Novel spectrophotometric method for determination of cinacalcet hydrochloride in its tablets via derivatization with 1,2-naphthoquinone-4-sulphonate

This study represents the first report on the development of a novel spectrophotometric method for determination of cinacalcet hydrochloride (CIN) in its tablet dosage forms. Studies were carried out to investigate the reaction between CIN and 1,2-naphthoquinone-4-sulphonate (NQS) reagent. In alkaline medium (pH 8.5), an orange red-colored product exhibiting maximum absorption peak (λmax) at 490 nm was produced. The stoichiometry and kinetic of the reaction were investigated and the reaction mechanism was postulated. This color-developing reaction was employed in the development of a simple and rapid visible-spectrophotometric method for determination of CIN in its tablets. Under the optimized reaction conditions, Beer's law correlating the absorbance with CIN concentration was obeyed in the range of 3 - 100 μg/ml with good correlation coefficient (0.9993). The molar absorptivity (ε) was 4.2 × 105 l/mol/cm. The limits of detection and quantification were 1.9 and 5.7 μg/ml, respectively. The precision of the method was satisfactory; the values of relative standard deviations (RSD) did not exceed 2%. No interference was observed from the excipients that are present in the tablets. The proposed method was applied successfully for the determination of CIN in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 100.80 - 102.23 ± 1.27 - 1.62%. The results were compared favorably with those of a reference pre-validated method. The method is practical and valuable in terms of its routine application in quality control laboratories

Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation

Background: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. Objective: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. Data sources: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. Review methods: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. Results: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks’ follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE’s usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. Limitations: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. Conclusions: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. Study registration: This study is registered as PROSPERO CRD42016039494. Funding: The National Institute for Health Research Health Technology Assessment programme

Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal Cancer

The monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor (EGFR) have expanded the range of treatment options for metastatic colorectal cancer. Initial evaluation of these agents as monotherapy in patients with EGFR-expressing chemotherapy-refractory tumors yielded response rates of approximately 10%. The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Oncogenic activation of signaling pathways downstream of the EGFR, such as mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer. Tumor KRAS mutations, which may be present in 35%–45% of patients with colorectal cancer, have emerged as an important predictive marker of resistance to panitumumab or cetuximab treatment. In addition, among colorectal tumors carrying wild-type KRAS, mutation of BRAF or PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment, although these additional biomarkers require further validation before incorporation into clinical practice. Additional knowledge of the molecular basis for sensitivity or resistance to EGFR-targeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance. The use of KRAS mutations as a selection biomarker for anti-EGFR monoclonal antibody (eg, panitumumab or cetuximab) treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer

Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes

BACKGROUND: Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events

G-CSF/anti-G-CSF antibody complexes drive the potent recovery and expansion of CD11b+Gr-1+ myeloid cells without compromising CD8+ T cell immune responses

BACKGROUND: Administration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo. METHODS: We evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice. RESULTS: We find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b(+)Gr-1(+) myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8(+) T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation. CONCLUSIONS: Our findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF