A Continuing Pharmacy Education (CPE) Program Assessing Cannabidiol (CBD) Knowledge and Confidence Among Practicing Pharmacists.

Background: Increased patient utilization of cannabidiol (CBD) leads to potential drug interactions with various medications and questions posed to pharmacists. Objective: To quantify the knowledge gap of pharmacists on CBD and CBD-containing products and assess the degree a continuing pharmacy education (CPE) program alters pharmacist confidence and competency on CBD knowledge. Methods: A 1-h CPE activity was offered as a home study from May 9, 2022, through September 30, 2022. Subjects were practicing pharmacy preceptors in Alabama who completed the pre-survey and post-survey for inclusion in matched-pair analyses. The primary outcome measure was participant score improvement between the pre-post surveys. Secondary measures involved pre-post comparisons on self-rated Likert questions concerning participant confidence in counseling, answering drug information questions, and ensuring patient safety regarding CBD. Results: A total of 124 participants completed the course. After matched pairing, 64 and 56 individuals were included in the knowledge-based and confidence ranking analyses, respectively. Participant scoring improved on the knowledge-based questions between the pre-post surveys (50.0% vs 87.8%, P < .001). There was a significant confidence improvement of participants from baseline on counseling patients about prescription or over-the-counter CBD products, answering questions from other healthcare professionals about these products, and ensuring patient safety while using these products (Average 5-level Likert scale increases of 1.75, 1.73, 1.70, respectively; all P < .001). Conclusion: Implementation of a CPE program improved practicing pharmacists' knowledge on information about CBD, which lead to increased competency on counseling patients, answering drug information questions, and promoting patient safety.

Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma.

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1ß and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+/-;Cdkn2a+/- mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.

In vitro metabolic biomodulation of irinotecan to increase potency and reduce dose-limiting toxicity by inhibition of SN-38 glucuronide formation.

OBJECTIVES: Colorectal cancer continues to have one of the highest incidents of occurrence with a rising rate of diagnosis among people under the age of 50. Chemotherapy with irinotecan results in severe gastrointestinal dose-limiting toxicity that is caused by the glucuronidated form of the active metabolite (SN-38G). This study evaluates herbal compounds and analogs to biomodulate the metabolism of IR to decrease dose-limiting toxicity while increasing the amount of the active metabolite. METHODS: In vitro metabolism using human liver microsomes was conducted with white willow bark (WWB) extract, select specific components of WWB, and analogues to evaluate biomodulation of the IR metabolism. Samples were analyzed using liquid chromatography-tandem mass spectrometry to measure metabolites between reactions with and without herbals components. RESULTS: WWB showed an optimal decrease (>80%) in SN-38G and a corresponding increase in SN-38 levels (128%) at a concentration of near 200 µg/mL. Tannic acid produced a 75% decrease in SN-38G with a 130% increase in SN-38 at 10 µg/mL, whereas the treatment with beta-pentagalloyl glucose and various analogues decreased SN-38G by 70% and increased SN-38 by 20% at 10 µg/mL. CONCLUSIONS: These results suggest naturally occurring compounds from WWB may have the potential to increase potency by increasing the conversion of IR to SN-38 and decrease dose-limiting toxicity of IR chemotherapy by reducing glucuronidation of SN-38.

Radiation Effects on Methamphetamine Pharmacokinetics and Pharmacodynamics in Rats.

BACKGROUND AND OBJECTIVES: Whole-body radiation exposure has been shown to alter the pharmacokinetics of certain drugs in both animal models and humans, but little is known about the effect of radiation on psychoactive medications. These drugs may have altered pharmacokinetics when administered during or after space travel or therapeutic or accidental radiation exposure, resulting in reduced efficacy or increased toxicity. METHODS: Methamphetamine was used to determine the effects of acutely administered 1, 3, and 6 Gy radiation on drug pharmacokinetics and pharmacodynamics. Male Wistar rats were exposed to 0, 1, 3, or 6 Gy X-ray radiation on day 0. The serum pharmacokinetics of subcutaneously administered 1 mg/kg methamphetamine was determined on day 3. Methamphetamine-induced (1 mg/kg) locomotor activity was measured on day 5. Brain methamphetamine concentrations were determined 2 h after methamphetamine administration (1 mg/kg) on day 6. Renal and hepatic serum biomarkers were assessed on days 3 and 6, with liver histology performed on day 6. RESULTS: While serum half-life and unchanged methamphetamine urine clearance were unaffected by any radiation dose, maximum methamphetamine concentrations and methamphetamine and amphetamine metabolite area under the serum concentration-time curve values from 0 to 300 min were significantly reduced after 6 Gy radiation exposure. Additionally, methamphetamine-induced locomotor activity and the brain to serum methamphetamine concentration ratio were significantly elevated after 6 Gy radiation. CONCLUSIONS: While 1-6 Gy radiation exposure did not affect methamphetamine elimination, 6 Gy exposure had effects on both subcutaneous absorption and brain distribution. These effects should be considered when administering drugs during or after radiation exposure.

Suppression of Colon Tumorigenesis in Mutant Apc Mice by a Novel PDE10 Inhibitor that Reduces Oncogenic ß-Catenin.

Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10. The concentration range by which ADT 061 inhibited colon cancer cell growth was identical to concentrations that inhibit recombinant PDE10. ADT 061 inhibited PDE10 by a competitive mechanism and did not affect the activity of other PDE isozymes at concentrations that inhibit colon cancer cell growth. Treatment of colon cancer cells with ADT 061 activated cGMP/PKG signaling, induced phosphorylation of oncogenic ß-catenin, inhibited Wnt-induced nuclear translocation of ß-catenin, and suppressed TCF/LEF transcription at concentrations that inhibit cancer cell growth. Oral administration of ADT 061 resulted in high concentrations in the colon mucosa and significantly suppressed the formation of colon adenomas in the Apc+/min-FCCC mouse model of colorectal cancer without discernable toxicity. These results support the development of ADT 061 for the treatment or prevention of adenomas in individuals at risk of developing colorectal cancer. PREVENTION RELEVANCE: PDE10 is overexpressed in colon tumors whereby inhibition activates cGMP/PKG signaling and suppresses Wnt/ß-catenin transcription to selectively induce apoptosis of colon cancer cells. ADT 061 is a novel PDE10 inhibitor that shows promising cancer chemopreventive activity and tolerance in a mouse model of colon cancer.

Effect of bile duct ligation-induced liver dysfunction on methamphetamine pharmacokinetics in male and female rats.

BACKGROUND: Several disease states commonly associated with methamphetamine (METH) use produce liver dysfunction, and in the bile duct ligation (BDL) model of hepatic dysfunction, rats with liver injury are more sensitive to METH effects. Additionally, both female rats and humans are known to be more sensitive to METH than males. In consideration of known sex-dependent differences in METH pharmacokinetics, this study sought to determine the potential interaction between sex and liver dysfunction variables on METH pharmacokinetics. METHODS: Sham or BDL surgery was performed on male and female rats on day 0. Serum biomarker and pharmacokinetics studies with 3 mg/kg subcutaneous (SC) METH were performed on day 7. METH-induced weight loss was measured on day 8. Liver histology evaluation and brain METH concentration measurements were performed on day 9. RESULTS: While BDL surgery produced significantly elevated alanine aminotransferase and bile duct proliferation in male compared to female rats, there were no significant interactions between sex and liver function in the pharmacokinetic parameters. Both liver dysfunction and female sex, however, were associated with significantly slower METH serum clearance and significantly higher brain METH concentrations (p < .05). CONCLUSIONS: BDL-induced hepatic dysfunction produces substantial reductions in METH clearance and increased brain METH concentrations in both male and female rats, despite less liver injury in females. This preclinical model may be useful to identify and correct potential liver dysfunction comorbidity-related problems with future pharmacotherapy for stimulant use disorder with METH prior to expensive clinical trials.

Investigations of Physical Compatibilities of Commonly Used Intravenous Medications with and without Parenteral Nutrition in Pediatric Cardiovascular Intensive Care Unit Patients.

Many pediatric intensive care patients require numerous specialized intravenous (IV) medications at various dosages in multiple fluids often with nutritional support. This requires several venous access points due to lack of Y-site compatibility data for combinations of two or more drugs. This project investigated physical compatibilities of intravenous medications: alprostadil, calcium gluconate, dexmedetomidine, epinephrine, norepinephrine, esmolol, furosemide, vasopressin, and milrinone with and without lipid-free total parenteral nutrition (TPN) commonly used in a pediatric cardiovascular intensive care unit (CVICU) patient. Actual drug combinations were evaluated using a simulated Y-site study design. Compatibility was determined based on observational data: odor (change/appearance), evolution of gas, and visual appearance combined with physical or chemical endpoints with predefined acceptance criteria: change in pH (± 1 unit), and turbidity (>0.5 NTU) at eight time points between 0 and 240 min. All binary drug combinations along with the four drug plus TPN combination were found to be physically compatible up to 240 min. The three drug combinations were determined to be incompatible and were not evaluated with TPN. This study demonstrates the utility of simulated Y-site study design to multi-drug combinations and increases the scientific body of knowledge related to medications used in a pediatric CVICU.

The Association Between Lithium in Drinking Water and Incidence of Suicide Across 15 Alabama Counties.

BACKGROUND: Recent studies have shown that lithium may be effective at reducing suicide at low doses, such as those found in drinking water. AIMS: The purpose of this study was to compare suicide rates with natural lithium levels in the drinking water of various Alabama counties. METHOD: Five drinking water samples from each of 15 Alabama counties were collected. Lithium levels were measured in triplicate using an inductively coupled plasma emission spectrophotometer and compared with suicide rate data for the period 1999-2013. Age, gender, and poverty were evaluated as potential confounding variables. RESULTS: The average measured lithium concentrations ranged from 0.4 ppb to 32.9 ppb between the counties tested. The plot of suicide rate versus lithium concentration showed a statistically significant inverse relationship ( r = -.6286, p = .0141). Evaluation of male-only suicide rate versus lithium concentration data also yielded significant results; however, the female-only rate was not significant. Age standardized suicide rates and poverty when individually compared against lithium levels were also found to be statistically significant; unexpectedly, however, poverty had a parallel trend with suicide rate. CONCLUSION: Lithium concentration in drinking water is inversely correlated with suicide rate in 15 Alabama counties.

Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas.

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.

Physical Compatibility of Micafungin With Sodium Bicarbonate Hydration Fluids Commonly Used With High-Dose Methotrexate Chemotherapy.

Purpose: The purpose of this study was to determine the physical compatibility of micafungin with commonly used concentrations of sodium bicarbonate hydration fluids administered via a Y-site connected to a central venous catheter (Y-site/CVC). Methods: Micafungin sodium (evaluated concentration of 1.5 mg/mL) was combined in a 3:1 (vehicle:drug) ratio with the following commonly used hydration vehicles: 40 mEq/L sodium bicarbonate in 5% dextrose in water with » normal saline (40SB-D5W-1/4NS), 75 mEq/L sodium bicarbonate in D5W (75SB-D5W), and 154 mEq/L sodium bicarbonate in D5W (154SB-D5W). A 3:1 ratio was used based on the flow rates (typically 125 mL/m2/h for bicarbonate-containing vehicles and 50 mL/h for micafungin) of the corresponding solutions in a clinical setting. Visual observations recorded to determine physical compatibility included visual inspection against different backgrounds (unaided, black, and white). Other physical observations were as follows: odor, evolution of gas, pH, and turbidity immediately recorded after mixing and at specified time points up to 2 hours. Evaluations at each time point were compared against baseline observation values at Time 0. Results: All combinations tested were found to be compatible up to 2 hours. Time points beyond 2 hours cannot be safely verified as compatible. Conclusion: Micafungin may be administered safely using a Y-site/CVC delivery system with all the vehicles tested in this study.

Small Molecules Revealed in a Screen Targeting Epithelial Scattering Are Inhibitors of Microtubule Polymerization.

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in the detachment of cell-cell junctions and initiation of cell migration. Instead of coordinating collective cell behavior within a tissue, cells become solitary and have few cell-cell interactions. Since epithelial scattering is recapitulated in cancer progression and since HGF signaling drives cancer metastasis in many cases, inhibitors of HGF signaling have been proposed to act as anticancer agents. We previously sought to better understand critical components required for HGF-induced epithelial scattering by performing a forward chemical genetics screen, which resulted in the identification of compounds with no previously reported biological activity that we report here. In efforts to determine the mechanism of these compounds, we find that many compounds have broad antiproliferative effects on cancer cell lines by arrest of cell division in G2/M with minimal induction of apoptosis. This effect is reminiscent of microtubule-targeting agents, and we find that several of these scaffolds directly inhibit microtubule polymerization. Compounds are assessed for their toxicity and pharmacokinetics in vivo. The identification of novel small-molecule inhibitors of microtubule polymerization highlights the role of the microtubule cytoskeleton in HGF-induced epithelial scattering.

Skin Permeation and Antinociception of Compounded Topical Cyclobenzaprine Hydrochloride Formulations.

Cyclobenzaprine has been commonly compounded by pharmacists into topically applied dosage forms for the treatment of pain disorders. However, the efficacy and transdermal penetration of topically applied compounded cyclobenzaprine is currently unknown. In this study, the transdermal penetration of cyclobenzaprine was studied in Franz diffusion cells using porcine skin. Cyclobenzaprine was compounded in two commercially available bases; Lipobase, Lipoderm, and a standard poloxamer lecithin organogel. In addition, cyclobenzaprine was tested in an in vivo formalin pain model. Cyclobenzaprine 5% compounded into all three bases yielded significant transdermal penetration and results in modest levels of cyclobenzaprine being retained in the skin tissue. Systemically administered cyclobenzaprine (10 mcg/kg), but not topically administered cyclobenzaprine (1% and 5%), attenuated nociception in a rodent formalin pain model.

In vitro inhibitory effects of herbal supplements on tamoxifen and irinotecan metabolism.

BACKGROUND: As the use of herbal supplements continues to rise throughout the world, the potential for drug-herbal interactions also increases. For chemotherapeutic prodrugs, this interaction could prevent the metabolic conversion of the prodrug to its active metabolite(s), thereby potentially resulting in subtherapeutic systemic exposure of the drug and reduced efficacy of the therapy. METHODS: In this study, in vitro metabolism with human liver microsomes is used to measure the impact of ten commonly used herbal supplements on the biotransformation of the chemotherapeutic prodrugs tamoxifen (TAM) and irinotecan (IR). RESULTS: Four of the herbals tested, echinacea, ginseng, lemon balm, and skullcap, were found to be strong inhibitors of the CYP450 enzymatic bioactivation pathways of TAM with IC50 values as percent of a single dose ranging from 0.019% to 0.34%. Two of the herbals, skullcap and lemon balm, were found to inhibit the carboxyesterase pathway of IR with values of 0.21 and 0.25, respectively. CONCLUSIONS: Our data suggests that based on the measured IC50 values that skullcap and lemon balm could have potential negative clinical impact on the bioactivation of TAM but not likely with IR.

Incidence, predictors and associated outcomes of renal cell carcinoma in long-term dialysis patients.

We carried out an analysis of the United States Renal Data System to determine the incidence, risk factors and prognosis of renal cell carcinoma (RCC) in a national population of patients receiving incident long-term dialysis. In Cox regression, male gender, older age, end-stage renal disease caused by obstruction, tuberous sclerosis, focal segmental glomerulosclerosis, as well as acquired renal cysts, were independently associated with RCC. Most cases of RCC in incident long-term dialysis patients occurred in patients without acquired renal cysts. A diagnosis of RCC was associated with increased risk of subsequent mortality overall and in all high-risk groups.

The effect of rotavirus immunization on rotavirus gastroenteritis hospitalization rates in military dependents.

We conducted a retrospective review of all U.S. military dependents less than 5 years old hospitalized with rotavirus-associated gastroenteritis from July 2003 to June 2009. The two post-vaccine seasons showed a significant reduction of 62.4% (95% CI, 58.6-65.8, P<0.001) in rotavirus gastroenteritis hospitalization rate compared to the three pre-vaccine seasons. Infants less than 12 months old showed the greatest reduction in incidence at 75.3%. A substantial decrease was also seen in unvaccinated children as well. Vaccine efficacy against hospitalization was 86.0% (95% CI, 77.7-91.3) after just a single dose. The overwhelming majority of children hospitalized for rotavirus since the introduction of the vaccine (ranging from 91.8 to 100% per season) had not received any of the rotavirus vaccine series.

A novel and rapid LC/MS/MS assay for bioanalysis of Azurin p28 in serum and its pharmacokinetics in mice.

Azurin p28 (NSC745104) is a 28 amino acid peptide fragment that inhibits proliferation of human solid and hematological malignancies in vitro and in vivo by reducing proteasomal degradation of oncogene p53. The present study aimed at developing a novel and fast liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the bioanalysis of p28 in mouse serum, and determining Azurin p28 stability and pharmacokinetics in mice after full method validation. Both Azurin p28 and its internal standard MP-1 were separated and extracted from serum by using perchloric acid (7%, v/v) without time-consuming reconstitution. Chromatographic separation of Azurin p28 and MP-1 from the serum matrix was achieved using a C18 column with a gradient elution profile consisting of 5 mM ammonium acetate and acetonitrile, both containing formic acid. Mass analysis was conducted using positive ion electrospray ionization (ESI) and multiple reaction monitoring (MRM). It took 7.5 min to analyze one sample. The validated concentration range of the method extended from 100 to 10,000 ng/ml with accuracies of 85-115% and inter-day precision (CV) of <15%. Inter-day accuracy ranged from 96.4% to 103% and CV ranged from 4.61% to 6.90%. The average recovery of Azurin p28 from mouse serum at three concentrations (200, 1000, and 5000 ng/ml) was determined to be 96.4%. Incubation of Azurin p28 at 37 degrees C for 24h resulted in its degradation 55% in monkey serum, 41% in human serum, and 32-34% in mouse and dog serum. Intravenous administration of Azurin p28 to mice showed its t(1/2 beta) 0.23 h, clearance 1.7 l/kg/h, and volume of distribution at steady state 4.1l/kg. In conclusion, the novel and fast bioanalytical method was proven to be useful for pharmacokinetic profiling of Azurin p28.