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Biomedical subjects

Dimitri P Mikhailidis

Publications and source records attributed to Dimitri P Mikhailidis.

At least 37 records · Page 2Linked to original sources
PubMed2006

Combined treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a review of the current evidence.

Several studies have shown that angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are useful in the treatment of hypertension, cardiovascular disease, chronic heart failure, and some types of nephropathy. In this context, dual renin-angiotensin system blockade with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may be more effective than treatment with each agent alone. Many clinical trials have demonstrated the beneficial effect of this combined treatment on proteinuria, hypertension, heart failure, and cardiovascular events. Moreover, these studies demonstrated that dual renin-angiotensin system blockade is generally safe and well tolerated. Long-term studies are under way to confirm these effects and also investigate the effectiveness of dual renin-angiotensin system blockade on cerebrovascular disease and prevention of type 2 diabetes mellitus. These studies are expected to define the optimal use of combination treatment in everyday clinical practice. This review considers the most important clinical trials that evaluated the effect of dual renin-angiotensin system blockade on blood pressure, heart failure, and renal function.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

The effect of apolipoprotein E polymorphism on the response to lipid-lowering treatment with atorvastatin or fenofibrate.

Although the effect of apolipoprotein E gene polymorphism on the response to treatment with statins has been studied, the results are conflicting. Moreover, little is known about the possible effect of apolipoprotein E alleles on the response to treatment with fibrates. The purpose of this study was to evaluate the effect of apolipoprotein E polymorphism on lipid-lowering response to treatment with atorvastatin and fenofibrate in patients with different types of dyslipidemia. The study population included 136 patients with heterozygous familial hypercholesterolemia (type IIA dyslipidemia) treated with atorvastatin (20 mg/day) and 136 patients with either primary hypertriglyceridemia (type IV dyslipidemia) or mixed hyperlipidemia (type IIB dyslipidemia) treated with micronized fenofibrate (200 mg/day). Overall, no significant associations were detected between apolipoprotein E genotype and response to treatment with atorvastatin. In patients treated with fenofibrate, significant associations were noted between apolipoprotein E genotype and changes in apolipoprotein B, apolipoprotein E and triglyceride levels. Specifically, in apolipoprotein E2, apolipoprotein E3, and apolipoprotein E4 individuals, apolipoprotein B reductions were 22%, 17%, and 8%, respectively (P = .003); apolipoprotein E reductions were 45%, 20%, and 15%, respectively (P = .006); whereas triglyceride reductions reached 53%, 36%, and 33%, respectively (P = .033). In conclusion, apolipoprotein E genotype had no significant effect on the response to treatment with atorvastatin in patients with heterozygous familial hypercholesterolemia, but in patients with primary hypertriglyceridemia or mixed hyperlipidemia, there was a clear association between apolipoprotein E genotype and response to treatment with fenofibrate.

Adult↗
PubMed2006

Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). There is no established treatment for NAFLD. AIM: To evaluate a multifactorial intervention in the treatment of NAFLD. METHODS: A prospective, open-label, randomised study in non-diabetic patients (n = 186) with MetS (follow-up: 54 weeks). All patients had both biochemical and ultrasonographic evidence of NAFLD at baseline. Other causes of liver disease were excluded. Patients received lifestyle advice and treatment for hypertension (mainly inhibitors of the renin-angiotensin system), impaired fasting glucose (metformin), obesity (orlistat) and dyslipidaemia [randomly allocated to atorvastatin 20 mg/day (n = 63) or micronised fenofibrate 200 mg/day (n = 62) or both drugs (n = 61)]. Liver ultrasonography was assessed at baseline and at the end of the study. RESULTS: At the end of treatment, 67% of patients on atorvastatin, 42% on fenofibrate and 70% on combination treatment no longer had biochemical plus ultrasonographic evidence of NAFLD (p < 0.05 vs. baseline for all comparisons). The percentage of patients who no longer had evidence of NAFLD was significantly higher (p < 0.009) in the atorvastatin and combination groups compared with the fenofibrate group. This effect was independently related to drug treatment, as well as to reductions in high-sensitivity C-reactive protein, waist circumference, body weight, triglycerides, low-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure and glucose. Four patients discontinued treatment because of adverse effects. CONCLUSIONS: Multifactorial intervention in MetS patients with both biochemical and ultrasonographic evidence of NAFLD offsets surrogate markers of NAFLD (i.e. elevated aminotransferase plus echogenic liver).

Anti-Obesity Agents↗
PubMed2006

Treating to target patients with primary hyperlipidaemia: comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study).

OBJECTIVES: In a 24-week, open-label, randomized, parallel-group study, we compared the efficacy and metabolic effects, beyond low density lipoprotein cholesterol (LDL-C)-lowering, of atorvastatin (ATV) and rosuvastatin (RSV) in cardiovascular disease-free subjects with primary hyperlipidaemia, treated to an LDL-C target (130 mg/dL). METHODS: After a 6-week dietary lead-in period, patients were randomized to RSV 10 mg/day (n = 60) or ATV 20 mg/day (n = 60). After 6 weeks on treatment the dose of the statin was increased (to RSV 20 mg/day or ATV 40 mg/day) if the treatment goal was not achieved. A control group of healthy volunteers (n = 60) was also included for the validation of baseline serum and urinary laboratory parameters. The primary outcome was the percentage of patients reaching the LDL-C goal; secondary outcomes were changes in lipid and non-lipid metabolic parameters. RESULTS: A total of 45 patients (75.0%) in the RSV-treated group and 43 (71.7%) in the ATV-treated group achieved the treatment target at the initial dose. Both regimens were generally well tolerated and there were no withdrawals due to treatment-related serious adverse events. Similar significant reductions in total cholesterol, LDL-C, apolipoprotein (apo) B, triglycerides, apoB/apoA1 ratio, fibrinogen and high-sensitivity C-reactive protein levels were seen. RSV had a significant high density lipoprotein cholesterol (HDL-C)-raising effect and showed a trend towards increasing apoA1 levels. Glycaemic control and renal function parameters were not influenced by statin therapy. ATV, but not RSV, showed a significant hypouricaemic effect. CONCLUSIONS: RSV and ATV were equally efficacious in achieving LDL-C treatment goals in patients with primary hyperlipidaemia at the initial dose and following dose titration. RSV seems to have a significantly higher HDL-C-raising effect, while ATV lowers serum uric acid levels.

Atorvastatin↗
PubMed2006

Ezetimibe/simvastatin single tablet versus rosuvastatin in patients with hypercholesterolemia.

Recent guidelines recommend strict goals for low density lipoprotein cholesterol (LDL-C) (70-100 mg/dL; 1.8-2.6 mmol/L). These goals were set following the publication of several trials. In the current issue of the journal, a study compares different doses of the combination tablet (ezetimibe/simvastatin) with statin monotherapy (rosuvastatin). In keeping with previous literature, the combination therapy was more effective in achieving LDL-C goals. This editorial comments on the potential disadvantages of using monotherapy with high-dose statins and considers the issue of statin-induced proteinuria. Combination therapy may need to be increasingly used to achieve the LDL-C targets set by recent guidelines.

Anticholesteremic Agents↗
PubMed2006

Reaching goal in hypercholesterolaemia: dual inhibition of cholesterol synthesis and absorption with simvastatin plus ezetimibe.

Lowering serum cholesterol levels reduces the risk of coronary heart disease (CHD)-related events. Statins are commonly prescribed as first-line treatment but many patients at high-risk for CHD still fail to reach their cholesterol or low-density lipoprotein cholesterol (LDL-C) goals with statin monotherapy. National and international guidelines for the prevention of CHD recommend the modification of lipid profiles and particularly LDL-C [e.g. the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; 2001) and Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (2003) Guidelines]. Several recent clinical trials indicated an added benefit from aggressive lowering of LDL-C levels. Based on these findings, the NCEP ATP III revised the LDL-C target from < 100 mg/dL (2.6 mmol/L) to < 70 mg/dL (1.8 mmol/L) (optional target) for very high-risk patients and < 130 mg/dL (3.4 mmol/L) to < 100 mg/dL (2.6 mmol/L) for moderately high-risk patients. For patients who fail to achieve their LDL-C target, inhibiting the two main sources of cholesterol - synthesis and uptake - can produce more effective lipid lowering, allowing more patients to reach their LDL-C goal. Ezetimibe is a highly-selective inhibitor of cholesterol absorption and simvastatin is an evidence-based inhibitor of cholesterol synthesis. The LDL-C-lowering efficacy of targeting both major sources of cholesterol with ezetimibe plus simvastatin was demonstrated in several multicentre, double-blind, placebo-controlled trials in patients with hypercholesterolaemia. For patients who do not reach their cholesterol goal with a statin, adding ezetimibe 10 mg significantly reduces LDL-C compared with statin monotherapy. Thus, this treatment option may help patients reach the new 'stricter' cholesterol goals. This review, based on a Medline database search from January 2000 to August 2005, considers the LDL-C-lowering efficacy of ezetimibe and discusses the role of this agent for patients who fail to achieve guideline cholesterol goals with statin monotherapy.

Anticholesteremic Agents↗
PubMed2006

Non-low-density lipoprotein cholesterol-associated actions of ezetimibe: an overview.

Ezetimibe, an intestinal cholesterol absorption inhibitor, lowers circulating low-density lipoprotein cholesterol (LDL-C) levels both when administered as monotherapy and in combination with other hypolipidaemic drugs, mostly statins. This review focuses on the effects of ezetimibe on non-LDL-C-associated variables. In most studies, ezetimibe effectively reduced triglyceride and increased high density lipoprotein cholesterol levels. The authors also consider the effect of ezetimibe on other variables such as C-reactive protein levels, insulin sensitivity and endothelial function. Ezetimibe is useful in patients with sitosterolaemia (a rare inherited disorder) as it significantly reduces plasma phytosterol concentrations. Ezetimibe fulfils two of the three essential characteristics of any drug (efficacy and safety). However, clinical studies are required to provide evidence of its ability to reduce vascular events.

Azetidines↗
PubMed2006

The role of thiols in liver ischemia-reperfusion injury.

Thiol-containing compounds have an essential role in many biochemical reactions due to their ability to be easily oxidised and then quickly regenerated. Main representatives are glutathione, lipoic acid and thioredoxin which are synthesised de novo in mammalian cells. N-acetylcysteine and Bucillamine are synthetic thiols which have been administered in experimental and clinical studies for treatment of conditions associated with oxidative stress. Ischemia and reperfusion (I/R) injury is characterised by significant oxidative stress, characteristic changes in the antioxidant system and organ injury leading to significant morbidity and mortality. I/R occurs in a variety of clinical settings such as liver resection, organ transplantation, haemorrhagic shock with fluid resuscitation, heart surgery, myocardial infarction followed by reperfusion and laparoscopic surgery. In these circumstances, the administration of antioxidant agents such as thiols, could provide protection from the harmful effects of I/R injury. However, the ability of thiol compounds to reduce free radicals is associated with the formation of thiyl radicals and the rate and efficiency of removal of thiyl radicals has a critical effect on antioxidant or prooxidant actions of thiols in the cells. The aim of this review is to present the mechanisms by which thiols act as antioxidants and signalling molecules and the experimental and clinical evidence regarding their role in I/R injury with a particular emphasis on liver I/R. The current evidence suggests that thiols ameliorate I/R injury and that their clinical significance should be further evaluated in large scale randomised clinical trials.

Animals↗
PubMed2006

Lipid lowering therapy in the elderly: is there a benefit?

The rising number of elderly people has a major impact on healthcare systems. Advancing age is a risk factor for the development of cardiovascular disease (CVD), which represents a major global healthcare problem. The clinical efficacy and safety of lipid lowering treatment (especially statins) is well established following a series of large-scale, randomised controlled trials, which mainly recruited patients under the age of 70 years. Subgroup analyses together with the findings of trials involving sufficient numbers of elderly participants, such as the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) and the Heart Protection Study (HPS) offer a basis for considering statin therapy in this population. Furthermore, since this population is at greater absolute risk of CVD, substantial benefits from adequate treatment may be anticipated. However, underevaluation and undertreatment appear to be common in the elderly. In this review, we provide a survey of potentially modifiable cardiovascular risk factors in association with old age, and discuss the relevant findings of large-scale end-point clinical studies as well as major considerations regarding lipid-lowering treatment in this population. It is concluded that the decision whether to treat hypercholesterolaemia in the elderly is currently individualised, depending upon the degree of risk, general health, willingness to receive treatment and financial concerns. Further, prospective randomised trials are required to guide physicians towards an effective management of older individuals at increased atherosclerotic risk.

Age Factors↗
PubMed2006

Leptin: a promising therapeutic target with pleiotropic action besides body weight regulation.

Leptin seems to regulate various physiological mechanisms besides body weight. Leptin plays a role in vascular biology and pathology as well as renal function. In addition, leptin has been implicated in the regulation of fertility and reproduction. The effect of pharmaceutical agents on circulating plasma leptin levels has been assessed. Among the drugs investigated are glitazones, statins, fibrates, serotonin reuptake inhibitors and cannabinoid-1 receptor antagonists. Since these agents are used to treat pathological conditions there is a potential role for leptin in these states. The degree of involvement of leptin in several pathophysiological states needs to be defined to aid in the development of potentially useful therapeutic agents.

Animals↗
PubMed2006

The management of phosphodiesterase-5 (PDE5) inhibitor failure.

The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the treatment of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, PDE5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of PDE5 inhibitor failure. Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Treatment failure may cause considerable distress. If dose titration, more attempts and continuous dosing of PDE5 inhibitors (taken on a daily basis) fail to resolve the initial PDE5 inhibitor failure, clinicians need to consider alternative treatments. These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Combination therapy like prostaglandin E(1) (PGE(1)) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT(2) antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide (NO) donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of PDE5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of PDE5 inhibitors may be maintained. Targeting the risk factors of ED (similar to those for arteriosclerosis) in the early stages of the disease may prevent the development or decrease the severity of ED.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Dyslipidaemia, hypercoagulability and the metabolic syndrome.

The metabolic syndrome is a clustering of risk factors including central obesity, insulin resistance, dyslipidaemia and hypertension. This syndrome is associated with increased risk of cardiovascular disease and is a common early abnormality in the development of type 2 diabetes. The pathogenesis of the syndrome has multiple origins. Obesity and sedentary lifestyle coupled with genetic factors interact to produce the syndrome. Here, we consider two components of the metabolic syndrome, dyslipidaemia and hypercoagulability.

Adipose Tissue↗
PubMed2006

Definitions of metabolic syndrome: Where are we now?

The metabolic syndrome (MetS) is a cluster of metabolic abnormalities including abdominal obesity, glucose intolerance, hypertension and dyslipidaemia and is associated with an increased risk of vascular events. Since the initial description of the MetS, several expert groups produced different definitions. This variability led to confusion and absence of comparability between studies. Although there is agreement that the MetS is a major public health challenge worldwide and consistent evidence stresses the need for intervention, the definition of the syndrome remains a matter of debate. This review considers the different definitions of the MetS. These include those proposed by the World Health Organisation, the European Group for the Study of Insulin Resistance, the National Cholesterol Education Program Adult Treatment Panel III, the American College of Endocrinology and American Association of Clinical Endocrinologists and the latest International Diabetes Federation definition which includes ethnic-specific waist circumference cut-off points. These definitions share several features but also include important differences; all have limitations. Selected (after a Medline search) studies comparing the different definitions are also considered. There is a need for a standardised definition of the MetS. Furthermore, a definition tailored for children and adolescents is essential. Prospective long-term studies are needed to validate the prognostic power of these definitions. As new information becomes available the definition of the MetS might be further modified.

Adolescent↗
PubMed2005

Smooth muscle and purinergic contraction of the human, rabbit, rat, and mouse testicular capsule.

The smooth-muscle cells of the testicular capsule (tunica albuginea) of man, rat, and mouse were examined by electron microscopy. They were characteristically flattened, elongated, branching cells and diffusely incorporated into the collagenous matrix and did not form a compact muscle layer. Contractile and synthetic smooth-muscle cell phenotypes were identified. Nerve varicosities in close apposition to smooth muscle were seen in human tissue. Contractions induced by adenosine 5'-triphosphate (ATP), alpha, beta-methylene ATP, noradrenaline (NA), acetylcholine (ACh), and electrical field stimulation (EFS) of autonomic nerves were investigated. Nerve-mediated responses of the rabbit and human tunica albuginea were recorded. The EFS-induced human responses were completely abolished by prazosin. In the rabbit, EFS-induced contractile responses were reduced by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid by 36% and by prazosin by 77%. Both antagonists together almost completely abolished all EFS-induced contractions. The human tunica albuginea was contracted by NA, ATP, and alpha, beta-methylene ATP, but not by ACh. The rabbit and rat tunica albuginea were contracted by NA, ATP, alpha, beta-methylene ATP, and ACh. The mouse tunica albuginea was contracted by ACh, ATP, and alpha, beta-methylene ATP, but relaxed to NA. Immunohistochemical studies showed that P2X1 (also known as P2RX1) and P2X2 (also known as P2RX2) receptors were expressed on the smooth muscle of the rodent testicular capsule, expression being less pronounced in man. The testicular capsule of the rat, mouse, rabbit, and man all contain contractile smooth muscle. ATP, released as a cotransmitter from sympathetic nerves, can stimulate the contraction of rabbit smooth muscle. Human, rat, and mouse testicular smooth muscle demonstrated purinergic responsiveness, probably mediated through the P2X1 and/or P2X2 receptors.

Acetylcholine↗
PubMed2005

Components of the metabolic syndrome and risk for first-ever acute ischemic nonembolic stroke in elderly subjects.

BACKGROUND AND PURPOSE: Metabolic syndrome (MetSyn) represents a constellation of lipid and nonlipid risk factors for cardiovascular disease and is a recognized target for increased behavioral therapy. OBJECTIVE: The association between acute ischemic/nonembolic stroke and the MetSyn in elderly individuals was assessed in a population-based case-control study in the prefecture of Ioannina, Greece. STUDY POPULATION: A total of 163 patients aged older than 70 years admitted with first-ever-in-a-lifetime acute ischemic/nonembolic stroke and 166 controls were included. RESULTS: The prevalence of MetSyn (defined according to NCEP/ATP III criteria) was high in stroke patients (46.0% versus 15.7%, P<0.001). Compared with controls as a group (with and without MetSyn), stroke patients with the MetSyn showed higher concentrations of triglycerides, lipoprotein(a), uric acid, and fibrinogen, and lower high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I levels. In logistic regression analysis, crude and adjusted odd ratios (ORs) for MetSyn were 5.33 (95% confidence interval [CI], 2.91 to 9.79; P<0.0001) and 2.59 (95% CI, 1.24 to 5.42; P=0.012), respectively. The analysis of interaction between MetSyn and its individual components revealed significant associations with abdominal obesity (adjusted OR, 2.74; 95% CI, 1.15 to 6.50; P=0.02), hypertension (OR, 2.03; 95% CI, 0.91 to 4.49; P=0.08), high fasting glucose levels (OR, 2.95; 95% CI, 1.19 to 7.35; P=0.02), high triglyceride (OR, 5.55; 95% CI, 2.71 to 11.37; P<0.0001]), and low HDL cholesterol (OR, 5.42; 95% CI, 2.85 to 10.30; P<0.0001). Notably, in stroke patients with the MetSyn the inverse relationship between HDL cholesterol levels and ischemic stroke was negated (OR, 1.04; 95% CI, 1.02 to 1.05; P<0.0001). CONCLUSIONS: MetSyn is associated with an increased risk for acute ischemic/nonembolic stroke in elderly subjects with significant contributions from its individual components. In the presence of MetSyn, HDL cholesterol loses its protective role against ischemic stroke.

Aged↗
PubMed2005

Targeting vascular risk in patients with metabolic syndrome but without diabetes.

There are no prospective data on the effect of a multitargeted treatment approach on cardiovascular disease (CVD) risk reduction in nondiabetic patients with metabolic syndrome (MetS). Furthermore, the optimal hypolipidemic drug treatment in these patients remains controversial. In this prospective, randomized, open-label, intention-to-treat, and parallel study, 300 nondiabetic patients with MetS, free of CVD at baseline, were studied for a period of 12 months. Age- and sex-matched subjects without MetS (n = 100) acted as controls. All patients received lifestyle advice and a stepwise-implemented drug treatment of hypertension, impaired fasting glucose, and obesity. For hypolipidemic treatment, the patients were randomly allocated to 3 treatment groups: atorvastatin (n = 100, 20 mg/d), micronized fenofibrate (n = 100, 200 mg/d), and both drugs (n = 100). Clinical and laboratory parameters, including the lipid profile and C-reactive protein (CRP), were assessed at the baseline and at the end of the study. The primary end point was the proportion of patients not having MetS or its component features at the end of the 12-month treatment period. The secondary end points were the difference in 10-year CVD risk (Prospective Cardiovascular Munster risk calculator) and the degree of CRP reduction. By the end of the study, 76% of the patients no longer had MetS, and 46% had only one diagnostic MetS factor. The estimated 10-year (Prospective Cardiovascular Munster) risk of all patients with MetS at baseline was 14.6%. This was reduced in the atorvastatin group to 6.4%, in the fenofibrate group to 9.2%, and in the combination group to 5.5% (P < .0001 for all vs baseline). The 10-year risks of the atorvastatin and combination groups were not different from that of the control group (5.0%). C-reactive protein was significantly reduced in all treatment groups, with the atorvastatin and combination groups having the greatest reduction (65% and 68%, respectively, P < .01 vs the fenofibrate group, 44%). Lipid values were significantly improved in all 3 treatment groups, with those on the combined treatment attaining lipid targets to a greater extent than those in the other 2 groups. A target-driven and intensified intervention aimed at multiple risk factors in nondiabetic patients with MetS substantially offsets its component factors and significantly reduces the estimated CVD risk. The atorvastatin-fenofibrate combination had the most beneficial effect on all lipid parameters and significantly improved their CVD risk status. Atorvastatin and combination treatment were more effective than fenofibrate alone in reducing CRP levels.

Aged↗