Link:  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm203776.htm

FDA NEWS RELEASE

For Immediate Release: March 9, 2010
Media Inquiries: Sandy Walsh, 301-796-4669; sandy.walsh@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA Approves Botox to Treat Spasticity in Flexor Muscles of the Elbow, Wrist and Fingers

The U.S. Food and Drug Administration today approved Botox (onabotulinumtoxin A) to treat spasticity in the flexor muscles of the elbow, wrist, and fingers in adults. Spasticity is common after stroke, traumatic brain injury, or the progression of multiple sclerosis.

“Muscles affected by spasticity have increased stiffness and tightness, which may lead to pain, difficulties with hygiene and other activities of daily living, and may affect how a patient looks,” said Russell Katz, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “In clinical trials, treatment with Botox was found to be beneficial to patients with upper limb spasticity.”

Botox works by temporarily blocking the connections between nerves and muscles, resulting in a temporary paralysis of the spastic muscle.

Botox has a Boxed Warning that says the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism. Those symptoms include swallowing and breathing difficulties that can be life-threatening.

The most common adverse reactions reported by patients with upper limb spasticity were nausea, fatigue, bronchitis, muscle weakness, and pain in the arms.

Botox has not been shown to be safe and effective treatment for other upper limb muscles, spasticity in the legs, or for treatment of fixed contracture – a condition that affects range of motion. Treatment with Botox is not intended to substitute for physical therapy or other rehabilitative care.

Botox is manufactured by Allergan Inc. of Irvine, Calif.

Link:  http://www.globalsecuritynewswire.org/gsn/nw_20100226_9517.php

Scientists at two U.S. universities have made progress in the search for a countermeasure for the toxin that causes botulism, which has been identified as a major biological weapons threat, Tufts University announced last week (see GSN, Jan. 21).

Scientists from the Massachusetts institution and Thomas Jefferson University in Philadelphia have developed a new way of cleansing the body of botulinum toxins that involves sending out binding agents that search for and then attach to the toxins. Each agent carries a shared “tag” that signals to a single matched antibody to join it and encircle the botulinum molecule. Once that occurs, the toxin is expelled from the body though the liver before it can cause damage.

Botulinum toxins are approximately 100 billion times more poisonous than cyanide. Research indicates that a single gram of the material could cause the death of more than 1 million people, according to a Tufts release. While there already are antitoxin treatments for botulism, they are expensive to produce, store, and transfer and do not have a long shelf life, the university said.

“We’ve proven this approach to protect against botulinum intoxication in mice and we hope this will lead to rapid development and deployment of many new anti-toxin therapies — for botulism and beyond,” said Tufts biomedical professor Charles Shoemaker, who authored a study on his team’s findings, in released comments.

The new antitoxin strategy would require only the development of new binding agents and not new antibodies. This could result in new antitoxin treatments for a large variety of poisons such as animal venom and ricin, researchers say (Tufts University release, Feb. 25).

Link:  http://www.physorg.com/wire-news/29152710/scientists-get-funding-to-design-anti-botulism-drugs.html

Scientists Get Funding to Design Anti-Botulism Drugs

March 4th, 2010 (PhysOrg.com) — U.S. Department of Energy’s Brookhaven National Laboratory and Stony Brook University’s Institute of Chemical Biology and Drug Discovery (ICB&DD) scientists were selected to receive up to $1.4 million in research funds from the Department of Defense to develop anti-botulism drugs.

Scientists at the U.S. Department of Energy’s Brookhaven National Laboratory (BNL), in collaboration with researchers at Stony Brook University’s Institute of Chemical Biology and Drug Discovery (ICB&DD), were selected to receive up to $1.4 million in applied research funds from the Department of Defense Defense Threat Reduction Agency (DTRA) to develop drugs that block the paralytic and deadly effects of botulinum neurotoxins.

“There are currently no reliable treatments for botulinum toxin exposure,” said Brookhaven biologist Subramanyam Swaminathan, who leads the collaborative effort. “It is important to develop a drug that combats the neurotoxic effects to mitigate fears associated with this deadly poison, including the fear of its potential use in bioterrorism attacks.”

Botulinum toxins are poisonous proteins produced by Clostridium botulinum bacteria. The toxins destroy essential components of nerve cells that control muscle movement, which prevents muscle functioning and leads to paralysis and death. Most commonly known for causing botulism poisoning from canned foods and for their use in cosmetic surgeries, botulinum toxins are the most potent neurotoxins known to humans and are considered extremely dangerous due to their potential use as a large-scale bioterrorism agent.

Fueling the need for developing new drugs is the fact that the current treatment for exposure to botulinum toxin is only effective if administered prior to the toxin infiltrating target cells — a critical time period that may pass before a diagnosis is even made.

The DTRA-funded project focuses on four main drug development goals, including:

deciphering the structure of enzyme-inhibitor complexes
screening large databases for candidate molecules and peptides that block the active sites of multiple botulinum toxin strains
synthesis of novel compounds and modification of molecules for broad spectrum use
and applying medicinal chemistry to optimize these compounds’ design.
Because there are seven different strains, or serotypes, of botulinum toxin — four of which affect humans — one important aspect of the project is developing a single drug that blocks the toxic effects of multiple strains.

“When inflicted by the neurotoxin, you don’t know which serotype you were infected with,” Swaminathan said. “Finding one common drug is useful because otherwise the specific serotype would need to be identified before treatment.”

Swaminathan has studied the botulinum neurotoxin proteins for over two decades and previously deciphered the structure of several strains of botulism toxin using x-ray crystallography data he collected at Brookhaven’s National Synchrontron Light Source (NSLS). The multi-disciplinary research project combines his enzyme-inhibitor structure work with the expertise and resources of Iwao Ojima and Peter Tonge of Stony Brook University’s Department of Chemistry and Robert Rizzo from the Department of Applied Mathematics and Statistics.

The drug development effort is the first consortium award between Brookhaven Lab and ICB&DD.

The NSLS is supported by the DOE Office of Science. The beamlines at NSLS used for this research are supported by the DOE Office of Science and the National Center for Research Resources at the National Institutes of Health.

Provided by Brookhaven National Laboratory

J of Pediatrics

Volume 156, Issue 3, Pages 402-408 (March 2010)

Presence of Soil-Dwelling Clostridia in Commercial

Powdered Infant Formulas

Jason R. Barash, CLS, MT(ASCP), Jennifer K. Hsia, MPHa, Stephen S. Arnon, MD

Objective

Because Clostridium botulinum was isolated from powdered infant formula (PIF) fed to an infant in the United Kingdom who subsequently developed infant botulism and from unopened PIF from the same manufacturer, we tested PIF manufactured in the United States for the presence of clostridial spores.

Study design

Thirty PIF ingested by 19 California infants with botulism within 4 weeks of onset of illness (48% of all patients fed PIF during study) in 2006-2007 were cultured anaerobically to isolate clostridia. All isolated clostridia were identified to the species level and enumerated with standard microbiologic and molecular methods.

Results

Five of 30 (17%) PIF samples ingested by patients contained clostridial spores. Spores were also found in 7 of 9 (78%) market-purchased PIF samples. Clostridium sporogenes was isolated most frequently, followed by Clostridium butyricum and at least 10 other soil-dwelling clostridial species. No neurotoxigenic clostridia were isolated. The most probable number of clostridial spores in PIF ranged between 1.1 to >23 per 100 g.

Conclusions

With the notable exception of production of botulinum neurotoxin, C sporogenes is physiologically comparable with proteolytic strains of C botulinum, and both share the same natural reservoir (soils and dust worldwide). The isolation of C sporogenes and potentially pathogenic clostridia from U.S.-manufactured PIF suggests that neurotoxigenic clostridial spores have the potential to be present in these products.

Link:  http://www.latimes.com/news/local/la-me-botox3-2010mar03,0,25189.story

LA Times, 3/3/10

An Orange County jury Tuesday declined to hold Botox maker Allergan Inc. liable in the death of a 7-year-old Texas girl being treated for cerebral palsy because it found the company’s warning labels adequate.

The closely watched case is believed to be the first to go to trial over allegations that the botulinum toxin-based drug contributed to a death. At issue was the safety of the blockbuster cosmetic drug in the higher dosages that are used in pediatric cerebral palsy cases and the adequacy of the Irvine manufacturer’s warning labels.

Kristen Spears, who was born with severe cerebral palsy, began receiving large doses of Botox at age 6 in an effort to reduce debilitating limb spasticity. The girl died Nov. 24, 2007, at the age of 7.

Best known as a face-lift-in-a-syringe, Botox can relax contorted muscles and sometimes help young patients walk without surgery. U.S. regulators have not specifically approved the use of Botox in children, but doctors may legally prescribe it as an “off-label” use. Dosages used in such patients are many times those recommended for facial wrinkle injections.

Dee Spears alleged that her daughter died as a result of an overdose of Botox, which led to respiratory failure and pneumonia, and that Allergan failed to adequately warn the girl’s pediatrician of the drug’s risks.

The jury, which deliberated for several hours over two days, did not agree. The panel found that Botox posed risks of “a substantial danger” that “ordinary consumers” would not have recognized, according to the verdict form.

But jurors concluded that Allergan did not breach its duty to warn of those potential risks and therefore could not be held responsible for any potential adverse effect.

In a statement, Allergan said the outcome supported the company’s position that “Botox played no role in the passing of Kristen Spears.

“The evidence presented in this case and acknowledged by the jury showed that Kristen died as a direct result of the progression of her condition, and that any symptoms or issues affecting Kristen’s health were present before Kristen first received treatment with Botox.”

Ray Chester, the lawyer for Dee Spears, said jurors never got to the question of whether Botox played a role in Kristen’s death because they found the company’s warnings adequate.

Chester said the verdict was frustrating because it came months after the U.S. Food and Drug Administration concluded that the Botox label did not reflect its full risk and ordered Allergan to replace it with a “black box” warning of potentially serious reactions.

“We still believe the warning was inadequate, and we will not give up the fight,” said Chester, who is representing plaintiffs in other Botox cases pending against Allergan.

Bryan Liang, executive director of the Institute of Health Law Studies at the California Western School of Law in San Diego, said that although the company may be pleased with the win, the verdict says nothing about whether Botox contributed to Kristen’s death.

Allergan faces another civil trial set for next month in Oklahoma City.

“The ball game isn’t over,” Liang said. “It may be with respect to Dee Spears, but certainly not with respect to Allergan.”

lisa.girion@latimes.com

Copyright © 2010, The Los Angeles Times

Link:  http://inyourface.freedomblogging.com/2010/02/25/jury-weighs-60-millon-in-botox-penalties/15425/

Jury weighs $60 millon in Botox penalties

February 25th, 2010, 5:42 pm

Imposing a $60 million judgment against Botox maker Allergan would “send a message heard around the world” that the company must admit the dangers of the drug, a lawyer suing the company told a Superior Court jury during closing arguments on Thursday.

Allergan’s lawyer responded that the plaintiff’s case was like a “shell game” trying to “dupe” the jury into blaming Allergan for deaths unrelated to Botox that occurred after Botox injections.

“Just because the rooster crows and the sun comes up, that doesn’t mean the rooster caused the sun to come up. That’s the case the plaintiffs put on,” said Vaughn Crawford, representing the Irvine-based company.

The focus of the trial is Kristen Spears, a seven-year-old cerebral palsy patient who died Nov. 24, 2007, in Amarillo, Tex., after receiving seven sets of Botox injections over a 17-month period to ease her leg spasms.

The jury began its deliberations late Thursday.

In the lawsuit, the girl’s mother, Dee Spears, is seeking $20 million in actual damages plus $40 million punitive damages from Allergan.

One of her attorneys, Pat Lochridge, told the jury in the Santa Ana courtroom that Allergan sells more than $1 billion a year of Botox for treatments that have not been approved by the Food and Drug Administration.

Confronted with reports of deaths and illnesses associated with Botox, “Allergan embarked on a path of concealment about the dangers of what they were selling so forcefully on the market,” he said.

Spears has not challenged doctors’ right to prescribe medications such as Botox for uses not approved by the FDA if they believe it’s in a patient’s best interest. Such off-label uses of Botox include all its cosmetic uses except for smoothing wrinkles between the eyebrows, which is the one FDA-approved cosmetic use for Botox.

Ray Chester, the plaintiff’s lead attorney, said Allergan didn’t warn doctors about known dangers of Botox, especially at doses far above what cosmetic doctors inject to smooth wrinkles. He contrasted a confidential Allergan document that said the maximum safe dose of Botox is 8 units per kilogram with Allergan-funded training sessions advocating doses of 15 units per kilogram.

“Why … put it into a confidential document and not tell any doctors in the United States? There’s only one reason I can think of – to protect sales, to protect profits,” he said.

Crawford, the lead lawyer for Allergan, told the jury that Kristen’s fatal pneumonia and respiratory failure were not caused by Botox.

“Sadly,” he said, “that is the natural progression of the disease in severely challenged children.”

He said Allergan couldn’t tell doctors the information about possible risks of non-FDA-authorized uses of Botox. “It would constitute promotion of off-label uses,” he said.

He challenged the credentials of toxicologist Michael Nicar (pictured right), an expert witness with a Ph.D. in environmental science. After studying Kristen’s case, Nicar concluded that she had botulism caused by Botox.

Calling him “non-Doctor Nicar,” Crawford told the jury, “He diagnoses botulism in the courtroom because he can’t diagnose it anywhere else in the world, because it would be illegal. He has no clue.”

Chester said Allergan and doctors who treat cerebral palsy with Botox “prey on the desperation of the parents with children with cerebral palsy. They ignore signs of botulism when it’s right under their nose. They’re blind to it.”

Both sides in the trial discussed a 2007 report to Allergan from the BioSoteria consulting firm, which listed 207 incidents of Botox patients suffering symptoms like those of botulism far from their injection site. Allergan had requested the study, seeking any evidence of Botox spreading in the body. Seven of those 207 incidents were fatalities.

Lochridge noted that the first list was pared down to 25 Botox-related incidents and no deaths for a report Allergan submitted to the FDA.

“When you change reports, that’s deceitful,” he said.

During the trial, BioSoteria founder Sally Van Doren (pictured right) said Allergan asked to eliminate incidents from the 207-item list if the medical problems had plausible causes other than Botox.

Only a few of the incidents involved cosmetic injections of Botox, which have much lower doses than therapeutic treatments such as Kristen’s.

Chester contrasted the size of Allergan’s 300-person sales staff with its three-person department charged with studying epidemiology and safety worldwide

“That tells you where their priorities lie,” he said. “Does anyone think it’s a good idea to sell a lethal neurotoxin on commission?”

Link:  http://www.healthcanal.com/immune-system/5945.html

Strategy proven for botulism; may lead to improved therapies for many toxins and some chronic diseases

North Grafton, Mass., – A study involving the world’s deadliest substance has yielded a new strategy to clear toxins from the body—which may lead to more efficient strategies against toxins that may be used in a bioterrorist event, as well as snake bites, scorpion stings, and even some important chronic diseases.

A Tufts-led team developed the new strategy to deliver small binding agents that seek out Botulinum toxin molecules and bind to them at several points. The binding agents each contain a common “tag” that is recognized by a single, co-administered anti-tag antibody. Once the toxin molecule is surrounded by bound antibodies, it is flushed out of the system through the liver before it can poison the body.

Botulinum toxin, which causes botulism, is the most acutely poisonous substance known and is considered among the most dangerous bioterrorist threats. Studies have shown that one gram of the toxin, which is produced by a bacterium that lives in soil, could kill upwards of a million people. Although currently available antitoxins can be mass produced and delivered in the event of an outbreak, they are costly to develop, house and deliver—and have a short shelf-life.

The Tufts study, in collaboration with researchers at Thomas Jefferson University in Philadelphia, is published this month in the journal Infection and Immunity and was funded by the National Institutes of Allergy and Infectious Diseases (NIAID) and the New England Regional Center for Excellence (NERCE) for Biodefense and Emerging Infectious Diseases.

“We’ve proven this approach to protect against Botulinum intoxication in mice and we hope this will lead to rapid development and deployment of many new anti-toxin therapies—for botulism and beyond,” said Charles B. Shoemaker, PhD, professor of biomedical sciences at Tufts University’s Cummings School of Veterinary Medicine and the study’s corresponding author.

The new findings expand on a 2002 breakthrough at the University of California at San Francisco, where scientists combined three monoclonal antibodies against Botulinum toxin that attached to different parts of the toxin molecule. Including three different antibodies dramatically increased the potency compared to fewer antibodies and prevented intoxication even following high-dose exposure. However, developing, producing, and stockpiling three different monoclonal antibodies against each toxin type is very expensive.

Instead of using three antibodies, the Tufts approach uses three small binding agents to direct a single monoclonal antibody to multiple sites on the biomolecule being targeted for clearance. The type of binding agents used can be selected from many scaffolds developed for commercial therapeutic applications (e.g. nanobodies, aptamers, darpins, FN3, microbodies, etc). These binding agents can be rapidly identified and improved using modern technologies and generally have excellent commercial production and product shelf-life properties. The single anti-tag monoclonal antibody can also be selected to have optimal isotype and commercialization properties.

What’s more, the binding agents can be produced with more than one tag, which enables them to direct more antibodies to the toxin—and synergistically improve target clearance from the body. Many binding agent scaffolds can be produced as functional multimers so that the different binding agents could be produced as “beads on a string,” leading to a single molecule that targets one, or even several, biomolecules for clearance from the body. 

Using this approach, the researchers say, one would only need to create new binding agents, not new antibodies, to create a therapy to clear a toxin from the body—paving the way for new therapies that combat toxins ranging from animal venom to bioterrorist agents such as ricin. Tufts researchers are currently targeting Shiga toxin and C. difficile along with other types of Botulinum toxin. Future plans include targeting clearance of pathogenic cytokines that are implicated in inflammation and autoimmune diseases.

Treatment for botulism usually requires many weeks of intensive-care hospitalization, and exposure of even a small number of people would seriously disrupt health care delivery in any major city, studies have indicated. A vaccine has been developed, but widespread use is not currently being considered, the researchers say, since the likelihood of exposure is uncertain. Also, vaccination would block accepted treatments for a number of overactive muscle conditions, including dystonias, which respond to the toxin when administered in very small doses.

The Division of Infectious Diseases at the Cummings School of Veterinary Medicine is Tufts University’s largest research division. In 2003, the division was awarded a $25-million, seven-year contract from the National Institutes of Health (NIH) to develop products to rapidly identify, prevent, treat, and diagnose food and waterborne diseases that threaten public health. Tufts established one of seven national research units within the new national Food and Waterborne Disease Integrated Research Network. The award also launched the Microbiology and Botulism Research Unit, which combines botulism research efforts from Tufts and other public and private institutions in the U.S. and U.K.

The division also oversees the New England Regional Biosafety Laboratory, a 41,000 square foot, level-2 and level-3 facility dedicated to the study of existing and emerging infectious, diseases, toxin-mediated diseases and medical countermeasures important to biodefense.

Cummings School of Veterinary Medicine at Tufts University

Founded in 1978 in North Grafton, Mass., Cummings School of Veterinary Medicine at Tufts University is internationally esteemed for academic programs that impact society and the practice of veterinary medicine; three hospitals and two clinics that combined treat more than 80,000 animals each year; and groundbreaking research that benefits animal, public, and environmental health.

###

About Tufts University

Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university’s schools is widely encouraged.

Contact:
Thomas Keppeler
508-839-7910
tom.keppeler@tufts.edu

Aboutlawsuits.com, 2/18/10 

Link:  http://www.aboutlawsuits.com/botox-lawsuit-alleges-brain-damage-8140/

A Virginia woman has filed a Botox lawsuit against Allergan, Inc., claiming that injections meant to cure a head tremor caused her to suffer brain injuries, movement disorders and dementia.

The complaint was filed by Cynthia Vandenboom in Richmond City Court, alleging that Allergan failed to warn consumers that Botox side effects can cause serious autoimmune responses, brain injury and botulism. The lawsuit is the latest in a series of claims against Allergan over problems with Botox.

Vandenboom indicates that she was given Botox injections to treat a head tremor. As a side effect of Botox, Vandenboom alleges that she suffered a variety of serious and permanent injuries caused by the injections. She experienced rashes, fever, vomiting, severe pain and confusion shortly after being given the injections. Eventually, she developed autoimmune encephalitis movement disorder, lost some of her cognitive functions and now trouble walking. As a result of the Botox injury, the lawsuit claims that she requires care and help from others to conduct a number of daily activities.

Botox is approved for both cosmetic use to reduce the appearance of wrinkles in the skin and to treat medical conditions such as strabismus (crossed eyes), hyperhidrosis (excess sweating), cervical dystonia (involuntary contractions of the neck muscles) and blepharospasms (involuntary blinking of the eye). However, it also commonly used off-label, such as for treatment of stiff and jerky movements associated with cerebral palsy in children.

Extremely minute quantities of Botulinum Toxin A are contained in Botox, which is the bacteria associated with the muscle paralyzing condition Botulism.

Vandenboom says Allergan should have warned users of the chance that Botox toxin, which the lawsuit describes as being 100 times stronger than cyanide, would migrate outside of the injection area and could cause significant injury. The lawsuit accuses Allergan of product liability, negligence and breach of warranty, and seeks $10 million in compensation and $1 million in punitive damages.

There is currently a Botox trial underway in California, filed on behalf of 15 people who also allege that they suffered severe or fatal side effects from Botox treatments. Among the plaintiffs in the case are the families of two young children who died after Botox injections to treat cerebral palsy.

The FDA warned about potential risks associated with Botox in February 2008, after a number of reports were received involving deaths, breathing problems and other adverse reactions associated with use of Botox. At that time, the FDA indicated that the adverse reactions were most commonly seen among children with cerebral palsy, where the typical dose of Botox injection used is substantially larger than what is normally prescribed for cosmetic purposes.

In August 2009, the FDA announced a new “black box” warning about the risk of Botox problems, including potentially life-threatening botulism-like side effects. The warning now alerts users that the toxin used in Botox and other some other products could spread from the area of the injection to other areas of the body. This could cause botulism symptoms, including life-threatening swallowing and breathing difficulties or death.

Link:  http://stonnington-leader.whereilive.com.au/news/story/feed-ban-to-stop-duck-deaths-in-malvern-east/

Stonnington Leader, 2/16/10: 

DUCK feeding is banned at a Malvern East pond in a bid to prevent another killer outbreak of avian botulism.

At least 18 ducks at Hedgeley Dene Gardens have died from avian botulism this summer.

And a close watch is being kept over new ducks arriving at the suburban sanctuary.

Tanker loads of bore and creek water were brought in to top up water levels and flow in the stagnant pond, after a pump broke in January.

But resident rumours that the pump had broken again were refuted by the council last week.

Stonnington chief executive Warren Roberts said the pump worked on a timer.

The pump’s operating hours were recently increased to combat evaporation caused by hot weather and stop the water stagnating, Mr Roberts said.

“(And) signs have been erected asking people not to feed the ducks, as excess food can have a detrimental effect on the water quality,” he said.

Botulism is caused by bacterial spores, which naturally occur in wetland areas.

New ducks have arrived at the pond since the outbreak.

The council said that the most practical method to break the cycle was to remove the ill and dead ducks. Wildlife authorities have been notified and the council continues to monitor the pond.

Link:  http://www.theepochtimes.com/n2/content/view/29729/

The Epoch Times, 2/15/10:  The Defense Threat Reduction Agency of the Department of Defense (DoD) has awarded the Institute of Chemical Biology and Drug Discovery at Stony Brook University, New York $1.4 million in grant money to find an antidote or cure for botulism. The goal of the research is to develop a drug that will be effective against different strains of botulism. The fear is that botulism, or rather the toxins that cause botulism, could be used as biological weapons by terrorists or other threats in the near future. The project is called the Structure-Based Discovery of Pan-Active Botulinum Neurotoxin Inhibitors. These neurotoxins (toxins that affect the nervous and muscular systems) that cause botulism are some of the most potent known to science. However, the toxins are very rare, especially in modern times in first world civilizations. The defense department believes these toxins could be used as weapons, so the time for an equally potent antidote is nigh.