Cedric Müntener

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 [1, 2]. 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 [2, 3]. In the present report, we conceptualize the idea that PARP is part of a DNA break signal mechanism [4, 5]. 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. (Mol Cell Biochem 193: 5–11,1999)

Comparison of Antimicrobial Consumption Patterns in the Swiss and Danish Cattle and Swine Production (2007-2013).

Veterinary antimicrobial consumption patterns vary considerably across Europe. These differences are not only limited to the total amount consumed but are also observed with regards to the relative proportion of the various antimicrobial classes used. Currently, most of the data on veterinary antimicrobials are reported at sales level without any information on the consumption by different animal species. This hinders a proper comparison of antimicrobial consumption at the species level between countries. However, it is imperative to improve our understanding on antimicrobial usage patterns at the species level, as well as on the drivers contributing to those differences. This will allow for development of tailored interventions with the lowest possible risk for human health, while ensuring effective treatment of diseased livestock. An important step to attain such an objective is to perform detailed comparisons of the antimicrobial consumption in each species between countries. We compared antimicrobial consumption estimates for cattle and pigs in Switzerland and Denmark, in order to distinguish species-specific patterns and trends in consumption from 2007 to 2013. Swiss data were obtained from a previous study that assessed methodologies to stratify antimicrobial sales per species; Danish antimicrobial consumption estimates were assembled from Danish Integrated Antimicrobial Resistance Monitoring and Research Programme reports. A decrease in antimicrobial consumption in milligrams per kilogram of biomass was observed for both countries (4.5% in Denmark and 34.7% in Switzerland) when comparing 2013 to 2007. For pigs and cattle, the overall consumption per kilogram of biomass of most antimicrobial classes was higher in Switzerland than in Denmark. Large variations in the relative consumption of different antimicrobial classes were also evident. Sulfonamides/trimethoprim and tetracyclines were consumed in a higher proportion in Switzerland than in Denmark, whereas the relative consumption of penicillins was higher in Denmark. The differences observed in veterinary antimicrobial consumption are not solely related to animal demographic characteristics in these two countries. Other factors, such as the level of biosecurity and farming practices, veterinarians and farmers’ education, or governmental/industry programs put in place might also partly explain these variations. These differences should be taken into account when aiming to implement targeted interventions to reduce antimicrobial consumption.

Gemeldete unerwünschte Wirkungen von Tierarzneimitteln im Jahr 2005

Im Jahr 2006 wurden insgesamt 190 unerwunschte Arzneimittelwirkungen gemeldet: 118 betrafen pharmakologisch aktive und 72 immunologische Arzneimittel. Die Mehrzahl der gemeldeten Reaktionen betraf die Anwendung von Antiparasitika (48%) und jede zweite Meldung betraf einen Hund. Danach folgten bei den Tierarzneimitteln, der Haufigkeit nach, die Antiinfektiva (20%) und die heterogene Gruppe der umgewidmeten Praparate (12%). Katzen bildeten die zweithaufigste betroffene Tiergruppe (24%), gefolgt von Rindern/Kalbern (16%). Bei immunologischen Arzneimitteln uberwiegen die Meldungen beim Hund (62%), gefolgt von Pferden (11%) und Rindern (10%). Am haufigsten wurde uber unerwunschte Wirkungen nach Anwendung eines Piroplasmose-Impfstoffs berichtet. Zusatzlich gingen 349 Anfragen beim STIZ ein. Wir prasentieren zudem eine schwerwiegende unerwunschte Reaktion in Form eines Stevens-Johnson Syndroms bei einer Katze, sowie einen Fall von Ketaminmissbrauch. Wir sind besonders erfreut uber die zunehmenden Teilnahmen der praktizierenden KollegInnen und arbeiten an zusatzlichen Anpassungen des etablierten Systems.

[Vigilance for veterinary medicinal products: declarations of adverse reactions in the year 2008].

With 106 reports of suspected adverse reactions to veterinary medicinal products (VMPs) there was a slight decrease in the year 2008 compared to 2007. However, the distribution according to species and drug classes remained grossly the same: dogs were involved in 45 % of the cases followed in frequency by cats (26 %) and cows or calves (21 %). Most often the reports described reactions following the use of either an antiparasitic drug (46 %) or an antibiotic (22 %). One particular case of off-label use and serious skin reactions are presented. For the vaccinovigilance a total of 310 reports were received, with 250 of them related to adverse events following vaccination against blue tongue disease. In most cases, aborts and elevated cell count in the milk were reported. A detailed evaluation of these cases is presented. Finally, 305 enquiries were received by the Swiss Toxicological Information Center in Zurich (concerning mostly dogs or cats). Most of the cases concerned either preparations for the nervous system or anti-inflammatory drugs (human medicinal products) or antiparasitics (VMPs).

Reported adverse reactions of veterinary drugs and vaccines in 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.Im Jahr 2005 wurden 105 Meldungen uber unerwunschten Arzneimittelwirkungen (UAWs) von pharmakologisch aktiven Substanzen und immunologischen Arzneimitteln eingereicht. Dies entspricht eine Zunahme von uber 35% gegenuber dem Jahr 2004. Eine Mehrzahl der Meldungen wurde durch praktizierende Tierarzte eingesandt. Wie in fruheren Jahren wurden hauptsachlich unerwunschte Wirkungen nach Anwendung von Tierarzneimitteln bei Kleintieren gemeldet (73%). Die am haufigsten betroffene Klasse ist wiederum diejenige der Antiparasitika (48%), welche hauptsachlich extern bei Kleintieren angewendet wurden. Danach folgten, der Haufigkeit nach, Praparate zur Behandlung von gastrointestinalen Storungen (11%) und die heterogene Gruppe der umgewidmeten Praparate (14%; Anwendung bei einer anderen Tierart oder fur eine andere Indikation). Zum ersten Mal wurden 2 Meldungen uber die irrtumliche Anwendung von Permethrin-haltigen Spot-on Praparaten bei Katzen ubermittelt. Die Auswertung von 20 Meldungen uber unerwunschte Wirkungen nach Anwendung von Impfstoffen wird mit dem Schwerpunkt Fibrosarkome bei Katzen prasentiert. Wir freuen uns uber die wachsende Beachtung des Vigilanzsystems bei praktizierenden Tierarztinnen und Tierarzten und hoffen, diese Zusammenarbeit weiter entwickeln zu konnen.

Risk Ranking of Antimicrobial‐Resistant Hazards Found in Meat in Switzerland

Human exposure to bacteria resistant to antimicrobials and transfer of related genes is a complex issue and occurs, among other pathways, via meat consumption. In a context of limited resources, the prioritization of risk management activities is essential. Since the antimicrobial resistance (AMR) situation differs substantially between countries, prioritization should be country specific. The objective of this study was to develop a systematic and transparent framework to rank combinations of bacteria species resistant to selected antimicrobial classes found in meat, based on the risk they represent for public health in Switzerland. A risk assessment model from slaughter to consumption was developed following the Codex Alimentarius guidelines for risk analysis of foodborne AMR. Using data from the Swiss AMR monitoring program, 208 combinations of animal species/bacteria/antimicrobial classes were identified as relevant hazards. Exposure assessment and hazard characterization scores were developed and combined using multicriteria decision analysis. The effect of changing weights of scores was explored with sensitivity analysis. Attributing equal weights to each score, poultry-associated combinations represented the highest risk. In particular, contamination with extended-spectrum β-lactamase/plasmidic AmpC-producing Escherichia coli in poultry meat ranked high for both exposure and hazard characterization. Tetracycline- or macrolide-resistant Enterococcus spp., as well as fluoroquinolone- or macrolide-resistant Campylobacter jejuni, ranked among combinations with the highest risk. This study provides a basis for prioritizing future activities to mitigate the risk associated with foodborne AMR in Switzerland. A user-friendly version of the model was provided to risk managers; it can easily be adjusted to the constantly evolving knowledge on AMR.

[Vigilance for veterinary medicinal products: declarations of suspected adverse reactions in the year 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 Zurich. 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.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.

Arzneimittelinteraktionen von Phenylbutazon und Phenprocoumon bei einem Warmblutpferd

Ein 15-jahriger Oldenburger Wallach wurde zur Therapie einer Hufrehe wahrend 3 Wochen einmal taglich oral mit 27 mg des Gerinnungshemmers Phenprocoumon bei gleichzeitiger Gabe von 2-4 g Phenylbutazon per os zweimal taglich. Nach dieser Behandlung wurde das Tier mit Kolikvorbericht und hochgradiger Schocksymptomatik an die Pferdeklinik der Universitat Zurich uberwiesen. Mittels der klinischen Untersuchung und der Laborwerte wurde eine erhohte Blutungsneigung aufgrund von Arneimittelinteraktionen diagnostiziert. Die Behandlung des Pferdes erfolgte mit Vitamin-K1 (0.5 mg/kg, subkutan). Da sich der Allgemeinzustand des Tieres jedoch weiter verschlechterte, wurde das Pferd euthanasiert. Die Sektion des Tieres ergab hochgradige multifokale Hamorrhagien der Serosen und der inneren Organe sowie Blutungen in die Korperhohlen. Dieser Fall zeigt, dass die gleichzeitige Gabe des Coumarinderivats Phenprocoumon mit Phenylbutazon Arzneimittelinteraktionen hervorrufen kann, die den antikoagulierenden Effekt des Coumarinderivats verstarken. Eine solche Kombinationstherapie ist aufgrund der erhohten Blutungsgefahr kontraindiziert. Eine sinnvolle Behandlung des Pferdes mit Gerinnungshemmern bedarf daher einer strengen Indikation mit regelmassiger Kontrolle des Gerinnungsstatus unter Beachtung von potentiellen Interaktionen. Schlusselworter: Pferd, Gerinnungshemmer, Phenprocoumon, Phenylbutazon, Arzneimittelinteraktionen A 15 year old Oldenburger gelding was treated during 3 weeks for laminitis with the anticoagulant phenprocoumone (27 mg orally, once daily) and concurrent administration of phenylbutazone (2-4 g orally, twice daily). After this treatment the animal was presented to the Equine Clinic University of Zurich with a history of acute colic and advanced symptoms of shock. On the basis of the clinical signs and laboratory values, a diagnosis of combined drug induced coagulopathy was made. The horse was treated with the antidote Vitamine- K1 (0.5 mg/kg, subcutaneously). Eventually, the general condition of the animal worsened and it was therefore euthanized. Necropsy revealed profound, multifocal hemorrhagic diathesis of the serosal surface of the viscera, as well as bleeding into the visceral cavities. This case shows that concurrent administration of phenprocoumone and phenylbutazone may lead to drug interactions that increase the anticoagulation effect of the coumarine-derivative. Simultaneous use of coumarine-derivatives and phenylbutazone is therefore contraindicated due to the higher risk of bleeding. A reasonable treatment of horses with anticoagulants requires regular monitoring with constant evaluation of coagulation status and special attention to potential drug interactions. Keywords: Horse, anticoagulants, phenprocoumon, phenylbutazone, drug interactions

Suspected adverse drug reactions in 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.

Expert opinion on livestock antimicrobial usage indications and patterns in Denmark, Portugal and Switzerland

We aimed at describing antimicrobial usage patterns throughout livestock production cycles, and comparing them across three countries from Northern, Central and Southern Europe. Given the difficulties to collect such detailed usage data, an expert opinion was deemed the most appropriate study design. This study provides new insights into the time periods and indications for which specific antimicrobial substances are used in different livestock sectors. Veterinary experts (n=67) from different livestock sectors (broilers, pigs, dairy cattle and veal/fattening calves) and countries (Denmark, Portugal and Switzerland) replied to a questionnaire focusing on the time periods in the production cycle when antimicrobial substances were administered, and the respective indications for treatment. Our results showed that for several antimicrobials, between-country and within-country variations exist regarding the temporal distributions of treatments and indications for use. These differences were also true for several critically important antimicrobials, which is a matter of concern. Furthermore, differences between countries were also evident regarding the antimicrobial substances licensed. Based on our results, it is recommended to establish and promote treatment guidelines, invest in the prevention of diseases during critical moments of the production cycle and target undifferentiated use of antimicrobials. Moreover, discrepancies between countries should be further investigated to better understand the factors underlying the identified patterns and to distinguish prudent from non-prudent use. The results can inform decision-making with the aim to foster antimicrobial prudent use in the veterinary setting and, therefore, protect public health from the threat of antimicrobial resistance.