Role of Topical 5-Fluorouracil in Demodex -Associated Blepharitis.

PURPOSE: The aim of this study was to report clinical observations suggesting the efficacy of topical 1% 5-fluorouracil (5-FU) in treating Demodex -associated blepharitis. METHODS: An observational retrospective review of 13 eyes from 13 individuals with conjunctival neoplastic lesions and concomitant Demodex lash infestation that received topical 1% 5-FU eye drops. Patients underwent slit-lamp examination at each follow-up visit. Clinical photographs of the lash line were obtained after treatment initiation. In a subset of patients, lashes were epilated bilaterally and microscopically analyzed for presence of Demodex mites before and after treatment initiation. RESULTS: The mean age of the population was 68 ± 14 years (range: 30-84 years) and 92% were male. In all 13 patients, a marked reduction in cylindrical dandruff was noted in the treated eye by slit-lamp examination after 2 cycles of 5-FU. There was complete resolution of cylindrical dandruff in 10 of 13 treated eyes compared with 0 resolution of cylindrical dandruff in untreated eyes ( P = 0.0001). In the 6 patients who received epilation, the lashes from the treated eye showed no Demodex , whereas lashes from the fellow untreated eye revealed persistent Demodex . CONCLUSIONS: Topical 1% 5-FU shows efficacy in treating Demodex -associated blepharitis. Further studies are indicated to reproduce our findings and evaluate the potential use of 5-FU as a treatment ingredient.

Outcomes of a Medication Optimization Virtual Interdisciplinary Geriatric Specialist (MOVING) Program: A Feasibility Study.

BACKGROUND: Adverse drug events among older adults result in significant mortality, morbidity and cost. This harm may be mitigated with appropriate prescribing and deprescribing. We sought to understand the prescribing outcomes of an interdisciplinary geriatric virtual consultation service. METHODS: We conducted a retrospective, before-and-after feasibility study to measure prescribing outcomes for a medication optimization virtual interdisciplinary geriatric specialist (MOVING) programme comprised of expertise from geriatric clinical pharmacology, pharmacy and psychiatry for older adults (aged ≥ 65 years) between June and December 2018, Ontario, Canada. The primary outcome was the number of distinct prescriptions and the presence of polypharmacy (defined as ≥ 4 medications) before and after the service. Secondary outcomes included the number of as needed and regularly administered prescriptions, number of potentially inappropriate prescriptions as defined by the Beers and STOPP criteria, and number of prescriptions for psychotropics, long-acting opioids and diabetic medications. RESULTS: We studied 40 patients with a mean age of 80.6 [standard deviation (SD) 8.8] years who received a MOVING consult. We found no significant change in the mean total number of prescriptions per patient before (12.02, SD 5.83) and after the intervention (11.58, SD 5.28), with a mean difference of -0.45 [95% confidence interval (CI) -0.94 to 0.04; p = 0.07]. We found statistically significant decreases in as needed prescriptions (mean difference - 0.30, 95% CI - 0.45 to - 0.15; p<0.001), and potentially harmful medications as identified by the Beers (mean difference -1.25, 95% CI -2.00 to -0.50; p = 0.002) and STOPP (mean difference -1.65, 95% CI -2.33 to -0.97; p < 0.001) scores. Without including the cost savings from hospital diversion by a MOVING consult, the costs of a MOVING consult were $545.80-$629.80 per person, compared with the costs associated with traditional in-person consults involving similar specialist clinical services ($904.89-$1270.69 per person). CONCLUSION: A MOVING model of care is associated with decreases in prescriptions for potentially inappropriate medications in older adults. These findings support further evaluation to ascertain health system impacts.

Correlates of Opioid Use Among Ontario Long-Term Care Residents and Variation by Pain Frequency and Intensity: A Cross-sectional Analysis.

BACKGROUND: Chronic non-cancer pain is common among older residents of long-term care (LTC) homes and often poorly recognized and treated. With heightened concerns regarding opioid prescribing in recent years, it is important to examine the current prevalence of opioid use and its association with resident characteristics to help identify those potentially at risk of medication harms as well as suboptimal pain management. OBJECTIVES: The aims were to estimate the prevalence and correlates of opioid use among non-palliative LTC residents and explore variation in opioid prevalence and correlates across strata defined by pain frequency and intensity. METHODS: We conducted a population-based cross-sectional study of all older (aged > 65 years) LTC residents (excluding those with cancer or receiving palliative care) in Ontario, Canada during 2018-2019. Health administrative databases were linked with standardized clinical assessment data to ascertain residents' health and pain characteristics and their opioid and other medication use. Modified Poisson regression models estimated unadjusted and adjusted associations between residents' characteristics and opioid use, overall and across strata capturing pain frequency and intensity. RESULTS: Among 75,020 eligible residents (mean age 85.1 years; 70% female), the prevalence of opioid use was 18.5% and pain was 29.4%. Opioid use ranged from 12.2% for residents with no current pain to 55.7% for those with severe pain. In adjusted models, residents newly admitted to LTC (adjusted risk ratio [aRR] = 0.60, 95% confidence interval [CI] 0.57-0.62) and with moderate to severe cognitive impairment (aRR = 0.69, 95% CI 0.66-0.72) or dementia (aRR = 0.76, 95% CI 0.74-0.79) were significantly less likely to receive an opioid, whereas residents with select conditions (e.g., arthritis, aRR = 1.37, 95% CI 1.32-1.41) and concurrently using gabapentinoids (aRR = 1.80, 95% CI 1.74-1.86), benzodiazepines (aRR = 1.33, 95% CI 1.28-1.38), or antidepressants (aRR = 1.31, 95% CI 1.27-1.35) were significantly more likely to receive an opioid. The associations observed for residents newly admitted, with dementia, and concurrently using gabapentinoids, benzodiazepines, or antidepressants were largely consistent across all pain strata. CONCLUSIONS: Our findings describe resident sub-groups at potentially higher risk of adverse health outcomes in relation to both opioid use and non-use. LTC clinical and policy changes informed by research are required to ensure the appropriate recognition and management of non-cancer pain in this setting.

A suppressor tRNA-mediated feedforward loop eliminates leaky gene expression in bacteria.

Ligand-inducible genetic systems are the mainstay of synthetic biology, allowing gene expression to be controlled by the presence of a small molecule. However, 'leaky' gene expression in the absence of inducer remains a persistent problem. We developed a leak dampener tool that drastically reduces the leak of inducible genetic systems while retaining signal in Escherichia coli. Our system relies on a coherent feedforward loop featuring a suppressor tRNA that enables conditional readthrough of silent non-sense mutations in a regulated gene, and this approach can be applied to any ligand-inducible transcription factor. We demonstrate proof-of-principle of our system with the lactate biosensor LldR and the arabinose biosensor AraC, which displayed a 70-fold and 630-fold change in output after induction of a fluorescence reporter, respectively, without any background subtraction. Application of the tool to an arabinose-inducible mutagenesis plasmid led to a 540-fold change in its output after induction, with leak decreasing to the level of background mutagenesis. This study provides a modular tool for reducing leak and improving the fold-induction within genetic circuits, demonstrated here using two types of biosensors relevant to cancer detection and genetic engineering.

GeriMedRisk, a telemedicine geriatric pharmacology consultation service to address adverse drug events in long-term care: a stepped-wedge cluster randomized feasibility trial protocol (ISRCTN17219647).

BACKGROUND: Multimorbidity, polypharmacy, and older age predispose seniors to adverse drug events (ADE). Seniors with an ADE experience greater morbidity, mortality, and health care utilization compared to their younger counterparts. To mitigate and manage ADEs among this vulnerable population, we designed a geriatric pharmacology consultation service connecting clinicians with specialist physicians and pharmacists and will investigate the feasibility and acceptability of this complex intervention in the long-term care setting, prior to conducting a larger efficacy trial. METHODS/DESIGN: We will conduct a cluster randomized feasibility trial and qualitative analysis of GeriMedRisk among four long-term care homes in the Waterloo-Wellington region from May 1 to December 31, 2017. The primary outcome is the feasibility and acceptability of GeriMedRisk and the stepped-wedge cluster randomized controlled trial design. We hypothesize that GeriMedRisk is a feasible intervention and its potential to decrease falls and drug-related hospital visits can be evaluated with a stepped-wedge cluster randomized controlled trial design. DISCUSSION: This mixed methods study will inform a larger efficacy trial of GeriMedRisk's ability to decrease adverse drug events among seniors in the long-term care setting. ETHICS AND DISSEMINATION: The Hamilton Integrated Research Ethics Board granted the approval for this study protocol 2812. We plan to disseminate the results of this study in peer-reviewed journals and also to our partners and stakeholders. TRIAL REGISTRATION: ISRCTN clinical trials registry, ISRCTN17219647 (March 27, 2017).

Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis.

BACKGROUND: Although serotonin (5-HT3) receptor antagonists are effective in reducing nausea and vomiting, they may be associated with increased cardiac risk. Our objective was to examine the comparative safety and effectiveness of 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron) alone or combined with steroids for patients undergoing chemotherapy. METHODS: We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception until December 2015 for studies comparing 5-HT3 receptor antagonists with each other or placebo in chemotherapy patients. The search results were screened, data were abstracted, and risk of bias was appraised by pairs of reviewers, independently. Random-effects meta-analyses and network meta-analyses (NMAs) were conducted. RESULTS: After screening 9226 citations and 970 full-text articles, we included 299 studies (n = 58,412 patients). None of the included studies reported harms for active treatment versus placebo. For NMAs on the risk of arrhythmia (primary outcome; three randomized controlled trials [RCTs], 627 adults) and mortality (secondary outcome; eight RCTs, 4823 adults), no statistically significant differences were observed between agents. A NMA on the risk of QTc prolongation showed a significantly greater risk for dolasetron + dexamethasone versus ondansetron + dexamethasone (four RCTs, 3358 children and adults, odds ratio 2.94, 95% confidence interval 2.13-4.17). For NMAs on the number of patients without nausea (44 RCTs, 11,664 adults, 12 treatments), number of patients without vomiting (63 RCTs, 15,460 adults, 12 treatments), and number of patients without chemotherapy-induced nausea or vomiting (27 RCTs, 10,924 adults, nine treatments), all agents were significantly superior to placebo. For a NMA on severe vomiting (10 RCTs, 917 adults), all treatments decreased the risk, but only ondansetron and ramosetron were significantly superior to placebo. According to a rank-heat plot with the surface under the cumulative ranking curve results, palonosetron + steroid was ranked the safest and most effective agent overall. CONCLUSIONS: Most 5-HT3 receptor antagonists were relatively safe when compared with each other, yet none of the studies compared active treatment with placebo for harms. However, dolasetron + dexamethasone may prolong the QTc compared to ondansetron + dexamethasone. All agents were effective for reducing risk of nausea, vomiting, and chemotherapy-induced nausea or vomiting. TRIAL REGISTRATION: This study was registered at PROSPERO: ( CRD42013003564 ).

Plasticity of sarcolemmal KATP channel surface expression: relevance during ischemia and ischemic preconditioning.

Myocardial ischemia remains the primary cause of morbidity and mortality in the United States. Ischemic preconditioning (IPC) is a powerful form of endogenous protection against myocardial infarction. We studied alterations in KATP channels surface density as a potential mechanism of the protection of IPC. Using cardiac-specific knockout of Kir6.2 subunits, we demonstrated an essential role for sarcolemmal KATP channels in the infarct-limiting effect of IPC in the mouse heart. With biochemical membrane fractionation, we demonstrated that sarcolemmal KATP channel subunits are distributed both to the sarcolemma and intracellular endosomal compartments. Global ischemia causes a loss of sarcolemmal KATP channel subunit distribution and internalization to endosomal compartments. Ischemia-induced internalization of KATP channels was prevented by CaMKII inhibition. KATP channel subcellular redistribution was also observed with immunohistochemistry. Ischemic preconditioning before the index ischemia reduced not only the infarct size but also prevented KATP channel internalization. Furthermore, not only did adenosine mimic IPC by preventing infarct size, but it also prevented ischemia-induced KATP channel internalization via a PKC-mediated pathway. We show that preventing endocytosis with dynasore reduced both KATP channel internalization and strongly mitigated infarct development. Our data demonstrate that plasticity of KATP channel surface expression must be considered as a potentially important mechanism of the protective effects of IPC and adenosine.

Microbiological profiles of fungal keratitis: a 10-year study at a tertiary referral center.

BACKGROUND: Given the rise in cases of fungal keratitis in recent years, this study was performed to better elucidate the microbiological profile, risk factors, and surgical intervention rates of fungal keratitis at a tertiary referral center in the Southeastern USA. FINDINGS: This is a retrospective case series of fungal keratitis infections treated at Duke University Eye Center from January 1, 1998, to October 6, 2008. Of the 4651 culture-proven corneal ulcers identified, 63 (1.4 %) were positive for fungal keratitis with a total of 69 fungal organisms isolated. The majority of isolates were filamentous species (44 of 69, 64 %), and the most commonly isolated organism was Curvularia (11 of 69, 16 %). Bacterial coinfections were found in 24 of the 63 cases (38 %). The most commonly associated risk factors were contact lens wear (n = 15, 24 %) and prior penetrating keratoplasty (PKP) (n = 15, 24 %). Twenty-three cases (37 %) required surgical intervention. The rate of surgical intervention was highest in patients with prior PKP (7/15, 47 %). CONCLUSIONS: In this study, the leading risk factors for fungal keratitis were contact lens wear and prior PKP. Filamentous species were the most common causative pathogens. A relatively high rate of mixed bacterial-fungal infections was found. Patients with prior PKP were more likely to require surgery than patients without history of keratoplasties.

Comparative efficacy of serotonin (5-HT3) receptor antagonists in patients undergoing surgery: a systematic review and network meta-analysis.

BACKGROUND: Serotonin (5-HT3) receptor antagonists are commonly used to decrease nausea and vomiting for surgery patients. We conducted a systematic review on the comparative efficacy of 5-HT3 receptor antagonists. METHODS: Searches were done in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify studies comparing 5-HT3 receptor antagonists with each other, placebo, and/or combined with other antiemetic agents for patients undergoing surgical procedures. Screening search results, data abstraction, and risk of bias assessment were conducted by two reviewers independently. Random-effects pairwise meta-analysis and network meta-analysis (NMA) were conducted. PROSPERO registry number: CRD42013003564. RESULTS: Overall, 450 studies and 80,410 patients were included after the screening of 7,608 citations and 1,014 full-text articles. Significantly fewer patients experienced nausea with any drug relative to placebo, except for ondansetron plus metoclopramide in a NMA including 195 RCTs and 24,230 patients. Significantly fewer patients experienced vomiting with any drug relative to placebo except for palonosetron plus dexamethasone in NMA including 238 RCTs and 12,781 patients. All agents resulted in significantly fewer patients with postoperative nausea and vomiting versus placebo in a NMA including 125 RCTs and 16,667 patients. CONCLUSIONS: Granisetron plus dexamethasone was often the most effective antiemetic, with the number needed to treat ranging from two to nine.

Comparative safety of serotonin (5-HT3) receptor antagonists in patients undergoing surgery: a systematic review and network meta-analysis.

BACKGROUND: Serotonin (5-HT3) receptor antagonists are commonly used to decrease nausea and vomiting for surgery patients, but these agents may be harmful. We conducted a systematic review on the comparative safety of 5-HT3 receptor antagonists. METHODS: Searches were done in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify studies comparing 5-HT3 receptor antagonists with each other, placebo, and/or other antiemetic agents for patients undergoing surgical procedures. Screening search results, data abstraction, and risk of bias assessment were conducted by two reviewers independently. Random-effects pairwise meta-analysis and network meta-analysis (NMA) were conducted. PROSPERO registry number: CRD42013003564. RESULTS: Overall, 120 studies and 27,787 patients were included after screening of 7,608 citations and 1,014 full-text articles. Significantly more patients receiving granisetron plus dexamethasone experienced an arrhythmia relative to placebo (odds ratio (OR) 2.96, 95 % confidence interval (CI) 1.11-7.94), ondansetron (OR 3.23, 95 % CI 1.17-8.95), dolasetron (OR 4.37, 95 % CI 1.51-12.62), tropisetron (OR 3.27, 95 % CI 1.02-10.43), and ondansetron plus dexamethasone (OR 5.75, 95 % CI 1.71-19.34) in a NMA including 31 randomized clinical trials (RCTs) and 6,623 patients of all ages. No statistically significant differences in delirium frequency were observed across all treatment comparisons in a NMA including 18 RCTs and 3,652 patients. CONCLUSION: Granisetron plus dexamethasone increases the risk of arrhythmia.

Advances in cataract surgery: preserving the corneal endothelium.

PURPOSE OF REVIEW: Cataract surgery is known to lead to some degree of corneal endothelial cell loss (ECL). The purpose of this review is to describe how recent technological advancements such as femtosecond laser-assisted cataract surgery (FLACS) affect corneal endothelium during cataract surgery. RECENT FINDINGS: It has been suggested that FLACS may reduce the amount of required ultrasound energy used in cataract surgery, a factor known to be directly related to ECL. Several recent studies demonstrate either no difference or less ECL with FLACS than with standard phacoemulsification 1-3 months after surgery. However, results at 6 months show comparable ECL between the two techniques. Other recent advancements in surgical technique, such as biaxial microincision surgery, result in similar ECL rates to that of standard phacoemulsification. The use of ultraviolet light in the newly developing light-adjustable intraocular lenses does not increase ECL. Studies show either similar results or less ECL with the use of the newer viscous-dispersives when compared with other viscoelastic devices. Other aspects such as the use of intracameral injections have no adverse effects on corneal endothelium. SUMMARY: Newly emerging cataract surgical techniques cause comparable ECL to that of conventional phacoemulsification. Femtosecond laser-assistance may reduce ECL, but likely only in the early postoperative period. Further studies are needed to better elucidate short and long-term effects of FLACS on the corneal endothelium. Viscous dispersives may offer equal or increased protection of the corneal endothelium during surgery compared with viscoelastic devices currently in wide use, but further studies are required to support these results.

Risk of heart failure and edema associated with the use of pregabalin: a systematic review.

BACKGROUND: Pregabalin is used in the treatment of postherpetic neuralgia, diabetic neuropathic pain, partial seizures, anxiety disorders and fibromyalgia. Recognized adverse effects associated with its use include cognitive impairment, somnolence and dizziness. Heart failure associated with pregabalin has been described, however the strength of this association has not been well characterized. To examine this further, we will conduct a systematic review of the risk of heart failure and edema associated with use of pregabalin. METHODS/DESIGN: We will include all studies (experimental, quasi-experimental, observational, case series/reports, drug regulatory reports) that examine the use of pregabalin compared to placebo, gabapentin or conventional care. Our primary outcome is heart failure and the secondary outcomes include edema and weight gain. We will search electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), and grey literature sources (trial registries, conference abstracts) to identify relevant studies. To ensure literature saturation, we will contact drug manufacturers, conduct forward citation searching, and scan the reference lists of key articles and included studies. We will not restrict inclusion by language or publication status.Two reviewers will screen citations (titles and abstracts) and full-text articles, conduct data abstraction, and appraise risk of bias. Random-effects meta-analysis will be conducted if the studies are deemed heterogeneous in terms of clinical, statistical and methodological factors but still suitable for meta-analysis. CONCLUSIONS: The results of this review will assist physicians to better appreciate pregabalin's risk for edema or congestive heart failure and will be pertinent to the thousands of patients worldwide who are administered this medication.Our protocol was registered in the PROSPERO database (CRD42012002948).

Serious events in older Ontario residents receiving bowel preparations for outpatient colonoscopy with various comorbidity profiles: a descriptive, population-based study.

BACKGROUND: Polyethylene glycol-based bowel preparations (PEGBPs) and sodium picosulfate (NaPS) are commonly used for bowel cleansing before colonoscopy. Little is known about adverse events associated with these preparations, particularly in older patients or patients with medical comorbidities. OBJECTIVE: To characterize the incidence of serious events following outpatient colonoscopy in patients using PEGBPs or NaPS. METHODS: The present population-based retrospective cohort study examined data from Ontario health care databases between April 1, 2005 and December 31, 2007, including patients >=66 years of age who received either PEGBP or NaPS for an outpatient colonoscopy. Patients with cardiac or renal disease, long-term care residents or patients receiving concurrent diuretic therapy were identified as high risk for adverse events. The primary outcome was a serious event (SE) defined as a composite of nonelective hospitalization, emergency department visit or death within seven days of the colonoscopy. RESULTS: Of the 50,660 outpatients >=66 years of age who underwent a colonoscopy, SEs were observed in 675 (2.4%) and 543 (2.4%) patients in the PEGBP and NaPS groups, respectively. Among high-risk patients (n=30,168), SEs occurred in 481 (2.8%) and 367 (2.8%) of patients receiving PEGBP and NaPS, respectively. CONCLUSIONS: The SE rate within seven days of outpatient colonoscopy was 24 per 1000 procedures, and among high-risk patients was 28 per 1000 procedures. The rates were similar for PEGBP and NaPS. Clinicians should be aware of the risks associated with colonoscopy in older patients with comorbidities.

Hypokalemia following polyethylene glycol-based bowel preparation for colonoscopy in older hospitalized patients with significant comorbidities.

BACKGROUND: Polyethylene glycol-based bowel preparations (PEGBPs) are widely perceived as safe and effective alternatives to oral sodium phosphate for bowel cleansing prior to colonoscopy. Most studies supporting this belief involve young patients with few comorbidities. OBJECTIVE: To characterize the incidence of electrolyte disturbances following PEGBPs administered prior to colonoscopy among elderly inpatients and hypothesize that PEGBP would be associated with hypokalemia in this setting. METHODS: This retrospective chart review, conducted at 3 tertiary care teaching hospitals in Toronto, Canada, from 2005 to 2007, included 96 consecutive patients aged 65 or older who were admitted to the hospital and given PEGBP prior to their first inpatient colonoscopy. Patients were excluded if they received additional cathartics, underwent colonoscopy while admitted to a critical care unit, or were admitted for a complication arising from an outpatient colonoscopy. The primary outcome was hypokalemia (serum potassium < or =3.2 mEq/L) within 48 hours of PEGBP. RESULTS: Of 96 patients, 73 had serum electrolytes measured at baseline and within 48 hours following PEGBP administration. Hypokalemia was identified in 4 patients (5.5%) prior to PEGBP and in 15 patients (20.5%) after PEGBP (p < 0.001). The incidence of significant hypokalemia, defined as serum potassium < or =3.0 mEq/L, in this group was 9.6% (p = 0.008). We found consistent results among patients with and without concomitant diuretic treatment. CONCLUSIONS: Among older patients, administration of PEGBP is commonly complicated by the development of hypokalemia, which is occasionally severe. Monitoring of electrolytes may be necessary following colonoscopy, particularly in patients with cardiac or renal disease.

Budget impact analysis of ixabepilone used according to FDA approved labeling in treatment-resistant metastatic breast cancer.

BACKGROUND: Breast cancer is one of the most common forms of cancer in the United States, with approximately 10% of newly diagnosed patients presenting with metastatic disease. Limited therapy options make the successful treatment of metastatic breast cancer (MBC) difficult. Current treatment options include drugs belonging to the classes of anthracyclines and taxanes as well as the drug capecitabine. Resistance to these classes of drugs is often acquired, thus highlighting the need for newer agents capable of managing treatment resistant disease. Ixabepilone is an antineoplastic agent from the epothilone class that was FDA-approved in October 2007 for the treatment of metastatic or locally advanced breast cancer. The FDA-approved indications for ixabepilone specify (a) use of ixabepilone in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer after (resistance to) treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated; and (b) ixabepilone as a monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to an anthracycline, a taxane, and capecitabine. OBJECTIVES: To estimate the 3-year projected impact on the annual pharmacy budget for a hypothetical 1 million-member commercial plan that introduces and reimburses ixabepilone therapy for its FDA-approved indications: either as a monotherapy for patients pretreated with combined anthracyclines, taxanes, and capecitabine (ATC-p) or in combination with capecitabine for patients pretreated with anthracyclines and taxanes (AT-p). METHODS: U.S. prevalence and treatment data for MBC patients were obtained from published and nonpublished sources. The MBC population was stratified into AT-p and ATC-p populations. These 2 groups comprised the assumed study population. The model considered 2 scenarios-without (pre) and with (post) ixabepilone, either as monotherapy for ATC-p or combination therapy with capecitabine for AT-p patients. Market share data for chemotherapeutic treatment options for MBC pre-ixabepilone and in the first year post-ixabepilone were obtained from nonpublished, proprietary, real-world drug utilization data collected by IntrinsiQ LLC (Waltham, MA), for 2007 and 2008, respectively. Market shares for the second and third years post-ixabepilone were forecasted by the study authors based on IntrinsiQ data collected from January 2008 to January 2009 and the observed switching patterns in the 2007 and 2008 IntrinsiQ data. Drug costs were based on First DataBank Inc. Wholesale Acquisition Cost (accessed March 2009). The results for each indication were analyzed individually and summed to reflect the total impact of ixabepilone. Results were also considered on a per member per month (PMPM) basis to examine the relative impact on the plan. Sensitivity of the results to model assumptions was tested using univariate sensitivity analyses on the prevalence of AT-p and ATC-p, the price of ixabepilone, the price of comparator medications, and the ixabepilone market uptake. A key assumption was that ixabepilone would be used only in accordance with its current labeled indications. RESULTS: In a health plan population of 1 million members, the estimated number of female patients aged 20 years or older with recurrent MBC and previous treatment with either AT or ATC was 15 over the 3-year time horizon used in this budget impact model. For AT-p patients, the estimated incremental cost PMPM was $0.002 for each of the 3 years. The estimated incremental cost PMPM for the ATC-p population was $0.003 for year 1 and $0.004 for both year 2 and year 3. In sensitivity analyses, the PMPM impact varied between -$0.01 and $0.02 over the 3-year period. The model was most sensitive to the cost of ixabepilone. CONCLUSION: Given the poor prognosis and limited number of treatment options for patients with MBC, the need for widespread coverage of ixabepilone in accordance with FDA-approved indications can clearly be established. Assuming that ixabepilone is used only for its currently labeled indications, both the number of patients eligible for ixabepilone treatment and the expected budget impact of covering ixabepilone for this group of patients are relatively small.

AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells.

Pancreatic carcinoma is a leading cause of cancer deaths, and recent clinical trials of a number of oncology therapeutics have not substantially improved clinical outcomes. We have evaluated the therapeutic potential of AMG 479, a fully human monoclonal antibody against insulin-like growth factor (IGF) type I receptor (IGF-IR), in two IGF-IR-expressing pancreatic carcinoma cell lines, BxPC-3 and MiaPaCa2, which also differentially express insulin receptor (INSR). AMG 479 bound to IGF-IR (K(D) 0.33 nmol/L) and blocked IGF-I and IGF-II binding (IC(50) < 0.6 nmol/L) without cross-reacting to INSR. AMG 479 completely inhibited ligand-induced (IGF-I, IGF-II, and insulin) activation of IGF-IR homodimers and IGF-IR/INSR hybrids (but not INSR homodimers) leading to reduced cellular viability in serum-deprived cultures. AMG 479 inhibited >80% of basal IGF-IR activity in BxPC-3 and MiaPaCa2 xenografts and prevented IGF-IR and IGF-IR/INSR hybrid activation following challenge with supraphysiologic concentrations of IGF-I. As a single agent, AMG 479 inhibited (∼ 80%) the growth of pancreatic carcinoma xenografts, and long-term treatment was associated with reduced IGF-IR signaling activity and expression. Efficacy seemed to be the result of two distinct biological effects: proapoptotic in BxPC-3 and antimitogenic in MiaPaCa2. The combination of AMG 479 with gemcitabine resulted in additive inhibitory activity both in vitro and in vivo. These results indicate that AMG 479 is a clinical candidate, both as a single agent and in combination with gemcitabine, for the treatment of patients with pancreatic carcinoma

Divergence of selenocysteine tRNA recognition by archaeal and eukaryotic O-phosphoseryl-tRNASec kinase.

Selenocysteine (Sec) biosynthesis in archaea and eukaryotes requires three steps: serylation of tRNA(Sec) by seryl-tRNA synthetase (SerRS), phosphorylation of Ser-tRNA(Sec) by O-phosphoseryl-tRNA(Sec) kinase (PSTK), and conversion of O-phosphoseryl-tRNA(Sec) (Sep-tRNA(Sec)) by Sep-tRNA:Sec-tRNA synthase (SepSecS) to Sec-tRNA(Sec). Although SerRS recognizes both tRNA(Sec) and tRNA(Ser) species, PSTK must discriminate Ser-tRNA(Sec) from Ser-tRNA(Ser). Based on a comparison of the sequences and secondary structures of archaeal tRNA(Sec) and tRNA(Ser), we introduced mutations into Methanococcus maripaludis tRNA(Sec) to investigate how Methanocaldococcus jannaschii PSTK distinguishes tRNA(Sec) from tRNA(Ser). Unlike eukaryotic PSTK, the archaeal enzyme was found to recognize the acceptor stem rather than the length and secondary structure of the D-stem. While the D-arm and T-loop provide minor identity elements, the acceptor stem base pairs G2-C71 and C3-G70 in tRNA(Sec) were crucial for discrimination from tRNA(Ser). Furthermore, the A5-U68 base pair in tRNA(Ser) has some antideterminant properties for PSTK. Transplantation of these identity elements into the tRNA(Ser)(UGA) scaffold resulted in phosphorylation of the chimeric Ser-tRNA. The chimera was able to stimulate the ATPase activity of PSTK albeit at a lower level than tRNA(Sec), whereas tRNA(Ser) did not. Additionally, the seryl moiety of Ser-tRNA(Sec) is not required for enzyme recognition, as PSTK efficiently phosphorylated Thr-tRNA(Sec).