A randomized, controlled, double-blinded clinical trial of gabapentin 300 versus 900 mg versus placebo for anxiety symptoms in breast cancer survivors.

Gabapentin is used for the treatment of hot flashes and neuropathic pain in breast cancer survivors, and is commonly used off-label for the treatment of anxiety. Yet, clinical trial evidence to support the use of gabapentin for anxiety symptoms is lacking. In a randomized, double-blinded controlled trial we compared 300 mg gabapentin versus 900 mg gabapentin versus placebo. Subjects were 420 breast cancer patients who had completed all chemotherapy cycles. Anxiety traits and current (state) anxiety were measured using the Speilberger Strait-Trait Anxiety Inventory at baseline, 4 and 8 weeks. Pain was measured at baseline using a 10-point scale. Analyses included analysis of covariance and ordinary least squares regression. At 4 weeks, state anxiety change scores were significantly better for gabapentin 300 and 900 mg (p = 0.005) compared to placebo. The magnitude of improvement was proportional to baseline state anxiety. At 8 weeks, the anxiolytic effects of gabapentin compared to placebo persisted (p < 0.005). We found no significant interactions. The lower dose (300 mg) was associated with the best treatment outcomes for all patients except those with the highest baseline anxiety. Given its similar pharmacology, efficacy in the treatment of hot flashes, and low cost, gabapentin may provide a low cost and parsimonious alternative treatment choice for breast cancer survivors presenting in primary care practices with anxiety symptoms. Gabapentin is effective for hot flashes, and, therefore, may provide therapeutic benefit for both anxiety and hot flashes at a generic drug price. For patients reluctant to take a controlled substance, such as a benzodiazepine, gabapentin may offer an alternative therapy. Similarly, patients with a history of substance use may benefit from gabapentin without risk of addiction or abuse. For cancer survivors experiencing both hot flashes and anxiety, gabapentin may provide a single effective treatment for both and is an alternative therapy for anxiety for patients unwilling to take a benzodiazepine or those with a history of substance use.

Variable within- and between-herd diversity of CTX-M cephalosporinase-bearing Escherichia coli isolates from dairy cattle.

bla(CTX-M) beta-lactamases confer resistance to critically important cephalosporin drugs. Recovered from both hospital- and community-acquired infections, bla(CTX-M) was first reported in U.S. livestock in 2010. It has been hypothesized that veterinary use of cephalosporins in livestock populations may lead to the dissemination of beta-lactamase-encoding genes. Therefore, our objectives were to estimate the frequency and distribution of coliform bacteria harboring bla(CTX-M) in the fecal flora of Ohio dairy cattle populations. In addition, we characterized the CTX-M alleles carried by the isolates, their plasmidic contexts, and the genetic diversity of the bacterial isolates themselves. We also evaluated the association between ceftiofur use and the likelihood of recovering cephalosporinase-producing bacteria. Thirty fresh fecal samples and owner-reported ceftiofur use data were collected from each of 25 Ohio dairy farms. Fecal samples (n = 747) yielded 70 bla(CTX-M)-positive Escherichia coli isolates from 5/25 herds, 715 bla(CMY-2) E. coli isolates from 25/25 herds, and 274 Salmonella spp. from 20/25 herds. The within-herd prevalence among bla(CTX-M)-positive herds ranged from 3.3 to 100% of samples. Multiple pulsed-field gel electrophoresis (PFGE) patterns, plasmid replicon types, and CTX-M genes were detected. Plasmids with CTX-M-1, -15, and -14 alleles were clonal by restriction fragment length polymorphism (RFLP) within herds, and specific plasmid incompatibility group markers were consistently associated with each bla(CTX-M) allele. PFGE of total bacterial DNA showed similar within-herd clustering, with the exception of one herd, which revealed at least 6 different PFGE signatures. We were unable to detect an association between owner-reported ceftiofur use and the probability of recovering E. coli carrying bla(CTX-M) or bla(CMY-2).

CTX-M-type extended-spectrum ß-lactamases present in Escherichia coli from the feces of cattle in Ohio, United States.

CTX-M extended-spectrum ß-lactamases are enzymes produced by bacteria that are capable of inhibiting the antimicrobial effects of cephalosporin drugs. Recently, the first domestically acquired Salmonella in the United States expressing bla(CTX-M) was reported. This is a concern because expanded-spectrum cephalosporins are the treatment of choice for invasive Gram-negative infections, including salmonellosis in children. Because Salmonella transmission is primarily foodborne, there is also concern that resistant enteric bacteria from livestock can be transferred through the food supply chain to consumers. bla(CTX-M) has not been previously identified in bacterial isolates from food animal populations in the United States. We report the recovery of CTX-M-type extended-spectrum ß-lactamases from fecal Escherichia coli of sick and healthy dairy cattle in Ohio. Four individual fecal samples yielded E. coli isolates representing three clonal strains that carried bla(CTX-M) on transferable plasmids. Two distinguishable plasmids were identified, each encoding bla(CTX-M-1) or bla(CTX-M-79). Transferrable bla(CTX-M) genes in bovine E. coli have the potential to serve as a reservoir of resistance for pathogens and may represent a public health concern.

A novel Gbetagamma-subunit inhibitor selectively modulates mu-opioid-dependent antinociception and attenuates acute morphine-induced antinociceptive tolerance and dependence.

The Gbetagamma subunit has been implicated in many downstream signaling events associated with opioids. We previously demonstrated that a small molecule inhibitor of Gbetagamma-subunit-dependent phospholipase (PLC) activation potentiated morphine-induced analgesia (Bonacci et al., 2006). Here, we demonstrate that this inhibitor, M119 (cyclohexanecarboxylic acid [2-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)-(9Cl)]), is selective for mu-opioid receptor-dependent analgesia and has additional efficacy in mouse models of acute tolerance and dependence. When administered by an intracerebroventricular injection in mice, M119 caused 10-fold and sevenfold increases in the potencies of morphine and the mu-selective peptide, DAMGO, respectively. M119 had little or no effect on analgesia induced by the kappa agonist U50,488 or delta agonists DPDPE or Deltorphin II. Similar results were obtained in vitro, as only activation of the mu-opioid receptor stimulated PLC activation, whereas no effect was seen with the kappa- and delta-opioid receptors. M119 inhibited mu-receptor-dependent PLC activation. In studies to further explore the in vivo efficacy of M119, systemic administration M119 also resulted in a fourfold shift increase in potency of systemically administered morphine. Of particular interest, M119 was also able to attenuate acute, antinociceptive tolerance and dependence in mice treated concomitantly with both M119 and morphine. These studies suggest that small organic molecules, such as M119, that specifically regulate Gbetagamma subunit signaling may have important therapeutic applications in enhancing opioid analgesia, while attenuating the development of tolerance and dependence.

In vivo characterization of (-)(-)MCL-144 and (+)(-)MCL-193: isomeric, bivalent ligands with mu/kappa agonist properties.

Once opioid receptor dimers were postulated, a goal has been to synthesize and screen novel opioids, with the hope of furthering our knowledge of the structure-activity relationship of opioid ligands with the opioid receptors. The aim of the current study was to address whether two isomeric bivalent ligands would have pharmacological differences after central administration, in vivo. The two compounds, (-) bis(N-cyclobutylmethyl-morphinan-3-yl) sebacoylate dihydrochloride (MCL-144) and 1-((+)N-cyclobutylmethylmorphinan-3-yl)-10-((-) N-cyclobutylmethylmorphinan-3-yl)sebacolyate (MCL-193) are each linked by a 10-carbon chain ester. The active (-) enantiomer for both ligands is 3-hydroxy-N-cyclobutylmethyl morphinan ((-)MCL-101), a N-cyclobutylmethyl analogue of cyclorphan (J Med Chem 43:114-122, 2000). MCL-144 contains two active levo rotatory (-)(-) pharmacophores, while MCL-193 contains one active (-) and one inactive (+) pharmacophore of MCL-101. In vitro analysis demonstrated that all three compounds, (-)(-)MCL-144, (+)(-)MCL-193 and (-)MCL-101 were kappa agonists and mu partial agonists. (-)(-)MCL-144 and (-)MCL-101 had much higher affinity for both the mu and kappa opioid receptors compared to (+)(-)MCL-193. In vivo, (-)(-)MCL-144 and (+)(-)MCL-193 produced full dose-response curves, in the 55 degrees C tail-flick test, with each compound having an ED(50) value of 3.0 nmol after intracerebroventricular (i.c.v.) administration. The analgesic properties of both compounds were antagonized by the mu-selective antagonist, beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. Concomitant, i.c.v., administration of either (-)(-)MCL-144 or (+)(-)MCL-193 with morphine, did not significantly antagonize morphine-induced antinociception at any dose tested. In antinociceptive tests, (-)(-)MCL-144 and (+)(-)MCL-193 had the same pharmacological properties, demonstrating that having two active pharmacophores separated by a 10-carbon spacer group did not increase the antinociceptive efficacy of the compound. Additionally, it was also of interest to compare (-)(-)MCL-145 and (-)(-)MCL-144, as the only difference between these bivalent ligands is the spacer region connecting the two pharmacophores, yet (-)(-)MCL-145 produced an ED(50) value 10-fold lower than (-)(-)MCL-144 (ED(50) values = 0.3 nmol and 3.0 nmol, respectively).

Lesbian, gay, bisexual, and transgender inclusion: Survey of campus climate in colleges and schools of pharmacy.

BACKGROUND AND PURPOSE: To quantify the implementation of inclusive policies and benefits as well as institutional commitment to support LGBT faculty, staff, and students in pharmacy schools nationwide. EDUCATIONAL ACTIVITY AND SETTING: An anonymous, electronic survey was sent to administrators at 130 pharmacy schools. Forty-four survey responses were received, indicating a 34% response rate. The survey included questions relating to campus climate, inclusive policies and benefits, and institutional commitments to the LGBT community. FINDINGS: Approximately half of the survey respondents reported that their school has public written statements about diversity and multiculturalism that include sexual orientation and/or gender identity. About one-fifth of the respondents indicated that their school has inclusive materials for faculty, staff, and student information regarding sexual orientation and gender identity. Nearly one-fourth of schools of pharmacy had participated in a voluntary LGBT training program, such as Safe Zone, Safe Space, or Ally Program. Over half of the respondents reported having access to LGBT organizations on campus, with two schools reporting having pharmacy organizations that specifically focus on LGBT student pharmacists and allies. Less than one-tenth of schools reported offering gender-neutral/single-occupancy restrooms and no schools reported knowledge of LGBT-related scholarships. SUMMARY: Room for improvement exists regarding the implementation of inclusive practices to improve campus climate for LGBT students, faculty, and staff. Areas with the largest room for improvement include accessible gender-neutral restrooms and availability of LGBT trainings, scholarships, and events.

Online Self-testing Resources Prepared by Peer Tutors as a Formative Assessment Tool in Pharmacology Courses.

Objective. To assess the effectiveness of optional online quizzes written by peer tutors in a pharmacology course for doctor of pharmacy students. Methods. Online quizzes were written by peer tutors for second-year pharmacy students. Quizzes reflected the material taught during lecture and were in a format similar to that of the examinations. Data related to performance on each quiz and each examination were collected throughout the semester. At the end of the semester, students and peer tutors were surveyed to gather information on the utility and success of the quizzes. Results. Students taking online quizzes performed significantly better on examinations than those who did not take quizzes. In addition, students received higher scores on examinations than when practicing with the quizzes. Surveys suggest that students liked the quizzes and felt they increased their confidence and performance on examinations. Conclusion. The quizzes were beneficial to student performance on examinations as well as student perception of performance and confidence going into the examinations. Quizzes were also beneficial learning experiences for peer tutors.

A transgender health care panel discussion in a required diversity course.

OBJECTIVES: To examine the impact of a panel discussion on transgender health care on first-year (P1) pharmacy students' knowledge and understanding of transgender experiences in an Introduction to Diversity course. DESIGN: The panel consisted of both transgender males and females. After panelists shared their healthcare experiences, students asked them questions in a moderated setting. Students completed evaluations on the presentation and learning outcomes. They also wrote a self-reflection paper on the experience. ASSESSMENT: Ninety-one percent of students agreed that they could describe methods for showing respect to a transgender patient and 91.0% evaluated the usefulness of the presentation to be very good or excellent. Qualitative analysis (phenomenological study) was conducted on the self-reflection papers and revealed 7 major themes. CONCLUSION: First-year students reported that they found the panel discussion to be eye opening and relevant to their pharmacy career. Our panel may serve as model for other pharmacy schools to implement.

Staphylococcus aureus shedding pattern throughout lactation in dairy cows with naturally occurring intramammary infection.

OBJECTIVE: To evaluate shedding patterns of Staphylococcus aureus, specifically the association between clonal relatedness and shedding patterns of S aureus for cows with naturally occurring S aureus intramammary infection. DESIGN: Longitudinal field study. SAMPLE: Milk samples from 22 lactating cows (29 mammary glands) of varied numbers of lactations on 2 dairies. Procedures-Foremilk samples were collected weekly for 26 to 44 weeks during lactation from individual mammary glands. Milk samples were cultured bacteriologically with a 0.01-mL inoculum. Samples were considered culture positive for S aureus if ≥ 1 colony-forming units were obtained. Milk samples from known S aureus-positive mammary glands that were culture negative for S aureus or culture positive with a single colony of S aureus were cultured bacteriologically a second time with a 0.1-mL inoculum. Longitudinal shedding patterns of S aureus and the effect of strain type on ln(colony forming unit count) were examined. RESULTS: With the 0.01-mL inoculum, 914 of 1,070 (85%) samples were culture positive. After reculturing of negative samples with a 0.1-mL inoculum, 1,011 (95%) of the samples were culture positive. There was no significant difference in the detection of S aureus between genotypic clusters when either the 0.01- or 0.1-mL inoculum was used. There was no significant difference in the amount of shedding between mammary glands infected with isolates in genotypic cluster 1 or 2. No consistent shedding patterns were identified among or within cows. There was a significant difference in mammary gland linear score and test day (composite) linear score between mammary glands infected with isolates in genotypic clusters 1 and 2. CONCLUSIONS AND CLINICAL RELEVANCE: S aureus was shed consistently in cows with naturally occurring intramammary infection in cows, and regardless of the pulsotype, variations in the amount of S aureus shedding had no significant effect on the ability to detect S aureus with a 0.1-mL inoculum.

Role-reversal exercise with Deaf Strong Hospital to teach communication competency and cultural awareness.

OBJECTIVE: To implement a role-reversal exercise to increase first-year pharmacy students' awareness of communication barriers in the health care setting, especially for deaf and hard-of-hearing patients. DESIGN: Volunteers from the local deaf community conducted Deaf Strong Hospital, a role-reversal exercise in which students were the "patients." Students navigated through a reception area, encounter with a physician, and having a prescription filled at a pharmacy without receiving or using any spoken language. ASSESSMENT: A debriefing session was held in which small groups of students had the opportunity to ask questions of a panel of deaf and hard-of-hearing volunteers. On a survey administered to assess students' learning, 97% agreed or strongly agreed that the experience would likely impact their attitudes and behavior in future interactions with patients who did not speak English. CONCLUSIONS: The role-reversal exercise was an effective method of teaching students that the delivery of health care is dependent on adequate communication between health care providers and the patient.

Variation in daily shedding patterns of Staphylococcus aureus in naturally occurring intramammary infections.

The goal of the current prospective field study was to examine the shedding patterns of naturally occurring Staphylococcus aureus intramammary infections and the association of pulsed field gel electrophoresis pulsotype with shedding. Milk samples from 5 multiparous and 2 primiparous cows identified with S. aureus intramammary infections were collected for 21 consecutive days, 3 times throughout the lactation (63 days total). Cyclicity of each quarter was evaluated using a locally weighted regression. Pulsed field gel electrophoresis was used for genotypic cluster comparisons to evaluate the association of strain type and shedding patterns. Although the amount of shedding varied greatly, 97.5% of the samples were culture positive. There were notable differences in S. aureus shedding patterns among cows as well as within cows; however, no consistent cyclic pattern was identified. Quarters infected with S. aureus isolates grouped in genotypic cluster 1 appeared to shed at consistently higher levels with a median cfu/0.01 ml of 154 (ln[cfu] = 5.0). In comparing ln(cfu)/0.01 ml between genotypic clusters over the first 21-day sample period, accounting for the effect of sample day, samples collected from quarters infected with S. aureus in genotypic cluster 1 had a 1.5 times greater ln(cfu) than those collected from quarters infected with strains in genotypic cluster 2. The ability to detect S. aureus from day to day was very consistent. The current study examining naturally occurring intramammary infections would support the conclusions of other studies suggesting that a single quarter sample would be adequate in determining S. aureus intramammary infections status.

Differential targeting of Gbetagamma-subunit signaling with small molecules.

G protein betagamma subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gbetagamma subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gbetagamma subunit functions. Several compounds bound to Gbetagamma subunits with affinities from 0.1 to 60 muM and selectively modulated functional Gbetagamma-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.

Characterization of a novel bivalent morphinan possessing kappa agonist and micro agonist/antagonist properties.

Previous research has shown that compounds with mixed kappa and mu activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a kappa opioid receptor agonist and a mu opioid receptor agonist/antagonist. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K(i) values of 0.078 and 0.20 nM for the kappa and mu opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5'-O -(3-[(35) S]thiotriphosphate) binding assay, MCL-145 produced an E(max) value of 80% for the kappa opioid receptor and 42% for the mu opioid receptor. The EC(50) values obtained for this compound were 4.3 and 3.1 nM for the kappa and mu opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55 degrees C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. MCL-145 also acted as a mu antagonist, as measured by the inhibition of morphine-induced antinociception.