ETD Search Results: instcode:ucin

1. ANTONOVICH, ROBERT STEVEN. APPLICABILITY OF MASS SPECTROMETRY TO DETECT COELUTING IMPURITIES IN HIGH PERFORMANCE LIQUID CHROMATOGRAPHY.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2002, University of Cincinnati

► n array of pharmaceutical compounds and impurities were used to investigate the… (more)

Keywords: pharmaceutical analysis; peak purity

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2. BALASUBRAMANIAN, SHREEKRIPA. DOSE AND VEHICLE EFFECTS ON THE PENETRATION RATE OF SELECTED PLANT POLYPHENOLS THROUGH HUMAN SKIN.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2002, University of Cincinnati

► Polyphenols, plant phytochemicals have demonstrated a wide variety of beneficial biological activities… (more)

▼ Polyphenols, plant phytochemicals have demonstrated a wide variety of beneficial biological activities including astringency, antioxidant, anticarcinogenic and phytoestrogenic properties, to name a few. Due to these attributes, extract of herbs containing these polyphenols have been incorporated in several consumer products. Hence, it is of interest to examine the skin penetration rates of polyphenolic compounds as topical cosmetic agents. The compounds studied kaempferol and catechin, are flavonols and flavanols respectively and are natural antioxidants found in many fruits, vegetables and tea. This study is part of an effort to ascertain the safety and utility of these compounds as skin care ingredients. Doses of 3 H-catechin and 3 H-kaempferol ranging from 0.2-7000 µg/cm 2 were applied to split thickness human cadaver skin mounted on Franz diffusion cells. The vehicle was either 95% ethanol or propylene glycol. Permeation of radiolabel into an aqueous buffer was measured over 72 hrs, and the amount of radioactivity in the receptor fluid was determined by liquid scintillation counting. Results were plotted as amount penetrated vs. time and as percent penetrated vs. time, and were then compared with a theoretical model for skin penetration from a finite dose. Kaempferol penetration was dose-related, in general agreement with the theoretical model. Total penetration increased with increasing dose, ranging from 0.1 µg/cm 2 in 72 h (ethanol, 0.2 µg/cm 2 dose) to 500 µg/cm 2 in 72 h (propylene glycol, 7000 µg/cm 2 dose). Percentage penetration decreased as dose increased, ranging from about 17% / 72 h at the lowest dose to 6.4 % / 72 h at the highest dose. The penetration rate peaked more rapidly than predicted by the model. Catechin penetration from both vehicles was very low (0.5% of dose/ 72 h) and was not dose-related. The reason for this is not yet clear and it may be attributed to chemical modifications of catechin in vehicles over a time period. The human skin penetration rate of kaempferol from solvent-deposited topical applic ations in vitro was in general accord with a physical properties-based model. Penetration of catechin was much lower than anticipated. The results contribute to the understanding of skin permeability of polyphenols such as kaempferol and catechin. We believe they can be extended to other classes of useful botanical ingredients by an appropriate combination of theory and experiments. Advisors/Committee Members: Kasting, Dr. G.B.

Subjects: Health Sciences, Pharmacy

Keywords: polyphenols; flavonoids; kaempferol; catechin; skin penetration

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3. BARAI, NAMRATA D. EFFECT OF HYDRATION ON SKIN PERMEABILITY.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2002, University of Cincinnati

► The water handling properties of the stratum corneum (SC) are key to… (more)

Subjects: Health Sciences, Pharmacy

Keywords: SKIN; HYDRATION; PERMEABILITY

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4. BARAI, NAMRATA D. EFFECT OF VERNIX CASEOSA ON EPIDERMAL BARRIER MATURATION AND REPAIR: IMPLICATIONS IN WOUND HEALING.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2005, University of Cincinnati

► Cultured skin substitutes (CSS) were used as a wound healing model to… (more)

▼ Cultured skin substitutes (CSS) were used as a wound healing model to evaluate the effects of vernix caseosa (VC) in vitro. The barrier development in these substitutes was first evaluated to get a detailed understanding of the time course of barrier maturation in vitro and post grafting ex vivo. Optimum barrier function in vitro was observed on day 14; however, the optimum values were far from those obtained with native human skin controls. Additional CSS were grafted on athymic mice on day 14, and skin was harvested 2 weeks and 6 weeks post grafting. Grafting brought about a substantial decrease in all measurements by 2 weeks and almost complete normalization of barrier function after 6 weeks. In order to grow these tissues in a format more suitable for in vitro testing, a modified method was developed. Post inoculation and lifting to air liquid interface (day 5 in vitro) the tissue was transferred to and maintained on Franz diffusion cells for the rest of the period of incubation. A significant improvement in barrier function was observed for tissue grown by this method. The effect of VC on barrier development was tested on CSS grown by this modified method. CSS with and without VC treatment were evaluated for changes in viability, morphology, barrier function and epidermal metabolism from day 7 to 21 of incubation in vitro. Lactate production was significantly higher in VC-treated tissue in the early phases of CSS development, when the barrier function was impaired. However, no significant improvement in barrier function was observed with VC treatment.The effect of VC in vivo was evaluated in a barrier repair clinical trial. Stratum corneum damage was created on 6 volar forearm sites by tape stripping until transepidermal water loss was 32-40 g/m2/hr, comparable to those of preterm infants of 26-27 wks gestation. Sites were treated with no occlusion, VC, complete occlusion, Aquaphor, oil-in-water emulsion and a semipermeable film. Transepidermal water loss, moisture accumulation rate, hydration and pH measurements were made at baseline, day 3 and 5. VC showed only significant improvement over complete occlusion. Advisors/Committee Members: Kasting, Dr. Gerald.

Subjects: Health Sciences, Pharmacy

Keywords: vernix caseosa, cultured skin substitutes, epidermal barrier

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5. Bharaj, Satinder Singh. Development of Extended Release Dextromethorphan Matrix Tablets.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2005, University of Cincinnati

► Dextromethorphan is a highly potent and commonly used anitussive agent. At present… (more)

▼ Dextromethorphan is a highly potent and commonly used anitussive agent. At present there are no extended release dextromethorphan matrix tablets available in the USA. The objective of this dissertation to develop and evaluate extended release dextromethorphan matrix tablets manufactured by the direct compression method. Formulation and process variables on the effect of hydroxypropylmethylcellulose (HPMC K100LV) in combination with anionic methacrylic acid copolymer (Eudragit L100-55); and polyvinyl acetate/povidone (PVAP) (Kollidon® SR) polymer concentrations in the tablet, filler excipient concentration, compression force, stability storage conditions and variable dissolution agitation rates were evaluated on the produced tablet characteristics. The extended release tablets were then compared to a marketed capsule product by applying the FDA dissolution recommended model independent f2 similarity test. Additionally, bioavailability and bioequivalence studies in healthy adult beagle dogs were performed. It was found that HPMC (K100LV) at 20% level in combination with methacrylic acid copolymer (Eudragit® L100-55) at 20% level produced extended release dextromethorphan matrix tablets that are similar to the marketed capsule product according to the model independent FDA guidelines (f2 factor). Polyvinyl acetate/povidone (PVAP) (Kollidon® SR) at 39.5% in combination with dibasic calcium phosphate also at 39.5% level produced extended release dextromethorphan tablets that are similar to the marketed capsule product according the model independent FDA guidelines (f2 factor). The extended release dextromethorphan matrix tablets followed square root of time dependent kinetics for drug release indicating a diffusion controlled release mechanism. The extended release dextromethorphan matrix tablets were not bioequivalent to the marketed capsule product, however, the tablets had higher bioavailability as shown by the AUC(0-inf). In vitro/invivo correlation between variable dissolution agitation rates and the dextromethorphan released and absorbed was not established for the extended release dextromethorphan matrix tablets. It was concluded that extended release dextromethorphan tablets were developed using HPMC (K100LV) in combination with methacrylic acid copolymer (Eudragit® L100-55); and PVAP (Kollidon® SR) as the release extending excipients. In vitro testing indicated that the produced tablets had similar dissolution behavior to the marketed capsule product according to the model independent FDA guideline (f2 factor). Advisors/Committee Members: Sakr, Dr. Adel.

Keywords: Dextromethorphan Matrix Tablets; HPMC and Eudragit; Kollidon SR, PVAP

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6. BHATT, VARSHA DILIP. ABSORPTION AND EVAPORATION OF PESTICIDES FROM HUMAN SKIN IN VITRO.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2007, University of Cincinnati

► Estimation of penetration rates of compounds through skin is an important for… (more)

▼ Estimation of penetration rates of compounds through skin is an important for assessment of either the efficacy of a topical formulation, its irritation potential, or its potential systemic exposure. Current risk assessment models often assume that 100 % of the applied dose is absorbed through the skin. This thesis provides experimental data to validate and calibrate a working diffusion/evaporation model for topically applied chemicals based on their physicochemical properties, the known biological properties of skin and principles of diffusion theory. Four compounds with varying physicochemical properties were studied under different conditions—benzyl alcohol (BA), diethyl-m-toluamide (DEET), tecnazene and malathion. Absorption of 14C – BA, a perfume ingredient, was studied at different doses (0.9 µg/cm 2– 10.6 mg/cm 2) through human cadaver skin and silicone membrane. The disposition of BA was satisfactorily described by the diffusion model using a variable diffusivity coefficient. The absorption and evaporation of the insect repellent 14C – DEET (127 µg/cm 2) was characterized at airflows ranging from 10 – 100 mL/min. The amount of DEET absorbed through the skin systematically decreased as the airflow increased. For tecnazene, a fungicide, and malathion, an insecticide, a Head space Solid Phase Micro Extraction technique was developed to analyze the receptor fluid following skin penetration experiments. The analysis was done using GC-MS. Absorption rate of tecnazene, was studied following application of 103 µg/cm 2and 864 µg/cm 2under open and occluded conditions. The absorption was much higher under occlusion and the overall recovery was also better for the occluded treatment. Additionally disposition of topically applied 14C – malathion (101, 0.5 and 0.1 µg/cm 2) was studied under open and occluded conditions and compared to GC-MS results from 101 µg/cm 2. A silicone membrane study was performed with all three doses of 14C – malathion. The model satisfactorily described the absorption of malathion and tecnazene through human skin in vitro. Key parameters that needed modification were k evap(evaporation mass transfer coefficient), K sc(partition coefficient of the stratum corneum, SC) and P sc(permeability of SC). Future work entails conducting partitioning studies of lipophilic compounds to get better understanding of disposition of such compounds in the lower skin layers. Advisors/Committee Members: Kasting, Dr. Gerald B.

Keywords: dermal absorption; pesticides; mathematical model; human skin; in vitro

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7. Bhide, Nirmal S. Tolerance to MDMA-induced serotonergic neurotoxicity.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2010, University of Cincinnati

► 3,4-Methylenedioxymethamphetamine (MDMA), an analog of the amphetamine class, is a psychostimulant and… (more)

▼ 3,4-Methylenedioxymethamphetamine (MDMA), an analog of the amphetamine class, is a psychostimulant and a popular drug of abuse. MDMA is considered to be selectively neurotoxic to serotonergic nerve terminals in different brain regions. Repeated exposure to MDMA during adolescence is neuroprotective against a subsequent neurotoxic regimen of MDMA in adulthood. This phenomenon is similar to ischemic preconditioning, where repeated exposure to sub-lethal insults results in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-toxic dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion and to evaluate the mechanisms involved. Preconditioning with MDMA (10 mg/kg i.p.) daily for 4 days provided significant protection against MDMA-induced 5-HT depletion in the striatum, hippocampus and cortex. Preconditioning with MDMA (10 mg/kg i.p.) daily for 4 days provided significant protection against methamphetamine (METH)-induced 5-HT, but not DA, depletion in the striatum. Since the neuroprotection is specific to the serotonergic neurons, it is possible that preconditioning with MDMA results in neuroadaptive changes in 5-HT containing neurons. The role for alterations in MDMA-induced hyperthermia and brain MDMA concentrations was ruled out. Repeated exposure to Clozapine, at doses known to produce 5-HT2 receptor downregulation, provided significant protection against MDMA-induced 5-HT depletion in the striatum, hippocampus and cortex. However, it is inconclusive whether repeated exposure to MDMA results in downregulation of 5-HT2 receptor function and expression. Repeated exposure to MDMA resulted in the downregulation of serotonin transporter (SERT) expression. Steady state 5-HT uptake in hippocampal synaptosomal preparations in rats previously exposed to MDMA was significantly reduced when compared to vehicle treated animals. SERT plays a key role in MDMA-induced 5-HT neurotoxicity and downregulation of SERT function after preconditioning with MDMA may contribute towards the neuroprotection. Taken together, these studies suggest that repeated exposure to MDMA provides protection against a 5-HT depleting dose of MDMA and that downregulation of SERT function may contribute towards this neuroprotective phenomenon. Advisors/Committee Members: Gudelsky, Gary.

Subjects: Pharmacology

Keywords: MDMA; Serotonin; preconditioning; tolerance; neurotoxicity; serotonin transporter

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8. CANNING, JENNIFER L. ASSESSMENT OF THE SKIN CONDITION OF HEALTH CARE WORKERS USING DIGITAL IMAGE PROCESSING.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

► Frequent handwashing has significant effects on the stratum corneum (SC) barrier and… (more)

▼ Frequent handwashing has significant effects on the stratum corneum (SC) barrier and can lead to dry skin, irritation and erythema. The effects of hand hygiene procedures on health care workers (HCWs) were investigated by evaluation of skin damage (dryness, erythema) on their hands. Live visual skin evaluation (LSG), digital image analysis (DIA), and visual perception evaluation of high resolution digital images (VPS) were used to measure skin condition in the spring and winter. Compared to non-HCW control subjects, HCW hands are appreciably comprised. The skin was damaged at the start of a work cycle, suggesting that the SC does not have sufficient time to repair itself. Use of test products (TP) resulted in significantly improved skin dryness (LSG) and irritation (VPS) relative to the current products (CP). However, skin erythema observed over a work cycle was similar for both CP and TP. Skin erythema was difficult to assess, most likely due to the compromise of the skin from baseline and the regional heterogeneity of the hands. DIA techniques were used to analyze erythema in the digital images. Redness observed using DIA techniques was significantly higher for the hands, particularly the knuckles, in the winter, an indication of poorer skin condition. The digital images were also viewed on a high resolution monitor in a paired comparison format to examine the effects over a cycle and during regression (VPS Imaging System, PandG). The positive correlations evaluated between LSG and VPS methods verify the fact that images could be collected (much more rapidly) and graded later using a comparison imaging system, i.e. VPS, to establish quantitative results. Only minimal correlations were present between DIA and the visual evaluations (LSG, VPS). High levels of erythema may have affected the correlations between DIA and the visual grades because it is often accompanied by other symptoms, making it more difficult to grade as it becomes more severe. The digital imaging process, used to analyze the digital images, shows to be able to objectively define erythema as a quantitative expression, however, further investigation is needed into the development of this DIA process because of minimal correlations with the visual methods. Further investigation needs to be done so that a quantification system can be established for the investigation of dryness in the digital images collected. Advisors/Committee Members: Wickett, R Randall.

Keywords: Digital Imaging; Health Care Workers; Skin Condition; Erythema; Digital Image Analysis

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9. Cavanaugh, Teresa M. Comprehensive Direct Medical Costs Associated with Six Months of Care Status Post Acute Rejection Events in Renal Transplant Recipients: A Single Center Retrospective Matched Case Control Analysis.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2009, University of Cincinnati

► The cost of health care is rising, and this trend is also… (more)

▼ The cost of health care is rising, and this trend is also seen in transplantation. One particularly important complication of transplantation is rejection; however, the cost of rejection has not been quantified in a manner that is comprehensive, generalizable and based on standard of care. The purpose of this research project was to quantify the cost of processes of care (diagnosis and management), both inpatient and outpatient, of acute rejection events and associated complications in renal transplant recipients in a real-world US practice setting. A retrospective matched case-control study was undertaken. A database of patients transplanted at The University Hospital, Cincinnati, Ohio, was analyzed to identify patients who had experienced a rejection episode. The same database was used to create a cohort of patients matched on age ± ten years, sex, ethnicity and type of transplant. There were 22 patients in each cohort. Data was collected for six months after the diagnosis of rejection, and the same time period post transplantation forward for six months in the matched controls. Costs were evaluated from the health-system perspective. Health-system costs were reported from the hospital cost accounting system and standardized to 2007 US dollars, outpatient medications were reported in average wholesale costs in 2009 dollars and outpatient clinic visit costs were derived from Medicare reimbursement, 2008 dollars. The total costs were significantly different between the groups for six months of care. The mean cost of care for rejection patients was $51,765 ($14,291-137,021) versus no rejection patients $32,784 ($10,358-78,109), p = 0.004. Total health-system costs were also significantly different: $30,000 ($405-400,961) versus 11,460 ($260-84,954), rejection versus no rejection, respectively, (p = 0.029). It was expected that diagnostic costs would be higher in the rejection group, and this was consistent with the findings. Radiology costs were significantly higher in the case cohort: control $2,371 ($233-11,286) vs , $432 ($57-2,057) (p< 0.001). Pathology costs were also significantly higher in the rejection group: $822 ($124-3,264) vs $359 ($116-844), (p = 0.003). Additionally, monitoring was significantly higher over the six month period of time for rejection patients as compared to no rejection patients: $866 ($15-1,446) versus $264 ($27-6,633), (p = 0.006). Total medication costs were not significantly different between the two groups: rejection $28,517 ($4,437-118,291) vs no rejection $22,238 ($8,609-48,070), p=0.56. In terms of resource utilization, more patients in the acute rejection group experienced hospitalization as compared to no rejection patients 19 (86%) versus 8 (35%), p=0.002. More rejection patients received care at the Transplant Ambulatory Care Unit as well. Additional monitoring also occurred in the rejection patients, laboratory monitoring, both inpatient and outpatient, as well as diagnostics including cultures, x-rays and ultrasounds. As expected, there were significant differences in cost, as well as healthcare utilization, for patients who experienced an acute rejection event. The mean difference attributable to rejection is $18,981. This amount could be applied to future studies demonstrating rejection cost avoidance and cost- effectiveness analyses of new modalities that prevent, detect or treat rejection. Advisors/Committee Members: Martin Boone, Jill.

Subjects: Biomedical research; Economics; Health; Health care; Immunology

Keywords: cost; rejection; kidney transplantation; cost of care

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10. CHAWLA, SMITA. EFFECT OF DEOXYARBUTIN AND ITS SECOND-GENERATION DERIVATIVES ON MELANOCYTE VIABILITY AND FUNCTION.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

► Therapeutic treatment of skin pigmentary disorders such as melasma, solar lentigines, and… (more)

▼ Therapeutic treatment of skin pigmentary disorders such as melasma, solar lentigines, and post inflammatory hyperpigmentation has been challenging and seldom completely successful. The majority of these therapies target tyrosinase, a key enzyme required for pigment synthesis. The lack of success is due to the less than desired efficacy and safety of tyrosinase inhibitors marketed as skin lightening agents (i.e. hydroquinone, kojic acid and arbutin). We propose that the tyrosinase inhibitor deoxyArbutin (dA) and second-generation derivatives of dA, deoxyFuran, thio-dA, and fluoro-dA, have the potential to be effective inhibitors of skin melanization. In this study, we have analyzed the modulating effects of dA and its derivatives on melanocyte function and viability. At safe concentrations, these compounds reversibly down-regulated melanogenesis by competitively inhibiting the key enzyme, tyrosinase. Lineweaver-Burk plot analysis revealed that these compounds had higher competitive inhibitor potencies against tyrosinase as compared to hydroquinone (HQ). Concentrations of these compounds that did compromise viability of melanocytes resulted in an inhibition of cell proliferation (i.e., cytostatic) as opposed to the induction of apoptosis (i.e., cytotoxic) that was induced by HQ. Melanogenic enzymes; tyrosinase and TRP-1 mediated this cytostatic effect of dA and its derivatives. A comparative evaluation of oxidative stress demonstrated that a minimal amount of Reactive Oxygen Species (ROS) was generated upon treatment with dA and derivatives, in contrast to the dramatic amount induced by HQ. This increase in ROS triggered an increase in activity of the endogenous antioxidant catalase in treated melanocytes. Endogenous catalase was sufficient to protect cells against ROS generated by dA and its derivatives, but not HQ, since treatment with exogenous antioxidants conferred protection against HQ, but not dA and derivatives. Thus, dA and second-generation derivatives demonstrate great potential for therapeutic use in hyperpigmentation because they are effective tyrosinase inhibitors and less toxic relative to the current gold standard, HQ. Advisors/Committee Members: Wickett, R. Randall.

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11. Cherian, Philip T. Exploring the PI3Kα and γ binding sites by homology modeling and inhibitors utilizing a 2,6-disubstituted isonicotinic scaffold.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2009, University of Cincinnati

► Phosphatidylinositol 3-OH kinases (PI3Ks) are dual specific lipid and protein kinases that… (more)

▼ Phosphatidylinositol 3-OH kinases (PI3Ks) are dual specific lipid and protein kinases that catalyze the synthesis of the lipid second messenger Phosphatidylinositol-3,4,5-trisphosphate (PIP3) and influence multiple cellular processes including cell growth, proliferation, survival and motility. PI3Ks are divided into three classes I, II and III and the class I contains four isoforms, namely p110α, β, δ and γ. Of these, the p110α isoform (PI3Kα) is an important therapeutic target in cancer as the PIK3CA gene that encodes the p110α catalytic subunit is frequently mutated in a variety of cancers. Though several classes of compounds that inhibit the class I enzymes have been reported, development of inhibitors selective for the PI3Kα still remains a major challenge. In accordance with the ongoing research efforts towards the development of isoform selective inhibitors, we explored the differences between the p110α and γ binding sites using a structure-based approach. The study entailed the building of a p110α homology model, development of a novel scaffold that provided the ease of assembly and diversification and designing of focused chemical libraries based on our modeling studies.Advancement in protein structure prediction methods has simplified the process of obtaining reliable 3D structures of target proteins. Using the p110α protein sequence and X-ray structure of p110γ, a homology model of p110α was constructed and refined. This model proved to be in good agreement with the later published X-ray structure of p110α (2rd0). Using this model and literature analysis of PI3K inhibitors, we designed the 2,6-disubstituted isonicotinic scaffold for our study. This scaffold was evaluated for its synthetic feasibility and biological activity by designing, synthesizing and testing an initial set of derivatives. These compounds inhibited the activity of the recombinant purified PI3Kα and γ in our in vitro lipid kinase assay and showed inhibition of PI3K-dependent survival of cell lines derived from the hematopoietic FL5.12 cells. The most potent compound in the series (compound 28) showed potency in the low micromolar range with 7-fold selectivity for PI3Kα. The chemistry developed during the synthesis of the above series provided straightforward access to three chemical libraries. Accordingly, the three regions of the scaffold were modified in order to explore the hydrogen bonding, bulk and polarity as predicted by our model. These modifications led to the development of compound 63 which showed >10-fold selectivity for PI3Kα vs. PI3Kγ and was more potent in the cell assay than previous compounds. Based on our docking studies, the selectivity of this compound can be attributed to its interaction with Arg770 and Trp780 of p110α. Overall we demonstrate the utility of homology modeling and the 2,6-disubstituted scaffold for exploring the p110α and γ binding sites and anticipate that the data generated during this study may be useful toward the development of more potent and selective PI3Kα and γ inhibitors. Advisors/Committee Members: Knittel, James.

Subjects: Biomedical research; Chemistry; Pharmaceuticals

Keywords: kinase inhibitors; homology modeling; SAR

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12. Cho, Jaeyong. HRPAP20 in Ovarian Cancer and Its Regulation of AP-2 in Breast Cancer.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2008, University of Cincinnati

► Hormone regulated proliferation associated protein 20 (HRPAP20), a hormoneregulated protein that promotes… (more)

▼ Hormone regulated proliferation associated protein 20 (HRPAP20), a hormoneregulated protein that promotes invasion, proliferation, and survival of breast cancer cells, has never been studied in ovarian cancer. Therefore, we initially measured the expression of HRPAP20 in ovarian cancer cells and confirmed its protein expression in three ovarian cancer cell lines, ES-2, SKOV-3 and OVCAR-3. Recent studies suggested that estrogen regulates HRPAP20 in ERα-positive breast cancer cell lines and that expression of HRPAP20 may be associated with tamoxifen resistance. Quantitative RT-PCR was performed to measure the mRNA expression of HRPAP20 in estrogen-, tamoxifen-, combination of both-, and PRL-treated three ovarian cancer cell lines and endometrial cell line, Ishikawa. Our results showed that estrogen, tamoxifen and combination of both did not have statistically significant effect on the mRNA expression of HRPAP20 in both ovarian cancer and endometrial cell lines. However, the mRNA expression of HRPAP20 in ERβ-positive ES-2 cells showed a significant increase with PRL treatment. We speculated that PRL-PRLR interaction mediates HRPAP20 mRNA expression in ERβ-positive ES-2 cells, but this also may be the effect of cross-talk between PRL-activated signal transducer and nuclear receptor ERβ based on other established data. With respect to HRPAP20 in breast cancer, our preliminary data showed an increase in DNA binding of transcription factor AP-2 in MCF-7 cells stably expressing HRPAP20 (MCF-7/HRPAP20 transfectants) and numerous studies suggest that AP-2α and AP-2γ play a role in tumor metastasis and cell growth in breast cancer. Therefore, we speculated that DNA binding by either AP-2α or AP-2γ is increased in MCF-7/HRPAP20 transfectants, possibly due to regulation of AP-2α or AP-2γ protein expression by HRPAP20. However, we did not observe any difference in protein expression of AP-2α and AP-2γ in MCF-7/HRPAP20 transfectants, empty vector controls and wild type MCF-7 cells. We speculated that serum may regulate the protein expression of AP-2α or AP-2γ and that the presence of serum in growth medium may interfere with our evaluation of the effect of HRPAP20 overexpression alone on AP-2α or AP-2γ protein expression. The immunoblot analysis showed that the protein expression of AP-2α was lost in absence of serum while its expression was not altered in all three cell lines with presence of serum. In addition, AP-2γ protein expression appeared to be inhibited by serum in wild type MCF-7 cells and empty vector controls while its protein expression remained same in MCF-7/HRPAP20 transfectants in presence or absence of serum. Therefore, we concluded that protein expression of AP-2α does not appear to be regulated by HRPAP20, and protein expression of both AP-2α and AP-2γ in MCF-7 may be regulated by serum by unknown mechanism. In addition, we suggest that HRPAP20 expression may suppress serum regulation of AP-2γ protein expression. We also speculated that increased DNA binding activity by AP-2 may occur by downregulating a co-repressor of AP-2s or post-transcriptional modifications. Furthermore, we suggest that it is also possible that DNA binding by other isoform of AP-2, AP-2β, AP-2δ or AP-2ε, might be the one that regulated by HRPAP20 in MCF-7/HRPAP20 transfectants. Advisors/Committee Members: Buckley, Arthur.

Subjects: Pharmacology

Keywords: HRPAP20; AP-2; Cancer; AP-2Î±; MCF-7; Ovarian Cancer; AP-2Î³

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13. Conroy, Eileen M. SPATIAL AND TEMPORAL CHARACTERIZATION OF SKIN TREATMENT PRODUCT DISTRIBUTION ON THE SKIN USING FLORESCENT STEREOMICROSCOPIC IMAGING.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2000, University of Cincinnati

► Improving skin hydration is one of the most important claims in the… (more)

Keywords: Skicon; Penetration; Glogerm; Forearm; Desquamation

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14. Darvesh, Altaf Sultan. Studies on the 3,4-methylenedioxymethamphetamine (MDMA)-induced dysregulation of energy metabolism and its neurochemical consequences.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2005, University of Cincinnati

► 3,4-Methylenedioxymethamphetamine (MDMA), an analog of the amphetamine class, is a psychostimulant and… (more)

▼ 3,4-Methylenedioxymethamphetamine (MDMA), an analog of the amphetamine class, is a psychostimulant and a popular drug of abuse. MDMA is considered to be selectively neurotoxic to serotonergic nerve terminals in different brain regions, however the exact mechanisms through which MDMA produces serotonin (5-HT) neurotoxicity remain unknown. Oxidative stress has been reported to play an important role in mediating this process. In addition to the potential role of oxidative stress in MDMA neurotoxicity, there is evidence that bioenergetic stress may play an important role in the toxicity produced by amphetamine analogs. The overall hypothesis, which provides the basis for the current proposal is that MDMA produces dysregulation of brain energy metabolism and this plays an important role in MDMA-induced neurotoxicity.The effect of MDMA on brain energy metabolism was investigated by examining the effect of MDMA on brain glycogen. MDMA produced a time and dose-dependent decrease in brain glycogen. Maintenance of rats at a cool ambient temperature of 17 0C or pretreatment with 5-HT2 antagonists, significantly attenuated the MDMA-induced hyperthermia and glycogenolysis. However, MDMA-induced hyperthermia, as well as glycogenolysis, was found to be neither sufficient nor necessary for the MDMA-induced long-term 5-HT depletion.Administration of substrates of energy metabolism, e.g., nicotinamide, ubiquinone, attenuated the MDMA-induced long-term 5-HT depletion. Nicotinamide also attenuated the long-term DA and 5-HT depletion produced by coperfusion of MDMA and the mitochondrial inhibitor malonate. A neurotoxic regimen of MDMA produced a significant depletion of ATP in the striatum and hippocampus. Dysregulation of energy metabolism and energy depletion results in increased intracellular Ca2+ levels in the mitochondria, which results in activation of nitric oxide synthase (NOS) and generation of nitric oxide (NO). A neurotoxic regimen of MDMA produced an increase in NO in the striatum. The MDMA and malonate-induced long-term DA and 5-HT depletion were attenuated by administration of NOS inhibitors, as well as a peroxynitrite decomposition catalyst. The neuronal NOS inhibitor S-methyl-L-thiocitrulline (S-MTC) attenuated the MDMA-induced long-term 5-HT depletion without attenuating the MDMA-induced hyperthermia.These results support the conclusion that MDMA produces dysregulation of energy metabolism and this bioenergetic stress contributes to MDMA-induced neurotoxicity. Advisors/Committee Members: Gudelsky, Dr. Gary A.

Subjects: Health Sciences, Pharmacy

Keywords: 3,4-Methylenedioxymethamphetamine; Neurotoxicity; Serotonin; Oxidative stress; Bioenergetic stress; Energy metabolism

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15. Davis, Jennifer A. Role of TNF-alpha polymorphism -308 in Irritant Contact Dermatitis and Neurosensory Response.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2009, University of Cincinnati

► Performance of repetitive hand hygiene procedures is required for health care workers… (more)

Subjects: Occupational safety

Keywords: TNF-alpha polymorphism -308; Irritant Contact Dermatitis; Neurosensory Irritation; Healthcare workers; Hand hygiene; Lactic Acid Sting Test

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16. DIXIT, SANTOSH G. INTERFERON-GAMMA MODULATES INTESTINAL P-GLYCOPROTEIN: MOLECULAR MECHANISM(S) AND CLINICAL IMPLICATIONS.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2005, University of Cincinnati

► Intestinal P-glycoprotein (P-gp) expression and luminal nitric oxide (NO) levels are significantly… (more)

▼ Intestinal P-glycoprotein (P-gp) expression and luminal nitric oxide (NO) levels are significantly greater in patients with refractory inflammatory bowel disease (IBD). We investigated whether the proinfammatory cytokine IFN-γ, the transcription factor NF-κB, and the signaling intermediate NO regulate the P-gp encoding ABCB1 gene using the Caco-2 cells as an in vitro model of human intestinal epithelial cells. To identify cytokine-mediated activation of signal transduction pathways, phosphorylation of JAK-2, cytosolic IκBα degradation and nuclear binding of NF-κB were determined in Caco-2 cells stimulated with 10 ng/ml of IFN-γ using immunoblot analysis and electrophoretic mobility shift assays, respectively. Changes in ABCB1 mRNA were measured by realtime PCR, total cellular P-gp protein was quantitatively assessed using immunoblot analysis, and digoxin uptake was used to determine P-gp efflux activity at the apical membrane. To further evaluate underlying molecular pathways, similar experiments were performed using Caco-2 cells expressing phosphorylation-deficient IκBα (Caco-2/ NF-κB-/-) in the presence or absence of the NF-κB inhibitor parthenolide (25 ìM), the iNOS inhibitor L-NIL (1 mM), and the NO donor SNAP (0.1-5 mM). Transactivation of the ABCB1 promoter was determined using a 1 kb ABCB1-luciferase construct that contained a functional or mutated NF-κB response element. Intracellular NO levels were determined by the Griess reaction. IFN-γ stimulation of Caco-2 cells enhanced phosphorylation of JAK-2, cytosolic degradation of IκBα, increased nuclear binding of NF-κB, and augmented NO production by 9-fold. In parallel, ABCB1 promoter activity was increased by 4-fold, ABCB1 mRNA by at least 2-fold, total cellular P-gp protein expression by 2-fold, and digoxin uptake reduced by ~40%. Significant NF-κB activation, NO generation, and changes in ABCB1 transcription and P-gp function were absent in Caco-2/NF-κB-/- or parental Caco-2 cells coincubated with parthenolide and LNIL, respectively. Incubation of Caco-2 cells with SNAP increased NO levels, IκBα degradation, nuclear binding of NF-κB, ABCB1 mRNA levels, and P-gp protein levels by 2-fold while digoxin uptake was reduced by 45%. We conclude that NO and NF-κB are crucial biochemical mediators in IFN-γ-induced transcriptional regulation of the ABCB1 gene in this in vitro cell culture model of human intestinal epithelial cells. Advisors/Committee Members: Pauletti, Giovanni M.

Subjects: Health Sciences, Pharmacy

Keywords: P-glycoprotein, Nitric Oxide, NF-Kappa B,; Inflammatory bowel disease, Parthenolide, ABCB1, Inducible nitric oxide synthase

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17. Draganoiu, Elena Simona. Evaluation Of Kollidon® SR for Ph-Independent Extended Release Matrix Systems.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2003, University of Cincinnati

► The characteristics of a new Polyvinylacetate/Povidone based excipient, Kollidon® SR were evaluated… (more)

▼ The characteristics of a new Polyvinylacetate/Povidone based excipient, Kollidon® SR were evaluated for application in extended release matrix tablets. The effects of the following formulation and process variables on tablet properties and drug release were tested: Kollidon® SR concentration in the tablet, addition of external binder for wet granulation, presence of an enteric polymer in the matrix, method of manufacturing and compression force. The similarities in release profiles were evaluated by applying the model independent f2 similarity factor. A pilot bioequivalence study was performed in human volunteers to confirm in vivo the extended release characteristics of the propranolol tablets manufactured with Kollidon® SR. It was found that Kollidon® SR is suitable for pH-independent extended release matrix tablets. A minimum concentration of 30% polymer was necessary to achieve a coherent matrix, able to extend the release of the incorporated drugs. Increasing the Kollidon® SR concentration in the tablet led to a slower drug release. Drug release followed square root of time dependent kinetics, thus indicating a diffusion-controlled release mechanism. The drug release was influenced by the aqueous solubility of the drug. The drug release rate was faster for wet granulation than direct compression, thus making direct compression the method of choice for manufacturing Kollidon® SR extended release systems. It was found that Kollidon® SR was the main release controlling agent in the presence of an external binder or enteric polymer in the matrix. A significant reduction in the dissolution rates associated with an increase in tablet hardness was observed during the stability test under accelerated conditions.The developed propranolol matrix tablets formulation was compared in a pilot bioequivalence study to the reference listed product (Inderal® LA capsules). It was found that the two products were not bioequivalent according to the FDA bioequivalence criteria. The tablets had higher bioavailability than the capsules as shown by higher Cmax and AUC 0-24h. For the developed tablet formulation the higher initial plasma concentrations correlated with the faster initial release observed in vitro. It was concluded that Kollidon® SR is a potentially useful excipient for the production of pH-independent extended release matrix tablets. Advisors/Committee Members: Sakr, Dr. Adel.

Subjects: Health Sciences, Pharmacy

Keywords: extended release; Matrix Tablet; Kollidon® SR

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18. EPPLER, ANGELA RAE. ASSESSMENT OF SKIN ABSORPTION AND IRRITATION POTENTIAL OF ARACHIDONIC ACID AND GLYCERYL ARACHIDONATE USING IN VITRO DIFFUSION CELL TECHNIQUES.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2005, University of Cincinnati

► The Cosmetic Ingredient Review Panel’s final report on the safety assessment of… (more)

▼ The Cosmetic Ingredient Review Panel’s final report on the safety assessment of arachidonic acid (AA) noted its use in cosmetic skin preparations although there is a lack of dermal absorption data. The safety concern of topical applied AA arises upon its metabolism to pro-inflammatory mediators. In vitro percutaneous absorption/metabolism studies were initiated in flow-through diffusion cells. AA, and its glycerin monoester, glyceryl arachidonate (GA), were each applied in an o/w emulsion to simulate cosmetic consumer use conditions. AA was analyzed for absorption/metabolism in viable rat and human skin while GA was tested in cultured (EpiDerm™), viable human, and human cadaver skin. Absorption data on both compounds was collected every 6hr over a 24hr period. The highest absorption was observed through EpiDerm™ (50%) and rat skin (20%). To a lesser extent, AA and GA penetrated human skin about 20%, of which ~2% absorbed. A reservoir of AA was observed in cadaver skin during an extended absorption study (72hr), in which absorption increased to 4%. Ester hydrolysis of GA occurred in each of the analyzed tissue samples. Additionally, in vitro methods (as an alternative to the Draize test) were evaluated for their prediction of skin irritation potential in conjunction with flow-through diffusion cell absorption/metabolism measurements. Model compounds, with known irritation potential in vivo, were evaluated in vitro by measuring transepidermal water loss (TEWL), cytokine release (IL-1á), and skin viability (MTT) of rat and cultured skin in flow-through diffusion cells. Irritation potential of the model compounds was less pronounced in the emulsion formulation compared to an aqueous vehicle. No significant irritation from AA in an emulsion vehicle was observed with the alternative methods. As a supplementary assessment, TEWL was analyzed for its relationship to the 3H2O skin barrier integrity test, however no direct correlation was found to exist. Absorption of topically applied AA and GA was observed, indicating a potential for systemic availability. Furthermore, ester hydrolysis of GA occurred during absorption. The in vitro alternative methods for measuring skin irritation in flow-through diffusion cells were able to differentiate between the potency of irritants in an aqueous but not an emulsion formulation. Advisors/Committee Members: Wickett, Dr. R. Randall.

Subjects: Health Sciences, Pharmacology

Keywords: Arachidonic Acid; Glyceryl Arachidonate; Percutaneous Absorption; In Vitro Alternative Methods

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19. GROVER, BRETT LORING. ALTERED RENAL ORGANIC CATION TRANSPORT IN STREPTOZOTOCIN-INDUCED DIABETES MELLITUS.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2002, University of Cincinnati

► The overall goal of this study was to examine the effect of… (more)

▼ The overall goal of this study was to examine the effect of streptozotocin (STZ)-induced diabetes on the function of the active renal organic cation transport system. Previous work completed in our laboratory demonstrated decreased tetraethylammonium (TEA) uptake in freshly isolated proximal tubule (PT) cells from diabetic rats. Because TEA uptake in cells represents both influx and efflux processes, conclusions are limited by nature of the method. Additional experiments were therefore necessary to better define the mechanisms mediating the observed transport impairment. This study was designed to test the hypothesis that impaired TEA uptake in PT cells is due, in part, to a decrease in uptake across the basolateral membrane (BLM) caused by a reduction in the number of functional transporters. Kinetic analysis of TEA uptake in isolated cells from 21-day diabetic rats revealed a significant 46% decrease in V max and a non-significant higher affinity constant, K m . Results from slice experiments, a model that predominately reflects BLM uptake, document a progressive decline in TEA accumulation with increasing duration of diabetes. A maximal decline of 40% occurred after 21 days of diabetes. The accumulation in slices was energy dependent, saturable, and quinine sensitive, indicating that the uptake was primarily mediated by the organic cation transport system. Normal oxygen consumption was found in diabetic slices, suggesting that the transport impairment at the BLM is not due to altered aerobic metabolism. Instead, the observed transport impairment in slices was attributable to molecular adaptations of the BLM organic cation transporters (OCTs). OCT1 and OCT2 protein expression was found to be decreased 50% and 70% respectively, in 21-day diabetic slices. Examination of OCT mRNA revealed OCT1 was unaltered, while OCT2 was decreased by 50% after 21 days of diabetes. These results suggest differential regulation exists for the cloned transporters. As expected, studies using insulin prevented all diabetes-associated impairments, arguing against the likelihood of either an acute toxic action of STZ or an artifact of the methods. This study implies diabetes-associated changes in the organic cation transport system may alter renal handling of drugs, toxins, and endogenous compounds. Advisors/Committee Members: Cacini, Dr. William.

Subjects: Health Sciences, Pharmacology

Keywords: streptozotocin (STZ); diabetes mellitus; renal organic cation transport; OCT

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20. GUNT, HEMALI B. WATER HANDLING PROPERTIES OF VERNIX CASEOSA.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2002, University of Cincinnati

► Vernix caseosa is a proteolipid film present on the skin surface of… (more)

▼ Vernix caseosa is a proteolipid film present on the skin surface of term newborn. It interfaces the developing fetus with the amniotic fluid during the last trimester of gestation. Vernix comprises of hydrated fetal corneocytes embedded in a nonlamellar lipid matrix. Vernix lipids consist of both, the stratum corneum lipids and the sebaceous lipids. At term, human infant possesses a highly competent epidermal barrier despite being immersed in the amniotic fluid. Preterm neonates lack this biological material, vernix, and also have a compromised skin barrier. Topical application of protective creams and semipermeable dressings have the ability to modulate epidermal barrier function and integrity. This investigation aimed at determining the water handling properties of vernix, cubosome formulations and comparing it with those of conventional skin care creams used in management practices of immature and damaged skin. The water loss profile of vernix films as a function of thickness and relative humidity was investigated. It was seen that with increase in film thickness and exposure to increasing relative humidity, the percent water loss from vernix decreased. Dried vernix when exposed to raised ambient humidity showed gain in weight due to water pick up. Isolated vernix components did not show this effect at raised ambient humidity. In vitro data showed that it was not only the lipid or cellular fraction but that the entire vernix composition was responsible for its hygroscopic nature. Increase in hydration as a function of relative humidity in vitro was seen to relate to increased water-holding capacity in vivo. Water vapor transport through vernix and its components showed that the lipid fraction of vernix was primarily responsible for providing a controlled water vapor transport.Vernix cells did not provide a barrier to water loss. Vernix and vernix lipids, thus behaved like semipermeable membranes. These findings suggested that vernix, like semipermeable membranes might provide an optimum water gradient required for development and restoration of the stratum corneum barrier. In summary, a synthetic vernix equivalent may facilitate barrier recovery in wounded skin and improve barrier function. Advisors/Committee Members: Wickett, Dr. R. Randall.

Subjects: Health Sciences, Pharmacy

Keywords: vernix caseosa; water handling properties; skin care creams

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21. Gunt, Hemali B. Hydration Effect on Human Nail Permeability.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

► It has been long known that hydration strongly affects transport and mechanical… (more)

▼ It has been long known that hydration strongly affects transport and mechanical properties of keratinized membranes. The most studied keratin structures are human stratum corneum, wool and hair. The effect of hydration on transport, however, has not been studied in human nails. This investigation is aimed at filling this gap. In the first phase of the work we have determined the equilibrium water sorption isotherm for human nail. The isotherm obtained in our laboratory was compared with available literature data for nail and other keratinized tissues. Results were described in terms of theoretical sorption models used in natural polymers and food systems including Guggenheim-Anderson-de Boer and D’Arcy-Watt isotherms. Of the models tested, D’Arcy-Watt gave the best description over the entire range of hydration. We further investigated transport properties in nail of water and the antifungal drug, ketoconazole as a function of nail hydration which was controlled by adjusting the relative humidity on one or both sides of the tissue. Diffusivity of water in nail was studied using both vapor phase and liquid phase sorption-desorption techniques. The values obtained ranged from D = 3.160 × 10-7 cm2/s at a water volume fraction phi1 = 0.4107 to D = 7.68 × 10-10 cm2/s at phi1 = 0.0431. They are interpreted in terms of a free volume theory. Transport parameters of ketoconazole were obtained by conducting permeation experiments using a single chamber diffusion cell designed specifically for nail permeation studies. Flux of ketoconazole solvent-deposited onto the nail from ethanol increased consistently with an increase in water content in the nail. Diffusivities estimated from these data can be described by Fujita theory. The findings show that hydration provides enormous increases in water transport through nail, but only a modest (2-3 fold) increase in ketoconazole permeation under conditions attainable in vivo. Thus, nail penetration enhancement by hydration is not large enough for it to be considered as the only factor in formulating a more effective topical treatment of nail disorders. The effect of hydration on diseased nail permeability remains to be evaluated. Advisors/Committee Members: Kasting, Gerald B.

Subjects: Health Sciences, Pharmacy

Keywords: nail; keratin; nail permeability; hydration; water

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22. Hamed, Ehab Ahmed Mamdouh. Application and Evaluation of Extended Release Technology to Loop Diuretics.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2002, University of Cincinnati

► Loop diuretics offer great advantages in treating edematous states associated with congestive… (more)

▼ Loop diuretics offer great advantages in treating edematous states associated with congestive heart failure, liver cirrhosis and kidney failure owing to their intense diuretic effect. Evidences suggested the diuretic effect can be exaggerated by careful control of the rate at which loop diuretics are made available to the urinary tubules. If optimally designed, peroral extended release formulation can provide better utilization of the same total dose of loop diuretic, an effect of utmost importance in edematous patients with high resistance to loop diuretics. Bumetanide multiparticulate immediate and extended release formulations were developed and tested in rabbits. A novel multiple response optimization technique based on superimposing contour diagrams was developed and successfully used to optimize bumetanide release. Instability in drug release from multiparticulate formulations after storage warrants in depth investigation of different formulation and processing factors controlling drug release. Curing time, temperature, plasticizer level, coating polymer lipophilicity, and the use of hydrophilic seal coat were explored in this study. The findings proved instability in bumetanide release is attributed to drug migration into the film coat during storage. Careful selection of plasticizer level and curing conditions together with the use of hydrophilic seal coat prevented drug migration and stabilized drug release after storage. When compared to immediate release formulation in rabbits, equivalent amounts of bumetanide were excreted from both formulations yet at different rates. The slow delivery of bumetanide from the extended release formulation improved its diuretic and natriuretic efficiencies within the first day after dosing. The activation of compensatory mechanisms is thought to diminish the response to extended release bumetanide formulation within the second day. While providing comparable diuretic and saliuretic effects to that of immediate release formulation, extended release bumetanide formulation can offer the advantage of avoiding the initial, unpleasant and intense diuretic effect experienced with immediate release formulations. Advisors/Committee Members: Sakr, Dr. Adel.

Subjects: Health Sciences, Pharmacy

Keywords: bumetanide; extended release; loop diuretics; multiparticulate coating; response surface methodology

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23. HAMED, SAJA H. EFFICACY AND MECHANISM OF ACTION OF A NEW TYROSINASE INHIBITORY AGENT.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2004, University of Cincinnati

► Acquired hyperpigmentation diseases, are common skin diseases. An example is melasma that… (more)

▼ Acquired hyperpigmentation diseases, are common skin diseases. An example is melasma that is permanent in middle-aged women. Hyperpigmentation diseases have psychosocial and cosmetic importance since they are common on sun-exposed areas of the face and the neck. Various treatments are available in the market, but none are completely satisfactory. Most popular skin depigmenting products use a tyrosinase inhibitor as the active ingredient as a result of the key role played by tyrosinase in melanin biosynthesis. The success of these products is limited for two basic reasons: safety or overall effectiveness. Because of the need to provide a skin depigmenting agent that is more efficacious, more stable and less cytotoxic we have analyzed a novel compound, deoxyarbutin (DA). DA was synthesized based on key structure/function relationships of tyrosinase inhibitors, for its tyrosinase inhibition and depigmenting efficacy. DA demonstrated less cytotoxicity, compared to hydroquinone (HQ), in the three normal human skin cell types (i.e., melanocytes, keratinocytes and fibroblasts). This cytotoxicity was not associated with dramatic changes on the morphology of the keratinocytes as in HQ. The lower cytotoxicity of DA as compared to HQ lends support to the stability of DA, lack of auto-oxidation, and the less harmful by-products generated from its metabolism by tyrosinase and/or other metabolic routes. DA was shown in our cell based assay to effectively inhibit tyrosinase activity and melanin synthesis. DA inhibition was reversible whereas HQ showed less or no reversibility. Further, DA reversed skin hyperpigmentation of human skin grafted onto immunocompromised mice with no irritation or negative effect on the graft histology. This lightening effect didn’t reach statistical significance and the sample size is small (n=3). In addition, evidence is provided for the need to standardize the methods used to screen for new tyrosinase inhibitory agents and that MTT assay is not the viability assay of choice when assessing the effect of DA and HQ on cell viability. Based on our viability and in vivo studies, deoxyarbutin has the potential to be a safe and effective depigmenting agent and to be an effective alternative to hydroquinone; the skin depigmenting standard with known safety drawbacks. Advisors/Committee Members: Wickett, Dr. Randall.

Subjects: Health Sciences, Pharmacy

Keywords: Deoxyarbutin; Hydroquinone; Skin depigmenting agents

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24. Hamid, Rezaei. EFFECT OF MOLECULAR WEIGHT OF POLYETHYLENE GLYCOLS ON THEIR FUNCTION AS LUBRICANT SPARING BINDERS IN TABLET TECHNOLOGY.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2001, University of Cincinnati

► The objective of this study was to determine the effect of molecular… (more)

▼ The objective of this study was to determine the effect of molecular weight on the function of polyethylene glycols (PEGs) as lubricant sparing binders in tabletting technology. Compression-force and ejection-force profiles were obtained using an instrumented Manesty D3B rotary tablet press. In order to determine the lubricating mechanism of PEGs, after storage in controlled settings, PEGs of different molecular weight were compressed. PEG-8000 resulted in compacts with the greatest crushing strength, PEG-3350 next, and PEG-20M last. Scanning electron microscopy showed, while PEG-20M compacted by plastic deformation, both PEG-3350, and PEG-8000 had compacted by brittle fracture, with evidence of melting during compression. It was concluded that lubrication properties of PEG-20M was due to its plastic deformation properties. PEGs were also studied for their binding mechanism. A full factorial experimental design using three binder levels and three compression forces, using 0.5% magnesium stearate was utilized. Low-shear wet granulation, high-shear wet granulation, and roller-compaction were utilized using acetaminophen as the model drug. Tablets with a target weight of 310 mg were compressed using 9-mm shallow concave punches at 19 RPM. ANOVA was used to analyze the results based on the PEG molecular weight, levels, and compression force (P < 0.05). PEG-20M proved to be the superior binder to all other polyethylene glycol binders using all three manufacturing methods, and comparable or superior to povidone. PEG-20M produced tablets with lower friability than PEG-8000 and PEG-3350. It also resulted in tablets with the highest dissolution rate for acetaminophen, including the reference binder. PEG-20M resulted in tablets with acceptable friability using low-shear and high-shear wet granulation, and roller compaction with significantly lower tablet ejection forces than other polyethylene glycols or povidone. It was concluded that PEG-20M is a unique molecule, with higher porosity, and flexibility than lower molecular weight PEGs. It is only a better binder than other PEGs, but also enhances the dissolution of acetaminophen, a poorly soluble drug (channeling agent). Under the conditions studied, PEG-20M had the best "binder efficiency", granule size flow and homogeneity, and tablet crushing strength friability and dissolution results. Advisors/Committee Members: Sakr, Adel.

Subjects: Health Sciences, Pharmacy

Keywords: solid; dosage; polyethylene; glycol; formulation

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25. Hariparsad, Niresh. Hepatic and Extra-Hepatic Induction of Drug Metabolizing Enzymes and Drug Transporters by Antiretrovirals, in the Presence and Absence of Viral Infection.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

► Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are important antiretroviral… (more)

▼ Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are important antiretroviral drugs (ARVs) included in the currently used highly active antiretroviral therapy (HAART) regimen. While these agents have significantly improved the morbidity and mortality associated with HIV/AIDS, their clinical use remains fraught with numerous drug-drug interactions (DDIs) including induction of drug clearance pathways. This study represents an attempt to better understand the impact of these agents on key drug-metabolizing enzymes and drug transporters (DMTs) in hepatic and extra-hepatic tissues. In preliminary studies we observed that NNRTI efavirenz, and PIs, nelfinavir and ritonavir, activate the pregnane-X receptor (PXR), a key transcriptional regulator of DMTs. Based on this observation and other published reports, we hypothesized that these agents induce hepatic and extra-hepatic (intestinal and CD4+ T-cells) DMTs, and that the magnitude of induction is modulated by disease state. In Aim 1, employing primary human hepatocytes and LS174T colon carcinoma cell line, a clinically relevant model for intestinal drug metabolism studies, we observed that these drugs have a profound effect on several DMTs. Our studies revealed that efavirenz is potent inducer of CYP3A4, whereas the PIs increase CYP3A4 mRNA levels without a correlative increase in CYP3A4 activity. The three drugs also induced CYP2B6, UGT1A1 and UGT1A6, but only nelfinavir induced UGT2B7. Both PIs markedly induced P-gp. In Aim 2, we evaluated the effect of these drugs on expression and activity of DMTs in CD4+ T-cells. While all three ARVs produced significant increases in the P-gp function in CD4+ T-cells, nelfinavir was the most potent P-gp inducer. In the third Specific Aim, we observed that exposure of nelfinavir-treated CD4+ T-cells to infectious-HIV decreased P-gp activity which corresponded with a reduction in hPXR expression levels. A comparison of the effects on exposed-infected and exposed-uninfected cells revealed a significant decrease of P-gp activity in nelfinavir-treated exposed-infected cells, but an increase in the exposed-uninfected cells. The expression of hPXR was lower in nelfinavir-treated exposed-infected cells than exposed-uninfected cells. Taken together, our studies have provided novel insights into the factors that may increase the potential for drug-drug interactions and alter the intracellular pharmacology of important ARVs. Advisors/Committee Members: Desai, Dr. Pankaj B.

Keywords: Induction; Hepatic and extra-hepatic; In vitro; Efavirenz, ritonavir, nelfinavir; Phase I and phase II drug metabolizing enzymes

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26. HAUSMAN-MANNING, DEBRA SUE. APPLICATION OF PROCESS ANALYTICAL TECHNOLOGY TO PHARMACEUTICAL PROCESSES.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2005, University of Cincinnati

► Process Analytical Technology (PAT) was utilized for on-line evaluation of drug hydration… (more)

▼ Process Analytical Technology (PAT) was utilized for on-line evaluation of drug hydration state and its effect on final product quality, as well as the effect of blending parameters on low dose blend and tablet uniformity. Experiments were conducted to elucidate the relationship between risedronate sodium (RS) hydration state and the physical stability of tablets containing RS. The RS crystal lattice contains channels occupied by water which is removed by drying processes at temperatures below the boiling point of water, causing a reversible contraction of the crystal lattice. In this study, RS was wet granulated followed by fluid bed drying and compression into tablets. During drying, RS solid-state form was continuously monitored using on-line Raman spectroscopy. It was determined that final granulation moisture had a significant effect on change in RS hydration state measured by Raman and on change in tablet thickness over time. In addition, change in RS hydration state during fluid bed drying, measured by on-line Raman, was correlated to the increase in tablet thickness and subsequent loss of tablet integrity. Evaluation of RS solid-state during drying with Raman enabled establishment of relationships between fundamental hydration dynamics associated with RS and final product performance attributes. On-line Raman was also used to evaluate the effect of blending parameters on uniformity of a low dose, 1%, blend of azimilide dihydrochloride. Parameters investigated were blend time, blender speed, azimilide placement in the blender, filler particle size and density, multiple tablet components, and sampling. At the 8qt scale used, there was no effect of azimilide placement in the blender on time to reach uniformity. However, there was an effect of filler particle size/density and blender speed on time to reach uniformity. On-line Raman analysis of blend uniformity provided more information about the blending process as compared to traditional thief sampling and off-line analysis, due to the feasibility of large numbers of samples across the run (sampling every 20 seconds) and the availability of spectral information on all blend components. Raman measurements of blend uniformity from univariate and multivariate analyses were significantly correlated to HPLC blend thief sample and tablet sample results. Advisors/Committee Members: Sakr, Dr. Adel.

Keywords: Raman spectroscopy; Process Analytical Technology; on-line monitoring; hydration state; fluid bed drying; stability; low dose blending; uniformity

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27. HEATON, PAMELA CHRISTINE. EFFECTIVENESS AND COST-BENEFIT ANALYSIS OF LEUKOTRIENE MODIFIERS IN PATIENTS WITH ASTHMA IN THE OHIO MEDICAID POPULATION.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2003, University of Cincinnati

► Objectives: To determine the impact of leukotriene modifiers on subsequent emergency room… (more)

▼ Objectives: To determine the impact of leukotriene modifiers on subsequent emergency room visits, hospitalizations and steroid bursts; and to estimate whether leukotriene modifier use is cost-effective. Methods: This study was a retrospective, longitudinal study of asthmatic patients in the fee-for-service Ohio Medicaid program. The study population included 11,533 adult patients and 18,563 pediatric patients who had an asthma diagnosis during 2001. The rate of adverse outcomes and logistic regression was used to determine the impact of leukotriene modifier use on three outcome measures: emergency room visits, hospitalizations, or steroid bursts. Propensity scores were used to control for the selection bias inherent in drug treatment selection. A cost-benefit analysis was also calculated. Results: In the adults, leukotriene modifier users had 16.4 events per one hundred patients versus the nonusers who had 10.3 events per one hundred patients, a difference of 6.1. This suggests that for every 15 adults treated, one will have an adverse outcome (Number needed to harm=1/0.061). In the children, leukotriene modifier users had 18.5 events per one hundred patients versus the nonusers who had 6.5 events per one hundred patients, a difference of 12. This suggests that for every 8.3 children treated, one will have an adverse outcome (Number needed to harm=1/0.12). In the logistic regression models, the use of leukotriene modifiers did not have a significant effect, positive or negative, on any of the outcome variables in adults. In children, however, there was a significant increased risk for requiring an emergency room visit (OR 1.0014, 95% CI 1.0002-1.0027) or a steroid burst (OR 1.0017, 95% CI 1.0001-1.0033). In both the adult and pediatric population, the cost benefit analysis shows that there was a total net loss to Ohio Medicaid. Conclusions: The results suggest that adult leukotriene modifier users do not have fewer adverse outcomes than nonusers and pediatric leukotriene modifier users have more adverse outcomes when compared to nonusers. The use of leukotriene modifiers resulted in a net loss to Ohio Medicaid. Advisors/Committee Members: Guo, Dr. Jeff.

Keywords: leukotriene modifiers; asthma; propensity score; retrospective database analysis

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28. HUANG, YAO-CHIN. EFFECTS OF ROBOTIC PRESCRIPTION DISPENSING SYSTEM ON OUTPATIENT PHARMACY OPERATIONS.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2002, University of Cincinnati

► The objective of this study was to evaluate the effects of implementing… (more)

Keywords: work sampling; automation; script pro; efficiency; manpower

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29. Ibrahim, Sarah A. A Structure-Enhancement Relationship and Mechanistic Study of Chemical Enhancers on Human Epidermal Membrane based on Maximum Enhancement Effect (Emax).

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2010, University of Cincinnati

► Transdermal pharmaceutical formulations, in most cases, contain chemical penetration enhancers. To properly… (more)

▼ Transdermal pharmaceutical formulations, in most cases, contain chemical penetration enhancers. To properly select efficient chemical enhancers, an understanding of their mechanism(s) of action is essential. This dissertation evaluated the enhancement effects of known topical or cosmetic ingredients on human epidermal membrane (HEM) permeation. Permeation enhancement effect, Emax, was identified as enhancement effect induced by the enhancer on HEM permeation as the enhancer approaches the thermodynamic activity of its pure state in equilibrium with HEM. A structure enhancement relationship was established for the chemical enhancers studied. Emax was shown to be dependent of the lipophilicities. A guideline for the selection of chemical enhancers based on efficiency and duration of enhancement was determined based on octanol/water partition coefficient and calculated n-octanol solubility. This dissertation also studied topical formulations consisting of a volatile carrier system containing the chemical enhancers. To fully understand the enhancer induced permeation enhancement mechanism, the transport domain of skin i.e., the stratum corneum (SC) lipid domain was probed. This involved the determination of both enhancer and permeant uptake into the lipid domain of SC following enhancer treatment. It was concluded that the permeation enhancement mechanism is attributed to the enhancement of permeant partitioning into the transport rate limiting domain. Liposomes formulated from extracted human stratum corneum lipids (EHSCLL) were characterized and used to directly study this domain. The uptake of the chemical enhancers within the EHSCLL was determined and the results suggested a quantitative relationship between enhancer uptake in EHSCLL and enhancer efficiency. DSC and ATR-FTIR studies using enhancer treated intact SC supported that the mechanism of chemical enhancers is via their fluidization and perturbation of the SC lipid bilayer. This finding suggests that the enhancers induce both a polarity shift in the SC lipid domain and a decrease in lipid microviscosity through lipid fluidization in the SC. Advisors/Committee Members: Li, Kevin.

Subjects: Pharmaceuticals

Keywords: Skin; Chemical Enhancers; DSC; ATR-FTIR; Transdermal; Liposomes

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30. Joshi, Ashish Vikas. HEALTH CARE UTILIZATION AND COSTS IN OHIO MEDICAID: MANAGED CARE VERSUS FEE-FOR-SERVICE.

Degree: MS, Pharmacy : Pharmaceutical Sciences, 2000, University of Cincinnati

► Increasing Medicaid costs have encouraged many state policy-makers to propose and implement… (more)

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