Drugs

Gibbons, Gary

doi: 10.2165/00003495-199700545-00003pmid: 9429840

The current challenge facing clinicians is to develop pharmacotherapies that move beyond the treatment of symptoms towards a new agenda in cardiovascular therapeutics that includes interventions to actually prevent the development of end-stage coronary heart disease. The development of new strategies to alter the natural history of cardiovascular disease will be fostered by gaining insights into the fundamental pathobiological mechanisms that promote the morbidity and mortality associated with these disorders. An emerging body of evidence indicates that locally generated vasoactive substances such as angiotensin II and nitric oxide are important determinants of the natural history of vascular disease. It is anticipated that ongoing clinical trials will extend the concept that modulating the activity of vasoactive substances generated by the endothelium has important implications for altering the course of coronary heart disease.

Mombouli, Jean-Vivien

doi: 10.2165/00003495-199700545-00004pmid: 9429841

In healthy coronary arteries, the endothelium plays an important role in the regulation of vascular smooth muscle growth and contractility. Furthermore, the endothelium inhibits overt platelet aggregation and prevents the adhesion of white blood cells to, and their infiltration into, the vascular wall. Among the mediators of these functions of endothelial cells, nitric oxide (NO) plays a central role. Moreover, the presence of local kinin-generating enzymatic systems associated with endothelial cells, vascular smooth muscle, platelets, neutrophils and monocytes suggests that bradykinin stimulates endothelial cells to release NO locally. The activation of endothelial cells by bradykinin is inhibited by kininase II, best known as angiotensin converting enzyme (ACE). Hence, ACE inhibitors, in addition to reducing the levels of angiotensin II (a potent stimulus to vascular smooth muscle growth and contraction), cause an amplification of the release of NO and other endothelial mediators that is induced by bradykinin.

Bönner, Gerd

doi: 10.2165/00003495-199700545-00005pmid: 9429842

Kinins are highly potent vasoactive peptides. They reduce blood pressure by vasodilation and are cardio- and vasoprotective. ACE inhibitors potentiate the actions of endogenous kinins by about 50-fold. Kinins are involved in the blood pressure-lowering effects of ACE inhibitors in all forms of hypertension associated with stimulation of the renin-angiotensin system. In addition, kinins play an important role in the metabolic, and cardio- and vasoprotective effects of ACE inhibitors.

Heusch, Gerd; Rose, Jochen; Ehring, Thomas

doi: 10.2165/00003495-199700545-00006pmid: 9429843

Myocardial ischaemia, when severe and sustained for more than 40 minutes, results in irreversible damage, i.e. myocardial infarction. However, with early reperfusion, damage is reversible. Complete recovery of contractile function requires some time, despite fully or almost fully restored blood flow. This phenomenon has been termed myocardial stunning. There is experimental evidence showing that angiotensin converting enzyme (ACE) inhibitors limit the development of infarct size, reduce the incidence of ischaemic and reperfusion arrhythmias, and enhance the recovery of contractile function of stunned myocardium. These cardioprotective effects of ACE inhibitors are mediated by an attenuated degradation of bradykinin.

Hornig, Burkhard; Drexler, Helmut

doi: 10.2165/00003495-199700545-00007pmid: 9429844

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors (EDRFs) under basal conditions. In addition, the endothelium can increase the release of EDRFs in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions, the most important stimulus to the release of EDRFs is an increase in blood flow leading to increased shear stress on endothelial cells. Recent experimental studies raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or a hyperpolarising factor [endothelium-derived hyperpolarising factor (EDHF)]. This concept is also supported by recent studies in humans demonstrating that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has now been shown to be important in both human peripheral and coronary arteries. Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II, but also increase bradykinin levels, since the angiotensin converting enzyme is identical to kininase II, an enzyme that degrades bradykinin. This raises the possibility that beneficial vascular effects of ACE inhibitors may be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect of ACE inhibition is bradykinin dependent. These findings raise the possibility that the beneficial effects of ACE inhibition in heart failure and coronary artery disease might be partly due to improved endothelial function.

Megarry, Simon; Sapsford, R.; Hall, A.; Ball, S.

doi: 10.2165/00003495-199700545-00008pmid: 9429845

Large randomised clinical trials have shown ACE inhibitors to improve survival after acute myocardial infarction (AMI). The precise mechanism underlying this benefit is not fully established, despite extensive research. There is also controversy with regard to the clinical use of these drugs, particularly the need for selection of patients prior to treatment and the timing of drug initiation and withdrawal for maximum benefit.

Remme, Willem

doi: 10.2165/00003495-199700545-00009pmid: 9429846

In addition to being accepted therapy in hypertension and heart failure, ACE inhibitors may well offer a new dimension in anti-ischaemic therapy. Currently, anti-ischaemic properties have been demonstrated by ACE inhibitors in selected patient groups, including patients with left ventricular dysfunction with or without a direct temporal relationship with myocardial infarction.

doi: 10.2165/00003495-199700545-00010pmid: N/A

Eadie, Mervyn

doi: 10.2165/00003495-199754050-00001pmid: 9360055

It is generally accepted that anticonvulsant therapy should be offered once a patient has experienced 2 or more seizures. However, there is controversy over whether treatment should be offered after a single seizure. The type of epileptic event that has occurred may determine whether or not a single episode will bring the individual to medical attention. In individuals who experience a single seizure, there is significantly increased risk of recurrence if neurological or paroxysmal electroencephalogram abnormalities are present or if the seizure is partial. Anticonvulsant therapy, if taken as prescribed after a single seizure, will substantially reduce the risk of seizure recurrence. Unless a further seizure would hold little disadvantage, early treatment probably offers distinctly more benefit than hazard. No data are available to indicate the most appropriate duration of therapy after a single seizure.

Alexander, Barbara; Perfect, John

doi: 10.2165/00003495-199754050-00002pmid: 9360056

Medical advances have led to increased numbers of immunocompromised patients living longer. Coinciding with this increase in the immunocompromised patient population is an increase in the number of clinically significant fungal infections. Unfortunately, widespread use of the limited numbers of antifungal agents to treat these infections has led to the development of drug resistance. Thus, in an attempt to sort out the mechanisms of resistance for each of the systemically useful antifungal agents, a comprehensive review of the literature has been carried out.