The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform
James E Cassat - One of the best experts on this subject based on the ideXlab platform.
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Diflunisal loaded poly propylene sulfide nanoparticles decrease s aureus mediated bone destruction during osteomyelitis
Journal of Orthopaedic Research, 2021Co-Authors: Caleb A Ford, Thomas J Spoonmore, Mukesh K Gupta, Craig L Duvall, Scott A Guelcher, James E CassatAbstract:Osteomyelitis is a debilitating infection of bone that results in substantial morbidity. Staphylococcus aureus is the most commonly isolated pathogen causing bone infections and features an arsenal of virulence factors that contribute to bone destruction and counteract immune responses. We previously demonstrated that Diflunisal, a nonsteroidal anti-inflammatory drug, decreases S. aureus-induced bone destruction during osteomyelitis when delivered locally from a resorbable drug delivery depot. However, local Diflunisal therapy was complicated by bacterial colonization of the depot's surface, highlighting a common pitfall of devices for local drug delivery to infected tissue. It is, therefore, critical to develop an alternative drug delivery method for Diflunisal to successfully repurpose this drug as an antivirulence therapy for osteomyelitis. We hypothesized that a nanoparticle-based parenteral delivery strategy would provide a method for delivering Diflunisal to infected tissue while circumventing the complications associated with local delivery. In this study, we demonstrate that poly(propylene sulfide) (PPS) nanoparticles accumulate at the infectious focus in a murine model of staphylococcal osteomyelitis and are capable of efficaciously delivering Diflunisal to infected bone. Moreover, Diflunisal-loaded PPS nanoparticles effectively decrease S. aureus-mediated bone destruction, establishing the feasibility of systemic delivery of an antivirulence compound to mitigate bone pathology during osteomyelitis.
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concurrent local delivery of Diflunisal limits bone destruction but fails to improve systemic vancomycin efficacy during staphylococcus aureus osteomyelitis
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Thomas J Spoonmore, Caleb A Ford, Scott A Guelcher, Jacob M Curry, James E CassatAbstract:Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathological bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug Diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, Diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because Diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard-of-care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local Diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of Diflunisal in vitro and in vivo Similarly, locally delivered Diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of subtherapeutic vancomycin. However, we also found that the resorbable polyester urethane (PUR) foams used to deliver Diflunisal serve as a nidus for infection. Taken together, these data demonstrate that Diflunisal does not significantly impact standard-of-care antibiotic therapy for S. aureus osteomyelitis, but they also highlight potential pitfalls encountered with local drug delivery.
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repurposing the nonsteroidal anti inflammatory drug Diflunisal as an osteoprotective antivirulence therapy for staphylococcus aureus osteomyelitis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Andrew S Hendrix, Thomas J Spoonmore, Scott A Guelcher, Aimee D Wilde, Nicole E Putnam, Neal D Hammer, Daniel J Snyder, Eric P Skaar, James E CassatAbstract:Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound Diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that Diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, Diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of Diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that Diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.
Thomas J Spoonmore - One of the best experts on this subject based on the ideXlab platform.
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Diflunisal loaded poly propylene sulfide nanoparticles decrease s aureus mediated bone destruction during osteomyelitis
Journal of Orthopaedic Research, 2021Co-Authors: Caleb A Ford, Thomas J Spoonmore, Mukesh K Gupta, Craig L Duvall, Scott A Guelcher, James E CassatAbstract:Osteomyelitis is a debilitating infection of bone that results in substantial morbidity. Staphylococcus aureus is the most commonly isolated pathogen causing bone infections and features an arsenal of virulence factors that contribute to bone destruction and counteract immune responses. We previously demonstrated that Diflunisal, a nonsteroidal anti-inflammatory drug, decreases S. aureus-induced bone destruction during osteomyelitis when delivered locally from a resorbable drug delivery depot. However, local Diflunisal therapy was complicated by bacterial colonization of the depot's surface, highlighting a common pitfall of devices for local drug delivery to infected tissue. It is, therefore, critical to develop an alternative drug delivery method for Diflunisal to successfully repurpose this drug as an antivirulence therapy for osteomyelitis. We hypothesized that a nanoparticle-based parenteral delivery strategy would provide a method for delivering Diflunisal to infected tissue while circumventing the complications associated with local delivery. In this study, we demonstrate that poly(propylene sulfide) (PPS) nanoparticles accumulate at the infectious focus in a murine model of staphylococcal osteomyelitis and are capable of efficaciously delivering Diflunisal to infected bone. Moreover, Diflunisal-loaded PPS nanoparticles effectively decrease S. aureus-mediated bone destruction, establishing the feasibility of systemic delivery of an antivirulence compound to mitigate bone pathology during osteomyelitis.
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concurrent local delivery of Diflunisal limits bone destruction but fails to improve systemic vancomycin efficacy during staphylococcus aureus osteomyelitis
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Thomas J Spoonmore, Caleb A Ford, Scott A Guelcher, Jacob M Curry, James E CassatAbstract:Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathological bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug Diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, Diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because Diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard-of-care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local Diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of Diflunisal in vitro and in vivo Similarly, locally delivered Diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of subtherapeutic vancomycin. However, we also found that the resorbable polyester urethane (PUR) foams used to deliver Diflunisal serve as a nidus for infection. Taken together, these data demonstrate that Diflunisal does not significantly impact standard-of-care antibiotic therapy for S. aureus osteomyelitis, but they also highlight potential pitfalls encountered with local drug delivery.
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repurposing the nonsteroidal anti inflammatory drug Diflunisal as an osteoprotective antivirulence therapy for staphylococcus aureus osteomyelitis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Andrew S Hendrix, Thomas J Spoonmore, Scott A Guelcher, Aimee D Wilde, Nicole E Putnam, Neal D Hammer, Daniel J Snyder, Eric P Skaar, James E CassatAbstract:Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound Diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that Diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, Diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of Diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that Diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.
Scott A Guelcher - One of the best experts on this subject based on the ideXlab platform.
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Diflunisal loaded poly propylene sulfide nanoparticles decrease s aureus mediated bone destruction during osteomyelitis
Journal of Orthopaedic Research, 2021Co-Authors: Caleb A Ford, Thomas J Spoonmore, Mukesh K Gupta, Craig L Duvall, Scott A Guelcher, James E CassatAbstract:Osteomyelitis is a debilitating infection of bone that results in substantial morbidity. Staphylococcus aureus is the most commonly isolated pathogen causing bone infections and features an arsenal of virulence factors that contribute to bone destruction and counteract immune responses. We previously demonstrated that Diflunisal, a nonsteroidal anti-inflammatory drug, decreases S. aureus-induced bone destruction during osteomyelitis when delivered locally from a resorbable drug delivery depot. However, local Diflunisal therapy was complicated by bacterial colonization of the depot's surface, highlighting a common pitfall of devices for local drug delivery to infected tissue. It is, therefore, critical to develop an alternative drug delivery method for Diflunisal to successfully repurpose this drug as an antivirulence therapy for osteomyelitis. We hypothesized that a nanoparticle-based parenteral delivery strategy would provide a method for delivering Diflunisal to infected tissue while circumventing the complications associated with local delivery. In this study, we demonstrate that poly(propylene sulfide) (PPS) nanoparticles accumulate at the infectious focus in a murine model of staphylococcal osteomyelitis and are capable of efficaciously delivering Diflunisal to infected bone. Moreover, Diflunisal-loaded PPS nanoparticles effectively decrease S. aureus-mediated bone destruction, establishing the feasibility of systemic delivery of an antivirulence compound to mitigate bone pathology during osteomyelitis.
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concurrent local delivery of Diflunisal limits bone destruction but fails to improve systemic vancomycin efficacy during staphylococcus aureus osteomyelitis
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Thomas J Spoonmore, Caleb A Ford, Scott A Guelcher, Jacob M Curry, James E CassatAbstract:Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathological bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug Diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, Diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because Diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard-of-care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local Diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of Diflunisal in vitro and in vivo Similarly, locally delivered Diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of subtherapeutic vancomycin. However, we also found that the resorbable polyester urethane (PUR) foams used to deliver Diflunisal serve as a nidus for infection. Taken together, these data demonstrate that Diflunisal does not significantly impact standard-of-care antibiotic therapy for S. aureus osteomyelitis, but they also highlight potential pitfalls encountered with local drug delivery.
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repurposing the nonsteroidal anti inflammatory drug Diflunisal as an osteoprotective antivirulence therapy for staphylococcus aureus osteomyelitis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Andrew S Hendrix, Thomas J Spoonmore, Scott A Guelcher, Aimee D Wilde, Nicole E Putnam, Neal D Hammer, Daniel J Snyder, Eric P Skaar, James E CassatAbstract:Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound Diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that Diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, Diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of Diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that Diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.
S. M. Pond - One of the best experts on this subject based on the ideXlab platform.
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Diflunisal and its conjugates in patients with renal failure.
British journal of clinical pharmacology, 1991Co-Authors: Ronald G. Dickinson, R. K. Verbeeck, Andrew R. King, A. C. Restifo, S. M. PondAbstract:Six patients with renal failure were given a single oral dose (250 mg) of Diflunisal. In contrast to the acyl glucuronide, the phenolic glucuronide and sulphate conjugates showed the capacity to accumulate in plasma, suggesting that systemic instability of the acyl glucuronide contributes, via hydrolysis, to plasma concentrations of Diflunisal itself. Although earlier studies in renal failure patients have almost certainly underestimated Diflunisal clearance (by overestimation of plasma Diflunisal concentrations through unrecognized acidic hydrolysis of Diflunisal sulphate during analysis), the present results suggest that the reported decrease in clearance was not attributable only to this analytical artifact.
Shuichi Ikeda - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of long term Diflunisal administration in hereditary transthyretin attr amyloidosis
Amyloid, 2015Co-Authors: Yoshiki Sekijima, Kana Tojo, Hiroshi Morita, Jun Koyama, Shuichi IkedaAbstract:AbstractBackground: A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, Diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term Diflunisal administration in hereditary ATTR amyloidosis.Methods: Diflunisal was administered orally at 500 mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean ± SD: 38.0 ± 31.2 months).Results: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered Diflunisal significantly increased serum TTR concentration (p = 0.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 m...
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safety and efficacy of long term Diflunisal administration in familial amyloid polyneuropathy pd1 009
Neurology, 2013Co-Authors: Yoshiki Sekijima, Kana Tojo, Hiroshi Morita, Jun Koyama, Haruki Koike, Gen Sobue, Shuichi IkedaAbstract:OBJECTIVE: To evaluate the safety and efficacy of long-term Diflunisal administration in late-onset familial amyloid polyneuropathy (FAP) patients with Val30Met mutation in the transthyretin (TTR) gene (ATTR Val30Met FAP). BACKGROUND: While the current standard form of care for FAP patients is liver transplantation, it has a number of limitations. Furthermore, many FAP patients are not good transplant candidates because of their age and/or advanced disease status. Therefore, it is desirable to develop a general, convenient, and non-invasive alternative therapeutic strategy to ameliorate FAP. DESIGN/METHODS: In this open-label historical control study, Diflunisal was administered orally at 500 mg/day to 18 late-onset ATTR Val30Met FAP patients. The observation period ranged from 2 to 84months (mean 35.0 ± 24.0 months). Treatment effect was assessed by serial measurements of ulnar and tibial nerve compound muscle action potential (CMAP) amplitudes, clinical FAP score, cardiac function tests, and serum TTR concentration and stability. The historical control group consisted of 27 late-onset ATTR Val30Met FAP patients. RESULTS: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulted in discontinuation of the study drug in two patients. Five patients dropped out due to reasons unrelated to Diflunisal. Orally administered Diflunisal significantly increased serum TTR concentration ( p =0.001) and stabilized TTR tetramer structure in each patient. The %decreases of ulnar nerve CMAP amplitude in the Diflunisal treatment group and the control group were 6.6% ± 14.7%/year and 30.5% ± 15.2%/year, respectively ( p =0.0003). The ratios of patients in whom tibial nerve CMAP became undetectable during the follow-up period were 33.3% (4/12) in the Diflunisal treatment group and 100% (10/10) in controls ( p =0.002). CONCLUSIONS: Diflunisal was well-tolerated by most FAP patients and increased serum TTR concentration and stability. This study provides Class III evidence that Diflunisal significantly slows the deterioration rates of ulnar and tibial nerve CMAP compared to the controls. Supported by: This study was supported by a Grant-in-aid for Scientific Research (23591237 to YS), a grant form Amyloidosis Research Committee, the Ministry of Health, Labour and Welfare, Japan, and a Group Research Grant for the Pathogenesis and Therapy for Intractable Neuropathy in Japan. Disclosure: Dr. Sekijima has nothing to disclose. Dr. Tojo has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Koyama has nothing to disclose. Dr. Koike has nothing to disclose. Dr. Sobue has nothing to disclose. Dr. Ikeda has nothing to disclose.