Relation of time course of plasma nitroglycerin levels to echocardiographic, arterial pressure and heart rate changes after sublingual administration of nitroglycerin

Despite the widespread use of nitroglycerin, a relation between plasma nitroglycerin concentrations and the associated cardiovascular effects has not been well established. It was hypothesized that nitroglycerin levels may help predict the hemodynamic responses. With use of a recently developed nitroglycerin assay technique, the relation between the time course of plasma nitroglycerin levels and echocardiographic changes after sublingual administration of 0.6 mg of the drug was evaluated in 12 normal volunteers. Mean plasma nitroglycerin levels were maximal at 2 (1.1 +/- 0.3 ng/ml) and 5 (1.4 +/- 0.6 ng/ml) minutes, when the changes in mean heart rate (+17 +/- 7 and +12 +/- 3 min-1) and decreases in echocardiographic left ventricular diastolic (-4.2 +/- 0.8 mm at 5 minutes) and systolic (-3.1 +/- 0.6 mm at 5 minutes) dimensions were also maximal. Parallel changes were noted in left atrial dimension, ventricular velocity of circumferential fiber shortening and systolic blood pressure, but not in diastolic blood pressure. These findings demonstrate the existence of a close relation between plasma nitroglycerin levels and variables that reflect the known responses to this drug.     

Pharmacokinetic-hemodynamic studies of transdermal nitroglycerin in congestive heart failure

Ten patients with chronic congestive heart failure were studied to assess the hemodynamic effects and bioavailability of a transdermal nitroglycerin delivery system. Nitrate sensitivity was defined by a prior 20 minute infusion of nitroglycerin, 21 micrograms/min. Five patients with a satisfactory hemodynamic response to intravenous nitroglycerin received two nitroglycerin patches of 10 cm2 each and five patients who did not achieve a satisfactory response to intravenous nitroglycerin (that is, greater than or equal to 25% reduction in left ventricular filling pressure) received larger doses of transdermal nitroglycerin. In the five nitrate-sensitive patients who received 20 cm2 of transdermal nitroglycerin, one study was terminated at 90 minutes, at which point there was no detectable hemodynamic response or arterial plasma nitroglycerin evident. Two patients had a minimal hemodynamic response and a peak plasma concentration of 1 ng/ml. A fourth patient had a short-lived hemodynamic response at 60 and 120 minutes and a plasma nitroglycerin concentration of 1 ng/ml at 60 minutes. A fifth patient had a hemodynamic response persisting for 24 hours and plasma concentrations between 0.6 and 1.1 ng/ml. The remaining five patients showed little or no hemodynamic response despite doses of transdermal nitroglycerin from 40 to 60 cm2. The highest plasma concentration achieved in these patients was 2 ng/ml and there was no relation between dose administered and plasma concentration achieved. In 4 of the 10 patients who subsequently received nitroglycerin ointment, there were a greater decrease in left- and right-sided filling pressures and greater increase in plasma nitroglycerin concentrations (from 1.6 to 4.8 ng/ml) than those that occurred with transdermal nitroglycerin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of skin site on bioavailability of nitroglycerin ointment in congestive heart failure

Nitroglycerin ointment (12.5 to 50 mg) was administered in randomized fashion to three skin sites, arm, chest, or thigh, to compare the hemodynamic effects and bioavailability in nine patients with severe congestive heart failure. Hemodynamic parameters and arterial nitroglycerin concentrations were measured frequently for 12 hours after each application and for 90 minutes after removal of the ointment. During the study, left ventricular filling pressures decreased from control values of 25.0 +/- 8.6 mm Hg (arm), 25.7 +/- 10.9 mm Hg (chest), and 23.7 +/- 8.4 mm Hg (thigh) to 20.4 +/- 8.6 mm Hg, 20.4 +/- 8.5 mm Hg, and 20.0 +/- 7.5 mm Hg; p less than 0.05, less than 0.01, and difference not significant respectively. Peak nitroglycerin concentrations were 5.1 +/- 4.3 ng/ml (arm), 6.2 +/- 6.0 ng/ml (chest), and 4.1 +/- 6.3 ng/ml (thigh). No significant difference was observed in mean arterial pressure, left ventricular filling pressure, right atrial pressure, or nitroglycerin concentration among the sites. These data show that nitroglycerin ointment has similar bioavailability on the arm, chest, or thigh and therefore can be used interchangeably on these skin sites.     

Comparison of diagnostic accuracy of sublingual nitroglycerin test and low-dose isoproterenol test in patients with unexplained syncope

Despite the widespread use of head-up tilt testing as a means for diagnosing vasovagal syncope, standardization of test methodology remains a controversial issue. The aim of this study was to compare the diagnostic value of head-up tilt testing potentiated with sublingual nitroglycerin with that of head-up tilt testing potentiated with low-dose isoproterenol. For this purpose, 71 patients with unexplained syncope (mean age 43 years) and 30 asymptomatic controls were studied. All underwent the sublingual nitroglycerin and low-dose isoproterenol tests on separate days in a randomized fashion. The protocol of the 2 tests was similar and consisted of 2 phases. Initially, subjects were tilted at 60 degrees for 20 minutes without medication; then, if syncope did not occur, patients and controls received sublingual nitroglycerin (300 microg) or low-dose intravenous isoproterenol (mean infusion rate 1.3 +/- 0.5 microg/min) and continued to be tilted at 60 degrees for a further 20 minutes. During the sublingual nitroglycerin test, a positive response (syncope associated with sudden hypotension and bradycardia) occurred in 35 patients (49%), a negative response in 36 (51%), and drug intolerance in none (0%). During the low-dose isoproterenol test, these percentages were 41%, 59%, and 6%, respectively. A concordant response was observed in 53 cases (75%). Among controls, 3 subjects (10%) had a positive response to the sublingual nitroglycerin test and 4 (13%) to the low-dose isoproterenol test. It is concluded that sublingual nitroglycerin and low-dose isoproterenol are equivalent tests for evaluating patients with unexplained syncope. The sublingual nitroglycerin test, however, is simpler, better tolerated, and safer than the low-dose isoproterenol test and, thus, more suitable for routine clinical use.     

Oral sustained-release nitroglycerin in chronic stable angina: a multicenter, double-blind, randomized crossover trial

Forty-six patients with stable angina pectoris were randomized to receive either oral sustained-release nitroglycerin (SRNG, 6.5 mg) or placebo (P) 3 times a day for a 2-week double-blind trial. They were investigated for the frequency of anginal episodes, for sublingual nitroglycerin consumption and for exercise tolerance. There was a slight but significant decrease in the number of anginal episodes (6.4 +/- 1.5 episodes/week with P, 4.9 +/- 1.7 with SRNG, p less than 0.005) and sublingual nitroglycerin consumption (3.9 +/- 1 tablets/week with P, 2.7 +/- 1 with SRNG, p less than 0.005). The patients performed 3 upright multistage (increments of 30 W every 3 minutes) exercise tests on a bicycle ergometer before the start of the study and 1 hour after the intake of SRNG or P, at the end of each double-blind phase. Exercise capacity, expressed as exercise duration, increased from 8.9 +/- 3.8 minutes with P to 10.2 +/- 3.8 minutes with SRNG (14.6%; p less than 0.001). At symptom-limited exercise, ST depression was significantly reduced (p less than 0.05) during the SRNG phase. Thirty-four patients (74%) reached a higher peak heart rate (139 beats/min with P, 145 beats/min with SRNG; p less than 0.001) and 35 patients (76%) a higher rate-pressure product (+6%; p less than 0.001). These changes in exercise tolerance are relatively modest and at least 11 patients would have benefited from larger doses of nitrates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic absorption of tetracycline and lidocaine following intrapleural instillation

Seven patients with symptomatic pleural effusions (six) and recurrent pneumothorax (one) underwent attempted pleurodesis using tetracycline. Lidocaine (150 mg), followed immediately by tetracycline (20 mg/kg), was instilled into the pleural space through a chest tube. Venous blood was obtained at 0, 15, 30, 60, and 120 minutes following instillation in order to determine concentrations of lidocaine and tetracycline. The mean peak serum concentration of lidocaine was 1.3 mu/ml +/- 0.4 microgram/ml (mean +/- SE) (range, 0.3 microgram/ml to 3.2 microgram/ml), and the mean time to peak serum concentration of lidocaine was 86 +/- 13 minutes. The mean peak serum concentration of tetracycline was 3.6 microgram/ml +/- 0.9 microgram/ml (range, 1.0 microgram/ml to 5.0 micrograms/ml), and the mean time to peak serum concentration of tetracycline was 96 +/- 16 minutes. Therapeutic serum concentrations of lidocaine were found in four of the seven patients and therapeutic serum levels of tetracycline in four of five patients. With systemic absorption of lidocaine and tetracycline following intrapleural instillation, patients are at risk for potential toxic effects. If lidocaine is used in a dosage of less than 3 mg/kg, toxic levels of the drug are unlikely to occur. Furthermore, use of tetracycline or lidocaine in pleurodesis is contraindicated in patients with known sensitivity to the drugs.     

Inhibition of nitrate tolerance without reducing vascular response during eccentric dosing of nitrates.

It has been reported that the nitrate tolerance related to continuous dosing of nitrates reduces drug efficacy, and therefore eccentric dosing of nitrates is recommended. In this study, we investigated the appearance of nitrate tolerance related to continuous dosing of nitrates and prevention of nitrate tolerance during eccentric dosing by comparing the grade of coronary dilatation after sublingual nitroglycerin. Of 26 patients with ischemic heart disease who underwent elective cardiac catheterization, 8 patients were continuously administered nitrates, 8 patients were eccentrically administered nitrates, and 10 patients were not treated. We compared the coronary response to sublingual nitroglycerin among the 3 groups. In a coronary vessel without significant stenosis, the coronary vessel area, coronary lumen area, and mean coronary blood flow velocity after sublingual nitroglycerin were measured using intravascular ultrasound (IVUS). In the continuous dosing group, the maximal rate of change in the vessel area after sublingual nitroglycerin was 105 +/- 1 (mean +/- SEM) %, significantly lower than those in the untreated group and the eccentric dosing group (114 +/- 2%, 114 +/- 2%) (p < 0.01, respectively). In conclusion, eccentric dosing of nitrates inhibited the appearance of nitrate tolerance without reducing vascular response.     

Impact of food on the pharmacokinetics and electrocardiographic effects of sustained release verapamil in normal subjects.

To evaluate the impact of food on the pharmacokinetics and electrocardiographic effects of sustained release (SR) verapamil tablets, 9 healthy men each received 3 single doses of verapamil in a randomized, crossover manner: 10 mg of intravenous verapamil, 240 mg SR verapamil on an empty stomach, and 240 mg SR verapamil with a standardized meal. PR intervals and racemic verapamil serum concentrations were measured serially over 30 hours after administration. The time to peak concentration was longer (7.5 +/- 3.0 vs 4.4 +/- 2.3 hours), resulting in a lower peak verapamil serum concentration (118 +/- 43 vs 175 +/- 50 ng/ml) when SR verapamil was administered with food (p < 0.05). Food tended to decrease the bioavailability of SR verapamil (34 +/- 12 vs 49 +/- 14%), although this difference did not reach statistical significance (p = 0.065). Precipitous or exaggerated release of verapamil from the SR tablet was not observed in any subject during the fasting state. Prolongation of the PR interval paralleled these alterations in serum concentration. The maximal change in the PR interval was greater (21 +/- 8 vs 14 +/- 5%; p < 0.05) when SR verapamil was given in the fasting state. Although an exaggerated verapamil release or effect was not observed, food significantly altered the absorption and electrocardiographic effects of a single dose of SR verapamil. Manipulation of the administration condition may be helpful in achieving desired outcomes.     

Methemoglobin levels following sublingual nitroglycerin in human volunteers

Sublingual nitroglycerin 0.8 mg every five minutes for a total of 4.8 mg was administered to 11 healthy volunteers. One volunteer had to withdraw due to a hypotensive bradycardic reaction after 2.4 mg. In the remaining subjects, methemoglobinemia over the next hour never significantly increased from baseline levels, reaching a peak of only 0.71%. We conclude that commonly used doses of sublingual nitroglycerin do not induce significant methemoglobinemia and that nitroglycerin would not be useful in the treatment of cyanide poisoning.     

Blood levels after sublingual nitroglycerin.

Pharmacokinetic analysis of nitroglycerin (GTN) has been hampered by the lack of a sensitive and specific method for measuring GTN in blood. Therefore, we examined the appearance of GTN in blood after administering 0.6 mg sublingually in 10 studies of normal volunteers. We used a gas-liquid chromatographic method with electron-capture detection and isosorbide dinitrate as the internal standard. GTN appeared in blood at 0.5 minutes, reached a peak of 2.3 +/- 0.36 ng/ml at 2 minutes, fell to 50% of peak value at 7.5 minutes and was barely detectable at 20 minutes. These blood levels paralleled the changes in heart rate and systolic blood pressure. These data show rapid appearance and disappearance of GTN from blood after sublingual administration, a large volume of distribution, and a rapid rate of total body clearance that precludes the liver from being the sole elimination site. This method for analysis of GTN and isosorbide dinitrate should be helpful in defining the role of chronic nitrate therapy.     

Bioavailability and pharmacological effects of two slow-release theophylline preparations: intrasubject tablet-to-tablet variability

The bioavailability and pharmacological effects of slow-release preparations oxtriphylline (Choledyl SA) and anhydrous theophylline (Theo-Dur) were compared in a single-blind, randomized, crossover study in 10 normal men. Subjects were administered three doses from the same lot of each preparation at weekly intervals. Plasma concentration of theophylline was measured at timed intervals for 33 hr by high-pressure liquid chromatography. Pharmacokinetic analysis showed that Choledyl SA peaked earlier (4.7 +/- 1.0 hr) than did Theo-Dur (9.6 +/- 8.2 hr), with higher peak concentrations, 6.4 +/- 0.7 micrograms/ml versus 4.1 +/- 0.5 micrograms/ml for Theo-Dur, and greater are under the curve, 102.4 +/- 15.7 micrograms/ml X hr versus 75.3 +/- 9.1 micrograms/ml X hr for Theo-Dur. 88% absorption was achieved in 6 hr with Choledyl SA versus 10 hr with Theo-Dur. Wide intra- and intersubject variations were observed with both preparations. Likewise, variable effects on systolic and diastolic blood pressure and pulse were observed with both preparations. The effects of both theophylline preparations on urine flow, osmolar clearance, and glomerular filtration rate were compared. Osmotic diuresis without detectable changes in the glomerular filtration rate was observed in subjects who received Choledyl SA versus Theo-Dur. Differences in the bioavailability and renal effects were observed between Choledyl SA and Theo-Dur. Wide intra- and intersubject tablet-to-tablet variability were observed with both preparations.     

Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina pectoris and acute myocardial infarction

The platelet aggregation response to adenosine diphosphate (ADP) and to thrombin was quantified in 10 patients, 5 with unstable angina pectoris and 5 with acute myocardial infarction, before, during and after a 45-minute infusion of nitroglycerin. An impedance aggregometer allowing rapid bedside studies in whole blood was used. The reproducibility of the methods was documented to be within 10%. Doses of nitroglycerin were titrated for a 10 mm Hg decrease in mean arterial blood pressure with mean doses being 1.2 +/- 0.2 (standard error of the mean) micrograms/kg/min. Nitroglycerin decreased the area under the aggregation curve induced by ADP from 43 +/- 3.6 to 30 +/- 6.3 cm2 (p = 0.007) and by thrombin from 8.9 +/- 1.7 to 4.1 +/- 0.9 cm2 (p = 0.003). Peak responses to ADP were decreased from 13.3 +/- 1 to 9.1 +/- 1.7 ohms (p = 0.005) and to thrombin from 9.3 +/- 2 to 5.0 +/- 1.2 ohms (p = 0.003). All patients had greater than or equal to 50% inhibition with 1 agent or the other and the inhibition was greater than 50% with each of the 2 aggregating agents in 6 patients. Analyses performed on blood withdrawn 15 minutes after the discontinuation of nitroglycerin showed a return to baseline before nitroglycerin results. When analyses were delayed and performed on blood preserved at room temperature for 30 minutes, no effect of nitroglycerin could be detected. Thus, bedside platelet aggregation studies document a significant and reversible effect of nitroglycerin at therapeutic doses on platelet function.     

Effects of nicorandil on exercise tolerance in patients with stable effort angina: a double-blind study

Effects of nicorandil, a recently introduced 2-nicotinamidethyl nitrate, on exercise performance were studied in 11 patients with stable effort angina. The duration of exercise before the onset of angina and time to the onset of ischemic ST depression 30 minutes after 20 mg of oral nicorandil were compared with events 30 minutes after oral placebo and 5 minutes after 0.3 mg of sublingual nitroglycerin. Nicorandil and placebo were given according to the randomized double-blind method. Nicorandil prolonged the duration of exercise in all 11 patients by 2.3 +/- 2.2 minutes (mean +/- SD, p less than 0.01) and delayed the onset of ischemic ST depression by 2.3 +/- 1.7 minutes compared to placebo (p less than 0.01). The increment of the duration of exercise and the time to the onset of ischemic ST depression following 20 mg of oral nicorandil were almost equivalent to findings after sublingual nitroglycerin (by 2.0 +/- 1.8 and 2.5 +/- 1.7 minutes, respectively). Nicorandil also increased the pressure-rate product at the time of angina compared with placebo (20,420 +/- 480 vs 17,480 +/- 370, p less than 0.05). These results indicate that oral administration of nicorandil should be considered for the clinical treatment of effort angina.     

Pentamidine pharmacokinetics in patients with AIDS with impaired renal function

In patients with normal renal function, pentamidine elimination half-life and plasma clearance (mean +/- SD) were 6.22 +/- 1.17 hr and 411 +/- 55 liters/hr, respectively. With creatinine clearances from 35 to 145 ml/min, neither the elimination half-life (P = .47) nor the plasma clearance (P = .40) was correlated with renal function. Plasma concentrations in patients receiving dialysis ranged between 5.9 and 582 ng/ml and appeared not to be significantly affected by dialysis. The number of prior doses and the elimination half-life estimated from the terminal slope were correlated (r = .81, P = .025), and the results suggested that the current assay technology is still not sensitive enough to detect true elimination half-life. Trough plasma concentrations ranged between 4.3 and 67.5 ng/ml (28.4 +/- 26.6 ng/ml) in patients who had received prior doses of pentamidine, a result suggesting that drug accumulation occurs with multiple dosing. The data suggest that dosage adjustments are not necessary with creatinine clearances of greater than 35 ml/min. Because multiple dosing leads to increased trough concentrations and drug accumulation, lower dose regimens may still be efficacious, yet associated with reduced toxicity.     

Portal hemodynamics during nitroglycerin administration in cirrhotic patients

Nitroglycerin is a potent venous dilator and a mild arterial vasodilator that has been shown to improve the hemodynamic response to vasopressin in portal hypertensive patients and to decrease portal pressure in experimental animals. In order to determine the effect of nitroglycerin on portal venous hemodynamics, we studied 11 patients with alcoholic cirrhosis before and during the administration of sublingual nitroglycerin (0.4 and 0.6 mg). The hepatic venous pressure gradient (which was obtained by subtracting the free hepatic venous pressure from the wedged hepatic venous pressure) decreased from 17.9 +/- 6.5 mm Hg (mean +/- S.D.) to 15.1 +/- 5.1 mm Hg (p less than 0.02) at the peak of the effect, which occurred from 2 to 12 min after nitroglycerin administration. The mean arterial pressure was reduced from 96 +/- 10 mm Hg to a peak decrease of 76 +/- 18 mmHg (p less than 0.001). The peak change in the hepatic venous pressure gradient induced by nitroglycerin correlated directly with the peak change in mean arterial pressure (r = 0.79, p less than 0.01). There was a moderate increase in heart rate in response to the decrease in blood pressure (73 +/- 15 to 83 +/- 15 beats per min, p less than 0.001). Two of the 11 patients did not reduce their hepatic venous pressure gradient after 0.6 mg nitroglycerin. Reductions in portal pressure were observed with both increases and moderate decreases in azygos blood flow, suggesting that, as observed in experimental animals, the portal-pressure-reducing effect of nitroglycerin could be due to two different and independent mechanisms, a reduction in portal blood flow or portal-collateral vasodilatation.     

Effect of nitrates on left ventricular size and function during exercise: Comparison of sublingual nitroglycerin and nitroglycerin paste

To compare the effects of sublingual nitroglycerin and nitroglycerin paste on left ventricular size and performance during supine bicycle exercise, equilibrium radionuclide angiography was performed in 36 persons classified into two groups of normal subjects and two groups of patients with angiographically proved coronary heart disease. Each group underwent a control exercise study, and then one group of normal subjects and one group of patients were restudied after the administration of 0.6 mg of nitroglycerin or 2 inches (5 cm) of nitroglycerin paste (but not both). Data were collected at rest and at peak exercise.In normal subjects exercise resulted in increased ejection fraction, decreased end-systolic volume and little change in end-diastolic volume. After either drug, volumes at rest markedly decreased, and during exercise, ejection fraction increased to levels comparable with pre-drug levels. After nitroglycerin paste the reduction in volume seen at rest persisted during exercise, but after sublingual nitroglycerin end-diastolic volume increased during exercise (88 ± 43 to 113 ± 30 ml [mean ± standard deviation]; p < 0.01). Peak exercise end-diastolic volume after nitroglycerin was still lower than that before nitroglycerin (113 ± 30 versus 120 ± 28 ml, p < 0.05).In patients with coronary disease, ejection fraction did not change during exercise, but both end-diastolic and end-systolic volumes increased. After either drug ejection fraction at rest was unchanged, although ventricular volumes were markedly lower (p < 0.05). Ejection fraction increased with exercise in both groups with coronary disease after either drug. After sublingual nitroglycerin, volumes increased during exercise although the peak exercise end-diastolic volume was still lower than the control value (113 ± 31 versus 145 ± 34 ml; p < 0.01). After paste administration, end-diastolic volume did not change during exercise, and end-systolic volume decreased (41 ± 20 to 36 ± 22 ml; p < 0.05).Thus, sublingual nitroglycerin and nitroglycerin paste improved left ventricular function during exercise. The effect of paste on end-diastolic volume appeared sustained, whereas that of sublingual nitroglycerin was transient, confirming the hypothesis that reduction in end-diastolic volume and, by implication, left ventricular wall tension, is a major mechanism of nitrate action.     

Sublingual administration of captopril in patients with acute myocardial ischemia.

To investigate the anti-ischemic capability of the angiotensin-converting enzyme inhibitor captopril, 10 patients with acute myocardial ischemia (angina pectoris less than 1 h, ST-segment depression greater than or equal to 0.1 mV, no rise in creatine phosphokinase) received 25 mg captopril sublingually after being treated with an intravenous infusion of nitroglycerin (3 mg/h) and heparin (1200 IU/h) for 1 hour. A control group of 10 patients received placebo instead of captopril. Results showed a decrease of the initial ST-segment depression from 0.25 +/- 0.04 to 0.2 +/- 0.03 mV (p less than 0.01) with nitroglycerin for the captopril group and from 0.26 +/- 0.05 to 0.21 +/- 0.05 mV (p less than 0.01) for the control group. An additional decrease to 0.13 +/- 0.03 mV (p less than 0.001) was measured after sublingual captopril, while no significant change was found in the placebo group (0.19 +/- 0.04 mV). In both groups, 3 patients had no incidents of angina after 1-h nitroglycerin infusion. An additional 6 patients resolved their complaints after captopril administration in contrast to only 1 after placebo. Two patients in the placebo group required increased doses of nitroglycerin because of impairment of anginal complaints. Hemodynamic measurements documented a significant drop of pulmonary vascular resistance after a 1-h infusion of nitroglycerin (-12.9% and -13.1%, respectively, p less than 0.05), while all other parameters remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Methionine restores the venodilative response to nitroglycerin after the development of tolerance

Depletion of sulfhydryl groups may contribute to nitroglycerin tolerance after long-term exposure. This study was performed to assess whether methionine, an amino acid capable of augmenting sulfhydryl availability, would restore the venodilative response to sublingual nitroglycerin once tolerance had developed. The venodilative response to organic nitrates was assessed with use of the equilibration technique of forearm plethysmography. Venous volume was measured before and after sublingual administration of 0.4 mg of nitroglycerin at baseline study and after 5 g of intravenous methionine. Retesting was performed 2 h after application of a 10 mg nitroglycerin patch and compared with the response after 74 h of nitroglycerin patch exposure before and after intravenous methionine. Methionine alone had no intrinsic venodilative action. Although the venous volume at rest was unchanged after methionine administration, the response to sublingual nitroglycerin was potentiated compared with baseline values (37 +/- 15% versus 32 +/- 13%, p less than 0.02). During nitroglycerin patch exposure, the response to sublingual nitroglycerin was significantly attenuated at 74 h compared with the response at 2 h of exposure (16 +/- 10% versus 31 +/- 13%, p less than 0.001). The venodilative response to sublingual nitroglycerin was restored at 74 h after methionine administration (35 +/- 14% versus 16 +/- 10%, p less than 0.001). Thus, methionine potentiates the venodilative effect of sublingual nitroglycerin both immediately and in the setting of nitrate tolerance.     

Busulfan disposition in children

Children receive busulfan orally as part of myeloablative therapy before bone marrow transplantation for malignant and nonmalignant conditions. Children have been reported to have a low incidence of severe toxicity and significant rates of failure to achieve full engraftment. We evaluated the disposition of busulfan in children between 2 months and 3.6 years of age with lysosomal storage diseases, leukemia, and immunodeficiency disorders receiving oral doses of 1 or 2 mg/kg using a gas chromatographic assay. Peak concentrations were lower than those previously reported for adults, ranging from 1.4 to 5.2 mumol/L. The harmonic mean of the elimination half-life was 92 minutes, which is only slightly faster than that for adults (140 minutes). However, the area under the curve ranged from 400 to 1,000 (715 +/- 240) mumol.min/L, substantially lower than in adults receiving 1 mg/kg (range, 710 to 5,100 mumol.min/L; mean +/- SD, 2,180 +/- 1,200). The apparent volume of distribution (assuming complete bioavailability) ranged from 0.28 to 3.53 L/kg (1.42 +/- 0.86), which is more than twice that reported for adults (0.60 +/- 0.42). Busulfan clearance rate normalized to surface area is twice as high in children (200 +/- 100 mL/min/m2) as it is in adults (95 +/- 54 mL/min/m2). Alterations in bioavailability (absorption or first pass elimination) or in actual volume of distribution may account for these differences in drug disposition. The observed differences suggest the need for separate phase I dose escalation studies in children with accompanying pharmacokinetic assessment.     

Enhanced oral bioavailability of meptazinol in cirrhosis.

Kinetic analysis was carried out after single intravenous (25 mg) and oral (200 mg) doses of the novel partial opioid agonist meptazinol (Meptid) in patients with non-cirrhotic liver disease (NCLD) and biopsy proven cirrhosis. Comparison was made with a group of patients with normal hepatic function. Elimination half-lives after the intravenous dose were slightly prolonged in the cirrhotics (n = 10; 4.2 +/- 0.6 h) compared with the control (n = 8; 2.7 +/- 0.2 h: p less than 0.05) and NCLD (n = 8; 3.2 +/- 0.5 h) groups. There was no significant difference in meptazinol plasma clearance between the groups (cirrhotics = 72 +/- 8 l/h; NCLD = 89 +/- 9 l/h; control = 83 +/- 10 l/h). After the oral dose, seven of 15 cirrhotic patients vomited but only one patient in each of the other groups was unable to tolerate the drug (p = 0.06). This may be explained by very much higher peak meptazinol concentrations in the cirrhotic (n = 8; 184 +/- 37 ng/ml, p less than 0.01) and NCLD (n = 8; 131 +/- 38 ng/ml, p less than 0.05) patients than those of the controls (n = 7; 53 +/- 12 ng/ml) reflecting a mean four-fold and two-fold increase in oral bioavailability respectively (cirrhotics: n = 8; 27.9 +/- 5.3%: p less than 0.001; NCLD: n = 7; 13.7 +/- 3.9% p less than 0.05; controls: n = 7; 6.5 +/- 1.3%). There was no evidence of accumulation after chronic dosing with 200 mg meptazinol four times daily for 13 doses in seven control, seven NCLD and six cirrhotic patients. There were no detectable differences in psychomotor function measured objectively using the Leeds Psychomotor Tester of subjectively by linear analogue scoring between the groups in all three parts of the study. The oral use of meptazinol in patients with chronic liver disease is associated more with the development of nausea and vomiting rather than excessive sedation. These data suggest that dosage reduction in cirrhotic patients is advisable particularly if the drug is taken by mouth.