Pharmacokinetics of flunixin in mature heifers following multiple intravenous administration.

The pharmacokinetics of flunixin meglumine was determined after its multiple (altogether 4 doses at 24-hours intervals) intravenous administration at a dose of 2.2 mg/kg body weight in six mature clinically healthy heifers. Plasma flunixin and its metabolite 5-hydroxyflunixin concentrations were analyzed with high-pressure liquid chromatography using an assay with a lower limit detection of 0.03 microg/ml for both substances. Plasma concentrations versus time curves were described by a two compartment open model. Mean plasma flunixin concentrations were similar on day 1 and 4, and than rapidly decreased (within 2 hours) from initial concentrations higher than 10 microg/ml to the concentrations lower than 1 microg/ml. The distribution phase of flunixin was short (t0.5 alpha = 0.29 +/- 0.16 and 0.18 +/- 0.04 on day 1 and 4, respectively) and the elimination phase was more prolonged (t0.5 beta = 3.30 +/- 0.60 and 3.26 +/- 0.22 on day 1 and 4, respectively). The mean residence time of flunixin was similar on day 1 (1.83 +/- 0.83) and 4 (1.88 +/- 0.46), and for 5-hydroxyflunixin this parameter was insignificantly (P > 0.05) higher on day 1 (5.49 +/- 2.22) as compared to that found on day 4 (3.99 +/- 2.17). The clearance of flunixin was similar on both examined days (0.23 +/- 0.12 on day 1 and 0.31 +/- 0.15 on day 4), and for 5-hydroxyflunixin was insignificantly (P > 0.05) lower on day 1 (2.37 +/- 1.21) as compared to that determined on day 4 (3.23 +/- 1.06). Our data indicate that multiple administration of flunixin did not alter significantly the parent drug and its metabolite concentrations in plasma, however may cause some small changes in pharmacokinetic parameters.

Influence of nitric oxide on the blood flow in the porcine uterine artery; an in vivo study.

The aim of this study was to investigate the role of nitric oxide (NO) in the regulation of blood flow in the porcine uterine artery during the course of the oestrous cycle. Experiments were carried out on animals on days 1-5, 8-13 and 17-20 of the oestrous cycle. After induction of anesthesia and opening of the abdominal cavity, blood samples were collected from the ovarian and uterine arteries and veins to determine nitrate and nitrite concentrations; on the opposite side to the blood sampling the branch of the uterine artery was prepared and a venous catheter was inserted into the artery. For measuring the changes in the blood pressure the catheter was connected via a polyvinyl cannula to a pressure transducer. Sodium nitroprusside (NP; 2.4 microg, 24 microg and 240 microg; a NO donor) or Nomega-nitro-L-arginine methyl ester (L-NAME; 2.2 microg, 22 microg, 220 microg and 2200 microg; an irreversible inhibitor of neuronal and endothelial NO synthase and reversible inhibitor of macrophage NO synthase) was administered via a bolus into the uterine artery. Nitrite/nitrate concentrations were: higher (P < 0.05) in the uterine vein as compared to the uterine artery on days 1-5 of the oestrous cycle; lower (P < 0.05) in the uterine artery as compared to the ovarian and uterine veins as well as in the ovarian artery as compared to the ovarian vein on days 8-13 of the cycle; lower (P < 0.05) in the uterine artery as compared to the ovarian artery and uterine and ovarian veins on days 17-20. Administration of NP at doses of 2.4 microg and 24 microg and L-NAME at all doses examined did not affect (P > 0.05) the blood pressure in the uterine artery in all periods examined. NP at a dose of 240 microg decreased (P < 0.001) the blood pressure in the arteries in all periods examined as compared to blood pressure before NP treatment. The results obtained indicate that NO is involved in the regulation of blood flow through the porcine reproductive tract. Moreover, our results suggest that the action of NP in the porcine uterine artery is not dependent on the phase of the oestrous cycle.

Pathogenesis of quinolone-induced arthropathy: a review of hypotheses.

The arthropathogenic effects of quinolones have been described in juvenile animals of multiple species such as dogs, rats, non-human primates, rabbits and guinea pigs. Several studies have been performed to clarify the exact mechanism leading to cartilage damage. In these studies, the investigators focused on the inhibitory effects of quinolones on DNA, collagen and proteoglycan synthesis and on the formation of oxygen-derived reactive molecules. Recently, it was suggested that quinolone-induced arthropathy is possibly associated with the magnesium-chelating properties of quinolones. However, the exact mechanism of quinolone-induced arthropathy is still unkown. This article reviews and summarizes several possible mechanisms for quinolone-induced arthropathy.

Genetic determinants of plasma ACE and renin activity in young normotensive twins.

OBJECTIVE: We investigated the determinants of plasma renin activity (PRA) and plasma levels of angiotensin-converting enzyme (pACE), including the effect of the D/I polymorphism of the angiotensin-converting enzyme (ACE) gene, in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: Sixty-nine pairs of twins underwent measurements of blood pressure, pACE and ACE D/I genotyping. In addition, in 30 pairs ambulatory blood pressure (ABP) monitoring was carried out. To ascertain twin's zygosity, some highly discriminating variable number of tandem repeats micro- and mini-satellite systems were analysed by polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis and silver staining. The D/I polymorphism was assessed by PCR; pACE was measured in triplicate with a colorimetric assay, and PRA by a commercial kit. In DZ twins, identity by descent of the D/I alleles was examined by PCR amplification of a highly polymorphic simple sequence repeat at the human growth hormone gene. RESULTS: pACE levels were significantly (P < 0.01) higher in DD (9.27 +/- 2.60 IU/l, mean +/-SD) than in II (6.68 +/- 3.0), with DI having intermediate levels (7.93 +/- 2.7). No difference of PRA between different D/I genotypes was found. Twin data analysis showed a statistically significant heritability of pACE, but not of PRA. No differences between MZ and DZ twins in PRA, pACE and the relationship of the D/I genotype with pACE was found. Besides showing that the D/I genotype was the most important predictor of pACE, a multivariate analysis demonstrated that identity by descent of the D/I allele, as assessed by growth hormone (GH) genotyping, also significantly affected pACE. CONCLUSIONS: In this study of normotensive twins, pACE and not PRA showed significant heritability, the former being tightly associated with the D/I ACE gene polymorphism, and/or with a quantitative trait locus in linkage disequilibrium with it.

Heritability of plasma leptin levels: a twin study.

OBJECTIVE: To examine the influence of genetic factors on plasma leptin levels. SUBJECTS AND METHODS: We measured plasma leptin levels, body mass index and body fat distribution in healthy young female monozygotic (n = 19) and dizygotic (n = 14) twins. The twin zygosity was verified by determination of short tandem repeat and amplified fragment length polymorphism systems. The genetic analysis included analysis of variance-based and maximum likelihood-based methods. RESULTS: Plasma leptin levels were correlated significantly with body mass index (r = 0.59, P < 0.001), waist circumference (r = 0.54, P < 0.001) and hip circumference (r = 0.63, P < 0.001), but not with age (r = -0.17) or the waist:hip ratio (r = 0.02). The heritability estimates derived from intraclass correlations were significant for body mass index (P = 0.001), waist circumference (P = 0.004), hip circumference (P = 0.01) and plasma leptin levels (P = 0.005), but not for the waist:hip ratio (P = 0.22). In the maximum likelihood-based path analysis, heritability was estimated at 79% for body mass index and at 73% for plasma leptin levels. After adjustment for body mass index, the heritability estimate for leptin levels from the model-fitting approach was 55%. CONCLUSIONS: Genetic factors are major determinants of plasma leptin levels in humans and may account for as much as half of the variance in leptin levels.

[Polymorphism of the ACE gene and left ventricular morphology and function in patients with borderline, mild and moderate hypertension]. / Polimorfizm genu ACE a morfologia i funkcja lewej komory serca u chorych z nadcisnieniem tetniczym granicznym, lagodnym i umiarkowanym.

It has been reported that the allel D of an insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene is associated with the conditions of increased cardiovascular risk, including the left ventricular hypertrophy and the dysfunction. We examined the relation between the genotype of ACE gene and the left ventricular function in normotensives and in borderline, mild and moderate hypertensives. We investigated 128 subjects, 47 first-diagnosed untreated hypertensives and 81 normotensives. The M-mode and Doppler echocardiography were used to quantify LV mass and function. The insertion/deletion ACE polymorphism was identified using polymerase chain reaction. Left ventricular indexes of the morphology and function were analyzed. We compared ambulatory blood pressure profiles between all genotypes in both groups. There were no significant differences in indexes of the left ventricular hypertrophy in studied normotensives and borderline to mild hypertensives. Our results indicate that allel I might be associated with selected parameters of diastolic function, while allel D with selected parameters of systolic function, of the left ventricle. Results of this study suggest also probable relation between allel D and variability of the diastolic arterial pressure in both investigated groups.

Ambulatory systolic blood pressure is related to the deletion allele of the angiotensin I converting enzyme gene in young normotensives with parental history of hypertension.

The aim of the present study was to evaluate the relationship between the angiotensin I converting enzyme (ACE) gene polymorphism and ambulatory blood pressure in young normotensive males with (n=45) and without (n=100) family history of hypertension. Twenty-four hour and daytime systolic blood pressure was significantly higher in subjects with a parental history of hypertension. Ambulatory blood pressure values did not differ significantly across ACE genotypes in subjects with negative family history of hypertension. In subjects with a parental history of hypertension, there was a significant positive association between the D allele of the ACE gene polymorphism and 24-h, daytime and nighttime systolic blood pressure. For twenty-four hour systolic blood pressure there was an average 9 mmHg difference between subjects with DD and II genotypes. The results indicate that in normotensive subjects with a genetic predisposition to hypertension, ambulatory systolic blood pressure is related to the D allele of the ACE gene.

No effect of genetic variation at the angiotensinogen locus on ambulatory blood pressure level in normotensive subjects.

The aim of the study was to evaluate the potential association between ambulatory blood pressure and the molecular variants T174M and M235T of the angiotensinogen gene in a random sample of young normotensive men (n = 145). The two point mutations were detected using restriction digests of a mispairing polymerase chain reaction product. Twenty-four-hour ambulatory blood pressure monitoring was performed with a SpaceLabs 90207 device. Ambulatory blood pressure levels did not vary according to T174M and M235T genotypes. When the subjects were grouped according to their blood pressure level (as indicated by tertiles of their 24-h ambulatory blood pressure), no significant differences in allele frequencies between the three groups were found. Our results indicate that the T174M and M235T molecular variants of the angiotensinogen gene have no major influence on ambulatory blood pressure in young normotensive subjects.

Genetic influences on insulinemia in normotensive twins.

The aim of this study was to establish the contribution of genetic factors to the variance of plasma insulin concentration in healthy, normotensive twins. Seventeen pairs of monozygotic (MZ) and 17 pairs of dizygotic (DZ) twins were investigated. The test of genetic variance revealed a significantly larger within-pair variance of fasting plasma insulin (FPI) and a relative insulin resistance (RIR) in the DZ twins, in comparison with the MZ twins. Both FPI and RIR had a higher intraclass correlation coefficient in the MZ twins than in the DZ twins; the corresponding heritability estimates were 0.54 for FPI and 0.66 for RIR. Adjusting for age, gender, and body mass index did not affect heritability estimates for either FPI or RIR. Our data indicate that genetic factors are important determinants of insulinemia in normal subjects, independent of body mass index.