ABSTRACT
OBJECTIVE: To audit whether hospital stay shortened without increasing readmissions after implementation of fast-track methodology for elective cesarean section and characterize what influences length of stay. METHODS: A fast-track program was initiated in November 2008, with a one year clinical audit and satisfaction survey. Discharge criteria were predefined and midwife home visits included if discharge was within 48 hours. Hospital stay by parity for women with elective section for singleton pregnancy between 1.11. 2008 - 31.10. 2009 (n=213, fast-track 182) was compared to 2003 (n=199) and 2007 (n=183). Readmissions and outpatient visits 2007 and 2008-9 were counted. Reasons for longer stay were recorded in fast-track, and body mass index. RESULT: Median hospital stay decreased significantly from 81 to 52 hours between 2007 and 2008-9. Readmissions were four in each period and outpatient visit rates similar. In 2008-9, 66% of all women were discharged within 48 hours. Women in the fast-track program were satisfied with early discharge. Hospital stay for parous women was shorter in 2007 compared to 2003, but unchanged for nulliparas. Parity had a minimal influence on length of stay in 2008-9, although nulliparous women ≤ 25 years were more likely to stay >48 hours. Body mass index did not correlate with length of stay. Pain was rarely the reason for a longer stay in the fast-track program and 90% were satisfied with pain-medication after discharge. CONCLUSION: Most healthy women can be discharged early after singleton birth by elective cesarean, without increasing readmissions.
Subject(s)
Cesarean Section , Home Care Services, Hospital-Based , Length of Stay , Midwifery , Patient Discharge , Ambulatory Care , Clinical Audit , Elective Surgical Procedures , Female , Health Care Surveys , Humans , Iceland , Parity , Patient Readmission , Patient Satisfaction , Pregnancy , Program Evaluation , Time FactorsABSTRACT
Novel piperidine and piperazine derivatives have been designed and tested as inhibitors of LTA(4) hydrolase (LTA(4)H). Most potent compounds showed good potency in both enzymatic and functional human whole blood assay. Crystallography studies further confirmed observed structure-activity relationship and LTA(4)H binding mode for analogs from the piperidine series.
Subject(s)
Anti-Inflammatory Agents/chemistry , Enzyme Inhibitors/chemistry , Epoxide Hydrolases/antagonists & inhibitors , Piperazines/chemistry , Piperidines/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/metabolism , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Structure-Activity RelationshipABSTRACT
A series of novel 1,7-disubstituted oxyindoles were shown to be potent and selective EP(3) receptor antagonists. Variation of substitution pattern at the C-3 position of indole enhanced in vitro metabolic stability of the resulting derivatives. Series 27a-c showed >1000-fold selectivity over a panel of prostanoid receptors including IP, FP, EP(1), EP(2) and EP(4). These agents also featured low CYP inhibition and good activity in the functional rat platelet aggregation assay.
Subject(s)
Indoles/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Indoles/chemistry , Platelet Aggregation Inhibitors/chemistry , Rats , Receptors, Prostaglandin E, EP3 SubtypeABSTRACT
Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.
Subject(s)
Butyrates/pharmacology , Cardiovascular Diseases/drug therapy , Drug Discovery/methods , Epoxide Hydrolases/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Biological Availability , Butyrates/chemistry , Butyrates/therapeutic use , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Epoxide Hydrolases/biosynthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/therapeutic use , Humans , Ligands , Myocardial Infarction/drug therapy , Peptide Fragments/chemistry , Solubility , Stroke/drug therapy , Structure-Activity RelationshipABSTRACT
We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP(3) receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels.
Subject(s)
Heterocyclic Compounds/pharmacology , Indoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Receptors, Prostaglandin E, EP3 Subtype , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.
