Brexanolone: A Novel Drug for the Treatment of Postpartum Depression.

OBJECTIVES: To review the pharmacology, efficacy, and safety of Brexanolone and define its role in the treatment of postpartum depression. DATE SOURCES: A MEDLINE/PubMed search was conducted (1980-May 2020) using the following keywords: postpartum depression, antidepressants, pharmacologic therapy, drug therapy, and brexanolone to identify relevant articles. STUDY SELECTION/DATA EXTRACTION: Literature search was limited to human studies published in the English language. Phase I, II, and III studies evaluating the pharmacology, efficacy, safety of brexanolone for postpartum depression were included. Bibliographies of relevant articles evaluating postpartum depression and treatment were reviewed for additional citations and background information. DATA SYNTHESIS: Brexanolone is a soluble, proprietary, injectable formulation of allopregnanolone, a neuroactive steroid that modulates neuronal excitability. Allopregnanolone levels increase during pregnancy and decrease substantially after birth. These fluctuations have profound effects on anxiety and depression. Three clinical trials established the efficacy and safety of brexanolone in the treatment of postpartum depression. In all 3 trials, brexanolone had an acceptable safety profile and was well tolerated. The most common adverse effects were loss of consciousness, sedation, dry mouth, headache, dizziness, and flushing. Due to sudden loss of consciousness and excessive sedation, continuous pulse oximetry is recommended. CONCLUSION: Brexanolone has a novel mechanism of action and appears to be safe and effective for the treatment of moderate to severe postpartum depression. At present, high cost, serious adverse effects, and restricted access may limit its use in clinical practice.

Use of Ranolazine for the Treatment of Coronary Microvascular Dysfunction.

Coronary microvascular dysfunction (CMD) is defined as a mismatch of myocardial blood supply and oxygen consumption due to a dysfunction of the coronary microvessels. Up to 20-30% of patients with CMD have progressive worsening of symptoms with significant impairment of quality of life. Large-scale randomized studies of the pharmacologic treatment of CMD are lacking. Classic anti-ischemic drugs are the initial form of treatment, but efficacy is often limited. Ranolazine has a unique mechanism of action that does not affect blood pressure or heart rate. When added to existing anti-anginal agents, ranolazine improved at least one domain in eight of ten studies in which a questionnaire was used to assess patient health status. Five studies evaluated coronary arterial flow reserve (CFR), reporting that patients with low values had significant improvement in CFR and suggesting that those with more severe CMD respond more favorably to ranolazine. In two studies, exercise duration and time to myocardial ischemia were significantly increased after treatment with ranolazine. Data are lacking for ranolazine use as the sole agent for CMD treatment. Some questions remain to be answered regarding ranolazine use for CMD. Larger studies of longer duration are needed to verify the effectiveness of ranolazine in the treatment of CMD.

Extended duration vancomycin in recurrent Clostridium difficile infection: a systematic review.

Clostridium difficile infections have a high recurrence rate following acute treatment. Extended duration vancomycin (EDV) is a mainstay for the treatment of recurrent Clostridium difficile infections (rCDI). Clinical disease guidelines recommend a variety of different vancomycin treatment regimens though based on weak, low-quality evidence. Patients typically receive an initial vancomycin treatment course of 7-14 days for the acute infection, followed by an extended duration vancomycin course. Multiple publications on the utility of EDV regimens have been published but few include reported effectiveness outcomes associated with a prescribed treatment regimen. The purpose of this review is to evaluate the safety and efficacy data on extended duration vancomycin regimens used in recurrent clostridium treatment. Five articles, three case series and two randomized open-label clinical trials, were identified which included both elements. Outcomes were evaluable in 174 patients, 31 from randomized trials, with prior average recurrent episodes ranging from 3 to 4. Vancomycin dose ranged from 3500 to >6800 mg with therapy durations extending from 21 days to over 60 days. Follow-up duration ranged from 10 weeks to 12 months. Case series reported success rates for EDV in rCDI from 61% to 100%, while randomized trials found lower success rates from 26% to 58%. Taper and pulse regimens reported superior outcomes compared to pulse-only regimens, 58-100% versus 26-81%, respectively. Comparative EDV data is limited. Current available data supports an EDV regimen which includes both a daily dosing taper followed by an every 48 or 72 h pulse.

Drug-Induced Restless Legs Syndrome.

OBJECTIVE: To review the literature on drug-induced restless legs syndrome (DI-RLS). DATA SOURCES: The review included a search for English-language literature from 1966 to December 2017 in the MEDLINE, PubMed, and Ovid databases using the following search terms: restless legs syndrome (RLS), periodic limb movement, adverse effects, and drug-induced. In addition, background articles on the pathophysiology, etiology, and epidemiology of RLS were retrieved. Bibliographies of relevant articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: All case reports, case series, and review articles of DI-RLS were identified and analyzed. There were only a small number of controlled clinical trials, and most data were from case reports and case series. RESULTS: Several drugs and drug classes have been implicated in DI-RLS, with antidepressants, antipsychotics, and antiepileptics having the most evidence. In addition, RLS may be linked with a number of disorders or underlying predisposing factors as well. CONCLUSIONS: The prevalence of RLS is variable and ranges from 3% to 19% in the general population. There are many predisposing factors to RLS, but an emerging body of evidence suggests that there is an association between numerous drugs and RLS.

Successful Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia with Ceftaroline Fosamil.

Objectives: To describe a case of successful treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with ceftaroline fosamil after failure with vancomycin and daptomycin. Case Summary: A 53-year-old female with a past medical history of cancer (unknown source/type) and hypothyroidism was admitted to the hospital with cervical and paravertebral abscess with suspected sepsis. In the emergency department (ED), magnetic resonance imaging (MRI) revealed possible spinal abscess and narrowing of the spinal canal. The patient was initiated on vancomycin 1,250 mg (~15 mg/kg) every 12 hours and cefepime 2 g every 8 hours empirically. On hospital day 4, blood and wound cultures revealed MRSA susceptible to vancomycin, but with a vancomycin minimum inhibitory concentration (MIC) of 2. Repeat blood cultures were also positive on hospital days 2 and 4. Per infectious disease team consult, therapy was converted to daptomycin 8 mg/kg/day. Although the patient responded well, acute kidney injury (AKI) on hospital day 15 prompted a change in therapy to ceftaroline fosamil 400 mg intravenous every 8 hours. For the remainder of the hospital stay, blood cultures were negative and white blood cell count was within normal limits. On day 20, the patient was discharged to a long-term care facility for continued ceftaroline treatment. Discussion: The management of MRSA bacteremia remains challenging due to increasing antimicrobial resistance. Although the standard therapy for serious MRSA infections is vancomycin, treatment failures are becoming common in clinical practice due to increasing MICs (≥2 µg/mL). Other therapies may include daptomycin and off-label treatment with telavancin, quinupristin/dalfopristin, or ceftaroline fosamil. This report describes a patient with paravertebral abscess and MRSA bacteremia failing 3 days of vancomycin therapy due to MIC greater than or equal to 2 µg/mL and persistent bacteremia. Treatment with ceftaroline fosamil was well tolerated and resulted in continued clinical improvement. Based on this case report, ceftaroline fosamil may be a reasonable alternative for invasive MRSA infections. Conclusions: This case report describes successful treatment of MRSA bacteremia with ceftaroline in a patient who responded poorly to conventional therapy, specifically vancomycin due to an elevated MIC (2 µg/mL).

Dextromethorphan/quinidine for the treatment of pseudobulbar affect.

OBJECTIVE: To evaluate the role of dextromethorphan/quinidine (DM/Q; Nuedexta™) in the treatment of pseudobulbar affect (PBA). DATA SOURCES: A literature search of MEDLINE/PubMed (January 1966-June 2013) was conducted using search terms pseudobulbar affect, pathological laughing and/or crying, emotional lability, dextromethorphan, and quinidine. STUDY SELECTION AND DATA EXTRACTION: English language clinical trials and case reports evaluating the safety and efficacy of DM/Q in PBA were included for review. Bibliographies of all relevant articles were reviewed for additional citations. DATA SYNTHESIS: PBA, a poorly understood disorder, is characterized by involuntary crying and/or laughing. In the past, antidepressants and antiepileptics have been used off-label with mixed results. Four clinical trials have evaluated the use of DM/Q for the treatment of PBA. Although the therapeutic outcomes with DM/Q have been positive, interpretation of the published evidence is limited by small sample size and short treatment duration. CONCLUSIONS: Based on the data available, DM/Q may be a viable, short-term treatment alternative for PBA. Long-term safety and efficacy data are lacking.

Drug-induced yawning--a review.

OBJECTIVE: To review the current literature on drug-induced yawning. DATA SOURCES: Literature was accessed through MEDLINE/PubMed (1996-July 2011), International Pharmaceutical Abstracts (1997-July 2011), and EMBASE, using the search terms yawning, drug-induced yawning, and adverse drug reactions. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials and case reports were selected and included to present background information. Bibliographies of all relevant articles were reviewed for additional citations. DATA SYNTHESIS: Yawning is a common stereotype behavior with unknown physiologic function that occurs in most vertebrates and humans as early as 15 weeks of intrauterine life. Yawning is under the control of several neurotransmitters and neuropeptides, including dopamine, serotonin, oxytocin, and acetylcholine. Among drugs, antidepressants, opioids, dopaminergic agents, benzodiazepines, and induction agents are the main pharmacologic classes associated with yawning. CONCLUSIONS: Yawning is rarely a serious adverse reaction and is not frequently listed in the drug summary. Most available data are based on case reports, small studies, and older literature. Clinicians should be aware of the agents commonly triggering this behavior.

Hemostatic mouthwashes in anticoagulated patients undergoing dental extraction.

OBJECTIVE: To evaluate the efficacy and safety of local acting hemostatic agents in patients who are undergoing dental extraction(s) and are taking oral anticoagulants. DATA SOURCES: A search of MEDLINE (1966-July 2006), International Pharmaceutical Abstracts (1970-July 2006), and EMBASE (1966-July 2006) was conducted using the key terms anticoagulation, warfarin, hemostatic mouthwashes, epsilon aminocaproic acid, tranexamic acid, dental extraction, and oral surgery. Bibliographies of relevant papers were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: English-language literature, including abstracts, clinical trials, and review articles, were reviewed. Clinical trials were included if they evaluated hemostatic mouthwashes in patients receiving continued anticoagulation and undergoing dental extractions or various oral surgeries including dental extraction. Eight clinical trials met study selection criteria for evaluation of hemostatic mouthwashes in anticoagulated patients undergoing dental extraction. Eight studies evaluated tranexamic acid; one assessed epsilon aminocaproic acid. All studies were reviewed for efficacy and safety of hemostatic mouthwashes and intensity of continued anticoagulation therapy. DATA SYNTHESIS: Eight small studies enrolled populations that varied in the indications for oral anticoagulation (OA), target INR ranges, and oral surgeries performed. Patients receiving uninterrupted OA and using hemostatic mouthwashes had no greater and, in some cases, lesser bleeding incidence compared with various other treatment groups (including interrupted OA, uninterrupted OA, autologous fibrin glue with uninterrupted OA, and reduced OA with heparin bridge). No severe adverse effects were reported. No studies assessed the risk of thromboembolism between the different treatment strategies. CONCLUSIONS: Findings in recent studies indicate that dental extractions in anticoagulated patients can be performed without temporary discontinuation of oral anticoagulant therapy with the use of hemostatic mouthwashes to control localized bleeding. This practice should be more widely adopted due to minimized bleeding and thromboembolic risks.

The future of statins: Alzheimer's disease?

OBJECTIVES: To review available clinical trial data and discuss the potential role of statins on the development of Alzheimer's disease (AD). DATA SOURCES: Searches of PubMed and MEDLINE (1985-February 2005) were conducted. STUDY SELECTION AND DATA EXTRACTION: English language articles, review papers, and human studies with special emphasis on those dealing with statin use and AD. DATA SYNTHESIS: Early data from retrospective trials indicate that patients receiving statins have a reduced risk of developing AD. Two large published prospective clinical trials with cognition as secondary endpoint found that statins did not show any benefit compared with placebo. Only one of two more recent cohort community-based studies of statins found a lower risk of dementia and cognitive impairment. A small placebo-controlled pilot study reported that atorvastatin slows the progression of AD. Case reports indicate that in rare cases, statins may be associated with cognitive impairment. The results of ongoing placebo-controlled trials in patients with cognitive impairment should yield more definitive answers. CONCLUSION: Current literature is conflicting with regard to the neuroprotective effects of statins on cognitive impairment. A firm conclusion regarding the effects of cholesterol or statins on human brain and cognitive function has not been well established, and it is premature to recommend statins for prevention and/or treatment of AD.

A review of methotrexate-induced accelerated nodulosis.

OBJECTIVE: To review the English-language literature on methotrexate-induced accelerated nodulosis, compile case reports of its occurrences, and make recommendations on the clinical management of patients. METHODS: A comprehensive search of MEDLINE, TOXLINE, and EMBASE databases was performed, along with a bibliographic search of key articles. Case reports were compiled separately. The Naranjo adverse drug reaction probability scale was used to assess causality. RESULTS: Twenty-seven case reports of patients with methotrexate-induced accelerated nodulosis were identified along with one series of 10 patients and one series of 21 patients. Probability assessment for most of the case reports was weak and left room for doubt regarding causality. Most patients were older than 50 years, were positive for rheumatoid factor, and had nodules on their fingers but did not have concurrent vasculitis. Some unusual sites of nodulosis were the larynx, lungs, Achilles tendon, and heart. Of 19 patients given hydroxychloroquine, colchicine, sulfasalazine, azathioprine, or D-penicillamine, all except two showed regression of the nodules; the response was unknown for one patient. CONCLUSION: Controversy surrounds the management of patients who develop accelerated nodulosis while receiving methotrexate therapy for rheumatoid arthritis. Our review of these data does not allow definitive conclusions because the available case reports and clinical trials are fragmented and incomplete.