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HgCl2 induces an autoimmune disease in the Brown Norway rat characterized by synthesis of autoantibodies (mainly, anti-GBM Abs), severe proteinuria and interstitial nephritis. Also, HgCl2- injected rats develop glomerular cell infiltrates consisting of ED1+ cells (monocyte/macrophage), starting on day 4 and reaching a maximum on day 8. Treatment with anti-TNF-α antiserum had preventative effects as it reduced the urinary protein levels to close to the normal range and also blocked the influx of inflammatory cells in the renal glomeruli and interstitium, but circulating anti-GBM and lineal glomerular IgG deposits were unmodified. In addition, whole isolated glomeruli from HgCl2-induced nephritis secreted TNF-α commencing on day 8, being maximally detected on day 11 and preceding, between 2 to 3 days, the development of proteinuria. The administration of anti-TNF-α antiserum or anti-α4 integrin mAb completely abrogated the synthesis of TNF-α in glomeruli isolated from the respective treated groups of animals, in addition to the proteinuria. Taken together our results confirm that TNF-α plays an important role in the induction and development of HgCl2-induced nephritis and highlights the pathogenic importance of the local release of TNF in those renal diseases in which prominent glomerular macrophage accumulation is a constant feature.

Cefuroxime (CFX) is a broad-spectrum second-generation cephalosporin and one of the best choices for antibiotic prophylaxis. However, when used in critically ill patients, it may present changes in its pharmacokinetic properties. Therefore, therapeutic drug monitoring of CFX is necessary for effective dosing strategies. A simple, rapid and sensitive liquid chromatographic method with UV detection was developed and validated for the quantification of CFX in plasma. The method involved a single-step precipitation of proteins with methanol and trifluoroacetic acid. Cefuroxime was analyzed on a Brisa LC 2 C 18 column in isocratic mode consisting of 0.1% trifluoroacetic acid in water and acetonitrile (75:25) with UV detection at a wavelength of 280 nm. The retention times of CFX and cephazolin (internal standard) were 9.8 and 7.4 min, respectively. The calibration curve was linear over a concentration range of 0.25-50 μg/ml. The limits of detection and quantification were 0.1 μg/ml and 0.25 μg/ml, respectively. The accuracy and precision were always <10%. The mean recovery was 93.52%. This fast and simple method could be applied in routine analysis and pharmacokinetic studies., (© 2021 The Authors. Biomedical Chromatography published by John Wiley & Sons Ltd.)

Background and Purpose: Atrial inotropic responses to 5-HT mediated through 5-HT(4) receptors fade, presumably through phosphodiesterase (PDE) activity. We investigated the influence of a selective inhibitor of PDE3 (cilostamide) or of PDE4 (rolipram) on the fade of 5-HT responses in atrial muscle., Experimental Approach: 5-HT responses were compared, ex vivo, on sinoatrial beating rate of newborn piglets, porcine atrial and ventricular force, and human atrial force. cAMP levels were assessed in piglet atrium., Key Results: 5-HT-evoked sinoatrial tachycardia did not fade and was not potentiated by cilostamide (300 nmol.L(-1)) or rolipram (1 micromol.L(-1)). Inotropic responses to 5-HT faded in atria from piglets, adolescent pigs and humans. Cilostamide reduced atrial fade of 5-HT responses in adolescent pigs and humans but not in newborn piglets. Cilostamide disclosed 5-HT ventricular responses in newborn, but not adolescent pigs. Rolipram reduced fade of atrial 5-HT responses in newborn and adolescent pigs but not in humans. Concurrent cilostamide + rolipram abolished fade of 5-HT responses in porcine left atria and facilitated ventricular 5-HT responses, but did not reduce residual fade in human atrium in the presence of cilostamide. 5-HT-evoked increases in cAMP faded; fade was abolished by concurrent cilostamide + rolipram., Conclusions and Implications: PDE3-induced control of porcine 5-HT responses differed in atrium and ventricle and changed with age. PDE3 and PDE4 jointly prevented fade of inotropic and cAMP responses to 5-HT in porcine atrium. Unlike porcine atria, only PDE3 induced fade of 5-HT responses in human atria.

Reasons for Performing Study: Danofloxacin is a fluoroquinolone developed for veterinary medicine showing an excellent activity. However, danofloxacin pharmacokinetics profile have not been studied in horses previously., Objective: To study the pharmacokinetics following i.v., i.m. and intragastric (i.g.) administration of 1.25 mg/kg bwt danofloxacin to 6 healthy horses., Methods: A cross-over design was used in 3 phases (2 x 2 x 2), with 2 washout periods of 15 days (n = 6). Danofloxacin (18%) was administered by i.v. and i.m. routes at single doses of 1.25 mg/kg bwt. For i.g. administration an oral solution was prepared and administered via nasogastric tube. Danofloxacin concentrations were determined by HPLC assay with fluorescence detection. Tolerability at the the site of i.m. injection was monitored by creatine kinase (CK) activity., Results: Danofloxacin plasma concentration vs. time data after i.v. and i.g. administration could best be described by a 2-compartment open model. The disposition of i.m. administered danofloxacin was best described by a one-compartment model. The terminal half-lives for i.v., i.m. and i.g. routes were 6.31, 5.36 and 4.74 h, respectively. Clearance value after i.v. dosing was 0.34 l/kg bwt/h. After i.m. administration, absolute bioavailability was mean +/- s.d. 88.48 +/- 11.10% and Cmax was 0.35 +/- 0.05 mg/l. After i.g. administration, absolute bioavailability was 22.36 +/- 6.84% and Cmax 0.21 +/- 0.07 mg/l. CK activity following i.m. dosing increased 3-fold over pre-injection levels 12 h after dosing and subsequently approached (but did not reach) normal values at 72 h post dose., Conclusions: Systemic danofloxacin exposure achieved in horses following i.m. administration was consistent with the predicted blood levels needed for a positive therapeutic outcome for many equine infections. Conversely, danofloxacin utility by the i.g. route was limited by low bioavailability. Tolerability associated with i.m. administration was high., Potential Relevance: Pharmacokinetics, blood levels and good tolerability of i.v. and i.m. administration of danofloxacin in horses indicates that it is likely to be effective for treating sensitive bacterial infections.

Aliphatic amides are often used in the synthesis of peptidomimetic compounds. Here we present the structure of two cyclic dimers of aminoundecanoic acid as determined by x-ray diffraction. Each dimer contains two peptide groups and twenty methylene units. In one of the crystal structures, water is associated with the peptide groups, forming a chain of hexagons similar to those found in crambin, and in other protein and nucleic acid crystals. The aminoundecanoic rings show a fold at the peptide group, similar to either beta-turn type III or V found in proteins. Such folds are an adequate model for the peptide bond structure in nylon crystallites and peptidomimetic compounds., (Copyright 2000 John Wiley & Sons, Inc.)

The pharmacokinetics of oxytetracycline were studied in goats, after the intravenous and intramuscular injection of a conventional and long-acting formulation. The antibiotic was distributed according to an open two-compartment model. The apparent volume of distribution (Vz) and the central compartment volume (Vc) were 1.443 litres/kg and 0.453 litre/kg, respectively, and the total body clearance was 0.156 litre/kg/hour. The mean half-lives (T1/2 lambda z) of the conventional formulation after intravenous and intramuscular administration were six hours 28 minutes and 10 hours 38 minutes, respectively, whereas the long-acting formulation had half-lives of six hours 36 seconds and 29 hours, respectively, after intravenous and intramuscular injection. From the results of these single administrations two intramuscular dosage regimens can be proposed that achieve minimum concentrations of over 0.5 mg/litre (the minimum inhibitory concentration for most susceptible pathogens): with the conventional formulation by administering an initial dose of 10 mg/kg and a maintenance dose of 8.5 mg/kg every 24 hours, and with the long-acting formulation by administering an initial dose of 20 mg/kg and a maintenance dose of 14 mg/kg every 48 hours.