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Peter S Macdonald

Publications and source records attributed to Peter S Macdonald.

13 recordsLinked to original sources
PubMed2006

Bosentan for the treatment of pulmonary arterial hypertension associated with congenital cardiac disease.

AIMS: Bosentan is efficacious in idiopathic pulmonary arterial hypertension, and the variants associated with connective tissue disease, but not currently approved for treatment of pulmonary arterial hypertension due to Eisenmenger's syndrome. We sought to evaluate its effect in adults with Eisenmenger's syndrome. METHODS: We administered bosentan on the basis of compassionate use in 23 patients with Eisenmenger's syndrome, aged 37 plus or minus 14 years. Of the patients, 17 had never received specific treatment for pulmonary arterial hypertension, five were transitioned from treprostinil, and one from beraprost to bosentan. We measured functional class, saturation of oxygen, haemoglobin levels and six-minute walk distance at baseline, one, six months and at most recent follow-up. RESULTS: Baseline functional class was IV in three, III in fifteen, and II in five patients. At follow-up, with a mean of 15 plus or minus 10 months, 13 of the 23 patients (57%) had improved by at least one functional class, from a median baseline of III to II (p equal to 0.016), mean saturation of oxygen at rest had increased from 81% to 84% (p equal to 0.001), and levels of haemoglobin had decreased from 178 plus or minus 26 grams per litre to 167 plus or minus 19 grams per litre (p equal to 0.001). Overall, the six-minute walk distance did not change from baseline of 335 metres. The distance walked by those not previously receiving specific therapy, however, improved from 318 plus or minus 129 to 345 plus or minus 123 metres (p equal to 0.03). CONCLUSION: Treatment of adults with Eisenmenger's syndrome using bosentan significantly improved functional class, saturation of oxygen at rest, and decreased levels of haemoglobin. Treatment with bosentan was associated with improvement in six-minute walk distance in those not previously receiving specific therapy. In patients already in receipt of specific therapy, transition to bosentan resulted in no clinical deterioration.

Adult↗
PubMed2006

Organ preservation.

The success of organ transplantation is critically dependent on the quality of the donor organ. Donor organ quality, in turn, is determined by a variety of factors including donor age and preexisting disease, the mechanism of brain death, donor management prior to organ procurement, the duration of hypothermic storage, and the circumstances of reperfusion. It has been recognized for some time that both the short- and long-term outcomes after cadaveric organ transplantation are significantly inferior to those obtained when the transplanted organ is obtained from a living donor, regardless of whether the donor is related or unrelated to the recipient. Brain death results in a series of hemodynamic, neurohormonal, and pro-inflammatory perturbations, all of which are thought to contribute to donor organ dysfunction. The process of transplantation exposes the donor organ to an obligatory period of ischemia and reperfusion. Traditionally, hypothermic storage of the donor organ has been used to protect it from ischemic injury, but donor organs differ markedly in their capacity to withstand hypothermic ischemia. Data from the Registry of the International Society for Heart and Lung Transplantation indicate that the risk of primary graft failure and death rises dramatically for both the heart and lung as ischemic time increases. Based on these data, maximum recommended ischemic times for the donor heart and lung are 6 and 8 h, respectively. In this chapter, strategies aimed at minimizing the adverse consequences of brain death and ischemia/reperfusion injury to the donor heart and lung are discussed. These strategies are likely to become increasingly important as the reliance on marginal donors increases to meet the growing demand for organ transplantation.

Brain Death↗
PubMed2006

The impact of baseline HR and BP on the tolerability of carvedilol in the elderly: the COLA (Carvedilol Open Label Assessment) II Study.

BACKGROUND: The COLA (Carvedilol Open Label Assessment) II Study prospectively evaluated the tolerability of carvedilol in 1030 patients >70 years of age with chronic heart failure (CHF). Tolerability, defined as patients receiving > or =3 months of carvedilol and achieving a maintenance dosage > or =12.5 mg/day, was 80%. In a multivariate analysis, advanced age, low DBP, left ventricular ejection fraction, obstructive airways disease, and a presence of diabetes mellitus were predictors of tolerability. The aim of this analysis was to evaluate further the relationship between baseline HR, SBP, DBP and tolerability in COLA II. METHODS: Baseline HR, SBP and DBP data were available in 1009 patients (98%). These data were analyzed as both continuous and categorical variables. For the latter analysis, the following categories were created: HR <70, 70 < or = HR <90, HR > or =90 bpm; SBP <120, 120 < or = SBP <160, SBP > or =160 mm Hg; DBP <70, 70 < or = DBP <90, DBP > or =90 mm Hg. RESULTS: Baseline HR did not differ between patients who tolerated carvedilol (T) and those who did not (non-T) [81 +/- 16 vs 79 +/- 16 bpm]. However, SBP and DBP were significantly lower in the non-T versus the T group (131 +/- 20 vs 139 +/- 22 mm Hg for SBP [p < 0.001] and 77 +/- 11 vs 81 +/- 12 mm Hg for DBP [p < 0.001]). Seventy-four percent of patients in the lowest category for baseline HR (<70 bpm tolerated carvedilol versus 82% and 79% of those in the higher categories (p = not significant). Seventy percent of patients in the lowest category of baseline SBP (<120 mm Hg) tolerated carvedilol versus 80% and 89% of those in the upper categories (p < 0.001). Similarly, 73% of patients in the lowest category for DBP (<70 mm Hg) tolerated carvedilol versus 78% and 87% of those in the upper categories (p < 0.005). CONCLUSIONS: Carvedilol is generally well tolerated by elderly patients with CHF, even in those with low baseline BP or HR. However, a low baseline SBP or DBP does identify patients who are less likely to tolerate the drug. Baseline HR does not appear to significantly affect tolerability in this population.

Adrenergic beta-Antagonists↗
PubMed2004

Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension.

Clinical studies have shown the importance of endothelin as a pathogenic mediator in pulmonary arterial hypertension (PAH). We describe the effects of bosentan, an oral dual endothelin receptor antagonist, in patients with PAH associated with human immunodeficiency virus (HIV) infection. In this prospective study, 16 patients with PAH associated with HIV infection in stable condition received bosentan for 16 weeks. Efficacy endpoints included exercise capacity, cardiopulmonary hemodynamics, Doppler echocardiography, New York Heart Association functional class, and quality of life (SF-36 and EQ-5D). Safety was assessed by laboratory tests, vital signs, and adverse events. Improvements were observed from baseline to Week 16 in all efficacy parameters: 6-minute walk distance (+91 +/- 60 m, p < 0.001), New York Heart Association class (14 patients improved), hemodynamics (cardiac index: +0.9 +/- 0.7 L/minute/m(2), p < 0.001), Doppler echocardiographic variables, and quality of life. During the study, no patient died and none required epoprostenol treatment. Hepatic tolerability was similar to that reported in patients with PAH. Bosentan had no negative impact on control of HIV infection. Although limited by uncontrolled design, small sample size and short duration, this study suggests that bosentan may benefit patients with PAH associated with HIV infection, and that endothelin is an important pathogenic mediator in this disease.

Adult↗
PubMed2003

Sodium-hydrogen exchanger inhibition, pharmacologic ischemic preconditioning, or both for extended cardiac allograft preservation.

BACKGROUND: The aim of this study was to determine the efficacy of cariporide (a sodium-hydrogen exchanger inhibitor), BMS180448 (a pharmacologic ischemic preconditioning agent), and the combination thereof, as adjuvant therapies for extended cardiac allograft preservation. METHODS: A porcine model of donor brain death and orthotopic heart transplantation was used. All hearts were arrested and stored for 14 hr in an extracellular preservation solution. Control hearts (CON; n=3) did not receive any additional treatment. Treated hearts received BMS180448 alone (BMS; n=3), cariporide alone (CAR; n=6), or both BMS180448 and cariporide (B+C; n=6). Donors of BMS180448-treated hearts received 2 mg/kg, 15 min before explantation. Donors and recipients of cariporide-treated hearts received 2 mg/kg, 15 min before explantation and reperfusion, respectively. RESULTS: The CON and BMS arms of the study were terminated after three transplantations because initial results in these groups were poor. Significantly, none of the control hearts could be weaned successfully from bypass, whereas all of the treated hearts were weaned successfully (CAR vs. CON and B+C vs. CON: P=0.012). The rate of troponin I release during the first 3 hr after reperfusion was significantly lower in CAR (P=0.0180) and B+C (P=0.0154) recipients than in CON recipients. Mean plasma troponin I levels (microg/mL) 3 hr after reperfusion were as follows: CON 633+/-177, BMS 576+/-110, CAR 346+/-93, and B+C 296+/-97. CONCLUSION: In this porcine model of extended cardiac allograft preservation, cariporide was more effective than BMS180448 as an adjuvant to our usual preservation solution. There was no additional benefit from the combination of the two therapies.

Animals↗
PubMed2003

Cariporide (HOE-642) improves cardiac allograft preservation in a porcine model of orthotopic heart transplantation.

BACKGROUND: Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury. METHODS: A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively. RESULTS: The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001). CONCLUSIONS: Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.

Animals↗
PubMed2003

The initial rate of troponin I release post-reperfusion reflects the effectiveness of myocardial protection during cardiac allograft preservation.

OBJECTIVE: To determine if the initial rate of troponin I release post-reperfusion reflects the effectiveness of myocardial protection during cardiac allograft preservation. METHODS: A porcine model of orthotopic heart transplantation was used. Data from two control groups (CON(4) and CON(14)) and two treatment groups (CAR(4) and CAR(14)) were analysed. Hearts in CON(4) (n=6) and CAR(4) (n=6) were subjected to 4 h of ischaemia while hearts in CON(14) (n=3) and CAR(14) (n=6) were subjected to 14 h of ischaemia. All hearts were arrested and stored in the same extracellular preservation solution. Both donor and recipient animals in the CAR(4) and CAR(14) groups received a single intravenous dose of cariporide (2 mg/kg), prior to explantation and reperfusion, respectively. RESULTS: Mean (SEM) plasma troponin I levels (microg/ml) 3 h post-reperfusion were: CON(4) 210+/-52, CAR(4) 68+/-21, CON(14) 633+/-177, CAR(14) 346+/-93. On multiple linear regression analysis, the rate of troponin I release over the first 3 h post-reperfusion was significantly lower in hearts stored for 4 h compared to hearts stored for 14 h (P<0.0001) and in hearts treated with cariporide compared to control hearts (P=0.0017). Early graft function was superior in hearts treated with cariporide, when compared to control hearts stored for the same period of time. All of the CAR(14) hearts could be weaned from cardiopulmonary bypass whereas none of the CON(14) could be weaned (6/6 vs. 0/3; P=0.012). While all hearts stored for 4 h could be weaned, contractility, as measured by the preload recruitable stroke work (PRSW) relationship, was significantly better preserved in CAR(4) hearts than in CON(4) hearts (P<0.0001). CONCLUSIONS: The initial rate of troponin I release post-reperfusion is determined by the duration of cardiac allograft ischaemia. Altering the myocardial preservation strategy can reduce the rate of release. Such reductions are associated with improvements in early graft function. These findings validate the initial rate of troponin I release post-reperfusion as an end-point when comparing cardiac allograft preservation strategies. In addition, the present study provides indirect evidence that troponin I degradation during ischaemia-reperfusion is related to the accumulation of intracellular calcium.

Animals↗
PubMed2003

Lazaroid (U74389G)-supplemented cardioplegia: results of a double-blind, randomized, controlled trial in a porcine model of orthotopic heart transplantation.

BACKGROUND: U74389G (16-desmethyl tirilazad), a 21-aminosteroid or "lazaroid," inhibits lipid peroxidation, which is an important element of ischemia-reperfusion injury. The aim of this study was to determine whether the addition of U74389G to the cardioplegic preservation solution could improve early cardiac allograft function. METHODS: A porcine model of donor brain death and orthotopic cardiac transplantation was used. Hearts were arrested and preserved for 6 hours in an aspartate-enriched extracellular cardioplegia that had been supplemented with either U74389G and its carrier (n = 7) or the carrier alone (n = 9). Epicardial sonomicrometry and transmyocardial micromanometry were used to obtain pressure-volume loops before and after transplantation. Left ventricular wall volume was measured by volume displacement. RESULTS: A higher proportion of U74389G-treated hearts were weaned successfully from cardiopulmonary bypass, but this difference did not achieve statistical significance (86% [6 of 7] vs 56% [5 of 9]; p = 0.308). In the hearts that were weaned successfully, preservation of left ventricular contractility, as judged by the pre-load recruitable stroke work relationship, was significantly better in the U74389G-treated hearts (p = 0.0271). In contrast, left ventricular compliance, as judged by the end-diastolic pressure-volume relationship, was significantly better preserved in the control group (p < 0.0001). U74389G-treated hearts developed less myocardial edema, as judged by the post-transplant left ventricular wall volume/baseline steady-state epicardial end-diastolic volume ratio (64 +/- 9% vs 76 +/- 11%; p = 0.045). CONCLUSIONS: The benefit obtained from U74389G-supplemented cardioplegic preservation solution was marginal for hearts stored for 6 hours. After longer ischemic times, the benefit may be clearer.

Animals↗
PubMed2003

Functional evidence of reversible ischemic injury immediately after the sympathetic storm associated with experimental brain death.

BACKGROUND: Acute brain death from increased intracranial pressure results in a transient increase in myocardial adenosine and lactate, which indicates that oxygen demand exceeds oxygen delivery during the sympathetic "storm". The aim of this study was to determine the functional significance of this period of ischemia. METHODS: Brain death was inflicted on 40 Westran pigs (36.5-68.0 kg) by inflating a 21-ml subdural balloon over 3 minutes. In 38 animals, micromanometry and sonomicrometry were used to obtain left ventricular pressure-volume loops to determine the preload recruitable stroke work (PRSW) relationship. Data files were recorded before and at 15-minute intervals after beginning balloon inflation. Plasma troponin I was measured before and 60 minutes after beginning balloon inflation in the 38 instrumented and 2 non-instrumented animals. RESULTS: All animals experienced the classical sympathetic storm. The slope of the PRSW relationship decreased, and the volume-axis intercept shifted to the right 15 minutes after beginning balloon inflation (p < 0.0001). Progressive incremental recovery (leftward shift) occurred between subsequent time points (p < or = 0.0018). In the instrumented animals, the mean plasma troponin I level increased from 1.4 +/- 1.6 microg/liter to 2.8 +/- 2.3 microg/liter (p < 0.001). However, troponin I was not detected before or after induction of brain death in the plasma of either non-instrumented animal (p = 0.001). CONCLUSIONS: The sympathetic storm produced transient contractile dysfunction, consistent with ischemic injury. However, troponin I release reflected surgical instrumentation and not brain death.

Animals↗
PubMed2002

The preload recruitable stroke work relationship as a measure of left ventricular contractile dysfunction in porcine cardiac allografts.

OBJECTIVE: Paradoxically, it has been reported that after 1.5-4 h of hypothermic ischaemic preservation there is complete recovery of contractile function in canine cardiac allografts, as assessed by the preload recruitable stroke work (PRSW) relationship. This raises questions about the suitability of the canine heart as a model for preservation research and the PRSW relationship as an end-point. The aim of the present study was to evaluate the PRSW relationship as an index of left ventricular contractility in porcine cardiac allografts. METHODS: Eighteen orthotopic heart transplants were performed in inbred Westran pigs. Brain death was induced in the donor pigs 1 h prior to explantation. The donor hearts were arrested with extracellular cardioplegia, which was stored in ice prior to administration. On explantation, the donor hearts were immersed in cardioplegia and stored in ice. The donor hearts were subjected to either 4 (IT4, n = 6), 6 (IT6, n = 9) or 14 (IT14, n = 3) h of ischaemia. Post-transplant, all hearts were supported with dobutamine (10 mcg/kg per min). The PRSW relationship was derived from pressure-volume loops obtained by epicardial sonomicrometry and transmyocardial micromanometry. Multiple linear regression was used to describe and compare the PRSW relationship before brain death in the donor and after weaning from bypass in the recipient. RESULTS: Eleven hearts were weaned successfully from cardiopulmonary bypass: IT4 100% (6/6), IT6 56% (5/9) and IT14 0% (0/3) (IT4 versus IT14: P = 0.012). Analysis of the PRSW relationship revealed a reduction in contractility in both the IT4 and IT6 groups (both P < 0.0001), but a greater reduction in the IT6 group (P < 0.0001). Notably, the volume-axis intercept of the PRSW relationship was found to be a better discriminator of post-preservation contractile dysfunction than the slope of the PRSW relationship. CONCLUSIONS: The porcine heart's susceptibility to ischaemic injury makes it ideal for evaluating the effect of different preservation strategies on contractile recovery. The PRSW relationship can be used to evaluate the differences in contractile recovery, though the nature of the effect of ischaemic preservation necessitates analysis by multiple linear regression.

Animals↗
PubMed2002

Reversal of chronic cyclosporine nephrotoxicity after heart transplantation-potential role of mycophenolate mofetil.

BACKGROUND: Chronic cyclosporine nephrotoxicity (CCN) after heart transplantation is a progressive condition that may lead to end-stage renal failure. The extent to which CCN is reversible with reduction or withdrawal of cyclosporine therapy is unknown. The aim of this study was to assess the reversibility of CCN and to assess the safety and efficacy of a strategy of cyclosporine dosage reduction, combined with conversion from azathioprine to mycophenolate mofetil (AZA/MMF switch) to maintain immunosuppression. METHODS: An AZA/MMF switch followed by cyclosporine dose reduction was undertaken in 30 heart transplant recipients (23 men, 7 women; mean age, 54 +/- 2 years) with established CCN at a mean of 90 +/- 9 months after transplantation (range, 17-182 months). The mean maintenance MMF dosage was 2.3 +/- 0.1 g/day (n = 28). Mean cyclosporine dosage was decreased from 2.3 +/- 0.2 mg/kg/day before AZA/MMF switch to 1.6 +/- 0.2 mg/kg/day. RESULTS: Three patients (10%) were withdrawn from MMF, 2 because of diarrhea and the third because of severe pneumonia that developed within 2 weeks of AZA/MMF switch. All 3 were restabilized with AZA. One patient (4%) experienced acute rejection 7 months after AZA/MMF switch. This resolved after an oral pulse of prednisolone. Systemic infections occurred in 6 patients within 12 months of AZA/MMF switch. Actuarial survival 1 year after AZA/MMF switch was 86% +/- 6%. One patient died of infection and 3 of other causes. Serum creatinine concentration decreased from 248 +/- 15 micromol/liter before cyclosporine dosage reduction to 193 +/- 11 micromol/liter and 206 +/- 19 micromol/liter at 3 and 12 months after dosage reduction (both p < 0.01 versus baseline, n = 23). Of the 23 patients who remained on MMF at 12 months, a decrease in serum creatinine was documented in 19 (83%). Four patients showed no improvement or showed deterioration in renal function, and three of these progressed to end-stage renal failure. CONCLUSIONS: Chronic cyclosporine nephrotoxicity has a significant reversible component in most patients. A strategy of AZA/MMF switch combined with cyclosporine dosage reduction is generally well tolerated and results in short-term improvement in renal function in most patients. Close vigilance is required during the first 12 months after AZA/MMF switch because both acute rejection and infection may occur.

Azathioprine↗
PubMed2002

Tolerability of carvedilol in patients with heart failure and concomitant chronic obstructive pulmonary disease or asthma.

BACKGROUND: A substantial proportion of the population with congestive heart failure (CHF) has concomitant airway disease. Little information exists on the tolerability of carvedilol in patients with chronic obstructive pulmonary disease (COPD). In this study, we assessed the tolerability and efficacy of carvedilol in patients with CHF and concomitant COPD or asthma. METHODS: Between 1996 and 2000, a total of 487 patients began receiving open-label carvedilol. Forty-three (9%) had COPD (n = 31) or asthma (n = 12). Spirometry supported clinical diagnosis in all, and full pulmonary function testing supported diagnosis in 71%. Sixty percent began carvedilol therapy in the hospital and underwent measurement of peak expiratory flow rates (PEFR) before and after dosing. RESULTS: In patients with COPD, mean forced expiratory volume in one second (FEV(1)) was 62% +/- 13% predicted, reversibility was 4% +/- 4% with bronchodilators, and FEV(1)/FVC was 62% +/- 8%. Mean PEFR was 325 +/- 115 liter/min before the dose and increased by 17% 2 hours after the carvedilol dose (p = 0.04). In patients with asthma, mean FEV(1) was 80% +/- 17% predicted, reversibility was 13% +/- 7%, and FEV(1)/FVC was 74% +/- 11%. Mean PEFR was 407 +/- 161 liter/min before the dose with no significant change 2 hours after the dose. Carvedilol was introduced safely in 84% of patients with COPD, with only 1 patient withdrawn from therapy for wheezing. In contrast, only 50% of patients with asthma tolerated carvedilol. Survival at 2.5 years was 72%. In survivors, left ventricular end-diastolic diameter decreased from 76 +/- 11 mm to 72 +/- 14 mm (p = 0.01), left ventricular end-systolic diameter decreased from 65 +/- 13 mm to 60 +/- 15 mm (p = 0.01), and fractional shortening increased from 14% +/- 7% to 17% +/- 7% (p = 0.05) at 12 months. CONCLUSIONS: Patients with CHF and COPD tolerated carvedilol well with no significant reversible airflow limitation, but patients with CHF and asthma tolerated carvedilol poorly. The effect of carvedilol on left ventricular dimensions and function in patients with concomitant airway diseases was similar to that seen in our general group of patients. Asthma remains a contraindication to beta-blockade.

Adrenergic beta-Antagonists↗