Medicinal and Pharmaceutical Chemistry Commons^™

Development Of A New Class Of Ligand-Targeted Chemotherapeutics With Enhanced Safety And Efficacy Profile, Arindom Pal

University of the Pacific Theses and Dissertations

The hydrophobicity of many chemotherapeutic agents usually results in their nonselective passive distribution into healthy cells and organs causing collateral toxicity. Ligand-targeted drugs (LTDs) are a promising class of targeted anticancer agents. The hydrophilicity of the targeting ligands in LTDs limits its nonselective passive tissue distribution and toxicity to healthy cells. In addition, the small size of LTDs allows for better tumor penetration, especially in the case of solid tumors. However, the short circulation half-life of LTDs, due to their hydrophilicity and small size, remains a significant challenge for achieving their full therapeutic potential. Therefore, extending the circulation half-life of …

Development And Ex Vivo Characterization Of Enteric Coated Chitosan Beads For Crohn’S Disease Management, Craig Mendonca

University Scholar Projects

Drug delivery is the process of transporting a drug to its site of action. It includes controlled delivery, where the drug is released at the tissue in a regulated manner. Additionally, it includes targeted delivery, where the drug is aimed at a specific tissue or region to avoid unwanted side effects (that would occur if the drug were distributed throughout the body). A cellulose acetate phthalate coated chitosan bead was developed as a formulation for controlled and targeted release of dexamethasone to the ilium and colon. This formulation was determined to be effective in delaying dexamethasone release until the formulation …

Synthesis Of Novel 6-Substituted And 5-Substituted Pyrrolo[2,3-D] Pyrimidine Antifolates As Targeted Anticancer Therapies, Xinxin Li

Electronic Theses and Dissertations

The dissertation will give an introduction, background and current research progress in the areas of antifolates and chemotherapy of anticancer. The design and synthesis of classical 6- substituted pyrrolo[2,3-d]pyrimidines and 5-substituted pyrrolo[2,3-d]pyrimidines as potential antifolates have been described. The design variations include: methylated thiophene regioisomers, fluorinated phenyl regioisomers, thionyl regioisomers on the side chain of pyrrolo[2,3-d]pyrimidines. As a part of this study, a series of new compounds have been synthesized and characterized. Of these, ten final compounds were submitted for biological evaluation.

Evaluation Of Antibiotic Prescribing Patterns For Community Acquired Pneumonia, Gregory Schaefer, Ann Wigton

Pharmacy Posters

Purpose: To evaluate duration of antibiotic therapy and prescribing patterns for non-ICU CAP at St Cloud Hospital, a tertiary community hospital.

Evaluation Of The Transition To A Fixed-Dose Prothrombin Complex Concentrate Regimen At A Tertiary Regional Medical Center, John Mullen, Lance Mcnab

Pharmacy Posters

Objective:

• Evaluate order set use in patients that received PCC for emergent warfarin reversal in the emergency department both before and after implementation of a fixed-dose protocol.
• Evaluate INR response to administration of PCC pre- and post- implementation and the percentage of post-infusion INRs that were less than 2 and 1.5.
• Assess cost of therapy before and after implementation of the fixed-dose protocol.

Evaluation Of Neonatal Abstinence Syndrome Management And Prescribing Patterns, Kaylee Erickson, Anthony Wieland, Kaia Ringwald

Pharmacy Posters

Purpose:

• Identify medications prescribed to manage NAS due to opioids and /or amphetamines.
• Evaluate average daily medication wean rates.
• Assess length of stay (LOS) and length of treatment (LOT)

Calcitriol And Calcipotriol Modulate Transport Activity Of Abc Transporters And Exhibit Selective Cytotoxicity In Mrp1-Overexpressing Cells, Kee W. Tan, Angelina Sampson, Bremansu Osa-Andrews, Surtaj H. Iram

Chemistry and Biochemistry Faculty Publications

Efflux transporters P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) can affect the efficacy and toxicity of a wide variety of drugs and are implicated in multidrug resistance (MDR). Eight test compounds, recently identified from an intramolecular FRET-based high throughput screening, were characterized for their interaction with MRP1. We report that the active metabolite of vitamin D3, calcitriol, and its analog calcipotriol are selectively cytotoxic to MRP1-overexpressing cells, besides inhibiting transport function of P-gp, MRP1, and BCRP. Calcitriol and calcipotriol consistently displayed a potent inhibitory activity on MRP1-mediated doxorubicin and calcein efflux in MRP1-overexpressing H69AR …

Development Of Multiple Microemulsion Eye Drops For Sustained Release Of New Glaucoma Drug, Doaa Nabih Ahmed Maria

Theses and Dissertations (ETD)

Persistent or repeated elevation of intraocular pressure (IOP) is a primary risk factor of visual field loss in glaucoma, therefore IOP reduction is the first-line therapeutic option in the disease management. Unfortunately, the current therapies are associated with a lot of deficiencies including several daily dosing, reduced efficacy and systemic side effects all of which resulted in poor patient compliance. Previously we have identified Calcium voltage-gated channel auxiliary subunit Alpha2delta 1 gene (Cacna2d1) as a novel modulator of IOP and confirmed that pregabalin targeted CACNA2D1 in eye tissues (ciliary body and trabecular meshwork) to lower IOP in a …

Efficacy And Renal Outcomes Of Sglt2 Inhibitors In Patients With Type 2 Diabetes And Chronic Kidney Disease, Michael S. Kelly, Jelena Lewis, Ashley M. Huntsberry, Lauren Dea, Ivan Portillo

Pharmacy Faculty Articles and Research

Objective: To review glucose-lowering efficacy and changes in renal function associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM).

Data sources: A literature search of MEDLINE and Cochrane databases was performed from 2000 to August 2018 using search terms: SGLT2 inhibitors, sodium glucose co-transporter 2, canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, and chronic kidney disease. References of identified articles were also reviewed.

Study selection and data extraction: English-language studies investigating glucose-lowering endpoints and/or changes in renal function with one of four U.S. approved SGLT2 inhibitors were included. A …

A Two Compartment Pharmacokinetic Model Describes The Intra‐Articular Delivery And Retention Of Rhprg4 Following Acl Transection In The Yucatan Mini Pig, Mark Hurtig, Iman Zaghoul, Heather Sheardown, Tannin A. Schmidt, Lina Liu, Ling Zhang, Khaled A. Elsaid, Gregory D. Jay

Pharmacy Faculty Articles and Research

Treatment of the injured joint with rhPRG4 is based on recent observations that inflammation diminishes expression of native PRG4. Re‐establishing lubrication between pressurized and sliding cartilage surfaces during locomotion promotes the nascent expression of PRG4 and thus intra‐articular (IA) treatment strategies should be supported by pharmacokinetic evidence establishing the residence time of rhPRG4. A total of 21 Yucatan minipigs weighing ∼55 Kg each received 4 mg of 131I‐rhPRG4 delivered by IA injection 5 days following surgical ACL transection. Animals were sequentially euthanized following IA rhPRG4 at 10 mins (time zero), 24, 72 hrs, 6, 13 and 20 days later. The …

Kinetics Of Dextromethorphan-O-Demethylase Activity And Distribution Of Cyp2d In Four Commonly-Used Subcellular Fractions Of Rat Brain, Barent N. Dubois, Farideh Amirrad, Reza Mehvar

Pharmacy Faculty Articles and Research

The purpose of this study was to compare the enzymatic kinetics and distribution of cytochrome P450 2D (CYP2D) among different rat brain subcellular fractions.

Rat brains were used to prepare total membrane, crude mitochondrial, purified mitochondrial, and microsomal fractions, in addition to total homogenate. Michaelis–Menten kinetics of the brain CYP2D activity was estimated based on the conversion of dextromethorphan (DXM) to dextrorphan using UPLC-MS/MS. Protein levels of CYP2D and subcellular markers were determined by Western blot.

Microsomal CYP2D exhibited high affinity and low capacity, compared with the mitochondrial CYP2D that had a much lower (∼50-fold) affinity but a higher (∼six-fold) …

Modulation Of Hypoxia-Induced Chemoresistance To Polymeric Micellar Cisplatin: The Effect Of Ligand Modification Of Micellar Carrier Versus Inhibition Of The Mediators Of Drug Resistance, Hoda Soleymani Abyaneh, Amir Hassan Soleimani, Mohammad Reza Vakili, Rania Soudy, Kamaljit Kaur, Francesco Cuda, Ali Tavassoli, Afsaneh Lavasanifar

Pharmacy Faculty Articles and Research

Hypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two strategies for the modulation of HICR against cisplatin micelles: a) the development of actively targeted micelles; and b) combination therapy with modulators of HICR in MDA-MB-231 cells. Actively targeted cisplatin micelles were prepared through surface modification of acetal-poly(ethylene oxide)-poly(-carboxyl-"-caprolactone) (acetal-PEO-PCCL) micelles with epidermal growth factor receptor (EGFR)-targeting peptide, GE11 (YHWYGYTPQNVI). Our results showed that hypoxia induced resistance against free and …

Correcting Glucose-6-Phosphate Dehydrogenase Deficiency With A Small-Molecule Activator, Sunhee Hwang, Karen Mruk, Simin Rahighi, Andrew G. Raub, Che-Hong Chen, Lisa E. Dorn, Naoki Horikoshi, Soichi Wakatsuki, James K. Chen, Daria Mochly-Rosen

Pharmacy Faculty Articles and Research

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the …

Development Of Novel Intramolecular Fret-Based Abc Transporter Biosensors To Identify New Substrates And Modulators, Bremansu Osa-Andrews, Kee W. Tan, Angelina Sampson, Surtaj H. Iram

Chemistry and Biochemistry Faculty Publications

Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and modulators of MRP1 by exploiting intramolecular fluorescence resonance energy transfer (FRET), we genetically engineered six different two-color MRP1 proteins by changing green fluorescent protein (GFP) insertion sites, while keeping the red fluorescent protein (RFP) at the C-terminal of MRP1. Four of six recombinant proteins showed normal expression, localization, and transport activity. We quantified intramolecular FRET using ensemble …

Uplc-Ms/Ms Analysis Of Dextromethorphan-O-Demethylation Kinetics In Rat Brain Microsomes, Barent N. Dubois, Reza Mehvar

Pharmacy Faculty Articles and Research

Formation of dextrorphan (DXT) from dextromethorphan (DXM) has been widely used to assess cytochrome P450 2D (CYP2D) activity. Additionally, the kinetics of CYP2D activity have been well characterized in the liver microsomes. However, studies in brain microsomes are limited due to the lower microsomal content and abundance of CYP2D in the brain relative to the liver. In the present study, we developed a micro-scale enzymatic incubation method, coupled with a sensitive UPLC-MS/MS assay for the quantitation of the rate of DXT formation from DXM in brain microsomes. Rat brain microsomes were incubated with different concentrations of DXM for various times. …

Astromimetics: The Dawn Of A New Era For (Bio)Materials Science?, Vuk Uskoković, Victoria M. Wu

Pharmacy Faculty Articles and Research

Composite, multifunctional fine particles are likely to be at the frontier of materials science in the foreseeable future. Here we present a submicron composite particle that mimics the stratified structure of the Earth by having a zero-valent iron core, a silicate/silicide mantle, and a thin carbonaceous crust resembling the biosphere and its biotic deposits. Particles were formulated in a stable colloidal form and made to interact with various types of healthy and cancer cells in vitro. A selective anticancer activity was observed, promising from the point of view of the intended use of the particles for tumor targeting across the …

Targeting Neuropeptides To Bone Fractures For Accelerated Healing, Nicholas A. Young, Jeffery J. Nielsen, Philip S. Low

The Summer Undergraduate Research Fellowship (SURF) Symposium

In patients over the age of 65 especially, bone fractures represent a significant disease burden. Non-invasive drug therapies are not available for bone fractures which represents a problem for this population. Vasoactive intestinal peptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), two neuromodulator peptides in the glucagon superfamily, have demonstrated positive regulation of osteoblast proliferation and activity. Using acidic oligopeptides, we have developed ligands that target to and accumulate at fracture sites. These targeting ligands can be synthesized in sequence with bone anabolic peptides to minimize off target effects and increase potency at the fracture site to create safer and …

Aminoflavone Inhibits Α6-Integrin And Growth Of Tamoxifen Resistant Breast Cancer, Petreena S. Campbell

Loma Linda University Electronic Theses, Dissertations & Projects

Approximately 40% of estrogen receptor positive (ER+) breast cancer patients develop resistance to standard of care agent tamoxifen, while ER negative (ER-) breast cancer patients are intrinsically resistant to tamoxifen. Resistance often promotes metastasis, recurrence and death. Tumor-initiating cells (TICs) represent key contributors to resistance and adhesion protein α6-integrin is a putative TIC biomarker. Investigational agent Aminoflavone (AF) demonstrates efficacy against breast cancer cells irrespective of ER status. Interestingly, we found tamoxifen resistant (TamR) cells and tumors exhibited elevated α6-integrin expression in comparison to their tamoxifen sensitive counterparts. AF effectively disrupted mammospheres enriched for TICs and reduced α6-integrin levels in …

Determining The Effect Of Locally Delivered Bioactive Modulators On Macrophage Activation At The Implantation Site Of Different Biomaterials In Rats, Kamel Alkhatib

Graduate Theses and Dissertations

Altering the foreign body reaction by targeting macrophages has been of interest in the biomaterials field to improve the integration of longevity of implanted biomedical devices. The objective of this dissertation was to study the effect of locally delivered bioactive modulators on macrophage activation at the implantation site of different biomaterials in rats. Iloprost, a prostacyclin analog, was tested for its ability to direct macrophages to their pro-wound healing phenotype after the implantation of microdialysis probe in the subcutaneous space of male Sprague Dawley rats. This study showed that iloprost can shift macrophage activation states in vivo to the pro-wound …

Antimalarial Proteasome Inhibitor Reveals Collateral Sensitivity From Intersubunit Interactions And Fitness Cost Of Resistance., Laura A. Kirkman, Wenhu Zhan, Joseph Visone, Alexis Dziedziech, Pradeep K. Singh, Hao Fan, Xinran Tong, Igor Bruzual, Ryoma Hara, Masanori Kawasaki, Toshihiro Imaeda, Rei Okamoto, Kenjiro Sato, Mayako Michino, Elena Fernandez Alvaro, Liselle F. Guiang, Laura M. Sanz, Daniel J. Mota, Kavitha Govindasamy, Rong Wang, Yan Ling, Patrick K. Tumwebaze, George Sukenick, Lei Shi, Jeremie Vendome, Purnima Bhanot, Philip J. Rosenthal, Kazuyoshi Aso, Michael A. Foley, Roland A. Cooper, Bjorn Kafsack, J Stone Doggett, Carl F. Nathan, Gang Lin

Natural Sciences and Mathematics | Faculty Scholarship

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained …