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Background Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food and Drug Administration approval for these indications. There is no consensus regarding optimal dosing of dalbavancin for these infections and no available pharmacokinetic studies to identify optimal dosing for long-term use. Methods An in silico pharmacokinetic simulation was performed to assess the predicted dalbavancin concentration resulting from commonly utilized dosing regimens, in addition to modified regimens. The primary endpoint evaluated was days of median 24-hour free area under the curve over the minimum inhibitory concentration (AUC/MIC) >27.1, the established PK target. Results A dosing regimen of 1500 mg on day 0 and day 7 resulted in median AUC/breakpoint value above the target for 57 days (lower 95% confidence interval [CI], 37 days). A modified regimen of 1500 mg on day 0 and day 21 resulted in an additional 11 days of median AUC/breakpoint target attainment. The other standard dosing regimen modeled was 1000 mg on day 0, then 500 mg weekly for 5 doses. This regimen achieved the AUC/breakpoint target for 76 days (lower 95% CI, 59 days). This regimen was modified to 1000 mg on day 0, then 500 mg on days 14 and 28, which shortened the median effective treatment duration by 14 days but required 3 fewer doses. Conclusions These simulated results, when combined with the favorable observational data, support the use of commonly reported dalbavancin regimens for prolonged therapy durations. In addition, these pharmacokinetic/pharmacodynamic data support extending the dosing interval beyond the frequently reported weekly regimens, which should be investigated further with a clinical trial. [ABSTRACT FROM AUTHOR]

Purpose: Molecular tumor boards provide precision treatment recommendations based on cancer genomic profile. However, practical barriers limit their benefits. We studied the clinical utility of the precision medicine molecular tumor board (PMMTB) and described challenges with PMMTB implementation. Methods: An observational cohort study included patients reviewed by the PMMTB between September 2015 to December 2017. Patients who had consented to the registry study were included. The primary endpoint of this study was time on treatment (ToT) ratio. Clinical utility was established if the primary endpoint had least 15% of patients achieving a ToT ratio of ≥1.3. Results: Overall, 278 patients were presented to the PMMTB and 113 cases were included in the final analysis. The PMMTB identified at least one nonstandard of care (SOC) clinically actionable mutation for 69.0% (78/113) of cases. In patients who received non-SOC treatment, 43.8% (7/16) achieved a ToT ratio of 1.3 or more (p < 0.001). Fifty-nine patients did not receive non-SOC recommendations. Reasons for not pursuing treatment included 35.6% having response to current treatment, 20.3% died prior to starting or considering PMMTB recommendations, 13.6% pursued other treatment options based on clinician discretion, another 10.2% pursued other treatment options because clinical trials recommended were not geographically accessible, 8.5% had rapid decline of performance status, 6.8% lacked of financial support for treatment, and 5.1% were excluded from clinical trials due to abnormal laboratory values. Conclusion: The regional PMMTB non-SOC recommendations benefitted a majority of patients and additional processes were implemented to assist with non-SOC treatment accessibility. [ABSTRACT FROM AUTHOR]

Psilocybin is being developed for treating major depressive disorder. Psilocybin is readily dephosphorylated to psilocin upon absorption. The potential for psilocin proarrhythmic effect was assessed using a concentration‐QTc interval (C‐QTc) analysis from an open‐label single ascending dose study of psilocybin. Psilocybin doses ranged from 0.3 to 0.6 mg/kg. This trial showed a significant but shallow C‐QTc relationship. At the clinical dose of 25 mg, the mean psilocin maximum concentration is 18.7 ng/mL, and the associated mean (upper 90% confidence interval of mean) QTcF change is 2.1 (6.6) milliseconds. Given the short half‐life of psilocin of about 4 hours, there would be no accumulation after monthly oral doses used in clinical trials. The upper limit of the 90% confidence interval of the model‐predicted mean ΔQTcF crossed 10 milliseconds at a psilocin concentration of 31.1 ng/mL. At a supraclinical psilocin maximum concentration of about 60 ng/mL, ΔQTcF remains low, with a mean (upper limit of the 90% confidence interval) of 9.1 (17.9) milliseconds. This analysis enabled the characterization of the C‐QTc relationship and prediction of QTc prolongation at the expected clinical and possible higher psilocybin doses. [ABSTRACT FROM AUTHOR]

Background: Antibiotics for the treatment of complicated, multidrug-resistant Gram-positive infections are limited, especially when prolonged treatment is necessary. Oritavancin is approved for the treatment of serious skin infections as a 1200 mg single-dose regimen, but case reports describe supplemental doses given at weekly intervals ranging from 800 mg to 1200 mg. Objective: This study determined population pharmacokinetic estimates for a 1200 mg single dose with and without an 800 mg dose 1 week apart. Methods: A simulated oritavancin 1200 mg dose was infused over 3 h followed 7 days later by a simulated 800 mg dose infused over 3 h for pharmacokinetic estimation. Results: The oritavancin dosing displayed predictable linear pharmacokinetics and therapeutic concentrations. The total and free oritavancin concentrations remained above the susceptibility breakpoint (0.12 mg/L) for 8 weeks and 4.6 weeks, respectively, with the two-dose regimen. This was significantly greater than the single-dose regimen. This regimen also results in a greater area under the drug concentration–time curve (AUC) above the susceptibility breakpoint compared to the single-dose regimen (p < 0.001), and it maintains a high AUC:minimum inhibitory concentration (MIC) ratio against organisms with MICs up to 0.25 mg/L. Conclusion: These results along with the observational clinical reports of success and safety with this dosing scheme of 1200 mg followed by 800 mg 7 days later provide evidence for further evaluation of this approach when prolonged oritavancin treatment may be indicated. [ABSTRACT FROM AUTHOR]

Aim: The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects.Methods: Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8-36.6 mg; 27.1-54.0 mg; 36.3-59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire.Results: There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience.Conclusions: High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes. [ABSTRACT FROM AUTHOR]

The article focuses on anticancer drug development and dosing strategies. Topics include understanding and appreciating modeling and simulation (M&S) approaches for anti-cancer drug development, history of chemotherapy and the evolution of anticancer drug development, and use of nitrogen mustard and folic acid antagonists in 1940s for treating cancer.

Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show–for the first time–that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process. [ABSTRACT FROM AUTHOR]

3, 4-Didehydroretinol (DR) metabolism was previously followed in vitamin A (VA)-replete lactating sows. This study followed DR appearance and clearance after dosage in serum and milk during 2 lactation cycles in sows (n = 8) fed VA-free feed for 3 gestation-lactation cycles. During lactations 2 and 3, 35 μmol 3, 4-didehydroretinyl acetate was given orally after overnight food deprivation. Blood and milk were collected at 0, 1.5, 3, 5, 7, 9, 16, 24, 36, 48, 60, and 72 h; livers were obtained at kill. Samples were analyzed for DR, retinol (R), and 3, 4-didehydroretinyl esters. During lactations 2 and 3, the 5-h serum DR:R ratios were 0.028 ± 0.017 and 0.069 ± 0.042, respectively, and serum R concentrations were 0.75 ± 0.23 and 0.86 ± 0.37 μmol/L, respectively. The DR:R ratio and serum R were 0.018 ± 0.013 and 0.94 ± 0.12 μmol/L, respectively, in VA-replete sows from the same herd. After lactation 3, liver VA was 0.23 ± 0.05 μmol/g, indicating low-normal VA status. Serum DR area-under-the curve from 0 to 48 h increased as liver stores decreased. Thirteen to 23% of DR dose was secreted into milk, consistent with VA-replete sows. Milk DR concentrations were greater during lactation 3 than 2. Peak concentration occurred earlier and the half-life was shorter for milk DR in the more VA-depleted sows. The milk and serum DR:R were correlated from 3 to 9 h (r = 0.70; P < 0.0001) and increased as VA stores decreased regardless of serum R concentration. Milk DR:R may replace serum measurements during lactation. [ABSTRACT FROM AUTHOR]

3, 4-Didehydroretinol (DR) metabolism was previously followed in vitamin A (VA)-replete lactating sows. This study followed DR appearance and clearance after dosage in serum and milk during 2 lactation cycles in sows (n = 8) fed VA-free feed for 3 gestation-lactation cycles. During lactations 2 and 3, 35 μmol 3, 4-didehydroretinyl acetate was given orally after overnight food deprivation. Blood and milk were collected at 0, 1.5, 3, 5, 7, 9, 16, 24, 36, 48, 60, and 72 h; livers were obtained at kill. Samples were analyzed for DR, retinol (RI, and 3, 4-didehydroretinyl esters. During lactations 2 and 3, the 5-h s'rum DR:R ratios were 0.028 ± 0.017 and 0.069 ± 0.042, respectively, and serum R concentrations were 0.75 ± 0.23 and q.86 ± 0.37 μmol/L, respectively. The DR:R ratio and serum R were 0.018 ± 0.013 and 0.94 ± 0.12 μmol/L, respectively, in VA-replete sows from the same herd. After lactation 3, liver VA was 0.23 ± 0.05 μmol/g, indicating low- normal VA status. Serum DR area-under-the curve from 0 to 48 h increased as liver stores decreased. Thirteen to 23% of DR dose was secreted into milk, consistent with VA-replete sows. Milk DR concentrations were greater during lactation 3 than. Peak concentration occurred earlier and the half-life was shorter for milk DR in the more VA-depleted sows. The < milk and serum DR:R were correlated from 3 to 9 h )r= 0.70; P < 0.0001) and increased as VA stores decreased regardless of serum R concentration. Milk DR:R may replace serum measurements during lactation. [ABSTRACT FROM AUTHOR]

Objectives: Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) have a higher predisposition to select for VISA with thickened cell walls upon vancomycin exposure, but the pharmacodynamic relationship of this occurrence with clinical doses is unknown. This study investigates the impact of clinical vancomycin dose simulations on cell wall thickness (CWT) and the emergence of resistance in hVISA in an in vitro pharmacodynamic model. [ABSTRACT FROM PUBLISHER]

Purpose: Testosterone administration can lead to increased antipyrine clearance in humans. Medical or surgical castration is a standard treatment of progressive prostate carcinoma, but the effect of the subsequent fall of testosterone concentrations upon drug metabolism has not been reported.Methods: Eleven men with a biopsy-proven diagnosis of progressive prostate cancer were enrolled after providing informed consent. CYP3A4 activity was determined using the erythromycin breath test (EBT) in each patient prior to their beginning with an LHRH-agonist (leuprolide or goserelin). No patients had elected to undergo orchiectomy during the period of subject accrual. Each subject underwent a second EBT 2 months after beginning LHRH suppression. Blood samples were collected at these time points to determine changes in testosterone and leutinizing hormone.Results: All subjects had a predictable drop in serum testosterone concentrations over the 8-week course of the study, but concentrations in three did not fall below castrate levels (<50 ng/dl). There was no statistically significant change in CYP3A4 activity using the EBT method (p = 0.88). The extent and direction of changes in CYP3A4 activity was highly variable, with three subjects experiencing an increase in activity, and five demonstrating a decrease in activity.Conclusion: There is no clinically significant change in CYP3A4 activity after medical castration. No changes in the clearance of docetaxel or other CYP3A4 substrates are likely during and after medical castration. Although similar findings are expected after orchiectomy, we were not able to test this presumption because of patient preference for medical castration. [ABSTRACT FROM AUTHOR]

Testosterone administration can lead to increased antipyrine clearance in humans. Medical or surgical castration is a standard treatment of progressive prostate carcinoma, but the effect of the subsequent fall of testosterone concentrations upon drug metabolism has not been reported. Eleven men with a biopsy-proven diagnosis of progressive prostate cancer were enrolled after providing informed consent. CYP3A4 activity was determined using the erythromycin breath test (EBT) in each patient prior to their beginning with an LHRH-agonist (leuprolide or goserelin). No patients had elected to undergo orchiectomy during the period of subject accrual. Each subject underwent a second EBT 2 months after beginning LHRH suppression. Blood samples were collected at these time points to determine changes in testosterone and leutinizing hormone. All subjects had a predictable drop in serum testosterone concentrations over the 8-week course of the study, but concentrations in three did not fall below castrate levels (<50 ng/dl). There was no statistically significant change in CYP3A4 activity using the EBT method ( p = 0.88). The extent and direction of changes in CYP3A4 activity was highly variable, with three subjects experiencing an increase in activity, and five demonstrating a decrease in activity. There is no clinically significant change in CYP3A4 activity after medical castration. No changes in the clearance of docetaxel or other CYP3A4 substrates are likely during and after medical castration. Although similar findings are expected after orchiectomy, we were not able to test this presumption because of patient preference for medical castration. [ABSTRACT FROM AUTHOR]