Drug-Induced Ototoxicity: A Comprehensive Review and Reference Guide.

OBJECTIVE: In an era of increasing polypharmacy, adverse drug effects such as ototoxicity have significant public health implications. Despite the availability of evidence, many health care professionals may not know the risk of ototoxicity in common medications. Therefore, the aim of this review is to provide a comprehensive, easy to use, ototoxic profile of medications with an assessment of supporting evidence. METHODS: Medications of interest were identified through adverse drug reaction reports derived from Micromedex (IBM), Lexicomp (Wolters Kluwer), and the textbook, Drug Induced Diseases: Prevention, Detection, and Management. Additional evidence was identified though a query of PubMed and the Cochrane database. Evidence of causality was graded according to the following: A (randomized, controlled clinical trials), B (nonrandomized clinical trials, prospective observational studies, cohort studies, retrospective studies, case-controlled studies, and/or postmarketing surveillance studies), and C (case reports/case series). RESULTS: A total of 194 systemically administered medications associated with ototoxicity were identified, most commonly antimicrobials (53), psychotropics (21), antihypertensive/antiarrhythmics (19), nonsteroidal antiinflammatory drugs (18), and antineoplastics (16). There was evidence of cochleotoxicity in 165 medications (evidence grading A [22], B [77], C [69]), vestibulotoxicity in 100 medications (evidence grading A [23], B [47], and C [30]), and dizziness in 142 medications (evidence grading A [50], B [76], and C [16]). In addition, a review of the evidence of ototoxicity in ototopical medications is also reviewed. CONCLUSION: The effect and severity of ototoxicity can vary immensely depending on pharmacological and individual patient risk factors. The intent of this comprehensive review was to help health care providers of all sectors obtain a deeper knowledge of drug-induced ototoxicity to make more informed management decisions for their patients.

Riociguat: a novel new drug for treatment of pulmonary hypertension.

Riociguat is the first approved medication from the novel class of soluble guanylate cyclase (sGC) stimulators and the only agent approved for treating both chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH). The novel mechanism of riociguat lies in its ability to restore the homeostatic and therapeutic effects of nitric oxide that are diminished as a result of phenotypic alterations associated with pulmonary hypertension (PH). Improvements in 6-minute walk distance (6MWD) in patients with PAH during the phase 3 PATENT-1 trial were comparable to other oral agents approved for the treatment of PAH. Improvements in 6MWD in patients with CTEPH during the phase 3 CHEST-1 trial were greater than those previously observed with other oral PAH-directed therapies. Hypotension is the dose-limiting adverse effect of riociguat and dose titration is performed gradually according to systolic blood pressure. Riociguat was tolerated at maximal doses by most patients during PATENT-1 and CHEST-1 and was well tolerated during long-term extension studies. Key factors to consider with riociguat are a patient's systolic blood pressure, drug interactions mediated by CYP1A1, CYP3A4, and P-glycoprotein, cost, and teratogenicity requiring enrollment in a Risk Evaluation and Mitigation Strategy program. Recently published guidelines recommend riociguat monotherapy as an option for treatment-naïve patients with World Health Organization Functional Class (WHO FC) II or III symptoms or as add-on therapy for patients with persistent WHO FC III or IV symptoms being treated with an ERA or inhaled prostanoid. Postmarketing experience and ongoing clinical investigations will further define the safety and role of riociguat in patients with PAH and other types of PH.

Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring.

BACKGROUND: Aerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable serum concentrations. We assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing. METHODS: Twenty adult CF patients admitted to the hospital for treatment of a pulmonary exacerbation were enrolled. PK parameters of tobramycin were calculated before and after introduction of TIS, which was given 5-9 h after the IV dose. RESULTS: Nine patients had a clinically significant change in tobramycin trough concentration. Fourteen patients had a reduced calculated elimination rate constant after TIS administration, which may be misinterpreted as a decreased clearance of IV tobramycin. CONCLUSION: Trough tobramycin concentrations were significantly influenced in some CF patients (45%), suggesting that timing of the inhaled dose should be considered when interpreting PK measures of IV tobramycin dosing.

Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.

BACKGROUND: Most issues concerning pharmacotherapy of pulmonary sarcoidosis have not been resolved in clinical trials. The objective was to survey sarcoidosis experts concerning the treatment of pulmonary sarcoidosis and attempt to reach a consensus by these experts using a Delphi method. METHODS: A 6-item questionnaire was developed. Experts were identified at the Diffuse Lung Disease Network at the annual CHEST meeting in October 2008. Three rounds of questionnaires were presented to the experts. Respondent feedback and supporting literature was incorporated into the questionnaires of subsequent rounds. RESULTS: Experts reached a consensus concerning the following issues: (a) corticosteroids are the initial therapy of choice; (b) initial use of inhaled corticosteroids are not recommended; (c) methotrexate was the preferred second-line drug; (d) 40mg of daily prednisone equivalent was the maximum dose recommended for the treatment of acute pulmonary sarcoidosis; (e) tapering to 10mg of daily prednisone equivalent for chronic pulmonary sarcoidosis was considered a successful taper. The experts could not resolve the following issues: (a) the initial corticosteroid dose for the treatment of acute pulmonary sarcoidosis; (b) the decision and timing of corticosteroid therapy in a patient with mild, Stage 2 pulmonary sarcoidosis. CONCLUSIONS: This Delphi study revealed that sarcoidosis experts reached a consensus concerning several aspects of the treatment of pulmonary sarcoidosis; these could be considered as appropriate approaches to therapy. Other issues concerning the therapy of pulmonary sarcoidosis remain unresolved by experts, and are areas where further clinical research could be directed.

Efficacy of short-course, low-dose corticosteroid therapy for acute pulmonary sarcoidosis exacerbations.

BACKGROUND: Although corticosteroids are the drug of choice for acute exacerbations of pulmonary sarcoidosis, the dose and duration of therapy is not standardized. We reviewed the short-term treatment outcome (median duration = 21 days) of 36 patients with acute exacerbations of pulmonary sarcoidosis using low-dose corticosteroid therapy (20 mg or less of daily prednisone equivalent). To the best of our knowledge, this is the shortest period of time over which the treatment of pulmonary sarcoidosis with corticosteroids has been assessed. METHODS: Patients were identified retrospectively from an institution-approved database. Patient symptoms and spirometry were obtained from chart review. Additional clinical data were obtained from chart and database review. RESULTS: Follow-up visits occurred a median of 21 days after the date of the exacerbation (mean 25 +/- 3 standard error of mean). The average prednisone dose was 19 mg +/- 0.4 standard error of mean. Patients had significant improvement in spirometry on this low-dose treatment regimen by the time of their short-term follow-up (forced vital capacity percent predicted improved from 68 to 82 [P < 0.0001] and was not significantly different from baseline; forced expiratory volume in 1 second percent predicted improved from 57 to 72 [P < 0.0001] and was not significantly different from baseline). Pulmonary symptoms also improved. CONCLUSIONS: Treatment of acute exacerbations of pulmonary sarcoidosis with 20 mg prednisone for a median of 21 days improved spirometry back to baseline and improved clinical symptoms. These data suggest that this corticosteroid dose can be safely used initially, and an attempt at tapering can be considered within the first month.