Medicinal and Pharmaceutical Chemistry Commons^™

New Dosing Schedules Of Dasatinib For Cml And Adverse Event Management, Siu Fun Wong

Pharmacy Faculty Articles and Research

Resistance to imatinib in patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has emerged as a significant clinical issue. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. Here, we review the clinical profile of dasatinib in imatinib-resistant and -intolerant patients and share clinical approaches for managing adverse events (AEs) to ensure maximum patient benefit. References were obtained through literature searches on PubMed as well as from the Proceedings …

Antibiotics, Herbs, And Magic: Health Practices In Contemporary St. Petersburg, Christine Shu

Honors Theses

In St. Petersburg, Russia, two seemingly conflicting health doctrines, western medicine and alternative medicine, play significant roles in residents' health culture. I define alternative medicine as all health practices that use such natural products as herbs, natural honey, water, seeds, berries, and even animal products, and as such unobtrusive body therapies as acupuncture, massage, yoga, or animal therapies. I define western medicine as all treatments that involve the manipulation of ingredients in a chemistry laboratory (such as antibiotics, antiviral drugs, antihistamines. or pain killers) and all body therapies intrusive to the body (such as operations). Through interviews with St. Petersburg …

Structure- And Ligand-Based Design Of Novel Antimicrobial Agents, Kirk Edward Hevener

Theses and Dissertations (ETD)

The use of computer based techniques in the design of novel therapeutic agents is a rapidly emerging field. Although the drug-design techniques utilized by Computational Medicinal Chemists vary greatly, they can roughly be classified into structure-based and ligand-based approaches. Structure-based methods utilize a solved structure of the design target, protein or DNA, usually obtained by X-ray or NMR methods to design or improve compounds with activity against the target. Ligand-based methods use active compounds with known affinity for a target that may yet be unresolved. These methods include Pharmacophore-based searching for novel active compounds or Quantitative Structure-Activity Relationship (QSAR) studies. …

Synthesis And Evaluation Of Tetramic Acids As Antimicrobial Agents, Jason B. Wilson

Theses and Dissertations (ETD)

As bacterial infectious diseases are a major cause of morbity and mortality throughout the world, and many causative organisms are resistant to currently available antibiotics, the motivation for the development of new drugs is readily apparent. A number of natural products exhibiting antimicrobial activity possess a tetramic acid (2,4-pyrrolidinedione) functional group. As their antibacterial mechanism of action is different from that of many of the currently available antibiotics, these compounds have potential to serve as a basis for a pharmacophore in synthetic compounds. However, toxicity to eukaryotic cells is frequently a problem with currently known tetramic acids. The purpose of …

Helical Peptides Derived From Lactoferrin Bind Hepatitis C Virus Envelope Protein E2, Reem Beleid, Donna Douglas, Norman Kneteman, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Hepatitis C virus is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma infecting more than 170 million people. Hepatitis C virus envelope 2 glycoprotein (E2) binds several cell‐surface molecules that act as receptor candidates mediating hepatitis C virus entry into hepatocytes. Peptides derived from human lactoferrin have been shown to bind hepatitis C virus‐E2 protein thereby preventing hepatitis C virus entry in cultured hepatocytes. In this study, starting from a 33‐residue human lactoferrin‐derived peptide, a number of biotin‐linked α‐peptides were synthesized and investigated for their E2 protein binding activity. E2 protein from hepatitis C virus genotype 1b …

Oxidative Stress-Mediated Anticancer Activity Of Novel Ahr Modulators Af & 5f203, Lancelot S. Mclean

Loma Linda University Electronic Theses, Dissertations & Projects

Estrogen receptor positive (ER+) breast cancer tends to respond to anti-estrogen agents such as Tamoxifen. Approximately 40% of ER+ breast cancer is resistant to these agents and those that initially respond often acquire resistance. Estrogen receptor negative (ER-) breast cancer remains largely unresponsive to these agents. It is therefore vital to discover drugs that are potent in both forms of breast cancer. Aminoflavone, (5-amino-2, 3-fluorophenyl)-6,8-difluoro-7-methyl-4H-l-benzopyran-4-one; AF; NSC 686288) and 5F203, (2-[-Amino-3-methy phenyl]-5-flurobenzothiazole) are novel anticancer candidate agents that display potent in vitro and in vivo anti-proliferative activity against select human tumor cells with a unique anticancer activity profile in the …

Flavonoids And Related Compounds As Nucleoside Transporter Inhibitors, Surekha Ravaji Pimple

Theses and Dissertations (ETD)

Mammalian nucleoside transporters can be classified into two main categories, namely, equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). ENTs are ubiquitous, and mediate sodium-independent bi-directional facilitated diffusion nucleoside transport processes. CNTs on the other hand, are secondary active unidirectional transporters that are sodium-dependent. Both the equilibrative and the concentrative nucleoside transporters have several family members which are ENT1 to ENT4 and CNT1 to CNT6. Over the past two decades, important advances in the understanding of nucleoside transporter functions have been made. Identification and molecular cloning of the ENT and CNT families from mammals and protozoan parasites have provided …

Regulation Of Apical Nhe3 Trafficking By Ouabain-Induced Activation Of Basolateral Na/K-Atpase Receptor Complex, Haiping Cai, Liang Wu, Weikai Qu, Deepak Malhotra, Zijian Xie, Joseph I. Shapiro, Jiang Liu

Pharmaceutical Science and Research

The long-term effects of ouabain on transepithelial Na⁺ transport involve transcriptional downregulation of apical Na⁺/H⁺ exchanger isoform 3 (NHE3). The aim of this study was to determine whether ouabain could acutely regulate NHE3 via a posttranscriptional mechanism in LLC-PK1 cells. We observed that the basolateral, but not apical, application of ouabain for 1 h significantly reduced transepithelial Na⁺ transport. This effect was not due to changes in the integrity of tight junctions or increases in the intracellular Na⁺ concentration. Ouabain regulated the trafficking of NHE3 and subsequently inhibited its activity, a process independent of …

Composites Comprising Cholesterol And Carboxymethyl Cellulose, Vuk Uskoković

Pharmacy Faculty Articles and Research

Whereby cholesterol presents one of the major fatty substances in human body, carboxymethyl cellulose is a water-soluble derivative of cellulose, the most abundant dietary fiber. Whereas on one hand in vivo precipitation of cholesterol is the major cause of atherosclerosis, dietary fibers are on the other hand known for their ability to clean the fatty plaque deposited on intestinal pathways, and prevent its build-up in other critical areas within the organism. In this work, a method for the preparation of a composite material comprising cholesterol and carboxymethyl cellulose from 1-hexanol/water biphase mixtures is reported. Specificity of the interaction between the …

Right-Handed 14-Helix In Β3-Peptides From L-Aspartic Acid Monomers, Kamaljit Kaur, Tara Sprules, Wael Soliman, Reem Beleid, Sahar Ahmed

Pharmacy Faculty Articles and Research

β-Peptides made from L-aspartic acid monomers form a new class of β³-peptides. Here we report the first three-dimensional NMR solution structure of a β³-hexapeptide (1) from L-aspartic acid monomers in 2,2,2-trifluoroethanol (TFE). We show that 1 forms a right-handed 14-helical structure in TFE. α-peptides from naturally occurring L-amino acids adopt a right-handed α-helix whereas β³-peptides formed from β³-amino acids derived from naturally occurring L-amino acids form left-handed 14-helices. The right-handed 14-helical conformation of 1 is a better mimic of α-peptide conformations. Using the NMR structure of 1 in TFE, we …

Different Requirements Of The Swi/Snf Complex For Robust Nucleosome Displacement At Promoters Of Heat Shock Factor And Msn2- And Msn4-Regulated Heat Shock Genes, Tamara Y. Erkina, P. A. Tschetter, Alexander M. Erkine

Scholarship and Professional Work – COPHS

The stress response in yeast cells is regulated by at least two classes of transcription activators—HSF and Msn2/4, which differentially affect promoter chromatin remodeling. We demonstrate that the deletion of SNF2, an ATPase activity-containing subunit of the chromatin remodeling SWI/SNF complex, eliminates histone displacement, RNA polymerase II recruitment, and heat shock factor (HSF) binding at the HSP12 promoter while delaying these processes at the HSP82 and SSA4 promoters. Out of the three promoters, the double deletion of MSN2 and MSN4 eliminates both chromatin remodeling and HSF binding only at the HSP12 promoter, suggesting that Msn2/4 activators are primary determinants of …

The Mechanism Of Silver Dissolution For Biomedical Devices And Hygienic Coating Applications., Yanmei Ma

Doctoral

This work focuses on the mechanism of silver dissolution for biomedical and hygienic coating applications. The research work began from the investigation of silver dissolution behaviour from pure silver and silver-platinum alloys in solutions with or without chloride using the technique of cyclic volammetry (CV). A zero resistance amperometry (ZRA) measurement was carried out to study the effect of platinum on the silver dissolution behaviour in 0.89%wt. NaCI solution. The mechanism of silver dissolution from pure silver and silver-platinum alloys in 0.89%wt. NaCI solution was proposed by an equivalent circuit model under the investigation of electrochemical impedance spectroscopy (EIS). It …

Analysis Of Residual Solvents In Pharmaceuticals By Comprehensive Two-Dimensional Gas Chromatography, Cristina Marie Crimi

Seton Hall University Dissertations and Theses (ETDs)

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Age-Associated Hepatic Drug Transporter Expression And Its Implications For Pediatric Pharmacotherapyflexibility Affect Dna Topoisomerase I Function, Lisa Tang

Theses and Dissertations (ETD)

Members of the ATP-binding cassette (ABC) family of drug transporter proteins translocate various endogenous and exogenous substrates across intra- and extracellular membranes. Two specific ABC transporters, the multidrug resistance 1/P-glycoprotein (MDR1/P-gp) and the multidrug resistance protein 2 (MRP2), serve as major hepatic transporters that mediate the biliary excretion of various organic anions and cations along with glutathione-, glucuronate-, or sulfate-conjugates of several drug substrates. However, very little is known about the expression of these transporters in the early infant and childhood ages of human development. We, therefore, characterized the ontogeny of these transporters by measuring their gene and protein expression. …

The Role Of Multi-Drug Resistance Associated Protein 4 And P-Glycoprotein In Resistance Of Neuroblastoma To Topotecan And Irinotecan, Patricia Kellie Turner

Theses and Dissertations (ETD)

High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with high-risk disease did not respond to the putatively effective topotecan systemic exposure. These children represent a subset …

Synthesis Of Novel Sulfonamide-Based Calpain Inhibitors And Their Potential As Anti-Tumor Agents, Jin Xu

Theses and Dissertations (ETD)

Calpain is a class of intracellular cytoplasmic cysteine proteases.1 The enzyme participates in different intracellular signaling pathways that are mediated by Ca2+.2 The two major isoforms of calpain universally distributed in most mammalian tissues are calpain 1 (µ-calpain) and calpain 2 (m-calpain). The exact in vivo function of the enzyme is not clear, but calpain has been implicated in a variety of physiological and pathological conditions,3 such as cancer, stroke, cardiac ischaemia, muscular dystrophy, cataract and Alzheimer’s disease. Calpain inhibitors are therefore of interest as therapeutic agents and as biomedical tools.

Several potent calpain inhibitors isolated from natural sources as …

Role Of Medial Prefrontal Cortical Group Ii Metabotropic Glutamate Receptor In The Development Of Cocaine Sensitization, Xiaohu Xie

Theses and Dissertations (ETD)

The current studies examined the role of medial prefrontal cortical (mPFC) group II metabotropic glutamate receptors (mGluR_2/3) in the development of cocaine sensitization. Initial studies demonstrated that intra-mPFC injection of the mGluR_2/3 receptor agonist, APDC, dose-dependently reduced acute behavioral response to cocaine (0.015-15 nmol/side with significant effects starting at 1.5nmol/side). The effects of APDC were prevented by intra-mPFC co-injections of an mGluR_2/3 antagonist, LY341495 (1.5 nmol/side). Repeated intra-mPFC APDC (1.5 nmol/side) injections also prevented the initiation of behavioral and neurochemical sensitization, which is defined as enhanced nucleus accumbens (NAc) dopamine response to cocaine. Once sensitization was …

A Role For Shps-1/Sirpα In Concanavalin A-Dependent Production Of Mmp-9, Arm R. Amin, M. Helal Uddin Biswas, Takeshi Senga, Gen-Sheng Feng, Reiji Kannagi, Munna L. Agarwal, Michinari Hamaguchi

Pharmaceutical Science and Research

SHPS‐1/SIRPα1 is a transmembrane glycoprotein that belongs to the immunoglobulin (Ig) super family. In the present study, we show that SHPS‐1 strongly associates with Concanavalin A (Con A), a plant lectin obtained from jack beans. Further studies with SHPS‐1 mutants reveal that the extracellular domain of SHPS‐1 containing the Ig sequence is responsible for its association with Con A. Con A treatment induces cross‐linking and multimerization of the SHPS‐1 protein in the plasma membrane, accompanied by its tyrosine phosphorylation and recruitment of SHP‐2. In contrast, Ricinus communis agglutinin (RCA), another lectin obtained from castor bean, does not bind or activate …

A Protein Interaction Map Of The Mitotic Spindle, Jonathan Wong, Yuko Nakajima, Stefan Westermann, Ching Shang, Jung-Seog Kang, Crystal Goodner, Pantea Houshmand, Stanley Fields, Clarence S.M. Chan, David Drubin, Georjana Barnes, Tony R. Hazbun

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

The mitotic spindle consists of a complex network of proteins that segregates chromosomes in eukaryotes. To strengthen our understanding of the molecular composition, organization, and regulation of the mitotic spindle, we performed a system-wide two-hybrid screen on 94 proteins implicated in spindle function in Saccharomyces cerevisiae. We report 604 predominantly novel interactions that were detected in multiple screens, involving 303 distinct prey proteins. We uncovered a pattern of extensive interactions between spindle proteins reflecting the intricate organization of the spindle. Furthermore, we observed novel connections between kinetochore complexes and chromatin-modifying proteins and used phosphorylation site mutants of NDC80/TID3 to gain …

Trypanothione Reductase: A Viable Chemotherapeutic Target For Antitrypanosomal And Antileishmanial Drug Design, M. O. Faruk Khan

Pharmaceutical Science and Research

Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The …

Tobramycin-Induced Hepatotoxicity, Sarah A. Nisly, Shaunta' M. Ray, Robert A. Moye

Scholarship and Professional Work – COPHS

OBJECTIVE. To report a case of tobramycin-induced hepatotoxicity. CASE

SUMMARY: A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3–6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased …

Antitrypanosomal, Antileishmanial, And Antimalarial Activities Of Quaternary Arylalkylammonium 2-Amino-4-Chlorophenyl Phenyl Sulfides, A New Class Of Trypanothione Reductase Inhibitor, And Of N-Acyl Derivatives Of 2-Amino-4-Chlorophenyl Phenyl Sulfide, Seheli Parveen, M. O. Faruk Khan, Susan E. Austin, Simon L. Croft, Vanessa Yardley, Peter Rock, Kenneth T. Douglas

Pharmaceutical Science and Research

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition ∼40-fold (3′,4′-dichlorobenzyl-[5-chloro-2-phenylsulfan- ylphenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 ( 0.2 µM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396′, P398′, and L399′), (ii) ionic interactions for the cationic nitrogen with Glu-466′ or -467′. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki′ ) 11.3-42.8 µM). The quaternized analogues of the 2-chlorophenyl phenylsulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. bruceirhodesiense STIB900, …

Probing Proteinase Active Sites Using Oriented Peptide Mixture Libraries – Adam-10, John L. Krstenansky, Jihong Wang, Gregg R. Chenail, Matthew R. Tiffany, Geoffrey M. Kuesters, Barbara C. Natke, John L. Nestor Jr.

Pharmaceutical Science and Research

Oriented Peptide Mixture Libraries can provide a full matrix of preferred and disfavored amino acids at each subsite of an optimal substrate for a new proteinase. This approach is rapid and convenient, requiring only two mixture libraries to complete the analysis. In this paper we demonstrate an extension of this type of analysis, using a focused library employing unnatural amino acids to probe the depth of the S1 position in the catalytic site of the alpha secretase ADAM-10. This analysis indicates that ADAM- 10 will accept amino acids with substantial length and hydrophobicity (e.g. 2- naphthylalanine), but suggests that the …

Riboflavin Synthase Of Schizosaccharomyces Pombe. Protein Dynamics Revealed By 19f Nmr Protein Perturbation Experiments., Markus Fischer, Ann-Kathrin Schott, Kristina Kemter, Richard Feicht, Gerald Richter, Boris Illarionov, Wolfgang Eisenreich, Stefan Gerhardt, Mark S. Cushman, Stefan Steinbacher, Robert Huber, Adelbert Bacher

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Background

Riboflavin synthase catalyzes the transformation of 6,7-dimethyl-8-ribityllumazine into riboflavin in the last step of the riboflavin biosynthetic pathway. Gram-negative bacteria and certain yeasts are unable to incorporate riboflavin from the environment and are therefore absolutely dependent on endogenous synthesis of the vitamin. Riboflavin synthase is therefore a potential target for the development of antiinfective drugs.

Results

A cDNA sequence from Schizosaccharomyces pombe comprising a hypothetical open reading frame with similarity to riboflavin synthase of Escherichia coli was expressed in a recombinant E. coli strain. The recombinant protein is a homotrimer of 23 kDa subunits as shown by sedimentation equilibrium …

Effects Of Mtad On Some Physical Properties Of Enamel And Dentin, Tanya Kristina Machnick

Loma Linda University Electronic Theses, Dissertations & Projects

Recently, a Mixture of Tetracycline, an Acid, and a Detergent (MTAD) has been advocated to remove smear layer and disinfect canals. The purpose of this study was to evaluate the effect of MTAD the flexural strength and modulus of elasticity of dentin as well as its effect on the bond strength to enamel and dentin. In Part I, dentin bars were randomly assigned to eight groups treated either with various concentrations of NaOCl (5.25%, 2.65%, 1.31%, 0.66%), 17% EDTA, MTAD, saline, or according to a clinical protocol with 1.3% NaOCl and then 5 min of MTAD. …

A Study Of 5-Aminolevulinic Acid And Its Methyl Ester Used In In Vitro And In Vivo Systems Of Human Bladder Cancer, Vanaja Manivasager, Paul Wan Sia Heng, Jinsong Hao, Wei Zheng, Khee Chee Soo, Malini Olivo

Pharmaceutical Science and Research

The use of 5-aminolevulinic acid and its esters to induce endogenous porphyrins for the purpose of detection of epithelial cancers is being studied extensively in many centres around the world. The challenge is to prepare an efficacious formulation for the purpose of cancer detection. Photodynamic diagnosis of cancer using 5-aminolevulinic acid (ALA) and its ester derivatives is being actively investigated. In this study, we compared ALA with ALA methyl ester (AME) derivative in terms of PpIX fluorescence intensity in in vitro and in vivo systems of bladder carcinoma. For the in vivo system consisting of RT112 xenografts, the modes of …

Macro-Microscopic Fluorescence Imaging Of Human Npc Xenografts In A Murine Model Using Topical Vs. Intravenous Administration Of 5-Aminolevulinic Acid, Vanaja Manivasager, Paul Wan Sia Heng, Jinsong Hao, Wei Zheng, Khee Chee Soo, Malini Olivo

Pharmaceutical Science and Research

The use of 5-aminolevulinic acid to induce endogenous porphyrins for the purpose of detection of epithelial cancers is being studied extensively in many centres around the world. The challenge is to prepare an efficacious formulation of 5-ALA for the purpose of cancer detection. In this study, we compared two formulations of topical 5-ALA applications with intravenous administration in NPC/CNE-2 xenografts on balb/c nude mice. One of the formulations was a gantrez muco-adhesive patch and the other was a polyvinyl-pyrolidone muco-adhesive patch. The Karl Storz fluorescence endoscopy system was used to obtain macroscopic fluorescence images. Microscopic fluorescence imaging was done by …

Antioxidation Activity Of Dhea And Its Mechanisms, Sun Yang, Han Rui

Pharmacy Faculty Articles and Research

Objective: The aim of this study was to determine the anti-oxidative activity of a new chemopreventive agent--dehydroepiandrosterone (DHEA), and the mechanisms of action by which DHEA protect the thymocytes and DNA from oxidative damage. Methods: Agarose gel electrophoresis, flow cytometry, single cel! gel electrophoresis, chemiluminescence assay, triazolyl blue tetrazolumbromide (MTT) colorimetry, and three dimensional collagen gel assay were used. Results: In agarose gel electrophoresis, 10 nmol/L DHEA blocked the typical DNA degradation (DNA Ladder) induced by H₂O₂. DHEA 2. 5 nmol/L and 10 nmol/L both significantly decreased the percentage of characteristic apoptotic DNA …

Ouabain Interaction With Cardiac Na+/K+-Atpase Initiates Signal Cascades Independent Of Changes In Intracellular Na+ And Ca2+, Jiang Liu, Jiang Tian, Michael Haas, Joseph I. Shapiro, Amir Askari, Zijian Xie

Pharmaceutical Science and Research

We have shown previously that partial inhibition of the cardiac myocyte Na⁺/K⁺-ATPase activates signal pathways that regulate myocyte growth and growth-related genes and that increases in intracellular Ca²⁺ concentration ([Ca²⁺]i) and reactive oxygen species (ROS) are two essential second messengers within these pathways. The aim of this work was to explore the relation between [Ca²⁺]i and ROS. When myocytes were in a Ca²⁺-free medium, ouabain caused no change in [Ca²⁺]i, but it increased ROS as it did when the cells were in …

Protein Adducts Of Iso[4]Levuglandin E2, A Product Of The Isoprostane Pathway, In Oxidized Low Density Lipoprotein, Robert G. Salomon, Wei Sha, Cynthia Brame, Kamaljit Kaur, Ganesamoorthy Subbanagounder, June O'Neil, Henry F. Hoff, L. Jackson Roberts Ii

Pharmacy Faculty Articles and Research

Levuglandin (LG) E₂, a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H₂, avidly binds to proteins. That LGE₂-protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE₂-LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radical-induced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now …