Swimming training attenuates remodeling, contractile dysfunction and congestive heart failure in rats with moderate and large myocardial infarctions

1. The aim of the present study was to evaluate the effect of swimming on myocardial remodelling after myocardial infarction (MI) in female rats induced by coronary occlusion, which was not performed in sham rats. 2. Rats were divided in six groups, three sedentary (sham (SSh; n = 14), moderate infarct (SMI; n = 8) and large infarct (SLI; n = 10)) and three trained (sham (TSh; n = 16), moderate infarct (TMI; n = 9) and large infarct (TLI; n = 8)) groups. Training (8 weeks, 60 min/day, 5 days/week) was initiated 4 weeks after MI or sham operation. Training did not affect mortality rate, but attenuated the increases in atrial/bodyweight (SSh: 0.07 +/- 0.02; TSh: 0.07 +/- 0.02; SMI: 0.11 +/- 0.03; TMI: 0.09 +/- 0.03; SLI: 0.17 +/- 0.09; TLI: 0.10 +/- 0.05 mg/g) and right ventricular/bodyweight (SSh: 0.15 +/- 0.02; TSh: 0.17 +/- 0.02; SMI: 0.17 +/- 0.07; TMI: 0.20 +/- 0.03; SLI: 0.29 +/- 0.13; TLI: 0.22 +/- 0.08 mg/g) ratios. Myocardial infarction increased pulmonary and myocardial water content in infarcted sedentary animals, whereas no changes were observed in trained infarcted rats. Sedentary infarcted rats showed inotropic and lusitropic depression proportional to the size of the infarct (SSh > SMI > SLI), whereas no differences were noted in trained rats (TLI = TMI = TSh). Indeed, in sedentary rats there was depression of +dT/dt (SSh: 68 +/- 25; TSh: 72 +/- 21; SMI: 53 +/- 20; TMI: 77 +/- 30; SLI: 33 +/- 15; TLI: 57 +/- 22 g/mm(2) per s) and -dT/dt (SSh: 33 +/- 13; TSh: 36 +/- 11; SMI: 24 +/- 5; TMI: 35 +/- 11; SLI: 15 +/- 4; TLI: 32 +/- 11 g/mm(2) per s) compared with trained rats. 3. In conclusion, swimming clearly favoured post-MI cardiac remodelling, attenuated myocardial hypertrophy, contractile and relaxation dysfunction and prevented pulmonary congestion.     

Comparative in vitro activity of nine antistaphylococcal agents against 275 recent isolates of Gram-positive cocci

The aim of this study was to compare the in vitro activities of 9 antistaphylococcal agents including teicoplanin (TEI) against 275 non-repetitive clinical strains representing 15 species of staphylococci and 27 strains of Enterococcus (E.) faecalis, isolated from various specimens between 1991-1992 at a Canadian teaching hospital. The NCCLS agar dilution method was used (10(4) colonyforming units/spot). In terms of MIC(90), TEI and vancomycin (VAN) appeared to be the most potent antibiotics against all staphylococci tested (TEI: 2.0-4.0 mug/ml; VAN: 1.0-2.0 mug/ml; ciprofloxacin (CPF): 0.25-32 mug/ml; cefazolin (CEF): 8.0-256 mug/ml; methicillin (MET): 2.0->256 mug/ml; imipenem (IMP): 1.0-32 mug/ml; erythromycin (ERT): 16->256 mug/ml; ampicillin (AMP): 16-128 mug/ml; fusidic acid (FSA): 0.5-16 mug/ml). Multiple resistant strains, including MET-resistant Staphylococcus (Staph.) aureus and Staph. epidermidis, were susceptible to TEI and VAN with respective MICs of 2-4 mug/ml and 1-2 mug/ml regardless of specimen type. Moreover, TEI was highly active against E. faecalis (MIC(90) for TEI and VAN: 0.5 and 4.0 mug/ml, respectively).     

Heteroscedasticity‐robust Cp model averaging

This paper proposes a new model‐averaging method, called the hetero‐scedasticity–robust (HR) method, for linear regression models with heteroscedastic errors. We provide a feasible form of the Mallows’ ‐like criterion for choosing the weight vector for averaging. Under some regularity conditions, we show that the HR method has asymptotic optimality. The simulation results show that our method works well and performs better than alternative methods in finite samples when the number of candidate models is large and/or the population coefficient of determination is not small.     

Identification and estimation of partially linear censored regression models with unknown heteroscedasticity

In this paper, we introduce a new identification and estimation strategy for partially linear regression models with a general form of unknown heteroscedasticity, that is, and , where ε is independent of and the functional forms of both and are left unspecified. We show that in such a model, β₀ and can be exactly identified while can be identified up to scale as long as permits sufficient nonlinearity in X. A two‐stage estimation procedure motivated by the identification strategy is described and its large sample properties are formally established. Moreover, our strategy is flexible enough to allow for both fixed and random censoring in the dependent variable. Simulation results show that the proposed estimator performs reasonably well in finite samples.     

Inactive Vibrio cholerae whole-cell vaccine-loaded biodegradable microparticles: in vitro release and oral vaccination

An approach is proposed using Vibrio cholerae (VC)-loaded microparticles as oral vaccine delivery systems for improved vaccine bioavailability and increased therapeutic efficacy. The VC-loaded microparticles were prepared with 50:50 poly(DL-lactide-co-glycolide) (PLG), 75:25 poly(DL-lactide-co-glycolide) and poly(lactide acid) (PLA)/PEG blend copolymers by the solvent evaporation method. VC was successfully entrapped in three types of microparticles with loading efficiencies and loading levels as follows: 50:50 PLG systems: 97.8% and 55.4 +/- 6.9 micro g/mg; 75:25 PLG systems: 89.2% and 46.5 +/- 4.4 micro g/mg; PLA/PEG-blended systems: 82.6% and 53.7 +/- 5.8 micro g/mg. The different distributions of VC in the core region and on the surface were as follows: 50:50 PLG systems 25.7 +/- 1.9 and 6.2 +/- 0.9 micro g/mg; 75:25 PLG systems: 25.8 +/- 2.2 and 3.6 +/- 0.4 micro g/mg; PLA/PEG-blended systems: 32.4 +/- 2.1 and 5.2 +/- 1.0 micro g/mg, respectively. In vitro active release of VC was affected mainly by matrix type and VC-loaded location in microparticles. The therapeutic immunogenic potential of VC loaded with 50:50 PLG, 75:25 PLG and PLA/PEG-blended microparticles was evaluated in adult mice by oral immunization. Significantly higher antibody responses and serum immunoglobin Ig G, IgA and IgM responses were obtained when sera from both VC-loaded 75:25 PLG and PLA/PEG-blended microparticles immunized mice were titrated against VC. The most immunogenicity in evoking serum IgG, IgA and IgM responses was immunized by VC-loaded PLA/PEG-blended microparticles, and with VC challenge in mice, the survival rate (91.7%).     

Ischemic and pharmacological induction of delayed cellular protection in iNOS gene-disrupted mice myocytes

Inducible nitric oxide synthase (iNOS) has been implicated as a mediator in myocardial protection, but this property of iNOS is still conflicting. Therefore, the present study was designed to assess whether iNOS really contributes to the ischemically and pharmacologically induced delayed cellular protection (DCP) in mice myocytes. The following groups of cultured iNOS gene-knockout (iNOS-/-), and its respective wild-type (wt) mice myocytes subjected to simulated ischemia (SI) at 20 h were studied: (a) wt + SI: with ischemia alone; (b) iNOS-/- + SI: with ischemia alone; (c) iNOS-/- + heat shock (HS): iNOS-/- and HS; (d) iNOS-/- + sub-lethal simulated ischemia (SSI): iNOS-/- and SSI; (e) iNOS-/- + A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA): iNOS-/- and 1 microM CCPA; (f) iNOS-/- + A1AR agonist (2S)-N6-[2-endo-norbomyl]adenosine (S-ENBA): iNOS-/- and 1 nM S-ENBA; (g) iNOS-/- + K(ATP) channel opener pinacidil (Pin): iNOS-/- and 0.05 microM Pin, and (h) iNOS-/- + mitochondrial K(ATP) channel opener diazoxide (Diazo): iNOS-/- and 100 microM Diazo. The release of LDH into the medium as well as the amount of LDH remaining in the cells was used as a marker of cellular injury and cell viability. The cellular resistance was acquired by iNOS-/- mice myocytes due to HS, SSI, CCPA, S-ENBA, pinacidil and diazoxide treatment, which was evidenced by reduction of LDH (U/L) release from 51.14 +/- 1.35 (iNOS-/-) to 42.20 +/- 1.01 (iNOS-/- + HS); 45.57 +/- 0.75 (iNOS-/- + SSI); 42.87 +/- 0.87 (iNOS-/- + CCPA); 43.21 +/- 0.70 (iNOS-/- + S-ENBA); 37.81 +/- 0.99 (iNOS-/- + Pin) and 36.79 +/- 0.68 (iNOS-/- + Diazo), p < 0.01. Our data suggest that heat shock (HS), sub-lethal simulated ischemia (SSI), A1 adenosine agonists CCPA, S-ENBA and K(ATP) channel openers pinacidil (membrane K(ATP) channel), diazoxide (mitochondrial K(ATP) channel) induce delayed cellular protection in mice myocytes against subsequent sustained simulated ischemia without the involvement of iNOS. Further, our data also suggest that pinacidil and diazoxide are more potent inducers of delayed cellular protection among others in iNOS-/- mice myocytes against sustained simulated ischemia.     

Pharmacokinetics of naftidrofuryl in patients with renal impairment

Naftidrofuryl (CAS 31329-57-4) is used, mainly in elderly patients, in the treatment of various vascular disorders. The aim of this study was to evaluate and compare the pharmacokinetics of naftidrofuryl after single oral administration of a 200 mg naftidrofuryl tablet (Praxilene) in caucasian male and female subjects with renal impairment versus healthy volunteers. This prospective and open study was conducted in three parallel groups: Group A = healthy subjects with a Cl(CR) > 80 ml/min, Group B = uraemic patients with a 20 < or = Cl(CR) < 40 ml/min, Group C = uraemic patients with a Cl(CR) < 20 ml/min. Blood samples were taken over a period of 32 h after dosing. The mean values (+/-SD) of the pharmacokinetic parameters of naftidrofuryl for group A were as follows: tmax: 1.3 h (median), Cmax: 174 +/- 46 ng/ml, t(1/2 beta): 4.4 +/- 1.1 h, AUC(0-infinity): 1541 +/- 384 ng x h/ml; for group B: tmax: 2.5 h (median), Cmax: 239 +/- 94 ng/ml, t(1/2 beta): 5.0 +/- 1.2 h, AUC(0-infinity): 2361 +/- 751 ng x h/ml; for group C: tmax: 3.0 h (median), Cmax: 236 +/- 104 ng/ml, t(1/2 beta): 5.0 +/- 2.1 h, AUC(0-infinity): 2488 +/- 2003 ng x h/ml. The statistical analysis was performed on the pharmacokinetic parameters with one-way ANOVA in order to compare each group. No significant difference between each group was observed. In conclusion, renal insufficiency did not appear to influence the pharmacokinetic profile of oral naftidrofuryl.     

Identification and determination of selected angiotensin II receptor antagonist group drugs by HPLC method

Losartan potassium, valsartan, telmisartan, irbesartan, eprosartan mesylate and candesartan cilexitil, the angiotensin II receptor antagonists, were analyzed in bulk substances and in tablets: Lorista tablets 50 mg, Diovan tablets 160 mg, Micardis tablets 20 mg, Aprovel tablets 300 mg, Teveten tablets 600 mg and Blopress tablets 16 mg. The conditions for identification by HPLC method in a gradient system and for determination of those compounds in isocratic systems were developed. The determination was carried out using Zorbax SB-Phenyl column with UV-VIS detector set at 230 nm and the following mobile phases: 0.1 mol/L sodium acetate (pH = 5.5) - acetonitrile - methanol in 35:9:6 v/v/v ratio for eprosartan mesylate and valsartan, in 15:6:4 v/v/v ratio for losartan potassium and irbesartan and in 10:9:6 v/v/v ratio for telmisartan and candesartan cilexitil. The recovery from simulated tablets was determined and amounted to: for eprosartan mesylate - 99.04%, valsartan - 100.0%, losartan potassium - 100.03%, irbesartan - 100.35%, telmisartan - 100.06% and candesartan cilexitil - 100.40%.     

糖尿病前期口服药物应用研究进展

糖尿病前期（Predibetes）是指血浆葡萄糖水平在正常人群与糖尿病人群之间的一种中间状态,又被称为糖调节受损（Impaired glucose regulation,IGR）,包括两种异常的糖代谢状态,即空腹血糖调节受损（IFG）和糖耐量受损（IGT）。IFG是指空腹血糖水平在6．1～7．0mmol／L而葡萄糖负荷后2h血糖〈7．8mmol／L;     

Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study

OBJECTIVE: To compare the effects of rosiglitazone added to metformin with dose escalation of metformin on cardiovascular risk biomarkers in type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Cardiovascular biomarkers were assessed in a sub-population of 122 subjects with type 2 diabetes mellitus (mean age 54.6 and 56.0 years, BMI 34.7 and 32.1 kg/m2; for the rosiglitazone plus metformin and metformin groups, respectively) from the multicenter (63 centers in the USA), double-blind, randomized parallel-group Escalation of Metformin theraPy vs. Initiation of Rosiglitazone Early (EMPIRE) study. Treatment group sizes were slightly imbalanced owing to central, rather than local, randomization. Subjects receiving metformin 1000 mg/day at baseline were randomized to rosiglitazone 4 mg/day plus metformin 1000 mg/day (RSG + MET) or metformin 1500 mg/day (up-titrated MET) for 24 weeks. At 8-weeks, rosiglitazone was increased to 8 mg/day in RSG + MET recipients and metformin to 2000 mg/day in up-titrated MET recipients. RESULTS: Reductions from baseline in HbA1c at week 24 (mean +/- SD) occurred in both groups (RSG + MET: -0.61% +/- 1.16%; up-titrated MET: -0.65% +/- 1.18%). Post-prandial glucose levels (AUC(0-3h)) decreased with RSG + MET (-3.5 mmol/L.h; 95% confidence interval [CI]: -5.2 to -1.8) and up-titrated MET (-1.3 mmol/L.h; 95% CI: -3.8 to 1.1). Homeostasis Model Assessment (HOMA)-estimated insulin sensitivity increased by 37.7% (95% CI: 22.8 to 54.5) in RSG + MET and 6.9% (95% CI: -6.2 to 21.9) in up-titrated MET recipients. RSG + MET reduced C-reactive protein (CRP; -23.9%; 95% CI: -40.4 to -2.8), plasminogen activator inhibitor-1 (PAI-1) activity (-30.1%; 95% CI: -44.5 to -11.9), PAI-1 antigen (-15.5%; 95% CI: -28.3 to -0.3) and matrix metalloproteinase-9 (MMP-9; -13.8%; 95% CI: -25.1 to -0.9), but increased tumor necrosis factor-alpha (TNF-alpha; 27.0%; 95% CI: 6.8 to 50.9). Corresponding values for up-titrated MET were CRP -9.3% (95% CI: -36.9 to 30.2), PAI-1 activity -7.2% (95% CI: -28.2 to 20.0), PAI-1 antigen -1.5% (95% CI: -17.4 to 17.5), MMP-9 29.0% (95% CI: -1.3 to 68.6) and TNF-alpha -6.0% (95% CI: -22.0 to 13.2). CONCLUSIONS: These results suggest that rosiglitazone plus metformin has positive cardiovascular effects against a background of similar glycemic improvements.     

Further studies on a mixture of fatty acids from sugar cane (Saccharum officinarum) wax oil in animal models of hypersensitivity

A mixture of fatty acids obtained from sugar cane wax oil, the main components of which are palmitic, oleic, linoleic and linolenic acids, was evaluated topically in two experimental models of hypersensitivity: the ear swelling response to ovalbumin in sensitized mice (ED50 edema: 0.63 +/- 0.06 mg/ear, ED50 myeloperoxidase: 0.56 +/- 0.04 mg/ear, ED50 degranulated cells: 0.70 +/- 0,08 mg/ear) and oxazolone-induced contact hypersensitivity in mice (ED50 edema: 1.63 +/- 0.26 mg/ear, ED50 myeloperoxidase: 1.50 +/- 0.28 mg/ear, ED50 degranulated cells: 1.69 +/- 0.08 mg/ear). Also, the effect of this mixture was studied on the chemotaxis induced by fmlp (ED50: 25 +/- 3 microg/mL). The mixture showed anti-inflammatory activity in both in vivo models of allergy and in the chemotaxis test. Therefore, these results provide evidence about the potential usefulness of the mixture of fatty acids from sugar cane wax oil in cutaneous inflammatory and allergic disorders.     

高效液相色谱法测定川续断中熊果酸、齐墩果酸、马钱苷和川续断皂苷Ⅵ的含量

目的:利用高效液相色谱法(HPLC)建立川续断中熊果酸、齐墩果酸、马钱苷和川续断皂苷Ⅵ4种指标成分的含量测定方法。方法:(1)测定熊果酸、齐墩果酸色谱条件为:色谱柱:Agilent ZORBAX SB-C₁₈(4.6 mm×250 mm,5 μm);流动相:甲醇-0.2%醋酸铵水溶液(86:14);流速:0.9 ml·min^-1;柱温:25 ℃;检测波长:210 nm。(2)测定马钱苷、川续断皂苷Ⅵ色谱条件为:色谱柱:Agilent ZORBAX SB-C₁₈(4.6 mm×250 mm,5 μm);流动相:0~8 min乙腈-水(15:85),8~10 min乙腈-水(25:75),10~28 min乙腈-水(30:70);流速:0.8 ml·min^-1;柱温:25 ℃;分别在240 nm、210 nm的波长条件下检测马钱苷和川续断皂苷Ⅵ。结果:(1)熊果酸在5.20~520 μg·ml^-1范围内线性关系良好,r=0.999 7;平均回收率为96.4%,RSD为0.96%;齐墩果酸在5.64~564 μg·ml^-1范围内线性关系良好,r=0.999 8;平均回收率为97.7%,RSD为1.66%。(2)马钱苷在6.04~604 μg·ml^-1范围内线性关系良好,r=0.999 9;平均回收率为99.4%, RSD为1.35%,川续断皂苷Ⅵ 6.28~628 μg·ml^-1范围内线性关系良好,r=1.000;平均回收率为97.7%,RSD为0.90%。结论:该方法简单、准确可行,结果稳定可靠,可为川续断的质量控制提供科学依据。     

Correction to: Altered baseline and amphetamine-mediated behavioral profiles in dopamine transporter Cre (DAT-Ires-Cre) mice compared to tyrosine hydroxylase Cre (TH-Cre) mice

Psychopharmacology - A Correction to this paper has been published: https://doi.org/10.1007/s00213-020-05718-2     

比较比索洛尔-氢氯噻嗪复合剂与缬沙坦对原发性高血压24小时动态血压的影响研究

目的:比较比索洛尔-氢氯噻嗪复合剂(Bisoprolol//HCTZ)与缬沙坦(Valsartan)对原发性高血压患者24小时动态血压的影响。方法:44例原发性高血压患者分别随机入组比索洛尔2.5~5 mg/氢氯噻嗪6.25 mg复合剂治疗组和缬沙坦80~160 mg治疗组,用法:1次/d,连续服药16周,每4周对患者进行用药前后24小时动态血压(ABP)进行监测。结果:44例患者入组(男性23例,女性21例)中,23例入组比索洛尔/氢氯噻嗪复合剂治疗组,21例入组缬沙坦治疗组。与治疗前相比,两组的动态血压都有显著的降低,24小时SBP/DBP(-16.9/-10.3 mmHg和-17.7/-10.9 mmHg),白天SBP/DBP分别为(-17.1/-9.4 mmHg和-17.6/-9.8 mmHg),夜晚SBP/DBP分别为(-17.0/-11.5 mmHg和-16.4/-11.6 mmHg)。结论:低剂量组合的比索洛尔和氢氯噻嗪对于原发性高血压患者24小时动态血压的降低有显著效果。     

Semi‐linear mode regression

In this paper, I estimate the slope coefficient parameter β of the regression model , where the error term e satisfies almost surely and ? is an unknown function. It is possible to achieve ‐consistency for estimating β when ? is known up to a finite‐dimensional parameter. I present a consistent and asymptotically normal estimator for β, which does not require prescribing a functional form for ?, let alone a parametrization. Furthermore, the rate of convergence in probability is equal to at least , and approaches if a certain density is sufficiently differentiable around the origin. This method allows both heteroscedasticity and skewness of the distribution of . Moreover, under suitable conditions, the proposed estimator exhibits an oracle property, namely the rate of convergence is identical to that when ? is known. A Monte Carlo study is conducted, and reveals the benefits of this estimator with fat‐tailed and/or skewed data. Moreover, I apply the proposed estimator to measure the effect of primogeniture on economic achievement.     

Steroid synthesis inhibition with ketoconazole and its effect upon the regulation of the hypothalamus-pituitary-adrenal system in healthy humans.

Steroid synthesis inhibitors are commonly used in the treatment of patients with Cushing's disease, but may also improve psychopathology in hypercortisolemic depressed patients. Since glucocorticoids exert a negative feedback at pituitary and supra-pituitary levels, the inhibition of steroid synthesis may lead to increased expression of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). We studied the effect of treatment with 800 mg ketoconazole (3 weeks) upon the concentrations of basal plasma cortisol in the evening, corticosteroid-binding globulin (CBG), dehydroepiandrosterone-sulfate (DHEA-S), and ACTH as well as the concentrations of cortisol, CRH, and AVP in cerebrospinal fluid (CSF) at 8.30 h in 10 healthy, male volunteers. While we found cortisol plasma concentrations to be unchanged, we noted a significant increase in ACTH (post: 45.1+/-43.5; pre: 14.2+/-5.2 pmol/l; F(1,8)=9.78, p<0.02) and CBG concentrations (post: 38.8+/-4.3; pre: 31.9+/-4.2 microg/l), but DHEA-S plasma concentrations declined (post: 1.75+/-1.83; pre: 2.75+/-2.80 mg/l; F(1,8)=7.9, p<0.03). CRH concentrations in CSF were unchanged after treatment (post: 62.5+/-15.9; pre: 63.7+/-13.9 pg/ml), while there was a trend for AVP concentrations to rise during treatment (post: 2.52+/-1.18; pre: 1.92+/-0.96 pg/ml; paired t=-1.9, p<0.1). Cortisol CSF concentrations declined in the elderly (pre: 52.5+/-23.2; post: 26.7+/-4.6 nmol/l), but not in the young subgroup (pre: 15.6+/-11.3; post: 27.7+/-9.4 nmol/l). We thus conclude that the treatment of healthy controls with steroid-synthesis inhibitors does not lead to a major increase in CRH secretion.     

Correction to: Mercury bioaccumulation in freshwater fishes of the Chesapeake Bay watershed

Ecotoxicology - A Correction to this paper has been published: https://doi.org/10.1007/s10646-021-02403-8     

Pharmacokinetics of levofloxacin during continuous venovenous hemodiafiltration and continuous venovenous hemofiltration in critically ill patients

STUDY OBJECTIVE: To assess the pharmacokinetics of levofloxacin during continuous venovenous hemodiafiltration (CVVHDF) and continuous venovenous hemofiltration (CVVH). DESIGN: Nonrandomized pharmacokinetic evaluation. SETTING: University surgical intensive care unit. PATIENTS: Six critically ill patients. INTERVENTION: Five patients received levofloxacin 500 mg/day and one patient received levofloxacin 125 mg/day All patients received continuous renal replacement therapy: CVVHDF on day 1 and CVVH on day 2, using an acrylonitrile hollow-fiber 0.9-m2 filter, constant blood flow rate of 90 ml/minute, substitution flow rate of 1 L/hour predilution, and dialysate flow rate of 1 L/hour (CVVHDF). MEASUREMENTS AND MAIN RESULTS: Serum, ultrafiltrate, and dialysate concentrations of levofloxacin were determined by high-performance liquid chromatography. Extracorporeal clearance was 26.05 +/- 4.66 ml/hour during CVVHDF and 15.71 +/- 2.73 ml/hour during CVVH (p<0.05). Elimination half-life was 28.08 +/- 4.5 hours and 45.9 +/- 17.7 hours, and distribution volume was 1.51 +/- 0.52 L/kg and 1.42 +/- 0.42 L/kg for CVVHDF and CVVH, respectively. Saturation was 0.76 +/- 0.13 for CVVHDF versus a sieving coefficient of 0.77 +/- 0.16 for CVVH. CONCLUSION: Marked extracorporeal elimination of levofloxacin occurs, requiring a dosage adjustment that can be calculated from the characteristics of CVVH and CVVHDF.     

Inhalation of the endothelin-A receptor antagonist LU-135252 at various doses in experimental acute lung injury

We studied the effects of the inhaled endothelin-A receptor antagonist LU-135252 at different doses on hemodynamics and gas exchange in an animal model of acute lung injury. Thirtysix piglets (27 +/- 1 kg) were anesthetized, mechanically ventilated (FiO2 1.0), and surfactant-depleted by repeated lung lavage. The animals were randomly assigned to receive either nebulized LU- 135252 for 30 minutes at a dose of 0.3 mg/kg (n = 12), or at a dose of 3.0 mg/kg (n = 12); n = 12 animals received no further treatment (Controls). Induction of acute lung injury decreased PaO2 from 566 +/- 8 mmHg to 53 +/- 2 mmHg (mean +/- SEM) and increased intrapulmonary shunt (QS/QT) from 13 +/- 1% to 57 +/- 2%. Inhalation of LU-135252 at either dose induced a significant and sustained increase in PaO2 (0.3 mg/kg: 349 +/- 39 mmHg; 3.0 mg/kg: 219 +/- 40 mmHg), and a significant decrease in QS/QT (0.3 mg/kg: 19 +/- 2%; 3.0 mg/kg: 27 +/- 3%) when compared with Controls (PaO2: 50 +/- 3 mmHg, QS/QT: 50 +/- 5%) (P < 0.05; values at 4 hours). Mean pulmonary artery pressure in LU-135252-treated animals (0.3 mg/kg: 31 +/- 2 mmHg; 3.0 mg/kg: 30 +/- 1 mmHg) was significantly lower than in Controls (40 +/- 2 mmHg), while there were no differences in mean arterial pressure and cardiac output. We conclude that inhalation of LU-135252 at either dose improved gas exchange and hemodynamics comparably, indicating that the lower dose was already sufficient to block the majority of endothelin-A receptors in ventilated regions of the injured lung.     

Biologic availability and hemodynamic actions following administration of sublingual glycerol trinitrate. A new delivery system]

Bioavailability and Hemodynamic Properties of Sublingually Applied Glyceryl Trinitrate/A new delivery system Bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) was investigated in 16 healthy subjects after sublingual application of 0.8 mg GTN from either a reference product (B) where GTN release is effected by fluorochlorohydrocarbon (FCH) or a test product (A) (Corangin Nitrospay) where GTN release is effected FCH-independently by a pumping system. Plasma concentrations of GTN and hemodynamic effects (digital plethysmography) were measured until 30 min after application. There was no significant difference (Wilcoxon's matched pairs signed rank test) in AUCo-t (A: 8.9 +/- 7.3 ng x h/ml; B: 8.3 +/- 7.6 ng x h/ml) and Cmax (A: 1.43 +/- 1.26 ng/ml; B: 1.13 +/- 1.06 ng/ml), but tmax was significantly shorter after application of the test product (A: 4.6 +/- 1.0 min; B: 6.7 +/- 2.7 min, p less than 0.01). Nonparametric confidence limits (90%) were 0.80-1.89 for AUCo-t (point estimator of the median 1.14), 0.92-2.78 for Cmax (point estimator 1.06) and 0.61-0.90 for tmax (point estimator 0.75). EC50-values obtained from the individual concentration/effect-curves were linked with the concentration/time-curves to establish the time of reaching EC50 (tEC50). GTN response did not differ for both preparations (EC50A: 0.25 +/- 0.24 ng/ml; EC50 B: 0.34 +/- 0.36 ng/ml), coincident with tmax, tEC50 was significantly shorter after administration of (A) (A: 1.8 +/- 0.3 min, B: 2.7 +/- 1.0 min). With respect to the variability of GTN pharmacokinetics, the test preparation shows superior bioavailability and a faster onset of hemodynamic action.