Establishment and evaluation of scalable COVID-19 vaccine clinics at a large university.

BACKGROUND: Previous large-scale vaccination clinics have been successful before the coronavirus disease 2019 (COVID-19) pandemic; however, owing to the strict storage requirements and pharmaceutical preparation needed for the COVID-19 vaccines, careful thought and planning were necessary to successfully deploy these clinics immediately after vaccine availability. The focus of this manuscript is to describe the development and implementation of COVID-19 vaccination clinics in a large public university, using professionals from within and outside of its health sciences schools. OBJECTIVES: The primary objective of this project was to (1) implement COVID-19 vaccination clinics for university faculty, staff, students, and community members. Additional objectives of the clinics were to (2) actively incorporate pharmacy, nursing, and medical students into the clinic workflow; (3) promote interprofessional collaboration among faculty and students; and (4) assess patient satisfaction. PRACTICE DESCRIPTION: The School of Pharmacy faculty, in conjunction with the Office of Strategic Initiatives, planned and coordinated COVID-19 vaccination clinics from December 2020 to July 2021. Students and faculty from schools of pharmacy, nursing, and medicine were used. COVID-19 vaccinations were offered to university faculty, staff, and students and community members based on the Centers for Disease Control and Prevention priority groups. The clinic processes were designed such that they could be scaled from 100 to 2,000 participants per day. PRACTICE INNOVATION: The School of Pharmacy led approach was adjustable depending on the number of patients, continuously monitored and adaptable. The importance of pharmacists as part of the interprofessional health care team was exemplified by faculty and students involved. EVALUATION METHODS: All patients receiving COVID-19 vaccinations at the clinics were e-mailed anonymous surveys for assessment of the quality of the vaccination encounter after completion of their primary vaccine series. RESULTS: More than 15,000 COVID-19 vaccinations were provided through the clinics from December 2020 to July 2021. Professional staffing totaled 3352 hours for the 48 clinics. Thirty-eight percent of the vaccinated patients responded to the clinic satisfaction survey with predominately excellent ratings. CONCLUSION: COVID-19 vaccination clinics can be successfully planned and implemented in a scalable fashion in a large university setting using an interprofessional team approach.

Student and faculty perceptions: appropriate consequences of lapses in academic integrity in health sciences education.

BACKGROUND: A breadth of evidence supports that academic dishonesty is prevalent among higher education students, including students in health sciences educational programs. Research suggest individuals who engage in academic dishonesty may continue to exhibit unethical behaviors in professional practice. Thus, it is imperative to appropriately address lapses in academic dishonesty among health sciences students to ensure the future safety of patients. However, students and faculty have varying perceptions of what constitutes academic dishonesty and the seriousness of breaches in academic dishonesty. The purpose of this study is to gain health sciences faculty and students' perceptions on the appropriate consequences of lapses in academic integrity. METHODS: Faculty and students from different health care disciplines were asked to complete the anonymous survey in which 10 different academic (non-clinical) and clinical scenarios were presented. For each scenario, students or faculty needed to address their concern and assign an academic consequence that they considered appropriate (ranked from no consequence to dismissal). A mixed-effects model was used to assess the difference of questionnaire scores between subgroups. The study was completed in the Spring of 2017. RESULTS: A total of 185 faculty and 295 students completed the electronic survey. Across all survey questions (clinical and non-clinical), the perceived severity of the behavior predicted the consequence chosen by the respondent, indicating that both faculty and students assigned what they felt to be appropriate consequences directly based on their values and perceptions. Both faculty and students show congruence in their opinions regarding the perceived seriousness of clinical cases (p = 0.220) and the recommended consequences assigned to such lapses (p = 0.110). However, faculty and students statistically significantly disagreed in their perception of the severity of non-clinical academic dishonesty scenarios and recommended consequences (p < 0.001). CONCLUSIONS: Our research supports the need for collaborative work between faculty and students in putting forth clear guidelines on how to manage and uphold rules related to lapses in academic integrity not only for non-clinical situations, but especially for clinical ones in a health care setting. Recommendations from this research include using an honor code utilized in clinical settings.

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.

Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways.

All three cytochrome P450 1 (CYP1) monooxygenases are believed to participate in lipid mediator biosynthesis and/or their local inactivation; however, distinct metabolic steps are unknown. We used multiple-reaction monitoring and liquid chromatography-UV coupled with tandem mass spectrometry-based lipid-mediator metabololipidomics to identify and quantify three lipid-mediator metabolomes in basal peritoneal and zymosan-stimulated inflammatory exudates, comparing Cyp1a1/1a2/1b1(⁻/⁻) C57BL/6J-background triple-knockout mice with C57BL/6J wild-type mice. Significant differences between untreated triple-knockout and wild-type mice were not found for peritoneal cell number or type or for basal CYP1 activities involving 11 identified metabolic steps. Following zymosan-initiated inflammation, 18 lipid mediators were identified, including members of the eicosanoids and specialized proresolving mediators (i.e., resolvins and protectins). Compared with wild-type mice, Cyp1 triple-knockout mice exhibited increased neutrophil recruitment in zymosan-treated peritoneal exudates. Zymosan stimulation was associated with eight statistically significantly altered metabolic steps: increased arachidonic acid-derived leukotriene B4 (LTB4) and decreased 5S-hydroxyeicosatetraenoic acid; decreased docosahexaenoic acid-derived neuroprotectin D1/protectin D1, 17S-hydroxydocosahexaenoic acid, and 14S-hydroxydocosahexaenoic acid; and decreased eicosapentaenoic acid-derived 18R-hydroxyeicosapentaenoic acid (HEPE), 15S-HEPE, and 12S-HEPE. In neutrophils analyzed ex vivo, elevated LTB4 levels were shown to parallel increased neutrophil numbers, and 20-hydroxy-LTB4 formation was found to be deficient in Cyp1 triple-knockout mice. Together, these results demonstrate novel contributions of CYP1 enzymes to the local metabolite profile of lipid mediators that regulate neutrophilic inflammation.

Context-dependent antagonism between Akt inhibitors and topoisomerase poisons.

Signaling through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which is aberrantly activated in >50% of carcinomas, inhibits apoptosis and contributes to drug resistance. Accordingly, several Akt inhibitors are currently undergoing preclinical or early clinical testing. To examine the effect of Akt inhibition on the activity of multiple widely used classes of antineoplastic agents, human cancer cell lines were treated with the Akt inhibitor A-443654 [(2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan-2-amine; ATP-competitive] or MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride; allosteric inhibitor) or with small interfering RNA (siRNA) targeting phosphoinositide-dependent kinase 1 (PDK1) along with cisplatin, melphalan, camptothecin, or etoposide and assayed for colony formation. Surprisingly different results were observed when Akt inhibitors were combined with different drugs. Synergistic effects were observed in multiple cell lines independent of PI3K pathway status when A-443654 or MK-2206 was combined with the DNA cross-linking agents cisplatin or melphalan. In contrast, effects of the Akt inhibitors in combination with camptothecin or etoposide were more complicated. In HCT116 and DLD1 cells, which harbor activating PI3KCA mutations, A-443654 over a broad concentration range enhanced the effects of camptothecin or etoposide. In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (>80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents. These results indicate that the effects of combining inhibitors of the PI3K/Akt pathway with certain classes of chemotherapeutic agents might be more complicated than previously recognized.

Tissue-Specific Induction of Mouse ZIP8 and ZIP14 Divalent Cation/Bicarbonate Symporters by, and Cytokine Response to, Inflammatory Signals.

Mouse Slc39a8 and Slc39a14 genes encode ZIP8 and ZIP14, respectively, which are ubiquitous divalent cation/(HCO3-)2 symporters responsible for uptake of Zn2+, Fe2+, and Mn2+ into cells. Cd2+ and other toxic nonessential metals can displace essential cations, thereby entering vertebrate cells. Whereas Slc39a8 encodes a single protein, Slc39a14 has 2 exons 4 which, via alternative splicing, give rise to ZIP14A and ZIP14B; why differences exist in cell type-specific expression of ZIP14A and ZIP14B remains unknown. Inflammatory stimuli have been associated with upregulation of ZIP8 and ZIP14, but a systematic study of many tissues simultaneously in a laboratory animal following inflammatory cytokine exposure has not yet been reported. Herein, we show that C57BL/6J male mice--treated intraperitoneally with lipopolysaccharide or the proinflammatory cytokines tumor necrosis factor (TNF) or interleukin-6 (IL6)--exhibited quantatively very different, highly tissue-specific, and markedly time-dependent up- and downregulation of ZIP8, ZIP14A, and ZIP14B messenger RNA (mRNA) levels in 12 tissues. The magnitude of inflammatory response was confirmed by measuring the proinflammatory cytokine TNF, IL6, and interleukin-1ß mRNA levels in the same tissues of these animals. Our data suggest that most if not all tissues use ZIP8, ZIP14A, and/or ZIP14B for Zn2+ uptake, some tissues under basal conditions and others moreso when inflammatory stressors are present; collectively, this might lead to substantial alterations in plasma Zn2+ levels due to Zn2+ redistribution not just in liver but across many vital organs. In the context of cadmium-mediated toxicity, our data suggest that tissues other than liver, kidney, and lung should also be considered.

Oral benzo[a]pyrene: understanding pharmacokinetics, detoxication, and consequences--Cyp1 knockout mouse lines as a paradigm.

Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH); this ubiquitous environmental carcinogenic agent is found in tobacco smoke, charcoal-grilled foods, and PAH-contaminated surfaces of roofs, playgrounds, and highways. Cytochrome P450 1 wild-type, Cyp1a2(-/-), Cyp1b1(-/-), or Cyp1a2/1b1(-/-) knockouts, and mice with Cyp1a1 expression deleted in hepatocytes can ingest large oral BaP doses (125 mg/kg/d) without apparent toxicity. Cyp1a1(-/-) and Cyp1a1/1a2(-/-) knockouts and mice with Cyp1a1 expression deleted in gastrointestinal (GI) tract epithelial cells develop immunotoxicity and die within 32 days, indicating that GI tract inducible CYP1A1 is absolutely required for detoxication of oral BaP. Cyp1a1/1b1(-/-) and Cyp1a1/1a2/1b1(-/-) mice are rescued from immunosuppression and early death due to absent metabolic activation of BaP by CYP1B1 in immune cells. Ten-fold lower oral BaP doses result in adenocarcinoma of the proximal small intestine (PSI) in Cyp1a1(-/-) mice; Cyp1a1/1b1(-/-) double-knockout mice show no PSI cancer but develop squamous cell carcinoma of the preputial gland duct (PGD). BaP-metabolizing CYP1B1 in the PSI and CYP3A59 in the PGD are the most likely candidates to participate in tumor initiation in the epithelial cells of these two tissues; oncogenes and tumor-suppressor genes upregulated and downregulated during tumorigenesis are completely different between these tissues. This "oral BaP Cyp1" mouse paradigm represents a powerful teaching tool, showing that gene-environment interactions depend on route-of-administration: the same oral, but not intraperitoneal, BaP exposure leads to dramatic differences in target-organ toxicity and tumor type as a function of dose and Cyp1 genotype.

Oral benzo[a]pyrene in Cyp1a1/1b1(-/-) double-knockout mice: Microarray analysis during squamous cell carcinoma formation in preputial gland duct.

Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1, CYP1B1) and other enzymes can activate PAHs to reactive oxygenated intermediates involved in mutagenesis and tumor initiation; also, CYP1 enzymes can detoxify PAHs. Cyp1(+/+) wild-type (WT) and Cyp1b1(-/-) knockout mice receiving oral BaP (12.5 mg/kg/day) remain healthy for >12 months. In contrast, we found that global knockout of the Cyp1a1 gene (1a1KO) results in proximal small intestine (PSI) adenocarcinoma within 8-12 weeks on this BaP regimen; striking compensatory increases in PSI CYP1B1 likely participate in initiation of adenocarcinoma in 1a1KO mice. Cyp1a1/1b1(-/-) double-knockout (DKO) mice on this BaP regimen show no PSI adenocarcinoma, but instead preputial gland duct (PGD) squamous cell carcinoma (SCC) occurs by 12 weeks. Herein, we compare microarray expression of PGD genes in WT, 1a1KO and DKO mice at 0, 4, 8, 12 and 16 weeks of oral BaP; about four dozen genes up- or down-regulated during most critical time-points were further verified by qRT-PCR. In DKO mice, CYP3A59 was unequivocally identified as the BaP-inducible and BaP-metabolizing best candidate responsible for initiation of BaP-induced SCC. Striking increases or decreases were found in 26 cancer-related genes plus eight Serpin genes in DKO, but not in 1a1KO or WT, mice on this BaP regimen; of the 26, 8 were RAS-related oncogenes. The mechanism by which cancer-related genes are responsible for SCC tumor progression in the PGD remains to be elucidated.

Development and Assessment of Integrated Virtual Escape Rooms to Reinforce Cardiology Content and Skills.

Objective. To describe the development and assessment of an integrated virtual escape room in a cardiology course.Methods. A virtual escape room was developed to reinforce therapeutics, pharmacology, pharmacokinetics, medicinal chemistry, pharmacogenomics, and calculations related to cardiology in an integrated pharmacy course and was completed by two student cohorts. Groups of four to five students had 40 minutes to complete virtual escape room puzzles, and each puzzle had to be solved correctly prior to advancing. After completion of the activity, learners met with facilitators to debrief. Students completed pre- and postsurveys to assess knowledge changes and their perceptions of the experience.Results. One hundred twenty-six second-year Doctor of Pharmacy (PharmD) students completed the escape room, and 79% (n=55) and 93% (n=52) of students completed pre- and postsurveys for the 2020 and 2021 cohorts, respectively. Results showed a significant improvement in student knowledge on pre- to postsurvey knowledge questions (2020 presurvey mean [SD]=43.1 [22.6], postsurvey mean [SD]=74.1 [19.6]; 2021 presurvey mean [SD]=52.0 [15.8], postsurvey mean [SD]=67.1 [19.2]). Most students in both cohorts (88%) agreed that logistics of the escape rooms were amenable to learning and applying information, and 86% enjoyed working through puzzles.Conclusion. The virtual escape room was well received by students and served as an effective tool for reinforcing and integrating cardiology concepts. The virtual nature of the activity makes it practical and easily replicable to implement at other institutions, which can benefit from using the format, logistics, and materials described in this study to decrease faculty workload and costs associated with implementing this educational technique.

Patient's perceptions of buprenorphine use receiving treatment for cancer.

OBJECTIVE: To assess knowledge and attitudes toward opioids and buprenorphine (BUP) of patients with cancer. DESIGN: Single-site, single-intervention telephone survey of patients under palliative care at the cancer center. OUTCOMES: Forty percent of the participants recognized the word "buprenorphine," and 28 percent recognized BUP indication for addiction treatment. Four percent addressed potential BUP misuse. None recognized BUP indication for pain. Seventy-one percent were not worried about addiction or dependency while using opioids to treat their cancer-related-pain, and 73 percent were not worried about being stigmatized in the healthcare setting about their pain regimens. Patients on opioids for less than 3 months were most strongly correlated with the fear of addiction and stigma. CONCLUSION: This study identifies patients' knowledge gap regarding BUP products for pain, which gives professionals the opportunity to provide education. This study identified that patients are most worried early on about addiction and stigma when using opioids.

Development of an integrated rheumatoid arthritis simulation that reinforces specialty pharmacy and managed care concepts.

BACKGROUND AND PURPOSE: As pharmacy services expand, it is critical for schools/colleges of pharmacy to prepare learners to provide patient care in a variety of settings and to subsequently assess skills that are necessary for clinical practice. The objectives of this study were to (1) develop and implement a simulation that required students to integrate knowledge from multiple courses and disciplines, (2) assess students' performance and perceptions of the activity, and (3) measure student confidence related to managed care, specialty pharmacy, and clinical and foundational concepts prior to and after the simulation. EDUCATIONAL ACTIVITY AND SETTING: Faculty developed an integrated simulation that required students to provide information for prior authorization of a new medication, counsel a patient on rheumatoid arthritis and the medication, and address patient questions about insurance formularies, cost, and prior authorization processes. Students completed pre- and post-surveys to determine changes in knowledge and perceptions of the simulation. Exam questions that corresponded to simulation concepts were also analyzed. FINDINGS: Analysis of pre-post surveys indicated that students' self-perceived knowledge and confidence significantly improved in all areas (P < .001 and P < .05, respectively). Student perceptions of the simulation were positive, with comments referencing the activity's realism. Correct answers on knowledge-based questions related to simulation concepts were selected by at least 90% of students on course examinations. SUMMARY: This integrated simulation was effective at increasing self-perceived student knowledge and confidence on concepts from all disciplines, and it can easily be replicated and adapted at other pharmacy institutions.

A Genetics-Focused Lens on Social Constructs in Pharmacy Education.

OBJECTIVE: Incorporating diversity, equity, inclusion, and anti-racism principles into clinical and didactic education is essential because each influence cognitive and affective attitudes in pharmacy practice. Educators must learn from the past to enlighten the future. For example, race is a social construct, not a biological construct. However, it persistently acts as a surrogate for determining medical diagnoses and treatment. FINDINGS: Precision medicine and pharmacogenomics can serve as a basis for deconstructing social constructs surrounding race and other social determinants of health. SUMMARY: In this review, the authors highlight why using race in health education will lead to less-than-optimal clinical decisions and discuss best practices for incorporating diversity, equity, inclusion, and anti-racism into health education from a pharmacogenomic-based perspective.

Advancing Pharmacogenomics-Based Care Through Interprofessional Education.

As genomic medicine becomes increasingly complex, pharmacists need to work collaboratively with other healthcare professionals to provide genomics-based care. The core pharmacist competencies in genomics were recently updated and mapped to the entrustable professional activities (EPAs). The new competency that is mapped to the "Interprofessional Team Member" EPA domain emphasizes the role of pharmacists as the pharmacogenomics experts in an interprofessional healthcare team. Interprofessional education (IPE) activities involving student pharmacists and students from other healthcare disciplines are crucial to prepare student pharmacists for a team-based approach to patient-centered care. This commentary discusses the pharmacogenomics-focused IPE activities implemented by 3 programs, the challenges faced, and the lessons learned. It also discusses strategies to develop pharmacogenomics-focused IPE activities based on existing resources. Developing pharmacogenomics-focused IPE activities will help prepare pharmacy graduates with the knowledge, skills, and attitudes to lead collaborative, interprofessional teams in the provision of pharmacogenomics-based care, consistent with the standards described in the genomics competencies for pharmacists.

Perceived stress, academic self-concept, and coping mechanisms among pharmacy students following a curricular revision.

INTRODUCTION: Pharmacy students experience high levels of perceived stress. Data regarding the impact of curricular revision on students' stress level are lacking. The primary objective of this study was to compare perceived stress, academic self-concept, and coping strategies between pharmacy students prior to and following a curricular revision. Secondary objectives included determining university resources used by students to deal with stress. METHODS: Students in the first, second, and third years of the pharmacy curriculum were asked to complete a survey, including the 14-item Perceived Stress Scale (PSS-14), Brief COPE, and Academic Self-Concept Scale (ASCS), and questions regarding use of university resources. Responses to the PSS-14, Brief COPE, and ASCS were compared to a student cohort prior to the curricular revision. RESULTS: Perceived stress was reduced to a small, statistically significant degree following a curricular revision. In both cohorts, increased stress was statistically significantly correlated with decreased academic self-concept. Students reported increased use of self-distraction, along with decreased use of active coping, substance abuse, and planning, as coping strategies when compared to the previous cohort. Approximately half of the student cohort reported no use of university resources. The most commonly used resources were financial aid and mental health services. CONCLUSIONS: Perceived stress decreased following the revision of a Doctor of Pharmacy curriculum. The most common coping strategies were positive and comparable with strategies reported by students in the former curriculum. The impact of curricular changes on student stress and the use of university resources in health professions students warrant further study.

Organ-specific roles of CYP1A1 during detoxication of dietary benzo[a]pyrene.

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental toxicants derived from sources that include cigarette smoke, petroleum distillation, gas- and diesel-engine exhaust, and charcoal-grilled food. The gastrointestinal tract is the principal route of PAH exposures, even when inhaled. The most thoroughly studied prototype of PAHs is benzo[a]pyrene (BaP), well known to be toxic, mutagenic, and carcinogenic in various tissues and cell types. This lab has previously shown that Cyp1a1(-/-) global knockout mice treated by oral administration of BaP die at 28 to 32 days with immunosuppression, whereas wild-type mice remain healthy for 1 year on high BaP doses (125 mg/kg/day). Thus, for oral BaP, CYP1A1 is more important in detoxication than in metabolic activation. After several days of oral BaP, we found surprisingly low CYP1A1 levels in liver, compared with that in small intestine; we postulated that this finding might reflect efficient detoxication of oral BaP in proximal small intestine such that significant amounts of the inducer BaP no longer reach the liver. In the present study, many parameters were therefore compared in wild-type, Cyp1a1(-/-) global knockout, intestinal epithelial cell-specific Cyp1a1 knockout, and hepatocyte-specific Cyp1a1 knockout mice as a function of long-term oral exposure to BaP. The peak of CYP1A1 (mRNA, protein) expression in liver occurred at 12 h, whereas highly induced CYP1A1 in small intestine persisted throughout the 30-day experiment. Hepatocyte-specific Cyp1a1 knockout mice remained as healthy as wild-type mice; intestinal epithelial cell-specific Cyp1a1 knockout mice behaved like Cyp1a1(-/-) mice, dying with immunosuppression approximately 30 days on oral BaP. We conclude that small intestine CYP1A1, and not liver CYP1A1, is critically important in oral BaP detoxication.

On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents.

The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.

Evaluation of lapatinib and topotecan combination therapy: tissue culture, murine xenograft, and phase I clinical trial data.

PURPOSE: Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial. EXPERIMENTAL DESIGN: The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial. RESULTS: Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m2 topotecan i.v. on days 1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization. CONCLUSIONS: The lapatinib/topotecan combination is well tolerated and warrants further study.

Overcoming S-phase checkpoint-mediated resistance: sequence-dependent synergy of gemcitabine and 7-ethyl-10-hydroxycamptothecin (SN-38) in human carcinoma cell lines.

Although agents that inhibit DNA synthesis are widely used in the treatment of cancer, the optimal method for combining such agents and the mechanism of their synergy is poorly understood. The present study examined the effects of combining gemcitabine (2',2'-difluoro 2'-deoxycytidine) and 7-ethyl-10-hydroxycamptothecin (SN-38; the active metabolite of irinotecan), two S-phaseselective agents that individually have broad antitumor activity, in human cancer cells in vitro. Colony-forming assays revealed that simultaneous treatment of Ovcar-5 ovarian cancer cells or BxPC-3 pancreatic cancer cells with gemcitabine and SN-38 resulted in antagonistic effects. In contrast, sequential treatment with these two agents in either order resulted in synergistic anti-proliferative effects, although the mechanism of synergy varied with the sequence. In particular, SN-38 arrested cells in S phase, enhanced the accumulation of gemcitabine metabolites, and diminished checkpoint kinase 1, thereby sensitizing cells in the SN-38 --> gemcitabine sequence. Gemcitabine treatment followed by removal allowed prolonged progression through S phase, contributing to synergy of the gemcitabine --> SN-38 sequence. These results collectively suggest that S-phase-selective agents might exhibit more cytotoxicity when administered sequentially rather than simultaneously.

Pharmacogenomics: From classroom to practice.

Perceptions and challenges connecting Pharmacogenomics taught in classrooms and translationing it to advance pharmacy practice rotations and healthcare settings and potential areas of development.