Evaluation of Private Payer and Patient Out-of-Pocket Costs Associated With the Surgical Management of Benign Prostatic Hyperplasia.

OBJECTIVE: To evaluate and compare the financial burden of various surgical interventions for the management of benign prostatic hyperplasia (BPH). METHODS: We identified commercially insured men with a diagnosis of BPH who underwent a procedure of interest (simple prostatectomy (SP), transurethral resection of the prostate (TURP), holmium laser enucleation of the prostate (HoLEP), photovaporization of the prostate (PVP), prostatic urethral lift (PUL), or water vapor thermal therapy (WVTT)) between 2015 and 2021 with the OptumLabs Data Warehouse. Primary outcome was total health care costs (THC) which included both patient out-of-pocket (OOP) and health plan paid costs for the index procedure and combined follow-up years 1-5. A generalized linear model was used to estimate adjusted costs controlling for demographic and clinical characteristics. Patients undergoing WVTT were excluded from extended follow-up analyses due to limited data. RESULTS: Among 25,407 patients with BPH, 10,117 (40%) underwent TURP, 6353 (25%) underwent PUL, 5411 (21%) underwent PVP, 1319 (5%) underwent SP, 1243 (5%) underwent WVTT, and 964 (4%) underwent HoLEP. Index procedure costs varied significantly with WVTT being the least costly [THC: $2637 (95% confidence interval (CI): $2513-$2761)], and SP being the costliest [THC: $14,423 (95% CI: $12,772-$16,075)]. For aggregate index and 5-year follow-up costs, HoLEP ($31,926 [95% CI: $29,704-$34,148]) was the least costly and PUL ($36,596 [95% CI: $35,369-37,823]) was the costliest. CONCLUSION: BPH surgical treatment is associated with significant system-level health care costs. The level of impact varies between procedures. Minimally invasive options, such as WVTT, may offer initial cost reductions; however, HoLEP and SP are associated with lower follow-up costs.

Is Race Associated with the Surgical Treatment for Benign Prostatic Hyperplasia? An Analysis of 30,000 Medicare Lives.

BACKGROUNDS: With an increased prevalence and burden of benign prostatic hyperplasia (BPH), effective and equitable treatment is a priority. Limited data exist evaluating treatment disparities for patients with BPH by race. This study examined the association between race and BPH surgical treatment rates among Medicare beneficiaries. METHODS: Medicare claims data were used to identify men newly diagnosed with BPH from January 1, 2010 through December 31, 2018. Patients were followed until their first BPH surgery, a diagnosis of prostate/bladder cancer, termination of Medicare enrollment, death, or end of study. Cox proportional hazards regression compared the likelihood of BPH surgery between men of different races (White vs. Black, Indigenous, and People of Color (BIPOC)), controlling for patients' geographical region, Charlson comorbidity score, and baseline comorbidities. RESULTS: The study included 31,699 patients (13.7% BIPOC). BIPOC men had significantly lower BPH surgery rates (9.5% BIPOC vs. 13.4% White; p=0.02). BIPOC race was associated with a 19% lower likelihood of receiving BPH surgery than White race (HR, 0.81; 95% CI 0.70, 0.94). Transurethral resection of the prostate was the most common surgery for both groups (49.4% Whites vs. 56.8% BIPOC; p=0.052). A higher proportion of BIPOC men underwent procedures in inpatient settings compared to White men (18.2% vs. 9.8%; p<0.001). CONCLUSIONS: Among a cohort of Medicare beneficiaries with BPH, there were notable treatment disparities by race. BIPOC men had lower rates of surgery than White men and were more likely to undergo procedures in the inpatient setting. Improving patient access to outpatient BPH surgical procedures may help address treatment disparities.

Dilated cardiomyopathy of possible dietary origin in a cat.

An 11-year-old spayed female domestic shorthaired cat was diagnosed with severe dilated cardiomyopathy (DCM) and congestive heart failure. The cat had been eating cat foods that were high in pulses (e.g. peas, lentils, chickpeas). Neither plasma nor whole blood taurine concentrations were deficient. Primary treatment included furosemide, pimobendan, and clopidogrel, and changing to diets that did not contain pulses (a taurine supplements was not administered). The cat's clinical signs improved, high-sensitivity cardiac troponin I concentrations decreased, and echocardiographic measurements stayed relatively stable for over one year after initiating cardiac medications and changing the diet. Ultimately, the cat was euthanized for worsening congestive heart failure 374 days after the diagnosis of DCM. Infectious disease testing during the time of clinical surveillance was negative. Routine histopathology of the heart was unremarkable, but electron microscopy of the left ventricle showed large numbers of mitochondria of variable size and structure. A moderate number of lamellar bodies and autophagic vacuoles also were noted. This case report illustrates an unusual case of a cat with DCM unrelated to taurine deficiency. The relative roles of diet change, cardiac medications, and a dedicated owner are unclear, but this cat's relatively long survival time is similar to that seen after diet change in dogs and cats with DCM eating high-pulse diets.

Developing an Implementation Blueprint for the NIH HEAL Initiative GRACE Trial: Perspectives on Acupuncture and Guided Relaxation for Chronic Sickle Cell Disease Pain.

Objective: This study aimed to explore perspectives of people living with sickle cell disease (SCD) and SCD clinic providers and staff about the use of acupuncture and guided relaxation for treating chronic SCD pain. Data obtained were to inform an implementation blueprint for an effectiveness implementation clinical trial (GRACE Trial) testing whether acupuncture or guided relaxation reduces chronic pain when compared with usual care. Design: Qualitative research design. Methods: We conducted 33 semistructured interviews with people with SCD and SCD clinic providers and staff. Interviews were transcribed and coded. A deductive content analysis process was used to identify themes. Results: Four themes were identified: Receptivity to Acupuncture and Guided Relaxation, Limited Awareness, Complementary and Integrative Health (CIH) Therapy Preference, and Access Barriers. Both patients and clinic providers and staff were open to the use of acupuncture and guided relaxation for chronic pain treatment. After learning about these CIH therapies, some patients expressed a preference for one therapy over the other. They also discussed their ability to successfully engage with each therapy. There is a need to dispel misconceptions about the therapies by increasing understanding of how each therapy is implemented and functions to reduce pain. We identified several potential barriers that might affect the success of the trial and future health system integration, including time, transportation, and technology. Conclusion: This study is one of the first to present perspectives of both patients with SCD and clinic providers and staff on the use of acupuncture and guided relaxation for chronic SCD pain. Stakeholders' early input and perspectives highlighted that they welcome nonpharmacological CIH therapies. Implementation of a clinical trial and future health system integration will require the addressing misinformation and identifying strategies to overcome access barriers. Clinical trial registration number: NCT04906447.

Hybrid effectiveness-implementation trial of guided relaxation and acupuncture for chronic sickle cell disease pain (GRACE): A protocol.

Background: People with sickle cell disease frequently use complementary and integrative therapies to cope with their pain, yet few studies have evaluated their effectiveness. The 3-arm, 3-site pragmatic Hybrid Effectiveness-implementation Trial of Guided Relaxation and Acupuncture for Chronic Sickle Cell Disease Pain (GRACE) has 3 priorities: (1) evaluate guided relaxation and acupuncture to improve pain control; (2) determine the most appropriate and effective treatment sequence for any given patient based on their unique characteristics; and (3) describe the processes and structures required to implement guided relaxation and acupuncture within health care systems. Methods: Participants (N = 366) are being recruited and randomized 1:1:1 to one of 2 intervention groups or usual care. The acupuncture intervention group receives 10 sessions over approximately 5 weeks. The guided relaxation intervention group receives access to video sessions ranging from 2 to 20 min each viewed daily over 5 weeks. The usual care group receives the standard of clinical care for sickle cell disease. Participants are re-randomized at 6 weeks depending on their pain impact score. Assessments occur at 6 weeks, 12 weeks, and 24 weeks. The primary outcome is the change in pain impact score and secondary measures include opioid use, anxiety, depression, sleep, pain catastrophizing, substance use, global impression of change, constipation, and hospitalizations. The GRACE study uses the Consolidated Framework for Implementation Research to plan, execute, and evaluate the associated implementation processes. Conclusion: The results from GRACE will represent a critical step toward improving management of pain affecting patients with sickle cell disease.ClinicalTrials.gov Identifier: NCT04906447.

Evaluation of the Cost-Effectiveness of Surgical Treatment Options for Benign Prostatic Hyperplasia.

OBJECTIVE: To compare the cost-effectiveness of surgical interventions for BPH. METHODS: Using a Markov model, a cost-utility analysis was performed comparing HoLEP, B-TURP, WVTT, and PUL for prostate size <80cc (index patient 1) and HoLEP and SP for prostate size >80cc (index patient 2). Model probabilities and utility values were drawn from the literature. Analysis was performed at a 5-year time horizon with extrapolation to a lifetime horizon. Primary outcomes included quality-adjusted life years (QALYs), 2021 Medicare costs, and incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100,000/QALY. Univariate and probabilistic sensitivity analyses were performed. RESULTS: At 5 years, costs per patient for index patient 1 were $3292 (WVTT), $6532 (HoLEP), $6670 (B-TURP), and $10,257 (PUL). HoLEP resulted in the highest QALYs (4.66), followed by B-TURP (4.60), PUL (4.38), and WVTT (4.38). This translated to HoLEP being most cost-effective (ICER $11,847). For index patient 2, HoLEP was less costly ($6,585 vs $15,404) and more effective (4.654 vs 4.650) relative to SP. On sensitivity analysis for index patient 1, B-TURP became most cost-effective if cost of HoLEP increased two-fold or chronic stress incontinence following HoLEP increased ten-fold. When follow-up time was varied, WVTT was preferred at very short follow up (<1 year), and HoLEP became more strongly preferred with longer follow up. CONCLUSION: At 5 years follow up, HoLEP is a cost-effective surgical treatment for BPH- independent of gland size.

Hepatotoxicity due to herbal dietary supplements: Past, present and the future.

Dietary supplements (DS) constitute a widely used group of products comprising vitamin, mineral, and botanical extract formulations. DS of botanical or herbal origins (HDS) comprise nearly 30% of all DS and are presented on the market either as single plant extracts or multi-extract-containing products. Despite generally safe toxicological profiles of most products currently present on the market, rising cases of liver injury caused by HDS - mostly by multi-ingredient and adulterated products - are of particular concern. Here we discuss the most prominent historical cases of HDS-induced hepatotoxicty - from Ephedra to Hydroxycut and OxyELITE Pro-NF, as well as products with suspected hepatotoxicity that are either currently on or are entering the market. We further provide discussion on overcoming the existing challenges with HDS-linked hepatotoxicity by introduction of advanced in silico, in vitro, in vivo, and microphysiological system approaches to address the matter of safety of those products before they reach the market.

Web-Based Mindfulness-Based Interventions for Well-being: Randomized Comparative Effectiveness Trial.

BACKGROUND: Mindfulness can improve overall well-being by training individuals to focus on the present moment without judging their thoughts. However, it is unknown how much mindfulness practice and training are necessary to improve well-being. OBJECTIVE: The primary aim of this study was to determine whether a standard 8-session web-based mindfulness-based cognitive therapy (MBCT) program, compared with a brief 3-session mindfulness intervention, improved overall participant well-being. In addition, we sought to explore whether the treatment effects differed based on the baseline characteristics of the participants (ie, moderators). METHODS: Participants were recruited from 17 patient-powered research networks, web-based communities of stakeholders interested in a common research area. Participants were randomized to either a standard 8-session MBCT or a brief 3-session mindfulness training intervention accessed on the web. The participants were followed for 12 weeks. The primary outcome of the study was well-being, as measured by the World Health Organization-Five Well-Being Index. We hypothesized that MBCT would be superior to a brief mindfulness training. RESULTS: We randomized 4411 participants, 3873 (87.80%) of whom were White and 3547 (80.41%) of female sex assigned at birth. The mean baseline World Health Organization-Five Well-Being Index score was 50.3 (SD 20.7). The average self-reported well-being in each group increased over the intervention period (baseline to 8 weeks; model-based slope for the MBCT group: 0.78, 95% CI 0.63-0.93, and brief mindfulness group: 0.76, 95% CI 0.60-0.91) as well as the full study period (ie, intervention plus follow-up; baseline to 20 weeks; model-based slope for MBCT group: 0.41, 95% CI 0.34-0.48; and brief mindfulness group: 0.33, 95% CI 0.26-0.40). Changes in self-reported well-being were not significantly different between MBCT and brief mindfulness during the intervention period (model-based difference in slopes: -0.02, 95% CI -0.24 to 0.19; P=.80) or during the intervention period plus 12-week follow-up (-0.08, 95% CI -0.18 to 0.02; P=.10). During the intervention period, younger participants (P=.05) and participants who completed a higher percentage of intervention sessions (P=.005) experienced greater improvements in well-being across both interventions, with effects that were stronger for participants in the MBCT condition. Attrition was high (ie, 2142/4411, 48.56%), which is an important limitation of this study. CONCLUSIONS: Standard MBCT improved well-being but was not superior to a brief mindfulness intervention. This finding suggests that shorter mindfulness programs could yield important benefits across the general population of individuals with various medical conditions. Younger people and participants who completed more intervention sessions reported greater improvements in well-being, an effect that was more pronounced for participants in the MBCT condition. This finding suggests that standard MBCT may be a better choice for younger people as well as treatment-adherent individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03844321; https://clinicaltrials.gov/ct2/show/NCT03844321.

Acupuncture for acute musculoskeletal pain management in the emergency department and continuity clinic: a protocol for an adaptive pragmatic randomised controlled trial.

INTRODUCTION: Chronic musculoskeletal pain causes a significant burden on health and quality of life and may result from inadequate treatment of acute musculoskeletal pain. The emergency department (ED) represents a novel setting in which to test non-pharmacological interventions early in the pain trajectory to prevent the transition from acute to chronic pain. Acupuncture is increasingly recognised as a safe, affordable and effective treatment for pain and anxiety in the clinic setting, but it has yet to be established as a primary treatment option in the ED. METHODS AND ANALYSIS: This pragmatic clinical trial uses a two-stage adaptive randomised design to determine the feasibility, acceptability and effectiveness of acupuncture initiated in the ED and continued in outpatient clinic for treating acute musculoskeletal pain. The objective of the first (treatment selection) stage is to determine the more effective style of ED-based acupuncture, auricular acupuncture or peripheral acupuncture, as compared with no acupuncture. All arms will receive usual care at the discretion of the ED provider blinded to treatment arm. The objective of the second (effectiveness confirmation) stage is to confirm the impact of the selected acupuncture arm on pain reduction. An interim analysis is planned at the end of stage 1 based on probability of being the best treatment, after which adaptations will be considered including dropping the less effective arm, sample size re-estimation and unequal treatment allocation ratio (eg, 1:2) for stage 2. Acupuncture treatments will be delivered by licensed acupuncturists in the ED and twice weekly for 1 month afterward in an outpatient clinic. ETHICS AND DISSEMINATION: This study has been reviewed and approved by the Duke University Health System Institutional Review Board. Informed consent will be obtained from all participants. Results will be disseminated through peer-review publications and public and conference presentations. TRIAL REGISTRATION NUMBER: NCT04290741.

Crop improvement influences on water quantity and quality processes in an agricultural watershed.

Field crop traits have and are experiencing significant changes due to genetic and agronomic improvements. How these changes affect regional water quantity and quality processes has not been clarified. The St. Joseph River Watershed (SJRW) located in the U.S. Corn Belt was selected as a case study area. Crop (corn and soybean) trait improvements in the past decades were reviewed and summarized and include changes of growing degree days (GDD), leaf area index (LAI), light utilization (LU), drought tolerance (DT), nutrient content (NC), and harvest index (HI). Based on a calibrated 9-year (from 2011 to 2019) SWAT (Soil and Water Assessment Tool) simulation in SJRW, sensitivities of the above crop traits to yield, ETa, stream flow, tile flow, surface runoff, and nutrient loads (NO3N, TN, soluble-P, and TP) were analyzed. Crop traits and their corresponding SWAT parameters for the 2010s were obtained from model calibration and used as the baseline/current scenario; for the 1980s, they were summarized from literature review and used as an historical scenario, while those for the 2040s were determined by assuming crop traits are changing linearly with time and projected as the future scenario. Water quantity and quality changes under the historical and future crop scenarios were compared with the baseline/current simulation. Results showed LU and DT were the most sensitive crop traits to water quantity (i.e., ETa, stream flow, tile flow, and surface runoff), while HI was the most sensitive to nutrient loads. The impacts of crop improvements on nutrient loads were more significant than on water budgets. Compared with the baseline, the historical and future scenarios resulted in 1.5 - 2.0% changes of stream flow, 6.8 - 18.6% changes of nitrogen loads (NO3N and TN) and 2.6 - 3.9% changes of phosphorus loads (soluble-P, and TP) in the stream flow, annually. Moreover, in certain months, these changes can reach about 12% for stream flow, 42% for nitrogen loads, and 12% for phosphorus loads. Nitrogen losses by tile drainage and percolation, and phosphorus losses by surface runoff and tile drainage were most significantly affected by the crop improvements. Future work should consider expected crop improvements when studying long-term hydrology and nutrient cycles in agricultural watersheds.

Limitations of bacterial culture, viral PCR, and tulathromycin susceptibility from upper respiratory tract samples in predicting clinical outcome of tulathromycin control or treatment of bovine respiratory disease in high-risk feeder heifers.

A cross-sectional prospective cohort study including 1026 heifers administered tulathromycin due to high risk of clinical signs of bovine respiratory disease (BRD), measured poor association between BRD clinical outcomes and results of bacterial culture and tulathromycin susceptibility from BRD isolates of deep nasopharyngeal swabs (DNS) and adequate association with viral polymerase chain reaction (PCR) results from nasal swabs. Isolation rates from DNS collected on day-0 and at 1st BRD-treatment respectively were: Mannheimia haemolytica (10.9% & 34.1%); Pasteurella multocida (10.4% & 7.4%); Mycoplasma bovis (1.0% & 36.6%); and Histophilus somni (0.7% & 6.3%). Prevalence of BRD viral nucleic acid on nasal swabs collected exclusively at 1st BRD-treatment were: bovine parainfluenza virus type-3 (bPIV-3) 34.1%; bovine viral diarrhea virus (BVDV) 26.3%; bovine herpes virus type-1 (BHV-1) 10.8%; and bovine respiratory syncytial virus (BRSV) 54.1%. Increased relative risk, at 95% confidence intervals, of 1st BRD-treatment failure was associated with positive viral PCR results: BVDV 1.39 (1.17-1.66), bPIV-3 1.26 (1.06-1.51), BHV-1 1.52 (1.25-1.83), and BRSV 1.35 (1.11-1.63) from nasal swabs collected at 1st BRD-treatment and culture of M. haemolytica 1.23 (1.00-1.51) from DNS collected at day-0. However, in this population of high-risk feeder heifers, the predictive values of susceptible and resistant isolates had inadequate association with BRD clinical outcome. These results indicate, that using tulathromycin susceptibility testing of isolates of M. haemolytica or P. multocida from DNS collected on arrival or at 1st BRD-treatment to evaluate tulathromycin clinical efficacy, is unreliable.

HoLEP: the new gold standard for surgical treatment of benign prostatic hyperplasia.

INTRODUCTION Transurethral resection of the prostate (TURP) was considered the "gold standard" surgical treatment for medication-refractory benign prostatic hyperplasia (BPH) for decades. With the desire to reduce hospital stay, complications, and cost, less invasive procedures gained usage in the 1990's. With the advent of a soft tissue morcellator, holmium laser enucleation of the prostate (HoLEP) was introduced as an efficacious alternative to TURP and due to its advantageous side effect profile compared to TURP, has grown in popularity ever since. HoLEP has become a size-independent guideline endorsed procedure of choice for the surgical treatment of BPH. MATERIALS AND METHODS: We provide a review on the evolution of HoLEP as a gold standard compared to the historical reference procedures for BPH, and provide a review of emerging laser technologies. RESULTS: A growing body of literature has shown HoLEP to be a safe and efficient procedure for the treatment of BPH for all prostate sizes. Long term studies have proven the durability of HoLEP, as a first line surgical therapy for BPH. CONCLUSIONS: HoLEP is a proven modality for the surgical treatment of BPH. It can be performed on patients with high risk for postoperative bleeding, or after previous prostate reducing procedures. HoLEP is the only procedure that is AUA guideline-endorsed for all prostate sizes for the surgical treatment of BPH. Given these considerations, HoLEP has become the new gold-standard for the surgical treatment of BPH.

The effects of dry needling on the thumb: A case report.

INTRODUCTION: Dry needling has been identified as a potential intervention for a variety of diagnoses. Limited evidence exists to support the use of dry needling following surgical intervention of a distal radius fracture. This case report demonstrates the impact of dry needling in the thumb following a distal radius fracture. METHODS: The patient was a 31-year-old healthy female who sustained a distal radius fracture and required surgical intervention. The patient required a volar plate removal and extensor tenolysis. The patient attended traditional occupational therapy with one session of dry needling to assist in improving range of motion and decreasing pain. RESULTS: The patient benefited from the use of dry needling. The patient had no pain with functional grasping and pinching following dry needling and improved on the Kapandji score from eight to nine out of ten. The patient also reported a decrease in overall pain, from seven to two on the Numeric Pain Rating Scale. DISCUSSION: The patient benefited from dry needling in the thumb to improve both range of motion and pain symptoms. While the evidence is limited, dry needling may be an appropriate intervention to assist in recovery and reduce thumb pain following distal radius fractures.

Meeting the Patient Care, Education, and Research Missions: Academic Medical Centers Must Comprehensively Address Sexual and Gender Minority Health.

While sociopolitical advances have improved the rights of sexual and gender minorities (i.e., lesbian, gay, bisexual, transgender, queer [LGBTQ+] persons), they continue to face a health system that discriminates against them and does not provide competent, comprehensive care. Despite calls for advancing research, there remains limited sexual and gender minority health research funding, mentorship, and institutional support. Academic medical centers are best suited to systematically tackle disparities and improve care for all sexual and gender minority people through their tripartite missions of patient care, education, and research. In this article, the authors outline discrimination experienced by LGBTQ+ persons and highlight the unique disparities they experience across access and outcomes. The authors posit that by systematically improving clinical care of, incorporating education and training about, and research with LGBTQ+ people into their core missions, academic medical centers can dramatically change the health care landscape. Academic medical centers can eliminate health disparities, expand necessary research endeavors about sexual and gender minorities, and prepare the health care workforce to address the unique needs of these overlooked populations.

Safety and Molecular-Toxicological Implications of Cannabidiol-Rich Cannabis Extract and Methylsulfonylmethane Co-Administration.

Cannabidiol (CBD) is a biologically active, non-psychotropic component of Cannabis sativa whose popularity has grown exponentially in recent years. Besides a wealth of potential health benefits, ingestion of CBD poses risks for a number of side effects, of which hepatotoxicity and CBD/herb-drug interactions are of particular concern. Here, we investigated the interaction potential between the cannabidiol-rich cannabis extract (CRCE) and methylsulfonylmethane (MSM), a popular dietary supplement, in the mouse model. For this purpose, 8-week-old male C57BL6/J mice received MSM-containing water (80 mg/100 mL) ad libitum for 17 days. During the last three days of treatment, mice received three doses of CRCE administered in sesame oil via oral gavage (123 mg/kg/day). Administration of MSM alone did not result in any evidence of liver toxicity and did not induce expression of mouse cytochrome P450 (CYP) enzymes. Administration of CRCE did produce significant (p < 0.05) increases in Cyp1a2, Cyp2b10, Cyp2c29, Cyp3a4, Cyp3a11, Cyp2c65, and Cyp2c66 messenger RNA, however, this effect was not amplified by MSM/CRCE co-treatment. Similarly, no evidence of liver toxicity was observed in MSM/CRCE dosed mice. In conclusion, short-term MSM/CRCE co-administration did not demonstrate any evidence of hepatotoxicity in the mouse model.

Models of care that avoid or improve transitions to hospital services for residential aged care facility residents: An integrative review.

Care transitions for older people moving from residential aged care facilities (RACFs) to hospital services are associated with greater challenges and poorer outcomes. An integrative review was conducted to investigate models of care designed to avoid or improve transitions for older people residing in RACFs to hospital settings. Twenty-one studies were included in the final analysis. Models of care aimed to either improve or avoid transitions of residents through enhanced primary care in RACFs, promoting quality improvement in RACFs, instilling comprehensive hospital care, conducting outreach services, transferring information, or involved a combination of outreach services and comprehensive hospital care. As standalone interventions, standardised communication tools may improve information transfer between RACFs and hospital services. For more complex models, providing quality improvement and outreach to RACFs may prevent some types of hospital admissions.

Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration.

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury-acetaminophen (APAP)-in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury-the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity.

Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model.

The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-week-old male B6C3F1 mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in EPIDIOLEX® (20 mg/kg). In the acute study, significant increases in liver-to-body weight (LBW) ratios, plasma ALT, AST, and total bilirubin were observed for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metabolism pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways associated with lipid and xenobiotic metabolism raises serious concerns about potential drug interactions as well as the safety of CBD.

Decaffeinated Green Tea Extract Does Not Elicit Hepatotoxic Effects and Modulates the Gut Microbiome in Lean B6C3F1 Mice.

The main purpose of this study was to investigate the hepatotoxic potential and effects on the gut microbiome of decaffeinated green tea extract (dGTE) in lean B6C3F1 mice. Gavaging dGTE over a range of 1X-10X mouse equivalent doses (MED) for up to two weeks did not elicit significant histomorphological, physiological, biochemical or molecular alterations in mouse livers. At the same time, administration of dGTE at MED comparable to those consumed by humans resulted in significant modulation of gut microflora, with increases in Akkermansia sp. being most pronounced. Results of this study demonstrate that administration of relevant-to-human-consumption MED of dGTE to non-fasting mice does not lead to hepatotoxicity. Furthermore, dGTE administered to lean mice, caused changes in gut microflora comparable to those observed in obese mice. This study provides further insight into the previously reported weight management properties of dGTE; however, future studies are needed to fully evaluate and understand this effect.