[Influence of the Verordnung über Tierärztliche Hausapotheken on antimicrobial use in dogs and cats in Bavaria]. / Einfluss der Verordnung über Tierärztliche Hausapotheken auf den Antibiotikaeinsatz bei Hund und Katze in Bayern.

OBJECTIVE: Aim of the study was to collect data concerning the use of antibiotics (AB) in dogs and cats in veterinary practices and clinics in Bavaria, Germany. It was evaluated, whether changes in the use of AB since the amendment of the Verordnung über Tierärztliche Hausapotheken (TÄHAV, German Regulation on the Veterinary In-house Pharmacy) in March 2018 could be documented. MATERIAL AND METHODS: Using 2 anonymous online surveys in 2017 and 2020, veterinarians treating dogs and cats in Bavaria were questioned about their usage of AB and their assessment of the current antimicrobial resistance situation. The results of both surveys were evaluated statistically and compared with each other. RESULTS: While in 2017 a total of 238 questionaries were evaluated, 160 could be included in 2020. The three most commonly used antibiotics for systemic therapy were Amoxicillin/Clavulanic acid (74.8 % of veterinarians), Enrofloxacin (56.7 %) and Amoxicillin (53.4 %) in 2017; and Amoxicillin/Clavulanic acid (88.8 %), Amoxicillin (67.5 %) and Metronidazole (33.8 %) in 2020, respectively. The participating veterinarians stated that their overall use of 3 rd and 4th generations cephalosporins (from 20.2 % of veterinarians in 2017 to 9.4 % in 2020, p = 0,005) as well as fluoroquinolones (from 80.3 % to 33.1 %, p < 0.001) had significantly declined. In 2020, the choice of AB in veterinarians was affected by legal requirements (83.8 %), tolerability (81.3 %), way of application (76.9 %), acceptance by the patient (70.0 %), and frequency of application (64.4 %), with the last parameter being significantly more important to veterinarians working in a practice (83.8 %, p = 0.004) than to veterinarians in a clinic. CONCLUSION: Veterinarians report a significantly reduced usage of fluoroquinolones and 3 rd and 4th generation cephalosporines in dogs and cats compared to 2017. These changes in prescribing practice could be a consequence of the amendment of the TÄHAV, which dictates a prohibition of rededication as well as an obligation for microbial sensitivity testing for these AB classes. CLINICAL RELEVANCE: Legal restrictions could have a positive influence on the amount and type of antibiotics used and therefore help to prevent antimicrobial resistance.

Animal models of diabetic macrovascular complications: key players in the development of new therapeutic approaches.

Diabetes mellitus is a lifelong, incapacitating metabolic disease associated with chronic macrovascular complications (coronary heart disease, stroke, and peripheral vascular disease) and microvascular disorders leading to damage of the kidneys (nephropathy) and eyes (retinopathy). Based on the current trends, the rising prevalence of diabetes worldwide will lead to increased cardiovascular morbidity and mortality. Therefore, novel means to prevent and treat these complications are needed. Under the auspices of the IMI (Innovative Medicines Initiative), the SUMMIT (SUrrogate markers for Micro- and Macrovascular hard end points for Innovative diabetes Tools) consortium is working on the development of novel animal models that better replicate vascular complications of diabetes and on the characterization of the available models. In the past years, with the high level of genomic information available and more advanced molecular tools, a very large number of models has been created. Selecting the right model for a specific study is not a trivial task and will have an impact on the study results and their interpretation. This review gathers information on the available experimental animal models of diabetic macrovascular complications and evaluates their pros and cons for research purposes as well as for drug development.

Novel ß-amino acid derivatives as inhibitors of cathepsin A.

Cathepsin A (CatA) is a serine carboxypeptidase distributed between lysosomes, cell membrane, and extracellular space. Several peptide hormones including bradykinin and angiotensin I have been described as substrates. Therefore, the inhibition of CatA has the potential for beneficial effects in cardiovascular diseases. Pharmacological inhibition of CatA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt-induced hypertension. However, so far no small molecule inhibitors of CatA with oral bioavailability have been described to allow further pharmacological profiling. In our work we identified novel ß-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led to the identification of a hitherto unknown pathophysiological role of CatA in cardiac hypertrophy. One of our inhibitors is currently undergoing phase I clinical trials.

Simvastatin improves left ventricular function after myocardial infarction in hypercholesterolemic rabbits by anti-inflammatory effects.

OBJECTIVES: Hypercholesterolemia contributes to coronary artery disease progression but little is known about its effect on left ventricular (LV) function after myocardial infarction (MI). The aim of this study was to investigate the effects of hypercholesterolemia and statin treatment in rabbits with experimental MI. METHODS AND RESULTS: New Zealand White rabbits on a normal or cholesterol-rich diet for 4 weeks, underwent permanent coronary artery ligation. Starting on the first day post-MI rabbits were treated with either placebo or simvastatin (5 mg/kg/day) for 9 weeks. Hypercholesterolemia itself did not affect LV function in sham-operated animals but further impaired LV systolic (dP/dtmax -42%) and diastolic (dP/dtmin -47%) function in MI rabbits on placebo. Simvastatin treatment not only prevented deterioration of LV function associated with hypercholesterolemia but improved LV function (dP/dtmax +130%; dP/dtmin +144%, P < 0.05). Simvastatin also attenuated the depression of LV function in normocholesterolemic MI rabbits (dP/dtmax +46%; dP/dtmin +53%, P < 0.05). Hypercholesterolemia in MI rabbits coincided with a significant increase in C-reactive protein levels (marker of inflammation) and Rac1-GTPase activity (marker of oxidative stress), and a reduction in cardiac sarcoplasmic-reticulum calcium ATPase-2 expression and endothelial nitric oxide synthase protein phosphorylation, all of which were normalised by simvastatin treatment. Elevated serum cholesterol levels were only partially reduced by simvastatin. CONCLUSIONS: Hypercholesterolemia further impaired the depressed LV function in rabbits post-MI. Statin treatment reversed this effect, and conferred additional protection, as in normocholesterolemic animals. Our study suggests that anti-inflammatory and anti-oxidative effects of simvastatin substantially contribute to its beneficial effects on cardiac function after MI.

Transcutaneous vascular ultrasound in hypercholesterolaemic rabbits: a new method to evaluate endothelial function.

Measurement of endothelial function in patients with atherosclerosis and lipid disorders is an important tool for the risk evaluation of a cardiovascular event, such as acute myocardial infarction and stroke. The feasibility of measuring endothelial function non-invasively in animal models has been limited so far. Therefore, we compared the assessment of endothelial function by in vivo transcutaneous vascular ultrasound (TVU) with the classical method of ex vivo organ bath, using the carotid artery of hypercholesterolaemic and normocholesterolaemic rabbits. The assessments of endothelial function by both techniques were performed on the same segments of the carotid artery. Vascular ultrasound detected impaired endothelium-dependent vasorelaxation induced by acetylcholine in the common carotid artery of hypercholesterolaemic rabbits. These results strongly correlated with measurements of endothelial function of isolated carotid artery rings. Furthermore, atherogenic diet caused significant fatty streak formation in the aorta, as well as significant increase of C-reactive protein and cholesterol levels. Endothelial function, an early marker of cardiovascular risk, could be non-invasively assessed and graded by TVU measurements. It correlated highly with vasoreactivity of isolated vessels in an organ bath (r(2)=0.68). We conclude that vascular ultrasound in hypercholesterolaemic rabbits is a valid method for evaluating endothelial function associated with atherosclerosis.

Effects of combined inhibition of the Na+-H+ exchanger and angiotensin-converting enzyme in rats with congestive heart failure after myocardial infarction.

1 We investigated the single vs the combined long-term inhibition of Na(+)-H(+) exchanger-1 (NHE-1) and ACE in rats with congestive heart failure induced by myocardial infarction (MI). 2 Rats with MI were randomized to receive either placebo, cariporide (3000 p.p.m. via chow), ramipril (1 mg kg(-1) day(-1) via drinking water) or their combination for 18 weeks starting on day 3 after surgery. 3 Cardiac morphology and function was assessed by echocardiography and by means of a 2.0 F conductance catheter to determine left ventricular (LV) pressure volume relationships. 4 MI for 18 weeks resulted in an increase in LV end-diastolic diameter (LVDed) in the placebo-treated group when compared to sham (placebo: 1.1+/-0.04 cm; sham: 0.86+/-0.01; P<0.05). Combined inhibition of NHE-1 and ACE, but not the monotherapies, significantly reduced LVDed (1.02+/-0.02 cm). 5 Preload recruitable stroke work (PRSW), dp/dt(max) (parameter of systolic function) and end-diastolic pressure volume relationship (EDPVR, diastolic function) were significantly impaired in placebo-treated MI group (PRSW: 39+/-7 mmHg; dp/dt(max): 5185+/-363 mmHg s(-1); EDPVR: 0.042+/-0.001 mmHg microl(-1); all P<0.05). Cariporide treatment significantly improved PRSW (64+/-7 mmHg), dp/dt(max) (8077+/-525 mmHg s(-1)) and EDPVR (0.026+/-0.014 mmHg microl(-1)), and reduced cardiac hypertrophy in rats with MI. Combined inhibition of NHE-1 and ACE had even a more pronounced effect on PRSW (72+/-5 mmHg) and EDPVR (0.026+/-0.014 mmHg microl(-1)), as well as cardiac hypertrophy that, however, did not reach statistical significance compared to cariporide treatment alone. 6 The NHE-1 inhibitor cariporide significantly improved LV remodeling and function in rats with congestive heart failure induced by MI. The effect of cariporide was comparable or tended to be stronger (e.g. systolic function) compared to ramipril. Combined treatment with cariporide and ramipril tended to be more effective on LV remodeling in rats with heart failure than the single treatments. Thus, inhibition of the NHE-1 may be a promising novel therapeutic approach for the treatment of congestive heart failure.