Extensive biliary excretion of the sulfasalazine analogue, susalimod, but different concentrations in the bile duct in various animal species correlating to species-specific hepatobiliary toxicity.

Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses > or =75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, > or =90%, mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 micromol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were < or =7000 micromol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (Påhlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.

Efficient biliary excretion of susalimod, probably via the bromosulphthalein carrier, studied in a chronic bile fistula model in dogs.

Susalimod is a structural analogue of sulphasalazine, known to be extensively excreted in the bile in various animal species and for inducing bile duct hyperplasia after long-term treatment of the dog with doses exceeding 25 mg kg(-1). In this study local concentrations of susalimod in the bile duct were determined after oral administration in dogs. A chronic bile fistula experimental model was designed to affect the bile duct as little as possible. The dogs received repeated oral doses of 25-150 mg kg(-1) day(-1) for 5 days; these doses had been used in previous toxicology studies. Extremely high biliary concentrations of unchanged susalimod (20,000-43,000 microM) were measured. Biliary excretion approached saturation at the higher doses, resulting in super-proportional increases in peripheral plasma concentrations as the dose was increased. The maximal bile/plasma concentration ratio was 4300. The high biliary clearance was indicative of almost complete first-pass elimination at doses below saturation of the elimination process. Interaction studies with the biliary excretion marker bromosulphthalein (BSP) demonstrated that susalimod and BSP probably share the same carrier transport system in biliary excretion. The elimination of BSP from plasma was prolonged 20 times and the biliary excretion rate was markedly reduced when susalimod was co-administered with BSP. These results show that susalimod is highly enriched in the bile, in a saturable manner, after oral administration. The compound interacts with the biliary excretion of BSP, suggesting that it shares the same carrier-mediated transport system.

Hereditary retinal degeneration in the Abyssinian cat: developmental studies using clinical electroretinography.

Electroretinography was performed in 10 Abyssinian cats, homozygous for a hereditary retinal degenerative disease but still with an ophthalmoscopically normal retina, and in 11 mixed-breed controls, all between the ages of 8 and 104 weeks. A significant reduction of maximum dark-adapted b-wave amplitude was found in affected kittens as young as 8-16 weeks when compared with controls, although there was no major difference in dark-adapted b-wave threshold or implicit time for the b-wave between affected and controls. For cats 33-104 weeks, similar results were obtained except for the b-wave threshold, which was elevated 2.5 log units in one of the affected cats. No significant difference in 30-Hz cone flicker responses were found between affected and controls at any age studied. In the time period 17-32 weeks affected Abyssinian kittens could not be differentiated from controls by means of the electroretinogram. The significant reduction in scotopic b-wave maximum amplitudes in young affected kittens (8-16 weeks) in conjunction with normal thresholds suggests an early drop-out of rods. It is clear that affected kittens can be differentiated electrophysiologically from controls long before there are ophthalmoscopic signs of retinal disease.

Rapidly developing tolerance to transdermal nitroglycerin in congestive heart failure.

We have reported early attenuation of hemodynamic effects of transdermal nitroglycerin in patients with heart failure. We now report nitroglycerin plasma levels in those same patients. We administered transdermal nitroglycerin, 60 mg/24 h, to eight patients or placebo to seven patients in a double-blind fashion, and monitored pulmonary wedge pressure and nitroglycerin plasma levels for 24 hours. After placebo administration, nitroglycerin plasma levels and pulmonary wedge pressure remained unchanged. During transdermal nitroglycerin administration, the plasma nitroglycerin level rose from 0.04 +/- 0.12 ng/mL at baseline to near peak levels at 2 hours (7.43 +/- 7.21 ng/mL). Between 2 and 24 hours, levels fluctuated at a steady state. Pulmonary wedge pressure fell from 22 +/- 7 mm Hg at control to a nadir of 14 +/- 5 mm Hg at 4 hours (p less than 0.01). Despite persistently high plasma nitroglycerin levels, by 18 hours pulmonary wedge pressure was no longer significantly reduced (20 +/- 9 mm Hg). These results indicate that rapid development of tolerance is the cause of attenuated hemodynamic efficacy of transdermal nitroglycerin.

Dose requirements and hemodynamic effects of transdermal nitroglycerin compared with placebo in patients with congestive heart failure.

The dose requirements and duration of effect of transdermal nitroglycerin in patients with heart failure are not clearly established. In a first series of eight patients with chronic heart failure we gave transdermal nitroglycerin in incremental doses until pulmonary capillary wedge pressure fell at least 30% within 4 hr in three consecutive patients. Thus we found that a single dose of 60 mg/24 hr (120 cm2) was the minimal effective dose. Transdermal nitroglycerin or placebo was then given as a single application of 60 mg/24 hr in random double-blind fashion to 15 additional patients with heart failure (eight received transdermal nitroglycerin and seven received placebo), and hemodynamics were monitored for up to 24 hr. After administration of transdermal nitroglycerin, the control pulmonary capillary wedge pressure of 22 +/- 7 mm Hg fell by 6 +/- 6 mm Hg at 2 hr (p less than .05) and reached maximal reduction of 8 +/- 6 mm Hg (p less than .01) at 4 hr. The reduction in wedge pressure remained significant through 12 hr but was no longer statistically significant by 18 hr after administration of the drug. Transdermal nitroglycerin also significantly reduced pulmonary arterial and right atrial pressures as well as pulmonary vascular resistance from 4 through 12 hr but did not affect systemic hemodynamics. No significant hemodynamic changes occurred after administration of placebo. Thus transdermal nitroglycerin is an effective vasodilator in patients with heart failure, but a dose of at least 60 mg/24 hr is needed. Even with this dose, hemodynamic effects do not last beyond 18 hr, suggesting altered absorption or development of tolerance.

Effects of enalapril, a new angiotensin-converting enzyme inhibitor, in a controlled trial in heart failure.

Angiotensin-converting enzyme inhibitors are effective vasodilators in the treatment of congestive heart failure. Enalapril, a new angiotensin-converting enzyme inhibitor, or placebo, in addition to digoxin and diuretic drugs, were given to 17 patients with chronic congestive heart failure who were followed up for 12 weeks. In random double-blind fashion, nine patients received enalapril and eight received placebo. Cardiac dimensions and function improved slightly but insignificantly in both groups. Treadmill exercise duration increased from a mean value (+/- standard deviation) of 9.1 +/- 3.2 to 12.0 +/- 3.5 minutes during enalapril administration (p less than 0.025) and was unchanged during placebo administration (10.1 +/- 3.7 versus 11.1 +/- 5.2 minutes). Maximal oxygen consumption also increased during enalapril therapy (15.8 +/- 3.4 to 18.4 +/- 4.4 ml/min per kg, p less than 0.05) and remained unchanged during placebo treatment (16.0 +/- 6.4 versus 17.0 +/- 4.6 ml/min per kg). Clinical functional class (Yale scale) improved 3.1 +/- 1.9 points (p less than 0.01) during enalapril treatment but not during placebo treatment (0.8 +/- 3.5 points, no significant difference). No significant side effects were observed. Thus, enalapril appears to be a clinically effective and useful new angiotensin-converting enzyme inhibitor for the management of chronic congestive heart failure.

Relation of right ventricular ejection fraction to exercise capacity in chronic left ventricular failure.

Although the left ventricle is traditionally viewed as the heart's main pumping chamber, no correlation has been shown between left ventricular (LV) ejection fraction (EF) at rest and exercise capacity in patients with chronic LV failure. Because vasodilators with venodilating activity increase exercise capacity more than predominant arterial dilators in patients with LV failure, right ventricular (RV) function may relate to exercise capacity in these patients. In 25 patients with chronic LV failure, caused by coronary artery disease in 12 patients and idiopathic dilated cardiomyopathy in 13 patients, RVEF and LVEF at rest were measured by radionuclide angiography. Maximal upright bicycle exercise testing was also performed to determine maximal oxygen consumption, which averaged only 13 +/- 4 ml/min/kg. The LVEF at rest was 26 +/- 10% and did not correlate with maximal oxygen consumption (r = 0.08). However, the RVEF was 41 +/- 12% and correlated with maximal oxygen consumption (r = 0.70, p less than 0.001) in the same patients. The correlation was stronger (r = 0.88) in patients with coronary artery disease than in those with idiopathic dilated cardiomyopathy (r = 0.60). Thus, RVEF at rest is more predictive of exercise capacity than LVEF in the same patients with chronic LV failure. These results are consistent with the clinical observation that only venodilating agents increase exercise capacity of patients with chronic LV failure.

Minoxidil in patients with chronic left heart failure: contrasting hemodynamic and clinical effects in a controlled trial.

Minoxidil, a potent predominant arterial dilator, improves hemodynamics over the short term in patients with heart failure. In random double-blind fashion 17 patients with chronic left heart failure were given minoxidil (nine patients) or placebo (eight patients) in addition to digoxin and diuretics for 3 months. Cardiac index and heart rate increased and mean arterial pressure and systemic vascular resistance fell within 4 hr of minoxidil administration. Right heart and pulmonary arterial pressures were unchanged over the short term but rose after long-term minoxidil. After 3 months of minoxidil treatment, systemic vascular resistance was still reduced (11.7 +/- 6.3[SD] vs 17.1 +/- 3.1 U at baseline; p less than .05). Hemodynamics were similar at baseline and remained unchanged during placebo treatment. Mean left ventricular ejection fraction rose from 29.6 +/- 17.7% to 42.7 +/- 22.3% (p less than .05) after 3 months of minoxidil treatment (this result was influenced largely by responses in two patients), and remained unchanged (at 25.1 +/- 16.6%) after 3 months of placebo. Exercise duration and maximal oxygen uptake during exercise were unchanged during minoxidil or placebo treatment. Total clinical events, including increased need for diuretics, angina, ventricular arrhythmias, worsening heart failure, and death were all more frequent during minoxidil vs placebo administration (21 vs seven total events; p less than .01). Thus, despite improving hemodynamics and left ventricular function, long-term minoxidil administration was associated with a poorer clinical course in patients with chronic left ventricular failure. Furthermore, this experience demonstrates that improvement of left ventricular function alone cannot be reliably interpreted as proof of clinical efficacy of therapeutic interventions in patients with heart failure.

Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure.

The cause of exercise intolerance in congestive heart failure is unclear. Hemodynamic and ventilatory responses were measured during symptomatic maximal upright bicycle exercise in 28 patients with chronic severe left ventricular failure who achieved a maximal oxygen uptake of only 12 +/- 4 ml/min/kg (+/- standard deviation). All patients reached anaerobic metabolism as the respiratory exchange ratio rose and arterial pH fell significantly. Pulmonary capillary wedge pressure increased from 20 +/- 10 mm Hg at rest to 38 +/- 9 mm Hg at peak exercise and cardiac index increased from 2.51 +/- 0.73 to 4.54 +/- 1.65 liters/min/m2 (both p less than 0.001). Systemic vascular resistance decreased, but pulmonary vascular resistance did not change during exercise. Despite the marked pulmonary venous hypertension at peak exercise, blood gases were unchanged (PaO2, 96 +/- 15 mm Hg; PaCO2, 35 +/- 7 mm Hg). Systemic arterial oxygen content increased from 16 +/- 2 to 17 +/- 2 vol% (p less than 0.01). Changes in pulmonary capillary wedge pressure did not correlate with changes in arterial oxygen content. Results were similar whether patients were limited by dyspnea or fatigue. Thus, exercise intolerance in patients with severe left ventricular failure is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension. These findings suggest that exercise ability in congestive heart failure is more dependent on cardiac output than on ventilatory consequences of pulmonary congestion.

Enalapril (MK-421), a new angiotensin-converting enzyme inhibitor. Acute and chronic effects in heart failure.

Enalapril (MK-421) is a new oral angiotensin-converting enzyme inhibitor which was administered to eight patients with chronic congestive heart failure. Four hours after enalapril administration (10 to 20 mg), mean arterial pressure fell from 95.6 +/- 11.4 (SD) to 84.8 +/- 17.6 mm Hg (p less than 0.05), systemic vascular resistance fell from 18.5 +/- 3.0 to 15.8 +/- 4.1 units (p less than 0.02), while pulmonary artery wedge pressure changed insignificantly from 17.5 +/- 9.2 to 14.5 +/- 10.2 mm Hg and cardiac index rose insignificantly from 2.63 +/- 0.46 to 2.82 +/- 0.75 L/min/m2. These hemodynamic effects persisted during one month of enalapril administration. Baseline plasma renin activity of 0.76 +/- 1.07 ng/ml/hr rose to 3.23 +/- 2.87 ng/ml/hr (p less than 0.05) after one month of enalapril administration. During the month of enalapril administration, maximal exercise duration rose from 465.1 +/- 233.0 to 572.3 +/- 233.7 seconds (p less than 0.05), and maximal oxygen uptake increased from 12.3 +/- 2.7 to 16 +/- 11.2 ml/min/kg (p less than 0.05). No major side effect occurred. These sustained effects may be clinically beneficial, and enalapril deserves further evaluation in the long-term treatment of patients with chronic congestive heart failure.

Effects of a new angiotensin converting enzyme inhibitor, enalapril, in acute and chronic left ventricular failure in dogs.

Enalapril (MK-421) is a new angiotensin converting enzyme inhibitor which effectively lowers elevated blood pressure and might also be useful in heart failure. Enalapril was infused into six awake dogs 2 hours after left circumflex coronary artery embolization (acute failure group) and into six other awake dogs two to six months after coronary embolization (chronic failure group). In the acute failure group 2 hours after embolization, increased left ventricular end-diastolic pressure and reduced cardiac output remained unchanged during enalapril infusion. In the chronic failure group, increased left ventricular end-diastolic pressure also remained unchanged during enalapril infusion, but cardiac output, which had fallen to 131.8 +/- 11.9 (S.D.) from 165.8 +/- 17.9 ml/min/kg (P less than 0.01) by two to six months in this group rose during enalapril infusion to 154.5 +/- 27.7 ml/min/kg (P less than 0.05). Heart rate and blood pressure were not changed during enalapril in either group, but stroke volume rose (26.0 +/- 5.9 to 29.2 +/- 6.9 ml, P less than 0.01) and systemic vascular resistance fell (58.5 +/- 10.3 to 39.3 +/- 4.3 units, P less than 0.01) during enalapril only in the chronic failure group. Plasma renin activity after embolization was slightly but not significantly higher in the acute failure group. Thus, enalapril appears to be an arterial vasodilator in dogs with chronic but not acute left ventricular failure.