International journal of clinical practice. Supplement最新文献

Enquiries about the management of patients possibly suffering from ibuprofen overdose account for over 5% of the total enquiry workload of the London Centre of the United Kingdom National Poisons Information Service. Unlike overdose with aspirin and paracetamol, no additional pathophysiological findings have been reported in ibuprofen overdose and all the demonstrated toxic effects relate to its known pharmacological actions and the effects of accumulation of the two acidic metabolites, 2-hydroxyibuprofen and 2-carboxylibuprofen. The most striking finding in reported cases is that the great majority of patients suffer no or only mild symptoms. In one series of 1,033 enquiries involving ingestion of ibuprofen alone, 705 (65%) patients were asymptomatic; 199 (18%) experienced mild symptoms; and 23 (2%) experienced moderate symptoms. We are aware of only seven case reports of fatal overdose with ibuprofen and in each case there are complicating factors related to other drugs and/or other disease processes. The management of ibuprofen overdose is generally straightforward and can be related to the dose ingested. Initial findings suggest even less evidence for toxicity associated with modified release formulations than with the conventional tablets. There is at present no reason to be concerned that co-ingestion of ethanol increases the risk of toxicity from ibuprofen overdose. Ibuprofen overdose is common but serious toxic effects are unusual and guidelines for treatment are straightforward.

Key elements of the metabolic syndrome include the development of insulin resistance, glucose intolerance, dyslipidaemia and hypertension, which lead to multiple effects on lipoprotein metabolism and vascular functions and, ultimately an increased risk of cardiovascular disease. There are probably multiple presentations of the metabolic syndrome, and these depend on the interplay of genetic variation and environmental factors. In particular, polymorphisms in genes that are expressed in adipose tissue may play a crucial role in the development of the metabolic syndrome. Elucidation of the aetiology of metabolic syndrome(s) will therefore play an important role in developing strategies to reduce adverse outcome. It is probable that pharmacological therapy will be needed for many patients with the metabolic syndrome to help reduce the risk of future cardiovascular events.

Over the past ten years it has become clear that cardiovascular disease (CVD) and atherosclerosis have a 'microinflammatory' component and are often associated with low levels of inflammatory markers that are in the upper part of the 'normal' range. In particular, diseases that predispose to CVD, such as the metabolic syndrome and type 2 diabetes, appear to have a very strong inflammatory component. While the inflammatory process is very complicated, single measures, such as C-reactive protein (CRP) or fibrinogen, have clear benefits as they summarise many different parts of the inflammatory process and are easy to apply. However, it is important to remember that the process of inflammation includes coagulation, fibrinolysis, complement activation, antioxidation, immune response and hormonal regulation through the hypothalamic-pituitary-adrenal axis. Furthermore, genetic variation, differences in exposure to environmental influences and the mass of inflammation-producing tissue (e.g. adipose tissue) can all influence responses. Thus, the relationship between atherosclerosis, the metabolic syndrome and inflammation is extraordinarily complex. Inflammatory markers such as CRP exhibit strong CVD-risk prediction that is consistent across sexes and a number of different populations. They reflect risk not only for 'vulnerable plaque' and myocardial infarction (MI) but also for other cardiovascular diseases. In fact, inflammation is associated with several, if not all, of the chronic diseases of old age, and it is now clear that there are important links between inflammation and general metabolism. For instance, visceral adiposity exerts a major influence on inflammation status. Medications that affect atherosclerosis appear to do so at least in part by influencing inflammation (for instance, the emerging pleiotropic effects of statins), and this has far-reaching ramifications for chronic diseases of old age and their treatment.

Augmented release of non-esterified fatty acids (NEFA) from insulin-resistant adipocytes appears to be the main cause of the 'atherogenic lipoprotein profile' associated with insulin resistance and type 2 diabetes. This atherogenic profile is characterised by large very-low-density lipoproteins (VLDL), small, dense low-density lipoproteins (LDL) and low levels of high-density lipoproteins (HDL), resulting in deposition of apo B lipoproteins in the vascular intima and subsequent inhibition of reverse cholesterol transport. This lipoprotein retention also results in a proinflammatory response from the vascular endothelium, which is increased in insulin resistance. Thus the ideal therapy for insulin resistance, and its complications, should both improve its associated dyslipidaemia and ameliorate the vascular atherogenic reaction. Some peroxisome proliferator-activated receptor (PPAR)-gamma and dual PPARalpha/gamma agonists improve insulin resistance and its dyslipidaemia, both in rodents and man, while in animal models they can show clear antiatherosclerotic effects. Nonetheless, it is difficult to evaluate how much of these antiatherosclerotic actions are caused by effects on the dyslipidaemia or by direct effects on vascular cells. Upregulation of PPARgamma and PPARalpha/gamma activity in macrophages can reduce secretion of proinflammatory cytokines and matrix metalloproteases, as well as increase HDL-mediated cholesterol efflux transport--all potentially antiatherosclerotic results. In addition, treatment of smooth muscle cells with PPARgamma agonists can partially revert possible atherogenic changes in the production of matrix proteoglycans induced by exposure to NEFA. Although these findings are still preliminary, and their relevance to human atherosclerosis has not been fully elaborated, these results suggest that improved PPARalpha/gamma agonism may positively modulate several of the metabolic steps connecting insulin resistance with dyslipidaemia and with the atherogenic response.

The worldwide epidemic of obesity is being mirrored in worldwide epidemics of metabolic syndrome and of type 2 diabetes. The theme of the 2002 Future Forum conference is that these conditions are a certainty, given that the changing worldwide environment requires less physical activity for daily living and assures an abundant, energy-dense food supply at all times. This paper focuses on the roles of physical activity and weight reduction in reducing the risk for development of type 2 diabetes and the metabolic syndrome. The mechanisms by which obesity and detraining lead to insulin resistance and type 2 diabetes are discussed and, conversely, the mechanisms by which insulin resistance might be reversed by physical activity are addressed. Finally, the evidence from recent randomised clinical trials is reviewed. The Finnish Diabetes Prevention Study and the Diabetes Prevention Program in the USA both demonstrate that lifestyle change can significantly reduce the risk of development of type 2 diabetes in individuals with impaired glucose tolerance. Furthermore, these studies demonstrate that modest weight change and achievable physical activity goals can translate into significant risk reduction. Societies cannot afford to ignore the evidence of health benefit associated with physical activity and healthy weight in favour of medicating when morbidities develop. For a successful public health approach to chronic disease prevention, we cannot rely completely on pharmaceuticals, but must implement environmental changes to encourage healthy lifestyles.

Obese patients with the metabolic syndrome generally have a visceral (apple-shaped) fat distribution and are at an increased risk of macrovascular disease, while those with peripheral (pear-shaped) obesity tend not to have metabolic abnormalities and are at less risk. This difference appears to be related to the differing metabolic functions (and secretory products) of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), as well as the fact that VAT drains directly into the liver. Thus, it appears that increased VAT, but not SAT, is associated with both hepatic and peripheral biochemical abnormalities leading to insulin resistance and the associated metabolic syndrome. Insulin resistance is associated with VAT products, such as free fatty acids and their metabolites, as well as cytokines, such as tumour necrosis factor alpha (TNF-alpha). These factors may activate components of the inflammatory pathway such as nuclear factor kappa-B (NFkappaB), and inhibit insulin signalling. Insulin resistance is further associated with decreased levels of another tissue product, adiponectin. The incidence and prevalence of obesity is increasing at an unprecedented rate. The classic treatment of obesity is weight loss via lifestyle modification. However, prevention of obesity comorbidity can also be achieved by modifying the mechanisms by which obesity causes these comorbid conditions. For instance, it is now known that the peroxisome proliferator-activated receptor (PPAR) family of transcriptional regulators are crucial in regulating adipose tissue development and metabolism; this helps explain why compounds with PPARgamma agonist activity, e.g. thiazolidinediones, increase insulin action through their effects in regulating adipose tissue metabolism.

Several landmark clinical trials have demonstrated the benefit of lipid-lowering with statins for the primary and secondary prevention of coronary heart disease. The clinical data in support of lowering cholesterol by statins are unequivocal. The established mechanism of action is via sterol regulatory element binding protein (SREBP) activation due to reduced hepatic cholesterol synthesis and secondary upregulation of the low-density lipoprotein (LDL)-receptor, leading to enhanced clearance of circulating cholesterol and lipids. Although it is widely accepted that most clinical benefit obtained with statins is a direct result of their lipid-lowering properties, there is still some debate as to whether the so-called 'pleiotropic effects' of statins contribute to the clinical outcome in vascular disease, or whether all the beneficial effects of statins are simply due to lipid-lowering. For example, these agents appear to display additional cholesterol-independent effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Thus, further studies are needed to understand the full impact of statin therapy on each of these processes and whether these effects contribute to the clinical benefits of statins in acute coronary syndromes and stroke.

For most patients who require lipid-lowering treatment, statin monotherapy is the appropriate treatment. However, in those patients where statin monotherapy does not produce optimal lipid levels, the combination of a statin with niacin, a bile acid sequestrant, a fibric acid derivative, a cholesterol absorption inhibitor or a fish oil preparation may provide improved control. The choice of combination therapy depends upon the patient's lipid profile and tolerability of the medication. Combination of a statin with niacin, a bile acid sequestrant or ezetimibe, a cholesterol absorption inhibitor, should be considered for patients with very high low-density lipoprotein cholesterol (LDL-C) levels, while combination with either a fibric acid derivative or a fish oil should be considered for patients with high LDL-C and high triglyceride levels. A number of new lipid-lowering agents are currently in development, including cholesteryl ester transfer protein (CETP) inhibitors, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, ileal bile acid transport (IBAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors and dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonists. Introduction of these novel therapies will provide opportunities for developing different combination strategies that may help to optimise lipid profiles in patients who are currently difficult to treat. The introduction of new combinations will require careful study to ensure that the risks of drug interactions and adverse events are minimised.

Buprenorphine, a powerful opioid, is newly available for delivery in a transdermal formulation. The transdermal system's matrix patch provides rate-controlled administration of the drug. Three double-blind, placebo-controlled trials were conducted to evaluate efficacy and tolerability of the buprenorphine transdermal system (buprenorphine TDS, Transtec). A total of 445 patients were enrolled in the studies. All suffered from moderate to severe and very severe pain, both cancer- or non-cancer-related. The percentage of responders increased as the rate of buprenorphine delivered by the transdermal system rose, ranging from a 29% (cancer) and 36% (non-cancer) response rate associated with the lowest dose (35 microg/h), to 40% (cancer) and 46% (non-cancer) with the highest dose (70 microg/h). Patients receiving buprenorphine TDS slept longer, uninterrupted by pain, than patients from the placebo group. Systemic adverse effects reported in the drug cohorts included nausea, vomiting and dizziness, and were typical of those reported in other studies of opioids; local adverse events, most commonly erythema and pruritus, were transient and mild to moderate. In an open-label, follow-up trial, in which 239 patients from the original clinical studies participated, 90% of patients reported that their analgesia was satisfactory or even better over a mean duration of 4.7 months; nearly 95% of patients found the patch to be user-friendly. The new buprenorphine TDS appears to be an important new modality for administering analgesia in patients with non-acute pain.

In Germany and many other countries, buprenorphine has been used for a long time for the management of pain in both cancer and non-cancer patients. Although a transdermal delivery system for buprenorphine (Transtec) has recently been introduced, the clinical experience in daily practice with this drug, delivered in a matrix patch, is only now being evaluated. In preliminary data from a survey of 3,255 patients with chronic pain, 26% had cancer pain, while the most common diagnoses of the other respondents included back pain (33%), osteoarthritis (22%), osteoporosis (17%), and neuropathic pain (10%, multiple entries). Before being switched to the buprenorphine patch, most patients had been pretreated with World Health Organization (WHO) Step II opioids (47%) or WHO Step III opioids (18%), including tramadol (in 35% of patients) and a tilidin/naloxone combination (15%); 9% had not been prescribed any opioids in advance of receiving transdermal buprenorphine. Most patients (77%) in the survey had been started on the lowest dose of the buprenorphine patch (35 microg/h), and nearly half (49%) were placed on adjuvant analgesics, including tramadol or tilidin/naloxone. Pain relief was rated as good or very good by 81% of the respondents. Adverse effects were similar to those seen on other opioids, although their intensity was mild in most cases. Local side effects, including erythema (4% of cases) and pruritus (1%), were transitory. Based on the survey results, transdermal buprenorphine is considered an effective opioid treatment for patients with stable cancer and non-cancer pain; it may prove particularly useful in patients who have experienced side effects taking oral analgesic preparations, as well as in those who are taking extensive co-medications.