The Development, Implementation, and Evaluation of a Pharmacist-Managed Therapeutic Drug Monitoring (TDM) Service for Vancomycin-A Pilot Study.

BACKGROUND: In recent years, pharmacists in Australia have been able to expand their scope to include the provision of a range of services. Although evidence has demonstrated the benefits of pharmacist-managed TDM services, recent studies have shown that these services are not prominent within Australia and that the current TDM workflow may not be optimal. METHODS: An interventional pilot study was conducted of a pharmacist-managed TDM program for vancomycin at a tertiary hospital in Australia. RESULTS: In total, 15 pharmacists participated in the program. They performed 50.5% of the medication-related pathology over the intervention period. Pharmacist involvement in the TDM process was more likely to lead to appropriate TDM sample collection (OR 87.1; 95% CI = 11.5, 661.1) and to an appropriate dose adjustment (OR 19.1; 95% CI = 1.7, 213.5). Pharmacists demonstrated increased confidence after the education and credentialling package was provided. CONCLUSIONS: This study demonstrated that a credentialling package for pharmacists can improve knowledge, skills, and confidence around the provision of pharmacist-managed TDM services for vancomycin. This may lead to the evolution of different roles and workflows enabling pharmacists to contribute more efficiently to improving medication safety and use.

Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2).

The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.

Tandem insertion of halocarbenoids and lithium acetylides into zirconacycles: a novel rearrangement to zirconium alkenylidenates by ß-addition to an alkynyl zirconocene.

Tandem insertion of 1,1-dihalo-1-lithio species (halocarbenoids) and lithium alkynides into zirconacyclopentenes and zirconcyclopentanes affords carbocyclic products in high yields via an unusual rearrangement that probably involves addition of an organolithium species to the ß-position of a zirconium-alkyne complex to give an alkenylidene-zirconate species. A wide variety of cyclopentanoid organic structures are rapidly assembled in good yield using this multicomponent coupling. The main side reaction, which becomes exclusive in some cases, is ß-hydride elimination of an intermediate cyclopentyl- or cyclopentenyl zirconocene.

Dimeric supramolecular motifs of two carboxylate-guanidinium compounds.

The structures of N-benzyl-N'-{6-[(4-carboxylatobenzyl)aminocarbonyl]-2-pyridylmethyl}guanidinium, C(23)H(23)N(5)O(3), (I), and N-[2-(benzylaminocarbonyl)ethyl]-N'-{6-[(4-carboxylatobenzyl)aminocarbonyl]-2-pyridylmethyl}guanidinium monohydrate, C(26)H(28)N(6)O(4).H(2)O, (II), both form three-dimensional supramolecular hydrogen-bonded networks based on a dimeric primary synthon involving carboxylate-guanidinium linkages. The differences in the geometries and hydrogen-bonding connectivities are driven by the additional methylpropionamide group and water of crystallization of (II).

Dimeric self-assembly of pyridyl guanidinium carboxylates in polar solvents.

A series of pyridyl guanidinium-carboxylates has been prepared and the dimeric self-assembly of these studied in H(2)O/DMSO mixtures, principally using dilution isothermal calorimetry. Compounds 5 and 6, incorporating an aromatic ring in the "tethering" region between the guanidinium and carboxylate groups, demonstrate the strongest dimerisation in neat DMSO. X-ray crystal structures of 5 and 6 reveal two different dimerisation architectures in the solid-state, but both involve carboxylate-guanidinium salt bridges as anticipated, and π-π interactions. Compounds 10-16 incorporating peptidic fragments between the guanidinium and carboxylate groups, showed reduced dimerisation strength with increased amino acid content, but also sustained dimerisation under increasingly aqueous conditions, up to 50% H(2)O/DMSO in the case of 14 and 15. The extent of our study in H(2)O/DMSO mixtures was determined by substrate solubility of 10-16, and not the limit of self-assembly.

Synthesis of dihydrodehydrodiconiferyl alcohol: the revised structure of lawsonicin.

Structural revision of lawsonicin, a natural product of Lawsonia alba, is reported based upon comparison of its spectral data with that of the naturally occurring dihydrobenzo[b]furan neolignan (rac)-trans-dihydrodehydrodiconiferyl alcohol, which is found to be identical. A concise synthesis of dihydrodehydrodiconiferyl alcohol, via Rh(2)[S-DOSP](4)-catalysed intramolecular C-H insertion, is described.

Selective binding of L-glutamate derivative in aqueous solvents.

A chiral bisguanidinium macrocycle binds N-Boc-L-glutamate in a 1 : 1 stoichiometry with significant selectivity in competitive solvent (DMSO-H(2)O).

A biaryl cross-coupling strategy for functionalisation of benzocrown ethers.

Preparation of (di)benzocrown-substituted aryl-zinc or -boron reagents and their palladium-catalysed cross-coupling with functionalised aryl halides is described for convenient synthesis of novel crown ether systems.

Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1.

We report the identification of substituted cis-bicyclo[3.3.0]-oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1.

Zirconium mediated total synthesis of crinitol, 9-hydroxyfarnesoic acid, 9-hydroxyfarnesol, 9-hydroxysargaquinone and the selectively-protected aglycone of moritoside and euplexide A.

Tandem formation of an unsaturated zirconacycle, insertion of methallyl carbenoid, and addition of an aldehyde provides a rapid synthetic route to several linear terpenoid and terpene-polyketide natural products.