Measurement Uncertainty and Validation for Quantitation of Salbutamol in Human Urine by Gas Chromatography-Tandem Mass Spectrometry.

A simple, rapid, sensitive and specific gas chromatography-tandem mass spectrometry (GC-MS/MS) method was developed for quantitation of salbutamol in human urine using salbutamol-d3 as the internal standard. The processing of urines samples includes deconjugation with enzymatic hydrolysis, solid phase extraction procedure utilizing XAD2 column and liquid-liquid extraction accompanied by the derivatization by means of MSTFA/IODO-TMS/DTE mixture. The GC column was a HP Ultra-1 (17 m × 0.22 mm × 0.11 µm) used to separate the peak of interest. The data for GC-MS/MS were acquired and processed utilizing GC Labs Solution and Insight GCMS Software. The detection of spectra was performed on TQ 8050. This method included a chromatographic run of 13.67 min and the linearity was found over the concentration range of 250-2000 ng/mL with a regression coefficient (r2) of 0.99. The coefficient of variation for intra and interday assay precision was between 1.85 and 2.85% and the accuracy was between 95.50 and 107.04% for low quality control (QC), medium QC and high QC. The recovery was adequate to reliable detect the analyte at or below the level recommended by the World Anti-Doping Agency i.e., threshold 1000 ng/mL. The limit of detection and limit of quantification were found to be 10 and 100 ng/mL, respectively. The expanded measurement uncertainty (Uexp%) was found to be 8.28%.

A rare anomaly: duodenal Dieulafoy's lesion in a preterm baby.

Neonatal Dieulafoy's lesion is a rare but serious condition that can be life-threatening if not diagnosed and intervened in a timely manner. It presents with episodes of sudden acute gastrointestinal haemorrhage in the form of blood in vomit and/or blood in stool. In general, most of the lesions are successfully treated with endoscopic or angiographic intervention. Surgery is usually reserved for cases that fail endoscopic or angiographic intervention. We present a neonatal case of duodenal Dieulafoy's lesion that occurred in a 29-week-old male baby with birth weight of 1.2 kg. He developed melena and haematemesis at 4 weeks of life. He required normal saline boluses and transfusion of blood products for acute blood loss. The lesion was successfully treated with endoscopic intervention.

Visibility and Analytics Network (VAN) approach to improve immunization supply chain and management performance system in Pakistan.

BACKGROUND: Pakistan has been experiencing several immunization related challenges. The supply chain management information system (MIS) is considered an important component of immunization services as it can improve visibility in key areas such as vaccine shortages or wastage. This study assessed the effectiveness of the Visibility and Analytics Network (VAN) approach in improving vaccine supply and availability of stocks by comparing the situation in intervention and non-intervention districts in Sindh province of Pakistan. METHODS: We utilized a quantitative and qualitative approach to collect data to assess the VAN approach in two districts of Sindh province in Pakistan. The data were collected between August and October 2017. VAN is a systematic monitoring system which measures the performance of vaccine supply chain management based on a set of indicators. We assessed storage facilities of the Expanded Programme on Immunization (EPI) in Sindh and interviewed personnel involved using a pre-tested data collection tool. We also conducted in depth interviews with senior management to assess performance of VAN, adoption mechanism and needs to scale up the VAN approach. RESULTS: We assessed 52 EPI facilities of Sindh province government. In the intervention district 83.3% managers were using MIS data for decision making related to vaccine supplies whereas in the non- intervention district no MIS based data were available. Ninety percent of stores were maintaining a stock registry and 100% supplies matched with requisitions in the intervention district compared to 40% and 35% in the non-intervention district for the same variables. Vaccine wastage was high in the non- intervention district (BCG 46.7% vs 33.9; OPV 13.5% vs 9.5%; pneumococcal 11.4% vs 7.4%). In-depth interview findings suggested that the VAN approach provided data guided monitoring in Pakistan for the first time. The approach also enabled district managers to make timely decisions. CONCLUSION: The VAN approach improves vaccine supply chain management. It should be scaled up and implemented at national or sub national especially in countries struggling with vaccine supply chain management.

Doxorubicin loaded carboxymethyl Assam bora rice starch coated superparamagnetic iron oxide nanoparticles as potential antitumor cargo.

In recent years, polysaccharide-decorated superparamagnetic iron oxide nanoparticles (SPIONs) have gained attention in the field of "nanotheranostics" with integrated diagnostic and therapeutic functions. Carboxymethyl Assam bora rice starch-stabilized SPIONs (CM-ABRS SPIONs), synthesized by co-precipitation method, has already shown exciting potential towards magnetic drug targeting potential. After establishing it as a promisable targeting carrier, the present study is focused on the next step i.e. to evaluate its In vitro anti-tumor potential by loading anticancer drug "Doxorubicin hydrochloride (DOX)" onto CM-ABRS SPIONs. DOX-loaded CM-ABRS SPIONs were physico-chemically characterized by DLS, zeta-potential, TEM, FT-IR, XRD, and VSM analysis. Spectroflourimetric analysis confirmed the maximum loading of DOX up to 6% (w/w) onto CM-ABRS SPIONs via electrostatic interactions. Further, molecular level drug performance was investigated by docking study against receptors (HER-2 and Folate receptor-α) over expressed in cancer cells and MTT assay (in MCF-7 and HeLa cell line), which conferred promisable results of DOX-CM-ABRS SPIONs as compared to standard DOX solution.

Carboxymethyl Assam Bora rice starch coated SPIONs: Synthesis, characterization and in vitro localization in a micro capillary for simulating a targeted drug delivery system.

Carboxymethyl Assam Bora rice starch coated superparamagnetic iron oxide nanoparticles (CM-ABRS SPIONs) were chemically synthesized by co-precipitation method and particle size reduction was controlled by high energy homogenization process. Effects of various process variables (polymer concentration, homogenization speed and cycles) were optimized on the basis of average particle size (Z-average) and polydispersity index (PDI) of CM-ABRS SPIONs. The optimized CM-ABRS SPIONs were characterized for their particle size, surface morphology, electrokinetic potential, chemical interactions, crystallinity, magnetic properties, and targeting potential in presence of external magnetic field. In vitro localization of CM-ABRS SPIONs in a suspension of FITC (Fluorescein isothiocyanate) labeled RBCs (Red blood cells; hematocrit value; 45% (v/v)) was conducted inside a square glass capillary (500 × 500 µm2 cross section) in the presence of an externally applied magnetic field (Ms = 150 mT), simulating the case of magnetic drug targeting (MDT) approach. The aggregation dynamics of CM-ABRS SPIONs inside a micro capillary was observed with respect to time (t = 0 to 600 s), which shows proportionality to time of exposure to the externally applied magnetic field. This in vitro study acts as an important platform for design and optimization of active targeted drug delivery system.

Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors.

A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC50 = 2.2 µM) and EGFR binding (IC50 = 0.97 µM) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G2/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds and two π-π interaction with binding energies ΔG = -34.581 Kcal/mol.

Pyridazinone hybrids: Design, synthesis and evaluation as potential anticonvulsant agents.

A series of new hybrid benzothiazole containing pyridazinones derivatives were designed and synthesized fulfilling all the pharmacophoric requirements essential for the anticonvulsant activity. In-silico and in vitro studies revealed that some of these hybrid derivatives demonstrated admirable GABA AT inhibitory activity. An attempt has also been made to validate the results of in vitro GABA AT inhibition of the most potent compound SPS-5F (IC50 9.10 µM) through in vivo anticonvulsant screening. Compound SPS-5F administration significantly increases the whole brain GABA level, might be through the inhibition of GABA AT enzyme.

Synthesis and characterization of novel carboxymethyl Assam Bora rice starch for the controlled release of cationic anticancer drug based on electrostatic interactions.

Carboxymethyl Assam Bora rice starch (CM-ABRS) was chemically synthesized in non-aqueous medium with the optimum degree of substitution (DS) of 1.23, and physicochemically characterized by FT-IR, DSC, XRD, and SEM analysis. Comparative evaluation of CM-ABRS with native starch (ABRS) for powder flow characteristics, swelling index, apparent solubility, rheological properties, textural properties, and mucoadhesive studies were carried out. The aim of the current work was to investigate the potential of CM-ABRS as a novel carrier for the water-soluble chemotherapeutic, doxorubicin hydrochloride (DOX). Formation of drug/polymer complex (DOX-CM-ABRS) via electrostatic interaction has been evaluated for the controlled release of DOX in three different pH media (phosphate-buffered saline (PBS), pH 7.4, 6.8, and 5.5). In vitro drug release studies illustrated faster release of drug in PBS at pH 5.5 as compared to pH 6.8 and pH 7.4, respectively, indicating the importance of pH-sensitive drug release from the DOX-CM-ABRS complex in malignant tissues.

Exploring 1,3,4-Oxadiazole Scaffold for Anti-inflammatory and Analgesic Activities: A Review of Literature From 2005-2016.

1,3,4-Oxadiazole derivatives are found to have a wide range of pharmacological activities and attracting the researchers to work on this nucleus. Literature survey indicates that many 1,3,4- oxadiazoles have been synthesized with the aim to get compounds of significant anti-inflammatory and analgesic activities with reduced adverse effects. The purpose of this review is to compile the reports on 1,3,4-oxadiazole derivatives possessing anti-inflammatory and analgesic activities. The review also includes the reports on 1,3,4-oxadiazole derivatives of existing NSAIDs in the last ten years.

Design, Synthesis, and Pharmacological Screening of Pyridazinone Hybrids as Anticonvulsant Agents.

A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized in accordance with the pharmacophoric requirements essential for the anticonvulsant activity. The synthesized compounds were evaluated for anticonvulsant activity on mice by the gold standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models. Among the compounds tested, SS-4F showed significant anticonvulsant activity in both the screens with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screens, respectively. Compound SS-4F emerged as safer and effective anticonvulsant due to its several-fold higher protective indices. Further, the gamma-aminobutyric acid (GABA) estimation result showed a marked increase in the GABA level (1.7-fold) as compared to the control, which was further confirmed by good binding properties with the GABAA receptor.

Chemical Modifications of Ketoprofen (NSAID) in Search of Better Lead Compounds: A Review of Literature From 2004-2016.

BACKGROUND: Ketoprofen, a potent anti-inflammatory, analgesic and anti-pyretic drug belonging to the propionic acid class was synthesized in 1968. Rapid absorption, simple metabolism, faster blood brain barrier crossing and high antinociceptive activity are the features responsible for its high use. But, free acidic moiety present in its structure is the major factor that declines its popularity by causing various gastric side effects. Many researchers have chemically modified this drug with the aim to discover an improved and safe NSAID candidate or a new drug with altered activity. We thoroughly searched the literature and found that during the period 2004-2016, more than fifty reports are available on chemical modification of ketoprofen. Along with this, many patents involving chemical modification of ketoprofen have also been reported. However, it was very surprising to note that there are only a few review articles available covering only its pharmacological and clinical properties. There is no review article available covering the chemistry part of ketoprofen. This motivated us to compile the information available on ketoprofen and its derivatives. The purpose of this article is to present an updated review about this topic. METHODS: We thoroughly searched the peer reviewed research literature and compiled all such reportings (2004 onwards) for the benefit of researchers who further want to work on ketoprofen or other NSAIDs. RESULTS: Studies have been conducted to invent strategies to reduce the ulcerogenic properties of ketoprofen and in the course of time, its modified and improved derivatives have been synthesized in search of safer NSAIDs. Along with the aim of reducing the gastric side-effects, researchers have also done chemical modifications in the structure of ketoprofen to improve its solubility, to alter its blood brain-barrierr permeability, to improve its pharmacodynamic profile and to get derivatives possessing antioxidant, antiviral, anticancer and immunomodulatory activities. CONCLUSION: The findings of the review confirm that chemical modifications of ketoprofen decrease ulcer producing side effect while maintaining its desirable actions. Some derivatives were also found to possess better activity profile compared to the parent drug.

Design and synthesis of quinazoline-3,4-(4H)-diamine endowed with thiazoline moiety as new class for DPP-4 and DPPH inhibitor.

New N3-benzylidene (substituted)-2-phenyl-N4-(thiazol-2-yl)-quinazoline-3,4-(4H)-diamine derivatives were design and synthesized by a sequence of reactions starting from appropriate 6-methyl anthranilic acid. The title compounds were screened for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity and diphenyl-2-picryl-hydrazyl (DPPH) assay and results showed significant to good activity in compared to Linagliptin for antidiabetic activity and Ascorbic acid for antioxidant activity. Compound 7g (IC50=0.76nM) exhibited most promising DPP-4 inhibitory activity and also showed good antioxid and result. Docking study was also performed to provide an insight about the binding mode into binding sites of DPP-4 enzyme. Hopefully in future, compound 7g could be used as a lead compound for developing new antidiabetic agent with good antioxidant property.

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives.

A novel series of quinazoline clubbed thiazoline derivatives was rationally designed and synthesized. The newly synthesized compounds were evaluated for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity. Compounds that showed good to moderate activity were compared using linagliptin as standard. Compound 4x (IC50 = 1.12 nM) exhibited the most promising results. The special chemical feature of compound 4x also imparts good inhibition selectivity for DPP-4 over DPP-8/9. Moreover, docking of compound 4x into the active site of DPP-4 illustrates its possible binding interactions.

Design, synthesis, docking and QSAR study of substituted benzimidazole linked oxadiazole as cytotoxic agents, EGFR and erbB2 receptor inhibitors.

The synthesis of benzimidazole linked oxadiazole derivatives designed as potential EGFR and erbB2 receptor inhibitors with anticancer and apoptotic activity were studied. Compounds 7a specifically inhibit EGFR and erbB2 receptor at 0.081 and 0.098 µM concentration. Some of the compounds showed strong, broad-spectrum antiproliferative activitiy when tested against five human cancer cell lines. Compounds 7a and 7n were more cytotoxic than 5-fluorouracil against MCF-7 cancer cell, with IC50 values of 5.0 and 2.55 µM whereas, only 7a led to cell cycle arrest at G2/M phase accompanied by an increase in apoptosis. Compounds 7a and 7n showed normal architecture of myofibrils in cardiomyopathy study whereas only compound 7a showed nearly equal biochemical parameters (SGOT and SGPT) when compared to control. Molecular docking & 3D-QSAR studies were used to establish interactions of 7a and 7n within the active site of enzyme for ATP binding site of kinase domain.

Synthesis and evaluation of benzimidazole derivatives as selective COX-2 inhibitors.

A new series of 1-{(5-substituted-alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl}-2-(piperidin-1-ylmethyl)-1Hbenzimidazoles (5a-5r) was synthesized and screened for their inhibitory activity against COX (1 and 2). In vivo antiinflammatory activity of potent compounds was done by carrageenan-induced rat paw edema model. In vitro anticancer activity of synthesized compounds was also performed at the National Cancer Institute (NCI) against NCI 60 cell lines panel. Out of the 18 compounds screened, 5h, 5i, 5j and 5l were found to be potent COX-2 inhibitors in the range of IC50 0.06-0.81 µM. In vivo anti-inflammatory screening results revealed that the compounds 5h and 5j manifested profound percent protection of 72.8 and 75.0%, respectively. Compound 5f exhibited moderate cytotoxicity with 58.79% growth inhibition against SNB-75 (CNS Cancer) cell lines and moderate activity against COX-2 (IC50 = 8.0 µM).

Design and synthesis of benzimidazole analogs endowed with oxadiazole as selective COX-2 inhibitor.

New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.

Synthesis and antihypertensive screening of new derivatives of quinazolines linked with isoxazole.

A series of 7-substituted-3-(4-(3-(4-substitutedphenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-substituted quinazolin-4(3H)-one (1-30) have been synthesized by the cyclization of (E)-3-(4-(3-substitutedphenyl)acrylolyl)phenyl)-2-(substitutedphenyl)-7-substituted quinazolin-4-(3H)-one with hydroxylamine hydrochloride. The synthesized compounds were examined for their in vivo antihypertensive activity using albino rats. All the titled compounds exhibited good to moderate antihypertensive activity. Compounds 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5- dihydroisoxazol-5-yl)phenyl)-2-p-tolylquinazolin-4(3H)-one (23) and 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-(4-methoxyphenyl)quinazolin-4(3H)-one (24) exhibited potent antihypertensive activity through their anticipated α 1-adrenergic receptor blocking property similar to its clinically used analogue, prazosin, without affecting heart rate with prolonged duration of action when tested in adrenaline induced hypertension in anaesthetized rats.

Pharmacokinetic interaction between febuxostat and morin in rats.

BACKGROUND: Due to wide consumption of flavonoids in the dietary supplement, and an imperative role of CYPs and P-glycoprotein inhibition in drug disposition. So there is increasing scientific interest in drug-flavonoid interactions. OBJECTIVE: The present study aims to investigate the effect of morin, a flavonoid, on the pharmacokinetics of febuxostat in rats. METHODS: A simple ultra-performance liquid chromatography method has been developed for the calculation of febuxostat in 100 µl rat plasma using febuxostat D7 as an internal standard (IS). The assay procedure involved a single-step, liquid-liquid extraction of febuxostat and IS from plasma with methanol. Pharmacokinetic parameters of febuxostat were determined in rats after an oral administration of febuxostat (5 mg/kg) to rats in the control, coadministered and pretreated groups of morin (10 mg/kg). RESULTS: Compared to the control rats given febuxostat alone, the Cmax and AUC of febuxostat increased by 18 - 20 and 47 - 50%, respectively, in rats pretreated with morin. The plasma half-life (t1/2) of the pretreated group is increased by 2.5-fold compared with the control group. Consequently, relative bioavailability values of febuxostat in the rats pretreated with morin were significantly higher (p < 0.05) than those from the control and coadministered groups. Increased bioavailability indicates that the presence of morin could be effective in inhibiting CYP1A1, CYP1A2 and CYP3A4-mediated metabolism and/or effective in inhibiting P-glycoprotein-mediated cellular efflux of febuxostat. CONCLUSION: The presence of morin significantly enhanced the oral exposure of febuxostat, suggesting that concurrent use of morin or morin-containing dietary supplements with febuxostat should be verified to avoid drug-flavonoid interactions.

Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents.

To explore the pharmacological and structure-activity relationship of a series of N-substituted-(4-oxo-2-substituted-phenylquinazolin-3-(4H)-yl), substituted benzene sulfonamide derivatives (1-25) were synthesized from substituted anthranilic acids derived amino quinazolines and substituted benzene sulphonamides. All the synthesized compounds were evaluated for their diuretic (by Lipschitz et al. method), antihypertensive activity by non-invasive blood pressure (NIBP) using the tail-cuff method and anti-diabetic potential in rats. Six compounds showing significantly excellent activity were compared with metolazone, prazosin and diazoxide as standards. Compound N-[7-chloro-2-(4-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl]-4 nitrobenzenesulfonamide (20) exhibited most potent of the series.