Hanne Villesen - Academia.edu (original) (raw)

Papers by Hanne Villesen

Research paper thumbnail of SQ HDM SLIT-tablet is effective in patients not well-controlled in GINA treatment steps 2-4

European Respiratory Journal, 2016

Research paper thumbnail of Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial

JAMA, Jan 26, 2016

The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel tr... more The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma. To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period. Double-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis. Key exclusion criteria were FEV1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months. 1:1:1 randomization to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [n = 275] or 12 SQ-HDM...

Research paper thumbnail of HDM sublingual AIT tablet is well-tolerated and effective in partly and uncontrolled allergic asthma

European Respiratory Journal, Sep 1, 2014

Research paper thumbnail of Pharmacokinetics of morphine and oxycodone following intravenous administration in elderly patients

Therapeutics and clinical risk management, 2007

An increased and prolonged duration of pain relief after morphine administration has been found i... more An increased and prolonged duration of pain relief after morphine administration has been found in elderly patients. Whether this is due to alterations in pharmacokinetics, receptor binding profile or other factors remains unsolved. The aims were to elucidate the pharmacokinetics after intravenous administration of morphine and oxycodone in elderly patients older than 70 years. A randomized non-blinded study with 16 patients aged older than 70 years scheduled for elective hip replacement receiving morphine or oxycodone 0.05 mg/kg as an IV infusion over 15 minutes. A 2-compartment pharmacokinetic model best described the disposition of morphine and oxycodone. The estimated elimination half-lives for morphine and oxycodone were (mean +/- SD) 2.7 +/- 3.6 (range 0.8-11.6) and 3.1 +/- 1.3 (range 1.1-4.8) hr, respectively. Volume of distribution at steady state was estimated to be 243 +/- 256 and 277 +/- 187 L, and clearance to be 1748 +/- 623 and 1206 +/- 546 ml/min for morphine and oxyc...

Research paper thumbnail of Defining moderate asthma exacerbations in clinicaltrials based on ats/ers joint statement

Respiratory Medicine, 2015

Exacerbations are a key outcome in clinical research, providing patient-relevant information abou... more Exacerbations are a key outcome in clinical research, providing patient-relevant information about symptomatic control, health state and disease progression. Generally considered as an episode of (sub)acute deterioration of respiratory symptoms, a precise, clinically useful definition is needed for use in clinical trials. Focussing on moderate exacerbations, this opinion piece reviews landmark trials and current guidelines to provide a practical definition of a moderate exacerbation. Specifically, we adapt the ATS/ERS consensus statement of terminology Reddel et al. (2009) [1] which provides a conceptual (or 'theoretical') definition for moderate exacerbations, to an operational (or 'practical') criterion suitable for use in clinical research. The proposed definition for a moderate exacerbation requires ≥1 of the following criteria combined with a change in treatment: a) nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights or an increase of ≥0.75 from baseline in daily symptom scores on 2 consecutive days; b) increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase: 4 puffs/day); c) ≥20% decrease in PEF from baseline on at least 2 consecutive mornings/evenings or ≥20% decrease in FEV1 from baseline and/or d) visit to the emergency room/trial site for asthma treatment not requiring systemic corticosteroids. A clinically and patient-relevant, operational definition of moderate exacerbations is needed. The proposed definition has been endorsed by the EMA Scientific Advice Working Party in 2011and needs to be trialled in forthcoming clinical studies.

Research paper thumbnail of Symptoms and side effects in chronic non-cancer pain: patient report vs. systematic assessment

Acta Anaesthesiologica Scandinavica, 2011

relieving distressing symptoms and managing the side effects of analgesics are essential in order... more relieving distressing symptoms and managing the side effects of analgesics are essential in order to improve quality of life and functional capacity in chronic non-cancer pain patients. A quick, reliable and valid tool for assessing symptoms and side effects is needed in order to optimize treatment. We aimed to investigate the symptoms reported by chronic non-cancer pain patients after open-ended questioning vs. a systematic assessment using a list of symptoms, and to assess whether the patients could distinguish between the symptoms and the side effects induced by analgesics. patients treated with either opioids and/or adjuvant analgesics were asked to report their symptoms spontaneously, followed by a 41-item investigator-developed symptom checklist. A control group also filled in the checklist. a total of 62 patients and 64 controls participated in the study. The numbers of symptoms reported by the patients (9.9 ± 5.9) were significantly higher than those reported by the controls (3.2 ± 3.9) (P<0.001). In the patient group, the number of spontaneously reported symptoms (1.3 ± 1.4) was significantly lower than the symptoms reported when using the symptom checklist (9.9 ± 5.9) (P<0.001). The six most frequently symptoms reported by the patients were: (1) Fatigue; (2) Memory deficits; (3) Dry mouth; (4) Concentration deficits; (5) Sweating; and (6) Weight gain. Out of the six most frequently reported symptoms, the share of side effects due to analgesics was: (1) Dry mouth (42%); (2) Sweating (34%); (3) Weight gain (29%); (4) Memory deficits (24%); (5) Fatigue (19%); and (6) Concentration deficits (19%). the number of symptoms reported using systematic assessment was eightfold higher than those reported voluntarily. Fatigue, cognitive dysfunction, dry mouth, sweating and weight gain were the most frequently reported. The patients reported the side effects of their analgesics to contribute substantially to the reported symptoms.

Research paper thumbnail of Pharmacokinetics of M6G following intravenous and oral administration in healthy volunteers

Acute Pain, 2006

... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical ... more ... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical analysis. GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, California, USA) was used for all statistical analyses. ...

Research paper thumbnail of Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

European Journal of Clinical Pharmacology, 2007

Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine... more Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. Methods Twenty-three healthy male volunteers aged 21-40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentrationtime profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM software. Results A three-compartment model best described the plasma concentration-time course. Body weight was found to be a significant covariate for elimination clearance in a linear fash-ion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V 1 , 81.8%), peripheral distribution volume 1 (V 2 , 23.7%) and inter-compartmental clearances between V 1 and V 2 (Q 2 , 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. Conclusion Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the Eur mode of administration should be used in the design of dose regimens of buprenorphine.

Research paper thumbnail of Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

European Journal of Clinical Pharmacology, 2007

Aim After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profi... more Aim After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers. Methods The study was conducted accordingly to a nonblinded, randomised, balanced three-way crossover design in eight healthy male subjects. The subjects received 200 mg oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood samples were collected until 72 h after M6G administration and until 9 h after morphine administration. Paracetamol and sulfasalazine were coadministered with M6G as markers for the gut contents reaching the duodenum and colon, respectively. Results The plasma concentration peaks of M6G were seen at 4.0 (2.0-6.0) and 18 (12.0-24.0) h after 200 mg M6G and at 3.5 (2.0-6.0) and 21.3 (10.0-23.3) h after 50 mg M6G, which was in agreement with previously published results. The K M6G_abs /K M6G_M6G ratio was found to be 10. Conclusion The pharmacokinetic profile of M6G after oral administration was confirmed and with the presence of M3G and morphine in plasma after oral administration of M6G, proof seems to be found of the constant and prolonged absorption of M6G. The K M6G_abs /K M6G_M6G ratio of 10 indicates that the second absorption peak of M6G consists of approximately 10 times more absorbed M6G than reglucuronidated M6G. However, further studies are required to determine the precise kinetics of the second absorption peak.

Research paper thumbnail of 330 Blood: Brain Distribution of M6G in Sheep

European Journal of Pain, 2006

Research paper thumbnail of Blood-brain distribution of morphine-6-glucuronide in sheep

British Journal of Pharmacology, 2006

Background and purpose:At present there are few data regarding the rate and extent of brain–blood... more Background and purpose:At present there are few data regarding the rate and extent of brain–blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep.At present there are few data regarding the rate and extent of brain–blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep.Experimental approach:Five sheep received an intravenous infusion of M6G 2.2 mg kg-1 over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements.Five sheep received an intravenous infusion of M6G 2.2 mg kg-1 over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements.Key results:A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min-1) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2.A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min-1) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2.Conclusion and Implications:Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.British Journal of Pharmacology (2006) 149, 754–760. doi:10.1038/sj.bjp.0706916Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.British Journal of Pharmacology (2006) 149, 754–760. doi:10.1038/sj.bjp.0706916

Research paper thumbnail of Cerebral kinetics of oxycodone in conscious sheep

Journal of Pharmaceutical Sciences, 2006

Oxycodone is an opioid analgesic that is administered orally or parenterally. The time-course of ... more Oxycodone is an opioid analgesic that is administered orally or parenterally. The time-course of opioid action is a function of the systemic kinetics of the opioid, and the rate and extent of its entry into the brain and central nervous system. The latter is incompletely understood for oxycodone. Therefore, the cerebral kinetics of oxycodone was quantified using a conscious chronically instrumented sheep preparation. Five sheep were administered oxycodone as intravenous infusions (30 mg over 4 min). Using hybrid physiologically based kinetic models, cerebral kinetics was estimated from arterio-sagittal sinus concentration gradients and cerebral blood flow (CBF). A two-compartment membrane-limited model best described the data. The volume of the first brain compartment was 35.4 mL with a half-life of equilibrium of 0.6 min. The brain:blood equilibration of oxycodone was relatively slow (half-life of 7.2 min), with a large deep cerebral distribution volume (222.8 mL) for the second compartment and a moderate membrane permeability of 54.8 mL/min, which exceeded the nominal CBF (40 mL/min). Drug retention in the brain was 1.3% after 45 min. In conclusion, pharmacokinetic modelling of oxycodone showed a delayed equilibration between brain and blood of a nature that would be affected by changes in both CBF and blood brain barrier permeability. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1666–1676, 2006

Research paper thumbnail of 330 BLOOD: BRAIN DISTRIBUTION OF M6G IN SHEEP

European Journal of Pain, 2006

Research paper thumbnail of Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

European Journal of Clinical Pharmacology, 2007

Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine... more Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. Methods Twenty-three healthy male volunteers aged 21–40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentration–time profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM software. Results A three-compartment model best described the plasma concentration–time course. Body weight was found to be a significant covariate for elimination clearance in a linear fashion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V1, 81.8%), peripheral distribution volume 1 (V2, 23.7%) and inter-compartmental clearances between V1 and V2 (Q2, 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. Conclusion Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the mode of administration should be used in the design of dose regimens of buprenorphine.

Research paper thumbnail of Pharmacokinetics of M6G following intravenous and oral administration in healthy volunteers

Acute Pain, 2006

... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical ... more ... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical analysis. GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, California, USA) was used for all statistical analyses. ...

Research paper thumbnail of Immunologic Effects and Tolerability Profile of In-Season Initiation of a Standardized-Quality Grass Allergy Immunotherapy Tablet: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial in Adults with Grass Pollen–Induced Rhinoconjunctivitis

Clinical Therapeutics, 2011

The summary of product characteristics of the grass allergy immunotherapy tablet (AIT) (Phleum pr... more The summary of product characteristics of the grass allergy immunotherapy tablet (AIT) (Phleum pratense grass pollen allergen extract) states that clinical effect may be observed in the first pollen season of treatment, if treatment is initiated ≥2 months (8 weeks) before the start of the grass pollen season. However, because patients with grass allergy may first present to physicians during the season, immediate treatment initiation (ie, in-season initiation) may increase treatment compliance and reduce the risk for disease progression compared with asking patients to return before the next pollen season to initiate treatment. This “in-season approach” may offer more patients the potentially beneficial treatment option of specific immunotherapy. However, to date, the immunomodulatory effects and tolerability of in-season treatment initiation is unknown.The aim of this study was to assess the immunologic effects and tolerability of in-season initiation of treatment with the grass AIT.This multicenter, randomized, double-blind, placebo-controlled trial was carried out in Germany and Austria. Adults with grass pollen allergy (positive skin-prick test and specific grass-pollen immunoglobulin [Ig] E) and grass pollen–induced moderate to severe persistent rhinoconjunctivitis were enrolled. Patients were randomly assigned to receive once-daily grass AIT or placebo, starting during the 2008 grass pollen season and continuing for 8 to 10 weeks. The primary end point was change from baseline in IgE-blocking factor (serum components competing with IgE for allergen binding). Secondary end points included changes from baseline in specific IgE and IgG4 and measures of tolerability (assessed mainly by adverse events [AEs]). Blood samples for immunologic assessment were obtained by the investigators at baseline and after treatment. All AEs observed by the investigator and/or reported by the patient were recorded throughout the trial and follow-up.A total of 276 patients were enrolled and formed the full analysis set (mean age, 35 years; 55% men, 45% women; 99% white; mean weight, 76 kg; history of asthma, 41%; mean duration of grass allergy, 15.1 years). No major differences in medical history were found between the grass AIT group (n = 219) and the placebo group (n = 57). The change from baseline in mean concentration of IgE-blocking factor was significantly greater with grass AIT compared with placebo (+0.14 vs +0.05; P < 0.0001). The changes from baseline in specific IgE and specific IgG4 concentrations were significantly greater with AIT compared with placebo (IgE, +0.59 vs +0.21 log kU/L; IgG4, +0.18 vs +0.04 log relative units; both, P < 0.0001). At least 1 AE was reported in 58% of patients in the AIT group and in 40% of patients in the placebo group. Most AEs considered related to AIT were mild or moderate events in the mouth, throat, and/or ears (eg, oral pruritus). Four serious AEs were reported in the AIT group (sinusitis, road traffic accident, salmonellosis, meniscus lesion), but all were considered unlikely to be related to treatment. Three percent of the grass AIT group and 2% of the placebo group were withdrawn from the trial due to an AE.In-season initiation of grass AIT was associated with an immunomodulatory response in terms of induction of IgE-blocking factor, specific IgE, and specific IgG4. In-season initiation of grass AIT was generally well tolerated in this group of adults with moderate to severe grass pollen–induced rhinoconjunctivitis. These findings are consistent with those related to the preseasonal initiation of AIT therapy. ClinicalTrials.gov identifier: NCT00773240.

Research paper thumbnail of SQ HDM SLIT-tablet is effective in patients not well-controlled in GINA treatment steps 2-4

European Respiratory Journal, 2016

Research paper thumbnail of Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial

JAMA, Jan 26, 2016

The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel tr... more The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma. To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period. Double-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis. Key exclusion criteria were FEV1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months. 1:1:1 randomization to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [n = 275] or 12 SQ-HDM...

Research paper thumbnail of HDM sublingual AIT tablet is well-tolerated and effective in partly and uncontrolled allergic asthma

European Respiratory Journal, Sep 1, 2014

Research paper thumbnail of Pharmacokinetics of morphine and oxycodone following intravenous administration in elderly patients

Therapeutics and clinical risk management, 2007

An increased and prolonged duration of pain relief after morphine administration has been found i... more An increased and prolonged duration of pain relief after morphine administration has been found in elderly patients. Whether this is due to alterations in pharmacokinetics, receptor binding profile or other factors remains unsolved. The aims were to elucidate the pharmacokinetics after intravenous administration of morphine and oxycodone in elderly patients older than 70 years. A randomized non-blinded study with 16 patients aged older than 70 years scheduled for elective hip replacement receiving morphine or oxycodone 0.05 mg/kg as an IV infusion over 15 minutes. A 2-compartment pharmacokinetic model best described the disposition of morphine and oxycodone. The estimated elimination half-lives for morphine and oxycodone were (mean +/- SD) 2.7 +/- 3.6 (range 0.8-11.6) and 3.1 +/- 1.3 (range 1.1-4.8) hr, respectively. Volume of distribution at steady state was estimated to be 243 +/- 256 and 277 +/- 187 L, and clearance to be 1748 +/- 623 and 1206 +/- 546 ml/min for morphine and oxyc...

Research paper thumbnail of Defining moderate asthma exacerbations in clinicaltrials based on ats/ers joint statement

Respiratory Medicine, 2015

Exacerbations are a key outcome in clinical research, providing patient-relevant information abou... more Exacerbations are a key outcome in clinical research, providing patient-relevant information about symptomatic control, health state and disease progression. Generally considered as an episode of (sub)acute deterioration of respiratory symptoms, a precise, clinically useful definition is needed for use in clinical trials. Focussing on moderate exacerbations, this opinion piece reviews landmark trials and current guidelines to provide a practical definition of a moderate exacerbation. Specifically, we adapt the ATS/ERS consensus statement of terminology Reddel et al. (2009) [1] which provides a conceptual (or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;theoretical&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;) definition for moderate exacerbations, to an operational (or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;practical&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;) criterion suitable for use in clinical research. The proposed definition for a moderate exacerbation requires ≥1 of the following criteria combined with a change in treatment: a) nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights or an increase of ≥0.75 from baseline in daily symptom scores on 2 consecutive days; b) increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase: 4 puffs/day); c) ≥20% decrease in PEF from baseline on at least 2 consecutive mornings/evenings or ≥20% decrease in FEV1 from baseline and/or d) visit to the emergency room/trial site for asthma treatment not requiring systemic corticosteroids. A clinically and patient-relevant, operational definition of moderate exacerbations is needed. The proposed definition has been endorsed by the EMA Scientific Advice Working Party in 2011and needs to be trialled in forthcoming clinical studies.

Research paper thumbnail of Symptoms and side effects in chronic non-cancer pain: patient report vs. systematic assessment

Acta Anaesthesiologica Scandinavica, 2011

relieving distressing symptoms and managing the side effects of analgesics are essential in order... more relieving distressing symptoms and managing the side effects of analgesics are essential in order to improve quality of life and functional capacity in chronic non-cancer pain patients. A quick, reliable and valid tool for assessing symptoms and side effects is needed in order to optimize treatment. We aimed to investigate the symptoms reported by chronic non-cancer pain patients after open-ended questioning vs. a systematic assessment using a list of symptoms, and to assess whether the patients could distinguish between the symptoms and the side effects induced by analgesics. patients treated with either opioids and/or adjuvant analgesics were asked to report their symptoms spontaneously, followed by a 41-item investigator-developed symptom checklist. A control group also filled in the checklist. a total of 62 patients and 64 controls participated in the study. The numbers of symptoms reported by the patients (9.9 ± 5.9) were significantly higher than those reported by the controls (3.2 ± 3.9) (P&lt;0.001). In the patient group, the number of spontaneously reported symptoms (1.3 ± 1.4) was significantly lower than the symptoms reported when using the symptom checklist (9.9 ± 5.9) (P&lt;0.001). The six most frequently symptoms reported by the patients were: (1) Fatigue; (2) Memory deficits; (3) Dry mouth; (4) Concentration deficits; (5) Sweating; and (6) Weight gain. Out of the six most frequently reported symptoms, the share of side effects due to analgesics was: (1) Dry mouth (42%); (2) Sweating (34%); (3) Weight gain (29%); (4) Memory deficits (24%); (5) Fatigue (19%); and (6) Concentration deficits (19%). the number of symptoms reported using systematic assessment was eightfold higher than those reported voluntarily. Fatigue, cognitive dysfunction, dry mouth, sweating and weight gain were the most frequently reported. The patients reported the side effects of their analgesics to contribute substantially to the reported symptoms.

Research paper thumbnail of Pharmacokinetics of M6G following intravenous and oral administration in healthy volunteers

Acute Pain, 2006

... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical ... more ... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical analysis. GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, California, USA) was used for all statistical analyses. ...

Research paper thumbnail of Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

European Journal of Clinical Pharmacology, 2007

Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine... more Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. Methods Twenty-three healthy male volunteers aged 21-40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentrationtime profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM software. Results A three-compartment model best described the plasma concentration-time course. Body weight was found to be a significant covariate for elimination clearance in a linear fash-ion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V 1 , 81.8%), peripheral distribution volume 1 (V 2 , 23.7%) and inter-compartmental clearances between V 1 and V 2 (Q 2 , 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. Conclusion Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the Eur mode of administration should be used in the design of dose regimens of buprenorphine.

Research paper thumbnail of Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

European Journal of Clinical Pharmacology, 2007

Aim After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profi... more Aim After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers. Methods The study was conducted accordingly to a nonblinded, randomised, balanced three-way crossover design in eight healthy male subjects. The subjects received 200 mg oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood samples were collected until 72 h after M6G administration and until 9 h after morphine administration. Paracetamol and sulfasalazine were coadministered with M6G as markers for the gut contents reaching the duodenum and colon, respectively. Results The plasma concentration peaks of M6G were seen at 4.0 (2.0-6.0) and 18 (12.0-24.0) h after 200 mg M6G and at 3.5 (2.0-6.0) and 21.3 (10.0-23.3) h after 50 mg M6G, which was in agreement with previously published results. The K M6G_abs /K M6G_M6G ratio was found to be 10. Conclusion The pharmacokinetic profile of M6G after oral administration was confirmed and with the presence of M3G and morphine in plasma after oral administration of M6G, proof seems to be found of the constant and prolonged absorption of M6G. The K M6G_abs /K M6G_M6G ratio of 10 indicates that the second absorption peak of M6G consists of approximately 10 times more absorbed M6G than reglucuronidated M6G. However, further studies are required to determine the precise kinetics of the second absorption peak.

Research paper thumbnail of 330 Blood: Brain Distribution of M6G in Sheep

European Journal of Pain, 2006

Research paper thumbnail of Blood-brain distribution of morphine-6-glucuronide in sheep

British Journal of Pharmacology, 2006

Background and purpose:At present there are few data regarding the rate and extent of brain–blood... more Background and purpose:At present there are few data regarding the rate and extent of brain–blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep.At present there are few data regarding the rate and extent of brain–blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep.Experimental approach:Five sheep received an intravenous infusion of M6G 2.2 mg kg-1 over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements.Five sheep received an intravenous infusion of M6G 2.2 mg kg-1 over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements.Key results:A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min-1) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2.A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min-1) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2.Conclusion and Implications:Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.British Journal of Pharmacology (2006) 149, 754–760. doi:10.1038/sj.bjp.0706916Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.British Journal of Pharmacology (2006) 149, 754–760. doi:10.1038/sj.bjp.0706916

Research paper thumbnail of Cerebral kinetics of oxycodone in conscious sheep

Journal of Pharmaceutical Sciences, 2006

Oxycodone is an opioid analgesic that is administered orally or parenterally. The time-course of ... more Oxycodone is an opioid analgesic that is administered orally or parenterally. The time-course of opioid action is a function of the systemic kinetics of the opioid, and the rate and extent of its entry into the brain and central nervous system. The latter is incompletely understood for oxycodone. Therefore, the cerebral kinetics of oxycodone was quantified using a conscious chronically instrumented sheep preparation. Five sheep were administered oxycodone as intravenous infusions (30 mg over 4 min). Using hybrid physiologically based kinetic models, cerebral kinetics was estimated from arterio-sagittal sinus concentration gradients and cerebral blood flow (CBF). A two-compartment membrane-limited model best described the data. The volume of the first brain compartment was 35.4 mL with a half-life of equilibrium of 0.6 min. The brain:blood equilibration of oxycodone was relatively slow (half-life of 7.2 min), with a large deep cerebral distribution volume (222.8 mL) for the second compartment and a moderate membrane permeability of 54.8 mL/min, which exceeded the nominal CBF (40 mL/min). Drug retention in the brain was 1.3% after 45 min. In conclusion, pharmacokinetic modelling of oxycodone showed a delayed equilibration between brain and blood of a nature that would be affected by changes in both CBF and blood brain barrier permeability. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1666–1676, 2006

Research paper thumbnail of 330 BLOOD: BRAIN DISTRIBUTION OF M6G IN SHEEP

European Journal of Pain, 2006

Research paper thumbnail of Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

European Journal of Clinical Pharmacology, 2007

Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine... more Objective The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. Methods Twenty-three healthy male volunteers aged 21–40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentration–time profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM software. Results A three-compartment model best described the plasma concentration–time course. Body weight was found to be a significant covariate for elimination clearance in a linear fashion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V1, 81.8%), peripheral distribution volume 1 (V2, 23.7%) and inter-compartmental clearances between V1 and V2 (Q2, 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. Conclusion Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the mode of administration should be used in the design of dose regimens of buprenorphine.

Research paper thumbnail of Pharmacokinetics of M6G following intravenous and oral administration in healthy volunteers

Acute Pain, 2006

... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical ... more ... volunteers. Based on the bioavailability found by Penson et al. ... dose. 2.6.3. Statistical analysis. GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, California, USA) was used for all statistical analyses. ...

Research paper thumbnail of Immunologic Effects and Tolerability Profile of In-Season Initiation of a Standardized-Quality Grass Allergy Immunotherapy Tablet: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial in Adults with Grass Pollen–Induced Rhinoconjunctivitis

Clinical Therapeutics, 2011

The summary of product characteristics of the grass allergy immunotherapy tablet (AIT) (Phleum pr... more The summary of product characteristics of the grass allergy immunotherapy tablet (AIT) (Phleum pratense grass pollen allergen extract) states that clinical effect may be observed in the first pollen season of treatment, if treatment is initiated ≥2 months (8 weeks) before the start of the grass pollen season. However, because patients with grass allergy may first present to physicians during the season, immediate treatment initiation (ie, in-season initiation) may increase treatment compliance and reduce the risk for disease progression compared with asking patients to return before the next pollen season to initiate treatment. This “in-season approach” may offer more patients the potentially beneficial treatment option of specific immunotherapy. However, to date, the immunomodulatory effects and tolerability of in-season treatment initiation is unknown.The aim of this study was to assess the immunologic effects and tolerability of in-season initiation of treatment with the grass AIT.This multicenter, randomized, double-blind, placebo-controlled trial was carried out in Germany and Austria. Adults with grass pollen allergy (positive skin-prick test and specific grass-pollen immunoglobulin [Ig] E) and grass pollen–induced moderate to severe persistent rhinoconjunctivitis were enrolled. Patients were randomly assigned to receive once-daily grass AIT or placebo, starting during the 2008 grass pollen season and continuing for 8 to 10 weeks. The primary end point was change from baseline in IgE-blocking factor (serum components competing with IgE for allergen binding). Secondary end points included changes from baseline in specific IgE and IgG4 and measures of tolerability (assessed mainly by adverse events [AEs]). Blood samples for immunologic assessment were obtained by the investigators at baseline and after treatment. All AEs observed by the investigator and/or reported by the patient were recorded throughout the trial and follow-up.A total of 276 patients were enrolled and formed the full analysis set (mean age, 35 years; 55% men, 45% women; 99% white; mean weight, 76 kg; history of asthma, 41%; mean duration of grass allergy, 15.1 years). No major differences in medical history were found between the grass AIT group (n = 219) and the placebo group (n = 57). The change from baseline in mean concentration of IgE-blocking factor was significantly greater with grass AIT compared with placebo (+0.14 vs +0.05; P < 0.0001). The changes from baseline in specific IgE and specific IgG4 concentrations were significantly greater with AIT compared with placebo (IgE, +0.59 vs +0.21 log kU/L; IgG4, +0.18 vs +0.04 log relative units; both, P < 0.0001). At least 1 AE was reported in 58% of patients in the AIT group and in 40% of patients in the placebo group. Most AEs considered related to AIT were mild or moderate events in the mouth, throat, and/or ears (eg, oral pruritus). Four serious AEs were reported in the AIT group (sinusitis, road traffic accident, salmonellosis, meniscus lesion), but all were considered unlikely to be related to treatment. Three percent of the grass AIT group and 2% of the placebo group were withdrawn from the trial due to an AE.In-season initiation of grass AIT was associated with an immunomodulatory response in terms of induction of IgE-blocking factor, specific IgE, and specific IgG4. In-season initiation of grass AIT was generally well tolerated in this group of adults with moderate to severe grass pollen–induced rhinoconjunctivitis. These findings are consistent with those related to the preseasonal initiation of AIT therapy. ClinicalTrials.gov identifier: NCT00773240.