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Effects of nicardipine hydrochloride in cardiac failure: A dose titration and tolerance study
Abstract
Ca2+-antagonists have a vasodilatory action which makes them useful in treatment of congestive heart failure (CHF). Nicardipine (N) has potent vasodilatory properties. Fifteen patients, mean age 62 years, with CHF, in class II-III, despite previous therapy, were studied. The individual optimal dose of N was titrated from 20 mg t.i.d. to 40 mg t.i.d. Treatment continued for 6 weeks. Weight, left and right ankle circumference, heart rate (HR), and blood pressure (BP) were recorded. Exercise test using a bicycle ergometer, chest x-rays calculating cardiac size in ml/m2 BSA, 24-hour continuous ECG monitoring and left ventricular ejection fraction (LVEF) were performed before and after treatment. Two patients responded to 20 mg t.i.d., 7 to 30 mg t.i.d. and 6 to 40 mg t.i.d. Two patients responded poorly to treatment. Mean weight decreased significantly from 87 to 78 kg (p < 0.001). Both ankle circumferences dropped significantly (p < 0.001) with a decrease of more than 4 cm. LVEF increased in 13 patients and cardiac size decreased. Maximum exercise time increased in 13 patients from 3 to 9 minutes (p < 0.001) and the total workload in these patients increased significantly (p < 0.001). Two patients did not show changes in weight, LVEF, cardiac size or ankle circumference. The NYHA classification did not change in these two while it improved in the other 13. No serious side effects were seen. Nicardipine was an effective treatment in congestive heart failure. These results indicate that Ca2+-antagonists with vasodilating properties can be used when treating patients with CHF, especially if the underlying pathology is coronary artery disease.
This chapter discusses antianginal and β-adrenoceptor blocking drugs. Cold extremities, patchy skin necrosis, and Raynaud's phenomenon are established side effects of beta-blocker therapy (SED-10, 320). It is not known whether ancillary properties of the individual agents play a role in the production of such side effects. It is well recognized that unmasked α-adrenergic effects can lead to hypertensive crises during beta-blocker use in patients with pheochromocytoma or hypoglycemia. Sotalol is an effective antiarrhythmic agent in supraventricular and ventricular tachyarrhytbmias by virtue of its Class III activity, but the Q-Tc prolongation it induces can provoke the serious ventricular arrhythmia. Psychotic reactions occur occasionally during beta-blocker, particularly propranolol, therapy and may assume affective or schizoid forms. Minor psychological symptoms, such as drowsiness, sleep disturbance, and vivid dreams are commonly associated with betablocker use and there is some evidence in man to suggest that such side effects parallel lipophilicity and hence passage across the blood–brain barrier. Tremors of various types have been successfully treated by β-adrenoreceptor antagonists and recent observations on the withdrawal of long-term therapy with atenolol or propranoiol may be relevant to the physiological mechanisms involved.
When, on 21st September 2006, 'The Economist' compared incumbent telecommunication operators with dinosaurs that could soon face extinction, most readers were ready to agree. The mixture of declining revenues and fierce competition was believed to shake the market and soon to dethrone former national champions. However, there are ways to fight that extinction and one way is to open up for competitive advantage. This paper reflects on a case study at Deutsche Telekom, the German national telecommunication operator. The aim of this study is to analyse to what extent the open innovation paradigm has been embraced inside this now multinational company. Using empirical evidence from 15 in-depth interviews, we identify 11 open innovation instruments and detail their value contribution. We can show that Deutsche Telekom has successfully enhanced its innovation capacity by opening up its traditional development process and embracing external creativity and knowledge resources.
The presence of calcium ions is essential to the normal function of the cardiovascular system. Drugs such as calcium antagonists can modulate the interaction between these ions and specific cells at different levels, interfering with myocardial contraction and relaxation, vascular tone, specific conduction tissues and neuromuscular function. Vascular beds play a crucial role in adjustment of myocardial function to different body oxygen requirements; compensatory mechanisms in congestive heart failure (CHF) involve the vascular system to a large extent and paradoxically may worsen myocardial performance.
Vasodilating drugs represent an important step forward in achieving better symptomatic results in CHF patients, and may also increase their survival. Of the different classes of vasodilator drugs calcium antagonists may represent an attractive alternative due to their anti-ischaemic and antiarrhythmic effects. Despite the overall good response to the acute use of these drugs in CHF, long term studies in which first generation calcium antagonists (nifedipine, diltiazem, verapamil) were used have produced disappointing results. Their main drawbacks were negative inotropism, lack of preload reduction and activation of neurohormonal mechanisms with a subsequent adverse effect on cardiovascular function, the latter effect being the most significant. A few long term studies, of between 1 and 52 months, have not demonstrated a consistent improvement in functional class in spite of apparently good initial results.
The second generation of calcium antagonists have more potent and selective vasodilating properties with less negative inotropic effects; these properties might justify their use in the therapy of CHF, but no clear recommendations can be given due to the lack of large, long term, controlled studies. Overall, the existing clinical trials with calcium antagonists in CHF have not proved the superiority of this group of drugs when compared to other vasodilators.
If the aetiology of CHF is related to the presence of coronary artery disease or arterial hypertension, calcium antagonists might be considered as additional therapeutic options. Diastolic dysfunction may be corrected or improved and coronary tone may be diminished, both of which may lead to a better myocardial oxygen supply. Systolic myocardial function must be evaluated in CHF patients before starting therapy with calcium antagonists in order to avoid possible deleterious effects.
Further studies may shed more light on this matter and may indicate decisively whether or not calcium antagonists should play a role in the therapeutic pharmacological arsenal of selected CHF patients.
Despite a well-established rationale for pharmacologically induced arterial and venous vasodilatation in congestive heart failure, the clinical usefulness of long-term vasodilator therapy without concomitant converting-enzyme inhibition generally has been disappointing. With the exception of nitrates and, possibly, the combination of nitrates and hydralazine, the use of converting-enzyme inhibitors in many aspects appears preferable in the majority of patients. This article reviews the pathophysiology of inappropriate vasoconstriction in heart failure, the cellular mode of action of the various vasodilators, hemodynamic effects with respect to the peripheral site of action, clinical usefulness and limitations of different vasodilators, and the various determinants of clinical efficacy. Finally, an attempt is made to assess when and how to introduce vasodilator treatment with and without concomitant ACE inhibition.
Nicardipine has been shown to lower blood pressure in patients with uncomplicated hypertension as well as in patients with concomitant renal impairment, coronary artery disease or congestive heart failure. The decrease in blood pressure induced by nicardipine is related to a concurrent decrease in total peripheral vascular resistance. The antihypertensive actions of nicardipine are maintained during long-term administration without the development of tachyphylaxis. In patients receiving diuretics or beta blockers, the addition of nicardipine has been shown to produce an additional decrease in blood pressure. The combined use of nicardipine and beta blockers may be beneficial in the treatment of hypertension: the increase in peripheral vascular resistance during beta blockade may be prevented by nicardipine-induced vasodilation; conversely, beta blockers may prevent reflex tachycardia and other consequences of peripheral vasodilatation. Although nicardipine may increase the heart rate acutely, tachycardia does not occur during long-term therapy. Preliminary data suggest that nicardipine exerts potent antihypertensive effects in patients with renal insufficiency without altering renal parameters. In patients with normal renal function, nicardipine has been shown to cause acute natriuresis and an increase in renal blood flow and glomerular filtration rate. Nicardipine also has a favorable effect on peripheral and cerebral blood flow. Like other dihydropyridines, nicardipine appears to have an antiatherogenetic effect in the experimental model. Short-term therapy with nicardipine does not affect serum lipid levels. Results from several studies suggest that nicardipine is an effective antihypertensive agent that can be used as monotherapy or in combination with other drugs such as beta blockers or diuretics.(ABSTRACT TRUNCATED AT 250 WORDS)
The newer dihydropyridine calcium antagonists are structurally related to nifedipine, but may provide greater vascular selectivity and wider clinical utility. Five new dihydropyridines-nisoldipine, nicardipine, nimodipine, felodipine and nitrendipine-are reviewed with regard to their preclinical pharmacology, haemodynamic effects and clinical indications. Nisoldipine is a potent arterial vasodilator with minimal electrophysiological and negative inotropic effects. Although data are still preliminary, the drug has shown some efficacy in both exertional angina and essential hypertension. The dosing interval is not yet clearly established, but may be twice daily. Utility in congestive heart failure awaits confirmation, but preliminary studies are promising. Nicardipine is an especially potent peripheral, cerebral and coronary arterial vasodilator that causes 10-fold less myocardial depression in animals than nifedipine, and may provide important cardioprotective effects during ischaemia. Human haemodynamic studies have confirmed nicardipine's lack of negative inotropism, its ability to reduce coronary and peripheral vascular resistance, and its lack of effect on cardiac conduction. Several controlled trials have documented its efficacy in exertional angina, vasospastic angina, and essential hypertension. Nicardipine's potential as an antiatherosclerotic agent is currently under investigation. Nimodipine is undergoing a unique clinical development programme aimed at cerebrovascular disorders. In almost all species, nimodipine selectively increases cerebral blood flow and reverses cerebral artery spasm without altering cerebral oxidative metabolism or systemic blood pressure. In humans, a large, double-blind, placebo-controlled trial in subarachnoid haemorrhage showed that nimodipine significantly reduced the severity of neurological deficits associated with delayed cerebral vasospasm. Several uncontrolled trials with larger numbers of patients support these results. Nimodipine has also proved useful in reducing cerebral artery spasm during intracranial surgery, and in the prophylactic treatment of migraine headaches. A preliminary study of nimodipine in acute stroke showed promising results in limiting neurological disability. Felodipine is a very potent systemic arterial vasodilator with negligible myocardial depressant activity. It is also a renal artery vasodilator. Unlike the other new dihydropyridines, felodipine prolongs the A-H interval on electrophysiological testing, but only to about 50% of that observed with verapamil. Felodipine is undergoing clinical trials in essential hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)
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