Lilly Research Center

Windlesham, United Kingdom

Lilly Research Center

Windlesham, United Kingdom
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Ma Y.L.,Lilly Research Laboratories | Zeng Q.Q.,Lilly Research Laboratories | Chiang A.Y.,Lilly Research Laboratories | Burr D.,Indiana University | And 7 more authors.
Bone | Year: 2014

Cortical bone, the dominant component of the human skeleton by volume, plays a key role in protecting bones from fracture. We analyzed the cortical bone effects of teriparatide treatment in postmenopausal women with osteoporosis who had previously received long-term alendronate (ALN) therapy or were treatment naïve (TN). Tetracycline-labeled paired iliac crest biopsies obtained from 29 ALN-pretreated and 16 TN women were evaluated for dynamic histomorphometric parameters of bone formation at the periosteal, endocortical and intracortical bone compartments, before and after 24. months of teriparatide treatment. At baseline, the frequency of specimens without any endocortical and periosteal tetracycline labeling, and the percentage of quiescent osteons, was higher in the ALN than the TN group. Endocortical and periosteal mineralizing surface (MS/BS%), periosteal bone formation rate (BFR/BS), mineral apposition rate (MAR) and the number of intracortical forming osteons were significantly lower in the ALN-pretreated patients than in the TN group. Following teriparatide treatment, the frequency of endocortical and periosteal unlabeled biopsies decreased; in the ALN-pretreated group the percentage of quiescent osteons decreased and, in contrast, forming and resorbing osteons were increased. Teriparatide treatment resulted in significant increases of MAR in the endocortical, and MS/BS% in the periosteal compartment in the ALN-pretreated group. Most indices of bone formation remained lower in the ALN-pretreated group compared with the TN group at study end. Endocortical wall width was increased in both ALN-pretreated and TN groups. Cortical porosity and cortical thickness were significantly increased in the ALN-pretreated group after teriparatide treatment. Our results suggest that 24. months of teriparatide treatment increases cortical bone formation and cortical turnover in patients who were either TN or had previous ALN therapy. © 2013 Elsevier Inc.

Gonzalez-Pinto A.,University of the Basque Country | Gonzalez-Pinto A.,Research Center Biomedica en Red en Salud Mental | Reed C.,Lilly Research Center | Novick D.,Lilly Research Center | And 3 more authors.
Pharmacopsychiatry | Year: 2010

This study aimed to identify factors associated with medication adherence in bipolar disorder (BPD) patients. Methods: EMBLEM is a 2-year, prospective, observational study on the outcomes of BPD patients initiating or changing treatment for a manic/mixed episode. Data were collected at baseline, during the first 12 weeks of treatment (acute phase) and up to 24 months of follow-up (maintenance phase). Adherence was assessed by investigators at every visit. Repeated measures logistic regression analyses identified variables associated with adherence. Results: Of 1831 patients included in the analysis, 76.6% were adherent and 23.4% were non-adherent with their BPD medication during the maintenance phase. Patients were more likely to be adherent if they had insight into their illness at week 12. Patients were less likely to be adherent if they had cannabis abuse/dependence during the acute phase, work impairment or higher CGI hallucinations/delusions at baseline Discussion: Psychotic symptoms, poor insight, cannabis abuse/dependence and work impairment are negatively related to medication adherence during maintenance therapy of bipolar disorder. Patients with these characteristics may need a different therapeutic approach. © Georg Thieme Verlag KG Stuttgart - New York.

Haro J.M.,Research Center Biomedica en Red en Salud Mental | Reed C.,Lilly Research Center | Gonzalez-Pinto A.,University of the Basque Country | Novick D.,Lilly Research Center | And 2 more authors.
European Neuropsychopharmacology | Year: 2011

EMBLEM is a 2-year, prospective, observational study that enrolled patients initiating/changing oral treatment for an acute manic/mixed episode. This paper analysed remission and functional recovery in 1656 patients who entered the 2-year long-term phase. Cox models identified variables significantly associated with achieving remission and functional recovery at 2. years. Of these patients, 64% achieved remission and 34% achieved functional recovery. Patients with a higher CGI-BP overall score at baseline, who had depressive episodes in the year before inclusion and who had poor social functioning (work or social impairment, not living independently or without a spouse/partner) were less likely to achieve remission or recovery. Prescription of typical antipsychotics and prescription of antidepressants at the first visit of the long-term treatment phase (12. weeks) were independent predictors of lower remission and recovery rates. In conclusion, functional recovery occurred in approximately half of those who achieved remission. Impairment of work and social functioning was consistently associated with lower remission and recovery rates. © 2010 Elsevier B.V.

Brunton S.,Faculty Development | Wang F.,Lilly United States LLC | Edwards S.B.,Lilly United States LLC | Crucitti A.S.,Lilly Research Center | And 3 more authors.
Drug Safety | Year: 2010

Background: The serotonin and noradrenaline (norepinephrine) reuptake inhibitor duloxetine has been approved in the US and elsewhere for a number of indications, including psychiatric illnesses and chronic pain conditions. Because the patient populations are diverse within these approved indications, and duloxetine is not yet approved for treatment of other conditions, we wanted to determine if adverse event profiles would differ among patients being treated for these various conditions. Objective: To provide detailed information on the adverse events associated with duloxetine and to identify differences in the adverse event profile between treatment indications and patient demographic subgroups. Methods: Data were analysed from all placebo-controlled trials of duloxetine completed as of December 2008. The 52 studies included 17 822 patients (duloxetine n = 10 326; placebo n = 7496) with major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, osteoarthritis knee pain (OAKP), chronic lower back pain and lower urinary tract disorders. The main outcome measures were rates of treatment-emergent adverse events (TEAEs) and adverse events reported as the reason for discontinuation. Results: The overall TEAE rate was 57.2% for placebo-treated patients and 72.4% for duloxetine-treated patients (p £ 0.001). Patients with OAKP had the lowest TEAE rate (placebo 36.7% vs duloxetine 50.2%, p£ 0.01), while patients with fibromyalgia had the highest rate (placebo 80.0% vs duloxetine 89.0%, p£ 0.001). The most common TEAE for all indications was nausea (placebo 7.2%vs duloxetine 23.4%, p £ 0.001), which was predominantly mild to moderate in severity. No statistically significant treatment-by-subgroup interactions for age were found between placebo and duloxetine treatment for the most common TEAEs. The rates of duloxetine-associated dry mouth and fatigue were greater in women than in men (13.1% vs 10.4%, interaction p = 0.004; and 9.4% vs 7.6%, interaction p = 0.03, respectively). Duloxetineassociated dry mouth incidence was higher in Caucasians than non-Caucasians (13.2%, 11.0%, interaction p = 0.04). Conclusions: Duloxetine treatment is associated with significantly higher rates of common TEAEs versus placebo, regardless of indication or demographic subgroup. Differences across indications are likely to be attributable to the underlying condition rather than duloxetine, as suggested by the similar trends observed in placebo-and duloxetine-treated patients. © 2010 Adis Data Information BV. All rights reserved.

Blumsohn A.,Sheffield Teaching Hospitals NHS Foundation Trust | Marin F.,Lilly Research Center | Nickelsen T.,Lilly Research Center | Brixen K.,Universitethospital | And 6 more authors.
Osteoporosis International | Year: 2011

Summary: We report the changes in biochemical markers of bone formation during the first 6 months of teriparatide therapy in postmenopausal women with osteoporosis according to previous antiresorptive treatment. Prior therapy does not adversely affect the response to teriparatide treatment. Similar bone markers levels are reached after 6 months of treatment. Introduction: The response of biochemical markers of bone turnover with teriparatide therapy in subjects who have previously received osteoporosis drugs is not fully elucidated. We examined biochemical markers of bone formation in women with osteoporosis treated with teriparatide and determined: (1) whether the response is associated with prior osteoporosis therapy, (2) which marker shows the best performance for detecting a response to therapy, and (3) the correlations between early changes in bone markers and subsequent bone mineral density (BMD) changes after 24 months of teriparatide. Methods: We conducted a prospective, open-label, 24-month study at 95 centers in 10 countries in 758 postmenopausal women with established osteoporosis (n=181 treatment-naïve) who had at least one post-baseline bone marker determination. Teriparatide (20 μg/day) was administered for up to 24 months. We measured procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (b-ALP), and total alkaline phosphatase (t-ALP) at baseline, 1 and 6 months, and change in BMD at the lumbar spine, total hip and femoral neck from baseline to 24 months. Results: Significant increases in formation markers occurred after 1 month of teriparatide regardless of prior osteoporosis therapy. The absolute increase at 1 month was lower in previously treated versus treatment-naïve patients, but after 6 months all groups reached similar levels. PINP showed the best signal-to-noise ratio. Baseline PINP correlated positively and significantly with BMD response at 24 months. Conclusions: This study suggests that the long-term responsiveness of bone formation markers to teriparatide is not affected in subjects previously treated with antiresorptive drugs. © The Author(s) 2010. This article is published with open access at

Rajzbaum G.,Groupe Hospitalier Paris Saint Joseph | Grados F.,Center Hospitalier University | Evans D.,Lilly France | Liu-Leage S.,Lilly France | And 2 more authors.
Joint Bone Spine | Year: 2014

Objectives: The European Forsteo Observational Study assessed the clinical fracture incidence, back pain, quality of life (QoL), and treatment persistence amongst post-menopausal women, who were prescribed teriparatide in routine care in eight European countries. We present the results for France, with health-insurance reimbursement criteria channel teriparatide to women with severe disease and limit treatment to 18. months. Methods: A representative sample of women initiating teriparatide in France was followed in routine care for 36. months. We described patients' characteristics at baseline and persistence to teriparatide (Kaplan-Meier analysis), fracture incidence, back pain, and QoL (EQ-5D) at baseline, 18 and 36. months follow-up (last-observation-carried-forward (LOCF) and mixed-models-for-repeated-measures (MMRM). Results: One hundred and sixteen rheumatologists included 309 patients, of whom 290 (93.9%) had at least one follow-up visit. Women's mean age (standard deviation) was 74.5. years (7.4) and 296 (95.8%) had greater or equal to two vertebral fractures prior to teriparatide initiation. Clinical fracture incidence, mainly vertebral fractures, decreased around 6. months after teriparatide initiation, and was sustained at 36. months (P=0.013) when most patients were treated by anti-resorptives. Back pain and EQ-5D measures improved significantly at 18 and 36. months (P<. 0.0001) in the LOCF analyses but did not improve in the EQ-5D VAS measure after covariate adjustment in the MMRM model. Median treatment duration was 17.4. months. Conclusion: French women initiating teriparatide in routine care had severe osteoporosis and showed good treatment persistence, consistent with France's insurance reimbursement criteria. Improvements in fracture risk and back pain began soon after treatment and was maintained at 36. months follow-up. © 2013 Société française de rhumatologie.

Gonzalez-Pinto A.,Hospital Santiago Apostol | Vieta E.,University of Barcelona | Reed C.,Lilly Research Center | Novick D.,Lilly Research Center | And 3 more authors.
Journal of Affective Disorders | Year: 2011

Background: This study compared the 2-year outcomes of patients with a manic/mixed episode of bipolar disorder taking olanzapine monotherapy or olanzapine in combination with other agents. Methods: EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 2-year, prospective, observational study of clinical and functional outcomes of bipolar patients with an index manic/mixed episode. The study consisted of two phases: acute (12 weeks) and maintenance (follow-up over 2 years). The longitudinal outcome measure was the Clinical Global Impression-Bipolar Disorder scale. Cox regression models compared outcomes of both therapy groups using intention-to-treat and switching medication analysis. Treatment-emergent adverse events were also assessed. Results: 1076 patients were included in this analysis. 29% took olanzapine as monotherapy (n = 313) and 71% as combination (n = 763) at 12-weeks post-baseline (end of study acute phase). After adjusting for patient characteristics using switching medication analysis, only relapse rates differed (p = 0.01) in favour of monotherapy-treated patients. There was no significant difference in rates of improvement, remission, and recovery. Patients treated with combination therapy reported more tremor (OR 2.37, 95%CI 1.44-3.89) and polyuria (OR 3.08, 95%CI 1.45-6.54) treatment-emergent events than monotherapy, although weight change was greater in the monotherapy group. Limitations: Unknown confounding and potential selection bias may differentially impact treatment outcomes. Conclusions: EMBLEM patients benefitted from the selected therapy to a similar extent. Differences in patient characteristics between those prescribed monotherapy and combination therapy appear to be clinically relevant in the treatment decision. Physicians must balance the benefits and risks when determining appropriate treatment for individual patients. © 2010 Elsevier B.V. All rights reserved.

Cure S.,The Cricket | Abrams K.,University of Leicester | Belger M.,Lilly Research Center | Dell'Agnello G.,Eli Lilly and Company | Happich M.,Lilly Deutschland GmbH
Journal of Alzheimer's Disease | Year: 2014

Background: Early diagnosis of Alzheimer's disease (AD) is crucial to implement the latest treatment strategies and management of AD symptoms. Diagnostic procedures play a major role in this detection process but evidence on their respective accuracy is still limited. Objective: To conduct a systematic literature on the sensitivity and specificity of different test modalities to identify AD patients and perform meta-analyses on the test accuracy values of studies focusing on autopsy-confirmation as the standard of truth. Methods: The systematic review identified all English papers published between 1984 and 2011 on diagnostic imaging tests and cerebrospinal fluid biomarkers including results on the newest technologies currently investigated in this area. Meta-analyses using bivariate fixed and random-effect models and hierarchical summary receiver operating curve (HSROC) random-effect model were applied. Results: Out of the 1,189 records, 20 publications were identified to report the accuracy of diagnostic tests in distinguishing autopsy-confirmed AD patients from other dementia types and healthy controls. Looking at all tests and comparator populations together, sensitivity was calculated at 85.4% (95% confidence interval [CI]: 80.9%-90.0%) and specificity at 77.7% (95% CI: 70.2%-85.1%). The area under the HSROC curve was 0.88. Sensitivity and specificity values were higher for imaging procedures, and slightly lower for CSF biomarkers. Test-specific random-effect models could not be calculated due to the small number of studies. Conclusion: The review and meta-analysis point to a slight advantage of imaging procedures in correctly detecting AD patients but also highlight the limited evidence on autopsy-confirmations and heterogeneity in study designs. © 2014 - IOS Press and the authors. All rights reserved.

Borggrefe J.,Universitatsklinikum Schleswig Holstein | Graeff C.,Universitatsklinikum Schleswig Holstein | Nickelsen T.N.,Lilly Research Center | Marin F.,Lilly Research Center | Gluer C.C.,Lilly Research Center
Journal of Bone and Mineral Research | Year: 2010

We studied the changes in bone distribution, geometry, and bone strength based on 3D quantitative computed tomography (QCT) of the femoral neck (FN) in subjects receiving teriparatide (TPTD). Fifty-two postmenopausal women with severe osteoporosis were analyzed. Patients were divided into three subgroups based on their prior treatment with osteoporosis drugs: treatment-naive (Tx-naive; n = 8), pretreated (pre-Tx; n = 12), and pretreated showing an inadequate response to treatment (inad. pre-Tx; n = 32). QCT scans were performed at baseline and after 6, 12, and 24 months of treatment and were analyzed with Mindways QCT-PRO BIT software. Minimum and maximum section modulus, buckling ratio (BR), and cross-sectional area (CSA) were calculated as measurements of bending strength, risk of buckling, and bone apposition, respectively. After 24 months of TPTD treatment, areal and volumetric FN BMD increased significantly by 4.0% and 3.0%, respectively, compared with baseline. Decreases in cortical volumetric BMD occurred in locations not adversely affecting minimum bending strength indicators. Cortical CSA increased by 4.3%, whereas total CSA remained unchanged over the study duration, indicating that endosteal but no periosteal growth was observed. Strength parameters for buckling did not change at 6 and 12 months but improved significantly at 24 months. Measures of bending strength showed a trend toward improvement. Changes tended to be larger in individuals at higher risk of buckling failure. Prior antiresorptive treatment may delay response to TPTD, but based on the small magnitude of the mostly insignificant changes at 6 months, this does not appear to lead to an interim phase of reduced bone strength. In summary, FN QCT provides a tool for detailed longitudinal investigation of bone strength indices in vivo for different loading modes, yields insight into underlying structural changes, and provides relevant mechanostructural information beyond dual-energy X-ray absorptiometry. Continuous TPTD treatment for 24 months improves FN bone strength parameters. © 2010 American Society for Bone and Mineral Research.

Ferrari F.D.,University of Glasgow | Ledgard A.J.,Lilly Research Center | Marquez R.,University of Glasgow
Tetrahedron | Year: 2011

The divergent syntheses of the spirocyclic pyran core of polymaxenolide and the spirocyclic piperidine core of pinnaic acid have been achieved. Our divergent approach takes advantage of highly efficient Achmatowicz and aza-Achmatowicz rearrangements to generate the highly functionalised cores, which are then regioselectively modified. © 2011 Elsevier Ltd. All rights reserved.

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