Dextromethorphan/Bupropion: A Novel Treatment for Patients With Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) affects millions of people and is the leading cause of disability worldwide. Patients report decreased quality of life and ability to perform activities of daily living. It is estimated that the current standard of care, which includes pharmacologic therapy with a selective serotonin reuptake inhibitor, is effective in 40%-60%. Additional treatment options are warranted. The combination of dextromethorphan (DEX) and bupropion (BUP) (Auveulty) was approved for treatment in 2022. This unique combination offers an interesting mechanism of action and favorable onset of action for patients with MDD. PHARMACODYNAMICS AND PHARMACOKINETICS: The mechanism of action of DEX-BUP when used in combination is unique. DEX is a noncompetitive N-methyl-d-aspartate receptor antagonist rapidly metabolized through the CYP450 2D6. BUP is an aminoketone and CYP2D6 inhibitor, which results in increased plasma levels of DEX through competitive CYP2D6 inhibition. CLINICAL TRIALS: In a phase 2 clinical study, the efficacy of DEX-BUP was compared with BUP alone in patients with clinically diagnosed MDD. At baseline, participants had moderate-to-severe depression using the Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impressions Severity (CGI-S) scales. There was a significant overall reduction in MADRS and CGI-S scores in the treatment group compared with the BUP monotherapy with improvement observed as early as week 1 of treatment. Later, a phase 3 study was conducted comparing DEX-BUP 45 mg/105 mg with placebo in patients with moderate-to-severe MDD. Similarly, MADRS and CGI-S scores were significantly reduced in the treatment group. Adverse effects were similar in all groups. THERAPEUTIC ADVANCE: Clinical response to first line treatment options for MDD are reported to be 40%-60%. Availability of additional treatment options, particularly those with reduced time to efficacy, may improve overall treatment and patient quality of life. DEX-BUP is a combination option that has been shown to improve depression symptoms as early as 1 week after initiation.

Anakinra-An Interleukin-1 Receptor Antagonist for COVID-19.

BACKGROUND: Coronavirus disease (COVID-19) caused by SARS-CoV-2 virus caused a global pandemic in 2019. There are limited pharmacologic options available. The Food and Drug Administration initiated an emergency use authorization process to expedite pharmacologic agents to treat COVID-19. There are several agents available through the emergency use authorization process, ritonavir-boosted nirmatrelvir, remdesivir, and baricitinib. Anakinra is an interleukin (IL)-1 receptor antagonist that exhibits properties in fighting against COVID-19. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Anakinra is a recombinant IL-1 receptor antagonist. The epithelial cell damage that may occur with COVID-19 enhances the release of IL-1, which plays a central role in severe cases. Thus, drugs that inhibit the IL-1 receptor may be beneficial in the management of COVID-19. Anakinra has good bioavailability after subcutaneous injection and a half-life of up to 6 hours. CLINICAL TRIALS: The SAVE-MORE, double-blind, randomized controlled trial, phase 3 evaluated the efficacy and safety of anakinra. Anakinra 100 mg was given subcutaneously daily for up to 10 days in patients with moderate and severe COVID-19 and plasma suPAR ≥6 ng/mL. Anakinra group had a 50.4% fully recovered with no viral RNA detected on day 28 versus 26.5% for placebo, and more than 50% of relative decrease in mortality. A significantly decreased risk of worse clinical outcome was observed. THERAPEUTIC ADVANCE: COVID-19 causes global pandemic and a serious viral disease. There are limited therapy options to combat this deadly disease. Anakinra is an IL-1 receptor antagonist and shown to be effective for the treatment of COVID-19 in some trials but not others. Anakinra, the first in this class, seems to have a mix result for the treatment of COVID-19.

Idarucizumab for Reversing Dabigatran-Induced Anticoagulation: A Systematic Review.

BACKGROUND: The approval of the oral direct thrombin inhibitor, dabigatran etexilate, gave patients an alternative to oral anticoagulation with warfarin. Like all anticoagulants, the primary adverse event (AE) associated with dabigatran is bleeding. Until the FDA approval of idarucizumab, there had been no reversal agent for dabigatran-induced anticoagulation in patients with life-threatening or uncontrollable bleeding, or those requiring emergent procedures. AREAS OF UNCERTAINTY: The primary purpose of this review is to summarize the safety and efficacy of idarucizumab, a monoclonal antibody fragment, and its use as a reversal agent for dabigatran. DATA SOURCES: A literature search was conducted through MEDLINE (1946 to November week 1 2015) and Embase (1980-2015 week 46) using the search term idarucizumab. Clinicaltrials.gov was consulted for a comprehensive list of ongoing and completed studies. Additional studies were identified through bibliographical citations. Clinical trials in animals and humans published in English evaluating the safety and efficacy of idarucizumab for reversal of anticoagulant treatment with dabigatran were included for review. RESULTS: Idarucizumab has been shown to significantly reverse the anticoagulant effects of dabigatran in both healthy volunteers and patients requiring a reversal agent because of either overt bleeding or an emergency surgery or invasive procedure. The most common AEs were headache, nasopharyngitis, back pain, skin irritation, hypokalemia, delirium, constipation, pyrexia, and pneumonia. Deaths reported in idarucizumab studies were attributed to either the index event or a preexisting comorbidity. Most adverse effects were minor, but 21 serious AEs have been reported in the published data including thrombotic events. CONCLUSIONS: Given the increased use of direct oral anticoagulants, such as dabigatran, a need for specific reversal agents exists. Idarucizumab has been shown to be safe and effective in the reversal of dabigatran-induced anticoagulation in patients requiring emergent or urgent surgery or in patients with severe bleeding.

Use of direct oral anticoagulants for the prevention and treatment of thromboembolic disease in patients with reduced renal function: a short review of the clinical evidence.

BACKGROUND: The use of direct oral anticoagulants (DOACs) is restricted by the limitations of clinical trials guiding therapy for patients with renal impairment, as many of these trials excluded patients with severe renal impairment. There are currently four agents available: dabigatran, rivaroxaban, apixaban, and edoxaban. The purpose of this review was to 1) describe current recommended dosing for each DOAC and published postmarketing data, including case reports, on the use of these agents in the renally impaired; and 2) discuss patient adherence and satisfaction and the cost of these agents. MATERIALS AND METHODS: A literature search was conducted using Medline and Embase with the terms "dabigatran" or "rivaroxaban" or "apixaban" or "edoxaban" and "renal impairment". Clinical trials and case reports describing the use of DOAC therapy in patients with renal impairment were reviewed. A second search was conducted to find articles evaluating patient adherence, patient satisfaction, and pharmacoeconomics of DOACs. RESULTS: There are a multitude of subgroup and post hoc analyses, as well as six case reports with dabigatran and one case report with apixaban, that provide insight for the clinical use of DOACs in patients with renal impairment. Dabigatran exhibits the greatest level of renal elimination, and there are data from clinical trials and several case reports that warrant reconsideration before use. Other DOACs may be a better option in patients with impaired renal function. Further, data from patient-adherence studies have suggested that DOACs that are dosed daily (rather than twice daily) are optimal and preferred. There does not appear to be a cost difference between DOACs and warfarin therapy. CONCLUSION: DOAC therapy in patients with impaired renal function requires more critical review of study data, as these patients may have increased risk of bleeding. It is also valuable to consider patient preferences and cost when selecting the appropriate option for oral anticoagulation.

New and Emerging Antibiotics for Complicated Intra-Abdominal Infections.

The purpose of this review is to evaluate the efficacy and safety of ceftazidime/avibactam and ceftolozane/tazobactam in patients with complicated intra-abdominal infections (cIAI), and review eravacycline and other agents in the pipeline for management of cIAI. The increasing incidence of multidrug resistant strains of bacteria has led to the need for additional antibiotics with activity against these organisms. There are 2 newly approved antibiotics, ceftazidime/avibactam and ceftolazane/tazobactam for treatment of cIAI. Both agents have been shown to exert activity against resistant bacteria, including extended-spectrum beta-lactamase-producing organisms. Several other antibiotics are currently under investigation for this indication. Included in the pipeline of agents is a new tetracycline, an aminoglycoside, 2 new fluroquinolones, and 2 new beta-lactamase inhibitor combinations with carbapenems. Although the mechanisms for these new agents are not novel, promising data have shown their ability to overcome class resistance. The passing of the Generating Antibiotic Incentives Now Act has led to an increasing number of fast tracked antibiotic approvals. In addition to recent approval of ceftazidime/avibactam and ceftolazane/tazobactam, several other emerging antibiotics are under investigation which will aid in the management of resistant cIAI.

Dosing of Target-Specific Oral Anticoagulants in Special Populations.

OBJECTIVE: To review current literature for target-specific oral anticoagulants (TSOACs) and provide critical analysis for dosing recommendations in special population groups. DATA SOURCES: A literature search was conducted in Medline (1996 to April week 2 2015) and Embase (1980 to 2015 week 16) using key terms dabigatran, rivaroxaban, apixaban, edoxaban, kidney diseases, liver diseases, elderly, obesity, and special populations. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials in English assessing efficacy and safety of TSOACs in healthy adults and special populations were selected for analysis. DATA SYNTHESIS: Phase 3 trials for TSOACs predominately excluded patients with severe renal impairment or active liver disease. There were no exclusion criteria based on age, body weight or body mass index. Additional conclusions were made in special populations, including those with renal or liver impairment and obese and elderly patients, based on secondary analyses, pharmacokinetic, and pharmacodynamic studies. CONCLUSIONS: Pharmacokinetic and pharmacodynamic changes associated special populations may alter clinical decision with regard to drug selection and dosing. It is valuable to understand the rationale for labeled dosing recommendations in nonvalvular atrial fibrillation and venous thromboembolism treatment and prevention, particularly in patients that fall into special population groups. Furthermore, the use of TSOACs is likely to increase as clinicians gain experience with these agents and additional TSOACs and indications are approved.

Daptomycin use in pediatric patients.

PURPOSE: Currently available evidence on the use of daptomycin in pediatric patients is reviewed and evaluated. SUMMARY: Although guidelines on the treatment of methicillin-resistant Staphylococcus aureus infections recommend daptomycin for use in pediatric patients, that recommendation is primarily based on expert opinion. A literature search for articles on pediatric daptomycin use identified three pharmacokinetic studies, three case reports, and one retrospective review. The limited body of published evidence indicates that pediatric patients may require higher daptomycin doses than adult patients in order to attain therapeutic serum concentrations. Pharmacokinetic studies in pediatric patients demonstrated faster daptomycin clearance (CL) and a decreased area under the concentration-time curve (AUC) relative to values reported in adults. Daptomycin appears to have a shorter half-life in patients 2-6 years of age relative to those 12-17 years of age. A retrospective review of 16 cases in which pediatric patients were treated with daptomycin for invasive gram-positive infections indicated positive outcomes after the addition of daptomycin to standard therapy. Overall, daptomycin appears to be well tolerated in pediatric patients. CONCLUSION: Due to the limited nature of the available literature, use of daptomycin in pediatric patients should be limited to situations in which other options are not viable due to toxicity, local susceptibility patterns, or likely treatment failure. As a result of faster drug CL and lower AUC values, higher doses may be necessary in pediatric patients to achieve serum concentrations similar to those seen with adult dosing.

Dosing of enoxaparin for venous thromboembolism prophylaxis in obese patients.

OBJECTIVE: To evaluate the appropriate dosing of enoxaparin as a venous thromboembolism (VTE) prophylaxis in hospitalized obese patients. DATA SOURCES: Literature articles were accessed through MEDLINE (1946 to August week 1, 2013) and EMBASE (1980 to 2013 week 33) searches using the terms enoxaparin, obesity, and thromboprophylaxis. STUDY SELECTION AND DATA EXTRACTION: All articles that involved human subjects and were published in the English language, evaluating the appropriate dose of enoxaparin for VTE prophylaxis in hospitalized, obese patients were included. DATA SYNTHESIS: Appropriate enoxaparin dosing for thromboprophylaxis in adult patients is 40 mg subcutaneously daily or 30 mg subcutaneously twice daily. Although obesity is considered one of the risk factors for thromboembolism, morbidly obese patients were excluded from most clinical trials; therefore, the appropriate enoxaparin preventive dose is not clear in this population. In recent years, the appropriate dose of enoxaparin for VTE prophylaxis in obese patients has been evaluated in 3 clinical studies. All studies enrolled patients with various risk factors for thromboembolism and evaluated different enoxaparin dosing regimens. End point analyses were all based on anti-Xa levels. CONCLUSIONS: Due to a lack of well-designed prospective, randomized control studies, varying doses of enoxaparin are used for VTE prophylaxis in hospitalized, obese patients. All doses studied were monitored using anti-Xa levels. Patient follow-up was of short duration in all studies and did not show long-term effectiveness of enoxaparin. Prospective, randomized controlled studies are warranted to show efficacy and safety of one dosage regimen over another.

Exenatide as a novel weight loss modality in patients without diabetes.

OBJECTIVE: To evaluate the potential role of exenatide for weight loss in overweight or obese adults without diabetes. DATA SOURCES: PubMed (1946-August 2012) and EMBASE (1974-August 2012) were used to conduct a literature search utilizing the terms exenatide, weight loss, obesity, and overweight. Additional references were identified by bibliographic review of relevant articles. STUDY SELECTION AND DATA EXTRACTION: Studies assessing the use of exenatide in adult subjects without type 2 diabetes or polycystic ovary syndrome and reporting effects on body weight were included. DATA SYNTHESIS: Five studies were identified that reported use of exenatide in nondiabetic adults and included weight change as an outcomes measure. In all 5 of these studies, subjects taking exenatide experienced statistically significant weight loss, which ranged from 2.0 ± 2.8 to 5.1 ± 0.5 kg. Two of the trials were randomized, placebo-controlled studies; 1 trial was a randomized, open-label investigation; 1 study had a prospective, open-label cohort design; and the remaining study was a chart review. Adverse events experienced with exenatide were primarily gastrointestinal in nature, although each trial reported the drug to be well tolerated. CONCLUSIONS: Obesity continues to be a national epidemic, while choices for effective pharmacologic treatments are extremely limited. Exenatide appears to have promising effects on weight in overweight or obese adults without type 2 diabetes. Further investigations with large, placebo-controlled trials assessing long-term weight loss as a primary outcome are warranted.

Practical considerations for optimal transdermal drug delivery.

PURPOSE: The properties of various transdermal drug delivery system (TDDS) products are reviewed, with safety recommendations and guidance on addressing questions frequently posed by patients and caregivers. SUMMARY: Drug delivery via a TDDS can offer many advantages over other methods of administration, but those benefits can be compromised by improper use or alteration of medication patches or a lack of awareness of the properties of different patch types (reservoir, matrix, drug-in-adhesive). To assess current TDDS technologies and recommended practices for safe and effective use of medication patches, a literature search for articles on commonly used TDDS products available in the United States was conducted; supplemental information was obtained from package inserts and through direct communication with manufacturers. In addition to recommendations on the site and duration of TDDS application and proper patch disposal, clinicians must consider (1) potential problems with cutting patches as a method of dosage adjustment, (2) safety concerns related to the electric conductivity of metal-containing patches, (3) appropriate strategies for managing patch adhesion failures, and (4) the advisability of writing on patches for medication safety or compliance reasons. Clinicians should also be prepared to counsel patients about TDDS-specific recommendations on the avoidance of sunlight and other external heat sources during the use of a medication patch. CONCLUSION: Practical considerations related to transdermal drug delivery include the appropriateness of cutting patches, the implications of their containing metallic components, and whether they may be covered with tape or written on. Manufacturers of patches provide some useful information on these topics.

Proton Pump Inhibitor use in Hospitalized Patients: Is Overutilization Becoming a Problem?

Proton pump inhibitors (PPIs) are among the most common classes of medications prescribed. Though they were previously thought of as safe, recent literature has shown risks associated with their use including increased risk for Clostridium difficile infection, pneumonia, and fractures. Due to these risks, it is important to determine if PPIs are being used appropriately. This review evaluates seven studies in hospitalized patients. Additionally, this review evaluates literature pertaining to recently discovered adverse reactions; all studies found PPIs are being overutilized. Findings highlight the importance of evaluating appropriate therapy with these agents and recommending discontinuation if a proper indication does not exist.

Rosiglitazone and pioglitazone for the treatment of Alzheimer's disease.

OBJECTIVE: To review the literature on the efficacy and safety of rosiglitazone and pioglitazone for the treatment of Alzheimer's disease (AD). DATA SOURCES: Literature was accessed through MEDLINE (1948-August 2011 week 2) and EMBASE (1980-2011 week 32) using the search terms rosiglita-zone, pioglitazone, and Alzheimer's disease. Results were limited to studies conducted in humans and published in English. STUDY SELECTION AND DATA EXTRACTION: Clinical trials evaluating the efficacy and safety of rosiglitazone or pioglitazone in patients with AD were critically evaluated. DATA SYNTHESIS: The mechanism for development of AD has been linked to both inflammation and decreased insulin sensitivity. Because of this, rosiglitazone and pioglitazone have been evaluated as potential treatments for AD because of their insulin-sensitizing and antiinflammatory effects. Five clinical trials were evaluated (3 assessing rosiglitazone, 2 assessing pioglitazone); 1 trial evaluating rosiglitazone demonstrated a beneficial effect on cognition in patients with probable AD. However, the largest randomized, double-blind, placebo-controlled trials conducted to date failed to demonstrate a difference between rosiglitazone and placebo when assessing primary endpoints. Two small trials evaluating pioglitazone produced conflicting results regarding efficacy in AD; numerous limitations make results difficult to interpret. The safety of these agents was also evaluated in these trials; edema was seen more commonly in patients receiving rosiglitazone or pioglitazone than in those receiving placebo; however, each drug was generally well tolerated. CONCLUSIONS: Results from clinical trials and current safety data suggest that rosiglitazone should not be used for the treatment of AD. Application of results from trials evaluating pioglitazone in the treatment of AD is limited because of major trial limitations; therefore, it should not be recommended at this time. Although these drugs are not commonly used in the treatment of AD, further pharmacoepidemiologic studies are warranted before their use can be recommended.

Thienopyridines in Acute Coronary Syndrome.

OBJECTIVE: To evaluate the safety and efficacy of the thienopyridines in order to identify their current place in therapy for the treatment of acute coronary syndrome (ACS). DATA SOURCES: Literature was accessed through MEDLINE (1966-October 2010 week 1), EMBASE (1980-2010 week 40), and a bibliographic review of published articles using the search terms acute coronary syndrome, clopidogrel, and prasugrel. Articles were limited to clinical trials conducted in humans and published in the English language. STUDY SELECTION AND DATA EXTRACTION: Head-to-head clinical trials evaluating the safety and efficacy of the thienopyridines in patients with ACS were critically reviewed. Trials evaluating ticlopidine were excluded due to its limited clinical use. DATA SYNTHESIS: Thienopyridines are an integral part of the treatment of ACS. Prior to the approval of prasugrel, clopidogrel was considered the agent of choice due to safety concerns associated with ticlopidine. A randomized controlled trial comparing prasugrel and clopidogrel has demonstrated superior efficacy with prasugrel, and post hoc analyses suggest additional benefit with prasugrel is derived in patients with ST-segment elevation myocardial infarction and patients with diabetes. However, safety concerns exist linking prasugrel with an increased risk of bleeding, which diminishes its advantage in elderly patients, underweight patients, and those with a history of stroke. Pharmacokinetic and pharmacodynamic studies discussing differences in response variability, platelet inhibition, interactions with proton pump inhibitors, and genetic factors between the thienopyridines are numerous, although more clinical data are needed to determine clinical implications. CONCLUSIONS: Clinical trial data have suggested prasugrel is superior to clopidogrel at preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention. However, this coincides with an increased risk of bleeding. Clinicians must carefully interpret the current evidence, including limitations in study design and pharmacologic differences between agents, in order to balance the risks and benefits as new data become available.