Acid reflux drug may be a promising therapy to reduce preterm birth

In continuation of my update on Lansoprazole

Lansoprazole, an over-the-counter acid reflux drug that is often taken by pregnant women, may be a promising therapy to reduce preterm birth, according to a computational drug repurposing study that also tested several of the drugs in mice.

The study also identified 12 other FDA-approved drugs that are deemed safe in pregnancy. While the drugs encompass a variety of modalities, the scientists said they all appear to act on biological pathways that affect the immune response, which is implicated in preterm birth.

"Inflammation clearly plays a role in initiating labor and preterm birth," said Marina Sirota, PhD, assistant professor of pediatrics, a member of the Bakar Computational Health Sciences Institute at UCSF, and the senior author of the study, published Feb. 13, 2020, in JCI Insight. "Immune pathways are very significantly dysregulated in women who end up delivering preterm, and they're also dysregulated in babies who are born early. However, we have seen from our previous work that there is an interaction between the maternal and fetal immune systems and a breakdown in maternal-fetal tolerance."

To identify candidate drugs that might be effective in preventing preterm birth, the scientists first looked at which genes were up- or down-regulated in the blood cells of women who experienced spontaneous preterm birth to identify a gene expression "signature." Then they looked for the opposite signature in cells that had been exposed to 1,309 different drugs, reasoning that if a drug could correct the effects that preterm birth had on the women's blood cells, the drugs might also prevent preterm birth itself.

The scientists identified 83 drug candidates, but when they excluded those found to have pregnancy risks in animal or human studies, they wound up with 13 drugs, ranked according to their "reversal score," a measure of the extent to which they were able to reverse the gene expression signature of preterm birth.

The other drugs identified by the computational screen included progesterone, which is already used to treat recurrent spontaneous preterm birth, folic acid, which is given to women during pregnancy to prevent birth defects, three antibiotics, an antifungal, an antidepressant, an anti-diabetic, and a blood pressure medication.

The fact that predictable drugs like progesterone came up in the screen gave the scientists confidence that the drugs they identified may turn out to be effective once they are tested in pregnant women. Three of the other drugs that came up in the screen--folic acid, clotrimazole and metformin--have also been shown in previous studies to be effective against preterm birth.

Finding progesterone on the list was a promising validating step. Four of the drugs on our list have seen effectiveness in past studies that were either experimental or retrospective. This leads us to believe in the biology behind the identification of these drugs."

Brian Le, PhD, postdoctoral scholar in the UCSF Department of Pediatrics and the Bakar Computational Health Sciences Institute, and the first author of the study

The scientists chose lansoprazole for further testing because, in addition to its high reversal score, it is available over the counter, and they know from their previous work that it affects a stress-response protein, heme oxygenase-1, that has been linked with pregnancy disorders. Lansoprazole, which is a proton-pump inhibitor marketed as Prevacid, had the second-highest reversal score of the 13 drugs identified as being safe and effective. Progesterone was further down the list.

The scientists tested lansoprazole in pregnant mice that had been given a bacterial component to induce inflammation, which causes some fetuses to die in utero, where they are reabsorbed. When these mice were given lansoprazole, they had more viable fetuses. Lansoprazole also worked better in these mice than progesterone.

Although it is a good measure of how inflammation affects pregnancy in mice, the scientists said the fetal resorption mouse model is not an adequate model of human preterm birth. They said more work, including studies in people, would need to be done before lansoprazole or any of the dozen other drugs they identified could be proven effective in pregnant women at risk for preterm birth. But the computational study provides leads for a condition that currently has few treatment options.

"This, basically, is a proof of concept that this drug has anti-inflammatory properties, which are not the properties the drug was designed for," said David K. Stevenson, MD, a professor of pediatrics at Stanford University and an author of the study. "This is a short way to get to new therapeutics for known diseases."

https://www.ucsf.edu/news/2020/02/416631/acid-reflux-drug-surprising-candidate-curb-preterm-birth

Acid reflux drug may cause heart disease, study suggests

In human tissue and mouse models, the researchers found PPIs (proton pump inhibitors) caused the constriction of blood vessels. If taken regularly, PPIs could lead to a variety of cardiovascular problems over time, including hypertension and a weakened heart. In the paper, the scientists call for a broad, large-scale study to determine whether PPIs are dangerous.

"The surprising effect that PPIs may impair vascular health needs further investigation," said John Cooke, M.D., Ph.D., the study's principal investigator. "Our work is consistent with previous reports that PPIs may increase the risk of a second heart attack in people that have been hospitalized with an acute coronary syndrome. Patients taking PPIs may wish to speak to their doctors about switching to another drug to protect their stomachs, if they are at risk for a heart attack."

Commonly used proton pump inhibitors in the United States are lansoprazole (below left) and omeprazole (below right), 

and these drugs are purchasable over the counter as brands or generics. The FDA estimates about 1 in 14 Americans has used them. In 2009, PPIs were the third-most taken type of drug in the U.S., accounting for $13 billion in sales. PPIs are used to treat a wide range of disorders, including gastroesophageal reflux disease, or GERD, infection by the ulcer-causing Helicobacter pylori, Zollinger-Ellison syndrome, and Barrett's esophagus.

Recent studies of proton pump inhibitors use by people who've already experienced severe cardiovascular events have raised concern about the anti-reflux drugs, at least for this subgroup of patients, said Cooke, chair of the Department of Cardiovascular Sciences and director of the Center for Cardiovascular Regeneration at Houston Methodist DeBakey Heart & Vascular Center.

PPIs are initially inert. After oral consumption, they are activated by specialized cells in the stomach. Once active, the molecules suppress the movement of protons into the intestine, which reduces the amount of acid present there and in the stomach.

In mouse models and cultures of human endothelial cells, Cooke and lead author Yohannes Ghebramariam, Ph.D., found that PPIs suppressed the enzyme DDAH, dimethylarginine dimethylaminohydrolase. That caused an increase in the blood levels of ADMA (asymmetric dimethylarginine), an important chemical messenger. They found ADMA in turn suppressed the production of another chemical messenger, nitric oxide, or NO, proven by 1998 Nobel Prize winners Furchgott, Ignarro, and Murad to impact cardiovascular function. Quantitative studies in mouse models showed animals fed PPIs were more likely than controls to have tense vascular tissue.

"We found that PPIs interfere with the ability of blood vessels to relax," said Ghebremariam, a Houston Methodist molecular biologist. "PPIs have this adverse effect by reducing the ability of human blood vessels to generate nitric oxide. Nitric oxide generated by the lining of the vessel is known to relax, and to protect, arteries and veins."

The researchers found PPIs led to an approximately 25 percent increase in ADMA in mouse and tissue cultures, and reduced the ability of mouse blood vessels to relax by over 30 percent on average.

Acid reflux drug may cause heart disease, study suggests