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Biomedical subjects

A H Gershlick

Publications and source records attributed to A H Gershlick.

At least 19 recordsLinked to original sources
PubMed2006

Drug eluting stents.

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Angioplasty, Balloon, Coronary↗
PubMed2005

Drug eluting stents in interventional cardiology -- current evidence and emerging uses.

Intervention in coronary artery disease is an area of cardiology where novel drugs, in the form of drug-eluting stents (DES), are being used increasingly commonly. DES are used across the whole range of coronary intervention, from stable angina patients with single or multivessel disease, acute coronary syndromes and acute myocardial infarction (i.e. primary angioplasty). Most recently, they are being tested in a particularly challenging subset of patients, those experiencing symptoms due to restenosis within a previously stented area of vessel (in-stent restenosis, ISR). This article summarises the rationale for the use of DES, across all these areas, focussing specifically on the emerging results of trials and registries examining the effectiveness of DES in acute myocardial infarction (AMI) and ISR. Drug-eluting stents represent a significant shift in the use of locally-delivered drugs in interventional cardiology. On the basis of encouraging trial data, including in the specific areas of in-stent restenosis and myocardial infarction, their use is becoming extremely widespread in place of bare-metal (drug-free) stents. This change is happening despite their high costs, relatively short follow-up data and concerns of possible unwanted effects, because of the weight of evidence that they are superior in preventing restenosis in many patient groups. This reduction is highly significant in angiographic terms and, to a lesser degree, in the prevention of clinically important restenosis requiring revascularisation, but not clearly in terms of overall mortality.

Animals↗
PubMed2004

Clopidogrel induced urticarial rash in a patient with left main stem percutaneous coronary intervention: management issues.

Clopidogrel, an ideal treatment for prevention of subacute stent thrombosis, may not be feasible to use in every patient. Ticlopidine (plus aspirin) is a very good alternative, although the risks of life threatening neutropenia should mandate regular monitoring of blood counts. It is proposed that patients undergoing angioplasty and stenting should carry a warning card in an effort to make the public and general practitioners aware that antiplatelet treatment after angioplasty plays an important part in ensuring successful outcome.

Aged↗
PubMed2002

Treating atherosclerosis: local drug delivery from laboratory studies to clinical trials.

Treating only the specific section of the vascular bed that is diseased appears to make sense. Giving drugs systematically to treat perhaps only a few centimetres of affected artery carries with it the risk of systemic side effects and reduced efficacy consequent on low concentrations of agent at the site of the problem. There has thus been great interest since the early 1990s in local drug delivery. Initial targets were the thrombotic response to plaque disruption but the problems arising from the incidental damage inflicted by devices used in interventional cardiology and the pathological consequences of this, namely smooth muscle cell initiated intimal hyperplasia, soon became the focus of pre-clinical studies. Problems to be overcome were the low efficiency of delivery of drugs and the low retention rates. Solutions to these problems included the development of strategies to target drugs, through the use of antibodies directed at antigens newly released at the site of damage. As it became clear that stents were becoming central to the attainment of a better clinical response to intervention by their inherent physical properties, it also became obvious that stents could be used to deliver agents. Issues such as which stent, how to load the drug onto the stent and what drug to use to inhibit the unwanted pathobiological response are ongoing issues.

Administration, Topical↗
PubMed2001

Plasminogen activator and plasminogen activator inhibitor gene expression in human saphenous vein organ culture.

We describe the expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) in saphenous vein culture. Smooth muscle cells (SMC) are quiescent in fresh tissue, whereas these cells acquire a proliferating phenotype when venous segments are cultured in the presence of serum. t-PA and PAI-1 were localized immunohistochemically and quantified using biochemical techniques. t-PA and PAI-1 mRNA was quantified by reverse transcription polymerase chain reaction (RT--PCR) assay. Immunostaining showed an increase in the positivity of proliferating cell nuclear antigen (PCNA) from 10-day tissue culture. Tissue sections from fresh vein showed minimal t-PA and maximal PAI-1 immunostaining. In contrast, 10-day cultures showed an increase in t-PA and a decline in PAI-1 staining. Biochemical analysis revealed a 118% increase in t-PA and a 50% decrease in PAI-1 antigen levels from 10-day tissue cultures. RT--PCR demonstrated that the mRNA encoding t-PA increased, while PAI-1 decreased after 10 days of culture. In conclusion, venous culture showed an up-regulation of t-PA and a repression of PAI-1 gene expression during SMC proliferation in the vessel wall. The PAI-1 repression observed in venous culture is in contrast to the situation observed in human atheroma. A shift in the t-PA/PAI-1 balance may have a role in vascular remodeling.

Blotting, Western↗
PubMed2001

The acute management of myocardial infarction.

Acute myocardial infarction (AMI) is a common and potentially fatal condition. Primary prevention by reducing the risk of developing coronary atheroma disease has had an important effect on the incidence of the disease. However, for many, the first clinical presentation of their coronary atheroma is the development of acute coronary occlusion. The acute nature of such presentation is the result of the dynamic nature of the plaque event. Thus while measures such as increasing public education in areas of primary prevention are always important it needs to be recognised that real differences in outcome need to and can be made even once the event has occurred. Individuals developing chest pain need to be encouraged to present early, especially if they have a history of ischaemic heart disease. Once they have arrived at point of medical contact, rapid triage, early diagnosis and the institution of therapies designed to reduce the extent of myocardial damage are paramount.

Angioplasty, Balloon, Coronary↗
PubMed2001

Keeping the coronary arteries open: current opportunities.

Thrombolysis has reduced mortality from myocardial infarction, but effective opening of the artery with normal flow continues to be an important goal. Thrombolysis is not always as successful as it should be; alternatives include adjunctive therapy and mechanical opening of the arteries. In patients with acute coronary occlusion opening the artery should continue to be the primary aim.

Angioplasty, Balloon, Coronary↗
PubMed2000

Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS).

BACKGROUND: Combination therapy with the ADP receptor antagonist ticlopidine plus aspirin has emerged as standard care after coronary stenting. Clopidogrel, a new ADP receptor antagonist, has greater molar potency than ticlopidine and better safety/tolerability. METHODS AND RESULTS: Patients (n=1020) were randomized after successful stent placement and initiated on a 28-day regimen of either (1) 300-mg clopidogrel loading dose and 325 mg/d aspirin on day 1, followed by 75 mg/d clopidogrel and 325 mg/d aspirin; (2) 75 mg/d clopidogrel and 325 mg/d aspirin; or (3) 250 mg BID ticlopidine and 325 mg/d aspirin. The primary end point consisted of major peripheral or bleeding complications, neutropenia, thrombocytopenia, or early discontinuation of study drug as the result of a noncardiac adverse event during the study-drug treatment period. The primary end point occurred in 9.1% of patients (n=31) in the ticlopidine group and 4.6% of patients (n=31) in the combined clopidogrel group (relative risk 0.50; 95% CI 0.31 to 0.81; P=0.005). Overall rates of major adverse cardiac events (cardiac death, myocardial infarction, target lesion revascularization) were low and comparable between treatment groups (0.9% with ticlopidine, 1.5% with 75 mg/d clopidogrel, 1.2% with the clopidogrel loading dose; P=NS for all comparisons). CONCLUSIONS: The safety/tolerability of clopidogrel (plus aspirin) is superior to that of ticlopidine (plus aspirin) (P=0.005). The 300-mg loading dose was well tolerated, notably with no increased risk of bleeding. Secondary end point data are consistent with the hypothesis that clopidogrel and ticlopidine have comparable efficacy with regard to cardiac events after successful stenting.

Aged↗
PubMed2000

In vitro evaluation of c7E3-Fab (ReoPro) eluting polymer-coated coronary stents.

OBJECTIVE: Stent thrombosis and in-stent restenosis remain problematic in certain patient sub-groups. c7E3-Fab (ReoPro, abciximab) inhibits the platelet glycoprotein IIb/IIIa receptor as well as the smooth muscle cell alpha(v)beta3 receptor, and thus may influence both processes, especially if high local concentrations could be achieved. We have studied the adsorption and elution characteristics of c7E3-Fab on commercially available polymer-coated stents. We have also investigated the effect of such antibody binding on platelet deposition in vitro, and on antibody deposition into ex vivo human saphenous vein wall to assess whether such stents may influence stent thrombosis and restenosis. METHODS AND RESULTS: Adsorption was measured using a radioisotope technique after immersing segments of polymer-coated stents in c7E3-Fab solutions. Uptake was dependent on antibody concentration and duration of immersion of wire in the solution. After 22 h (at 5 mg ml(-1)), 1146+/-101 ng cm(-1) wire was adsorbed. In an in vitro perfusion circuit, the antibody eluted slowly, with 53% remaining after 12 days washing. To determine the value that such stents might have in clinical practise, adsorption to balloon-mounted stents was assessed at room temperature, using commercially available c7E3-Fab (2 mg ml(-1)). Efficacy of eluting c7E3-Fab was determined by measuring deposition of 111-Indium platelets. Immersing stents in c7E3-Fab for 20 min inhibited platelet deposition by 82.3% compared to controls (P=0.018). Deployment of treated stents in ex vivo saphenous vein resulted in the deposition of c7E3-Fab in the intima and media. CONCLUSIONS: c7E3-Fab can be passively adsorbed onto polymer-coated stents. It elutes slowly and in a predictable manner, significantly inhibiting platelet deposition in vitro. These studies pave the way to developing stent-based delivery of a potent anti-platelet agent that may additionally affect smooth muscle cell activity.

Abciximab↗
PubMed2000

Inhibition of vascular smooth muscle cell adhesion and migration by c7E3 Fab (abciximab): a possible mechanism for influencing restenosis.

OBJECTIVES: Brief intravenous administration of chimeric antibody c7E3 Fab during coronary angioplasty has been shown in some studies to provide long term protection against coronary events. Smooth muscle cell (SMC) adhesion and migration are key initial steps in the development of restenosis. The purpose of this study was to investigate the effect of c7E3 Fab on adhesion and migration of SMC to the extracellular matrix (ECM) proteins osteopontin (Opn) and vitronectin (Vn). METHODS: Adhesion of human vascular SMCs to ECM proteins was quantified using a CyQUANT assay kit. Migration of SMCs to Vn, Opn and PDGF was studied using a modified Boyden's chamber migration assay. Integrin expression was determined by immunoprecipitation. RESULTS: c7E3 Fab reduced SMC adhesion on Vn and Opn to 69.2+/-3.3% (P<0.001) and 52.5+/-4.8% (P<0.001) respectively, compared to adhesion without antibody present. This reduction was the same as that for anti-alpha(v)beta(3) integrin antibody LM609 (P=0.5). The combination of anti-alpha(v)beta(5) integrin antibody and c7E3 Fab had a greater effect than either antibody alone (P<0.001). c7E3 Fab reduced SMC migration to Vn and Opn to 51.6+/-8.9% (P<0.001) and 20.3+/-6.1% (P<0.001) respectively, compared to migration in the absence of antibodies. Again, similar results were seen with LM609. PDGF-induced SMC migration was also inhibited by c7E3 Fab (P=0.004) and LM609 (P=0.001), but to much less an extent. The migration SMCs from a culture found not to express the alpha(v)beta(3) integrin was unaffected by these antibodies, strengthening the argument that c7E3 Fab inhibits SMC function via this integrin. CONCLUSIONS: c7E3 Fab inhibits the adhesion and migration of SMCs via the alpha(v)beta(3) integrin. The inhibition, however, is partial, and varied depending on type of ECM protein and alpha(v)beta(3) integrin expression. Some of the clinical benefits of c7E3 Fab may be due to its effect on SMCs.

Abciximab↗
PubMed2000

Effect of vitamin E supplementation on circulating cell adhesion molecules pre- and post-coronary angioplasty.

The soluble adhesion molecules P-selectin (sP-selectin) and intercellular adhesion molecule-1 (sICAM-1) are derived from platelets and endothelial cells. Circulating concentrations of these soluble adhesion molecules are raised in patients with atherosclerosis and following percutaneous transluminal coronary angioplasty (PTCA). We have investigated the effects of vitamin E supplements (800 IU/day) on circulating plasma ICAM-1 and P-selectin levels pre- and post-PTCA. Patients, randomized to group, were pre-treated with vitamin E or placebo (soybean oil) for 1 month before routine PTCA. Plasma sICAM-1 and sP-selectin were measured by enzyme-linked immunosorbent assay on blood taken immediately pre- and post-PTCA. Total protein and alpha-tocopherol were measured on the same samples. Plasma alpha-tocopherol concentrations increased in patients receiving vitamin E: 19.1 (1.5) [mean (standard error of the mean, SEM)] mg/mL post-PTCA versus 13.9 (0.6) mg/mL pre-PTCA (n=23; P<0.01). Plasma sP-selectin and sICAM-1 levels were not significantly increased following PTCA in the vitamin E group. Pre-angioplasty mean (SEM) plasma sP-selectin concentration in the vitamin E group was 8.83 (0.97) ng/mg protein; the corresponding mean post-angioplasty value was 9.34 (0.89) ng/mg protein (P=0.85). The mean (SEM) pre-angioplasty sICAM-1 concentration in this group was 2.18 (0.24) ng/mg protein, and was 2.20 (0.23) ng/mg protein following angioplasty (P = 0.84). In the placebo group (n = 24) there was a significant increase in mean (SEM) sP-selectin concentration following angioplasty, from 7.48 (0.73) to 9.70 (0.78) ng/mg protein (P<0.05). The change (mean, SEM) in plasma sP-selectin concentration following angioplasty was significantly greater for the placebo group [2.22 (0.50) ng/mg protein] than for the group receiving vitamin E [0.50 (0.50) ng/mg protein] (P<0.02). This difference remained significant (P<0.05) even after adjustment for pre-angioplasty P-selectin concentrations. Mean (SEM) plasma sICAM-1 concentrations remained unchanged following angioplasty [pre-angioplasty: 2.16 (0.20) ng/mg protein; post-angioplasty: 1.97 (0.13) ng/mg protein]. Vitamin E may therefore limit platelet or endothelial activation during PTCA.

Adult↗