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Suicide by ingestion of barium is exceptionally rare. Adverse health effects depend on the solubility of the barium compound. Severe hypokalemia, which generally occurs within 2 hours after ingestion, is the predominating feature of acute barium toxicity, subsequently leading to adverse effects on muscular activity and cardiac automaticity. We report one case of acute poisoning with barium nitrate, a soluble barium compound. A 75-year-old woman was hospitalized after suicidal ingestion of a burrow mole fumigant containing 12.375 g of barium nitrate. About 1 hour post-ingestion, she was only complaining of abdominal pain. The ECG recording demonstrated polymorphic ventricular premature complexes (VPCs). Laboratory data revealed profound hypokalemia (2.1 mmol/L). She made a complete and uneventful recovery after early and massive potassium supplementation combined with oral magnesium sulphate to prevent barium nitrate absorption.

A rational medical, occupational and toxicological approach is instrumental to select objectively among pregnant women exposed to chemicals at the workplace those who should be withdrawn or benefit from improvements of working conditions. Risk assessment is based on a comprehensive review of compounds' hazards and a thorough evaluation of the actual exposure including biomonitoring whenever as possible. Since 1996, the Lyon Poison Center has been conducting a prospective follow-up of pregnant women exposed to chemicals at the workplace. Of these, 206 exposed to organic solvents since conception were selected and matched with 206 exposed to a non-embryotoxic agent. Total withdrawal from the workplace was recommended in 22% of cases, but exposure was not considered to be hazardous to pregnancy in 51%. Overall, no increase in adverse outcomes was found. Maintaining pregnant women at their workplace, particularly most of the laboratory technicians, is reasonably possible after careful toxicological risk assessment., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Many immunosuppressive drugs are associated with an increased risk of B-cell lymphoma, squamous cell carcinoma, and Kaposi sarcoma. Thirteen immunosuppressive drugs have been tested in 2-year carcinogenicity studies (abatacept; azathioprine; busulfan; cyclophosphamide; cyclosporine; dexamethasone; everolimus; leflunomide; methotrexate; mycophenolate mofetil; prednisone; sirolimus; and tacrolimus) and in additional models including neonatal and genetically modified mice; chemical, viral, ultraviolet, and ionizing radiation co-carcinogenesis, and in models with transplanted tumor cells. The purpose of this review is to outline the mechanisms by which immunosuppressive drugs can influence neoplasia, to summarize the available preclinical data on the 13 drugs, and to critically review the performance of the models. A combination of primary tumor and metastasis assays conducted with transplanted cells may provide the highest value for hazard identification and can be applied on a case-by-case basis. However, for both small molecules and therapeutic proteins, determining the relative risk to patients from preclinical data remains problematic. Classifying immunosuppressive drugs based on their mechanism of action and hazard identification from preclinical studies and a prospective pharmacovigilance program to monitor carcinogenic risk may be a feasible way to manage patient safety during the clinical development program and postmarketing.

The histopathological examination of lymphoid organs together with a T-dependent antibody (TDAR) assay are the primary components of preclinical immunotoxicity assessment. Additional testing including measurement of cellular immunity may be considered. Besides ex vivo lymphocyte proliferation assays, either delayed or contact hypersensitivity models can be used. Contact hypersensitivity testing is typically performed either in mice or in guinea pigs and is directly derived from classical models used for the detection of contact sensitizing chemicals. Whatever the selected model, it is comprised of a sensitizing phase where the animals are applied a strong contact sensitizer topically, then a rest phase, and finally an eliciting phase where sensitized animals are challenged topically with the same contact sensitizer.In mice, the ear-swelling test is the reference procedure in which mice are sensitized to the ear or shaved abdominal skin and then challenged on the ear. Ear swelling usually measured from ear thickness reflects a cell-mediated immune response. In guinea pigs, a strong sensitizer is applied on the shaved skin of the abdomen or the interscapular area. The sensitized animals are challenged on another area of the shaved abdomen, and the cell-mediated response is assessed semiquantitatively from the magnitude of induced erythema inconsistently associated with edema. Treatment or exposure with immunosuppressive chemicals can result in a significantly decreased ear swelling or skin reaction. Contact hypersensitivity models are seldom used nowadays in preclinical immunotoxicity testing, most likely because of the lack of standardization and extensive validation as well as their use being restricted to mice or guinea pigs.

Proton pump inhibitors (PPIs) are widely used drugs in the treatment or prophylaxis of peptic ulcer and gastro-oesophageal reflux disease. In addition to their well documented efficacy, these drugs are generally well tolerated with only rare serious adverse effects having been reported. Neutropenia and agranulocytosis are rare adverse events associated with PPI treatment. All previously published cases of isolated neutropenia have involved omeprazole, but leukopenia is labelled as a possible adverse effect in the summary of product characteristics of the other PPIs. In this report, we describe a case of omeprazole-induced neutropenia with further recurrence upon pantoprazole treatment. A 60-year-old man with chronic alcoholism and a medical history of pulmonary tuberculosis, untreated chronic C hepatitis, peripheral artery disease, chronic obstructive pulmonary disease and stable stage 3 chronic kidney disease was admitted with dehydration and malnutrition. Omeprazole 20 mg/day and sucralfate 3 g/day were started for diffuse gastritis on gastric endoscopy. While the patient's blood cell count had been within the normal range before this treatment, routine laboratory examination revealed moderate neutropenia (0.9 x 109/L) after 9 days of treatment. His blood cell count returned to the normal range after discontinuation of omeprazole and no further episodes of neutropenia were noted in the following months. One year later, oesophago-gastroscopy revealed a hiatal hernia with an extensive zone of Barrett's oesophagus. As the lesions did not improve with ranitidine and sucralfate therapy, the patient was started on pantoprazole 40 mg/day. His initial white blood cell count was normal, but moderate neutropenia (0.8 x 109/L) was again noted after only 2 days of pantoprazole treatment. Complete and further stable normalization was obtained within 3 days after replacement of pantoprazole with ranitidine. Toxic and immune-mediated mechanisms are the two commonly proposed mechanisms to explain the pathogenesis of drug-induced neutropenia. This report suggests that PPI-induced neutropenia is immune mediated and argues for a possible cross-reactivity between the two PPIs, as has already been described for PPI-induced hypersensitivity reactions. The report also indicates that patients with a history of neutropenia induced by one PPI may be at risk of recurrence of neutropenia if given another member of this drug class. In these patients, close haematological monitoring is proposed.

Introduction: Current unusual environmental sources of lead exposure mainly include traditional medicines, either ayurvedic remedies or others, traditional cosmetics (kohl, surma), and the use of traditional earthenware, for storage or cooking., Case Reports: We report two cases of lead poisoning in adults initially identified by paroxysmal abdominal pain or anemia. In both cases, the environmental investigation evidenced one main source of lead exposure, namely a lead-glazed earthenware jug in which a drink was stored, "kefir" in the first case, and "kombucha" tea in the second one., Conclusion: It is recommended to search for lead intoxication in patients with unexplained anemia. Environmental sources of lead can be multiple. Their relative importance has to be ranked during the environmental investigation and among these, lead-glazed earthenware must be considered as a source of high lead exposure when drinks are stored inside and thus can soak.

Unlabelled: One case of analytical interference between cannabis and niflumic acid resulting in a false-positive screening in a 3-year-old girl is described., Case Report: The child was hospitalized because of behavioral disturbances of unknown origin. The only noteworthy finding in her medical history was a drug treatment including suppositories of niflumic acid, started 5 days before. The initial urinary toxicological screening was positive for cannabinoids, but the child's parents strongly denied the exposure. Another analysis was performed by the same laboratory on the same urine sample using chromatography and confirmed the absence of any cannabinoids, while clearly identifying the presence of niflumic acid., Comments: Immunoanalysis for toxicological analysis has various limitations that must be known. False-positive results of the urinary screening for cannabis in patients treated with niflumic acid are well recognized although seldom reported. All usual screening tests are not concerned by this ill-explained interference with niflumic acid and all formulations can be involved except transcutaneous formulations. Because of the wide use of this nonsteroidal anti-inflammatory drug, particularly in pediatric patients, it is important to know that this type of interference can occur with various screening tests for cannabis so that misleading conclusions can be avoided.

Unlabelled: We describe an accidental ecstasy poisoning in a 10-month-old girl., Case Report: A 10-month-old infant suddenly exhibited behavior disorders with restlessness, hypertonia, and repetitive movements. She was immediately taken to the Emergency Department. Cardiovascular (tachycardia and hypertension) and neurological disorders (major agitation, mydriasis, and nystagmus) were the predominating clinical features. The most common differential diagnoses including febrile convulsion, cranial trauma, or encephalitis were progressively ruled out. The urinary toxicological screen was positive for methamphetamine. MDMA, its main metabolite, and caffeine were subsequently detected in the infant's urine using gas chromatography/mass spectrometry. The child had completely recovered the next morning., Comment: Pediatric poisoning with ecstasy remains uncommon. To date, about 10 cases have been reported. All were due to accidental ingestion. Today, the use of ecstasy is no longer restricted to recreational purposes (rave parties, etc.) and it seems to be developing in private parties and in the home. The intrusion of this amphetamine-like drug into the domestic environment may expose young children to the accidental ingestion of ecstasy tablets.

Neuroleptics are a suspected cause of sudden death in psychiatric patients, especially in those with pre-existing cardiac lesions. As these lesions were previously shown to be associated with selenium (Se) deficiency, the aim of the present study was to evidence the possible protective effect of Se supplementation against cardiac lesions induced by the combination of the neuroleptic drugs levomepromazine and risperidone in the rabbit. Two groups of 6 rabbits were treated with 3 mg/kg of levomepromazine daily intramuscularly combined with 1 mg/kg of risperidone intramuscularly every other week for 3 consecutive months, and one group additionally received a solution of sodium selenite (2 microg/kg/day) intramuscularly during the whole treatment period. Furthermore, one group of six untreated animals was given the Se supplementation and another group of six control animals received saline daily. Blood samples were drawn before and at the end of the treatment period for the measurement of serum Se levels. At the end of the study, all animals were sacrificed and their hearts were removed for the measurement of tissue Se concentrations. In addition, the hearts were prepared for histopathological examination. A variety of cardiac lesions was found in the neuroleptics-treated animals without supplementation and to a lesser extent in the control and Se-supplemented untreated animals. Importantly, only rare cardiac lesions were observed in neuroleptics-Se-treated animals. The most striking differences in Se concentrations were noted in the myocardium: as compared to controls, there was a 43% reduction in neuroleptics-treated, but non-Se-supplemented animals (p < .01), at the end of the treatment period, whereas only a 14% reduction (p < .05) was noted in the neuroleptics-Se-treated animals. These results confirm that neuroleptics induce cardiac lesions associated with Se deficiency. Selenium supplementation markedly decreased the incidence and severity of neuroleptics-induced cardiac lesions and these findings may serve as a basis for further evaluation of the protective role of Se supplementation in neuroleptics-treated patients. However, Se supplementation in normal animals without Se deficiency was also shown to be cardiotoxic.

Among 15,000 forensic post-mortem examinations performed on the coroner's order over a 24-year period (January 1981-December 2004) in the area of Lyon, France (population: 2,000,000), 2250 cases of unexpected cardiac sudden death were identified retrospectively according to WHO criteria. Of these, 108 occurred during recreational sport and 12 occurred in athletes. In the latter category, a history of anabolic steroid abuse was found in 6 cases, whereas pre-existing ordinary cardiac lesions were observed in the 6 remaining cases. To shed light on the possible role of anabolic steroids in the induction of cardiac lesions, an experimental study was conducted in rabbits that were treated orally with norethandrolone 8mg/kg/day for 60 days, and sacrificed at day 90. The histopathological examination of the heart from treated animals showed coronary thrombosis associated with left ventricle hypertrophy in 3 cases, and lesions analogous to toxic or adrenergic myocarditis in all other treated animals. These findings were very similar to those observed after cardiac sudden death in the 6 athletes with a history of anabolic steroid abuse. In addition, elevated caspase-3 activity in the heart of treated rabbits as compared to controls suggests that apoptosis is involved in the induction of norethandrolone-induced cardiac lesions. These results confirm the cardiotoxic potential of anabolic steroid abuse.

Further to our previous observation of post-mortem cardiac lesions after sudden death in several athletes with a history of anabolic steroid abuse, this study was intended to reproduce these lesions in rabbits administered testosterone oenanthate, a prototypic anabolic steroid abused by athletes, and to provide evidence for the protective effects of trimetazidine and dexrazoxane that are used as antianginal and cardioprotective drugs, respectively. Groups of six rabbits each were administered saline, testosterone, or a combination of testosterone and either trimetazidine or dexrazoxane for 3 months. Histologic cardiac lesions including necrosis, misshapen cell nuclei, interstitial and endocardial fibrosis, lymphocytic infiltrates, and vascular dystrophies were observed in testosterone-treated rabbits. In contrast, no significant lesions were observed in the animals treated with testosterone combined with either trimetazidine or dexrazoxane. This is the first study providing evidence for testosterone cardiotoxicity following sub-chronic exposure in laboratory animals. In addition, these results suggest the protective role of trimetazidine and dexrazoxane.

Monoclonal antibodies (mAbs) are large molecules intended to bind to specific targets often expressed on the immune system, and to treat various immunopathological conditions. Therefore, mAbs can be considered to have a high potential for immunotoxicity, which is reflected in the clinical experience accumulated on mAbs-induced adverse effects related to immunosuppression, immunostimulation and hypersensitivity (immunogenicity). So far, non clinical immunotoxicity studies have been inadequate to address all safety issues in relation to the possible immunotoxicity of mAbs, because they are fraught with limitations and pitfalls primarily related to the lack of relevant animal species. In addition, clinical studies rarely include validated end-points dedicated to the prediction of immunotoxicity. With the ongoing development of mAbs as novel therapeutic strategies for a wide variety of diseases, efforts should be paid to improve our understanding of mAbs-induced immunotoxic effects and design dedicated strategies to assess their immunological safety, both non clinically and clinically.

Background: Tachycardia often facilitates ischemic ventricular fibrillation (VF)., Objective: This study assessed the impact of ivabradine (IVA), a selective inhibitor of the cardiac pacemaker If current, on ventricular fibrillation threshold (VFT) during acute myocardial ischemia., Methods: The experiments were conducted on a total of 54 domestic pigs. Myocardial ischemia was induced in anesthetized pigs by total 1-minute coronary occlusion at baseline and then on 2 occasions after intravenous administration of saline or 0.5 mg/kg of IVA. VF was triggered by electrical stimuli of increasing intensity at a fixed rate. Heart rate (HR), VFT, monophasic action potential duration, and peak of the time derivative of left ventricular pressure (LV dP/dt max) were monitored on each occasion. The activity of mitochondrial succinodehydrogenase was measured on heart sections., Results: Compared with controls, IVA induced a 31% reduction in HR, a 2.9-fold increase in VFT, and prevented ischemia-induced monophasic action potential duration shortening (+1 +/- 12 vs. -14 +/- 11 milliseconds) without affecting peak LV dP/dt. This beneficial effect on VFT was mainly due to HR reduction and was accompanied by a significant reduction in the hypoxic area (26% +/- 1% vs. 38% +/- 1%, P < 0.0001)., Conclusion: HR reduction and the decrease in myocardial damage induced by IVA protected against primary ischemic VF without altering myocardial contractility.

Acute poisonings involving chloroquine are common in sharp contrast to those involving proguanil, another antimalarial drug. A 39-year-old woman ingested a combination of 11.2 g chloroquine and 22.4 g proguanil (i.e., 112 tablets of the commercial product Savarine). She presented with cardiovascular disorders typically associated with chloroquine overdose, but unexpectedly bone marrow aplasia developed on day 3 post-ingestion that required granulocyte-colony stimulating factor administration, and recovered on days 10-14. Toxicological analysis evidenced both chloroquine and proguanil in the patient's serum and ruled out the involvement of any major myelotoxic drug. This is seemingly the first report of bone marrow aplasia following acute poisoning with chloroquine and proguanil. The antifolinic effect of proguanil is hypothesized to have potentiated the still debated myelotoxicity of chloroquine in this patient.

Therapeutic proteins are proteins engineered in the laboratory for pharmaceutical use. Although they tend to offer a better safety margin than most synthetic small molecules because they are processed by the same pathways as natural proteins in the human body, or mimic or replace natural proteins that are missing or defective, they can induce a variety of adverse effects in human patients among which immunotoxic effects deserve particular attention. Infectious complications and virus-induced neoplasias are the main consequences of intended or unexpected immunosuppression. They have been primarily described with anti-TNF-alpha drugs and anticancer monoclonal antibodies (mAbs) whose immunosuppressive effects can be largely anticipated from their mechanism of action. Cytokine release-associated adverse reactions ranging from mild-to-moderate flu-like reactions to severe cytokine release syndromes, or exceptionally cytokine storm, are now an issue of chief concern. They have been observed with most of the therapeutic proteins in current use. Acute infusion reactions whose clinical features are somewhat similar have been variably described with many mAbs. Immunostimulatory properties are suspected to account for the occurrence of more frequent autoimmune diseases as seen in patients treated with recombinant cytokines such as the IFNs-alpha and rIL-2. The risk of more frequent hypersensitivity reactions to unrelated allergens is also suspected to be a potential consequence of immunostimulation but compelling evidence is limited to radiocontrast media-induced hypersensitivity reactions in IL-2 treated cancer patients. In addition, recombinant cytokines can inhibit cytochrome P450 dependent biotransformation pathways with resulting alterations in the pharmacokinetics of the combined drugs at therapeutic dose. Because of their structure and origin, therapeutic proteins are intrinsically immunogenic. Despite extensive laboratory and clinical studies that were instrumental in delineating general concepts about key factors involved in immunogenicity, it is impossible nowadays to anticipate to what extent a novel therapeutic protein will be immunogenic in human patients. Specific antibodies are frequently detected in the sera of treated patients. They are often inconsequential but can also be neutralizing and result in decreased efficacy. Anaphylactic reactions induced by human therapeutic proteins have been rarely reported and true serum sickness extremely rarely. Because the immunotoxic effects of therapeutic proteins are frequent, sometimes severe and even potentially life-threatening, there is an urgent need to improve our capacity to anticipate the immunotoxic risks of novel therapeutic proteins and this could be achieved by the development of clinical immunotoxicology.

The intra-arterial injection of crushed tablets can lead to severe vascular disorders including necrosis. A 35-year-old patient was hospitalized after the involuntary intra-radial injection of a crushed tablet of zolpidem. As the initial treatment with heparin and vasodilators was inefficient, iloprost injections were proposed. A recovery of most lesions was obtained, but the middle finger distal phalange had to be amputated. Iloprost has already been used successfully in the treatment of lesions caused by the intra-arterial injections of drugs of abuse. It can limit ischemia and even lead to necrosis healing, thus being an alternative to conventional treatments when they are ineffective.

A 37-year-old man was admitted to hospital after complaining of abdominal pain for the past two weeks. On admission the abdominal radiograph showed multiple radio-opaque flecks dispersed throughout the gastrointestinal tract. Blood testing showed hemoglobin level 8.7 g/dL and a blood lead level of 112.4 microg/dL. The family interview revealed that the patient had pica-like behavior since childhood. He was a site foreman and had been ingesting pieces of roofing plates for a few weeks. The patient was treated with laxatives and CaNa(2)EDTA therapy was initiated. The blood lead level then dropped to 69.9 microg/dL. The patient received two subsequent courses of oral succimer and the blood lead level decreased to 59 microg/dL 21 days after the first course. The follow-up abdominal X-ray 20 days after the first examination was normal. Four months later, an outpatient follow-up visit showed a blood lead level within normal limits (14.5 microg/dL) and a psychiatric follow-up was initiated. Lead poisoning following the ingestion of lead-containing foreign bodies is particularly rare in adults, while it is sometimes observed in children. Pica behavior is a well-identified risk factor of lead intoxication in children but is quite exceptional in adults, where it is usually considered to be a psychiatric condition. Other unusual sources of lead poisoning include the ingestion of lead bullets, ceramic lead glaze or glazed earthenware, lead-contaminated candies, ethnic or herbal remedies.

Organic and/or functional heart lesions sometimes resulting in sudden death have been described in psychiatric patients treated with neuroleptics. As selenium has been suggested previously to play a role in the development of such lesions, the present study was undertaken to determine whether a correlation could be found between heart lesions induced by neuroleptics and changes in blood selenium as well as myocardial tissue concentrations in the rabbit. Twelve NZW adult rabbits were treated intramuscularly with both levomepromazine (3 mg kg(-1) day(-1)) and risperidone (1 mg kg(-1) once every other week) for 3 months, and compared with 12 saline-treated controls. Blood samples were drawn before and at the end of the study. Tissue samples from the heart, liver and kidneys were obtained at the end of treatment, and the hearts were examined histologically. Heart lesions including disorganization of cardiac fibers, myolysis, interstitial and endocardial fibrosis, and necrosis were noted in treated animals, but not in controls. There was a 20% decrease in selenium blood levels and a 50% decrease in selenium myocardial tissue levels in treated animals compared with controls (P < 0.001). In contrast, no differences in selenium levels in liver and kidneys were found across the experimental groups. These results suggest a possible correlation between selenium depletion and neuroleptics-induced heart lesions.

Purpose: Ventricular fibrillation (VF) is a possible consequence of brief myocardial ischemia. Such a short ischemia does not provoke cell damage, but induces changes in intracellular cardiac metabolism due to diminished oxygen supply to the heart. Trimetazidine (TMZ) is a drug able to restore the metabolic balance between fatty acid and glucose oxidation in ischemic myocardial cells. The aim of this double-blind study was to investigate TMZ effect on VF in pigs during short-term ischemia., Methods: Ischemia was induced after thoracotomy by complete, but brief (1 min) occlusion of the left anterior descending coronary artery under electrical stimulation. The ventricular fibrillation threshold (VFT), heart rate (HR), various hemodynamic parameters and malondialdehyde (MDA) blood levels were measured before and during ischemia in two groups of eight anesthetized pigs. The mass of ischemic myocardial tissue was also evaluated., Results: No effects on either the HR or the hemodynamic parameters were observed during myocardial ischemia, whereas TMZ increased the VFT and decreased both MDA blood levels (an index of lipid peroxidation) and the ischemic area., Conclusions: TMZ limited ischemia-induced electrical dysfunction leading to cardiac susceptibility to VF by decreasing lipid peroxidation and maintaining ionic homeostasis. TMZ could therefore provide protection against ischemia-induced VF.

Glycol ethers (GE) belong to two main series: series E, which include ethylene glycol ethers (EGE) and series P which include propylene glycol ethers (PGE). GE are widely used as solvents in a large number of industrial, household and cosmetic applications. EGE can be found in water paints, varnishes, inks, household products. Severe adverse effects have been noted with pharmaceutical formulations containing diethylene glycol monoethyl-ethers and this led to withdrawal from the French market. The toxicity of GE depends on the molecular weight and the metabolites generated. It can manifest following acute or chronic exposure by disorders of the nervous system, bone marrow, immune system, kidneys as well as fertility, reproduction and embryofetal development. Several EGE are mutagenic. The carcinogenic risk is not known. The most toxic derivatives EGME, EGMEA, EGEE and EGEEA alter male and female fertility, and induce malformations. Taking these toxic effects into consideration, what is the place of GE as absorption promoting agents? An example is DEGEE, which facilitates estradiol penetration when used as a gel in the treatment of estrogen deficiency. This review is intended to address this issue.

A surgical procedure was evaluated to allow bile collection from the freely moving male Sprague-Dawley rats for the assessment of drug biliary excretion during regulatory safety studies. A catheter was implanted into the bile duct to divert the bile flow via an exteriorized loop. Following recovery from the surgery and verification of normal hepatic function, the exteriorized catheter was sectioned to allow collection of the bile and replacement with a commercial bile salt solution. Approximately 80% of the catheterized animals (10 females and 10 males) had normal serum liver enzyme levels 2 days after surgery. Then, the effect of acute or repeated administrations of the immunosuppressant tacrolimus on the biliary excretion of 14C diazepam was studied to validate the technique. A first group of 12 rats received an intravenous injection of 10 mg/kg 14C-diazepam and the total and sequential amounts of diazepam excreted in the bile were measured over 72 h. Biliary excretion accounted for 80% of diazepam elimination. These rats were then given an oral administration of 3 mg/kg tacrolimus on days 7 and 8 followed by the same intravenous dose of 14C-diazepam. Another group of 10 catheterized rats was given 21 daily oral doses of 3 mg/kg tacrolimus followed by a single intravenous administration of 14C-diazepam. No significant changes in diazepam biliary excretion were observed following either acute or repeated administration of tacrolimus. This study demonstrates the feasibility of drug biliary excretion investigations under Good Laboratory Practices conditions as a complement to regulatory acute or repeated dose safety studies.

Cardiotoxicity is a rare, but well-recognized complication of treatments with the anti-cancer drug 5-fluorouracil (5FU). The underlying mechanism, however, is not fully elucidated. A spasm of the coronary arteries is often considered to be the leading cause of myocardial ischemia and decreased contractility associated with 5FU. As spasm cannot account for all reported adverse cardiac effects, the present study was undertaken to search for alternative mechanisms. Groups of six rabbits were given either a single intravenous dose of 50 mg/kg 5FU or four intravenous doses of 15 mg/kg 5FU at 7-day intervals. A third group served as control. The heart was removed shortly after death or scheduled sacrifice of the animals, to perform macroscopic and microscopic examinations of the heart and to evidence apoptosis by the TUNEL method. Following a single dose of 50 mg/kg 5FU, all animals rapidly developed a massive hemorrhagic myocardial infarct with spasms of the proximal coronary arteries. Repeated infusions of 15 mg/kg 5FU induced left ventricular hypertrophy, foci of myocardial necrosis, thickening of intra-myocardial arterioles, and disseminated apoptosis in myocardial cells of the epicardium, as well as endothelial cells of the distal coronary arteries. These results indicate that a spasm of the coronary arteries is not the only mechanism of 5FU cardiotoxicity, and that apoptosis of myocardial and endothelial cells can result in inflammatory lesions mimicking toxic myocarditis.

Unlabelled: Several studies have suggested the usefulness of a test dose of paclitaxel to reduce the incidence of hypersensitivity reactions and the resulting cost of drug wastage. The aim of this study was to assess the utility of implementing such a test dose., Method: We retrospectively reviewed the medical charts of patients who had received one or two courses of single-agent paclitaxel or a combination chemotherapy regimen to calculate hypersensitivity reaction incidence and the cost of drug wastage. Thereafter, a paclitaxel test-dose program was routinely implemented during the first and second cycles of paclitaxel treatment for all patients. Hypersensitivity reaction incidence and drug wastage cost were again assessed., Results: Before the routine use of a test dose, 162 patients received one or two paclitaxel infusions alone or in combination therapy from January 1, 1997 to February 28, 2003. Ten (6.2%) patients experienced a hypersensitivity reaction; one of them was severe. After implementation of the test-dose program, 130 patients received 244 test doses (12 mg paclitaxel/10 mL normal saline) with an intensified premedication regimen at the first and second cycles of chemotherapy from June 28, 2003 to March 2, 2005. Three patients (2.3%) experienced a minor hypersensitivity reaction, one immediately after the test dose and two during infusion of the full dose despite a well-tolerated test dose. Thus, the negative predictive value of the test dose was 98.4%. The overall incidence of hypersensitivity reactions experienced during the first or second cycle of paclitaxel chemotherapy decreased about 63% compared with the incidence before implementation of the test dose (P < 0.20). The test-dose program resulted in a 29% increase in the cost of chemotherapy (approximately 6100 dollars for 130 patients)., Conclusion: To our knowledge, this is the largest study ever reported to test the potential cost-saving benefit of the implementation of a paclitaxel test-dose program to prevent hypersensitivity reactions. The results suggest that the routine use of a test dose is not a cost-effective measure.

Immunotoxicology is an important aspect of the safety evaluation of drugs and chemicals. Immunosuppression, (unspecific) immunostimulation, hypersensitivity and autoimmunity are the four types of immune-mediated adverse effects. However, the nonclinical assessment of immunotoxicity is at present often restricted to animal models and assays to predict unexpected immunosuppression. There is, however, no general consensus that a variety of assays can be considered depending on the compound to be tested. A major issue is whether histological examination of the thymus, spleen, lymphoid organs and Peyer's patches is a reliable predictor of immunosuppression or whether immune function should also be assessed. A T-dependent antibody response assay, either the plaque-forming cell assay or anti-keyhole limpet haemocyanin enzyme-linked immunosorbant assay, is recommended as a first-line assay. A variety of assays, including lymphocyte subset analysis, natural killer-cell activity, lymphocyte proliferation, delayed-type hypersensitivity, cytotoxic T-lymphocyte activity and macrophage/neutrophil function assays, can also be used. In certain circumstances, host resistance assays can be considered. With the exception of contact sensitisation, very few animal models and assays can reliably predict the potential for (unspecific) immunostimulation, hypersensitivity or autoimmunity. A major limitation of immunotoxicity risk assessment is the lack of human data. Immunological end points and clinical criteria to be included in clinical trials and epidemiological studies have to be carefully standardised and validated.

To show the nature and magnitude of EKG anomalies subsequent to 5-fluorouracil (5FU) administration and determine whether the onset is dependent on a pre-existing cardiovascular pathological condition. 1,350 patients were treated by 5FU between 1995 and 2000. EKG were recorded in all patients before each administration of 5FU. All cases of 5FU related cardiotoxicity were analyzed and recorded by the Lyon Pharmacovigilance Center. Clinical symptoms included chest pain in 10 patients with an infarct-like pattern in 2 (including one death), and heart failure in one. Three patients suffered from anginal pain without EKG changes and two had electrocardiographic changes without clinical symptoms. Coronary disorders resolved completely on cessation of 5FU therapy, except in one patient who died two months later of heart infarct. The patient with heart failure required specific treatment. Based on both the clinical and electrocardiographic changes, the causative role of 5FU is highly likely. The incidence of cardiotoxicity was 1.2% among these patients, which is close to previous data from the literature. These 16 case reports confirm the cardiotoxic potential of 5FU and argue for the need of a careful cardiac monitoring of 5FU treated cancer patients. The mechanism of 5FU cardiotoxicity is not elucidated. Coronary spasm is the most commonly suspected hypothesis, but further studies are warranted to seek for toxic inflammatory lesions of the myocardium (apoptosis, necrosis, fibrosis).

A major risk associated with bupivacaine during myocardial ischemia is ventricular fibrillation. We investigated the influence of ropivacaine on cardiac contractility and the propensity to ventricular fibrillation before and after myocardial ischemia in a placebo-controlled pig study. Anesthetized domestic pigs were administered 1 mg.kg(-1) of ropivacaine intravenously over 1 min and then 0.03 mg.kg(-1).min(-1) as a 30-min infusion, or saline. The following endpoints were measured before and after ropivacaine administration: (1) the ventricular fibrillation threshold (VFT) before and during myocardial ischemia induced by total transient ligation of the anterior interventricular artery and (2) electrophysiological (sinus heart rate, duration of QRS and QT intervals) and hemodynamic (blood pressure, the time derivative of left ventricular pressure [peak LV dP/dt]) parameters. Ropivacaine induced no changes in sinus heart rate, QRS, and or QT before or during ischemia. In contrast, there was a mild increase in the VFT before ischemia, which was drastically and significantly reduced during ischemia. The reduction of peak LV dP/dt during ischemia was further increased by ropivacaine. We also found that the effect of ropivacaine on the VFT was coronary blood flow-dependent, with a markedly decreased threshold in the presence of ischemia. Similar effects have been observed in humans with several other local anesthetics, as well as with class I antiarrhythmic drugs. The results of this study should be taken into account by anesthesiologists when administering ropivacaine to coronary patients.

Background: Octogen (HMX) is a polynitramine explosive closely related to hexogen, a known occupational toxin in military munitions plants. No acute human poisoning with octogen has ever been reported., Case Report: A 28-year-old man with no history of epilepsy was admitted to the Emergency Department for seizures that had developed during the night after a full working day when he manually sieved large amounts of dry octogen. On admission, the clinical examination was normal and all other examinations could not substantiate the development of essential or secondary epilepsy. Elevated octogen concentrations were measured in his plasma, which confirmed occupational exposure to the explosive., Conclusion: The rarity of acute human poisonings by octogen is due to the infrequent use of this explosive and, more importantly, its very low oral bioavailability. However, acute poisoning can occur, but should be easily avoided by implementing adequate preventive measures.

Sudden death seems to be more frequent following treatment with neuroleptic drugs in patients with pre-existing cardiac lesions, especially dilated and hypertrophic myocardiopathy. The present study was undertaken to confirm the hypothesis that myocardial lesions can be induced by neuroleptic drugs. Eight groups of 6 New-Zealand White rabbits were treated for 3 months: group I: controls (saline); group II: 15 mg/kg/day amisulpride; group III: 0.20 mg/kg/day haloperidol; group IV: 3 mg/kg/day levomepromazine; group V: 0.30 mg/kg/day olanzapine; group VI: 1.0 mg/kg risperidone, every 15 days; group VII: levomepromazine+haloperidol, same dose levels as single treatments; group VIII: levomepromazine+risperidone, same dose levels as single treatments. The hearts were immediately weighted and fixed, and paraffin sections were prepared and examined. Ventricular hypertrophy was observed following treatment with olanzapine and was still more marked with the combinations levomepromazine+haloperidol and levomepromazine+risperidone. Amisulpride and haloperidol induced necrotic lesions and levomepromazine, endocardial fibrosis. There was a lack of severe cardiac lesions following treatment with risperidone. The observed cardiac lesions can be compared to those seen in toxic myocarditis. These findings confirm the hypothesis that some neuroleptic drugs induce myocardial lesions. Further studies are warranted to demonstrate the effects of treatments of longer duration and the influence of pre-existing cardiac lesions.

Unlabelled: After consumption of mushrooms containing amatoxins (Amanita, Lepiota, and Galerina species), symptoms usually develop after a long delay (>6 h). Initial symptoms start as severe gastroenteritis, progressing to liver failure and possibly death as a result of hepatic coma. Since the survival rate of poisoned patients is claimed to depend on the time of beginning of efficient treatment, fast and reliable assays for amatoxins in biological fluids are essential. Described analytical methods for amatoxins include high performance liquid chromatography and radioimmunoassay (RIA). Recently, a new enzyme-linked immunosorbent assay (Bühlmann Amanitin ELISA kit) has been introduced as an alternative method to RIA. This ELISA-based assay offers several advantages: no complex extraction procedure is required (vs. HPLC) and no safety precautions concerning radioactivity have to be taken (vs. RIA). From August 2004 to October 2005, a pilot study was performed to test the practicability and the clinical utility of this method in emergency situations., Results: ten urines, 9 serums and 1 faeces from 10 patients suffering from acute gastroenteritis after mushroom ingestions (7 contaminated meals) were analyzed. Definitive diagnosis of amatoxin poisoning was made in 4 cases (3 contaminated meals) on the basis of the anamnesis, laboratory results, and clinical course. A patient developed a severe amatoxin poisoning with urinary amanitins level < 1.5 microg/L (urines were collected more than 72 h after mushroom ingestion). Two patients were paucisymptomatic with urinary amanitins levels >10 microg/L (urines were collected before the 36th hour)., Conclusion: Urine is the sample of choice for the determination of amatoxins. The most critical factor to invalidate the usefulness of this analysis is time. After 36 h, the sensitivity is unreliable.

As natural killer cells play a significant role in innate immunity against viruses and neoplasia, the measurement of natural killer cell activity has long been recommended for nonclinical immunotoxicity evaluation. A number of agrochemical, industrial and environmental chemicals have been shown to impair natural killer cell activity. However, direct evidence for clinically significant pathologic consequences, such as infections or immunosuppression-related cancer in human beings exposed to these chemicals, is lacking. In addition, extremely few pharmaceuticals, including potent immunosuppressive drugs, have been shown to depress natural killer cell activity reproducibly. Due to this ambiguous situation, the value of measuring natural killer cell activity for the prediction of immunotoxicity is debatable, as reflected by recommendations included in recent guidelines for the nonclinical safety assessment of human pharmaceuticals. Limitations of current analyses of natural killer cell activity may explain this situation. Progress is expected from the utilization of most recent techniques to identify more relevant natural killer cell activation markers or from studying underlying mechanisms.

The popliteal lymph node assay (PLNA) derives from the hypothesis that some supposedly immune-mediated adverse effects induced by certain pharmaceuticals involve a mechanism resembling a graft-versus-host reaction. The injection of many but not all of these compounds into the footpad of mice or rats produces an increase in the weight and/or cellularity of the popliteal lymph node in the treated limb (direct PLNA). Some of the compounds known to cause these adverse effects in humans, however, failed to induce a positive PLNA response, leading to refinements of the technique to include pretreatment with enzyme inducers, depletion of CD4(+) T cells or additional endpoints such as histological examination, lymphocyte subset analysis and cytokine fingerprinting. Alternative approaches have been used to improve further the predictability of the assay. In the secondary PLNA, the test compound is injected twice in order to illicit a greater secondary response, thus suggesting a memory-specific T cell response. In the adoptive PLNA, popliteal lymph node cells from treated mice are injected into the footpad of naive mice; a marked response to a subsequent footpad challenge demonstrates the involvement of T cells. Finally, the reporter antigens TNP-Ficoll and TNP-ovalbumin are used to differentiate compounds that induce responses involving neo-antigen help or co-stimulatory signals (modified PLNA). The PLNA is increasingly considered as a tool for detection of the potential to induce both sensitization and autoimmune reactions. A major current limitation is validation. A small inter-laboratory validation study of the direct PLNA found consistent results. No such study has been performed using an alternative protocol. Other issues include selection of the optimal protocol for an improved prediction of sensitization vs autoimmunity, and the elimination of false-positive responses due to primary irritation. Finally, a better understanding of underlying mechanisms is essential to determine the most relevant endpoints. The confusion resulting from use of the PLNA to predict autoimmune-like reactions as well as sensitization should be clarified. Interestingly, most drugs that were positive in the direct PLNA are also known to cause drug hypersensitivity syndrome in treated patients. This observation is expected to open new avenues of research., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

The concept of toxicovigilance encompasses the active detection, validation and follow-up of clinical adverse events related to toxic exposures in human beings. Poison centers are key players in this function as poisoning statistics are essential to define the cause, incidence and severity of poisonings occurring in the general population. In addition, the systematic search for unexpected shifts in the recorded causes of poisonings, e.g., following the introduction of a new product, or change in the formulation or recommended use of an old product, allows for a rapid detection of potential adverse health consequences and the implementation of preventive or corrective measures. However, toxicovigilance is genuinely a medical and not only a statistical approach of human toxicity issues. In contrast to epidemiology, toxicovigilance is based on the in-depth medical assessment of acute or chronic intoxications on an individual basis, which requires detailed information that poison centers can rarely obtain via emergency telephone calls and that epidemiologists cannot collect or process. Validation of this medical information must primarily be based on toxicological expertise to help identify causal links between otherwise unexplained pathological conditions and documented toxic exposures. Thus, toxicovigilance can contribute to hazard identification and risk assessment by providing medically validated data which are often overlooked in the process of risk assessment. So far, very few structured toxicovigilance systems have been set up and hopefully national and international initiatives will bridge this gap in our knowledge of the toxicity of many chemicals and commercial products in human beings.

Pre-existing or contributing risk factors, including genetic predisposition and environmental influences, are largely thought to play a crucial (though ill-elucidated) role in the development of autoimmunity. Trichloroethylene (TCE) is a widely used organic solvent, which has been suspected of increasing the prevalence of autoimmune diseases, e.g., lupus, following environmental contamination. Although few epidemiological data are available, several studies reported an accelerated and more severe disease in TCE-exposed autoimmunity-prone MRL(+/+) mice. To test whether TCE can exert similar deleterious effects on organ-specific autoimmune diseases, non obese diabetic (NOD) mice were given 5 mg/ml TCE via the drinking water for 12 weeks. TCE administration induced a decrease in CD44(+) splenic T-cells and CD45RB(high), CD54(+) blood and splenic T-cells. Conversely, the number of CD45RB(low) splenocytes was increased. Interestingly, the progressive increase in serum TNF-alpha and IFN-gamma levels normally seen with age in these mice was inhibited by TCE. There was also a relative lower incidence of histological changes in the pancreas of TCE-exposed NOD mice than in unexposed mice. Contrary to what has been found in systemic models of autoimmunity, TCE did not accelerate the diabetes of NOD mice and may have a protective effect. This finding suggests that comparative studies using different genetically related autoimmune-prone models are needed to investigate the role of xenobiotics in the precipitation of autoimmunity, particularly in sensitive populations.

This is the report of a workshop organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAM's main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods that are of importance to the biosciences and which replace, reduce or refine the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures. It was decided that this would be best achieved by the organization of ECVAM workshops on specific topics, at which small groups of invited experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward (Anonymous, 1994). The workshop on "The use of in vitro systems for evaluating Immunotoxicity" was held at ECVAM (Ispra), Italy, on 24th-26th November 2003. The participants represented academia, national organizations, international regulatory bodies and industry. The aim of the workshop was to review the state-of-the-art in the field of in vitro immunotoxicology, and to develop strategies towards the replacement of in vivo testing. At the end of this report are listed the recommendations that should be considered for prevalidation and validation of relevant and reliable procedures, that could replace the use of animals in chemical and cosmetics toxicity testing.

Hypersensitivity reactions to systemically administered drugs cannot be predicted using available preclinical models. This research is a collaborative project to evaluate the ability of the Lymph Node Proliferation Assay (LNPA) to predict systemic hypersensitivity caused by pharmaceuticals. The assay design is a modification of the Local Lymph Node Assay with the major modification being injection of the test substance subcutaneously to achieve a known systemic exposure to the drug. Fourteen compounds were evaluated in the LNPA. These were two clinically negative drugs (Metformin, phenobarbital), an assay positive control (streptozotocin), eight human hypersensitivity positive drugs (sulfamethoxazole, procainamide, clonidine, ofloxacin, nevirapine, abacavir, lamotrigine, zomepirac), and 3 investigational drugs (CM40874, CM40954 and CM40420), one of which caused hypersensitivity in primates. Hypersensitivity-positive drugs were classified as such based on at least two of three independent data sources: U.S. FDA postmarketing database, drug labeling information, and clinical trial data. All drugs were tested in multiple laboratories for a total of 2-12 evaluations per compound. The pure drug substance was used for testing if it could be obtained commercially, otherwise the marketed drug formulation was used. Neither of the negative control drugs showed a positive reaction in the test system. Four of the eight hypersensitivity positive drugs showed a mixed or positive reaction. Two of the three investigational compounds gave a positive response. A smaller number of LNPAs were run concurrently using footpad injection and evaluation of the popliteal lymph node and gave generally comparable results. Additional development may increase the reproducibility of the assay and facilitate detection of drugs that require metabolic activation to become allergenic, or drugs for which there is dose-limiting toxicity. The data suggest that this method might be useful as a first-line screen to identify candidate drugs that are more likely to cause a high prevalence of human drug hypersensitivity.

The immunotoxic effects of drugs are divided into immunosuppression, immunostimulation, hypersensitivity and autoimmunity. The major adverse consequences of immunosuppression are infectious complications and virus-induced malignancies. Flu-like reactions, more frequent autoimmune diseases and hypersensitivity reactions to unrelated allergens, and inhibition of drug-metabolising enzymes are the adverse effects related to immunostimulation. Hypersensitivity reactions are the most frequent immunotoxic effects of drugs. They include immune-mediated ('allergic') and non immune-mediated ('pseudoallergic') reactions. Drug-induced autoimmune reactions, either systemic or organ-specific, are seemingly rare. A review of drug-induced immunotoxic effects demonstrates that immunotoxicity is a significant cause of morbidity and even mortality. As immunotoxicologists have long focused on immunosuppression, the nonclinical immunotoxicity safety assessment of unexpected immunosuppression is based on a number of relatively well standardised and validated animal models and assays. However, there is no general consensus regarding the minimal requirement for this assessment. Many different assays can be used to extend the assessment case by case. Few animal models and assays have been validated for use in the nonclinical safety assessment of unexpected immunostimulation. The situation is worse regarding the prediction of hypersensitivity and autoimmune reactions. Our limited understanding of the molecular and cellular mechanisms of immunotoxicity accounts, at least partly, for this situation. Recent guidelines for the immunotoxicity safety assessment of drugs, even though conflicting on several points, will serve as an impetus not only to refine current animal models and assays, but also to search for better alternatives. The new data generated will have to be interpreted and extended to animal species other than just rodents. Likewise, animal results will have to be compared with findings in humans. The search for immunological endpoints that can be used in several animal species and in humans will therefore become essential. Specific endpoints and clinical criteria that can be included in clinical trials to further investigate the potential for immunotoxicity of new drugs will have to be defined. Because immunotoxicity plays a key role in drug-induced adverse effects, the role of immunotoxicology in drug safety assessment is indisputable and the systematic nonclinical as well as clinical immunotoxicity assessment of every new drug is deemed essential.

Objective: To assess the risk of major malformations in pregnant women with chronic inflammatory disorders treated with low dose methotrexate (MTX) during the first trimester of pregnancy. Secondary outcomes included the rate of miscarriage, birth weight, and gestational age at delivery., Methods: Data from the French network of 31 pharmacovigilance centers and 2 teratology information services were analyzed. The outcome of pregnancy was prospectively assessed in women exposed during the first trimester of pregnancy. Data on maternal history and drug exposure were collected at the initial inquiry, and on the outcome of pregnancy at followup., Results: Twenty-eight cases were available for analysis. MTX exposure ended before 8 weeks of gestation in 26 patients. Miscarriages occurred in 4 patients and 5 had elective termination of pregnancy. There were 19 live births, among whom 3 were premature. Birth weights in full-term children were within the expected range. One child exposed until 8.5 weeks of gestation had only minor anomalies (metatarsus varus and eyelid angioma)., Conclusion: Although no definitive conclusion can be drawn, our results and the analysis of the literature support the conclusion that no strong teratogenic risk is associated with low dose MTX provided that the drug is discontinued as early as possible in pregnant women.

The popliteal lymph node (PLN) assay was proposed to detect the potential of immunotoxicants for inducing systemic autoimmune-like reactions, but also xenobiotics that are sensitizing or exert immunostimulatory properties. Results on over 100 chemicals, mostly pharmaceuticals, are available with the PLN assay and show many correlations between rodent data and the clinical experience. A major issue is that the mechanisms involved have not been fully elucidated. In order to provide mechanistic clues to improve the predictability of the PLN assay, the effects of streptozotocin (STZ) were compared to those of ethanol and acetone in normal C57Bl/6 mice as well as mice depleted in CD4+ or CD8+ T-cells by treatment with specific monoclonal antibodies. STZ, ethanol and acetone gave similar positive responses in normal mice. Neither CD4+ nor CD8+ T-cell depletion influenced the PLN responses to ethanol or acetone, whereas CD8+ in contrast to CD4+ T-cell depletion abolished the response to STZ. There was an increase in the production of IL-6 and IFN-gamma mRNAs measured by RT-PCR in STZ-, but not in ethanol- or acetone-treated normal mice. The production of TNFalpha, IL-1alpha, IL-1beta, IL-2R and IL-12 mRNAs was increased whatever the treatment, but increases were 2- to 3-fold greater after STZ than ethanol or acetone. These results suggest that PLN responses to primary irritants such as ethanol and acetone essentially reflect non-specific inflammation, whereas PLN responses to an autoimmunogenic compound such as STZ involve CD8+ T lymphocytes and the production of IFN-gamma and IL-6. These findings may prove useful to improve the predictability of the PLN assay.

This study was conducted to review the progression with age of renal and other changes in (NZB x NZW) F1 females obtained from a commercial colony, housed under SPF conditions. Sixty-two mice were given food and water ad libitum and sacrificed at intervals up to 47 weeks of age. Routine haematology and urinalysis were performed at regular intervals. The serum levels of IgA, IgG, IgM and antinuclear antibody levels were monitored along with urinary protein. Major organs and tissues from all animals were preserved and examined. Special attention was paid to the kidneys: in addition to routine 4-microm paraffin sections, 1-microm resin sections were prepared and examined. Positive levels of urinary protein (> 1 g/L) were only found in 50% of the animals, even at 32 weeks of age. Histopathologically, the expected type of glomerular damage was present; but the incidence and severity of the change were low, with only 33% of the mice affected at 32 weeks of age. Most mice had fatty vacuolation in the liver. At 24 weeks of age, 50% of the mice sacrificed had haemorrhagic degeneration of the liver. This was not seen at later time points. Only two mice survived until 47 weeks of age. In summary, these findings were of the expected type, but at a much lower incidence and severity than formerly reported. The background of the strain and the experimental conditions are of great importance in the progress of these renal lesions. The lack of homogeneity of the renal changes would make it difficult to determine any influence of xenobiotics on the progress of autoimmune diseases.

The popliteal lymph node assay (PLNA) is being considered as a tool to predict the potential of drugs for inducing systemic autoimmune and hypersensitivity reactions. Despite the use of different technical approaches and the evaluation of over 130 compounds, the sensitivity and specificity of the PLNA are still debatable due to many false positive and negative responses. In this study, cytokine production was assessed as a possible endpoint to improve the direct (primary) PLNA. Diclofenac, imipramine, hydralazine, glafenin and minocycline were tested using the classical procedure. TH1 cytokines (IL-2 and IFN-gamma), TH2 cytokines (IL-4 and IL-5) and pro-inflammatory cytokines (IL-6, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), IL-12p70 and IL-10) were measured in the serum and in suspensions of popliteal lymph node cells of female Balb/c mice by flow cytometry 7 days after drug administration. Only diclofenac and imipramine induced a cellularity index above 5 (considered as a positive response). Of the five tested drugs, only diclofenac induced a slight increase in TH1 cytokines, but there were no effects on TH2 cytokine production whatever the drug tested. Diclofenac increased the production of pro-inflammatory cytokines, whereas the production of MCP-1 was increased by minocycline and decreased by imipramine. No changes in serum cytokine levels were evident. These results suggest that measuring cytokine release is unlikely to improve the sensitivity and specificity of the direct PLNA.

Objectives and Methods: To describe cases of fusidic acid-associated sideroblastic anaemia from the French Pharmacovigilance database., Results: Six cases of sideroblastic anaemia associated with oral fusidic acid treatment were retrieved. Four females and two males (mean age 65.3 yr) developed severe anaemia (mean haemoglobin level: 6.9 g/dL) within 32-190 d (mean: 81 d) of treatment. Bone marrow aspirates showed dyserythropoiesis and ringed sideroblasts in all patients. Four patients required repeated blood transfusions. After fusidic acid discontinuation in five patients, complete recovery was obtained. In one patient, rechallenge with fusidic acid resulted in recurrence of anaemia that resolved after definitive discontinuation of the drug., Conclusion: Our data indicate that fusidic acid should be added to the list of drugs that can cause sideroblastic anaemia.

Objective: To determine the optimal evaluation and management of renal injuries by review of the world's English-language literature on the subject., Methods: A consensus conference convened by the World Health Organization and the Societé Internationale d'Urologie met to critically review reports of the diagnosis and treatment of renal trauma. The English-language literature about renal trauma was identified using Medline, and additional cited works not detected in the initial search obtained. Evidence-based recommendations for the diagnosis and management of renal trauma were made with reference to a five-point scale., Results: There were many Level 3 and 4 citations, few Level 2, and one Level 1 which supported clinical practice patterns. Findings of nearly 200 reviewed citations are summarized., Conclusions: Published reports on renal trauma still rely heavily on expert opinion and single-institution retrospective case series. Prospective trials of the most significant issues, when possible, might improve the quality of evidence that dictates the behaviour of practitioners.