Researchers find that allergy medicine could assist patients with a rare genetic disorder in avoiding liver transplants.
Recent research from Rutgers Health suggests that a widely used antihistamine might provide solutions for individuals suffering from a rare genetic disorder that can cause significant liver damage, potentially requiring a transplant.
The study published in Cellular and Molecular Gastroenterology and Hepatology reveals that chlorcyclizine, an established allergy treatment, may offer therapeutic benefits for erythropoietic protoporphyria (EPP). This disorder leads to extreme sensitivity to sunlight and can cause harmful levels of protoporphyrin to accumulate in the liver, bone marrow, red blood cells, and plasma.
“These patients have significant medical needs,” noted Bishr Omary, Rutgers Health’s senior vice chancellor for academic affairs and research and the study’s senior author. “Currently, the main treatment for severe liver damage is a liver transplant, a complex and life-saving procedure dependent on donor organ availability.”
EPP is considered rare, with approximately 4,000 individuals affected in the U.S. However, only a small fraction experiences enough liver damage to need a transplant. Consequently, it’s improbable that pharmaceutical companies will focus on developing specific medications for this condition, prompting Omary and his team to investigate existing drugs.
The research group examined over 2,500 compounds, including various FDA-approved medications, using a zebrafish larvae model for EPP developed by Omary’s lab. This innovative model enables researchers to easily observe toxic compound accumulation and test potential treatments.
“During their larval stage, zebrafish are transparent, allowing us to visualize and measure porphyrin, which is fluorescent,” explained Ning Kuo, the lead author of the study who collaborated with Omary at the University of Michigan before moving to Rutgers and then to the University of California, San Diego for her PhD. “Using a microscope, I could determine the efficacy of each treatment; glowing porphyrin indicated no effectiveness, while the absence of it suggested that the treatment helped the liver eliminate it into the water.”
Upon administering chlorcyclizine to mice with EPP, the researchers observed that female mice showed a reduction in liver protoporphyrin accumulation and injury, a decrease in protoporphyrin levels in bone marrow and red blood cells, and an increase in protoporphyrin excretion in feces. This gender-specific response seems connected to differences in how quickly the male mice process the drug.
“In studies on rats, the liver metabolizes chlorcyclizine at a rate eight times faster in males than in females,” Omary indicated. “Fortunately, we have no evidence of similar metabolism differences for chlorcyclizine in humans.”
The research team, including a researcher from Michigan, successfully validated their findings using another mouse model of toxin-induced EPP. They also demonstrated that the histamine pathway contributes to porphyrin accumulation, which is inhibited by allergy medications like chlorcyclizine and fexofenadine, as well as drugs that reduce stomach acid like cimetidine and ranitidine.
In-depth analysis suggests that chlorcyclizine functions through various mechanisms, aiding the liver in eliminating toxic porphyrin build-up and decreasing inflammation. It also lowered the quantity of mast cells, which are immune cells responsible for producing histamine.
For those affected by EPP, these findings could potentially pave the way for a much easier treatment option than liver transplantation by preventing liver damage at an early stage. The antihistamine medications have been used safely for many years, which may facilitate quicker progress towards clinical trials for this new application.
The researchers aspire to obtain backing for clinical trials to evaluate the effectiveness of chlorcyclizine in EPP patients concerning both liver and skin symptoms. A phase 2 clinical trial is already underway, assessing the use of the antacid cimetidine for treating the skin issues associated with EPP. There is a possibility that various antihistamines may enhance each other’s effects when used together.
“Considering their well-documented safety, we aim to expedite the trials of chlorcyclizine, either on its own or in combination with cimetidine,” Kuo remarked.