Identification and management of contraindicated drug-drug interactions through pharmaceutical care programs: Experience in direct-acting antivirals therapy.

BACKGROUND/PURPOSE: To investigate the impact of pharmaceutical care programs for the management of contraindicated drug-drug interactions (DDIs) in direct-acting antivirals (DAAs) therapy. METHODS: A prospective observational study was performed at Dalin Tzu Chi Hospital between January 2018 and December 2019. Pharmacists screened DDIs for all hepatitis C patients before DAA therapy. The study outcome included the frequency of contraindicated DDIs, acceptance rate, and cost avoidance of the pharmaceutical care program. RESULTS: A total of 1053 patients were enrolled in the study, with a mean age of 67.1 ± 11.9 years. Most patients received therapy with sofosbuvir/ledipasvir (37.1%; n = 391), elbasvir/grazoprevir (23.8%; n = 251), or glecaprevir/pibrentasvir (21.1%; n = 222). A total of 796 (75.6%) patients received at least one co-medication, with the average number of co-medications being 5.2 per patient (SD: 4.4/patient). In total, 1356 DDIs were identified, with the average DDIs per patient of 1.3 (SD: 1.7). For patients with contraindicated DDIs (2%, n = 102), statins and amiodarone were the most common co-medications. Physicians often accepted pharmacists' recommendations (acceptance rate of 72.5%) or withheld co-medication to avoid severe adverse drug events (ADEs). The estimated cost avoidance of preventable ADEs was USD 14,033 for contraindicated DDIs with pharmaceutical care programs. CONCLUSION: The implementation of pharmaceutical care programs in DAA therapy provides a favorable outcome and substantial cost avoidance.

Molecular Insights into How the Dimetal Center in Dihydropyrimidinase Can Bind the Thymine Antagonist 5-Aminouracil: A Different Binding Mode from the Anticancer Drug 5-Fluorouracil.

Dihydropyrimidinase (DHPase) is a key enzyme for pyrimidine degradation. DHPase contains a binuclear metal center in which two Zn ions are bridged by a posttranslationally carbamylated lysine. DHPase catalyzes the hydrolysis of dihydrouracil to N-carbamoyl-ß-alanine. Whether 5-aminouracil (5-AU), a thymine antagonist and an anticancer drug that can block DNA synthesis and induce replication stress, can interact with DHPase remains to be investigated. In this study, we determined the crystal structure of Pseudomonas aeruginosa DHPase (PaDHPase) complexed with 5-AU at 2.1 Å resolution (PDB entry 7E3U). This complexed structure revealed that 5-AU interacts with Znα (3.2 Å), Znß (3.0 Å), the main chains of residues Ser289 (2.8 Å) and Asn337 (3.3 Å), and the side chain of residue Tyr155 (2.8 Å). These residues are also known as the substrate-binding sites of DHPase. Dynamic loop I (amino acid residues Pro65-Val70) in PaDHPase is not involved in the binding of 5-AU. The fluorescence quenching analysis and site-directed mutagenesis were used to confirm the binding mode revealed by the complexed crystal structure. The 5-AU binding mode of PaDHPase is, however, different from that of 5-fluorouracil, the best-known fluoropyrimidine used for anticancer therapy. These results provide molecular insights that may facilitate the development of new inhibitors targeting DHPase and constitute the 5-AU interactome.

Development of Ultrapure and Potent Tannic Acids as a Pan-coronal Antiviral Therapeutic.

The rampageous transmission of SARS-CoV-2 has been devastatingly impacting human life and public health since late 2019. The waves of pandemic events caused by distinct coronaviruses at present and over the past decades have prompted the need to develop broad-spectrum antiviral drugs against them. In this study, our Pentarlandir ultrapure and potent tannic acids (UPPTA) showed activities against two coronaviral strains, SARS-CoV-2 and HCoV-OC43, the earliest-known coronaviruses. The mode of inhibition of Pentarlandir UPPTA is likely to act on 3-chymotrypsin-like protease (3CLpro) to prevent viral replication, as supported by results of biochemical analysis, a 3CLpro assay, and a "gain-of-function" 3CLpro overexpressed cell-based method. Even in the 3CLpro overexpressed environment, Pentarlandir UPPTA remained its antiviral characteristic. Utilizing cell-based virucidal and cytotoxicity assays, the 50% effective concentrations (EC50) and 50% cytotoxicity concentration (CC50) of Pentarlandir UPPTA were determined to be ∼0.5 and 52.5 µM against SARS-CoV-2, while they were 1.3 and 205.9 µM against HCoV-OC43, respectively. In the pharmacokinetic studies, Pentarlandir UPPTA was distributable at a high level to the lung tissue with no accumulation in the body, although the distribution was affected by the food effect. With further investigation in toxicology, Pentarlandir UPPTA demonstrated an overall safe toxicology profile. Taking these findings together, Pentarlandir UPPTA is considered to be a safe and efficacious pancoronal antiviral drug candidate that has been advanced to clinical development.

Untypical [VOPO4]- layer in vanadyl phosphates with variant interlayer gap of double-tiered template.

Four new organically templated layered vanadyl(IV) phosphates, (Hcha)VOPO(4) x 0.5 H(2)O (cha = cyclohexylamine) (1), (Hchpa)VOPO(4) x 0.5 H(2)O (chpa = cycloheptylamine) (2), (Hcha)(0.5)(Hchpa)(0.5)VOPO(4) x 0.5 H(2)O (3), and (H(2)aepip)[(VOPO(4))(2)(H(2)O)] x H(2)O (aepip = N-(2-aminoethyl)piperazine) (4), have been synthesized under mild hydrothermal conditions and characterized by single-crystal X-ray diffraction, thermogravimetric analysis, magnetic susceptibility, and electron paramagnetic resonance (EPR) spectroscopy. They displayed a large interlayer gap propped up by an unprecedented double-tiered monoamine in vertical angles generating the lightest layered VPO material ever prepared and characterized. The anionic [VOPO(4)](-) sheets for all four compounds are constructed by a common secondary building unit consisting of one copper-acetate-type {(V(IV)O)(2)(mu(2)-PO(4))(4)} cluster and two vanadium polyhedra. The d(1) state was confirmed by both magnetic susceptibility studies and EPR spectra. Moreover, compounds 1 and 4 showed antiferromagnetism with T(N) at 30 K, the highest ever observed in layered vanadyl phosphates. The structural relationship, template arrangement, magnetic property, thermal stability, and correlation between interlayer gaps and densities are discussed. Compounds 1-3 crystallized in the monoclinic space group P2(1)/c (no. 14) with Z = 8, whereas compound 4 crystallized in the orthorhombic space group Pbca (no. 61) with Z = 4. Crystal data of 1, a = 16.3461(9) A, b = 14.2641(8) A, c = 9.4037(5) A, beta = 94.519(1) degrees, V = 2185.8(2) A(3); 2, a = 17.0773(5) A, b = 14.3449(4) A, c = 9.4251(3) A, beta = 93.976(1) degrees, V = 2303.3(1) A(3); 3, a = 16.6765(4) A, b = 14.2927(3) A, c = 9.4120(3) A, beta = 95.389(1) degrees, V = 2233.5(1) A(3); 4, a = 14.2517(9) A, b = 9.4012(6) A, c = 24.442(2) A, V = 3274.8(4) A(3).