Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: An optical coherence tomography study

BACKGROUND Pathology studies have shown delayed arterial healing in culprit lesions of patients with acute coronary syndrome (ACS) compared with stable coronary artery disease (CAD) after placement of drug-eluting stents (DES). It is unknown whether similar differences exist in-vivo during long-term follow-up. Using optical coherence tomography (OCT), we assessed differences in arterial healing between patients with ACS and stable CAD five years after DES implantation. METHODS AND RESULTS A total of 88 patients comprised of 53 ACS lesions with 7864 struts and 35 stable lesions with 5298 struts were suitable for final OCT analysis five years after DES implantation. The analytical approach was based on a hierarchical Bayesian random-effects model. OCT endpoints were strut coverage, malapposition, protrusion, evaginations and cluster formation. Uncovered (1.7% vs. 0.7%, adjusted p=0.041) or protruding struts (0.50% vs. 0.13%, adjusted p=0.038) were more frequent among ACS compared with stable CAD lesions. A similar trend was observed for malapposed struts (1.33% vs. 0.45%, adj. p=0.072). Clusters of uncovered or malapposed/protruding struts were present in 34.0% of ACS and 14.1% of stable patients (adj. p=0.041). Coronary evaginations were more frequent in patients with ST-elevation myocardial infarction compared with stable CAD patients (0.16 vs. 0.13 per cross section, p=0.027). CONCLUSION Uncovered, malapposed, and protruding stent struts as well as clusters of delayed healing may be more frequent in culprit lesions of ACS compared with stable CAD patients late after DES implantation. Our observational findings suggest a differential healing response attributable to lesion characteristics of patients with ACS compared with stable CAD in-vivo.

Long-term outcomes of biodegradable versus durable polymer drug-eluting stents in patients with acute ST-segment elevation myocardial infarction: a pooled analysis of individual patient data from three randomised trials

Aims: Arterial plaque rupture and thrombus characterise ST-elevation myocardial infarction (STEMI) and may aggravate delayed arterial healing following durable polymer drug-eluting stent (DP-DES) implantation. Biodegradable polymer (BP) may improve biocompatibility. We compared long-term outcomes in STEMI patients receiving BP-DES vs. durable polymer sirolimus-eluting stents (DP-SES). Methods and results: We pooled individual patient-level data from three randomised clinical trials (ISAR-TEST-3, ISAR-TEST-4 and LEADERS) comparing outcomes from BP-DES with DP-SES at four years. The primary endpoint (MACE) comprised cardiac death, MI, or target lesion revascularisation (TLR). Secondary endpoints were TLR, cardiac death or MI, and definite or probable stent thrombosis. Of 497 patients with STEMI, 291 received BP-DES and 206 DP-SES. At four years, MACE was significantly reduced following treatment with BP-DES (hazard ratio [HR] 0.59, 95% CI: 0.39-0.90; p=0.01) driven by reduced TLR (HR 0.54, 95% CI: 0.30-0.98; p=0.04). Trends towards reduction were seen for cardiac death or MI (HR 0.63, 95% CI: 0.37-1.05; p=0.07) and definite or probable stent thrombosis (3.6% vs. 7.1%; HR 0.49, 95% CI: 0.22-1.11; p=0.09). Conclusions: In STEMI, BP-DES demonstrated superior clinical outcomes to DP-SES at four years. Trends towards reduced cardiac death or myocardial infarction and reduced stent thrombosis require corroboration in specifically powered trials.

Drug-eluting stents compared to bare-metal stents improve short-term survival in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: a nationwide prospective analysis of the AMIS Plus registry

BACKGROUND Recently, it has been suggested that the type of stent used in primary percutaneous coronary interventions (pPCI) might impact upon the outcomes of patients with acute myocardial infarction (AMI). Indeed, drug-eluting stents (DES) reduce neointimal hyperplasia compared to bare-metal stents (BMS). Moreover, the later generation DES, due to its biocompatible polymer coatings and stent design, allows for greater deliverability, improved endothelial healing and therefore less restenosis and thrombus generation. However, data on the safety and performance of DES in large cohorts of AMI is still limited. AIM To compare the early outcome of DES vs. BMS in AMI patients. METHODS This was a prospective, multicentre analysis containing patients from 64 hospitals in Switzerland with AMI undergoing pPCI between 2005 and 2013. The primary endpoint was in-hospital all-cause death, whereas the secondary endpoint included a composite measure of major adverse cardiac and cerebrovascular events (MACCE) of death, reinfarction, and cerebrovascular event. RESULTS Of 20,464 patients with a primary diagnosis of AMI and enrolled to the AMIS Plus registry, 15,026 were referred for pPCI and 13,442 received stent implantation. 10,094 patients were implanted with DES and 2,260 with BMS. The overall in-hospital mortality was significantly lower in patients with DES compared to those with BMS implantation (2.6% vs. 7.1%,p < 0.001). The overall in-hospital MACCE after DES was similarly lower compared to BMS (3.5% vs. 7.6%, p < 0.001). After adjusting for all confounding covariables, DES remained an independent predictor for lower in-hospital mortality (OR 0.51,95% CI 0.40-0.67, p < 0.001). Since groups differed as regards to baseline characteristics and pharmacological treatment, we performed a propensity score matching (PSM) to limit potential biases. Even after the PSM, DES implantation remained independently associated with a reduced risk of in-hospital mortality (adjusted OR 0.54, 95% CI 0.39-0.76, p < 0.001). CONCLUSIONS In unselected patients from a nationwide, real-world cohort, we found DES, compared to BMS, was associated with lower in-hospital mortality and MACCE. The identification of optimal treatment strategies of patients with AMI needs further randomised evaluation; however, our findings suggest a potential benefit with DES.

Extent of coronary artery disease and outcomes after ticagrelor administration in patients with an acute coronary syndrome: Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial.

BACKGROUND Extensive coronary artery disease (CAD) is associated with higher risk. In this substudy of the PLATO trial, we examined the effects of randomized treatment on outcome events and safety in relation to the extent of CAD. METHODS Patients were classified according to presence of extensive CAD (defined as 3-vessel disease, left main disease, or prior coronary artery bypass graft surgery). The trial's primary and secondary end points were compared using Cox proportional hazards regression. RESULTS Among 15,388 study patients for whom the extent of CAD was known, 4,646 (30%) had extensive CAD. Patients with extensive CAD had more high-risk characteristics and experienced more clinical events during follow-up. They were less likely to undergo percutaneous coronary intervention (58% vs 79%, P < .001) but more likely to undergo coronary artery bypass graft surgery (16% vs 2%, P < .001). Ticagrelor, compared with clopidogrel, reduced the composite of cardiovascular death, myocardial infarction, and stroke in patients with extensive CAD (14.9% vs 17.6%, hazard ratio [HR] 0.85 [0.73-0.98]) similar to its reduction in those without extensive CAD (6.8% vs 8.0%, HR 0.85 [0.74-0.98], Pinteraction = .99). Major bleeding was similar with ticagrelor vs clopidogrel among patients with (25.7% vs 25.5%, HR 1.02 [0.90-1.15]) and without (7.3% vs 6.4%, HR 1.14 [0.98-1.33], Pinteraction = .24) extensive CAD. CONCLUSIONS Patients with extensive CAD have higher rates of recurrent cardiovascular events and bleeding. Ticagrelor reduced ischemic events to a similar extent both in patients with and without extensive CAD, with bleeding rates similar to clopidogrel.

Alcohol, Drug Abuse, and Mental Health Administration research programs.

Mode of access: Internet.

Alcohol, Drug Abuse, and Mental Health Administration public advisory committees : authority, structure, function, members.

Mode of access: Internet.

Host and Environmental Correlates of Multi-Drug Resistance in Kenyan Children with Acute Bacterial Diarrhea

Thesis (Master's)--University of Washington, 2016-06

Acute cadmium chloride administration induces hepatic and renal CYP2A5 mRNA, protein and activity in the mouse: involvement of transcription factor NRF2

Modulation of the cytochrome P450 (CYP) monooxygenase system by cadmium was investigated in male, adult DBA/2J mice treated with a single dose (16 mumol/kg body weight, i.p.) of cadmium chloride (CdCl2). Total CYP content of liver and kidney microsomes decreased maximally (56% and 85%, respectively) 24 and 18 h, respectively, after CdCl2 treatment. Progressive increases of hepatic coumarin 7-hydroxylase (COH) activity; indicative of CYP2A5 activity, relative to the total CYP content were seen at 8 h (2-fold), 12 h (3-fold), 18 h (12-fold), and 24 h (15-fold). Similar changes were seen in the kidney. Liver and kidney CYP2A5 mRNA levels increased maximally 12 and 4 h after treatment and decreased to almost half 6 h later. In contrast, kidney and liver CYP2A5 protein levels increased maximally at 18 and 24 h. The CYP2A5 mRNA levels in the kidney and liver increased after Cd treatment in Nrf2 +/+ but not in Nrf2 -/- mouse. This study demonstrates that hepatic and kidney CYP2A5 is upregulated by cadmium with a somewhat faster response in the kidney than the liver. The strong upregulation of the CYP2A5 both at mRNA and enzyme activity levels, with a simultaneous decrease in the total CYP concentration suggest an unusual mode of regulation of CYP2A5 in response to cadmium exposure, amongst the CYP enzymes. The observed decrease in the mRNA but not in protein levels after maximal induction may suggest involvement of post-trancriptional mechanisms in the regulation. Upregulation of CYP2A5 by cadmium in the Nrf2 +/+ mice but not in the Nrf2 -/- mice indicates a role for this transcription factor in the regulation. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

A prospective multicentre study of pharmacist initiated changes to drug therapy and patient management in acute care government funded hospitals

Aims To determine the cost savings of pharmacist initiated changes to hospitalized patients' drug therapy or management in eight major acute care government funded teaching hospitals in Australia. Methods This was a prospective study performed in eight hospitals examining resource implications of pharmacists' interventions assessed by an independent clinical panel. Pharmacists providing clinical services to inpatients recorded details of interventions, defined as any action that directly resulted in a change to patient management or therapy. An independent clinical review panel, convened at each participating centre, confirmed or rejected the clinical pharmacist's assessment of the impact on length of stay (LOS), readmission probability, medical procedures and laboratory monitoring and quantified the resultant changes, which were then costed. Results A total of 1399 interventions were documented. Eight hundred and thirty-five interventions impacted on drug costs alone. Five hundred and eleven interventions were evaluated by the independent panels with three quarters of these confirmed as having an impact on one or more of: length of stay, readmission probability, medical procedures or laboratory monitoring. There were 96 interventions deemed by the independent panels to have reduced LOS and 156 reduced the potential for readmission. The calculated savings was $263 221 for the eight hospitals during the period of the study. This included $150 307 for length of stay reduction, $111 848 for readmission reduction. Conclusions The annualized cost savings relating to length of stay, readmission, drugs, medical procedures and laboratory monitoring as a result of clinical pharmacist initiated changes to hospitalized patient management or therapy was $4 444 794 for eight major acute care government funded teaching hospitals in Australia.

Acute cadmium chloride administration induces hepatic and renal cytochrome P450 2A5 in the mouse

Modulation of the cytochrome P450 (CYP) monooxygenase system by cadmium was investigated in male, adult DBA/2J mice treated with a single dose (16 Amol/kg body weight, i.p.) of cadmium chloride (CdCl2) at various time points. The total CYP content of kidney microsomes started to decrease 4 hours earlier than in the liver (P < 0.05), with maximal decreases at 24 hours of 56% and 85% in the liver and kidney, respectively. In contrast, both hepatic and renal coumarin 7-hydroxylase (COH) activity (indicative of CYP2A5 activity) relative to total CYP content started to progressively increase at 8 hours, with renal activity 61 times higher than the hepatic activity. Maximum increases were observed, 15-fold in the liver and 64-fold in the kidney after 24 hours. Liver and kidney CYP2A5 mRNA levels increased maximally 12 and 4 hours after treatment, respectively and decreased to almost half 6 hours later. In contrast, kidney and liver CYP2A5 protein levels increased maximally at 18 and 24 hours. This study demonstrates that hepatic and renal CYP2A5 is upregulated by cadmium with a faster response in the kidney than in the liver. This observation is concordant with the fact that kidney is the target organ for cadmium toxicity. The observed increase in the mRNA but not in protein levels after maximal induction suggests involvement of post-transcriptional mechanisms in the regulation of CYP2A5 expression by cadmium.

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure

Administration of human recombinant erythropoietin ( EPO) at time of acute ischemic renal injury ( IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa ( DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats ( N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation ( T0), or post-treated ( 6 h after the onset of reperfusion, T6) with EPO ( 5000 IU/kg), DPO ( 25 mu g/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.08 +/- 0.03mmol/l vs EPO-IRI 0.04 +/- 0.01mmol/l, P = 0.01). Delayed administration of DPO or EPO ( T6) also significantly abrogated subsequent renal dysfunction ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.06 +/- 0.01mmol/l vs EPO-IRI 0.03 +/- 0.03mmol/l, P = 0.01). There was also significantly decreased tissue injury ( apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.

Paracetamol [acetaminophen]-induced gastrotoxicity: Revealed by induced hyperacidity in combination with acute or chronic inflammation

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-β-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Drug combination: pharmaceutical technologies applied to the manufacturing of combined dosage forms for oral administration

Lo scopo di questa ricerca di dottorato è stato lo studio di una forma di dosaggio flessibile e personalizzabile, indirizzata alle necessità individuali di ogni paziente, per il trattamento dell’iperplasia prostatica benigna. La terapia proposta prevede l’utilizzo di due farmaci, un alfa bloccante (farmaco A) e un inibitore delle 5- fosfodiesterasi (farmaco B) e, somministrati in una singola forma di dosaggio contenenti differenti dosi e combinazioni dei due farmaci. Lo sviluppo di un sistema di rilascio per la somministrazione orale di farmaco A e farmaco B è stato realizzato grazie alla tecnologia Dome Matrix. La tecnologia si basa sull’assemblaggio di moduli utilizzati come elementi di controllo del rilascio. L’assemblaggio dei moduli può essere ottenuto attraverso diverse configurazioni. Sono stati quindi realizzati sistemi assemblati in grado di galleggiare sul contenuto gastrico; la prolungata permanenza della forma farmaceutica nello stomaco favorisce la solubilizzazione dei due principi attivi che quindi potrebbero raggiungere il sito di assorbimento nel primo tratto intestinale già in dispersione molecolare, condizione ideale per essere assorbiti. La prima parte della ricerca è stata focalizzata sulla realizzazione di un sistema assemblato a rilascio modificato di farmaco A. Moduli contenenti diversi dosaggi di farmaco sono stati assemblati in varie configurazioni e dosi differenti per ottenere una forma di dosaggio flessibile, adattabile alle esigenze terapeutiche del paziente. La seconda parte del lavoro di tesi ha riguardato la realizzazione di un sistema assemblato, contenente entrambi i farmaci in associazione. L’ultima parte della ricerca è stata svolta presso la “University of Texas at Austin” sotto la supervisione del Professor Nicholas Peppas. Il lavoro svolto è stato focalizzato sullo studio delle caratteristiche di rigonfiamento dei singoli moduli di farmaco e dei loro sistemi assemblati; il comportamento di tali sistemi è stato investigato anche grazie all’utilizzo della tecnica di tomografia computerizzata a raggi X.