Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF).

OBJECTIVE: VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. METHODS: Healthy volunteers (N = 200) aged 18-55 years and with body mass index of 18.5-29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. RESULTS: The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0-1344, AUC0-∞, and Cmax for both groups were entirely within the standard 80-125% bioequivalence acceptance range at 101.88% (93.31-111.23%), 105.38% (95.06-116.81%), and 91.29% (84.38-98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. CONCLUSIONS: Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. CLINICAL TRIAL REGISTRATION: NCT05203289.

The effect of bradykinin 1 receptor antagonist BI 1026706 on pulmonary inflammation after segmental lipopolysaccharide challenge in healthy smokers.

BACKGROUND: Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx. METHODS: In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema. RESULTS: After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups. CONCLUSIONS: Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model. TRIAL REGISTRATION: The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).

N1 -Methylnicotinamide as Biomarker for MATE-Mediated Renal Drug-Drug Interactions: Impact of Cimetidine, Rifampin, Verapamil, and Probenecid.

N1 -methylnicotinamide (NMN) has been proposed as endogenous biomarker for drug-drug interactions mediated by inhibition of multidrug and toxin extrusion proteins (MATEs) at the renal proximal tubule. We analyzed NMN in plasma and urine samples of two clinical trials investigating a new probe drug cocktail (consisting of digoxin, metformin, furosemide, and rosuvastatin) dedicated to clinically relevant drug transporters. In trial 1, NMN was investigated after single-dose treatment with individual cocktail components or after cocktail treatment. In trial 2, NMN was investigated after treatment with cocktail alone or with cocktail + inhibitor (cimetidine, a MATE inhibitor; or rifampin, verapamil, or probenecid, inhibitors of other transporters). In trial 1, NMN kinetics in plasma and urine were essentially not affected by individual cocktail components or after cocktail treatment. In trial 2, NMN renal clearance from 0 to 12 hours (CLR,0-12 ) geometric mean ratio (GMR) after cocktail + cimetidine vs. cocktail alone was 75% (90% confidence interval (CI): 65-87%). NMN CLR GMR after cocktail + verapamil, + rifampin, or + probenecid vs. cocktail alone was 99% (90% CI: 81-121%), 91% (90% CI: 75-111%), and 107% (90% CI: 91-126%), respectively. Compared with creatinine CLR and creatinine area under the plasma-concentration time curve, NMN CLR was more specific and more sensitive for renal MATE inhibition. Absence of impact of the cocktail on NMN in trial 1 allows for utilization of NMN in studies using this transporter cocktail. Trial 2 data support that NMN CLR is a specific and sensitive marker for MATE-mediated renal drug-drug interactions.

Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, With Cytochrome P450 and P-Glycoprotein Substrates: Findings From In Vitro Analyses and an Open-Label, Single-Sequence Phase I Study.

PURPOSE/BACKGROUND: Glycine transporter-1 inhibitors may ameliorate cognitive deficits in schizophrenia. This study evaluated potential drug-drug interactions with the glycine transporter-1 inhibitor BI 425809. METHODS/PROCEDURES: Interactions with cytochromes P450 (CYP) and P-glycoprotein (P-gp) were assessed in in vitro assays using human hepatocytes and Caco-2 cells, respectively. Pharmacokinetic characteristics of probe drugs were subsequently assessed in a Phase I, open-label, single-sequence crossover study in healthy male participants. Participants received a probe-drug cocktail containing midazolam (CYP3A4), warfarin (CYP2C9), and omeprazole (CYP2C19) and a separate dose of digoxin (P-gp), alone and on a background of steady-state BI 425809 25 mg once daily in 2 treatment periods. Adverse events were monitored. FINDINGS/RESULTS: In vitro assays revealed concentration-dependent induction of CYP3A4 and inhibition of P-gp by BI 425809. In the clinical study, 12 of 13 participants completed both periods. With BI 425809, area under the plasma concentration curve from administration to the last measurement (AUC 0-tz ) and maximum plasma concentration ( Cmax ) for midazolam were lower than when administered alone. Adjusted geometric mean ratios (90% confidence interval) were 70.6% (63.9%-78.1%) for AUC 0-tz and 77.6% (67.3%-89.4%) for Cmax . For warfarin and digoxin, AUC 0-tz and Cmax were similar with and without BI 425809. For omeprazole, BI 425809 slightly reduced AUC 0-tz but not Cmax versus omeprazole alone. No new safety signals were identified. IMPLICATIONS/CONCLUSIONS: These findings indicate induction of CYP3A4 by once-daily BI 425809 25 mg (the assumed highest therapeutic dose) and no meaningful effects on CYP2C9, CYP2C19, or P-gp in vivo.

Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine.

BACKGROUND AND OBJECTIVE: A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug-drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics. METHODS: In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure. RESULTS: The results were generally in accordance with known in vitro and/or clinical drug-drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration-time curve up to the last quantifiable concentration (AUC0-tz) by 248% and maximum plasma concentration (Cmax) by 1025%. Probenecid increased furosemide AUC0-tz by 172% and Cmax by 23%. Cimetidine reduced metformin renal clearance by 26%. The effect of single-dose verapamil on digoxin systemic exposure was less than expected from multiple-dose studies (AUC0-tz unaltered, Cmax + 22%). CONCLUSIONS: Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug-drug interactions in drug development. CLINICAL TRIAL REGISTRATION: EudraCT number 2017-001549-29.

No relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone.

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug-drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (group 2, n=17) continued to receive pirfenidone alone (801 mg thrice daily) for 7 days, then co-administered with nintedanib (150 mg twice daily) for a further 7 days, before single doses of both treatments on day 16.In group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax), respectively. In group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when co-administered in IPF patients.

Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions.

AIMS: Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin. METHODS: In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and Cmax (maximum plasma concentration) of each probe drug. RESULTS: Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for Cmax and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI. CONCLUSIONS: Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI.

Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail.

BACKGROUND: In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics. METHODS: This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin C max (maximum plasma concentration) and AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration). RESULTS: The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC0-tz (90% CI 135-171%) and 154% for C max (90% CI 132-180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC0-tz (90% CI 102-132%) and 118% for C max (90% CI 98-142%). CONCLUSION: The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction. EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845.

Relative bioavailability study of linagliptin/metformin tablets in healthy Chinese subjects.

OBJECTIVE: To evaluate the relative bioavailability of single pill combination (SPC) tablets of linagliptin and metformin compared with separate tablets co-administered in healthy Chinese subjects. MATERIALS AND METHODS: This was an open-label, single-dose, randomized, two-period, crossover study in healthy Chinese subjects with two dose groups: linagliptin 2.5 mg/metformin 850 mg and linagliptin 2.5 mg/metformin 500 mg. Within each group (n=24), subjects received one dose of the SPC tablet in one period and one dose of the separate tablets in the other. Primary endpoints were area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72) and maximum plasma concentration (Cmax) for linagliptin, and AUC from 0 to the last quantifiable concentration (AUC0-tz) and Cmax for metformin. RESULTS: With the linagliptin 2.5 mg/metformin 850 mg dose, the adjusted geometric mean ratio of the SPC to the separate tablets for linagliptin was 99.53% (90% confidence interval (CI): 94.75-104.55) for AUC0-72 and 101.93% (90% CI: 95.36-108.95) for Cmax; for metformin the ratio was 96.99% (90% CI: 90.62-103.81) for AUC0-tz and 94.64% (90% CI: 85.43-104.84) for Cmax. With the linagliptin 2.5 mg/metformin 500 mg dose, the ratio with linagliptin for AUC0-72 and Cmax was 100.81% (90% CI: 95.14-106.82) and 111.37% (90% CI: 100.40-123.54), respectively; the same statistical parameters with metformin for AUC0-tz and Cmax were 102.95% (90% CI: 96.24-110.12) and 102.46% (90% CI: 92.20-113.87), respectively. CONCLUSIONS: SPC tablets of linagliptin and metformin were bioequivalent to separate tablets co-administered in healthy Chinese subjects.

Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials.

OBJECTIVE: The objectives of the studies reported here were to determine the relative bioavailability of linagliptin and metformin when administered in a fixed-dose combination (FDC) tablet with and without food, and to investigate the relative bioavailability of linagliptin and metformin FDC tablets from two treatment batches with different dissolution behavior. METHODS: These studies were open-label, single-dose, randomized, two-way crossover trials. After an overnight fast, healthy volunteers received an FDC tablet once (with/without food in the food-effect study; or from one of two batches with differing dissolution behavior in the tablet-dissolution study). On a separate visit, following a washout period of 35 days, participants received the alternative treatment. In the food-effect study the primary endpoints were maximum measured concentration in plasma (C(max)) for linagliptin and metformin, area under the plasma concentration-time curve from 0 to 72 hours (AUC(0-72)) for linagliptin and from 0 to infinity (AUC(0-inf)) for metformin. In the tablet-dissolution study the primary endpoints were Cmax for both analytes, AUC(0-72) for linagliptin, and from 0 to the time of the last quantifiable data point (AUC(0-t)) for metformin. RESULTS: The administration of the FDC tablet with food had no influence on the relative bioavailability of linagliptin and metformin with regard to the extent of exposure as determined by AUC(0-72) (linagliptin) and AUC(0-inf) (metformin) compared with FDC tablet administration while fasting. After food intake, peak plasma concentrations of linagliptin were slightly lowered (from 4.99 to 4.56 nmol L⁻¹), but the 90% confidence interval (CI) of the geometric mean test/reference ratio was still located within the generally applied bioequivalence acceptance limits of 80 - 125%. The median time from dosing to the maximum concentration of linagliptin in plasma (t(max)) was similar under both conditions. Administration with food reduced the rate of absorption of metformin indicated by a prolongation in median tmax (from 2 to 4 hours) and a decrease in Cmax by ~ 18%. There were no notable differences between the two treatment groups with respect to safety and tolerability. In the tablet-dissolution study, bioequivalence was demonstrated between linagliptin/metformin FDC tablets with normal and slower dissolution characteristics. For both linagliptin and metformin, the 90% CI of all pharmacokinetic (PK) parameters were well within the bioequivalence acceptance limits of 80 - 125%. Tablets from both batches were well tolerated with no unexpected adverse events. CONCLUSIONS: Food did not have a relevant impact on the bioavailability of linagliptin from the FDC tablet. The effect of food on the metformin component was comparable to that previously demonstrated. Furthermore, differences in tablet-dissolution characteristics did not have an impact on the bioavailability of linagliptin or metformin from the FDC tablet.

Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers.

OBJECTIVES: Empagliflozin is an orally available, potent and highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2). This study was undertaken to investigate the effect of food on the pharmacokinetics of 25 mg empagliflozin and to assess dose proportionality between 10 mg and 25 mg empagliflozin under fasted conditions. MATERIALS AND METHODS: In this open-label, 3-way, cross-over study, 18 healthy volunteers received 3 single doses of empagliflozin in a randomized sequence (25 mg empagliflozin under fasted conditions, 25 mg empagliflozin after a high-fat, high-calorie breakfast and 10 mg empagliflozin under fasted conditions), each separated by a washout period of at least 7 days. Serial plasma samples were collected at selected time points over a period of 72 hours. RESULTS: Administration with food had no clinically relevant effect on the area under the plasma concentration-time curve (AUC0-∞) of empagliflozin (geometric mean ratio (GMR): 84.04, 90% confidence interval (CI): 80.86 - 87.34). The decrease observed in the maximum plasma concentrations (Cmax) of empagliflozin (GMR: 63.22, 90% CI: 56.74 - 70.44) when administered with food was not considered clinically meaningful. The increases in AUC0-∞ and Cmax for 10 mg vs. 25 mg empagliflozin administered under fasting conditions were roughly dose-proportional, as demonstrated by the slope ß of the regression lines being slightly less than 1 (slope ß for AUC0-∞: 0.94, 95% CI: 0.90 - 0.97; slope ß for Cmax: 0.91, 95% CI: 0.80 - 1.01). Empagliflozin was well tolerated under fed and fasting conditions. CONCLUSIONS: The results support administration of empagliflozin tablets independently of food. Increases in empagliflozin exposure under fasting conditions were roughly dose-proportional between 10 mg and 25 mg empagliflozin.

Training effects of combined resistance and proprioceptive neck muscle exercising.

OBJECTIVES: To investigate training effects of two different resistance and proprioceptive exercising concepts of neck muscles. MATERIAL AND METHOD: Twenty-six healthy women participated in a randomized pilot trial. The test persons were randomized to two different neck-training programs (resistance training (RT) and proprioceptive resistance training (PRT)). They performed a standardized training program for the duration of ten weeks two times weekly. The neck strength, the cross-sectional area of three neck muscle groups (1. sternocleidomastoid muscles; 2. multifidus and semispinalis cervicis muscles; 3. semispinalis capitis and splenius muscles) and the proprioceptive capability evaluated by the dynamic joint repositioning error (DJRE) of the head were assessed pre- and post-intervention. RESULTS: Strength gain did not differ significantly between the two resistance training groups (PRT group: 8.2% to 29.3%; RT group: 1.4% to 19.8%). Change of hypertrophy of all neck muscle groups was significantly (p< 0.001 to p=0.013) greater in the PRT group (18.9% to 32.3%) than in the RT group (1.5% to 12.9%). The DJRE deteriorated with 35% in the RT group and did not change in PRT group (-2.0%). CONCLUSION: In combination with resistance training, proprioceptive training led to a significantly higher muscle hypertrophy and didn't effect a significant deterioration of the proprioceptive capability compared to isolated resistance training.

The need for pressure changes in CPAP therapy 2-3 months after initial treatment: a prospective trial in 905 patients with sleep-disordered breathing.

OBJECTIVE: The aim of the study was to investigate the need for pressure change in patients with sleep-disordered breathing (SDB) several weeks after therapy initiation. We prospectively studied 905 consecutive patients (740 men and 165 women) with SDB and therapeutic intervention with continuous positive airway pressure (CPAP)/bilevel PAP. METHODS: Several weeks after therapy initiation, patients were restudied for control, and pressure was optimized if it was necessary. The differences in CPAP pressure from initial treatment and control night were assessed. Anthropometric data, polysomnography data, Epworth sleepiness scale, and Berlin questionnaire scores were correlated to pressure differences from the first and control titration nights. RESULTS: Pressure change was needed in 511 patients (58.2%). Pressure increase was more frequent than pressure reduction (41.7% vs. 11.7%). Mean pressure increase in CPAP was 1.3 mbar, and mean decrease, 1.6 mbar. In the bilevel PAP group, the mean increase in inspiratory pressure was 1.2 mbar, and in expiratory pressure, 0.8 mbar; the mean decrease in inspiratory pressure was 1.9 mbar, and in expiratory pressure, 1.4 mbar. No correlation was found between anthropometric data, sleep efficacy, the amount of rapid eye movement sleep per night, or questionnaire scores and pressure change. CONCLUSION: Our results show that pressure changes are necessary in the majority of patients several weeks after therapy initiation. Therefore, re-evaluation of therapy pressure is useful.

Multidetector computed tomography coronary angiography: sublingual nitroglycerine improves image quality significantly because of peripheral coronary vasodilatation.

PURPOSE: In this study, we investigated the influence of sublingual nitroglycerine (NTG) on the peripheral diameter, intraluminal contrast agent density, and image quality of coronary arteries during computed tomography coronary angiography (CTCA). MATERIALS AND METHODS: Thirty patients with sublingual NTG application were matched to 30 patients without NTG. The diameters of the left anterior descending coronary artery (LAD), the left circumflex coronary artery and the right coronary artery were measured at 1-, 4-, and 8-cm length of each vessel as well as the intraluminal contrast agent density along the LAD. Vessel diameters and contrast attenuation at 4 and 8 cm were referenced against the values at 1 cm and processed as percentage reduction. Image quality of the posterior descending artery was assessed subjectively by 2 independent observers. RESULTS: The percentage of peripheral vessel diameter reduction and the peripheral attenuation of contrast agent density for all measured coronary arteries was significantly smaller in the group with NTG administration. The image quality of the posterior descending artery was significantly higher in the group with NTG. CONCLUSIONS: Sublingual administration of NTG before CTCA results in improved diagnostic image quality because of a significant dilatation and improved intraluminal contrast agent density of the peripheral vessels.

[(11)C]choline PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy.

OBJECTIVE: To evaluate [(11)C]choline positron emission tomography/computed tomography ([(11)C]choline PET/CT) for the detection of a biochemical recurrence of prostate cancer after radical prostatectomy. METHODS: Retrospective analysis of [(11)C]choline PET/CT performed in 41 consecutive prostate cancer patients with a rising PSA. The mean time to biochemical relapse was 24 months. PSA levels were determined at time of examination, and patients received either a targeted biopsy or surgery. Histopathology reports served as reference for the evaluation of the [(11)C]choline PET/CT findings. RESULTS: Mean PSA in [(11)C]choline PET/CT positive patients was 3.1 ng/ml (median 2.2 ng/ml, range 0.5-11.6 ng/ml) and 0.86 ng/ml in [(11)C]choline PET/CT negative patients (median 0.83 ng/ml, range 0.41-1.40 ng/ml). Six of 12 patients with PSA < 1.5 ng/ml [(11)C]choline PET/CT revealed a pathological uptake. Histopathology was positive in 6/12 patients in this group. At PSA levels ranging from 1.5 to 2.5 ng/ml all [(11)C]choline PET/CT were positive (n = 16), a positive histology was found in 12/16 patients (75%) and at PSA 2.5-5 ng/ml [(11)C]choline PET/CT was positive in 8/8 patients, confirmed by histology in 7/8 patients. Finally, at PSA higher than 5 ng/ml [(11)C]choline PET/CT identified 5/5 patients positive all confirmed by histology. The sensitivity of [(11)C]choline PET/CT for the detection of recurrence at PSA < 2.5 ng/ml was 89% with a positive predictive value of 72%. CONCLUSION: [(11)C]choline PET/CT is useful for re-staging of prostate cancer in patients with rising PSA even at levels below 1.5 ng/ml. Our study confirms results from other published studies on [(11)C]choline PET/CT in prostate cancer relapse.

Reliability of a new virtual reality test to measure cervicocephalic kinaesthesia.

The aim of this study was to investigate the cervicocephalic kinaesthesia of healthy subjects for gender and age effects and its reliability in a new virtual reality test procedure. 57 healthy subjects (30 male, 27 females; 18-64 years) were immersed into a virtual 3D scene via a headmounted display, which generated specific head movements. The joint repositioning error was determined in a static and dynamic test at the times T0, T1 (T0+10 minutes) and T2 (T0+24 hours). The intrasession reliability (T0-T1) and the intersession reliability (T0-T2) were analysed. In both tests no gender- or age-specific effects were found. In the overall group the means of the static test were 6.2 degrees -6.9 degrees and of the dynamic test were 4.5 degrees -4.9 degrees . The intratest difference in the static test was -0.16 degrees and the intertest difference was 0.47 degrees . The intratest difference in the dynamic test was 0.42 degrees and the intertest difference was 0.37 degrees . The static and dynamic test was reproducible in healthy subjects, with minor deviations, irrespective of gender and age. The smaller interindividual differences in the dynamic test could be beneficial in the comparison of healthy individuals and individuals with cervical spine disorders.

The weak evidence base for antibiotic prophylaxis in severe acute pancreatitis.

BACKGROUND/AIMS: The incidence of acute pancreatitis varies from 5 to 80 per 100,000 inhabitants throughout the world. The most common cause of death in these patients is infection of pancreatic necrosis by enteric bacteria, spurring the discussion of whether or not prophylactic antibiotic administration could be a beneficial approach. We therefore analyzed randomized clinical trials, which form the basis of guidelines and recommendations on this topic. RESULTS: One trial demonstrated that antibiotic prophylaxis reduces mortality, but the statistical design of this trial was questionable. Another important trial, showing an effect of antibiotic prophylaxis on the incidence of pancreatic sepsis, used the wrong statistical test to analyze their data. An analysis with the correct test could not confirm this effect. Three randomized clinical trials demonstrated that antibiotic prophylaxis in severe acute pancreatitis could reduce the incidence of extrapancreatic infections. Two trials showed a significant reduction of the overall infection rate; while in one of them peripancreatic and extrapancreatic infections alone were not significantly different. Two double blinded studies could not demonstrate a significant effect of antibiotic prophylaxis on pancreatic/peripancreatic infection, extrapancreatic infection or mortality. CONCLUSION: Our analysis shows that some of the reported significant effects of prophylactic antibiotic treatment are either questionable or less clinically relevant. With regards to reduction in mortality and the incidence of infected pancreatic necrosis, no convincing evidence exists which supports the routine administration of prophylactic antibiotics in severe acute pancreatitis.

Choosing the optimal fit function: comparison of the Akaike information criterion and the F-test.

In many circumstances of data fitting one has to choose the optimal fitting function or model among several alternatives. Criteria or tests on which this decision is based are necessary and have to be well selected. In this preliminary analysis the application of the corrected Akaike information criterion is demonstrated considering the example of determining pharmacokinetic parameters for the blood serum time activity curves of 111In-labeled anti-CD66 antibody. Another model selection criterion, the F-test, is used for comparison. For the investigated data the corrected Akaike information criterion has proved to be an effective and efficient approach, applicable to nested and non-nested models.

Evaluation of [11C]-choline positron-emission/computed tomography in patients with increasing prostate-specific antigen levels after primary treatment for prostate cancer.

OBJECTIVE: To evaluate [(11)C]-choline positron-emission tomography (PET)/computed tomography (CT) for detecting clinical recurrence after primary treatment for prostate cancer. PATIENTS AND METHODS: In all, 50 patients with prostate cancer who had had initial therapy (radical prostatectomy in 40, external beam radiation in three and interstitial brachytherapy in seven) had PET/CT using [(11)C]-choline in the presence of an increased or increasing prostate-specific antigen (PSA) level. The mean (range) time to biochemical progression was 22 (2-136) months. Current PSA levels were determined in all patients at the time of examination. The results were correlated with the histopathology reports after targeted biopsy or surgery, and with the clinical follow-up. RESULTS: The mean (median, range) PSA level in patients with positive PET/CT was 3.62 (2.42, 0.5-13.1) ng/mL, and that in patients with a negative scan was 0.90 (0.95, 0.41-1.40) ng/mL. PET/CT was positive in seven of 13 patients with a PSA level of <1.5 ng/mL, and histology was positive in this group in nine. In 17 patients with PSA levels of 1.5-2.5 ng/mL PET/CT was positive in all and the histology was positive in 13; in 11 men with a PSA level of 2.5-5 ng/mL PET/CT was positive in all 11 and the histology was positive in 10; in nine men with PSA levels of >5 ng/mL PET/CT identified all as positive and the histology was positive in eight. The sensitivity at a PSA level of <2.5 ng/mL of PET/CT for detecting recurrence was 91% (95% confidence interval, 71-99%) with a specificity of 50% (16-84)%. CONCLUSION: [(11)C]-choline PET/CT seems to be useful for re-staging prostate cancer after curative therapy and with increasing PSA levels; this was verified by histological examination. We recommend this method at PSA levels of <2.5 ng/mL.

11C-choline positron-emission tomography/computed tomography and transrectal ultrasonography for staging localized prostate cancer.

OBJECTIVE: To evaluate and compare the role of (11)C-choline positron emission tomography (PET) and transrectal ultrasonography (TRUS) in the preoperative staging of clinically localized prostate cancer. PATIENTS AND METHODS: Fifty-five consecutive patients with biopsy-confirmed prostate cancer had TRUS and (11)C-choline PET as a part of their clinical staging programme before radical retropubic prostatectomy (RP). The PET images were prospectively interpreted by a consensus decision of two nuclear medicine physicians and one radiologist with special expertise in the field. The TRUS was done by one experienced urologist. The criteria evaluated prospectively in each patient were extracapsular extension (ECE), seminal vesicle invasion (SVI) and bladder neck invasion (BNI). The results were compared with the histopathological findings after RP. RESULTS: At pathology, 32 patients were classified pT2, 16 as pT3a and three had pT3b lesions. In four patients the histopathological examination showed pT4 with BNI. The overall accuracy of PET in defining local tumour stage (pT2 and pT3a-4) was 70%; the overall accuracy by TRUS was 26%. PET was more sensitive than TRUS for detecting ECE (pT3a) and SVI (pT3b) in advanced stages, and in pT4 stages. The sensitivity and positive predictive value (PPV) (95% confidence interval) in stages pT3a-pT4 for PET were 36 (17-59)% and 73 (39-89)%. The sensitivity and PPV in stages pT3a-pT4 for TRUS were 14 (3-35)% and 100 (29-100)%. CONCLUSIONS: (11)C-choline PET and TRUS tended to understage prostate cancer. This series shows the current limited value of TRUS and PET for making treatment decisions in patients with clinically localized prostate cancer, especially if a nerve-sparing RP is considered. Treatment decisions should not be based on TRUS and (11)C-choline PET findings alone. In future studies, the combination of metabolic and anatomical information of PET and endorectal magnetic resonance imaging should be evaluated, as this might optimize the preoperative staging in prostate cancer.