Pharmacology
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21694
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Item Methylone: "Ecstasy" by another name(2017-03-14) Gatch, Michael B.; Dolan, Sean B.Purpose: Following increased governmental intervention regarding the sale of novel psychoactive substances, the synthetic cathinone derivative methylone has been diverted from “bath salts” into “Ecstasy” formulations in lieu of MDMA; however, it is unknown what effects substitution with methylone may have on “Ecstasy” use. In the current study, we evaluated the pharmacology of methylone in parallel with MDMA using in vitro and in vivo techniques in order to assess its potential for compulsive abuse. Methods: We assessed the activity of methylone and MDMA at SERT using whole-cell patch clamp electrophysiology. We determined the dopaminergic and serotonergic contributions to the discriminative stimulus effects of both compounds in rats trained to discriminate methamphetamine, DOM, or MDMA from vehicle and utilized the D1-selective antagonist SCH23390 and the 5-HT2A/2C antagonist pirenperone to further probe mechanistic differences. Furthermore, we tested for substitution of methylone and MDMA in rats trained to self-administer methamphetamine under continuous and progressive ratio schedules of reinforcement. Results: Methylone, like MDMA, produced an inward current at SERT, indicative of an amphetamine-like substrate mechanism. Both methylone and MDMA fully substituted for the discriminative stimulus effects of methamphetamine and MDMA, but only partially for DOM. In methamphetamine-trained rats, SCH2330 fully and dose-dependently attenuated methamphetamine-appropriate responding by methylone and MDMA with similar potencies. SCH23390 and pirenperone both partially attenuated MDMA-appropriate responding by methylone and MDMA, but both antagonists were less efficacious against methylone than MDMA. Methylone and MDMA were both readily self-administered, but there were no significant differences in reinforcing efficacy between the two drugs under either schedule of reinforcement. Conclusions: These data indicate that methylone possesses similar mechanistic and reinforcing effects as MDMA, and its inclusion in “Ecstasy” formulations is unlikely to produce different subjective effects or increased compulsive use.Item Modafinil as a Pharmaceutical Therapy for Cocaine Withdrawal(2017-03-14) Forster, Michael; McMahan, DanielPurpose: Modafinil has been proposed as a possible pharmaceutical adjunct therapy for cocaine withdrawal. This study tested Modafinil’s interaction with cocaine to determine its usefulness in a clinical setting. Materials and Methods: This study used a total of 48 mice separated into the following groups of 8 mice each: Group 1 – Dose 1 [5 mg Modafinil] + Dose 2 [Vehicle (Saline)] Group 2 – Dose 1 [10 mg Modafinil] + Dose 2 [Vehicle (Saline)] Group 3 – Dose 1 [5 mg Modafinil] + Dose 2 [8 mg Cocaine] Group 4 – Dose 1 [10 mg Modafinil] + Dose 2 [8 mg Cocaine] Group 5 – Dose 1 [Vehicle (Methyl Cellulose)] + Dose 2 [8 mg Cocaine] Group 6 – Dose 1 [Vehicle (Methyl Cellulose)] + Dose 2 [Vehicle (Saline)] *Each dose contained 0.33 mL of bracketed [] solution. All Modafinil drug preparations were made by mixing Modafinil with methyl cellulose. A 25G needle was used to inject “Dose 1” (Modafinil drug preparation) into the left-lower abdominal quadrant of Groups 1-4. The same gauge needle was also used for injecting “Dose 1” to Groups 5-6; however, these doses excluded Modafinil and only contained methyl cellulose. All Cocaine drug preparations were made by mixing Cocaine with normal saline. A 28G needle was used to inject “Dose 2” (Cocaine drug preparation) into a different location in the left-lower abdominal quadrant of Groups 3-5. The same gauge needle was also used for injecting “Dose 2” to Groups 1, 2, 6; however, these doses excluded Cocaine and only contained normal saline. All groups of mice were given “Dose 1” and allowed to wait for 15 minutes (“pretreatment time”). After this pretreatment time, all groups of mice were administered “Dose 2” and immediately placed in separate locomotor activity (“LMA”) boxes for 120 minutes. The data was obtained from said LMA boxes and analyzed to determine the effects of the above various concentrations of drugs on the mice’ locomotor activity. Summary: The average horizontal ambulation count for Group 6 was 2,586. This was used as a baseline for judging the effects of the various drug combinations. The average horizontal ambulation count for the remaining groups was as follows: Group 1 – 3,265; Group 2 – 3,741; Group 3 – 4,436; Group 4 – 5,508; Group 5 – 3,434. In summary, Modafinil alone increased the locomotor activity above baseline in proportion to its dosage. When cocaine was subsequently added, the ambulation count grew even higher. Conclusions: This study suggests that Modafinil and cocaine act via a common pathway. It is known that Modafinil is an atypical inhibitor of the dopamine transporter (DAT) and cocaine is a typical inhibitor of DAT. It is hypothesized that this pathway is responsible for the increased locomotor activity observed in this study. The results obtained suggest that Modafinil and cocaine in combination produce an additive effect on locomotor activity in mice. Increasing the Modafinil dosage from 5-10mg, while leaving cocaine constant at 8 mg, produced an increased ambulation count. Further testing must be done in order to elucidate whether or not cocaine and Modafinil truly act via a common pathway. It is suggested that repeating this study by using a 20 mg cocaine dosage would effectively answer this question. Prior research suggests that administering [greater than] 20mg cocaine to mice effectively decreases locomotor activity; therefore, progressive decreases in locomotor activity when administering progressive increases in Modafinil in combination with a constant 20 mg dose of cocaine would suggest that Modafinil acts via a common pathway. This research would need to be conducted before a judgment could be made regarding Modafinil’s value in treating cocaine withdrawal.Item A multidisciplinary team-based approach to reduce non-alcoholic fatty liver disease-related fibrosis in patients with psoriasis(2017-03-14) White, PharmD, MS, PhD, Annesha; Rungruangphol, PatraPurpose: Psoriasis impacts approximately 7.5 million people in the United States and recent studies support the link between psoriasis and non-alcoholic fatty liver disease (NALFD). The majority of psoriasis patients are not being screened for NAFLD. All clinicians must be aware of this association so they can recognize and provide a proper follow-up and medication selection in psoriasis patients to prevent NAFLD. The aim of this review is to explore the current evidence within the last decade with respect to the association between the pathophysiological mechanisms of psoriasis and NAFLD. A secondary aim is to highlight the importance of utilizing a multidisciplinary patient care team to manage moderate-to-severe psoriasis. Methods: A systematic review was conducted using Pubmed, Scopus, and International Pharmaceutical Abstracts databases between 2006-2016. Key search terms included ‘Psoriasis,’ ‘Patient Care Team,’ ‘Multidisciplinary approach,’ ‘Metabolic Disease,’ ‘Obesity,’ ‘Psoriatic Arthritis,’ and ‘Mental disorders.’ Abstracts were screened against inclusion criteria and selected based upon relevance and quality. Randomized controlled trials, prospective and retrospective studies were excluded if they were not in English or lacked information on moderate and severe psoriasis. Once articles were retrieved, they were evaluated based on the Oxford Centre for Evidence-Based Medicine and summarized in a table structured by Title, Author, Research Question, Inclusion Criteria, Resources, Findings, and Quality. Results: The search yielded a total of 33 studies for review. The articles retrieved have shown a strong association between NAFLD and psoriasis. Psoriasis patients should be routinely screened for NAFLD and the presence of NAFLD should be taken into consideration when choosing pharmacological treatment to reduce the progression of liver disease. Multidisciplinary patient care team management (pharmacists, dermatologists, psychologists and dietitians) should include monitoring for metabolic disease, osteoporosis, and mental health assessment. Conclusions: Psoriasis patients who have multiple comorbidities can benefit from multidisciplinary team care. A unique opportunity exists to screen psoriasis patients with multiple comorbidities or not well managed on current therapy for NAFLD, which is predicted to be the leading cause of liver transplantation by 2020. Few studies have explored the supportive role of pharmacists for patients with psoriasis. Future research is warranted.Item A Biotechnology Platform for Fighting Mosquito-Borne Disease Transmission(2017-03-14) Dalwadi, Dhwanil; Schetz, John; Wang, HuanyuBackground: Zika, West Nile virus, dengue and malaria are infectious diseases transmitted by the bite of a mosquito. Thus, technologies that prevent biting will prevent infectious disease transmission. Octopamine is a biogenic amine that controls key physiological responses including those related to fine motor control. Since biting requires fine motor control, disruption of octopaminergic systems appears to be an attractive approach to prevent mosquito biting. Every year, over a billion mosquito-borne disease cases were reported and increasing resistance of mosquitoes to first-line control measures is a cause for growing concern. To address this concern we seek to discover and develop new chemical classes of arthropod octopamine receptor deterrents to prevent biting. Our hypothesis is that at mosquito octopamine receptor activators will prevent mosquito biting. Methodology: Cloned octopamine receptors from two species of mosquitoes Anopheles gambiae (AgOctR) and Aedes egypti (AeOctR) were functionally expressed in mammalian cells. The expression levels of these receptors were quantified using radioligand binding. The ability of octopamine and experimental compounds to active the Gq-PLC-IP3-Ca2+ signaling pathway was assessed by measuring changes in intracellular calcium. Results: Specific binding of a radioligand to cells transfected with mosquito OctR DNA confirmed the successful high expression of OctR protein from both genera of mosquitoes. Functional assays with the endogenous ligand octopamine showed the expressed receptors are truly octopamine receptors given the dose-response nature of the response and the ability of an OctR antagonist to block the response. High potency of octopamine at the receptors over tyramine confirmed these receptors as OctRs instead of closely related tyramine receptor. Robust Gq-PLC-IP3-Ca2+ signaling responses indicate these receptors are Gq-coupled consistent with their identity specifically as α-like OctRs. These systems were used to begin to characterize novel experimental compounds, some of which act as potent OctR agonists. Conclusions: In this study, we created cell lines stably expressing cloned mosquito OctRs and validated that the sequences code for bona fide α-like OctRs. Correlation of the agonistic effect of experimental compounds at these cloned mosquito OctR with protection against biting suggest that this molecular platform could serve as a useful biotechnology of discovering novel mosquito deterrents.Item Concurrent Use of Benzodiazepine with Buprenorphine and Potential Risks for ADRs and Overdose(2017-03-14) Sureja, Rushil; White, Annesha; Vernachio, Kimberly; Slate, BradleyObjective: Benzodiazepines (BZDs) are known to negate the “plateau” properties of buprenorphine, concealing the purported safety advantages of buprenorphine vs. other opioids. One question is, does the literature show an increase in overdose or respiratory depression when these two drugs are combined, and whether the benefits of using the combination equal the risk of other opioids that do not have buprenorphine’s partial agonist/antagonist properties? The objective of this study was to examine the literature within the last decade and determine if combined use of BZDs with buprenorphine increased the risk for adverse drug reactions or overdose. Methods: Journal articles were retrieved through the databases PubMed and Google Scholar from January 2007 to January 2017. The journal articles keywords were: ‘BZDs, ‘buprenorphine’, ‘pain’, and ‘opioids’. Articles were selected to include adverse effect, overdose, and death-potential when BZDs were used with buprenorphine. Articles that focused on the effect that dose or formulation had on severity were utilized to give context to the severity of coadministration. The articles were graded using Oxford Center of Evidence Based Medicine to address bias. Results: A total of eight peer-reviewed studies were used, representing both randomized controlled trials and observational studies. The sample sizes of the examined studies ranged from 72 to 692. Due to the low number of existing studies at this time, there is insufficient evidence to determine if the benefits of concurrent use of BZDs and buprenorphine outweigh the risks of serious, and sometimes fatal, adverse effects. However, animal research revealed that using a lower strength BZD will reduce adverse effects significantly. Conclusions: The literature supports the risk of accidental overdose and death in the use of opioids and BZDs. Although there is little published research, there is support for our hypothesis in that a significant degree of adverse events and overdose were realized once the buprenorphine component was added to BZDs. There appears to be a large amount of variability in severity depending on the administered dose. Future research, including an observational study, will provide valuable information.Item Authentic Leadership in Managed Care Pharmacy: Career Advice for Pharmacy Students and Professionals(2017-03-14) White, Annesha; Lee, Seina; Beaty, Silky; Snoubar, NoraBackground: Descriptive summaries and research on influential factors affecting leadership among student pharmacists career choices has been utilized by practitioners to aid student development, enhance educational experiences, and plan for future career goals. There is currently little research that summarizes different managed care focused leadership paths for student pharmacists as they advance their career. Objective: The purposes of this research are to (1) review the literature from the past decade on managed care pharmacy leadership paths and (2) describe the views of experienced pharmacists with regard to leadership in managed care. Methods: A literature search of various healthcare journal databases, including Medline and Pubmed, was conducted using keywords leadership in managed pharmacy, careers in managed care pharmacy, and career planning for pharmacy. The full text of each article was reviewed and articles were excluded if they did not relate directly. Additionally, 15 experienced pharmacists were interviewed on managed care leadership development. Data was analyzed qualitatively using NVIVO software to identify common themes and word frequencies. Results: Fifteen different managed care pharmacy careers were identified based on the results of the literature search. Specific requirements for leadership paths were noted. Some of the leadership positions listed were pharmacists in the community, hospital, PBM, consultant and pharmaceutical industry settings. Qualitative analysis of pharmacists’ interviews revealed that goals were to remain in a leadership position for at least 10 years and to leave with people who were prepared to take over the department. Furthermore, the pharmacists interviewed suggested creating a career roadmap, the importance of identifying how to progress or change career paths, and a focus on obtaining a good mentor. Conclusions: This research has presented many contemporary leadership paths in the managed care arena. Pharmacists’ insights are provided from experience, which could serve as a great resource for student pharmacists for their career planning and development. Identifying how to progress or change career paths will allow for a smooth transition into a new era in which pharmacists are critical components of every health care team. A strong leadership pipeline is key to future of the pharmacy profession.Item Creation of a Technology Platform for Fighting Mosquito Bites(2017-03-14) Dalwadi, Dhwanil; Wang, Huanyu; Schetz, John; Deshmukh, RashmiObjective: Octopamine receptor (OctR) based deterrents are a potentially better way of preventing mosquito bites, because the mechanism of action is not toxicity which encourages resistance. The OctR belongs to a class of primitive heterotrimeric G protein-coupled receptors (GCPR) found only in invertebrates and plays an important role in biting-related behaviors. This study focuses on developing a testing system that will accelerate the discovery of ecofriendly deterrents free of the perils of current repellent technologies. Materials and Methods: The Anopheles gambiae mosquito which is the vector for malaria was recently reported to have two splice variants of an OctR gene named AgAOctR and AgBOctR that have N-terminal halves in common. The full length AgBOctR sequence was obtained by removing the C-terminal half of the AgAOctR with restriction enzymes and ligating its remaining N-terminal region with the unique half of the synthesized AgBOctR sequence. The AgBOctR gene was then functionally expressed in mammalian cells via calcium phosphate-mediated transfection. Radioligand binding was then used to detect the functionally expressed proteins in transfected cells and stable clones were selected. Fluorescent detection of changes in intracellular calcium was used as a measure of activation of the Gq-PLC-IP3-Ca2+-mediated signaling pathway. Results: Differential restriction digest followed by size determination via agarose gel electrophoresis of the newly created AgBOctR sequence was used to verify its length and composition. When expressed in mammalian cells the AgBOctR gene was found to code for a protein that specifically binds an octopamine receptor radioligand, while no specific radioligand binding was detected in untransfected cells. Further these AgBOctR-expressing cells were activated by octopamine with a higher potency than tyramine indicating that the gene truly encodes for an octopamine receptor rather than a closely related tyramine receptor. That OctR signaling could be readily detected via monitoring of the Gq-PLC-IP3-Ca2+ signaling pathway suggests that AgBOctR is specifically an alpha-like OctR, because beta-like OctRs utilize a different signaling pathway. Conclusions: A technology system has been created that will allow us to correlate the mosquito OctR activity of compounds with their ability to prevent mosquito biting. This will accelerate the discovery of innovative mosquito deterrents that prevent infectious disease transmission.