Pharmacokinetics, pharmacodynamics and therapeutics of pradofloxacin in the dog and cat.

Pradofloxacin is a third-generation fluoroquinolone, licensed in the EU for use in a range of indications in the dog and cat and authorized more recently in the USA for one therapeutic indication (skin infections) in the cat. This review summarizes and appraises current knowledge on the physico-chemical, pharmacological [pharmacokinetics (PK) and pharmacodynamics (PD)], safety and therapeutic properties of pradofloxacin in the target species. Pradofloxacin contains two centres of asymmetry and is the pure SS enantiomer. After oral dosing of tablets (dog) or tablets and oral suspension (cat), maximum plasma concentrations (Cmax ) are achieved in less than 3.0 h, and terminal half-life is of the order of 5-10 h. Accumulation is slight or absent with once daily oral dosing. Free drug concentrations in plasma are in the range of 63-71% of total concentration. As for other fluoroquinolones, antibacterial activity is attributable to inhibition of bacterial replication at two sites, subunit A of topoisomerase II and topoisomerase IV. The antimicrobial spectrum includes gram-negative and gram-positive organisms, anaerobes, Mycoplasma spp. and some intracellular organisms (Rickettsia spp. and Mycobacterium spp.). The killing action is of the concentration-dependent type. Pradofloxacin has high potency (low MIC values) in comparison with first- and second-generation fluoroquinolones. Integration of in vivo PK and in vitro PD data provides values of Cmax /MIC and area under plasma concentration-time curve (AUC24 h )/MIC ratios predictive of good clinical efficacy against sensitive organisms, when administered at recommended dose rates. Clinical trial evaluation of pradofloxacin, in comparison with other authorized antimicrobial drugs, has demonstrated either noninferiority or superiority of pradofloxacin. Data indicating clinical and, in some instances, bacteriological cure have been reported: (i) in cats, for wound infections, abscesses, upper respiratory tract infections, conjunctivitis, feline infectious anaemia and lower urinary tract infections and (ii) in dogs, for wound infections, superficial and deep pyoderma, acute urinary tract infections and adjunctive treatment of infections of gingival and periodontal tissues. At clinical dose rates pradofloxacin was well tolerated in preclinical studies and in clinical trials. Among the advantages of pradofloxacin are (i) successful treatment of infections caused by strains resistant to some other fluoroquinolones, as predicted by PK/PD data, but depending on the specific MIC of the target strain and (ii) a reduced propensity for resistance development based on MPC measurements. The preclinical and clinical data on pradofloxacin suggest that this drug should commonly be the fluoroquinolone of choice when a drug of this class is indicated. However, the PK/PD data on pradofloxacin, in comparison with other fluoroquinolones, are not a factor that leads automatically to greater clinical efficacy.

Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product.

A mucosal mist formulation of meloxicam, administered as a spray into the mouth (test article), was compared for bioequivalence to a pioneer meloxicam suspension for oral administration (reference article). Pharmacokinetic profiles and average bioequivalence were investigated in 20 dogs. The study design comprised a two-period, two-sequence, two-treatment cross-over design, with maximum concentration (C(max)) and area under plasma concentration-time curve to last sampling time (AUC(last)) used as pivotal bioequivalence variables. Bioequivalence of the products was confirmed, based on relative ratios of geometric mean concentrations (and 90% confidence intervals within the range 0.80-1.25) for C(max) of 101.9 (97.99-106.0) and for AUC(last) of 97.24 (94.44-100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical C(max) values for the two products. Mean elimination half-lives were 29.6 h (test article) and 30.0 h (reference article). The meloxicam plasma concentration-time profiles were considered in relation to published data on the inhibition of the cyclooxygenase-1 (COX-1) and COX-2 isoenzymes by meloxicam.

Chromium and disease: review of epidemiologic studies with particular reference to etiologic information provided by measures of exposure.

Dozens of epidemiologic studies have been conducted since the late 1940s in an attempt to elucidate the relationship between exposure to chromium compounds and increased rates of certain cancers observed in several industries. The relationship between employment in industries producing chromium compounds from chromite ore and lung cancer has been well established in numerous studies. The relationship between exposure to certain chromium-based pigments and chromic acid and lung cancer, although not as strong, is fairly well accepted. The data concerning emissions from stainless-steel manufacturing and disease are contradictory. Although individual studies have indicated excesses of gastrointestinal and occasionally other cancers in these industries, results are not consistent and not universally accepted. There is general agreement that chromite ore does not have an associated risk of cancer. Although the chromium compound (or compounds) responsible for disease have yet to be identified, there is general agreement that hexavalent species are responsible for these diseases and that the trivalent species are not. Hypotheses about the carcinogenicity of specific chromium compounds generally relate to their solubility in body fluids. These hypotheses, however, have generally been produced as a result of toxicologic, not epidemiologic, investigation. Well-designed epidemiologic studies incorporating detailed assessments of worker exposures have the potential to help elucidate causality, identify specific carcinogenic compounds, and quantify risk in humans, eliminating the need to extrapolate from animal data. Although the need for exposure data crucial to this effort was identified in the earliest epidemiologic studies of chromium, such studies have not been conducted. As a result, little more is known today about the relationship between this chemical and disease in humans than was known 40 years ago.

Evaluation of integrity of gloves used in a flow cytometry laboratory.

This study was conducted to evaluate the effect of normal use on latex glove integrity in a flow cytometry laboratory. The gloves were tested using the 1,000 microL water-tight test and met industrial standards (less than 4% leakage) before, but not after use. More durable gloves, or more frequent changes of gloves, may be needed to ensure adequate barrier protection for laboratory workers during routine procedures.

Isolation of equine peripheral blood mononuclear cells using Percoll.

The concentration of Percoll required for isolating equine peripheral blood mononuclear cells has been reinvestigated. A poor cell yield was obtained at the 60 per cent concentration already reported. It is recommended that workers specifically interested in high yields of mononuclear cells, for investigation of lymphocyte and monocyte functions, use a concentration of 65 per cent Percoll. However, workers wishing to isolate pure populations of equine neutrophils might consider a concentration of 70 per cent in the upper layer of Percoll used to retain the mononuclear cells.

Biochemical and haematological effects of phenylbutazone in horses.

Five matched pairs of horses were used to investigate the effects of phenylbutazone on a range of physiological, biochemical and haematological variables. The drug was given by mouth daily for 15 consecutive days at the manufacturer's recommended dose rates to one group of horses (Group A); the second group (Group B) received equivalent doses of a placebo. For some of the measured parameters, significant changes were recorded in both groups, indicating background instability. Significant decreases in serum total protein, albumin, plasma pH, viscosity and magnesium, and an increase in albumin: globulin ratio occurred in Group A, but not in Group B. These changes were, therefore, attributed to phenylbutazone or its metabolites. Toxicologically, the change in pH is probably unimportant but the decrease in protein concentration may have resulted from a protein losing enteropathy and/or from decreased synthesis in the liver. In one animal which received phenylbutazone, clinical signs of toxicity (lethargy, inappetence, oedema) were observed and evidence of hepatotoxicity and haematological changes were also noted in this horse. It is concluded that recommended dose rates of phenylbutazone should never be exceeded and that the period for which the highest dose (4.4 mg/kg body weight twice daily for four days) is administered should be reduced. In clinical cases, where phenylbutazone toxicity is suspected, measurement of serum or plasma protein concentration might provide an indication of the need to reduce dose levels or stop therapy.

Phenobarbitone concentrations in the hair, saliva and plasma of eight epileptic dogs.

Samples of plasma, saliva and hair were collected from eight dogs receiving phenobarbitone for idiopathic epilepsy. The concentrations of phenobarbitone in hair and plasma were correlated with the daily dose rate, and the concentrations in hair were also correlated with the concentration in plasma, the dose rate of the drug over the preceding six months and the ratio of the six-month dose to body surface area. The concentration of phenobarbitone in saliva was not correlated with either the concentration in plasma or the dose rate of the drug.

A nationwide study to investigate current opinion amongst maxillo-facial and neurological surgeons with regard to access surgery for neurosurgical procedures.

Over the past two decades there has been much interest in the use of craniofacial disassembly techniques to improve difficult access to some neurosurgical lesions, However, it is not known to what extent these techniques have been adopted throughout the UK. The aim of this study was to establish how many maxillofacial surgeons and neurosurgeons are currently involved in this type of collaborative surgery and to determine current opinion regarding the use of these procedures. A self-completion questionnaire was sent to all consultant maxillofacial surgeons and neurosurgeons within the UK. The results of the questionnaire suggest that there is a high level of interest in this type of collaborative surgery within the UK. It has demonstrated some interesting differences of emphasis regarding possible advantages and disadvantages of these procedures, and the areas to which access can be particularly improved. In addition, the future of this type of collaborative surgery and some of the difficulties involved in its organization were highlighted.