Lifestyle or life-saving medicines? A primary healthcare professional and consumer opinion survey on over-the-counter statins.

BACKGROUND: Over-the-counter (OTC) simvastatin 10 mg became available in the UK in July 2004 with the aim of improving primary prevention of ischemic heart disease. OBJECTIVE: To document the views of the main stakeholders (general practitioners [GPs], community pharmacists, and consumers) on issues pertaining to the reclassification of simvastatin to OTC availability, highlight differences between stakeholder groups, and identify factors likely to influence consumer behavior. METHODS: A self-administered questionnaire survey of GPs, community pharmacists, and potentially eligible consumers was carried out 8 months after the UK launch of OTC simvastatin. Participants were asked about their awareness of the drug, their willingness to use such medicines, and their views on relevant management practices. RESULTS: Awareness of OTC simvastatin was high among GPs but limited among consumers. Although OTC availability was favored by pharmacists, consumers and GPs generally thought it was not a good idea. GPs and pharmacists cited increased consumer choice as the most important likely benefit; consumers thought potential savings to the National Health Service were equally important. Medication misuse and neglect of lifestyle risk factors were unanimously considered to be the most important likely risks. Unlike the majority of pharmacists, most GPs thought that current dosing guidelines were inappropriate, but there was consensus that long-term nonadherence would probably curtail any treatment benefit. Most respondents agreed that GPs should be informed if their patients were using OTC statins but disagreed as to the best way to communicate this information. CONCLUSIONS: OTC availability of statins did not appear to be considered a popular public health intervention by consumers and GPs, as the drugs were widely perceived as being prone to misuse. However, OTC availability was favored by pharmacists, who saw this as empowering both for consumers and themselves. Key issues in dispensing, managing, and evaluating the public health impact of this intervention remain outstanding.

Three's company: regulation of cell fate by statins.

Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (statins), the rate-limiting enzyme of the mevalonate biosynthetic pathway, are currently the leading prescription drugs worldwide. Programmed cell death (apoptosis) is a powerful physiological regulator of cellular development, function and dynamics. Statins are known to induce cellular apoptosis in vitro; however, the clinical relevance of this action remains controversial. This paper draws from 15 years' worth of research to explore the impact of statin treatment on cell fate, as represented by the interlinked processes of cellular growth, differentiation and apoptosis. In particular, I outline our current understanding of the pertinent molecular mechanisms; and discuss the evidence for clinical relevance of statin-induced apoptosis.

HMG-CoA reductase inhibition aborts functional differentiation and triggers apoptosis in cultured primary human monocytes: a potential mechanism of statin-mediated vasculoprotection.

BACKGROUND: Statins effectively lower blood cholesterol and the risk of cardiovascular death. Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds. Since macrophages participate in several vascular pathologies, we examined the effect of statin treatment on the survival and differentiation of primary human monocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy individuals were cultured in the presence or absence of mevastatin. Apoptosis was monitored by annexin V / PI staining and flow cytometry. In parallel experiments, cultures were stimulated with LPS in the presence or absence of mevastatin and the release of IL-1beta and IL-1Ra was measured by ELISA. RESULTS: Among PBMCs, mevastatin-treated monocytes were particularly susceptible to apoptosis, which occurred at doses >1 microM and was already maximal at 5 microM. However, even at the highest mevastatin dose used (10 microM), apoptosis occurred only after 24 h of culture, possibly reflecting a requirement for cell commitment to differentiation. After 72 h of treatment the vast majority (>50%) of monocytes were undergoing apoptosis. Stimulation with LPS revealed that mevastatin-treated monocytes retained the high IL-1beta output characteristic of undifferentiated cells; conversely, IL-1Ra release was inhibited. Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation. CONCLUSIONS: Our findings indicate that statins arrest the functional differentiation of monocytes into macrophages and steer these cells into apoptosis, suggesting a novel mechanism for the vasculoprotective properties of HMG-CoA reductase inhibitors.

Synergistic suppression of rat neointimal hyperplasia by rapamycin and imatinib mesylate: implications for the prevention of accelerated arteriosclerosis.

BACKGROUND: Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia. METHODS: Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV. RESULTS: Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5-1.5 mg/kg/day) or imatinib (2- 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance. CONCLUSIONS: Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.

A mouse model of aortic angioplasty for genomic studies of neointimal hyperplasia.

We describe here a mouse model of diffuse aortic remodelling triggered by combined endothelial denudation/vascular distension injury using a novel balloon microcatheter. We validated this model in both outbred (NMRI) and inbred (BALB/c, C57BL/6) mouse strains and found evidence for differential strain susceptibility to neointimal hyperplasia, possibly attributable to genetic factors. Neointimal lesions were approximately 50% smaller in the inbred strains, a finding associated with profound cell loss in the aortic media at the early stages of the response to injury. A further insight from this model suggests an essential role for platelets in the initiation of neointimal hyperplasia, which apparently progresses through monocyte influx from the peripheral circulation. Our findings are consistent with monocyte recruitment driving neointimal growth, a minority expressing the endothelial cell marker FVIII. Overall, the time course and gross histological features of vascular remodelling seen here resemble those seen in other rodent models. However, this new mouse model offers distinct advantages over existing ones in that it involves the actual use of a catheter in a clinical manner, and because it allows the recovery of intact RNA from injured vessels in sufficient quantities for downstream molecular analyses.

Interleukin 1 and chronic rejection: possible genetic links in human heart allografts.

Chronic rejection is a leading cause of graft loss in thoracic transplant recipients. Studies on the pathogenesis of chronic rejection have suggested a contributory role for certain cytokines and growth factors. The activity of these mediators is subject to genetic variation if a polymorphism alters expression, or function, of the ligand or its receptor. Here we have asked if certain cytokine and growth factor gene polymorphisms correlate with chronic rejection in recipients of thoracic allografts. In a retrospective analysis of 179 recipients of thoracic organ transplants (128 heart; 36 heart-lung; and 15 lung), polymorphisms in 8 genes that influence the inflammatory process, namely IL1B, IL1R1, IL1RN, IL6, IL10, TNFA, TGFB1 and FCGRIIA, were examined. Genotypic data from recipients who had either died or been re-transplanted as a result of chronic rejection (n = 96) were then compared to those of recipients who had a functioning graft for more than 11 years (n=83). In the heart graft recipients, only those polymorphisms that influenced expression of the IL1 receptor antagonist gene had a significant correlation with graft survival, with homozygosity for the IL1RN*1 allele being associated with rejection. The alternative, less frequent IL1RN alleles emerged as genomic predictors of long-term allograft survival. This association was especially strong when IL1 region haplotypes were considered, particularly when analysis was confined to heart transplant recipients who had had multiple acute rejection episodes (OR>20). This case-control study indicates that gene polymorphisms which influence IL1 bioactivity also influence the progression of chronic rejection in heart grafts.