Publications by authors named "Mahmood Ahmed"

64 Publications

Letter to the editor in Response to Komen et al. 2021.

Eur Heart J Cardiovasc Pharmacother 2021 Mar 12. Epub 2021 Mar 12.

Tahir Heart institute, Rabwah, Pakistan.

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http://dx.doi.org/10.1093/ehjcvp/pvab020DOI Listing
March 2021

LocationSpark: In-memory Distributed Spatial Query Processing and Optimization.

Front Big Data 2020 16;3:30. Epub 2020 Oct 16.

Department of Computer Science, Purdue University, West Lafayette, IN, United States.

Due to the ubiquity of spatial data applications and the large amounts of spatial data that these applications generate and process, there is a pressing need for scalable spatial query processing. In this paper, we present new techniques for spatial query processing and optimization in an in-memory and distributed setup to address scalability. More specifically, we introduce new techniques for handling query skew that commonly happens in practice, and minimizes communication costs accordingly. We propose a distributed query scheduler that uses a new cost model to minimize the cost of spatial query processing. The scheduler generates query execution plans that minimize the effect of query skew. The query scheduler utilizes new spatial indexing techniques based on bitmap filters to forward queries to the appropriate local nodes. Each local computation node is responsible for optimizing and selecting its best local query execution plan based on the indexes and the nature of the spatial queries in that node. All the proposed spatial query processing and optimization techniques are prototyped inside Spark, a distributed memory-based computation system. Our prototype system is termed LocationSpark. The experimental study is based on real datasets and demonstrates that LocationSpark can enhance distributed spatial query processing by up to an order of magnitude over existing in-memory and distributed spatial systems.
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http://dx.doi.org/10.3389/fdata.2020.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931877PMC
October 2020

Sex disparities in cardiovascular disease outcomes among geriatric patients with prediabetes.

Prim Care Diabetes 2021 02 4;15(1):95-100. Epub 2020 Jul 4.

Department of Internal Medicine, Texas Health Arlington Memorial Hospital, Arlington, TX, USA.

Aims: To analyze the sex-based differences in the prevalence of cardiovascular disease risk factors and outcomes in older patients with prediabetes using demographically matched national cohorts of hospitalized patients aged ≥65 years.

Methods: We queried the 2007-2014 National Inpatient Database to identify older patients (>65 years) admitted with prediabetes using ICD-9 Clinical Modification codes. The older patients were then subcategorized based on sex. Comparative analyses of their baseline characteristics, the prevalence of cardiovascular(CV) disease comorbidities, hospitalization outcomes, and mortality rates were performed on propensity-matched cohorts for demographics.

Results: A total of 1,197,978 older patients with prediabetes (599,223 males; mean age 75years and 598,755 females; mean age 76years) were identified. Higher admission rates were found commonly among older white males (84.1%) and females (81.7%). Prediabetic older males showed a higher frequency of cardiovascular comorbidities compared to females. Prediabetic older males had higher all-cause in-hospital mortality (4.2% vs. 3.6%, p < 0.001), acute myocardial infarction (7.0% vs. 4.7%, p < 0.001), arrhythmia (36.3% vs. 30.5%, p < 0.001), stroke (4.8% vs. 4.6%, p < 0.001), venous thromboembolism (3.3% vs. 3.0%, p < 0.001) and percutaneous coronary intervention (3.1% vs. 1.5%, p < 0.001) compared to females.

Conclusions: Our analysis revealed that among older patients hospitalized with prediabetes, males suffered worse in-hospital CV outcomes and survival rates compared to females.
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http://dx.doi.org/10.1016/j.pcd.2020.06.005DOI Listing
February 2021

Prevalence, trends and in-hospital outcomes of takotsubo syndrome among United States cannabis users.

Int J Cardiol 2020 10 6;316:43-46. Epub 2020 Jun 6.

Division of Cardiology, Atlanta VA Medical Center, Decatur, GA, USA; Division of Cardiology, Medical College of Georgia, Augusta, GA, USA; Division of Cardiology, Morehouse School of Medicine, Atlanta, GA, USA.

Background: Recent reports suggest a link between increased cannabis (marijuana) use and stress-cardiomyopathy (Takotsubo Syndrome, TTS) and related complications. Amidst recent trends in cannabis legalization and a paucity of data, it remains essential to evaluate the prevalence, trends and outcomes of TTS in cannabis users on a large-scale.

Method: We studied prevalence and trends in TTS among adult cannabis users vs. non-users using the National Inpatient Sample (2007-2014). Baseline characteristics, comorbidities, and in-hospital outcomes of TTS were compared between cannabis users vs. non-users. Weighted logistic regression was performed adjusting for confounders to estimate the inpatient outcomes of TTS with vs. without cannabis use.

Results: The overall prevalence of TTS in cannabis users (47/100,000) was lower as compared to non-users (62/100,000). Rising trends in TTS among cannabis users (<11 to 82, ~8-fold) were more pronounced as compared to non-users (19 to 108, ~6 fold) per 100,000 hospitalizations from 2007 to 2014 (p<0.001). Of all inpatient encounters for TTS (n=156,506), 1565 (0.1%) reported cannabis use. Polysubstance use including alcohol (4.1% vs. 24.4%), cocaine (0.4% vs. 8.5%), amphetamine (0.2% vs. 8.0%), and smoking (31.2% vs. 64.8%) was significantly higher in TTS-cannabis cohort. Although cardiovascular comorbidities were lower in TTS-cannabis cohort, the adjusted odds of all-cause mortality (aOR1.50, p<.05) were 50% higher in cannabis users compared to non-users without statistically significant difference in cardiac complications.

Conclusions: Cannabis users showed lower prevalence but a more pronounced rising trend of TTS and subsequent risk of in-hospital mortality compared to non-users.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.088DOI Listing
October 2020

Designing indenothiophene-based acceptor materials with efficient photovoltaic parameters for fullerene-free organic solar cells.

J Mol Model 2020 May 13;26(6):137. Epub 2020 May 13.

Department of Chemistry, Khwaja Fareed University of Engineering & Information Technology, Rahim Yar Khan, 64200, Pakistan.

Non-fullerene small molecular acceptors (NFSMAs) exhibit promising photovoltaic performance which promoted the rapid progress of organic solar cells (OSCs). In this study, an attempt is done to explore indenothiophene-based high-performance small molecular electron acceptors for organic solar cells. We have designed five acceptor molecules (M1-M5) with strong donor moiety indenothiophene linked to five different end-capped group acceptor moieties: diflouro-2-methylene-3-oxo-2,3-dihydroindene-1-ylidene)malononitrile (A1), 1-(dicyanomethylene)-2-methylene-3-oxo-2,3-dihydro-1H-indene-5,6-dicarbonitrile (A2), methyl-6-cyano-3-(dicyanomethylene)-2-methylene-1-oxo-2,3-dihydro-1H-indene-5-carboylate (A3), 2-(6-cyano-5-fluoro-2-methylene-3-oxo-2,3 dihydro-1H-indene-1-ylidene)malononitrile (A4), and (Z)-methyl 3-(benzo [c][1,2,5]thiadiazol-4-yl)-2-cyanoacrylate (A5) respectively. The structure-property relationship was studied and effects of structural modification on the optoelectronic properties of these acceptors (M1-M5) were determined systematically by comparing it with reference molecule R, which is recently reported as excellent non-fullerene-based small acceptor molecule. Among all designed molecules, M5 is proven as a suitable candidate for organic solar cell applications due to better photovoltaic properties including narrow HOMO-LUMO energy gap (2.11 eV), smallest electron mobility (λ = 0.0038 eV), highest λ values (702.82 nm in gas) and (663.09 nm in chloroform solvent) and highest open-circuit voltage (V = 1.49 V) with respect to HOMO-LUMO. Our results indicate that introducing more end-capped electron-accepting units is a simple and effective alternative strategy for the design of promising NFSMAs. This theoretical framework also proves that the conceptualized NFSMAs are superior and thus are recommended for the future construction of high-performance organic solar cell devices. Graphical abstract.
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http://dx.doi.org/10.1007/s00894-020-04386-5DOI Listing
May 2020

Hepatocellular Carcinoma (HCC), Where do we stand? Current situation.

Pak J Med Sci 2020 Mar-Apr;36(3):344-348

Dr. Faheem-ur-Rehman, FCPS (Med). Department of Medicine, Combined Military Hospital (CMH), Bahawalpur, Pakistan.

Objective: To identify the stage of Hepatocellular Carcinoma (HCC) at the time of presentation.

Methods: This cross sectional observational prospective study was carried out at Gastro Department of Combined Military Hospital (CMH) Multan from August 2017 to December 2018. Patients were diagnosed on the basis of alpha fetoprotein, abdominal ultrasound, triphasic contrast enhanced computerized tomography (CECT). They were evaluated for etiology including Hepatitis B, C and non B & C. The patients were inquired about the previous treatment and when they came to know about the HCC. Staging of the tumor was done on the basis BCLC (Barcelona cancer liver clinic) and Melan's criteria. Performance status (PS) of the patient was checked by Eastern Cooperative Oncology Group (ECOG) criteria. Severity of cirrhosis was assessed by CTP (Child Turcotte Pugh) and Model for end stage liver disease (MELD) score. The data was analyzed in IBM SPSS version 22.

Results: Out of 135 patients 78% were males and 22% females. Age Mean SD was 58.81± 9.366. Frequency of hepatitis C, B, combined B, C and non-B non-C was 80%, 11%, 2.8% and 6.2% respectively. 96(73.8%) never got the treatment before for Hepatitis. 81(62.3%) came to know first time on this index admission. Maximum numbers of patients were in BCLC stage B i.e. 82(55.2%) with ECOG grade of one i.e.57 (39.3%), at the time of presentation. Mean MELD and CTP score were 12.24, 7.34 (class B) respectively.

Conclusion: HCV was the most common in HCC, never treated before, presented for the first time in advance stage of the disease where very limited treatment options left behind.
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http://dx.doi.org/10.12669/pjms.36.3.1594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150378PMC
April 2020

Adsorption of Phosgene Gas on Pristine and Copper-Decorated BN Nanocages: A Comparative DFT Study.

ACS Omega 2020 Apr 26;5(13):7641-7650. Epub 2020 Mar 26.

Department of Chemistry, COMSATS University, Abbottabad Campus, Abbottabad 22060, Pakistan.

Nanostructured gas sensors find diverse applications in environmental and agricultural monitoring. Herein, adsorption of phosgene (COCl) on pure and copper-decorated BN (Cu-BN) is analyzed through density functional theory (DFT) calculations. Adsorption of copper on BN results in two optimized geometries, named Cu@b and Cu@b, with adsorption energies of -193.81 and -198.45 kJ/mol, respectively. The adsorption/interaction energies of COCl on pure BN nanocages are -9.30, -6.90, and -3.70 kJ/mol in , , and geometries, respectively, whereas the interaction energies of COCl on copper-decorated BN are -1.66 and -16.95 kJ/mol for and , respectively. To examine the changes in the properties of pure and Cu-BN nanocages, geometric parameters, dipole moment, , frontier molecular orbitals, and partial density of states (PDOS) are analyzed to comprehensively illustrate the interaction mechanism. The results of these parameters reveal that COCl binds more strongly onto copper-doped BN nanocages. Moreover, a higher charge separation is observed in COCl-Cu-BN geometries as compared to copper-decorated BN geometries. Therefore, these nanocages may be considered as potential candidates for application in phosgene sensors.
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http://dx.doi.org/10.1021/acsomega.0c00507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144133PMC
April 2020

De-escalation of Antiplatelets After Percutaneous Coronary Intervention: A Bayesian Network Meta-Analysis of Various De-escalation Strategies.

Eur Heart J Cardiovasc Pharmacother 2020 Apr 9. Epub 2020 Apr 9.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Aims: To compare early de-escalation of dual antiplatelet therapy (DAPT) (1-3 months) to monotherapy with either P2Y12 inhibitor or aspirin versus 12 months DAPT after percutaneous coronary intervention (PCI) with drug-eluting stent (DES).

Methods And Results: Electronic databases of Medline, Embase, Cochrane library were searched through February 2020 to identify randomized controlled trials. A Bayesian network meta-analysis was conducted with random effects model. The main endpoints of interest were cardiovascular mortality and total bleeding events. Among 7 trials (35,821 patients), 52.6% patients were presented with acute coronary syndrome. A total of 3,359 patients and 14,530 patients were deescalated to aspirin and P2Y12 inhibitor monotherapy, respectively. At a median follow-up of 12-months, compared with 12-months of DAPT, there was no significant difference in cardiovascular mortality between 1-month DAPT followed by P2Y12 inhibitor monotherapy (Hazard ratio [HR], 0.84 [95% credible interval, 0.29-2.43]), 3-months of DAPT followed by P2Y12 inhibitor monotherapy (HR, 0.74 [0.39-1.46]), or 3 months of DAPT (HR, 1.00 [0.54-1.86]) followed by aspirin monotherapy. Except for de-escalation of DAPT to aspirin monotherapy after 3-months (HR, 0.75 [0.43-1.20]), de-escalation to P2Y12 inhibitor monotherapy after 1-month (HR, 0.28 [0.10-0.83]), or 3-months (HR, 0.57 [0.33-0.98]) were associated with significant decrease in total bleeding events. There were no significant differences in terms of ischemic endpoints among different DAPT strategies.

Conclusion: Early de-escalation of DAPT (1-3 months) to monotherapy with a P2Y12 inhibitor instead of aspirin might be a safer and equally effective approach compared with 12 months of DAPT in patients with PCI and DES.
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http://dx.doi.org/10.1093/ehjcvp/pvaa025DOI Listing
April 2020

The Anti-Rheumatoid Activity of Niclosamide in Collagen-Induced Arthritis in Rats.

Arch Rheumatol 2019 Dec 23;34(4):426-433. Epub 2019 Jan 23.

Al-Isra'a University, Pharmacy, Baghdad, Iraq.

Objectives: This study aims to evaluate the anti-arthritic effect of orally administered niclosamide (NCL) on collagen-induced arthritis (CIA) in rats.

Materials And Methods: The study included 35 Sprague Dawley rats (age range, 3 to 4 months; average weight, 100±10 g) of which seven were used as a negative control group (group A) whereas 28, in which arthritis was induced by injection of collagen type II emulsified by incomplete Freund's adjuvant and which were considered as CIA rats, were randomly divided equally into four groups and treated for 28 days with: normal saline (group B), low-dose NCL (group C), high-dose NCL (group D), and diclofenac sodium (group E). Body weight, arthritis index, ankle swelling, and footpad thickness were monitored before and after treatment in all groups. At the end of the treatment period, serum levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6 were measured together with a collection of articular synovial tissue to evaluate the pathological changes.

Results: After four weeks of treatment period, a high dose of orally administered NCL significantly reduced the arthritis index, footpad thickness, and ankle swelling. Significantly decreased serum levels of inflammatory biomarkers including TNF-α, IL-1β, and IL-6 were observed in rats treated with high-dose oral NCL or intramuscular injection of diclofenac sodium, compared with groups B and C. Histopathological examination revealed that a high dose of NCL significantly reduced the infiltration of inflammatory cells, synovial hyperplasia, and bone and cartilage destruction.

Conclusion: Niclosamide can effectively decrease the clinical scores, joint swelling, inflammatory markers, and pathological changes in arthritic rats.
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http://dx.doi.org/10.5606/ArchRheumatol.2019.7100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974393PMC
December 2019

Formulation, characterization and in vivo evaluation of Hedera helix L., topical dosage forms.

Pak J Pharm Sci 2019 Nov;32(6):2605-2610

Institute of Pharmaceutical Sciences, People's University of Medical and Health Sciences, Nawabshah, Pakistan.

The purpose of this study was to prepare topical formulations of micro emulsion, gel and ointment containing the Hedera helix L. extracts against asthma and to evaluate the physicochemical characteristics. A validated HPLC method was used for the analysis of blood plasma. In-vivo studies of the drugs were compared in rabbit plasma with oral dosing. Stability studies were performed for 3 months. The results showed that formulations were stable. No Skin irritation observed on rabbits. The optimized micro emulsion and gel showed fast absorption. Maximal plasma concentration (c) and the maximal time to reach cmax (tmax) were 70.226μg/mL, 75.26μg/mL and 2 hours for the micro emulsion and gel, 90.11μg/mL and 1 hour for the oral drug syrup respectively. Pharmacokinetic parameters such as t, c and AUC of the selected formulations and oral dosing were significantly different (P < 0.01).
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November 2019

Extraction, formulation and characterization of an in vitro and ex-vivo evaluation of Thymus serpyllum L. (Thymus oil) from topical preparations using dialysis cellulose membrane and natural rabbit skin.

Pak J Pharm Sci 2019 Jul;32(4):1563-1570

Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan.

Herbal remedies like the Thymus serpyllum L. is useful in traditional medicine for the treatment of many diseases especially congestion, and bronchitis. The purpose of this study was to formulate a micro-emulsion, a gel and an ointment containing the plant hydro distilled thymus oil extracted from Thymus serpyllum L. collected from Ziarat, Balochistan. The prepared formulations were subjected to in-vitro and ex vivo study release, High performance Liquid Chromatography (HPLC), Thin Layer Chromatography (TLC), to justify their suitability for topical use. The in-vitro and ex-Vivo release was studied using Franz Cells and using two different kinds of membrane synthetic dialysis cellulose membrane and natural rabbit skin and the amount of drug released was determined by HPLC at λ 274nm. The three formulations result obtained through dialysis cellulose membrane showed the faster release than the natural rabbit skin. However, the micro-emulsion, gel formulation showed the same release except ointment. The release from the above mentioned formulation can be arranged in the following descending order. micro-emulsion > Gel > Ointment. The best fit of release kinetics was achieved by Krosmeyer- Peppas, the TLC and HPLC identifies the Thymol, isolation and quantification of the marker. This study demonstrates that it is necessary to assess the impact of release and permeability pattern of different formulations. In vitro and ex-vivo diffusion cell experiments can be utilized to develop formulations of traditional medicines identifies.
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July 2019

Hemodialysis performance and anticoagulant activities of PVP-k25 and carboxylic-multiwall nanotube composite blended Polyethersulfone membrane.

Mater Sci Eng C Mater Biol Appl 2019 Oct 18;103:109769. Epub 2019 May 18.

Institute of Bioproduct Development, Department of Bioprocess and Polymer Engineering, Faculty of Chemical and Energy Engineering, Universiti Teknologi Malaysia, 81310 UTM Johor Bahru, Johor, Malaysia. Electronic address:

Non-covalent electrostatic interaction between amide nitrogen and carbonyl carbon of shorter chain length of polyvinylpyrrolidone (PVP-k25) was developed with in-house carboxylic oxidized multiwall carbon nanotubes (O-MWCNT) and then blended with Polyethersulfone (PES) polymer. FTIR analysis was utilized to confirm bonding nature of nano-composites (NCs) of O-MWCNT/PVP-k25 and casting membranes. Non-solvent induces phase separation process developed regular finger-like channels in composite membranes whereas pristine PES exhibited spongy entities as studied by cross sectional analysis report of FESEM. Further, FESEM instrument was also utilized to observe the dispersion of O-MWCNT/PVP based nanocomposite (NCs) with PES and membranes leaching phenomena analysis. Contact angle experiments described 24% improvement of hydrophilic behaviour, leaching ratio of additives was reduced to 1.89%, whereas water flux enhanced up to 6 times. Bovine serum albumin (BSA) and lysozyme based antifouling analysis shown up to 25% improvement, whereas 84% of water flux was regained after protein fouling than pristine PES. Anticoagulant activity was reported by estimating prothrombin, thrombin, plasma re-calcification times and production of fibrinogen cluster with platelets-adhesions photographs and hemolysis experiments. Composite membranes exhibited 3.4 and 3 times better dialysis clearance ratios of urea and creatinine solutes as compared to the raw PES membrane.
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http://dx.doi.org/10.1016/j.msec.2019.109769DOI Listing
October 2019

PromISR-6, a Guanabenz Analogue, Improves Cellular Survival in an Experimental Model of Huntington's Disease.

ACS Chem Neurosci 2019 08 30;10(8):3575-3589. Epub 2019 Jul 30.

National Neuroscience Institute of Singapore , 11 Jalan Tan Tock Seng , Singapore 308433.

Guanabenz (GBZ), an α-adrenergic agonist, demonstrated off-target effects that restored protein homeostasis and ameliorated pathobiology in experimental models of neurodegenerative disease. However, GBZ did not directly activate the integrated stress response (ISR), and its proposed mode of action remains controversial. Utilizing an iterative screen of over 10,000 GBZ analogues, we analyzed 432 representative compounds for cytotoxicity in Wild-type, PPP1R15A-/-, and PPP1R15B-/- mouse embryonic fibroblasts. Nine compounds clustering into three functional groups were studied in detail using cell biological and biochemical assays. Our studies demonstrated that PromISR-6 is a potent GBZ analogue that selectively activated ISR, eliciting sustained eIF2α phosphorylation. ISRIB, an ISR inhibitor, counteracted PromISR-6-mediated translational inhibition and reduction in intracellular mutant Huntingtin aggregates. Reduced protein synthesis combined with PromISR-6-stimulated autophagic clearance made PromISR-6 the most efficacious GBZ analogue to reduce Huntingtin aggregates and promote survival in a cellular model of Huntington's disease.
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http://dx.doi.org/10.1021/acschemneuro.9b00185DOI Listing
August 2019

Stability-indicating HPLC-PDA assay for simultaneous determination of paracetamol, thiamine and pyridoxal phosphate in tablet formulations.

Acta Pharm 2019 Jun;69(2):249-259

Institute of Chemistry University of the Punjab, Lahore 54590 Pakistan.

With the increased number of multi-drug formulations, there is a need to develop new methods for simultaneous determinations of drugs. A precise, accurate and reliable liquid chromatographic method was developed for simultaneous determination of paracetamol, thiamine, and pyridoxal phosphate in pharmaceutical formulations. Separation of analytes was carried out with an Agilent Poroshell C18 column. A mixture of ammonium phosphate buffer (pH = 3.0), acetonitrile and methanol in the ratio of 86:7:7 (V/V/V) was used as the mobile phase pumped at a flow rate of 1.8 mL min-1. Detection of all three components, impurities and degradation products was performed at the selected wavelength of 270 nm. The developed method was validated in terms of linearity, specificity, precision, accuracy, LOD and LOQ as per ICH guidelines. Linearity of the developed method was found in the range 17.5-30 µg mL-1 for thiamine, 35-60 µg mL-1 for pyridoxal phosphate and 87.5-150 µg mL-1 for paracetamol. The coefficient of determination was ≥ 0.9981 for all three analytes. The proposed HPLC method was found to be simple and reliable for the routine simultaneous analysis of paracetamol, thiamine and pyridoxal phosphate in tablet formulations. Complete separation of analytes in the presence of degradation products indicated selectivity of the method.
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http://dx.doi.org/10.2478/acph-2019-0017DOI Listing
June 2019

Probing Mitochondrial Permeability Transition Pore Activity in Nucleated Cells and Platelets by High-Throughput Screening Assays Suggests Involvement of Protein Phosphatase 2B in Mitochondrial Dynamics.

Assay Drug Dev Technol 2018 12 27;16(8):445-455. Epub 2018 Nov 27.

GlaxoSmithKline R&D , Stevenage, United Kingdom .

Mitochondrial permeability transition pore (mPTP) formation is well documented in isolated mitochondria. However, convincing detection of mPTP in whole cells remains elusive. In this study, we describe a high-throughput assay for Ca-activated mPTP opening in platelets using HyperCyt flow cytometry. In addition, we demonstrate that in several nucleated cells, using multiple approaches, the detection of cyclophilin D-dependent mPTP opening is highly challenging. Results with the mitochondrial-targeted Ca-sensing green fluorescent protein (mito-Case12) suggest the involvement of protein phosphatase 2B (PP2B; calcineurin) in regulating mitochondrial dynamics. Our results highlight the danger of relying on cyclosporine A alone as a pharmacological tool, and the need for comprehensive studies of mPTP in the cell.
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http://dx.doi.org/10.1089/adt.2018.872DOI Listing
December 2018

Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches.

Molecules 2018 Jun 25;23(7). Epub 2018 Jun 25.

Department of Biosciences, COMSATS University Islamabad, Park Road, 45550 Islamabad, Pakistan.

The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR) molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r²), leave-one-out (LOO) cross validated correlation coefficient (q²), bootstrapping, and Fisher's randomization test. The highly reliable and predictive CoMFA (q² = 0.569, r² = 0.979) and CoMSIA (q² = 0.500, r² = 0.982) models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94). The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein's active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds.
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http://dx.doi.org/10.3390/molecules23071527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099705PMC
June 2018

Niclosamide as an adjuvant to etanercept in treatment patients with active rheumatoid arthritis: an 8-week randomized controlled pilot study.

Clin Rheumatol 2018 Oct 7;37(10):2633-2641. Epub 2018 Jun 7.

Department of Pharmacy, Al-Isra'a University, Baghdad, Iraq.

This study designed to identify the therapeutic efficacy of niclosamide (NCL) in Iraqi patients suffering from active rheumatoid arthritis (RA) who were using etanercept (ETN) for more than 3 months and still had high or moderate active RA. One hundred ten patients suffering from active rheumatoid arthritis (RA) who were using etanercept (ETN) for more than 3 months and still had high or moderate active RA were allocated randomly into two equal groups: one of them treated with 1000 mg/day NCL and the other treated with 1000 mg/day lactose in capsule dosage form. The study duration was 8 weeks. Clinical efficacy of the NCL was measured depending on scoring of the 28-joint Disease Activity Score (DAS28), simple disease activity index (SDAI), clinical disease activity index (CDAI), and Health Assessment Questionnaire Disability Index (HAQ-DI) at the baseline and at the end of the 8-week treatment period. Moreover, blood sample were taken from the patients at baseline and at after 8 weeks of treatment for measurement of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin 1β (IL-1 β), interleukin-6, tumor necrosis factor (TNF-α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. At the end of the clinical study, patients had good response to NCL when added to the ETN with a high significant improvement in the SJC, TJC, DAS-28, CDAI, SDAI, and HAQ-DI compared to patients who were received placebo drug. In addition to that, 33% of patients achieved an ACR 20% response (ACR20) on NCL and ETN. Of these, 4% achieved ACR50 and another 4% achieved ACR70 response. While those group treated by placebo + ETN, 5% achieved ACR20 response and no one reached to ACR50 or ACR70 response. Twenty-seven percent of RA patients who have taken the NCL achieved moderate EULAR score while only 17% from the group that taken placebo with ETN achieved moderate response. On the other hand, no significant reduction was found in CRP, ESR, TNF-α, and IL-6, while IL-1 β reduced significantly after treatment with NCL. Treatment with NCL also exerts a significant lowering in the serum level of the E-selectin, ICAM1, and VCAM1 when compared to their value in baseline level. In RA disease, the use of NCL as adjuvant with ETN has resulted in a marked reduction in clinical assessment scoring indices and significantly decreased the E-selectin, ICAM-1, and VCAM-1 with marked improvement in the quality of life of patients.
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http://dx.doi.org/10.1007/s10067-018-4164-5DOI Listing
October 2018

Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS.

Cell Death Dis 2018 05 22;9(6):596. Epub 2018 May 22.

Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1 mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer's disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1 motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPKα) was the sole isoform responsible for SOD1-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPKα inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1 mice. Our findings demonstrate the pathogenic effect of p38 MAPKα on axonal retrograde transport and identify a potential therapeutic strategy for ALS.
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http://dx.doi.org/10.1038/s41419-018-0624-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964181PMC
May 2018

Sulfonamides containing curcumin scaffold: Synthesis, characterization, carbonic anhydrase inhibition and molecular docking studies.

Bioorg Chem 2018 02 20;76:218-227. Epub 2017 Nov 20.

Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan. Electronic address:

Curcumin is a multi-functional pharmacologically safe natural agent with proven cytoprotective effects to healthy human cells. In this study, a new series of sulfonamides with curcumin scaffold were synthesized, characterized and investigated for their carbonic anhydrase isoenzyme I (human) and II (bovine) isoforms. The structures of newly synthesized compounds were described by IR, H NMR and C NMR spectral data. Compound 14 showed the K value of 0.99 µM with highest inhibitory activity among all other synthesized compounds against hCA-I enzyme. Similarly enzyme kinetic studies of compound 14, 16 and 30 against bCAII enzyme showed Ki values of 0.71, 0.67 and 0.71 µM respectively. Our biological assays results showed that most of active compounds have similar inhibitory activities compared to standard acetazolamide drug. The molecular docking predicted binding modes showed that these compounds bind with hCA-1 enzyme in similar fashion.
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http://dx.doi.org/10.1016/j.bioorg.2017.11.015DOI Listing
February 2018

UHPLC-PDA Assay for Simultaneous Determination of Vitamin D and Menaquinone-7 in Pharmaceutical Solid Dosage Formulation.

J Anal Methods Chem 2017 21;2017:1208753. Epub 2017 Aug 21.

Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan.

A newly developed method based on ultrahigh performance liquid chromatography (UHPLC) was optimized for the simultaneous determination of vitamin D and menaquinone-7 (MK-7) in tablet formulation in the present study. UHPLC separation of vitamin D and MK-7 was performed with ACE Excel 2 C18-PFP column (2 m, 2.1 × 100 mm) at 0.6 mL min flow rate, whereas the mobile phase consisted of methanol/water (19 : 1, v/v, phase A) and isopropyl alcohol (99.9%, phase B) containing 0.5% triethylamine. Isocratic separation of both the analytes was performed at 40°C by pumping the mobile phases A and B in the ratio of 50 : 50 (v/v, pH, 6.0). Both analytes were detected at a wavelength of 265 nm and the injection volume was 1.0 L. The overall runtime per sample was 4.5 min with retention time of 1.26 and 3.64 min for vitamin D and MK-7, respectively. The calibration curve was linear from 5.0 to 100 g mL for vitamin D and MK-7 with a coefficient of determination () ≥ 0.9981, while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.46 and 2.21%, respectively. The proposed HPLC method was demonstrated to be simple and rapid for the determination of vitamin D and MK-7 in tablets.
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http://dx.doi.org/10.1155/2017/1208753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585589PMC
August 2017

Curcumin: Synthesis optimization and in silico interaction with cyclin dependent kinase.

Acta Pharm 2017 Sep;67(3):385-395

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Curcumin is a natural product with enormous biological potential. In this study, curcumin synthesis was revisited using different reaction solvents, a catalyst (n-butylamine) and a water scavenger [(n-BuO)3B], to develop the optimal procedure for its rapid acquisition. During synthesis, solvent choice was found to be an important parameter for better curcumin yield and high purity. In a typical reaction, acetyl acetone was treated with boron trioxide, followed by condensation with vanillin in the presence of tri-n-butyl borate as water scavenger and n-butylamine as catalyst at 80 °C in ethyl acetate to afford curcumin. Moreover, curcumin was also extracted from turmeric powder and spectroscopic properties such as IR, MS, 1H NMR and 13C NMR with synthetic curcumin were established to identify any impurity. The purity of synthetic and extracted curcumin was also checked by TLC and HPLC-DAD. To computationally assess its therapeutic potential against cyclin dependent kinases (CDKs), curcumin was docked in different isoforms of CDKs. It was observed that it did not dock at the active sites of CDK2 and CDK6. However, it could enter into weak interactions with CDK4 protein.
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http://dx.doi.org/10.1515/acph-2017-0023DOI Listing
September 2017

Screening of curcumin-derived isoxazole, pyrazoles, and pyrimidines for their anti-inflammatory, antinociceptive, and cyclooxygenase-2 inhibition.

Chem Biol Drug Des 2018 01 14;91(1):338-343. Epub 2017 Aug 14.

Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.

Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In this study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles, and pyrimidines and then the synthesized molecules were evaluated for their anti-inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration. Any behavioral and neurological changes were observed at dose of 10 mg/kg body weight. Additionally, cyclooxygenase-2 (COX-2) enzyme inhibition studies were performed through in vitro assays. In vivo anti-inflammatory studies showed that curcumin with pyrimidines was the most potent anti-inflammatory agent which inhibited induced edema from 74.7% to 75.9%. Compounds 7, 9, and 12 exhibited relatively higher prevention of writhing episodes than any other compound with antinociceptive activity of 73.2%, 74.9%, and 71.8%, respectively. This was better than diclofenac sodium (reference drug, 67.1% inhibition). Similarly, COX-2 in vitro inhibition assays results revealed that compound 12 (75.3% inhibition) was the most potent compound. Molecular docking studies of 10, 11, and 12 compounds in human COX-2 binding site revealed the similar binding modes as that of other COX-2-selective inhibitors.
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http://dx.doi.org/10.1111/cbdd.13076DOI Listing
January 2018

Azomethines, isoxazole, N-substituted pyrazoles and pyrimidine containing curcumin derivatives: Urease inhibition and molecular modeling studies.

Biochem Biophys Res Commun 2017 08 13;490(2):434-440. Epub 2017 Jun 13.

Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan. Electronic address:

Curcumin has shown large number of pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its various derivatives for diverse biological functions. In this study, curcumin derived azomethine, isoxazole, pyrimidines and N-substituted pyrazoles were synthesized to investigate their urease enzyme inhibition. The structures of newly synthesized compounds were described by IR, MS, H NMR and C NMR spectral data. Urease enzyme inhibition was evaluated through in vitro assays in which compound 8b was found to be the most potent (IC = 2.44 ± 0.07 μM) among the tested compounds. The compounds with diazine ring system except the 4d showed better urease inhibition (IC = 11.43 ± 0.21-19.63 ± 0.28 μM) than the standard urease inhibitor thiourea (IC = 22.61 ± 0.23 μM). Similarly enzyme kinetics data revealed that compounds 3c-3e and 8b were competitive inhibitors with Ki values of 20.0, 19.87, 20.23 and 19.11 μM respectively while the compounds 4b, 4c and 4e were mixed type of inhibitors with Ki values 6.72, 19.69 and 6.72 μM respectively. Molecular docking studies were also performed to identify the plausible binding modes of the most active compounds.
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http://dx.doi.org/10.1016/j.bbrc.2017.06.059DOI Listing
August 2017

Stability Indicating UHPLC-PDA Assay for Simultaneous Determination of Antazoline Hydrochloride and Naphazoline Hydrochloride in Ophthalmic Formulations.

Acta Chim Slov 2017 06;64(2):332-341

In the present study, a newly developed method based on ultrahigh performance liquid chromatography (UHPLC) was optimized for the simultaneous determination of antazoline hydrochloride (ANZ) and naphazoline hydrochloride (NFZ) in ophthalmic formulations. Isocratic separation of ANZ and NFZ was performed at 40 °C with an ACE Excel 2 C18-PFP column (2 μm, 2.1 × 100 mm) at a flow rate of 0.6 mL min-1 whereas the mobile phase consisted of acetonitrile/phosphate buffer (60:40, v/v, pH 3.0) containing 0.5% triethylamine. Both analytes were detected at a wavelength of 285 nm and the injection volume was 1.0 μL. The overall run time per sample was 4.5 min with retention time of 0.92 and 1.86 min for NFZ and ANZ, respectively. The calibration curve was linear from 0.500-100 μg mL-1 for ANZ and NFZ with a correlation coefficient ≥ 0.9981 while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.28 and 2.14%, respectively. In comparison with high-performance liquid chromatography (HPLC), the developed UHPLC method had remarkable advantages over HPLC as the run time was significantly reduced by 3.4-fold with a 5-fold decreased solvent consumption. Forced degradation studies indicated a complete separation of the analytes in the presence of their degradation products providing high degree of method specificity. The proposed UHPLC method was demonstrated to be simple and rapid for the determination of ANZ and NFZ in commercially available ophthalmic formulations providing recoveries between 99.6 and 100.4%.
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http://dx.doi.org/10.17344/acsi.2017.3166DOI Listing
June 2017

Compromised Neurotrophic and Angiogenic Regenerative Capability during Tendon Healing in a Rat Model of Type-II Diabetes.

PLoS One 2017 25;12(1):e0170748. Epub 2017 Jan 25.

Karolinska Institutet, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Stockholm, Sweden.

Metabolic diseases such as diabetes mellitus type-II (DM-II) may increase the risk of suffering painful connective tissue disorders and tendon ruptures. The pathomechanisms, however, by which diabetes adversely affects connective tissue matrix metabolism and regeneration, still need better definition. Our aim was to study the effect of DM-II on expressional changes of neuro- and angiotrophic mediators and receptors in intact and healing Achilles tendon. The right Achilles tendon was transected in 5 male DM-II Goto-Kakizaki (GK) and 4 age-matched Wistar control rats. The left Achilles tendons were left intact. At week 2 post-injury, NGF, BDNF, TSP, and receptors TrkA, TrkB and Nk1 gene expression was studied by quantitative RT-PCR (qRT-PCR) and their protein distribution by immunohistochemistry in intact and injured tendons. The expression of tendon-related markers, Scleraxis (SCX) and Tenomodulin (TNMD), was evaluated by qRT-PCR in intact and injured tendons. Injured tendons of diabetic GK rats exhibited significantly down-regulated Ngf and Tsp1 mRNA and corresponding protein levels, and down-regulated Trka gene expression compared to injured Wistar controls. Intact tendons of DM-II GK rats displayed reduced mRNA levels for Ngf, Tsp1 and Trkb compared to corresponding intact non-diabetic tendons. Up-regulated Scx and Tnmd gene expression was observed in injured tendons of normal and diabetic GK rats compared to intact Wistar controls. However, these molecules were not up-regulated in injured DM-II GK rats compared to their corresponding controls. Our results suggest that DM-II has detrimental effects on neuro- and angiotrophic pathways, and such effects may reflect the compromised repair seen in diabetic Achilles tendon. Thus, novel approaches for regeneration of injured, including tendinopathic, and surgically repaired diabetic tendons may include therapeutic molecular modulation of neurotrophic pathways such as NGF and its receptors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266316PMC
August 2017

Synthesis, antibacterial and antifungal possession of amino acids containing sulfonamide moieties.

Pak J Pharm Sci 2016 Sep;29(5):1609-1613

Govt Kinnaird College, Lahore, Pakistan.

Sulfonamides were developed by the simple reaction of amino acid with p-toluenesulfonyl chloride and structures of the new products (2a, 2b and 2c) were confirmed by elemental and spectral analysis (FT-IR, 1HNMR and13CNMR). In vitro, developed compounds were screened for their antibacterial and antifungal activities against two sensitive bacteria belonging to both gram positive and gram-negative types and two fungi. The synthesized sulfonamides (2a, 2b, 2c) exhibited excellent antifungal activities against the tested fungi. Among the tested compounds 2a and 2b have marked activity against E. coli with zone of inhibition (mm) 22.3±0.11and 20.2±0.26 (MIC: 12.5µg/mL, 12.5µg/mL) and S. aureus with zone of inhibition (mm) 20.2±0.26 and 23.2±0.55 (MIC: 12.5µg/mL, 6.25µg/mL). Compound 2c is moderately efficient towards E. coli (zone of inhibition (mm) 14.2±0.64, MIC: 100µg/mL) and no activity against S. aureus.
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September 2016

Analytical Method for the Identification and Assay of Kojic Acid, Methylparaben, and Propylparaben in Cosmetic Products Using UPLC: Application of ISO 12787:2011 Standard.

J AOAC Int 2016 Sep 21;99(5):1191-6. Epub 2016 Jun 21.

University of the Punjab, Institute of Chemistry, Canal Rd, Lahore 54590, Pakistan.

A straightforward, fast UPLC method is developed for the identification and quantification of kojic acid (KA), methylparaben (MP), and propylparaben (PP) in 15 cosmetic products (skin whitening creams and lotions). Chromatographic separations for KA, MP, and PP were obtained in 3.5 min on an Acquity BEH-C18 column (100 × 2.1 mm, 1.7 μm particle size) as the stationary phase at 260 nm (diode-array detector), with the mobile phase comprising a mixture of 0.01 M dibasic potassium phosphate and methanol-acetonitrile (50 + 50). Validation studies were performed according to in-house established criteria. There was a linear function of concentrations over the range of 0.4-1.6 μg/mL for KA, MP, and PP. The LOQ for all components was 0.2 μg/mL using the S/N method. Good separation of analytes was observed, with acceptable values of resolution and tailing. The analytical approach defined in the ISO 12787:2011 standard ("Cosmetics-Analytical methods-Validation criteria for analytical results using chromatographic techniques") was used for the assay of cosmetic samples.
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http://dx.doi.org/10.5740/jaoacint.16-0026DOI Listing
September 2016

Synthesis, antimicrobial and antifungal possessions of tramadol esters: In vitro studies.

Pak J Pharm Sci 2015 Jul;28(4):1307-10

Institute of chemistry, University of Punjab, Lahore, Pakistan.

Tramadol esters were prepared by refluxing equimolar concentration of tramadol with leucine and asparagine separately with methanol, sulphuric acid and phthalic anhydride for 10 hours and temperature was maintained at 75°C. After refluxing, the colour of sample solutions were changed from colorless to yellow, blank solution was prepared in the same way as the sample solution except the Tramadol. Both the products and blank were neutralized with sodium carbonate and excess of sodium bicarbonate was precipitated as sodium sulphate, which was washed with acetone. The structures of both the products were confirmed with spectral data (FT-IR, 1HNMR and 13CNMR). Antimicrobial and anti-fungal property of derivative of analgesic tramadol drug was tested with one fungus and three sensitive bacteria belonging to both gram positive and gram-negative types. Esterified product of tramadol with leucine and asparagine showed moderate activity against Escherichia coli and Tricophyton rubrum. Both the products showed marked activity against Staphylococcus aureus and found no activity against Salmonella spp.
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July 2015

A Novel Method for the Synthesis of (99m)Tc-Ofloxacin Kits Using D-Penicillamine as Coligand and Their Application as Infection Imaging Agent.

Biomed Res Int 2015 19;2015:502680. Epub 2015 May 19.

Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan.

The employment of radiopharmaceuticals is increasing nowadays for infection imaging and early execution of patients having infectious or inflammatory complaints. The main aim of this study was to discover a novel method for the labeling of ofloxacin with (99m)Tc, optimization of labelling conditions to get higher percent yield, to assess kits radiochemical purity, in vitro stability, partition coefficient, protein binding, and intracellular accumulation in Pseudomonas aeruginosa, Salmonella typhi, and Escherichia coli in infected rabbits. Maximum labeling efficiency was achieved when 1.5 mg ofloxacin was labeled with 10-20 mCi sodium pertechnetate in the presence of 3 mg D-penicillamine, 75 μg SnCl₂. In vitro binding and biodistribution in Pseudomonas aeruginosa, Salmonella typhi, and Escherichia coli showed good results. This new complex is efficient for the imaging of infections caused by Gram-positive and Gram-negative bacteria.
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http://dx.doi.org/10.1155/2015/502680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452244PMC
March 2016