Crystal Engineering of Isostructural Quaternary Multicomponent Crystal Forms of Olanzapine

Pharmaceutical cocrystals have gained increased attention at least in part because of their potential for enhancing physicochemical and biopharmaceutical properties of existing drugs. As a result, design, screening, and large-scale preparation of pharmaceutical cocrystals have been emphasized in recent research. The design of pharmaceutical cocrystals has focused primarily on determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach is typically less predictive when considering drugs that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. In this manuscript, we report a crystal engineering design strategy to facilitate the synthesis of multicomponent crystal forms of the atypical antipsychotic drug olanzapine, marketed as a drug product under the trade name Zyprexa. Comprehensive analysis and data mining of existing crystal structures of olanzapine were followed by grouping into categories according to the crystal packing exhibited and systematically using this information to crystal engineer new compositions. This approach afforded isostructural, quaternary multicomponent crystal forms of olanzapine composed of a stoichiometric ratio of four molecular components: olanzapine; a cocrystal former; water; solvent (isopropylacetate). To our knowledge this study is unprecedented in that the observed quaternary structures can be classified as solvates, hydrates, or cocrystals

Crystal Engineering of Isostructural Quaternary Multicomponent Crystal Forms of Olanzapine

Pharmaceutical cocrystals have gained increased attention at least in part because of their potential for enhancing physicochemical and biopharmaceutical properties of existing drugs. As a result, design, screening, and large-scale preparation of pharmaceutical cocrystals have been emphasized in recent research. The design of pharmaceutical cocrystals has focused primarily on determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach is typically less predictive when considering drugs that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. In this manuscript, we report a crystal engineering design strategy to facilitate the synthesis of multicomponent crystal forms of the atypical antipsychotic drug olanzapine, marketed as a drug product under the trade name Zyprexa. Comprehensive analysis and data mining of existing crystal structures of olanzapine were followed by grouping into categories according to the crystal packing exhibited and systematically using this information to crystal engineer new compositions. This approach afforded isostructural, quaternary multicomponent crystal forms of olanzapine composed of a stoichiometric ratio of four molecular components: olanzapine; a cocrystal former; water; solvent (isopropylacetate). To our knowledge this study is unprecedented in that the observed quaternary structures can be classified as solvates, hydrates, or cocrystals

Temporal patterns of late bowel and bladder radiotherapy toxicity in a randomised controlled trial assessing duration of neo-adjuvant hormones in prostate cancer

<div><p></p><p><b>Background.</b> To assess the temporal patterns of late gastrointestinal (GI) and genitourinary (GU) radiotherapy toxicity and resolution rates in a randomised controlled trial (All-Ireland Cooperative Oncology Research Group 97-01) assessing duration of neo-adjuvant (NA) hormone therapy for localised prostate cancer.</p><p><b>Material and methods.</b> Node negative patients with > 1 of: PSA > 20 ng/mL, Gleason score ≥ 7, and stage T3 or more, were included. Follow-up, including toxicity assessment, was three-monthly in the early stages and yearly thereafter.</p><p><b>Results.</b> Median follow-up from the end of RT was 6.8 years. In the interval between 90 days following the end of RT and the last toxicity assessment, GI and GU toxicity (any grade) was found in 50% and 51% of 240 and 241 patients, respectively. For those who did develop toxicity, the median time from end of RT until the first development of any grade GI or GU toxicity was 1.2 years and 1.6 years, respectively, whilst median time to final resolution was 1.6 years and 2.2 years, respectively. Grade 2 (G2) or greater GI and GU toxicity occurred in 29 (12.1%) and 40 (16.6%) patients, respectively. The proportion with unresolved G2 + GI and GU toxicity was 89% and 79%, respectively, in year 1, 69% and 65% in year 2, 59% and 52% in year 3 and 27% and 32% in year 5.</p><p><b>Conclusion.</b> Long-term toxicities continue to occur many years after NA hormone therapy and RT. The rate of occurrence does not appear to reduce within the time frame during which our patients were followed. The percentage of patients suffering from G2 + toxicity at any time is however low. Resolution of these toxicities continues for the duration of the follow-up.</p></div

Predictive modelling of response to neoadjuvant therapy in HER2+ breast cancer

HER2-positive (HER2+) breast cancer accounts for 20–25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10–05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients. Here we report predictive modelling of neoadjuvant therapy response using clinicopathological and genomic features of pre-treatment tumour biopsies identified age, estrogen receptor (ER) status and level of immune cell infiltration may together be important for predicting response. Clonal evolution analysis of longitudinally collected tumour samples show subclonal diversity and dynamics are evident with potential therapy resistant subclones detected. The sources of greater pre-treatment immunogenicity associated with a pathological complete response is largely unexplored in HER2+ tumours. However, here we point to the possibility of APOBEC associated mutagenesis, specifically in the ER-neg/HER2+ subtype as a potential mediator of this immunogenic phenotype

Additional file 1: Table S1. of Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies

Non-synonymous somatic mutations in PIK3CA and ERBB family genes. (DOCX 15 kb

Additional file 2: Table S2. of Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies

Specific somatic mutations in PIK3CA, EGFR, ERBB3, ERBB4 and PIK3CA detected in our patient cohort. (DOCX 13 kb

Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08–10 trial.

Background: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients.Methods: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF).Results: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients versus 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity.Conclusions: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further.Trial registration: ClinicalTrials.gov Identifier: NCT00911716.</p