text:
Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast.
This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 μg tablet once daily; Day 2-18) and concomitant formoterol (24 μg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 μg twice daily; Day 2-18) and concomitant roflumilast (500 μg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study.
Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic assessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns were seen after concomitant administration. No severe or serious adverse events were reported, and no adverse events led to premature study discontinuation.
No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral roflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation. Roflumilast was well tolerated.
Trial Registration
Clinicaltrials.gov NCT00940329
Roflumilast (3-cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide; CAS Registry number: 162401-32-3; molecular formula: C17H14Cl2F2N2O3) is a selective, oral, once-daily phosphodiesterase 4 (PDE4) inhibitor that has shown anti-inflammatory activity in pre-clinical studies [1-4], and in patients with chronic obstructive pulmonary disease (COPD) [5]. In large randomised clinical studies, roflumilast consistently improved lung function in patients with moderate-to-severe COPD [6], severe COPD [7], or severe airflow obstruction plus chronic bronchitis [8] compared with placebo.
Long-acting bronchodilators such as the β2-adrenoceptor agonists formoterol and salmeterol and the anticholinergic tiotropium [9-11] are central to the treatment of COPD; however, some patients have poor symptom control with these agents, particularly patients with more severe disease [12]. Two large clinical trials have investigated whether the addition of roflumilast improves lung function in patients with moderate-to-severe COPD who are already receiving long-acting bronchodilators [13]. In these trials, patients already receiving salmeterol or tiotropium were randomised to receive either oral roflumilast 500 μg or placebo once daily for 24 weeks, in addition to continued salmeterol or tiotropium treatment [13]. Compared with placebo, the addition of roflumilast improved mean pre-bronchodilator forced expiratory volume in both trials (p < 0.0001). Further, in a separate in vitro study, formoterol increased the inhibitory effect of roflumilast on cytokine and tumour necrosis factor-α production from human parenchymal and bronchial explants [14].
Both PDE inhibitors and β2-adrenoceptor agonists lead to an accumulation of intracellular cyclic adenosine monophosphate [15-17], which plays a key role in the regulation of cardiac function [18]. It is known that β2-adrenoceptor agonists are associated with adverse cardiac events [19]. In contrast, a previous study demonstrated that roflumilast had no significant effect on cardiac repolarisation (QT/QTc interval) in healthy subjects [20].
When administered as a single, oral 500 μg dose, roflumilast is readily and almost totally absorbed in healthy individuals, with a mean bioavailability of 79% [21] and dose-proportional pharmacokinetics observed within the 250-1000 μg dose range [22]. Repeated-dose pharmacokinetic profiles of roflumilast and its active metabolite roflumilast N-oxide have been well characterised, with median time to maximum plasma concentration (tmax) values of 1 hour and 8 hours, respectively, and median effective plasma half-lives of 17 hours and 30 hours, respectively [22-24]. Roflumilast N-oxide has a PDE selectivity profile and potency in vivo similar to that of roflumilast, and a substantially (10-fold) greater area under the plasma concentration-time curve (AUC) [4,22]. It is therefore estimated to account for about 90% of the overall PDE4 inhibitory activity of roflumilast. To estimate the combined PDE4 inhibition of roflumilast and roflumilast N-oxide in humans following administration of roflumilast, the parameter termed 'total PDE4 inhibitory activity' (tPDE4i) has been established [23,25]. This parameter represents the sum of the overall exposure to roflumilast and roflumilast N-oxide by accounting for differences in intrinsic activity (IC50), free fraction (protein binding) and in vivo exposure (AUC values) of both compounds.
Roflumilast is metabolised to roflumilast N-oxide mainly through biotransformation via the cytochrome P450 (CYP) enzymes CYP3A4 and CYP1A2, and roflumilast N-oxide is cleared by CYP3A4. The CYP3A4 inhibitors erythromycin and ketoconazole have been shown to increase tPDE4i by 8-9% [26,27]; the CYP1A2 inhibitor fluvoxamine and the dual CYP3A4/1A2 inhibitors enoxacin and cimetidine increase tPDE4i by 59%, 25% and 47%, respectively [28-30]. Conversely, administration of the cytochrome P450 enzyme inducer rifampicin results in a reduction in tPDE4i by 58% [31].
Roflumilast and formoterol have a low potential for pharmacokinetic interaction because formoterol is eliminated mainly by direct glucuronidation and does not inhibit CYP isoenzymes at therapeutically relevant concentrations [32]. Following inhalation, formoterol is rapidly absorbed, with plasma concentrations increasing linearly with dose [32]. The kinetics of formoterol are similar after single and repeated administration, indicating no auto-induction or inhibition of metabolism [32]; however, there is a modest and self-limiting accumulation in plasma after repeated dosing in patients with COPD [32]. In a previous Phase I study, no apparent drug-drug interaction was found between roflumilast and orally co-administered formoterol (unpublished data; Nycomed GmbH, 2002). The nature and extent of a pharmacokinetic drug-drug interaction may, however, differ when formoterol is inhaled [33].
Since roflumilast is likely to be used concomitantly with a β2-adrenoceptor agonist in some patients, it is of interest to investigate whether and to what extent concomitant administration results in relevant pharmacokinetic and pharmacodynamic drug-drug interactions with a focus on cardiovascular effects.
The protocol (Clinicaltrials.gov registration NCT00940329) was reviewed and approved by an independent ethics committee (Ethik-Kommission Landesärztekammer Rheinland-Pfalz Körperschaft des öffentlichen Rechts, Mainz, Germany) and competent health authorities (Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM] Fachregistratur Klinische Prüfung, Bonn, Germany). The study was planned, conducted, analysed and reported in accordance with the principles of Good Clinical Practice, the Declaration of Helsinki and the provisions for the orderly conduct of clinical trials in the country of conduct.
Eligibility of subjects was evaluated on the basis of an extensive screening investigation performed within 3 weeks before admission to the study clinic, which included demography, medical history, review of co-medications, physical examination, recumbent blood pressure and pulse rate, electrocardiograms (ECGs), and laboratory safety tests (haematology, clinical chemistry, urinalysis, hepatitis and HIV serology).
Eligible subjects included Caucasian males aged 18 to 45 years with a body mass index between 18 and 30 kg/m2, and a body weight of > 50 kg. All subjects were willing and able to provide informed consent.
Exclusion criteria were as follows: previous participation in the study or in any other study; donation of blood or plasma within the last 30 days; presence of acute or chronic disease; presence of clinically relevant findings in the laboratory tests (including hepatitis and HIV serology and tests for alcohol and social drugs); signs or history of cardiac disease including QTc interval (Bazett's correction) ≥ 430 ms and PQ interval ≥ 220 ms; susceptibility to symptomatic orthostatic hypotension; previous gastrointestinal surgery other than appendectomy and herniotomy; use of any medication within the last 2 weeks or within less than 10 times the elimination half-life of the respective drug; history of any clinically relevant hypersensitivity (in particular to formoterol or other β2-adrenoceptor agonists, to roflumilast or to any inactive ingredient in the trial medication); smoking more than 10 cigarettes/day or equivalent; evidence or suspicion of alcohol or social drug abuse; excessive xanthine consumption; and any concern of lack of compliance or willingness to adhere to the study directives and restrictions.
This was an open-label, randomised, actively controlled, multiple-dose, parallel-group study with a fixed-administration sequence. Screening took place between Day -21 and Day -1; the study period lasted from Day -1 to Day 19; and the post-study examination was conducted within 1 week of the last intake of the study medication. Subjects were admitted to the clinic from the evening of Day -1 to the morning of Day 19. Subjects were instructed to avoid strenuous physical exercise from Day -3 until the post-study examination. Smokers were required to keep their smoking habits stable, but were not allowed to smoke during the main profiling days. Alcohol- and caffeine-containing beverages, as well as grapefruit juice, were not allowed from Day -2 to Day 19. In compliance with European guidelines, both drugs were given at the maximum recommended therapeutic dosage.
For Regimen A, subjects received 500 μg oral roflumilast once daily (daily dose: one tablet of roflumilast 500 μg) from the morning of Day 2 to the morning of Day 18. From the morning of Day 12 to the evening of Day 18 subjects also received 24 μg formoterol for oral inhalation delivered by a dry powder inhaler (DPI) device (Foradil® P, Novartis Pharma GmbH, Vienna, Austria) twice daily, once in the morning and once in the evening (daily dose: 48 μg formoterol). For Regimen B, subjects received 24 μg formoterol for oral inhalation delivered by a DPI device (Foradil® P) twice daily, once in the morning and once in the evening from the morning of Day 2 to the evening of Day 18. From the morning of Day 9 to the morning of Day 18 subjects also received 500 μg roflumilast once daily. The start of the concomitant phases for each regimen was dependent on the pharmacokinetic characteristics of roflumilast and formoterol; as more time is needed to achieve steady state for roflumilast than formoterol, the timings were different between Regimen A and Regimen B.
Roflumilast was taken orally with 240 mL plain water after an overnight fast and rest; after intake, a mouth check was performed for compliance control. No fluids were allowed within 2 hours after each dose on the profile days. On days when the two medications were co-administered, formoterol was administered within 1 minute of roflumilast being administered.
The main profiling days were scheduled on Days 1, 11 and 18 for Regimen A, and on Days 1, 8 and 18 for Regimen B. On these days, subjects continued their fast from the previous evening until 8 hours after morning dosing, and standardised meals were served at 8 hours (lunch) and 12.5 hours after morning dosing (dinner).
Pharmacokinetic methods
Blood samples for pharmacokinetic assessments were taken on Days 11 and 18 for Regimen A and Days 8 and 18 for Regimen B, 30 minutes before dosing and 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 12 hours after dosing, with additional samples taken at 14 and 24 hours for roflumilast (Days 11 and 18 for Regimen A, and Day 18 for Regimen B). Pre-dose blood samples for determination of trough levels were taken on Days 9 and 10 for Regimen A (morning only), and on Days 6 and 7 (morning and evening) for Regimen B. Blood samples (4.5 mL) were collected in heparinised tubes and plasma was obtained by centrifugation at 1550 g for 15 minutes. Plasma samples were stored at -20°C or below for roflumilast, and at -70°C for formoterol. Plasma concentrations of roflumilast and roflumilast N-oxide were determined using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Before the sample analysis we determined that formoterol did not interfere with the quantification of roflumilast or roflumilast N-oxide. The lower limit of quantitation (LLOQ) was 0.1 ng/L using a sample volume of 0.4 mL for both roflumilast and roflumilast N-oxide. The inter-day precision of this assay, as determined by the analysis of quality control (QC) samples, ranged from 5.3% to 10.0% for both analytes. The inter-day accuracy of the assay, as determined by the analysis of the QC samples, ranged from -6.8% to +2.5% for both analytes. Roflumilast and roflumilast N-oxide standard curves were valid up to 20 ng/mL and 40 ng/mL, respectively. Determination of roflumilast and roflumilast N-oxide was performed at Altana Pharma AG, Konstanz, Germany (Nycomed GmbH). Plasma concentrations of formoterol were determined using HPLC-MS/MS. The LLOQ in plasma was 0.4 pg/mL using a sample volume of 1.0 mL. Formoterol standard curves were valid up to 99.9 pg/mL. The intra-day precision for QC samples ranged from 0.5% to 13.1%. The intra-day accuracy of the formoterol QC samples ranged from -10.5% to +13.6%, the inter-day precision from 6.4% to 7.6%, and the inter-day accuracy from 0.7% to 7.1%. Determination of formoterol was performed at pharm-analyt Labor GmbH, Baden, Austria, under the supervision of Altana Pharma AG(Nycomed GmbH).
For roflumilast, roflumilast N-oxide and formoterol, the maximum plasma concentration (Cmax) was derived directly from the plasma concentrations. The AUC from time zero to the time of the last quantifiable concentration, which corresponded to the dosing interval of each analyte (AUC0-τ), was estimated using the linear trapezoidal method. Apparent clearance at steady state (CL/F; calculated by dose/AUCτ) was reported for roflumilast only. Pharmacokinetic variables were calculated by non-compartmental analysis using WinNonLin professional, version 4.01 (PharSight, Mountain View, California, USA). The calculation of tPDE4i was based on the equation described in Lahu et al. [27].
Cardiovascular methods: blood pressure and transthoracic impedance cardiography
Cardiovascular effects were evaluated non-invasively by means of ECGs (cardiac rhythm, intra-cardiac conduction and ventricular repolarisation), oscillometric blood pressure and transthoracic impedance cardiography (ZCG; systolic time intervals, contractility indices and estimates of stroke volume and cardiac output). Cardiovascular assessments (oscillometric blood pressure, pulse rate, 12-lead ECG, and three-lead ZCG) were recorded before dosing and at 10, 20, 40 and 60 minutes, and at 2, 3, 4, 5, 6, 7 and 8 hours after morning dosing. Blood pressure, pulse rate and ECGs were also assessed at 12 hours after dosing, and on the morning of Day 19. All cardiovascular measurements were carried out after the subjects had been recumbent for at least 10 minutes; they generally stayed in bed from 1 hour before until 8 hours after morning dosing.
Systolic time intervals (STIs) and ZCG estimates of the systolic cardiac pump performance were derived from the simultaneous registration of a one-lead ECG, a phonocardiogram (PCG), and the rate of change of the transthoracic impedance (dZ/dt) to an AC current applied through the thoracic cage (CARDIODYNAGRAPH; Diefenbach GmbH, Wiesbaden, Germany). Tracings were captured and stored digitally during the study and subsequently analysed after the study by displaying the analogue ECG, PCG and ZCG signals on a computer screen. The relevant signal amplitudes and time intervals were delineated manually by operator-steered cursors; measurements were made for at least 10 artefact-free consecutive cardiac cycles [34,35]. From these tracings, the following variables were derived by direct measurement: RR interval (ms), total electromechanic systole (QS2 [ms]), ventricular ejection time (VET [ms]), baseline transthoracic impedance (Z0 [Ω]), and maximum negative velocity of transthoracic impedance changes during the cardiac cycle (dZ/dtmax [Ω/s]). These variables were analysed for the 10 cycles and their means were used in the calculations of the following variables: heart rate (HR [bpm]), pre-ejection period (PEP [ms] = QS2 - VET), HR-corrected STIs (STIc and STIi according to Weissler et al. [36]), ZCG estimates of stroke volume (SV [mL] according to Kubicek's equation [37] using the equation of Geddes and Sadler for the specific resistance of blood [38]), cardiac output (CO [mL/min]), and total peripheral resistance (TPR [dyn.s.cm-5]). For the latter variable, the mean blood pressure (MBP [mmHg]) was used as calculated according to Wezler and Böger [39] from the systolic blood pressure (mmHg) and the diastolic blood pressure (mmHg).
ZCG analysis was carried out by a single analyst who was blinded with regard to subject, study regimen, profiling day within regimen, and time during the day. The time courses of ZCG variables were evaluated in two main data formats: untransformed (U, all profiling days) and time-matched for control Day 1 (δ, profiling days except control Day 1); the time courses of U- and δ-data were characterised by their morning pre-dose baseline values (BLU and BLδ) and the observed minimum (dmin) and maximum (dmax) values over the post-dosing time. Selected variables (HR, PEP, QS2, dZ/dtmax, CO, and TPR) were compared by non-parametric estimates of the differences between the profiling days (point estimate and 95% confidence interval [CI] according to Hodges and Lehmann) [40].
Digital 12-lead ECGs were recorded immediately after each ZCG recording. Tracings were analysed off-study by regimen-blinded qualified analysts, using previously reported methodology [20]. For each time point, three cycles were measured with regard to the RR, PQ and QT-intervals [ms]. The means of the three measurements were used for the calculation of HR and HR-corrected QTc intervals, according to Bazett's equation (QTcB = QT/RR1/2) [41] and Fridericia's equation (QTcF = QT/RR1/3) [41,42].
Biological markers
During the main profiling days, blood was sampled at each ZCG time point for the determination of serum glucose and potassium concentrations. Samples were also collected 12 and 24 hours after morning dosing.
Safety and tolerability
Blood and urine samples for conventional clinical laboratory safety tests were obtained at the screening visit, in the morning of each main profiling day, and on Day 19. Adverse events (AEs) were monitored throughout the study.
Twenty-seven healthy male subjects were enrolled and received the assigned investigational medication at least once (see Table 1 for demographic data). For Regimen A, 12 subjects were enrolled and all completed the study in accordance with the protocol specifications. For Regimen B, 15 subjects were enrolled: one withdrew consent on Day 11 and two were discontinued prematurely after erroneous dosing on Day 2, leaving 12 subjects who completed the study in accordance with the protocol.
Table 1. Subject demographics for the study population (all enrolled subjects)
The time courses of geometric mean plasma concentrations of roflumilast, roflumilast N-oxide and formoterol are shown in Figures 1, 2 and 3. Geometric means and their 68% ranges of steady-state pharmacokinetics of roflumilast, roflumilast N-oxide and formoterol are shown in Tables 2 and 3. There were no relevant changes in steady-state pharmacokinetics of roflumilast and roflumilast N-oxide when formoterol was added; similarly, there were no changes in steady-state pharmacokinetics of formoterol when roflumilast was added. There were some between-group effects, since steady-state AUC and Cmax values for roflumilast and roflumilast N-oxide were about 10-15% lower when roflumilast was co-administered with formoterol (Regimen B, Day 18), compared with roflumilast alone (Regimen A, Day 11) or roflumilast after addition of formoterol (Regimen A, Day 18).
Figure 1. Time course of the geometric mean (68% range) plasma concentrations of roflumilast (linear scale). R alone: roflumilast 500 μg once daily at steady state (Regimen A: Day 11; n = 12); RF: roflumilast 500 μg once daily and formoterol 24 μg twice daily at steady state (Regimen A: Day 18; n = 12); FR: formoterol 24 μg twice daily and roflumilast 500 μg once daily at steady state (Regimen B: Day 18; n = 12).
Figure 2. Time course of the geometric mean (68% range) plasma concentrations of roflumilast N-oxide (linear scale). R alone: roflumilast 500 μg once daily at steady state (Regimen A: Day 11; n = 12); RF: roflumilast 500 μg once daily and formoterol 24 μg twice daily at steady state (Regimen A: Day 18; n = 12); FR: formoterol 24 μg twice daily and roflumilast 500 μg once daily at steady state (Regimen B: Day 18; n = 12).
Figure 3. Time course of the geometric mean (68% range) plasma concentrations of formoterol (linear scale). Regimen A: Day 18 (roflumilast 500 μg once daily and formoterol 24 μg twice daily at steady state; n = 12); Regimen B: Day 8 (formoterol 24 μg twice daily at steady state; n = 13) and Day 18 (formoterol 24 μg twice daily and roflumilast 500 μg once daily at steady state; n = 12).
Table 2. Geometric means (68% inter-percentile range) of the main pharmacokinetic variables for roflumilast and roflumilast N-oxide at steady state
Table 3. Geometric means (68% inter-percentile range) of the main pharmacokinetic variables for formoterol at steady state
Impedance cardiography
Regimen A
The treatment medians for baseline Day 1, roflumilast monotherapy alone (R; Day 11), and concomitant roflumilast plus formoterol treatment (R+F; Day 18) are shown in Table 4 for untransformed morning pre-dosing values, untransformed dmax and dmin post-dosing values (including contrast of R vs D1), and time-matched dmax and dmin post-dosing values (including contrast of R+F vs R).
Table 4. Pharmacodynamic measures - Regimen A: treatment medians and treatment contrasts
Roflumilast alone had little effect on cardiovascular function and there were only small changes in the ZCG/STI variables. Concomitant administration of formoterol resulted in a protracted rise in HR compared with roflumilast alone (Figure 4), which was associated with a rise in CO (Figure 5) and a drop in TPR within 10 minutes (Figure 6). Formoterol co-administration was also associated with an increase in dZ/dtmax, particularly in the first hour after dosing, and an overall shortening of QS2 and PEP, which were mostly related to the rise in HR since they were less evident for the HR-corrected STIs (Table 4). These changes were small and within the normal physiological range.
Figure 4. Time course of the median heart rate throughout the main profiling days. Regimen A: baseline Day 1 (NO treatment), Day 11 (R alone: roflumilast 500 μg once daily) and Day 18 (RF: roflumilast 500 μg once daily and formoterol 24 μg twice daily). Regimen B: baseline Day 1 (NO treatment), Day 8 (F alone: formoterol 24 μg twice daily) and Day 18 (FR: formoterol 24 μg twice daily and roflumilast 500 μg once daily).
Figure 5. Time course of the median cardiac output (CO) estimated by transthoracic impedance cardiography throughout the main profiling days. Regimen A: baseline Day 1 (NO treatment), Day 11 (R alone: roflumilast 500 μg once daily) and Day 18 (RF: roflumilast 500 μg once daily and formoterol 24 μg twice daily). Regimen B: baseline Day 1 (NO treatment), Day 8 (F alone: formoterol 24 μg twice daily) and Day 18 (FR: formoterol 24 μg twice daily and roflumilast 500 μg once daily).
Figure 6. Time course of the median total peripheral resistance (TPR) estimated by transthoracic impedance cardiography throughout the main profiling days. Regimen A: baseline Day 1 (NO treatment), Day 11 (R alone: roflumilast 500 μg once daily) and Day 18 (RF: roflumilast 500 μg once daily and formoterol 24 μg twice daily). Regimen B: baseline Day 1 (NO treatment), Day 8 (F alone: formoterol 24 μg twice daily) and Day 18 (FR: formoterol 24 μg twice daily and roflumilast 500 μg once daily).
Regimen B
The treatment medians for baseline Day 1, formoterol monotherapy alone (F; Day 8) and concomitant formoterol plus roflumilast (F+R; Day 18) and their contrasts are shown in Table 5. Compared with baseline, formoterol administration was associated with an increase in HR (Figure 4), a rise in CO (Figure 5) and a decrease in TPR (Figure 6), which were associated with an increased dZ/dtmax, and an overall shortening in QS2 and PEP. These effects were clearly apparent on Day 8 and were not amplified by the concomitant administration of roflumilast.
Table 5. Pharmacodynamic measures - Regimen B: treatment medians and treatment contrasts
Both roflumilast and formoterol were associated with a slight increase in HR and, correspondingly, a decrease in the duration of the QT interval. QTc values, either uncorrected or corrected using Bazett's formula or Fridericia's formula, showed no clinically relevant changes. Categorical analyses of QT/QTc interval data did not reveal differences in the incidence of outliers between regimens, and the incidence of outliers was small. None of the subjects developed abnormal QT/QTc prolongation, and all QT/QTc intervals remained below 450 ms. No clinically relevant drug-related changes in PR or QRS intervals were observed. No clinically relevant regimen-related changes in ECG waveform morphology were detected.
Serum glucose
With Regimen A, the median pre-dose serum glucose decreased from Day 1 (4.97 mmol/L) to Day 11 (4.75 mmol/L) and Day 18 (4.52 mmol/L). During Day 11 (roflumilast alone), glucose levels tended to remain slightly lower than pre-dose levels; in contrast, on Day 18, with concomitant formoterol plus roflumilast, there was a post-dose increase in serum glucose level that was close to the values throughout Day 1 (although the pre-dose levels had been lower).
With Regimen B, there was a slight post-dose increase in serum glucose throughout Day 8 compared with Day 1; addition of roflumilast did not appear to change this formoterol effect.
Serum potassium
With Regimen A, the median pre-dose serum potassium level was lower during roflumilast administration (4.16 mmol/L) than at Day 1 (4.34 mmol/L) or during concomitant administration of the two agents (4.35 mmol/L) on Day 18. During Day 11, when roflumilast was administered alone, serum potassium levels remained slightly lower than levels throughout Day 1. On Day 18, with concomitant formoterol plus roflumilast, serum potassium levels tended to decrease from baseline, particularly between 1 and 6 hours after morning dosing.
With Regimen B, pre-dose concentrations were similar during formoterol administration (4.38 mmol/L) on Day 8 and during concomitant administration of formoterol and roflumilast (4.32 mmol/L) on Day 18 compared with Day 1 (4.48 mmol/L). On both Day 8 (formoterol) and Day 18 (concomitant administration), serum potassium levels tended to decrease from baseline throughout the course of the day.
For Regimen A, during administration of roflumilast alone (Day 2 to Day 11), 7 subjects experienced 17 AEs; during subsequent concomitant administration of roflumilast and formoterol (Day 12 to Day 18), 8 subjects experienced 22 AEs. The most common AE was tremor, which was seen exclusively after addition of formoterol to roflumilast (11 of 22 AEs). Dizziness and myalgia were each reported on four occasions when roflumilast was administered alone; myalgia was also reported on four occasions when formoterol was added.
For Regimen B, during administration of formoterol alone (Day 2 to Day 8), no AEs were reported. Subsequently, during concomitant administration of formoterol and roflumilast (Day 9 to Day 18), 17 AEs were reported for 6 subjects; dizziness and headache were each reported on five occasions and tremor on two occasions.
All AEs were considered to be of mild (35/39 and 16/17 AEs reported with Regimens A and B, respectively) or moderate (4/39 and 1/17 AEs reported with Regimens A and B, respectively) intensity, and most were considered likely related to the investigational medication (35/39 and 14/17 AEs reported with Regimens A and B, respectively). There were no severe or serious AEs and no AEs led to premature discontinuation from the trial.
Roflumilast improves lung function in patients with COPD who are also treated with a long-acting bronchodilator [13]; accordingly, the concomitant administration of roflumilast and a β2-adrenoceptor agonist in patients with COPD is of interest. The present study investigated whether relevant drug-drug interactions might occur with the combination of oral roflumilast and inhaled formoterol. The steady-state plasma pharmacokinetics of roflumilast and its active metabolite roflumilast N-oxide were not altered by the addition of formoterol; similarly, the steady-state pharmacokinetics of formoterol were unaffected by the addition of roflumilast. Concomitant administration of inhaled formoterol resulted in changes that were less than 1% in peak concentration and exposure compared with roflumilast alone treatment Therefore, this co-administration is unlikely to result in clinically relevant interactions.
Cardiovascular effects were investigated by ZCG, which enabled measurement of STIs and allowed derivation of method-specific non-invasive estimates of systolic pump function [35,43]. These ZCG/STI methods are particularly sensitive to within-subject positive inotropic and vasodilatory cardiovascular changes, especially when chronotropic and inotropic reflexes are triggered by vasodilatation ('chrono-inodilatory' responses) [34,44]. Such measures are affected by changes in posture and food intake [45-47]. In all these measures the detectable effects were small. With formoterol alone there was a discrete trend towards a slightly higher HR, shorter PEP, increased CO and decreased TPR; these changes are likely to reflect a vasodilatory effect of formoterol [48,49]. Roflumilast had no effect on the ZCG/STI criteria and did not appear to potentiate the effects of formoterol.
Electrocardiographic investigations confirmed a slight increase in HR for formoterol, which was associated with an HR-dependent shortening of the QT interval with no change in HR-corrected QTc. Accordingly, there was no indication of a safety-relevant cardiovascular drug-drug interaction.
There was a slight decrease in fasting serum glucose level with roflumilast, which did not induce any hypoglycaemia. This effect was blunted when formoterol was administered concomitantly. Formoterol is known to increase serum glucose concentrations at supra-therapeutic levels [50]; however, at the 24 μg dose used in this study, there was only a slight increase in serum glucose level when formoterol was administered both alone and in combination with roflumilast. Supra-therapeutic doses of β2-agonists are also associated with decreased serum potassium concentrations [50,51]; in this study, a mild but consistent decrease was seen with formoterol, which was unaffected by concomitant roflumilast. A mild decrease in serum potassium level was also seen with roflumilast.
None of the other parameters examined (blood pressure, body temperature, clinical laboratory tests) showed safety-relevant changes that might be attributable to roflumilast, formoterol or their combination. The reported AEs were generally mild, with no severe or serious AEs, and mostly reflected the known properties of the investigated medications. There were some differences between the two regimens with regard to the incidence of tremor: tremor was reported 13 times when formoterol was added to roflumilast (11 times in Regimen A and twice in Regimen B), but was not observed when roflumilast or formoterol were administered alone (Regimens A and B respectively).
Although this study was performed in healthy men, results from clinical trials conducted in the roflumilast target population - patients with severe COPD, chronic bronchitis and a history of exacerbations - also support the absence of any relevant interaction between roflumilast and long-acting β2-adrenoreceptor agonists. The two 1-year roflumilast pivotal studies (M2-124 and M2-125) were conducted in 3091 patients, approximately half of whom were receiving concomitant β2-adrenoreceptor agonists [8]. In a pooled analysis of the two studies, roflumilast proved effective irrespective of β2-adrenoreceptor agonist use, and the overall pattern of AEs with or without concomitant β2-adrenoreceptor agonists was similar to that reported across all patients; there was no indication that roflumilast increased AEs associated with β2-adrenoreceptor agonists (such as tachycardia or cardiovascular events), and the co-administration of the two drugs did not increase the frequency of events associated with roflumilast alone [52]. Similar results were observed in a 6-month study (M2-127) conducted in patients with moderate to severe COPD receiving concomitant salmeterol [13]. Furthermore, a population pharmacokinetic analysis of roflumilast and roflumilast N-oxide [53] indicated that only a slight increase (12.6%) in tPDE4i is expected in patients with COPD compared with healthy individuals. The fact that during the clinical development of roflumilast the co-administration with long-acting β2-adrenoreceptor agonists was evaluated in patients with COPD for periods of up to 1 year also suggests that safety issues can be excluded, not only in the short term considered in this crossover study, but also in chronic use.
Given that β2-adrenoreceptor agonists can be used in combination with inhaled corticosteroids in the symptomatic treatment of severe COPD, concerns may arise regarding the addition of roflumilast to this therapeutic combination. Results from two 1-year randomised clinical trials (M2-111 and M2-112) in patients with severe and very severe COPD showed that the co-administration of inhaled corticosteroids does not affect the AE profile of roflumilast [55]. Furthermore, a drug-drug interaction study evaluating the effects of the co-administration of roflumilast and budesonide, a commonly used inhaled corticosteroid metabolised by CYP3A enzymes [54], revealed no relevant pharmacokinetic interactions and no alteration of the safety and tolerability profiles of either drug in healthy volunteers [24]. As mentioned earlier, roflumilast is metabolised by parallel CYP pathways, which suggests that specific CYP inducers or inhibitors are unlikely to alter its pharmacokinetic profile significantly. Although the combination of roflumilast, formoterol and inhaled corticosteroids has not been specifically investigated, based on these observations it is unlikely that the concomitant administration of the three drugs will cause relevant drug-drug interactions.
In summary, the study results demonstrate that concomitant administration of oral roflumilast and inhaled formoterol under steady-state conditions does not affect the pharmacodynamics or pharmacokinetics of either drug. In particular, there was no evidence of a relevant pharmacodynamic interaction with regard to myocardial repolarisation or cardiac function in general. Moreover, the concomitant administration of roflumilast and formoterol did not negatively influence the safety profile of either drug.
Competing interests
This study was sponsored by Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, Germany. CdM has received financial support for research and consulting services from Nycomed GmbH. NN and GL are employees of Nycomed GmbH, Konstanz, Germany.
Authors' contributions
CdM served as a study investigator and was responsible for the acquisition of trial data. In addition he was involved in the study conception and design, in collaboration with GL. All three authors (CdM, GL and NN) contributed significantly to the analysis and interpretation of data; were involved in drafting the manuscript or revising it critically for important intellectual content; and gave final approval of the version to be published.
Acknowledgements and Funding
The authors thank Polly Field, DPhil, of Caudex Medical Ltd, Oxford, UK (supported by Nycomed GmbH, Konstanz, Germany [formerly ALTANA Pharma AG]) for editorial assistance with the preparation of the manuscript; Dr Robert Hermann (CR Appliance, Radolfzell, Germany) for his contribution to conceptual study design and data interpretation; and Dr Andreas Huennemeyer and Dr Markus Hinder of Nycomed GmbH for their contribution to the preparation of the manuscript and critical evaluation of the data. Nycomed GmbH provided funding for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R, Schudt C, Tenor H: The preclinical pharmacology of roflumilast - a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease.
Pulm Pharmacol Ther 2010, 23:235-256. PubMed Abstract | Publisher Full Text
Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R: In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor.
J Pharmacol Exp Ther 2001, 297:280-290. PubMed Abstract | Publisher Full Text
Jones NA, Boswell-Smith V, Lever R, Page CP: The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro.
Pulm Pharmacol Ther 2005, 18:93-101. PubMed Abstract | Publisher Full Text
Hatzelmann A, Schudt C: Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro.
J Pharmacol Exp Ther 2001, 297:267-279. PubMed Abstract | Publisher Full Text
Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF: Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.
Thorax 2007, 62:1081-1087. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD: Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial.
Lancet 2005, 366:563-571. PubMed Abstract | Publisher Full Text
Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM: Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2007, 176:154-161. PubMed Abstract | Publisher Full Text
Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ: Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.
Lancet 2009, 374:685-694. PubMed Abstract | Publisher Full Text
Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated 2009). Bethesda: National Heart, Lung and Blood Institute; 2009.
O'Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J, Marciniuk D, Balter M, Ford G, Gervais A, Lacasse Y, Maltais F, Road J, Rocker G, Sin D, Sinuff T, Voduc N: Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2008 update - highlights for primary care.
Can Respir J 2008, 15(Suppl A):1A-8A. PubMed Abstract | PubMed Central Full Text
Celli BR, MacNee W: Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
Eur Respir J 2004, 23:932-946. PubMed Abstract | Publisher Full Text
Calverley PM: COPD: what is the unmet need?
Br J Pharmacol 2008, 155:487-493. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF: Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.
Lancet 2009, 374:695-703. PubMed Abstract | Publisher Full Text
Buenestado A, Naline EN, Chapelier AC, Bellamy JFB, Devillier PD: Roflumilast and its active metabolite inhibit LPS-induced cytokines production from human parenchymal and bronchial explants: interaction with formoterol [abstract].
Spina D: Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease.
Drugs 2003, 63:2575-2594. PubMed Abstract | Publisher Full Text
Spina D: PDE4 inhibitors: current status.
Br J Pharmacol 2008, 155:308-315. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Anderson GP: Current issues with beta2-adrenoceptor agonists: pharmacology and molecular and cellular mechanisms.
Clin Rev Allergy Immunol 2006, 31:119-130. PubMed Abstract | Publisher Full Text
Zaccolo M, Movsesian MA: cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology.
Circ Res 2007, 100:1569-1578. PubMed Abstract | Publisher Full Text
Cazzola M, Matera MG, Donner CF: Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease.
Drugs 2005, 65:1595-1610. PubMed Abstract | Publisher Full Text
Hermann R, Lahu G, Huennemyer A, Knoerzer D, Bethke TD, Haverkamp W: No effect of roflumilast on cardiac repolarization in healthy subjects [abstract].
David M, Zech K, Seiberling M, Weimar C, Bethke TD: Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high oral bioavailability.
Bethke TD, Böhmer GM, Hermann R, Hauns B, Fux R, Morike K, David M, Knoerzer D, Wurst W, Gleiter CH: Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.
J Clin Pharmacol 2007, 47:26-36. PubMed Abstract | Publisher Full Text
Hermann R, Nassr N, Lahu G, Peterfai E, Knoerzer D, Herzog R, Zech K, de Mey C: Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis.
Clin Pharmacokinet 2007, 46:403-416. PubMed Abstract | Publisher Full Text
Hermann R, Siegmund W, Giessmann T, Westphal K, Weinbrenner A, Hauns B, Reutter F, Lahu G, Zech K, Bethke TD: The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide.
J Clin Pharmacol 2007, 47:1005-1013. PubMed Abstract | Publisher Full Text
Hermann R, Lahu G, Hauns B, Bethke T, Zech K: Total PDE4 inhibitory activity: a concept for evaluating pharmacokinetic alterations of roflumilast and roflumilast N-oxide in special populations and drug-drug interactions [abstract].
Lahu G, Hünnemeyer A, Herzog R, McCracken N, Hermann R, Elmlinger M, Zech K: Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.
Int J Clin Pharmacol Ther 2009, 47:236-245. PubMed Abstract
Lahu G, Hünnemeyer A, von Richter O, Hermann R, Herzog R, McCracken N, Zech K: Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide.
J Clin Pharmacol 2008, 48:1339-1349. PubMed Abstract | Publisher Full Text
von Richter O, Lahu G, Hünnemeyer A, Herzog R, Zech K, Hermann R: Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.
Clin Pharmacokinet 2007, 46:613-622. PubMed Abstract | Publisher Full Text
Lahu G, Nassr N, Herzog R, Elmlinger M, Ruth P, Hinder M, Huennemeyer A: Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-Oxide.
J Clin Pharmacol 2011, 51:586-593. PubMed Abstract | Publisher Full Text
Bohmer GM, Gleiter CH, Morike K, Nassr N, Walz A, Lahu G: No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine.
J Clin Pharmacol 2011, 51:594-602. PubMed Abstract | Publisher Full Text
Nassr N, Huennemeyer A, Herzog R, von RO, Hermann R, Koch M, Duffy K, Zech K, Lahu G: Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.
Br J Clin Pharmacol 2009, 68:580-587. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Electronic Medicines Compendium: Formoterol summary of product characteristics. [http:/ / www.medicines.org.uk/ EMC/ medicine/ 19503/ SPC/ Formoterol+Easyhaler+12+micrograms+ per+actuation+inhalation+powder/ ] webcite
Lecaillon JB, Kaiser G, Palmisano M, Morgan J, Della CG: Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer.
Eur J Clin Pharmacol 1999, 55:131-138. PubMed Abstract | Publisher Full Text
de Mey C, Erb K, Schroeter V, Belz GG: Differentiation of inodilatory responses by non-invasive measures of cardiovascular performance in healthy man.
Int J Clin Pharmacol Ther 1996, 34:525-532. PubMed Abstract
de Mey C, Erb KA: Usefulness, usability, and quality criteria for noninvasive methods in cardiovascular clinical pharmacology.
J Clin Pharmacol 1997, 37:11S-20S. PubMed Abstract | Publisher Full Text
Weissler AM, Harris WS, Schoenfeld CD: Systolic time intervals in heart failure in man.
Circulation 1968, 37:149-159. PubMed Abstract | Publisher Full Text
Kubicek WG, Karnegis JN, Patterson RP, Witsoe DA, Mattson RH: Development and evaluation of an impedance cardiac output system.
Aerosp Med 1966, 37:1208-1212. PubMed Abstract
Geddes LA, Sadler C: The specific resistance of blood at body temperature.
Med Biol Eng 1973, 11:336-339. PubMed Abstract | Publisher Full Text
Wezler K, Boeger A: Die dynamik des arteriellen. Systems.
Hodges JL, Lehmann EL: The efficiency of some nonparametric competitors of the t-test.
Ann Math Statist 1956, 27:324-335. Publisher Full Text
Bazett HC: An analysis of the time-relations of electrocardiograms.
Fridericia LS: Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken.
de Mey C, Belz GG, Nixdorf U, Butzer R, Schroeter V, Meyer J, Erbel R: Relative sensitivity of four noninvasive methods in assessing systolic cardiovascular effects of isoproterenol in healthy volunteers.
Clin Pharmacol Ther 1992, 52:609-619. PubMed Abstract | Publisher Full Text
de Mey C, Enterling D, Hanft G: Noninvasive assessment of the inodilator action of amrinone in healthy man.
Eur J Clin Pharmacol 1991, 40:373-378. PubMed Abstract | Publisher Full Text
de Mey C, Enterling D: Non-invasive estimates of cardiac performance during and immediately after single and repeated passive upright tilt in normal man: volume dependency of systolic time intervals and maximum velocity of transthoracic impedance changes.
de Mey C, Hansen-Schmidt S, Enterling D: Food intake as a source of methodological bias in cardiovascular clinical pharmacology.
de Mey C, Hansen-Schmidt S, Enterling D: Postprandial haemodynamic changes: a source of bias in cardiovascular research affected by its own methodological bias.
Cardiovasc Res 1988, 22:703-707. PubMed Abstract | Publisher Full Text
Kirby DA, Vatner SF: Enhanced responsiveness to carotid baroreceptor unloading in conscious dogs during development of perinephritic hypertension.
Circ Res 1987, 61:678-686. PubMed Abstract | Publisher Full Text
Carlsson E, Dahlof CG, Hedberg A, Persson H, Tangstrand B: Differentiation of cardiac chronotropic and inotropic effects of beta-adrenoceptor agonists.
Naunyn Schmiedebergs Arch Pharmacol 1977, 300:101-105. PubMed Abstract | Publisher Full Text
Bennett JA, Tattersfield AE: Time course and relative dose potency of systemic effects from salmeterol and salbutamol in healthy subjects.
Thorax 1997, 52:458-464. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Palmqvist M, Ibsen T, Mellen A, Lotvall J: Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients.
Am J Respir Crit Care Med 1999, 160:244-249. PubMed Abstract | Publisher Full Text
Bateman ED, Rabe K, Calverley PMA, Goehring UM, Brose M, Bredenbrocker D, Fabbri LM: Roflumilast with long-acting β2 agonists for COPD: influence of exacerbation history.
Lahu G, Hünnemeyer A, Diletti E, Elmlinger M, Ruth P, Zech K, McCracken N, Facius A: Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase 4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model.
Clin Pharmacokinet 2010, 49:589-606. PubMed Abstract | Publisher Full Text
Jonsson G, Astrom A, Andersson P: Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver.
Drug Metab Dispos 1995, 23:137-142. PubMed Abstract | Publisher Full Text
Rennard SI, Calverley PM, Goehring UM, Bredenbroker D, Martinez FJ: Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD.
Respir Res 2011, 12:18. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
Pre-publication history
The pre-publication history for this paper can be accessed here:


text:
For over fifty years, Keystone Electronics has been manufacturing precision electronic interconnect components and hardware, supplying quality products at competitive prices to industry, worldwide.
While our catalog products meet most standard requirements, modifications as well as custom fabrications can be manufactured to meet your special needs. Design and engineering, precision tool and die capabilities, close tolerance Stamping, Machining, and Assembly, computer based quality control and responsive customer service are all vital in-house resources which constitute our Custom Manufacturing Division's capabilities.
© Allied Electronics, Inc.
2015. All rights reserved.

subset: commoncrawl


text:
Can You Catch AIDS From Sharing A Joint
Here's a taste of what TheBody.com has to offer on this topic:
Ask the Experts
Want to share this video on HIV and AIDS research (AIDS DENIALISTS, 2010)I Doctor. I watched this video and wanted to pass it on to you so if you ever get the time to watch it, perhaps you can give your opinions on it. This research Virologist I believe is his expert field in the 1980-90's, suggested then that HIV exists...
Response from Robert J. Frascino, M.D.
The Robert James Frascino AIDS Foundation...Don't be duped by these dimwits.Dr. BobAids Dissident (AIDS DENIALISM, 2010) May 11, 2010I am currently undergoing tests for HIV post exposure. I am also trying to start a non for profit organization. To keep a long story short the graphic... Read more »
Marijuana "Joint" sharing and possible transmission?Three weeks ago I was at a party and shared a joint with two other people, one of whom was gay. I... Read more »
sharing a room with someone who is HIV+Hi,I am a 23 years old male.I have been sharing a room with an HIV+ person for the past one... Read more »
NIH Announces It Will Share IP Rights to Some AIDS Drugs in UNITAID Patent Pool...the protease inhibitor class of HIV medicines, which is primarily used to treat drug-resistant HIV infection," according to a joint press release issued by NIH, UNITAID and Medicines Patent Pool. "The NIH Office of Technology Transfer has... Read more »
Zambia to Share Global Funds on HIV/AIDS...Lewis said he would get in touch with those responsible for the global fund for HIV/AIDS to ensure the country receives its share. Lewis stressed that HIV/AIDS has further compounded the hunger crisis in Zambia. He said the UN intended to study... Read more »
Men, Women Should Share Responsibility for HIV/AIDS Prevention, Treatment, Malaysian Official Says... Men and women should share equal responsibility for preventing HIV/AIDS and providing treatment to people living with the diseases, Ng Yen Yen -- Malaysian Read more »
Join an Oct. 7 Conference Call -- Share Your Ideas for Making the U.S. National HIV/AIDS Strategy Work for Women... Imagine a National AIDS Strategy that truly works for women. A National AIDS Strategy that prevents new HIV infections in women; increases women's access to care, and reduces disparities for women affected by HIV. What would it look Read more »
Connect With Others
Important: Share YOUR take on Living With HIV.Read more »
Important: share your take on Living With HIVRead more »
Important: share YOUR take on Living With HIV.Read more »
Important: Share YOUR take on Living With HIV.
Posted by BrokenWingedBird, 2 Replies...if you wish. http://www.worldaidsday.org/ The exact page for telling your own story is at: http://www.worldaidsday.org/Share-your-story.aspx Writing your view of "Living with HIV" could help change important policies. Best Wishes. BWB. Read more »
Resource Centers
Guides for People With HIV


text:
By clicking Continue, I agree to the Terms of Service and Privacy Statement
Already have an account?
Variety of wine made in small batches, including table wine, seasonal wine, and fortified wine
Glunz Family Winery
$25 $15
Farmyard and Attractions Experience for Two or Four or Charitable Donation at Lambs Farm (Up to 50% Off)
Lambs Farm
Farmyard run by non-profit organization houses a petting zoo with over 50 farm animals to pet and a mini-golf course
View Deal
$18 for a Tour for Two at The Gold Pyramid ($30 Value). Twenty-Two Dates Available.
The Gold Pyramid
Built as a private home in 1977, the 17,000 sq. ft. pyramid features statues, a moat, a three-pyramid garage, and Egyptian-style furnishings
Animal Petting Farm Visit for Two or Four at Green Meadows Petting Farm in Waterford (Up to 47% Off)
Green Meadows Petting Farm
East Troy
Fuzzy fleeces, soft feathers, and bristly hides rub against hands at a petting zoo where kids can also ride a pony and milk a cow
$149 for a Helicopter Flying Lesson and Flight from Bachman Aero ($295 Value)
Bachman Aero
The 30-minute helicopter flying lesson puts students in control of the craft at 500 feet with instruction from a FAA Certified Pilot
Admission for Four Adults, or Membership for One Adult or Family at Elgin History Museum (Up to 51% Off)
Elgin History Museum
Eastside Elgin
Two floors of history exhibits reflecting Elgin's rich past, including a collection of Elgin Watches and Elgin Road Race memorabilia
Three-Hour Elgin Cemetery Ghost Hunt for Two or Four from Haunted Hometowns (51% Off)
Haunted Hometowns, Corp.
Ghost-seekers walk through moon-lit cemeteries in the dead of night during tour as guides relate tales of local specters
Illinois Holocaust Museum & Education Center Membership for a Family or Individual (Up to 40% Off)
Illinois Holocaust Museum & Education Center
The museum honors Holocaust victims, telling their stories with artifacts and interactive exhibits that urge visitors to fight intolerance
Tour of Dawes House/Evanston History Center for 2, 4, or 5–10 People (Up to 45% Off)
Evanston History Center
Visit the National Historic Landmark Dawes House, where more than a century of history about the city is preserved in a beautiful chateau
The Zoo at Jo-Don Farms Admission for Two, Four, or Six to Jo-Don Farms (40% Off)
The Zoo at Jo-Don Farms
Jo-Don Farms
Guests greet more than 300 critters, from camels to tigers, at zoo open for 40 years
40-Minute Ride in a Extra 300L Stunt Airplane or T-6 Texan Trainer Warplane from Gauntlet Warbirds (41% Off)
Gauntlet Warbirds
Sugar Grove
A seasoned flight instructor leads a 40-minute joy ride aboard an Extra 300L aerobatic plane or a T-6 Texan warplane
$30 for a One-Year Rialto-Level Membership in the Theatre Historical Society of America ($60 Value)
Theatre Historical Society of America
Theatre Historical Society
Receive research, event, and merchandise discounts from a historical society that celebrates the architecture and culture of the theatre
Winery Tour for Two Plus Two Bottles to Take Home at Acquaviva Winery (Up to 37% Off)
Acquaviva Winery
Maple Park
Tour a picturesque winery with striking architecture before enjoying a glass of wine in the tasting room and selecting a bottle to take home
Geneva Lake Museum Visit for Two, Four, or Six (Up to 50% Off)
Geneva Lake Museum
Museum fills historic Power & Light building and replicates Lake Geneva Main Street of late 19th and early 20th centuries
Loading ...


text:
I'd like to know how can I match the external functions called by a binary with their linked shared library. For example, I can see the functions looking at the .plt section of a disassembled file, and I can find out the used libraries using ldd (or looking at the ELF dynamic section); but how can I match each function with its library?
Take the 2-minute tour ×
Stack Overflow is a question and answer site for professional and enthusiast programmers. It's 100% free, no registration required.
I followed the Laszio hint and I've created a little python function which get a binary file name and by mixing ldd and nm, returns a dictionary which contains the external functions with their shared libraries. Maybe it is a little confusing, but it works :) Here it is the code


text:
Shop now and get Free Value Shipping on most orders over $49 to the contiguous 48 states, DC and to all U.S. Military APO/FPO/DPO addresses.
We want to ensure that making a return is as easy and hassle-free as possible! If for any reason you decide that your purchase just isn't for you, simply return the item within 30 days of receipt and we'll cover the cost of return shipping. Learn more about our Return Policy.
This product is on clearance and is priced to move! Once it's gone, it's gone! See more clearance items
Energizer Eveready Gold Alkaline AA Batteries designed to deliver superior run time for high-tech devices like digital cameras, flashlights, trail cameras, MP3 players, digital camera binoculars and electronic toys. EvGold 1.5-Volts AA Alkaline Batteries from Energizer provide an economical power source for electronic products. Energizer Alkaline AA Batteries are long lasting batteries that go on for long periods of time when used in power hungry electronic devices. Energizer Eveready Gold Alkaline Batteries are more compact that most other alkaline batteries. Energizer is also environmentally friendly in their AA batteries, Energizer 1.5-Volt Eveready Alkaline AA Batteries use no mercury that makes them environmentally conscious and they can be disposed of with regular household trash.
Available Energizer Alkaline AA Batteries packs:
Connect with OpticsPlanet
Become our fan, follow us, & subscribe for the latest updates and deals
Subscribe to our email list
Sign up and receive $5 Off and get exclusive access to promotions, sales
events, pre-order sales & more!
Contact Information
Toll-Free: 800-504-5897
Intl.: 847-513-6201
Fax: 847-919-3003
Email: email@example.com
Hours of Operation
7AM-8PM CST Mon-Fri9AM-5PM CST Sat-Sun
Our Guarantees


text:
GQ's digital edition designed specially for your device
Only £1 an issue!
Jay Z is set to launch Tidal, his own music-streaming site tonight, billed as the world's "first premier music streaming service" and an "artist-friendly" site. The reaction from artists on Twitter has certainly been friendly: a number of big name musicians, including the likes of Kanye West, Arcade Fire and Madonna, are already onboard with the rapper's new project tweeting along with the #TIDALforALL hashtag.Read
The legendary British record producer and trance DJ shares his favourite tracks with us (plus a few of his own).Read
From Rhodes to Underworld, and Sam Smith to Lionel Richie, these are the gigs you need to go to this month.Read
The GQ guide to the best record shops in the UK. (Because sometimes digital downloads just won't do.)Read
Singer, actor, designer and one of GQ's hottest women in the world, Rita Ora is hot property right now. As she prepares to launch her second album, we caught 5 minutes with the 50 Shades of Grey star as she celebrated the iconic Coca-Cola bottle's 100 year anniversary.Read
You've doubtless marveled at Chris Evans' incredible physique in Captain America. But in order to get him in comic-book shape, the producers turned to a Brit: former Royal Marine turned personal trainer Simon Waterson. Read


text:
In just over two weeks, Mormons around the world will gather for the church's semiannual General Conference, broadcast around the world via satellite from Salt Lake City. During five two-hour sessions over two days, top LDS leaders will teach and inspire members with spiritual...
Iran, powers explore nuclear compromises as Israel hopes for failure
Italy's top court acquits Amanda Knox of murder
Woman arrested for sexual abuse of teenagers at a bar mitzvah
Jury rules gender not reason Silicon Valley executive not promoted
New restrictions on L.A. residential development
Following grave desecration, Tunisian president vows to defend Jews
Holocaust survivors to restore Polish Torah scroll
Ukrainian Jewish surgeon claims attackers shouted anti-Semitic epithets
Tag: Salt Lake City
View the most popular tags overall?
General Conference and The Forward's top rabbis
March 20, 2013 | 11:26 pm
If Romney wins: Five things every Jew should know about Mormonism
October 19, 2012 | 1:33 pm
Conversations From Twitter – Part 7
June 27, 2012 | 12:13 am
I was very much looking forward to talking to Twitter's @AsianPosh1. She has been following me on Twitter for a long time and has been truly lovely. She defends me to the haters, reads my reality blog and my lifestyle blog, and always has a kind word for everyone who needs it. ...
At Sundance, view of Israel ranges from critical to abysmal
January 23, 2012 | 2:59 pm
For Israel fans, it's all pain and anguish this year at the Sundance Film Festival.
Unlike in years past at America's top independent film fest, when feature films exploring the nuances of Israeli life offset some hard-hitting documentaries – such as in 2007 when the...
Niceness, by the Book
March 30, 2011 | 10:59 am
Ice Capades
January 24, 2002 | 7:00 pm
Torch Song Trilogy
January 17, 2002 | 7:00 pm
Linda Gach Ray has been carrying the torch for years.
This week, she made it official by running the Olympic flame down a stretch of Figueroa Street as the torch was relayed through Southern California on its way to the Winter Olympic Games in Salt Lake City, which begin Feb. 8....
A Jewish New Wave
February 12, 1998 | 7:00 pm
Jewish filmmakers descended on this snowy townlast month for their annual 11-day-long holiday ritual of schmoozing,skiing and screenings, better known as the Sundance FilmFestival.
That's hardly big news in an industry with morethan a few Jewish members. What is news is that Jews were...


text:
Spotlight Article:
Contributors: November/December 2014
Sean Bleything "Behavior Change Requires a Human Touch" While writing this month's article, Bleything learned that "in order to motivate and inspire homeowners to save energy, there needs to be ...
Keep Reading
LETTERS: January/February 1995
archive CONTENT
More Waterbed Data, Waterbeds Unplugged, Fireplace Questions, Where to Find Efficient Wood Fireplaces? [continue reading]
LETTERS: November/December 1994
archive CONTENT
Consumers Union's Test Methods, The GreenPlug Predicament, The Takeback Controversy, More on CO Poisoning [continue reading]
LETTERS: September/October 1994
archive CONTENT
Of Energy Purists and Pragmatists, Sun Frost Refrigerator Test Conditions, Refrigerator Myths, Leveraging the Landlords, Cellulose Insulation Density, Solar Savings?, Capturing Conservation in Iowa, Software "Solutions"? [continue reading]
LETTERS: July/August 1994
archive CONTENT
Putting Education and Technology Together, Water-Heater Temperature Settings [continue reading]
Dense-packing Low-density Cellulose?: May/June 1994
archive CONTENT
Cellulose-blown fiber insulation is now being manufactured in a different, more-efficient manner. Most large manufacturers are employing a new method called "fiberization." [continue reading]
The Landlord-Tenant Quandary: March/April 1994
archive CONTENT
As a residential energy auditor for a western New York utility, and with several hundred audits completed, it has become obvious to me where the greatest energy savings potential exists. [continue reading]
Leslie McDowell
BPI Introduces New BPI.org for Consumers
The Building Performance Institute, Inc. (BPI) recently introduced www.bpi.org for consumers, a new interactive website designed to educate ...
Mike Knezovich
PHIUS to Launch North American Passive Building Standard at Event in Seattle
The Passive House Institute US (PHIUS) recently announced that Executive Director Katrin Klingenberg will formally launch the new PHIUS+ 2015 passive ...


text:
should I pull these tomatoes?
I planted them out a week ago since they weren't looking so great in pots and I figured they would do better in a bed. They are looking really sick, there is barely any green on them, leaves are yellowing, turning brown and dying. Yesterday I thought maybe it's a nitrogen deficiency and added some blood meal. Don't know how fast it's supposed to act but they are still awful looking. We've also been getting heavy downpours for the past few days... I am ready to pull these and plant seedling I was given a few days ago. What if the same thing happens to those, though? Do these have a chance? Thanks!
Pull and start over. Even if a couple of them do somewhat recover they will never be healthy.
Something went really wrong with these. Whether it was because they were planted too early, planted so shallowly, in bad soil, over-watered or whatever I can't say with the info provided. Let's hope it was the rain.
What is the bed filled with and how deep is it?
That's too bad since I grew the seedling from seed. The same ones did really great last year...
I kept them for now since I am trying to figure out what went wrong. I am still clueless.
The bed was put together with leaf mold and top soil from the store about three year ago. We've been adding mulched leaves since but that's all. Could it be that the leaves are causing this problem?
Think I will pull them today but I am afraid to plant anything else in that bed. However, cilantro is doing really well in the same bed. I just don't know.
Thanks for the feedback!
I think they'll do well eventually if you bury them up to those top leaves. It could be a million things gone wrong on some level, but I'm willing to bet either no grow light was used, or way too far from the seedlings, and you didn't harden them off. I say that because they are both leggy and sunburned.
Have the soil tested for pH. Depending on the type of leaves and amount used you may discover that adding all the leaf mold and shredded leaves has turned it very acidic.
Also shredded leaves that have not turned to leaf mold before mixing them in the bed can bind up all the nitrogen in the soil as they continue to decompose. Shredded leaves can work as a mulch but not mixed in.
Lots of discussions over on the Soil & Compost forum here about folks who have added lots of shredded leaves and tilled them in only to discover nothing will grow now.
Try giving the whole bed a heavy dose of fast acting nitrogen (if the pH is ok) to off-set the N binding. Bloodmeal, cottonseed meal, alfalfa meal, even a granular high N fert should make a big difference quickly IF that is the issue.
I didn't use grow lights but I didn't use them last year, either. Everything did fine last year. I have a very sunny, south-facing window sil and thought it was enough.
Maybe I didn't harden them off properly. That is probably part of the issue.
Thanks for letting me know, Dave, about the problem of adding leaves. I need to learn more about soil and compost. I really lack knowledge and skill in that area, and it's so important.
I did add blood meal last week but so far it hasn't made any difference.
Thanks, again!
Half of my tomato plants look identical to yours and I'm also debating whether I should pull them or not. Here's some background on my situation which may shed some light on what's happening to both of our plants.
I planted some of my tomato plants in one garden plot. I had tilled compost into this plot several years ago. After that, I simply cover the plot with leaves in the fall, the leaves which remain in spring act as mulch. These tomato plants are doing fine.
I planted other tomato plants in my second plot. I built up this second plot using the lasagne gardening method by piling on coffee grounds, leaves, and grass clippings atop a bed of cardboard. I did this two years ago, and all my tomato plants grew well in this plot last year. I also cover this plot with leaves in the fall. This season, all of my tomato plants in this plot look like the ones in your photo.
I have planted some identical tomato plants in both plots, yet they are not doing well in the second plot. All tomato plants were planted at the same time, May 15, with the same additives in the holes (fish, bonemeal, epson salt, tomato tone). It was warm when they were planted, then it cooled off significantly, and it is now warming up again. We have also had a significant amount of rain since May 15th.
If the additives or weather were a factor, I think it would have affected all of my plants rather than just those in the second plot. This leads me to believe there is something about the soil in my second plot that is affecting the plants.
Strange how we both have similar looking tomato plants in similar soil. I do not till my soil in either plots so the leaves sit on top until they decompose.
This post was edited by jaidog on Thu, May 30, 13 at 19:03


text:
The Cordova Inn
No availability found through our partners. Please contact the business directly or check some of our recommended alternatives.
TripAdvisor Reviews The Cordova Inn Ocean Grove
Travel Blogs from Ocean Grove
Ocean Grove - Holy Land on the Shore
... same everywhere I go, but only in New Jersey do people regularly stick up their middle finger at me. Maybe it's just a matter of squeezing too many people and too many cars into a small area, but I think the overly restrictive laws and aggressive police enforcement of them have a lot to do with the bad moods.
Among the examples of the Joizee nanny state, Governor Chubbie just vetoed a bill passed by the legislature banning smoking in all public parks and beaches in the ...
USA - Day 3 - Wildebeest, Vultures and Blackbirds
... the American robin, not actually a robin but indeed one of the thrush family. It is called a robin because of the colour of its breast. Back at Sasha's we defrosted with a hot drink. Angus and Sasha went for a walk on the beach and lasted about 5 minutes out in the cold. Snake has not been seen since arriving in New Jersey, I think he has headed back to Bora Bora for a few days until we get somewhere warmer. (Angus) I don't believe ...
Empire State of Mind
... the rail line itself. The walk was really nice with really great view of the New York streets and lower Manhattan. However there is a lot of apartments around the area that you can see right into their homes. Subash took a lot of very nice photos, and I would recommend whoever goes to New York to go here. We ended our walk near "Magnolia Bakery" where we got our last cupcake before heading to a burger joint where we had some nice burgers. The day was coming to an end. ...
Wurst Music
... Yes, this is a tourist place, but it is not a rip off
Dinner for two (burp) was $ 40 USD.
Oh yes, we had dessert, a sacher torte, at the Sacher Hotel and desserts were $ 20 USD
for more see ...
Prior to Departure - Planning and Organization
... we choose Nepal-side base camp, we needed to identify the appropriate time to go considering weather conditions. There are two main trekking seasons for reaching EBC, Autumn (Sept - Nov) and Spring (Mar - May). Trekkers are permitted to enter Sagarmatha National Park in Winter and Summer, but, heavy snow and rain respectively make for less than optimal hiking. Here is a quick snapshot of the monthly entries into Sagarmatha NP since 1998:
Other places to stay in Ocean Grove
The Ocean View Inn22 Ocean Pathway , Ocean Grove | B&Bfrom $75
The Park View Inn23 Seaview Avenue, Ocean Grove | B&Bfrom $80
Angel Nook Inn Bed & Breakfast14 Surf Avenue, Ocean Grove | B&Bfrom $95
The Majestic Hotel19 Main Ave, Ocean Grove | 3 star b&bfrom $172
Carriage House B&B18 Heck Avenue, Ocean Grove | 3 star b&bfrom $134
The Sea Spray Inn19 Broadway, Ocean Grove | B&Bfrom $140


text:
You have 2 remaining free articles this month
Try unlimited digital access
link your account for free access. Start here
Paving, street reconstruction and bridge work will dot much of the Pittsburgh region's landscape this year.
The tunnel will close at 10 tonight and reopen by 6 a.m. Monday. The posted detour uses West Carson Street to reach the West End Bypass.
Investigators of the Germanwings crash that killed 150 believe a rogue co-pilot locked out his colleague.
Senate Bill 4, a proposed state constitutional amendment, faces scrutiny in the House and may not make fall ballot.
With Dave Schuilenburg out, Ms. Harris faces Bobby Wilson, Randy Zotter and Mark Brentley Sr., who may be removed in a legal challenge.
Under the five-year agreement, the Pittsburgh Stadium Authority and Alco Parking will pay $1.2 million to continue the service.
"I want to be able to go out at the top of my game," Mr. Reid, 75, said.
Students from Japan visited Norwin schools through a program called Kakehashi, which means "a bridge connecting two sides with differences.
Commissioner Kristen Linfante informs the board she is resigning due to health issues.
Also, German prosecutors say they found evidence that Andreas Lubitz appears to have hidden evidence of an illness from his employers.
The censure motion March 18 by commissioner Jessica Cardillo-Wagenhoffer was approved by a 4-0 vote.
Fixing landslide damage to a portion of Camp Meeting Road in Bell Acres likely will take until the end of the year.
Plan will set priorities for surface maintenance in the community.
Norah Carter, a fifth-grader at Eden Hall Upper Elementary School, won the districtwide competition with her recipe for Garden Pops.
A friend described Charles "Chuck" Coffey as "a plain, simple, nice man" who practiced dentistry for 25 years in Squirrel Hill.
The policy requiring volunteers to obtain criminal clearances, modeled after a new state law, was introduced at the March 18 meeting.
With her round face, shy smile and soft fleshy hands that were never idle, my Nonna Sestili preceded in appearance the Pillsbury Doughboy.
This is the third time that a group of students from Mt. Lebanon High School will perform at the famed music hall.
A life devoted to family and community theater remembered.
Officials with Imagine Penn Hills Charter School of Entrepreneurship expect enrollment to increase in 2015-16.
A hydrogeologist is to determine whether gas and oil exploration can be done in the township and, if so, where.
The initiative strives to increase the number of students taking Advance Placement courses.
Montour school directors continued the process of addressing issues left open by the previous administration.
As part of a budget presentation to the school board, Curt Baker discussed salary ranges being negotiated between the union and district.
Officials are concerned that students who do not live in Penn Hills may be fraudulently attending school in the district.
About 10 Fox Chapel students are getting a real-world work experience at Massaro CM Services, the high school construction contractor.
The Settler's Ridge Homeowner's Association doesn't want Speedway to build on Route 286 near Logans Ferry Road in Murrysville.
Scott Stickney, enrichment facilitator at Hampton High School, enlisted students to illustrate his story about a camp for gifted students.
Some scholars questioned the image of Richard that has come down through the centuries: a hideous, bloodstained villain.
The measure spares doctors a 21 percent pay cut if it passes a Senate vote. The bill requires high-income earners to pay higher premiums.
North Versailles residents near the new bridge on Greensburg Pike say drivers now speed through the area.
Fears are grouping that there could be a disruption to oil supplies,and that conflict could lead to a wider sectarian war.
Too great or abrupt a withdrawal by militia forces, analysts said, could complicate the entire Iraqi counteroffensive.
Glenn Haggstrom was the principal executive director of the Office of Acquisition, Logistics and Construction.
The governor agreed to allow a needle exchange in an effort to curb the outbreak, which has resulted in at least 70 cases.
Hillel has attempted to stop local chapters from hosting events that involve speakers or groups deemed to be anti-Israel.
The report does not specify the country where the parties occurred, but an official familiar with the matter identified it as Colombia.
The Consumer Financial Protection Bureau proposed rules Thursday to protect Americans from stumbling into what it calls a "debt trap."
The two vaccines, each given in a single injection, are being tested for safety and efficacy on more than 600 people in Liberia.
The vote came after Tracy Montgomery, mother of the student Kaitlin, addressed the board.
Plus: Netanyahu chided; Prince Charles letters; arrests in nun's rape; and more.
Plus: Conservative budget OK'd; Indiana religious freedom bill; Illinois guardsman charged; and more.
School news from throughout the west communities.
School news from Pittsburgh region's north communities.
The Steel Valley school board will decide tonight if a special needs student's use of a faculty bathroom violates the teachers contract.
The traffic restriction will be in effect from 9 a.m. to 2 p.m. today.
Work will occur from 9 a.m. to 3 p.m. weekdays through April 20.
The sinkhole is in the 2800 block of Laketon Road, just east of the intersection with Crab Hollow Road.
Tracy Montgomery's daughter Kaitlin, 10, is the subject of a grievance filed by the Steel Valley Education Association.
The teachers union had filed a grievance over the issue at Park Elementary School in Munhall.


text:
Thank You to Everyone Who Helped 'Can the Griz'!
The Bobcat community won the 15th annual Can the Griz Food Drive! Everyone wins when we stock our food banks. Check out the impressive final numbers here.
The Bobcat community won the 15th annual Can the Griz Food Drive! Everyone wins when we stock our food banks. Check out the impressive final numbers here.
"Pints With Purpose" will benefit Buffalo Field Campaign at Bridger Brewing on Monday, Nov. 24 from 5 - 8 p.m. Have a pint or three and help preserve the wild buffalo herds that live in and around Yellowstone National Park!
The good folks from The Gallatin Valley Food Bank have informed us that this year's Can The Griz food drive is very close. There's still time to beat Missoula! Can The Griz ends at halftime of the football game this Saturday. Your last drop off location for nonperishable food will be at The Club Tavern & Grill (inside the GranTree Inn) on Saturday from 8 am - 3 pm.
National Geographic just ranked Bozeman and Whitefish as top 10 ski towns...in the world!
Wrap two presents with one bow at the first annual Christmas Bazaar fundraiser on Saturday, November 29 at Buck's T4 from 12 pm - 8 pm, featuring local vendors, artists, and crafters. Portions of some vendor sales and raffle proceeds will go to Women in Action, a local non-profit working to serve the community of Big Sky.
Donations are still being accepted as part of the 15th annual Can the Griz food drive, which will officially end at halftime of the Cat/Griz "Brawl of the Wild" football game this Saturday, November 22. A complimentary ticket to the game will be given to the individual or business making the single largest nonperishable food donation to the Gallatin Valley Food Bank.
Big Sky Resort is once again encouraging people to give to local food banks and thanking them with a FREE day of skiing! Big Sky Resort will host the 8th annual Turkey for a Ticket fundraiser for the Gallatin Valley Food Bank, Madison Valley Food Bank, and the Big Sky Food Bank on Friday, Dec. 12 at the Madison Base Area starting at 8:30 a.m.
JJ Grey & Mofro will release their 7th studio album, Ol' Glory, on February 24, 2015. Ol' Glory contains 12 new songs that feature the deep, gritty blend of soulful blues, rock, folk, funk, gospel, R&B and personal, Southern-inspired narratives that JJ Grey & Mofro is known for. Check out the album trailer!
The Broads are back! Don't miss the 15th Anniversary Show of ALL NEW material at Bozeman's Emerson Center Thursday, November 20 - Saturday, November 22.
Don't Close Your Eyes: Live Radio Theatre presents their 3rd annual Holiday Cancer Benefit show, Don't "Claus" Your Eyes, at Live from the Divide on Saturday, December 13 at 8 pm.
Christmas tree permits are available for purchase across all seven districts on the Custer Gallatin National Forest.


text:
last time when i had installed busy box through flashtools, after that few days more, my xperia zl got sudden death error, n finally i had replaced it from sony service centre, so inatalling busybox causes sudden death error in xperia zl ?
XDA Developers was founded by developers, for developers. It is now a valuable resource for people who want to make the most of their mobile devices, from customizing the look and feel to adding new functionality.
Are you a developer?
Copyright © xda-developers. Hosted by Leaseweb


text:
Hôtel Vauban, Brest
Situated in the heart of Brest, Hôtel Vauban is close to Clermont-Tonnerre Hospital, Musee National de la Marine, and Brest Castle. Also nearby are Tour Tanguy and University of Western Brittany.
Hotel Features.
The hotel offers a restaurant. Complimentary wireless Internet access is available in public areas. Additional amenities include a nightclub, a terrace, and multilingual staff.
The 51 guestrooms at Hôtel Vauban include hair dryers and complimentary toiletries. Complimentary wireless high-speed Internet access is provided. Televisions are equipped with digital channels. All accommodations provide desks and phones.
Spent 2 nights here with a coleague. Very enjoyable stay. The room and facilities were…
Every thing good about this hotel. Have stayed 5 times. Best to get a room on the 3/4/ or…
Enter dates to check prices
Hotel Info: 866-539-8117from $64
- Classic Double Room
- Classic Twin Room
- Classic Single Room
- Classic Twin Room
Recommended hotels
At a glance
Key facts
Hotel size
- This hotel has 51 rooms
- This hotel is arranged over 5 floors
- Check-in time 2 PM-midnight
- Check-out time is 11 AM
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
- Minimum check-in age is 18
Travelling with others
- No pets or service animals allowed
Extra people
- Roll-away beds available, charges may apply*
- Free WiFi in public areas
- Free WiFi in rooms
- No parking
Nearby Three Star Brest hotels
In the hotel
- Buffet breakfast daily (surcharge)
- Restaurant
- Room service (during limited hours)
- Nightclub
- Number of meeting rooms -
- One meeting room
- 24-hour front desk
- Number of buildings/towers - 1
- Year Built 1951
- Elevator/lift
- Terrace
- Accessible bathroom
- In-room accessibility
- Roll-in shower
In the room
- Blackout drapes/curtains
- Premium bedding
- Free toiletries
- Hair dryer
- Digital TV channels
- Desk
- Free WiFi
- Phone
Top Brest hotels
Recently reviewed hotels in Brest
- Hôtel le RégentFrom
"I stayed 4 nights in this lovely small, economy hotel. When I arrived, I was greeted by the lady at the front desk. She was very friendly and was willing to talk in English (I…"Oct 26, 2014
- Hôtel Vent d'IroiseFrom
"Great place in a great town. Great for hiking. Resort town with a lot to do in the evening"Sep 30, 2014
- Brit Hotel IroiseFrom
"The staff were very friendly, and the place was clean. Breakfast was good for a continental one. Liked proximity to water activities and to local parks for sight-seeing. Also…"Jun 11, 2012
- Relais du Silence Le Clos de VallombreuseFrom
"Amazing jewel a bit off the path in Douarnenez. Hotel staff very helpful and friendly. It has a very nice view of the ocean and the pool looked clean and inviting (it was too cool…"May 13, 2012
Nearby hotels
Special features
DiningLe Vauban - This brasserie specializes in French cuisine and serves breakfast, lunch, and dinner. Guests can enjoy drinks at the bar. A children's menu is available. Open select days.
Hôtel Vauban, Brest's small print
Also known as
- Hotel Vauban Brest
- Brest Hotel Vauban
- Vauban Brest Northern FinistFre
Mandatory fees
You'll be asked to pay the following charges at check in or check out:
- A tax is imposed by the city: EUR 1.10 per person, per night. This tax does not apply to children under 18 years of age.
- Resort fee: EUR 1.10 per person, per night
Optional extras
Buffet breakfast is offered for an extra charge of EUR 9.00 per person (approximately)
Cribs/Infant beds are available for an extra charge
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.


text:
realmagick.com The shrine of knowledge.
Marketization Definition
A selection of articles related to marketization definition.
Original articles from our library related to the Marketization Definition. See Table of Contents for further available material (downloadable resources) on Marketization Definition.
- The 'W' Word (Witch), What Does it Mean?
- The other day I sat down and again tried to define what it is that I am doing. We are talking about beginning our church next year, but a church of what? I am the type that is most comfortable with a clear and complete understanding, so I began at the...
Religions >> Paganism & Wicca
- What is Hypnosis?
- Hypnosis refers to just about any situation where we respond to verbal suggestions in a particular special way. This involves a mentally very flexible condition where our imagination and fantasy are more free and more vivid. A series of instructions, called...
Parapsychology >> Hypnosis
- Aspects of Religion: A Wiccan Viewpoint
- Among early Pagans, religion was a fact taken for granted, "requiring no explanation." There was no need to define religion because religion was a part of each persons being. "We have not yet encountered in Egyptian and Babylonian literature a...
Religion & Philosophy >> Religions
- Raising the World Mind (GM10-11)
- Part 1 | Part 2 Part 1 The wise live in accord with natural laws. It is they who understand that the laws of nature are much higher than the laws of man, because breaking them implies penalties far greater than a fine or prison sentence. When a person...
Mind >> World Mind
- Wicca: It's Traditions and Concepts
- What is Wicca? | Wiccan Traditions | Wiccan Concepts What is Wicca? 'An it Harm None, Do what Thou Will' shall be the whole of the law. It's the rede that most Wiccan witches around the world bind themselves to. What exactly is Wicca? It's a religion based on...
Religions >> Paganism & Wicca
- Our Pagan Village: The Importance and Persuit of Honor
- Candlelight flickers over the Beltaine revels. Food is laid out in the circle for the feast. Only one rule – no one can feed themselves. Each is dependent on friends and loved ones for sustenance, joy and delight. After an hour of laughter and revels and way...
Paganism & Wicca >> Daily Life
Marketization Definition is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Marketization Definition books and related discussion.
Suggested Pdf Resources
- New directions in the social studies of market(ization)s
- The second part of the paper presents our definition of economization in general and marketization in particular.
- www.rethinkingeconomies.org.uk
- International Relations
- Oct 15, 2008 predicted a '"Common Marketization" of world politics', meaning that a liberal world would be much more preoccupied with.
- www.fpvmv.umb.sk
- Neo-liberalism and Marketisation: the implications for higher education
- that elitism is being reinvigorated as marketisation and commercialisation have taken .
- firgoa.usc.es
- 1 The Impact of Marketisation on UK Voluntary and Community
- www.ncvo-vol.org.uk
Suggested Web Resources
- Marketization - Definition and More from the Free Merriam-Webster
- mar·ket·i·za·tion. noun \ˌmär-kə-tə-ˈzā-shən\. Definition of MARKETIZATION.
- www.merriam-webster.com
- Marketize | Define Marketize at Dictionary.com
- Copy & paste this link to your blog or website to reference this page. Did you know:ADHD doesn't stand for attention deficit disorder. What does the h represent?
- dictionary.reference.com
- definition of marketization from Oxford Dictionaries Online
- marketization: definition, pronunciation, and examples from free Oxford Dictionaries Online. Also marketize.
- oxforddictionaries.com
- New directions in the social studies of market(ization)s
- The second part of the paper presents our definition of economization in general and marketization in particular.
- www.rethinkingeconomies.org.uk
- Marketization Definition | RM.com ®
- Marketization Definition articles, reference materials. Need more on Marketization Definition?
- www.realmagick.com
Great care has been taken to prepare the information on this page. Elements of the content come from factual and lexical knowledge databases, realmagick.com library and third-party sources. We appreciate your suggestions and comments on further improvements of the site.
Marketization Definition Topics
Related searchesyona kosashvili
genuine progress indicator
disgraceful conduct
sauerkraut geographical spread
newsgroup how newsgroups work
polish history
About - Contact - Advertising
© 2000 - 2015 Realmagick.com, All Rights Reserved.
© 2000 - 2015 Realmagick.com, All Rights Reserved.


text:
White fly control
eddy1208June 28, 2013
Hello everyone in wellington.
I had whiteflies in my coconut and guava trees. My coconut trees are young and so they are not that tall.
I spent 100 dollars for all sorts of pesticides including ones that are for systemic control. The whiteflies were killing the leaves.
I found a solution., I am a medical doctor so I happen to know how chemicals work in an animal.
So, after giving serious thoughts, I sprayed all the plants with 5% vinegar with red pepper powder. The vinegar is acid. It will cause acidosis leading to death. The red pepper has capsaicin. It will affect the nerves. 2 days later, there is 0 whitefly in all the plants. Wow/...please try it. Use a pressure sprayer.


text:
Australia's World Cup Celebration
The World Cup After-Party
World Cup: The Winning Moments
World Cup 2015: The Top Stats
BCCI will fight out the injustice meted out to Jadeja: Rajeev Shukla
Hales determined to prove England credentials
Isam: Shakib absence a big blow to Bangladesh
'Dickwella handled mental challenges well'
'China's Outer Lands' - the plight of ethnic minorities in China
Embrace your skin colour. Or not.
What the week has in store for you
Babri demolition: SC notice to Advani, Joshi, Uma Bharti
Deepika launches her short film 'My Choice'