ABSTRACT
AIM: Invasive mold diseases (IMDs) are associated with significant morbidity and mortality. Approved treatments include voriconazole (VORI), liposomal amphotericin B (L-AMB), posaconazole (POSA) and isavuconazole (ISAV). A UK-based economic model was developed to explore the cost of treating IMDs with ISAV versus L-AMB followed by POSA. MATERIALS & METHODS: As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration & monitoring, and hospitalization costs were evaluated from the healthcare system perspective. RESULTS: Per-patient costs were UK£14,842 with ISAV versus UK£18,612 with L-AMB followed by POSA. Savings were driven by drug acquisition, and administration & monitoring costs. CONCLUSION: ISAV has the potential to reduce IMD treatment costs relative to L-AMB followed by POSA.
Subject(s)
Amphotericin B/economics , Antifungal Agents/economics , Aspergillosis/economics , Health Care Costs , Mucormycosis/economics , Nitriles/economics , Pyridines/economics , Triazoles/economics , Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Costs and Cost Analysis , Drug Costs , Humans , Models, Economic , Mucormycosis/drug therapy , Nitriles/therapeutic use , Pyridines/therapeutic use , Treatment Outcome , Triazoles/therapeutic use , United KingdomABSTRACT
AIM: Mucormycosis is a fungal infection associated with high mortality. Until recently, the only licensed treatments were amphotericin B (AMB) formulations. Isavuconazole (ISAV) is a new mucormycosis treatment. A UK-based economic model explored treatment costs with ISAV versus liposomal AMB followed by posaconazole. MATERIALS & METHODS: As a matched case-control analysis showed similar efficacy for ISAV and AMB, a cost-minimization approach was taken. Direct costs - drug acquisition, monitoring and administration, and hospitalization costs - were estimated from the National Health Service perspective. RESULTS: Per-patient costs for ISAV and liposomal AMB + posaconazole were UK£26,810 and UK£41,855, respectively, with savings primarily driven by drug acquisition and hospitalization costs. CONCLUSION: ISAV may reduce costs compared with standard mucormycosis therapy.
Subject(s)
Antifungal Agents/economics , Mucormycosis/drug therapy , Nitriles/economics , Pyridines/economics , Triazoles/economics , Amphotericin B/economics , Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Case-Control Studies , Drug Costs , Hospitalization/economics , Hospitalization/statistics & numerical data , Humans , Invasive Fungal Infections/drug therapy , Invasive Fungal Infections/epidemiology , Models, Economic , Nitriles/therapeutic use , Pyridines/therapeutic use , Triazoles/therapeutic use , United Kingdom/epidemiologyABSTRACT
In the present study, we cloned and sequenced the mRNAs of the Sod3 [extracellular Cu Zn SOD (superoxide dismutase)] gene in Drosophila and identified two mRNA products formed by alternative splicing. These products code for a long and short protein derived from the four transcripts found in global expression studies (Flybase numbers Dmel\CG9027, FBgn0033631). Both mRNA process variants contain an extracellular signalling sequence, a region of high homology to the Sod1 (cytoplasmic Cu Zn SOD) including a conserved AUG start, with the longer form also containing a hydrophobic tail. The two fully processed transcripts are homologous to Caenorhabditis elegans Sod3 mRNA showing the same processing pattern. Using an established KG p-element+ insertion line (KG06029), we demonstrate that the Sod3 codes for an active Cu Zn SOD. We found differing expression patterns across sex with higher levels of expression of Sod3 in females. There is a correlation of Sod1 and Sod3 gene expression and activity that can explain why Sod3 was not seen in earlier studies of Sod1. Finally, we found no effect on lifespan with the Sod3 hypomorph mutation (Sod3KG06029) but did observe a significant increase in resistance to paraquat and H2O2 (hydrogen peroxide).
Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Gene Expression Regulation, Enzymologic , Superoxide Dismutase/genetics , Amino Acid Sequence , Animals , Cloning, Molecular , Drosophila Proteins/metabolism , Drosophila melanogaster/drug effects , Drosophila melanogaster/enzymology , Extracellular Space/enzymology , Female , Herbicides/pharmacology , Hydrogen Peroxide/pharmacology , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Molecular Sequence Data , Mutation , Oxidants/pharmacology , Paraquat/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Amino Acid , Sex Factors , Superoxide Dismutase/metabolism , Survival AnalysisABSTRACT
FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.
Subject(s)
Factor IXa/antagonists & inhibitors , Fibrinolytic Agents/chemical synthesis , Thiophenes/chemical synthesis , Crystallography, X-Ray , Factor IXa/chemistry , Fibrinolytic Agents/chemistry , Humans , Models, Molecular , Protein Binding , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.