Therapeutics

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial Background: This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss. Study Question: Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight? Study Design: We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18–65 years of age without diabetes and with the body mass index (BMI) of 30–45 kg/m2. Measures and Outcomes: The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points. Results: Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were −1.99%, −1.69%, and −1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin ≥12mU/L (3.5%). Conclusions: Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30–39.9 kg/m2, especially participants with hyperinsulinemia.

Inappropriate Use of Aztreonam Background: Aztreonam is not a preferred empiric antibiotic because of variable susceptibilities compared with alternative agents. In addition, it has no Gram-positive activity, necessitating coadministration with vancomycin when used empirically, and is more costly when compared with other Gram-negative active agents. Aztreonam is often given to patients with a reported penicillin allergy without further investigation into the reaction or other relevant allergy information. Study Question: How frequently is aztreonam being used inappropriately? Study Design: We conducted a retrospective chart review at an academic medical center to assess the appropriateness of our aztreonam use. Measures and Outcomes: Our primary outcome was frequency of appropriate aztreonam use, based on a true IgE-mediated allergy reported for each patient. We evaluated whether the patients had tolerated a beta-lactam in the past, and what the reported allergic reaction was. Results: We included 165 patients and found that 46.7% of our aztreonam use was inappropriate, based on previous use of a beta-lactam, or no documentation of an IgE-mediated response. Of the patients with a documented beta-lactam allergy, 63 (38.2%) patients had no allergy manifestation listed, and 37 (22.4%) patients had a non–IgE-mediated allergy manifestation. Of the total population, 61 (37%) patients had tolerated a beta-lactam in the past. Conclusions: Aztreonam should be avoided, except in the case of a true IgE-mediated allergic reaction. Our goal was to reduce the inappropriate use of aztreonam at our institution by one or more of the following: educating providers, reviewing aztreonam orders, requiring answering of order questions, or requiring an indication for use. Penicillin skin testing and desensitization are options as well.

Prevalence of Colorectal Neoplasms and Mortality in New Users of Low-Dose Aspirin With Lower Gastrointestinal Bleeding Background: Aspirin inhibits platelet function and may therefore accelerate early lower gastrointestinal bleeding (LGIB) from colorectal cancer (CRC) precursor polyps. The bleeding may increase endoscopic polyp detection. Study Question: To estimate the prevalence of polyps and CRC comparing new users of low-dose aspirin with nonusers who all received a diagnosis of LGIB and to investigate the mortality among these patients. Study Design: Using Danish nationwide health registries, we conducted a cohort study (2006–2013) of all new aspirin users who also received a diagnosis of LGIB (n = 40,578). Each new user was matched with 5 nonusers with LGIB by gender and age at the LGIB diagnosis date. Measures and Outcomes: We computed the prevalence and prevalence ratios (PRs) of colorectal polyps and CRCs, and the mortality ratios within 6 months after the LGIB, comparing new users with nonusers. Results: We identified 1038 new aspirin users and 5190 nonusers with LGIB. We observed 220 new users and 950 nonusers recorded with endoscopically detected polyps. New aspirin users had a higher prevalence of conventional {PR = 1.28 [95% confidence interval (CI): 1.06–1.55]} and serrated [PR = 1.31 (95% CI: 0.95–1.80)] polyps. New users and nonusers had a similar prevalence of CRC [PR = 1.04 (95% CI: 0.77–1.39)]. However, after stratifying by location of CRC, the prevalence of proximal tumors was lower [PR = 0.71 (95% CI: 0.35–1.43)] in new users than in nonusers. No difference in mortality was observed. Conclusions: These findings indicate that new use of low-dose aspirin is associated with an increased detection of colorectal polyps compared with nonuse.

Antithrombotic Therapy and Outcomes of Patients With New-Onset Transient Atrial Fibrillation After ST-Segment Elevation Myocardial Infarction Background: Atrial fibrillation (AF) is a common complication of ST-segment elevation myocardial infarction (STEMI), and AF might require anticoagulant treatment in some conditions. Study Question: There are no clear recommendations about vitamin K antagonist (VKA) use in patients with STEMI who complicated with new-onset transient AF. In this study, we examined the association of concomitant use of VKA and dual antiplatelet therapy (DAPT) with clinical outcomes of this patient population. Study Design: A total of 4086 patients with STEMI who underwent primary percutaneous coronary intervention retrospectively investigated. Among these patients, a total of 286 patients who developed new-onset transient AF during hospitalization were enrolled. VKA group consisted of 116 patients treated with warfarin, aspirin, and clopidogrel, and DAPT group consisted of 170 patients treated with aspirin and clopidogrel. Measures and Outcomes: One-year mortality, ischemic stroke, major, and minor bleeding were determined as clinical outcomes. Results: Although VKA group had proportionally lower mortality (17.2% vs. 20.0%) and ischemic stroke (7.8% vs. 11.8%) compared with DAPT group, the differences did not reach to statistical significance, whereas the 1-year major bleeding had higher rates at VKA group and that had 3.5-times higher major bleeding than DAPT group. This relationship was persisted after multivariable analysis (hazard ratio = 3.37, 95% CI, 1.76–10.04, P = 0.012). Conclusions: There is not a widely accepted treatment algorithm in patients with STEMI who complicated with new-onset AF in clinical guidelines. The current study indicated that transient form of new-onset AF might not require long-term VKA. Besides, addition of VKA to DAPT therapy may increase the rates of major and minor bleeding.

Topical Nifedipine for the Treatment of Pressure Ulcer: A Randomized, Placebo-Controlled Clinical Trial Background: Effect of nifedipine on pressure ulcer (PU) healing has not been evaluated in the human subjects yet. Study question: In this study, the effect of topical application of nifedipine 3% ointment on PU healing in critically ill patients was investigated. Study design: This was a randomized, double-blind, placebo-controlled clinical. Measures and outcomes: In this study, 200 patients with stage I or II PU according to 2-digit Stirling Pressure Ulcer Severity Scale were randomized to receive topical nifedipine 3% ointment or placebo twice daily for 14 days. Changes in the size and stage of the ulcers were considered as primary outcome of the study. The stage of the ulcers at baseline and on day 7 and day 14 of study was determined by using 2-digit stirling scale. In addition, the surface area of the wounds was estimated by multiplying width by length. Results: In total, 83 patients in each group completed the study. The groups were matched for the baseline stage and size of PUs. Mean decrease in the stage of PU in the nifedipine group was significantly higher than the placebo group on day 7 (−1.71 vs. −0.16, respectively, P < 0.001) and day 14 (−0.78 vs. −0.09, respectively, P < 0.001). Furthermore, the mean decrease in the surface area of PU was significantly higher in the nifedipine group compared with the placebo group on day 7 (−1.44 vs. −0.32, respectively, P < 0.001) and day 14 (−2.51 vs. −0.24, respectively, P < 0.001) of study. Conclusions: Topical application of nifedipine 3% ointment for 14 days significantly improved the healing process of stage I or II PUs in critically ill patients.

Comparing Nonopioids Versus Opioids for Acute Pain in the Emergency Department: A Literature Review Background: Pain is the most common reason for patient visits in the emergency department (ED). Opioids have been long considered the standard of care for acute pain in the ED. Because of the opioid crisis, investigation and implementation of novel practices to manage pain is needed. The use of various nonopioids has been suggested as a plausible alternative to opioids, with emerging literature to support its use for acute pain in the ED. Study Question: To evaluate the safety, efficacy, opioid-sparing effects of nonopioids in patients who present with acute pain in the ED. Data Sources: We systematically searched PubMed and EMBASE (July 1970 to January 2019). Study Design: Randomized controlled trials that evaluated nonopioids versus opioids in the ED were eligible. The clinical outcomes measured were change in pain scores compared with baseline, the incidence of adverse events, and use of rescue analgesia. Results: Twenty-five randomized controlled trials that evaluated the use of nonopioids in 2323 patients [acetaminophen (APAP) (n = 651), diclofenac (n = 547), ketamine (n = 272), ketorolac (n = 225), lidocaine (n = 219), ibuprofen (n = 162), ibuprofen & APAP (n = 162), hydroxyzine & dihydroergotamine (n = 85)] met inclusion criteria. Four trials found significant greater reductions in pain scores, favoring nonopioids. In all trials, the duration of pain relief provided by nonopioids was not sustained over an extended period. Eighteen trials reported no significant differences in reduction of pain scores. Two trials reported improved pain reduction with opioids and one trial reported noninferiority. Conclusions: Evidence from primary literature suggests that nonopioids could be a feasible alternative to opioids for management of acute pain in the ED as it is effective, safe, and decreases the need for rescue analgesia.

Treatment Failures of Direct Oral Anticoagulants Background: Use of direct oral anticoagulants (DOACs) has increased over the years, because they have become a safe and effective alternative to the Vitamin-K antagonists in various clinical scenarios. With their increased use, reports have emerged describing their failure. Study Question: What are the patient characteristics and clinical settings in which DOAC treatment failure manifests? Data Sources: We searched published reports in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until March 2019. Study Design: Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. Primary endpoints were new thrombus formation, failure of resolution of an existing thrombus, or discovery of subtherapeutic drug level. Other endpoints were time to treatment failure, manifestations of treatment failure, and new treatment after DOAC failure. Results: Our search yielded 51 manuscripts, describing 79 patients who exhibited DOAC failure. The most common treatment failures were in patients with antiphospholipid syndrome (44.3%), atrial fibrillation (30.4%), and deep venous thrombosis (6.3%). There was a trend toward higher failure rate for rivaroxaban (65.8%) followed by dabigatran (27.8%), apixaban (7.6%), and then edoxaban (1.3%). Each agent had different median failure times. Most common manifestations of treatment failure were stroke/transient ischemic attack (20.3%), pulmonary embolism (19.0%), and deep venous thrombosis (19.0%). More than half of patients were transitioned to a Vitamin-K antagonist after DOAC failure (55.7%). Conclusions: Our analysis illustrates that DOACs may fail in the setting of Food and Drug Administration and non–Food and Drug Administration- approved indications. In clinical practice, it may be best to choose between available anticoagulant drugs on a case-by-case basis.

Sodium–Glucose Cotransporter-2 Inhibitors and the Risk of Amputation: What Is Currently Known? Background: Diabetes mellitus is a major cause of morbidity and mortality in the United States. Twelve medication classes on the market reduce serum glucose including sodium–glucose cotransporter-2 (SGLT2) inhibitors. Potential benefits of these agents include improved glycemic control, weight loss, reduction in blood pressure, and possible reduction in cardiovascular events in patients with elevated cardiovascular risk. Areas of Uncertainty: Recently, several adverse events have been identified including increased possible risk of amputation associated with SGLT2 inhibitor therapy. Data Source: We conducted a review of published literature and identified 32 trials reviewing incidence of SGLT2 inhibitor-related amputation. Results: The potential increased risk for amputation is mostly of the lower extremities. Of the SGLT2 inhibitors currently available, canagliflozin has the highest association with an increased risk of lower extremity amputation and is the only agent with a Food and drug Administration Black Box Warning. Most canagliflozin amputation occurred in a single study. Risk factors for amputation with SGLT2 inhibitors may include those who have a history of amputations, susceptible to foot ulcers and those with baseline cardiovascular disease. Conclusions: For at-risk patients who desire an agent from this drug class, empagliflozin or dapagliflozin should be considered, as studies have not found a significant increase in amputations when compared with placebo or in retrospective reviews. Despite the increased risk of amputation found with canagliflozin, providers can use SGLT2 inhibitors with frequent monitoring to safely manage diabetes in low-risk patients. Patient education on associated risks is warranted. Diabetes educators can inform patients of risk factors to assist with monitoring.

Drug Repositioning in Oncology Background: The worldwide increase in the occurrence of cancer associated with the limitations of immunotherapy and the emergence of resistance have impaired the prognosis of cancer patients, which leads to the search for alternative treatment methods. Drug repositioning, a well-established process approved by regulatory agencies, is considered an alternative strategy for the fast identification of drugs, because it is relatively less costly and represents lower risks for patients. Areas of Uncertainty: We report the most relevant studies about drug repositioning in oncology, emphasizing that its implementation faces financial and regulatory obstacles, making the creation of incentives necessary to stimulate the involvement of the pharmaceutical industry. Data Sources: We present 63 studies in which 52 non-anticancer drugs with anticancer activity against a number of malignancies are described. Therapeutic Innovations: Some have already been the target of phase III studies, such as the Add-Aspirin trial for nonmetastatic solid tumors, as well as 9 other drugs (aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, and sertraline) in the CUSP9* clinical trial for the treatment of recurrent glioblastoma. Others have already been successful in repositioning such as thalidomide, zoledronic acid, celecoxib, methotrexate, and gemcitabine. Conclusions: Therefore, drug repositioning represents a promising alternative for the treatment of oncological disorders; however, the support from funding agencies and from the government is still needed, the latter regarding regulatory issues.

A New Safety Scoring System for the Use of Psychotropic Drugs During Lactation Background: Psychotropic drugs are frequently used to treat postpartum women with psychiatric diagnoses, especially psychotic disorder, major depression, and bipolar mood episodes. Pharmacotherapy in breastfeeding mothers is a major challenge. Study Question: This article presents a new safety scoring system for the use of psychotropic drugs during lactation. Study Design: The scoring system is based on the following 6 safety parameters: reported total sample, reported maximum relative infant dose, reported sample size for relative infant dose, infant plasma drug levels, prevalence of reported any adverse effect, and reported serious adverse effects. The total score ranges from 0 to 10. Higher scores represent a higher safety profile. Results: According to this scoring system, sertraline and paroxetine, respectively, had the highest scores representing "very good safety profile." Citalopram, olanzapine, and midazolam were assigned to "good safety profile." Among drugs evaluated in this article, trifluoperazine, aripiprazole, amisulpride, clozapine, doxepin, zaleplon, and zolpidem are not recommended owing to safety scores ≤3. Conclusions: Most psychotropic drugs examined in this article have "moderate" or "low" safety profile.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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