Larry K Golightly

University of Colorado Hospital, Denver, Colorado, United States

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Publications (9)17.78 Total impact

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    ABSTRACT: Abstract Background: Acute muscle injury and potentially fatal rhabdomyolysis may occur with use of statins and certain interacting medications. This investigation assessed risk for myopathy in patients receiving treatment with a statin in combination with daptomycin, a medication also associated with muscle injury. Methods: Patients hospitalized from July 1, 2005, through June 30, 2010, who received simvastatin or rosuvastatin concurrently with daptomycin were identified and their medical records were examined. Patients were judged to have treatment-related muscle injury if their records contained evidence of myalgia with or without weakness and secondarily impaired mobility together with elevated creatine kinase (CK) levels. These assessments were compared with similar data from hospitalized patients who received a statin alone. Results: A total of 52 patients received 66 courses of concurrent treatment with simvastatin or rosuvastatin and daptomycin. Of these, no patient (0%) met evidentiary requirements for diagnosis of myopathy or related complications. No patient (0%) developed muscle pain or discomfort and none developed markedly elevated CK levels. The incidence of asymptomatic elevations of CK in these simvastatin or rosuvastatin plus daptomycin recipients (9%) was statistically indistinguishable from the incidence of CK elevations found in a cohort of 105 inpatients who received simvastatin or rosuvastatin alone (21%; p=0.135). Conclusions: In patients receiving treatment with simvastatin or rosuvastatin and daptomycin, no symptoms or objective evidence of muscle injury attributable to a drug interaction were identified. These findings are consistent with data indicating that the myopathic effects of statins and daptomycin are incited by disparate and perhaps unique pharmacological mechanisms. Risk of muscle injury therefore appears to be no greater when a statin is administered with daptomycin than when either medication is used alone.
    Drug metabolism and drug interactions 01/2013;
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    ABSTRACT: Dipeptidyl peptidase-4 (DPP-4) inhibitors collectively comprise a presently unique form of disease management for persons with type 2 diabetes mellitus. The aim of this review is to compare the clinical pharmacokinetics of available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin) for the purpose of identifying potential selection preferences according to individual patient variables and co-morbidities. DPP-4 inhibitors are readily absorbed orally. Following oral ingestion, absorption occurs mainly in the small intestine, with median times to maximum (peak) plasma concentration ranging from 1 to 3 hours. The fraction of each dose absorbed ranges from approximately 30% with linagliptin to 75-87% for all others. Numerical differences in maximum (peak) plasma drug concentrations and areas under the plasma concentration-time curve among the DPP-4 inhibitors vary by an order of magnitude. However, functional capacity measured in terms of glucose-lowering ability remains comparable among all available DPP-4 inhibitors. Distribution of DPP-4 inhibitors is strongly influenced by both lipophilicity and protein binding. Apparent volumes of distribution (V(d)) for most agents range from 70 to 300 L. Linagliptin exhibits a V(d) of more than 1000 L, indicating widespread distribution into tissues. Binding to target proteins in plasma and peripheral tissues exerts a major influence upon broadening linagliptin distribution. DPP-4 inhibitor metabolism is widely variable, with reported terminal half-lives ranging from approximately 3 to more than 200 hours. Complex relationships between rates of receptor binding and dissociation appear to strongly influence the durations of action of those DPP-4 inhibitors with comparatively shorter half-lives. Durations of activity often are not reflective of clearance and, with the exception of vildagliptin which may be administered either once daily in the evening or twice daily, these medications are effective when used with a once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With the exception of the primary hydroxylated metabolite of saxagliptin, which is 2-fold less potent than its parent molecule, metabolic products of hepatic biotransformation are minimally active and none appreciably contribute to either the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Accordingly, the number of clinically significant drug-drug interactions associated with these agents is minimal, with only saxagliptin necessitating dose adjustment if administered concurrently with medications that strongly inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large majority (85%) of the absorbed dose eliminated in faeces via biliary excretion. Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of each dose eliminated as unchanged parent compound in the urine. Systematic reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors in patients with type 2 diabetes generally is similar. Apart from these generalizations, pharmacokinetic distinctions that potentially influence product selection are tentative. When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.
    Clinical Pharmacokinetics 06/2012; 51(8):501-14. · 5.49 Impact Factor
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    Michael A Jones, Larry K Golightly, Nancy M Stolpman
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    ABSTRACT: Measurement of serum creatinine concentration is central to evaluation of kidney function. Recent efforts to increase the accuracy of this evaluation have led to recalibration of laboratory instruments. Recalibrated creatinine concentrations often are lower than previously reported. To derive a method for converting recalibrated serum creatinine (RSCr) concentrations into values that are compatible with recommended equations for calculation of estimated creatinine clearance. Beginning with a proprietary array of recalibrated and corresponding non-recalibrated serum creatinine (NR-SCr) numerical data provided by the instrument manufacturer, relationships were examined with exponential and linear regression analyses. The validity of derived values for NR-SCr obtained through these analyses was tested by comparison of proprietary and derived serum creatinine concentrations and calculated creatinine clearance values. Analyses revealed that relationships between R-SCr and NR-SCr creatinine were essentially linear. Rearranging and solving the equation for a straight line described this relationship as x = (y - b)/m, where x is the derived creatinine value, y is the R-SCr concentration, and, for our laboratory instrument, best parameters for m and b equal to 0.987 and -0.07, respectively. Use of these parameters to derive NR-SCr values was shown to significantly decrease positive bias in subsequent creatinine clearance calculations. As compared to R-SCr concentrations, use of derived NR-SCr values can improve the predictive performance of conventional equations used to calculate estimated creatinine clearance.
    Annals of Pharmacotherapy 06/2011; 45(6):748-56. · 2.92 Impact Factor
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    ABSTRACT: Prompted by the advent of potentially life-threatening neuromuscular symptoms following initiation of linezolid therapy in two patients receiving treatment with a serotonin reuptake inhibitor antidepressant, an evaluation was conducted to determine the incidence and characteristics of symptomatic serotonin toxicity among hospitalized patients receiving combined treatment with these medications. Patients admitted between January 1, 2006 and August 30, 2008 who received linezolid concurrently with citalopram or escitalopram were identified and their medical records were examined. Patients were judged to have serotonin toxicity if their records contained documentation of clinical evidence adequate to fulfill requisites of the Hunter Serotonin Toxicity Criteria. Severity of serotonin-related symptoms was graded according to previously established criteria. During the period of observation, 24 patients received concurrent treatment with linezolid and citalopram or escitalopram. Of these, one patient (4%) treated with citalopram met evidentiary requirements for diagnosis of serotonin toxicity. The severity of symptoms in this patient was graded as mild. No evidence of serious harm related to a possible drug interaction was identified. Severe symptoms associated with serotonin toxicity were shown to be uncommon in patients receiving linezolid and selected serotonin reuptake inhibitors. Nonetheless, serious interaction-related toxicity has been observed at our institution and reported in detail by others. Accordingly, concurrent use of these medications is categorized as contraindicated. Alternative antimicrobial therapy should be instituted in most cases. If no suitable alternative is available, recipient patients should be hospitalized for expectant observation and rigorous monitoring.
    Drug metabolism and drug interactions 12/2010; 25(1-4):41-7.
  • Amy C. Go, Larry K. Golightly
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    ABSTRACT: Purpose: The oxazolidinone antibiotic linezolid is a nonselective reversible monoamine oxidase inhibitor. Prompted by the advent of life-threatening neuromuscular symptoms following initiation of linezolid therapy in a patient receiving treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant, this evaluation was conducted to determine the incidence and characteristics of symptomatic serotonin toxicity among hospitalized patients receiving combined treatment with these medications. Methods: Patients admitted between January 1, 2006 and August 30, 2008 who received linezolid concurrently with citalopram or escitalopram were identified and their medical records were examined. Patients were judged to have serotonin toxicity if their records contained documentation of clinical evidence adequate to fulfill requisites of the Hunter Serotonin toxicity Criteria (myoclonus, agitation, diaphoresis, tremor, and/or hyperreflexia [Dunkley et al, Q J Med 2003;96:635-42]). Severity of serotonin-related symptoms was graded according to standard criteria (Boyer et al, N Engl J Med 2005;232:1112-20). Results: During the period of observation, 24 patients received concurrent treatment with linezolid and citalopram or escitalopram. Of these, one patient (4%) treated with linezolid and citalopram met evidentiary requirements for diagnosis of serotonin toxicity. The severity of symptoms in this patient was graded as mild. No evidence of serious harm related to a possible drug interaction was identified. Conclusions: As suggested by other surveillance reports, severe symptoms associated with serotonin toxicity were shown to be uncommon in patients receiving linezolid and selected SSRIs. Nonetheless, serious interaction-related toxicity has been reported in detail and these medications in combination accordingly are categorized as contraindicated. When ordered, individual prescribers should be fully informed and alternative antimicrobial therapy should be considered. If no suitable alternative is available, recipient patients should be carefully monitored.
    2009 American College of Clinical Pharmacy Annual Meeting; 10/2009
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    ABSTRACT: To evaluate the drug interactions between valproic acid (VPA) and carbapenem antibiotics. The effects of concurrent use of VPA and carbapenem antibiotics were evaluated in a retrospective observational study of hospitalized adults. Patients receiving both VPA and a carbapenem with at least two plasma VPA concentrations serially measured prior to, during, and/or after this combined treatment were included. Six critically ill VPA-treated patients were identified who concurrently received meropenem (n=4), imipenem (n=1), or ertapenem (n=1). As compared with values obtained while not receiving treatment with the carbapenem, mean plasma VPA trough concentrations decreased by 58% (from 51.7 [95% confidence interval {CI} 28.0-75.4] to 21.8 [95% CI 11.1-32.5] mg/L; p = 0.025). Estimated mean VPA clearance increased by 191% (from 0.0158 [95% CI 0.0041-0.0275] to 0.0302 [95% CI 0.0169-0.0591] L/h/kg; p = 0.007). All VPA concentrations measured during concurrent VPA-carbapenem treatment were below the lower boundary of the usual therapeutic range. Five patients (83%) experienced generalized seizures during concurrent VPA-carbapenem treatment, including two with no prior history of seizures or epilepsy. All recipients showed evidence of a complex pharmacokinetic and pharmacodynamic drug interaction between VPA and a carbapenem. Concurrent use of these medications should be avoided.
    Drug metabolism and drug interactions 01/2009; 24(2-4):153-82.
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    ABSTRACT: Recombinant human coagulation factor VIIa (rVIIa) is a procoagulant indicated for treatment of bleeding in patients with hemophilia. A large proportion of rVIIa utilization is for off-label administration in nonhemophiliac patients with acute hemorrhage. Concerns of potentially inappropriate use, safety, and cost of rVIIa led to efforts to standardize use of this agent. To comparatively describe the utilization of rVIIa upon implementation of an evidence-based guideline at a university hospital. With advisory direction from a multidisciplinary task force, an evidence-based guideline for use of rVIIa was developed, approved, and fully implemented. Assessment of appropriateness of use and retrospective review were required for all cases. Effects of these actions were evaluated by auditing and comparing rVIIa use in patients treated in two 6-month observation periods before and after guideline implementation. Outcomes assessed were proportions of patients deemed appropriate to receive rVIIa, compliance with dosing recommendations, and acquisition costs. Twenty-two and 29 patients were treated in the periods before and after guideline implementation, respectively. Patient characteristics were similar, except more cardiothoracic surgeries were performed in patients treated before implementation of the guideline. Indications for rVIIa use were judged appropriate in 21 (95.5%) before-cases and in all (100%) after-cases. The dose was compliant in 1 (4.6%) before-case and 27 (93.1%) after-cases (p < 0.001). Mean dosages of rVIIa administered were 81.8 microg/kg and 45.3 microg/kg in before- and after-cases, respectively (p < 0.001). During the respective periods of observation, amounts of rVIIa purchased monthly averaged 42.6 mg and 21.8 mg, a 49% difference. Semiannual expenditures for rVIIa decreased approximately $110,000 following guideline implementation. Patient outcomes were similar. A guideline based on currently available evidence can serve to sustain the clinical appropriateness of rVIIa therapy and substantially decrease costs.
    Annals of Pharmacotherapy 06/2008; 42(6):771-6. · 2.92 Impact Factor
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    ABSTRACT: To determine the efficiency and effectiveness of current prescribing practices relative to short- and intermediate-acting insulins in the prevention or treatment of acute hyperglycemic episodes in hospitalized patients with diabetes mellitus or hyperglycemia, and to identify clinical findings that influence the effectiveness of insulin therapy in these patients. Retrospective observational study. University-affiliated hospital. Ninety consecutive adult inpatients who had orders placed for as-needed subcutaneous regular or lispro sliding-scale insulin. Medical records were reviewed for patients' clinical characteristics and responses to administered insulin that were recorded during each of the first 5 days of hospitalization in which sliding-scale insulin therapy was used. Despite the immediate or bedside availability of both computerized and manual means to record finger-stick blood glucose levels and insulin injections, uncertainties or missing information related to execution, timing, blood glucose levels, or insulin dose were present in approximately 30% of all anticipated points of care involving insulin. Ten episodes of hypoglycemia in six patients were associated with sliding-scale insulin. Appropriately timed, successive glucose measurements documented a decrement in elevated blood glucose values to within the target range of 90-130 mg/dl after 76 (12%) of 621 sliding-scale insulin injections. Glucose levels remained elevated, and insulin effects were therefore subtherapeutic after 523 injections (84%). Despite blood glucose levels that remained persistently elevated, corresponding adjustments in either the timing or the dose of insulin were made infrequently. Sliding-scale insulin regimens were never adjusted in 73 patients (81%). Through 5 days of therapy, the proportion of patients who attained good glycemic control ranged from 2-10% (mean 6%). The mode of overall glycemic control was poor, with 51-68% of patients in this category on any given day. Overall, treated diabetic and hyperglycemic patients were more likely to be poorly controlled than relatively well controlled. Our findings reveal outcomes associated with sliding-scale insulin that are widely variable, often ineffectual, and prone to deficiencies in monitoring, documentation, and prescribing soundness. Efforts to improve glycemic control in hospitalized patients are clearly needed.
    Pharmacotherapy 11/2006; 26(10):1421-32. · 2.31 Impact Factor
  • Larry K Golightly, Leon S Greos
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    ABSTRACT: Antihistamines are useful medications for the treatment of a variety of allergic disorders. Second-generation antihistamines avidly and selectively bind to peripheral histamine H1 receptors and, consequently, provide gratifying relief of histamine-mediated symptoms in a majority of atopic patients. This tight receptor specificity additionally leads to few effects on other neuronal or hormonal systems, with the result that adverse effects associated with these medications, with the exception of noticeable sedation in about 10% of cetirizine-treated patients, resemble those of placebo overall. Similarly, serious adverse drug reactions and interactions are uncommon with these medicines. Therapeutic interchange to one of the available second-generation antihistamines is a reasonable approach to limiting an institutional formulary, and adoption of such a policy has proven capable of creating substantial cost savings. Differences in overall efficacy and safety between available second-generation antihistamines, when administered in equivalent dosages, are not large. However, among the antihistamines presently available, fexofenadine may offer the best overall balance of effectiveness and safety, and this agent is an appropriate selection for initial or switch therapy for most patients with mild or moderate allergic symptoms. Cetirizine is the most potent antihistamine available and has been subjected to more clinical study than any other. This agent is appropriate for patients proven unresponsive to other antihistamines and for those with the most severe symptoms who might benefit from antihistamine treatment of the highest potency that can be dose-titrated up to maximal intensity.
    Drugs 02/2005; 65(3):341-84. · 4.13 Impact Factor