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To compare blood pressure (BP), intraocular pressure (IOP), ophthalmic artery flow (OAF) velocity, retinal nerve fiber layer (RNFL) thickness, and visual fields in newly diagnosed hypertension (HT) patients (before treatment), chronic HT (on antihypertensive medications >5 years) and normotensives. A prospective, cross-sectional study at a tertiary care centre in India. Three groups of 45 patients each: group 1 - early HT, group 2 - chronic HT, and Group 3 - normotensives, underwent evaluation of BP, IOP by Goldmann applanation tonometry (GAT), OAF velocity by transcranial doppler (TCD), RNFL analysis by spectral-domain optical coherence tomography (SD-OCT), and visual fields. The BP was highest in early HT > chronic HT > normotensives (p < 0.001). The IOP of early HT, chronic HT, and normotensives were 15.87 ± 2.19 mmHg, 13.47 ± 1.92 mmHg, and 15.67 ± SD 1.75 mmHg (p < 0.001). The OAF velocity [peak systolic velocity (PSV), end-diastolic velocity (EDV) in cm/sec] was lowest in chronic HT (30.80 ± 7.05, 8.58 ± 1.58) < early HT (35.47 ± 5.34, 10.02 ± 1.74) < normotensives (36.29 ± 4.43, 10.44 ± 2.29), (p < 0.001). The average RNFL thickness was significantly lower in chronic HT (p = 0.022). The PSV, EDV, and MFV showed significant correlation with IOP (r = 0.247, p = 0.004; r = 0.206, p = 0.016; r = 0.266, p = 0.002) and average RNFL thickness (r = 0.309, p= <0.001; r = 0.277, p = 0.001; r = 0.341, p < 0.001) Patients with chronic HT demonstrated the lowest retrobulbar flows, IOP and lower RNFL measurements. Lower ocular perfusion may be associated with lower IOP and may be a risk factor for end-organ damage (RNFL) independent of IOP. [ABSTRACT FROM AUTHOR]

Context: Combating human immunodeficiency virus/acquired immunodeficiency syndrome epidemic has been possible due to advances in prevention strategies and Antiretroviral therapy (ART). Optimal adherence to ART is a major factor in achieving the desired immunological, virological, and patient well‑being outcomes. Several socio‑demographic, patient, treatment, and health‑care system‑related factors influence nonadherent behavior to ART. Aims: This study was planned to assess (1) ART adherence level, (2) factors and reasons associated with nonadherence, and (3) impact of suboptimal adherence on treatment outcomes. Settings and Design: This was a cross‑sectional analytical study of 300 patients in a tertiary care hospital in Puducherry, India. Methods: Random sampling was used to collect data from patient treatment cards and a predesigned structured questionnaire. The pill count method was used to calculate adherence level. Statistical Analysis Used: Nonadherence was chosen as a dependent variable and factors affecting adherence were chosen as independent variables. Test for significance was carried out by Chi‑square test and Fisher’s exact test. Results: Optimal adherence was seen in 68.3%. Factors significantly associated with nonadherence were lower education level, high prior CD4 count, irregular follow‑up, missing doses in the past, and being late for pharmacy pill refills. Adherence was positively associated with mean increase in CD4 count over 6 months. Conclusions: In our study, the adherence rate is suboptimal which can lead to failure of ART. Nonadherence was associated with a decrease in CD4 count overtime. Most of the factors significantly affecting ART adherence were patient behavior related. These factors can be used for target intervention during reinforcement adherence counseling. [ABSTRACT FROM AUTHOR]

This investigation is done for augmentation of steady-state voltage stability in microgrid with doubly fed induction wind generator for the growing need of DG systems in distribution and transmission network. A poor stability in voltage reduces the efficiency of the distributed generation system (DGs). Double Fed Induction Generator (DFIG) is a type of induction generator interconnected into microgrid and it acting an essential role during the performance of microgrid in distributed generation systems of distribution network. The performance characteristics of microgrid with DFIG is analyzed and improved by control strategy. The PI (proportional and integral) control strategy of microgrid with DFIG rooted in double-fed induction generator (DFIG) in pitch angle control in the energy storage system (ESS). The performance analysis microgrid with DFIG is implemented by means of simulink platform in MATLAB software. The outcome was evaluated in this article in favor of steady-state voltage stability enhancement in microgrid with DFIG. This work is done for the achievement of a stable operation microgrid in DG system against disturbances in wind. The proposed work is intended to produce 1.58 MW of reactive power without controller and 0.48 MW, 0.36 MW, and 0.32 MW of power with P, PI, and PID (Proportional–Integral–Derivative) controller with PAC. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of reducing blood pressure (BP) by atenolol and amlodipine on (1) intraocular pressure (IOP) and (2) ophthalmic artery blood flow (OAF) velocity in new hypertensives. Methods: A prospective, observational cohort study conducted at a tertiary care center in India after IRB approval. New hypertensives treated with atenolol 25 mg or amlodipine 5 mg were divided into 2 groups of 30 patients each. BP, IOP by Goldmann applanation tonometry and OAF velocity by transcranial doppler sonography was performed before medication and post medication on day 1, 7, and 30. Results: There was a significant decrease in IOP with both drugs; the effect was greater with atenolol. Atenolol: premedication IOP - 16.06 ± 2.13 mmHg and day 30-12.46 ± 1.94 (22.4%) [P < 0.001], amlodipine: premedication IOP-15.13 ± 2.55 mmHg and day 30- 13.06 ± 2.14 (13.68%) [P < 0.001]. A decrease of 0.5 mmHg in IOP with every 10 mmHg (95% CI: 0.121-0.826, P value = 0.01) decrease in systolic BP was noted after oral atenolol. The OAF peak systolic velocity and mean flow velocity were equally reduced with both drugs (P < 0.001). The end-diastolic velocity, reduced only with atenolol (P = 0.049) but returned to baseline with amlodipine at 1 month. Conclusions: BP reduction by atenolol and amlodipine led to decreases in IOP and OAF velocity, greater with atenolol. The IOP decrease was likely due to reduced blood flow. A slight decrease in the diastolic flow of the ophthalmic artery was noted with atenolol. [ABSTRACT FROM AUTHOR]

In this study, wastewater obtained from a sewage treatment plant was treated successively by using microbial consortium and macroalgae Kappaphycus alvarezii to generate microbial sludge and algal biomass. The production of green fuel was carried out via co-gasification of microbial sludge and macroalgae Kappaphycus alvarezii for a duration of 60 min, feedstock to solvent ratio (5 to 20 g of feedstock in 200 mL), sludge to algae ratio (ranging from 1:1 to 3:1) and temperature (300–400 °C) respectively. Maximum bio-hydrogen yield was 36.1% and methane yield was 38.4% at a temperature of 360 °C at a feedstock to solvent ratio of 15:200 g/mL and sludge to algae ratio of 2:1 individually. The liquid by product of co-gasification process was later subjected to photocatalytic reforming, resulted in an enhanced hydrogen composition of 61.25%. [Display omitted] • Kappaphycus alvarezii and sludge was processed for bio-hydrogen production. • Hydrothermal gasification resulted in syngas, biochar and liquid phase formation. • Maximum bio-hydrogen yield was 36.1% for 2:1 (sludge: algae) at 360 °C. • Methane yield was 38.4%, carbon dioxide was 19% for 2:1 ratio at 360 °C. • Reforming of aqueous phase with 7.5 wt% catalyst showed 61.25% of bio-hydrogen. [ABSTRACT FROM AUTHOR]

Background: Curcumin is a naturally derived yellow polyphenolic compound from the rhizome Curcuma longa. Curcumin modulates various signalling pathways, such as Cyclooxygenase-2 (COX-2), Matrix metallopeptidases (MMPs), glutathione, protein kinase C, ATPase, nuclear Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kb), Activator protein 1 (AP-1), P-glycoprotein 1 (P-gp), Multidrug resistance-associated proteins (MRP-1, MRP-2), Receptor tyrosine-protein kinase (ErbB2), Alpha-1-acid glycoprotein AGP), Cyclin D1 etc. Curcumin, as a free drug, has a short plasma half-life because it is rapidly metabolised in the liver. Its oral bioavailability is extremely poor, and hence Curcumin is classified as a class IV compound in the BCS system. Materials and Methods: Authors of the current study have formulated Liposomal Curcumin and conducted a Relative Oral Bioavailability Study of Liposomal Curcumin in comparison with plain Curcumin in rats. The treatment group was given Curcumin 25% I lipo at the dose of 500 mg/kg body weight and the control group was given plain Curcumin 500 mg/ kg body weight of the rats. Observations: Oral administration of Liposomal Curcumin showed rapid absorption (tmax =15 min) with Peak plasma concentration (Cmax), Area under Curve (AUC) and half-life (t1/2) of 42.3 ng/ml, 244 ng.h/ml and 5.5 h, respectively. In the control group, the Curcumin levels were below the level of quantitation (5.43 ng/ml). Conclusion: This study shows that Liposomal Curcumin has higher bioavailability as compared to the marketed formulations of Curcumin. Further extensive clinical studies are needed to prove efficacy of Liposomal Curcumin in various human applications. [ABSTRACT FROM AUTHOR]

This paper focuses on implementation of differential equation of the single-phase source-load system based control algorithm for three-phase distribution static compensator (DSTATCOM) in a power distribution system with a stiff source. The DSTATCOM has been adopted to alleviate the power quality issues such as load unbalancing, reactive power, and current harmonics, which are caused by solid-state equipment and devices. The proposed control algorithm is employed for extraction of fundamental active and reactive current components of polluted load currents, which are used for estimation of reference source currents. The control algorithm carries out computations by using a sliding sampling window that has a width of half of the fundamental cycle. The primary advantages of this control algorithm are immune to noise, not influenced from DC component that may exist in load current, and being less affected from frequency deviations. A prototype of voltage source converter (VSC)-based DSTATCOM is developed using a field programmable gate array (FPGA) processor to validate the proposed control algorithm and its performance is analyzed under steady-state and dynamic conditions. Experimental results demonstrate satisfactory performance of the DSTATCOM with the proposed control algorithm under linear and non-linear loads. [ABSTRACT FROM AUTHOR]

We present the first display panels exploiting the nVerPix CNVOLET technology that reduces the pixel circuit of the conventional AMOLED display to two discrete components: the switching transistor and the CN-VOLET. This permits high aperture ratio bottom emission displays-as high as 70% here- and greatly simplifies the manufacturing. Mono-color QVGA AMOLED displays (6.4 cm diagonal) playing video will be shown. [ABSTRACT FROM AUTHOR]

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheu-matoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhi-bition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB 1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Purpose: To compare topical and peribulbar anesthesia in cataract surgery for hemodynamic changes, rate of complications and pain score in patients with cardiovascular disease., Methods: A prospective comparative study at a tertiary care center in India. Patients >40 years old with treated/controlled hypertension and cardiovascular disease scheduled for cataract surgery under topical or peribulbar anesthesia were recruited. Heart rate, blood pressure, and ophthalmic and systemic complications were noted: preoperatively, immediately after block, intraoperatively, immediately postoperatively and 1 hour postoperatively. A visual analog scale was used to assess the pain score., Results: A total of 150 patients (75 in each group) underwent cataract surgery. There was a significant rise in pulse rate and blood pressure after peribulbar injection and intraoperatively, which gradually reduced to baseline 1 hour after surgery in both groups (p < 0.001), with systolic blood pressure intraoperatively being significantly greater in the peribulbar group (155.49 ±18.14 mmHg vs. 147.95 ±17.71 mmHg, p = 0.01). The topical group had slightly lower visual analog scale scores (1.12 ± 0.99) than the peribulbar group (1.44 ± 0.90, p = 0.04)., Conclusions: Cataract surgery appears safe in patients with adequately controlled cardiovascular disease, and topical anesthesia may be preferable due to noninvasiveness, adequate analgesia, and minimal effect on hemodynamic parameters. Therefore, hemodynamically stable patients of cardiovascular disease undergoing uncomplicated cataract surgery may be counselled for topical anesthesia.

The neutropenic mouse infection model is extensively used to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of anti-infective agents. However, it is difficult to evaluate agents following intravenous (i.v.) infusions using this model. Furthermore, in many drug discovery programs, lead identification and optimization is performed in rats, and pharmacology is performed in mice. Alternative models of infection are needed for robust predictions of PK/PD in humans. The rat is an alternative model of infection which can overcome the shortcomings of the mouse model. However, the rat neutropenic thigh infection (NTI) model has not been adequately characterized for evaluation of the PK/PD of anti-infectives. The aim of this study was to characterize the PK/PD of ciprofloxacin against bacterial pathogens in a rat NTI model. We studied the PK/PD relationships of ciprofloxacin against wild-type Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae in neutropenic Wistar rats following administration of 10, 30, and 100 mg/kg as single intravenous boluses and 30- and 60-min infusions. The PK/PD of ciprofloxacin against all four pathogens was AUC/MIC dependent and independent of the duration of administration at 10, 30, and 100 mg/kg. At human-equivalent rat doses, the PK/PD targets of ciprofloxacin achieved in rats for microbiological cure were similar to those reported in human patients. The neutropenic rat thigh infection model can be used to evaluate anti-infective agents intended to be administered as infusions in the clinic, and it complements the mouse model, increasing the robustness of PK/PD predictions in humans. IMPORTANCE Many antibiotics are administered as intravenous infusions in the clinic, especially in intensive care units. Anti-infective drug discovery companies develop clinical candidates that are intended to be administered as i.v. infusions in the clinic. However, there are no well-characterized models with which they can evaluate the PK/PD of the candidates following i.v. infusions. The neutropenic rat thigh infection model reported in this study helps in evaluating anti-infective agents that are intended to be administered as i.v. infusions in the clinic. The rat model is useful for simulating the clinical conditions for i.v. infusions for treatment of infections, such as acute bacterial skin and skin structure, lung, and urinary tract infections. This model is predictive of efficacy in humans and can serve as an additional confirmatory model, along with the mouse model, for determining the proof of concept and for making robust predictions of efficacy in humans., Competing Interests: The authors declare no conflict of interest.

Background: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI)., Objective: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients., Methods: Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, and other clinical signs were assessed twenty-four hours post-treatment., Results: CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC=1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2=0.979), kidney (r2=0.951) and rectal temperature (r2=0.67). A plasma AUC/MIC ratio of 412 was associated with maximum PD effect of Imax=3.7 Log10CFU/bladder and Imax=1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC ratio showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80) followed by Cmax/MIC ratio in bladder (r2=0.68)., Conclusion: Plasma AUC/MIC showed the highest correlation with the efficacy of Ciprofloxacin on E. coli in diabetic mice with cUTI., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The mechanism of efflux is a tour-de-force in the bacterial armoury that has thwarted the development of novel antibiotics. We report the discovery of a novel chemical series with potent antibacterial properties that was engineered to overcome efflux liability. Compounds liable to efflux specifically via the Resistance Nodulation and cell Division (RND) pump, AcrAB-TolC were chosen for a hit to lead progression. Using structure-based design, the compounds were optimised to lose their binding to the efflux pump, thereby making them potent on wild-type bacteria. We discovered these compounds to be pro-drugs that require activation in E. coli by specific bacterial nitroreductases NfsA and NfsB. Hit to lead chemistry led to the generation of compounds that were potent on wild-type and multi-drug resistant clinical isolates of E. coli, Shigella spp., and Salmonella spp. These compounds are bactericidal and efficacious in a mouse thigh infection model.

The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and in vivo in preclinical species and humans. Pacritinib showed ~5 fold higher affinity to human plasma proteins relative to mouse in vitro. It was metabolized by human CYP3A4 in vitro, and did not significantly induce CYP3A and 1A2 in human hepatocytes. In vitro metabolism studies with mouse and human liver microsomes showed the presence of four major metabolites of Pacritinib -M1 (oxidation), M2 (dealkylation), M3 (oxidation), M4 (reduction). The in vitro and in vivo metabolic patterns observed in mice and humans were in good agreement. Qualitatively and quantitatively, none of the metabolites formed in vivo was >10% of Pacritinib in mouse, dog and humans. Pacritinib showed systemic clearance of 8.0, 1.6, 1.6 l/h/kg, volume of distribution of 14.2, 7.9, 8.5 l/kg, t1/2 of 5.6, 6.0, 4.6 h, and oral bioavailability of 39, 10, and 24% in mouse, rat and dog, respectively. In radiolabeled mass balance and QWBA studies in mice, ~91% of the dose was recovered in feces, suggesting biliary clearance, and maximum radioactivity was seen in the gastrointestinal tract followed by the kidney, heart and low activity in the brain. The relatively high exposures of Pacritinib in humans might be attributed to its very high plasma protein binding, low metabolic and/or biliary clearance.

Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC(50) = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC(50): PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials., (©2012 AACR.)

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed > 99% binding to plasma from mice, dog and humans. It was metabolically stable in human and dog liver microsomes relative to mouse and rat. SB1317 was mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 did not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). SB1317 did not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro. The metabolic profiles in liver microsomes from preclinical species were qualitatively similar to humans. In pharmacokinetic studies SB1317 showed moderate to high systemic clearance (relative to liver blood flow), high volume of distribution ( > 0.6 L/kg), oral bioavailability of 24%, ∼ 4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice. The favorable ADME of SB1317 supported its preclinical development as an oral drug candidate.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 μM) but inhibited 2C19 (IC(50) = 5.8 μM). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ∼84 and 94%. The blood-to-plasma ratio was ∼1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l · h(-1) · kg(-1) and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and ∼3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.

SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 μg of protein lysate. AcH3 levels of liver, spleen, PBMCs, bone marrow and tumor were measured in BALB/c mice, HCT-116 xenografted BALB/c nude mice, or in SCID mice orthotopically engrafted with AML (HL-60) after oral treatment with SB939. AcH3 could only be detected after treatment. In all tissues, the highest signal detected was at the 3-hour time point on day 1. On day 15, the signal decreased in normal tissues but increased in cancerous tissues and became detectable in the bone marrow of leukemic mice. In all tissues, acH3 correlated with SB939 dose levels (r(2)=0.76-0.94). When applied to PBMCs from 30 patients with advanced solid malignancies in a phase I clinical trial, a dose-dependent (10-80 mg) increase in relative acH3 was observed 3-hour postdose on day 1, correlating with C(max) and AUC of SB939 concentrations in plasma (r=0.97, P=0.014). Our data show that the favorable pharmacokinetic and pharmacodynamic properties of SB939 are translated from preclinical models to patients., (© 2011 American Association for Cancer Research.)

The large current densities attained by carbon nanotube enabled vertical field effect transistors using crystalline organic channel materials are somewhat unexpected given the known large anisotropy in the mobility of crystalline organics and their conventional ordering on dielectric surfaces which tends to orient their high mobility axes parallel to the surface. This seeming contradiction is resolved by the finding that the nanotubes induce a molecular ordering that reorients the high mobility axes to favor current flow in a direction perpendicular to the substrate surface.