Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris.

Horowitz, John D.; Henry, Christine; Syrjanen, Marie L.; Louis, William J.; Fish, R. David; Smith, Tom W.; Antman, Elliott M.

doi:10.1161/01.cir.77.4.787

Cited by 110 publications

(25 citation statements)

References 43 publications

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“…However, by 24 hours, heart rate was not different from the pretreatment values ( Figure 1B). In the intermittent therapy group, there was a significant increase in heart rate after patch application on each of the three treatment days ( Figure 1D).…”

Section: Hormonal Measurementsmentioning

confidence: 74%

Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

et al. 1991

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BACKGROUND Vasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN). METHODS AND RESULTS Standing systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval. CONCLUSIONS Continuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.

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Section: Hormonal Measurementsmentioning

confidence: 74%

Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

et al. 1991

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“…However, other potential interactions of NAC and nitroglycerin, such as the proposed extracellular formation of the nitric oxide radical and the potentiation of nitroglycerininduced inhibition of platelet aggregation by NAC,45 are not excluded by our study and may become therapeutically relevant in the future. 46 …”

Section: Extracellular Enhancement Of Nitrate-induced Guanylate Cyclamentioning

confidence: 99%

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.

et al. 1989

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N-acetylcysteine is assumed to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, but data on interactions of N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of Nacetylcysteine on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n=12) during long-term nitroglycerin treatment (1.5 ,g/kg/min i.v. for 5-6 days). In dogs with nitroglycerin-specific tolerance (shift of venous or epicardial artery dilation to 15-17-fold higher dosages), N-acetylcysteine (100 mg/ kg i.v.) had no dilator effect and did not alter the dose-response relations of nitroglycerin. Yet, in nontolerant dogs (n=17), N-acetylcysteine augmented (1.5-2.0-fold) the dilation of epicardial arteries and the reduction of peripheral vascular resistance induced by 0.5-1.5 ,ug/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 ,M) was potentiated by N-acetylcysteine (0.01-1.0 mM) in saline or in canine plasma, but N-acetylcysteine alone was ineffective. We conclude that 1) N-acetylcysteine does not restore nitroglycerin responsiveness in tolerant epicardial arteries or veins in vivo, 2) a small, tolerance-independent augmentation of nitroglycerin-induced dilation may result from Nacetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin. (Circulation 1989;79:188-197) D uring continued administration of organic nitrates, their anti-ischemic effects are severely blunted. 1-5 Proposed mechanisms of this phenomenon of tolerance include alterations in intracellular nitrate metabolism6,7 or the activation of neurohumoral systems counteracting the vasodilator potency of nitrates.8-11 In vitro findings stressed the critical role of intracellular sulfhydryl groups in activation of guanylate cyclase6.12,'3 and nitrate tolerance development.These observations led to the study of the interactions between nitroglycerin and the sulfhydryl donor N-acetylcysteine (NAC) in nontolerant and tolerant

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“…N-acetylcysteine (NAC), a precursor of cysteine, has been in clinical use for more than 25 years as a mucolytic agent, 1 a protective agent against the toxicity of drugs used for cancer chemotherapy, 2±4 for reversal of acquired tolerance to organic nitrates in cardiovascular disease, 5 and as an effective antidote in paracetamol poisoning.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of N‐acetylcysteine are altered in patients with chronic liver disease

Jones

Jarvie

Simpson

et al. 1997

Aliment Pharmacol Ther

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Background: The threshold plasma paracetamol concentration at which N‐acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously. In addition, there is increasing use of NAC in patients with chronic liver disease for multiorgan failure or hepatorenal syndrome. Little is known of NAC's pharmacokinetic properties in patients with cirrhosis. Aim: The aim was to determine if the pharmacokinetics of NAC are altered by chronic liver disease. Subjects and methods: NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsy‐proven cirrhosis (Child's grade; 1 A, 4 B, 4 C; aetiology: 7 alcohol‐related, 1 primary biliary cirrhosis, 1 secondary biliary stenosis) and six healthy matched controls. Venous blood was taken at 20, 40, 60 and 90 min then at 2, 3, 4, 6, 8 and 10 h after NAC administration. Serum NAC was estimated by HPLC. The data were normalized to a standard body weight of 70 kg. Results: The area under the serum concentration–time curve was increased (152.34 mg/L.h ± 50.38 s.d.) in cirrhotics compared with normal controls; (93.86 mg/L.h ± 9.60 s.d.) (P < 0.05). The clearance of NAC was reduced in patients with chronic liver disease (4.52 L/h ± 1.87 s.d.) compared with controls (6.47 L/h ± 0.78; P < 0.01). Conclusions: Increased vigilance for untoward anaphylactoid reactions is necessary in cirrhotics as they may have higher plasma NAC concentrations. Further studies to determine the optimum dosage regimen in such patients are required.

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Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris.

Cited by 110 publications

References 43 publications

Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.

Pharmacokinetics of N‐acetylcysteine are altered in patients with chronic liver disease

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