Clinical therapeutics最新文献

Purpose: This systematic review was conducted to determine which type of oral medication for obesity provides the best weight loss effect.

Methods: This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guideline. For this systematic review, we used 3 databases for journal searches: PubMed, ScienceDirect, and Scopus. This study only included randomized controlled trials or open-label clinical trials. There was no year limit used in the journal search for this systematic review.

Findings: Eighteen randomized controlled trials, with a total population of 12,259 patients, were included. Of 18 studies, 15 were used for network meta-analysis. Based on the results of the network meta-analysis, weight loss was found in phentermine/topiramate (mean difference [MD], -3.28; 95% CI, -4.47 to -2.09), semaglutide (MD, -2.92; 95% CI, -4.38 to -1.46), phentermine (MD, -2.31; 95% CI, -3.82 to -0.81), naltrexone/bupropion (MD, -1.68; 95% CI, -2.87 to -0.49), topiramate (MD, -1.67; 95% CI, -2.86 to -0.48), and orlistat (MD, -1.44; 95% CI, -2.32 to -0.55). There were no significant differences among the groups. However, compared with placebo, all oral obesity therapies provide better benefits in weight loss (MD, -2.12; 95% CI, -2.64 to -1.59; P ≤ 0.00001).

Implications: Oral antiobesity drugs provide better weight loss than placebo. However, some side effects can be incurred by utilizing the drug for weight loss, especially related to the gastrointestinal system. Nonetheless, in clinical settings, consideration should be given to particular patients to reduce risk of side effects.

Purpose: Posaconazole is a broad-spectrum antifungal for treating and preventing invasive fungal infections (IFIs) in immunocompromised individuals, including children as young as 2 years. Available in delayed-release (DR) oral suspension, intravenous formulation, and older immediate-release (IR) formulation (off-label in younger children), dosing harmonization across age groups and formulations remains inconsistent. This inconsistency arises from the unique physiology of young children and posaconazole's pH-dependent absorption. Limited pharmacokinetic (PK) data for children under 2 years complicates dosing, as absorption, distribution, metabolism, and excretion processes are underdeveloped and age-dependent. This work aims to harmonize pediatric dosing for children aged 2 to 7 years and extend dosing guidance for those aged 6 months to 2 years using physiologically-based PK (PBPK) modeling.

Methods: An adult PBPK model was created using posaconazole's physicochemical properties and ADME characteristics with virtual populations from PK-Sim. Calibrated with single-dose data from healthy subjects, the model was verified by predicting PK following multiple doses in adults at risk for IFIs. The model was then scaled to children, accounting for developmental anatomy and physiology, including UGT1A4 ontogeny. The pediatric model was evaluated against observed data from children aged 2 to 7 years. Simulations were conducted to harmonize dosing across formulations and extend dosing to children as young as 6 months, acknowledging standard plasma concentration targets for treatment of IFIs (1000 ng/mL) as well as prophylaxis (700 ng/mL).

Findings: The pediatric model adequately captured observed PK data from literature following all three formulations. The IR oral suspension is impractical and likely subtherapeutic for most children under 7 years due to solubility limits. Intravenous doses of 11-13 mg/kg once daily (QD) may be optimal for treatment, and 8 to 9 mg/kg QD for prophylaxis, varying by age. Oral DR suspension doses of 12 to 14 mg/kg QD for treatment and 8.5 to 10 mg/kg QD for prophylaxis may be optimal, also age-dependent. Dividing the total daily dose by a factor of 0.7 and administering twice daily can achieve similar trough levels.

Implications: PBPK modeling for posaconazole bridges the gap between PK principles and clinical practice, potentially improving therapeutic outcomes and minimizing risks associated with inadequate dosing in pediatric patients.

Purpose: Injectable once weekly semaglutide for diabetes (OW sema) is a medication approved in 2017 for the treatment of patients with type 2 diabetes (T2DM). In clinical trials, OW sema has been shown to be effective at helping patients achieve glycemic targets. However, more data are needed to understand how patients who initiate treatment with OW sema are treated in the real world and to aid prescribers in making treatment decisions. This study characterized noninsulin antidiabetic medication use patterns among US patients with T2DM initiating treatment with OW sema.

Methods: In this retrospective, claims-based study, patients (15,588) were included if they had at least 1 claim for OW sema between January 1, 2018 and December 31, 2019, were at least 18 years old, were continuously enrolled in the health plan, and had at least 1 claim indicating a diagnosis of T2DM. All patients had at least 1 line of therapy (LOT) that started on the date of the first fill for OW sema. Data related to pre-index date demographics and clinical characteristics were collected, as were data on patient regimens and LOTs. The length of the LOT was calculated, and the top 10 noninsulin treatment regimens were reported in each LOT.

Findings: In the first LOT, OW sema monotherapy was the most common regimen. More than one third (36.5%) of patients had 1 LOT until the end of follow-up and most patients who had a second (52.1%) or third (72.0%) LOT continued it to the end of the study. Among the top 10 regimens, 42.2% of patients with a second LOT and 45.8% of patients with a third LOT had an LOT that included OW sema.

Implications: This study describes medication regimens within the first year of OW sema use. Among patients initiating OW sema, monotherapy was the most common regimen. These results provide insight into real-world usage patterns of this medication.

Purpose: Rett syndrome (RTT) is a rare neurodevelopmental disorder that mainly affects girls and women. Trofinetide is approved for the treatment of RTT in adults and children aged ≥2 years. To gain insight into experiences with RTT and effects of trofinetide treatment at different stages of RTT, interviews with caregivers of individuals with RTT were conducted upon their exit from the open-label trofinetide trials.

Methods: Interviews were conducted with caregivers of participants in the LILAC/LILAC-2 open-label extension trials of the phase 3 LAVENDER trial in participants aged 5 to 20 years, and in DAFFODIL, an open-label trial in participants aged 2 to 4 years. Caregivers were asked about the RTT effects, experiences with trofinetide, meaningfulness of treatment effects, and satisfaction. Qualitative thematic analysis was performed.

Findings: Caregivers of 33 participants from the open-label trials were interviewed, including 26 from LILAC/LILAC-2 (mean age, 12.3 years) and 7 from DAFFODIL (mean age, 4.5 years). The most commonly reported effects of RTT in LILAC/LILAC-2 were no verbal communication (24/26 [92.3%]), unable to use hands (15/26 [57.7%]), repetitive hand movements (15/26 [57.7%]), unable to walk (15/26 [57.7%]), and seizures (14/26 [53.8%]). In DAFFODIL, the most commonly reported effects of RTT were no verbal communication (7/7 [100%]), impaired balance (4/7 [57.1%]), unable to use hands (3/7 [42.9%]), repetitive hand movements (3/7 [42.9%]), mood disturbance (3/7 [42.9%]), constipation (3/7 [42.9%]), and limited ability to use hands (3/7 [42.9%]). Caregivers most commonly reported improvements in hand use (11/26 [42.3%]), engagement with others (11/26 [42.3%]), eye gaze (8/26 [30.8%]), use of the Tobii eye tracking device (7/26 [26.9%]), and attention/focus/concentration (7/26 [26.9%]) in LILAC/LILAC-2. In DAFFODIL, caregivers reported improvements in new words (5/7 [71.4%]), hand use (4/7 [57.1%]), and eye contact (4/7 [57.1%]). Nearly all (31/32) caregivers were very satisfied or satisfied with trofinetide.

Implications: Caregivers of participants in open-label trofinetide trials reported improvements in RTT with meaningful impact in areas of motor function, communication, and engagement.

Purpose: The aim of this study was to propose a lateral oscillating device for the prevention of pressure ulcers by understanding the mechanisms of tissue protection in healthy individuals during prolonged decubitus. We also sought to determine the optimal time interval for oscillation, considering peak pressure peaks and tolerable pressure limits as a function of individual characteristics such as age, weight, height, gender, and BMI.

Methods: A quasi-experimental, descriptive and analytical observational study was conducted between January 2022 and June 2023 with a sample of 25 healthy volunteers. Sacral, heel and trochanter pressure measurements were performed using sensors. Descriptive and bivariate statistical analyses were applied, and a linear regression model was used to analyze the relationship between independent variables and peak pressures recorded.

Findings: Peak pressure at the trochanter was significantly associated with age, weight and gender, while pressure at the sacrum showed a relationship only with gender. No significant associations were found for other variables. The 80th percentile was used to determine the maximum tolerable pressure, and the independent variables collectively explained 60% of the variance in maximum trochanter pressure (R² = 0.60; p = 0.0006). These findings helped to establish optimal time intervals for lateral oscillation, tailored to individual variability.

Implications: The designed lateral oscillating device proved to be effective in promoting tissue perfusion and reducing pressure build-up, thus contributing to pressure ulcer prevention. This personalized approach could significantly improve the care of immobilized patients in clinical settings.

Purpose: Major depressive disorder with acute suicidal ideation or behavior (MDSI) is a substantial humanistic, economic, and clinical burden on patients. Data on health care resource use (HRU) and costs among patients with MDSI initiated on esketamine nasal spray relative to traditional treatments are limited. This study sought to describe HRU and medical costs of patients with MDSI initiated on esketamine, electroconvulsive therapy (ECT), antidepressant with second-generation antipsychotic (SGA) augmentation, and antidepressant monotherapy in the United States.

Methods: Adults with MDSI from Merative® MarketScan® Commercial Databases (January 2016 to January 2022) were categorized into esketamine, ECT, SGA augmentation, and antidepressant monotherapy cohorts based on treatments initiated on or after August 5, 2020 (index date). Baseline period spanned 12 months before index date; follow-up period spanned from the index date till the end of data/health plan eligibility. Acute care HRU (inpatient and emergency department days) and medical costs excluding index treatment costs were described per-patient-per-month among all cohorts.

Findings: The number of patients in the respective cohorts was 122 for esketamine, 336 for ECT, 9958 for SGA augmentation, and 4496 for antidepressant monotherapy. Across cohorts, mean patient age ranged from 29.1 to 41.2 years, and the majority of patients were female (range, 57.2%-65.6%). During the follow-up period, mean all-cause acute care HRU was 0.59 days in the esketamine cohort, which trended lower than in the ECT (3.17 days) and SGA augmentation (0.92 days) cohorts, and higher than in the antidepressant monotherapy cohort (0.32 days). Mean acute care HRU decreased from baseline in the esketamine, SGA augmentation, and antidepressant monotherapy cohorts by 58%, 21%, and 37% and increased in the ECT cohort by 44%. Mean follow-up medical costs per-patient-per-month were $1869 in the esketamine cohort, which trended lower than in the ECT ($4624) and SGA augmentation ($2163) cohorts, and higher than in the antidepressant monotherapy ($863) cohort. Relative to baseline, medical costs decreased in all cohorts (esketamine, 50%; ECT, 22%; SGA augmentation, 17%; antidepressant monotherapy, 32%).

Implications: Acute care HRU and medical costs trended lower among patients with MDSI initiated on esketamine nasal spray versus ECT or SGA augmentation; HRU and costs reduced most from pretreatment levels among patients treated with esketamine nasal spray versus patients treated with ECT, SGA augmentation, and antidepressant monotherapy. Results of this study may aid physicians in determining optimal treatments for the vulnerable MDSI population.

Anti-interleukin-5 (IL-5), anti-IL-5 receptor and anti-interleukin-4 (IL-4) have emerged as potential treatments for severe eosinophilic asthma, yet their role in treating chronic obstructive pulmonary disease (COPD) is unclear. A literature review was conducted up to May 31, 2024. Only randomized controlled trials (RCTs) assessing the clinical efficacy and adverse effects of biological treatment (anti-IL-5/ anti-IL-5 receptor /anti-IL-4) in COPD patients were included in this meta-analysis. Primary outcomes focused on COPD exacerbation risk, with secondary outcomes examining lung function, quality of life, and adverse events. Four articles comprising 6 RCTs were analyzed. Among 2837 patients receiving anti-IL-5/anti-IL-5 receptor therapies, 468 receiving anti-IL-4 therapies, and 1913 receiving placebo. Overall, biological treatment therapies collectively demonstrated a reduced risk of COPD exacerbation compared to placebo (rate ratio, 0.88; 95% CI, 0.80-0.97, I² = 53%). Specifically, dupilumab statistically significant reduction in exacerbation risk (rate ratio 0.70, 95% CI 0.58-0.84). Benralizumab showed a borderline reduction in exacerbation risk (rate ratio, 0.92; 95% CI, 0.85-1.00, I² = 0%, while Mepolizumab exhibited a trend towards lower exacerbation risk that did not reach statistical significance (rate ratio 0.90, 95% CI 0.77-1.06, I² = 62%). Subgroup analysis showed that patients with COPD and eosinophils ≥300 per cubic millimeter who received biological treatment may experience a reduced risk of acute exacerbation. Changes in lung function from baseline did not significantly differ between biological therapies and placebo. Analysis of St. George's Respiratory Questionnaire (SGRQ) scores indicated significant improvements with biological therapies compared to placebo (mean difference -1.30, 95% CI -2.46 to -0.14, I² = 28%). Biological therapies showed comparable risks of adverse events compared to placebo. This meta-analysis suggests that biological therapies may reduce the risk of acute exacerbations and improve quality of life in COPD patients compared to placebo. However, these therapies did not demonstrate significant improvements in pulmonary function. Future studies are needed to delineate the role of these biologic therapies in managing COPD exacerbations.

Purpose: Mesalazine and thiopurines are important therapeutic agents for pediatric patients with ulcerative colitis (UC). Mesalazine, which may be administered in different forms depending on delivery mechanisms, can affect thiopurine metabolism, leading to increased 6-thioguanine nucleotides (6-TGN) levels. Therefore, when using these two drugs simultaneously, their interactions must be considered. This study aimed to analyze 6-TGN according to mesalazine formulation in pediatric patients with UC.

Methods: We retrospectively reviewed the data of 236 pediatric patients with UC who visited a single health center between January 2021 and December 2023. Among the enrolled patients, 198 were administered thiopurines, and of these, 136 underwent testing for 6-TGN.

Findings: The mean dose of azathioprine (AZA) was 0.66 mg/kg, and the mean 6-TGN level was 211.64 pmol/8 × 10^8 red blood cells (RBCs). The mean 6-TGN level for the group concurrently using time-dependent mesalazine and AZA was 245.00 pmol/8 × 10^8 RBCs, while that for the group concurrently using multimatrix mesalazine (MMX) and AZA was 141.97 pmol/8 × 10^8 RBCs (P < 0.001). In the same patients, the mean 6-TGN level during time-dependent mesalazine treatment was 290.34 pmol/8 × 108 RBCs, whereas the mean 6-TGN level measured after switching to MMX was 148.54 pmol/8 × 108 RBCs (P = 0.016).

Implications: The group treated with MMX and AZA had a lower mean 6-TGN level than the group treated with time-dependent mesalazine and AZA. The mean 6-TGN level significantly decreased after switching from time-dependent mesalazine to MMX in the same patients. Therefore, when administering MMX, a higher dose of AZA is necessary to reach the target 6-TGN level, compared to the dose required when using time-dependent mesalazine.

Purpose: Dexmedetomidine is a sedative-analgesic that is widely used in sepsis. However, its effect on septic shock remains unclear. This study aimed to investigate dexmedetomidine's effect on inflammatory biomarkers in septic shock.

Methods: The present study was a randomized controlled clinical trial. Patients with inclusion criteria were randomly allocated into either the dexmedetomidine (n = 24) or morphine + midazolam group (n = 24). The primary outcome was changes in inflammatory factors, including IL-1, IL-6, TNF-α, ESR, and CRP. The serum levels of inflammatory factors were measured at baseline and the end of the intervention. Secondary outcomes included the change in norepinephrine dose, vital signs, and SOFA scores.

Findings: Of the 48 subjects, 52.08% were male. After intervention, IL-1, IL-6, and TNF-α levels significantly differed between the 2 groups (p = 0.011 and p < 0.001 and p < 0.001, respectively). Heart rate and systolic blood pressure decreased over time, but the two groups had no significant difference (p-value > 0.05). In addition, there was no significant difference in norepinephrine dose and SOFA score between the 2 groups (p-value > 0.05).

Implications: Sedation with dexmedetomidine can attenuate the inflammatory factors in septic shock. Also, dexmedetomidine did not worsen the hemodynamic parameters in septic shock patients.