Dominique Hillaire-Buys

Immediate hypersensitivity to ceftriaxone

despite treatment. Inhalation challenges were carried out 6 years later. At that time, he was treated with inhaled ̄uticasone dipropionate 500 mg b.i.d. and inhaled salbutamol when required. He had smoked 10 cigarettes a day for 15 years. Baseline spirometry showed FEV1 of 2.70 l (75% predicted value) with an FEV1/FVC ratio of 74%. Histamine PC20 was 0.125 mg/ml. After a control challenge with a paint diluent, the subject sprayed an insecticide formulation containing 0.2% tetramethrin and 0.1% fenitrothion, which resulted in a dual asthmatic reaction (Fig. 1, upper graph). Five months later, the subject was challenged with pure tetramethrin powder (diluted 1/10 in lactose) (Fig. 1, lower graph). Exposure to tetramethrin caused a 31% fall in FEV1. The subject refused further challenge with pyrethrins or other pyrethroids. Skin prick testing with common inhalant allergens and tetramethrin (diluted 1/1000, 1/100, and 1/10 in saline) gave negative results. To our knowledge, this is the ®rst account of asthmatic reactions provoked by tetramethrin, although it remains unknown what mechanisms were responsible for the induction of these reactions. Pyrethrins do not exhibit anticholinesterase activity; they act directly on axons by altering transmembrane sodium conductance (1). Several reports have documented asthmatic reactions (2±5), as well as a hypersensitivity pneumonitis-like syndrome (6), in subjects exposed to insecticides containing pyrethrum or pyrethrins. Skin tests with pyrethrum extracts were positive in some of the reported subjects (2, 3, 6), although these reactions could have been caused by allergenic impurities derived from C. cinerariifolium. The respiratory effects of an aerosol insecticide containing a mixture of pyrethrins and tetramethrin have been prospectively evaluated in seven asthmatic subjects who reported a history of chest tightness on exposure to sprayed insecticides (4). Although exposure to the insecticide spray produced respiratory symptoms in all subjects, signi®cant changes (.20%) in FEV1 were documented in only one of them. This report indicates that the impact of pyrethroids on respiratory health deserves further investigation.

Antipsychotics‐induced ischaemic colitis and gastrointestinal necrosis: a review of the French pharmacovigilance database

First‐ and second‐generation antipsychotics commonly cause mild gastrointestinal hypomotility. Intestinal necrosis may be a consequence of such gastrointestinal perturbations.

Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!

Between 1995 and 2000, many peroxisome proliferatoractivated receptor (PPAR) agonists were developed for the treatment of type 2 diabetes mellitus. Whereas PPARα agonists (fibrates) improve lipid metabolism, PPARγ agonists (thiazolidinediones) sensitize insulin action and improve glycemic control. The search for a wider pharmacodynamic effect with synergism on lipid and glucose homeostasis in patients with metabolic syndrome or type 2 diabetes led to the concept of dual-acting PPARα and PPARγ agonists [1, 2]. These dual agonists, named glitazars, were all stopped during preclinical or clinical development, mainly because of carcinogenic effects in animals, especially bladder tumors in male rats [3]. In September 2010, the U.S. Food and Drug Administration issued an alert in connection with a potential relationship between the occurrence of bladder cancers in patients and the prescription of pioglitazone at high doses and for long periods [4]. Reviewing the PROactive study safety data, we reported that the incidence of bladder cancers was significantly higher in the pioglitazone-treated group than in the placebo group, with an estimated crude relative risk of 2.83 (95 % CI 1.02–7.85) [5]. This result is supported by a recent study from Neumann et al. [6], showing a dose-dependent increase in the incidence of bladder cancer in pioglitazone-exposed diabetic patients. Analysis of the pharmacological data published so far gives evidence that pioglitazone has a pharmacodynamic profile comparable to that of the glitazar compounds (Table 1); specifically, it has a dual pharmacological effect on both PPARα and PPARγ that can be obtained in humans at the concentrations clinically used. In order to explain hyperplasia and bladder cancers in male rats during the preclinical development of pioglitazone, the Takeda group favored the hypothesis of urolithiasis [4, 7]. This hypothesis is supported by the presence of crystals causing continuous irritation, particularly in ventral bladder. Recently, Sato and colleagues reported data from a 24-month mechanistic study showing decreased formation of urinary microcrystals when using an acidifying diet [7]; under these conditions, the elevated incidence of advanced proliferative changes in pioglitazone-treated animals was significantly decreased. However, the incidence of hyperplasia was not reduced, and the incidence of D. Hillaire-Buys Department of Medical Pharmacology and Toxicology, CHRU Montpellier and INSERM U1058, Montpellier, France

Examples of how the pharmaceutical industries distort the evidence of drug safety: the case of pioglitazone and the bladder cancer issue.

Pioglitazone is an antidiabetic drug marketed since 2000 under the brand name Actos® by the firm Takeda with initial co-promotion by Eli Lilly. In pre-marketing animal studies, bladder cancers were identified in male rats exposed to pioglitazone, but it is in June 2011 that the US Food and Drug Administration (FDA) and the European Medicine Agency concluded that there was a slight increase of risk of bladder cancer associated with the use of pioglitazone and recommended the application of safety measures such as restriction of use and patients monitoring. After these warnings, numerous pioglitazone users claimed that the drug caused them to develop bladder cancer, and the firms involved were sued in several lawsuits in the USA. The firms’ behavior in the pioglitazone bladder cancer affair has already been criticized for several aspects: (i) the wrong pharmacological presentation of pioglitazone as a selective peroxisome proliferatoractivated receptor γ (PPAR γ) agonist whereas it belongs to the dual PPAR γ/α agonists, a class that has been associated with bladder tumors;1 (ii) the mistaken number of bladder cancer cases in the placebo group of the PROactive trial hiding a statistically significant risk of bladder cancer;2 or (iii) the alleged lack of reporting of post-marketing bladder cancers to the FDA.3 In the context of one of the first pioglitazone lawsuits, the US District Court for the Western District of Louisiana made accessible through its website the 68-page legal memorandum of sworn testimonies supporting the arguments against the firm.4 These documents reveal unknown examples of the firms’ poor conduct regarding drug safety assessment and management of pioglitazone. We discuss here the most relevant pieces of information.