Inhibitor-treated Patients Research Articles

A role for phosphodiesterase type-4 inhibitors in COPD?

Millions of smokers develop chronic obstructive pulmonary disease (COPD). This disease is associated with debilitating symptoms, such as cough and breathlessness, which persist and progress despite stopping smoking. However, only about 15% of active smokers develop COPD, 1 US Surgeon General.The health consequences of smoking: chronic obstructive lung disease. DHHS Publication No. 84-50205. US Department of Health and Human Services, Washington, DC1984 Google Scholar which suggests that other factors are involved. Genetic factors known to affect the risk of COPD are mutations of the α1-antitrypsin gene and a haplotype associated with decreased function of microsomal epoxide hydrolase. 2 Sandford AJ Chagani T Weir TD Connett JE Anthonisen NR Pare PD Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med. 2001; 163: 469-473 Crossref PubMed Scopus (247) Google Scholar Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging studyCilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway. Full-Text PDF

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study

Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease. We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat. Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups. Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

The Effect of Nevirapine in Combination With Nelfinavir in Heavily Pretreated HIV-1–Infected Patients

To determine whether initiation of antiretroviral therapy that includes the protease inhibitor indinavir causes insulin resistance or abnormal B-cell function in study subjects with HIV infection. Methods: Nonwasted, HIV-infected study subjects who did not have concurrent diabetes were prospectively evaluated by oral and intravenous glucose tolerance testing at baseline, at 2 weeks after starting indinavir monotherapy, and at another 6 weeks after initiating indinavir-based triple-therapy. Results: Mean CD4 count at entry was 282 cells/μl and median HIV RNA was 33,000 copies/ml; all experienced a virologic response. Fasting glucose increased from 83.2 ± 3.7 mg/dl at baseline to 86.8 ± 3.2 at week 2 and 91.7 ± 3.5 at week 8 (p = .003). Insulin sensitivity by minimal model analysis decreased by 30.5% over 8 weeks, from 3.83 ± 0.63 min-1 per μU/ml × 10-4 to 3.09 ± 0.53 at week 2 and 2.66 ± 0.35 at week 8 (p = .01). Insulin secretion by the acute insulin response to intravenous glucose did not change (baseline 822 ± 283 μU/ml × min, week 8 880 ± 289; p = 0.4), and the insulin response to oral glucose (30 minute insulin:glucose ratio) fell from 1.69 ± 0.54 μU/ml per mg/dl at baseline to 1.18 ± 0.34 at week 8 (p = .05). Conclusion: During 8 weeks of indinavir-based therapy, fasting glucose increased and insulin sensitivity decreased, without a compensatory increase in insulin release. This combination of insulin resistance without augmented B-cell response may explain the hyperglycemia and other metabolic abnormalities seen in some protease inhibitortreated patients.

Osteonecrosis in Protease Inhibitor-Treated Patients

The introduction of protease inhibitors has proven a watershed in human immunodeficiency virus infection therapy and has initiated an era of highly active antiretroviral therapy. However, the numerous data on the effectiveness of these therapeutic regimens have been cited with an ever-growing number of communications concerning adverse reactions. In particular, the widescale use of protease inhibitors has underlined a series of events not evidenced in the controlled clinical studies that permitted the registration of these drugs. We are conducting a cohort multicenter study to evaluate the incidence of adverse events during treatment with protease inhibitors. To date, 4 cases of bilateral osteonecrosis of the femoral head have been reported out of 1073 person-years. While the pathogenesis of this event is unclear, it may be a long-term complication of protease inhibitor treatment.

Hormones, drugs, remodeling and outcome in heart failure and after myocardial infarction.

Sustained neurohormonal activation commonly occurs after large myocardial infarctions (MI) and in chronic heart failure. This activation is thought to be a critical contributor to the progressive left ventricular structural remodeling that accompanies these syndromes and appears to shorten life expectancy [1]. The clinical efficacy of beta blockers after MI was demonstrated before the structural remodeling process was understood [2] and thus the mandate for their use in this setting is based on outcome not on mechanism. In contrast, the mandate for angiotensin convertingenzyme (ACE) inhibitors is based on both outcome and a favorable effect on remodeling after MI [3,4]. The sequence of investigation was reversed in heart failure, in which ACE inhibitors were first demonstrated to be effective on both remodeling and outcome [5,6] whereas the beta blocker efficacy on these end-points could only be studied in ACE inhibitor-treated patients [7,8]. This historical discrepancy has left evidence-based zealots without the proof that beta blockers work as well without ACE inhibitors in heart failure and without the proof that beta blockers inhibit remodeling after acute MI. And it is hard to turn back the clock to accumulate these data, since ACE inhibitors are mandated therapy in chronic heart failure and beta blocker use is a mandated guide to good clinical management after acute MI. Insightful clinical scientists recognize that the mechanisms contributing to adverse outcomes and their response to therapy are probably similar in patients with different disease entities such as myocardial infarction and heart failure. So we comfortably utilize the two drug groups together in both syndromes, with the assumption that they are contributing independently to a favorable effect on both remodeling and outcome. That independence is better demonstrated in chronic heart failure than it is in the postinfarction period. Furthermore, the therapeutic choices have recently been expanded by the availability of angiotensin receptor blockers [9] and the demonstration that spironolactone may also exert a favorable effect on outcome [10], possibly through an anti-remodeling action. So physicians are confused and conflicted. Should they use all the drugs together because of their likely independent effects? Should they accept the high cost, potential side effects and complexity of this polypharmacy? Or should they be selective by trying in the absence of persuasive data to determine who should receive an ACE inhibitor, who a beta blocker, and who both? The CARMEN trial, described in this issue of Cardiovascular Drugs and Therapy [11], should help to answer some of these questions. Furthermore, by studying the effect of an unusual beta blocker, carvedilol, with additional pharmacological properties, including alpha 1-adrenergic blockade and antioxidant properties, the protocol should provide valuable new therapeutic efficacy data. Could this single drug produce an effect as great as an ACE inhibitor-beta blocker combined? Or will the study corroborate the clinical suspicion that beta blockers exert a synergistic effect with ACE inhibitors? For those who are dedicated to reducing the use of multiple drugs in the absence of demonstrated independent efficacy, this could be an important study. The problem facing the CARMEN investigators in designing the study was that it could not easily be powered for morbid events. Thus a more sensitive marker for efficacy was both necessary and preferable. Indeed, morbid events are likely to occur in only a small fraction of the patients entering a study like CARMEN, and thus the majority of randomized patients would not contribute to the end-point. Monitoring structural changes in the left ventricle provides an end-point to which all patients should contribute and also might provide a mechanistic marker that could be used in clinical management. The problem is not simple, however. Echocardiography is notoriously unreliable in multicenter studies, and the primary end-point selected by the investigators— end systolic volume—is particularly difficult to quantitate in assymetic ventricles after MI. We have recently been using magnetic resonance imaging technology in an effort to improve the precision of quantitation. The analysis of these clinical and echo data will strain the

Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue.

Lymphoid tissue provides a reservoir where HIV can persist. However, therapies incorporating a protease inhibitor can target this reservoir. This study was designed to investigate the relative long-term effects on lymph-node viral load and cellular architecture of regimens containing multiple nucleosides alone or in combination with protease inhibitors. Axillary lymph-node biopsies from 12 patients with undetectable viraemia (viral load < 20 copies/ml: mean CD4 cells 525 x 10(6)/l) for a mean period of 25 months (range, 10-52 months) were investigated for the presence of HIV by in situ hybridization and coculture. Four patients were receiving multiple nucleoside analogues alone or in one case with a suboptimally dosed protease inhibitor (group I). Protease inhibitor was added to the regimen of seven patients at least 6 months prior to lymph-node biopsy (group II). Standard flow cytometry and virological data were obtained from peripheral blood every 3 months. By in situ hybridization, more productively infected CD4+ T cells were found in the lymph nodes of group I patients treated with nucleoside analogues alone. Very low numbers of productively infected lymph node cells were detected in the protease inhibitor-treated group II. No trapping of virions on the follicular dendritic cell (FDC) network was detectable in protease inhibitor-treated patients. In contrast, large deposits of FDC-bound virions were observed in three out of five patients from group I. Virus cultures from lymph node cells were positive in these three group I patients compared with only one out of seven patients from group II. Sequencing reverse transcriptase and protease genes from these isolates revealed typical mutations conferring resistance to the previously administered nucleoside analogue. A more preserved lymph node architecture and less signs of immunopathological change were also observed in protease inhibitor-treated patients. Undetectable plasma viraemia using the ultrasensitive PCR assay for prolonged periods of time does not always reflect complete HIV-1 suppression within the lymphoid compartment. Our results suggest that protease inhibitor-containing regimens target HIV reservoirs in lymphoid tissue more effectively and preserve or restore lymph node architecture.

A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors.

While many point mutations in the HIV-1 reverse transcriptase (RT) confer resistance to antiretroviral drugs, inserts or deletions in this gene have not been previously characterized. In this report, 14 RT inhibitor-treated patients were found to have HIV-1 strains possessing a 6-basepair insert between codons 69 and 70 of the RT gene. Known drug resistance mutations were also observed in these strains, with T215Y appearing in all strains. Genotypic analysis indicated that the inserts had substantial nucleotide variability that resulted in relatively restricted sets of amino acid sequences. Linkage of patients' treatment histories with longitudinal sequencing data showed that insert strains appeared during drug regimens containing ddI or ddC, with prior or concurrent AZT treatment. Drug susceptibility tests of recombinant patient isolates showed reduced susceptibility to nearly all nucleoside RT inhibitors. Site- directed mutagenesis studies confirmed the role of the inserts alone in conferring reduced susceptibility to most RT inhibitors. The addition of AZT-associated drug resistance mutations further increased the range and magnitude of resistance. These results establish that inserts, like point mutations, are selected in vivo during antiretroviral therapy and provide resistance to multiple nucleoside analogs.

Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients.

We have studied the phenotypic impact of adaptative Gag cleavage site mutations in patient-derived human immunodeficiency virus type 1 (HIV-1) variants having developed resistance to the protease inhibitor ritonavir or saquinavir. We found that Gag mutations occurred in a minority of resistant viruses, regardless of the duration of the treatment and of the protease mutation profile. Gag mutations exerted only a partial corrective effect on resistance-associated loss of viral fitness. Reconstructed viruses with resistant proteases displayed multiple Gag cleavage defects, and in spite of Gag adaptation, several of these defects remained, explaining the limited corrective effect of cleavage site mutations on fitness. Our data provide clear evidence of the interplay between resistance and fitness in HIV-1 evolution in patients treated with protease inhibitors.

Long-Term Angiotensin-Converting Enzyme Inhibitor Treatment Attenuates Adrenergic Responsiveness Without Altering Hemodynamic Control in Patients Undergoing Cardiac Surgery

Background : The sympathoadrenal and the renin-angiotensin systems are involved in blood pressure regulation and are known to be markedly activated during cardiac surgery. Because unexpected hypotensive events have been reported repeatedly during anesthesia in patients chronically treated with angiotensin-converting enzyme (ACE) inhibitors, the authors questioned whether renin-angiotensin system blockade would alter the hemodynamic control through attenuation of the endocrine response to surgery and/or through attenuation of the pressor effects of exogenous catecholamines. Methods : Patients with preserved left ventricular function undergoing mitral valve replacement or coronary revascularization were divided into two groups according to preoperative drug therapy : patients receiving ACE inhibitors for at least 3 months (ACEI group, n = 22) and those receiving other cardiovascular drug therapy (control group, n = 19). Anesthesia was induced using fentanyl and midazolam. Systemic hemodynamic variables were recorded before surgery, after anesthesia induction, during sternotomy, after aortic cross-clamping, after aortic unclamping, as well as after separation from cardiopulmonary bypass (CPB) and during skin closure. Blood was sampled repeatedly up to 24 h after surgery for hormone analysis. To test adrenergic responsiveness, incremental doses of norepinephrine were infused intravenously during hypothermic CPB and after separation from CPB. From the dose-response curves, pressor (defined as mean arterial pressure changes), and vasoconstrictor (defined as systemic vascular resistance changes) effects were analyzed, and the slopes and the dose of norepinephrine required to increase mean arterial pressure by 20% were calculated (PD 20 ). Results : At no time did the systemic hemodynamics and the need for vasopressor support differ between the two treatment groups. However, for anesthesia induction, significantly less fentanyl and midazolam were given in the ACEI group. Although plasma renin activity was significantly greater in the ACEI group throughout the whole 24-h study period, plasma concentrations of angiotensin II did not differ between the two groups. Similar changes in catecholamines, angiotensin II, and plasma renin activity were found in the two groups in response to surgery and CPB. The pressor and constrictor effects of norepinephrine infusion were attenuated markedly in the ACEI group : the dose-response curves were shifted to the right and the slopes were decreased at the two study periods; PD 20 was significantly greater during hypothermic CPB (0.08 μg/kg in the ACEI group vs. 0.03 μg/kg in the control group ; P < 0.05) and after separation from CPB (0.52 μg/kg in the ACEI group vs. 0.13 μg/kg in the control group ; P < 0.05). In both groups, PD 20 was significantly less during hypothermic CPB than in the period immediately after CPB. Conclusions : Long-term ACE inhibitor treatment in patients with preserved left ventricular function alters neither the endocrine response nor the hemodynamic stability during cardiac surgery. However, a significantly attenuated adrenergic responsiveness associated with incomplete blockade of the plasma renin-angiotensin system supports the hypothesis that inhibition of angiotensin II generation and of bradykinin degradation within the vascular wall mediates some of the vasodilatory effects of ACE inhibitors.

Impact of the renin-angiotensin-aldosterone system on blood pressure response to intravenous enalaprilat in patients with hypertensive crises

The purpose of the study was to evalute the impact of the renin-angiotensin-aldosterone (RAA) system on blood pressure (BP) response in patients with hypertensive emergencies and urgencies treated with intravenous enalaprilat. Thirty-five patients with a systolic BP (SBP) >210 mm Hg and/or diastolic BP (DBP) >110 mm Hg received 5 mg enalaprilat intravenously. The extent of systolic and DBP reduction was correlated with pretreatment concentrations of angiotensin II (ANGII) (SBP: r = -0.47; P = 0.006; DBP: r = -0.55; P = 0.001) and plasma renin activity (PRA) (SBP: r = -0.49; P = 0.003; DBP: r = 0.48; P = 0.007). Non-responders to enalaprilat exhibited significant lower pretreatment levels of PRA, angiotensin-converting enzyme (ACE) and ANG II compared to responders (PRA: 5.5 +/- 3.7 vs 1.1 +/- 2.2 ng/ml/h, P < 0.001; ACE: 12.8 +/- 3.5 vs 8.2 +/- 4.8 U/l, P = 0.003; ANG 11:8.7 +/- 6.2 vs 5.0 +/- 3.8 pg/ml, P = 0.04). In patients with severe hypotension following application of enalaprilat ANG II concentrations were significantly higher compared to patients with mean arterial BP reduction <25% (12.3 +/- 6.7 vs 5.6 +/- 4.0 pg/ml,P = 0.013). These data indicate that PRA and ANG II are the major determinants for BP response to enalaprilat. This relation between BP response and RAA system activity have important clinical implications for the treatment of patients with severe hypertension. Primary therapeutic failure indicates that the RAA system contributes very little to the hypertensive status of the patient. Thus, repetitive application on an ACE inhibitor in primary responders is clinically unhelpful and may result in an unnecessary delay of an effective BP reduction. In contrast, high ANG II concentrations are associated with a considerable risk for severe hypotension after enolanalaprilat application. Therefore, the status of the RAA system determines the efficacy as well as the safety of ACE inhibitor treatment in patients with severe hypertension.

Implications for the use of topoisomerase I inhibitors in treatment of patients with systemic sclerosis.

Implications for the use of topoisomerase I inhibitors in treatment of patients with systemic sclerosis.

Hormonal and renal differences between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with chronic heart failure.

To assess the differential effects of low dose (5 mg) and high dose (20 mg) lisinopril treatment on cardiovascular hormones, renal function, and blood pressure over 24 hours in patients with heart failure. Double-blind crossover study. Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee. 19 patients with chronic heart failure and left ventricular ejection fraction < or = 45%. Plasma concentrations of aldosterone and endothelin were lower on the 20 mg dose (plasma aldosterone mean at peak drug effect: 90.7 v 152.0 pg/ml, P < 0.001; mean at trough effect: 124.7 v 174.4 pg/ml, P < 0.01; plasma endothelin at trough effect 4.70 v 6.04 pmol/l, P = 0.03). Creatinine clearance was lower on 20 mg lisinopril (68.7 v 82.1 ml/min, P < 0.05). The area under the curve for diastolic blood pressure over 24 hours was significantly lower on 20 mg (mean difference 3.0 mm Hg, P = 0.04); for systolic blood pressure there was a similar trend (mean difference 5.7 mmHg, P = 0.05). Plasma concentrations of atrial natriuretic peptide (ANP) and B-type natriuretic peptide were similar for both doses; urinary excretion of ANP was lower on 20 mg (12.2 v 13.6 pmol, P < 0.05). These results indicate that within the usual therapeutic range, high doses of lisinopril cause greater suppression of selected cardiovascular hormones than low doses in heart failure, but are associated with lower creatinine clearance in some patients.

Long-term angiotensin-converting enzyme inhibitor treatment attenuates adrenergic responsiveness without altering hemodynamic control in patients undergoing cardiac surgery.

The sympathoadrenal and the renin-angiotensin systems are involved in blood pressure regulation and are known to be markedly activated during cardiac surgery. Because unexpected hypotensive events have been reported repeatedly during anesthesia in patients chronically treated with angiotensin-converting enzyme (ACE) inhibitors, the authors questioned whether renin-angiotensin system blockade would alter the hemodynamic control through attenuation of the endocrine response to surgery and/or through attenuation of the pressor effects of exogenous catecholamines. Patients with preserved left ventricular function undergoing mitral valve replacement or coronary revascularization were divided into two groups according to preoperative drug therapy: patients receiving ACE inhibitors for at least 3 months (ACEI) group, n = 22) and those receiving other cardiovascular drug therapy (control group, n = 19). Anesthesia was induced using fentanyl and midazolam. Systemic hemodynamic variables were recorded before surgery, after anesthesia induction, during sternotomy, after aortic cross-clamping, after aortic unclamping, as well as after separation from cardiopulmonary bypass (CPB) and during skin closure. Blood was sampled repeatedly up to 24 h after surgery for hormone analysis. To test adrenergic responsiveness, incremental doses of norepinephrine were infused intravenously during hypothermic CPB and after separation from CPB. From the dose-response curves, pressor (defined as mean arterial pressure changes), and vasoconstrictor (defined as systemic vascular resistance changes) effects were analyzed, and the slopes and the dose of norepinephrine required to increase mean arterial pressure by 20% were calculated (PD(20)). At no time did the systemic hemodynamics and the need for vasopressor support differ between the two treatment groups. However, for anesthesia induction, significantly less fentanyl and midazolam were given in the ACEI group. Although plasma renin activity was significantly greater in the ACEI group throughout the whole 24-h study period, plasma concentrations of angiotensin II did not differ between the two groups. Similar changes in catecholamines angiotensin II, and plasma renin activity were found in the two groups in response to surgery and CPB. The pressor and constrictor effects of norepinephrine infusion were attenuated markedly in the ACEI group: the dose-response curves were shifted to the right and the slopes were decreased at the two study periods; PD(20) was significantly greater during hypothermic CPB (0.08 micro/kg in the ACEI group vs. 0.03 micro/kg in the control group; P < 0.05) and after separation from CPB (0.52 micro/kg in the ACEI group vs. 0.1 micro/kg in the control group; P < 0.05). In both groups, PD(20) was significantly less during hypothermic CPB than in the period immediately after CPB. Long-term ACE inhibitor treatment in patients with preserved left ventricular function alters neither the endocrine response nor the hemodynamic stability during cardiac surgery. However, a significantly attenuated adrenergic responsiveness associated with incomplete blockade of the plasma renin-angiotensin system supports the hypothesis that inhibition of angiotensin II generation and of bradykinin degradation within the vascular wall mediates some of the vasodilatory effects of ACE inhibitors.

"Cardioprotection" by ACE-inhibitors in acute myocardial ischemia and infarction?

Coronary artery occlusion results in the acute activation of the renin-angiotensin system and production of angiotensin II, a potent vasoconstrictor and positive inotropic agent. This has raised the possibility that angiotensin converting enzyme (ACE) inhibitors might be "cardioprotective" (that is, might attenuate myocardial injury, dysfunction and necrosis) in the setting of acute ischemia and infarction. Captopril, enalapril and ramipril have, in fact, been reported to acutely limit myocardial injury and necrosis in models of permanent coronary artery occlusion. The mechanisms responsible for this cardioprotection are complex, but include favorable alterations in myocardial oxygen supply/demand, and, in some instances, inhibition of bradykinin metabolism and/or increased prostaglandin synthesis. Other studies, however, have failed to document a reduction in infarct size with ACE inhibitor treatment. Results obtained in models of coronary occlusion/reperfusion have also been mixed. In models of brief transient ischemia not associated with necrosis, captopril and zofenopril have consistently been found to attenuate postischemic contractile dysfunction of the viable but "stunned" myocardium during the early hours following relief of ischemia. In contrast, there is no consensus on the effects of enalapril on the stunned myocardium: both positive and negative results have been obtained. Similar disparity has been reported in models of more prolonged ischemia/reperfusion resulting in subendocardial necrosis: some studies have reported myocardial salvage, while others have provided disturbing evidence of apparent exacerbation of myocardial necrosis with captopril and enalapril therapy. Thus, after a decade of investigative effort, the question of whether ACE inhibitors are "cardioprotective" in the setting of acute myocardial ischemia and infarction remains unresolved. Nonetheless, clinical protocols are in progress to assess the effects of early ACE inhibitor treatment in patients with acute myocardial infarction.

The effect of treatment with angiotensin-converting enzyme inhibitors on survival of pediatric patients with dilated cardiomyopathy

Outcome in 81 pediatric patients with dilated cardiomyopathy was reviewed to assess whether treatment with angiotensin-converting enzyme (ACE) inhibitors affected survival. Age at onset was 3.6 +/- 0.6 years. Twenty-seven children (group 1) were treated with ACE inhibitors. Conventional therapy was used in the remaining 54 patients (group 2). There were no significant differences between the two groups in age at onset, left ventricular shortening fraction, left ventricular end-diastolic pressure, or mean pulmonary artery pressure. Patients treated with ACE inhibitors had a significantly better survival during the first year (p < 0.05) with continuation of this trend throughout the second year (p = 0.06). Beyond 2 years there was a tendency toward better survival in ACE inhibitor-treated patients, but the differences were no longer significant (p = 0.14). These data, along with observations in adult patients with chronic cardiac failure, indicate that converting enzyme inhibitors have a beneficial effect on prolonging survival of infants and children with severe left ventricular dysfunction from dilated cardiomyopathy.

Management of Monoamine Oxidase Inhibitor-treated Patients in the Emergency and Critical Care Setting

Monoamine oxidase inhibitors (MAOIs) are the most effective treatment for some forms of depression. Unfortunately, these agents cause many adverse reactions and interact with a number of other drugs. We review the pharmacology, side effects, and interactions of MAOIs, and focus on how MAOI-treated patients can be safely managed in critical care settings.