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Kim, Yoon-Myung, Mi-Sun Yum, Sun Hee Heo, et al. "Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy." Journal of Medical Genetics 57, no. 2 (2019): 124–31. http://dx.doi.org/10.1136/jmedgenet-2019-106132.
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BackgroundAmbroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD.MethodsABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.ResultsEnhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2–8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.ConclusionsLong-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.
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Medler, Corey J., Lejla Jakupovic, Allison J. Weinmann, Rachel Kenney, Susan L. Davis, and Susan L. Davis. "391. Outcomes of Empiric Antimicrobial Therapy in COVID-19 Positive Patients." Open Forum Infectious Diseases 7, Supplement_1 (2020): S264—S265. http://dx.doi.org/10.1093/ofid/ofaa439.586.
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Abstract Background The COVID-19 pandemic has revealed new challenges for antimicrobial stewardship. Optimal medical treatment is not completely understood at this time. The epidemiology and outcomes of bacterial co-infections are not well-established; however, empiric antibiotic (abx) use is anecdotally common. The purpose of this study is to characterize empiric antimicrobial drug selection and timing in COVID-19 and evaluate the impact on patient outcomes. Methods Cross-sectional cohort study for COVID-19 positive inpatients from March 1, 2020 to June 1, 2020 at an academic medical center and 4 community hospitals. Inclusion: patients with a documented positive COVID-19 PCR nasopharyngeal swab. Exclusion: patients less than 18 years; deceased or transitioned to hospice within 24 hours of admission. Primary endpoint: empiric abx drug, initiation, duration and indication. Additional data collected: severity of illness, co-infection diagnosis, microbiology, and adverse drug effects (ADE). Clinical outcomes included time to recovery by COVID-19 ordinal outcome, clinical status at day 15, and readmission. Results 400 patients were included with 27% from the ICU. COVID symptom category included mild (23.8%), moderate (53%), severe (15%), and critical (8.3%). 322 (80.5%) received abx at any time during hospital stay, 301 (93.5%) started within 1 day of admission. Most common documented indication community-acquired pneumonia (69%). Identified 43 (10.8%) microbiologically confirmed co-infections, including 5 MRSA and 7 Pseudomonas. Median duration of initial abx 4 days. 54/322 (16.8%) had abx restarted after discontinuation. Median days to recovery without abx was 10 days (7 – 14) and 14 days (9 – 20) with abx. Patient characteristics and outcomes described in table 1. 74 abx related ADE were identified: gastrointestinal 37 and renal 22. Conclusion It’s difficult to distinguish bacterial and Covid-19 in coinfections in patients ill enough to be hospitalized. Longer courses of empiric abx therapy were prevalent as the severity of illness increased. However, the low frequency of microbiologically confirmed bacterial co-infections results in potentially unnecessary abx exposure. This exposure increases risk of abx ADE and may not improve clinical outcome. Disclosures All Authors: No reported disclosures
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Shah, Ruta M., Zbigniew M. Szczepiorkowski, Miriam K. Leach, MS, MT, and Richard A. Zuckerman. "The Significance of Anti-Platelet Antibodies Associated with Antibiotic Use, A Descriptive Analysis." Blood 114, no. 22 (2009): 4470. http://dx.doi.org/10.1182/blood.v114.22.4470.4470.
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Abstract Abstract 4470 Introduction Antibiotics (Abx) have been implicated in immune thrombocytopenia via drug dependent platelet antibodies (DDPA). Our institution has had a DDPA assay available since 1994 which is used to guide clinical decisions. We performed a retrospective review to determine the significance of DDPA. Methods We reviewed the medical records of patients (pts) who tested positive for abx DDPA between 1994 and 2006 and performed a descriptive analysis. Detection of DDPAs was performed using a previously described, modified solid phase red cell adherence assay that detects hapten or immune complex reactions. Results A total of 71 pts were included in this analysis. Multiple classes of abx were tested. Platelet nadir was <50 in 70%, between 50 and 100 in 26% and over 100 in 4% of pts. Pts had between 1 and 4 abx tested: 37% had 1, 37% had 2, 15% had 3, and 11% had 4 tested; 65% of pts had one abx positive and 35% had >1 abx positive for DDPA. Of those with >1 abx tested (n=45), 14 (31%) had all tested abx positive. 53% of abx testing took place on or after the abx stop date and 32% of abx tested were administered for <=3 days. Only 29 of 38 pts receiving heparin were tested for heparin-associated antibodies, and 14 had positive results. 49 pts had other non-abx drugs tested, 19 with positive DDPA. Thus, 35% had alternative non-abx testing positive for DDPA. 31% of pts had bleeding complications and 35% of pts died during hospitalization. Excluding pts who died and those with non-abx positive DDPA left 25 pts, median platelet counts were: abx start=142; nadir=22, abx discontinuation=46, hospital discharge=192. Conclusions Antibiotic DDPA testing is usually performed in ill pts with multiple medical complications and comorbidities. Abx were stopped for concern of DDPA in a number of pts for whom typical immune thrombocytopenia was not present or alternative explanations could be found. Though some pts exhibited improvement in platelet count after abx were stopped, a clear understanding of which pts may benefit from DDPA testing could not be determined based on the retrospective nature of this study and the complexity of pts histories. Further research is necessary to clarify the clinical applicability of DPPA testing. Disclosures: Szczepiorkowski: Cersus Corporation: Research Funding; CaridianBCT: Research Funding; BASF: Research Funding; Terumo Corporation: Research Funding; Fenwel, Inc - Scientific Advisory Board: Research Funding.
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Weinstock, Chana, Pradeep Bandaru, Laura L. Fernandes, et al. "Impact of timing of antibiotic use on clinical outcomes in patients with urothelial cancer treated with immune checkpoint inhibitors (ICIs)." Journal of Clinical Oncology 38, no. 15_suppl (2020): 5045. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5045.
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5045 Background: Although recent evidence has suggested that patients who receive antibiotics (ABX) during the course of ICI treatment might decrease overall survival (OS) (1), our previous analysis did not support a difference in OS in urothelial cancer patients who did and did not use ABX during the course of ICI treatment without regard to timing (2). This updated analysis aims to addresses the question of timing; specifically, use of ABX in the 30-day window pre- or post- initiation of ICI treatment. Methods: We pooled data from 7 trials that led to drug approval and which included 1747 patients with advanced urothelial cancer treated with an ICI. Five trials enrolled patients who received prior platinum and 2 enrolled cisplatin-ineligible patients. Concomitant medication datasets were searched for systemic ABX use. The association between ABX use and survival was evaluated using Kaplan-Meier estimates and Cox proportional hazards regression models stratified by study. Results: Overall, 56% of patients were exposed to antibiotics (ABX+) and 43% were not exposed (ABX-). In an exploratory analysis, median OS was similar between arms: 9.7 vs. 9.3 months in ABX+ vs. ABX- patients, respectively (HR 0.96). However, OS results differed in the 27% of patients who were exposed to antibiotics in the 30-day window pre- or post- initiation of ICI treatment, for whom median OS was 4.7 months vs. 11.5 months in the ABX+ vs. ABX- patients, respectively (HR 1.8). This remained true after controlling for baseline risk prognostic factors (Bajorin and Bellmunt scores). Similar trends were observed for progression-free survival (PFS). Conclusions: Patients treated with ABX while on therapy with an ICI for urothelial cancer had similar OS outcomes to those not treated with ABX. However, in an exploratory analysis looking at ABX use in the 30-day window pre- or post-initiation of ICI treatment, OS appeared decreased in ABX+ vs ABX- patients. Our exploratory analyses appear to show an association of OS/PFS with timing of antibiotics. References: 1) Routy B, Science (2017) 2) Weinstock C, ASCO 2019, abstract. [Table: see text]
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Park, Jenny, Mohamed Nakeshbandi, Subodh Saggi, and Roopali Sharma. "1084. A Pre- and Post-Intervention Study to Implement a Successful Antimicrobial Stewardship Program at an Urban Chronic Hemodialysis Center." Open Forum Infectious Diseases 6, Supplement_2 (2019): S385. http://dx.doi.org/10.1093/ofid/ofz360.948.
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Abstract Background Patients receiving chronic outpatient hemodialysis (CHD) are at high risk for bloodstream and vascular access infections due to the immune-compromised status of patients and repeated vascular access. CHD patients are especially vulnerable to multidrug-resistant organisms due to extensive exposure to antibiotics (ABX). It is estimated that more than 40% of CHD patients receive ≥1 ABX course each year. As data characterizing ABX use and reasons for inappropriate prescribing is still scarce in CHD patients, our objective was to assess ABX use pre- and post-implementation of antimicrobial stewardship program (ASP). Methods A retrospective cohort study to analyze appropriate ABX use from 2015–2018 in CHD patients was conducted. Starting January 15, 2019, ASP was established at the hemodialysis center and tracked all ABX doses including appropriate indication, dosage, frequency, route, therapeutic drug monitoring (TDM) and duration of therapy. All results are presented as descriptive statistics. Results Of the 250 accounts of antibiotics that were assessed retrospectively in all patients from ages 12 to 95 years old, 50% of antibiotics ordered were inappropriately prescribed. The following were the reasons for inappropriateness: indication (59%), duration (14%), culture susceptibility (7%), dose (12%), narrow-spectrum warranted (2%), TDM (6%). Twenty-three accounts were assessed post-implementation phase. ASP implementation led to 100% compliance with regards to the appropriateness of ABX usage (indication, dose, and duration). Additional, ASP interventions included recommendations to obtain blood cultures and conduct TDM in 47% of patients. Conclusion This study identified inappropriateness of antibiotic usage without an established ASP in CHD patients. Implementation of ASP was associated with a positive impact on all ABX doses prescribed and this can have a significant outcome on optimizing ABX use in CHD patients. Disclosures All authors: No reported disclosures.
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Rowinsky, Eric K., Garry H. Schwartz, Jared A. Gollob, et al. "Safety, Pharmacokinetics, and Activity of ABX-EGF, a Fully Human Anti–Epidermal Growth Factor Receptor Monoclonal Antibody in Patients With Metastatic Renal Cell Cancer." Journal of Clinical Oncology 22, no. 15 (2004): 3003–15. http://dx.doi.org/10.1200/jco.2004.11.061.
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Purpose To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. Patients and Methods The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. Results Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. Conclusion ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.
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Yin, Xin, Nkuchia M. M’ikanatha, Lisa Dettinger, et al. "623. Antimicrobial Resistance in Non-Typhoidal Salmonella from Retail Poultry Meat by Antibiotic Usage-related Production Claims—Pennsylvania, 2008–2017." Open Forum Infectious Diseases 6, Supplement_2 (2019): S289. http://dx.doi.org/10.1093/ofid/ofz360.691.
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Abstract Background Antimicrobial-resistant (AMR) nontyphoidal Salmonella infections are a public health concern. Injudicious use of antimicrobials fuels emergence of resistance. The National Antimicrobial Resistance Monitoring System (NARMS) tracks AMR in Salmonella from humans, animals and foods. There is limited evidence regarding antimicrobial use in food animals and AMR bacteria in retail meat. Methods We reviewed antimicrobial susceptibility and whole-genome sequencing data from 320 Salmonella isolated from poultry meat in Pennsylvania as part of NARMS activities. Salmonella strains were isolated from 3,481 samples purchased from randomly selected retail outlets during 2008–2017. Antibiotic usage claims on meat packages were used to compare AMR Salmonella from conventional and antibiotic-free/organic (Abx-free) samples. Genetic mechanisms for AMR were investigated in a subset of isolates. Results The prevalence of Salmonella in conventional poultry meat 10.2% (280/2,733) was significantly higher than the prevalence in poultry meat labeled as Abx-free (5.3%, 40/748; P < 0.0001). Salmonella from conventional poultry meat was more likely to be resistant to 3 or more drugs (55.0%, 154/280) compared with poultry meat labeled as Abx-free (27.5%, 11/40; P = 0.0011). Salmonella from conventional poultry exhibited significantly higher resistance to 4 drug classes including β-lactams (P = 0.006) (figure). One hundred isolates from conventional poultry meat and 8 isolates from antibiotic-free/organic samples harbored a gene conferring resistance to the β-lactam class; 24.3% (68/280) of isolates from conventional and 7.5% (3/40) of isolates from Abx-free samples (P = 0.0145) contained the extended-spectrum β-lactamase (ESBL) gene blaCMY-2. Conclusion Meat samples from conventionally-raised poultry were more likely to be contaminated with AMR Salmonella strains and have genes that reduce the effectiveness of antimicrobial drugs recommended for treatment of severe infections. Contamination of poultry with AMR Salmonella strains is concerning as is the presence of genes that decrease the power of critical antibiotics such as β-lactams. These findings highlight the importance of judicious use of antibiotics in food-producing animals. Disclosures All authors: No reported disclosures.
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Weinstock, Chana, Virginia Ellen Maher, Laura L. Fernandes, et al. "Impact of antibiotic use on clinical outcomes in patients with urothelial cancer receiving a programmed death protein 1 or programmed death ligand 1 (anti-PD-1/L1) antibody." Journal of Clinical Oncology 37, no. 15_suppl (2019): 4557. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4557.
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4557 Background: Previous data has suggested that patients treated with anti-PD-1/L1 antibodies who receive antibiotics during their therapy might have dramatically decreased progression-free and overall survival 1,2. This has clinical implications for management of patients with suspected bacterial infection while on treatment with these agents. We assessed the relationship between antibiotic use and tumor response rate, progression-free survival, and overall survival in a large dataset of patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. Six were single arm trials and one was a randomized controlled trial whose control arm is not included in these analyses. Concomitant medication datasets were searched for systemic antibiotic used by each patient while on treatment. Results: Overall, 51% of patients (n=892) were exposed to antibiotics (ABX+) and 49% (n=855) were not exposed (ABX-). In these exploratory analyses, small numeric differences in OS, PFS, and ORR were seen in ABX+ vs. ABX- patients. Median OS was 9.23 vs. 9.86 months, median PFS was 105 vs 101 days, and ORR was 20% vs. 21% in ABX+ vs. ABX- patients, respectively. Conclusions: Patients who were treated with antibiotics while on therapy with an anti-PD-1/L1 antibody for urothelial cancer had similar outcomes to those who were not treated with antibiotics. Numeric differences in outcomes were not significant and did not duplicate previous analysis demonstrating a median OS that was doubled in ABX- patients1. Our exploratory analyses do not appear to demonstrate a clear need for practitioners to avoid antibiotic use in patients treated with PD-1/L1 agents for fear of significantly impacting clinical outcomes. References: 1) Tinsley et. al., ASCO annual meeting 2018, abstract 3010 2) Routy et. al., Science 05 Jan 2018: Vol. 359, Issue 6371. [Table: see text]
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Geum, Min Jung, Chungsoo Kim, Ji Eun Kang, et al. "Broad-Spectrum Antibiotic Regimen Affects Survival in Patients Receiving Nivolumab for Non-Small Cell Lung Cancer." Pharmaceuticals 14, no. 5 (2021): 445. http://dx.doi.org/10.3390/ph14050445.
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Antibiotic-induced dysbiosis may affect the efficacy of immune checkpoint inhibitors. We investigated the impact of antibiotics on the clinical outcomes of nivolumab in patients with non-small cell lung cancer (NSCLC). Patients who received nivolumab for NSCLC between July 2015 and June 2018 and who were followed up until June 2020 were included in a retrospective cohort analysis. Of 140 eligible patients, 70 were on antibiotics. Overall survival (OS) was shorter in patients on antibiotics (ABX) compared to those not on antibiotics (NoABX) (p = 0.014). OS was negatively associated with piperacillin/tazobactam (PTZ) (HR = 3.31, 95% CI: 1.77–6.18), days of therapy (DOT) ≥ 2 weeks (HR = 2.56, 95% CI: 1.30–5.22) and DOT of PTZ. The defined daily dose (DDD) in PTZ (r = 0.27) and glycopeptides (r = 0.21) showed weak correlations with mortality. There was no difference in progression-free survival (PFS) between ABX and NoABX; however, PFS was negatively associated with the antibiotic class PTZ and DOT of PTZ. Therefore, the use of a broad-spectrum antibiotic, such as PTZ, the long-term use of antibiotics more than 2 weeks in total and the large amount of defined daily dose of specific antibiotics were associated with decreased survival in patients receiving nivolumab for NSCLC.
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Wang, Elaine E. L., Thomas Einarson, James D. Kellner, and John Conly. "Antibiotic (ABX) Prescribing for Respiratory Tact Infections in Preschool Children: Analysis of the Saskatchewan Drug Database † 550." Pediatric Research 43 (April 1998): 96. http://dx.doi.org/10.1203/00006450-199804001-00571.
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Cisar, Justin S., Olivia D. Weber, Jason R. Clapper, et al. "Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders." Journal of Medicinal Chemistry 61, no. 20 (2018): 9062–84. http://dx.doi.org/10.1021/acs.jmedchem.8b00951.
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Jiang, Ming, and Mario van der Stelt. "Activity-Based Protein Profiling Delivers Selective Drug Candidate ABX-1431, a Monoacylglycerol Lipase Inhibitor, To Control Lipid Metabolism in Neurological Disorders." Journal of Medicinal Chemistry 61, no. 20 (2018): 9059–61. http://dx.doi.org/10.1021/acs.jmedchem.8b01405.
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Beaver, Ryan, Hosoon Choi, Chetan Jinadatha, et al. "849. Whole Genome Sequencing Analysis of Klebsiella pneumoniae Isolates Reveals Diversity in Genetic Antibiotic Resistance Patterns." Open Forum Infectious Diseases 7, Supplement_1 (2020): S464—S466. http://dx.doi.org/10.1093/ofid/ofaa439.1038.
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Abstract Background Klebsiella pneumoniae is among the leading causes of healthcare-associated infections (HAI). Multidrug-resistant (MDR) Klebsiella variants are difficult to treat and have been reported with increasing frequency in hospitals. Whole genome multi-locus sequence typing (wg-MLST) of K. pneumoniae HAI isolates was used to compare antibiotic resistance genetic patterns against epidemiologic typing. Figure 1. Prevalence of ABX resistance genes for each drug class. Figure 2. Prevalence of ABX resistance genes by hospital. Methods Forty-six clinical bacterial HAI isolates were collected from patients admitted to two disparate tertiary care hospitals in Detroit, Michigan between 2017 and 2019. Data output from wg-MLST was de novo assembled using SPAdes (version 3.7.1) assembler on the Bionumerics calculation engine. Minimum spanning tree (MST) analysis categorized isolates into unique MLST Pasteur serotypes (ST). Antimicrobial resistance genes and/or chromosomal mutations were identified using the ResFinder Database (version 3.2). K. pneumoniae isolates were compared for antibiotic-resistance patterns by hospital, unit, and ST. Figure 3. Hospital 1 clusters and strains that detected gene qnr1, arranged by unit for visual comparison. Figure 4. Sample of clinically significant genes and prevalence, excluding SHV family of genes for simplicity. Results There was significant genetic diversity among the isolates, and no predominant strain was identified. MST analysis revealed 17 unique strains. Only six strains had genetically unique resistance genes detected in more than one isolate, and only three of six were hospital-specific; none were unit-specific. Out of the 75 unique resistance genes detected, only 8 genes had a prevalence >50%: oqxA (100%), oqxB (100%), fosA (89%), blaCTX-M-15 (76%), aac(6’)-Ib-cr (61%), blaTEM-1B (52%), blaOXA-1 (52%), and catB3 (52%). No colistin resistance genes were detected. Of the remaining 69 low-prevalence resistance genes, only 8 hospital-specific genes were detected in more than one isolate (qnrB1, blaSHV-1, blaSHV-110, ac(6’)-Ib3, blaCTX-M-3, blaSHV-36, blaSHV-80, blaSHV-178) with a prevalence range of 4%-22%. Conclusion Our genetic analysis of antibiotic resistance patterns and wg-MLST revealed significant heterogeneity among the isolates, indicating no common source of transmission for either hospital. Although K. pneumoniae is a very common nosocomial pathogen, etiologic analysis suggests diverse community strains (e.g., gut colonization) may actually be responsible for previously-designated HAI. Disclosures Chetan Jinadatha, MD, MPH, AHRQ (Research Grant or Support)Department of Veterans Affairs (Other Financial or Material Support, Owner: Department of Veterans Affairs. Licensed to: Xenex Disinfection System, San Antonio, TX)Inventor (Other Financial or Material Support, Methods for organizing the disinfection of one or more items contaminated with biological agents)NiH/NINR (Research Grant or Support)NSF (Research Grant or Support)Xenex Healthcare Services (Research Grant or Support) Mark Stibich, PhD MHS, Xenex Disinfection Services, Inc (Board Member, Employee)
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Yao, Hsien-Tsung, Jia-Hsuan Lin, Yun-Ta Liu, Mei-Ling Li, and Wenchang Chiang. "Food–Drug Interaction between the Adlay Bran Oil and Drugs in Rats." Nutrients 11, no. 10 (2019): 2473. http://dx.doi.org/10.3390/nu11102473.
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Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) contains various phytonutrients for treating many diseases in Asia. To investigate whether orally administered adlay bran oil (ABO) can cause drug interactions, the effects of ABO on the pharmacokinetics of five cytochrome P450 (CYP) probe drugs were evaluated. Rats were given a single oral dose (2.5 mL/kg BW) of ABO 1 h before administration of a drug cocktail either orally or intravenously, and blood was collected at various time points. A single oral dose of ABO administration did not affect the pharmacokinetics of five probe drugs when given as a drug cocktail intravenously. However, ABO increased plasma theophylline (+28.4%), dextromethorphan (+48.7%), and diltiazem (+46.7%) when co-administered an oral drug cocktail. After 7 days of feeding with an ABO-containing diet, plasma concentrations of theophylline (+45.4%) and chlorzoxazone (+53.6%) were increased after the oral administration of the drug cocktail. The major CYP enzyme activities in the liver and intestinal tract were not affected by ABO treatment. Results from this study indicate that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs. ABO is likely to enhance intestinal drug absorption. Therefore, caution is needed to avoid food–drug interactions between ABO and co-administered drugs.
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Mihani, Joana, and Suela Këlliçi. "Patterns of Antibiotic Prescription in Children: Tirana, Albania Region." Open Access Macedonian Journal of Medical Sciences 6, no. 4 (2018): 719–22. http://dx.doi.org/10.3889/oamjms.2018.150.
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BACKGROUND: Antibiotics (abx) constitute the most prescribed therapeutic agent in the world. There is little data regarding antibiotic consumption by young children in Albania.AIM: This study aims to evaluate antibiotic prescription in children in quantitative and qualitative terms, and therefore, propose recommendations to improve overall clinical outcomes.METHODS: A retrospective, cross-sectional drug utilisation study was conducted based on unreimbursed prescriptions collected in 25 pharmacies, randomly selected within the district of Tirana, during the period beginning December 2015 to January 2016. They contain at least one antibacterial therapeutic agent prescribed for children 0-15 years old, for systemic use. The data were analysed using SPSS 20.RESULTS: A group of 904 prescriptions meet inclusion criteria, 54.1% patient were female, and 45.9% were male. The most exposed age group were 2-6 years old. The most common diagnosis was respiratory tract infections: bronchitis (59.2%), tonsillitis (17%) followed by bronchopneumonia (9.6%). The most prescribed antibiotic classes are Penicillins (33%), Cephalosporins (33.2%) and Macrolides (21,5%). Amoxicillin (19.4%), Azithromycin (14.7%), the combination of Amoxicillin and Clavulanic acid (13.5%) and Cefaclor (11.7%) were the most commonly prescribed. We observed short duration therapies, with a mean duration of 5.21 days and in 17.4 % of cases with a duration of ≤ 2 days.CONCLUSIONS: We observed a large use of broad-spectrum antibiotics for common respiratory tract infection in children less than 6 years old. We would recommend the creation of an electronic database of patient’s record in order to monitor the quality of prescription and education of the healthcare professionals and patient of risks related to antibiotic resistance.
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Trofimov, A. V., V. A. Atanesyan, A. M. Ischenko, et al. "Preparation of polyclonal and monoclonal anti-idiotypic antibodies against morphine-specific immunoglobulins." Medical Immunology (Russia) 22, no. 1 (2020): 187–96. http://dx.doi.org/10.15789/1563-0625-pop-1658.
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The preparation and study of anti-idiotypic (secondary) antibodies (Ab2) against monoclonal primary antibodies (Ab1) specific to biologically active molecules with a known structure is of great scientific and practical importance. Due to partial antigenic similarity of Ab2 and the initial antigen structures, these antibodies can be the basis of the vaccine, if the antigen usage is not possible, or is limited by law. In particular, one may create Ab2-based preparations, designed for immunization, in order to prevent and treat the drug addiction. The value of Ab2 properties increases even more if Ab1, used to obtain them, recognize different parts of the antigen molecule, which makes it possible to obtain second-generation antibodies with a wide range of specificity. In this work, the morphine-like polyclonal and monoclonal Ab2 were obtained. In each case, as the first-generation immunoglobulins for immunization, we used two murine monoclonal antibodies (mAbs) specific to different morphine derivatives: 3K11 antibodies to 3-0-carboxymethyl (CMM) and 2-p-carboxyphenylazomethyl (FAM) derivatives, as well as 6G1 antibodies to 6-hemisuccinyl derivative (GSM). After immunization of the horse with Ab1 and development of immune response, three pools of specific polyclonal antibodies were isolated from the animal blood serum: horse anti-species antibodies to the total mouse immunoglobulins (HAM); horse anti-idiotypic antibodies against 3K11 antibodies (HAM-K11), and against 6G1 antibodies (HAM-G1). In parallel, immunization of mice with 3K11 and 6G1 antibodies and fusion of obtained lymphocytes with Sp2/0 mouse myeloma cells by the Milstein-Köhler method resulted in three producers of anti-idiotypic antibodies: a clone producing mouse monoclonal Ab2 specific for mAb-6G1 (AIG1), as well as clones producing anti-mAb-3K11 antibodies (AI-K11A and AI-K11B). The physico-chemical and antigenic properties of all the Ab2 obtained were characterized. It was shown that the horse anti-idiotypic immunoglobulins not only belong to different classes, but are also polyvalent, while all monoclonal Ab2 obtained are represented by IgM immunoglobulins, being also strictly specific to the corresponding first-generation antibodies. Subsequently, the morphine-like properties of the first domestic polyclonal and monoclonal Ab2 obtained in the work will be investigated in a cellular model. Likewise, we shall study their ability to induce Ab3 as well as morphine-specific Ab1.
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Xiong, Jie, Ding-an Mao, and Li-qun Liu. "Research Progress on the Role of ABC Transporters in the Drug Resistance Mechanism of Intractable Epilepsy." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/194541.
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The pathogenesis of intractable epilepsy is not fully clear. In recent years, both animal and clinical trials have shown that the expression of ATP-binding cassette (ABC) transporters is increased in patients with intractable epilepsy; additionally, epileptic seizures can lead to an increase in the number of sites that express ABC transporters. These findings suggest that ABC transporters play an important role in the drug resistance mechanism of epilepsy. ABC transporters can perform the funcions of a drug efflux pump, which can reduce the effective drug concentration at epilepsy lesions by reducing the permeability of the blood brain barrier to antiepileptic drugs, thus causing resistance to antiepileptic drugs. Given the important role of ABC transporters in refractory epilepsy drug resistance, antiepileptic drugs that are not substrates of ABC transporters were used to obtain ABC transporter inhibitors with strong specificity, high safety, and few side effects, making them suitable for long-term use; therefore, these drugs can be used for future clinical treatment of intractable epilepsy.
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Xu, Chunliang, Sungkyun Lee, and Paul S. Frenette. "The Gut Microbiome Regulates Psychological Stress-Induced Inflammation in Sickle Cell Disease." Blood 134, Supplement_1 (2019): 205. http://dx.doi.org/10.1182/blood-2019-122331.
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Psychological stress (PS) is reported to precipitate vaso-occlusive episides (VOE) in sickle cell disease (SCD), but the mechanisms by which it does, are largely unknown. We subjected humanized (Berkeley) SCD mice to restraint stress and analyzed VOE using intravital microscopy. We found that stress exacerbated VOE as shown by reduced venular blood flow rates (control: 494 ± 30 × 103 pL/s; stress: 380 ± 20 × 103 pL/s; n = 25 - 43; p = 0.009) and reduced survival time (median survival time in control and stress groups: 394 min and 175 min, respectively; p = 0.02, Log-rank test). As previous studies show that adherent polymorphonuclear neutrophils (PMNs), especially aged PMNs marked by low CD62L and high CXCR4 expression, contribute to VOEs, we evaluated the behavior of leukocytes in live mice and observed a robust PMN response manifested by significantly increased adhesion and interactions with sickle RBC in stressed SCD animals. Flow cytometry analysis revealed a striking increase in aged PMNs in stressed SCD mice (control: 0.7 ± 0.1 × 106/ml; stress: 2.9 ± 0.3 × 106/ml; n = 3 - 4; p = 0.001), suggesting that the aged PMN expansion induced by stress may lead to the exacerbation of VOE in stressed SCD mice. Since aged PMN numbers are regulated by microbiota under steady state, we investigated whether response to PS also required the presence of the microbiota. Depletion of microbiota with broad-spectrum antibiotics (ABX) in SCD mice significantly prevented stress-induced aged PMN expansion (control: 4.8 ± 1.2 × 106/ml; ABX: 1.2 ± 0.3× 106/ml; n = 4 - 5; p = 0.0006), which was further confirmed using C57BL/6 germ-free (GF) mice (control: 1.1 ± 0.3 × 106/ml; GF: 0.2 ± 0.1 × 106/ml; n = 4; p = 0.003). Interestingly, analysis of inflammatory cytokines revealed a microbiota-dependent augmentation of IL-17A in the stressed mice. To investigate the role of IL-17A in the stress response, we neutralized IL-17A using an antibody (Ab) in C57BL/6 mice and found that IL-17A inhibition significantly dampened the aged PMN expansion induced by stress (isotype control Ab: 0.6 ± 0.1 × 106/ml; anti-IL-17A: 0.1 ± 0.0 × 106/ml; n = 4 - 5; p = 0.0004), which was also confirmed using IL-17A-/- mice. Further analyses revealed that Th17 lymphocytes were the major IL-17A-producing cells contributing to the stress response. In addition, depletion of microbiota with ABX or neutralization of IL-17A significantly alleviated stress-exacerbated VOE as measured by reduced PMN activation, improved blood flow rate and prolonged SCD mouse survival. As segmented filamentous bacteria (SFB) commensals were previously found to induce a Th17 response, we next tested the hypothesis that SFB was the driving bacteria in the stress response. Indeed, we found that PS-induced aged PMN expansion was greater in SFB+ mice (from Taconic) than in SFB- mice (from Jackson lab) (Taconic: 0.64 ± 0.11× 106/ml; Jax: 0.13 ± 0.02 × 106/ml; n = 4 - 5; p = 0.005). Depletion of SFB using vancomycin, a drug that eliminates Gram+ bacteria (including SFB), significantly reduced stress-induced aged PMN expansion. Furthermore, colonization of GF mice with SFB augmented aged PMN expansion after stress compared to stress control GF mice (control GF: 0.08 ± 0.02 × 106/ml; GF + SFB: 0.34 ± 0.10× 106/ml; n = 4 - 5; p = 0.04), suggesting that SFB was the key bacteria promoting aged PMN expansion during stress. The stress mechanisms involved the hypothalamic-pituitary-adrenal (HPA) axis since the blockade of glucocorticoid (GC) production using metyrapone or following adrenalectomy significantly prevented aged PMN expansion in stressed mice (PBS: 0.5 ± 0.1 × 106/ml; metyrapone: 0.1 ± 0.1× 106/ml; n = 5; p = 0.02. sham: 1.2 ± 0.2 × 106/ml; adrenalectomy: 0.4 ± 0.2 × 106/ml; n = 4 - 5; p = 0.01). Moreover, PS and dexamethasone greatly increased the gut permeability. Blockade of GC synthesis using metyrapone significantly alleviated stress-induced exacerbation of VOE manifested by reduced inflammation, improved the blood flow rate and prolonged SCD mice survival (median survival time in control and metyrapone groups: 155 min and 200 min, respectively; p = 0.02, Log-rank test). Overall, our results suggest that stress activation of the HPA axis increases the intestinal permeability, thereby promoting exposure to commensals that stimulate Th17 cells to produce IL-17A, which enables the expansion of aged polymorphonuclear neutrophils driving vaso-occlusion in SCD. Disclosures Frenette: Albert Einstein College of Medicine, Inc: Patents & Royalties; Ironwood Pharmaceuticals: Research Funding; Cygnal Therapeutics: Equity Ownership; Pfizer: Consultancy.
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Glodkowska-Mrowka, Eliza, Piotr Mrowka, Magdalena Winiarska, et al. "Statins Increase Antileukemic Potency of Imatinib Through the Inhibition of MDR/ABCB1 and BCRP/ABCG2 Drug Transporters Activity." Blood 118, no. 21 (2011): 2742. http://dx.doi.org/10.1182/blood.v118.21.2742.2742.
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Abstract Abstract 2742 The treatment of chronic myeloid leukemia (CML) was revolutionized by the introduction of tyrosine kinase inhibitors (TKIs) to the clinical practice. However, there is still a significant group of patients who due to drug resistance do not fully benefit from the therapy. Among various reasons of drug resistance, the changes of intracellular concentration of TKIs caused by the activity of drug transporters may have profound effect on clinical activity of the drug. Intracellular concentration of imatinib is a result of: drug influx into the cell and drug efflux out of the cell. The latter is mediated by ATP-binding casette (ABC) transporters - MDR/ABCB1 and BCRP/ABCG2. According to the recent knowledge modulation of membrane cholesterol level may change the activity of ABC transporters by changing their conformation. Hence we decided to evaluate potential effect of statins, widely used hypocholesterolemic drugs, on antileukemic activity of imatinib in cell lines transformed with BCR/ABL oncoprotein and primary human CML CD34+ cells. In a set of experiments involving cytotoxic assays (i.e. clonogenic assay, XTT, trypan blue exclusion assay) we revealed that lovastatin, a member of statin family, is able to enhance imatinib cytotoxicity both in established cell lines (32Dcl3 BCR/ABL+, K562) as well as in primary CML CD34+ cells obtained from patients in various stages of the disease, including those clinically resistant to imatinib with no detectable ABL kinase domain mutations. In the same time, lovastatin alone and in combination with imatinib did not influence BCR/ABL negative cells (32Dcl3 wild type, HL-60, CD34+ cells obtained from healthy blood donors). As measured using specific, fluorescent-labeled substrates for ABC transporters (rhodamine-123 and Bodipy-FL-prazosin respectively), lovastatin significantly inhibits MDR/ABCB1- and BCRP/ABCG2-mediated efflux capacity. Similar effects were observed for other statins. The addition of cholesterol to the samples previously incubated with lovastatin completely reversed inhibitory activity of statins. To confirm these results we examined direct changes of intracellular concentration of imatinib itself using radiolabeled 14C-imatinib. In these settings, statins caused 2–3-fold increase in intracellular imatinib concentration in murine and human cell lines (32Dcl3 BCR/ABL+, K562) and also in primary CML CD34+ cells including clones resistant to imatinib (Figure 1). Statins did not influence initial concentration of imatinib what may suggest that their effects on imatinib concentration are not mediated by changes in OCT-1 activity. In addition, statins did not influence expression of MDR/ABCB1 and BCRP/ABCG2 drug transporters measured using qPCR nor ABC proteins levels measured using Wester blotting. Combination of imatinib and lovastatin induced cell cycle arrest and increased percentage of apoptotic leukemic cells measured using flow cytometric analysis after propidium iodide staining. Lovastatin also reduced imatinib-induced phosphorylation of the adaptor protein CrkL. In summary, we show that statins are able to increase therapeutic efficacy of imatinib through the inhibition of drug efflux mediated by MDR/ABCB1 and BCRP/ABCG2 transporters. Our results suggest that statin-mediated depletion of cholesterol in the cell may change conformational status of the efflux pumps, including MDR/ABCB1 and BCRP/ABCG2 pumps involved in the transport of imatinib, and in that way modulate intracellular concentration of the drug. The addition of statins may become attractive treatment modality for the selected group of patients in chronic phase and blast crisis.Fig. 1Statins increase intracellular concentration of imatinib in BCR/ABL-positive cells.Fig. 1. Statins increase intracellular concentration of imatinib in BCR/ABL-positive cells. CML-CP, CML-BP–CD34+ cells obtained from CML patient in chronic phase or blast crisis respectively; *p<0,05 Disclosures: No relevant conflicts of interest to declare.
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Zhang, Bin, John Groffen, and Nora Heisterkamp. "Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a." Blood 106, no. 4 (2005): 1355–61. http://dx.doi.org/10.1182/blood-2004-09-3655.
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AbstractResistance to cytotoxic drugs frequently emerges during treatment of leukemia with conventional chemotherapy. New classes of anticancer drugs, such as the farnesyltransferase inhibitors (FTIs), show therapeutic promise, but whether cells will easily develop resistance against them is not known. Here, we grew breakpoint cluster region/Abelson murine leukemia (Bcr/Abl) P190 lymphoblasts on stroma and made them resistant to the FTI SCH66336/lonafarnib to model emerging drug resistance in a patient. These cells exhibited greatly increased (> 100-fold) expression levels of a novel ATP (adenosine triphosphate)-binding cassette (ABC) transporter-homologous gene, ATP11A. We showed that overexpression of this gene provided protection against the effects of SCH66336, whereas knockdown of endogenous ATP11a using small interfering RNA (siRNA) made cells more sensitive to this drug. The lymphoblasts that were resistant to this FTI were also more resistant to FTI-276 and to GGTI-298, 2 other structurally similar inhibitors. Surprisingly, the cells were also able to survive higher concentrations of imatinib mesylate, the Bcr/Abl tyrosine kinase inhibitor. However, the cells remained sensitive to vincristine. Our results show that elevated levels of ATP11a can protect malignant lymphoblastic leukemia cells against several novel small molecule signal transduction inhibitors. A determination of the expression levels of this gene may have prognostic value when treatment with such classes of drugs is contemplated. (Blood. 2005;106: 1355-1361)
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Reddy, Y. Bala Suresh Kumar, and Sankar K. "Pharmacoeconomic analysis of drug expenditure in government medical college and hospital, Vijayawada, India." International Journal of Basic & Clinical Pharmacology 7, no. 5 (2018): 873. http://dx.doi.org/10.18203/2319-2003.ijbcp20181627.
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Background: To conduct economic analysis in tertiary care hospital with a view to identify the categories of drugs needing stringent management control.Methods: The annual consumption and expenditure data is obtained from the drug store of government general hospital, Vijayawada, for the period of April 2015 to March 2016. ABC-VED analysis of the drugs are done based on cost and criticality criteria respectively. ABC-VED matrix analysis was done to classify drugs into category I, II, III.Results: The total annual drug expenditure incurred on 299 drug items for the year 2015-2016 was found to be Rs:4,47,04,446. On ABC analysis, 4%, 9.36%, 86.64% of drugs were found to be Always, Better, and Control category items respectively, amounting to 68.92%, 20.05%, 11.03% of annual drug expenditure. VED analysis showed that 32.10%, 45.5%, 22.4% of drug items were Vital, Essential, and Desirable category items respectively, amounting to 35.3%, 37.1%, 27.6% of annual drug expenditure respectively. By ABC-VED matrix analysis, 34.11%, 46.49%, 19.4% of drug items were found to be category I (high stringent), II (medium stringent), III (low stringent) respectively, amounting to 80.76%, 17.46%, 1.77% of annual drug expenditure respectively.Conclusions: The study identified 34.11% of drug items belonging to category I which require high priority monitoring. Inventory management tools must be routinely used for the better control and judicious use of the resources.
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Kheddouci, Lylia. "Adverse drug reactions related to drug interactions." Batna Journal of Medical Sciences (BJMS) 1, no. 2 (2014): 111–15. http://dx.doi.org/10.48087/bjmstf.2014.1213.
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Adverse drug reactions are numerous and steadily increasing as the emergence of new drugs on the market, the wide use within the population, and/or polypharmacy. Even if many drug interactions have an insignificant impact on the patient, others are causing an increase in hospitalization, morbidity, and mortality and therefore the cost. This article is a non-exhaustive review of published literature regarding adverse events related to drug interactions: their impacts, the factors favoring their occurrence, and the problematic around this theme. Most published studies are pharmaco-epidemiological and results vary depending on various factors.
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Gupta, Ravi K., Namrata Makkar, and Sonali Shamdasani. "Always, better and control - vital, essential, desirable matrix analysis of the drug store of a tertiary care teaching hospital of North India." International Journal of Research in Medical Sciences 7, no. 12 (2019): 4728. http://dx.doi.org/10.18203/2320-6012.ijrms20195546.
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Background: Substantial improvement can be brought about in the hospital inventory and drug expenditure by inventory control techniques. These include ABC (always, better and control), VED (vital, essential and desirable) and ABC-VED matrix analysis. The objective of the study was to categorize the drugs based on cost and criticality and identify those which require stringent managerial control.Methods: ABC analysis according to drug expenditure, VED analysis according to criticality of the drugs, ABC-VED matrix analysis to classify drugs into category I, II and III was done for drug store of a tertiary care teaching hospital of North India for the period of April, 2018 to March, 2019.Results: The total number of the drug items used by the drug store was 315. The total drug expenditure was Rs. 9,61,29,859. By ABC analysis, it was found that 15.24%, 22.54% and 62.22% items belonged to A, B and C category respectively, accounting for 70%, 20% and 10% of Annual Drug Expenditure (ADE). VED analysis showed that 31.11%, 60.32% and 8.57% were V, E, and D category items respectively, accounting for 30.44%, 57.12% and 12.44% of ADE. By ABC-VED matrix analysis, 42.86%, 52.38% and 4.76% items were category I, II and III items respectively, accounting for 78.91%, 20.15% and 0.94% of ADE.Conclusions: The study depicted the items belonging to category I which requires top managerial control, also the items belonging to categories II and III which require control by middle and lower managerial level respectively.
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López-Fernández, Luis A. "ATP-Binding Cassette Transporters in the Clinical Implementation of Pharmacogenetics." Journal of Personalized Medicine 8, no. 4 (2018): 40. http://dx.doi.org/10.3390/jpm8040040.
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ATP-binding cassette (ABC) transporters are involved in a large number of processes and contribute to various human genetic diseases. Among other functions, ABC proteins are involved in the transport of multiple drugs through cells. Most of the genes coding for these transporters are highly polymorphic and DNA variants in these genes can affect the normal functioning of these proteins, affecting the way drugs are transported, increasing or decreasing drug levels. These changes in the intracellular and extracellular drug levels may be associated with altered drug effectiveness or severe drug-induced adverse events. This review presents a state-of-art of the most pharmacogenetics clinically relevant ABC transporters closed to the clinical implementation.
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Nisa, Anna Fitrotun. "ANALISIS PENGENDALIAN PERSEDIAAN OBAT BERDASARKAN METODE ABC, EOQ DAN ROP." MANAJERIAL 6, no. 01 (2019): 17. http://dx.doi.org/10.30587/manajerial.v6i01.852.
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In the supply of medicines in the pharmacy warehouse of Muhammadiyah Gresik Hospital, there has been drug void and expired date. This research was conducted by using descriptive qualitative research approach. Based on the analysis of ABC, the use of drugs in group A was 43 drugs or 7.75% of all drug supplies with 90323 items or 69.59% of total drug usage. Medicines belonging to group B are 78 types of drugs or 14.05% of all types of drug supplies with the amount of use as much as 26371 items or 20.32% of total drug usage. While the drugs that include group C as much as 434 types of drugs or 78.25% of all types of drug supplies with the amount of use as much as 13103 items or 10.09% of total drug usage. Based on analysis of ABC Investment classified as A is as much as 78 types of drugs or 14.5% of all drugs with an investment of Rp 250,733,719.00 or 69.28% of the total drug investment. The drugs belonging to group B are as many as 135 types of drugs or 24.32% of all drugs with an investment value of Rp 82,624,061.00 or 22.83% of the total drug investment. While the drugs belonging to group C are as many as 342 types of drugs or 61.63% of all drugs with an investment of Rp 28,513,928.00 or 7.89% of the total drug investment. Based on EOQ analysis then the optimum order amount from Group A with high investment value varies from 1-2565 items. While according to ROP analysis obtained point reorder/time reorder for 78 drugs that belong to group A with high investment value varies from 1-2861 item.
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Styczyński, Jan, Mariusz Wysocki, Robert Debski, et al. "The influence of intracellular idarubicin and daunorubicin levels on drug cytotoxicity in childhood acute leukemia." Acta Biochimica Polonica 49, no. 1 (2002): 99–107. http://dx.doi.org/10.18388/abp.2002_3826.
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Uptake and efflux of two anthracyclines, idarubicin (IDA) and daunorubicin (DNR), was studied in childhood acute leukemia samples. A comparison of IDA and DNR transport phenomena in relation to drug cytotoxicity and expression of P-glycoprotein (PGP) was made. Intracellular content of IDA/DNR was determined by flow cytometry using the fluorescent properties of the drugs. In vitro drug cytotoxicity was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. PGP expression was analysed by flow cytometry. The uptake and efflux rates were non-significantly higher for IDA than DNR. There were no differences between three types of leukemia with respect to drug content during accumulation and retention. After correction for the cell volume, intracellular concentration of both drugs in each moment of uptake and efflux was significantly lower in relapsed ALL and AML samples in comparison with initial ALL cells. Efflux, but not uptake, of both drugs was inversely correlated with PGP expression and IDA, but not DNR, cytotoxicity. The cytotoxicity was correlated with drug accumulation for both drugs and with drug retention for IDA. In conclusion, it seems that (1) intracellular content was related to the lipophilic properties of the drugs rather than to the type of leukemia, (2) decreased intracellular concentration of both drugs might have an impact on compromised therapy results in AML and relapsed ALL children, (3) IDA presents higher cytotoxicity, which possibly might be decreased by the presence of PGP. These results might have a practical impact on the rational design of new chemotherapy protocols.
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Abdessadek, Mohammed, Rabia Magoul, Afaf Amarti, Seloua El Ouezzani, and Youssef Khabbal. "Customizing dosage drugs what contribution in therapeutic drug monitoring?" Annales de biologie clinique 72, no. 1 (2014): 15–24. http://dx.doi.org/10.1684/abc.2013.0923.
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Bougie, Daniel W., Jessica Birenbaum, Scott Ahl, and Richard H. Aster. "Drug-Dependent Murine Monoclonal Antibodies (mAbs) Mimic Antibodies Found in Patients with Drug-Induced Immune Thrombocytopenia (TP)." Blood 106, no. 11 (2005): 731. http://dx.doi.org/10.1182/blood.v106.11.731.731.
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Abstract Drug-induced immune thrombocytopenia (DITP) is a serious and sometimes life-threatening complication of treatment with many drugs. In most instances (excluding heparin-induced TP), platelet (plt) destruction is caused by antibodies (abs) that recognize distinct epitopes on platelet membrane glycoproteins (GP) only when the sensitizing drug is present in soluble form. How drug at pharmacological levels promotes tight binding of antibody to a specific target is unknown, in part because only polyclonal human abs have been available for study. We sought to produce monoclonal abs (mAbs) that mimic the behavior of human drug-dependent abs to create tools that can be used to study the molecular basis for this interaction. Mice were immunized with GPIIb/IIIa isolated from human platelets together with soluble quinine (Qn), tirofiban (Tf), or eptifibatide (Ef), three drugs that commonly cause DITP. Hybridomas were prepared from splenic B cells using a standard protocol and approximately 550 supernatants from each cultured hybrid line were screened for DDAbs by flow cytometry using normal platelets as targets. To date, 11 Abs that react with GPIIb/IIIa only in the presence of the immunizing drug (2 Qn-, 3 Tf- and 6 Ef-specific) have been identified. Preliminary studies show that the Qn-specific abs bind reversibly to GPIIb/IIIa at 50 nM Qn, a concentration much lower than is achieved pharmacologically, and are not inhibited by Qn at 5 mM, the limit of solubility. Quinidine (Qd) the diastereoisomer of Qn, supports only weak ab binding at a concentration of 50 uM. The tirofiban and eptifibatide-dependent abs recognize GPIIb/IIIa occupied by these RGD ligand-mimetic GPIIb/IIIa inhibitors. In each of these respects, reaction patterns of the three groups of mAbs closely resemble those of abs from patients experiencing TP after treatment with one of these drugs. These findings show that mAbs mimicking the behavior of human drug-dependent abs can be produced by immunizing mice with GP and soluble drug to produce probes suitable for characterizing the molecular basis of ab-drug-target interactions leading to platelet destruction in DITP. It is noteworthy that these mAbs were induced using soluble drug and protein for immunization because this suggests that the immune response leading to DITP does not require the sensitizing drug to be covalently linked to a protein, i.e, does not require the drug to act as a classical hapten.
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Nilchan, Napon, Xiuling Li, Lee Pedzisa, Alex R. Nanna, William R. Roush, and Christoph Rader. "Dual-mechanistic antibody-drug conjugate via site-specific selenocysteine/cysteine conjugation." Antibody Therapeutics 2, no. 4 (2019): 71–78. http://dx.doi.org/10.1093/abt/tbz009.
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Abstract Background While all clinically translated antibody-drug conjugates (ADCs) contain a single-drug payload, most systemic cancer chemotherapies involve use of a combination of drugs. These regimens improve treatment outcomes and slow development of drug resistance. We here report the generation of an ADC with a dual-drug payload that combines two distinct mechanisms of action. Methods Virtual DNA crosslinking agent PNU-159682 and tubulin polymerization inhibitor monomethyl auristatin F (MMAF) were conjugated to a HER2-targeting antibody via site-specific conjugation at engineered selenocysteine and cysteine residues (thio-selenomab). Results The dual-drug ADC showed selective and potent cytotoxicity against HER2-expressing cell lines and exhibited dual mechanisms of action consistent with the attached drugs. While PNU-159682 caused S-phase cell cycle arrest due to its DNA-damaging activity, MMAF simultaneously inhibited tubulin polymerization and caused G2/M-phase cell cycle arrest. Conclusion The thio-selenomab platform enables the assembly of dual-drug ADCs with two distinct mechanisms of action.
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T., Chethana, Babitha Rajan, Archana Selvaraj, and Pruthvish S. "ABC analysis of drugs used in health camps organized in villages of Chintamani taluk, Karnataka, India." International Journal Of Community Medicine And Public Health 4, no. 1 (2016): 186. http://dx.doi.org/10.18203/2394-6040.ijcmph20164735.
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Background: Tracking of drug acquisition, storage, distribution, and utilization are to be handled properly with utmost care to eliminate wastage and to ensure scientific continuity of supplies. The present study was done with the objective to conduct the economic analysis of drug expenditure and to identify the categories of items needing stringent management control for health camps. Methods: The study was done among health camps conducted in the 10 villages of Chintamani taluk during December 2015. For Always Better Control (ABC) analysis, the consumption of all the drugs was calculated after multiplying unit cost by total consumption and resulting figures were arranged in descending order of rupee value.Results: The drugs were classified in to A B C groups according to total cost consumed 70%, 20%, and 10% respectively. The total cost incurred for procurement of drugs in these camps was Indian rupees 12872.93. We found that 15.78% of drugs were in category A. If we were to manage drug inventory solely based on ABC analysis, supervision of only 6 drugs would have resulted in control over approximately 70% of the drug budget. Conclusions: Thus ABC inventory management analysis of health camps will promote effective management of drug inventory with minimal monetary resources and will contribute to provision of uncompromised patient care.
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Lolo, Widya Astuty, Weny Indayany Widodo, and Deby Afriani Mpila. "Analisis Perencanaan Dan Pengadaan Obat Antibiotik Berdasarkan Metode ABC Indeks Kritis Di Instalasi Farmasi Rumah Sakit Advent Manado." Jurnal MIPA 10, no. 1 (2020): 10. http://dx.doi.org/10.35799/jmuo.10.1.2021.30639.
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Perencanaan dan pengadaan obat merupakan salah satu fungsi penting dalam tahapan manajemen logistik obat, termasuk obat antibiotik. Sistem pengelolaan yang baik akan menjamin tersedianya obat sesuai dengan kebutuhan pasien. Analisis ABC Indeks Kritis dapat digunakan untuk menentukan prioritas obat yang akan diadakan. Penelitian ini bertujuan untuk menganalisis perencanaan dan pengadaan obat antibiotik di Instalasi Farmasi Rumah Sakit Advent Manado menggunakan analisis ABC Indeks Kritis. Penelitian ini merupakan penelitian deskriptif kuantitatif. Data primer diperoleh dari 8 orang responden yang mengisi kuesioner dan data sekunder diperoleh dari Instalasi Farmasi, Bagian Logistik dan Bagian Keuangan. Data yang diperoleh dianalisis dengan metode ABC Indeks Kritis. Hasil penelitian menunjukkan bahwa dari total 63 item obat antibiotik, 6 item merupakan kelompok A (9,52%), 29 item merupakan kelompok B (46,03%), dan 28 item merupakan kelompok C (44,44%). Metode ABC Indeks Kritis dapat membantu rumah sakit dalam melakukan perencanaan dan pengadaan obat secara efisien dengan mempertimbangkan nilai pakai, nilai investasi dan nilai kritis obat.Drug planning and procurement is one of the most important function in steps of logistics management, include antibiotic drugs. A good management system will ensure the medical availability of drugs according to patient needs. The ABC critical index analysis can be used to prioritize drug procurement. This study aim to analyze the planning and procurement of antibiotic drugs in Pharmacy Installation at Manado Adventist Hospital by using ABC critical index analysis. The design of this research was quantitative descriptive study. Primary data were obtained from 8 respondents who filled the questionnaires; and secondary data were obtained from Pharmacy Installation, Logistic Division and Finance Division. Data were analyzed with ABC critical index method. The result of ABC critical index analysis showed that 63 antibiotic drug items were found, respectively, amounting for 6 (9.52%), 29 (46.03%) and 28 (44.44%) of drug items were found to be category A, B and C items. ABC critical index method can help hospital drug management in order to planning and procurement the drug efficiently by considering the use value, investment value, and critical value of drug.
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Saib, Sonia, and Xavier Delavenne. "Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition." Pharmaceutics 13, no. 10 (2021): 1544. http://dx.doi.org/10.3390/pharmaceutics13101544.
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The ATP-binding cassette (ABC) transporters play a key role in drug pharmacokinetics. These membrane transporters expressed within physiological barriers can be a source of pharmacokinetic variability. Changes in ABC transporter expression and functionality may consequently affect the disposition of substrate drugs, resulting in different drug exposure. Inflammation, present in several acute and chronic diseases, has been identified as a source of modulation in drug transporter expression leading to variability in drug response. Its regulation may be particularly dangerous for drugs with a narrow therapeutic index. In this context, numerous in vitro and in vivo models have shown up- or downregulation in the expression and functionality of ABC transporters under inflammatory conditions. Nevertheless, the existence of contradictory data and the lack of standardization for the models used have led to a less conclusive interpretation of these data.
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Capritasari, Rafiastiana, and Dwiky Ramadhani Kurniawati. "Analisis perencanaan dan pengadaan guna menjamin ketersediaan obat di rumah sakit." Sasambo Journal of Pharmacy 2, no. 1 (2021): 32–36. http://dx.doi.org/10.29303/sjp.v2i1.71.
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Management of drug is one of the factors which contribute to the quality of hospital services. This study aimed at finding out drug planning in Pharmacy Unit of Adelia Surgical Hospital by using ABC analysis method. This research is qualitative descriptive study involving informants. Primary data were collected by interview with respondents and secondary data report of general drugs purchased period of May 2018 – May 2019. The Result using ABC analysis indicate that there are 23 (17,42%) kindof drugs in group A, 35 (26,52%) in group B and 74 (56,06%) in grup C. Group A if in the event of an excess or deficiency will couse harm to the hospital. ABC analysis method will effectively improve hospital drug consumption plan.
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Singh, Harpreet, Anang A. Shelat, Amandeep Singh, Nidal Boulos, Richard T. Williams, and R. Kiplin Guy. "A Screening-Based Approach to Circumvent Tumor Microenvironment-Driven Intrinsic Resistance to BCR-ABL+ Inhibitors in Ph+ Acute Lymphoblastic Leukemia." Journal of Biomolecular Screening 19, no. 1 (2013): 158–67. http://dx.doi.org/10.1177/1087057113501081.
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Signaling by the BCR-ABL fusion kinase drives Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Despite their clinical activity in many patients with CML, the BCR-ABL kinase inhibitors (BCR-ABL-KIs) imatinib, dasatinib, and nilotinib provide only transient leukemia reduction in patients with Ph+ ALL. While host-derived growth factors in the leukemia microenvironment have been invoked to explain this drug resistance, their relative contribution remains uncertain. Using genetically defined murine Ph+ ALL cells, we identified interleukin 7 (IL-7) as the dominant host factor that attenuates response to BCR-ABL-KIs. To identify potential combination drugs that could overcome this IL-7–dependent BCR-ABL-KI–resistant phenotype, we screened a small-molecule library including Food and Drug Administration–approved drugs. Among the validated hits, the well-tolerated antimalarial drug dihydroartemisinin (DHA) displayed potent activity in vitro and modest in vivo monotherapy activity against engineered murine BCR-ABL-KI–resistant Ph+ ALL. Strikingly, cotreatment with DHA and dasatinib in vivo strongly reduced primary leukemia burden and improved long-term survival in a murine model that faithfully captures the BCR-ABL-KI–resistant phenotype of human Ph+ ALL. This cotreatment protocol durably cured 90% of treated animals, suggesting that this cell-based screening approach efficiently identified drugs that could be rapidly moved to human clinical testing.
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Rasmussen, Mark, Daniel W. Bougie, Gregory H. Denomme, and Richard H. Aster. "Serologic Characterization of Antibodies in Patients Experiencing Piperacillin-Induced Immune Thrombocytopenia." Blood 134, Supplement_1 (2019): 1078. http://dx.doi.org/10.1182/blood-2019-130966.
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Beta lactam antibiotics (penicillins, cephalosporins, etc) are relatively common triggers for immune hemolytic anemia, neutropenia and drug-induced thrombocytopenia (DITP) but the mechanism(s) responsible for this side effect are not well understood. The ureidopenicillin, piperacillin, is one of the beta lactam drugs implicated most often as a trigger for immune cytopenia. We characterized drug-dependent reactions of antibodies (abs) identified in 18 patients with piperacillin-associated thrombocytopenia. Each of the 18 patients had an ab that reacted strongly (flow cytometry) with normal platelets but not RBC when soluble piperacillin was present. These reactions were not inhibited by the highest drug concentration that could be achieved in the reaction mixture and similar antibodies were not found in normal serum. These reactions are similar to those obtained with drug-dependent antibodies (DDAbs) found in patients sensitive to quinine, vancomycin, and many other drugs known to cause DITP. Evidence suggests that such drugs promote binding of DDAbs to their targets by reacting with antibody CDR3 and modifying its specificity (Blood 2015;126:2138). Beta-lactam drugs differ from most other medications in their ability to spontaneously link covalently to free amino groups on membrane proteins to produce potentially immunogenic haptens that could induce abs theoretically capable of contributing to thrombocytopenia in piperacillin-treated patients. We optimized conditions for "haptenization" of platelets and RBCs with piperacillin and tested patient and normal sera for abs that recognize piperacillin-coated cells. Complete inhibition of binding by excess soluble drug was a criterion for a "positive" reaction. As shown in Table 1, IgG and IgM abs reactive with piperacillin-coated RBCs were found in each of 18 patient and 20 normal sera tested; IgM abs reactive with piperacillin-coated platelets were found in nearly all of both groups and similar IgG abs were found in about half. Reaction strength of IgM abs against piperacillin-coated RBCs correlated closely with that against piperacillin-coated platelets The findings demonstrate two distinctly different types of piperacillin-specific abs in patients experiencing piperacillin-induced thrombocytopenia. The first is usually IgG, binds to platelets but not RBCs only when soluble drug is present, is not inhibited by excess drug, even at high concentrations, correlates with exposure to piperacillin and development of thrombocytopenia and is not found in normal persons. This behavior is similar to that of DDAbs induced by quinine, vancomycin and many other drugs. The second is commonly IgM and less often IgG, binds to piperacillin-coated platelets and RBCs, is inhibited by soluble drug and, as the IgM isoform, is found in nearly all normal subjects. Failure of abs that recognize piperacillin-coated cells to distinguish between platelets and RBCs in any consistent way argues against the possibility that they play a role in the pathogenesis of piperacillin-induced DITP. "Naturally-occurring" IgM abs that recognize piperacillin-coated RBC were previously described by Garratty et al (Transfusion 2008;48:2429) and could reflect widespread environmental exposure to beta-lactam antibiotics. Disclosures No relevant conflicts of interest to declare.
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Kovalskaya, Galina N., Dina Y. Zhukova, and Ekaterina N. Mikhalevich. "Interaction of Drugs Used for the Treatment of Cardiovascular Diseases." Acta Biomedica Scientifica 4, no. 1 (2019): 36–42. http://dx.doi.org/10.29413/abs.2019-4.1.6.
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Combined therapy in cardiology is currently the most recognized method of treatment, especially in patients with hypertension. Approximately in 50 % of patients with hypertension, monotherapy is effective. However to achieve the desired effect in the remaining half of patients, simultaneous administration of two and sometimes three drugs is required. Numerous drugs with a fixed combination of two (and even three) antihypertensive drugs, often used in clinical practice, greatly simplify the dosage regimen of drugs and improve patients’ adherence to treatment. Unfortunately, simultaneous prescription of several drugs increases sharply the probability of inter-drug interaction with the increase in the number of prescribed drugs. The result of drug-drug intereaction may be unpredictable. Therefore, the ability to predict the possible adverse reactions in patients with cardiovascular diseases and to prescribe rationally combined pharmacotherapy is a guarantee of highly efficient and safe treatment.Currently, rational combinations of antihypertensive drugs of different groups make hypertension therapy more comfortable and increases patients’ adherence to treatment. The authors present topical combinations of antihypertensive drugs in one drug: angiotensin converting enzyme inhibitor + diuretic, β-adrenoblocker + diuretic; diuretic + angiotensin receptor antagonist; calcium antagonist + angiotensin receptor antagonist; calcium antagonist + β-adrenoblocker, and others.The article presents an overview of both rational (calcium antagonist + diuretic, β-adrenoblocker + diuretic,) and irrational (angiotensin converting enzyme Inhibitor + potassium-sparing diuretic, angiotensin receptor blocker + potassium-sparing diuretic) combinations of antihypertensive drugs. Combinations of some hypotensive and antianginal drugs with drugs of other groups with a high risk of adverse reactions are presented.
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Ambudkar, Suresh V., Barry P. Rosen, and Michael M. Gottesman. "Workshop on ABC Transporters and Human Diseases." Drug Resistance Updates 3, no. 1 (2000): 51–54. http://dx.doi.org/10.1054/drup.2000.0125.
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Bougie, Daniel W., Mark Rasmussen, Jieqing Zhu та Richard H. Aster. "Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin". Blood 119, № 26 (2012): 6317–25. http://dx.doi.org/10.1182/blood-2012-01-406322.
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Arginine-glycine-aspartic acid (RGD)–mimetic platelet inhibitors act by occupying the RGD recognition site of αIIb/β3 integrin (GPIIb/IIIa), thereby preventing the activated integrin from reacting with fibrinogen. Thrombocytopenia is a well-known side effect of treatment with this class of drugs and is caused by Abs, often naturally occurring, that recognize αIIb/β3 in a complex with the drug being administered. RGD peptide and RGD-mimetic drugs are known to induce epitopes (ligand-induced binding sites [LIBS]) in αIIb/β3 that are recognized by certain mAbs. It has been speculated, but not shown experimentally, that Abs from patients who develop thrombocytopenia when treated with an RGD-mimetic inhibitor similarly recognize LIBS determinants. We addressed this question by comparing the reactions of patient Abs and LIBS-specific mAbs against αIIb/β3 in a complex with RGD and RGD-mimetic drugs, and by examining the ability of selected non-LIBS mAbs to block binding of patient Abs to the liganded integrin. Findings made provide evidence that the patient Abs recognize subtle, drug-induced structural changes in the integrin head region that are clustered about the RGD recognition site. The target epitopes differ from classic LIBS determinants, however, both in their location and by virtue of being largely drug-specific.
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Kang, Joohyun, Jae-Ung Hwang, Miyoung Lee, et al. "PDR-type ABC transporter mediates cellular uptake of the phytohormone abscisic acid." Proceedings of the National Academy of Sciences 107, no. 5 (2010): 2355–60. http://dx.doi.org/10.1073/pnas.0909222107.
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Abscisic acid (ABA) is a ubiquitous phytohormone involved in many developmental processes and stress responses of plants. ABA moves within the plant, and intracellular receptors for ABA have been recently identified; however, no ABA transporter has been described to date. Here, we report the identification of the ATP-binding cassette (ABC) transporter Arabidopsis thaliana Pleiotropic drug resistance transporter PDR12 (AtPDR12)/ABCG40 as a plasma membrane ABA uptake transporter. Uptake of ABA into yeast and BY2 cells expressing AtABCG40 was increased, whereas ABA uptake into protoplasts of atabcg40 plants was decreased compared with control cells. In response to exogenous ABA, the up-regulation of ABA responsive genes was strongly delayed in atabcg40 plants, indicating that ABCG40 is necessary for timely responses to ABA. Stomata of loss-of-function atabcg40 mutants closed more slowly in response to ABA, resulting in reduced drought tolerance. Our results integrate ABA-dependent signaling and transport processes and open another avenue for the engineering of drought-tolerant plants.
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Wang, Yuanyuan, Muh Akbar Bahar, Anouk M. E. Jansen, et al. "Improving antibacterial prescribing safety in the management of COPD exacerbations: systematic review of observational and clinical studies on potential drug interactions associated with frequently prescribed antibacterials among COPD patients." Journal of Antimicrobial Chemotherapy 74, no. 10 (2019): 2848–64. http://dx.doi.org/10.1093/jac/dkz221.
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Abstract Background Guidelines advise the use of antibacterials (ABs) in the management of COPD exacerbations. COPD patients often have multiple comorbidities, such as diabetes mellitus and cardiac diseases, leading to polypharmacy. Consequently, drug–drug interactions (DDIs) may frequently occur, and may cause serious adverse events and treatment failure. Objectives (i) To review DDIs related to frequently prescribed ABs among COPD patients from observational and clinical studies. (ii) To improve AB prescribing safety in clinical practice by structuring DDIs according to comorbidities of COPD. Methods We conducted a systematic review by searching PubMed and Embase up to 8 February 2018 for clinical trials, cohort and case–control studies reporting DDIs of ABs used for COPD. Study design, subjects, sample size, pharmacological mechanism of DDI and effect of interaction were extracted. We evaluated levels of DDIs and quality of evidence according to established criteria and structured the data by possible comorbidities. Results In all, 318 articles were eligible for review, describing a wide range of drugs used for comorbidities and their potential DDIs with ABs. DDIs between ABs and co-administered drugs could be subdivided into: (i) co-administered drugs altering the pharmacokinetics of ABs; and (ii) ABs interfering with the pharmacokinetics of co-administered drugs. The DDIs could lead to therapeutic failures or toxicities. Conclusions DDIs related to ABs with clinical significance may involve a wide range of indicated drugs to treat comorbidities in COPD. The evidence presented can support (computer-supported) decision-making by health practitioners when prescribing ABs during COPD exacerbations in the case of co-medication.
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Klein, Cornelia, Karl Kuchler, and Martin Valachovic. "ABC proteins in yeast and fungal pathogens." Essays in Biochemistry 50 (September 7, 2011): 101–19. http://dx.doi.org/10.1042/bse0500101.
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All fungal genomes harbour numerous ABC (ATP-binding cassette) proteins located in various cellular compartments such as the plasma membrane, vacuoles, peroxisomes and mitochondria. Most of them have initially been discovered through their ability to confer resistance to a multitude of drugs, a phenomenon called PDR (pleiotropic drug resistance) or MDR (multidrug resistance). Studying the mechanisms underlying PDR/MDR in yeast is of importance in two ways: first, ABC proteins can confer drug resistance on pathogenic fungi such as Candida spp., Aspergillus spp. or Cryptococcus neoformans; secondly, the well-established genetic, biochemical and cell biological tractability of Saccharomyces cerevisiae makes it an ideal tool to study basic mechanisms of drug transport by ABC proteins. In the past, knowledge from yeast has complemented work on human ABC transporters involved in anticancer drug resistance or genetic diseases. Interestingly, increasing evidence available from yeast and other organisms suggests that ABC proteins play a physiological role in membrane homoeostasis and lipid distribution, although this is being intensely debated in the literature.
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Rix, Uwe, Oliver Hantschel, Gerhard Dürnberger, et al. "Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets." Blood 110, no. 12 (2007): 4055–63. http://dx.doi.org/10.1182/blood-2007-07-102061.
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Abstract The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia. Because many patients develop imatinib resistance, 2 second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed. To predict potential side effects and novel medical uses, we generated comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs. Our studies yielded 4 major findings: (1) The interaction profiles of the 3 drugs displayed strong differences and only a small overlap covering the ABL kinases. (2) Dasatinib bound in excess of 30 Tyr and Ser/Thr kinases, including major regulators of the immune system, suggesting that dasatinib might have a particular impact on immune function. (3) Despite the high specificity of nilotinib, the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. (4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs.
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Michaelis, Martin, Florian Rothweiler, Thomas Nerreter, Mohsen Sharifi, Taravat Ghafourian, and Jindrich Cinatl. "Karanjin interferes with ABCB1, ABCC1, and ABCG2." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 1 (2014): 92. http://dx.doi.org/10.18433/j3bw2s.
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PURPOSE: The prominent ATP-binding cassette (ABC) transporters ABCB1, ABCC1, and ABCG2 are involved in substance transport across physiological barriers and therefore in drug absorption, distribution, and elimination. They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB1, ABCC1, and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin. METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3ABCB1, UKF-NB-3rVCR10; ABCC1: G62, PC-3rVCR20; ABCG2: UKF-NB-3ABCG2) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities. RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1µM. CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3ABCB1, UKF-NB-3rVCR10; ABCC1: G62, PC-3rVCR20; ABCG2: UKF-NB-3ABCG2) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities.RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1µM.CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs.
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Gomez-Zepeda, David, Méryam Taghi, Jean-Michel Scherrmann, Xavier Decleves, and Marie-Claude Menet. "ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas." Pharmaceutics 12, no. 1 (2019): 20. http://dx.doi.org/10.3390/pharmaceutics12010020.
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Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.
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Gherardi, Samuele, Simona Soverini, Nunzio Iraci, et al. "C-Myc Mediated Regulation of Multidrug Resistance Genes in Chronic Myeloid Leukaemia Cd34+ Cell Progenitors." Blood 114, no. 22 (2009): 3252. http://dx.doi.org/10.1182/blood.v114.22.3252.3252.
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Abstract Abstract 3252 Poster Board III-1 A better understanding of the mechanisms which regulate drug resistance is critical for improving therapy for patients at risk of poor response. Even for CML patients the long-term benefits of the treatment are limited by the emergence of resistance, although the therapy has been dramatically improved by Imatinib Mesylate, which inhibits Bcr-Abl activity. One of the most important mechanisms of resistance is the disregulation of various members of the highly conserved family of transmembrane proteins characterized by an ATP-binding cassette domain, called ABC superfamily of transporters (Dean et al., Genome Res 2001). In CML cells an aberrant expression of ABC transporter genes has been described to be mediated by specific transcription factors, which are in turn affected by an aberrant activity of Bcr-Abl. It has been shown that Bcr-Abl can indirectly activate c-Myc via the JAK2 pathway, which increases a translation of c-Myc mRNA. In addition, in a subgroup of CML patients a chromosome 8 trysomy, has been observed, which can be associated with c-Myc amplification. In this study we have investigated whether c-Myc can regulate transcription of ABC tranporter genes in CML. Initially, ABC transporter gene expression has been monitored in HL60, a human promyelocytic cell line in which c-MYC is overexpressed. We have examined the expression level of all 48 human ABCs transporters as a function of c-MYC silencing. Our results have demonstrated that c-Myc regulates the transcription of several ABC genes, such as ABCA2, ABCB9, ABCB10, ABCC1, ABCC4, ABCE1, ABCF1, ABCF2, a majority of which has been found implicated in drug resistance. Furthermore, by performing chromatin immunoprecipitation (ChIP) we have shown a direct binding of c-Myc to the promoters of those ABC transporter genes in HL60 cell line. In addition, by ChIP we have demonstrated that c-MYC is physically bound to the promoter of tested ABC genes in CML cell lines KG-1a and K562. Based on those findings we have investigated the expression level of c-Myc in CD34+ progenitor cells derived from CML patients. Also, we have evaluated the effects of highly expressed c-Myc on ABC transporters. Our results have shown in a group of 20 newly diagnosed chronic phase (CP)-CML patients an increased expression of c-Myc in CD34+ cell fraction, when compared to the expression level of c-Myc in the entire population of mononuclear cells from which CD34+ cell fraction has been purified. In those cells we have identified in association with an increased level of c-Myc an increased expression of the same subset of ABC genes, which we have observed in cell lines. Furthermore, we have evaluated whether a differential expression of c-Myc and ABC transporter genes is associated with low Sokal risk and high Sokal risk patients. This analysis has been performed on CD34+ cells purified from 19 CML patients of whom 12 were scored as low Sokal risk and 7 as high Sokal risk. Our results have shown that expression of c-Myc and ABCC4 is different in those two patients population (p<0.05). Overall, our results highlight a novel aspect of the Bcr-Abl/c-Myc crosstalk with important implications on ABC genes upregulation in CML cells. These data suggest that inhibitors of Bcr-Abl, as exemplified by Gleevec may affect pathways involved in the regulation of drug resistance. To our knowledge this is the first identification of a small set of genes which reflect Sokal risk dichotomization, a key determinant of optimal and suboptimal response in CML patients. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: No relevant conflicts of interest to declare.
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Vallie, S., and S. Naidoo. "Quality Assurance in Drug Assaying and Pharmacokinetics-Blood Protein Evaluation in Calibration Curves." International Journal of Pharmaceutical Quality Assurance 11, no. 01 (2020): 45–52. http://dx.doi.org/10.25258/ijpqa.11.1.7.
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In bioanalytical drug assays, plasma protein/albumin content can challenge the biomatrix and reduce drug recovery through the albumin-binding affinity (ABA) of drug molecules. Global quality assurance in sample preparation for analyte quantification during bioavailability assessments has evolved extensively, and the quality standards of the strictly regulated current global quality controlled drug manufacturing processes (cGQMP) now apply in pharmacokinetics (PK) studies. Previous analyses in large clinical trials had found that laboratory-prepared calibrator plasma/serum protein levels differed significantly from those of patients with occasional hyperproteinemia/hypoproteinemia and disease-related hyperalbuminemia/hypoalbuminemia. We, therefore, investigated improving assay accuracy by including adjustments for patient plasma/serum protein levels in protein evaluation calibrations curves (PROTEC). Using a combined PROTEC of two calibrators (with 1.6 ± 0.5 g/dL and 4.3g/dL albumin, respectively) to test rifampicin recovery from patients with hypoalbuminemia (1.6 ± 0.5 g/dL), we found that relative accuracy of drug recovery differed by minimum 0.1% for low ABA drugs and maximum >20% for moderate ABA drugs. Assay accuracy improved after accommodating for varying patient plasma/serum protein levels. We, therefore, propose using patient-calibrator PROTEC-PK in validation assay development/therapeutic drug monitoring to ensure that patient albumin levels are within acceptable validation accuracy ranges.
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Kozubek, A., J. Gubernator, E. Przeworska, and M. Stasiuk. "Liposomal drug delivery, a novel approach: PLARosomes." Acta Biochimica Polonica 47, no. 3 (2000): 639–49. http://dx.doi.org/10.18388/abp.2000_3985.
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Almost from the time of their rediscovery in the 60's and the demonstration of their entrapment potential, liposomal vesicles have drawn attention of researchers as potential carriers of various bioactive molecules that could be used for therapeutic applications in humans and animals. Several commercial liposome-based drugs have already been discovered, registered and introduced with great success on the pharmaceutical market. However, further studies, focusing on the elaboration of more efficient and stable amphiphile-based vesicular (or non-viral) drug carriers are still under investigation. In this review we present the achievements of our group in this field. We have discovered that natural amphiphilic dihydroxyphenols and their semisynthetic derivatives are promising additives to liposomal lipid compositions. The presence of these compounds in lipid composition enhances liposomal drug encapsulation, reduces the amount of the lipid carrier necessary for efficient entrapment of anthracycline drugs by a factor of two, stabilizes liposomal formulation of the drug (both in suspension and in a lyophilized powder), does not influence liposomal fate in the blood circulation system and benefits from other biological activities of their resorcinolic lipid modifiers.
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Yeo, Pei Ling, Chooi Ling Lim, Soi Moi Chye, Anna Pick Kiong Ling, and Rhun Yian Koh. "Niosomes: a review of their structure, properties, methods of preparation, and medical applications." Asian Biomedicine 11, no. 4 (2018): 301–14. http://dx.doi.org/10.1515/abm-2018-0002.
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AbstractTarget-specific drug-delivery systems for the administration of pharmaceutical compounds enable the localization of drugs to diseased sites. Various types of drug-delivery systems utilize carriers, such as immunoglobulins, serum proteins, synthetic polymers, liposomes, and microspheres. The vesicular system of niosomes, with their bilayer structure assembled by nonionic surfactants, is able to enhance the bioavailability of a drug to a predetermined area for a period. The amphiphilic nature of niosomes promotes their efficiency in encapsulating lipophilic or hydrophilic drugs. Other additives, such as cholesterol, can be used to maintain the rigidity of the niosomes’ structure. This narrative review describes fundamental aspects of niosomes, including their structural components, methods of preparation, limitations, and current applications to various diseases.
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Peel, Sheila A. "The ABC transporter genes of Plasmodium falciparum and drug resistance." Drug Resistance Updates 4, no. 1 (2001): 66–74. http://dx.doi.org/10.1054/drup.2001.0183.
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Maryana, Tutik, Kusrini Kusrini, and Hanif Al Fatta. "Analisys Of Demand and Optimization Of Medicine Prediction Using ABC Analysis and SVR Method In The “MORBIS” Aplication." CCIT Journal 13, no. 2 (2020): 147–54. http://dx.doi.org/10.33050/ccit.v13i2.1098.
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The problem that occurs in hospitals regarding the processing of drug supplies is about the condition of out of stock medicines because hospitals spend around 33% of the total investment in one year only for the investment costs of drugs. To deal with the above problems the hospital must have good logistics management, one way of managing it is by doing good planning. In this research, the writer will use ABC Analysis and Support Vector Regression (SVR) algorithm. For the use of these methods, the following ABC Analysis will be used for the drug classification process, namely by dividing the torch into three main groups based on interests, namely groups A, B and C. Henceforth, the writer will use the SVR motedo to calculate drug predictions. The results that the authors get from this study are ABC analyys classify drugs. Into three groups namely group A with a total of 276 items with a percentage of 22.96% of the total number of items, group B with a total of 396 items with a percentage of 33.11% and C with a total of 528 with a percentage of 43.94% with a total of 1202 drug items. Prediction testing is done by taking a sample of five drugs derived from group classification. The SVR calculation process is done by comparing linear scaling and z normalization preprocessing methods. The result of this research is that MAPE shows that preprocessing with linear scaling produces a better value than compared to z nomrlization and calculation with ABC analysis.