[Vigilance for veterinary medicinal products: reports of adverse reactions in the year 2012]. / Vigilance der Tierarzneimittel: Gemeldete unerwünschte Wirkungen im Jahr 2012.

197 adverse reactions of Swissmedic-authorized veterinary medicinal products were reported during the year 2012 (2011: 167). Species and drug classes remain unchanged over the years: most of the reports related to reactions following the use of antiparasitic products (37.6 %), antiinfectives (15.7 %) or non-steroidal antiinflammatory drugs (11.7 %) in companion animals (94 dogs and 53 cats) followed by cattle/calves (29). Additionally, 45 cases transmitted by the Swiss Toxicological Information Centre in Zürich were processed. We discuss a paradoxical reaction under the potential influence of acepromazine as well as a modified protocol for treating permethrin intoxication in cats. Finally, the vaccinovigilance program received 95 declarations following the application of various vaccines, mainly to dogs or cats.

En 2012, on a enregistré 197 annonces de réactions après application de médicaments vétérinaires autorisés par Swissmedic (2011: 167). La répartition de ces annonces, tant en ce qui concerne les espèces que les classes de médicaments, est inchangée par rapport aux années précédentes: on a annoncé le plus souvent des réactions à des produits antiparasitaires (37.6 %), antiinfectieux (15.7 %) ou antiinflammatoires (11.7 %) chez les petits animaux (94 annonces concernaient des chiens, 53 des chats) suivis par les bovins (29 annonces). En outre 45 cas annoncés par le Centre suisse d'information toxicologique de Zürich dans le cadre de ses activités de conseil ont été étudiés. Une réaction paradoxale d'agressivité sous l'effet possible de l'acépromazine et un protocole modifié pour le traitement des intoxications à la perméthrine chez le chat sont présentés. Pour ce qui est de la vaccinovigilance effectuée par l'IVI, on a enregistré 95 annonces de réactions après l'application de divers vaccins, principalement chez des chiens et des chats.

[Vigilance for veterinary medicinal products: declarations of adverse reactions in the year 2010]. / Vigilance der Tierarzneimittel: Gemeldete unerwünschte Wirkungen im Jahr 2010.

In 2010, we observed again an increase in the number of declarations reported to the vigilance system for veterinary medicinal products up to a total of 160. The species and drug classes reported remained the same as in previous years: the majority of adverse drug reactions (ADRs) concerned either dogs or cats and the most frequently involved drugs were either antiparasitic products or antiinfectives. Adverse reactions following reconversions and 8 cases of suspected allergic reactions following the use of amoxicillin-clavulanic acid combinations in dogs were reported. Additional enquiries were processed by the Swiss Toxicological Information Centre and transmitted to Swiss medic. 11 of these reported accidental ingestions of flavoured tablets in overdose by dogs and some cats. The vaccino vigilance program received 179 declarations following immunization against blue tongue disease as well as 82 declarations following the application of other vaccines. The vigilance system increases the chance to identify rare reactions or interactions and thereby contributes to the security of veterinary medicinal products.

[Vigilance for veterinary medicinal products: declarations of adverse reactions in the year 2009]. / Vigilance der Tierarzneimittel: Gemeldete unerwünschte Wirkungen im Jahr 2009.

During the year 2009, 134 reports of suspected adverse drug reactions (ADRs) to veterinary medicinal products (VMPs) were received (106 in the year 2008). The distribution according to species and drug classes remained in line with previous years. Companion animals were involved in most of the reports (46 % dogs, 19 % cats), followed by cattle or calves (22 %). Antiparasitic drugs made the biggest part with 30 % of the reports, followed by antiinfectives (19 %) and hormones (13 %). Some reactions following their use are specifically discussed. 95 additional enquiries about ADRs of VMPs were received by the Swiss Toxicological Information Centre in Zürich. Most of them concerned dogs or cats and antiparasitics or anti-inflammatory drugs. In the vaccinovigilance program, a total of 1020 reports were received, of which 1000 were related to the vaccination against blue tongue disease. The most frequently reported adverse reactions were aborts, mastitis or alterations of milk quality and they are specifically discussed.

[Vigilance for veterinary medicinal products: declarations of suspected adverse reactions in the year 2007]. / Vigilance der Tierarzneimittel: Gemeldete unerwünschte Wirkungen im Jahr 2007.

163 reports of suspected adverse reactions were received in the year 2007: 111 for veterinary medicinal (VMPs) and 52 for immunologic products. Half of the reported reactions for VMPs concerned either an antiparasitic drug (26%) or an antibiotic (24%). Reconversions (use in another target species or for another indication as registered) made the third most frequently mentioned group with 11 reports. For immunologicals, half of the declarations were related to an adverse reaction in dogs, the most frequently reported reaction in companion animals being allergies. Moreover, 272 enquiries were received by the Swiss Toxicological Information Center in Zürich. Most of these were related to dogs (73%) and the number of enquiries regarding VMPs correlated positively with the most frequently used therapeutic classes like antiparasitics (47%) and anti-inflammatory drugs (23%). The complexity of proscessing reports regarding the detection of residues in milk after prescribed withdrawal times is discussed in detail. In conclusion, the year 2007 is seen as a consolidation of the established system with a tendency towards increase in the number of complex cases.

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death.

Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved.

[Reported adverse reactions due to veterinary drugs in 2006]. / Gemeldete unerwünschte Wirkungen von Tierarzneimitteln im Jahr 2006.

We received 190 reports of suspected adverse events (SARs) following the use of veterinary drugs for the year 2006: 118 declarations for veterinary drugs and 72 declarations following the application of immunolgical medicinal products. Most of the 118 declarations relate to the use of antiparasitic drugs (48%) and every second declaration to drug use in dogs. Other drug classes concerned were, in decreasing order, antiinfectives (20%) and drugs used off-label (12%; other target species or other indication). For the vaccines, most of the reactions occurred in dogs (62%) followed by horses (11%) and cattle (10%). The most frequently reported reactions concerned the use of a vaccine against piroplasmosis. Another 349 requests for information were processed by the Swiss Toxicological Information center. We also present a case of a serious adverse reaction in form of a Stevens-Johnson syndrome in a cat as well as a case of ketamine abuse. We note the growing interest of practicing veterinarians with pleasure and are currently working on further adaptations to the system.

[Reported adverse reactions of veterinary drugs and vaccines in 2005]. / Gemeldete unerwünschte Wirkungen von Tierarzneimitteln im Jahr 2005.

We received 105 reports of suspected adverse events (SARs) following the use of veterinary drugs for the year 2005. This corresponds to a 35% increase compared to 2004. Practicing veterinarians sent most of these declarations. 73% of these concerned drugs used on companion animals. Antiparasitic drugs approved for topical use were the most frequently represented group with 48%, followed by drugs used to treat gastrointestinal disorders (11%) and drugs used off-label (14%; other target species or other indication). For the first time 2 declarations concerning the application of permethrin containing spot-on preparations used by mistake on cats were received. An overview of 20 declarations about adverse reactions following application of different vaccines is also presented with emphasis on the problem of fibrosarcoma in cats. We are pleased by the growing interest shown by practicing veterinarians for the vigilance system and hope to further develop this collaboration in the future.

[Swiss veterinary drug compendium as a tool for reconversions]. / Das Tierarzneimittelkompendium als Umwidmungshilfe.

The new Swiss ordinance on veterinary drugs poses a new challenge to the veterinarians, specially those working with farm animals. A complete overview about the registered veterinary drugs and immunobiologicals is absolutely necessary to cope with these new tasks: the internet version of the Swiss Veterinary Drug Compendium is a versatile tool to satisfy this needs (http://www.tierarzneimittel.ch). Due to the frequent updates and powerful search possibilities, this database is a reliable and comprehensive information system regarding Swiss veterinary drugs. We will demonstrate how this system can be used as a valuable help in the case of reconversions of drugs (e.g. use of small animal drugs in farm animals).

[Suspected adverse drug reactions in 2004]. / Meldungen zu unerwünschten Wirkungen von Tierarzneimitteln im Jahr 2004.

We received 62 reports of suspected adverse events (SARs) for the year 2004. Their number and repartition according to affected animals and active substances were comparable with the previous year. The distributors or manufacturers submitted most of the declarations, but the proportion submitted by practicing veterinarians is slowly growing. 72% of the declarations dealt with adverse reactions in small animals (cats and dogs), followed by cattle and horses. Antiparasitics, anti-inflammatory drugs and immunologicals were the most frequently mentioned therapeutic classes, which are listed here according to the international ATCvet classification. A report from abroad about a fatality following injection of an antibiotic preparation for cattle prompted Swissmedic to review the security of this medication also sold on the Swiss market. It was decided to modify the package insert to warn about the danger of inadvertent self-injection in humans, to reduce the risk of similar accidents in Switzerland. We hope that the pharmacovigilance system will enjoy an increasing awareness by the practicing veterinarians.

[Pharmacovigilance for veterinary drugs in Switzerland]. / Pharmacovigilance für Tierarzneimittel in der Schweiz.

Pharmacovigilance is a system concerned with the acquisition, evaluation and classification of informations about suspected adverse drug reactions (SADR). Such a system was developed in Switzerland under the supervision of Swissmedic after the introduction of the federal law on therapeutic products on January 1st 2002. By sending declarations about SADRs, veterinary practitioners play a central role in this scheme. The reports are processed according to international standards (ABON) and provide useful hints to enhance the safety of drug usage by both patients and owners. The system acquired 58 reports in its first complete year of operation (2003). Analysis of these reveals that trends observed in foreign countries are also applicable to Switzerland: most of the reports concerned the use of antiparasitic or antibiotic drugs in small animals. The first year also revealed a high percentage of declarations coming from the pharmaceutical companies and the authors would therefore like to encourage practitioners to take a more active part in this scheme.

[Computer-based information system (CliniTox) for the management of poisoning in small animals]. / Computergestütztes Informationssystem für Vergiftungen (CliniTox) beim Kleintier.

Because cases of poisoning are observed rarely, veterinary practitioners have only limited knowledge of clinical toxicology and may face considerable problems in handling toxicological emergencies. In this report, we describe a novel decision support system for the management of poisonings in companion animals that provides rapid access to the current knowledge of clinical toxicology. For that purpose, relevant reports from the peer-reviewed literature were evaluated and organised according to the requirements of a structured database. The information provided for each toxic substance includes a summary of its chemical and physical properties, sources, commercial uses or natural occurrences, toxicokinetic data, mechanisms of action, threshold doses, clinical symptoms with brief case reports, sampling and analytical results, post-mortem findings, differential diagnoses, therapeutic guidelines and references to the literature. This decision support system has been programmed with two user-friendly search functions: a search tool that allows to choose clinical symptoms, and another function that serves to find a substance using its chemical name, the class of compounds to wich it belongs, a possible source or one of its main applications. CliniTox can be accessed directly via our webserver (http://www.clinitox.ch).

Poly ADP-ribosylation in two L5178Y murine lymphoma sublines differentially sensitive to DNA-damaging agents.

PURPOSE: To characterize the response to X-irradiation of the poly ADP-ribosylation system in two closely related murine lymphoma sublines, L5178Y-R (LY-R) and L5178Y-S (LY-S), with differential sensitivity to various DNA damaging agents (UV-C and ionizing radiation, hydrogen peroxide). MATERIALS AND METHODS: LY cells were X-irradiated (2 Gy). NAD+ was determined in cell extracts by high-pressure liquid chromatography. ADP-ribose polymers were purified and analysed by densitometry after polyacrylamide gel electrophoresis. Nuclear matrix proteins were separated by SDS-polyacrylamide gel electrophoresis and processed for ADP-ribose polymer blots to estimate their ability to bind poly(ADP-ribose). RESULTS: In the radiosensitive LY-S cells, the constitutive levels of ADP-ribose polymers were twofold higher than in radioresistant LY-R cells, but unresponsive to a challenge with 2 Gy X-rays. The concentrations of NAD+ - the substrate for poly(ADP-ribose) synthesis - were identical in the two cell lines. X-rays (2 Gy) depleted NAD+ only in LY-S cells. These cells also produced shorter poly(ADP-ribose) molecules as compared with LY-R cells. Nuclear matrix preparations of LY-S cells exhibited lower poly(ADP-ribose)-binding capacity than those of LY-R cells. CONCLUSION: The results demonstrate disturbances in the poly ADP-ribosylation response of the radiosensitive LY-S cells and reduced poly(ADP-ribose)-binding affinity of the nuclear matrix of these cells.

Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins.

Poly(ADP-ribose) is formed in possibly all multicellular organisms by a familiy of poly(ADP-ribose) polymerases (PARPs). PARP-1, the best understood and until recently the only known member of this family, is a DNA damage signal protein catalyzing its automodification with multiple, variably sized ADP-ribose polymers that may contain up to 200 residues and several branching points. Through these polymers, PARP-1 can interact noncovalently with other proteins and alter their functions. Here we report the discovery of a poly(ADP-ribose)-binding sequence motif in several important DNA damage checkpoint proteins. The 20-amino acid motif contains two conserved regions: (i) a cluster rich in basic amino acids and (ii) a pattern of hydrophobic amino acids interspersed with basic residues. Using a combination of alanine scanning, polymer blot analysis, and photoaffinity labeling, we have identified poly(ADP-ribose)-binding sites in the following proteins: p53, p21(CIP1/WAF1), xeroderma pigmentosum group A complementing protein, MSH6, DNA ligase III, XRCC1, DNA polymerase epsilon, DNA-PK(CS), Ku70, NF-kappaB, inducible nitric-oxide synthase, caspase-activated DNase, and telomerase. The poly(ADP-ribose)-binding motif was found to overlap with five important functional domains responsible for (i) protein-protein interactions, (ii) DNA binding, (iii) nuclear localization, (iv) nuclear export, and (v) protein degradation. Thus, PARPs may target specific signal network proteins via poly(ADP-ribose) and regulate their domain functions.

[Computer-supported poisonous plant information system for veterinary medicine]. / Computer-unterstütztes Giftpflanzen-Informationssystem für die Veterinärmedizin.

Animals poisoned by plants are the subject of an increasing number of inquiries made to poison control centres. The most frequent questions are concerned with the identification of potentially toxic species and the choice of adequate therapeutic strategies. To meet this growing demand for information, we generated a database on poisonous plants to be used by veterinary practitioners. Relevant data were selected from the scientific literature and organised according to the requirements of a structured database. As a result, we now introduce a user-friendly decision support system that is equipped with several search functions for fast and efficient retrieval of data. The information provided for each plant includes the degree of toxicity, major toxic constituents, their mechanism of action, pathological findings, clinical symptoms with brief case reports, therapeutic guidelines and references. In addition, each species is accompanied by a botanical description with photographic illustrations. This information tool on poisonous plants is available via the internet (http:www.vetpharm.unizh.ch) or compact disc, and can be accessed on Macintosh, Windows or UNIX using a browser that supports HTML 3.

Poly ADP-ribosylation: a DNA break signal mechanism.

Recent evidence obtained with transgenic knockout mice suggests that the enzyme poly(ADP-ribose)polymerase (PARP) does not play a direct role in DNA break processing. Nevertheless, inactivation of the catalytic or the DNA nick-binding functions of PARP affects cellular responses to genotoxins at the level of cell survival, sister chromatid exchanges and apoptosis. In the present report, we conceptualize the idea that PARP is part of a DNA break signal mechanism. In vitro screening studies revealed the existence of a protein family containing a polymer-binding motif of about 22 amino acids. This motif is present in p53 protein as well as in MARCKS, a protein involved in the regulation of the actin cytoskeleton. Biochemical analyses showed that these sequences are directly targeted by PARP-associated polymers in vitro, and this alters several molecular functions of p53- and MARCKS protein. PARP-deficient knockout mice from transgenic mice were found to exhibit several phenotypic features compatible with altered DNA damage signaling, such as downregulation and lack of responsiveness of p53 protein to genotoxins, and morphological changes compatible with MARCKS-related cytoskeletal dysfunction. The knockout phenotype could be rescued by stable expression of the PARP gene. We propose that PARP-associated polymers may recruit signal proteins to sites of DNA breakage and reprogram their functions.

[Ban on antimicrobial growth promoters: a safety advantage for consumers?]. / Verzicht auf antimikrobielle Leistungsförderer: ein Sicherheitsgewinn für die Konsumenten?

The general ban of antimicrobial growth promoters seems reasonable and desirable to consumers, but is nevertheless problematic in a veterinary medical and political perspective. Rational risk management would imply that restrictive government decisions are evidence-based and provide the consumer with a higher safety level. The recent decision of the European Commission to ban avoparcin from the market was explicitly not based on scientific evidence, and apart from temporarily reducing consumer fears, the risk balance could even turn negative. The prejudicial nature of the avoparcin ban may encourage far reaching governmental interference on the market leading to the withdrawal of therapeutically important veterinary drugs on the basis of suspected side effects alone. Rational risk management would call for balancing the elimination of risks with the risks of elimination.

Selected nuclear matrix proteins are targets for poly(ADP-ribose)-binding.

Recent evidence suggests that poly(ADP-ribose) may take part in DNA strand break signalling due to its ability to interact with and affect the function of specific target proteins. Using a poly(ADP-ribose) blot assay, we have found that several nuclear matrix proteins from human and murine cells bind ADP-ribose polymers with high affinity. The binding was observed regardless of the procedure used to isolate nuclear matrices, and it proved resistant to high salt concentrations. In murine lymphoma LY-cell cultures, the spontaneous appearance of radiosensitive LY-S sublines was associated with a loss of poly(ADP-ribose)-binding of several nuclear matrix proteins. Because of the importance of the nuclear matrix in DNA processing reactions, the targeting of matrix proteins could be an important aspect of DNA damage signalling via the poly ADP-ribosylation system.

Poly(ADP-ribose) modulates the properties of MARCKS proteins.

In mammalian cells, the formation of DNA strand breaks is accompanied by synthesis of poly(ADP-ribose). This nucleic acid-like homopolymer may modulate protein functions by covalent and/or noncovalent interactions. Here we show that poly(ADP-ribose) binds strongly to the proteins of the myristoylated alanine-rich C kinase substrate (MARCKS) family, MARCKS and MARCKS-related protein (also MacMARCKS or F52). MARCKS proteins are myristoylated proteins associated with membranes and the actin cytoskeleton. As targets for both protein kinase C (PKC) and calmodulin (CaM), MARCKS proteins are thought to mediate cross-talk between these two signal transduction pathways. Dot blot assays show that poly(ADP-ribose) binds to MARCKS proteins at the highly basic effector domain. Complex formation between MARCKS-related protein and CaM as well as phosphorylation of MARCKS-related protein by the catalytic subunit of PKC are strongly inhibited by equimolar amounts of poly(ADP-ribose), suggesting a high affinity of poly(ADP-ribose) for MARCKS-related protein. Binding of MARCKS-related protein to membranes is also inhibited by poly(ADP-ribose). Finally, poly(ADP-ribose) efficiently reverses the actin-filament bundling activity of a peptide corresponding to the effector domain and inhibits the formation of actin filaments in vitro. Our results suggest that MARCKS proteins and actin could be targets of the poly(ADP-ribose) DNA damage signal pathway.

Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions.

DNA strand breaks are potential interaction sites for the nuclear enzyme poly(ADP-ribose) polymerase (PARP; E.C. 2.4.2.30) and the tumor suppressor protein p53. Both proteins bind and respond to DNA breaks and both play a role in DNA damage signaling. A temporary colocalization and complex formation between these proteins has been demonstrated in mammalian cells. Here we show that free and poly(ADP-ribose) polymerase-bound ADP-ribose polymers target three domains in p53 protein for strong noncovalent interactions. The polymer binding sites could be mapped to two amino acid sequences in the sequence-specific core DNA binding domain of p53 (amino acid positions 153-178 and 231-253) and another one in the oligomerization domain (amino acids 326-348). In mobility shift experiments, poly(ADP-ribose) effectively prevented and reversed p53 binding to the palindromic p53 consensus sequence. Additionally, poly(ADP-ribose) also interfered with the DNA single strand end binding of p53. The results suggest that ADP-ribose polymers could play a role in regulating the DNA binding properties of p53.

[Veterinary services on the Internet]. / Veterinärmedizinische Dienstleistungen auf dem Internet.

The world wide web (www) on the internet is already a rich source of veterinary informations and offers several world wide discussion fora for problems of veterinary practice. With this article, we provide practical tips for first-time users of the www and encourage exploration of this new information technology for continuing education. The Swiss Drug Compendium is now accessible on www and-in the near future-the exchange and interpretation of laboratory results and diagnostic images via internet seems feasible.