Annals of Pharmacotherapy最新文献

Background: Pharmacotherapy with stimulant or nonstimulant medications is recommended as first-line treatment for attention-deficit/hyperactivity disorder (ADHD). Among patients prescribed stimulants, concomitant opioid use may increase the risk of drug dependence, exacerbate comorbid conditions, and compromise treatment adherence. However, limited evidence exists on the risk factors for initial opioid prescription in this population.

Objective: To identify factors associated with incident opioid prescriptions among patients with ADHD prescribed stimulant therapy.

Methods: We conducted a retrospective cohort study using the Merative® MarketScan® Commercial Claims and Encounters Database (2010-2020). We identified patients with ADHD who initiated stimulant therapy and followed them for 1 year to assess incident opioid prescription. Cox proportional hazards models were used to evaluate factors associated with opioid initiation.

Results: Among 380 494 patients with ADHD initiating stimulants (mean age: 21.2 years; 56.5% male), 14.2% received an opioid prescription within 1 year. Factors significantly associated with incident opioid prescription included age ≥35 years (adjusted hazard ratio [aHR]: 10.84; 95% CI: 10.43-11.26), gender(aHR [female]:1.29; 95% CI: 1.27-1.31), geographic region (aHR [West]: 1.58; 95% CI: 1.52-1.64), multiple chronic conditions (aHR: 1.61; 95% CI: 1.54-1.67), anxiety (aHR: 1.19; 95% CI: 1.17-1.22), depression (aHR: 1.16; 95% CI: 1.14-1.19), severe mental illnesses (aHR: 1.18; 95% CI: 1.13-1.23), substance use disorders (SUDs) (aHR: 1.69; 95% CI: 1.63-1.75). Receipt of behavioral therapy before ADHD pharmacotherapy (aHR: 0.89; 95% CI: 0.87-0.92) was associated with a lower risk of receiving incident opioid prescriptions.

Conclusions and relevance: Several demographic factors (e.g., age, gender, geographic region) and clinical factors (e.g., history of mental health conditions and SUDs) are associated with opioid initiation among stimulant-treated patients with ADHD. These findings may inform clinical strategies to mitigate unnecessary opioid exposure and associated harms.

Background: Supraventricular tachycardia (SVT) accounts for ~50 000 emergency department (ED) visits annually. Adenosine is a commonly used pharmacologic intervention, but predictors of success remain unclear. Erythrocytes rapidly clear adenosine from circulation and whether hematologic variables influence cardioversion outcomes is unknown.

Objective: To evaluate whether hematocrit, hemoglobin or red blood cell (RBC) count, are associated with adenosine efficacy in treating SVT.

Methods: This multicenter retrospective cohort study included adult ED patients treated with adenosine for SVT between January 2021 to August 2024. Logistic regression evaluated the association between hematologic variables and adenosine conversion, adjusting for weight-based dose and total calcium.

Results: Of the 303 encounters representing 256 unique patients, 61% converted after the first adenosine dose and 70% converted overall. Hematologic variables were not associated with first-dose cardioversion. For total conversion, higher hematocrit (per 10%-unit increase) was significantly associated with reduced odds (OR 0.60; 95% CI 0.36-0.99; P = 0.045) of cardioversion, but only in calcium adjusted model. Among patients requiring multiple doses, higher hematocrit (per 10%-unit; OR 0.23; 95% CI 0.09-0.58; P = 0.002), hemoglobin (per 1 g/dL; OR 0.67; 95% CI 0.53-0.85; P < 0.001), and RBC count (per 1 million/µL; OR 0.44; 95% CI 0.21-0.93; P = 0.031) were associated with reduced odds of subsequent cardioversion in calcium adjusted models.

Conclusion and relevance: Hematologic variables were not associated with initial adenosine cardioversion, but in patients requiring additional doses, higher erythrocyte markers were associated with reduced conversion, once accounting for total calcium. This may be due to increased erythrocyte mediated drug clearance. These findings warrant further research to inform clinical relevance.

Background: Ketamine has analgesic and sedative properties that are thought to reduce opioid tolerance and opioid-induced hyperalgesia. For this reason, ketamine may be used to manage pain and agitation, although the literature evaluating its use for this purpose is limited.

Objective: To describe the prescribing practices of ketamine in the medical intensive care unit (MICU) as it pertains to pain and agitation, as well as assess measures of safety and efficacy.

Methods: This was a single-center, retrospective cohort study of critically ill patients who received a ketamine infusion for pain and/or agitation between June 2021 and August 2024. The primary outcome was opioid consumption, reported in oral morphine milligram equivalents (MME), and sedative use pre- versus post-ketamine initiation. Secondary outcomes included paired mean pain scores, proportion of time within goal Richmond Agitation-Sedation Scale score range, and incidence of adverse events.

Results: For the 78 patients included, there was no difference in analgesic use pre- versus post-ketamine initiation (60 vs 45 MME; P = 0.677). No differences were observed in sedative doses required pre- versus post-ketamine initiation (5.3 vs 3.4 mg of benzodiazepines; P = 0.508, 0.9 vs 1.1 μg/kg/h of dexmedetomidine; P = 0.062, and 44 vs 44 μg/kg/min of propofol; P = 0.180). There was a median paired difference of -1 point on the pain scale ([interquartile range -1, 0]; P = 0.030) after ketamine initiation. Ketamine was associated with an increased incidence of hallucinations (1.3% vs 6.4%; P = 0.046).

Conclusion and relevance: To the authors' knowledge, this is the first study examining the use of ketamine for pain and/or agitation that specifically focuses on MICU patients. The clinical benefit of the routine use of ketamine for these indications in this patient population is unclear and may increase patients' risk of adverse effects such as hallucinations.

Background: Norepinephrine has been widely established as the first-line agent for hemodynamic support in septic shock. The timing and order of initiation of vasopressin and hydrocortisone as adjunctive agents remains highly debated, with recent literature suggesting lower mortality with early hydrocortisone initiation.

Objective: The aim of the study was to evaluate the effectiveness and safety of vasopressin compared to hydrocortisone as adjuncts to norepinephrine in septic shock.

Methods: This was a multicenter, retrospective, observational study conducted in adult patients with septic shock admitted to the intensive care unit (ICU) between February 2020 and July 2023. Patients were divided into 2 cohorts based on the initial adjunctive agent administered following norepinephrine initiation: vasopressin (0.03-0.04 units/min) or hydrocortisone (200-300 mg/day). Individuals who received both study drugs within 6 hours of each other were excluded. The primary outcome was in-hospital mortality. Secondary outcomes included ICU length of stay (LOS), hospital LOS, time to vasopressor discontinuation, renal replacement therapy (RRT) initiation, and safety outcomes.

Results: A total of 628 patients were included: 193 patients (30.7%) received hydrocortisone, and 435 patients (69.3%) received vasopressin. Hydrocortisone was associated with lower in-hospital mortality (53.3% vs. 37.3%, adjusted hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.19-2.74, P = 0.006). Shorter hospital LOS and lower RRT initiation were observed with hydrocortisone. A longer time to initiation of the initial adjunctive agent was associated with an increased risk of in-hospital mortality (HR 1.08, 95% CI 1.04-1.11, P < 0.001).

Conclusion and relevance: Administration of hydrocortisone as an adjunct to norepinephrine in septic shock was associated with lower in-hospital mortality compared to vasopressin. The addition of hydrocortisone as the initial adjunct to norepinephrine may improve clinical outcomes in septic shock, and early initiation should be considered in patients with escalating norepinephrine requirements.

Objective: To describe garadacimab-gxii, an antibody that inhibits factor XII, indicated for hereditary angioedema (HAE) prophylaxis, approved by the Food and Drug Administration in June 2025 for patients 12 years and older.

Data sources: A PubMed search used the keywords "garadacimab," "hereditary angioedema," and "garadacimab clinical trials," from origin to October 15, 2025. We included phase I to III trials of garadacimab for HAE, post hoc analysis, and the package insert.

Study selection and data extraction: We compiled 2 phase I, 1 phase II, 2 phase III trials, and 1 post hoc analysis to formulate an evidence-based review.

Data synthesis: In the phase II trial, garadacimab reduced mean monthly attack rate by up to 97.7%. In phase III trials, mean monthly attack rate was reduced by 91% while 62% of patients remained attack-free. In the open-label extension trial, mean monthly attack rate decreased by 95% and 60% of patients remained attack-free. No serious drug-related adverse events were reported.Relevance to patient care and clinical practice in comparison with existing drugs:By inhibiting factor XII, a novel target that prevents activation of the HAE cascade upstream of other agents, garadacimab may have more favorable outcomes than other drugs currently used in prophylactic treatment of HAE.

Conclusion and relevance: Garadacimab reduces the frequency of HAE attacks with a safety profile comparable with existing prophylactic treatments. Its mechanism of targeting activated factor XII offers an alternative approach to HAE management. Ongoing monitoring and post-marketing data may further define its role in clinical practice.

Objective: The objective is to review the potential impact of sphingosine-1-phosphate (S1P) receptor modulators on insulin resistance in patients with multiple sclerosis, including underlying mechanisms and clinical evidence.

Data sources: A literature search was conducted in PubMed for publications from inception through November 2025. Additional sources, including therapeutic positioning reports and official product information (Summary of Product Characteristics), were also reviewed.

Study selection and data extraction: Relevant English and Spanish language articles were extracted and evaluated.

Data synthesis: Sphingosine-1-phosphate receptors (S1PR) regulate both immunological and metabolic functions, representing a key therapeutic target in multiple sclerosis. Agents such as fingolimod, siponimod, ozanimod and ponesimod bind to these receptors, thereby preventing lymphocyte migration into the central nervous system. Preclinical evidence suggests that S1P signaling participates in insulin receptor and Akt pathways, affecting glycogen synthesis, glucose uptake and β-cell survival. Clinical experience, including a case of a patient with type 1 diabetes and multiple sclerosis treated with ponesimod, indicates potential increases in insulin requirements and hyperglycemia, although formal human studies are lacking.

Relevance to patient care and clinical practice: Clinicians should monitor glycemic control in patients with multiple sclerosis receiving S1PR modulators, especially those with pre-existing metabolic disorders. Awareness of potential insulin resistance may guide drug selection and metabolic management. Further prospective studies are warranted to clarify clinical implications.

Conclusions: S1PR modulators are effective disease-modifying therapies in multiple sclerosis, but emerging evidence suggests a possible impact on insulin signaling and glucose metabolism. Vigilance in metabolic monitoring is recommended, particularly in patients with diabetes or other risk factors for insulin resistance.

Consumers precluded from obtaining semaglutide or tirzepatide by clinicians or insurers are turning to natural "GLP-1" transdermal patches. The Dietary Supplement Health and Education Act specifies dietary supplement products must be swallowed, so all these products are illegal. We identified 24 transdermal patch dietary supplement products and 1 transdermal gel product with an average of 7 ± 4 natural ingredients (berberine, glutamine/glutamate, cinnamon, and pomegranate most listed). No certificates of analysis were posted, many products lacked the Food and Drug Administration disclaimer, and many products used deceptive advertising. Several products had 1- to 2-star reviews and consumer comments suggesting lack of efficacy or adverse events.

Background: Diltiazem and verapamil are combined p-glycoprotein and moderate CYP3A4 inhibitors which significantly increase the concentrations of direct oral anticoagulants (DOACs) and may increase the risks of bleeding. Multiple real-world studies compared the concomitant therapy of diltiazem/verapamil and DOACs versus the DOAC monotherapy groups, but their main findings were contradictory.

Objective: To evaluate the risks of bleeding and stroke between the concomitant therapy of diltiazem/verapamil and DOACs and DOAC monotherapy.

Methods: A meta-analysis was performed to compare the concomitant therapy of diltiazem/verapamil and DOACs versus DOACs. Database searches through November 16, 2024 were performed using MEDLINE and Google Scholar. The primary outcome was major bleeding. The secondary outcomes included stroke or systemic embolism and gastrointestinal bleeding.

Results: A total of 6 studies were included in this meta-analysis. It showed that the concomitant therapy of DOAC and diltiazem/verapamil was significantly associated with increased risks of major bleeding (odds ratio [OR] = 1.38; 95% CI = 1.24, 1.54; P < 0.01; I² = 0%) and gastrointestinal bleeding (OR = 1.19; 95% CI = 1.03, 1.37; P = 0.01; I² = 0%) compared with the DOAC monotherapy group. The concomitant therapy group was also significantly associated with the lower risk of stroke or systemic embolism compared with the DOAC monotherapy group (OR = 0.83; 95% CI = 0.73, 0.93; I² = 0%).

Conclusion and relevance: This meta-analysis found that the concomitant therapy of DOACs with diltiazem/verapamil increases the risks of bleeding outcomes compared with the DOAC monotherapy group.

Background: Antipsychotic medications continue to be frequently prescribed by clinicians in the intensive care unit (ICU) for delirium, despite inconclusive data.

Objective: To determine if using a combination of antipsychotics reduces the time patients spend in delirium compared with monotherapy.

Methods: This was a single-center, retrospective, cohort medical record review of patients who scored positive on Confusion Assessment Method for the ICU (CAM-ICU) and received antipsychotic therapy. Patients were excluded if they received any antipsychotics prior to hospital admission or had a Richmond Agitation-Sedation Scale (RASS) scores of -4 or -5 at the time of CAM-ICU assessment. The primary outcome was duration of delirium. The secondary outcomes included ICU length of stay (LOS), hospital LOS, overall mortality, occurrence of adverse events (AEs), and whether antipsychotics were continued at hospital discharge.

Results: A total of 84 patients were included, of these 45 and 39 received monotherapy and combination therapy, respectively. Median Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were significantly higher in the monotherapy group (18 vs 13, P = 0.006). Median duration of delirium was not significantly different between the monotherapy and combination therapy groups (8 vs 8 days, P = 0.932). Median ICU and hospital LOS, and occurrence of AEs were not significantly different. A significant difference in mortality was found between monotherapy and combination therapy (31% vs 10%, P = 0.02). Antipsychotics were continued at hospital discharge in 64% of the monotherapy and in 44% of the combination therapy group.

Conclusion and relevance: In patients with ICU delirium, there was no difference in duration of delirium among patients receiving monotherapy compared with combination therapy with antipsychotics, though they may be sicker and have a higher mortality. Patients commonly remain on antipsychotics at hospital discharge, the implications of which warrant further study.

Objective: The objective of this article is to review the pharmacologic and clinical profile of denosumab-bbdz (GP2411, SDZ-deno), the first interchangeable RANK ligand inhibitor biosimilar for the treatment of osteoporosis and to increase bone mass.

Data sources: PubMed was searched for all indexed literature published prior to January 1, 2025, using the keywords GP2411, SDZ-deno, and denosumab-bbdz. Information was also extracted from the denosumab-bbdz package insert and a gray literature search.

Study selection and data extraction: Phase I and III studies of the pharmacokinetic, pharmacodynamic, and clinical profile of denosumab-bbdz were reviewed.

Data synthesis: Denosumab-bbdz received Food and Drug Administration approval based on the phase I/III ROSALIA trial which demonstrated similar pharmacokinetics, pharmacodynamics, efficacy via bone turnover rates, immunogenicity, and safety between denosumab-bbdz and reference product denosumab. Denosumab-bbdz carries a boxed warning and Risk Evaluation and Mitigation Strategy for severe hypocalcemia in patients with advanced chronic kidney disease.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:Denosumab-bbdz has interchangeable status which allows substitutions without prescriber approval and reduces costs. Denosumab-bbdz assumes the same place in therapy as other denosumab products. In addition to other indications, it is a first-line option for postmenopausal osteoporosis with high or very high fracture risk after achieving equivalence in pharmacologic properties, safety, and markers for bone formation.

Conclusions: Denosumab-bbdz is the first interchangeable biosimilar for denosumab. This approval has the potential to reduce costs to patients and the healthcare system and sets an encouraging future for the potential of biosimilars.