Induce Hypersensitivity Reactions Research Articles

SEVERE HYPERSENSITIVITY TO ANTIEPILEPTIC DRUGS: BRITISH NEUROLOGICAL SURVEILLANCE UNIT (BNSU)

Hypersensitivity reactions account for 2–6% of all hospital admissions. Severe hypersensitivity reactions such as hypersensitivity syndrome (HSS), acute generalised exanthematous pustulosis (AGEP), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)...

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Candida is a common commensal of mucous membrane, skin and gastrointestinal tract, which can become pathogen in mucosal surface in patients consuming long duration corticosteroids, antibiotics, diabetes mellitus, pregnancy, oral contraceptive pills, Cushing's disease and debilitated conditions like HIV. Candida albicans (C. albicans) is the commonest opportunistic infection of the oral cavity. The three broad group of mucosal candida are: (a) acute candidiasis, (b) chronic candidiasis, and (c) angular cheilitis. It is believed that, the different clinical types depend on the breakdown of the local immune response and ability to induce hypersensitivity reaction against the Candida antigens. The fungus also produces extracellular proteinases, which are significantly differing within and between species and thereby play role in the genesis of the different clinical variants. We report a case of C. albicans in a known diabetes patient, presenting as painful erosions on the tongue, angle of mouth and retrosternal pain. KOH examination of scraping and culture for fungus from the scraping showed fungal hyphae. The treatment with fluconazole 100 mg daily showed significant response on the 3 rd day of treatment. The purpose of our presentation of the present case is that, the prolonged diabetes may cause impaired immunity that could change the morphological presentation of oral candida. So, there is a need for all physicians to be aware of the uncommon presentation of C. albicans in immunocompromised cases.

Immediate-type hypersensitivity reactions to proton pump inhibitors: usefulness of skin tests in the diagnosis and assessment of cross-reactivity

Data are limited about the value of skin tests in the diagnosis of proton pump inhibitor (PPI)-induced hypersensitivity reactions and the cross-reactivity between PPIs. We aimed to assess the role of skin testing in the diagnosis of PPI-related immediate hypersensitivity reactions and the cross-reactivity patterns among PPIs. The study was designed in a prospective, national, multicentre nature. Sixty-five patients with a suggestive history of a PPI-induced immediate hypersensitivity reaction and 30 control subjects were included. Standardized skin prick and intradermal tests were carried out with a panel of PPIs. Single-blind, placebo-controlled oral provocation tests (OPTs) with the PPIs other than the culprit PPI that displayed negative results in skin tests (n = 61) and diagnostic OPTs with the suspected PPI (n = 12) were performed. The suspected PPIs were lansoprazole (n = 52), esomeprazole (n = 11), pantoprazole (n = 9), rabeprazole (n = 2), and omeprazole (n = 1). The sensitivity, specificity, and negative and positive predictive values of the skin tests with PPIs were 58.8%, 100%, 70.8%, and 100%, respectively. Fifteen of the 31 patients with a hypersensitivity reaction to lansoprazole had a positive OPT or skin test result with at least one of the alternative PPIs (8/52 pantoprazole, 6/52 omeprazole, 5/52 esomeprazole, 3/52 rabeprazole). Considering the high specificity, skin testing seems to be a useful method for the diagnosis of immediate-type hypersensitivity reactions to PPIs and for the evaluation of cross-reactivity among PPIs. However, OPT should be performed in case of negativity on skin tests.

Metal hypersensitivity and metal ion levels in patients with coated or uncoated total knee arthroplasty: a randomised controlled study.

Metal ion release by orthopaedic implants may cause local and systemic effects and induce hypersensitivity reactions. Coated implants have been developed to prevent or reduce these effects. This study was initiated to investigate the safety of a novel coating for total knee arthroplasty (TKA) implants. A total of 120 patients undergoing primary TKA with no history of hypersensitivity and no other metal implant were randomised to receive either a coated or uncoated implant. Chromium (Cr), cobalt (Co), molybdenum (Mb) and nickel (Ni) hypersensitivity patch testing and plasma ion concentrations were evaluated pre-operatively and one year post-operatively. At the one year follow-up both groups demonstrated significant improvement in knee function and quality of life. One new weakly positive reaction to Co in the TKA group with coated implant and two doubtful skin reactions to Ni (one in each group) were noted. Even with sensitisation to implant materials no skin reactions were observed. Plasma metal ion concentrations did not increase and were not elevated at the one year follow-up in either group. Sensitisation after TKA was rare and had no influence on clinical results. TKA with coated implant and standard TKA demonstrated no plasma metal ion elevation.

Safety of using anti-TNF-α blockers in cardiac failure associated with systemic inflammatory disease and the risk of Kounis syndrome

Tumor necrosis factor (TNF-α) is a multifunctional cytokine that plays an important role in inflammation and immunity, as well as in the control of cell proliferation, differentiation and apoptosis. In the paper published in Int J Cardiol [1] and dealing with the safety of using anti-TNF-α blockers for systemic inflammatory disease the authors wisely wondered if it is safe to use TNF-α blockers for systemic inflammatory disease especially for rheumatoid arthritis with concomitant cardiac failure. Current guidelines, suggest that anti TNF-a therapy for rheumatoid arthritis associated with mild cardiac failure should be given with extreme caution, while higher doses should be avoided in all patients with a NYHA III and IV class [2]. It has been speculated that anti TNF-a therapy could induce cardiac toxicity [1]. In clinical practice there are five TNF-α blockers used for the treatment of inflammatory diseases: one fusion proteinmimicking the TNF receptor 2, the etanercept and four anti TNF-α chimeric monoclonal antibodies namely infliximab, adalimumab, golimumab and certolizumab. Other chimeric antibodies such as cetuximab and panitumumab targeting epidermal growth factor receptor are effective in treatment of metastatic colorectal cancer. Several clinical studies have shown the participation of proinflammatory cytokines in the pathogenesis of cardiac diseases [3]. The levels of circulating proinflammatory cytokines TNF-α and IL-1 and -6 are elevated in patients with myocarditis associated with or no heart failure [4, 5]. One, therefore, could expect that anti-TNF-α therapy would be beneficial for treating such conditions. However, in the antiTNF Therapy Against Congestive Heart Failure (ATTACH) trial [6] 10 mg/kg of infliximab deteriorated cardiac function while 5 mg/kg had no different effect than placebo. Infliximab is a genetically produced chimeric monoclonal antibody against TNF-a, which is widely used for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and systemic vasculitis. It consists of 25% murine sequences in the variable region of antibody and some patients have developed antichimeric antibodies against infliximab [7]. Indeed, such antichimeric antibodies have been found in 14.5– 17.1% of patients with Crohn's disease. In a recent study [7], including patients with rheumatoid arthritis, systemic vasculitis and spondylarthropathies, 11 out of 71 patients, receiving infliximab, developed hypersensitivity reactions such as urticaria, chest tightness, vomiting and oxygen desaturation. These patients had IgE, IgM and IgG antibodies against infliximab detectable in their serum. The antibodies were detected in the sera collected before the 2nd and the 3rd infliximab infusion, and their appearance was strictly related to the timing of the reaction. Furthermore, in rheumatoid arthritis, important effector cells such as mast cells, macrophages and few eosinophils have been found in inflamed rheumatoid synovial tissue and sites of cartilage. Such findings are at variance with those in allergic inflammation, in which the presence of inflammatory cells has been reported to be regulated by specific chemokines and adhesion molecules. Therefore an association with Kounis syndrome [8] cannot be excluded. The medical literature is replete with a variety of early or delayed hypersensitivity reactions that are associated with anti TNF-a therapy; some of which could be dangerous. Such reactions associated with the use of infliximab include [9]: anaphylaxis, atopic dermatitis, acne, allergic contact dermatitis, allergic pulmonary aspergillosis, alopecia areata, atopic dermatitis, cutaneous vasculitis, eruption, erythema nodosum, eczematoid eruption, eczematoid dermatitis, eczematiclike purpura of Doukas–Kapetanakis, granuloma annulare, lichen planus, necrotizing fasciitis, niacin-like reaction, nummular eczema, psoriasiform eruption, pustular eruption, redman syndrome (striking, “glowing” red discoloration of the skin), serum sickness, urticarial rash and urticarial vasculitis. Type I variant of Kounis syndrome has been also described [10]. Therefore, one should be always bring in mind that monoclonal chimeric antibodies used for treatment of inflammatory diseases can lead to the production of antichimeric antibodies, induce hypersensitivity reaction and worsen overt or incipient cardiac failure. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

Successful desensitization for vancomycin hypersensitivity

Vancomycin frequently induces hypersensitivity reactions including red man syndrome (RMS) and anaphylaxis. Lowering infusion rate with antihistamine premedication is usually effective to reduce RMS, however, desensitization should be considered for severe reactions not responding to usual measures. Here, we report a case of a patient with pyogenic spondylitis who had developed hypersensitivity reaction to vancomycin, got a full recovery with vancomycin desensitization. A 63-year-old man was transferred to our hospital for back pain, proved to pyogenic spondylitis. As methicillin-resistant Staphylococci aureus infection was suspected, vancomycin was administrated. But, he showed hypersensitivity reactions such as hypotension, dyspnea and severe flushing after vancomycin administration at previous hospital. Readministration of vancomycin at a lower infusion rate with premedication was tried. Three hours after vancomycin infusion, he developed fever, chills, rash and hypotension. Thrombocytopenia was occurred after administration of other antibiotics including cefazolin and teicoplanin. Vancomycin administration was attempted according to a rapid desensitization protocol. The infusion rate of vancomycin was increased to the standard rate. After the desensitization, he successfully completed the full course of treatment with vancomycin. Vancomycin desensitization could be the option for the vancomycin hypersensitivity when other antibiotics are not feasible. (�������� ������ ������ ������������������

Implementation of guidelines, allergy programs, and the October issue

As the prevalence of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis increased worldwide, the role of not only allergy specialists but also general practitioners has become more important. During past years, international guidelines and consensus statement on allergic diseases have been developed. However, there is still huge gap between recommendations from guidelines and real practice. This issue of Asia Pacific Allergy features important issue on the management of allergic rhinitis in general practitioners by Wang [1]. The author describes that allergic rhinitis is one of the top-ten reasons for a visit to the primary care clinics and that allergic rhinitis was estimated to be 10-40% of the total patient visits in about 50% of the primary care clinics. Thus implementation of guidelines in general practitioners is essential for the standard management. For the successful implementation of guidelines, internal barriers such as doctor's prescription habits and preference and external barriers such as health insurance policy should be analyzed [2]. We have to find a way to overcome these barriers. In the same issue, Haahtela et al. [3] described the Finnish Allergy Program 2008-2018 and the scientific rationale and practical implementation. The 10-year implementation program is aimed to reduce burden of allergies both at the individual and societal levels. As an outcome, not only the awareness of healthcare professionals and allergic patients improved, but also emergency visits and hospital days caused by asthma are in steady decline (54% during the last 10 years). The authors suggest that networking of allergy experts with primary care doctors and nurses as well with pharmacists is the key for effective implementation. In Asia Pacific region, many countries such as Australia and Korea also run government-supported Allergy Programs [4]. It will be worthy to compare Allergy Programs from each country and to organize international network for Allergy Programs. Readers of this journal will also find a review article on eosinophilic esophagitis whose prevalence is increasing in both adult and children. Ridolo et al. [5] address the possible role of food and inhalant allergens in eosinophilic esophagitis. Radiocontrast media is a major cause of drug induced hypersensitivity reactions whose incidence is 3.8 to 12.7% (severe reactions: 0.1-0.4%) for hyperosmolar ionic contrast and 0.7 to 3.1% (severe reactions: 0.02-0.04%) for low-osmolar ionic contrast [6]. Ho et al. [7] reported the immediate hypersensitivity reactions to IV non-ionic iodinated contrast in computed tomography from Australia in this issue including a seasonal variation in the incidence. Readers will find original articles on differences in airway inflammation according to atopic status in patients with chronic rhinitis [8], the effect of interferon-alpha on airway eosinophila and hyperresponsiveness in a guinea pig asthma model [9], and contribution of serum IL-4 and IgE to the early prediction of horse serum allergies in guinea pigs [10]. Readers may have an idea how to tell the patients of atopic dermatitis about the effect of bathing during summer season [11]. This issue contains an interesting case report of biphasic anaphylaxis to gemifloxacin [12]. The prevalence of biphasic anaphylaxis is about 2.2-23% [13-15]. Intramuscular injection of epinephrine is the treatment of choice for anaphylaxis. Even anaphylaxis resolved immediately after epinephrine administration, it is recommended to observe patients for several hours for possible biphasic anaphylaxis. For example, patients with moderate respiratory or cardiovascular compromise should be monitored for at least 4 hours, and if indicated, for 8-10 hours or longer, and patients with severe or protracted anaphylaxis might require monitoring and interventions for days [15].

Occupational Exposure to Aspergillus by Swine and Poultry Farm Workers in Portugal

Aspergillus is among a growing list of allergens that aggravate asthmatic responses. Significant pulmonary pathology is associated with Aspergillus-induced allergic and asthmatic lung disease. Environments with high levels of exposure to fungi are found in animal production facilities such as for swine and poultry, and farmers working with these are at increased risk for occupational respiratory diseases. Seven Portuguese poultry and seven swine farms were analyzed in order to estimate the prevalence, amount, and distribution of Aspergillus species, as well as to determine the presence of clinical symptoms associated with asthma and other allergy diseases in these highly contaminated settings. From the collected fungal isolates (699), an average incidence of 22% Aspergillus was detected in poultry farms, while the prevalence at swine farms was 14%. The most frequently isolated Aspergillus species were A. versicolor, A. flavus, and A. fumigatus. In poultry farms, A. flavus presented the highest level of airborne spores (>2000 CFU/m3), whereas in swine farms the highest was A. versicolor, with an incidence fourfold greater higher than the other mentioned species. Eighty workers in these settings were analyzed, ranging in age from 17 to 93 yr. The potentially hazardous exposure of poultry workers to mold allergens using sensitization markers was evaluated. Although no significant positive association was found between fungal contamination and sensitization to fungal antigens, a high incidence of respiratory symptoms in professionals without asthma was observed, namely, wheezing associated with dyspnea (23.8%) and dyspnea after strenuous activities (12.3%), suggesting underdiagnosed respiratory disturbances. Further, 32.5% of all exposed workers noted an improvement of respiratory ability during resting and holidays. From all the analyzed workers, seven were previously diagnosed with asthma and four reported the first attack after the age of 40 yr, which may be associated with their occupational exposure. Some of the fungi, namely, the Aspergillus species detected in this study, are known to induce hypersensitivity reactions in humans. This study confirmed the presence and distribution of Aspergillus in Portuguese poultry and swine farms, suggesting a possible occupational health problem and raising the need for preventive and protective measures to apply to avoid exposure in both occupational settings.

Ferumoxytol: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud?

Intravenous iron therapy is pivotal in the treatment of anemia of chronic kidney disease to optimize the response of hemoglobin to erythropoiesis-stimulating agents. Intravenous iron use in patients with chronic kidney disease is on the rise. Recent clinical trial data prompting safety concerns regarding the use of erythropoiesis-stimulating agents has stimulated new US Food and Drug Administration label changes and restrictions for these agents, and has encouraged more aggressive use of intravenous iron. The currently available intravenous iron products differ with regard to the stability of the iron-carbohydrate complex and potential to induce hypersensitivity reactions. Ferumoxytol is a newer large molecular weight intravenous iron formulation that is a colloidal iron oxide nanoparticle suspension coated with polyglucose sorbitol carboxymethyl ether. Ferumoxytol has robust iron-carbohydrate complex stability with minimal dissociation or appearance of free iron in the serum, allowing the drug to be given in relatively large doses with a rapid rate of administration. Clinical trials have demonstrated the superior efficacy of ferumoxytol versus oral iron with minimal adverse effects. However, recent postmarketing data have demonstrated a risk of hypersensitivity that has prompted new changes to the product information mandated by the Food and Drug Administration. Additionally, the long-term safety of this agent has not been evaluated, and its place in the treatment of anemia of chronic kidney disease has not been fully elucidated.

A regimen of weekly nab-paclitaxel with weekly carboplatin in recurrent ovarian cancer: A retrospective analysis.

e15516 Background: The standard of care for patients with recurrent platinum resistant ovarian cancer is treatment with non cross-resistant drugs. Carboplatin retreatment is usually not an option in the platinum resistant population. Weekly paclitaxel has been tried in recurrent patients. But paclitaxel can cause hypersensitivity reactions due to its Cremophor based solvent. nab-paclitaxel being a nano-particle albumin bound paclitaxel is devoid of this toxictity. Also, it is thought that nab-paclitaxel may have a higher intratumoral uptake leading to enhanced anti-tumor action. We looked at a regimen using weekly carboplatin with weekly nab-paclitaxel in platinum resistantrelapsed carcinoma ovary who had failed multiple lines of treatment. Methods: We treated 10 patients with recurrent platinum resistant ovarian cancer with measurable disease with nab-paclitaxel 100mg/m2 on days 1,8,15 with carboplatin at AUC 1.5 on days 1,8,15 intravenously, repeated every 28 days for 4 cycles. All patients had received 3 or more lines of chemotherapy for recurrent disease. We looked for response rate, progression free survival and toxicities. Results: Three patients had complete response, 5 patients had partial response and 2 patients had disease progression. Median PFS was 6 months. There were no instances of paclitaxel induced hypersensitivity reactions. Two patients developed grade 3 neutropenia. One patient developed grade 3 thrombocytopenia. Three patients required blood transfusions. One patient developed grade 3 neuropathy. Conclusions: Weekly combination of nab-paclitaxel with weekly carboplatin is a safe and potentially active treatment in recurrent platinum resistant ovarian cancers who had failed multiple lines of treatment. Considering the efficacy and favorable toxicity profile, this weekly combination needs to be tested in a larger number of patients.

34 Immunologic Evaluation of the Patients With Ranitidine Anaphylaxis

BackgroundThere have been a few reports of hypersensitivity reactions to Ranitidine and cross-reactivities between H2-receptor antagonists. The pathogenic mechanisms of H2 receptor antagonist induced hypersensitivity reactions are not understood. The purpose of this study was to observe the clinical characteristics of the patients with Ranitidine anaphylaxis and investigate the pathogenic mechanisms with detection of serum specific IgE antibody to Ranitidine-HSA conjugate.MethodsTen patients with anaphylaxis to Ranitidine were enrolled from Ajou University Hospital and Seoul National University Bundang Hospital. Skin prick test (SPT) using Ranitidine extract were performed in 7 patients. Serum specific IgE and G1 antibodies were detected by ELISA using Ranitidine-HSA conjugate. The study subjects were divided into 2 groups according to the presence of serum specific IgE antibody to Ranitidine-HSA conjugate: 3 subjects had high serum specific IgE (Group I) and 7 subjects showed negative results (Group II), when positive cut off value was determined from mean + 3 SD of absorbance values of healthy controls.ResultsSix (60%) were female and 9 (90%) were atopics. 6 (86%) patients had positive responses to ranitidine on SPT, however, high serum specific IgE to Ranitidine-HSA conjugate was detected in only 3 patients (30%), while serum specific IgG1 was detectable in one patient (10%). There were no significant differences in clinical characteristics including age, sex, atopy and serum total IgE level between group I and II.ConclusionsWe confirmed the presence of serum specific IgE to Ranitidine-HSA conjugate by ELISA, suggesting that IgE mediated response is a major pathogenic mechanism of Ranitidine induced anaphylaxis. Further studies will be needed to investigate other immunologic and non-immunologic mechanisms and cross-reactivity among other H2 receptor antagonists.

Chickpea (Cicer arietinum) proteins induce allergic responses in nasobronchial allergic patients and BALB/c mice

Allergy to chickpea or Garbanzo bean (Cicer arietinum) has been reported in the Indian population. Little information is found regarding allergenic events involved in the chickpea allergy; therefore, chickpea allergenicity assessment was undertaken. In vivo and ex vivo studies were carried out using BALB/c mice. Chickpea skin prick test positive patients have been used to extend this study in humans. Identification of allergens was carried out by simulated gastric fluids assay for pepsin resistant polypeptides and validated by IgE western blotting using chickpea sensitive humans and sensitized mice sera. Our data have shown the occurrence of a systemic anaphylactic reaction resulting in reduced body temperature after challenge along with significantly increased levels of IgE, IgG1, MMCP-1, CCL-2 as well as histamine. Further, increased Th1/Th2 (mixed) cytokine response was observed in spleen cell culture supernatants. Jejunum, lungs and spleen showed prominent histopathological changes specific for allergic inflammation. Immunoblotting with pooled sera of either sensitized mice or human sera recognized seven similar IgE binding polypeptides that may be responsible for chickpea induced hypersensitivity reactions. This study has addressed the allergenic manifestations associated with chickpea consumption and identifies the proteins responsible for allergenicity which may prove useful in diagnosis and management of allergenicity of legumes especially chickpea.

Dexamethasone as a Means Not Only for Controlling Vascular Pain Caused by the Administration of Oxaliplatin Via the Peripheral Vein But Also for Controlling Oxaliplatin- Induced Hypersensitivity Reactions

Background and Aims: With the recent development of capecitabine and oxaliplatin (XELOX) therapy, implantation of a Central Venous (CV) port can be now avoided. However, vascular pain occasionally requires switching of the drip infusion route. Some investigators reported that addition of steroids to oxaliplatin drip infusion is useful in controlling vascular pain. However, the pharmacological use of steroids can make oxaliplatin unstable due to the elevation of pH; further, the effectiveness of steroid in this therapy is unknown. This study was undertaken to evaluate the effectiveness of dexamethasone (DEX) for controlling vascular pain caused by the administration of oxaliplatin via the peripheral vein. Study design: Retrospective study. Place and duration of the Study: Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine, between April 2010 and November 2011. Methodology: The study included 69 patients who received XELOX + bevacizumab therapy for advanced or recurrent colorectal cancer. In all the patients, oxaliplatin (130 mg/m 2 ) was administered in combination with DEX (6.6 mg) via the peripheral vein. Results: Vascular pain developed in 47 patients (68.1%), but it was transient. No patients required CV port implantation. Grade 3 or higher hemotoxicity was noted in 14.5% of the patients, and grade 3 or higher nonhematological toxicity was noted in 20.3% of the Research Article British Journal of Medicine & Medical Research, 2(2): 132-141, 2012 133 patients. The response rate was 59.4%. One patient experienced hypersensitivity reactions to oxaliplatin. Conclusions: The recorded response rate combined with the use of DEX suggests that DEX probably does not exert adverse effects on the therapy, ie, it does not affect the stability of oxaliplatin by elevating the pH. DEX may be useful not only for controlling vascular pain caused by the administration of oxaliplatin via the peripheral vein but also for controlling oxaliplatin-induced hypersensitivity reactions.

Etravirine Induced Severe Hypersensitivity Reaction and Fulminant Hepatitis: A Case Report and Review of the Literature

We report the first published case of etravirine induced hypersensitivity reaction leading to fulminant hepatic failure in a 49-year-old female patient with Human Immunodefi ciency Virus. She presented with a life threatening rash and end stage organ damage requiring intensive care unit supportive care. Liver biopsy supported the diagnosis of drug-induced hypersensitivity. The patient recovered after withdrawal of etravirine and the use of systemic corticosteroids. The authors describe etravirine drug hypersensitivity as a clinically important reaction and that early recognition can improve survival.

Curativo de biomembrana vegetal e hipersensibilidade

The natural biomembrane of latex extracted from Hevea brasiliensis has been used as a dressing for skin ulcers. To evaluate how safe the natural biomembrane is in relation to hypersensitivity to latex when used as a dressing. We selected patients with skin ulcers, forming the following groups: control - low occupational exposure to latex (n = 17); latex-exposed control - high occupational exposure (n = 14); ulcerated, using the natural biomembrane (n = 13); ulcerated control, not using the natural biomembrane (n = 14); and new cases (n = 9), assessed before and after 3 months of using the natural biomembrane. All patients underwent clinical and epidemiological evaluation for latex hypersensitivity and specific IgE (UniCap(®)), and the control and latex-exposed control groups underwent the patch test. Hypersensitivity was positive in 64.7% of the patients in the control group, 71.4% of the patients in the latex-exposed control group, 61.5% of the ulcerated using the natural biomembrane, 35.7% of the ulcerated control, and only 22 , 2% of the new cases. In the patch test of the control and latex-exposed control groups, only one individual in the control group (low contact) showed erythema in the first reading, which became negative in the second. The mean contact with latex in the latex-exposed control group was 3.42 hours / day. In the fluoroimmunoenzymatic assay, most of the sera was classified as zero (range 0-6). No serum was rated above 2, which is not considered significant for hypersensitivity (classification > 4). The natural biomembrane proved to be safe as a dressing, for it did not induce hypersensitivity reactions among the volunteers who underwent the patch test or among users of the natural biomembrane, as it was clinically and immunologically demonstrated by IgE levels.

Brenneria salicis Associated with Watermark Disease Symptoms on Salix alba in Italy.

From 1999 to 2010, withering of white willow was observed on trees growing along roads or irrigation canals in Torino, Alessandria, and Vercelli provinces of Italy, with incidence varying from 15, 25, and 30%, respectively. In spring and autumn 2008, six samples from withering branches with bark cankers were collected. On the bark surface near the cankers, iridescent traces of dried ooze were found. Tissues immediately below the cankers were dark with water-soaked, olive-colored edges. In some cases, the xylem appeared affected. Small fragments taken from the affected tissue on both edges of bark alterations and darkened vessels were crushed into mortars with sterile saline. Ten-fold serial dilutions (10-1, 10-2) were also performed. Aliquots of 0.1 ml were plated on nutrient agar and incubated at 25°C for 4 days. Bacterial colonies were ivory to white, circular, and bright, with a diameter of ~2 mm. Isolates were negative for Gram staining, presence of arginine dehydrolase, oxidase, phenylalanine deaminase, urease, hydrolysis of gelatin and starch, nitrate reduction, acidity from d-arabinose, cellobiose, lactose, maltose, trehalose, xylose, and pectinolytic activity on potato slices; positive for the presence of catalase and levan, fermentative metabolism of glucose, acid production from aesculin, l-arabinose, dextrose, d-galactose, inositol, d-mannitol, α-methylglucoside, raffinose, salicin and sucrose, H2S production from cysteine, and bright yellow pigment production on autoclaved potato tissue. They were not fluorescent on King's medium B and did not induce hypersensitivity reaction on tobacco leaf. Similar results were obtained with Brenneria salicis control strain, LMG 6089, except for acid production from α-methylglucoside (negative) and l-arabinose (negative). Acid production from α-methylglucoside has been reported for the Japanese strains of B. salicis, which do not produce acidity from inositol (4). Genomic DNA was extracted (1) from three isolates, and PCR reactions were performed with Es1A and Es4B primers (2) that amplify a 553-bp fragment from the 16S rDNA of B. salicis. The isolates showed a PCR product of expected size, like the positive control LMB 6089. On the basis of colony features, biochemical tests, and the PCR assay, we conclude that the isolates belong to B. salicis, a pathogen reported in Belgium, Germany, Great Britain, the Netherlands, Hungary, Japan, and New Zealand (2,3) but, as well as watermark disease symptoms, never previously reported in Italy. In summer 2009, pathogenicity tests were performed by inoculating young, white willow plants with B. salicis suspensions of ~1 to 2 × 109 CFU/ml placed with a syringe at the intersection of 1-year-old branches on the trunk. However, a year later, no symptoms of disease have been noted on the inoculated plants. According to the literature, pathogenicity tests rarely lead to the expected results because the bacterium can survive for many years in latent form, breaking out only when proper environmental conditions occur (3). Also the tests with B. salicis LMG 6089 gave negative results. Further investigation is necessary to clarify the relationships between this bacterium and the environment in causing withering of white willows in Piedmont.

Clinical evaluation of food effects on pharmacokinetics of the novel oral taxane, tesetaxel.

e13059 Background: Tesetaxel is a novel, advanced-generation taxane that is orally bioavailable. The drug does not induce hypersensitivity reactions (thus avoiding premedication requirements) and is not a substrate for P-glycoprotein. Although multiple clinical trials of tesetaxel have been conducted (with positive results in breast and gastric cancer), treatment to date has required administration after an overnight fast owing to lack of information regarding food interactions. We undertook this study to determine whether co-administration of food (as a high-fat meal) would substantially alter the bioavailability and pharmacokinetics (PK) of tesetaxel. Methods: The study employed a randomized, open-label, crossover design. Patients (pts) with advanced solid tumors (age 18-75 yrs) and adequate organ function were randomized to 1 of 2 treatment sequences: tesetaxel in the fed state in period 1 and fasted state in period 2; or the reverse sequence. The second dose of tesetaxel was administered 35 days (~ 4.7 half-lives of tesetaxel) after the first dose. Serial blood sampling was performed in both periods for PK analysis. The primary comparison was determination of the ratios of fed-to-fasted state PK parameters. Results: Twelve pts completed the 2 treatment periods. Mean (standard deviation) PK values in the fed state were: Cmax 3.9 (1.0) ng/mL, Tmax 5 (2) h, t1/2 220 (103) h, AUC0-t 148 (43) ng/mL x h, Vss/F 7.2 (2.6) L/m2, and CL/F 0.025 (0.009) L/h/m2. The corresponding values for the fasted state were: Cmax 4.1 (0.9) ng/mL, Tmax 2 (3) h, t1/2 165 (84) h, AUC0-t 134 (25) ng/mL x h, Vss/F, 6.9 (2.7) L/m2, and CL/F 0.033 (0.011) L/h/m2. Thus, PK analyses in fed and fasted subjects appeared similar and displayed no clinically relevant differences. Conclusions: Tesetaxel can be orally administered in the fed state without detriment to its bioavailablity or pharmacokinetic behavior, which should facilitate its further clinical development.

Hypersensitivity reactions and contrast medium injection: Are they always related?

Hypersensitivity (allergic or non-allergic) reactions that occur after contrast medium (CM) injection are usually related to the CM. Recent studies, and case reports lack the analysis of alternate causes that could be also responsible in individual cases. We investigated the individual relevant factor/causative agent of adult patients with hypersensitivity reactions that occurred in radiological units during CM-enhanced procedures (CT, angiography, urography, or MR-examinations). Both immediate and non-immediate (delayed) reactions were included. To find out the relevant agent a detailed patients' history was carefully analyzed. In addition, the records were retrospectively reviewed, and if indicated and possible laboratory (e.g. basophil activation test) and skin tests (e.g. prick) and/or provocations with CM-injections under routine conditions were performed. 38 patients (men n=21) suspected for CM-hypersensitivity reactions were identified. These reactions were in most cases mild (n=21), moderate reactions occurred in 13 cases, and four patients had severe reactions. In 28 patients the reactions were induced by the CM (iodinated CM in 25 cases). Four patients had reactions that were not CM-related (latex allergy, adenosine reaction, vasovagal reaction, unknown cause) and in six cases the reaction was partly CM-related (immunological activation was present due to the patients' diseases). Our data support the hypothesis that in CM-enhanced procedures not only contrast materials but also a broad range of other factors may also induce hypersensitivity reactions. Therefore, the number of CM-induced hypersensitivity is smaller than initially suspected. The knowledge of the cause of a reaction is essential to effectively prevent its recurrence and to improve safety aspects in patients undergoing CM-injection. Larger trials should be performed to more specifically assess alternate causes in patients who acquire hypersensitivity reactions in CM-enhanced diagnostic procedures.

Development of an Enzyme-Linked Immunosorbent Assay System to Determine the Presence of Antibodies Specific for Taxane Structures

Taxanes, which are widely used in treatment of numerous cancer types, are well-known to induce hypersensitivity reactions (HSR), especially in the case of paclitaxel. Although the cause of the HSR is commonly thought to be a non-immunological direct effect of the diluent which is used to dissolve paclitaxel, some reports suggest the possibility of the presence of an immunological reaction to the common taxane structure. The aim of this study was to establish a method to determine the presence of anti-taxane antibodies in body fluids of patients who have previously received paclitaxel, in order to estimate the risk of the occurrence of HSR to other taxane compounds, such as docetaxel. To prepare an enzyme-linked immunosorbent assay (ELISA) plate for determining taxanes, 10-deacetylbaccatin III (DAB) was first succinylated by use of dimethylaminopyridine and succinic anhydride in dried pyridine. After the succinylation reaction, three different products were obtained, and these were confirmed as 7-succinoyl DAB (7-DAB), 10-succinoyl DAB (10-DAB), and 7,10-disuccinoyl DAB (7,10-DAB) by (1)H-NMR analysis. Each of these three products was conjugated with bovine serum albumin (BSA), and adsorbed on an ELISA plate. By using a commercially available anti-taxane monoclonal antibody as a model antibody, the detection limit of the anti-taxane antibodies on the 7-DAB-BSA-, 10-DAB-BSA-, and 7,10-DAB-BSA-conjugated ELISA plate was estimated as 0.3, 1 and 10 ng/ml, respectively. The ELISA system established in this study may therefore be useful for estimating the risk of HSR to taxanes in a patient prior to the use of these drugs.

Minocycline in Acne Vulgaris

Minocycline is a semi-synthetic, second-generation tetracycline. It was introduced in 1972 and has both antibacterial and anti-inflammatory properties. Minocycline is used for a variety of infectious diseases and in acne. Even today, new indications beyond the antibacterial indications are being investigated such as its use in neurologic diseases. Formerly, minocycline was thought to have a superior efficacy in the treatment of inflammatory acne, especially with respect to antibacterial-resistant Propionibacterium acnes. A thorough review of the literature, however, shows that minocycline is not more effective in acne than other tetracyclines. Compared with first-generation tetracyclines, minocycline has a better pharmacokinetic profile, and compared with doxycycline it is not phototoxic. However, minocycline has an increased risk of severe adverse effects compared with other tetracyclines. It may induce hypersensitivity reactions affecting the liver, lung, kidneys, or multiple organs (Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS] syndrome) in the first weeks of treatment and, with long-term treatment, may cause autoimmune reactions (systemic lupus erythematosus, autoimmune hepatitis). In addition, CNS symptoms, such as dizziness, are more frequent compared with other tetracyclines. Long-term treatment may induce hyperpigmentation of the skin or other organs. Resistance of P. acnes to minocycline also occurs, dependent on the prescribing behavior. Considering the aspects of efficacy, its adverse effect profile, resistance, price, and alternatives, minocycline is no longer considered the first-line antibacterial in the treatment of acne.