Unlocking Amides: A General Method for the Self-Immolative Release of Amide-Containing Molecules.

The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload-release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide-containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof of concept, the FDA-approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method.

Disulfide re-bridging reagents for single-payload antibody-drug conjugates.

Numerous antibody-drug conjugate (ADC) linker technologies exist for the synthesis of ADCs with drug-to-antibody ratios (DARs) being an even integer (typically 2, 4 or 8). However, ADCs with odd-integer DARs are significantly harder to synthesise. Here, we report the synthesis of ADCs loaded with a single warhead, using TetraDVP linkers which simultaneously re-bridge all four interchain disulfides of an IgG1 antibody.

Percutaneous coronary intervention at centers with and without on-site surgery: a meta-analysis.

CONTEXT: Percutaneous coronary interventions are performed at centers without onsite surgery, despite current guidelines discouraging this. OBJECTIVE: To assess literature comparing rates of in-hospital mortality and emergency coronary artery bypass grafting surgery at centers with and without on-site surgery. DATA SOURCES: A systematic search of studies published between January 1990 and May 2010 was conducted using MEDLINE, EMBASE, and Cochrane Review databases. STUDY SELECTION: English-language studies of percutaneous coronary intervention performed at centers with and without on-site surgery providing data on in-hospital mortality and emergency bypass were identified. Two study authors independently reviewed the 1029 articles originally identified and selected 40 for analysis. DATA EXTRACTION: Study title, time period, indication for angioplasty, and outcomes were extracted manually from all selected studies, and quality of each study was assessed using the strengthening the reporting of observational studies in epidemiology (STROBE) checklist. DATA SYNTHESIS: High-quality studies of percutaneous coronary interventions performed at centers with and without on-site surgery were included. Pooled-effect estimates were calculated with random-effects models. Analyses of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction of 124,074 patients demonstrated no increase in in-hospital mortality (no on-site surgery vs on-site surgery: observed risk, 4.6% vs 7.2%; odds ratio [OR], 0.96; 95% CI, 0.88-1.05; I(2) = 0%) or emergency bypass (observed risk, 0.22% vs 1.03%; OR, 0.53; 95% CI, 0.35-0.79; I(2) = 20%) at centers without on-site surgery. For nonprimary percutaneous coronary interventions (elective and urgent, n = 914,288), the rates of in-hospital mortality (observed risk, 1.4% vs 2.1%; OR, 1.15; 95% CI, 0.93-1.41; I(2) = 46%) and emergency bypass (observed risk, 0.17% vs 0.29%; OR, 1.21; 95% CI, 0.52-2.85; I(2) = 5%) were not significantly different at centers without or with on-site surgery. CONCLUSION: Percutaneous coronary interventions performed at centers without on-site surgery, compared with centers with on-site surgery, were not associated with a higher incidence of in-hospital mortality or emergency bypass surgery.

Percutaneous coronary intervention with off-site cardiac surgery backup for acute myocardial infarction as a strategy to reduce door-to-balloon time.

We investigated whether primary percutaneous coronary intervention (PCI) for patients admitted with an acute ST-segment elevation myocardial infarction could be performed more rapidly and with comparable outcomes in a community hospital versus a tertiary center with cardiac surgery. We started the first PCI with an off-site surgery program in The Netherlands in 2002 and report the results of 439 consecutive patients. In the safety phase, 199 patients presenting with ST-segment elevation myocardial infarction were randomly assigned to treatment at our off-site center versus a more distant cardiac surgery center. In the confirmation phase, 240 consecutive patients were treated in the off-site hospital. Safety and efficacy end points were the rate of an angiographically successful PCI procedure (diameter stenosis <50% and Thrombolysis In Myocardial Infarction grade 3 flow) in the absence of major adverse cardiac and cerebrovascular events at 30 days. The randomization phase showed a 37-minute decrease in door-to-balloon time (p <0.001) with comparable procedural and clinical successes (91% Thrombolysis In Myocardial Infarction grade 3 flow in the 2 groups). In the confirmation phase, the 30-day rate without major adverse cardiac and cerebrovascular events was 95%. None of the 439 patients in the study required emergency surgery for failed primary PCI. In conclusion, time to treatment with primary PCI can be significantly shortened when treating patients in a community hospital setting with off-site cardiac surgery backup compared with transport for PCI to a referral center with on-site surgery. PCI at hospitals with off-site cardiac surgery backup can be considered a needed strategy to improve access to primary PCI for a larger segment of the population and can be delivered with a very favorable safety profile.

Nonemergent percutaneous coronary intervention with off-site surgery backup: an emerging new path to access.

Nonemergent primary coronary intervention (PCI) at hospitals with off-site cardiac surgery backup is currently given a "Class III" indication by the American College of Cardiology/American Heart Association (ACC/AHA) PCI Guidelines on the basis of "consensus opinion of experts," not on trials or studies (Level of Evidence C). Yet the evidence is mounting, both in the US and abroad, that urgent and elective PCI can be performed safely and effectively at qualified nonsurgical hospitals in controlled circumstances. As the need for PCI grows, especially in the large population with high-risk acute coronary syndromes (ACS), the lack of local access to and underutilization of timely PCI can demonstrably result in inferior outcomes. The multiple clinical, performance, and economic advantages of the broader availability of PCI are discussed extensively in this paper. Removing the requirement for on-site cardiac surgery from nonemergent PCI can also increase procedural volumes at the growing numbers of primary angioplasty programs at hospitals with off-site backup, while also reducing the pressure to build new low-volume cardiac surgery programs merely to support PCI programs. The many US hospitals that are already participating in this growing movement to provide PCI with off-site backup are encouraged to enroll in the ACC National Cardiovascular Data Registry to assure that this strategy is fairly assessed and monitored on a national level. We anticipate that state regulations and national guidelines will continue to evolve and keep pace with this growing movement and with the already-evolving guidelines from abroad.

Primary angioplasty in acute myocardial infarction at hospitals with no surgery on-site (the PAMI-No SOS study) versus transfer to surgical centers for primary angioplasty.

OBJECTIVES: To investigate primary angioplasty (PA) for high-risk acute myocardial infarction (AMI) at hospitals with no cardiac surgery on-site (No SOS), we hypothesized that a nonrandomized registry of such patients treated with PA would show clinical outcomes similar to those of a group randomized to transfer for PA, and that reperfusion would occur faster. BACKGROUND: Primary angioplasty provides outcomes superior to fibrinolytic therapy in AMI, but its use in community hospitals with No SOS has been limited. METHODS: Fibrinolytic-eligible patients with high-risk AMI prospectively consented if they had one or more high-risk characteristic. Nineteen hospitals with No SOS prospectively enrolled 500 patients for PA on-site. Seventy-one similar Air Primary Angioplasty in Myocardial Infarction trial patients were randomized to transfer for PA. RESULTS: Primary angioplasty was performed in 88% of patients. Patients transferred for PA had a longer mean time to treatment (187 vs. 120 min; p < 0.0001). Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 was achieved in 96% for on-site PA, 86% in the transfer group (p = 0.004). The combined primary end point of 30-day mortality, re-infarction, and disabling stroke occurred in 27 (5%) on-site PA patients and 6 (8.5%) transfer patients (p = 0.27). Unadjusted one-year mortality was improved in on-site PA patients compared with those transferred (6% vs. 13%, p = 0.043), but after adjustment for differences in baseline variables, this difference was not significant. CONCLUSIONS: On-site PA and transfer groups had similar 30-day outcomes and more rapid reperfusion for on-site PA. Primary angioplasty in high-risk AMI patients at hospitals with No SOS is safe, effective, and faster than PA after transfer to a surgical facility.