Management of patients at risk of adrenal crisis in the dental setting: a review of current practice in UK dental teaching hospitals.

Introduction Patients with impaired corticosteroid response due to Addison's disease or systemic glucocorticoid use are at risk of adrenal crisis when undergoing dental treatment. There is a lack of conclusive evidence to support dental teams in identifying patients at risk and their management to prevent an adrenal crisis.Aim To review the current practice in UK dental teaching hospitals regarding the management of patients at risk of adrenal crisis in the dental setting.Methods An electronic survey focused on patients who may be at risk of adrenal crisis due to systemic glucocorticoid therapy was sent to all 18 UK dental teaching hospitals. Information on the use of a policy or guidance was requested. Responses were evaluated for clinical decision-making, patient risk assessment and steroid cover dosing regimens.Results A 78% response rate was achieved. Only 29% of institutions had a written policy or guidance document. Variation exists in the threshold of steroid dose and duration of treatment in identifying patients at risk of adrenal suppression. Furthermore, the dose regime for steroid cover varied.Conclusion Further evidence on the management of patients at risk of adrenal crisis is required to inform national guidance and reduce variation in patient management.

'The principles of a future pharmacology': Johann Christian Reil (1759-1813) and his role in the development of clinical pharmacology.

AIM: Johann Christian Reil was an eighteenth-century German physician and clinical academic with wide interests. These included building the scientific foundations of modern medical practice. In 1799, he published a work specifically calling for a scientific approach to pharmacology in medical practice. In this paper, I aim to present the key parts of that work for the first time in English translation. METHODS: Reil's 1799 work was translated into English and evaluated against current standards of practice in clinical pharmacology to highlight his 'modern' approach to our subject. RESULTS: Reil defines pharmacology and presents a series of eight rules or principles that should be followed by those wishing to evaluate drugs in humans. These rules highlight the need for scientific rigour, including the use of multiple controlled experiments, and call for the introduction of a specialized vocabulary to facilitate the exchange of ideas between pharmacological researchers. CONCLUSIONS: Although rarely mentioned in the pharmacological literature today, Reil's work in the late eighteenth century is an important precursor of our modern approach to the evaluation and testing of drugs in clinical practice. This English translation of the key sections of his work may now allow others to properly evaluate his contribution.

Effect of atorvastatin on circulating hsCRP concentrations: a sub-study of the achieve cholesterol targets fast with atorvastatin stratified titration (ACTFAST) study.

BACKGROUND: Elevated C-reactive protein (CRP) concentration is a risk factor for cardiovascular events that may add prognostic information. Statin treatment is associated with significant reductions in CRP concentrations, which appear to be unrelated to the magnitude of LDL-cholesterol reduction. We investigated the effect of atorvastatin, across its dose range, on high sensitivity (hs)CRP in subjects at high cardiovascular risk. METHODS: ACTFAST was a 12 week, prospective, multicenter, open-label trial in which high-risk subjects were assigned a starting dose of atorvastatin (10, 20, 40 or 80 mg/d) based on LDL-C and status of statin use at screening (1345 statin-free [SF] and 772 previously statin-treated [ST]). RESULTS: At baseline, ST subjects had significantly lower hsCRP levels than SF subjects (ST group 2.31, 95% CI 2.15, 2.48 mg/L vs. SF group 3.16, 95% CI 2.98, 3.34 mg/L, p<0.05). In the SF group, atorvastatin 10 to 80 mg significantly (p<0.01) reduced hsCRP levels in a dose dependent-manner. In ST group, additional hsCRP reductions were observed over the statin used at baseline, which were not dose-dependent. Atorvastatin significantly decreased hsCRP concentrations in subjects with or without diabetes or the metabolic syndrome. CONCLUSIONS: Atorvastatin treatment at different doses, particularly 80 mg, significantly reduced hsCRP serum concentrations. This reduction was observed in both SF and ST groups and was independent of the presence of metabolic syndrome and/or diabetes. The beneficial effect of atorvastatin was evident at 6 weeks, supporting the practice of early introduction of higher doses of atorvastatin in high-risk patients.

Dynamic regulation of the endocannabinoid system: implications for analgesia.

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study.

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study.

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

A multicentre, open study to assess the effect of individualizing starting doses of atorvastatin according to baseline LDL-C levels on achieving cholesterol targets: the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST-2) study.

OBJECTIVES: ACTFAST-2 was designed to match the starting dose of a statin to the baseline low density lipoprotein-cholesterol (LDL-C) value, to allow high-risk European subjects to achieve LDL-C targets within 12 weeks with the initial dose or one up-titration. RESEARCH DESIGN AND METHODS: This was a 12-week, prospective, open-label trial that enrolled 610 high-risk subjects from 8 European countries. Subjects with LDL-C > 2.6 mmol/L (> 100 mg/dL), but < or = 5.7 mmol/L (< or = 220 mg/dL) were assigned a starting dose of atorvastatin (10, 20, 40, 80 mg/day) according to LDL-C level and status of statin use at baseline (either statin-free or statin-treated), with a single up-titration at 6 weeks if needed. RESULTS: At 12 weeks, 68.0% of subjects overall, including 73.5% of statin-free and 60.5% of statin-treated subjects, achieved LDL-C target (< 2.6 mmol/L (< 100 mg/dL). The total cholesterol/high density lipoprotein-cholesterol (TC/HDL-C) ratio target was achieved by 75.2% of subjects overall, including 78.1% of statin-free and 71.2% of statin-treated subjects. In the statin-free group, LDL-C decreased by a mean of 42%. In the statin-treated group, atorvastatin led to an additional 31% reduction in LDL-C over the statin used at baseline. Mean decreases in TC/HDL-C ratio were 30% and 20% in the statin-free and statin-treated groups, respectively. The incidence of AST/ALT greater than 3 times of upper limit of normal range in all patients was 0.8% and no rhabdomyolysis was reported. CONCLUSION: This study confirms that use of a flexible starting dose of atorvastatin allows the large majority of high-risk subjects to achieve their LDL-C target safely within 12 weeks with an initial dose or just a single up-titration.

Genetic variation in the interleukin-10 gene promoter and risk of coronary and cerebrovascular events: the PROSPER study.

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, -1082GA, -592CA, and -2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the -592A variant allele) and risk of coronary events (P = 0.019). Moreover, analysis of separate SNPs found a significant association between -2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04-2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role.

Effect of individualizing starting doses of a statin according to baseline LDL-cholesterol levels on achieving cholesterol targets: the achieve cholesterol targets fast with atorvastatin stratified titration (ACTFAST) study.

AIMS: To investigate whether selecting the starting dose of atorvastatin according to baseline and target (<2.6 mmol/L) LDL-cholesterol (LDL-C) values would allow high-risk subjects to achieve target LDL-C concentration within 12 weeks, with the initial dose or a single uptitration. METHODS AND RESULTS: Twelve-week, prospective, open-label trial that enrolled 2117 high-risk subjects (statin-free [SF] or statin-treated [ST]). Subjects with LDL-C >2.6 mmol/L (100mg/dL) but

The care gap: underuse of statin therapy in the elderly.

Atherosclerotic diseases are responsible for the majority of deaths in the elderly, and they can also increase the risk of disability. Statins are first-line therapies for lowering lipid levels and have been shown to reduce the risk of cardiovascular events in large-scale clinical trials. There is a growing body of evidence that statins are as efficacious at lowering lipid levels and reducing the risk of coronary heart disease (CHD) in elderly patients as in younger individuals. Furthermore, as this population is at a greater absolute risk of CHD, they may receive greater absolute benefits from treatment. However, despite these benefits, many elderly individuals at risk of CHD and stroke are not receiving adequate lipid-lowering therapy, which could help them to maintain their health and independence. Further, prospective randomised trials are required to guide physicians in the treatment of elderly patients at risk of atherosclerotic disease, thereby resolving the current undertreatment.

Are we negating the benefits of CABG by forgetting secondary prevention?

UNLABELLED: The objective of the study was to examine medically managed secondary prevention at one year after coronary artery bypass grafting (CABG). In all, 214 consecutive patients undergoing isolated elective CABG seen four weeks preoperatively and one year post-operatively. Preoperative systolic blood pressure averaged 135+/-20 mmHg, which increased to 148+/-25 mmHg (P<0.0001) as did diastolic pressure (81+/-12 to 87+/-13 mmHg; P<0.0001). Anginal symptoms were reported by 45.1% (P<0.0001) although median severity scored lower (4.0 [3.0-5.4] vs 0 [0-2.0]; P<0.0001). Breathlessness decreased from 93% to 64% (P<0.0001) and was scored less severely (4.0 [2.0-5.0] vs 2.0 [0-4.0]; P<0.0001. In all, 88% with postoperative angina reported dyspnoea against 44% of those without (P<0.0001). Calcium antagonist use was more common in patients with angina (27.2% vs 5.1%; P<0.0001), but not nitrates (P=0.8695), diuretics (P=0.4218), digoxin (P=0.2565), beta-blockers (P=0.0820), or ACE inhibitors (P=0.7256). Preoperatively 166 patients (80.2%) took aspirin vs 69.2% afterwards (P=0.0131). Twelve patients (6.5%) received warfarin after operation vs none preoperatively. Two took digoxin (0.97%) preoperatively and 14 (7.7%) postoperatively (P=0.001) for chronic atrial fibrillation. One of these took warfarin. Long-acting nitrate use fell from 63.4% to 15.8% (P <0.0001). Short-acting nitrate use fell similarly (P<0.0001). Preoperatively 37 patients (17.9%) took ACE inhibitors vs 44 postoperatively (24.2%); 39 had not received them before. Preoperatively 48 (23.2%) took diuretics vs 30 (16.5%) postoperatively (P=0.127); 24 had not previously taken diuretics. More patients took HMGCoA inhibitors postoperatively (P=0.0068) and total cholesterol was significantly reduced with a concomitant increase in HDL fraction. Smoking habit was virtually unchanged from 17.8% to 15.1% (P=0.5023). IN CONCLUSION: angina was common. Apart from statin prescribing, postoperative secondary prevention measures were poorly applied, less widespread and less effective than preoperatively. The implications are disturbing.

The anatomy of a clinical trial. The West of Scotland Coronary Prevention Study.

OBJECTIVE: Treatment of hyperlipidemia to reduce the risk of ischemic heart disease was, prior to the statin era, disappointingly limited in its ability to yield the benefits expected from the strong relationship known to exist between serum cholesterol and coronary death. Three primary prevention trials, using clofibrate, cholestyramine and gemfibrozil, had achieved modest reductions in fatal and nonfatal coronary events but none was able to extend life overall or even to reduce cardiovascular mortality; and combined analyses of the three raised disquiet over potential links between cholesterol reduction, cancer and aggressive or violent behaviour. The time was therefore ripe to determine whether statins could help prevent that first and all important myocardial infarction. METHODS: The West of Scotland Coronary Prevention Study recruited 6,595 45- to 64-year-old men with no history of prior myocardial infarction and with low-density lipoprotein cholesterol in the range 4-6 mmol/l (155-232 mg/dl). Subjects who had undergone coronary revascularisation or had been hospitalised for angina pectoris in the previous 12 months were excluded, as were those with significant electrocardiographic abnormalities. Participants were randomised to receive pravastatin 40 mg/day or matching placebo and were followed for an average of 4.9 years. RESULTS: Treatment with pravastatin reduced the combined risk of fatal and nonfatal myocardial infarction by 31%. Cardiovascular death overall fell by 32% and the need for coronary revascularisation procedures was reduced by 37%. All of these endpoint benefits were statistically significant. Because there was no increase in non-cardiovascular mortality, the reduction in death from any cause also proved to be statistically significant (p = 0.051 by log rank test and p = 0.037 after adjustment for baseline risk factors). CONCLUSIONS: The West of Scotland Coronary Prevention Study is the first to show that cholesterol reduction with pravastatin helps avoid the first myocardial infarction, reduces coronary mortality and extends life. Ongoing exploration of the study database continues to unearth additional surprisingly beneficial effects of the treatment and permits authoritative decision-making on the effective use of lipid-lowering drugs.

Testing cognitive function in elderly populations: the PROSPER study. PROspective Study of Pravastatin in the Elderly at Risk.

OBJECTIVES: For large scale follow up studies with non-demented patients in which cognition is an endpoint, there is a need for short, inexpensive, sensitive, and reliable neuropsychological tests that are suitable for repeated measurements. The commonly used Mini-Mental-State-Examination fulfils only the first two requirements. METHODS: In the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), 5804 elderly subjects aged 70 to 82 years were examined using a learning test (memory), a coding test (general speed), and a short version of the Stroop test (attention). Data presented here were collected at dual baseline, before randomisation for active treatment. RESULTS: The tests proved to be reliable (with test/retest reliabilities ranging from acceptable (r=0.63) to high (r=0.88) and sensitive to detect small differences in subjects from different age categories. All tests showed significant practice effects: performance increased from the first measurement to the first follow up after two weeks. CONCLUSION: Normative data are provided that can be used for one time neuropsychological testing as well as for assessing individual and group change. Methods for analysing cognitive change are proposed.

Primary prevention: a simple, effective means of risk reduction.

Individuals without overt coronary heart disease (CHD) may nevertheless be at significant risk for future CHD events based on lipid and other risk factors. Recognition of this fact is reflected in the inclusion of measures of global risk in current CHD prevention guidelines. Given the fact that many patients in the primary prevention setting fail to achieve target lipid levels, simplicity of treatment can be considered to be of great importance. Drug treatment that can improve achievement of low-density lipoprotein cholesterol (LDL-C) targets and produce beneficial effects on other lipid risk factors at starting doses would be of considerable utility in this setting. A new statin, rosuvastatin, has been shown to produce greater reductions in LDL-C and to permit more patients to reach target levels than currently available statins, and has also demonstrated favorable effects on other lipid variables. Rosuvastatin may thus be a prime candidate for use in clinical practice to achieve the lipid goals recommended in guidelines for primary prevention of CHD.

Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS).

BACKGROUND: Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity. Therefore, we hypothesized that raised leptin levels may identify men at increased risk of a coronary event in the West of Scotland Coronary Prevention Study (WOSCOPS). Methods and Results- Plasma leptin levels were measured at baseline in 377 men (cases) who subsequently experienced a coronary event and in 783 men (controls) who remained free of an event during the 5-year follow-up period of the study. Controls were matched to cases on the basis of age and smoking history and were representative of the entire WOSCOPS cohort. Leptin levels were significantly higher in cases than controls (5.87+/-2.04 ng/mL versus 5.04+/-2.09 ng/mL, P<0.001). In univariate analysis, for each 1 SD increase in leptin, the relative risk (RR) of an event increased by 1.25 (95% confidence interval [CI], 1.10 to 1.43; P<0.001). There was minimal change in this RR with correction for body mass index (RR, 1.24; 95% CI, 1.06 to 1.45; P=0.006) or with further correction for classic risk factors, including age, lipids, and systolic blood pressure (RR, 1.20; 95% CI, 1.02 to 1.42; P=0.03). Leptin correlated with C-reactive protein (r=0.24, P<0.001) and, even with this variable added to the model, leptin retained significance as a predictor of coronary events (RR, 1.18; 95% CI, 1.00 to 1.39; P=0.05) at the expense of C-reactive protein. CONCLUSIONS: We show, for the first time, in a large prospective study that leptin is a novel, independent risk factor for coronary heart disease.

Statins--similarities and differences.

The number of statins available to physicians continues to grow, leading to the question: Are all statins alike? Comparisons of side effects and safety profiles and the dose-response relationship among the different drugs show similar results. The cholesterol-lowering action of each depends on its ability to lower low-density lipoprotein cholesterol (LDL-C). On the other hand, the molecular structures of the newer statins are not similar and could have an effect on the mechanism of action of the compounds. Differences in metabolism also suggest the possibility of serious drug-drug interactions, and differences in levels of lipid reduction at varying dosages among the statins point to clinical variation as well.

Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.

BACKGROUND: We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. METHODS AND RESULTS: Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of >/=7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of >/=7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. CONCLUSIONS: We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P:=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Simvastatin: building on success.

Over a decade after launch, simvastatin remains the most widely-prescribed statin in the UK. This has resulted from a growing body of long-term outcome data, a steadily expanded range of indications, an extended dose range and proven cost-efficacy.

Parathyroid hormone potentiates nucleotide-induced [Ca2+]i release in rat osteoblasts independently of Gq activation or cyclic monophosphate accumulation. A mechanism for localizing systemic responses in bone.

The regulation of tissue turnover requires the coordinated activity of both local and systemic factors. Nucleotides exist transiently in the extracellular environment, where they serve as ligands to P2 receptors. Here we report that the localized release of these nucleotides can sensitize osteoblasts to the activity of systemic factors. We have investigated the ability of parathyroid hormone (PTH), a principal regulator of bone resorption and formation, to potentiate signals arising from nucleotide stimulation of UMR-106 clonal rat osteoblasts. PTH receptor activation alone did not lead to [Ca(2+)](i) elevation in these cells, indicating no G(q) coupling, however, activation of G(q)-coupled P2Y(1) receptors resulted in characteristic [Ca(2+)](i) release. PTH potentiated this nucleotide-induced Ca(2+) release, independently of Ca(2+) influx. PTH-(1-31), which activates only G(s), mimicked the actions of PTH-(1-34), whereas PTH-(3-34), which only activates G(q), was unable to potentiate nucleotide-induced [Ca(2+)](i) release. Despite this coupling of the PTHR to G(s), cAMP accumulation or protein kinase A activation did not contribute to the potentiation. 3-Isobutyl-1-methylxanthine, but not forskolin effectively potentiated nucleotide-induced [Ca(2+)](i) release, however, further experiments proved that cyclic monophosphates were not involved in the potentiation mechanism. Costimulation of UMR-106 cells with P2Y(1) agonists and PTH led to increased levels of cAMP response element-binding protein phosphorylation and a synergistic effect was observed on endogenous c-fos gene expression following costimulation. In fact the calcium responsive Ca/cAMP response element of the c-fos promoter alone was effective at driving this synergistic gene expression. These findings demonstrate that nucleotides can provide a targeted response to systemic factors, such as PTH, and have important implications for PTH-induced signaling in bone.