published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

The main objective of this work was to develop Poloxamer 407 (Pluronic F127)-based formulations for controlled ocular delivery of pilocarpine as a model drug. Various additives such as polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC), were incorporated into formulations containing 25% PF127, 1% pilocarpine hydrochloride (PHCL) alone or containing one of the additives. The release of PHCL from the PF127 formulations and the dissolution profile of the formulations are obtained simultaneously at RT and 34°C. The formulations with 25% PF127, 1% PHCL and either 5% MC or 3% HPMC showed the slowest dissolution and also released the drug the slowest of the formulations evaluated in vitro. The PHCL release from the two formulations exhibited a zero-order release and the mechanism of PHCL release seem to be dissolution controlled. Therefore the MC- and HPMC-containing PF127 formulations of PHCL were selected for further in-vivo studies. The miotic response to equal administered volumes of an isotonic solution of 1% PHCL and the MC-containing PF127 formulation of PHCL was measured. The PF127 formulation showed a statistically significant increase in the duration of miosis and the intensity of the miotic response (i.e., higher ocular bioavailability) compared to the same instilled volume of the Isotonic PHCL solution. In the next phase of this work pilocarpine-incorporated polyisobutylcyanoacrylate nanocapsules (PIBCA-NC) were prepared, characterized in vitro and evaluated in vivo in albino rabbit eyes. Here the PIBCA-NC of PHCL containing 1% pilocarpine, of which about 13.5% was incorporated into the nanocapsules, were administered alone or using the aforementioned MC-containing PF127 formulation with 25% PF127 and 5% MC as a vehicle. The in vivo results indicated that the PIBCA-NC dispersion of 1% pilocarpine, when administered using the MC-containing PF127 gel vehicle, significantly improved the duration and the intensity of the miotic response compared to the administration of the same volume of the PIBCA-NC dispersion of 1% pilocarpine alone. Therefore, the PF127 formulations of pilocarpine developed and evaluated thus far, offer considerable promise in terms of their potential to be used for the controlled release ocular delivery of pilocarpine.

The startup of the Bill Gatton College of Pharmacy has allowed the introduction of novel means of engaging students in a variety of programs. The Concentration in Pharmacy Research (CPRx) is designed to give students focused experience in conducting research in Pharmaceutical Sciences and Pharmacy Practice. Initiated by faculty desire to engage PharmD students productively in the lab to augment our degree program, the CPRx arose because of student desire for recognition of their research efforts. The CPRx was formalized by developing a proposal that contained input from students, faculty and staff, passed through both departments and then the Faculty Council. Successful fulfillment of the CPRx requires students to complete a total of 12 credits in designated research elective courses, offered in both departments. A capstone APPE is also required where each student drafts a publication of his or her work and submits the paper for publication. The demand for research elective participation has been large. Currently, a total of 61 2nd and 3rd year PharmD students are enrolled in research courses. Of these, 15 are formally enrolled in the CPRx. To date, 73 abstracts and presentations and 25 peer-reviewed papers have been authored by Gatton students. The overall success of this program shows the powerful enthusiasm that arises from faculty and student engagement in active and productive research. The CPRx provides a unique means for Gatton students, especially those seeking residencies, to individualize their PharmD degree and enable greater success and diversity of career choices.

Erythromycin (ERY) is a macrolide antibiotic which is used in the treatment of acne vulgaris.Acne is a common skin condition that occurs when the sebaceous glands and hair shafts become infected by the bacteria Propionibacterium acnes. Acne is a chronic condition that may last for years and the severity of the effects of the disease on patients is often undermined especially in third world countries where more emphasis is placed on other more life-threatening diseases. It may cause considerable physical and emotional distress to sufferers along with the possibility of permanent scarring. Although use of topical ERY formulations is not the first line of treatment it has proven to be effective in treating inflammation of skin and skin structures cause by the responsible bacteria. To-date there are a variety of vehicles which are used in preparing topical ERY formulations namely ointment and gel bases, alcoholic solutions and pledgets. All the gel formulations on the market contain hydroxypropyl cellulose, alcohol and water along with the active ingredient(s). However, some gel formulations contain propylene glycol in addition to these excipients an example being Emgel®. Propylene glycol has been shown to affect the penetration of topically applied drugs through the skin suggesting that it would be highly likely that those formulations which contain propylene glycol may release more ERY into the skin following application. With this in mind, two ERY gel formulations were produced which contained different percentages of propylene glycol. According to the FDA guidelines, pharmacokinetic measurements in blood, plasma and/or urine of topical dermatological drug products are not feasible to document bioequivalence since the active ingredient(s) in topical formulations is/are not intended to be absorbed into the systemic circulation and in addition, concentrations in extracutaneous biological tissues would generally not be measurable. This limits determination of bioavailability and assessment of bioequivalence of such products to pharmacodynamic measurements, clinical trials and dermatopharmacokinetic (DPK) measurements such as tape stripping (TS) and microdialysis (MD).TS is a sampling technique which involves sequential removal of layers of the stratum corneum using strips of adhesive tape. This technique has found increasing use in DPK studies for investigation of drug kinetics in the skin following the application of a topical formulation. The technique has also been used as a diagnostic tool in assessing the quality of the stratum corneum in diseased skin. In the current research study, the tape stripping technique was used to investigate the pharmaceutical/biological availability of topical gel formulations containing ERY. MD is another DPK sampling technique which has been used to determine the amount of a topically applied drug that penetrates through the stratum corneum to reach deeper tissues of the skin. The in vivo sampling technique involves the insertion of microdialysis probes beneath the skin surface in the dermal tissue and allows for real-time sampling of the analyte at its target site. Recently in vitro MD has also been successfully used to assess the pharmaceutical availability of a topical corticosteroid, mometesone furoate, from topical formulations. Based on this work, microdialysis was used to determine the pharmaceutical availability of ERY from gel formulations which were developed for use in this research. The results of the pharmaceutical availability of ERY from in vivo tape stripping studies and the in vitro microdialysis studies were compared to establish correlation between the data. Pharmaceutical equivalence and bioequivalence data obtained from the respective studies on the gel formulations were investigated by statistical analysis of the data generated from both the in vitro and in vivo experiments. In summary the objectives of this research were: 1. To develop and validate a high performance liquid chromatography method suitable to analyse ERY concentrations obtained from in vitro microdialysis studies and in vivo tape stripping studies. 2. To prepare two different ERY gel formulations with different percentage content of propylene glycol. 3. To determine the pharmaceutical availability of ERY from two different gel formulations using in vitro microdialysis. 4. To develop and validate a tape stripping technique which could be used to determine percutaneous penetration and bioequivalence of the gel formulations. 5. To compare in vitro microdialysis and in vivo tape stripping data and attempt to establish a correlation between the two different approaches.

This non-experimental, retrospective, descriptive and correlational study investigated adherence to antiretroviral drugs among HIV positive patients at Mpilo Central Hospital in Bulawayo Zimbabwe. Data among 118 patients was extracted from clinic registers and patient facility held medical records to determine level of adherence to ART using pharmacy refills (a non-immunological adherence parameter) and compared to CD4 cell count ( an immunological adherence parameter). Adherence levels obtained in this study using pharmacy refills was low (62.7%) and a relatively high non-adherence level of 37.3%. The pharmacy refill adherence level obtained was comparable to CD4 cell count adherence level of 64.6% (as indicated by a 50% CD4 cell count gain). These findings would seem to indicate the need for more education on the importance of adherence and further the need for better adherence monitoring systems / Health Studies / M.A. (Public Health)

This non-experimental, retrospective, descriptive and correlational study investigated adherence to antiretroviral drugs among HIV positive patients at Mpilo Central Hospital in Bulawayo Zimbabwe. Data among 118 patients was extracted from clinic registers and patient facility held medical records to determine level of adherence to ART using pharmacy refills (a non-immunological adherence parameter) and compared to CD4 cell count ( an immunological adherence parameter). Adherence levels obtained in this study using pharmacy refills was low (62.7%) and a relatively high non-adherence level of 37.3%. The pharmacy refill adherence level obtained was comparable to CD4 cell count adherence level of 64.6% (as indicated by a 50% CD4 cell count gain). These findings would seem to indicate the need for more education on the importance of adherence and further the need for better adherence monitoring systems / Health Studies / M.A. (Public Health)

Indiana University-Purdue University Indianapolis (IUPUI) / Drug-drug interactions (DDIs) refer to situations where one drug affects the pharmacokinetics or pharmacodynamics of another. DDIs represent a major cause of morbidity and mortality. A common adverse drug reaction (ADR) that can result from, or be exacerbated by DDIs is drug-induced myopathy. Identifying DDIs and understanding their underlying mechanisms is key to the prevention of undesirable effects of DDIs and to efforts to optimize therapeutic outcomes. This dissertation is dedicated to identification of clinically important myopathic DDIs and to elucidation of their underlying mechanisms. Using data mined from the published cytochrome P450 (CYP) drug interaction literature, 13,197 drug pairs were predicted to potentially interact by pairing a substrate and an inhibitor of a major CYP isoform in humans. Prescribing data for these drug pairs and their associations with myopathy were then examined in a large electronic medical record database. The analyses identified fifteen drug pairs as DDIs significantly associated with an increased risk of myopathy. These significant myopathic DDIs involved clinically important drugs including alprazolam, chloroquine, duloxetine, hydroxychloroquine, loratadine, omeprazole, promethazine, quetiapine, risperidone, ropinirole, trazodone and simvastatin. Data from in vitro experiments indicated that the interaction between quetiapine and chloroquine (risk ratio, RR, 2.17, p-value 5.29E-05) may result from the inhibitory effects of quetiapine on chloroquine metabolism by cytochrome P450s (CYPs). The in vitro data also suggested that the interaction between simvastatin and loratadine (RR 1.6, p-value 4.75E-07) may result from synergistic toxicity of simvastatin and desloratadine, the major metabolite of loratadine, to muscle cells, and from the inhibitory effect of simvastatin acid, the active metabolite of simvastatin, on the hepatic uptake of desloratadine via OATP1B1/1B3. Our data not only identified unknown myopathic DDIs of clinical consequence, but also shed light on their underlying pharmacokinetic and pharmacodynamic mechanisms. More importantly, our approach exemplified a new strategy for identification and investigation of DDIs, one that combined literature mining using bioinformatic algorithms, ADR detection using a pharmacoepidemiologic design, and mechanistic studies employing in vitro experimental models.