Background: In the United States, standard enoxaparin treatment dosing in pregnant patients is 1 mg/kg subcutaneously twice daily. For nonpregnant patients with obesity (body mass index (BMI) ≥30 kg/m 2 ), literature supports empiric dose reductions to 0.8 mg/kg subcutaneously twice daily. Objective: To investigate whether pregnant patients with obesity require empiric enoxaparin treatment dose adjustments compared to pregnant patients without obesity. Methods: This retrospective chart review included pregnant adults who received therapeutic enoxaparin and had appropriately timed low-molecular-weight heparin (LMWH) anti-factor Xa levels. The primary endpoint compared initial LMWH anti-factor Xa levels between patients with and without obesity. Secondary endpoints included the frequency and extent of enoxaparin dose adjustments by BMI, among those with nontherapeutic initial levels. Safety was assessed by number and severity of bleeding events. Statistical analyses included the Kruskal-Wallis test, Student’s T-test, and one-way ANOVA. Results: Of 121 patients identified, 74 met inclusion criteria. Participants were classified as nonobese (n = 33) or obese (n = 41). Initial LMWH anti-factor Xa levels differed significantly between groups ( P = 0.045). The mean BMI of patients with a subtherapeutic initial level (29.02 kg/m 2 ) differed significantly from those with a supratherapeutic initial level (35.8 kg/m 2 ) ( P = 0.030). No significant difference was found in adjusted enoxaparin dose between participants with and without obesity, but a significant difference existed between subtherapeutic and supratherapeutic groups ( P < 0.001). Each group had 1 clinically relevant nonmajor bleed. Limitations included single-center design and small sample size. Conclusions and Relevance: Pregnant patients with obesity receiving treatment enoxaparin are likely to achieve target LMWH anti-factor Xa levels without initial dose adjustments. Morbidly obese patients, however, may still risk supratherapeutic levels. Pregnant patients without obesity were prone to subtherapeutic LMWH anti-factor Xa levels necessitating enoxaparin dose adjustments. Routine LMWH anti-factor Xa monitoring may be beneficial for obstetric patients receiving therapeutic enoxaparin, regardless of BMI.

Background: Although the SCCM PADIS guidelines suggest fentanyl or hydromorphone infusions for analgesia during mechanical ventilation (MV), few studies compare patient-centered outcomes. Objective: This study evaluated therapeutic outcomes and adverse effects of fentanyl and hydromorphone in MV intensive care unit patients. Methods: This single-center, retrospective cohort study evaluated adult MV patients who were intubated for 1 to 14 days and received either hydromorphone or fentanyl infusion for analgesia, while targeting light sedation. The primary endpoint was 28-day MV-free survival. Select secondary endpoints included cumulative and hourly opioid doses during MV, duration of MV, and time within goal pain and sedation score ranges during MV. Multivariate regression analysis was performed for patients intubated more than 72 hours. Results: A total of 238 patients were included; 144 received fentanyl and 94 received hydromorphone. Baseline characteristics were similar between groups with a median age of 66 years, weight 78 kg, and 33% female. Median 28-day MV-free survival was 22 and 21 days for the fentanyl and hydromorphone groups, respectively ( P = 0.36). Patients given fentanyl received higher cumulative opioid doses, expressed in fentanyl equivalents, during MV compared to hydromorphone-treated patients, 4241 (interquartile range [IQR] 1817-8146) mcg and 2448 (IQR 1012-4926) mcg ( P < 0.001), respectively, and higher hourly average doses, 55 (IQR 39-75) mcg/h and 37 (IQR 29-51) mcg/h ( P < 0.001), respectively. Conclusion and Relevance: There was no difference in 28-day MV-free survival with fentanyl- and hydromorphone-based analgesia, but hydromorphone was associated with lower cumulative and hourly opioid requirements.

This article assesses the efficacy, safety, pharmacology, and clinical applications of topical sirolimus 0.2% gel for the treatment of tuberous sclerosis complex (TSC)-associated facial angiofibromas. A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor, and tuberous sclerosis. Articles written in English and relevant to the topic were included. In the phase 2 trial, the mean improvement factor, a composite measure of improved tumor size and redness, was achieved in all patient groups (P < 0.001) with significant responses among the adult and pediatric subgroups at week 12. There were no serious adverse events recorded. In the phase 3 trial, 60% of participants responded to treatment in the sirolimus group compared with 0% in the placebo group with different response rates between the adult and pediatric subgroups at week 12. Sirolimus gel had no serious adverse events, and dry skin was the most common adverse reaction. Patients who had completed the 12-week trials were then enrolled in a long-term trial; angiofibromas had response rates of 78.2% to 0.2% sirolimus gel. Topical sirolimus 0.2% is a first-in-class, newly Food and Drug Administration (FDA)-approved, mammalian target of rapamycin (mTOR) inhibitor that is a promising and safe, noninvasive alternative to surgical procedures for TSC-associated angiofibromas. Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile.

Over the past 2 years of the several strategies recommended to help fight COVID-19, nirmatrelvir/ritonavir is a novel drug shown in the EPIC-HR phase 2 to 3 clinical trial to lower COVID-19-related death or hospitalization at day 28 when compared with placebo. Our study's aim was to explore the reported adverse events (AEs) associated with nirmatrelvir/ritonavir use for COVID-19. We conducted a retrospective analysis using the FDA Adverse Event Reporting System (FAERS) database for AEs, listing nirmatrelvir/ritonavir as the primary drug between January and June 2022. The primary outcome was the incidence of reported AEs associated with nirmatrelvir/ritonavir. The OpenFDA database was queried using Python 3.10 to collect the AEs and Stata 17 was used to analyze the database. Adverse events were analyzed by associated medication, with "Covid-19" excluded. A total of 8098 reports were identified between January and June 2022. Most reported complaints in the AE system were COVID-19 and disease recurrence. The most common symptomatic AEs were dysgeusia, diarrhea, cough, fatigue, and headache. Event rates significantly rose between April and May. Disease recurrence and dysgeusia were the most commonly reported complaints for the top 8 concomitant drugs identified. Cardiac arrest, tremor, akathisia, and death were reported in 1, 3, 67, and 5 cases, respectively. This is the first retrospective study done on reported AEs associated with nirmatrelvir/ritonavir use for COVID-19. COVID-19 and disease recurrence were the most reported AEs. Further monitoring of the FAERS database is warranted to periodically reassess the safety profile of this medication.

The optimal dosing for enoxaparin venous thromboembolism (VTE) prophylaxis in low-weight trauma patients is unknown. Estimated blood volume (EBV) has shown promise as a dose modifier. To characterize the association of enoxaparin dose per EBV with the prevalence of VTE and bleeding in low-weight trauma patients. This was a retrospective study of trauma patients admitted over a 4-year period. Included patients were adults weighing <60 kg who received a minimum of 3 consecutive doses of enoxaparin. The primary endpoint was a comparison of enoxaparin dose per EBV in patients experiencing bleeding and VTE. Secondary endpoints included comparisons of dose per body mass index (BMI) and total body weight (TBW) and the ability of dose per EBV to predict clinical endpoints. Subgroup analyses for patients weighing <50 kg were performed for all endpoints. A total of 189 patients were included. Statistical comparisons for VTE were not performed because of low prevalence. The dose of enoxaparin per EBV was not statistically different between patients who did and did not bleed in all analyses. Doses per BMI and TBW were also not statistically different between the groups. In patients weighing <50 kg, numerically higher doses per EBV, BMI, and TBW were noted in patients that bled versus those that did not. Enoxaparin dose per EBV was not a statistically significant predictor of bleeding in logistic regression models. No significant associations between enoxaparin dose per EBV, BMI, or TBW and bleeding were noted in the study. Future analyses of EBV and other dose modifiers should consider inclusion of patients weighing <50 kg.

The objective of this study was to review the available literature for dexmedetomidine sublingual film use in the treatment of acute agitation associated with schizophrenia and bipolar disorders. A literature search of PubMed (January 2017-March 2023) and EMBASE (January 2017-March 2023) was performed using the terms: Igalmi, dexmedetomidine, schizophrenia, bipolar disorder, and agitation. Additional information sources include ClinicalTrials.gov, scientific posters, and articles identified through review of references from clinical trials publications. Relevant English-language articles conducted in humans were considered, with a preference for phase 3 clinical trials. Trial analyses and articles discussing pharmacology, pharmacokinetics, efficacy, and safety were also evaluated. Dexmedetomidine sublingual film was evaluated for use in schizophrenia in the SERENITY 1 pivotal trial and for bipolar disorders in the SERENITY 2 pivotal trial. Both studies found treatment of mild to moderate agitation with dexmedetomidine sublingual film 180 and 120 μg to be superior to placebo in reducing the severity of agitation. Treatment effect was seen as early as 20 minutes. Somnolence was the most common adverse effect in both studies. Cardiovascular adverse effects were mild and transient in most cases. Dexmedetomidine sublingual film is a new and novel treatment for agitation and gives clinicians an alternative to antipsychotic and benzodiazepine use. It has advantageous properties including its noninvasive route of administration, fast absorption, and rapid onset of effect. Cost may limit its use. Dexmedetomidine sublingual film provides an alternative approach to treatment of acute agitation in adults with schizophrenia and bipolar disorders based on both mechanism of action and route of administration.

To review pharmacology, efficacy, safety, and considerations for use, of second-generation androgen receptor (AR) antagonists in treatment of nonmetastatic castrate-resistant prostate cancer (M0CRPC). Conducted search in PubMed and Google scholar (January, 1, 2002-December 31, 2022), using relevant terms. Relevant English-language studies, conducted in humans evaluating second-generation AR antagonists for M0CRPC, and additional articles and package inserts were considered. Apalutamide, darolutamide, and enzalutamide are effective in delaying the time to development of metastatic prostate cancer in men with M0CRPC with a rapid prostate-specific antigen (PSA) doubling time (<10 months). No head-to-head, randomized, clinical trials have been conducted. The most common adverse effects include fatigue and hypertension, and quality of life is maintained in most patients. Cost is similar among the agents (~$15,000/month). Drug-drug interactions vary among these agents and should be considered, when selecting therapy as well as likely adherence. Darolutamide is administered twice daily with the others once daily. Second-generation AR antagonists are effective in reducing time to development of metastatic disease and prolonging overall survival in patients with M0CRPC and a PSA doubling time of <10 months. Recent imaging advances may alter how we evaluate outcomes. Second-generation AR antagonists improve disease control and overall survival. Generally, they are well tolerated and QOL is maintained. Selection of the best agent is based on the adverse effect profile, potential for drug- and disease-interactions, administration, cost, and patient preference.

Increased analgosedation requirements have been described in patients with acute respiratory distress syndrome (ARDS) on extracorporeal membrane oxygenation (ECMO) support due to unique pharmacokinetic challenges. There is a paucity of data comparing sedation requirements in patients on ECMO for ARDS secondary to SARS-CoV-2 versus other etiologies of respiratory failure. To compare sedation and analgesia requirements in adult patients with SARS-CoV-2 versus non-SARS-CoV-2 ARDS requiring veno-venous (VV) ECMO support. We performed a retrospective cohort study of adult patients receiving sedation and analgesia on VV-ECMO support. Patients were excluded if cannulated at an outside hospital for greater than 24 hours, expired within 48 hours of ECMO cannulation, or received neuromuscular blocking agents for greater than 7 consecutive days following ECMO cannulation. We evaluated 108 patients on VV-ECMO support, including 44 with non-SARS-CoV-2 ARDS and 64 with SARS-CoV-2 ARDS. The median daily dexmedetomidine requirements were significantly higher in the SARS-CoV-2 cohort (16.7 vs 13.4 mcg/kg/day, P = 0.03), while the median propofol daily requirements were significantly higher in the non-SARS-CoV-2 cohort (40.3 vs 53.5 mg/kg/day, P < 0.01). There was no difference in daily requirements of opioids, benzodiazepines, and ketamine between groups. Use of adjunct agents to facilitate weaning was significantly higher in the SARS-CoV-2 cohort (78.1% vs 43.2%, P < 0.01). Patients with ARDS on VV-ECMO support require multiple analgosedative agents with concomitant use of nonparenteral adjunct agents. Further studies are needed to evaluate optimal analgosedation strategies in patients on ECMO support.

The combinations of BRAF + MEK inhibitors-encorafenib (ENC) + binimetinib (BIN), cobimetinib (COB) + vemurafenib (VEM), and dabrafenib (DAB) + trametinib (TRA)-are recommended for the treatment of BRAF-mutated advanced melanoma. To assess the cost-effectiveness and cost-utility of ENC + BIN versus COB + VEM versus DAB + TRA from a US payer perspective. A Markov model was constructed to simulate a hypothetical cohort over a time horizon of 10 years. The overall survival (OS) and progression-free survival (PFS) curves were independently digitized from a randomized controlled trial for ENC + BIN and fitted using R software. Published and indirectly estimated hazard ratios were used to fit OS and PFS curves for COB + VEM and DAB + TRA. Costs, life-year gains, and quality-adjusted life years (QALYs) associated with the 3 treatment combinations were estimated. A base case analysis and probabilistic sensitivity analysis (PSA) were conducted to estimate the incremental cost-utility ratio (ICUR). A discount rate of 3.5% was applied on cost and outcomes. The ENC + BIN versus COB + VEM comparison was associated with an ICUR of $656 233 per QALY gained. The ENC + BIN versus DAB + TRA comparison was associated with an ICUR of $3 135 269 per QALY gained. The DAB + TRA combination dominated COB + VEM. The base case analysis estimates were confirmed by the PSA estimates. ENC + BIN was the most cost-effective combination at a high willingness-to-pay (WTP) threshold of $573 000 per QALY and $1.5 million/QALY when compared to COB + VEM and DAB + TRA, respectively. Given current prices and acceptable WTP thresholds, our study suggests that DAB + TRA is the optimum treatment. In this study, ENC + BIN was cost-effective only at a very high WTP per QALY threshold.