The Noscapine Chronicle: A Pharmaco‐Historic Biography of the Opiate Alkaloid Family and its Clinical Applications

Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable “Renaissance drug” worthy of commemoration. Perhaps the only facet of noscapine's profile more astounding than its versatility is its virtual lack of side effects and addictive properties, which distinguishes it from other denizens of Papaver somniferum. This review intimately chronicles the rich intellectual and pharmacological history behind the noscapine family of compounds, the length of whose arms was revealed over decades of patient scholarship and experimentation. We discuss the intriguing story of this family of nontoxic alkaloids, from noscapine's purification from opium at the turn of the 19th century in Paris to the recent torrent of rationally designed analogs with tremendous anticancer potential. In between, noscapine's unique pharmacology; impact on cellular signaling pathways, the mitotic spindle, and centrosome clustering; use as an antimalarial drug and cough suppressant; and exceptional potential as a treatment for polycystic ovarian syndrome, strokes, and diverse malignancies are catalogued. Seminal experiments involving some of its more promising analogs, such as amino‐noscapine, 9‐nitronoscapine, 9‐bromonoscapine, and reduced bromonoscapine, are also detailed. Finally, the bright future of these oftentimes even more exceptional derivatives is described, rounding out a portrait of a truly remarkable family of compounds.     

An unusual case of phenotype switch between AML FAB subtypes

Phenotypic switch between any leukemia subtypes is of concern to a treating physician and more so, in acute myelocytic leukemia (AML) as the mechanisms for switch and subsequent chemotherapy regimen to be used remain unclear. AML‐non‐M3 from AML‐M3 subtype needs special mention as this has been unheard off.     

CYP2C19*2/ABCB1-C3435T polymorphism and risk of cardiovascular events in coronary artery disease patients on clopidogrel: Is clinical testing helpful?

BackgroundStudies evaluating CYP2C19*2 and ABCB1-C3435T polymorphisms have shown conflicting results. We performed this meta-analysis to evaluate role of clinical testing for these polymorphisms in CAD patients on clopidogrel.Methods19,601 patients from 14 trials were analyzed. The endpoints were major adverse cardiovascular events (MACE), cardiovascular (CV) death, stent thrombosis (ST), myocardial infarction (MI), stroke and major bleeding. Combined relative risks (RR) with 95% confidence intervals (CI) were computed for each outcome by using standard methods of meta-analysis and test parameters were computed.ResultsCYP2C19*2 polymorphism was associated with higher risk of MACE [RR: 1.28, CI: 1.06–1.54; p = 0.009], CV death [RR: 3.21, CI: 1.65–6.23; p = 0.001], MI [RR: 1.36, CI: 1.12–1.65; p = 0.002], ST [RR: 2.41, CI: 1.69–3.41; p < 0.001]. No difference was seen in major bleeding events [RR: 1.02, CI: 0.86–1.20; p = 0.83]. Subgroup analysis showed similar results for elective PCI [RR: 1.34, CI: 1.01–1.76; p = 0.03], and PCI with DES [RR: 1.53, CI: 1.029–1.269; p = 0.03]. CYP2C19*2 polymorphism has very low sensitivity (28–58%), specificity (71–73%), positive predictive value (3–10%) but good negative predictive value (92–99%). ABCB1-C3435T polymorphism analysis revealed similar MACE [RR: 1.13, CI: 0.99–1.29; p = 0.06], ST [RR: 0.88, CI: 0.52–1.47; p = 0.63] and major bleeding [RR: 1.04, CI: 0.87–1.25; p = 0.62] in both groups.ConclusionIn CAD patients on clopidogrel therapy, CYP2C19*2 polymorphism is associated with significantly increased adverse cardiovascular events. However, due to the low positive predictive value, routine genetic testing cannot be recommended at present.     

Multicenter precision of cortical and trabecular bone quality measures assessed by high‐resolution peripheral quantitative computed tomography

High‐resolution peripheral quantitative computed tomography (HR‐pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technology to address important skeletal health questions requires translation to standardized multicenter data pools. Our goal was to evaluate the feasibility of pooling data in multicenter HR‐pQCT imaging trials. Reproducibility imaging experiments were performed using structure and composition‐realistic phantoms constructed from cadaveric radii. Single‐center precision was determined by repeat scanning over short‐term (<72 hours), intermediate‐term (3–5 months), and long‐term intervals (28 months). Multicenter precision was determined by imaging the phantoms at nine different HR‐pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters. Single‐center short‐term RMSCVs were <1% for all parameters except cortical thickness (Ct.Th) (1.1%), spatial variability in cortical thickness (Ct.Th.SD) (2.6%), standard deviation of trabecular separation (Tb.Sp.SD) (1.8%), and porosity measures (6% to 8%). Intermediate‐term RMSCVs were generally not statistically different from short‐term values. Long‐term variability was significantly greater for all density measures (0.7% to 2.0%; p < 0.05 versus short‐term) and several structure measures: cortical thickness (Ct.Th) (3.4%; p < 0.01 versus short‐term), cortical porosity (Ct.Po) (15.4%; p < 0.01 versus short‐term), and trabecular thickness (Tb.Th) (2.2%; p < 0.01 versus short‐term). Multicenter RMSCVs were also significantly higher than short‐term values: 2% to 4% for density and micro–finite element analysis (µFE) measures (p < 0.0001), 2.6% to 5.3% for morphometric measures (p < 0.001), whereas Ct.Po was 16.2% (p < 0.001). In the absence of subject motion, multicenter precision errors for HR‐pQCT parameters were generally less than 5%. Phantom‐based multicenter precision was comparable to previously reported in in vivo single‐center precision errors, although this was approximately two to five times worse than ex vivo short‐term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multicenter study designs. © 2013 American Society for Bone and Mineral Research.