Addressing overdose from OTC drugs — Wakayama Medical University confirms reduction of fulminant hepatitis-caused deaths and effectiveness of 'sivelestat,' a drug for treating acute respiratory failure

Using mouse experiments, the research group led by Professor Toshikazu Kondo and Associate Professor Yuko Ishida of the Forensic Medicine Lecture, the School of Medicine, Wakayama Medical University revealed the efficacy of sivelestat, a drug for treating acute respiratory failure, for drug-induced liver injury due to overdose from acetaminophen and other drugs. The result was published in the International Journal of Molecular Sciences.

The liver, known as a 'silent organ,' plays an important role in life activities through its synthesis of essential substances, and detoxification and excretion of harmful substances. Although acute hepatitis caused by viruses, bacteria, and drugs can result in short-term inflammation and reduced functioning of the liver, the organ usually heals naturally, and no special treatment is required for most patients with acute hepatitis because stem cells have a high regenerative capacity. However, in acute liver failure (fulminant hepatitis), hepatocytes are destroyed at a scale that their proliferation is unable to catch up with, and death frequently results if proper treatment is not provided.

Acetaminophen is one of the causes of acute liver failure. Acetaminophen, a mild analgesic (i.e., pain-relieving) and antipyretic (i.e., fever-reducing) drug, is a component in approximately 70% of over-the-counter (OTC) multi-ingredient cold medications. Although there is generally no problem with this drug when taken in adequate amounts, it has been associated with many cases of accidental ingestion by children and is a drug with one of the highest frequencies of causing acute drug addiction.

In 2020, the Japan Poison Information Center received 142 consultations related to acetaminophen, which was the highest number among the 585 reported cases of poisoning from combination antipyretic, analgesic, and anti-inflammatory drugs.

Kondo explained, "Approximately 20 years ago, an autopsy of a body with drug poisoning revealed acetaminophen as the cause of that person's death. We have also detected acetaminophen in investigations of drug poisoning in patients. Consequently, we have been advancing our research."

So far, the research group has found that knocking out neutrophils in leukocytes (a type of white blood cell) in knockout mice can improve liver damage. Neutrophils are present in the blood and accumulate in areas damaged by invading viruses and wounds. During inflammation, neutrophils release the enzyme neutrophil elastase, which degrades microorganisms and foreign bodies and can attack self-tissue.

Sivelestat, a therapeutic agent for acute lung injury associated with systemic inflammatory response syndrome, exerts its efficacy by selectively inhibiting neutrophil elastase. After overdosing mice with acetaminophen to induce acute liver injury, the researchers administered sivelestat to some of the overdosed mice 30 minutes later and analyzed the therapeutic effect.

After 48 hours, the group treated with sivelestat had survived, whereas 50% of the group without sivelestat treatment had died. Examination of the mouse hepatocytes revealed that sivelestat alleviated acetaminophen-induced liver damage and reduced neutrophil infiltration into the liver by approximately half. It also attenuated (i.e., reduced) the expression of inflammatory cytokines and chemokines in the liver. Furthermore, the production of nitric oxide, a factor exacerbating (i.e., worsening) liver damage, was almost suppressed by the sivelestat treatment.

Additionally, the researchers compared the therapeutic effects of sivelestat when administered 3 or 5 hours after acetaminophen overdose. The mortality rate was 70−80% in the non-treated group, whereas it was only approximately 10% and 40% in the groups treated at 3 and 5 hours after overdose, respectively. The improvements in indicators of liver damage, neutrophil infiltration, and nitric oxide production confirmed that therapeutic sivelestat administration was effective.

Ishida stated, "In this study, we found that sivelestat suppresses excessive inflammatory reactions and has a therapeutic effect on acetaminophen-induced liver damage. I believe that if the role of neutrophil elastase is clarified in the future, the findings will help to improve the treatment and prevention of more diseases."

Kondo added, "Since we are in the Forensic Medicine Lecture Class, we would like to cooperate with clinical doctors to proceed with investigator-initiated clinical trials."

Journal Information
Publication: International Journal of Molecular Sciences
Title: Essential Involvement of Neutrophil Elastase in Acute Acetaminophen Hepatotoxicity Using BALB/c Mice
DOI: 10.3390/ijms24097845