Women who take selective serotonin reuptake inhibitors late in pregnancy may have a small but significant risk of giving birth to a child with persistent pulmonary hypertension of the newborn (PPHN), according to a in the Feb. 9 issue of the 

    This severe respiratory disorder occurs when the newborn has difficulty beginning to breathe with it’s own lungs, or dies when it cannot live without receiving oxygen from the mother’s blood supply, explained Christina Chambers, lead author and professor of pediatrics, and family and preventive medicine at the University of California, San Diego. This can happen as a result of certain rare birth defects. But it can also be brought on by other, incompletely understood causes. Some risk factors include a mother who smokes and a non-head first presentation of the baby, Chambers said.

    The new study may add SSRIs to the list of risks factors for PPHN. Chambers emphasized, however, that the disorder was present in the babies of only 1 percent of women who took Paxil (paroxetine), Prozac (fluoxetine), or Zoloft (sertraline) in the second half of pregnancy.

    But Sheldon Preskorn, professor and chair of the Department of Psychiatry and Behavioral Sciences at the University of Kansas in Wichita, cautioned that this study’s results could indicate that depression, not SSRIs, is the increased risk factor for PPHN. He noted that the some of the women in the control group were taking tri-cyclic antidepressants, which are prescribed for conditions other than depression. If enough of these mothers were taking tri-cyclic antidepressants for other reasons, the results might not sufficiently eliminate depression itself as the risk factor.

    In addition, Preskorn noted that women taking Effexor (venlafaxine) were included in the control group. But since this drug also works on serotonin receptors, he would have liked to see an additional data analysis with mothers taking Effexor included in the SSRI group.

    “Even if it is the drugs, why does it affect so few infants since all of them would be exposed?” Preskorn asked. “There must be other factors at play, because it’s a minority who develop it.”

The study’s results do not give any clues about to how SSRI’s could work to increase the risk of PPHN. But the authors speculate that it could be related to serotonin’s known ability to constrict the blood vessels in the lung, making it difficult for the heart to pump blood into the lungs. This happens when serotonin binds to certain serotonin receptors in the pulmonary system, explained Yuichiro Suzuki, professor of pharmacology at Georgetown University. Suzuki was not one of the study’s authors.

    Serotonin could be present in higher-than-usual concentrations if the mother is taking a drug that prevents the neurotransmitter from being taken into the cell. As a result, its effect on the pulmonary system could be exaggerated.

    Serotonin is also known to stimulate smooth muscle growth in the pulmonary system by entering the cells through the serotonin transporter. This action, if exaggerated, could potentially cause a thickening of the blood vessels in the lungs, which, in turn, increases resistance to pumping blood into the lungs, Suzuki said.

    “Serotonin plays a key role in the control of pulmonary vascular tone,” Saadia Eddahibi, member of the physiology faculty at Henri Mondor hospital in Créteil, France, said via email.

 paper’s authors also hypothesized that serotonin could be acting to inhibit an enzyme that produces nitric oxide, which is known to dilate blood vessels in the lungs. In a different study, Prozac was demonstrated to inhibit nitric oxide production in a joint cell culture. But it is unknown whether this action would carry over to lung tissue.

Because the mechanisms underlying the risk of PPHN are not well understood, it is difficult to assess how the few of mothers who birth babies with this condition differs from the many who do not. Because the risk suggested by this study is low, doctors and mothers should weigh whether or not to discontinue SSRI use on a case-by-case basis, Chambers said.

    This is especially significant in light of another study published in the Feb. 1 issue of the Journal of the American Medical Association. This paper showed that women who stop taking antidepressants during pregnancy are five times more likely to relapse into depressionthan women who keep taking the drugs.

    The next step, Chambers said, is to use existing databases to confirm or refute the risk associating SSRIs and PPHN. If the findings are corroborated, researchers must try to understand why the SSRIs act differently in the one percent of mothers who give birth to babies with PPHN.

Articles

One percent of mothers taking SSRI’s during the second half of pregnancy gave birth to babies with pulmonary hypertension, a recent study found. But the mechanisms that connect increased serotonin with this disorder are unknown.

Common Antidepressants Increase Risk of Infant Respiratory Disorder

In what is likely the first approval of its kind, the Department of Agriculture gave the thumbs up to a plant-derived vaccine that inoculates chickens against the lethal Newcastle disease. Dow AgroSciences, the vaccine’s manufacturer, said it was the first plant-derived vaccine approved in the world. 

    The USDA confirmed that this was the first plant-made vaccine approved by the department. 

    The Dow vaccine contains a protein from the Newcastle disease, which is grown and harvested in a plant cell culture. This process is similar to the way recombinant proteins are grown in bacterial cell lines, explained Butch Mercer, global business leader for the Animal Health division of Dow AgroSciences.

    Growing the protein in a plant cell line, according to Mercer, eliminates fear of contamination from animal pathogens. Instead of introducing the Newcastle virus into the system, the vaccine contains only the protein necessary to activate a chicken’s immune system and cause it to produce antibodies against the Newcastle virus.

    The cell culture could theoretically grow a plant pathogen, Mercer said. So to win approval from the USDA, Dow had to demonstrate that its production system is free of plant contaminants in order to win USDA approval.

As part of the approval process, USDA verified that the protein produced is equivalent to other Newcastle vaccines using the same protein, said spokeswoman Suzan Holl. The agency also had to expand its testing in order to evaluate the plant-cell media and culture techniques. 

    Growing the protein in a plant cell line, rather than whole plants, eliminates the possibility that recombinant genetic material will travel into other plants via pollen, Mercer said. 

    This is one of the major regulatory concerns associated with plant-made vaccines. FDA guidance requires manufacturers using bioengineered plants to demonstrate that their procedures prevent recombinant plant material from mixing with food crops, according to Paul Richards, an FDA spokesman. 

    “All applicable regulatory and good manufacturing practice (GMP) requirements are in place for this type of product,” Richards said. 

    The importance of avoiding contamination was also discussed at an informal meeting about plant-derived vaccines organized by the World Health Organization in Geneva in January 2005. The meeting concluded that existing guidelines for the developing and evaluating traditional vaccines are applicable to plant-derived vaccines, according to a WHO report. 

    The development may pave the way for more plant-derived vaccines for animal and eventually human diseases, according to Mercer. He predicted that the availability of plant-made vaccines would usher in a new era of immunity within the next 20 years. The company is already working on other plant-made products for birds, horses, and dogs.

    The World Health Organization believes plant-made vaccines hold great promise for protecting people who live in developing countries. 

The door to growing vaccine proteins in plants is officially opened with a USDA-approved veterinary product. Is the FDA prepared for human vaccines grown in plants?

The First Plant-Derived Vaccine Approved for Chickens

Generic drug advocates are up in arms about the proposed fiscal year 2007 budget. The government plans no funding increases for  FDA’s Office of Generic Drugs in a year when an estimated $20 billion worth of brand drugs are expected to go off patent.

    Although the agency fully approved 361 generic drugs in 2005, an additonal 850 generic drug applications still await approval, according to FDA spokeswoman Karen Mahoney. Submissions increased 36 percent between 2004 and 2005.

    The best way to shorten this queue would be to increase funding for the generic approval process, said Ed Thwaite, president of generic consulting firm E.W. Thwaite Associates. Modest funding increases for OGD could translate into billions of dollars saved on drugs down the line, he continued. An increase of $15 million would be enough to see substantial savings in the future, according to Generic Pharmacuetical Association spokeswoman, Andrea Hofelich.

    In spite of this tremendous backlog at OGD, the generic approval process has become faster in recent years. The average approval time for generic drugs in 2005 was 16.5 months, Mahoney said via email. This is up from 16.3 months for 2004 but down from 17.3 months in 2003 and 18.3 months in 2002, according to agency budget documents.

    Hofelich claimed this increased efficiency is due to collaborative efforts between the industry and OGD, such as electronic filing and online databases to guide the review process.

    Next year, the agency aims to speed the approval process for 25 percent of generic drugs by two weeks. But Hofelich said the generic approval process could not get any faster without increased funding to hire more staff at OGD.

    Although FDA hopes to increase efficiency, two generic drug initiatives are among the eight programs at the agency scheduled for funding cuts next year, according to FDA budget documents. Generic drug research contracts, and an initiative to improve information processing for generics will be among the programs  cut as  FDA reallocates approximately $7 million for higher-priority programs such as the Critical Path Initiative.

    But even with the growing backlog of drugs awaiting approval, generics manufacturers are not interested in adopting user fees, Hofelich said. User fees for brand companies will increase in 2007, bringing more money to the agency.

    External pitfalls such as legal challenges and citizen’s petitions can slow down the generic approval process beyond the control of the agency, according to Hofelich. As a result, even if a generic manufacturer paid the user fee, there is no guarantee it would speed the process enough to make the investment worthwhile.

    In addition, most generic drug companies operate on very small margins. Price competition in the industry is so fierce that few manufacturers are willing to spend money on user fees, Hofelich explained.

    But Thwaite added that as generic companies continue to consolidate and grow larger, user fees “might become a worthwhile opportunity.” He expects the issue to be raised again in the near future.

Generic drug advocates say flat funding for the Office of Generic Drugs in the 2007 FY budget will do nothing to decrease the growing backlog of products waiting for approval. They claim other streamlining techniques will not reverse this trend.

Pharmaceutical Executive-02-14-2006

Common Antidepressants Increase Risk of Infant Respiratory Disorder

The First Plant-Derived Vaccine Approved for Chickens

850 Generic Drugs Awaiting Approval