Friday, May 31, 2013

Seeking a SimplyThick Answer

The Ongoing SimplyThick Infant Formula Experiment

FDA—SimplyThick necrotizing enterocolitis—communications were last issued in September 2012. In spite of these health risk notifications SimplyThick remains a marketed infant product. To date SimplyThick usage has been associated with nine U. S. infant deaths and multiple necrotizing enterocolitis incidents.

Health Canada has also reported SimplyThick necrotizing enterocolitis occurrences. Per the FDA, the SimplyThick additive was sold in Puerto Rico, Guatemala, Ecuador, Panama, Barbados, Cayman Islands and Italy.

The John L. Holahan designed SimplyThick product was prescribed for neonatal infants in 2003. In addition to hospital facilities, Mr. Holahan has SimplyThick contracts with nursing home centers, home health agencies and state Medicaid agencies.

Previous SimplyThick reports:

FDA Findings: Xanthan Gum Primary Source of Bacterial Endotoxins

John L. Holahan Issues SimplyThick® Necrotizing Enterocolitis Advisory

Warning Too Late for Some InfantsThe New York Times

SimplyThick Neonatal Intensive Care Practices

FDA "SimplyThick" Infant Health Risk Warnings are Complicated

Thermo Pac, LLC—SimplyThick— Processing Deficiencies

Infant— SimplyThick—Alert: Health Canada October 18, 2012

John L. Holahan—SimplyThick—Xanthan Gum—Necrotizing Enterocolitis

John L. Holahan: Burdock Group SimplyThick Safe for Infant Formula Approval 2001

SimplyThick Infant Formula Experiment

Jeannette Cooperman's reprinted June 2013 article provides an update on the SimplyThick case.

Simply Thick: A Tragedy No One Saw Coming

St. Louis Magazine—Jeannette Cooperman—June 2013

A St. Louis entrepreneur’s brilliant idea won instant FDA approval. Eight years later, babies started dying. Was there a connection?
In late January 2001, John L. Holahan III showed up for the first meeting of “The Startup Game,” an entrepreneurship course at Washington University. He was 31, married, and working on his MBA. The course sounded like fun—and it might prove useful. A chemical engineer, he had recently been laid off from Monsanto, and he was thinking of starting his own company.

He even had an idea: He’d been working for the Monsanto division that made xanthan gum, a food thickener. (You’ve eaten it many times, probably in your favorite bottled salad dressing, for starters.) Monsanto was selling its biogums business, which hadn’t exactly popped any revenue records. But what if he could turn xanthan gum into a flavorless gel and use it to thicken liquids? So many people had trouble swallowing after strokes, or when their airways narrowed as they aged. A thickener bought them precious extra seconds to close their airway, so they could swallow without choking. But there weren’t many thickeners to choose from—especially if you didn’t want one that tasted funny, clouded the liquid, or gunked it up.

Holahan presented his idea in class, and his team loved it. They divided up the work, taking charge of marketing, manufacturing and packaging, regulatory issues… The further they got, the more convinced they were that it could work. Go for it, they urged him.

He developed the gel, which he named SimplyThick, and took it to food-safety experts who help make sure products comply with U.S. Food and Drug Administration regulations. The consultants said SimplyThick wouldn’t even need a warning label. Xanthan gum was just a food, and the FDA had long ago proclaimed it safe.
Sure enough, in October 2001—just six months after that MBA class ended—the FDA approved SimplyThick for sale. Two guys who’d gone through the same Wash. U. entrepreneurship program joined Holahan as principals, and they raised more than $600,000, almost a third of it from their former classmates.

On October 21 of that year, a news release announced “the next-generation instant food thickener,” a “revolutionary, patent-pending thickening agent.” It did not affect flavor, leave particles in the bottom of the glass, cloud the liquid, or congeal. It was quick and easy to use, and it came in different-size packets that could produce the consistencies of nectar, honey, or pudding. SimplyThick could even be used to thicken beer or wine.

Or, Holahan soon realized, breast milk.

The American Dietetic Association met in St. Louis that month, so the new team staffed a booth. Holahan later told the St. Louis Post-Dispatch, “Within two or three hours of launching our product at the trade show, we were cornered by neonatal dietitians, asking us, ‘Does it work in breast milk?’” The enzymes in breast milk broke down other thickeners.

Sarah Holahan was helping out at the booth, and she’d been expressing milk for their daughter so John could help feed her. The Holahans went home and dissolved SimplyThick into her milk. It mixed smoothly and stayed stable—yet another selling point.

Holahan knew of no reason to worry about the safety of xanthan gum. It’s made from the outer shell of a little bacterium named Xanthomonas campestris. Bob’s Red Mill, a wholesome, folksy maker of natural stuff like muesli, steel-cut oats, and whole-wheat flour, extols its virtues for thickening gravies and sauces, and says it’s an ideal substitute for that new villain, gluten.

SimplyThick’s adult users sent grateful, glowing feedback. After a stroke, cancer, trauma, or just the maddening frustration of aging and having to worry about choking to death in a restaurant…this product brought their lives a few notches back toward normal.

As for the consumers Holahan hadn’t planned on, premature infants, they often had trouble coordinating the suck-swallow-breathe sequence—which actually is pretty complicated when you think about it—and thickening breast milk or formula made the process much easier. Some neonatologists thought thickening helped with reflux, too. And nurses on the floor loved SimplyThick, because it stayed mixed; it didn’t get all gloppy like rice-cereal thickeners. When you’re feeding lots of tiny mouths at once, timing’s crazily important. The nurses happily sent packets home with parents when the babies were discharged.

“When I talked to parents about what they were going through before SimplyThick came along, their gratitude makes me know it was the right thing to do,” Holahan told the Post in 2003. Sales grew steadily for the next six years.

September 2009. Six weeks after her premature birth, Jennifer and Shane Umphress’ daughter was sent home from the hospital with well wishes and packets of SimplyThick. Soon after she got settled in her comfy new crib, though, the diarrhea started. She was clearly in pain, and she started having trouble breathing. Her parents raced her to a nearby hospital in Las Cruces, N.M., which airlifted her to the University of New Mexico Children’s Hospital in Albuquerque. Diagnosis: NEC, or necrotizing enterocolitis, a condition that kills the tissue that lines the intestinal wall. She lived, but her parents say her stomach remains distended, and she’s often in pain.

November 2009. Kim Petroni gave birth to a premature son. In February, he was sent home with packets of SimplyThick. Days later, his stomach bloated painfully. Diagnosis: NEC. After another six weeks in the hospital, he recovered. Once again, he was sent home with instructions to use SimplyThick. The NEC came right back. This time, he had to have a portion of his intestines surgically removed. His parents say that his stomach, like the Umphress baby’s, is permanently distended, with increased risk of bowel obstructions.

December 2009. SimplyThick received its U.S. patent.

May 2010. Devon Addonizio’s premature daughter was fed SimplyThick during her last few days at Weill Cornell Medical Center, then sent home May 4 with instructions to continue use. Addonizio ordered more thickener right away from the company’s website. By May 7, she says, her daughter was screaming in pain, moaning in her sleep, and passing large amounts of gas. On May 13, Addonizio found her grunting for air and deathly pale, the skin around her mouth bluish. In the ambulance, while unconscious, she vomited gushes of liquid. She underwent two bowel surgeries for NEC and spent four months in a critical-care unit.

December 2010. Jaden Santos and his twin sister were born at 27 weeks. Jaden reached a sturdy 5 pounds before his sister, and he got to go home on March 31, 2011. He’d been started on SimplyThick a few days earlier, and the hospital sent packets home with him, to be mixed with his mother’s breast milk. The next morning, Jaden had more than 20 episodes of diarrhea. When his mother reached the end of the 24-pack box of diapers, she looked at her husband wordlessly. The next morning, he had 12 more episodes. The parents say their pediatrician didn’t know SimplyThick could be a problem and said to continue using it. The diarrhea tapered off a bit. But on April 8, the Santoses woke up and saw that their baby’s skin had turned bluish. His stomach was pushed out, the skin stretched like a malnourished child’s. By the time they got him to the E.R., his heart had stopped.

His twin, who was never given SimplyThick, thrived.

February 2011. Jack Mahoney and his twin sister were born prematurely in Raleigh, N.C. He was fed SimplyThick; she was not. By April, Jack was dead of NEC.

Dustin and Julie Mueller’s 6-year-old son and 3-year-old daughter burst into Julie’s hospital room right after their baby sister was born, excited to get to hold her. She’d arrived right on schedule, and the delivery had gone smoothly. That first evening, though—December 12, 2011—Addison had some reflux and choked a little. A swallow test showed her having trouble with thin liquids. “Oh my gosh,” Julie said, “what do we do?” Test her again in six weeks, the speech therapist said calmly; she’ll probably outgrow it. In the meantime, just thicken her milk. Julie was relieved—“such a simple fix”—and thrilled when the therapist recommended a product, SimplyThick, that worked great with breast milk.

A few days later, back home in Eau Claire, Wisc., Julie noticed that Addison’s stools were different. Just to make sure nothing else is wrong, her pediatrician said, let’s get her checked over thoroughly. “So we went up to Mayo [Clinic],” says Julie, “and every test turned out perfectly normal. They said, ‘You have a normal, healthy baby. Take her home and enjoy her.’”

Christmas was two days past, but Addison’s stocking was waiting, stuffed with baby rattles. “The kids couldn’t get enough of her, and my parents came—she was probably never put down!” Julie says. “She was definitely loved. The only thing concerning to me was, the stool seemed to be getting worse. And she seemed little to me; she wasn’t plumping up.”

At Addison’s January 3 follow-up appointment, her pediatrician said she hadn’t gained weight, her color didn’t look good, and bloodwork showed anemia. But why?
They rushed her to the Mayo Clinic. “We’ll figure it out. We’ll figure it out. She’ll be OK,” they kept telling each other. But in the middle of that night, “Addison started screaming,” Julie says. “Her belly was completely distended. I was holding her, and she started spitting up a whole lot.”

At 7 a.m., doctors told the Muellers they had to operate, fast; X-rays showed perforations in the bowel. “Why is this happening?” Julie wailed. “She was healthy! They did tests!”

After surgery, the anesthesiologist came to tell the Muellers that Addison was back in her room. “Will she be OK?” they asked. He said the doctor would talk to them.
“The surgeon came in and said Addison had necrotizing enterocolitis, and explained what that was,” Julie says, her voice dull. “He said he had to remove her small intestine, and the large one was starting to die off. I don’t know if I was just in denial—I wasn’t even thinking death. I said, ‘OK, what do we do to fix her?’ and he looked at me and said, ‘You’ve just got to let her go.’”

Julie couldn’t bring herself to take her baby off life support, but Addison worsened on her own. Around 8 p.m., a nurse said, “It’s time to let you hold her.”
“She took one breath, and that was it,” Julie says. She and Dustin went home in shock. “Even the head pediatrician at Mayo, who sees everything, said he didn’t have any answers for us.” The Muellers asked for a full autopsy and genetic and metabolic tests. Everything, Julie says, came back perfectly normal.

Then they remembered the SimplyThick.

And when Julie started researching, she found SimplyThick had no clinical trials of any sort, and could cite no studies with babies of any age—just a 1987 adult-male study of xanthan gum’s safety. “Are you kidding me?”

By May 13, 2011, Dr. Benson Silverman, a neonatologist with the FDA, had received enough calls and MedWatch reports to suspect the problems were more than anecdotal. The FDA launched an investigation.

One week later, the FDA issued a warning: SimplyThick should not be used for premature infants.

In September 2011, the Umphress family filed suit against SimplyThick and the product’s manufacturer, Thermo Pac.

It was January 2012 when Addison Mueller died, at 23 days of age. She’d been born full-term, not premature. Julie Mueller talked to FDA officials. “I was upset because a lot of the preemies were full-term age when they ingested the SimplyThick, so why would you limit the warning to preemies?” Julie says. “If they had included all infants, Addison might still be alive.”

In February 2012, the Petroni family filed suit in the Circuit Court of St. Louis County. (Two of the lawsuits were filed here, because SimplyThick’s office is in St. Louis; other lawsuits were filed in the families’ home states, the manufacturer’s state, or federal court.)

Three months later, Silverman and colleagues at the FDA published a case review in the Journal of Pediatrics that outlined a “distinct illness pattern” in 22 cases involving SimplyThick. In September, the FDA extended its warning to include infants of any age.

SimplyThick’s website has the FDA warning on its Recall page and its own warning, on its front page and Frequently Asked Questions page, for infants and children under 12 with a history of NEC. But the FAQ warning is the ninth of 10 links, and it doesn’t appear on any of the specific product-information or ordering pages. At press time, the only other caution was on a Recipe Gallery page—and that one only mentioned premature infants.

In October 2012, the Muellers filed suit in the Circuit Court of St. Louis County. “Defendants continued to market SimplyThick by providing false and misleading information with regard to the safety and efficacy of SimplyThick,” the lawsuit alleges, “and failed to timely warn of the product’s risks when used in any infant.”
In November 2012, the Santos family filed suit in Florida. Holahan emailed the Orlando Sentinel a restrained formal statement: “We offer our sincere condolences to the Santos family. Nothing is more important to us than the health and safety of our customers.”

What else could he say?

The nightmare wasn’t over: Cases continued to surface, and the matter turned tabloid when a slew of personal-injury law firms blared warnings online, trolling for clients. announced that its “experienced, aggressive lawyers are now investigating claims… Call NOW! Help is available 24 hours a day…”
We first tried to reach Holahan at his Clayton office this February. He forwarded the message to Suzanne Turner, a communications strategist in D.C. She said SimplyThick had no comment.

At press time, 25 lawsuits and unfiled claims still waited in limbo, as dark-suited attorneys negotiated, behind closed doors, a possible group settlement.

About 25 percent of the babies who get NEC die—and for cases that require surgery, the percentage doubles. Dr. Brad Warner, the surgeon-in-chief at
St. Louis Children’s Hospital, operates on many of those babies; his wife, neonatologist Dr. Barbara Warner, treats them, and she was one of the reviewers of the FDA team’s Journal of Pediatrics review.

The Warners are both professors at Washington University School of Medicine. And both find NEC—the most common surgical emergency in newborns—insidious and maddening. It’s caused by bacteria, inflammation, decreased blood flow, and an immature gut, but there hasn’t been a way to tease out, from that list, a single route to prevention or even a single predictive, primary cause.

“You can’t have NEC without bacteria,” observes Barb, who’s been working with The Genome Institute for four years, studying microbes within the neonatal gut.

“But when we look at the bowel that’s dead, we see clots in the blood vessels,” inserts Brad.

What else does he see? “It can be paper-thin, where you can actually see the formula inside the lumen of the intestine, like wet tissue paper. Or it can look gangrenous, greenish-brownish gray. It can have an actual hole, a perforation, because it’s gotten so necrotic that it’s punctured the wall.” He sighs. “Some of these kids, when you operate on them, everything is dead, from the stomach to the rectum. It’s called a peek-and-shriek. You have to close and hand the child to her parents.”

Back in 2003, Holahan went on KETC Channel 9’s Stl Biz to talk about how invaluable it was for SimplyThick to outsource its production. “We didn’t want to take on the risks of building a manufacturing plant and packaging a food product that we didn’t know anyone would buy,” he said. “Because we started the company right when the recession was hitting, we were able to get a very large manufacturer to make this product for us… There’s no way we would have started our company without outsourcing.” The large manufacturer was the H.J. Heinz Company. In July 2008, Heinz sold one of its facilities, in Stone Mountain, Ga., to Thermo Pac.

On May 23, 2011, a week after the FDA began investigating SimplyThick, FDA inspectors showed up at the Stone Mountain plant.

Ten days later, on June 3, they handed over their report. On June 4, SimplyThick recalled all thickening gel processed at the Stone Mountain plant since June 2009.

The company’s press release emphasized the recall was voluntary, issued because the FDA “advised the company that Thermo Pac, LLC failed to file with the FDA a scheduled process designed to ensure that vegetative cells (harmful bacteria) of possible public health significance are destroyed during the manufacturing process.”

To the lay reader, this sounded like a paperwork snafu. When the Shrader & Associates law firm chronicled the SimplyThick saga, it noted a “failure to file for a routine process.” A parenting blog said the “recall is occurring because of a failure to file paperwork to the FDA.” A blogger on Gizmodo wrote, “This was pulled because they didn’t file paperwork or something boring like that. The name just keeps cracking me up.”

It was only funny if you didn’t read the full report—or the June 22 response from a Thermo Pac senior vice president acknowledging the FDA had found Bacillus cereus, a type of bacteria that can cause diarrhea or vomiting, in 11 finished samples of SimplyThick and one raw sample of xanthan gum.

After saying the proper schedules hadn’t been filed, the inspection report noted that the thickener was being cold-filled as an acidified food—meaning it was “not thermally processed to an extent that is sufficient to destroy the vegetative cells of microorganisms of public health significance.”

The report also noted that plant supervisors were not adequately trained. Equipment wasn’t sufficiently cleaned after allergens were found. And in 2010, sanitation failures continued for four months after they were detected.

The Santoses still have two of the 30-gram packets the hospital gave them. According to their attorney, Joe Taraska of Morgan & Morgan, the product code stamped in the foil matches the code of packets that would be recalled—eight weeks after their son’s death.

Did the cold processing method and the failures in sanitation cause NEC?

Nobody’s sure. The FDA’s current theory is that the problem is the xanthan-gum thickeners themselves, because of the way they interact with an immature gut.
Most of the SimplyThick lawsuits cited both the xanthan gum and possible bacterial contamination as potential causes, though, and they named Thermo Pac and its current owner, AmeriQual Group, an Indiana company that makes ready-to-eat meals for the military. (There’s confusion about AmeriQual’s role—its website says its owners acquired Thermo Pac in 2008, but Taraska says the company denies any direct connection to Thermo Pac during the period spanned by the lawsuits. “We believe they either did own them…or are intertwined in such a fashion that they are not separate entities,” he says. “It will be an issue in the litigation.”)

AmeriQual and Thermo Pac refused to comment for this story. Holahan eventually gave us a single statement: “The safety of our customers is our number one concern, and SimplyThick worked very closely with the FDA in its investigation. To date the FDA has not indicated to SimplyThick that there is any type of causal link between our thickening gel product and any injury to infants.”

The FDA authors conceded that point in the Journal of Pediatrics article: “A case series cannot prove an association between SimplyThick and NEC; a well-designed analytic study is necessary to establish if a true association exists.” But it went on: “Nonetheless, several features of the cases described here distinguish them from previously reported cases, leading us to propose that SimplyThick usage in this population may increase risk of NEC.”

A later article in the Journal of Perinatology stated that feeding premature infants SimplyThick “not only stimulates the immature gut by increase in water, sugars, [short-chain fatty acids] and bile acids,” but may also trigger inflammation. The authors recommended that SimplyThick not be used for premature infants and concluded, “However, because of its special biological properties, [SimplyThick] might be useful in research into the pathogenesis of NEC.”

Many of the SimplyThick lawsuits also named H.J. Heinz Company, because it developed the cold-fill process. Thor Tobin Mathison of Bryan Cave, one of H.J. Heinz’s attorneys, emails that “during the time that Heinz owned the facility there were no safety issues and no product contamination. Heinz sold the plant in July, 2008 and has had no involvement in production of SimplyThick after that time.” Mathison says Heinz cannot comment on “the reasons for the quality problems apparently encountered in 2010 and 2011” and says most of the plaintiffs have chosen to dismiss their claims against Heinz.

Thermo Pac, however, has not. In a third-party petition filed in the Circuit Court of St. Louis County, Thermo Pac asked that Heinz indemnify it against any damages and court costs. Thermo Pac’s position is that Heinz “warranted and represented” that the cold-fill manufacturing process had been approved by the regulatory authorities for use. If the food giant’s scientists and food-safety experts had signed off, and the regulatory authorities had signed off, Thermo Pac wasn’t worried.

At press time, Heinz had refused to indemnify Thermo Pac, which was asking for a trial by jury.

“If a manufacturer creates a process but then sells it to someone else, it is generally the last person in line who’s going to be responsible,” Taraska says. “However, if Heinz in any way warranted that process…

“It’s the method they use to make ketchup, by the way,” he adds, sounding like a detective in a noir film. In the end, though, this story’s more of a Shakespearean tragedy.

On one hand, it’s a miracle anyone connected an innocuous thickener to what at that point were 22 cases of illness and death scattered across the country, all but one occurring in fragile preemies already vulnerable to NEC.

On the other hand, to the parents of the babies affected, it seems unconscionable that a new product, even a foodstuff, could have been used for infants without any clinical trials whatsoever.

Especially since this wasn’t the first red flag about thickeners.

British neonatologists wrote a paper questioning the safety of a carob bean–based thickener some time ago—and were quick to point that out when SimplyThick’s problems went public. In other cases, babies have developed NEC after pectin- or cellulose-based thickeners were used. And some powdered formulas have been associated with NEC because they were not sterile.

The FDA was alerted “through MedWatch and other reports that came in on SimplyThick,” says spokesperson Tamara Ward. According to the agency’s website, “FDA first learned of bad side effects possibly linked to SimplyThick on May 13, 2011.”

But a New York Times article this February stated that “in early 2011,” Silverman “was alerted to an online forum where doctors had reported 15 cases of NEC among infants given SimplyThick.” And Taraska says “it appears that for at least six months before the warning, there were complaints being made to the FDA. The FDA was getting what they considered anecdotal reports.” The Mueller lawsuit, filed in St. Louis, states that “for approximately six months preceding May 13, 2011, FDA received numerous reports of adverse events linked to SimplyThick.”

Ward said we’d need to file a federal Freedom of Information Act request to learn the date of the first report. (The FDA denied our request to expedite it, and had not responded at press time.) But no matter how early the alerts started coming in, it would have been hard to see a pattern in scattered, anecdotal reports.

What’s clear is that in May 2011, the warnings from neonatologists reached critical mass.

What’s also clear is that not all customers registered the danger.

In February of this year, after the FDA had issued two warnings and published a paper in a medical journal and The New York Times had written about the issue, we called one of SimplyThick’s local distributors. “Oh, it’s a wonderful product. The beauty of it is, you don’t smell it or taste it,” a dietitian said. “Oh yeah, we have several children on it. There are some babies. We’ve had children and babies on it. We always keep it in stock.”

Asked for a current count of babies who have fallen ill or died after taking SimplyThick, Ward, the FDA spokesperson, replied by email, “The original data reported included 21 premature infants and one full term infant.”

This May, plaintiffs’ attorneys counted 25 claims, nine deaths.

Asked about FDA inspections of the Stone Mountain facility prior to 2011, Ward sent a link to the 2011 inspection report. Asked why the cold-fill method, never approved, wasn’t questioned before 2011, she said the FDA could not comment because the matter is still under investigation.

She did confirm that the facility was required to submit information about its cold-process method to the FDA. And nobody—not SimplyThick; not H.J. Heinz, which developed the method; and not Thermo Pac, which then used the method—submitted that data. So why didn’t previous inspections turn up the inadequacy, or at least the lack of official approval, for the cold-fill method?

"It is mind-boggling how you can market a product and sell it to a patient population knowing absolutely nothing about how it will affect them,” says Fred Pritzker. His Minneapolis law firm, Pritzker-Olsen, specializes in foodborne illness cases and is representing seven of the families whose babies got sick or died after drinking SimplyThick.

Catherine Saint Louis, the reporter who did the New York Times piece, said in a companion audio interview, “John Holahan, the president of SimplyThick…told me that in fact he never envisioned this being used in preemie babies.”

Maybe not, but he repeatedly noted his product’s use in breast milk in his U.S., Canadian, and Australian patent applications. And the babies most likely to need thickened breast milk are the preemies.

Besides, a full-term baby died, too.

If any possible bacterial contamination was irrelevant, and xanthan gum is the sole culprit, are there other “safe foods” that might need special review for use with infants? “We are not aware of any other foods at this time,” Ward replied.

But even the old reliable rice-cereal thickeners have never been tested in clinical trials, Dr. Barb Warner points out. Over-the-counter probiotics might actually help protect against NEC, she adds, but—a rueful laugh—“we’re actually waiting for FDA approval to do multicenter clinical trials.”

She remembers the day the FDA sent out its first consumer advisory warning about SimplyThick. “We talked about it right away, and we did change our practices because of it.” Had they worried about SimplyThick prior to the warning? “Never. But we thought the kids were past that time period for NEC. Most of the babies who developed NEC were 2 or 3 months old, and had reached an age equivalence of full term. That’s very late to develop NEC. And half of them happened at home”—which was also unprecedented.

The larger question hasn’t dissolved: Does the regulatory system need to build in more precautions for infants?

“The breast is best,” quips Dr. Brad Warner. “Anything that is synthetically made suffers the possibility of introducing something that could potentially play a role in developing NEC—or could leave out something that is protective against NEC.”

“That’s why we are big proponents of clinical trials,” Barb says, “and not just doing stuff in your kitchen. The trials do delay things. But…do no harm.”

Sunday, May 19, 2013

Genetic Mutations Probable Cause of Some Infant Heart Defects

Congenital heart defect (CHD), the most common U. S. birth abnormality, affects approximately one in a thousand or 4,000 infants annually.

Research conducted by the Pediatric Cardiac Genomics Consortium, sponsored in part by the NIH, indicates that malfunctioning genes are causative factors for some of these developed in utero heart defects. DNA mapping of the CHD infants and their respective parents found no inherited heart disease link in 10% of the population study.
WSJ—"New Mutations Tied to Kids' Heart Ills"— May 2013

So the unresolved study question is, what substance or agents are negatively influencing genetic behavior?

Possible Suspect: Biotech Food Engineering

Foods Derived from New Plant Varieties—FDA Policy Statement

The FDA acknowledged in 1992 that the ability to genetically modify plants through recombinant DNA and cell fusion technologies might result in unintended harmful consequences. The genetically enhanced novel food products:
may include but are not limited to, significantly increased levels of plant toxicants or anti-nutrients, reduction of important nutrients, new allergens, or the presence in the food of an unapproved food additive.
FDA Guidance:
It is prudent practice for developers of new varieties to consult with the agency on safety and regulatory questions, especially with regard to products developed through new technology.
Scientific Issues Relevant to Public Health
Mutagenic techniques include both random mutagenesis, resulting from treatment with chemical and physical mutagens, and somaclonal variation, whereby, with the use of tissue culture techniques, plants are regenerated from callus or leaf tissue explants. The regenerated plants often have properties not found in the progenitor plant, reflecting both preexisting cellular genetic differences and tissue-culture induced mutations. The mutations range from single gene changes to chromosomal rearrangements. Mutagenesis techniques are limited, however, by their inability to target a desired trait. Somaclonal variants also frequently are unstable or infertile.
Recombinant DNA techniques involve the isolation and subsequent introduction of discrete DNA segments containing the gene(s) of interest into recipient (host) plants. The DNA segments can come from any organism (microbial, animal, or plant). In theory, essentially any trait whose gene has been identified can be introduced into virtually any plant, and can be introduced without extraneous unwanted genetic material. Since these techniques are more precise, they increase the potential for safe, better-characterized, and more predictable foods.
Unexpected Effects
Virtually all breeding techniques have potential to create unexpected (including pleiotropic{5} effects. For example, mutations unrelated to the desired modification may be induced; undesirable traits may be introduced along with the desired traits; newly introduced DNA may physically insert into a transcriptionally active site on the chromosome, and may thereby inactivate a host gene or alter control of its expression; the introduced gene product or a metabolic product affected by the genetic change may interact with other cellular products to produce a deleterious effect. Plant breeders using well established practices have successfully identified and eliminated plants that exhibit unexpected, adverse traits prior to commercial use.

Tuesday, May 14, 2013

FDA Findings: Xanthan Gum Primary Source of Bacterial Endotoxins

Xanthan Gum Pharmaceutical Applications

Xanthan gum, derived from the gram-negative xanthomonas campestris bacterium, is a common excipient in prescription drugs and over-the-counter medications.

Many infectious-disease professionals and the National Institutes of Health report that gram-negative bacteria may be more dangerous than the methicillin-resistant Staphylococcus aureus (MRSA) organism.

The 2008 patent application—"METHOD FOR REMOVING IMPURITIES FROM BIOPOLYMER MATERIAL"—provides the following re the endotoxins emanating from pharmaceutical-grade biopolymers such as alginate, xanthan gum and gelatine:
In pharmaceutical production, it is necessary to remove LPSs from drug product containers as even small amounts of this endotoxin will cause illness, but not disease, in humans.
LPSs are in large part responsible for the dramatic clinical manifestations of infections with pathogenic gram-negative bacteria, such as Neisseria meningitis, the pathogen that causes fulminate meningitis.
According to the FDA, xanthan gum is generally the source of this unwarranted bacterial activity.

In 2009 the Center for Drug Research and Evaluation found the following Tobradex ST microbiology issue:
Xanthan gum is the primary source of bacterial endotoxin since it is produced by bacterial fermentation. The proposed manufacturing changes were made in processing xanthan gum to achieve reduction in endotoxin level and maintaining high viscosity of the solution.
FDA standards regarding permissible endotoxin limits are not disclosed. Endotoxin data was redacted in the Tobradex ST review.

It may be circumstantial, but many pharmaceutical products containing xanthan gum are linked to necrotizing (cell death) events. Adverse events include, but are not limited to, toxic epidermal necrosis and Stevens-Johnson.

Research papers—"Bacterial Endotoxin in Human Disease"—and "Concordance of Endotoxemia with Gram-Negative Bacteremia in Patients with Gram-Negative Sepsis: a Meta-Analysis" document that endotoxins release tumor necrosis factor receptors.

Medications absent xanthan gum are also known to cause necrolysis.

The study of interaction of various pharmaceutical agents is challenging but it has been established that antibiotics can initiate endotoxin activity. This subject is discussed in "Effects of Different Types and Combinations of Antimicrobial Agents on Endotoxin Release from Gram-negative Bacteria: An In-Vitro and In-Vivo Study."

The EuroSCAR-study "Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs" and the All India Institute of Medical Sciences "Stevens Johnson syndrome, toxic epidermal necrolysis and SJS-TEN overlap: A retrospective study of causative drugs and clinical outcome" report provide further data.

Xanthomonas campestris—Xanthan Gum

Xanthomonas campestris pv. campestris is the cause of "black rot" necrotic plant disease. Fermentation of the xanthomonas campestris pathogen and its numerous molecularly-altered strains produce xanthan gum.

Xanthan gum is under FDA investigation as the presumed cause of the deadly SimplyThick infant necrotizing enterocolitis incidents.

SimplyThick® Xanthan Gum Product Health Risk Update

FDA advisories—May 2011/September 2012— warned that the SimplyThick® xanthan gum product may cause necrotizing enterocolitis in premature and post-term infants.

For unknown reasons, the SimplyThick® manufacturer expanded the health risk profile in 2013 to include all consumers with a history of necrotizing enterocolitis:
WARNING - [SimpyThick] NOT intended for use with preterm or infants under 12 months of age. Or children under the age of 12 years with a history of NEC [necrotizing enterocolitis].
Although no definitive link between NEC and SimplyThick® brand products has been found or established, in an abundance of caution, anyone at risk for or with a significant risk factor for developing NEC should not use SimplyThick® products
Gram-Negative Bacteria

Xanthomonas campestris, a gram negative bacterium, contains endotoxin (lipopolysaccharide) layers (LPSxcc). The transformation (lysis) of xanthomonas campestris to xanthan gum releases lipopolysaccharides which are known to provoke harmful immune defense mechanisms in plants and humans.

Gram-negative bacteria is mutable, often antibiotic resistant and will spark endotoxin activity. Reference: "Bacteroides: the Good, the Bad, and the Nitty-Gritty"
Clinical Microbiology Reviews 2007

Plant Pathogen Crossover

The National Institutes of Health has identified various plant pathogens and their related strains as disease prompting agents. This plant-to-human transmission phenomena is called crossover. The plant bacteria xanthonomas campestris pv. campestris is known to cause bacteremia.

The Code of Federal Regulations re Xanthan Gum Formulated Pharmaceuticals

The Code of Federal Regulations prescribe that food/pharmaceutical grade xanthan gum be extracted from non pathogenic/non toxigenic Xanthomonas campestris strains and not contain active Xanthomonas campestris cells.

Patent applications reveal that xanthan gum endotoxin-reduction methods are complex. For instance, KELTROL T [ Kelco Biopolymers] xanthan gum contains more than
one million endotoxin units per gram.

Xanthan gum was classified a Generally Recognized as Safe (GRAS) food additive in 1969 and was approved for pharmaceutical usage in 2004.

Xanthan Gum Manufacturers

Xanthan gum, manufactured in China, France, U.S. and Austria, is ubiquitous in food and pharmaceuticals. This biopolymer is classified Quantum satis. In other
words, amounts in consumer items are left to manufacturers' discretion.

Water supplies also contain the Xanthomonas campestris bacteria because industrial-grade xanthan gum is utilized by oil/gas producers as a lubricating fracking agent.

Domestic and foreign Xanthomonas campestris fermentation facilities, rarely inspected by the FDA, produce both consumer and industrial grade xanthan gum. Dual-use production sites raise quality control concerns.

The question of whether the original Xanthomonas campestris bacterium and its related mutated strains are benign excipients deserves review. Preclinical xanthan gum safety studies are dated. 

Xanthomonas Campestris Mutatations

Since the 60s interested parties have been experimenting with the Xanthomonas campestris bacteria and its progeny to achieve greater xanthan gum production.

For example, Syntro Inc. sponsored 1980s research determined that two classes of Xanthomonas campestris, mutant strain B1459, increased xanthan gum quantity but were antibiotic resistant. These findings, "Improved strains for production of xanthan gum by fermentation of Xanthomonas campestris," were published in the Journal of Industrial Microbiology (1989) 55-64.

Companies holding patents on genetically-altered Xanthomonas campestris strains are exempt from product safety trials and pre marketing constraints because the novel products are deemed substantially equivalent to the parent bacterium.

The substantially-equivalent theory is explained in "THE DOSSIER IN SUPPORT OF THE GENERALLY RECOGNIZED AS SAFE (GRAS) STATUS OF REDUCED-PYRUVATE XANTHAN GUM (RPXG) AS A FOOD INGREDIENT." This report was presented to the FDA in June 2006 by the Burdock Group on behalf of CP Kelco.

Pharmaceutical Stevens-Johnson Syndrome Associations

In defense of their products, manufacturers maintain that pharmaceutical-induced necrolysis incidents are rare. This allegation and other relevant matters are before the Supreme Court in Mutual Pharmaceutical Co. v. Bartlett (12-142). Mutual Pharmaceutical is arguing that the company should not be held responsible for the defendant's sulindac-caused toxic epidermal necrolysis illness. Sulindac, according to the product label, does not contain xanthan gum.

Rare harmful drug events can be expected to occur in > than 1/10,000 and < 1/1,000 patients.

Responsible parties acknowledge that mortality/morbidity incidence reports are subject to change because clinical trials often do not reflect reality.

For example the rotavirus (anti-diarrheal) inoculation, RotaShield (Wythe), was determined safe for infants and children until pernicious events proved otherwise.
The FDA RotaShield post-prescription advisory is:
AUG 1998: RotaShield® (Wyeth Laboratories, Inc.) Live oral rhesus-based, tetravalent, 3-dose series— Increased risk of intussusception reported following vaccination— Voluntarily withdrawn by the manufacturer in October, 1999—License revoked by FDA in November, 2002.
Xanthan Gum Excipient Pharmaceuticals and Stevens-Johnson Syndrome

The following xanthan gum formulated medications are linked to the Stevens-Johnson Syndrome. This list is not inclusive.

Rotarix—human rotavirus RIX4414 strain—xanthan gum—Stevens-Johnson Syndrome — The FDA became aware in 2010 that Rotarix and RotaTeq rotavirus vaccines contained porcine circovirus. These foreign DNA components
are not FDA-considered health risks.—"Rotarix rotavirus vaccine contaminated, officials say"

Infants'/Children's Motrin—Ibuprofen—xanthan gum—Stevens Johnson Syndrome—"Ibuprofen is safe, doctor says, despite severe injuries girl suffered after taking Motrin"—"Motrin Lawsuit: Jury Awards Girl $10 Million for Burns and Blindness"

Aldara— imiquimod—xanthan gum—Stevens-Johnson Syndrome

Lipitor—atorvastatin calcium—xanthan gum—Stevens-Johnson Syndrome

Allegra Oral Suspension—fexofenadine hydrochloride —xanthan gum—Stevens-Johnson Syndrome

Timolol GFS—timolol maleate—xanthan gum—Stevens-Johnson Syndromebacteremia

Duricef Oral Suspension—cefadroxil—xanthan gum—Stevens Johnson Syndrome

Risperdal M-Tabs—risperidone—xanthan gum—Stevens-Johnson Syndrome 1

Moxeza—moxifloxacin hydrochloride—xanthan gum—Stevens-Johnson Syndrome [xanthan gum data deleted in the FDA clinical review]

Erythromycin E.E.S. from the Saccharopolyspora erythraea strain—xanthan gum— Stevens-Johnson Syndrome

Zmax—azithromycin—xanthan gum—Stevens-Johnson Syndrome— Pfzier's warning that allergic reactions may recurr post-azithromycin exposure:
These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined.
ZEGERID Oral suspension powder—omeprazole/sodium bicarbonate—xanthan gum—Stevens-Johnson Syndrome

TAMIFLU oral suspension—oseltamivir phosphate—xanthan gum—Stevens-Johnson Syndrome — "The Myth of Tamiflu: 5 Things You Should Know"— Forbes

BIAXIN Granules for oral suspension—Clarithromycin—xanthan gum—Stevens-Johnson Syndrome

AUGMENTIN XR—amoxicillin/clavulanate potassium—xanthan gum—Stevens-Johnson Syndrome

VIOXX Oral Suspension —rofecoxib—xanthan gum—Stevens-Johnson Syndrome—Vioxx has been attributed to 27,000 heart attacks or sudden cardiac deaths while prescribed 1999-2003—Vigor Study

MEGACE —megestrol acetate—xanthan gum—Stevens-Johnson Syndrome —no mutagenesis studies conducted— "New Jersey pharmaceutical company pleads guilty to illegal marketing" of Megace to elder care facility physicians.

Cedax (ceftibuten) Cedax Oral Suspension—xanthan gum—Stevens-Johnson SyndromeFDA Cedax False Advertising Warning Letter

Tegretol Oral Suspension— carbamazepine—xanthan gum— Stevens-Johnson Syndrome

Xanthan Gum Endotoxins

It is disconcerting to learn that contrary to the information published in the Code of Federal Regulations, xanthan gum endotoxins are permitted in pharmaceutical products.