Tigecycline in critically ill patients on continuous renal replacement therapy: a population pharmacokinetic study.

BACKGROUND: Tigecycline is a vital antibiotic treatment option for infections caused by multiresistant bacteria in the intensive care unit (ICU). Acute kidney injury (AKI) is a common complication in the ICU requiring continuous renal replacement therapy (CRRT), but pharmacokinetic data for tigecycline in patients receiving CRRT are lacking. METHODS: Eleven patients mainly with intra-abdominal infections receiving either continuous veno-venous hemodialysis (CVVHD, n = 8) or hemodiafiltration (CVVHDF, n = 3) were enrolled, and plasma as well as effluent samples were collected according to a rich sampling schedule. Total and free tigecycline was determined by ultrafiltration and high-performance liquid chromatography (HPLC)-UV. Population pharmacokinetic modeling using NONMEM® 7.4 was used to determine the pharmacokinetic parameters as well as the clearance of CVVHD and CVVHDF. Pharmacokinetic/pharmacodynamic target attainment analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT. RESULTS: A two-compartment population pharmacokinetic (PK) model was suitable to simultaneously describe the plasma PK and effluent measurements of tigecycline. Tigecycline dialysability was high, as indicated by the high mean saturation coefficients of 0.79 and 0.90 for CVVHD and CVVHDF, respectively, and in range of the concentration-dependent unbound fraction of tigecycline (45-94%). However, the contribution of CRRT to tigecycline clearance (CL) was only moderate (CLCVVHD: 1.69 L/h, CLCVVHDF: 2.71 L/h) in comparison with CLbody (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CLbody in our collective, reducing the observed interindividual variability on CLbody from 58.6% to 43.6%. The probability of target attainment under CRRT for abdominal infections was ≥ 0.88 for minimal inhibitory concentration (MIC) values ≤ 0.5 mg/L and similar to patients without AKI. CONCLUSIONS: Despite high dialysability, dialysis clearance displayed only a minor contribution to tigecycline elimination, being in the range of renal elimination in patients without AKI. No dose adjustment of tigecycline seems necessary in CRRT. TRIAL REGISTRATION: EudraCT, 2012-005617-39 . Registered on 7 August 2013.

Image quality and metal artifact reduction in total hip arthroplasty CT: deep learning-based algorithm versus virtual monoenergetic imaging and orthopedic metal artifact reduction.

BACKGROUND: To compare image quality, metal artifacts, and diagnostic confidence of conventional computed tomography (CT) images of unilateral total hip arthroplasty patients (THA) with deep learning-based metal artifact reduction (DL-MAR) to conventional CT and 130-keV monoenergetic images with and without orthopedic metal artifact reduction (O-MAR). METHODS: Conventional CT and 130-keV monoenergetic images with and without O-MAR and DL-MAR images of 28 unilateral THA patients were reconstructed. Image quality, metal artifacts, and diagnostic confidence in bone, pelvic organs, and soft tissue adjacent to the prosthesis were jointly scored by two experienced musculoskeletal radiologists. Contrast-to-noise ratios (CNR) between bladder and fat and muscle and fat were measured. Wilcoxon signed-rank tests with Holm-Bonferroni correction were used. RESULTS: Significantly higher image quality, higher diagnostic confidence, and less severe metal artifacts were observed on DL-MAR and images with O-MAR compared to images without O-MAR (p < 0.001 for all comparisons). Higher image quality, higher diagnostic confidence for bone and soft tissue adjacent to the prosthesis, and less severe metal artifacts were observed on DL-MAR when compared to conventional images and 130-keV monoenergetic images with O-MAR (p ≤ 0.014). CNRs were higher for DL-MAR and images with O-MAR compared to images without O-MAR (p < 0.001). Higher CNRs were observed on DL-MAR images compared to conventional images and 130-keV monoenergetic images with O-MAR (p ≤ 0.010). CONCLUSIONS: DL-MAR showed higher image quality, diagnostic confidence, and superior metal artifact reduction compared to conventional CT images and 130-keV monoenergetic images with and without O-MAR in unilateral THA patients. RELEVANCE STATEMENT: DL-MAR resulted into improved image quality, stronger reduction of metal artifacts, and improved diagnostic confidence compared to conventional and virtual monoenergetic images with and without metal artifact reduction, bringing DL-based metal artifact reduction closer to clinical application. KEY POINTS: • Metal artifacts introduced by total hip arthroplasty hamper radiologic assessment on CT. • A deep-learning algorithm (DL-MAR) was compared to dual-layer CT images with O-MAR. • DL-MAR showed best image quality and diagnostic confidence. • Highest contrast-to-noise ratios were observed on the DL-MAR images.

Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: impact of exogenous neuropeptide Y.

BACKGROUND & AIMS: Splanchnic vasodilation is an essential disturbance in portal hypertension. Increased systemic sympathetic nerve activity is well known, but potential corresponding vascular desensitization is incompletely characterized. Release of splanchnic sympathetic neurotransmitters noradrenaline (NA) and co-transmitter neuropeptide Y (NPY) remains to be elucidated. Finally, the effects of exogenous NPY on these mechanisms are unexplored. METHODS: Portal vein ligated cirrhotic, and control rats were used for in vitro perfusion of mesenteric arteries. Depletion of vascular pressure response was induced by repetitive electric sympathetic perivascular nerve stimulation (PNS) and performed in the absence and presence of exogenous NPY. Additionally, PNS-induced release of NA and NPY was measured. RESULTS: Mesenteric PNS-induced pressure response was lower in portal hypertension. Depletion of the pressure response to PNS, representing the degree of desensitization, was enhanced in portal hypertension. NA release was elevated, whereas NPY release was attenuated in cirrhosis. Administration of exogenous NPY led to marked recovery from desensitization and vasoconstrictive improvement in cirrhotic rats, being associated with more pronounced decrease of NA release. CONCLUSIONS: Pronounced depletion of splanchnic arterial pressure-response to repetitive sympathetic nerve stimulation in cirrhosis is partly attributable to altered NA release as well as to deficient NPY release. External NPY restores vascular contractility and attenuates pathologically elevated NA release in the portal hypertensive mesenteric vasculature, revealing post-, and prejunctional effects at the vascular smooth muscle motor endplate; therefore outlining encouraging therapeutic strategies.

Double inversion recovery MRI versus contrast-enhanced MRI for evaluation of knee synovitis in juvenile idiopathic arthritis.

BACKGROUND: Double inversion recovery (DIR) MRI has the potential to accentuate the synovium without using contrast agents, as it allows simultaneous signal suppression of fluid and fat. The purpose of this study was (1) to compare DIR MRI to conventional contrast-enhanced (CE) MRI for delineation of the synovium in the knee in children with juvenile idiopathic arthritis (JIA) and (2) to assess the agreement between DIR MRI and CE-MRI regarding maximal synovial thickness measurements. RESULTS: In this prospective study, 26 children with JIA who consecutively underwent 3.0-T knee MRI between January 2018 and January 2021 were included (presence of knee arthritis: 13 [50%]; median age: 14 years [interquartile range [IQR]: 11-17]; 14 girls). Median confidence to depict the synovium (0-100 mm visual analogue scale; scored by 2 readers [consensus based]) was 88 (IQR: 79-97) for DIR MRI versus 100 (IQR: 100-100) for CE-MRI (p value = < .001). Maximal synovial thickness per child (millimeters; scored by 4 individual readers) on DIR MRI was greater (p value = < .001) in the children with knee arthritis (2.4 mm [IQR: 2.1-3.1]) than in those without knee arthritis (1.4 mm [IQR: 1.0-1.6]). Good inter-technique agreement for maximal synovial thickness per child was observed (rs = 0.93 [p value = < .001]; inter-reader reliability: ICC DIR MRI = 0.87 [p value = < .001], ICC CE-MRI = 0.90 [p value = < .001]). CONCLUSION: DIR MRI adequately delineated the synovium in the knee of children with JIA and enabled synovial thickness measurement similar to that of CE-MRI. Our results demonstrate that DIR MRI should be considered as a child-friendly alternative to CE-MRI for evaluation of synovitis in children with (suspected) JIA.

Bone tissue and plasma concentrations of linezolid and vancomycin in rabbits with prosthesis-related infection due to MRSA.

BACKGROUND: Due to its safety profile and ease of oral administration, linezolid became an alternative to vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of our study was to compare bone tissue and plasma concentrations of linezolid and vancomycin in prosthesis-related MRSA infection in a rabbit model. MATERIAL AND METHODS: During implantation of titanium cylinders into the femurs of nine rabbits, a bacterial suspension of MRSA was added to induce infection. Antibiotic treatment was started eight hours later. Antibiotic concentrations in plasma (day one, three and seven) and bone (day seven) were determined by HPLC analysis. RESULTS: At steady state the mean peak and trough plasma levels of linezolid were 29.0 microg/mL and 8.2 microg/ mL and for vancomycin 39.1 microg/mL and 28.2 microg/mL. On day seven the mean peak concentration of linezolid in plasma was 28.5 microg/mL and after six hours 26.3 microg/mL and for vancomycin 53.8 microg/mL and 29.1 microg/mL after six hours. Vancomycin showed a penetration into the infected bone (femur) of 53% of plasma concentration, into the uninfected 28%, linezolid 11% (for both six hours after administration). CONCLUSION: In conclusion, we observed a higher rate of tissue penetration for vancomycin than for linezolid into femur bone in this animal model. As linezolid offers the option for oral treatment of gram-positive organisms, results of further studies comparing vancomycin and linezolid are keenly awaited.

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients - A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial.

BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. METHODS: We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m2 for obese or between 18.5 and 30 kg/m2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0-8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC0-8) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. DISCUSSION: Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. TRIAL REGISTRATION: EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776).

Concentrations of moxifloxacin in plasma and urine, and penetration into prostatic fluid and ejaculate, following single oral administration of 400 mg to healthy volunteers.

The spectrum of chronic bacterial prostatitis (CBP) comprises Gram-negative, Gram-positive and atypical pathogens. Because of its broad spectrum of activity, moxifloxacin might be a suitable antibiotic for the treatment of CBP. In this pharmacokinetic study, plasma concentrations and the penetration of moxifloxacin into prostatic fluid and ejaculate were investigated. Twelve healthy male volunteers received a single oral dose of 400mg moxifloxacin and at the same time received 3.24 g of iohexol intravenously to assess urinary contamination of prostatic fluid and ejaculate. Plasma concentrations were determined at 0, 0.5, 1, 2, 3 and 4h and prostatic fluid and ejaculate (mean+/-standard deviation (S.D.)) were determined at 3.5+/-0.4h and 3.6+/-0.4h, respectively, following administration of drugs. Urinary concentrations were determined in the urine collected from 0-4.5h. Concentrations of moxifloxacin and iohexol in plasma, secretions and urine were determined by high-performance liquid chromatography. The mean+/-S.D. peak plasma concentration of moxifloxacin was 2.8+/-0.5 mg/L observed after 1.6+/-0.9h. In prostatic fluid, the concentration of moxifloxacin was 3.8+/-1.2 mg/L and the prostatic fluid/plasma ratio was 1.6+/-0.5. In ejaculate, the concentration was 2.5+/-0.7 mg/L and the ejaculate/plasma ratio was 1.0+/-0.2. Moxifloxacin concentrations in prostatic fluid were ca. 60% (P<0.05) higher than in plasma and concentrations in ejaculate were approximately the same as in plasma. Therefore, moxifloxacin might be a good alternative for the treatment of CBP, but further studies are warranted to establish this indication.

Nutritive value of corn distiller's dried grains with solubles steeped without or with exogenous feed enzymes for 24 h and fed to growing pigs.

The use of corn distillers dried grains with solubles (DDGS) in pig diets is limited due to high fiber concentration. Steeping with exogenous fiber-degrading enzymes (FDE) may improve their feeding value. We evaluated apparent ileal digestibility (AID), standardized ileal digestibility (SID), and apparent total tract digestibility (ATTD) of components and DE content in DDGS steeped without or with two commercial FDE (A and B). Mixture of 350 g of DDGS, FDE (none for control), and 1.5 liters of water was incubated at 40 °C for 24 h with 15 min agitation every 40 min. FDE-A (pure combination) supplied 5,500 U of xylanase and 1,050 U of ß-glucanase while FDE-B (multienzyme complex) supplied 1,200 U of xylanase, 150 U of ß-glucanase, 500 U of cellulase, and 5,000 U of protease per kg of DDGS plus side activities. Samples were taken at time 0, 4, 8, and 24 h for organic acids and pH measurements. Three semi-purified corn starch-based diets were formulated with steeped DDGS as the sole source of CP. The basal mixture contained 0.2% TiO2 as indigestible marker. Six ileal-cannulated pigs (20 kg BW) were fed the three diets in a replicated 3 × 3 Latin square design to give six replicates per diet. Pigs were fed at 2.8× maintenance energy requirements and had free access to water. In each period, pigs were adjusted to diets for 7 d followed by 2 d for grab fecal and 2 d of 8 h continuous ileal digesta collection. There were no (P > 0.05) treatment and sampling time interaction or treatment effects on pH and lactic concentration. Lactic and acetic acids increased, and pH decreased (P < 0.05) over time points. The AID of CP, NDF, and crude fat and SID of CP were not different (P > 0.05) among treatments. Steeping DDGS with FDE-A had lower (P = 0.01) ATTD of NDF than control but higher (P = 0.001) ATTD of crude fat compared with the control or DDGS steeped with FDE-B. Values for DE content in steeped DDGS were not different (P > 0.05) and amounted to 4,095, 4,039, and 3,974 kcal/kg DM for the control, FDE-A, and FDE-B, respectively. In conclusion, under conditions of the study, steeping DDGS with exogenous enzymes did not improve fiber and energy digestibility.

Systematic assessment of the growth plates of the wrist in young gymnasts: development and validation of the Amsterdam MRI assessment of the Physis (AMPHYS) protocol.

OBJECTIVES: To develop and validate a protocol for MRI assessment of the distal radial and ulnar periphyseal area in gymnasts and non-gymnasts. METHODS: Twenty-four gymnasts with wrist pain, 18 asymptomatic gymnasts and 24 non-gymnastic controls (33 girls) underwent MRI of the wrist on a 3T scanner. Sequences included coronal proton density-weighted images with and without fat saturation, and three-dimensional water-selective cartilage scan and T2 Dixon series. Skeletal age was determined using hand radiographs. Three experienced musculoskeletal radiologists established a checklist of possible (peri)physeal abnormalities based on literature and clinical experience. Five other musculoskeletal radiologists and residents evaluated 30 MRI scans (10 from each group) using this checklist and reliability was determined using the intraclass correlation coefficient (ICC) and Fleiss' kappa. A final evaluation protocol was established containing only items with fair to excellent reliability. RESULTS: Twenty-seven items were assessed for reliability. Intra-rater and inter-rater agreement was good to excellent (respective ICCs 0.60-0.91 and 0.60-0.78) for four epiphyseal bone marrow oedema-related items, physeal signal intensity, metaphyseal junction and depth of metaphyseal intrusions. For physeal thickness, thickness compared with proximal physis of first metacarpal, metaphyseal intrusions, physeal connection of intrusions and metaphyseal bone marrow signal intensity, intra-rater agreement was fair to excellent (ICC/kappa 0.55-0.85) and inter-rater agreement was fair (ICC/kappa 0.41-0.59). Twelve items were included in the final protocol. CONCLUSION: The Amsterdam MRI assessment of the Physis protocol facilitates patient-friendly and reliable assessment of the (peri)physeal area in the radius and ulna.

Neoimmun versus Neoral: a bioequivalence study in healthy volunteers and influence of a fat-rich meal on the bioavailability of Neoimmun.

In two crossover studies with 12 (6 males/6 females) healthy young volunteers each, we compared the bioavailability of Neoimmun capsules with the microemulsion Neoral and the influence of a fat-rich breakfast on the bioavailability of Neoimmun. Each volunteer received a single dose of 200 mg cyclosporine A in each period. Blood samples were taken up to 24 h and analysed for cyclosporine A by high-performance liquid chromatography (HPLC) and photometric detection. The pharmacokinetic parameters were determined by non-compartmental analysis. The treatments were tested for bioequivalence and significant differences. The bioavailability of Neoimmun was significantly lower compared to Neoral, albeit Neoimmun met the bioequivalence criterion (90% confidence interval of AUC 0.80-0.94) or missed the criterion only marginally (90% confidence interval of c (max) 0.75-0.91). The bioavailability of Neoimmun as determined by area under the blood concentration-time curve (AUC) increased by nearly 20% after a fat-rich breakfast. However, mean peak concentrations after food were only higher in male subjects, whereas mean peak concentrations in female subjects were lower compared to fasting administration. In conclusion, our data show that Neoimmun exhibits a lower bioavailability than the microemulsion Neoral and that food has a significant but variable and sex-dependent impact on the bioavailability of Neoimmun capsules.

Comparison of the pharmacokinetics of piperacillin and sulbactam during intermittent and continuous intravenous infusion.

BACKGROUND: The antibacterial effect of piperacillin/sulbactam depends on the time of drug concentration above the minimal inhibitory concentration (MIC). Therefore, continuous infusion (CI) may be a more rational approach than standard intermittent short-term infusion (SI). The study investigated whether CI achieves effective drug concentrations comparable with SI. METHODS: Seven intensive care unit patients received either piperacillin/sulbactam as 4/1 g intravenous infusion over 15-20 min every 8 h or as 4/1 g intravenous loading dose (15-20 min) followed by 8/2 g intravenous CI per 24 h. After 2 days, regimes were crossed over. RESULTS: Pharmacokinetic parameters (mean +/- SD) for SI piperacillin/sulbactam were: (1) peak serum concentration: piperacillin 231 +/- 66 mg/l, sulbactam 53.1 +/- 15.0 mg/l; (2) minimum serum concentration: piperacillin 11.5 +/- 14.8 mg/l, sulbactam 4.2 +/- 3.5 mg/l; (3) clearance: piperacillin 197 +/- 72 ml/min (CI 269 +/- 123 ml/min), sulbactam 167 +/- 61 ml/min (CI 212 +/- 109 ml/min); (4) half-life: piperacillin 2.4 +/- 1.2 h, sulbactam 3.1 +/- 1.6 h. Steady-state concentrations during CI were 25.5 +/- 14.5 mg/l for piperacillin and 8.0 +/- 3.7 mg/l for sulbactam. Average serum concentrations were comparable in both regimens. CONCLUSION: A large German survey demonstrated that approximately 89% of Pseudomonas aerugionsa have an MIC < or =16 mg/l and approximately 82% have an MIC < or =8 mg/l. According to this threshold, appropriate anti-bacterial concentrations of piperacillin/sulbactam were achievable with CI. CI dosing has the additional advantage that less drug is necessary. Further prospective studies are warranted to compare the clinical efficacy of CI and SI regimens in bacterial infections.

Serum and prostatic tissue concentrations of moxifloxacin in patients undergoing transurethral resection of the prostate.

The spectrum of pathogens causing chronic bacterial prostatitis comprises Gram-negative, Gram-positive and atypical microorganisms. Because of its broad spectrum of activity, the group 4 fluoroquinolone moxifloxacin might be a suitable antibiotic for treatment of bacterial prostatitis. The aim of this prospective study was to investigate the penetration of moxifloxacin into prostatic tissue in patients with benign prostatic hyperplasia. Patients received a single dose of moxifloxacin 400 mg in an 1 hour lasting infusion (250 ml) for perioperative prophylaxis before undergoing transurethral resection of the prostate (TURP). Serum concentrations were determined in all patients before infusion, at the end of infusion (time point 0), 0.5, 1 and 2 h after the end of infusion. Patients were randomized for tissue sampling either 0, 0.5, 1 or 2 h after the end of infusion. At beginning of TURP approximately 1 g of tissue was sampled for analysis. Concentrations of moxifloxacin in serum and tissue were determined by HPLC. 39 patients were evaluated. Median serum and prostatic tissue concentrations peaked at 0 h (4.94 mg/ L and 8.50 mg/ kg, respectively). The lowest concentrations were quantified at 2 h after the end of infusion (2.46 mg/ L and 3.88 mg/ kg, respectively). The prostatic tissue concentrations of moxifloxacin were approximately twice as high as in corresponding serum. At the end of infusion the tissue and serum concentrations seemed to be already equilibrated, as their ratios did not differ significantly during the time of investigation. After an intravenous infusion of 400 mg the serum and prostatic tissue concentrations of moxifloxacin were well above the MIC values of most important prostatic pathogens. The high tissue/ serum ratio and the extended antibacterial spectrum suggests active concentration in the prostate which may translate into increased efficacy compared to group 2 and 3 fluoroquinolones in the treatment of chronic bacterial prostatitis.

Low sodium and furosemide-induced stimulation of the renin system in man is mediated by cyclooxygenase 2.

The aim of this study was to examine the effects of highly selective inhibition of cyclooxygenase 2 (COX-2) with rofecoxib on the renin system during long-term stimulation and after short-term stimulation. Six healthy male volunteers received, in a randomized crossover design, a low-sodium diet for days 1 through 9 with or without 25 mg rofecoxib twice daily on days 5 through 9 and, in addition, 20 mg of furosemide intravenously on day 8. Plasma renin activity increased 2 to 3 times over baseline with a low-sodium diet and 5 times over baseline 30 minutes after intravenous furosemide; it was still elevated nearly 5 times on day 9. These effects were completely blocked by rofecoxib. Plasma aldosterone and urinary aldosterone concentrations basically reflected the findings with plasma renin activity. Urinary sodium excretion decreased during a low-sodium diet and increased after intravenous furosemide without being significantly affected by rofecoxib. We have concluded that low-sodium and furosemide-stimulated renin and aldosterone secretion is completely blocked in healthy volunteers during COX-2 inhibition with rofecoxib, suggesting that intact COX-2 is of major importance for stimulation of the renin system under these conditions in man.

Role of sympathetic nerves for the stimulation of the renin system by angiotensin II receptor blockade.

OBJECTIVE: To assess the relevance of sympathetic nerves for the stimulation of renin secretion and renin gene expression during effective angiotensin II type 1 receptor blockade in vivo. METHODS: Male Sprague-Dawley rats were treated with the angiotensin II type 1-receptor blocker losartan (40 mg/kg) for 3 days. To examine the role of renal sympathetic nerves in the stimulation of the renin system by losartan, left kidneys were denervated 4 days prior to the treatment with losartan. Also, to examine the role of circulating catecholamines in the stimulation of the renin system by losartan, the animals were administered a combination treatment of losartan with the beta1-adrenoreceptor blocker metoprolol (50 mg/kg per day) for 3 days. RESULTS: Losartan treatment increased plasma renin activity about sevenfold and renal renin messenger RNA (mRNA) levels about fivefold and decreased systolic blood pressure from 118 to 95 mmHg. Administration of losartan elevated renin mRNA both in the innervated and in the denervated kidneys to the same level as it did in kidneys of normal animals. Losartan treatment increased plasma renin activity and renal renin mRNA levels in the beta1-blocker-treated rats to the same extent as it did in animals administered losartan only. CONCLUSION: These findings suggest that, under sub-chronic treatment with hypotensive doses of angiotensin II receptor blockers, sympathetic outflow plays no important mediator role in the characteristic stimulation of renin secretion and renin gene expression, suggesting that it is mainly a direct disinhibition of angiotensin II's action on the level of juxtaglomerular cells that accounts for the effect.

Pharmacological properties of parenteral cephalosporins: rationale for ambulatory use.

Parenteral cephalosporins are among the most frequently used antibiotics in hospital therapy. They are characterised by an extended spectrum of activity against gram-positive and gram-negative bacteria, and some also have good activity against anaerobes. They kill proliferating bacterial cells rapidly, and generally show only a low tendency to select resistant mutants. However, there are cephalosporin compounds which induce cephalosporinases very rapidly in certain microorganisms. Together with other beta-lactam antibiotics, parenteral cephalosporins interfere with bacterial cell wall synthesis by inhibiting peptidoglycan cross-linkage. Because of this specific target, they are nontoxic to mammalian cells, and have a very favourable adverse effect profile. The chemical stability of parenteral cephalosporins in aqueous solution is good. After intravenous injection, high concentrations of these agents are achieved in serum and tissue. Most cephalosporins are eliminated unchanged via the kidney, with a half-life of 1 to 2 hours. But there are also derivatives with a serum half-life of more than 2 and up to 8 hours, allowing 12- or 24-hour dosage intervals. Because of their reliable efficacy and low risk of adverse effects, the parenteral cephalosporins offer a high degree of tolerability even in the setting of outpatient antibiotic therapy. In particular, the derivatives of the third generation are characterised by unique pharmacological properties.

In vitro activity and concentrations in serum, urine, prostatic secretion and adenoma tissue of ofloxacin in urological patients.

Studies in vitro showed that at concentrations of 1 and 4 mg/L ofloxacin inhibited 94 and 99% of the Gram-negative pathogens in isolates cultured from the urine of patients with complicated urinary tract infections (UTI). Against Gram-positive bacteria, 60 and 100% were inhibited at the corresponding concentrations. Comparisons of the MIC90 values of 8 quinolones showed the decreasing order of in vitro antibacterial activity to be ciprofloxacin, ofloxacin, norfloxacin, pefloxacin, enoxacin, pipemidic acid, nalidixic acid and cinoxacin. After an oral dose of ofloxacin 400mg, the mean peak serum concentration in 10 elderly patients was 5.5 mg/L and mean renal excretion during 24 hours was 41%. In 17 patients undergoing transurethral resection of the prostate, ofloxacin 400mg was given for perioperative prophylaxis. Two to 4.5 hours after administration, the median concentrations in prostatic secretion (5 patients) and prostatic adenoma tissue were 4.0 mg/L and 4.1 mg/kg, respectively. The corresponding serum concentrations of ofloxacin were 3.4 and 3.9 mg/L, respectively. In a group of 10 patients, 14.5 to 19.5 hours after oral administration of ofloxacin 400mg the median serum and prostatic adenoma tissue concentrations of ofloxacin were 1.9 mg/L and 1.2 mg/kg, respectively. The in vitro activity of ofloxacin concentrations attained in serum, urine, prostatic secretion and adenoma tissue show that it appears to be well suited for the treatment of complicated UTI.

Influence of age on the steady state disposition of drugs commonly used for the eradication of Helicobacter pylori.

BACKGROUND: The success of eradication therapy for Helicobacter pylori might be affected by the age of patients. AIM: To investigate whether disposition of drugs commonly used for H. pylori eradication is age-dependent. METHODS: Trough steady state serum levels of lansoprazole or ranitidine, amoxycillin, clarithromycin and metronidazole were monitored in 232 patients during the last dosing interval of a 5-day quadruple H. pylori eradication regimen. Detailed pharmacokinetic analysis was performed in 28 patients. RESULTS: Linear correlations between age and trough serum levels were observed with lansoprazole (r=0.25; P=0.002), ranitidine (r=0. 38; P=0.001) and clarithromycin (r=0.36; P < 0.0001). These associations were also inversely dependent of creatinine clearance for ranitidine (r=0.36; P=0.001) and clarithromycin (r=0.30; P < 0. 0001). Multiple linear regression revealed age as an important factor influencing trough serum levels of lansoprazole, clarithromycin and ranitidine. There were significant inverse relationships between creatinine clearance and area under curve of ranitidine (r=0.88; P < 0.0001) and amoxycillin (r=0.56; P=0.002). Multiple linear regression revealed serum creatinine as the most important factor influencing the area under curve of ranitidine, clarithromycin and amoxycillin. CONCLUSIONS: Age per se has little influence on pharmacokinetics of amoxycillin and ranitidine, which depend more on age-dependent decline in renal function. The influence of age, but not renal function was established for lansoprazole. Age and renal function have independent impacts on clarithromycin disposition.

Pharmacokinetic interaction between proton pump inhibitors and roxithromycin in volunteers.

BACKGROUND: Triple therapy including two antibiotics and a proton pump inhibitor is a rational approach to the treatment of Helicobacter pylori induced peptic ulcer disease. The interaction of antimicrobial therapy and acid suppression is not yet well elucidated. AIMS: To investigate the effects of proton pump inhibitors on roxithromycin levels in plasma and gastric tissue under steady-state conditions in volunteers. METHODS: In two crossover studies omeprazole 20 mg b.d., lansoprazole 30 mg b.d., roxithromycin 300 mg b.d., and the combination of roxithromycin with either omeprazole or lansoprazole were administered to 12 healthy volunteers over 6 days. Blood plasma levels of the drugs were measured. In addition, roxithromycin concentrations were also determined in gastric juice and gastric tissue obtained during endoscopy. RESULTS: The proton pump inhibitors and roxithromycin did not alter the blood plasma pharmacokinetics of each other. When compared to roxithromycin administered alone, its combination with a proton pump inhibitor significantly increased the roxithromycin concentrations in gastric juice (3.0-5.0 microg/mL vs. 0.3-0.4 microg/mL) and gastric tissue (antrum: 3.8-4.0 vs. 2.8 microg/g, fundus: 5.9-7.4 vs. 4.2-4.4 microg/g). CONCLUSIONS: Proton pump inhibitors and roxithromycin do not alter the systemic bioavailability of each other. However, proton pump inhibitors increase the local concentration of roxithromycin in the stomach which may contribute to the clinically proven synergic beneficial action in eradication therapy of H. pylori.

Pharmacokinetics of levofloxacin during continuous veno-venous hemofiltration.

OBJECTIVE: To study the effect of continuous veno-venous hemofiltration (CVVHF) on the pharmacokinetics of levofloxacin in critically ill patients with acute renal failure. DESIGN: Open-label study. SETTING: Anesthesiology ICU, University Hospital of Regensburg. PATIENTS: Six critically ill patients treated with CVVHF because of acute renal failure needing antimicrobial therapy. INTERVENTIONS: Levofloxacin i.v. 250 mg qd with a starting dose of 500 mg. CVVHF with the following characteristics: hemofilter AN69 hollow fibers of 0.90 m2 area, blood flow 150 ml/min, ultrafiltrate flow 1.3 l/h, filtrate substitution in post-dilution mode. MEASUREMENTS AND RESULTS: The plasma pharmacokinetics and clearance of levofloxacin by hemofiltration were established on day 1 and day 4-6 of treatment. Levofloxacin was determined by high-performance liquid chromatography (HPLC). Mean (range) peak plasma concentrations after levofloxacin 500 mg single dose (s.d.) and 250 mg multiple dose (m.d.) were 6.4 (2.7-9.4) and 8.2 (4.7-10.3) mg/l, trough levels 2.7 (1.4-5.0) and 2.9 (1.7-3.9) mg/l, half-life 28 (19-38) and 22 (17-31) h, volume of distribution 1.2 (0.72-1.6) l/kg and 0.91 (0.52-2.0) l/kg, respectively. The mean sieving coefficient was 0.96 (0.79-1.09), mean total clearance 47 (20-89) ml/min, and mean clearance by hemofiltration 21 (13-27) ml/min, respectively. CONCLUSIONS: A dosage schedule of levofloxacin 250 mg qd with a 500 mg loading dose seems appropriate for anuric patients during CVVHF. Sufficiently high steady-state concentrations of levofloxacin were achieved after the first dose. Undesired accumulation of levofloxacin was not observed.

Effects of hypoxia on renin secretion and renal renin gene expression.

Plasma renin activity (PRA) and renal renin mRNA levels were measured in male rats exposed to hypoxia (8% O2) or to carbon monoxide (CO; 0.1%) for six hours. PRA increased fourfold and 3.3-fold, and renin mRNA levels increased to 220% and 200% of control, respectively. In primary cultures of renal juxtaglomerular (JG) cells, hypoxia (lowering medium O2 from 20% to 3% or 1%) for 6 or 20 hours did not affect renin secretion or gene expression. Renal denervation did not prevent stimulation of the renin system by hypoxia. Because norepinephrine increased 1.7-fold and 3.2-fold and plasma epinephrine increased 3.9-fold and 7.8-fold during hypoxia and CO inhalation, respectively, circulating catecholamines might mediate the stimulatory effects of hypoxia on renin secretion and renin gene expression. Stimulation of beta-adrenergic receptors by continuous infusion of 160 microg/kg/hr isoproterenol increased PRA 17-fold and 20-fold after three and six hours, respectively, and renin mRNA by 130% after six hours. In rats with a stimulated renin system (low-sodium diet), isoproterenol did not stimulate PRA or renal renin mRNA further. In summary, both arterial and venous hypoxia can stimulate renin secretion and renin gene expression powerfully in vivo but not in vitro. These effects seem not to be mediated by renal nerves or by a direct effect on JG cells but might be mediated by circulating catecholamines.