Coronary calcification hinders stent delivery and expansion and is associated with adverse outcomes. Intravascular lithotripsy (IVL) delivers acoustic pressure waves to modify calcium, enhancing ...vessel compliance and optimizing stent deployment.
The purpose of this study was to assess the safety and effectiveness of IVL in severely calcified de novo coronary lesions.
Disrupt CAD III (NCT03595176) was a prospective, single-arm multicenter study designed for regulatory approval of coronary IVL. The primary safety endpoint was freedom from major adverse cardiovascular events (cardiac death, myocardial infarction, or target vessel revascularization) at 30 days. The primary effectiveness endpoint was procedural success. Both endpoints were compared with a pre-specified performance goal (PG). The mechanism of calcium modification was assessed in an optical coherence tomography (OCT) substudy.
Patients (n = 431) were enrolled at 47 sites in 4 countries. The primary safety endpoint of the 30-day freedom from major adverse cardiovascular events was 92.2%; the lower bound of the 95% confidence interval was 89.9%, which exceeded the PG of 84.4% (p < 0.0001). The primary effectiveness endpoint of procedural success was 92.4%; the lower bound of the 95% confidence interval was 90.2%, which exceeded the PG of 83.4% (p < 0.0001). Mean calcified segment length was 47.9 ± 18.8 mm, calcium angle was 292.5 ± 76.5°, and calcium thickness was 0.96 ± 0.25 mm at the site of maximum calcification. OCT demonstrated multiplane and longitudinal calcium fractures after IVL in 67.4% of lesions. Minimum stent area was 6.5 ± 2.1 mm2 and was similar regardless of demonstrable fractures on OCT.
Coronary IVL safely and effectively facilitated stent implantation in severely calcified lesions.
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Reply to: Letter to the Editor Riley, Robert F.
Catheterization and cardiovascular interventions,
November 2020, 2020-11-00, 20201101, Letnik:
96, Številka:
5
Journal Article
•We propose properties related to drug–transporter interactions and drug attrition.•This space consists of compounds with PSA>75 and clogP<3.•This space overlaps with BDDCS class III and known ...drug-transporters interaction.•We demonstrate differences between physical-property and drug–transporter attrition.•We propose an index to identify compounds at risk of drug-transporter interactions.
Improving the efficiency of drug discovery remains a major focus for the pharmaceutical industry. Toxicity accounts for 90% of withdrawals and major early-stage terminations relate to suboptimal efficacy and safety. Traditional oral drug space is well defined with respect to physicochemical properties and ADMET risks but increased focus on ligand-lipophilicity efficiency, maximizing enthalpy contributions and new target classes challenge this paradigm. A hybrid space has been identified that combines physical properties and key interactions attributable to drug transporters. A novel algorithm is proposed that incorporates drug–transporter interactions and its utility evaluated against popular ligand efficiency indices. Simply reducing the bulk properties of compounds can exchange one problem for another and creates high-risk areas that challenge the successful delivery from a balanced portfolio.
The traditional physical-property-based argument for drug attrition is developed and extended to one that incorporates drug–transporter interactions. A new algorithm is proposed that facilitates the evaluation of this hybrid property space.
: Prediction of human absorption, distribution, metabolism, and excretion (ADME) properties, therapeutic dose and exposure has become an integral part of compound optimization in discovery. ...Incorporation of drug metabolism and pharmacokinetics into discovery projects has largely tempered historical drug failure due to sub-optimal ADME. In the current era, inadequate safety and efficacy are leading culprits for attrition; both of which are dependent upon drug exposure. Therefore, prediction of human pharmacokinetics (PK) and dose are core components of de-risking strategies in discovery.
: The authors provide an overview of human dose prediction methods and present a toolbox of PK parameter prediction models with a proposed framework for a consensus approach valid throughout the discovery value chain. Mechanistic considerations and indicators for their application are discussed which may impact the dose prediction approach. Examples are provided to illustrate how implementation of the proposed strategy throughout discovery can assist project progression.
: Anticipation of human ADME, therapeutic dose and exposure must be deliberated throughout drug discovery from virtual/initial synthesis where key properties are considered and similar molecules ranked, into development where advanced compounds can be subject to prediction with greater mechanistic understanding and data-driven model selection.
Maxillomandibular advancement (MMA) is an invasive yet effective surgical option for obstructive sleep apnea (OSA) that achieves enlargement of the upper airway by physically expanding the facial ...skeletal framework.
To identify criteria associated with surgical outcomes of MMA using aggregated individual patient data from multiple studies.
The Cochrane Library, Scopus, Web of Science, and MEDLINE from June 1, 2014, to March 16, 2015, using the Medical Subject Heading keywords maxillomandibular advancement, orthognathic surgery, maxillary osteotomy, mandibular advancement, sleep apnea, surgical, surgery, sleep apnea syndrome, and obstructive sleep apnea.
Inclusion criteria consisted of studies in all languages of (1) adult patients who underwent MMA as treatment for OSA; (2) report of preoperative and postoperative quantitative outcomes for the apnea-hypopnea index (AHI) and/or respiratory disturbance index (RDI); and (3) report of individual patient data. Studies of patients who underwent adjunctive procedures at the time of MMA (including tonsillectomy, uvulopalatopharyngoplasty, and partial glossectomy) were excluded.
Three coauthors systematically reviewed the articles and updated the review through March 16, 2015. The PRISMA statement was followed. Data were pooled using a random-effects model and analyzed from July 1, 2014, to September 23, 2015.
The primary outcomes were changes in the AHI and RDI after MMA for each patient. Secondary outcomes included surgical success, defined as the percentage of patients with more than 50% reduction of the AHI to fewer than 20 events/h, and OSA cure, defined as a post-MMA AHI of fewer than 5 events/h.
Forty-five studies with individual data from 518 unique patients/interventions were included. Among patients for whom data were available, 197 of 268 (73.5%) had undergone prior surgery for OSA. Mean (SD) postoperative changes in the AHI and RDI after MMA were -47.8 (25.0) and -44.4 (33.0), respectively; mean (SE) reductions of AHI and RDI outcomes were 80.1% (1.8%) and 64.6% (4.0%), respectively; and 512 of 518 patients (98.8%) showed improvement. Significant improvements were also seen in the mean (SD) postoperative oxygen saturation nadir (70.1% 15.6% to 87.0% 5.2%; P < .001) and Epworth Sleepiness Scale score (13.5 5.2 to 3.2 3.2; P < .001). Rates of surgical success and cure were 389 (85.5%) and 175 (38.5%), respectively, among 455 patients with AHI data and 44 (64.7%) and 13 (19.1%), respectively, among 68 patients with RDI data. Preoperative AHI of fewer than 60 events/h was the factor most strongly associated with the highest incidence of surgical cure. Nevertheless, patients with a preoperative AHI of more than 60 events/h experienced large and substantial net improvements despite modest surgical cure rates.
Maxillomandibular advancement is an effective treatment for OSA. Most patients with high residual AHI and RDI after other unsuccessful surgical procedures for OSA are likely to benefit from MMA.
Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in ...clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.
Basidiomycota (basidiomycetes) make up 32% of the described fungi and include most wood-decaying species, as well as pathogens and mutualistic symbionts. Wood-decaying basidiomycetes have typically ...been classified as either white rot or brown rot, based on the ability (in white rot only) to degrade lignin along with cellulose and hemicellulose. Prior genomic comparisons suggested that the two decay modes can be distinguished based on the presence or absence of ligninolytic class II peroxidases (PODs), as well as the abundance of enzymes acting directly on crystalline cellulose (reduced in brown rot). To assess the generality of the white-rot/brown-rot classification paradigm, we compared the genomes of 33 basidiomycetes, including four newly sequenced wood decayers, and performed phylogenetically informed principal-components analysis (PCA) of a broad range of gene families encoding plant biomass-degrading enzymes. The newly sequenced Botryobasidium botryosum and Jaapia argillacea genomes lack PODs but possess diverse enzymes acting on crystalline cellulose, and they group close to the model white-rot species Phanerochaete chrysosporium in the PCA. Furthermore, laboratory assays showed that both B. botryosum and J. argillacea can degrade all polymeric components of woody plant cell walls, a characteristic of white rot. We also found expansions in reducing polyketide synthase genes specific to the brown-rot fungi. Our results suggest a continuum rather than a dichotomy between the white-rot and brown-rot modes of wood decay. A more nuanced categorization of rot types is needed, based on an improved understanding of the genomics and biochemistry of wood decay.
Treatment of mitral regurgitation (MR) in the setting of severe mitral annular calcification (MAC) is challenging due to the high risk for fatal atrioventricular groove disruption and significant ...paravalvular leak.
The objective of this study was to evaluate the potential for transcatheter mitral valve replacement in patients with severe MAC using an anatomically designed mitral prosthesis.
Nine patients (77 ± 6 years of age; 5 men) were treated with the valve, using transapical delivery performed under general anesthesia and with guidance from transesophageal echocardiography and fluoroscopy.
Device implantation was successful with relief of MR in all 9 patients. There were no procedural deaths. In 1 patient, left ventricular outflow tract obstruction occurred due to malrotation of the prosthesis, and successful alcohol septal ablation was performed. During a median follow-up of 12 months (range 1 to 28 months), there was 1 cardiac death, 1 noncardiac death, no other mortality, and no prosthetic dysfunction, and MR remained absent in all treated patients. Rehospitalization for heart failure occurred in 2 patients who did not die subsequently. Clinical improvement with mild or no symptoms occurred in all patients alive at the end of follow-up.
Transcatheter mitral valve replacement in severe mitral annular calcification with a dedicated prosthesis is feasible and can result in MR relief with symptom improvement. Further evaluation of this approach for these high-risk patients is warranted.
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The authors developed a global chronic total occlusion crossing algorithm following 10 steps: 1) dual angiography; 2) careful angiographic review focusing on proximal cap morphology, occlusion ...segment, distal vessel quality, and collateral circulation; 3) approaching proximal cap ambiguity using intravascular ultrasound, retrograde, and move-the-cap techniques; 4) approaching poor distal vessel quality using the retrograde approach and bifurcation at the distal cap by use of a dual-lumen catheter and intravascular ultrasound; 5) feasibility of retrograde crossing through grafts and septal and epicardial collateral vessels; 6) antegrade wiring strategies; 7) retrograde approach; 8) changing strategy when failing to achieve progress; 9) considering performing an investment procedure if crossing attempts fail; and 10) stopping when reaching high radiation or contrast dose or in case of long procedural time, occurrence of a serious complication, operator and patient fatigue, or lack of expertise or equipment. This algorithm can improve outcomes and expand discussion, research, and collaboration.
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