Nasal Drug Delivery Systems: An Overview

Since ancient times, drugs have been administered via the nasal route for therapeutic and recreational purposes. The interest in, and importance, of the systemic effects of drugs administered through the nasal route, have expanded over recent decades. Intra-nasal administration of drugs offers an interesting alternative for achieving systemic therapeutic effects of drugs that are comparable to the parenteral route, which can be inconvenient at times or oral administration, which can result in unacceptably low drug bioavailability. So, it is important to understand the potential and limitations of various nasal drug delivery systems. Therefore, the aim of this review article is to discuss the various pharmaceutical dosage forms that have the potential to be utilised for local or systemic drug administration. It is intuitively expected that this review will help to understand and further to develop suitable intra-nasal formulations to achieve specific therapeutic objectives

Antidiabetic Activity of Vinca rosea Extracts in Alloxan-Induced Diabetic Rats

The present study was carried out to evaluate the antidiabetic activity of Vinca rosea methanolic whole plant extracts in alloxan induced diabetic rats for 14 days. The methanolic whole plant extract at high dose (500 mg/kg) exhibited significant anti-hyperglycemic activity than whole plant extract at low dose (300 mg/kg) in diabetic rats. The methanolic extracts also showed improvement in parameters like body weight and lipid profile as well as regeneration of β-cells of pancreas in diabetic rats. Histopathological studies reinforce the healing of pancreas, by methanolic Vinca rosea extracts, as a possible mechanism of their antidiabetic activity

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.We acknowledge support from Cancer Research UK (C5047/A22530, C309/A11566, C368/A6743, A368/A7990, C14303/A17197) and the Dallaglio Foundation. We also acknowledge support from the National Institute of Health Research (NIHR) (The Biomedical Research Centre at The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust and the project "Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)" [G0500966/75466]). We thank the Wellcome Trust, Bob Champion Cancer Trust, The Orchid Cancer appeal, The RoseTrees Trust, The North West Cancer Research Fund, Big C, The King family, and The Masonic Charitable Foundation for funding. This research is supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Simultaneous determination of ofloxacin, tetrahydrozoline hydrochloride, and prednisolone acetate by high-performance liquid chromatography

A simple, specific, and precise high-performance liquid chromatographic method has been developed for the simultaneous determination of ofloxacin (OFX), tetrahydrozoline hydrochloride (THC), and prednisolone acetate (PAC) in ophthalmic suspension using propylparaben (POP) as the internal standard. The mobile phase consists of 0.05M phosphate buffer-acetonitrile (65:35, v/v), and the pH is adjusted to 2.7 with orthophosphoric acid. A column containing octadecyl silane chemically bonded to porous silica particles (Waters Spherisorb, 5 μm ODS 1, 4.6 × 150 mm) is used as the stationary phase. The detection is carried out using a variable wavelength UV-vis detector set at 210 nm for OFX and THC and 254 nm for POP (internal standard) and PAC. The solutions are chromatographed at a constant flow rate of 1.2 mL/min. Retention times for OFX, THC, POP, and PAC are approximately 2.5, 4.5, 7.8, and 9.5 min, respectively. The relative retention times are approximately 0.14 min for OFX, 0.35 min for THC, 1.00 min for POP, and 1.22 min for PAC. The linearity range and percent recoveries for OFX, THC, and PAC are 24-120, 4-16, and 16-80 μg/mL and 100.48%, 100.34%, and 100.21%, respectively

Stability indicating simultaneous determination of domperidone (DP), methylparaben (MP) and propylparaben by high performance liquid chromatography (HPLC)

A simple, specific and precise high performance liquid chromatographic method has been developed and validated for the simultaneous determination of methylparaben (MP), propylparaben (PP), and domperidone (DP) in oral suspension. Isocratic mobile phase consists of 0.5% w/v aqueous ammonium acetate buffer:methanol, 40:60 (v/v). Column containing octylsilyl chemically bonded to porous silica particles (Optimapak, OP C8, 150 mm × 4.6 mm, 5 μm, stainless steel analytical column from RS tech) is used as stationary phase. The detection is carried out using variable wavelength UV-vis detector set at 280 nm. The solutions are chromatographed at constant flow rate of 1.0 mL/min. The method separates MP, PP, DP and droperidol (DR) impurity in less than 12 min with good resolution, peak shapes and minimal tailing. Retention times (RT) for MP, PP, DP and DR are about 3.4, 7.0, 9.0 and 10.9 min, respectively. Linearity range and percent recoveries for MP, PP and DP are 90-270, 10-30, 50-1500 μg/mL and 100.30%, 100.78% and 100.48%, respectively. Method was validated according to ICH guidelines and proved to be suitable for stability testing, homogeneity testing and quality control of these compounds in pharmaceutical preparations. © 2005 Elsevier B.V. All rights reserved

Simultaneous determination of metformin hydrochloride, cyanoguanidine and melamine in tablets by mixed-mode HILIC

A simple and specific hydrophilic interaction liquid chromatography (HILIC) procedure for the quantification of metformin hydrochloride (MFH) and its impurities in bulk pharmaceuticals and finished dosage forms has been developed. The method is based on hydrophilic interaction of the analytes with silica. The influence of the weaker solvent, acetonitrile, pH and the nature and ionic strength of the buffer was studied. Linearity range and percent recoveries for MFH were 100-400 μg mL-1 and 100.62%, respectively. Good validation data were obtained for all compounds. The method separates impurities cyanoguanidine (CGD), melamine (MLN) and other degradation products with a run time of less than 13 min. Degradation studies involved thermal stress, hydrolysis at various pHs and chemical and photolytic oxidation. © 2008 Friedr. Vieweg & Sohn Verlag/GWV Fachverlage GmbH

Simultaneous determination of paracetamol, chlorzoxazone, and related impurities 4-aminophenol, 4′-chloroacetanilide, and p-chlorophenol in pharmaceutical preparations by high-performance liquid chromatography

This paper presents a simple, specific, and precise high-performance liquid Chromatographic method for the simultaneous determination of paracetamol (PCM), chlorzoxazone (CXZ), and their related impurities in bulk raw materials and solid dosage forms. The mobile phase consisted of watermethanol-glacial acetic acid (60 + 40 + 2, v/v/v). A column containing octadecylsilane chemically bonded to porous silica particles (Spherisorb ODS 1, 25 cm × 4.6 mm, 5 μm) was used as stationary phase. Detection was performed using a variable wavelength ultraviolet-visible detector set at 272 nm for all compounds. Solutions were injected into the Chromatograph under isocratic condition at a constant flow rate of 1.2 mL/min. The method was validated according to International Conference on Harmonization requirements and demonstrates good accuracy and precision and a wide linearity range. The method separates PCM, CXZ, and 3 major impurities [4-aminophenol (4AP), 4′-chloracetanilide (4CA), and p-chlorophenol (PCP)] with fair resolution in less than 15 min. The developed method is rapid and sensitive (limit of detection for 4AP, 4CA, and PCP established at 31.25, 39.06, and 65.16 ng/mL, respectively) and, therefore, suitable for quality control and stability studies of these compounds in dosage forms