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.
•Four trials testing psilocybin for anxiety and depression were meta-analyzed.•Within-group effects were large (Hedges’ gs = 1.16 to 1.47).•Placebo-controlled effects were large (gs = 0.82 to 0.83) ...across three trials.•Potential risk for bias was identified in several domains.
The current meta-analysis examined the effects of psilocybin in combination with behavioral interventions on anxiety and depression in samples with elevated symptoms. Across four studies (one uncontrolled; three randomized, placebo-controlled; N = 117), within-group pre-post and pre-follow-up effects on anxiety and depression were large (Hedges’ gs=1.16 to 1.47) and statistically significant. Across three placebo-controlled studies, pre-post placebo-controlled effects were also large (gs = 0.82 to 0.83) and statistically significant. No serious adverse events were reported. Limitations include the small number of studies and risk for bias within studies. Results tentatively support future research on psilocybin for the treatment of anxiety and depression.
Psilocybin shows promise as a treatment for major depressive disorder (MDD).
To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in ...patients with MDD.
In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing.
Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support.
The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment.
A total of 104 participants (mean SD age, 41.1 11.3 years; 52 50% women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 95% CI, -17.5 to -7.2; P <.001) and from baseline to day 8 (mean difference, -12.0 95% CI, -16.6 to -7.4; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 95% CI, 3.50-1.11; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs.
Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD.
ClinicalTrials.gov Identifier: NCT03866174.
Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of ...psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.
Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods.
No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied.
The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose.
NCT02163707.
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 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.
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