Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 156-165). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references (leaves 144-154). Available also in a digital version from Dissertation Abstracts.

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Thesis (M.S.)--University of Wisconsin--Madison, 1940. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 24-27).

Due to the lack of an effective cure for human immunodeficiency virus (HIV-1), with approximately twenty million new infections expected by 2031, research has moved towards optimised prevention strategies. Drug transporters, characterised extensively in the human liver, kidney and gastrointestinal tract, can be manipulated to improve the pharmacokinetic properties of orally delivered anti-retrovirals (ARV's). There is paucity in knowledge of drug transporter expression in the human cervicovaginal (CV) tract and representative pre-clinical models, where characterisation and manipulation may enable optimisation of topically applied ARVs for prevention of sexual transmission of HIV-1. In this thesis, RT-qPCR was used to characterise drug transporter profiles of CV pre-clinical models (in vitro, ex vivo and in vivo) for comparison with human CV tissue profiles, where distinguishable differences were observed, most notably in the efflux transporters P-gp and MRP2-4. This may explain the contrasting efficacy observed between pre-clinical and clinical trials of ARV-microbicides. Additionally, CV physiological factors (hormones, immunoregulatory proteins, microbes, pH) and microbicide candidate ARV's (dapivirine and darunavir) were shown to modulate expression of ARV-relevant drug transporters in CV cell lines. This highlights the potential intra-variability and inter-variability challenges associated with microbicide development and optimisation, in addition to potential drug-drug interactions in combination ARV-microbicides. Modulation of cellular pharmacokinetic properties in response to physiological pH levels and pro-inflammatory cytokines, observed within drug transport experiments, further emphasises these challenges. Molecular cloning experiments demonstrated the potential to develop a robust high throughout in vitro screening tool for the development of optimised microbicides. In conclusion, this thesis provides evidence exposing the limitations of pre-clinical CV models commonly used during ARV-microbicide screening, development and optimisation. The potential clinical implications of physiologically-induced and ARV-induced modulation of ARV accumulation in the CV tract when topically applied is highlighted within this thesis. It is imperative these key factors be incorporated into the pre-clinical screening and development of optimised microbicides.

Class of 2006 Abstract / Objective: To determine the degree of knowledge of clinically significant drug-drug interactions by third-year pharmacy students at two schools of pharmacy located in the Western U.S., hereafter referred to as School A and School B. The purpose was also to determine if the degree of knowledge of drug interactions was related to the amount of work experience as well as exposure to drug interaction information in the curriculum of the pharmacy school at which these students are completing their degrees. The hypothesis of this study was that there would be no difference in knowledge of clinically significant drug-drug interactions by pharmacy students at School A and School B. Methods: A two-page questionnaire was distributed to third year pharmacy students at School A and School B. The first page of the questionnaire contained 10 questions on potential drug-drug interactions and asked the students to indicate if an interaction was present and also rank their confidence for the response provided to the interaction question using a scale of 0 (not confident) to 10 (very confident). For each drug-drug pair, there were three response choices: (A) Should not be used together-contraindicated, (B) May be used together with monitoring, and (C) May be used together without monitoring. The second page of the questionnaire requested information regarding demographics such as age, gender, whether or not the students currently work in a pharmacy setting outside of pharmacy school and if they do, which pharmacy setting and for how many years, where the students believe most of their knowledge regarding drug-drug interactions is from, whether the students would like to have more class-time dedicated to drug-drug interactions, and asked the students’ opinion of how important it is for pharmacists to be aware of drug-drug interactions. In order to determine whether or not exposure to drug interaction information during the curriculum affected the degree of knowledge of drug interactions, a survey of the amount of time devoted to drug-drug interactions during pharmacy school was given to a representative from each school. This survey asked whether or not the curriculum at the particular school had a required course that was in whole or part specific to drug-drug interactions, how many hours were devoted to drug-drug interactions in Therapeutics, Pharmacology, Medicinal Chemistry, and other non-elective courses, and asked for an estimated total number of hours devoted to drug-drug interactions during pharmacy school. Results: A total of 182 students completed and returned the questionnaire, 68 from School A and 114 from School B. There was no significant difference regarding the knowledge of DDIs between students at School A versus School B. The average (SD) number of drug interaction questions answered correctly was 54% (±17%) correct and 56% (±15%) correct respectively. There was no significant difference in subject characteristics including mean age, gender, and type of pharmacy-related work experience between the schools. The results of the survey indicated that the majority of students at both schools work in a community setting for a pharmacy- related job (58 students (88%) and 94 students (75%) for Schools A and B, respectively). A regression analysis showed that student confidence in their ability to correctly identify interactions was the only significant predictor of DDI knowledge (p=0.0138). However, there was only a weak correlation found between correctly answered questions and confidence in the ability to answer the question correctly (r = 0.22). The majority of subjects at both schools indicated that more time should be devoted to DDIs and that DDI information is very important. Conclusion: The study found that third year pharmacy students correctly identified approximately 55% of the drug-drug interactions. There was no significant difference in drug-drug interaction knowledge between the two schools surveyed. In addition, there was only a weak correlation between drug interaction knowledge and the student’s in their ability to correctly identify interactions. After controlling for age, gender, and work experience, we found that confidence was the only significant predictor of DDI knowledge. The majority of the students at both schools believe that drug-drug interaction knowledge is very important and that there should be more exposure to drug-drug interaction information throughout their curriculum. Future studies that survey drug-drug interaction knowledge at more schools may be warranted in order to incorporate changes in curriculums that will further develop the knowledge of drug-drug interactions in future pharmacists.

Background: There is a potential drug interaction between linezolid and antidepressants resulting in serotonin syndrome. Thus, clinicians often avoid this drug combination. However, little empirical data exists to support this avoidance. The objective of this study was to describe the risk of serotonin syndrome in patients receiving linezolid and how this risk changed with concomitant antidepressant use. Methods: A population based retrospective cohort study was conducted using the administrative databases at ICES. The patient population consisted of outpatients aged 66 years or older who were prescribed oral linezolid of any duration from 2014 to 2021 in Ontario, Canada. Patients who were also taking antidepressants during linezolid treatment were compared to patients not on antidepressants during linezolid treatment. The primary outcome was clinically significant serotonin syndrome requiring emergency room visit or hospitalization based on physician diagnosis, Sternbach criteria or Hunter criteria within 30 days of starting linezolid. Secondary outcomes included altered mental status, hospitalization and death due to any cause within 30 days. Results: Of 1,134 patients who were prescribed linezolid, 215 (19.0%) patients were also taking antidepressants. Less than 6 (<0.5%) patients had serotonin syndrome. The proportion of patients with serotonin syndrome was numerically lower in the antidepressant group. In a propensity score matched cohort, the adjusted risk difference for serotonin syndrome in the antidepressant group minus the no antidepressant group was -1.2% (95% CI -2.9% to 0.5%). The risk of altered mental status, hospitalization and death were similar between the two groups. Conclusions: The risk of serotonin syndrome was low in patients taking linezolid. Concurrent antidepressants did not significantly increase the risk of serotonin syndrome. These findings suggest that linezolid can be safely used in patients also on antidepressants when indicated. / Thesis / Master of Science (MSc) / Linezolid is an antibiotic that can potentially cause serotonin syndrome as an adverse effect when combined with antidepressants. In serotonin syndrome, dysfunction of the nervous system leads to a variety of symptoms that can be life threatening. This study examined people in Ontario aged 66 years or older who were prescribed linezolid from 2014 to 2021 to describe the risk of serotonin syndrome due to linezolid and how antidepressants change this risk. Patients were followed for 30 days from start of linezolid treatment to determine if they had serotonin syndrome based on diagnoses in emergency room or hospital visit records. Of 1,134 patients in the study, 215 (19.0%) patients took antidepressants. The risk of serotonin syndrome was low at less than 0.5%. This risk was not significantly different in patients on antidepressants when compared to those who were not. Therefore, linezolid is likely safe for patients receiving antidepressants.

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BACKGROUND:Clinicians often encounter information about drug-drug interactions (DDIs) during clinical practice. This information is found within product information (hardcopy and electronic) and various electronic systems. Prescribers may receive medication-related communications in practice that are distributed by facsimile (fax), mail, or telephone from pharmacies and pharmacy benefit managers (PBMs). The purpose of this study was to determine if near-real time fax alerts for potential drug-drug interactions (PDDIs) would influence prescribing.METHODS:A prospective study, in cooperation with a pharmacy benefit manager (PBM), was conducted targeting 18 clinically important PDDIs. Fax alerts included an individualized letter to the prescriber with a list of the interacting drugs, PDDI evidence summaries with citations, and recommended clinical management strategies. Among the 18 PDDIs, 13 PDDIs could be assessed for prescription therapy changes using pharmacy claims data. A prospective cohort design was used to evaluate changes in prescription dispensing 90-days following a PDDI fax alert.RESULTS:A total of 8,075 fax alerts were sent to prescribers and there were 4,712 alerts for the 13 PDDIs that could be assessed for change using pharmacy claims data. There were 2,019 patients (interventions) for which fax alerts were sent to their prescribers who were matched with a control group consisting of patients with the same PDDIs but for whom no fax alert was sent. Overall, this study found 154 (7.6%) of patients in the fax alert group compared to 132 (6.5%) in the control group had changes in therapy (p=0.177).CONCLUSIONS:This fax alert intervention program observed no statistically significant differences in prescribing with a fax alert compared to the control group. If PBMs chose to send individualized, evidence-based information to clinicians regarding drug-drug interactions, this study suggests it may not be an effective intervention to mitigate harm.

Class of 2009 Abstract / OBJECTIVES: To assess the performance of drug-drug interaction (DDI) software programs utilized in community and hospital pharmacies located in urban and rural settings. METHODS: A fictitious patient profile with 18 drugs and a penicillin allergy was entered into pharmacy computer systems throughout Arizona. Researchers recorded the software systems’ responses to 20 targeted combinations, 14 of which should have produced an alert and 6 that were not true interactions. The number of true positive, true negative, false positive and false negative responses was determined for each system. These data were subsequently used to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) overall and at each site. RESULTS: There were 35 participating pharmacies that used a total of 18 different software programs. The overall sensitivity was 0.8, and ranged from 0.21 to 1 between sites. Computer software failed to detect important interactions 20% of the time. The specificity ranged from 0.83 to 1; PPV ranged from 0.89 to 1; and NPV ranged from to 0.35 to 1. Nine sites, using five different software programs returned perfect results. However, some of those programs produced different results at other sites. CONCLUSIONS: This study shows that improvements are needed in software programs to help pharmacists accurately identify DDIs which could prevent potential adverse drug events. Many clinically important interactions remain undetected by software programs, and users should be mindful of current limitations in technology.