RESUMO
AIM: To evaluate the effects of canagliflozin on plasma volume, urinary glucose excretion (UGE), fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) and additional measures of fluid/electrolyte balance in patients with type 2 diabetes on background therapy with metformin and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. METHODS: Patients (N = 36) were randomized (1:1) to receive canagliflozin 300 mg or placebo for 12 weeks. Pharmacodynamic parameters were assessed at baseline and at weeks 1 and 12. RESULTS: Increased 24-h UGE was seen in the canagliflozin group compared with a reduction in the placebo group at both week 1 (91.8 vs. -2.4 g) and week 12 (82.6 vs. -0.4 g). Canagliflozin also reduced both FPG and HbA1c. Reductions in body weight and blood pressure were observed at weeks 1 and 12. Canagliflozin decreased plasma volume compared with an increase with placebo at week 1 (-5.4 vs. 4.3%; p = 0.02), but this was largely attenuated at week 12 (4.6 vs. 5.8%; p = 0.76). A modest numerical increase in urine volume was observed with canagliflozin at week 1 that was attenuated at week 12; other measures of volume status (i.e. blood urea nitrogen, serum creatinine and haematocrit) remained modestly increased with canagliflozin at week 12. CONCLUSION: Canagliflozin provided sustained effects on UGE and FPG over 12 weeks and a transient reduction in plasma volume that was largely attenuated by week 12.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Glucosídeos/uso terapêutico , Hipertensão/prevenção & controle , Volume Plasmático/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose , Tiofenos/uso terapêutico , Adulto , Idoso , Anti-Hipertensivos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Canagliflozina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Jejum , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Redução de Peso/efeitos dos fármacosRESUMO
Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150-180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1-2 hypertension with AZL-M was more effective than RAM and better tolerated.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Benzimidazóis/uso terapêutico , Hipertensão/tratamento farmacológico , Oxidiazóis/uso terapêutico , Ramipril/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Previously, we showed that curcumin prevents chronic kidney disease (CKD) development in ⅚ nephrectomized (Nx) rats when given within 1 wk after Nx (Ghosh SS, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, Fakhry I, Gehr TW. Am J Physiol Renal Physiol 296: F1146-F1157, 2009). To better mimic the scenario for renal disease in humans, we began curcumin and enalapril therapy when proteinuria was already established. We hypothesized that curcumin, by blocking the inflammatory mediators TNF-α and IL-1ß, could also reduce cyclooxygenase (COX) and phospholipase expression in the kidney. Nx animals were divided into untreated Nx, curcumin-treated, and enalapril-treated groups. Curcumin (75 mg/kg) and enalapril (10 mg/kg) were administered for 10 wk. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was comparably reduced by curcumin and enalapril, with only enalapril significantly lowering blood pressure. Compared with controls, Nx animals had higher plasma/kidney TNF-α and IL-1ß, which were reduced by curcumin and enalapril treatment. Nx animals had significantly elevated kidney levels of cytosolic PLA(2), calcium-independent intracellular PLA(2), COX 1, and COX 2, which were comparably reduced by curcumin and enalapril. Studies in mesangial cells and macrophages were carried out to establish that the in vivo increase in PLA(2) and COX were mediated by TNF-α and IL-1ß and that curcumin, by antagonizing the cytokines, could significantly reduce both PLA(2) and COX. We conclude that curcumin ameliorates CKD by blocking inflammatory signals even if it is given at a later stage of the disease.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Curcumina/uso terapêutico , Enalapril/uso terapêutico , Inflamação/tratamento farmacológico , Fosfolipases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Insuficiência Renal/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Hipertensivos/farmacologia , Curcumina/farmacologia , Enalapril/farmacologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Nefrectomia , Ratos , Insuficiência Renal/enzimologia , Insuficiência Renal/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
TNF-alpha and NF-kappaB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-alpha-elicited NF-kappaB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-alpha, which was associated with NF-kappaB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-alpha. Curcumin dose dependently antagonized the TNF-alpha-mediated decrease in PPARgamma and blocked transactivation of NF-kappaB and repression of PPARgamma, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Curcumina/farmacologia , Falência Renal Crônica/tratamento farmacológico , Nefrite/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Células Cultivadas , Creatinina/sangue , Modelos Animais de Doenças , Enalapril/farmacologia , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/imunologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/patologia , Macrófagos/patologia , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/imunologia , NF-kappa B/genética , NF-kappa B/metabolismo , Nefrectomia , Nefrite/imunologia , Nefrite/patologia , PPAR gama/genética , PPAR gama/metabolismo , Proteinúria/tratamento farmacológico , Proteinúria/imunologia , Proteinúria/patologia , Ratos , Ratos Sprague-Dawley , Transfecção , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Each year in the USA approximately 7-8 million patients with non-traumatic chest pain come to hospital emergency rooms. It is estimated that approximately 2-5% of these patients are experiencing cardiac ischaemia, but due to the shortcomings of the available testing methods they are incorrectly diagnosed and discharged without appropriate therapy having been provided. Preliminary data with a globally ischaemic mouse heart model has demonstrated that endogenous inosine might be a potential biomarker of initial cardiac ischaemia before cardiac tissue necrosis. A high-performance liquid chromatographic diode array detection (HPLC-DAD) method was utilized for the detection and quantification of inosine in Krebs-Henseleit (Krebs) buffer solution perfusing from surgically removed and isolated mouse hearts undergoing global cardiac ischaemia. A C18 column at a flow rate of 0.6 ml min-1 with an aqueous mobile phase of trifluoroacetic acid (0.05% trifluoroacetic acid in deionized water, pH 2.2, v/v) and methanol gradient was used for component separation. The assay detection limit for inosine in Krebs buffer solution was 500 ng ml-1 using a 100-microl neat injection. The HPLC results were used to determine total cardiac effluxed inosine into the Krebs effluent for each mouse during oxidative stress and compared with the per cent cardiac ventricular functional recovery rate to determine if a relationship exists amongst this cardiovascular parameter during periods of cardiac oxidative stress.
Assuntos
Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Inosina/metabolismo , Isquemia Miocárdica/metabolismo , Animais , Peso Corporal , Radicais Livres/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/metabolismo , Tamanho do Órgão , Reprodutibilidade dos TestesRESUMO
Not uncommonly the effective treatment of hypertension requires multi-drug therapy. Multi-drug combinations that dominate clinical practice typically include a thiazide-type diuretic together with either an angiotensin-converting enzyme inhibitor, or an angiotensin-receptor blocker, or a beta-blocker. On the other hand, there are several medication choices that provide incremental blood pressure reduction but all too often go under-appreciated as to their effectiveness. Such drug combinations include within class switching of diuretics, combining a thiazide-type diuretic with a calcium-channel blocker, utilizing 2 calcium-channel blockers from different classes, giving an ACE inhibitor together with an angiotensin-receptor blocker, adding an aldosterone receptor antagonist to any of several other drug classes, as well as adding nitrate therapy to any of several other drug classes. Such novel pharmacologic approaches offer useful options for treatment in the otherwise difficult to control hypertensive patient.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Ensaios Clínicos como Assunto , Diuréticos/uso terapêutico , Quimioterapia Combinada , Humanos , Resultado do TratamentoRESUMO
OBJECTIVE: The objective of this study was to determine the effect of multiple impairments in drug elimination on the pharmacokinetics and pharmacodynamics (effect on QTc interval), using clarithromycin as a comparator. METHODS: Thirty-two subjects aged > or = 60 years with renal impairment who were otherwise medically stable were recruited into this parallel-group study. Following stratification according to creatinine clearance (CL(CR)), subjects were randomized to a five-day treatment with ketoconazole (400 mg once daily) alone, or a five-day treatment with ketoconazole (400 mg once daily) and telithromycin (800 mg once daily) given concomitantly or a five-day treatment with ketoconazole (400 mg once daily) and clarithromycin (500 mg twice daily) given concomitantly. Steady-state pharmacokinetics and safety, including serial electrocardiograms, were assessed. RESULTS: In subjects with CL(CR) 30 - 80 ml/min, the mean maximal telithromycin concentration at steady state (C(max),ss) was 3.6 mg/l and the steady state area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-24 h) ss) was 33.4 mg x h/l. The mean C(max), ss and AUC(0-12 h)ss for clarithromycin were 6.2 mg/l and 56.1 mg x h/l, respectively. The increases in telithromycin C(max) ss and AUC(0-24 h) ss compared to corresponding data for healthy young subjects were 1.6- and 2.7-fold, respectively, whereas corresponding increases for clarithromycin were 2.2- and 3.3-fold, respectively. In the telithromycin plus ketoconazole group deltaQTc values were equal or < 60 ms. All QTc values were equal or < 450 ms in males and equal or < 470 ms in females. CONCLUSIONS: The increase in telithromycin plasma concentrations during ketoconazole-mediated inhibition of CYP3A4 in subjects aged 60 years or older with renal impairment was similar to that for clarithromycin under the same conditions. Telithromycin was well tolerated and produced no clinically significant prolongations in the QTc interval.
Assuntos
Antibacterianos/farmacocinética , Antifúngicos/farmacologia , Claritromicina/farmacocinética , Cetoconazol/farmacologia , Cetolídeos/farmacocinética , Nefropatias/metabolismo , Idoso , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Claritromicina/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Cetolídeos/efeitos adversos , Cetolídeos/farmacologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-IdadeRESUMO
Eplerenone is a new aldosterone receptor antagonist that will be used in the treatment of hypertension. Like spironolactone, it is a compound that can be associated with the development of hyperkalemia. Therefore, the same prescription considerations that are applied to spironolactone should be directed to its use. Unfortunately, the label for eplerenone will place more stringent restrictions on its use than is the case for spironolactone. The basis for the multiple contraindications to the use of eplerenone is primarily that of concern for the development of hyperkalemia. This may occur with eplerenone, as has been the case with spironolactone. The presumption in the prescribing information that certain patient subsets, such as diabetics with microalbuminuria and/or patients with mild renal failure, would be highly prone to developing clinically relevant hyperkalemia with eplerenone is not, however, grounded in fact. The favorable experience with spironolactone is important. It should provide us with the landmarks for advancing knowledge on the role of newer aldosterone receptor antagonists in disease state management and one would think, help in establishing criteria for the safe use of new compounds. New compounds in a drug class typically provide advantages over earlier entries into a drug class but not if regressive labeling has occurred. Time and additional clinical experience with eplerenone will establish its safety profile and determine if the original label for this compound was correct.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Espironolactona/análogos & derivados , Espironolactona/farmacologia , Contraindicações , Rotulagem de Medicamentos , Eplerenona , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
The pivotal role of potassium (K+) in cardiovascular disease and the importance of preserving potassium balance have become clinical hot points, particularly as relates to new and emerging cardioprotective and renoprotective therapies that promote potassium retention. Although clinicians may be aware of the critical nature of this relationship, quite frequently there is some uncertainty as to the best way to monitor potassium levels in the face of a host of pathologic states and/or accompanying drug therapies that affect serum levels and/or total body potassium balance. Moreover, guidelines for monitoring of serum potassium levels are at best tentative and oftentimes are translated according to the level of concern of the respective physician. To address these uncertainties, an expert group was convened that included representatives from multiple disciplines. They attempted to reach consensus on the importance of K+ in hypertension, stroke, and arrhythmias as well as practical issues on maintaining K+ balance and avoiding K+ depletion. Because of the complexity of this topic, issues of hyperkalemia will be addressed in a forthcoming manuscript.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Potássio/metabolismo , Prevenção Primária/métodos , Doenças Cardiovasculares/fisiopatologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Canais de Potássio/metabolismo , Potássio na Dieta , Sensibilidade e Especificidade , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
Controlled clinical trials in cardiovascular disease are the cornerstone for therapeutic advances in this field of medicine. Since the introduction of the concept of controlled clinical trials there has been substantial progress in the design, conduct, and analysis of such studies. A growing awareness of ethical issues emerging from such trials has heightened public awareness, increased investigator scrutiny, and reinforced the need for interim data analysis. A benefit of such interim analyses is that either an entire clinical trial or a specific treatment limb can be stopped if the observed findings argue for premature termination. For example, highly positive findings, as were noted in the HOPE Study (Heart Outcomes Prevention Evaluation), led to its being stopped after 4.5 years of treatment, which was 1 year early. Alternatively, the doxazosin treatment limb of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) and the amlodipine treatment limb of AASK (African American Study of Kidney Disease and Hypertension) were stopped early because of negative findings with each respectively. Finally, economic considerations can enter into the decision to close a study early as was the case in the CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular End Points) trial. Most such decisions rely heavily on information obtained from independent data and safety monitoring boards. Such boards ensure patient safety by providing an unbiased ongoing review of data, which would otherwise be unavailable until a study's completion. Early termination of a clinical trial can have important clinical implications and, in particular, can redirect patterns of clinical practice.
Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Hipertensão/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Doenças Cardiovasculares/etiologia , Feminino , Seguimentos , Guias como Assunto , Humanos , Hipertensão/complicações , Masculino , Medição de Risco , Síndrome de Abstinência a Substâncias , Fatores de TempoRESUMO
Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are commonly used to treat hypertension and/or a range of progressive end-organ diseases. The success of each of these drug classes in disease-state management is without dispute, and has led to speculation that given together the observed response would improve upon that observed with a member of each drug class individually given. Few studies are available, however, which carefully address the effect(s) of the combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker. Review of available studies would seem not to strongly support combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker as preferred therapy in the broad base of general hypertensive patients with or without end-organ disease. Additional clarifying studies are needed to determine if specific patient subsets exist that might benefit from such combination therapy.
Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Receptores de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Humanos , Hipertensão/tratamento farmacológicoRESUMO
Effective control of blood pressure is usually achieved only with the use of two or more antihypertensive medications. The treatment options for hypertension are numerous, and the number of possible combinations large. The selection of a specific combination drug regimen has often been linked to the perceived need for diuretic therapy as first- or second-step therapy; thus, the popularity of such drug combinations as an angiotensin-converting enzyme (ACE) inhibitor/diuretic, an angiotensin-receptor blocker/diuretic, or a beta blocker/diuretic. Rational alternatives exist, including an ACE inhibitor/calcium channel blocker (CCB) or a dihydropyridine CCB/b blocker combination. Traditionally, recommendations have advised against the use of combination therapy with two drugs from the same therapeutic class. However, because of the different binding and pharmacologic characteristics of CCBs, a rationale exists for combining different agents in this class in the management of hypertension and/or symptomatic coronary artery disease. In the treatment of either hypertension or angina, combination CCB therapy can prove uniquely successful.
Assuntos
Angina Pectoris/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Quimioterapia Combinada , HumanosAssuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , American Heart Association , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Contraindicações , Gerenciamento Clínico , Taxa de Filtração Glomerular/efeitos dos fármacos , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Hiperpotassemia/etiologia , Hiperpotassemia/terapia , Volume Plasmático , Diálise Renal , Fatores de Risco , Cirurgia TorácicaRESUMO
Perindopril erbumine is a once-daily angiotensin-converting enzyme (ACE) inhibitor that effectively lowers systolic and diastolic blood pressure (BP) in patients with mild-to-moderate hypertension. Converted from the prodrug ester perindopril, the active diacid perindoprilat is distributed rapidly and extensively, primarily to tissues with high ACE activity. Its ability to lower BP is comparable to or better than that of other antihypertensive agents, both of its own class and other classes, and its trough-peak ratio is consistently between 75% and 100%, translating into 24 hours of true efficacy per dose. First-dose hypotension caused by an initial acute BP depression occurs less frequently with perindopril than with other ACE inhibitors, an advantage in volume-contracted patients and those whose BP is angiotensin II dependent, such as patients with congestive heart failure. A missed-dose study showed that most of the antihypertensive effect of perindopril remains for 24 to 48 hours after dosing, a characteristic that confers protection to patients who miss a dose. Perindopril improves the distensibility and compliance of large and small arteries, which are compromised in hypertension, and can effect vascular remodeling by a mechanism independent of BP lowering. The clinical implications of these effects are being investigated in large trials. Perindopril is well tolerated in the elderly, and combination therapy with a diuretic was shown to yield significant additional BP reduction. Perindoprilat is cleared renally; dosage should be adjusted in patients with renal impairment.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Hipertensão/prevenção & controle , Perindopril/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Perindopril/farmacocinética , Perindopril/farmacologiaRESUMO
In September, 2000, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health called an early halt to the amlodipine arm of the African American Study of Kidney Disease and Hypertension (AASK) trial after careful deliberation by an independent data and safety monitoring board. An interim analysis of the AASK at 3 years revealed a renoprotective effect of the angiotensin-converting enzyme inhibitor ramipril as compared to the dihydropyridine calcium channel blocker (DHP-CCB) amlodipine in patients with mild to moderate renal insufficiency. This differential effect was independent of the blood pressure (BP) levels reached and was evident in proteinuric patients and suggestive in patients with baseline proteinuria < 300 mg/d, but was not conclusive. The AASK trial data suggest that DHP-CCBs should be used cautiously in the presence of mild to moderate renal insufficiency. Judgment should be reserved for the use of other CCBs, such as verapamil or diltiazem, since these are fundamentally different CCBs with the potential for a different impact on hypertensive nephrosclerosis. The blinded observation period for AASK will be completed at the end of September, 2001, at which time additional, clinically useful information is expected to become available. (c)2001 Le Jacq Communications, Inc.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/fisiopatologia , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Anlodipino/uso terapêutico , Feminino , Humanos , Masculino , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Ramipril/uso terapêutico , Fatores de TempoRESUMO
The Heart Outcomes Prevention Evaluation study was a landmark study employing the angiotensin-converting enzyme inhibitor ramipril in a patient population pre-destined for vascular events. This study found that a 10 mg dose of ramipril in comparison with placebo reduced the incidence of death, myocardial infarction, stroke, and death from cardiovascular causes by 22%. This improvement in outcome was viewed as a direct consequence of ramipril, although the fact that blood pressure was reduced with ramipril has cast some considerable doubt on this supposition. Whether the observed findings in this study are a 'class effect' for all angiotensin-converting enzyme inhibitors is unclear. To its credit, ramipril is the first angiotensin-converting enzyme inhibitor shown to prevent ischemic events in high-risk patients without discernible left ventricular dysfunction. Other similar trials are underway, which are studying similar populations to those included in this landmark study and should resolve the question of whether the cardioprotective effects of angiotensin-converting enzyme inhibitors are a 'class effect'.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Ramipril/uso terapêutico , Doenças Cardiovasculares/mortalidade , Ensaios Clínicos Controlados como Assunto , Estudos de Avaliação como Assunto , Humanos , Estudos Multicêntricos como Assunto , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/prevenção & controleRESUMO
Controlled clinical trials in cardiovascular disease are the cornerstone for therapeutic advances in this field of medicine. Since the introduction of the concept of controlled clinical trials, there has been substantial progress in the design, conduct, and analysis of such studies. A growing awareness of ethical issues emerging from such trials has led to increased public and investigator scrutiny, and the routine requirement for interim data analysis. A benefit of such interim analysis is that either an entire clinical trial or a specific treatment limb can be stopped if the observed findings warrant premature termination. For example, highly positive findings, as were noted in the Heart Outcomes Prevention Evaluation (HOPE) study, led to its closure about 1 year early after 4.5 years of treatment. Alternatively, the doxazosin treatment limb of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the amlodipine treatment limb of the African-American Study of Kidney Disease and Hypertension (AASK) were stopped early because of negative findings. Finally, economic considerations can enter into the decision to close a study early as was the case in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial. Most such decisions rely heavily on information obtained from independent data and safety monitoring boards. Such boards ensure patient safety by providing an unbiased ongoing review of data, which would otherwise be unavailable until a study's completion. Early termination of a clinical trial can have important clinical implications and, in particular, can redirect patterns of clinical practice.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Ensaios Clínicos Controlados como Assunto , Humanos , Fatores de TempoRESUMO
The treatment of hypertension has become increasingly refined during the past decade. Although a variety of antihypertensive medication classes exist, drugs that interrupt the renin-angiotensin axis have gained a favored position in the treatment of hypertension and its attendant end-organ complications. In this regard, two drug classes, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are most commonly used. Angiotensin receptor blockers have proven highly effective in the management of hypertension. This class is fairly heterogeneous with individual class members having somewhat distinctive pharmacologic properties. Eprosartan is a recent entry into this class. This compound compares favorably to others in this class relative to blood pressure reduction. In addition, preliminary studies indicate that this compound may uniquely interrupt the sympathetic nervous system and thereby preferentially reduce systolic blood pressure.
Assuntos
Acrilatos/farmacologia , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Imidazóis/farmacologia , Tiofenos , Anti-Hipertensivos/farmacologia , Humanos , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Resultado do TratamentoRESUMO
Minoxidil is a direct vasodilator that has been in use for over two decades. It is used primarily to reduce blood pressure in hypertensives who have been poorly controlled on various multidrug regimens. Although minoxidil is extremely effective, its usefulness is limited by its tendency to increase the pulse rate and to trigger salt and water retention. The latter may be incapacitating in some patients. Therefore, minoxidil is typically administered with both a diuretic and an agent that can control the pulse rate, such as a beta blocker. Minoxidil has several other side effects that may limit its use, including hypertrichosis, aggravation of myocardial ischemia and/or left ventricular hypertrophy, and (infrequently) pericardial effusions. If a patient's hypertensive pattern is sufficiently severe to warrant contemplation of minoxidil therapy, referring the patient to a hypertension specialist should be strongly considered. (c) 2001 by LeJacq Communications, Inc.