DESIGN & DEVELOPMENT OF SOLID SELF MICRO-EMULSIFYING OSMOTIC DRUG DELIVERY SYSTEM FOR ISRADIPINE

Objective: The objective of the study was to design and develop self-microemulsifying osmotic pump tablet Isradipine, a BCS Class IV antihypertensive agent for improved solubility and obtain controlled release characteristics. Material & Methods: Methodology for undertaken project involved pre-formulation studies, comprising of analytical method adoption and drug: excipient compatibility studies. Further steps involve formulation and characterization of liquid SMEDDS of Isradipine. Developed SMEDDS was incorporated into selected adsorbent and compressed with osmotic agents, a binder and lubricant into tablet. Tablets were film coated with semi-permeable membrane and drilled with orifice. Final formulation was optimized for various formulation components and evaluated on various dimensions, among dissolution profiling and stability studies. Results and Discussion: Solubility studies in oils, surfactants and co-surfactants were carried out and SMEDDS formulation was finalized as Isradipine (11.63%), Gelucire 50/13 (34.88%), Lutrol F127 (30.23%) and Transcutol P (23.26%). Neusilin US 2 was selected as adsorbent in 1:1 ratio based on excellent adsorption and huge surface area. Final optimized formulation of tablet comprises of core tablet and functional coatings of cellulose acetate (60%) and PEG 400 (40%) with 5% film coating build up. Developed formulation was optimized for various formulation components and evaluated for release kinetics and accelerated stability study. Conclusion: The developed novel SME-OPT of Isradipine will be a promising template for formulating controlled release dosage form of BCS Class II and IV bioactive agents. The technology used for the preparation of SME-OPT is relatively simple manufacturing technology which can be easily adopted in industrial units on a commercial scale

REVIEW OF RECENT STUDIES ON STATISTICAL OPTIMIZATION IN DRUG DELIVERY TECHNOLOGIES

Statistical modeling and experimental design are essential tools in field of drug delivery during product development and can be divided into formula and process optimization. Experimental design allows efficient experimentation in which all or a large subset of factors are together varied over a set of experiments, in contrast to the traditional approach of varying only one variable at time (OVAT). Good estimates for the required composition, geometry, dimensions and preparation procedure of various types of delivery systems will be available, taking into account the desired administration route, drug dose and release profile. Thus, the number of required experimental studies during product development can be significantly reduced, saving time and reducing costs. The present review discusses types of designs and methodologies used recently in academic as well as industrial research for optimization of novel drug delivery systems

Full-scale testing of a damaged reinforced concrete frame in fire

Fires are a relatively likely event following earthquakes in urban locations and in general are an integral part of the emergency response strategies, which are focused on life safety in most developed economies. Similarly, building regulations in most countries require engineers to consider the effect of seismic and fire loading on structures to provide an adequate level of resistance to these hazards; however, this is only on a separate basis. To the authors' knowledge there are no current regulations that require buildings to consider these hazards in a sequential manner to quantify the compound loading and design for the required resistance. This paper provides a first and early report from a novel set of tests on a full-scale reinforced concrete frame subjected to simulated earthquake and fire loads. The results from the first test indicate that the test frame could withstand a pre-damage corresponding to a seismic performance level and subsequent 1 h fire exposure without collapse. Important observations have been made about the development of temperatures and displacements in the various structural elements during the mechanical loading and subsequent fire excursion

Full-scale fire test on an earthquake-damaged reinforced concrete frame

Fire, in the aftermath of an earthquake has evolved as a severely destructive force since the last century [1]. Codes and regulations exist in countries situated in seismically active regions of the world in order to ensure safety of buildings and their occupants in the event of an earthquake; it is however rare to find regulations that also require the consideration of fire following an earthquake, thereby leaving this possibility to be dealt with entirely by emergency responders on an ad-hoc basis with little preparedness. Fire following earthquake (FFE) events in the past, although rare, have sometimes been as destructive as the original earthquake. The aim of this study was to carry out a set of full-scale loading tests on an earthquake damaged, reinforced concrete frame subsequently exposed to fire. The sequential loading was devised in the form of a three phase testing procedure - simulated earthquake loading facilitated by cyclic quasi-static lateral loads; followed by a compartment fire; and finally by subjecting the earthquake and fire damaged frame to a monotonic pushover loading to assess its residual capacity. The reinforced concrete frame was well instrumented with numerous sensors, consisting of thermocouples, strain gauges, linear variable differential transducers (LVDTs) and pressure sensors. A large database of results consisting of temperature profiles, displacements and strains has been generated and salient observations have been made during each stage of loading. This paper describes the experimental investigation and serves as a vehicle for dissemination of the key findings and all the important test data to the engineering community which could be used for validating numerical simulations for further advancing the knowledge and understanding in this relatively poorly researched area

Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitor may address some limitations

Gemcitabine Plus Bevacizumab Compared With Gemcitabine Plus Placebo in Patients With Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303)

The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients

Development of Second-Generation VEGFR Tyrosine Kinase Inhibitors: Current Status

The vascular endothelial growth factor (VEGF) signaling pathway appears to be the dominant pathway involved in tumor angiogenesis, providing a rationale for targeting the VEGF receptors (VEGFR-1, -2, and -3) in the treatment of cancers. In particular, VEGF signaling is thought to be important in renal cell carcinoma (RCC) because of the deregulation of the pathway through nearly uniform loss of the von Hippel Lindau protein. The tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib are approved by the US Food and Drug Administration for the treatment of advanced RCC; however, these multitargeted agents inhibit a wide range of kinase targets in addition to the VEGFRs, resulting in a range of adverse effects unrelated to efficient VEGF blockade. This article reviews recent advances in the development of the second-generation VEGFR TKIs, including the more selective VEGFR TKIs tivozanib and axitinib, and focuses on the potential benefits of novel inhibitors with improved potency and selectivity

Targeting Lactate Dehydrogenase-A Inhibits Tumorigenesis and Tumor Progression in Mouse Models of Lung Cancer and Impacts Tumor-Initiating Cells

The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the interconversion of pyruvate and lactate, is upregulated in human cancers, and is associated with aggressive tumor outcomes. Here we use an inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by reactivation of mitochondrial function in vitro, but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer-initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC, including cancer stem cell-dependent drug-resistant tumors

Transient Gastric Irritation in the Neonatal Rats Leads to Changes in Hypothalamic CRF Expression, Depression- and Anxiety-Like Behavior as Adults

A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them.Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8-10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured.Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated ratsThe present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders