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1.
Food Chem Toxicol ; 145: 111591, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32739454

RESUMO

The present study investigated whether a single pretreatment with clofibric acid suppresses liver injury in rats after CCl4 intoxication. Rats received a single pretreatment with clofibric acid (100 mg/kg, i.p.) 1 h prior to a CCl4 (1 mL/kg, p.o.) challenge, and were euthanized 24 h after the CCl4 administration. A single pretreatment with clofibric acid effectively suppressed increases in the serum aminotransferase activities and the severity of necrosis following the CCl4 challenge, whereas the pretreatment did not protect against CCl4-induced fatty liver. The clofibric acid pretreatment did not affect blood concentrations of CCl4 in the early stage after CCl4 dosing, or the level of the CCl4 reaching the liver 1 h after the CCl4 challenge. Moreover, the clofibric acid pretreatment did not affect the intensity of the covalent binding of the [14C]CCl4 metabolite to microsomal proteins and lipids. The clofibric acid pretreatment did not alter microsomal cytochrome P450 2E1 activity. Based on these results, we conclude that protection against CCl4-induced hepatocellular necrosis by a clofibric acid pretreatment does not require its repeated administration, and that a single and brief pre-exposure to clofibric acid prior to CCl4 dosing markedly suppresses necrosis without affecting the development and progression of steatosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ácido Clofíbrico/uso terapêutico , Necrose/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Tetracloreto de Carbono/metabolismo , Tetracloreto de Carbono/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Fígado/patologia , Masculino , Microssomos Hepáticos , Necrose/induzido quimicamente , Necrose/patologia , Ratos Wistar
2.
Asian Pac J Cancer Prev ; 17(2): 775-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26925679

RESUMO

BACKGROUND: The current study examined the effectiveness of concurrent therapy using photodynamic therapy (PDT) and clofibric acid (CA) to treat peritoneal carcinomatosis resulting from ovarian cancer. MATERIALS AND METHODS: Nude rats were used to create a model of peritoneal carcinomatosis resulting from ovarian cancer and the effectiveness of PDT with 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA-PDT) was determined. The survival time of rats receiving that therapy was compared to the survival time of a control group. Rats with peritoneal carcinomatosis resulting from ovarian cancer were divided into 3 groups: a group that received debulking surgery (DS) alone, a group that received DS+methyl-ALA-PDT, and a group that received DS+methyl-ALA-PDT+CA. The survival time of the 3 groups was compared. Protoporphyrin, a metabolite of methyl-ALA, produces a photochemical action when activated by light. The level of protoporphyrin (the concentration) that reached organs in the abdomen was measured with HPLC. RESULTS: Rats receiving methyl- ALA-PDT had a significantly longer survival time compared to the controls. Rats with peritoneal carcinomatosis that received DS+methyl-ALA-PDT+CA had a significantly longer survival time compared to the rats that received DS alone. Some of the rats that received concurrent therapy survived for a prolonged period. Protoporphyrin was highly concentrated in peritoneal metastases, but only small amounts reached major organs in the abdomen. PDT was not found to result in necrosis in the intestines. CONCLUSIONS: The results indicated that concurrent therapy consisting of PDT with methyl-ALA and CA is effective at treating peritoneal carcinomatosis resulting from ovarian cancer without damaging organs.


Assuntos
Ácido Aminolevulínico/análogos & derivados , Ácido Clofíbrico/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Ácido Aminolevulínico/uso terapêutico , Animais , Feminino , Hipolipemiantes/uso terapêutico , Luz , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Ratos , Ratos Endogâmicos F344
3.
J. bras. med ; 101(4): 7-12, jul.-ago. 2013.
Artigo em Português | LILACS | ID: lil-699658

RESUMO

Neste artigo revisaremos o tratamento antiplaquetário e antilipêmico, controle da pressão arterial e controle da frequência cardíaca e sua influência na mortalidade e novos eventos, aplicável a todo paciente portador de doença coronariana crônica.


We review the antiplatelet and hypolipidemic treatment, blood pressure and heart rate control and its influence on mortality and new events, applicable to all patients with chronic coronary disease.


Assuntos
Humanos , Masculino , Feminino , Doença das Coronárias/terapia , Hipolipemiantes/administração & dosagem , Hipolipemiantes/uso terapêutico , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Ácido Clofíbrico/uso terapêutico , Aspirina/administração & dosagem , Dieta com Restrição de Gorduras , Interações Medicamentosas , Frequência Cardíaca , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Estilo de Vida , Pressão Arterial
4.
N Z Med J ; 123(1324): 74-8, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20953225

RESUMO

Because most of the cardiac risk remains despite successful statin therapy there has been renewed interest in fibrate therapy for persisting hyperlipidaemia. Fibrate therapy lowers triglycerides but causes the urinary loss of betaine, which is an essential metabolite that is involved in osmoregulation, in methyl group metabolism, and which also affects lipid partitioning in the body. Loss of betaine is associated with an elevation of homocysteine and may compromise the potential benefits of fibrate therapy. However, betaine deficiency could be easily and inexpensively corrected by concurrent betaine supplementation. Clinical trials of combinations of betaine and fibrate, to complement statin therapy, are needed to determine the value of these agents in reducing the residual cardiovascular disease risk.


Assuntos
Betaína/uso terapêutico , Ácido Clofíbrico/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Lipotrópicos/uso terapêutico , Quimioterapia Combinada , Humanos , Hiperlipidemias/metabolismo , Resultado do Tratamento
7.
Cardiovasc Drugs Ther ; 23(5): 395-401, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19653086

RESUMO

PURPOSE: Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion. METHODS: We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups. RESULTS: Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013). CONCLUSIONS: Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.


Assuntos
Betaína/urina , Ácido Clofíbrico/efeitos adversos , Homocisteína/sangue , Hipolipemiantes/efeitos adversos , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/urina , Idoso , Ácido Clofíbrico/uso terapêutico , Estudos de Coortes , Complicações do Diabetes/sangue , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/urina , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Masculino , S-Adenosilmetionina/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/urina
8.
Curr Cancer Drug Targets ; 9(3): 366-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19442055

RESUMO

Anthracyclines are an important reagent in many chemotherapy regimes for treating a wide range of tumors. One of the primary mechanisms of anthracycline action involves DNA damage caused by inhibition of topoisomerase II. Enzymatic detoxification of anthracycline is a major critical factor that determines anthracycline resistance. Natural product, daunorubicin a toxic analogue of anthracycline is reduced to less toxic daunorubicinol by the AKR1B10, enzyme, which is overexpressed in most cases of smoking associate squamous cell carcinoma (SCC) and adenocarcinoma. In addition, AKR1B10 was discovered as an enzyme overexpressed in human liver, cervical and endometrial cancer cases in samples from uterine cancer patients. Also, the expression of AKR1B10 was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma in cervical cancer and estimated to have the potential as a tumor intervention target colorectal cancer cells (HCT-8) and diagnostic marker for non-small-cell lung cancer. This article presents the mechanism of daunorubicin action and a method to improve the effectiveness of daunorubicin by modulating the activity of AKR1B10.


Assuntos
Ácido Clofíbrico/uso terapêutico , Daunorrubicina/uso terapêutico , Neoplasias/tratamento farmacológico , Aldeído Redutase/química , Aldeído Redutase/efeitos dos fármacos , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Aldo-Ceto Redutases , Antibióticos Antineoplásicos/uso terapêutico , Ácido Clofíbrico/farmacologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Cinética , Modelos Moleculares , Neoplasias/enzimologia , Especificidade por Substrato
9.
Endocrinol Metab Clin North Am ; 38(1): 185-206, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19217519

RESUMO

Elderly individuals are at higher risk for cardiovascular events, and thus this population stands to gain a greater reduction in events from lipid therapy than younger individuals. Multiple primary and secondary prevention trials have demonstrated that the benefits of statins in geriatric patients are equivalent to, or greater than, those seen in younger patients. Combination therapy with non-statin agents should be considered in patients who do not meet cholesterol goals or who have concomitant hypertriglyceridemia or low levels of high-density lipoprotein cholesterol. Although increased side effects may occur with high-dose statin therapy, careful vigilance of drug interactions and limiting polypharmacy can reduce these effects.


Assuntos
Idoso/fisiologia , Dislipidemias/terapia , Hipolipemiantes/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , Ácido Clofíbrico/uso terapêutico , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Quimioterapia Combinada , Dislipidemias/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Niacina/uso terapêutico , Fatores de Risco
10.
J Am Coll Cardiol ; 53(4): 316-22, 2009 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-19161879

RESUMO

OBJECTIVES: To determine the relationship between non-high-density lipoprotein cholesterol (HDL-C) lowering and coronary heart disease (CHD) risk reduction for various lipid-modifying therapies. BACKGROUND: Non-HDL-C is the second lipid target of therapy after low-density lipoprotein cholesterol (LDL-C). METHODS: Randomized placebo or active-controlled trials were evaluated. The effect of mean non-HDL-C reduction on the relative risk of nonfatal myocardial infarction and CHD death was estimated using Bayesian random-effects meta-analysis models adjusted for study duration. Cochrane's Q was used to test for heterogeneity. RESULTS: Inclusion criteria were met by 14 statin (n = 100,827), 7 fibrate (n = 21,647), and 6 niacin (n = 4,445) trials, and 1 trial each of a bile acid sequestrant (n = 3,806), diet (n = 458), and ileal bypass surgery (n = 838). For statins, each 1% decrease in non-HDL-C resulted in an estimated 4.5-year CHD relative risk of 0.99 (95% Bayesian confidence interval: 0.98 to 1.00). The fibrate model did not differ from the statin model (Bayes factor K = 0.49) with no evidence of heterogeneity. The niacin model was moderately different from the statin model (K = 7.43), with heterogeneity among the trials (Q = 11.8, 5 df; p = 0.038). The only niacin monotherapy trial (n = 3,908) had a 1:1 relationship between non-HDL-C and risk reduction. No consistent relationships were apparent for the 5 small trials of niacin in combination. The 95% confidence intervals for the single trials of diet, bile acid sequestrants, and surgery also included the 1:1 relationship. CONCLUSIONS: Non-HDL-C is an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have an approximately 1:1 relationship between percent non-HDL-C lowering and CHD reduction.


Assuntos
LDL-Colesterol/sangue , Ácido Clofíbrico/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Niacina/uso terapêutico , HDL-Colesterol/sangue , Doença das Coronárias/sangue , Feminino , Humanos , Masculino , Fatores de Risco
11.
Am J Cardiol ; 103(3): 381-6, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19166693

RESUMO

Lipid-lowering drugs are one of the most prescribed drugs worldwide. The aim was to compare 10-year all-cause mortality according to initial dyslipidemia status and lipid-lowering drug exposure. The PRIME study was a multicenter population-based prospective cohort study of men recruited in 1991 to 1993, aged 50 to 59 years at baseline, and followed up for 10 years. The 4 groups compared were normolipidemic, untreated dyslipidemic, and dyslipidemic subjects on fibrate or statin therapy. Data were analyzed using multivariate Cox models. The cohort included 7,722 French men (statin group 4.0%, fibrate group 7.9%, untreated dyslipidemic subjects 19.0%, and normolipidemic subjects 69.1%). After 10 years, 4.8% of the sample was lost to follow-up and 416 deaths occurred (cancers 53.1%, cardiovascular diseases 17.1%, and other 29.8%). After adjustment for center, age, educational level, cardiovascular risk factors, lipids, alcohol intake, and history of cardiovascular and severe chronic diseases, hazard ratios (HRs) for all-cause mortality were 0.49 (95% confidence interval [CI] 0.26 to 0.94, p = 0.031) for subjects treated with a statin, 0.65 (95% CI 0.42 to 0.99, p = 0.046) for those on fibrate therapy, and 0.76 (95% CI 0.56 to 1.03, p = 0.080) for normolipidemic men compared with untreated dyslipidemic subjects. In the statin group, HRs for death from cardiovascular disease, cancer, and other causes were 0.55 (p = 0.348), 0.41 (p = 0.067), and 0.68 (p = 0.546) compared with dyslipidemic subjects, respectively. In the fibrate group, HRs were 0.76 (p = 0.499), 0.52 (p = 0.041), and 0.87 (p = 0.746). In conclusion, in this cohort study carried out in a real-life setting, all-cause mortality was significantly lower in dyslipidemic subjects on fibrate or statin therapy than in untreated dyslipidemic patients. No excess risk of noncardiovascular death was observed.


Assuntos
Ácido Clofíbrico/uso terapêutico , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/uso terapêutico , Causas de Morte , Dislipidemias/mortalidade , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade
12.
Postgrad Med J ; 84(997): 590-8, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19103817

RESUMO

The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.6 mmol/l (100 mg/dl), the risk of a major cardiovascular event in patients with established coronary artery disease remains significant at a level approaching an annual risk of 9%, paving the way for new strategies for reducing the residual cardiovascular risk in this patient group. Early epidemiological studies have identified low levels of high-density lipoprotein cholesterol (HDL-C) (<1.0 mmol/l or 40 mg/dl), a common feature of type 2 diabetes mellitus and the metabolic syndrome, to be an independent determinant of increased cardiovascular risk. The beneficial effects of HDL-C on the cardiovascular system have been attributed to its ability to remove cellular cholesterol, as well as its anti-inflammatory, antioxidant and antithrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk. As such, raising HDL-C in patients with aggressively lowered LDL-C provides an additional strategy for addressing the residual cardiovascular risk present in these patients groups. Studies suggest that for every 0.03 mmol/l (1.0 mg/dl) increase in HDL-C, cardiovascular risk is reduced by 2-3%. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means, the former of which include smoking cessation, aerobic exercise, weight loss and dietary manipulation. Therapeutic strategies have included niacin, fibrates, thiazolidinediones and bile acid sequestrants. Newly developed pharmacological agents include apolipoprotein A-I mimetics and the cholesteryl ester transfer protein (CETP) inhibitors, JTT-705 and torcetrapib, the latter of which has been recently withdrawn from clinical testing because of serious adverse effects. Emerging experimental studies investigating the complex pathways of HDL metabolism have identified several new targets for raising HDL-C with new pharmaceutical agents currently in development. For the time being, the long-acting formulations of nicotinic acid remain the most effective and best tolerated pharmacological strategy for raising HDL-C in patients already on statin therapy to control LDL-C. Therefore, raising HDL-C represents an important strategy for reducing residual cardiovascular risk in patients already optimally treated with statins, and should lead to further improvements in clinical outcomes in these patient groups.


Assuntos
Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antioxidantes/fisiologia , Apolipoproteína A-I/metabolismo , Apoptose , Disponibilidade Biológica , Doenças Cardiovasculares/metabolismo , Ácido Clofíbrico/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estilo de Vida , Niacina/uso terapêutico , Óxido Nítrico/metabolismo , Fatores de Risco , Comportamento de Redução do Risco , Trombose/prevenção & controle
13.
Rev Assoc Med Bras (1992) ; 54(4): 369-76, 2008.
Artigo em Espanhol | MEDLINE | ID: mdl-18719798

RESUMO

After having reached the objective for the LDL cholesterol levels, it becomes imperative to reach the objective for HDL cholesterol, known for its anti-atherogenic properties, generally confirmed in many epidemiological studies. This review deals, in a clear and concise manner, with the different alternatives available in daily clinical practice to raise the HDL cholesterol levels of patients, to achieve better outcomes in terms of morbidity and mortality in cardiovascular disease.


Assuntos
Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/metabolismo , Hipolipemiantes/uso terapêutico , Doenças Cardiovasculares/metabolismo , LDL-Colesterol/metabolismo , Ácido Clofíbrico/uso terapêutico , Exercício Físico , Humanos , Metanálise como Assunto , Niacina/uso terapêutico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Rimonabanto , Fatores de Risco , Fumar/efeitos adversos , Tiazolidinedionas/uso terapêutico
15.
Rev. Assoc. Med. Bras. (1992, Impr.) ; 54(4): 369-376, jul.-ago. 2008. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-489623

RESUMO

Após atingir as metas para os níveis de LDL-colesterol, é imperativo alcançar a meta do HDL-colesterol, por suas conhecidas propriedades antiaterogênicas confirmadas amplamente em muitos estudos epidemiológicos. Esta revisão analisa de maneira objetiva e concisa as diversas alternativas disponíveis na prática clínica diária para aumentar os níveis de HDL-colesterol em nosoos pacientes, com o objetivo de alcançar melhores prognósticos em termos de morbimortalidade cardiovascular.


After having reached the objective for the LDL cholesterol levels, it becomes imperative to reach the objective for HDL cholesterol, known for its anti-atherogenic properties, generally confirmed in many epidemiological studies. This review deals, in a clear and concise manner, with the different alternatives available in daily clinical practice to raise the HDL cholesterol levels of patients, to achieve better outcomes in terms of morbidity and mortality in cardiovascular disease.


Assuntos
Humanos , Hipolipemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/metabolismo , Doenças Cardiovasculares/metabolismo , LDL-Colesterol/metabolismo , Ácido Clofíbrico/uso terapêutico , Exercício Físico , Metanálise como Assunto , Niacina/uso terapêutico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Fatores de Risco , Fumar/efeitos adversos , Tiazolidinedionas/uso terapêutico
16.
Heart ; 94(6): 706-14, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18480348

RESUMO

The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.6 mmol/l (100 mg/dl), the risk of a major cardiovascular event in patients with established coronary artery disease remains significant at a level approaching an annual risk of 9%, paving the way for new strategies for reducing the residual cardiovascular risk in this patient group. Early epidemiological studies have identified low levels of high-density lipoprotein cholesterol (HDL-C) (<1.0 mmol/l or 40 mg/dl), a common feature of type 2 diabetes mellitus and the metabolic syndrome, to be an independent determinant of increased cardiovascular risk. The beneficial effects of HDL-C on the cardiovascular system have been attributed to its ability to remove cellular cholesterol, as well as its anti-inflammatory, antioxidant and antithrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk. As such, raising HDL-C in patients with aggressively lowered LDL-C provides an additional strategy for addressing the residual cardiovascular risk present in these patients groups. Studies suggest that for every 0.03 mmol/l (1.0 mg/dl) increase in HDL-C, cardiovascular risk is reduced by 2-3%. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means, the former of which include smoking cessation, aerobic exercise, weight loss and dietary manipulation. Therapeutic strategies have included niacin, fibrates, thiazolidinediones and bile acid sequestrants. Newly developed pharmacological agents include apolipoprotein A-I mimetics and the cholesteryl ester transfer protein (CETP) inhibitors, JTT-705 and torcetrapib, the latter of which has been recently withdrawn from clinical testing because of serious adverse effects. Emerging experimental studies investigating the complex pathways of HDL metabolism have identified several new targets for raising HDL-C with new pharmaceutical agents currently in development. For the time being, the long-acting formulations of nicotinic acid remain the most effective and best tolerated pharmacological strategy for raising HDL-C in patients already on statin therapy to control LDL-C. Therefore, raising HDL-C represents an important strategy for reducing residual cardiovascular risk in patients already optimally treated with statins, and should lead to further improvements in clinical outcomes in these patient groups.


Assuntos
Anticolesterolemiantes/uso terapêutico , HDL-Colesterol/fisiologia , Doença da Artéria Coronariana/prevenção & controle , Angiopatias Diabéticas/tratamento farmacológico , HDL-Colesterol/efeitos dos fármacos , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Ácido Clofíbrico/uso terapêutico , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Comportamento de Redução do Risco , Tiazolidinedionas/uso terapêutico
17.
Drug Saf ; 31(5): 399-407, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18422380

RESUMO

BACKGROUND: Case reports have related the use of HMG-CoA reductase inhibitors ('statins') to Parkinson's disease (PD). Paradoxically, however, statins may have potentially beneficial effects on neurodegenerative diseases due to their anti-inflammatory properties. OBJECTIVE: To explore the risk of the development of PD in association with untreated hyperlipidaemia and with hyperlipidaemia treated with lipid-lowering drugs in the UK primary care setting. METHODS: We conducted a case-control analysis using the UK-based General Practice Research Database (GPRD). Cases were incident PD cases > or =40 years of age between 1994 and 2005. One control was matched to each PD case based on age, sex, general practice and index date. Lipid-lowering drug use was assessed by exposure timing (current vs past use) and by exposure duration (1-9, 10-29 or > or =30 prescriptions) prior to the index date for both cases and controls. Odds ratios (OR) were calculated using conditional logistic regression, adjusted for body mass index, smoking and various cardiovascular, metabolic and psychiatric co-morbidities. RESULTS: We identified 3637 cases with an incident idiopathic PD diagnosis, and the same number of controls. Compared with patients without hyperlipidaemia, those with untreated hyperlipidaemia did not have an altered relative PD risk (adjusted OR 0.98, 95% CI 0.74, 1.30). The adjusted ORs for current use of > or =30 prescriptions for statins or fibrates compared with non-use of statins or fibrates were 1.06 (95% CI 0.75, 1.51) and 1.25 (95% CI 0.51, 3.06), respectively. CONCLUSIONS: In this observational study, the long-term use of statins or fibrates was not associated with a substantially altered relative risk of developing PD.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doença de Parkinson/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Casos e Controles , Ácido Clofíbrico/efeitos adversos , Ácido Clofíbrico/uso terapêutico , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reprodutibilidade dos Testes , Estudos Retrospectivos , Risco , Reino Unido/epidemiologia
18.
ScientificWorldJournal ; 8: 98-120, 2008 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-18264628

RESUMO

Retinopathy is the most feared complication of diabetes, compromising quality of life in most sufferers. Almost all patients with type 1 diabetes will develop retinopathy over a 15- to 20-year period, and approximately 20-30% will advance to the blinding stage of the disease[1]. Greater than 60% of patients with type 2 diabetes will have retinopathy. This situation is highlighted by the frightening statistic that diabetic retinopathy (DR) remains the most common cause of vision impairment in people of working age in Western society. With the global epidemic of type 2 diabetes, this predicament is set to worsen as over 360 million people are projected to suffer from diabetes and its complications by 2030. Vision loss from diabetes is due to a number of factors, including haemorrhage from new and poorly formed blood vessels, retinal detachment due to contraction of deposited fibrous tissue, and neovascular glaucoma resulting in an increase in intraocular pressure. Diabetic macular oedema is now the principal cause of vision loss in diabetes and involves leakage from a disrupted blood-retinal barrier. In terms of treatment, there is clear evidence that strict metabolic and blood pressure control can lower the risk of developing DR and reduce disease progression. Laser photocoagulation and vitrectomy are effective in preventing severe vision loss in DR, particularly in the most advanced stages of the disease. However, both procedures have limitations. This review examines evidence from preclinical and clinical studies that shows that targeting inhibition of the renin-angiotensin system, vascular endothelial growth factor, corticosteroids, protein kinase C, growth hormone, and advanced glycation end-products are potential treatments for DR.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/terapia , Corticosteroides/uso terapêutico , Aldeído Redutase/antagonistas & inibidores , Angiotensina II/fisiologia , Anti-Hipertensivos/uso terapêutico , Glicemia/metabolismo , Ácido Clofíbrico/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/cirurgia , Dislipidemias/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Produtos Finais de Glicação Avançada/fisiologia , Hormônio do Crescimento Humano/fisiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/prevenção & controle , Insulina/administração & dosagem , Fotocoagulação a Laser , Proteína Quinase C/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Vitamina E/uso terapêutico
19.
J Biol Chem ; 283(15): 9666-73, 2008 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-18245819

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with familial autosomal dominant hypercholesterolemia and is a natural inhibitor of the LDL receptor (LDLr). PCSK9 is degraded by other proprotein convertases: PC5/6A and furin. Both PCSK9 and the LDLr are up-regulated by the hypocholesterolemic statins. Thus, inhibitors or repressors of PCSK9 should amplify their beneficial effects. In the present study, we showed that PPARalpha activation counteracts PCSK9 induction by statins by repressing PCSK9 promoter activity and by increasing PC5/6A and furin expression. Quantification of mRNA and protein levels showed that various fibrates decreased PCSK9 and increased PC5/6A and furin expression. Fenofibric acid (FA) reduced PCSK9 protein content in immortalized human hepatocytes (IHH) as well as its cellular secretion. FA suppressed PCSK9 induction by statins or by the liver X receptor agonist TO901317. PCSK9 repression is occurring at the promoter level. We showed that PC5/6A and furin fibrate-mediated up-regulation is PPARalpha-dependent. As a functional test, we observed that FA increased by 30% the effect of pravastatin on the LDLr activity in vitro. In conclusion, fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPARalpha activation in proprotein convertase-mediated lipid homeostasis. Moreover, this study validates the functional relevance of a combined therapy associating PCSK9 repressors and statins.


Assuntos
Anticolesterolemiantes/farmacologia , Ácido Clofíbrico/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/enzimologia , PPAR alfa/metabolismo , Serina Endopeptidases/biossíntese , Anticolesterolemiantes/uso terapêutico , Linhagem Celular Tumoral , Ácido Clofíbrico/uso terapêutico , Proteínas de Ligação a DNA/metabolismo , Fenofibrato/análogos & derivados , Fenofibrato/farmacologia , Furina/biossíntese , Furina/genética , Regulação Enzimológica da Expressão Gênica/genética , Humanos , Hidrocarbonetos Fluorados , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/enzimologia , Hiperlipoproteinemia Tipo II/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Receptores X do Fígado , Receptores Nucleares Órfãos , PPAR alfa/genética , Pravastatina/farmacologia , Pravastatina/uso terapêutico , Regiões Promotoras Genéticas/genética , Pró-Proteína Convertase 5/biossíntese , Pró-Proteína Convertase 5/genética , Pró-Proteína Convertase 9 , Pró-Proteína Convertases , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Serina Endopeptidases/genética , Sulfonamidas/farmacologia , Regulação para Cima/efeitos dos fármacos
20.
Am J Med ; 121(1): 10-2, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18187065

RESUMO

Chylomicronemia is present when triglyceride levels exceed 1000 mg/dL. Chylomicronemia, when accompanied by eruptive xanthoma, lipemia retinalis, or abdominal symptoms, is referred to as the "chylomicronemia syndrome" and can cause acute pancreatitis. Treatment aimed at reducing triglyceride levels includes lifestyle modifications to promote weight loss with diet and physical activity coupled with medications, including fibrates, n-3 polyunsaturated fatty acids, and nicotinic acid. Chylomicronemic patients with acute pancreatitis require insulinization in an inpatient setting to abolish chylomicronemia.


Assuntos
Quilomícrons/sangue , Ácidos Graxos Ômega-3/uso terapêutico , Hipertrigliceridemia , Hipolipemiantes/uso terapêutico , Ácido Clofíbrico/uso terapêutico , Diagnóstico Diferencial , Humanos , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/terapia , Estilo de Vida , Síndrome , Triglicerídeos/sangue
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