The poor orally available lopinavir was successfully encapsulated in glyceryl behenate based solid lipid nanoparticles (Lo-SLN) for its ultimate use to target intestinal lymphatic vessels in combined ...chemotherapy—the so-called Highly Active Anti-Retroviral Therapy (HAART). SLN with mean particle size of 230
nm (polydispersity index, PDI
<
0.27) and surface electrical charge of approx. −27
mV, were produced by hot homogenization process followed by ultrasonication. Particles were characterized using differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and atomic force microscopy (AFM) to confirm their solid character and the homogeneous distribution of drug within the lipid matrix. In vitro release studies at pH 6.8 phosphate buffer (PBS) and at pH 1.2 HCl 0.1
N showed a slow release in both media. From the intestinal lymphatic transport study it became evident that SLN increased the cumulative percentage dose of lopinavir secreted into the lymph, which was 4.91-fold higher when compared with a conventional drug solution in methyl cellulose 0.5% (w/v) as suspending agent (Lo-MC). The percentage bioavailability was significantly enhanced. The AUC for the Lo-SLN was 2.13-fold higher than that obtained for the Lo-MC of similar concentration. The accelerated stability studies showed that there was no significant change in the mean particle size and PDI after storage at 25
±
2
°C/60
±
5% RH. The shelf life of optimized formulation was assessed based on the remained drug content in the stabilized formulation and was shown to be 21.46 months.
Bortezomib (Velcade, PS341) was licensed in 2003 as a first-in-class 20S proteasome inhibitor indicated for treatment of multiple myeloma, and is currently being evaluated clinically in a range of ...solid tumours. The mechanisms underlying its cancer cell toxicity are complex. A growing body of evidence suggests proteasome inhibition-dependent regulation of the BCL-2 family is a critical requirement. In particular, the stabilization of BH3-only proteins BIK, NOXA and BIM, appear to be essential for effecting BAX- and BAK-dependent cell death. These mechanisms are reviewed and the implications for favourable novel drug interactions are highlighted.
Background
Cogmed Working Memory Training (CWMT) has received considerable attention as a promising intervention for the treatment of Attention‐Deficit/Hyperactivity Disorder (ADHD) in children. At ...the same time, methodological weaknesses in previous clinical trials call into question reported efficacy of CWMT. In particular, lack of equivalence in key aspects of CWMT (i.e., contingent reinforcement, time‐on‐task with computer training, parent–child interactions, supportive coaching) between CWMT and placebo versions of CWMT used in previous trials may account for the beneficial outcomes favoring CWMT.
Methods
Eighty‐five 7‐ to 11‐year old school‐age children with ADHD (66 male; 78%) were randomized to either standard CWMT (CWMT Active) or a well‐controlled CWMT placebo condition (CWMT Placebo) and evaluated before and 3 weeks after treatment. Dependent measures included parent and teacher ratings of ADHD symptoms; objective measures of attention, activity level, and impulsivity; and psychometric indices of working memory and academic achievement (Clinical trial title: Combined cognitive remediation and behavioral intervention for the treatment of Attention‐Deficit/Hyperactivity Disorder; http://clinicaltrials.gov/ct2/show/NCT01137318).
Results
CWMT Active participants demonstrated significantly greater improvements in verbal and nonverbal working memory storage, but evidenced no discernible gains in working memory storage plus processing/manipulation. In addition, no treatment group differences were observed for any other outcome measures.
Conclusions
When a more rigorous comparison condition is utilized, CWMT demonstrates effects on certain aspects of working memory in children with ADHD; however, CWMT does not appear to foster treatment generalization to other domains of functioning. As such, CWMT should not be considered a viable treatment for children with ADHD.
Haemophagocytic Lymphohistiocytosis (HLH)1 is a hyper inflammatory condition triggered by infectious agents, rheumatologic conditions, malignant process or metabolic conditions(secondary) or by gene ...mutation affecting cytotoxic function(familial).This results in unchecked activation of the macrophages and lymphocytes leading to multi organ failure, central nervous system dysfunction and bacterial or fungal infection.HLH1 carries significant risk of mortality unless treatment is promptly initiated.HLH1 could pose a diagnostic challenge as it shares features with sepsis and systemic inflammatory response syndrome. The key signs and symptoms include prolonged fever, hepatosplenomegaly, and cytopenias with characteristic laboratory abnormalities of elevated ferritin, triglycerides, transaminases, bilirubin, LDH2 and low fibrinogen. I am presenting the experience from a District General Hospital in England where diagnosis of 3 confirmed HLH1 were made in the last 4 years.In our case series one was triggered by EBV3, second following varicella zoster while the third one was idiopathic with genetic tests being negative. One of these children was treated as Incomplete Kawasaki Disease before the diagnosis of HLH1 was made (also had extensive rash). All the three had varied modes of presentations with differing clinical signs with one even having elevated cell and platelet count as against the expected cytopenia. Also having proven cause (Varicella and EBV3 in our case) shouldn’t deter us from thinking about other diagnosis including HLH1 if the dots don’t join up. Owing to the shared features with other conditions and HLH1 being a rare condition, potential delay could be avoided if we think about it early and include the screening tests in the initial work up itself. Conclusions to be drawn from these three cases from a secondary level paediatric practice areConsider HLH1 early in the diagnosis of any prolonged and resistant fever.Be vigilant as it mimics clinical features with sepsis and SIRS4 c. Run triglycerides, ferritin, fibrinogen and LDH2 early on so that diagnostic delay can be avoided of potentially fatal but treatable condition.All the three children underwent chemotherapy achieving remission and are under follow up.HLH –Haemophagocytic LymphohistiocytosisLDH –Lactate dehydrogenaseEBV –Epstein Bar VirusSIRS –Systemic inflammatory response syndrome
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► Taguchi orthogonal design was used to optimize chitosan microspheres loaded with insulin, by emulsion cross-linking method. ► Hypoglycemic effect was maintained only up to 5h after ...s.c. insulin injection, whereas for microspheres it reached 12h. ► Chitosan microspheres depicted higher pharmacological activity than chitosan-insulin oral solution (15.8% versus 1.12%). ► Taguchi design was shown very useful to develop an optimized formulation with a minimum number of experiments.
Insulin-loaded chitosan microspheres were engineered by emulsion cross-linking method using glutaraldehyde as cross-linker. Taguchi orthogonal method was applied to optimize the production time and reduce the number of experiments required to obtain an optimized formulation. Three variables were evaluated, i.e. chitosan and glutaraldehyde concentrations, and cross-linking time at three levels. The dependent variables were the mean particle size and the encapsulation efficiency. The optimal formulation was obtained with chitosan 3% (w/v), glutaraldehyde 3.5% (v/v), and cross-linking time of 5h, characterized by microspheres with a mean particle size of 29.5μm, and insulin encapsulation efficiency of 71.6±1.3%. In vivo studies were carried out using male Wistar albino rats, revealing a significant reduction in blood glucose level after administration of the optimized formulation, in comparison to a subcutaneous insulin injection. Chitosan microspheres were superior in terms of sustaining protein release over conventional insulin therapy.
Low concentrations of serum 25-hydroxyvitamin D 25(OH)D may be associated with cardiometabolic disorders; however, little is known about their relation to intermediate metabolic and lipid markers.
We ...investigated the relation of serum 25(OH)D concentrations to fasting insulin, glucose, dyslipidemia, adiposity, and prevalent metabolic syndrome.
We conducted this cross-sectional analysis in 292 postmenopausal women aged 50-79 y in the Women's Health Initiative Calcium-Vitamin D (WHI-CaD) trial. Data were collected from 3 nested case-control studies that measured baseline serum 25(OH)D concentrations. Inverse probability weighting was used to approximate parameter estimates for the WHI-CaD population.
In weighted linear regression models adjusted for age, race-ethnicity, month of blood draw, region, case-control status, smoking, alcohol, physical activity, and history of cardiometabolic risk factors, there was an inverse association of serum 25(OH)D with adiposity body mass index (BMI): β = -1.12 ± 0.30, P = 0.0002; waist circumference: β = -3.57 ± 0.49, P < 0.0001; waist-hip ratio: β = -0.01 ± 0.002, P < 0.0001, triglycerides (β = -0.10 ± 0.02, P < 0.0001), and triglyceride:HDL-cholesterol ratio (β = -0.11 ± 0.03, P = 0.0003). The multivariable-adjusted odds ratio for metabolic syndrome for the highest (≥52 nmol/L) compared with the lowest (<35 nmol/L) tertile of serum 25(OH)D concentrations was 0.28 (95% CI: 0.14, 0.56). Significant associations remained after adjustment for BMI. We observed no significant associations with LDL cholesterol, HDL cholesterol, insulin, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), or homeostatic model assessment of β cell function (HOMA-β).
Higher serum 25(OH)D concentrations may be inversely associated with adiposity, triglycerides, triglyceride:HDL-cholesterol ratio, and metabolic syndrome but are not associated with LDL and HDL cholesterol, insulin, glucose, HOMA-IR, or HOMA-β in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.
Insulin-loaded microspheres composed of chitosan 3% (w/v), and loading 120 IU insulin were produced by emulsion cross-linking method. Cross-linking time was 5 h and glutaraldehyde 3.5% (v/v) was used ...as cross-linker. Swelling ratio studies were evaluated to predict release of insulin from chitosan microspheres. Bacitracin and sodium taurocholate were incorporated in the formulations as proteolytic enzyme inhibitor and absorption enhancer, respectively. In vitro insulin release studies were performed in phosphate buffer pH 7.4 and also in HCl pH 2 with and without trypsin. Activity of bacitracin was also evaluated. In vitro release showed a controlled profile up to 12 h and the formulation containing 0.15% (w/v) of bacitracin revealed a maximum biological activity of about 49.1 ± 4.1%. Mathematical modeling using Higuchi and Korsmeyer–Peppas suggested a non-Fickian diffusion as the mechanism of insulin release. Insulin-loaded chitosan microspheres for oral delivery showed to be an innovative and reliable delivery system to overcome conventional insulin therapy.
Display omitted In vitro insulin release studies of 120 IU insulin loading cross-linked chitosan microspheres were performed in phosphate buffer pH 7.4 containing trypsin. Activity of bacitracin was also evaluated. In vitro release showed a controlled profile up to 12 h and the formulation containing 0.15% (w/v) of bacitracin revealed a maximum biological activity of about 49.1 ± 4.1%. Mathematical modeling following Higuchi and Korsmeyer–Peppas suggested a non-Fickian diffusion as the mechanism of insulin release.
► Insulin release was analyzed by zero order, first order, Higuchi and Korsmeyer–Peppas models. ► Cross-linked chitosan microspheres promoted a slow swelling at pH 2. ► Following Korsmeyer–Peppas model, the diffusional release was reported non-Fickian.
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus ...formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa K i = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.
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