Moxonidine normalizes sympathetic hyperactivity in patients with eprosartan-treated chronic renal failure. (73/539)

Enalapril and losartan reduce but not normalize sympathetic hyperactivity in patients with hypertensive chronic renal failure (CRF). This study assessed the effect of chronic eprosartan on BP and sympathetic activity, and assessed the effect of moxonidine during chronic eprosartan treatment. In 11 stable patients with CRF (creatinine clearance 47 +/- 10 ml/min), muscle sympathetic nerve activity (MSNA; peroneal nerve), BP, and baroreceptor sensitivity were measured in the absence of antihypertensive drugs (except diuretics) during chronic eprosartan therapy (600 mg for 6 wk) and in 9 patients after moxonidine (0.2 mg for 6 wk) was added. Normovolemia was controlled by diuretics and confirmed by extracellular fluid volume measurements. BP, heart rate, and MSNA were higher in patients than in 22 controls. During eprosartan therapy, mean arterial pressure (111 +/- 9 to 98 +/- 7 mmHg, P < 0.001), heart rate (71 +/- 10 to 65 +/- 8 bpm, P < 0.001), and MSNA (35 +/- 10 to 27 +/- 8 bursts/min, P < 0.001) decreased. After the addition of moxonidine (n = 9), a further reduction of mean arterial pressure to 89 +/- 7 mmHg (P < 0.05) and of MSNA to 20 +/- 10 bursts/min (P < 0.05) occurred. Sympathetic activity in patients with CRF can be normalized, and angiotensin II-independent sympathetic hyperactivity contributes to the pathogenesis of renal hypertension. Sympathetic hyperactivity is associated with poor cardiovascular outcomes, implying that reduction might be beneficial to the patients. The addition of moxonidine to angiotensin II antagonist treatment might be appropriate.  (+info)

Formation and protein binding of the acyl glucuronide of a leukotriene B4 antagonist (SB-209247): relation to species differences in hepatotoxicity. (74/539)

SB-209247 [(E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-p ropenoic acid], an anti-inflammatory leukotriene B4 receptor antagonist, was associated in beagle dogs but not male rats with an inflammatory hepatopathy. It also produced a concentration-dependent (10-1000 microM) but equal leakage of enzymes from dog and rat precision-cut liver slices. The hepatic metabolism of SB-209247 was investigated with reference to the formation of reactive acyl glucuronides. [14C]SB-209247 (100 micromol/kg) administered i.v. to anesthetized male rats was eliminated by biliary excretion of the acyl glucuronides of the drug and its sulfoxide. After 5 h, 1.03 +/- 0.14% (mean +/- S.E.M., n = 4) of the dose was bound irreversibly to liver tissue. The sulfoxide glucuronide underwent pH-dependent rearrangement in bile more rapidly than did the SB-209247 conjugate. [14C]SB-209247 was metabolized by sulfoxidation and glucuronidation in rat and dog hepatocytes, and approximately 1 to 2% of [14C]SB-209247 (100 microM) became irreversibly bound to cellular material. [14C]SB-209247 sulfoxide and glucuronide were the only metabolites produced by dog, rat, and human liver microsomes in the presence of NADPH and UDP-glucuronic acid (UDPGA), respectively. V(max) values for [14C]SB-209247 glucuronidation by dog, rat, and human microsomes were 2.6 +/- 0.1, 1.2 +/- 0.1, and 0.4 +/- 0.0 nmol/min/mg protein, respectively. Hepatic microsomes from all three species catalyzed UDPGA-dependent but not NADPH-dependent irreversible binding of [14C]SB-209247 (100-250 microM) to microsomal protein. Although a reactive acyl glucuronide was formed by microsomes from every species, the binding did not differ between species. Therefore, neither the acute cellular injury nor glucuronidation-driven irreversible protein binding in vitro is predictive of the drug-induced hepatopathy.  (+info)

Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy: effects of laser photocoagulation and angiotensin receptor blockade. (75/539)

BACKGROUND: Proliferative diabetic retinopathy (PDR) may be a response to abnormal angiogenic growth factors such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and the soluble angiopoietin receptor tie-2. The authors hypothesised the following: (a) there are differences in plasma levels of these growth factors in different grades of diabetic retinopathy; and (b) that the effects of intervention with panretinal laser photocoagulation (PRP) for PDR, and angiotensin receptor blockade (using eprosartan) for patients with other grades of diabetic retinopathy will be to reduce levels of the growth factors. METHODS: Cross sectional and interventional study (using PRP and eprosartan) in diabetic patients. VEGF, Ang-2, and tie-2 were measured by ELISA. RESULTS: VEGF (p<0.001) and Ang-2 levels (p<0.001) were significantly higher in 93 diabetic patients compared to 20 healthy controls, with the highest levels in grade 2 and grade 3 diabetic retinopathy (p<0.05). Tie-2 was lower in diabetics compared to controls (p = 0.008), with no significant differences between the diabetic subgroups. Overall, VEGF significantly correlated with Ang-2 (p<0.001) and tie-2 (p = 0.004) but the correlation between Ang-2 and tie-2 levels was not significant (p = 0.065). Among diabetic patients only, VEGF levels were significantly correlated with Ang-2 (p<0.001) and tie-2 (p<0.001); the correlation between Ang-2 and tie-2 levels was also significant (p<0.001). There were no statistically significant effects of laser photocoagulation on plasma VEGF, Ang-2, and tie-2 in the 19 patients with PDR, or any effects of eprosartan in the 28 patients with non-proliferative diabetic retinopathy. CONCLUSION: Increased plasma levels of VEGF and Ang-2, as well as lower soluble tie-2, were found in diabetic patients. The highest VEGF and Ang-2 levels were seen among patients with pre-proliferative and proliferative retinopathy, but there was no relation of tie-2 to the severity of retinopathy. As the majority of previous research into Ang-2 and tie-2 has been in relation to angiogenesis and malignancy, the present study would suggest that Ang-2 and tie-2 may be used as potential indices of angiogenesis in diabetes mellitus (in addition to VEGF) and may help elucidate the role of the angiopoietin/tie-2 system in this condition.  (+info)

Bayesian latent variable models for mixed discrete outcomes. (76/539)

In studies of complex health conditions, mixtures of discrete outcomes (event time, count, binary, ordered categorical) are commonly collected. For example, studies of skin tumorigenesis record latency time prior to the first tumor, increases in the number of tumors at each week, and the occurrence of internal tumors at the time of death. Motivated by this application, we propose a general underlying Poisson variable framework for mixed discrete outcomes, accommodating dependency through an additive gamma frailty model for the Poisson means. The model has log-linear, complementary log-log, and proportional hazards forms for count, binary and discrete event time outcomes, respectively. Simple closed form expressions can be derived for the marginal expectations, variances, and correlations. Following a Bayesian approach to inference, conditionally-conjugate prior distributions are chosen that facilitate posterior computation via an MCMC algorithm. The methods are illustrated using data from a Tg.AC mouse bioassay study.  (+info)

Losartan increases bradykinin levels in hypertensive humans. (77/539)

BACKGROUND: Studies in animals and humans indicate a role for kinins in the actions of angiotensin type 1 (AT1) receptor blockers. However, the effect of these compounds on kinin levels in humans is unknown. METHODS AND RESULTS: We measured angiotensin (Ang), bradykinin (BK), and kallidin peptides in subjects with essential hypertension administered placebo, losartan (50 mg OD), and eprosartan (600 mg OD) in randomized order in a double-blind, 3-period, 3-treatment, crossover trial. Peptides were measured in arterial blood using high-performance liquid chromatography-based radioimmunoassays. Losartan increased blood levels of BK-(1-9) and hydroxylated BK-(1-9) by approximately 2-fold and reduced the BK-(1-7)/BK-(1-9) ratio by 55%. There was a trend for eprosartan to produce similar changes in bradykinin levels. There were no changes in blood kallidin levels. Both losartan and eprosartan increased plasma levels of Ang I, Ang II, and Ang-(2-8), and eprosartan increased Ang-(3-8) levels. Ang-(1-7) and Ang-(1-9) levels were unchanged. There was an associated 30% to 35% reduction in Ang II/Ang I ratio and 63% to 69% reduction in Ang-(1-7)/Ang I ratio. Plasma ACE activity was unchanged. CONCLUSIONS: Losartan increases bradykinin levels. The reductions in BK-(1-7)/BK-(1-9), Ang II/Ang I, and Ang-(1-7)/Ang I ratios suggest that the increased bradykinin levels were the result of reduced metabolism by ACE and neutral endopeptidase. Increased bradykinin levels may represent a class effect of AT1 receptor blockers that contributes to their therapeutic actions and may also contribute to the angioedema that may accompany this therapy.  (+info)

A new cannula to ease cement injection during vertebroplasty. (78/539)

One of the main limitations of vertebroplasty is the excessive pressure required to inject a sufficient amount of cement into a vertebral body. Based on previous work that shows that approximately 95% of the injection pressure is required to deliver the cement through the cannula, we proposed a new cannula design with a larger internal diameter in the proximal section. The objective of this study is to determine whether the new cannula geometry significantly reduces the delivery pressure and eases cement injection during vertebroplasty. Two different methods were employed to examine the delivery pressure in a conventional and two redesigned cannulae: (1) analytical model: Hagen-Poisseuille's flow through a tube was used to predict the pressure drop in the cannulae; (2) experiment: first a Newtonian silicone oil and then an acrylic bone cement was injected through the cannulae at a constant rate of 4 cc/min, and the delivery pressure was recorded. Both the experimental and analytical findings confirmed that the redesigned cannula reduces the delivery pressure significantly. Specifically, when the internal diameter of the proximal section was increased by a factor of two, which is clinically feasible, the delivery pressure dropped by about 63%. The redesigned cannula appears to have the potential to improve vertebroplasty. The key benefits are that (1) it eases cement injection, (2) it can be easily integrated into the existing procedure, and (3) it is cost-effective.  (+info)

2-Haloacrylate reductase, a novel enzyme of the medium chain dehydrogenase/reductase superfamily that catalyzes the reduction of a carbon-carbon double bond of unsaturated organohalogen compounds. (79/539)

A soil bacterium, Burkholderia sp. WS, grows on 2-chloroacrylate as the sole carbon source. To identify the enzymes metabolizing 2-chloroacrylate, we carried out comparative two-dimensional gel electrophoresis of the proteins from 2-chloroacrylate- and lactate-grown bacterial cells. As a result, we found that a protein named CAA43 was inducibly synthesized when the cells were grown on 2-chloroacrylate. The CAA43 gene was cloned and shown to encode a protein of 333 amino acid residues (M(r) 35,788) that shared a significant sequence similarity with NADPH-dependent quinone oxidoreductase from Escherichia coli (38.2% identity). CAA43 was overproduced in E. coli and purified to homogeneity. The purified protein catalyzed the NADPH-dependent reduction of the carbon-carbon double bond of 2-chloroacrylate to produce (S)-2-chloropropionate, which is probably further metabolized to (R)-lactate by (S)-2-haloacid dehalogenase in Burkholderia sp. WS. NADH did not serve as a reductant. Despite the sequence similarity to quinone oxidoreductases, CAA43 did not act on 1,4-benzoquinone and 1,4-naphthoquinone. 2-Chloroacrylate analogs, such as acrylate and methacrylate, were also inert as the substrates. In contrast, 2-bromoacrylate served as the substrate. Thus, we named this novel enzyme 2-haloacrylate reductase. This study revealed a new pathway for the degradation of unsaturated organohalogen compounds. It is also notable that the enzyme is useful for the production of (S)-2-chloropropionate, which is used for the industrial production of aryloxyphenoxypropionic acid herbicides.  (+info)

A TAT-streptavidin fusion protein directs uptake of biotinylated cargo into mammalian cells. (80/539)

The HIV-1 TAT peptide has been used extensively for directing the intracellular delivery of an assortment of cargo, including DNA, liposomes and macromolecules. For protein delivery, a variety of TAT-fusion proteins have been described which link the TAT coding sequence to the protein coding sequence of interest. Streptavidin represents a potentially useful TAT-fusion protein because it could be used to deliver a wide array of biotinylated cargo. Here we have characterized a TAT-streptavidin (TAT-SA) fusion protein, which retains the ability to bind biotinylated cargo while directing their efficient cellular uptake. Fluorescence activated cell sorting (FACS) analysis and confocal microscopy characterization showed that TAT-SA is internalized by Jurkat T-cells and NIH 3T3 cells alone and when complexed to phycoerythrin, whereas the native streptavidin is not. Additionally, biotinylated alkaline phosphatase is successfully internalized and retains its activity when complexed to TAT-SA and incubated with Jurkat T-cells. Confocal microscopy suggested, however, that internalized TAT-SA and TAT-SA complexes were largely compartmentalized in vesicular compartments, rather than freely diffusing in the cytoplasmic compartment. To effect cytoplasmic delivery, the endosomal releasing polymer, poly(propylacrylic acid) (PPAA), was biotinylated and complexed to TAT-SA. Endosomal release and cytoplasmic delivery of fluorescently labeled TAT-SA complexes with PPAA was shown by the diffuse distribution of fluorescent protein in the cytoplasm. Taken together, these results demonstrate that TAT-SA can be used to direct intracellular delivery of large biotinylated cargo to intracellular compartments and that biotinylated PPAA can direct cytoplasmic delivery where desired.  (+info)