Potentially clinically significant
            
              anti‐Di
              b
            
            identified by monocyte monolayer assay before transfusion

TPS2622 Background: BMS-936558 is a fully human IgG4 monoclonal antibody targeted against human Programed Death-1 (PD1) receptor on activated T and B lymphocytes. Blocking of PD-1 prevents these activated cells from becoming anergic, thereby maintaining anti-tumor immunologic activity. Methods: The PK of BMS-936558 was characterized with data from a single ascending dose (SAD) and a multiple ascending dose (MAD) study in subjects with advanced solid malignancies. Subjects received a single IV infusion of 0.3 to 10 mg/kg BMS-936558 in the SAD study (MDX-1106-01 Study) and 0.1 to 10 mg/kg BMS-936558 every two weeks in the MAD study (MDX-1106-03/CA209003 Study). The PK of BMS-936558 was characterized by non-compartmental analysis of intensively sampled PK data from a SAD study, as well as by population PK analysis of available intensive and sparse PK data from the SAD and MAD studies, respectively. Results: The PK of BMS-936558 is linear in the studied dose range with dose-proportional increase in Cmax and AUC with low to moderate (20-44%) inter-subject variability. Geometric mean clearance ranged from 0.13 - 0.19 mL/h/kg, whereas mean volume of distribution ranged from 83 -113 mL/kg. The range of mean terminal elimination half-life of BMS-936558 is 17 to 25 days which is consistent with half-life of endogenous IgG4. BMS-936558 PK was adequately described by a linear two-compartment model, and there was no evidence of a contribution of target mediated drug disposition to drug elimination within tested dose range. Body weight and gender are potentially clinically significant covariate for both clearance and volume of distribution (> 20% effect); and baseline CRP, LDH, and albumin are potentially clinically significant covariates for CL. The body weight normalized dosing employed produces trough concentrations that are approximately constant over a wide range of body weights. Conclusions: The pharmacokinetics of BMS-936558 is dose-proportional and body weight normalized dosing is appropriate to ensure consistent exposure over a wide range of body weights.

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Interaction between Warfarin and Trazodone

Annals of Pharmacotherapy ◽

10.1345/aph.19336 ◽

2000 ◽

Vol 34 (6) ◽

pp. 734-736 ◽

Cited By ~ 12

Author(s):

Nancy L Small ◽

Kathy A Giamonna

Keyword(s):

Chart Review ◽

Retrospective Chart Review ◽

International Normalized Ratio ◽

Potential Interaction ◽

Case Summary ◽

Subsequent Decrease ◽

Clinically Significant ◽

Few Data ◽

Time To Onset ◽

Potentially Clinically Significant

BACKGROUND: It is well known that there are many drug interactions involving warfarin. However, few data have been supplied to guide clinicians concerning the interaction between trazodone and warfarin. CASE SUMMARY: Three clinically significant cases of suspected trazodone and warfarin interactions were identified in a retrospective chart review based on changes in the prothrombin time (PT) and international normalized ratio (INR) that were not explained by other factors. In each of the cases, the INR changed by ≥1.0 after the initiation or discontinuation of trazodone. In the patients who started trazodone, a subsequent decrease in the PT and INR resulted; conversely, the PT and INR increased in the patient who stopped trazodone therapy. Although none of the patients experienced adverse effects due to the marked changes in PT and INR, the warfarin dosages had to be adjusted accordingly on initiation and discontinuation of trazodone. DISCUSSION: These cases show that there is a potentially clinically significant interaction between trazodone and warfarin. The time to onset of the interaction is variable; the mechanism behind it is not known, but it may involve substrate or protein-binding competition. CONCLUSIONS: The use of trazodone on an as-needed basis for sleep is strongly discouraged in patients who are receiving warfarin, due to the difficulty of achieving a therapeutic PT and INR. Until more is known, patients and clinicians should be educated about this potential interaction and monitor for changes in the anticoagulant effects when trazodone is initiated or stopped.

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Economic analysis of the prevalence and clinical and economic burden of medication error in England

BMJ Quality & Safety ◽

10.1136/bmjqs-2019-010206 ◽

2020 ◽

pp. bmjqs-2019-010206 ◽

Cited By ~ 8

Author(s):

Rachel Ann Elliott ◽

Elizabeth Camacho ◽

Dina Jankovic ◽

Mark J Sculpher ◽

Rita Faria

Keyword(s):

Primary Care ◽

Medication Errors ◽

Resource Use ◽

Economic Burden ◽

Secondary Care ◽

Healthcare Resource ◽

Annual Number ◽

Healthcare Resource Use ◽

Clinically Significant ◽

Potentially Clinically Significant

ObjectivesTo provide national estimates of the number and clinical and economic burden of medication errors in the National Health Service (NHS) in England.MethodsWe used UK-based prevalence of medication errors (in prescribing, dispensing, administration and monitoring) in primary care, secondary care and care home settings, and associated healthcare resource use, to estimate annual number and burden of errors to the NHS. Burden (healthcare resource use and deaths) was estimated from harm associated with avoidable adverse drug events (ADEs).ResultsWe estimated that 237 million medication errors occur at some point in the medication process in England annually, 38.4% occurring in primary care; 72% have little/no potential for harm and 66 million are potentially clinically significant. Prescribing in primary care accounts for 34% of all potentially clinically significant errors. Definitely avoidable ADEs are estimated to cost the NHS £98 462 582 per year, consuming 181 626 bed-days, and causing/contributing to 1708 deaths. This comprises primary care ADEs leading to hospital admission (£83.7 million; causing 627 deaths), and secondary care ADEs leading to longer hospital stay (£14.8 million; causing or contributing to 1081 deaths).ConclusionsUbiquitous medicines use in health care leads unsurprisingly to high numbers of medication errors, although most are not clinically important. There is significant uncertainty around estimates due to the assumption that avoidable ADEs correspond to medication errors, data quality, and lack of data around longer-term impacts of errors. Data linkage between errors and patient outcomes is essential to progress understanding in this area.

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How Much Scaphoid Can be Safely Resected? A Biomechanical Analysis of the Effects of Distal Scaphoid Resection

Hand ◽

10.1177/1558944720966717 ◽

2020 ◽

pp. 155894472096671

Author(s):

Assaf Kadar ◽

Ruby Grewal ◽

Clare E. Padmore ◽

Stacy Fan ◽

Daniel G. Langohr ◽

...

Keyword(s):

Biomechanical Analysis ◽

Wrist Flexion ◽

Extended Position ◽

Flexion Extension ◽

Simple Alternative ◽

Carpal Kinematics ◽

Wrist Fusion ◽

Clinically Significant ◽

Dorsal Intercalated Segment Instability ◽

Potentially Clinically Significant

Background: Resection of the distal pole of the scaphoid has been advocated as a simple alternative to other wrist salvage procedures for scaphoid nonunion advanced collapse and scaphotrapezio-trapezoid arthritis. However, the extent of scaphoid that may be resected without adversely affecting carpal kinematics has never been clearly defined. Methods: Seven cadaveric upper extremities were tested in a custom motion wrist simulator. A 3-stage sequential sectioning of the distal scaphoid protocol was performed in 25% increments then cyclic active wrist flexion-extension and dart thrower’s motion trials were recorded. Results: The extent of distal scaphoid resection had no effect on overall wrist range of motion. The lunate assumed a more extended position following resection of the distal scaphoid compared to intact. At 25%, 50%, and 75% of distal scaphoid resection, the lunate extended to 13.32° ± 9.4°, 23.43° ± 7.5°, and 15.81° ± 16.9°, respectively. The capitate migrated proximally with 25% and 50% distal scaphoidectomy, and proximally and radially with 75% of the scaphoid resected. Resection of 75% of the scaphoid resulted in unstable wrist kinematics. Conclusions: Resection of up to 25% of the distal scaphoid did not significantly influence carpal kinematics and induced mild lunate extension deformity. Resection of 50% of the scaphoid induced further and potentially clinically significant lunate extension and dorsal intercalated segment instability. Further removal of 75% of the distal scaphoid induced capitate migration radially and unpredictable wrist kinematics. Consequently, removal of over 25% of the scaphoid should be avoided or supplemented with partial wrist fusion.

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The Prevalence of Incidental Findings at Cardiac MRI

The Open Cardiovascular Medicine Journal ◽

10.2174/1874192400802010020 ◽

2008 ◽

Vol 2 (1) ◽

pp. 20-25 ◽

Cited By ~ 42

Author(s):

David A McKenna ◽

Monish Laxpati ◽

Patrick M Colletti

Keyword(s):

Cardiac Mri ◽

Incidental Findings ◽

Field Of View ◽

Significant Finding ◽

Ssfp Cine ◽

Aortic Pathology ◽

Significant Difference ◽

Clinically Significant ◽

Work Up ◽

Potentially Clinically Significant

Object or purpose of study: As the field of view of cardiac magnetic resonance imaging (CMR) includes the thorax and upper abdomen, it is not surprising that these studies can reveal incidental extra-cardiac abnormalities. The purpose of this study is to determine the prevalence of these incidental findings. Materials, Methods and Procedures: 132 volunteer participants with a mean age of 74.2 years (range, 61-89 years; 127 males and 5 females) had CMR with 7 sequences. All images were retrospectively reviewed by a radiologist, specifically assessing for non-cardiac findings. Visualized abnormalities were noted and categorized according to significance. Clinically significant findings were defined as those requiring further clinical or radiological work-up, with moderately significant findings defined as those that may affect patient care depending on medical history or symptoms. Remaining findings were considered clinically insignificant. Results: Within the group, 107 participants (81%) had extra-cardiac findings, with 63 (48%) having multiple findings. A total of 224 incidental findings were visualized, with at least one clinically significant and moderately significant finding found in 23 (17%) and 43 (33 %) of the subjects, respectively. Potentially clinically significant findings included pulmonary nodules, solid or complex lesions of the solid abdominal viscera and thyroid, and aortic pathology including aneurysm. The most prevalent incidental findings were however benign appearing, including renal and hepatic cysts, hemangiomas, and atelectasis. The SSFP coronal localizer, SSFP axial localizer, and short axis SSFP cine oblique sequences were most sensitive at detecting incidental findings (p = 0.013 vs four other sequences) with 47%, 46%, and 41% detection respectively, with no significant difference between these three multislice sequences (p = 0.369). Significance of the conclusions: In total, 81% of our volunteers had extra-cardiac findings, of which 17% were potentially clinically significant, necessitating further work up. We believe that these numbers appear high compared to prior similar studies performed at Cardiac CT. This may be related to the relatively older cohort examined here. In conclusion it is important to look beyond the heart when reviewing cardiac MRI studies and carefully assess the entire field of view for abnormalities.

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Systematic Assessment of Culture Review as a Tool to Assess Errors in the Clinical Microbiology Laboratory

Archives of Pathology & Laboratory Medicine ◽

10.5858/132.11.1792 ◽

2008 ◽

Vol 132 (11) ◽

pp. 1792-1795

Author(s):

Nancy Goodyear ◽

Bruce K. Ulness ◽

Jennifer L. Prentice ◽

Brad T. Cookson ◽

Ajit P. Limaye

Keyword(s):

Clinical Microbiology ◽

Susceptibility Testing ◽

Positive Culture ◽

The United States ◽

Error Rates ◽

Clinical Microbiology Laboratory ◽

Microbiology Laboratory ◽

Negative Culture ◽

Clinically Significant ◽

Potentially Clinically Significant

Abstract Context.—Daily supervisory review is a common practice in microbiology laboratories; however, there are no publications describing errors corrected by this practice. Objective.—To determine (1) the correction rates for routinely reviewed positive cultures, (2) the correction rates for negative cultures, and (3) the types of corrections that are found, including the number with potential clinical significance. Design.—We prospectively assessed errors identified during culture report review for all positive (10-month period) and negative (1-month period) cultures at a single, university-based clinical microbiology laboratory in the United States. Errors were classified using predefined categories, and total and per category error rates were determined. A χ2 test was used to assess significant differences between error rates. Results.—A total of 112 108 culture reports were examined; 914 reports required a total of 1043 corrections. Of 101 703 positive culture reports, 786 (0.8%) required 900 corrections, 302 (0.3%) of which were potentially clinically significant. Of 10 405 negative culture reports, 128 (1.2%) required 143 corrections, 5 (0.05%) of which were potentially clinically significant. The rate of potentially clinically significant errors was significantly higher among positive versus negative culture reports (P < .001). Errors from positive culture reports most commonly involved susceptibility (374 [42%]), reporting (275 [31%]), and identification workup (217 [24%]). Most potentially significant errors from positive culture reports involved susceptibility testing (n = 253) and specimens from wound or lower respiratory tract (P < .001). Conclusions.—Review of culture reports from positive cultures from nonsterile sites with special attention to antimicrobial susceptibility testing and reporting would be most likely to detect potentially significant errors within the clinical microbiology laboratory.

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Electrocardiogram Changes and Therapeutic Desipramine and 2-Hydroxy-Desipramine Concentrations in Elderly Depressives

The British Journal of Psychiatry ◽

10.1192/bjp.148.6.676 ◽

1986 ◽

Vol 148 (6) ◽

pp. 676-679 ◽

Cited By ~ 25

Author(s):

S. P. Kutcher ◽

K. Reid ◽

J. D. Dubbin ◽

K. I. Shulman

Keyword(s):

Steady State ◽

The Elderly ◽

Major Metabolite ◽

Qtc Interval ◽

Cardiac Safety ◽

Drug Concentrations ◽

Clinically Significant ◽

Potentially Clinically Significant

ECG parameters in elderly depressed in-patients were assessed during routine despramine treatment. Significant changes (prolonged PR and PRS intervals and a decreased QTc interval) were found, related only to steady state concentrations of desipramine's major metabolite—2-hydroxy-desipramine. Potentially clinically significant changes developed in 40% of the patients. All serum drug concentrations were within therapeutic limits. Previous assurances about despiramines's cardiac safety in the elderly may need to be re-evaluated.

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Revisiting Oral Fluoroquinolone and Multivalent Cation Drug-Drug Interactions: Are They Still Relevant?

Antibiotics ◽

10.3390/antibiotics8030108 ◽

2019 ◽

Vol 8 (3) ◽

pp. 108 ◽

Cited By ~ 4

Author(s):

Pitman ◽

Hoang ◽

Wi ◽

Alsheikh ◽

Hiner ◽

...

Keyword(s):

Drug Interactions ◽

Management Strategies ◽

Oral Drug ◽

Systemic Absorption ◽

Resistant Bacteria ◽

Oral Formulations ◽

Multivalent Cation ◽

Clinically Significant ◽

High Bioavailability ◽

Potentially Clinically Significant

Fluoroquinolones are a widely-prescribed, broad-spectrum class of antibiotics with several oral formulations notable for their high bioavailability. For certain infections, fluoroquinolones are the first line or only treatment choice. When administered orally, fluoroquinolones require proper administration to ensure adequate systemic absorption and, thereby, protect patients from treatment failure. Oral drug preparations that contain multivalent cations are well known to chelate with fluoroquinolones in the gastrointestinal tract; co-administration may lead to clinically significant decreases in oral fluoroquinolone bioavailability and an overall increase in fluoroquinolone-resistant bacteria. Based on a search and evaluation of the literature, this focused review describes oral fluoroquinolone-multivalent cation drug-drug interactions and their magnitude and offers several clinical management strategies for these potentially clinically significant interactions.

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