sedative purposes. A clinical study has also shown a neuroprotective effect of C+P on patients with cerebral hemorrhage and subarachnoid hemorrhage. The safety, feasibility, and preliminary efficacy of intravenous administration of C+P in AIS patients within 24 h of onset will be elucidated.

Methods: A prospective randomized controlled trial is proposed with AIS patients. Participants will be randomly allocated to an intervention group and a control group with a 1:1 ratio (n = 30) and will be treated with standard therapies according to the current stroke guidelines. Participants allocated to the intervention group will receive intravenous administration of C+P (chlorpromazine 50 mg and promethazine 50 mg) within 24 h of symptom onset. The primary outcome is safety (mainly hypotension), while the secondary outcomes include changes in functional outcome and infarction volume.

Discussions: This study on Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-like Effect in Stroke (RICHES) will be the first prospective randomized controlled trial to ascertain the safety, feasibility, and preliminary efficacy of intravenous C+P as a neuroprotection strategy in AIS patients. These results will provide parameters for future studies, provide insights into treatment effects, and neuroprotection with phenothiazine in AIS.

Clinical Trial Registration: www.chictr.org.cn, identifier: ChiCTR2000038727.

Introduction

Due to its high rate of mortality and morbidity, ischemic stroke is a devastating public health concern which also results in a high socioeconomic burden (1, 2). Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) is an important method for the treatment of acute ischemic stroke. However, due to the narrow time window, disparate national health awareness, uneven distribution of medical resources, traffic congestion, and potential complications, only around 2.4% of patients receive this treatment currently in China (3). The mortality at 3–6 months after intravenous thrombolysis was not significantly reduced, and is as high as 17.9%, with 2/3 of the patients having varying degrees of disability (3–5). Therefore, attention must be given to both vascular recanalization and neuroprotection. Exploring fast and effective neuroprotection strategies to save time for recanalization strategies and improve prognosis will become a key strategy in the treatment of AIS. We believe chlorpromazine and promethazine (C+P) may benefit patients in the acute setting of AIS.

Hibernation is an altered physiological state during times of food shortage and is characterized by drastic decreases in both body temperature and metabolic rate. Animals in hibernation withstand the decline of cerebral blood flow without experiencing brain damage (6, 7). In acute ischemic stroke, the cascade reaction caused by ischemia leads to irreversible damage to the brain within minutes (8). If a hibernation-like state can be induced in AIS patients, it may reduce brain metabolism allowing the patient to reach a balance point between energy supply and demand. This may increase tolerance to ischemia and hypoxia. C+P are the two most widely used phenothiazine drugs to induce hibernation (9). C+P are both FDA-approved and routinely used in severe brain injury, brain edema, central high fever with restlessness, mental illness and delirium (9, 10). Existing data reveal that C+P is safe for most patients (11, 12). A previous clinical study found that a mixture of drugs, including chlorpromazine 50 mg + promethazine 50 mg + dolantin (pethidine) 100 mg, named as “lytic cocktail” was injected intravenously to produce sedation, analgesia, amnesia, hypotension, hypothermia, and blockade of the functions of the sympathetic and parasympathetic nervous systems during an event (9). The drugs reduced the mortality and neurological deficit of patients with acute cerebral hemorrhage and subarachnoid hemorrhage (13). Although a neuroprotective role was not investigated in acute ischemic stroke, the safety of an oral C+P regimen has been demonstrated by our group in stroke patients (14). In addition, our previous studies have demonstrated a neuroprotective effect of C+P in rat ischemic stroke models (15). The neuroprotective effect was due to the reduction in reactive oxygen species (ROS)-mediated oxidative injury (15), brain inflammation (16), apoptosis (17), and reduction in blood-brain barrier (BBB) dysfunction after ischemic stroke (18). Importantly, this neuroprotection was not completely dependent upon the reduction of body temperature. As a safe, effective, cost-efficient “old drug,” C+P may be repurposed as a promising new therapy to achieve neuroprotection in AIS patients. We thus designed this single-center, prospective randomized controlled study on Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-like Effect in Stroke (RICHES) to verify the safety, feasibility, and preliminary efficacy of immediate intravenous administration of C+P at a dose as previously reported for AIS.

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