Pharmacokinetics and pharmacodynamics of five distinct commercially available hemp-derived topical cannabidiol products.

Products containing cannabidiol (CBD) have proliferated after the 2018 Farm Bill legalized hemp (cannabis with ≤0.3% delta-9-tetrahydrocannabinol (Δ9-THC)). CBD-containing topical products have surged in popularity, but controlled clinical studies on them are limited. This study characterized the effects of five commercially available hemp-derived high CBD/low Δ9-THC topical products. Healthy adults (N = 46) received one of six study drugs: a CBD-containing cream (N = 8), lotion (N = 8), patch (N = 7), balm (N = 8), gel (N = 6) or placebo (N = 9; matched to an active formulation). The protocol included three phases conducted over 17 days: (i) an acute drug application laboratory session, (ii) a 9-day outpatient phase with twice daily product application (visits occurred on Days 2, 3, 7 and 10) (iii) a 1-week washout phase. In each phase, whole blood, oral fluid and urine specimens were collected and analyzed via liquid chromatography with tandem mass spectrometry (LC-MS-MS) for CBD, Δ9-THC and primary metabolites of each and pharmacodynamic outcomes (subjective, cognitive/psychomotor and physiological effects) were assessed. Transdermal absorption of CBD was observed for three active products. On average, CBD/metabolite concentrations peaked after 7-10 days of product use and were highest for the lotion, which contained the most CBD and a permeation enhancer (vitamin E). Δ9-THC/metabolites were below the limit of detection in blood for all products, and no urine samples tested "positive" for cannabis using current US federal workplace drug testing criteria (immunoassay cut-off of 50 ng/mL and confirmatory LC-MS-MS cut-off of 15 ng/mL). Unexpectedly, nine participants (seven lotions, one patch and one gel) exhibited Δ9-THC oral fluid concentrations ≥2 ng/mL (current US federal workplace threshold for a "positive" test). Products did not produce discernable pharmacodynamic effects and were well-tolerated. This study provides important initial data on the acute/chronic effects of hemp-derived topical CBD products, but more research is needed given the diversity of products in this market.

Inhibition of Wnt/ß-catenin pathway overcomes therapeutic resistance to abiraterone in castration-resistant prostate cancer.

Abiraterone acetate has been clinically approved for the treatment of patients with advanced-stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha-hydroxylase. Despite improved survival outcomes with abiraterone, almost all patients develop therapeutic resistance and disease recurrence, progressing to a more aggressive and lethal phenotype. Bioinformatics analyses predicted activation of canonical Wnt/ß-catenin and involvement of stem cell plasticity in abiraterone-resistant prostate cancer. Increased expression of androgen receptor (AR) and ß-catenin and their crosstalk causes activation of AR target genes and regulatory networks for which overcoming acquired resistance remains a major challenge. Here we show that co-treatment with abiraterone and ICG001, a ß-catenin inhibitor, overcomes therapeutic resistance and significantly inhibited markers of stem cell and cellular proliferation in abiraterone-resistant prostate cancer cells. Importantly, this combined treatment abrogated the association between AR and ß-catenin; diminished SOX9 expression from the complex more prominently in abiraterone-resistant cells. In addition, combined treatment inhibited tumor growth in an in vivo abiraterone-resistant xenograft model, blocked stemness, migration, invasion, and colony formation ability of cancer cells. This study opens new therapeutic opportunity for advanced-stage castration-resistant prostate cancer patients.

Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration-resistant prostate cancer.

Enzalutamide (XTANDI®), an antiandrogen, is used for the treatment of advanced-stage prostate cancer. Approximately, 60% of patients receiving enzalutamide show initial remission followed by disease relapse with the emergence of highly aggressive castration-resistant prostate cancer. Solute carrier (SLC) proteins play a critical role in the development of drug resistance by altering cellular metabolism. Transcriptome analysis revealed the predominance of SLC25A17 and SLC27A6 in enzalutamide-resistant prostate cancer cells; however, their role in antiandrogen resistance has not been elucidated. sgRNA-mediated knockdown of SLC25A17 and SLC27A6 suppressed cell proliferation and migration in enzalutamide-resistant cells. An induction of G1/S cell cycle arrest and abundance of hypo-diploid cells along with the reduction in the protein expression CyclinD1 and CDK6, the checkpoint factors, was observed including increased cell death as evident by BAX upregulation in knockdown cells. Inhibition of SLC25A17 and SLC27A6 resulted in downregulation of fatty acid synthase and acetyl-CoA carboxylase with parallel decrease in the levels of lactic acid in enzalutamide resistant cells. However, downregulation of triglyceride and citric acid was only observed in SLC25A17 silenced cells. The protein-protein interaction of SLC25A17 and SLC27A6 revealed alteration in some common drug-resistant and metabolism-related genes. Analysis of The Cancer Genome Atlas database exhibiting high SLC25A17 and SLC27A6 gene expression in prostate cancer patients were associated with poor survival than those with low expression of these proteins. In conclusion, SLC25A17 and SLC27A6 and its interactive network play an essential role in the development of enzalutamide resistance through metabolic reprogramming and may be identified as therapeutic target(s) to circumvent drug resistance.

Identification of Key Genes Associated with Progression and Prognosis of Bladder Cancer through Integrated Bioinformatics Analysis.

Bladder cancer prognosis remains dismal due to lack of appropriate biomarkers that can predict its progression. The study aims to identify novel prognostic biomarkers associated with the progression of bladder cancer by utilizing three Gene Expression Omnibus (GEO) datasets to screen differentially expressed genes (DEGs). A total of 1516 DEGs were identified between non-muscle invasive and muscle invasive bladder cancer specimens. To identify genes of prognostic value, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A total of seven genes, including CDKN2A, CDC20, CTSV, FOXM1, MAGEA6, KRT23, and S100A9 were confirmed with strong prognostic values in bladder cancer and validated by qRT-PCR conducted in various human bladder cancer cells representing stage-specific disease progression. ULCAN, human protein atlas and The Cancer Genome Atlas datasets were used to confirm the predictive value of these genes in bladder cancer progression. Moreover, Kaplan-Meier analysis and Cox hazard ratio analysis were performed to determine the prognostic role of these genes. Univariate analysis performed on a validation set identified a 3-panel gene set viz. CDKN2A, CTSV and FOXM1 with 95.5% sensitivity and 100% specificity in predicting bladder cancer progression. In summary, our study screened and confirmed a 3-panel biomarker that could accurately predict the progression and prognosis of bladder cancer.

How to Avoid Life-Threatening Complications Associated with Implant Surgery.

Life-threatening complications of dental implant surgery are rare, but include hematoma/hemorrhage of the floor of the mouth, aspiration, and ingestion. Prevention of lethal hemorrhagic complications stem from knowledge of anatomic structures and precise surgical planning. Prevention of aspiration and ingestion can be improved by simple techniques while understanding clinical settings and factors that put patients at higher risk. In the event of these potential lethal situations, early recognition of signs and symptoms along with immediate action followed by transfer to an emergency department is often necessary.

Neuropathic Pain and Burning Mouth Syndrome: An Overview and Current Update.

Burning mouth syndrome/glossodynia and trigeminal neuropathic conditions can have serious negative impact on a patient's overall quality of life. These conditions are often hard to diagnose and even harder to fully treat and manage, but it is important for dentists/oral and maxillofacial surgeons to be aware of these conditions and modalities of their treatment. Often the only method for arriving at the proper diagnosis is for patients to undergo traditional approaches for treatment of presenting signs and symptoms, and it is the unexpected failure of interventional therapies that leads ultimately to a proper diagnosis.

Salivary flow rate after conventional and intensity-modulated radiation therapy.

BACKGROUND: Conventional 3-dimensional conformal radiation therapy (3DCRT) for head and neck cancer (HNC) can cause hyposalivation, leading to caries and tooth extraction-related osteoradionecrosis. Intensity-modulated radiation therapy (IMRT) delivers more focused radiation than does 3DCRT. To reduce hyposalivation, the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines limit salivary gland radiation dose. In this study, the authors compared the salivary flow rate in patients receiving 3DCRT and those receiving IMRT and evaluated the effect of their treatment satisfying the QUANTEC guidelines on hyposalivation. METHODS: The authors evaluated findings in 96 patients with HNC who received radiation therapy (RT); 20 received unilateral 3DCRT, 17 received bilateral 3DCRT, and 59 received IMRT. The authors measured stimulated whole saliva before radiation and 3 and 12 months after radiation. The authors defined hyposalivation as stimulated whole saliva less than 3.5 grams per 5 minutes. RESULTS: At 12 months, 50% and 54% of patients receiving unilateral 3DCRT and IMRT, respectively, exhibited nonstatistically significant hyposalivation compared with 71% of patients receiving bilateral 3DCRT (P = .2). A lower proportion of patients receiving IMRT (27%) and unilateral 3DCRT (5%) had decreased salivary flow (< 25% of baseline) than did those receiving bilateral 3DCRT (59%; P < .004); fewer patients whose treatment satisfied the QUANTEC guidelines exhibited hyposalivation than patients whose treatment did not fullfill QUANTEC guidelines (39% versus 71%; P < .002). CONCLUSIONS: Twelve months after RT for HNC, treatment satisfying the QUANTEC guidelines resulted in decreased hyposalivation. Unilateral 3DCRT and IMRT may result in less hyposalivation than does bilateral 3DCRT. PRACTICAL IMPLICATIONS: Patients with HNC treated with modern RT techniques have a lower risk of developing hyposalivation, particularly if the QUANTEC guidelines are met, which also may result in decreased dental caries, tooth extractions, and postextraction osteoradionecrosis. Management of HNC requires a multidisciplinary team, including dentists and radiation oncologists.

The effect of class-specific protease inhibitors on the stabilization of B-type natriuretic peptide in human plasma.

BACKGROUND: B-type natriuretic peptide (BNP) is a cardiac hormone that regulates hemodynamic equilibrium. In the circulation, its activity is controlled by proteolytic factors. Accurate measurement of BNP in a patient's plasma may be affected by degradation due to proteolysis. OBJECTIVE: We report on the identification and performance of classes of protease inhibitors that stabilize BNP in plasma. DESIGN AND METHODS: Using the Bayer ADVIA Centaur BNP assay, we measured the effect of arginine, serine and/or specific kallikrein protease inhibitors (PIs) on exogenous spiked or endogenous BNP in patient plasma. RESULTS: Compared to controls without inhibitor, all PIs were capable, to varying degrees, of retarding the rate of proteolytic degradation. The kallikrein-specific inhibitor, D-Phe-Phe-Arg-chloromethylketone (PPACK II) was most effective as a single constituent and was able to eliminate BNP degradation in patient samples for up to 6-10 days when stored at 2-8 degrees C. CONCLUSIONS: The stability of BNP was markedly increased in the presence of kallikrein-specific PPACK II and a broad spectrum of serine PIs. Use of these compounds offers a simple method of extending sample handling and storage of plasma samples containing BNP.