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Articles 271 - 292 of 292

Full-Text Articles in Chemicals and Drugs

Pharmacokinetic/Pharmacodynamic (Pk/Pd) Modeling Of Anti-Neoplastic Agents, Daniel Lexcen, Ahmed H. Salem, Walid F. Elkhatib, Virginia Haynes, Ayman Noreddin Apr 2012

Pharmacokinetic/Pharmacodynamic (Pk/Pd) Modeling Of Anti-Neoplastic Agents, Daniel Lexcen, Ahmed H. Salem, Walid F. Elkhatib, Virginia Haynes, Ayman Noreddin

Pharmacy Faculty Books and Book Chapters

"Development of tumor resistance to chemotherapeutics is related to inherent tumor variations regarding sensitivity to chemotherapeutics and to sub-optimal dosing regimens, including variation in patient pharmacokinetics that result in suboptimal exposure of tumor cells to anti-neoplastic drugs [1, 2]. The rate and extent of drug efficacy depends on the extent of drug exposure at the tumor site and the time above the effective concentration [3]. In vitro models that incorporate these pharmacokinetic and pharmacodynamic (PK/PD) principles to optimize therapeutic response may be considered the method of choice for optimizing dosing schedules before translating data from static assays to animals and …


Synthetic Peptides Derived From The Sequence Of A Lasso Peptide Microcin J25 Show Antibacterial Activity, Rania Soudy, Liru Wang, Kamaljit Kaur Jan 2012

Synthetic Peptides Derived From The Sequence Of A Lasso Peptide Microcin J25 Show Antibacterial Activity, Rania Soudy, Liru Wang, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Microcin J25 (MccJ25) is a plasmid-encoded, ribosomally synthesized antibacterial peptide with a unique lasso structure. The lasso structure, produced with the aid of two processing enzymes, provides exceptional stability to MccJ25. We report the synthesis of six peptides (16), derived from the MccJ25 sequence, that are designed to form folded conformation by disulfide bond formation and electrostatic or hydrophobic interactions. Two peptides (1 and 6) display good activity against Salmonella newport, and are the first synthetic derivatives of MccJ25 that are bactericidal. Peptide 1 displays potent activity against several Salmonella strains including two …


Compound 49b: A Novel Beta-Adrenergic Receptor Agonist In The Treatment Of Diabetic Retinopathy, Kimberly Williams-Guy Dec 2011

Compound 49b: A Novel Beta-Adrenergic Receptor Agonist In The Treatment Of Diabetic Retinopathy, Kimberly Williams-Guy

Theses and Dissertations (ETD)

Diabetic retinopathy is the leading cause of blindness in working Americans. While there are therapeutic regimens for the disease, more effective methods are needed. We have previously shown that a non-specific beta-adrenergic receptor agonist, isoproterenol, was effective in preventing functional and morphological changes associated with diabetic retinopathy in the rat. Isoproterenol also produced left ventricle remodeling suggesting it entered the systemic circulation. We therefore synthesized various novel beta-adrenergic receptor compounds and screened these compounds in vitro for their ability to reduce markers of inflammation and apoptosis. Of the various compounds tested, Compound 49b was able to reduce both inflammation and …


Click Chemistry Inspired One-Pot Synthesis Of 1, 4-Disubstituted 1, 2, 3-Triazoles And Their Src Kinase Inhibitory Activity, Dalip Kumar, V. Buchi Reddy, Anil Kumar, Deendayal Mandal, Rakesh Tiwari, Keykavous Parang Jan 2011

Click Chemistry Inspired One-Pot Synthesis Of 1, 4-Disubstituted 1, 2, 3-Triazoles And Their Src Kinase Inhibitory Activity, Dalip Kumar, V. Buchi Reddy, Anil Kumar, Deendayal Mandal, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Two classes of 1,4-disubstituted 1,2,3-triazoles were synthesized using one-pot reaction of α-tosyloxy ketones/α-halo ketones, sodium azide, and terminal alkynes in the presence of aq. PEG (1:1, v/v) using the click chemistry approach and evaluated for Src kinase inhibitory activity. Structure-activity relationship analysis demonstrated that insertion of C6H5- and 4-CH3C6H4- at position 4 for both classes and less bulkier aromatic group at position 1 in class 1 contribute critically to the modest Src inhibition activity (IC50 = 32-43 µM) of 1,4-disubstituted 1,2,3-triazoles.


Thiazolyl N-Benzyl-Substituted Acetamide Derivatives: Synthesis, Src Kinase Inhibitory And Anticancer Activities, Asal Fallah-Tafti, Alireza Foroumadi, Rakesh Tiwari, Amir Nasrolahi Shirazi, David G. Hangauer, Yahao Bu, Tahmineh Akbarzadeh, Keykavous Parang, Abbas Shafiee Jan 2011

Thiazolyl N-Benzyl-Substituted Acetamide Derivatives: Synthesis, Src Kinase Inhibitory And Anticancer Activities, Asal Fallah-Tafti, Alireza Foroumadi, Rakesh Tiwari, Amir Nasrolahi Shirazi, David G. Hangauer, Yahao Bu, Tahmineh Akbarzadeh, Keykavous Parang, Abbas Shafiee

Pharmacy Faculty Articles and Research

KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI50 values of 1.34 μM and 2.30 M in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. …


3-Substitued Indoles: One Pot Synthesis And Evaluation Of Anticancer And Src Kinase Inhibitory Activities, V. Kameshwara Rao, Bhupender S. Chhikara, Amir Nasrolahi Shirazi, Rakesh Tiwari, Keykavous Parang, Anil Kumar Jan 2011

3-Substitued Indoles: One Pot Synthesis And Evaluation Of Anticancer And Src Kinase Inhibitory Activities, V. Kameshwara Rao, Bhupender S. Chhikara, Amir Nasrolahi Shirazi, Rakesh Tiwari, Keykavous Parang, Anil Kumar

Pharmacy Faculty Articles and Research

An efficient and economical method was developed for the synthesis of 3-substituted indoles by one pot three-component coupling reaction of a substituted or unsubstituted benzaldehyde, N-methylaniline, and indole or N-methylindole using Yb(OTf)3-SiO2 as a catalyst. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. The 4-methylphenyl (4o and 4p) and 4-methoxyphenyl (4q) indole derivatives inhibited the cell proliferation of SK-OV-3 and HT-29 cells by 7077% at a concentration of 50 μM. The unsubstituted phenyl (4d) and 3-nitrophenyl (4l) derivatives showed the inhibition of c-Src kinase …


Fatty Acyl Amide Dderivatives Of Doxorubicin: Synthesis And In Vitro Anticancer Activities, Bhupender S. Chhikara, Nicole St. Jean, Deendayal Mandal, Anil Kumar, Keykavous Parang Jan 2011

Fatty Acyl Amide Dderivatives Of Doxorubicin: Synthesis And In Vitro Anticancer Activities, Bhupender S. Chhikara, Nicole St. Jean, Deendayal Mandal, Anil Kumar, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin is an anticancer drug extensively used in anticancer therapy. Doxorubicin is highly hydrophilic, has short half-life, and its use is associated with severe side effects at high doses. Fatty acyl amide derivatives of doxorubicin were synthesized with the expectation to improve the lipophilicity and anticancer activity of the drug. The lipophilicity was enhanced with the increase in chain length of fatty acyl moiety. Conjugation of 4-amino group with fatty acids through an amide bond reduced the anticancer activity in leukemia, breast, ovarian, and colon cancer cell lines, suggesting that the presence of free amino group is required for anticancer …


Synthesis Of 3-Phenylpyrazolopyrimidine-1,2,3-Triazole Conjugates And Evaluation Of Their Src Kinase Inhibitory And Anticancer Activities, Anil Kumar, Israr Ahmad, Bhupender S. Chhikara, Rakesh Tiwari, Deendayal Mandal, Keykavous Parang Jan 2011

Synthesis Of 3-Phenylpyrazolopyrimidine-1,2,3-Triazole Conjugates And Evaluation Of Their Src Kinase Inhibitory And Anticancer Activities, Anil Kumar, Israr Ahmad, Bhupender S. Chhikara, Rakesh Tiwari, Deendayal Mandal, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of two classes of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates were synthesized using click chemistry approach. All compounds were evaluated for inhibition of Src kinase and human ovarian adenocarcinoma (SK-Ov-3), breast carcinoma (MDA-MB-361), and colon adenocarcinoma (HT-29). Hexyl triazolyl-substituted 3-phenylpyrazolopyrimidine exhibited inhibition of Src kinase with an IC50 value of 5.6 µM. 4-Methoxyphenyl triazolyl-substituted 3-phenylpyrazolopyrimidine inhibited the cell proliferation of HT-29 and SK-Ov-3 by 73% and 58%, respectively, at a concentration of 50 µM.


Discovery Of Quinic Acid Derivatives As Oral Anti-Inflammatory Agents, Kui Zeng May 2010

Discovery Of Quinic Acid Derivatives As Oral Anti-Inflammatory Agents, Kui Zeng

Theses and Dissertations (ETD)

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at …


Functional Interplay Between Chromatin Remodeling Complexes Rsc, Swi/Snf And Iswi In Regulation Of Yeast Heat Shock Genes, Tamara Y. Erkina, Y. Zou, S. Freeling, V. I. Vorobyev, Alexander M. Erkine Jan 2010

Functional Interplay Between Chromatin Remodeling Complexes Rsc, Swi/Snf And Iswi In Regulation Of Yeast Heat Shock Genes, Tamara Y. Erkina, Y. Zou, S. Freeling, V. I. Vorobyev, Alexander M. Erkine

Scholarship and Professional Work – COPHS

Chromatin remodeling is an essential part of transcription initiation. We show that at heat shock gene promoters functional interactions between individual ATP-dependent chromatin remodeling complexes play critical role in both nucleosome displacement and Pol II recruitment. Using HSP12, HSP82 and SSA4 gene promoters as reporters, we demonstrated that while inactivation of SNF2, a critical ATPase of the SWI/SNF complex, primarily affects the HSP12 promoter, depletion of STH1- a SNF2 homolog from the RSC complex reduces histone displacement and abolishes the Pol II recruitment at all three promoters. From these results, we conclude that redundancy between SWI/SNF and RSC complexes …


Development Of Cytarabine Prodrugs And Delivery Systems For Leukemia Treatment, Bhupender S. Chhikara, Keykavous Parang Jan 2010

Development Of Cytarabine Prodrugs And Delivery Systems For Leukemia Treatment, Bhupender S. Chhikara, Keykavous Parang

Pharmacy Faculty Articles and Research

Importance of the field: Cytarabine is a polar nucleoside drug used for the treatment of myeloid leukemia and non-Hodgkin’s lymphoma. The drug has a short plasma half-life, low stability, and limited bioavailability. Overdosing of patients with continuous infusions may lead to side effects. Thus, various prodrug strategies and delivery systems have been extensively explored to enhance the half-life, stability, and delivery of cytarabine. Among the recent cytarabine prodrugs, amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 (in phase 3 trials) have been investigated for the treatment of leukemia and solid tumors, respectively. Alternatively, delivery systems of cytarabine have …


The Proteolytic Stability And Cytotoxicity Studies Of L‐Aspartic Acid And L‐Diaminopropionic Acid Derived Β‐Peptides And A Mixed Α/Β‐Peptide, Sahar Ahmed, Kamaljit Kaur Apr 2009

The Proteolytic Stability And Cytotoxicity Studies Of L‐Aspartic Acid And L‐Diaminopropionic Acid Derived Β‐Peptides And A Mixed Α/Β‐Peptide, Sahar Ahmed, Kamaljit Kaur

Pharmacy Faculty Articles and Research

The use of peptides as drugs in pharmaceutical applications is hindered by their susceptibility to proteolysis and therefore low bioavailability. β‐Peptides that contain an additional methylene group in the backbone, are gaining recognition from a pharmaceutical stand point as they are considerably more resilient to proteolysis and metabolism. Recently, we reported two new classes of β‐peptides, β3‐ and β2‐peptides derived from l‐aspartic acid and l‐diaminopropionic acid, respectively. Here, we report the proteolytic stability of these β‐peptidic compounds and a mixed α /β‐peptide against three enzymes (pronase, trypsin and elastase), as well as, human serum. The …


New Dosing Schedules Of Dasatinib For Cml And Adverse Event Management, Siu Fun Wong Feb 2009

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 …


Helical Peptides Derived From Lactoferrin Bind Hepatitis C Virus Envelope Protein E2, Reem Beleid, Donna Douglas, Norman Kneteman, Kamaljit Kaur Oct 2008

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 …


Composites Comprising Cholesterol And Carboxymethyl Cellulose, Vuk Uskoković Feb 2008

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 Jan 2008

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 Jan 2008

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 Role Of Multi-Drug Resistance Associated Protein 4 And P-Glycoprotein In Resistance Of Neuroblastoma To Topotecan And Irinotecan, Patricia Kellie Turner Dec 2007

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 …


Antioxidation Activity Of Dhea And Its Mechanisms, Sun Yang, Han Rui Jan 2001

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 …


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 Jul 1999

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 …


What Is The Risk Of Teratogenicity With The Use Of Selective Serotonin Reuptake Inhibitors During Pregnancy?, Michael Z. Wincor, Mary Gutierrez, Ann Nguyen Jan 1996

What Is The Risk Of Teratogenicity With The Use Of Selective Serotonin Reuptake Inhibitors During Pregnancy?, Michael Z. Wincor, Mary Gutierrez, Ann Nguyen

Pharmacy Faculty Articles and Research

"The lifetime prevalence of major depressive disorder in women is 10 to 25%, with an average age of onset in the mid-20s.1 Over the nine years that the selective serotonin reuptake inhibitors (SSRis) have been available, for many prescribers, they have become first-line agents in the treatment of depression. In addition, sorne of them are also being used in the treatment of obsessive- compulsive disorder and panic disorder. In light of these facts, itis not unlikely that women of childbearing age would be treated with one of the SSRis. In considering the risks of exposing a fetus to an SSRI, …


Meal Interference With Antibiotics Administered Orally In Kentucky Hospitals, Shirley Harper May 1982

Meal Interference With Antibiotics Administered Orally In Kentucky Hospitals, Shirley Harper

Masters Theses & Specialist Projects

Hospitals within the State of Kentucky were surveyed to determine if the size of the hospitals influence the frequency of potential meal interference with the administration of oral antibiotics where the "empty stomach" concept must be fulfilled. One hundred and ten hospitals responded to the mailed survey. Of the responding hospitals 103 were short-term and 7 were long-term hospitals. The frequency of conflict was greater for nourishments than with meal interference. Ninety-three and six tenths percent or 103 answered yes when asked if all patients received nourishments on request. The conflicts of potential meal interference ranged from 15 to 40 …