NKp46+ cells express granulysin in multiple cutaneous adverse drug reactions

The spectrum of cutaneous adverse drug reactions (cADRs) ranges from benign presentations to severe life-threatening forms such as toxic epidermal necrolysis (TEN). In TEN, granulysin has been shown to be the key cytotoxic molecule. Still, little is known about the expression of granulysin in other cADRs. As an important source of granulysin, natural killer (NK) cells are of major interest in cADRs. Recently, NKp46 has been identified as the most selective NK-cell marker. However, the role of NKp46(+) cells in cADRs and their contribution to granulysin expression remain to be elucidated.

[Pharmacotherapy of hyperthyreosis--adverse drug reactions]

The antithyroid drugs mainly include thioimidazole (carbimazole, methimazole=thiamazole) and propylthiouracil. After absorption, carbimazole is rapidly metabolized to methimazole and thus switching between these two drugs should not be considered in case of side effects. Furthermore, in case of side effects, sometimes even cross reactions between thioimidazoles and propylthiouracil occur. Common and typical adverse reactions of antithyroid drugs include dose dependent hypothyroidism and thus thyroid function should be repeatedly checked while the patient is on antithyroid drugs. Furthermore, pruritus and rash may develop. In this case, one might try to switch from thioimidazoles to propylthiouracil or vice versa. Antithyroid drugs may cause mild dose dependent neutropenia or severe allergy-mediated agranulocytosis, which typically occurs during the first three months of treatment, has an incidence of 3 per 10,000 patients and cross reactivity between thioimidazoles to propylthiouracil may occur. Rarely, antithyroid drugs can cause aplastic anemia. Mainly propylthiouracil, but sometimes also methimazole may lead to an asymptomatic transient increase in liver enzymes or to severe, even lethal liver injury of cholestatic or hepatocellular pattern. Since propylthiouracil associated liver injury was observed increasingly among children and adolescent, it has been suggested to prefer thioimidazoles for these patients. Because of these potential serious adverse effects, physicians should advise patients to immediately seek medical help if they get a fever or sore throat or malaise, abdominal complaints or jaundice, respectively. Furthermore, arthralgias may develop in 1-5% of patients under both antithyroid drugs. Since arthralgias may be the first symptom of more serious immunologic side effects, it is recommended to stop the antithyroid drug in this case. Drug induced polyarthritis mainly develops during the first month of therapy, whereas ANCA-positive vasculitis is generally observed only after long term exposure to propylthiouracil or very rarely with the thioimidazoles. The teratogenic risk of the thioimidazoles is somewhat higher (Aplasia cutis congenita), that is why one generally recommends preferring propylthiouracil during pregnancy. During breast feeding both, thioimidazoles or propylthiouracil, may be administered. Nowadays, perchlorate is only used short term in case of latent hyperthyroidism before administering iodine-containing contrast agents. Therefore, the known side effects, which usually are only observed after long term treatment, are not an issue any more.

Potential drug-drug interactions and adverse drug reactions in patients with liver cirrhosis

Patients with liver cirrhosis may be at risk for potential drug-drug interactions (pDDIs) and/or adverse drug reactions (ADRs) due to the severity of their disease and comorbidities associated with polypharmacy.

Etiology and pathogenesis of adverse drug reactions

In clinical routine, adverse drug reactions (ADR) are common, and they should be included in the differential diagnosis in all patients undergoing drug treatment. Only part of those ADR are immune-mediated hypersensitivity reactions and thus true drug allergies. Far more common are non-immune-mediated ADR, e.g. due to the pharmacological properties of the drug or to the individual predisposition of the patient (enzymopathies, cytokine dysbalance, mast cell hyperreactivity). In true drug allergiesT cell- and immunoglobulin E (lgE)-mediated reactions dominate the clinical presentation. T cell-mediated ADR usually have a delayed appearance and include skin eruptions in most cases. Nevertheless, it should not be forgotten that they may involve systemic T cell activation and thus take a severe, sometimes lethal turn. Clinical danger signs are involvement of mucosal surfaces, blistering within the exanthematous skin areas and systemic symptoms, e.g. fever or malaise. Drug presentation via antigen-presenting cells to T cells can either involve the classical pathway of haptenization of endogenous proteins or be directly mediated via noncovalent binding to immune receptors (MHC molecules or T cell receptors), the so-called p-i concept. Flare-up reactions during the acute phase of T cell-mediated ADR should not be mistaken for true drug allergies, as they only occur in the setting of a highly activated T cell pool. IgE-mediated ADR are less frequent and involve mast cells and/or basophils as peripheral effector cells. Recent data suggest that certain patients with drug allergy have a preexistent sensitization although they have never been exposed to the culprit drug, probably due to cross-reactivity. Thus, allergic drug reactions on first encounter are possible. In general, the extent of cross-reactivity is higher in IgE-compared to T cell-mediated ADR. Based on a specific ethnic background and only for severe T cell-mediated ADR to certain drugs, a strong HLA association has been established recently.

Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations

To assess drug-related problems in patients with liver cirrhosis by investigating the prevalence of inadequately dosed drugs and their association with adverse drug reactions (ADRs) and hospitalizations.

Critical incidence reporting systems - an option in equine anaesthesia? Results from a panel meeting.

OBJECTIVE To provide a brief introduction into Critical Incident Reporting Systems (CIRS) as used in human medicine, and to report the discussion from a recent panel meeting discussion with 23 equine anaesthetists in preparation for a new CEPEF-4 (Confidential Enquiry into Perioperative Equine Fatalities) study. STUDY DESIGN Moderated group discussions, and review of literature. METHODS The first group discussion focused on the definition of 'preventable critical incidents' and/or 'near misses' in the context of equine anaesthesia. The second group discussion focused on categorizing critical incidents according to an established framework for analysing risk and safety in clinical medicine. RESULTS While critical incidents do occur in equine anaesthesia, no critical incident reporting system including systematic collection and analysis of critical incidents is in place. CONCLUSIONS AND CLINICAL RELEVANCE Critical incident reporting systems could be used to improve safety in equine anaesthesia - in addition to other study types such as mortality studies.

Optimized CUDA-Based PDE Solver for Reaction Diffusion Systems on Arbitrary Surfaces

Partial differential equation (PDE) solvers are commonly employed to study and characterize the parameter space for reaction-diffusion (RD) systems while investigating biological pattern formation. Increasingly, biologists wish to perform such studies with arbitrary surfaces representing ‘real’ 3D geometries for better insights. In this paper, we present a highly optimized CUDA-based solver for RD equations on triangulated meshes in 3D. We demonstrate our solver using a chemotactic model that can be used to study snakeskin pigmentation, for example. We employ a finite element based approach to perform explicit Euler time integrations. We compare our approach to a naive GPU implementation and provide an in-depth performance analysis, demonstrating the significant speedup afforded by our optimizations. The optimization strategies that we exploit could be generalized to other mesh based processing applications with PDE simulations.

Bifurcation Analysis of Reaction Diffusion Systems on Arbitrary Surfaces

In this article we present a computational framework for isolating spatial patterns arising in the steady states of reaction-diffusion systems. Such systems have been used to model many different phenomena in areas such as developmental and cancer biology, cell motility and material science. Often one is interested in identifying parameters which will lead to a particular pattern. To attempt to answer this, we compute eigenpairs of the Laplacian on a variety of domains and use linear stability analysis to determine parameter values for the system that will lead to spatially inhomogeneous steady states whose patterns correspond to particular eigenfunctions. This method has previously been used on domains and surfaces where the eigenvalues and eigenfunctions are found analytically in closed form. Our contribution to this methodology is that we numerically compute eigenpairs on arbitrary domains and surfaces. Here we present various examples and demonstrate that mode isolation is straightforward especially for low eigenvalues. Additionally we see that if two or more eigenvalues are in a permissible range then the inhomogeneous steady state can be a linear combination of the respective eigenfunctions. Finally we show an example which suggests that pattern formation is robust on similar surfaces in cases that the surface either has or does not have a boundary.

CD8+ T cells and NK cells from blister fluid of an EEM/SJS overlap highly express Fas ligand and Granulysin

INTRODUCTION Erythema exsudativum multiforme majus (EEMM) and Stevens-Johnson Syndrome (SJS) are severe cutaneous reaction patterns caused by infections or drug hypersensitivity. The mechanism by which widespread keratinocyte death is mediated by the immune system in EEMM/SJS are still to be elucidated. Here, we characterized the blister cells isolated from a patient with EEMM/SJS overlap and investigated its cause. METHODS Clinical classification of the cutaneous eruption was done according to the consensus definition of severe blistering skin reactions and histological analysis. Common infectious causes of EEMM were investigated using standard clinical techniques. T cell reactivity for potentially causative drugs was assessed by lymphocyte transformation tests (LTT). Lymphocytes isolated from blister fluid were analyzed for their expression of activation markers and cytotoxic molecules using flow cytometry. RESULTS The healthy 58 year-old woman suffered from mild respiratory tract infection and therefore started treatment with the secretolytic drug Ambroxol. One week later, she presented with large palmar and plantar blisters, painful mucosal erosions, and flat atypical target lesions and maculae on the trunc, thus showing the clinical picture of an EEMM/SJS overlap (Fig. 1). This diagnosis was supported by histology, where also eosinophils were found to infiltrate the upper dermis, thus pointing towards a cutaneous adverse drug reaction (cADR). Analysis of blister cells showed that they mainly consisted of CD8+ and CD4+ T cells and a smaller population of NK cells. Both the CD8+ T cells and the NK cells were highly activated and expressed Fas ligand and the cytotoxic molecule granulysin (Fig. 2). In addition, in comparison to NK cells from PBMC, NK cells in blister fluids strongly upregulated the expression of the skin-homing chemokine receptor CCR4 (Fig 4). Surprisingly, the LTT performed on PBMCs in the acute phase was positive for Ambroxol (SI=2.9) whereas a LTT from a healthy but exposed individual did not show unspecific proliferation. Laboratory tests for common infectious causes of EEMM were negative (HSV-1/-2, M. pneumoniae, Parvovirus B19). However, 6 weeks later, specific proliferation to Ambroxol could no longer be observed in the LTT (Fig 4.).

A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer

Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

Approach to the patient with drug allergy

Clinicians commonly encounter patients who report to have drug allergy. In a large part, such allergy corresponds to adverse drug reactions, which are not immune mediated. The incriminated drug need not always be avoided for further therapy. On the other hand, drug allergy may manifest in many unexpected clinical pictures and thus not be recognized. There is no single standardized diagnostic test to confirm the immune-mediated mechanism and to identify the causative drug. Therefore, immune-mediated drug hypersensitivity reactions and their causative drugs have to be considered by the constellation of exposure, timing, and clinical features, including the pattern of organ manifestation. Prior experience with the drug is also an important feature. An allergologic workup with additional investigation may provide some help. Patients should be informed carefully about their drug allergy, whereby symptoms, drug that elicits reaction, modes of diagnosis of drug allergy, and possibly alternatives should be indicated in their allergy passport.

Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism

Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations.

Systematic review of medication safety assessment methods

Purpose The accuracy, efficiency, and efficacy of four commonly recommended medication safety assessment methodologies were systematically reviewed. Methods Medical literature databases were systematically searched for any comparative study conducted between January 2000 and October 2009 in which at least two of the four methodologies—incident report review, direct observation, chart review, and trigger tool—were compared with one another. Any study that compared two or more methodologies for quantitative accuracy (adequacy of the assessment of medication errors and adverse drug events) efficiency (effort and cost), and efficacy and that provided numerical data was included in the analysis. Results Twenty-eight studies were included in this review. Of these, 22 compared two of the methodologies, and 6 compared three methods. Direct observation identified the greatest number of reports of drug-related problems (DRPs), while incident report review identified the fewest. However, incident report review generally showed a higher specificity compared to the other methods and most effectively captured severe DRPs. In contrast, the sensitivity of incident report review was lower when compared with trigger tool. While trigger tool was the least labor-intensive of the four methodologies, incident report review appeared to be the least expensive, but only when linked with concomitant automated reporting systems and targeted follow-up. Conclusion All four medication safety assessment techniques—incident report review, chart review, direct observation, and trigger tool—have different strengths and weaknesses. Overlap between different methods in identifying DRPs is minimal. While trigger tool appeared to be the most effective and labor-efficient method, incident report review best identified high-severity DRPs.

Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.