Publications by authors named "Stefano Milleri"

18 Publications

  • Page 1 of 1

A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial.

Ther Adv Med Oncol 2020 4;12:1758835920947969. Epub 2020 Sep 4.

Digestive Molecular Clinical Oncology Unit, Section of Medical Oncology, Department of Medicine, University of Verona, AOUI Verona - Policlinico "G.B. Rossi", Piazzale L.A. Scuro, 10, Verona 37134, Italy.

Background: Up-front surgery followed by postoperative chemotherapy remains the standard paradigm for the treatment of patients with resectable pancreatic cancer. However, the risk for positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the common metastatic relapse limit the overall clinical outcomes achieved with this strategy. Polychemotherapeutic combinations are valid options for postoperative treatment in patients with good performance status. liposomal irinotecan (Nal-IRI) is a novel nanoliposome formulation of irinotecan that accumulates in tumor-associated macrophages improving the therapeutic index of irinotecan and has been approved for the treatment of patients with metastatic pancreatic cancer after progression under gemcitabine-based therapy. Thus, it remains of the outmost urgency to investigate introduction of the most novel agents, such as nal-IRI, in perioperative approaches aimed at increasing the long-term effectiveness of surgery.

Methods: The nITRO trial is a phase II, single-arm, open-label study to assess the safety and the activity of nal-IRI with fluorouracil/leucovorin (5-FU/LV) and oxaliplatin in the perioperative treatment of patients with resectable pancreatic cancer. The primary tumor must be resectable with no involvement of the major arteries and no involvement or <180° interface between tumor and vessel wall of the major veins. A total of 72 patients will be enrolled to receive a perioperative treatment of three cycles before and three cycles after surgical resection with nal-IRI 50 mg/m, oxaliplatin 60 mg/m, leucovorin 200 mg/m, and 5-fluorouracil 2400 mg/m2, days 1 and 15 of a 28-day cycle. The primary objective is to improve from 40% to 55% the proportion of patients achieving R0 resection after preoperative treatment.

Discussion: The nITRO trial will contribute to strengthen the clinical evidence supporting perioperative strategies in resectable pancreatic cancer patients. Moreover, this study represents a unique opportunity for translational analyses aimed to identify novel immune-related prognostic and predictive factors in this setting.

Trial Registration: Clinicaltrial.gov: NCT03528785. Trial registration data: 1 January 2018Protocol number: CRC 2017_01EudraCT Number: 2017-000345-46.
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http://dx.doi.org/10.1177/1758835920947969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745557PMC
September 2020

A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial.

Ther Adv Med Oncol 2020 4;12:1758835920947969. Epub 2020 Sep 4.

Digestive Molecular Clinical Oncology Unit, Section of Medical Oncology, Department of Medicine, University of Verona, AOUI Verona - Policlinico "G.B. Rossi", Piazzale L.A. Scuro, 10, Verona 37134, Italy.

Background: Up-front surgery followed by postoperative chemotherapy remains the standard paradigm for the treatment of patients with resectable pancreatic cancer. However, the risk for positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the common metastatic relapse limit the overall clinical outcomes achieved with this strategy. Polychemotherapeutic combinations are valid options for postoperative treatment in patients with good performance status. liposomal irinotecan (Nal-IRI) is a novel nanoliposome formulation of irinotecan that accumulates in tumor-associated macrophages improving the therapeutic index of irinotecan and has been approved for the treatment of patients with metastatic pancreatic cancer after progression under gemcitabine-based therapy. Thus, it remains of the outmost urgency to investigate introduction of the most novel agents, such as nal-IRI, in perioperative approaches aimed at increasing the long-term effectiveness of surgery.

Methods: The nITRO trial is a phase II, single-arm, open-label study to assess the safety and the activity of nal-IRI with fluorouracil/leucovorin (5-FU/LV) and oxaliplatin in the perioperative treatment of patients with resectable pancreatic cancer. The primary tumor must be resectable with no involvement of the major arteries and no involvement or <180° interface between tumor and vessel wall of the major veins. A total of 72 patients will be enrolled to receive a perioperative treatment of three cycles before and three cycles after surgical resection with nal-IRI 50 mg/m, oxaliplatin 60 mg/m, leucovorin 200 mg/m, and 5-fluorouracil 2400 mg/m2, days 1 and 15 of a 28-day cycle. The primary objective is to improve from 40% to 55% the proportion of patients achieving R0 resection after preoperative treatment.

Discussion: The nITRO trial will contribute to strengthen the clinical evidence supporting perioperative strategies in resectable pancreatic cancer patients. Moreover, this study represents a unique opportunity for translational analyses aimed to identify novel immune-related prognostic and predictive factors in this setting.

Trial Registration: Clinicaltrial.gov: NCT03528785. Trial registration data: 1 January 2018Protocol number: CRC 2017_01EudraCT Number: 2017-000345-46.
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http://dx.doi.org/10.1177/1758835920947969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745557PMC
September 2020

A phase II trial of the FGFR inhibitor pemigatinib in patients with metastatic esophageal-gastric junction/gastric cancer trastuzumab resistant: the FiGhTeR trial.

Ther Adv Med Oncol 2020 7;12:1758835920937889. Epub 2020 Jul 7.

Digestive Molecular Clinical Oncology unit, Section of Medical Oncology, Department of Medicine, University of Verona, AOUI Verona - Policlinico "G.B. Rossi", Piazzale L.A. Scuro,10, Verona, 37134, Italy.

Background: Prognosis of patients affected by metastatic esophageal-gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3.

Methods: The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib.

Discussion: Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance.

Protocol Number: CRC2017_02.

Eudract Number: 2017-004522-14.
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http://dx.doi.org/10.1177/1758835920937889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346700PMC
July 2020

Pharmacokinetics of Oral Cholecalciferol in Healthy Subjects with Vitamin D Deficiency: A Randomized Open-Label Study.

Nutrients 2020 May 27;12(6). Epub 2020 May 27.

Rheumatology Unit, University of Verona, 37131 Verona, Italy.

Background: the aim of this study was to investigate the pharmacokinetic (PK) and safety profile of high-dose vitamin D supplementation, comparing different schedules (daily, weekly, or bi-weekly) in an otherwise healthy vitamin D-deficient population. Methods single-center, open-label study on healthy subjects deficient in vitamin D (25 (OH)D < 20 ng/mL), randomized to receive cholecalciferol (DIBASE, Abiogen Pharma, Italy) using three different schedules: Group A: 10,000 IU/day for eight weeks followed by 1000 IU/day for four weeks; Group B: 50,000 IU/week for 12 weeks, Group C: 100,000 IU/every other week for 12 weeks. Total cumulative doses were: 588,000 IU, 600,000 IU, 600,000 IU. The treatment regimens corresponded to the highest doses allowed for cholecalciferol for the correction of vitamin D deficiency in adults in Italy.

Results: mean 25 (OH)D plasma levels significantly increased from baseline 13.5 ± 3.7 ng/mL to peak values of 81.0 ± 15.0 ng/mL in Group A, 63.6 ± 7.9 ng/mL in Group B and 59.4 ± 12 ng/mL in Group C. On day 28, all subjects showed 25 (OH)D levels ≥ 20 ng/mL and 93.1% had 25 (OH)D levels ≥ 30 ng/mL. On day 56 and 84, all subjects had 25 (OH)D levels ≥ 30 ng/mL. No serious adverse events occurred during the study.

Conclusions: normalization of 25 (OH)D serum levels was quickly attained with all the studied regimens. A more refracted schedule provided a higher systemic 25 (OH)D exposure.
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http://dx.doi.org/10.3390/nu12061553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352201PMC
May 2020

Effect of a multistrain probiotic (Lactoflorene Plus) on inflammatory parameters and microbiota composition in subjects with stress-related symptoms.

Neurobiol Stress 2019 Feb 7;10:100138. Epub 2018 Nov 7.

Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, P.le Golgi 2, 27100, Pavia, Italy.

Stress affects the immune system and intestinal microbiota composition and can lead to imbalance between pro- and anti-inflammatory cytokines or to uncontrolled production of cytokines. The effect of emotional stress on secretory IgA levels also indicates that stress decreases mucosal integrity. Our aim was to evaluate whether a probiotic product (Lactoflorene Plus) can prevent alterations in the immune response associated with self-reported stress and microbiota composition. Healthy adult volunteers who self-reported psychological stress were enrolled and randomised into a placebo and a probiotic group. Salivary stress markers (α-amylase, cortisol, chromogranin A) and immunological parameters (sIgA, NK cell activity, IL-8, IL-10, TNF-α) in feces and the composition of intestinal microbiota were evaluated. Administration of the product did not exert a direct effect on the salivary stress markers or NK cell activity but did reduce abdominal pain and increase faecal IgA and IL-10 levels. The probiotic product induced a moderate increase in and spp., as expected, and in spp., and decreased the size of the spp. and and populations. Administration of the product helped protect the mucosal barrier by supporting the number of short-chain fatty acid producers and decreasing the load of potentially harmful bacteria, thus reducing intestinal inflammation and abdominal discomfort.

Clinicaltrialsgov: NCT03234452.
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http://dx.doi.org/10.1016/j.ynstr.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430185PMC
February 2019

Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study).

BMJ Open 2019 02 19;9(2):e023715. Epub 2019 Feb 19.

University of L'Aquila, L'Aquila, Italy.

Objectives: To compare efficacy/safety of oral tramadol 75 mg/dexketoprofen 25 mg (TRAM/DKP) and TRAM 75 mg/paracetamol 650 mg (TRAM/paracetamol) in moderate to severe pain following surgical removal of impacted lower third molar.

Design: Multicentre, randomised, double-blind, placebo-controlled, phase IIIb study.

Participants: Healthy adult patients scheduled for surgical extraction of at least one fully/partially impacted lower third molar requiring bone manipulation. 654 patients were randomised and 653 were eligible for analysis.

Interventions: Surgery was performed under local anaesthetic. No sedation was permitted. Patients rated pain intensity (PI) using an 11-Numerical Rating Scale (NRS) (0 no pain; 10 worst pain). Participants experiencing moderate/severe pain (≥4) within 4 hours of surgery were randomised (2:2:1 ratio) to a single oral dose of TRAM/DKP 75/25 mg, TRAM/paracetamol 75/650 mg or placebo.

Main Outcome Measures: Efficacy was based patients' electronic diaries. Analgesia and pain were recorded as follows: pain relief (PAR) on a 5-point Verbal Rating Scale (0='no relief', 1='a little (perceptible) relief', 2='some (meaningful) relief', 3='lot of relief', 4='complete relief') at the predefined postdose time points t15 min, t30 min, t1 hour, t1.5 hour, t2 hour, t4 hour, t6 hour and t8 hour and PI on the 11-point NRS at t0 and at the same predefined postdose time points. Onset of analgesia documented using double stopwatch method over a 2-hour period. Primary endpoint was total pain relief over 6 hours (TOTPAR6). Rescue medication was available during the treatment period.

Results: TRAM/DKP was superior to TRAM/paracetamol and placebo at the primary endpoint TOTPAR6 (p<0.0001). Mean (SD) TOTPAR6 in the TRAM/DKP group was 13 (6.97), while those in the active control and placebo groups were 9.2 (7.65) and 1.9 (3.89), respectively. Superiority of TRAM/DKP over active comparator and placebo was observed at all secondary endpoints. Incidence of adverse events was comparable between active groups.

Conclusions: TRAM/DKP (75/25 mg) is effective and superior to TRAM/paracetamol (75/650 mg) in relieving moderate to severe acute pain following surgical removal of impacted lower third molar, with a faster onset of action, greater and durable analgesia, together with a favourable safety profile.

Trial Registration Number: EudraCT 2015-004152-22 and NCT02777970.
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http://dx.doi.org/10.1136/bmjopen-2018-023715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377526PMC
February 2019

Stress and Immune Function: There is a Role for the Gut Microbiota?

J Clin Gastroenterol 2018 Nov/Dec;52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017:S66-S67

Department of Pediatrics, IRCCS Policlinico San Matteo Foundation, Pavia.

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http://dx.doi.org/10.1097/MCG.0000000000001056DOI Listing
October 2019

Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial.

PLoS One 2014 19;9(5):e97803. Epub 2014 May 19.

Oncology Translational Medicine, Novartis Basel, Switzerland.

Unlabelled: The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS.

Trial Registration: ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097803PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026380PMC
January 2015

Anxiolytic effects of vestipitant in a sub-group of healthy volunteers known to be sensitive to CO2 challenge.

J Psychopharmacol 2014 May 9;28(5):491-7. Epub 2013 Oct 9.

1Department of Neuroscience, University of Padova, Italy.

The pharmacological properties of two NK1 antagonists were studied in comparison with a benzodiazepine during a 7% CO2 challenge in a population of healthy volunteers selected for a high sensitivity to the challenge. In total, 19 healthy subjects, pre-screened for their responsiveness to the 7% CO2 test, took part in the randomised, double-blind, cross-over, incomplete block design study. After receiving treatment or placebo, the volunteers were subjected to three 7% CO2 challenges each for a time of 20 min. The treatment consisted of the administration of the following three active drugs: a single dose of benzodiazepine alprazolam (0.75 mg) and a single dose of the NK1 antagonists vestipitant (GW597599) (15 mg) and vofopitant (GR205171) (25 mg). Anxiety during the challenge was evaluated with Visual Analogue Scale-Anxiety (VAS-A) and with Panic Symptom List (PSL III-R). Respiratory parameters, heart rate and skin conductance were also recorded. Compared with placebo, vestipitant showed a significant reduction (p<0.05) in anxiety assessed on the VAS-A scale (ΔVAS-A%) while alprazolam significantly (p<0.01) attenuated the PSL III-R total score. Vofopitant did not show any anxiolytic effect. In the comparison analysis between placebo and drugs, none of the respiratory and other physiological parameters showed a statistically significant difference.
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http://dx.doi.org/10.1177/0269881113507641DOI Listing
May 2014

Changes in neuroactive steroid secretion associated with CO2-induced panic attacks in normal individuals.

Psychoneuroendocrinology 2013 Oct 20;38(10):2234-42. Epub 2013 May 20.

Department of Psychiatry, Sacco Hospital, Milano 20157, Italy. Electronic address:

Neuroactive steroids modulate anxiety in experimental animals and possibly in humans. The secretion of these compounds has been found to be altered in panic disorder (PD), with such alterations having been suggested to be a possible cause or effect of panic symptomatology. Panic-like attacks can be induced in healthy individuals by administration of panicogenic agents or by physical procedures, and we have now measured the plasma concentrations of neuroactive steroids in such individuals before, during, and after panicogenic inhalation of CO2 in order to investigate whether abnormalities of neuroactive steroid secretion might contribute to the pathogenesis of PD. Fifty-nine psychologically and physically healthy subjects, including 42 women (11 in the follicular phase of the menstrual cycle, 14 in the luteal phase, and 17 taking contraceptive pills) and 17 men, who experienced a panic-like attack on previous exposure to 7% CO2 were again administered 7% CO2 for 20min. Thirty-three of these individuals (responders) again experienced a panic-like attack, whereas the remaining 26 subjects did not (nonresponders). All subjects were examined with the VAS-A and PSL-III-R scales for anxiety and panic symptomatology before and after CO2 inhalation. The plasma concentrations of progesterone, 3α,5α-tetrahydroprogesterone (3α,5α-THPROG=allopregnanolone), 3α,5α-tetrahydrodesoxycorticosterone (3α,5α-THDOC), dehydroepiandrosterone (DHEA), and cortisol were measured 15min and immediately before the onset of CO2 administration as well as immediately, 10, 30, and 50min after the end of CO2 inhalation. Neuroactive steroids were measured in the laboratory of Prof. Biggio in Cagliari, Sardinia, Italy. Neurosteroid levels did not change significantly in both responders and nonresponders before, during, or after CO2 inhalation. These data suggest that neuroactive steroid concentrations before, during, or after CO2 inhalation do not seem to correlate with panic symptomatology during panic-like attacks in subjects not affected by PD, and they therefore do not support the notion that abnormalities in neuroactive steroid secretion are either a cause or an effect of such attacks.
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http://dx.doi.org/10.1016/j.psyneuen.2013.04.008DOI Listing
October 2013

A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction.

Clin J Pain 2011 Oct;27(8):668-76

Neurology Discovery Medicine Unit, GlaxoSmithKline R&D, Harlow, UK.

Objectives: To evaluate the postoperative analgesic efficacy of GW842166, a noncannabinoid CB2 agonist, in patients undergoing third molar tooth extraction.

Methods: This randomized, double-blind, placebo-controlled study compared the analgesic efficacy of single doses of GW842166 (100 or 800 mg) or ibuprofen with placebo in patients undergoing extraction of at least 1 fully or partially impacted third molar tooth. Eligible participants were dosed preoperatively within 1 hour of surgery. Participants allocated to active comparator received a second dose of ibuprofen (400 mg), 4 hours after the first 800 mg dose. Participants in the GW842166 and placebo groups received placebo at 4 hours. Procedures for the assessment of efficacy included a visual analog scale and verbal rating scale for scoring pain up to 10 hours postsurgery, duration of analgesia, patient global evaluation, proportion of patients requiring rescue medication, and elapsed time to rescue analgesia. Analysis of covariance was used to compare efficacy variables. Patient global evaluation was analyzed using Wilcoxon rank-sum tests and time to data was analyzed using the log-rank test.

Results: Ibuprofen was significantly more effective than placebo across all endpoints. Trends for an improvement in pain scores for GW842166 800 mg failed to be of either clinical or statistical significance. GW842166 100 mg showed little separation from placebo. There was no evidence for any beneficial adjunctive effect after coadministration of rescue analgesia with GW842166. All treatments were well tolerated.

Discussion: In comparison to ibuprofen, single doses of GW842166 (100 and 800 mg) failed to demonstrate clinically meaningful analgesia in the setting of acute dental pain.
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http://dx.doi.org/10.1097/AJP.0b013e318219799aDOI Listing
October 2011

A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction.

Clin J Pain 2011 Oct;27(8):668-76

Neurology Discovery Medicine Unit, GlaxoSmithKline R&D, Harlow, UK.

Objectives: To evaluate the postoperative analgesic efficacy of GW842166, a noncannabinoid CB2 agonist, in patients undergoing third molar tooth extraction.

Methods: This randomized, double-blind, placebo-controlled study compared the analgesic efficacy of single doses of GW842166 (100 or 800 mg) or ibuprofen with placebo in patients undergoing extraction of at least 1 fully or partially impacted third molar tooth. Eligible participants were dosed preoperatively within 1 hour of surgery. Participants allocated to active comparator received a second dose of ibuprofen (400 mg), 4 hours after the first 800 mg dose. Participants in the GW842166 and placebo groups received placebo at 4 hours. Procedures for the assessment of efficacy included a visual analog scale and verbal rating scale for scoring pain up to 10 hours postsurgery, duration of analgesia, patient global evaluation, proportion of patients requiring rescue medication, and elapsed time to rescue analgesia. Analysis of covariance was used to compare efficacy variables. Patient global evaluation was analyzed using Wilcoxon rank-sum tests and time to data was analyzed using the log-rank test.

Results: Ibuprofen was significantly more effective than placebo across all endpoints. Trends for an improvement in pain scores for GW842166 800 mg failed to be of either clinical or statistical significance. GW842166 100 mg showed little separation from placebo. There was no evidence for any beneficial adjunctive effect after coadministration of rescue analgesia with GW842166. All treatments were well tolerated.

Discussion: In comparison to ibuprofen, single doses of GW842166 (100 and 800 mg) failed to demonstrate clinically meaningful analgesia in the setting of acute dental pain.
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http://dx.doi.org/10.1097/AJP.0b013e318219799aDOI Listing
October 2011

Characterization of a 7% carbon dioxide (CO2) inhalation paradigm to evoke anxiety symptoms in healthy subjects.

J Psychopharmacol 2005 Sep;19(5):494-503

Psychiatry Centre of Excellence for Drug Discovery, Medical Research Centre, GlaxoSmithKline, Verona, Italy.

The present study is aimed at characterizing the carbon dioxide (CO2) procedure in healthy subjects to achieve reliable provocation of anxiety symptoms. Thirty healthy subjects inhaled in single-blind both compressed air and 7% CO2 mixture. Panic Symptom List (PSLIII-R), Visual Analogue Scale-Anxiety (VAS-A), State Anxiety Inventory (STAI-Y/1), respiratory parameters and skin conductance were measured. 'Responders' were classified depending on PSLIII-R scores after CO2. Twelve out of the 21 'responders' performed a second test to assess test-retest repeatability. In 21 subjects Delta%VAS-A (45.4 +/- 32.1) and PSLIII-R (pre-test 2.3 +/-2.1, post-test 17.5 +/- 8.2) but not STAI-Y/1, significantly increased during CO2 inhalation. Respiratory Rate, Minute Volume, end-Tidal CO2 and skin conductance rose in 'responders'. Repeatability was studied with Bland-Altman plots, revealing mean difference between tests close to 0 for both Delta%VAS-A and PSLIII-R. Among physiologic parameters, end-Tidal CO2 and Respiratory Rate showed good repeatability, with a within-subject CV of 9.2% and 6%, respectively. The challenge produced measurable response in healthy subjects. Good test-retest repeatability was observed in 'responders'. These data indicate that the test can be suitable for testing putative anti-panic or anxiolytic drugs in clinical studies using a within subject, crossover design.
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http://dx.doi.org/10.1177/0269881105056533DOI Listing
September 2005

Effect of sustained-release (SR) bupropion on craving and withdrawal in smokers deprived of cigarettes for 72 h.

Psychopharmacology (Berl) 2005 Nov 22;183(1):1-12. Epub 2005 Oct 22.

GlaxoSmithKline, Via A. Fleming N 4, Verona 37135, Italy.

Rationale: Sustained-release (SR) bupropion enhances quit rates of smokers, generally decreases tobacco withdrawal, and in some studies, reduces craving.

Objective: Investigate the effects of SR bupropion on craving and withdrawal during cigarette abstinence.

Methods: Twenty three smokers participated in three 17-day periods composed of 14 out-patient days followed by 3 (72 h) in-patient days. During the out-patient days, subjects received SR bupropion, placebo, or no drug. During the in-patient days, subjects were abstinent from cigarettes on two occasions while receiving either SR bupropion or placebo and smoked freely during the other occasion. SR bupropion was titrated over the first three out-patient days followed by a fixed dose (300 mg/day) for 14 days (including the three in-patient abstinence days). Cigarette craving, withdrawal, and selected physiological measures were assessed repeatedly over the 72-h periods.

Results: During the 72-h periods, craving intensity was significantly lower with free smoke and SR bupropion than with placebo, and significantly lower during free smoke than during SR bupropion. Overall withdrawal symptoms were significantly lower with free smoke than with either placebo or SR bupropion. Among individual withdrawal symptoms (excluding craving), appetite increase was significantly reduced during SR bupropion compared to placebo. During placebo and SR bupropion, craving intensity displayed a circadian pattern that was different from that observed during free smoke.

Conclusions: SR bupropion reduced craving and appetite increase during smoking abstinence. These findings support the hypothesis that craving and withdrawal symptoms may be controlled by distinct central nervous system pathways.
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http://dx.doi.org/10.1007/s00213-005-0145-xDOI Listing
November 2005

EEG power spectra and auditory P300 during free smoking and enforced smoking abstinence.

Pharmacol Biochem Behav 2004 Jan;77(1):103-9

Discovery Medicine, GlaxoSmithKline SpA, Via Fleming 4, 37135, Verona, Italy.

We investigated resting EEG and auditory P300 during free smoking and 36 h of enforced smoking abstinence in 12 healthy volunteers. Resting EEG was recorded on 19 scalp leads and auditory P300 was obtained by an oddball paradigm task. Spectral analysis of EEG (absolute and relative power, mean frequency), latency and amplitude of auditory P300 were considered for statistical analysis. EEG changes were not significant during free smoking but were significant during smoking abstinence. Theta absolute power increased by +57% (P<.001), whereas alpha and delta absolute power increased by +26% (P<.01) and +19% (P<.01), respectively; theta absolute power change was delayed and prolonged. Alpha mean frequency reduced by -0.31 Hz (P<.001), whereas delta, theta and beta1 mean frequency increased by +0.13 Hz (P<.05), +0.09 Hz (P<.05) and +0.23 Hz (P<.01), respectively. Auditory P300 amplitude and latency were unaffected by smoking abstinence. Resting EEG, but not auditory P300, was sufficiently sensitive to detect changes during enforced smoking abstinence, and EEG bands had different temporal changes.
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http://dx.doi.org/10.1016/j.pbb.2003.10.002DOI Listing
January 2004

Dose linearity of lacidipine pharmacokinetics after single and repeated oral doses in healthy volunteers.

Clin Pharmacokinet 2003 ;42(1):99-106

GlaxoSmithKline Medicine Research Center, Verona, Italy.

Objective: To assess the dose proportionality of lacidipine after single and repeated oral doses, and to obtain new information on the pharmacokinetics of the compound since improvement of the plasma assay method.

Design: Open, randomised, four-way cross-over trial.

Participants: 24 healthy male and female volunteers, aged 18-46 years.

Methods: Lacidipine was administered as single doses of 2, 4, 6 and 8 mg, and as multiple doses of 2, 4 and 6 mg for 8 days. Pharmacokinetic evaluations were performed on study days 1 and 8. Plasma concentrations of lacidipine were determined by a validated high-performance liquid chromatography-radioimmunoassay method. The ratios of dose-normalised peak plasma concentration (C(max)) and area under the concentration-time curve (AUC) were calculated and then compared across dose groups by analysis of variance to assess dose linearity against a 4 mg reference dose. A power model was also applied as an alternative method for the evaluation of linearity.

Results: After repeated 2, 4 and 6 mg doses of lacidipine, geometric least square mean values (95% CI) were 1.76 (1.46-2.12), 3.56 (2.96-4.29) and 5.23 (4.34--6.30) microg/L for C(max) and 5.29 (4.57-6.11), 11.42 (9.87-13.20) and 17.55 (15.18-20.29) microg x h/L for AUC over the administration interval at steady state (AUC(tau)), respectively. Mean half-life ranged between 13.2 hours and 18.7 hours. Precision of these estimates was limited by the small number of sampling timepoints collected in the final part of the curve. After administration of single doses, no statistically significant deviation from linearity was found except for the 8 mg dose, but a trend of greater than proportional exposure was evident with increasing dose. Following repeated administration, dose linearity over the therapeutic range was observed. No statistically significant difference was observed between AUC to infinity (AUC( infinity)) on day 1 and AUC(tau) on day 8, suggesting time-invariance of pharmacokinetics.

Conclusions: Lacidipine exhibited linear kinetics after repeated doses in the therapeutic range of 2-6 mg once daily. The two different methodologies for assessing linearity gave consistent results. Only the single 8 mg dose, which is outside the recommended therapeutic range, resulted in greater than predicted exposure. After low doses, the analytical method still does not allow complete characterisation of kinetics. Time-invariance of lacidipine kinetics is suggested.
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http://dx.doi.org/10.2165/00003088-200342010-00004DOI Listing
April 2003

Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal.

Psychopharmacology (Berl) 2002 Nov 27;164(2):177-87. Epub 2002 Aug 27.

GlaxoSmithKline SpA, Medicine Research Centre, Via A. Fleming N 4, 37135 Verona, Italy.

Rationale: Research on the effects of nicotine abstinence and nicotine replacement has not provided consistent information about the impact of replacement therapies on tobacco withdrawal and craving.

Objective: . This study investigated craving and withdrawal symptoms over a 72-h period of abstinence from cigarettes.

Methods: . Twenty-four healthy volunteers, not intending to quit smoking, were housed in an experimental unit during three 72-h conditions, consisting of either free smoking, enforced smoking cessation with nicotine replacement therapy (NRT) patches, or enforced smoking cessation with placebo patches. The conditions were adhered to using a randomized crossover design, each separated by at least 10 days of washout. Patches, administered in a double-blind fashion, were given as nicotine (21 mg/24 h) and placebo every 24 h. Self-reported cigarette craving and withdrawal were assessed using multi-item scales at fixed intervals over each condition period. Urinary and plasma cortisol levels were also assayed at fixed intervals over each period.

Results: Craving intensity was significantly lower with free smoke than with placebo and with NRT patches than with placebo. No difference in craving levels was found between those who smoked or those who had NRT patches. Withdrawal symptoms were significantly lower with free smoke than with either placebo or NRT patches, but there was no difference in levels of withdrawal between those on NRT patches and those on placebo. During the placebo and NRT patch periods, craving intensity displayed a circadian rhythm, with craving levels lowest in the morning and peaking in the evening. Nicotine delivered via the patch had no impact on these circadian variations in craving. There was no evidence of systematic temporal variations in craving levels during the free smoking period.

Conclusions: The data suggested that craving and withdrawal symptoms may be sustained by different physiological pathways, and that only selected components of cigarette craving are influenced by NRT.
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http://dx.doi.org/10.1007/s00213-002-1176-1DOI Listing
November 2002

Correlation and predictive performances of saliva and plasma nicotine concentration on tobacco withdrawal-induced craving.

Br J Clin Pharmacol 2002 Oct;54(4):407-14

GlaxoSmithKline, Via A. Fleming 2, 37135 Verona, Italy.

Aims: To investigate whether saliva is a useful alternative to plasma for routine monitoring of nicotine and evaluate the predictive performances of saliva and plasma concentration on craving estimated by a Tiffany Questionnaire on Smoking Urge-Brief Form.

Methods: Thirteen healthy smokers were enrolled in a randomized, two period, crossover trial. Linear and power models were evaluated to predict the plasma nicotine concentrations from the saliva measurements, whereas a population PK/PD indirect response model was used to predict craving using either saliva or plasma nicotine concentration as the independent variable.

Results: The results of the analysis revealed that the power model was preferred over the linear one. The bias on the predicted plasma concentrations was of 0.47 ng ml-1 with a 95% confidence interval of [-0.57, 1.52] and a precision of 5.68 ng ml-1. The placebo effect model was initially fitted to data, then the indirect response approach (with inhibition in k(in)) was used to model the craving scores using plasma and saliva nicotine concentrations as independent variables. The two indirect response PK/PD models based on saliva and plasma nicotine concentrations, adequately described the onset, extent, and duration of craving. The maximal inhibition I(max) was 0.722 and 1 for saliva and plasma concentrations while the estimated nicotine concentrations giving 50% of the maximal inhibition were 269 ng ml-1 and 24.3 ng ml-1 for saliva and plasma, respectively.

Conclusions: A good correlation between plasma and saliva nicotine concentrations has been found using a power model. Comparable values of bias and precision on the model-predicted craving indicate that plasma and saliva concentration can equally well be used to predict the onset of tobacco withdrawal induced craving. Analysis of saliva definitely offers a potentially more attractive way to assess nicotine concentration values, as samples can be collected easily and noninvasively. In addition, saliva sampling avoids the pain and discomfort involved in venepuncture. In studies that assess psychological measures, such as subjective mood, blood collection could present a possible confounding factor because of the anxiety and pain that accompanies it. For these reasons saliva can reasonably be considered as the ideal sampling site for all clinical studies conducted for the evaluation of the potential activity of drugs on nicotine deprivation symptoms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874443PMC
http://dx.doi.org/10.1046/j.0306-5251.2002.01650.xDOI Listing
October 2002