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1.
Early vascular benefits of statin therapy   总被引:29,自引:0,他引:29  
Large-scale trials established that statin administration in hypercholesterolaemic individuals and patients with coronary heart disease (CHD) significantly reduces the risk of vascular events and death. This benefit was primarily attributed to their actions on lipids. This review focuses on the benefits (clinical and experimental) of statins observed soon (approximately 12 weeks) after their administration. Statins rapidly increase nitric oxide production and improve endothelial function (e.g. increased flow-mediated dilatation). Similarly, antioxidant properties decrease the susceptibility of low density lipoprotein cholesterol to oxidation. Statins inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect and the stabilisation of atherosclerotic plaques. Anti-inflammatory effects include a reduction in serum C-reactive protein levels, inflammatory and proinflammatory cytokines (e.g. IL-6, IL-8), adhesion molecules (e.g. ICAM-1, VCAM-1) and other acute phase proteins. Statins influence the haemostatic system. They reduce tissue factor expression and platelet activity, whereas fibrinolysis can be enhanced. Statins improve microalbuminuria, renal function, hypertension and arterial wall stiffness. A significant reduction of the carotid intima media thickness (IMT) was also reported early after statin treatment. These early effects of statins probably contribute to the significant reduction in vascular events seen in some 'short-term' studies. There is a need to further elucidate the rapid and non-lipid lowering properties of statins.  相似文献   

2.
The effects of 1,2-bis(nicotinamido)propane (AVS) on platelet function and vascular endothelium were investigated using various experimental thrombosis and vascular endothelial injury models. Neither in vitro platelet aggregation induced by ADP, collagen or arachidonate nor ex vivo platelet aggregation by ADP or collagen could be antagonized by AVS. On the other hand, AVS prevented mice, rats and rabbits from death induced by acute cerebral or pulmonary thromboembolism following the injection of arachidonate or collagen. These activities were as potent as those of acetylsalicylic acid. The disrupting actions of citrate and/or lipidperoxide (13-hydroperoxy linoleic acid) on endothelium were well inhibited by the pretreatment of AVS. AVS did not inhibit cyclooxygenase, increased prostacyclin (PGI2)/thromboxane A2 (TXA2) ratio in the coupled system of platelets and aortic microsomes. In conclusion, AVS inhibited thrombus formation in vivo while it was ineffective in vitro platelet alone system, which may result from the actions of this agent on both platelets and vascular endothelium. The above-mentioned results clearly show that AVS may be a new potent anti-vascular damaging agent with both endothelium stabilizing and PGI2 enhancing activities.  相似文献   

3.
Raised plasma fibrinogen levels are associated with an increased risk of vascular events. This may be mediated by adverse effects of fibrinogen on plasma viscosity, coagulation, platelet activity, inflammation and atherogenesis. However, there is as yet no drug that specifically lowers plasma fibrinogen levels on a long-term basis. Thus, we do not have intervention trials demonstrating that lowering plasma fibrinogen levels will result in a decreased risk of vascular events. However, such a trial may never happen unless a specific agent is discovered or designed. Several drugs that are used in vascular disease prevention (e.g. lipid lowering agents and antihypertensives) may influence plasma fibrinogen levels. Whether such an additional effect accounts for variations in the benefit resulting from the use of different drugs within the same class remains to be established. The debate continues as to whether fibrinogen is just a marker of vascular risk or whether lowering its circulating levels will result in a significant decrease in clinically relevant endpoints. Whatever the case, the measurement of plasma fibrinogen levels is likely to provide a more comprehensive estimation of risk.  相似文献   

4.
BP is the most important determinant of the risk of stroke. A small reduction in BP results in a substantial reduction of both ischemic and hemorrhagic stroke. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental evidence has linked the renin-angiotensin system (RAS) to the development and progression of cerebrovascular disease. Inhibition of the RAS has beneficial cerebrovascular effects and may reduce the risk of stroke in a manner possibly independent from the alterations of BP. Some clinical trials even suggest that ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) exert cerebroprotective effects beyond BP lowering, but the evidence is controversial. Studies on specific protective actions of antihypertensive drugs are generally hampered by the fact that any treatment-related difference in BP may play a dominant role in the prevention of stroke. There are also indications that the protective potency of ARBs might be superior to that of ACE inhibitors, due to their differential activation of angiotensin II type 2 receptors, but the clinical relevance of this mechanism is unclear. Some studies in primary prevention of stroke, acute stroke, and secondary prevention show advantages for ARBs beyond controlling BP alone. In primary prevention, the LIFE randomized trial showed a significant difference in stroke rate in favor of losartan compared with atenolol despite similar reductions in BP. In acute stroke, the role of hypertension and its treatment remains controversial. ACCESS, however, suggested that an ARB is safe in hypertensive acute stroke patients and may offer advantages independent from BP control. In secondary stroke prevention, there are very few antihypertensive trials. These trials show that BP lowering is at least as successful as in primary prevention, but the absolute stroke risk is much higher. An ACE inhibitor was effective compared with placebo in the PROGRESS trial. The MOSES study showed that eprosartan prevented vascular events more effectively than nitrendipine, despite similar BP-lowering effects. Hypertension is not only the most important risk factor for stroke, but is also closely correlated with cognitive decline and dementia. Therefore, prevention of cognitive decline or even improvement of slightly diminished brain function should be an important goal for antihypertensive treatment in the future. Some clinical data suggest advantages for ACE inhibitors, ARBs, and calcium channel antagonists. Currently, however, the existing data are not sufficient for clinical recommendations. Therefore, ongoing trials will further define the exact role of inhibitors of the RAS and are urgently needed in secondary prevention, in acute stroke, and in the prevention of cognitive decline.  相似文献   

5.
The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.  相似文献   

6.
Statins may have additional properties beyond diminishing low-density lipoprotein (LDL) cholesterol levels. These actions could reduce the risk of vascular events. For example, these lipid lowering drugs act on the vascular endothelium, smooth muscle, haemostatic factors and the vessel wall. There are several differences in how statins act on these systems. These observations, in turn, lead to the conclusion that all statins may not be equally effective in terms of vascular disease prevention.  相似文献   

7.
Abnormal platelet reactivity has been linked to unstable angina, myocardial infarction, post angioplasty stenosis, cerebral ischemia, thrombotic stroke and a variety of inflammatory vascular disorders associated with transplantation. Drugs that inhibit blood coagulation, promote fibrinolysis or block platelet activation are important therapeutic agents in cardiovascular medicine. However, many of the current antiplatelet modalities are nonspecific, ineffective or associated with severe side effects that limit their usefulness. In this article, we discuss some basic aspects of platelet pathophysiology to illustrate the importance of ADP stimulation and signaling in platelet activation. CD39, the ATP diphosphohydrolase (ATPDase) expressed on quiescent vascular endothelium, modulates platelet purinoreceptor activity by the sequential hydrolysis of extracellular ATP or ADP directly to AMP. This thromboregulatory potential of CD39 has been recently demonstrated by the generation of mutant mice with disruption of the gene, and by a series of experiments where high level ATPDase expression has been attained by adenoviral vectors in the injured vasculature. Systemic administration of soluble derivatives of CD39 or targeted expression of the native protein to sites of vascular injury may have future therapeutic application.  相似文献   

8.
Beyond allopurinol and the well-established uricosuric drugs, several other agents can decrease serum uric acid (SUA) levels, such as losartan, fenofibrate and some non-steroidal anti-inflammatory drugs (NSAIDs). Some of these drugs increase renal urate excretion. Hyperuricaemia and gout are common problems (at least 1% of Western men are affected by gout). Raised SUA levels increase the incidence of acute gout and renal calculi. Hyperuricaemia may also predict an increased risk of vascular events. Therefore, lowering SUA levels is of clinical relevance. In this review we consider the effect on SUA levels of drugs that are prescribed for indications other than treating hyperuricaemia. These drugs may obviate the need for specific treatment (e.g. allopurinol) aimed at lowering SUA levels. Furthermore, because hyperuricaemic patients may already be on several drugs (e.g. due to associated dyslipidaemia, hypertension and/or arthritis) compliance may be improved by avoiding additional medication. The potential for adverse effects associated with polypharmacy would also be decreased.  相似文献   

9.
Essential hypertension may be a consequence of structural and functional alterations of the microvascular network growth resulting partly from abnormal regulation of vascular endothelial growth factor (VEGF), one of the most potent known angiogenic factors. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a proliferation and migration factor, is also a maintenance and protection factor for endothelial cells, whose altered regulation may cause a disturbance of vascular homeostasis. Elevated VEGF levels in hypertensive patients were shown to correlate with cardiovascular risk, early microvascular and target organ damage; accordingly treatment of hypertension significantly reduced VEGF levels. Recently and in agreement with the theory that impaired angiogenesis can contribute to increased peripheral resistance and raised blood pressure (BP), an involvement of VEGF gene promoter polymorphisms in the pathophysiology of hypertension has been hypothesized. In the last decade, anti-VEGF drugs have been used in clinical practice, especially in the oncology field. This review will summarize the present understanding of the contribution of VEGF to neoangiogenesis in hypertension and its possible role as a marker of vascular damage. Given the well established effects that antihypertensive drugs exert on the vasculature beyond BP lowering (pleiotropic effects), we will also discuss the effects of antihypertensive treatment on circulating VEGF levels. The biological mechanism and clinical impact of hypertensive complications during anti-angiogenic treatments will also be reviewed.  相似文献   

10.
Renal protection and antihypertensive drugs: current status.   总被引:3,自引:0,他引:3  
A Salvetti  P Mattei  I Sudano 《Drugs》1999,57(5):665-693
The renal protective effect of antihypertensive drugs is linked to 2 mechanisms. First, reduction in blood pressure (BP) is a fundamental prerequisite common to all antihypertensive drugs. The exact definition of the level to which BP should be reduced remains to be established, although there is some evidence that BP should be reduced below 130/85 mm Hg in patients with diabetic and nondiabetic nephropathies and below 125/75 mm Hg in patients with nondiabetic nephropathies and proteinuria >1 g/day. However, available data suggest that tight BP control (BP<140/80 mm Hg) can reduce the risk of cardiovascular complications in hypertensive patients with type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus; NIDDM). Secondly, intrarenal actions on mechanisms such as glomerular hypertension and hypertrophy, proteinuria, mesangial cell proliferation, mesangial matrix production and probably endothelial dysfunction, which can cause and/or worsen renal failure, are relevant for the renal protective action of some drug classes. ACE inhibitors possess such properties and also seem to lower proteinuria more than other antihypertensive drugs, despite a similar BP lowering effect. Calcium antagonists likewise exert beneficial intrarenal effects, but with some differences among subclasses. It remains to be evaluated whether angiotensin II-receptor antagonists can exert intrarenal effects and antiproteinuric actions similar to those of ACE inhibitors. While primary prevention of diabetic nephropathy is still an unsolved problem. there is convincing evidence that in patients with type 1 (insulin-dependent diabetes mellitus; IDDM) or 2 diabetes mellitus and incipient nephropathy ACE inhibitors reduce urinary albumin excretion and slow the progression to overt nephropathy. Similar effects have been reported with some long-acting dihydropyridine calcium antagonists, although less consistently than with ACE inhibitors. In patients with diabetic overt nephropathy, ACE inhibitors and nondihydropyridine calcium antagonists are particularly effective in reducing proteinuria and both drugs can slow the decline in glomerular filtration rate more successfully than other antihypertensive treatment. Available data in patients with nondiabetic nephropathies indicate that ACE inhibitors can be beneficial, principally in patients with significant proteinuria, in slowing the progression of renal failure. However, it is still unclear whether this beneficial effect of ACE inhibitors is particularly evident in patients with mild and/or more advanced renal failure and whether calcium antagonists possess a similar nephroprotective effect. Overall, data from clinical trials thus seem to indicate that ACE inhibitors and possibly calcium antagonists should be preferred in the treatment of patients with diabetic and nondiabetic nephropathies. However, further information is needed to understand renal protection.  相似文献   

11.
Impaired vascular relaxation is a common aetiology in many cardiovascular diseases and, in most cases, disequilibria in the amounts of endothelium-derived relaxing and constricting factors is the root of problem. Endothelium-derived vasoactive factors modulate vascular tone, smooth muscle cell proliferation, blood coagulation and fibrinolysis, lipoprotein metabolism and the interaction of platelet and leukocyte with the vascular wall. Although the synthesis and release of endothelium-derived vasoactive substances are vulnerable to pathogenic insults, endothelial dysfunction can be corrected pharmacologically using inhibitors of the renin–angiotensin system, endothelin antagonists, inductors of angiogenesis and other compounds. Many recent patents have provided novel formulations of drugs targeting dysfunctional endothelium. Optimised pharmacodynamic and pharmacokinetic properties of these drugs would greatly improve their clinical applications.  相似文献   

12.
The present study examined the effects of antihypertensive drugs (hydrochlorothiazide and guanethidine) on blood pressure and tyrosine hydroxylase (TH) activity in the spontaneously hypertensive rat (SHR). Hydrochlorothiazide (50 mg/kg X 4 days) lowered blood pressure in the SHR to a degree equivalent to that produced by reserpine (0.3 mg/kg X 3 days). However, while reserpine increased vascular and adrenal TH activity, hydrochlorothiazide had no effect. Guanethidine (30 mg/kg X 2 days) reduced blood pressure in the SHR and also depleted cardiac, vascular and adrenal gland catecholamines; However, guanethidine administration did not increase TH activity in the mesenteric vasculature or adrenal glands. These studies indicate that at equieffective blood pressure lowering doses, different antihypertensive drugs have different effects on TH activity in the SHR. Neither blood pressure reduction nor catecholamine depletion in peripheral tissues are sufficient prerequisties for increasing TH activity. The data support the suggestion, however, that amine depletion in the central nervous system or ganglia may be an important factor in the regulation of TH.  相似文献   

13.
This study describes a modification of Vane’s blood-bathed organ technique (BBOT). This new technique consisted of replacing the cascade of contractile smooth muscle organs within the traditional BBOT by a single collagen strip cut from a rabbit’s hind leg tendon. Utilizing the extracorporeal circulation of an anesthetized heparinized mongrel cat or Wistar rat, arterial blood was dripped (1–3 ml min–1) over a collagen strip. This resulted in a gain in weight of the strip, which was due to the deposition of platelet aggregates and a few blood cells trapped over the strip. Arterial blood that had been used for the superfusion was pumped back into the animal’s venous system. However, when this technique is adapted to human volunteers, the superfusing blood should be discarded. In animal experiments, intravenous injections of a variety of classic fibrinolytic agents (e.g., streptokinase) promoted the formation of platelet thrombi. Nitric oxide donors (e.g., SIN-1) at non-hypotensive doses hardly affected the mass of platelet thrombi deposited over the collagen strip, whereas endogenous prostacyclin (e.g., released from vascular endothelium by bradykinin) or exogenous prostacyclin and its stable analogues (e.g., iloprost) dissipated platelet thrombi as measured by a loss in the weight of the blood superfused collagen strip. This model allowed us to assay numerous drugs for their releasing properties of endogenous prostacyclin from vascular endothelium. These drugs included lipophilic angiotensin converting enzyme inhibitors (ACE-Is), which act in vivo as bradykinin potentiating factors (BPF). Other PGI2-releasers included statins (e.g., atorvastatin and simvastatin), thienopyridines (e.g., ticlopidine and clopidogrel), a number of thromboxane synthase inhibitors, flavonoids, bradykinin itself, cholinergic M receptor agonists and nicotinic acid derivatives. The thrombolytic actions of lipophilic ACE-Is (e.g., quinapril and perindopril) were prevented by pretreatment with either bradykinin B2 receptor antagonists (e.g., icatibant) or with endothelial COX-2 inhibitors (e.g., rofecoxib, celecoxib and high dose aspirin). The inhibition of endothelial nitric oxide synthetase (eNOS) by L-NAME hardly blunted the thrombolytic response to ACE-Is. Hence, it can be concluded that many recognized cardiovascular drugs apart from their known basic mechanisms of action, may also behave as releasers of endogenous endothelial prostacyclin. Furthermore, in many instances, this effect may be the primary mechanism of their therapeutic efficacy.  相似文献   

14.
Wenzel RR 《Drugs》2005,65(Z2):29-39
Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from a trial in diabetic patients who had uncontrolled hypertension and microalbuminuria despite optimal therapy with an ACE inhibitor or an ARB suggest that manidipine may be an excellent antihypertensive drug in combination with RAS inhibitor treatment in order to normalise BP and albumin excretion in patients with diabetes.  相似文献   

15.
Abnormal platelet reactivity has been linked to unstable angina, myocardial infarction, post-angioplasty stenosis, cerebral ischaemia, thrombotic stroke and a variety of inflammatory vascular disorders associated with organ or cell transplantation. Drugs that inhibit blood coagulation, promote fibrinolysis or block platelet activation are important pharmacological agents in these clinical areas. However, current antiplatelet modalities have multiple limitations that preclude widespread and effective therapeutic intervention. Extracellular nucleotide stimulation and purinergic/pyrimidinegic receptor (P2) mediated signalling are key components of platelet and vascular endothelial cell activation responses that culminate in vascular thrombosis. CD39, the nucleoside or adenosine triphosphate diphosphohydrolase (NTPDase or ATPDase) is highly expressed on quiescent endothelium and is the dominant vascular ectonucleotidase hydrolysing plasma ATP and ADP to AMP. The thromboregulatory potential of CD39 has been recently demonstrated by our generation of mutant mice with disruption of the gene. These mice exhibit markedly disordered thromboregulation but also show perturbations in haemostasis secondary to platelet P2Y1-receptor desensitisation. In addition, we have demonstrated in several animal models that administration of soluble NTPDase and induction of high level CD39 expression by adenoviral vectors consistently results in substantial amelioration of vascular injury. Systemic administration of soluble derivatives of CD39 or targeted expression of the native protein to sites of arterial injury may have future therapeutic application in vascular diseases.  相似文献   

16.
《General pharmacology》1996,27(2):221-238
  • 1.1. Alterations in the function of the endothelium and arterial smooth muscle may be important in the establishment of hypertension. Thus, the possible favorable influences of blood pressure-lowering agents on vascular responsiveness may be important in the chronic antihypertensive actions of these compounds.
  • 2.2. A number of reports have suggested that ACE inhibitors can improve arterial function in hypertension, whereas the knowledge about the vascular effects of other antihypertensive drugs, like β-blockers, calcium channel blockers, and diuretics remains rather limited.
  • 3.3. In this article, the effects of antihypertensive therapy on arterial function in human and experimental hypertension are reviewed.
  相似文献   

17.
1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.  相似文献   

18.
There is evidence showing that serum uric acid (SUA) levels predict the risk for vascular events. For example, up to 29% of the reduction in the primary composite endpoint seen in the LIFE trial (favouring losartan versus atenolol) can be attributed to a fall in SUA levels. We also discuss the findings of the GREACE study (treating to target with atorvastatin versus 'usual' care) in relation to SUA levels. In this brief comment we extend this argument to consider the SUA-lowering effect of other drugs commonly prescribed in patients with vascular disease (e.g. statins, fibrates and antihypertensive agents). A judicious use of drugs (alone or in combination) will result in small reductions in SUA levels. These changes may translate into a substantial reduction in the risk of vascular events. Results retrieved from completed trials together with new prospective findings will support or refute the proposed association between lowering SUA levels and reducing vascular morbidity and mortality.  相似文献   

19.
M D Fotherby  B Panayiotou 《Drugs》1999,58(4):663-674
It is clear that antihypertensive regimens based on a low dose thiazide diuretic are effective for the primary prevention of stroke, particularly in older patients. In patients with diabetes mellitus who are at a higher risk of stroke, low dose thiazide diuretics and ACE inhibitors are of benefit. In those with isolated systolic hypertension, long-acting dihydropyridine calcium antagonists, in addition tolow dose thiazide diuretics, have also been shown to significantly reduce stroke risk. However, to attain sufficient lowering of blood pressure (BP) to most effectively reduce the risk of stroke (i.e. to levels of 140-150/80-85 mm Hg or lower and perhaps to <140/<80 mm Hg in patients with diabetes mellitus) combination therapy will be required. Immediately following stroke BP tends to fall spontaneously and therapy is probably not required in the great majority of patients during the first few days poststroke. If treatment is required shortly after this period, agents with a slow and gentle onset of action appear to be preferable; some preliminary data suggest that ACE inhibitors, despite lowering systemic BP, have no significant effect on cerebral blood flow. However, there is little clinical outcome data to clearly define the role of antihypertensive treatment in the early poststroke period. Whether existing antihypertensive therapy should be continued following stroke is also unclear, but such decisions may be influenced by factors such as the actual BP level, other indications for treatment (e.g. angina pectoris or cardiac failure) or the presence of dysphagia. There is more evidence to suggest that, some weeks to months following stroke (particularly a minor stroke), lower rather than higher BP is favourable, and better control of high BP with therapy reduces stroke recurrence.  相似文献   

20.
The kidney as a primary excretory organ is a major route of elimination for numerous xenobiotic agents. In the process, it is liable to the hemodynamic and injurious actions of drugs due to their concentration in the kidney. In this brief review, a number of methods for assessing kidney function (e.g., serum creatinine, enzymuria, inulin, and PAH clearances, etc.), with their advantages and limitations, are described. Various acute and chronic animal models (rats and dogs) commonly used in performing safety evaluation of drugs are described; several antihypertensive drugs are cited as examples. These models can be modified with varying number of measurements, depending on the pharmacological activity of test drugs, animal species, specific issues (e.g., vascular vs. tubular effects), pathophysiological conditions, etc.  相似文献   

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