Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension.

INTRODUCTION: An excess of angiotensin II (Ang II) causes hypertension and vascular injury. Activation of mitogen-activated protein kinase p38 (p38-MAPK) plays a substantial role in Ang II-dependent organ damage. Recently, we showed that p38-MAPK activation regulates the pressor response to Ang II. This study evaluates the effect of chronic p38-MAPK inhibition in Ang II-dependent hypertension. MATERIALS AND METHODS: C57Bl/6J mice were infused with Ang II for 14 days and either treated with the p38-MAPK inhibitor BIRB796 (50 mg/kg/day) or the vehicle as the control. We assessed vascular function in the aorta and isolated perfused kidneys. RESULTS: Chronic p38-MAPK inhibition did not alter blood pressure at the baseline, but attenuated Ang II-induced hypertension significantly (baseline: 122 ± 2 versus 119 ± 4 mmHg; Ang II: 173 ± 3 versus 155 ± 3 mmHg; p < 0.001). In addition, BIRB796 treatment improved vascular remodeling by reducing the aortic media-to-lumen ratio and decreasing the expression of the membrane metalloproteinases (MMP) MMP-1 and MMP-9. Moreover, renal vascular dysfunction induced by chronic Ang II infusion was significantly ameliorated in the BIRP796-treated mice. Acute p38-MAPK inhibition also improved vascular function in the aorta and kidneys of Ang II-treated mice, highlighting the important role of p38-MAPK activation in the pathogenesis of vascular dysfunction. CONCLUSIONS: Our findings indicated there is an important role for p38-MAPK in regulating blood pressure and vascular injury, and highlighted its potential as a pharmaceutical target.

The management of risk arising from the use of antimicrobial agents in veterinary medicine in EU/EEA countries - a review.

Antimicrobials are essential medicines for the treatment of many microbial infections in humans and animals. Only a small number of antimicrobial agents with new mechanisms of action have been authorized in recent years for use in either humans or animals. Antimicrobial resistance (AMR) arising from the use of antimicrobial agents in veterinary medicine is a concern for public health due to the detection of increasing levels of resistance in foodborne zoonotic bacteria, particularly gram-negative bacteria, and due to the detection of determinants of resistance such as Extended-spectrum beta-lactamases (ESBL) in bacteria from animals and in foodstuffs of animal origin. The importance and the extent of the emergence and spread of AMR from animals to humans has yet to be quantified. Likewise, the relative contribution that the use of antimicrobial agents in animals makes to the overall risk to human from AMR is currently a subject of debate that can only be resolved through further research. Nevertheless, risk managers have agreed that the impact on public health of the use of antimicrobials in animals should be minimized as far as possible and a variety of measures have been introduced by different authorities in the EU to achieve this objective. This article reviews a range of measures that have been implemented within European countries to reduce the occurrence and the risk of transmission of AMR to humans following the use of antimicrobial agents in animals and briefly describes some of the alternatives to the use of antimicrobial agents that are being developed.

The prescription rate of antibacterial agents in dogs in Norway - geographical patterns and trends during the period 2004-2008.

The aim of the present study was to describe the prescription rate and patterns of antibacterial agents in the Norwegian dog population in relation to time and place during 2004-2008. Prescription data were collected from the Norwegian prescription database (NorPD), whereas an estimate of the dog population was obtained from the Norwegian Kennel Club (NKK). Maps of the geographical prescription rate patterns were generated in the software ArcGIS 9.2. This study indicates an increased usage of antibacterial agents in dogs in Norway during the study period in which antibacterial agents for systemic use and especially the combination amoxicillin and clavulanic acid accounted for the major part. Among antibacterial agents defined as critically important for human medicine, an increase was observed in the prescription rate of quinolones. The geographical prescription rate patterns were stable during the study period, which indicated that the identified increase in usage of antimicrobial agents occurred all over the country, but that there were regional differences in the prescribing behaviour. Prescription data from the NorPD of antibacterial agents to dogs can be used as a basis to perform a risk-based sampling approach to detect emerging antimicrobial resistance in the dog population.

Consumption of drugs for sea lice infestations in Norwegian fish farms: methods for assessment of treatment patterns and treatment rate.

Sea lice are a major problem in Norwegian fish farms; however, data on drug treatment patterns or treatment rates of sea lice infestations are not available. Such data are important for analysing resistance patterns against drugs used for such infestations. The main objective of the present study was to develop a method to estimate the treatment patterns and treatment rates for drugs used in the treatment against sea lice (Lepeophtheirus salmonis and Caligus elongatus) in farm salmonids by means of national sales statistics. Annual sales figures, as weight of active substances, were obtained from the drug wholesalers and the feed mills. The weight of active drug substances is not useful as a unit of measurement of drug use in an epidemiological context because it does not correct for dosage differences and number of repeat treatments. To correct for these factors, we introduced approved daily dose (ADD(farm fish)) and treatment course-doses(farm fish) kg(-1) live-weight fish. To express the drug treatment patterns, the biomass (in weight) of farm salmonids treated with 1 course of a drug were estimated. When measured as kg active substance, the quantities of drugs for the treatment of sea lice infestations declined by 98% during the study period (1989 to 2002) but this figure increased 5-fold when it was corrected for differences in dosage. To correct for amounts of farm salmonids liable to require treatment we estimated the annual treatment rate, defined as the number of treatments for sea lice infestations per biomass slaughtered Atlantic salmon Salmo salar and rainbow trout Oncorhynchus mykiss. The annual treatment rate increased gradually during the study period; however, it varied considerably (range 0.45 to 1.34, mean 0.90). Before 1995, organophosphates were the most frequently used drugs against sea lice; since then pyrethroids have become the dominating drug group.

Epidemiology of bacterial diseases in Norwegian aquaculture--a description based on antibiotic prescription data for the ten-year period 1991 to 2000.

In Norway, antibacterial drugs for use in farmed fishes have to be prescribed by a veterinarian. Moreover, a national surveillance programme requires that copies of all prescriptions be sent to the Directorate of Fisheries. The prescriptions give information regarding fish farm and locality, weight and species of fish to be medicated, diagnosis, type and amount of drug prescribed, and date. These prescription data for the 10 yr period 1991 to 2000 have been recorded and systematised. A total of 6322 prescriptions issued for 11 fish species were registered; Atlantic salmon represented 87% of the prescriptions, rainbow trout 4.5%, arctic char 0.3%, turbot 3.8%, halibut 2.1%, Atlantic cod 1.2%, and European eel 0.3%. European sea-bass, wolf-fish, coalfish and wrasse represented a total of 0.4% of the prescriptions. Furunculosis was the most frequently given diagnosis in Atlantic salmon, accounting for 79% of all prescriptions for this species. Furunculosis was more frequent during the summer and early autumn, and in the western parts of Norway. Fish weighing more than 1 kg seemed to be the most susceptible. However, furunculosis has almost disappeared in Norwegian aquaculture since 1993. Vibriosis gave cause for antibiotic treatments in almost all fish species, and was the most common diagnosis in rainbow trout, halibut, turbot, cod and European eel. In Atlantic salmon, fish of small and medium size (up to 1 kg) seemed to be more at risk from vibriosis, and outbreaks were more frequent during summer, and in the western counties. Cold-water vibriosis was the second most frequently treated disease in Atlantic salmon, creating severe problems mainly in larger fish, in the northern parts of the country, and during winter and spring. The seasonal distribution was similar for winter ulcer disease, the only disease which seemed to be of increasing importance in Atlantic salmon. Non-specific diagnoses, such as 'bacterial infection' and 'fry disease', were given in a much higher proportion of prescriptions for marine fish species than in prescriptions for salmonids.

Antibacterial drugs prescribed for dogs and cats in Sweden and Norway 1990-1998.

The usage of veterinary antibacterial drugs in dogs and cats in Sweden and Norway for the period 1990-1998 was investigated by use of drug wholesalers' statistics. Additionally, usage of human antibacterial drugs in these species in Sweden was investigated by use of prescription data for the period 1996-1998. On average, more than 50% of the prescribed veterinary antibacterials in Sweden were beta-lactam antibiotics. In Norway, about 75% of the preparations prescribed for dogs and cats contained sulfonamides and trimethoprim. Furthermore, the prescription data from Sweden showed a reduced usage of human antibacterials prescribed for dogs and cats since the beginning of the 1980s. Approximately 20% of the prescribed packages for dogs in the years 1996-1998 were human approved drugs. The corresponding figure for cats was 13%. The differences between the countries in the choice of antibacterial drugs can be explained by differences in the availability of approved preparations during the study period. The consumption of veterinary antibacterials in dogs and cats in Sweden during the period was in the range of 3% to 8% of the total use of veterinary antibacterials. The corresponding figures in Norway were in the range of 3% to 7%. It is of vital importance to study usage patterns of antibacterial drugs in dogs and cats in surveillance and control of bacterial resistance, but also in discussions of therapeutic appropriateness. Therefore, further research is needed in this area.

Prudent use of antibacterial drugs in Norwegian aquaculture? Surveillance by the use of prescription data.

Antibacterial drug treatment in aquaculture during 1991-1996 was investigated using prescription data provided by the Norwegian Government Fish Inspection and Quality Control Service (NFCS). The majority of prescriptions (n = 5401) were for Atlantic salmon and rainbow trout (salmonids), while 383 prescriptions were for other species. Of the 13 different single substances or combinations prescribed during the study period, only 5 were approved for or had been subjected to clinical trials in salmonids. Of the prescriptions for the salmonids, 99% were for approved drugs or drugs subjected to clinical trials. The major proportion of the antibacterial drugs prescribed for other fish species were drugs which were approved for or which had been subjected to clinical trials in salmonids. In all fish species, the prescribing of antibacterial drugs which were neither approved for nor had been subjected to clinical trials was mainly for fish far below slaughter weight. The prescription data were validated against the drug statistics from the wholesalers and feed mills. It was concluded that the data indeed represented antibacterial drug prescribing in Norwegian aquaculture. The prescribing of antibacterial drugs proved to be almost completely reported to NFCS, which is responsible for the control of drug residues in farmed fish in Norway.

The usage of veterinary antibacterial drugs for mastitis in cattle in Norway and Sweden during 1990-1997.

The prescribing patterns and annual incidence of use of antibacterial drugs for the treatment of mastitis in cattle in Norway and Sweden during the period 1990-1997 were estimated from drug wholesaler statistics. Although the drugs included in this study are also used in other species and/or other indications, mastitis in cattle is by far the most-common indication for their use. We used these sales figures to evaluate trends in the use of antibacterial drugs and changes in the incidence of treatment in bovine mastitis in Norway and Sweden. To facilitate comparisons (correcting for differences in activity and dosage) between the relative proportions of antibacterial drugs used in bovine mastitis, we introduced defined daily dose cow (DDDcow) as unit of measurement. Tentative DDDcow for the various injectable drugs were derived from doses recommended in Norway and Sweden. For intramammary drugs administered in the form of single-dose applicators, one applicator was defined as the DDDcow. The prescribing patterns of antibacterial drugs in bovine mastitis in Norway and Sweden during the study period seemed to be influenced by treatment policies, substances and formulations approved and treatment cost; length of the withdrawal period also seemed to play a role.

Compliance with short-term oral antibacterial drug treatment in dogs.

Compliance with a 10-day course of oral antibacterial drugs in dogs being treated as outpatients at a veterinary clinic was assessed by use of pill count data obtained by telephone interview. The association between compliance and several possible determinants of compliance was investigated. Ninety-five animal owners were included in the study, with 44 per cent reporting 100 per cent compliance with the treatment regimen and as many as 88 per cent reporting a compliance level of 80 per cent or more. The compliance level was significantly higher (P < 0.002) when the animal owners felt that the veterinarians spent enough time on the consultation. Moreover, compliance was significantly higher (P < 0.05) for dogs being treated for gastrointestinal infections compared with those being treated for other diseases.

Surveillance of the overall consumption of antibacterial drugs in humans, domestic animals and farmed fish in Norway in 1992 and 1996.

The annual overall consumption of antibacterial drugs in Norway, categorized into human use, use in domestic animals and in farmed fish, was estimated from wholesaler and feed-mill sales statistics. Comprehensive data on drug consumption in human medicine in Norway are published on a regular basis on behalf of the drug authorities. These data, including use of antibacterial drugs, are expressed as the number of defined daily doses (DDD)/1000 inhabitants/year. DDD cannot be employed to compare antibiotic consumption in human and veterinary medicine as it is possible to calculate such data for only a few veterinary drugs. The only parameter for which data are generally available, so far, is the amount used in kilograms of active substance, which is the unit of measurement chosen in this study. It was found that annual overall sales of antibacterial drugs in Norway, including antibacterial and ionophore feed additives, decreased from 77 tonnes in 1992 to 49 tonnes in 1996, a 37% reduction. The use in 1996 in human medicine, animals and farmed fish was 35 tonnes, 13 tonnes and 1 tonne, respectively. While the annual amounts used in human medicine remained unchanged from 1992 to 1996, therapeutic use in fish farming declined by 96%. In domestic animals, therapeutic use and use as feed additives declined by 17% and 5%, respectively. During the study period, the size of the human and domestic animal populations at risk remained almost constant, while the biomass (weight) of farmed fish at risk increased by > 100%. This implies that both the absolute and relative consumption of antibacterial drugs in Norway decreased substantially during the study period. The use of antibacterial drugs, both in humans and in domestic animals, has changed in favour of penicillins, this being in accordance with general recommendations. The reduction in the use of antibacterial drugs in farmed fish has been almost solely due to the introduction of oil-adjuvanted vaccines against furuncolosis. It is concluded that the decline in the amount of antibacterial drugs used in domestic animals, and the changes with regard to choice of drugs, could be mainly attributed to changes in prescribing behaviour following advice and recommendations. Moreover, the overall use of antibacterial drugs in Norway is very low compared with that in most other countries and has been significantly reduced during the 1990s.

Reduction of antibacterial drug use in Norwegian fish farming due to vaccination.

Sales statistics for antibacterial drugs and vaccines intended for use in farmed salmonids in Norway were collected and analysed. In 1993, there was a substantial reduction in annual sales figures for antibacterial drugs, which continued in 1994 and 1995. Oil-adjuvanted vaccines containing antigens against furunculosis were introduced in the fall of 1992. Introduction of oil-adjuvanted vaccines has been the single most important cause for the substantial reduction in use of antibacterial drugs in Norwegian fish farming industry.

Comparison in prescribing patterns of antibacterial drugs in salmonid farming in Norway during the periods 1980-1988 and 1989-1994.

The choice of antibacterial drugs for the treatment of bacterial diseases in farmed salmonids changed dramatically during the period 1980-1994. In terms of treatment doses, oxytetracycline chloride was the most frequently prescribed antibacterial drug during the periods 1980-1983 and 1985-1986. In 1984, prescriptions changed in favour of furazolidone and trimethoprim/ sulphadiazine (1:5). Oxolinic acid was introduced for use in farmed fish in Norway in 1987, and immediately became the drug of choice, comprising 36% and 50% of the prescribed treatment doses in 1987 and 1988, respectively. In 1989, flumequine was temporarily approved for use in farmed salmonids, and during the period 1989-1994 antibacterial drug therapy in farmed salmonids acquired the character of "mono-therapy' with the quinolones flumequine and oxolinic acid. This rapid change-over in the choice of drug may partly be explained by the development of bacterial drug resistance in farmed salmonids, both to oxytetracycline and trimethoprim/sulphadiazine. The prescribing of furazolidone declined to zero during the study period. The morbidity caused by bacterial infections was defined as the number of treatment doses of antibacterial drugs per kg biomass of farmed salmonids per year. It was estimated that during the period 1988-1995, an average of 39% (mean value) of farmed salmon received, in theory, an antibacterial cure once each year. In comparison, the corresponding figure for the period 1981-1988 was 60%. However, in 1993 this figure fell to 13%, and declined even further in 1994 to 2.3%. The practice of on-farm mixing of medicated feed, using prescribed raw materials (pure drug substances) or premix formulations, declined significantly during the period 1992-1994. This was due to the introduction, in 1992, of new regulations on the prescribing of drugs to farmed fish.

Prescribing of drugs for food-producing animals in Norway. Information about withdrawal times.

The prescribing of drugs for food-producing animals in Norway was investigated with special emphasis on written information given about withdrawal times. The study was designed as a cross-sectional prescription survey. Of 1518 prescriptions for food-producing animals, it was concluded that 1224 of the prescriptions were for drugs requiring withdrawal times for meat, milk or eggs. Of these 1224 prescriptions, 82.8% were for veterinary preparations, 6.6% were for human preparations and 10.6% were for other drugs. For 20.8% of the prescriptions, information about withdrawal time(s) was missing. For prescriptions for veterinary preparations this figure was 5.9%, and for prescriptions for human preparations and other drugs 95.1% and 90.8%, respectively. For veterinary preparations approved for the intended species, as many as 99.2% gave information about withdrawal times on the drug container label. Lack of information about withdrawal times might give rise to drug residues in food for human consumption and thus pose a potential hazard to human health.

Prescribing of veterinary and human preparations for animals in Norway. Was the preparation approved for the animal species for which it was prescribed?

The prescribing of drugs for use in veterinary medicine in Norway was investigated through a cross-sectional survey. Of the 8741 prescriptions issued for animals included in this study 22% were for drug use in veterinarians' practices. Drugs from all but one therapeutic group were prescribed for use in animals. On average, 49% of the prescriptions were for veterinary preparations, 43% were for human preparations, and 8% were for formulations prepared by pharmacies. Of prescriptions for specific animal species, 27% of the preparations were not approved for the intended animal species. The corresponding figures for prescriptions of veterinary and human preparations were 7% and 41%, respectively. Of prescriptions for production animals 17% of the preparations were not approved for the intended animal species, and for pets this figure was 30%.

An evaluation of the information given on veterinary prescriptions in Norway. Compliance with the legal regulations.

Compliance with Norwegian legal regulations for veterinary prescriptions was investigated and evaluated. The study was designed as a cross-sectional prescription survey, and the prescriptions were recorded in Dbase III. Of the 6505 written and telephone prescriptions collected only about one in five fulfilled the legal requirements, namely, giving information about the animal species the drug was intended for, indication for the prescribed drug and directions for use. On average 86% contained information about the animal species, while 26% and 80%, respectively, contained formation about the indication for the prescribed drug and directions for use. The number of prescriptions on which indication and directions for use were given, was significantly higher for written prescriptions than for telephone prescriptions, and for prescriptions of human preparations compared with prescriptions of veterinary preparations. For pets, the number of prescriptions containing directions for use was significantly higher than for production animals. The proportion of prescriptions for pets giving a statement of the indication was not significantly different from prescriptions for production animals.

Utilization of dichlorvos and trichlorfon in salmonid farming in Norway during 1981-1988.

The main objectives of this investigation were to quantify the use of dichlorvos and trichlorfon in the treatment of salmon lice infestations, to evaluate the prescribing of these drugs, and to estimate possible changes in the salmon lice problem by use of drug statistics. This study has shown that the use of trichlorfon increased from 4.9 tons in 1981 to 28.3 tons in 1985. This figure declined to 3.2 tons in 1988. The use of dichlorvos increased from 0.3 tons in 1986 to 3.2 tons in 1988. The change in the prescribing from trichlorfon to dichlorvos has dramatically reduced the pollution caused by these substances in the marine environment. Moreover, if necessary safety rules are observed, this change reduces the exposure of the workers on fish farms to these drugs, and also reduces the possibilities of intoxications of the fish during the treatment procedure. The sales figures of dichlorvos and trichlorfon, related to the calculated biomass of farmed salmonids in the sea, indicate a dramatic increase in the salmon lice problem.

Clinical use of dichlorvos (Nuvan) and trichlorfon (Neguvon) in the treatment of salmon louse, Lepeophtheirus salmonis. Compliance with the recommended treatment procedures.

Veterinarians representing one third of the Norwegian fish farms were asked about the clinical use of dichlorvos and trichlorfon by use of a questionnaire. A total of 45 veterinarians had experience in treatment of salmon lice with these organophosphates. Fourty-nine percent of the veterinarians reported that the fish farmers in their region solely used the recommended treatment equipment when delousing the fish, of these 1/4 always oxygenated the treatment solution. Repeated treatment were always prescribed by 24% of the veterinarians, while 44% did this occasionally. Of the 45 veterinarians 7% were often present and 44% were occasionally present at the fish farms in connection with the treatment. The answers showed that compliance with the recommended treatment procedures was unsatisfactory.