Patients with curable early-stage breast cancer died from chemotherapy solvent
A chemotherapy drug that is supposed to help save cancer patients’ lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A new study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA’s Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent – a derivative of castor oil — that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern’s Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

“The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them,” Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

“The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment,” said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

“Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication,” Bennett said. “Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor.”

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

“The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent,” said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.

Reference: Northwestern University, Common chemotherapy drug triggers fatal allergic reactions, Press Release, 8-Jun-2009

Letter from Martin L. Pall, Saturday 6th June 2009:

I was delighted when I was asked by the three editors of the future publication, “General and Applied Toxicology, 3rd Edition” (John Wiley and Sons) to write a review on multiple chemical sensitivity (MCS) for this prestigious multivolume set. MCS, as I am sure you know, has been largely ignored by toxicologists in general and I was delighted that these three prominent scientists, all of whom had extensive published research on the actions of chemicals implicated in MCS, asked me to write such an article. This was important recognition not only for my own work on MCS but also that MCS is now recognized as a toxicological phenomenon.

The paper, entitled Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms is the most extensively documented publication on MCS, and will be a 54 page chapter in this multivolume set. While the majority of this paper comes from my earlier publications on MCS, it also contains several very important sections that are largely novel.

1. There are seven classes of chemicals implicated in MCS and all seven of these can indirectly produce a common response in the body, increased NMDA activity. Furthermore, animal studies have shown that members of all seven of these classes of chemicals can have their toxic responses lowered by using an NMDA antagonist. This clearly demonstrates not only that they produce such increased NMDA activity but those increases play an important role in producing the toxic responses to these chemicals. Given that we previously had six types of evidence implicating excessive NMDA activity in MCS, we now have compelling evidence that this common response plays a key role in MCS.

2. The role of these chemicals acting as toxicants in MCS has been confirmed by four genetic studies, showing that genes that determine the rate of metabolism of these chemicals, influence susceptibility to MCS (only three were available when the review was written). These studies implicate six genes as determining such susceptibility, all of which have roles in the metabolism of chemicals otherwise implicated in initiating cases of MCS. It follows that the roles of chemicals in initiating cases of MCS is undeniable.

3. There have been a series of published studies reporting objectively measurable responses to low level chemical exposure among MCS cases that are distinct from any responses in normals. At least three of these should be practical specific biomarker tests that can be applied in clinical settings. All of these studies are consistent with the NO/ONOO- cycle mechanism as it is thought to play out in MCS and all provide, therefore, evidence supporting this mechanism. We have been in great need for such specific biomarker tests for MCS and these and other approaches to developing such tests must be further studied and may provide recognized specific biomarker tests in the near future, in my judgment.

4. All except one of the elements of the NO/ONOO- cycle as it is thought to play out in MCS have been studied in animal models and all elements studied are implicated in these animal models. It follows that one can make a strong case for a NO/ONOO- cycle mechanism based on animal model studies alone.

5. The paper finishes with a list of five areas of future research which are in most need of further study, in my judgment.

We do have observational evidence that a protocol based on down-regulating the NO/ONOO- cycle mechanism is helpful in the treatment of most cases of MCS as well as most cases of ME/CFS and most cases of fibromyalgia. However, at this point this treatment fails to produce any substantial number of cures and seems to be quite variable in the extent of improvements apparently produced by it. Nevertheless, this approach does produce substantial apparent improvements in many people who have been ill for one, two or more decades. It is my hope that we will be able to add a second phase to such treatment that may start to produce at least some such cures, but that is a hope at this point.

Autor: Martin L. Pall, Professor Emeritus of Biochemistry and  Basic Medical Sciences, Saturday 6th June 2009

(Letter reprinted by CSN with personal permission)

Paris, France – June 04, 2009 – The cause of Parkinson’s disease (PD), the second most frequent neurodegenerative disease after Alzheimer’s disease, is unknown, but in most cases it is believed to involve a combination of environmental risk factors and genetic susceptibility. Laboratory studies in rats have shown that injecting the insecticide rotenone leads to an animal model of PD and several epidemiological studies have shown an association between pesticides and PD, but most have not identified specific pesticides or studied the amount of exposure relating to the association.  

A new epidemiological study involving the exposure of French farm workers to pesticides found that professional exposure is associated with PD, especially for organochlorine insecticides. The study is published in Annals of Neurology, the official journal of the American Neurological Association.  

Led by Alexis Elbaz M.D., Ph.D., of Inserm, the national French institute for health research in Paris, and University Pierre et Marie Curie (UPMC, Paris 6), the study involved individuals affiliated with the French health insurance organization for agricultural workers who were frequently exposed to pesticides in the course of their work. Occupational health physicians constructed a detailed lifetime exposure history to pesticides by interviewing participants, visiting farms, and collecting a large amount of data on pesticide exposure. These included farm size, type of crops, animal breeding, which pesticides were used, time period of use, frequency and duration of exposure per year, and spraying method. 

The study found that PD patients had been exposed to pesticides through their work more frequently and for a greater number of years/hours than those without PD. Among the three main classes of pesticides (insecticides, herbicides, fungicides), researchers found the largest difference for insecticides: men who had used insecticides had a two-fold increase in the risk of PD. 

“Our findings support the hypothesis that environmental risk factors such as professional pesticide exposure may lead to neurodegeneration,” notes Dr. Elbaz.  

The study highlights the need to educate workers applying pesticides as to how these products should be used and the importance of promoting and encouraging the use of protective devices. In addition to the significance of the study for those with a high level of exposure to pesticides, it also raises the question about the role of lower-level environmental exposure through air, water and food, and additional studies are needed to address this question.  

Reference: Alexis Elbaz, Jacqueline Clavel, Paul J. Rathouz, PhD 6, Frédéric Moisan Jean-Philippe Galanaud, Bernard Delemotte, Annick Alpérovitch, Christophe Tzourio, Professional exposure to pesticides and Parkinson’s disease, Annals of Neurology, Press Release Wiley Blackwell, June 4, 2009

Pyrethrin and Pyrethroide insecticides are commonly applied in homes and businesses and on some agricultural crops. This research used a two-state regional approach to analyze reports of acute pesticide poisonings due to Pyrethrin and Pyrethroide insecticides.  

The Washington State Department of Health and the Oregon Public Health Division collected pesticide poisoning surveillance data from 2001 through 2005. Cases were included if they involved exposure to at least one Pyrethrin or Pyrethroide insecticide. Descriptive statistics were calculated; differences between categories were assessed using Chi-square analysis.  

A total of 407 cases fit our definition. Overall, the rate of poisoning in Oregon was significantly higher than in Washington (incidence rate ratio 1.70, 95% confidence interval 1.40, 2.07), and rates for both states generally increased during the time period. For both states, most exposures resulted in low severity illnesses (92%), and most were classified as possible cases (73%). Only about one-fourth of cases were related to a person’s work. The most common category of clinical signs and symptoms of illness was respiratory (52% of cases), followed by neurological (40% of cases). Exposure route was predominantly inhalation; there was no association between route and case severity. There was a significant association between illness severity and losing time from work or regular activities (p<0.0001).  

Although the majority of Pyrethrin and Pyrethroide poisoning cases were low in severity, adverse reactions have occurred, as transpired in Oregon in 2005. Regional analysis has the potential to improve the surveillance system and provide unique opportunities for targeting preventive interventions. 

Reference:

Walters JK, Boswell LE, Green MK, Heumann MA, Karam LE, Morrissey BF, Waltz JE., Pyrethrin and Pyrethroide illnesses in the Pacific Northwest: a five-year review, Oregon Department of Human Services, Public Health Division, Office of Environmental Public Health, Toxicology, Assessment, & Tracking Services, Oregon Worker Illness and Injury Prevention Program, Portland, OR 97232, USA, Public Health Rep. 2009 Jan-Feb;124(1):149-59.

Researchers at the Johns Hopkins University School of Medicine have found that a chemical commonly used in the production of such medical plastic devices as intravenous (IV) bags and catheters can impair heart function in rats. Reporting online this week in the American Journal of Physiology, these new findings suggest a possible new reason for some of the common side effects—loss of taste, short term memory loss–of medical procedures that require blood to be circulated through plastic tubing outside the body, such as heart bypass surgery or kidney dialysis. These new findings also have strong implications for the future of medical plastics manufacturing.

In addition to loss of taste and memory, coronary bypass patients often complain of swelling and fatigue. These usually resolve within a few months after surgery, but they are troubling, sometimes hinder recovery, but generally go away.

His personal experience with coronary bypass surgery propelled his search for a root cause for the loss of taste phenomenon, reports principal investigator Artin Shoukas, Ph.D., professor of biomedical engineering, physiology and anesthesiology and critical care medicine at Johns Hopkins. “I’m a chocoholic, and after my bypass surgery everything tasted awful, and chocolate tasted like charcoal for months.”

Shoukas and Caitlin Thompson-Torgerson, PhD, a postdoctoral fellow in anesthesiology and critical care medicine suspected the trigger for these side effects might be a chemical compound of some kind.

To test their theory, Shoukas and his team of researchers took liquid samples from IV bags and bypass machines before they were used on patients. The team analyzed the fluids in another machine that can identify unknown chemicals and found the liquid to contain a chemical compound called cyclohexanone. The researchers thought that the cyclohexanone in the fluid samples might have leached from the plastic. Although the amount of cyclohexanone leaching from these devices varied greatly, all fluid samples contained at least some detectable level of the chemical.

The researchers then injected rats with either a salt solution or a salt solution containing cyclohexanone and measured heart function. Rats that got only salt solution pumped approximately 200 microliters of blood per heartbeat and had an average heart rate of 358 beats per minute, while rats injected with cyclohexanone pumped only about 150 microliters of blood per heartbeat with an average heart rate of 287 beats per minute.

In addition to pumping less blood more slowly, rats injected with cyclohexanone had weaker heart contractions. The team calculated that cyclohexanone caused a 50 percent reduction in the strength of each heart contraction. They also found that the reflex that helps control and maintain blood pressure is much less sensitive after cyclohexanone exposure. Finally, the team observed increased fluid retention and swelling in the rats after cyclohexanone injections.

According to Thompson-Torgerson and Shoukas, they would like to figure out how these side effects—decreased heart function and swelling—occur and to what degree cyclohexanone is involved. Despite the findings in this study, they emphasize that patients should listen carefully to the advice of their physicians. “We would never recommend that patients decline this type of treatment if they need it,” says Shoukas. “On the contrary, such technologies are life-saving medical advances, and their benefits still far outweigh the risks of the associated side effects. As scientists, we are simply trying to understand how the side effects are triggered and what the best method will be to mitigate, and ultimately remedy, these morbidities.”

Authors on the paper are Caitlin S. Thompson-Torgerson, Hunter C. Champion, Lakshmi Santhanam, Z. Leah Harris and Artin A. Shoukas, all of Johns Hopkins University School of Medicine.

Reference:
Johns Hopkins, Chemical found in medical devices impairs heart function, Press Release, May 1, 2009