ABSTRACT
BACKGROUND: The purpose of this study was to explore the budget impact of dutasteride plus tamsulosin fixed-dose combination (DUT + TAM FDC) versus tamsulosin monotherapy, in the treatment of patients with benign prostatic hyperplasia (BPH) from the perspective of the Greek healthcare insurance system. METHODS: A Microsoft Excel-based model was developed to estimate the financial consequences of adopting DUT + TAM FDC within the Greek healthcare setting. The model, compared six mutually exclusive health states in two alternative treatment options: current standard of care and the introduction of DUT + TAM FDC in the market. The model used clinical inputs from the CombAT study; data on resource use associated with the management of BPH in Greece were derived from expert panel, and unit cost data were derived from official reimbursement tariffs. A payer perspective was taken into account. As patient distribution data between public and private sectors are not available in Greece two scenarios were investigated, considering the whole eligible population in each scenario. A 4 year time horizon was taken into account and included treatment costs, number of transurethral resections of the prostate (TURPs) and acute urinary retention (AUR) episodes avoided. RESULTS: The clinical benefit from the market adoption of DUT + TAM FDC in Greece was 1,758 TURPs and 972 episodes of AUR avoided cumulatively in a four year period. The increase in total costs from the gradual introduction of DUT + TAM FDC to the Greek healthcare system ranges from 1.3 million in the first year to 5.8 million in the fourth year, for the public sector, and 1.2 million to 4.0 million, for the private sector. This represents an increase of 1.91% to 7.94% for the public sector and 1.10% 3.29% in the private sector, during the 4-year time horizon. CONCLUSIONS: Budget impact analysis (BIA) results indicated that the gradual introduction of DUT + TAM FDC, would increase the overall budget of the disease, however providing better clinical outcomes. DUT + TAM FDC drug acquisition cost is partly offset by the reduction in the costs associated with the treatment of the disease.
Subject(s)
Azasteroids/economics , Azasteroids/therapeutic use , Budgets , Prostatic Hyperplasia/drug therapy , Sulfonamides/economics , Sulfonamides/therapeutic use , Urological Agents/economics , Urological Agents/therapeutic use , Cost-Benefit Analysis , Drug Therapy, Combination , Dutasteride , Greece , Humans , Male , Middle Aged , Office Visits/statistics & numerical data , Prostatic Hyperplasia/surgery , Tamsulosin , Transurethral Resection of Prostate/statistics & numerical data , Urinary Retention/prevention & controlSubject(s)
Bacteria/drug effects , Ethers, Cyclic/chemical synthesis , Ethers, Cyclic/pharmacology , Ribosomes/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Binding Sites , Click Chemistry , Ethers, Cyclic/chemistry , Models, Molecular , Molecular Structure , Ribosomes/metabolism , Spiro Compounds/chemistryABSTRACT
The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.
Subject(s)
Drug Design , RNA, Ribosomal/metabolism , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Alkenes/chemistry , Base Sequence , Glycosides/chemistry , Hydroxylation , Ketones/chemistry , Models, Molecular , Molecular Conformation , Organometallic Compounds/chemistry , RNA, Bacterial/chemistry , RNA, Bacterial/genetics , RNA, Bacterial/metabolism , RNA, Ribosomal/chemistry , RNA, Ribosomal/genetics , Spiro Compounds/chemical synthesis , Static ElectricityABSTRACT
Previous work from our group described the synthesis and biological evaluation of new rigid, 6,6- and 6,7-spiro aminoglycosidic scaffolds targeting the bacterial ribosome. Herein we describe an improved synthetic protocol for their construction, and extend our study by further amino-functionalization of their 6,7-spiro analogs. The synthetic strategy, preparation and evaluation of some representative examples are reported.
Subject(s)
Anti-Bacterial Agents/chemistry , Bacteria/genetics , RNA, Ribosomal, 16S/chemistry , Spiro Compounds/chemistry , Aminoglycosides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Binding Sites , Computer Simulation , RNA, Ribosomal, 16S/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacologySubject(s)
Aminoglycosides/pharmacology , Anti-Bacterial Agents/pharmacology , Escherichia coli/chemistry , RNA, Ribosomal/drug effects , Ribosomes/drug effects , Aminoglycosides/chemical synthesis , Aminoglycosides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Binding Sites , Crystallography, X-Ray , Drug Design , Escherichia coli/drug effects , Models, Molecular , Molecular Conformation , Molecular Weight , RNA, Ribosomal/chemistry , RNA, Ribosomal/genetics , Ribosomes/chemistry , Ribosomes/genetics , StereoisomerismABSTRACT
[reaction: see text] The pseudo-C(2)() symmetry of the C1 to C13 stretch of the discodermolide structure offers a potential strategic advantage for synthetic design. Two approaches based on this recognition were devised, and one was shown to be effective in a model series.
