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.

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.

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).

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.

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.

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.

Omeprazole impairs the absorption of mycophenolate mofetil but not of enteric-coated mycophenolate sodium in healthy volunteers.

In 2 crossover studies, 12 healthy volunteers (6 male/6 female) received a single oral dose of mycophenolate mofetil (MMF) 1000 mg or an equimolar dose of enteric-coated mycophenolate sodium (EC-MPS) 720 mg fasting with and without coadministered omeprazole 20 mg bid. The plasma concentrations of mycophenolic acid (MPA) and of the inactive metabolite mycophenolic acid glucuronide (MPA-G) were measured by high-performance liquid chromatography (HPLC). In addition, dissolution of MMF 500 mg or EC-MPS 360 mg tablets was determined using an USP paddle apparatus in aqueous buffer of pH 1 to 7. The bioavailability of MPA following administration of MMF or EC-MPS was similar except for the time to peak concentration, which was longer in the EC-MPS group. Concomitant treatment with omeprazole lowered significantly C(max) and AUC(12h) of MPA following administration of MMF. The pharmacokinetics of EC-MPS was not affected. Dissolution of MMF in aqueous buffer decreased dramatically at pH above 4.5. The EC-MPS tablet was stable up to pH 5. Above, EC-MPS was quantitatively disintegrated and MPS quantitatively dissolved. There is strong evidence that impaired absorption of MMF with concomitant proton pump inhibitors is due to incomplete dissolution of MMF in the stomach at elevated pH.

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.

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.

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.

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.

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.

Key role of the sympathetic microenvironment for the interplay of tumour necrosis factor and interleukin 6 in normal but not in inflamed mouse colon mucosa.

BACKGROUND: In the intestinal tract, the role of sympathetic neurotransmitters has been largely ignored in mucosal neuroimmunology. AIM: Our aim was to investigate the influence of the sympathetic microenvironment on the mucosal interplay of tumour necrosis factor (TNF) and interleukin 6 (IL-6). METHODS: Colon strips of normal and colitic BALB/c mice were superfused in vitro. Tissue was electrically stimulated to investigate the influence of endogenous norepinephrine (NE) on secretion of IL-6, with or without anti-TNF antibodies (anti-TNF) and adrenoceptor antagonists. IL-6 was secreted from macrophages. RESULTS: Superfusion with anti-TNF stimulated IL-6 secretion in normal but not in colitic colon (p<0.005). Parallel superfusion with a beta-adrenergic antagonist abrogated this phenomenon. Anti-TNF increased release of NE from normal colonic strips (p<0.05), which demonstrates TNF induced inhibition of preterminal NE release. In colitic mice, anti-TNF did not change NE release. In the presence of anti-TNF, exogenous and endogenous NE stimulated colonic IL-6 secretion via beta-adrenoceptors in normal (p<0.001) but not in colitic mice. In the absence of anti-TNF, endogenous and exogenous NE inhibited IL-6 secretion via the beta-adrenoceptor in normal but not in colitic mice (p<0.01). Colitic mice demonstrated loss of sympathetic nerve fibres. CONCLUSIONS: Modulation of mucosal IL-6 is largely dependent on the sympathetic microenvironment and availability of local TNF in normal but not in colitic mice. Anti-TNF strategies may lead to an increase in the proinflammatory cytokine depending on adrenergic tone. This would be relevant with normal sympathetic innervation, which is lost in colitic mice. We present a model of sympathetic regulation of colonic macrophage TNF and IL-6 secretion.

Penetration of telithromycin into the nasal mucosa and ethmoid bone of patients undergoing rhinosurgery for chronic sinusitis.

OBJECTIVES: Telithromycin has a broad spectrum of activity against respiratory tract pathogens including penicillin- and macrolide-resistant streptococci. The aim of the study was to investigate the penetration of telithromycin into nasal tissue following a single oral dose of 800 mg. PATIENTS AND METHODS: A total of 29 patients undergoing rhinosurgery for chronic sinusitis were evaluated. Samples of blood, nasal mucus, nasal mucosa and ethmoid bone were collected during surgery in groups of 5-6 patients after 3, 6, 9, 15 and 24 h following a single oral dose of 800 mg telithromycin. Drug concentrations were determined by HPLC with fluorimetric detection. RESULTS: The highest telithromycin concentrations were observed after 3 h in plasma as well as in all tissues sampled. The mean plasma concentrations were 0.73 mg/L in the 3 h group and 0.02 mg/L in the 24 h group. The concomitant tissue concentrations were higher. The tissue penetration, expressed by the ratio of the area under the concentration-time curve in tissue versus plasma, was 1.0 for nasal mucus, 5.9 for nasal mucosa and 1.6 for ethmoid bone. CONCLUSIONS: Telithromycin achieved tissue concentrations that were generally above the MIC(90) for common pathogens in upper respiratory tract infections. These results indicate that telithromycin diffuses rapidly into the nasal tissues and achieves high and prolonged concentrations in nasal mucosa and ethmoid bone.

Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus.

BACKGROUND: In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), patients demonstrate low levels of adrenal hormones. OBJECTIVE: To investigate whether increased renal clearance and daily excretion contribute to this phenomenon. METHODS: Thirty patients with RA, 32 with SLE, and 54 healthy subjects (HS) participated. Serum and urinary levels of cortisol, cortisone, 17-hydroxyprogesterone (17OHP), androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEAS) were measured. RESULTS: Clearance of DHEAS and DHEA was lower in patients than in HS, and clearance of androstenedione was somewhat higher in patients than in HS, but daily excretion of this latter hormone was low. Clearance of cortisol, cortisone, and 17OHP was similar between the groups. The total molar amount per hour of excreted DHEA, DHEAS, and androstenedione was lower in patients than HS (but similar for cortisol). Serum DHEAS levels correlated with urinary DHEAS levels in HS and patients, whereby HS excreted 5-10 times more of this hormone than excreted by patients. Low serum levels of adrenal androgens and cortisol in patients as compared with HS were confirmed, and proteinuria was not associated with changes of measured renal parameters. CONCLUSIONS: This study in patients with RA and SLE demonstrates that low serum levels of adrenal androgens and cortisol are not due to increased renal clearance and daily loss of these hormones. Decreased adrenal production or increased conversion or conjugation to downstream hormones are the most likely causes of inadequately low serum levels of adrenal hormones in RA and SLE.

Cicloral versus neoral: a bioequivalence study in healthy volunteers on the influence of a fat-rich meal on the bioavailability of cicloral.

The bioavailability of cyclosporine a (CyA) was assessed in 2 cross-over studies with 12 healthy male volunteers each. Study A compared the bioavailability of Cicloral (test) with the microemulsion Neoral (reference) in the fasting state. Study B examined the influence of a fat-rich meal composed according to the Food and Drug Administration (FDA) recommendations on the bioavailability of Cicloral. Each volunteer received a single dose of 200 mg CyA in each period. Whole blood CyA concentrations were determined using HPLC up to 48 hours after drug administration. The pharmacokinetic parameters were determined using standard noncompartmental methods. The mean bioavailability of Cicloral compared with Neoral amounted to 83% (AUC) and 78% (Cmax), respectively. When administered after a fat-rich meal, the bioavailability of Cicloral was 121% (AUC) and 132% (Cmax) compared with fasting administration. Time to Cmax was 1.3 to 1.4 hours for both medications and modes of administration. Bioequivalence could not be proven either between Cicloral and Neoral, or between Cicloral fasting versus after a fat-rich meal. We conclude that the lower bioavailability and the influence of food on the bioavailability of Cicloral must be taken into account when switching from Neoral to the generic formulation.

Do cytochrome enzymes influence the therapeutic effect of tropisetron in fibromyalgia?

It is well known that the 5-HT3 receptor tropisetron shows a bell-shaped dose-response curve in the treatment of pain associated with fibromyalgia. The best results are achieved with a daily oral dose of 5 mg for 10 days. Dosages of 10 and 15 mg per day have a much weaker effect. If tropisetron is administered by intravenous injection, a regimen of 5 mg per day over 5 days will suffice to reduce pain substantially. An open study of selected cases revealed that 2 mg of tropisetron daily for 5 days also yielded satisfactory pain reduction, whereas this was not observed in a placebo-controlled double-blind study. We therefore investigated which factors might be responsible for the different effects of the drug. Judging from the above-mentioned studies, the effect of a minimum dosage of tropisetron could be assumed to be partly attributable to the different half-life periods. This is supported by the markedly different rates of constipation, a characteristic side effect of the drug, reported by the two studies.

Effect of roxithromycin on the pharmacokinetics of lovastatin in volunteers.

OBJECTIVE: To investigate the influence of concomitant administration of roxithromycin on the plasma pharmacokinetics of lovastatin. METHODS: In an open, randomized, crossover study, 12 healthy volunteers received 80 mg lovastatin orally either alone or concomitantly with 300 mg roxithromycin after 5-day pretreatment with roxithromycin 300 mg daily. Plasma concentrations of lovastatin (lactone and acid) were determined using high-performance liquid chromatography, and the pharmacokinetic parameters were estimated. RESULTS: The mean (+/- SD) pharmacokinetic parameters of lovastatin lactone with and without roxithromycin were maximum concentration (Cmax) 8.49+/-6.80/16.3+/-9.4 ng ml(-1), time to Cmax (tmax) 1.8+/-0.4/1.7+/-0.6 h, terminal plasma half-life (t1/2) 4.3+/-2.0/3.7+/-2.5 h, area under the plasma concentration-time curve from zero to infinity (AUC0-infinity) 53+/-60/85+/-67 ng ml(-1) h. The respective parameters of lovastatin acid were Cmax 24.6+/-13.4/17.8+/-11.0 ng ml(-1), tmax 3.7+/-1.1/4.1+/-0.7 h, t1/2 3.2+/-2.5/4.3+/-2.8 h, AUC0-infinity 149+/-123/105+/-58 ng ml(-1) h. Mean bioavailability of lovastatin lactone was lower and that of lovastatin acid was higher with concomitant treatment. However, the differences were significant only with respect to lovastatin lactone (AUC and Cmax) and Cmax of lovastatin acid. CONCLUSION: Roxithromycin does not influence the pharmacokinetics of lovastatin in such a way that dosage adjustment of lovastatin seems to be necessary during co-administration.

Role of renal nerves in stimulation of renin, COX-2, and nNOS in rat renal cortex during salt deficiency.

We investigated a possible involvement of the sympathetic nervous system in the parallel increase of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase (nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys induced by salt deficiency. Therefore, we determined the effects of renal denervation and the beta-adrenoreceptor antagonist metoprolol (50 mg/kg body wt po, twice a day) on renocortical expression of renin, COX-2, and nNOS in rats fed a low-salt (0.02% wt/wt) diet or treated for 1 wk with ramipril (10 mg/kg body wt) in combination with a low-salt diet. We found that a low-salt diet in combination with ramipril strongly increased renocortical mRNA levels of renin, COX-2, and nNOS 9-, 7-, and 2.5-fold, respectively. Treatment with metoprolol did not change basal expression of the three genes or induction of renin and COX-2 gene expression, while induction of nNOS expression was clearly attenuated. Similarly, unilateral renal denervation attenuated induction of nNOS expression but had no effect on all other parameters. These findings suggest that beta-adrenergic stimulation is not required for stimulation of renin and COX-2 gene expression in the juxtaglomerular apparatus during salt deficiency. However, beta-adrenoreceptor activity or renal nerve activity appears to be required for the full stimulation of nNOS expression by low salt intake or combined with angiotensin-converting enzyme inhibition.