Placenta-on-a-chip paves the path forward for easy drug screening during pregnancy

Courtesy: Penn State News Letter

Going forward with the concept of ‘organs-on-chip’ that mimic the physiological conditions in-vivo, researchers at the University of Pennsylvania’s School of Engineering and Applied Science have developed ‘placenta-on-a-chip’ to look at the placental barrier and drug transport in pregnancy.  

This is a real breakthrough to study the maternal-fetal drug transport across the placenta, as the placental barrier can never be exactly replicated in the lab and in-vivo studies in humans are not ethical. Pregnant women are not included as research subjects because of the risk of teratogenicity. Animal models are not exactly able to mimic human physiology.

We are all aware of the famous ‘Thalidomide’ disaster, in which a drug for morning sickness, crossed the placental barrier in humans and caused multiple birth defects, collectively known as ‘fetal thalidomide syndrome’ and deaths.

To address these issues, a team of researchers led by Dan Huh, Wilf Family Term Assistant Professor in Bioengineering at Penn and Cassidy Blundell, a graduate student in the Huh lab have developed a placenta-on-a-chip, using microfluidic channels in silicone casing.

The study was also published in the journal Advanced Healthcare Materials.

The two channels house human trophoblast cells on one side and endothelial cells on the other separated by a porous membrane. The unit mimics placental barrier and hence the permeability of the barrier to different drugs can be tested.

A blood-like fluid flows through the maternal side of the channel and the researchers can experiment by adding different drugs to the fluid and see the rate, amount of drug transferred to the fetal side of the channel.

“Ex vivo placental perfusion is a great method,” Huh said, “but it has a pretty high failure rate, and the experimental set-up is complicated: it’s prone to leaks and needs a high level of expertise. Most pharmaceutical companies are not going to be able to test their drugs using this method.”

Currently, to validate their model, the team has tested 2 drugs that they have already studied via ex vivo placental perfusion: heparin, an anticoagulant, and glyburide, used in the treatment of diabetes.

The placenta on the chip was able to simulate the drug transfer of these two drugs as it happens in human placenta and fetal interface. Heparin did not pass through the chip model as it is too large a molecule to breach the placental barrier and glyburide transfer was also limited as in real placenta to protect the fetus.

Huh further added, “We’re getting close, this study has given us confidence that the placenta-on-a-chip has tremendous potential as a screening platform to assess and predict drug transport in the human placenta.”

Besides its use by the pharmaceutical company to test various drugs, the ‘placenta-on-a-chip’ has tremendous potential in testing the transfer of supplements other than drugs like vitamins and nutritional supplement.

Penn State News Release

Abstract in Advanced Healthcare Materials

Novel flu drug that kills the virus in 1 day get clearance in Japan

Japanese pharmaceutical company Shionogi claims that treatment with baloxavir marboxil, effectively kills influenza A and B virus in just 24 hours as opposed to the current user oseltamivir (sold under the brand name Tamiflu), which takes 72 hours to kill the virus.

Japan’s health ministry recently approved the drug and will be sold under the brand name Xofluza.

This is a welcome announcement in healthcare and pharma industry, in the midst of worst Flu season that the USA has experienced. Probably it could make the next flu season safer.  

Baloxavir marboxil prevents the replication of the virus by cap-dependent endonuclease activity of the viral polymerase unlike the existing drug oseltamivir (Tamiflu, Genentech), which acts by inhibiting the neuraminidase enzyme.

It’s prescription as single dose treatment irrespective of age greatly improves patients’ compliance as opposed to the twice-daily dose of oseltamivir for 5 days.

Baloxavir marboxil was tested in a randomized, double-blind, parallel-group, multicenter, placebo- and active-controlled study (CAPSTONE-1), which enrolled 1,436 otherwise healthy patients diagnosed with influenza. 

These patients with age between 20-64 years were randomized in a ratio of 2:1:2 to receive a single 1-time oral dose of 40 or 80 mg of baloxavir marboxil based on body weight or a placebo, or 75 mg BID of oseltamivir for 5 days.

Patients between 12-19 years of age were given baloxavir marboxil based on body weight. Those who weighed less than 80 kg received 40 mg of the drug while patients weighing more than 80 kg were given 80 mg.

The trial results showed that:

•   Patients who received Baloxavir marboxil had significantly lower viral titer at 1, 2 and 4 days
• Viral shedding in Baloxavir marboxil group was significantly less at 24 hours as compared to 72 hours in patients on oseltamivir and 96 hours in patients on placebo.
• The patients in the study group were afebrile in 24 hours vs 42 hours in the placebo group.
• The time to alleviation of symptoms (TTAS) was significantly shortened in the study group (53.7 hours) vs (80.2 hours) in the placebo group (p<0.0001). 
• The new drug was also well tolerated with significantly fewer side effects (20.7%) as compared to placebo (24.6%) or oseltamivir (24.8%).  

Shionogi is currently conducting another phase 3 trials with the drug in patients who are at high risk for Influenza.

Following the approval by Japanese health ministry in February, the drug could be on sale in Japan as early as May.

The head of co-developer Roche's pharma unit, Daniel O'Day, told Bloomberg, "The advantage is that it's one pill once, versus a course of therapy, so particularly for pandemic planning, this could be an advantage, you don't have the potential resistance that comes with not completing your course of therapy."

Shionogi and the Tamiflu maker Roche share the rights to sell Baloxavir marboxil in international market, but it will be almost a year before the drug enters US market.

Shionogi News Release

Menopausal HT may help protect against development of age-related stooped posture

A new North American study found that women who are continuous or remote users menopausal hormone therapy have less evident kyphosis in their mid-eighties as compared to never users. The study is published ahead of print on February 16, 2018, in menopausal society journal Menopause.

Age-related hyperkyphosis is exaggerated anterior curvature of the spine is common in men and post-menopausal women and is associated with increased bone loss, degenerative disc diseases, and vertical compression fractures. It causes difficulty in performing activities of daily living and reduces the quality of life.

The Women’s Health Initiative study has also shown that hormone therapy (HT) reduces the odds of vertebral fractures. Based on the same hypothesis, this study also confirmed the protective effect of HT against the development of kyphosis or dowager’s hump.

The significant decline in estrogen levels after menopause results in accelerated bone loss resulting in the compression fracture of the vertebra. After a woman is put on HT, bone loss increases steadily in 3 years and is maintained by continuous use.

The authors of this study looked at data from nearly 10,000, community-dwelling women aged 65 and older from the landmark Study of Osteoporotic Fractures (SOF) and followed them for a period of 15 years. This study is a multicentric, observational study started in 1986 and closed after 31 years in September 2017.

Kyphosis was measured by mapping the Cobb angle in lateral radiograph spine and correlated with HT use.

The mean age of study participants was 83.7 ± 3.3 years and a mean Cobb angle of 51.3 ± 14.6°. 

Nearly half of the women reported having never used HRT, while 25% reported using it remotely in past, 17% reported that they used HT intermittently while only 12% reported continuous use.

After accounting for confounders, women who used HT in remote past and continuous users had nearly 3.0° less kyphosis compared with never users. Intermittent use did not confer any protection and the women had the same Cobb angle as never users.

The SOF findings also showed that women who lose more than two inches in height have an increased risk for fracture and early death.

NAMS executive director Dr. JoAnn Pinkerton concluded, “Women who reported the early use of HT were less likely to develop age-related kyphosis, and the protective benefits continued even after stopping HT. This supports a benefit of prescribing HT close to menopause.”

Abstract

NAMS press release