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)

To determine which topical pharmaceutical products marketed in Belgium contain fragrances and to examine the nature of the fragrance allergens in specific pharmaceutical products having caused iatrogenic contact dermatitis.  

All topical pharmaceutical products marketed in Belgium, which is 3820 products, were examined as to their fragrance content as labelled. Data of 18, 960 patients investigated for contact allergy between 1978 and 2008 were retrieved from our database, including information on the nature of the topical pharmaceutical products used, the results of patch tests, and the sensitization sources.  

Three hundred and seventy (10%) of 3280 of the topical pharmaceutical products were found to contain a total of 66 fragrance substances. Among 3378 patients suffering from iatrogenic allergic contact dermatitis, 127 were found to react to 48 specific products, for which 38 different fragrance substances gave relevant positive reactions. Women were more affected than men, and legs, hands, and face were the most commonly affected body sites.  

Fragrances, the presence of which is in most cases unnecessary, do contribute to iatrogenic allergic contact dermatitis. Moreover, sensitized patients have difficulties in avoiding their specific allergens because standardized labelling of the ingredients in pharmaceutical products is lacking. 

Reference: Nardelli A, D’Hooghe E, Drieghe J, Dooms M, Goossens A., Allergic contact dermatitis from fragrance components in specific topical pharmaceutical products in Belgium, Department of Dermatology, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium, Contact Dermatitis. 2009 Jun; 60(6):303-13.

The repetitive behaviors exhibited by some children and teens with autism spectrum disorders are not reduced with the antidepressant citalopram, according to a study in the June issue of Archives of General Psychiatry, one of the JAMA/Archives journals. Lawrence Scahill, professor at Yale University School of Nursing and the Child Study Center was the principal investigator at Yale for the multi-center study. Yale Child Study Center Director Fred R. Volkmar, M.D., authored an accompanying editorial.

Repetitive behaviors in children with autism – including inflexible routines and repetitive play – tend to persist over time and often interfere with everyday life. The United States Food and Drug Administration has not approved any drugs to treat the core symptoms of autism and related disorders, but medications like citalopram are increasingly being used in these populations, the authors write.

Citalopram is in the class of antidepressants called selective serotonin reuptake inhibitors (SSRIs), which alter how the brain regulates the neurotransmitter serotonin. Scahill said that citalopram has been prescribed because of similarities between the repetitive behavior of autism spectrum disorders and that of obsessive-compulsive disorder. There is also some evidence suggesting that there may be abnormalities of the serotonin system in autism. Because the SSRIs work for adults and children with obsessive-compulsive disorder, he noted, some believed it could also be adapted for use in children with autism.

“Despite the limited evidence supporting their use in children with autism, SSRIs are among the most frequently used medications in this population. This is due in part because of their perceived safety,” said Scahill.

Scahill, along with colleagues at various institutions conducted a randomized controlled trial to determine the safety and efficacy of citalopram in children with autism spectrum disorders who had at least moderate levels of repetitive behavior. Of 149 children age 5 to 17 who participated, 73 were randomly assigned to receive citalopram and 76 received a placebo for 12 weeks.

At the end of the treatment period, there were no differences between the citalopram group and the placebo group in percentage of children showing overall improvement or on scales measuring repetitive behavior. Indeed, noted the researchers, citalopram was more likely than placebo to be associated with adverse events, such as hyperactivity, insomnia, impulsiveness, decreased concentration, stereotypy (abnormal repetitive movements), diarrhea and dry skin.

“These results highlight the importance of placebo-controlled trials of medications commonly used for children with autism spectrum disorders to determine whether risks of medications outweigh benefits,” said Scahill.

In the accompanying editorial on the study, Yale Child Study Center Director Fred R. Volkmar, M.D., said the data might change the practice of prescribing SSRIs to children with autism.

“Previous double-blind, placebo-controlled studies with SSRIs in adults with autism showed a reduction in levels of repetitive behaviors,” Volkmar writes. “Given the frequency of such behaviors in children with autism and their association with other features such as anxiety, depression and rigidity, selective serotonin reuptake inhibitors would seem to have, at the least in theory, some therapeutic potential.”

Volkmar added, “Although the findings in the study were negative, the results are not difficult to interpret. The medication does not appear to be useful for repetitive behaviors in children with autism and related conditions. We need more studies of this kind to advance research and guide clinical practice.”

The National Institutes of Health via STAART center contracts funded the study. The work was also funded in part by a Clinical and Translational Science Award (CTSA) from the National Center for Research Resources at the National Institutes of Health.

Other authors on the study include first author Bryan H. King, M.D., Eric Hollander, M.D., Linmarie Sikich, M.D., James T. McCracken, M.D., Joel D. Bregman, M.D., Craig L. Donnelly, M.D., Evdokia Anagnostou, M.D., Kimberly Dukes, Lisa Sullivan, Deborah Hirtz, M.D, Ann Wagner, and Louise Ritz.

Citation: Arch Gen Psychiatry Vol. 66 (no. 6) 492 (June 2009).

Reference: Yale, Antidepressants Offer No Relief for Repetitive Behaviors in Children with Autism, Press Release, June 1. 2009

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