Statin-Associated Autoimmune Myopathy: Review of the Literature.

Objective: Statin-associated autoimmune myopathy (SAAM) is a rare adverse event characterized by progressive muscle symptoms despite discontinuation, requiring immunosuppressive therapy for remission. The objective of this review was to characterize SAAM, for timely detection, while examining the literature for effective treatment considerations. Methods: PubMed search was conducted from 2010 to 2020 was for relevant case series and studies of at least 8 patients displaying muscle discomfort or weakness, anti-HMGCR antibodies, exposure to statins, and biopsies consistent with SAAM. Results: Three case series and 3 case cohort studies identified 199 patients with SAAM. Exhibiting a mean age of 63.74 years, patients were more likely Caucasian (81%) and female (1.2X), and required a mean duration of 4.75 years before symptomatic. The presentation involved proximal muscle weakness (94%), myalgias (37%) and dysphagia (23%), accompanied by a mean creatinine kinase of 6383 IU/L. Most patients (57%) required 2 or more immunosuppressive (IMS) agents to achieve 62% remission. After 2 years of treatment, 15% of patients without remission reported symptomatic improvement, while another 12% were refractory to treatment. Conclusion: Delayed onset of SAAM greater than 4 years from statin initiation may create a low index of suspicion. However, progression of symptoms beyond 2 months from statin discontinuation and positive anti-HMGCR antibodies requires immunosuppressive agents. Data and expert opinion support use of at least two IMS medications upon diagnosis for a minimum of 2 years. Therapy success depends on timely recognition and initiation of IMS combinations to achieve earlier remission and symptomatic improvement.

Statin Associated Autoimmune Myonecrosis: Case Report With Delayed Onset and Treatment Challenges.

PURPOSE: A case of delayed statin associated autoimmune myopathy (SAAM) is presented along with review of clinical findings and treatment strategies. SUMMARY: A 54 year old male presented with proximal extremity weakness, difficulty ambulating, and dysphagia. Symptoms began when restarting atorvastatin 40 mg daily for a recent NSTEMI, following 10 years of statin use, interrupted after diagnosis of NASH. Relevant labs included CK of 13,618 IU/L, ALT/ AST of 568/407 IU/L, while additional liver, renal, and toxicology tests were normal. Following treatment response to prednisone 40 mg daily for 3 days, outpatient testing for anti-HMGCR antibodies was ordered.Twelve days from discharge, the patient was readmitted for myalgia and dysphagia, CK = 6042 IU/L, ALT/AST = 360/112 IU/L, and positive anti-HMGCR antibodies. Newly diagnosed with SAAM, symptoms improved with methylprednisolone and intravenous immunoglobulin (IVIG), continuing outpatient as daily prednisone and monthly IVIG. Four days later, the patient relapsed with worsened weakness and dysphagia, CK = 5812 IU/L, and ALT/AST = 647/337 IU/L. After response to methylprednisolone and rituximab, the patient was discharged on a corticosteroid taper, biweekly rituximab, and monthly IVIG. Two weeks later, a final admission involved a syncopal episode and fall, with a CK = 1461 IU/L. Treatment included IVIG, rituximab, and corticosteroid taper, which lead to remission for greater than 6 months. CONCLUSION: Statin associated autoimmune myopathy occurred when restarting atorvastatin, following 10 years of statin use. Clinical findings and positive anti-HMGCR antibodies confirmed the diagnosis. Recurrent relapses required triple combination therapy including addition of rituximab to achieve remission.

Succinylcholine-Induced Rhabdomyolysis in Adults: Case Report and Review of the Literature.

PURPOSE: A case of succinylcholine (SCh) and sevoflurane as a probable cause of rhabdomyolysis in an adult is presented, along with a review of the relevant literature and strategies for prevention. SUMMARY: A nondiabetic, morbidly obese 32-year-old female developed rhabdomyolysis after administration of SCh and sevoflurane for diagnostic procedures of 30 minutes' duration. Thirty-three hours following anesthesia, the patient developed diffuse muscle tenderness and progressive weakness with a creatinine kinase (CK) of 4319 U/L. Urinalysis findings indicated contamination, a white blood cells of 12.1 × 103/µL was stress induced, while all other labs were normal. Following 26 hours of intravenous fluids, the patient's CK decreased to 1243 U/L, with pain responsive to acetaminophen and improved mobility, resulting in discharge. With a lack of reasonable alternative causes and a temporal association of symptoms, procedural medication-induced rhabdomyolysis was suspected. Based on Naranjo scale evaluation, SCh and sevoflurane were probable causes of rhabdomyolysis. We reviewed the literature for SCh-induced rhabdomyolysis among adults and found 10 cases. The majority of patients received halogenated anesthesia (HA) and prophylaxis for SCh myopathy, with no known personal or family history of neuromuscular disorders (NMD) reported. CONCLUSION: Rhabdomyolysis was observed in a woman following the administration of SCh and sevoflurane for diagnostic procedures lasting 30 minutes. While avoidance is possible in adults with histories of NMDs, a high index of suspicion for occurrence of rhabdomyolysis is needed whenever combining SCh with HA in all adults.

Low-Dose Naloxone for Prophylaxis of Postoperative Nausea and Vomiting: A Systematic Review and Meta-analysis.

STUDY OBJECTIVE: To determine whether postoperative administration of low-dose intravenous naloxone decreases the incidence of postoperative nausea and vomiting (PONV) and its impact on postoperative opioid requirements and pain scores. DESIGN: Meta-analysis of nine randomized controlled trials. PATIENTS: A total of 946 adult and pediatric patients who received low-dose intravenous naloxone for 24 hours after various surgeries. MEASUREMENTS AND MAIN RESULTS: Systemic literature searches of the Cochrane Central Register of Controlled Trials, Evidence-Based Medicine Reviews, PubMed, and Ovid MEDLINE databases were conducted. Among the relevant studies, data extraction and bias assessment determined the trials for inclusion in this meta-analysis. Nine randomized controlled trials met inclusion criteria. Naloxone demonstrated a reduced risk of postoperative nausea (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.67-0.95, p=0.01) in a pooled analysis of eight of the nine studies. However, naloxone did not decrease the risk of postoperative vomiting in a collective assessment of all nine trials (RR 0.83, 95% CI 0.63-1.09, p=0.18). Subgroup analysis of continuous-infusion naloxone found further reductions in nausea and vomiting, but these findings were limited to 186 of the 946 patients. Three studies recorded antiemetic doses and found an overall dose reduction (RR 0.64, 95% CI 0.42-0.96, p=0.03). Compared with controls, naloxone prophylaxis of PONV did not significantly change cumulative postoperative opioid needs (mean difference 0.29 mg, 95% CI -3.55 to 4.13 mg, p=0.88) among five trials, nor visual analog scale pain scores (mean difference -0.11, 95% CI -0.26 to 0.05, p=0.18) in six studies. CONCLUSION: This pooled analysis of data suggests that low-dose naloxone plays no role in preventing PONV, while exhibiting no significant effects on postoperative opioid needs and pain scores. The reduction demonstrated in postoperative nausea did not translate into decreases in postoperative vomiting.

The Roles of ACE Inhibitors in Lower Extremity Peripheral Artery Disease.

Peripheral artery disease (PAD) is an age-dependent atherosclerotic disorder associated with an increased prevalence of cardiovascular morbidity and mortality. Approximately 35% of patients with PAD complain of lower extremity claudication, which may worsen to impair daily function. ACE inhibitors may possess vasoactive properties that improve symptoms of claudication. We designed a meta-analysis to quantify the effectiveness of ACE inhibitors on walking capacities in patients with lower extremity PAD. We reviewed MEDLINE and Cochrane databases from 1966 to 2013, in addition to relevant bibliographies to obtain our clinical trials. From the original findings, 4 randomized, placebo-controlled, double-blind studies qualified for inclusion. Using a random-effects model, ACE inhibitors were associated with an increase of 126 m [95% confidence interval (CI), -95 to 346] (P = 0.264) in maximal walking distance and a rise in Ankle-Brachial Index of 0.09 (95% CI, 0.024-0.205) (P = 0.12). However, pain-free walking distance was significantly increased by 86 m (95% CI, 13-156) (P = 0.021). Contradictions in study outcomes between more recent and earlier trials of ACE inhibitors in claudication impeded the interpretation of effectiveness. Early trials failed to demonstrate improvement in walking capacities, possibly because of omissions in patient enrollment criteria and inadequate sample size. Recent guidelines recommend consideration of ACE inhibitors in patients with PAD for cardioprotective effects. Although ACE inhibitors were well tolerated, vigilance for clinical predictors of renal arterial stenosis and renal instability after initiation will ensure safe administration in all patients with PAD.

Aclidinium bromide: an alternative long-acting inhaled anticholinergic in the management of chronic obstructive pulmonary disease.

OBJECTIVE: To evaluate the efficacy and safety of aclidinium bromide, a novel, long-acting inhaled muscarinic receptor antagonist approved by the Food and Drug Administration (FDA) in July 2012, as a treatment in the management of moderate to severe chronic obstructive pulmonary disease (COPD). DATA SOURCES: Literature was identified through PubMed/MEDLINE (2000-March 2013) and International Pharmaceutical Abstracts using the search terms aclidinium, COPD, chronic bronchitis, emphysema, anticholinergic, and muscarinic antagonist. In addition, US government websites, including fda.gov and clinicaltrials.gov, were reviewed for pertinent information. Forest Laboratories, Inc provided previously unpublished clinical trial data. All reference citations from identified publications were reviewed for possible inclusion. STUDY SELECTION AND DATA EXTRACTION: All identified Phase 1, 2a, 2b, and 3 studies evaluating the safety and efficacy of aclidinium bromide were reviewed. DATA SYNTHESIS: Once- and twice-daily aclidinium bromide was assessed for efficacy and safety in patients with moderate to severe COPD. In comparison to placebo, aclidinium significantly improves trough and peak forced expiratory volume in 1 second (FEV1). Significant increases in trough and peak FEV1 were sustainable for up to 64 weeks. In addition to improvement in trough and peak FEV1, twice-daily aclidinium 400 µg induced clinically meaningful improvements in the health status of patients with moderate to severe COPD. Aclidinium was generally well tolerated, with headache, cough, diarrhea, and nasopharyngitis the most common treatment-related adverse effects noted in clinical trials. Aclidinium did not demonstrate a difference in the incidence of systemic anticholinergic-associated adverse effects in comparison to placebo or active comparator. CONCLUSIONS: Aclidinium bromide is a novel, inhaled, long-acting anticholinergic that, when administered at the FDA-approved dose, safely produces clinically and statistically significant bronchodilation and improves health status in patients with moderate to severe COPD. Long-term clinical trials assessing the efficacy and safety of aclidinium are warranted.

Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease.

PURPOSE: Special considerations in the selection of medication inhaler devices for elderly patients with chronic obstructive pulmonary disease (COPD) in the ambulatory care setting are reviewed. SUMMARY: Substantial deficiencies in inhaler device technique and medication adherence are evident in patients with COPD, leading to suboptimal health outcomes. As the prevalence of COPD rises with age, elderly patients pose special challenges with regard to inhaler device selection. In elderly patients with sufficient cognitive function, manual dexterity, and hand strength, the most influential factors in inhaler selection are cost reimbursement, device availability, device convenience, and patient preference. Cost reimbursement may be a deciding factor in device selection, as nearly all elderly patients are Medicare beneficiaries. Nebulizers provide a cost-effective alternative to pressurized metered-dose inhaler (pMDI) and dry powder inhaler (DPI) devices. DPI device availability is limited to "controller" medications, while pMDI devices and nebulizers provide complete symptomatic coverage. Multiple-dose DPIs offer the convenience of rapid medication administration, ease of handling, and integral dose counters. Given the availability and expenses of medication devices, ambulatory patients may prefer combining the convenience of a hand-held inhaler (i.e., pMDI) as a rescue medication during the active hours of midday with the cost savings of a nebulized controller medication in the morning and at night. CONCLUSION: In elderly patients with sufficient cognitive function, manual dexterity, and hand strength, the most important factors in inhaler device selection are cost reimbursement issues, device availability, device convenience, and patient preference. Pharmacist knowledge of appropriate inhaler technique, competent patient education and demonstration, and follow-up assessment are instrumental in optimizing device competency and medication adherence.

Urate-lowering therapy for gout: focus on febuxostat.

Gout is a common, painful, and often debilitating rheumatologic disorder that remains one of the few arthritic conditions that can be diagnosed with certainty and cured with appropriate therapy. Allopurinol is the most frequently prescribed agent for gout in the United States. Unfortunately, most patients treated with allopurinol do not achieve target serum uric acid (sUA) levels, possibly due to a perceived intolerability to allopurinol in doses above 300 mg and the need for reduced doses in patients with renal insufficiency. Febuxostat, an orally administered, nonpurine inhibitor of xanthine oxidase, was recently approved by the U.S. Food and Drug administration for chronic management of hyperuricemia in patients with gout. Patients treated with febuxostat achieve rapid and substantial reductions in sUA levels. Compared with allopurinol-treated patients, patients receiving febuxostat 80 mg/day were more likely to achieve sUA concentrations less than 6 mg/dl. In long-term studies (up to 5 yrs), febuxostat demonstrated sustained reductions in sUA levels, nearly complete elimination of gout flares, and a frequency of adverse effects comparable to allopurinol. The most commonly reported adverse effects were liver function abnormalities, rash, nausea, and arthralgias. The recommended starting dose of febuxostat is 40 mg/day, which may be increased to 80 mg/day after 2 weeks if patients do not achieve sUA levels less than 6 mg/dl. Dosage adjustment in mild-to-moderate renal insufficiency is unnecessary; however, data are lacking on the safety of febuxostat in patients with severe renal impairment. Although more costly than allopurinol, febuxostat appears to be an acceptable alternative for the treatment of gout and hyperuricemia, and may be advantageous in patients with renal impairment, intolerance to allopurinol, or the inability to attain sUA levels less than 6 mg/dl despite adequate therapy with available agents.

Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review.

BACKGROUND: Lactobacilli are the dominant bacteria of the vaginal flora and possess antimicrobial properties that regulate other urogenital microbiota. Incomplete cure and recurrence of genitourinary infections lead to a shift in the local flora from a predominance of lactobacilli to coliform uropathogens. Use of Lactobacillus-containing probiotics to restore commensal vaginal flora has been proposed for the treatment and prophylaxis of bacterial urogenital infections. OBJECTIVE: This review summarizes randomized controlled trials that have assessed the therapeutic efficacy and tolerability of lactobacilli in bacterial vaginosis (BV) and urinary tract infection (UTI). METHODS: Relevant randomized controlled trials published in English were identified through a search of MEDLINE (through November 2007), ClinicalTrials.gov, and the Cochrane Database (second quarter 2007). The search terms included probiotics, Lactobacillus, lactobacilli, urinary, urogenic, bacterial vaginosis, vaginal, colonization, bacteremia, sepsis, pathogenic, taxonomy, diagnosis, and infections. RESULTS: Eleven randomized controlled trials were identified that investigated the effects of lactobacilli in the treatment and prophylaxis of bacterial urogenital infections. In the 2 studies that reported a beneficial effect for probiotics in the treatment of BV, cure rates for lactobacilli at 30 days were 60% (P=0.004) and 88% (P<0.005), more than double the effect of controls. One trial reported a 35% reduction in recurrent episodes of BV compared with placebo (P=0.004). Among the 4 trials involving treatment of UTI, 1 reported a 73% reduction in episodes of recurrent UTI compared with the previous year (P=0.001). Seven studies found no therapeutic effect of lactobacilli in the treatment or prophylaxis of BV or UTI. Only 2 of the identified trials attempted to validate the probiotic dosing strategy by obtaining quantitative evidence of local colonization with lactobacilli and had sufficient power to detect treatment effects, and only 1 trial addressed the stability of the probiotic product at the end of the study. CONCLUSIONS: Despite enhanced cure rates in some studies, concerns about product stability and limited documentation of strain-specific effects prevent recommendations for the use of Lactobacillus-containing probiotics in the treatment of BV. The results of studies of lactobacilli for the prophylaxis of UTI remain inconclusive as a result of small sample sizes and use of unvalidated dosing strategies.

Evaluation of personal digital assistant software for drug interactions.

PURPOSE: The accuracy, comprehensiveness, and ease of use of drug interaction software used with personal digital assistants (PDAs) were studied. METHODS: Each program was assessed for accuracy using 40 clinically important and 40 clinically unimportant drug interaction pairs. Accuracy was scored through the summation of software sensitivity, specificity, and positive and negative predictive values. The comprehensiveness of each program was determined by the number of components in the drug interaction monograph. Time needed to identify the management of five important drug interactions defined each program's ease of use. The aggregate scores for accuracy, comprehensiveness, and ease of use were calculated. RESULTS: Scoring 777 and 756 out of a possible 800 points, iFacts and Lexi-lnteract, respectively, provided the most competent, complete, use-friendly compendia for assessment of drug interactions. Mosby's Drug Consult and Mobile Micromedex ranked third and fourth, scoring 688 and 655 points, respectively, while ePocrates Rx v. 6.0 rated seventh, with a score of 559. All drug interaction resources suffer from limitations in the quality or relevance of evidence for the interaction, an absence of identifiable patient and medication risk factors, and a lack of standardization in assigning significance to the interaction. Consequently, clinicians must interpret the importance of the interaction based on all available evidence. Discussion of such evidence was available for only iFacts and Lexi-Interact. CONCLUSION: Both iFacts and Lexi-Interact excelled as PDA pharmacopoeia for assessing drug interactions. However, clinicians should understand the limitations of all current drug interaction resources and exercise vigilance in prevention and recognition of interactions relevant to their patients.

A Review of Post--Cardiopulmonary Bypass Bleeding, Aminocaproic Acid, Tranexamic Acid, and Aprotinin.

OBJECTIVE: To review the mechanism and cause of hemostatic defects following cardiopulmonary bypass (CPB) and determine the safety and efficacy of antifibrinolytic agents for use in cardiac surgery and patients likely to benefit. DATA SOURCES: A MEDLINE search (1966 to present) of the English-language literature pertaining to aminocaproic acid (ACA), tranexamic acid (TA), and aprotinin was performed. Additional literature was obtained from reference citations of pertinent articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: While all articles of relevance were considered for inclusion, this review evaluates only clinical trials with emphasis on prospective, randomized, controlled studies. DATA SYNTHESIS: In reported trials, ACA and TA each reduce mediastinal blood losses by about one-third, while transfusion needs remain unchanged. ACA and TA dosing inconsistencies, omission of transfusion criteria, and unidentified surgical risk factors prevent optimal findings. Thromboembolic complications could not be ascribed to either ACA or TA in more than 950 patients studied. Aprotinin decreased mean mediastinal blood losses by 42%, 67% and 48% in primary coronary artery bypass grafting (CABG), reoperative CABG, and in CABG patients receiving aspirin, respectively. Transfusion needs were reduced 42% in primary CABG patients and 55% to 88% in high-risk patients. Patients at high risk of bleeding (i.e., reoperative CABG and patients on aspirin) demonstrated greater transfusion needs and blood loss than primary CABG patients. As blood conservation measures may eliminate the need for transfusions among primary CABG patients, patients at higher risk may benefit most from the addition of antifibrinolytic prophylaxis. CONCLUSION: The efficacy of all antifibrinolytic agents in cardiac surgery has been established, but comparative data is inconclusive to suggest an agent of choice. Thromboembolic complications have been rare and difficult to ascribe to antifibrinolytic agents. Future trials comparing efficacy of agents in high risk patients and rigorously evaluating thromboembolic events will allow unconditional recommendations.