ABSTRACT
BACKGROUND: Personal protective equipment (PPE) offers protection from infections and hazardous materials. Advances in technology have seen rapid improvement of respiratory PPEs but real-world evaluations are needed to understand whether newer devices offer greater usability and overcome common barriers to correct use. AIM: To survey the user experiences of a new PPE device, CleanSpace® HALO™, in comparison to existing masks and respirators to determine advantages and disadvantages. METHODS: Frontline healthcare workers of a large healthcare provider cluster in Singapore with practical experience of using respiratory PPE, including the CleanSpace® HALO™, were surveyed. Ease of communication, comfort, usability, ability to provide care, perceived effectiveness, barriers, and enablers to respiratory PPE use were investigated. FINDINGS: A total of 93 respondents were included in the analysis. CleanSpace® HALO™ was rated highly in terms of perceived safety (92%), comfort (40%), and ease of donning and doffing (53%). CleanSpace® HALO™ was less disruptive to patient care (8%), although the ability to communicate effectively remained an obstacle (22%). Respondents also noted the incomplete facial protection provided by CleanSpace® HALO™. CONCLUSION: Respiratory protective devices are integral to effective infection control protocols, but their usefulness is limited by their impact on care delivery and incorrect use. The CleanSpace® HALO™ demonstrated advantages over existing powered air purifying respirator devices but some issues remain. Future iterations must strive to overcome communication challenges and address common side-effects. Better education is also needed to improve user confidence with CleanSpace® HALO™.
Subject(s)
Personal Protective Equipment , Respiratory Protective Devices , Health Personnel , Humans , Infection Control/methods , MasksABSTRACT
The 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) embodies a motif that allows it to dock to the active site of (chymo)trypsin-like proteases in a predictable and substrate-like fashion. Consequently, inhibitors derived from this heterocyclic scaffold interact with both the S and S' subsites of an enzyme. Exploitation of binding interactions with both the S and S' subsites of a target enzyme may lead to compounds with greatly enhanced enzyme selectivity and inhibitory potency. This preliminary report describes the use of a series of compounds having the heterocyclic scaffold linked to various amino acids to probe the S' subsites of human leukocyte elastase (HLE), proteinase 3 (PR 3), and cathepsin G (Cat G). For comparative purposes, a series of compounds derived from a related scaffold, isothiazolidin-3-one 1,1 dioxide (II), was also generated. Several of the compounds were found to be highly potent and selective time-dependent inhibitors of HLE, PR 3, and Cat G.
Subject(s)
Chymotrypsin/chemistry , Cyclic S-Oxides/chemistry , Molecular Probes/chemistry , Serine Endopeptidases/chemistry , Thiazoles/chemistry , Cathepsin G , Cathepsins/chemistry , Cathepsins/metabolism , Humans , Kinetics , Leukocyte Elastase/chemistry , Leukocyte Elastase/metabolism , Models, Chemical , Myeloblastin , Protein Binding , Serine Endopeptidases/metabolism , Temperature , Time FactorsABSTRACT
A series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds has been synthesized and the inhibitory profile of these compounds toward human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3) was then determined. Most of the compounds were found to be potent, time-dependent inhibitors of elastase, with some of the compounds exhibiting k(inact)/K1 values as high as 4,928,300 M(-1) s(-1). The inhibitory potency of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide platform was found to be influenced by both the pKa and the inherent structure of the leaving group. Proper selection of the primary specificity group (R(I)) was found to lead to selective inhibition of HLE over Cat G, however, those compounds that inhibited HLE also inhibited PR 3, albeit less efficiently. The predictable mode of binding of these compounds suggests that, among closely-related serine proteases, highly selective inhibitors of a particular serine protease can be fashioned by exploiting subtle differences in their S' subsites. This study has also demonstrated that the degradative action of elastase on elastin can be abrogated in the presence of inhibitor 17.
Subject(s)
Cyclic S-Oxides/chemistry , Serine Proteinase Inhibitors/chemistry , Thiadiazoles/chemistry , Drug Design , Elastin/metabolism , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Amino acid-derived phthalimide and saccharin derivatives have been investigated for their inhibitory activity toward the serine proteinases human leukocyte elastase, cathepsin G, and proteinase 3. The saccharin derivatives were found to be effective time-dependent inhibitors of elastase and proteinase 3 (kobs/[I] values ranged between 180 and 3620 M-1 S-1) and showed weak or no inhibition toward cathepsin G. The corresponding phthalimide derivatives were found to be inactive.
Subject(s)
Cathepsins/antagonists & inhibitors , Leukocyte Elastase/antagonists & inhibitors , Phthalimides/pharmacology , Saccharin/analogs & derivatives , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , Amino Acid Sequence , Animals , Binding Sites , Cathepsin G , Drug Design , Humans , Hydrogen Bonding , In Vitro Techniques , Leukocyte Elastase/chemistry , Leukocyte Elastase/genetics , Leukocytes/enzymology , Models, Molecular , Molecular Sequence Data , Myeloblastin , Phthalimides/chemistry , Protein Conformation , Saccharin/chemistry , Saccharin/pharmacology , Serine Proteinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Structure-activity relationship study and in vitro biochemical studies with human leukocyte elastase, cathepsin G and proteinase 3 were conducted using a series of succinimide derivatives.
Subject(s)
Cathepsins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pancreatic Elastase/antagonists & inhibitors , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/pharmacology , Succinimides/chemistry , Succinimides/pharmacology , Amino Acids/chemistry , Cathepsin G , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Leukocyte Elastase , Myeloblastin , Structure-Activity Relationship , Succinimides/chemical synthesis , Time FactorsSubject(s)
Cathepsins/antagonists & inhibitors , Isoxazoles/pharmacology , Pancreatic Elastase/antagonists & inhibitors , Protease Inhibitors/pharmacology , Serine Endopeptidases/drug effects , Cathepsin G , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Kinetics , Leukocyte Elastase , Magnetic Resonance Spectroscopy , Molecular Structure , Myeloblastin , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The results of a structure-activity relationship study focusing on the interaction of a series of phthalimide and saccharin derivatives with leukocyte elastase, cathepsin G and proteinase 3 are described. The phthalimide derivatives were found to be inactive while some of the saccharin derivatives were found to be fair inhibitors of these enzymes.
Subject(s)
Cathepsins/antagonists & inhibitors , Pancreatic Elastase/antagonists & inhibitors , Phthalimides/chemical synthesis , Saccharin/analogs & derivatives , Serine Endopeptidases/drug effects , Cathepsin G , Humans , Leukocyte Elastase , Magnetic Resonance Spectroscopy , Myeloblastin , Phthalimides/chemistry , Phthalimides/pharmacology , Saccharin/chemical synthesis , Saccharin/chemistry , Saccharin/pharmacology , Structure-Activity RelationshipABSTRACT
A structure-activity relationship study was conducted in order to probe the nature of the interaction between some 3-alkyl-N-hydroxysuccinimide derivatives and human leukocyte elastase. The structural features in substituent X (structure I) that lead to the manifestation and optimization of inhibitory activity have been examined. The data suggest that the presence of an alkyl or aryl(sulfonyloxy) group in the active compounds may serve a triple purpose, namely, it functions as a good leaving group as dictated by the established mechanism of action of this class of compounds, secondly, it may enhance binding by assuming a favorable spatial orientation and, thirdly, it may increase the chemical reactivity of the carbonyl carbon in the bioactive compounds.
Subject(s)
Leukocyte Elastase/antagonists & inhibitors , Leukocytes/enzymology , Pancreatic Elastase/antagonists & inhibitors , Succinimides/chemistry , Chemical Phenomena , Chemistry, Physical , Crystallography, X-Ray , Humans , Leukocyte Elastase/chemistry , Magnetic Resonance Spectroscopy , Pancreatic Elastase/chemistry , Structure-Activity Relationship , Succinimides/pharmacologyABSTRACT
A series of heterocyclic compounds designed to function as mechanism-based inhibitors of human leukocyte elastase and cathepsin G has been synthesized and their inhibitory activity was investigated. These isothiazolidin-3-one derivatives were found to be effective inhibitors of cathepsin G.
Subject(s)
Cathepsins/antagonists & inhibitors , Leukocytes/enzymology , Pancreatic Elastase/antagonists & inhibitors , Protease Inhibitors/pharmacology , Thiazoles/pharmacology , Cathepsin G , Cathepsins/blood , Humans , Kinetics , Leukocyte Elastase , Molecular Structure , Protease Inhibitors/chemical synthesis , Serine Endopeptidases , Structure-Activity Relationship , Thiazoles/chemical synthesisABSTRACT
A series of saccharin derivatives I has been synthesized and evaluated for their inhibitory activity toward human leukocyte elastase and cathepsin G. Most of the compounds were found to be efficient and time-dependent inhibitors of elastase. Inactivated elastase was found to regain its activity almost fully after 24 h (80-90% activity) and the half-lives of reactivation ranged between 12-15 h. Addition of hydroxylamine to fully-inactivated enzyme led to rapid and complete recovery of enzymatic activity. A tentative mechanism of action is proposed on the basis of biochemical and model studies.
Subject(s)
Cathepsins/antagonists & inhibitors , Pancreatic Elastase/antagonists & inhibitors , Saccharin/analogs & derivatives , Cathepsin G , Humans , Leukocyte Elastase , Serine Endopeptidases , Structure-Activity RelationshipABSTRACT
A series of 3-(alkylthio)-N-hydroxysuccinimide derivatives was synthesized and their inhibitory activity towards human leukocyte elastase (HLE) was investigated. The interaction of the compounds having a 3-alkylthioether side chain (compounds 1 and 2) with HLE was found to involve rapid acylation of the enzyme, followed by total regain of enzymatic activity within 3 h. Interestingly, compounds 3-8, having an oxidized thioether side chain, were found to be highly effective, time-dependent, irreversible inhibitors of the enzyme. The k(obs)/I values for compounds 3-8 ranged between 890 and 24,000 M-1 s-1. These findings demonstrate that, unlike the physiological inhibitor of HLE (alpha-1-proteinase inhibitor), which is inactivated upon oxidation, low-molecular-weight compounds retain and/or show enhanced inhibitory activity towards HLE upon oxidation of the thioether side chain and lay the groundwork for the development of compounds that embody proteinase inhibitory and antioxidant activity.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Leukocytes/enzymology , Pancreatic Elastase/antagonists & inhibitors , Succinimides/chemical synthesis , Sulfides/chemical synthesis , Acylation , Humans , Models, Molecular , Structure-Activity Relationship , Succinimides/chemistry , Succinimides/pharmacology , Sulfides/chemistry , Sulfides/pharmacology , alpha 1-Antitrypsin/pharmacologyABSTRACT
Neutrophil-derived mediators such as, for example, the serine proteinase elastase, cathepsin G and proteinase 3, play a critical role in inflammatory lung disease. This report describes the design, synthesis and in vitro inhibitory activity of some novel mechanism-based inhibitors of human leukocyte elastase and cathepsin G. The design of the inhibitors is based on the Gabriel-Colman rearrangement. The behavior of the synthesized compounds toward elastase and cathepsin G with respect to inhibitory prowess, mode of interaction, specificity, etc., has been found to be dependent on the recognition and reactivity elements present in each inhibitor.
Subject(s)
Cathepsins/antagonists & inhibitors , Leukocytes/enzymology , Pancreatic Elastase/antagonists & inhibitors , Amino Acid Sequence , Cathepsin G , Drug Design , Humans , Molecular Sequence Data , Serine EndopeptidasesABSTRACT
Loxapine was introduced to the British market two years ago although it has been used in North America for eight years. We report the first probable case of neuroleptic malignant syndrome (NMS) secondary to loxapine in Britain. Two previous cases have been reported in North America (manufacturer's data).
