Renal tumor size: comparison between computed tomography and surgical measurements.

OBJECTIVE: We studied the agreement between renal tumor size as assessed on computed tomography (CT) before surgery and that measured during histopathological examination on the radical nephrectomy specimen. METHODS: We retrospectively analyzed the records of 100 consecutive patients treated with radical nephrectomy for a renal tumor. The tumor size was determined in all patients by the largest diameter shown within the month before surgery on contrast-enhanced CT and as measured postoperatively by the pathologist. A possible influence of the clinical and pathological parameters was assessed in a multivariate analysis. RESULTS: CT estimate and surgical measurement of tumor size were highly correlated (r = 0.9; p<0.001). Median (range) tumor size was 70.0 mm (13-180) and 60.0 mm (10-180) as measured, respectively, on CT and in the specimen, with a significant difference (p = 0.005). Multiple regression did not reveal any significant influence of tumor side, location, type, nuclear grade as well as patient gender, body mass index and radiological center (p>0.3 in all cases). The extent of difference between CT and surgical measurements was significantly influenced by the surgical size of the tumor (p = 0.03): the smaller the tumor, the more the CT overestimated the tumor size. If nephron-sparing surgery had been planned for tumors equal to or less than 40 mm, 24 patients would have been selected following the CT estimate, while 27 patients would have met this criterion on the surgical measurement. CONCLUSION: Renal tumors were statistically smaller than the estimate from CT, although this was not systematically the case. This should be kept in mind when issuing recommendations on the optimal cutoff size value under which nephron-sparing surgery is considered equivalent to radical nephrectomy.

Double-blind multicenter study comparing alprostadil alpha-cyclodextrin with moxisylyte chlorhydrate in patients with chronic erectile dysfunction.

PURPOSE: We compared the efficacy and safety of alprostadil alpha-cyclodextrin and moxisylyte chlorhydrate to induce erections adequate for sexual intercourse in a prospective, randomized, parallel double-blind study in patients with erectile dysfunction. MATERIALS AND METHODS: A total of 156 men with erectile dysfunction due to organic, nonorganic and mixed origin was randomized into 2 parallel treatment groups receiving titrations of an individual optimum dose of alprostadil alpha-cyclodextrin or moxisylyte chlorhydrate. Erectile response was measured by the buckling test. A positive test was associated with axial erection rigidity that did not buckle/deform to 1.0 kg. load. The buckling test was repeated every 10 minutes for up to 60 minutes. RESULTS: A total of 56 patients (75%) in the alprostadil alpha-cyclodextrin group and 32 patients (40%) in the moxisylyte chlorhydrate group responded with at least 1 positive buckling test during the office period. Investigators assessed erections after alprostadil alpha-cyclodextrin to be adequate for sexual intercourse in 61 patients (81%) compared to 37 patients (46%) after moxisylyte chlorhydrate. All efficacy parameters in office reached statistical significance of p < 0.001 in favor of alprostadil alpha-cyclodextrin. During self-injection therapy at home 58 patients (85%) reported at least 1 rigid erection after alprostadil alpha-cyclodextrin compared to 37 patients (61%) after moxisylyte chlorhydrate. Patient and partner opinion of treatment achieved statistically significantly better scores in the alprostadil alpha-cyclodextrin group compared to the moxisylyte chlorhydrate group. CONCLUSIONS: Alprostadil alpha-cyclodextrin is significantly more effective than moxisylyte chlorhydrate in producing full penile rigidity in office and at home. Injection related side effects occur with the same frequency but moxisylyte results in more systemic side effects and alprostadil results in more painful and prolonged erections. Patients and partners are significantly more satisfied with alprostadil alpha-cyclodextrin.

Oral pharmacokinetics of bisoprolol in resting and exercising healthy volunteers.

The effects of exercise on bisoprolol oral pharmacokinetics were studied in eight healthy male volunteers in an open, randomized, three-period, crossover trial. Oral bisoprolol (20 mg) was given either at rest during 24 h or with iterative stress tests before and 2.5, 5, 10, and 24 h after dosing. Exercise tests were repeated on a third placebo period. Bisoprolol was assayed in plasma and urines, and plasma catecholamines were measured before and after stress tests, Cmax, Tmax, elimination t1/2, and renal clearance of bisoprolol were not significantly modified by exercise. AUC0-infinity significantly decreased by 7.5% (p less than 0.05) with stress test resulting in an increase in apparent oral clearance. The beta-blocking effect peaked at 2.5 h, lasted greater than 24 h, and was related to plasma levels. The exercise-induced increase in plasma norepinephrine levels was significantly augmented with bisoprolol. These results suggest that repeated exercise tests exerted only limited effects on the oral pharmacokinetics of bisoprolol.

A comparative pharmacokinetic and pharmacodynamic study of conventional and sustained-release preparations of acebutolol in healthy volunteers.

Pharmacokinetics and the degree of beta-blockade of sustained release (SR) acebutolol (500 mg/day) and conventional acebutolol (200 mg tid) were examined after the first oral dose and after 10 days of treatment in ten healthy volunteers. After the first dose, acebutolol Cmax did not significantly differ between the two formulations; however, on day 10 acebutolol Cmax was significantly higher after SR formulation. Cmax of diacetolol, the major metabolite, did not differ between SR and conventional acebutolol neither on day 1 nor on day 10. The dose-corrected relative bio-availability of acebutolol was not different from 100% on day 1 and day 10; however the dose-corrected diacetolol AUC, SR/conventional ratio, was significantly lower than 100% on days 1 and 10. Both acebutolol preparations exerted a significant reduction in exercise tachycardia over 24 h on day 1 and day 10; however, conventional acebutolol exhibited a greater reduction 24 h after the first dose. Exercise-induced increase in systolic blood pressure was similarly inhibited by both treatments except for 24 h after the first dose when systolic blood pressure was significantly higher with SR than with conventional acebutolol. The percent reduction in heart rate during exercise was linearly correlated with log acebutolol plasma concentrations for each treatment regimen. These results suggest that beta-blockade exerted by SR acebutolol in healthy volunteers is equivalent to that of conventional acebutolol.

Effects of bepridil and CERM 4205 (ORG 30701) on the relation between cardiac cycle length and QT duration in healthy volunteers.

Bepridil is a calcium antagonist that prolongs the duration of ventricular repolarization, whereas CERM 4205, another calcium antagonist, seems to be devoid of any effect on QT interval. The aim of this study was to compare the effects of bepridil and CERM 4205 on the QT-RR relation at different heart rates during rest and exercise and the results of pharmacologic tests designed to vary neurovegetative tone. Twelve healthy men (21 to 37 years) participated in a placebo-controlled, randomized, crossover, double-blind study and received either bepridil (200 mg/day twice daily) or CERM 4205 (200 mg/day twice daily), or matching placebo during three 14-day treatment periods at 2-week intervals. Bepridil, but not CERM 4205, caused a significant prolongation of resting QT interval. The RR-QT relation was monoexponential for all subjects during resting and exercising physiologic conditions and remained unchanged after 14 days with placebo or CERM 4205. Bepridil significantly shifted the relation upward, resulting in a rate-dependent QT prolongation that predominated during bradycardia. After isoprenaline, QT no longer adapted to changes in heart rate, whereas atropine resulted in a rate-dependent shortening in QT. These results suggest that bepridil and CERM 4205 exert different effects on ventricular repolarization, since only bepridil significantly prolonged QT duration. Bepridil-induced prolongation of QT increased at slow heart rates, which could explain the greater incidence of torsades de pointes in bradycardia.

Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients.

The pharmacokinetics of pentoxifylline were investigated in six healthy volunteers and in 10 patients with alcoholic cirrhosis. After a 100 mg intravenous infusion, pentoxifylline elimination half-life was prolonged in cirrhotic patients (2.12 +/- 1.22 hours versus 0.83 +/- 0.29 hours, p less than 0.05) because of a decrease in its plasma clearance (1.44 +/- 0.46 L.hr-1.kg-1 in patients with cirrhosis versus 3.62 +/- 0.75 L.hr-1.kg-1 in volunteers, p less than 0.001). The elimination half-life of the metabolite (5-hydroxypentoxifylline) was similar to that of the parent compound. After oral administration of a 400 mg sustained-released tablet, absolute bioavailability of pentoxifylline increased in cirrhotic patients (0.71 +/- 0.24 versus 0.33 +/- 0.13, p less than 0.01). Although plasma concentrations of pentoxifylline and hydroxypentoxifylline were significantly increased in cirrhotic patients, the AUCpentoxifylline/AUChydroxypentoxifylline ratio remained unchanged in both groups after either intravenous or oral administration. These findings show that liver cirrhosis profoundly alters the pharmacokinetics of pentoxifylline. However the formation of hydroxypentoxifylline is not modified in these patients, suggesting an extrahepatic metabolism.

Influence of food on the pharmacokinetics of perindopril and the time course of angiotensin-converting enzyme inhibition in serum.

Food has been shown to reduce the bioavailability of the angiotensin-converting enzyme inhibitor captopril, but not the bioavailability of inhibitors administered as ester prodrugs. Perindopril is the ester pro-drug of the angiotensin-converting enzyme inhibitor perindoprilat. The influence of food on the pharmacokinetics of perindopril (4 mg administered orally) and the time course of angiotensin-converting enzyme inhibition in serum was studied in a randomized crossover short-term study of 12 healthy subjects. Food significantly decreased the relative availability of perindoprilat by 35% +/- 42%, the fractional urinary excretion of perindoprilat from 19% +/- 7% to 13% +/- 4% (p less than 0.05), and the partial metabolic clearance of perindopril to perindoprilat from 102 +/- 57 ml.min-1 to 72 +/- 32 ml.min-1 (p less than 0.05). These changes were associated with a significant decrease in the area under the percent angiotensin-converting enzyme inhibition-versus-time curve by 15% (p less than 0.05). Food did not alter the total amount of drug recovered in urine as perindopril and its metabolites, and it did not alter perindoprilat renal clearance. We concluded that food alters the conversion of perindopril to its active metabolite perindoprilat after single-dose administration of perindopril.

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers.

The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg.kg-1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg.kg-1 i.v. of dl-sotalol. There was no significant difference in the disposition of the d-enantiomer and the racemate. The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l.h-1.kg-1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).

Physiologic relation between cardiac cycle and QT duration in healthy volunteers.

To determine the relation between QT duration and RR interval on the electrocardiogram, 2 studies were undertaken in 23 young healthy volunteers (mean age 24 years). In study 1, the electrocardiogram (paper speed at 50 mm/s, 800 measurements/subject) was recorded in 11 subjects (5 men, 6 women) at rest, during dynamic exercise and after rapid intravenous injections of isoproterenol (0.2 to 12.8 micrograms), before and after intravenous atropine (2 mg). In study 2, the QT-RR relation was studied at rest and during exercise in 12 subjects (6 men, 6 women) before and after oral propranolol (80 mg). The results confirmed a monoexponential individual relation of the QT and RR intervals during rest and exercise: QT = A-B.Exp (-k.RR). By pooling the RR-QT plots from the 11 subjects in study 1, we found that the measured QT interval = 425-676.Exp (-3.7.10(-3) RR. During isoproterenol-induced tachycardia, QT either did not change or increased and this may indicate an increase in temporal dispersion of ventricular repolarization. Atropine-induced tachycardia produced changes similar to those resulting from exercise testing. Propranolol did not change the QT-RR relation despite a lengthening in RR intervals. These results suggest that physiologic QT-RR adaptation is mainly under parasympathetic control.

Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients.

Nalbuphine is a new agonist and antagonist opioid analgesic agent that undergoes an important hepatic metabolism. In this study, we compared the pharmacokinetics of intravenous and oral nalbuphine in three groups of subjects: group I consisted of 14 children from 1 1/2 to 5 years of age (group IA) and from 5 through 8 1/2 years of age (group IB), group II consisted of 9 healthy male volunteers from 23 to 32 years of age, and group III consisted of 9 elderly patients from 65 to 90 years of age. All subjects and patients had normal hepatic and renal functions. The children received an intravenous injection of nalbuphine (0.2 mg/kg), and the subjects and patients in groups II and III received, at random, 10 mg intravenous injections and 30 mg oral doses of nalbuphine on two separate occasions. The distribution of nalbuphine was not modified with age. Elimination half-life (t1/2) was significantly shorter in group I (0.9 hour) than it was in group II (1.9 hours) and in group III (2.3 hours). Systemic clearance of nalbuphine decreased significantly with age. Absolute bioavailability of nalbuphine increased from F = 12% in group II to 46.3% in group III (p less than 0.01). These findings suggest that doses and rates of administration of nalbuphine should be adapted in younger patients and in elderly patients.

Effects of falipamil (AQ-A 39) on heart rate and blood pressure in resting and exercising healthy volunteers.

Falipamil (AQ-A 39) is a new verapamil derivative which exerts antitachycardic effects by a direct action on the sinus node. Its effects on heart rate (HR), blood pressure (BP) and ECG intervals were studied in 12 healthy volunteers, at rest and during bicycle exercise tests. In a double-blind, cross-over, single-dose study, the effects of falipamil (100 and 200 mg) during 8-h post-dosing were compared with those of placebo. Falipamil did not modify resting HR, BP, and electrocardiogram (ECG) intervals significantly. Maximal exercise HR significantly decreased by 5.3 +/- 2.9 (SD)% and 11.2 +/- 3.6% 2 h after the 100- and 200-mg dose respectively, whereas placebo had no effect. Exercise BP was not significantly modified by falipamil. The slopes of HR-workload relationships significantly decreased with falipamil. Peak plasma concentrations of falipamil occurred 1-1.5 h after absorption, and the falipamil-induced decrease in exercise HR over 8 h postdosing was proportional to falipamil plasma concentrations. These results suggest that falipamil decreases HR at exercise in normal subjects and may exert antianginal effects in patients with myocardial ischemia.

Pharmacokinetics and effects on exercise heart rate of PK 11195 (52028 RP), an antagonist of peripheral benzodiazepine receptors, in healthy volunteers.

PK 11195 (or 52028 RP; 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide), an antagonist of the peripheral-type benzodiazepine receptors which are coupled to calcium channels, was administered to 10 healthy volunteers in order to study the pharmacokinetics and cardiovascular effects of the drug. PK 11195 was randomly administered intravenously (10 mg) and orally in three single dosages (100, 200 and 400 mg). Placebo was only given orally. Heart rate and blood pressure were recorded at rest and during exercise tests which were performed at 0, 1, 3, 6 and 24 h after dosing on each study day. The results showed that after IV administration, PK 11195 was rapidly distributed in two or three open compartments. Its elimination T 1/2 was short (3.7 +/- 3.0 h) with high interindividual variability. After oral ingestion the pharmacokinetics of PK 11195 were linear over the range of 100-400 mg single oral doses with a stable absolute bioavailability (33%). T 1/2 elimination was prolonged (7-12 h) and the presence of secondary increases in plasma concentration at 8-10 h and 22-24 h after drug absorption may have been related to enterohepatic cycling. No unchanged PK 11195 could be detected in urine. PK 11195 did not significantly modify heart rate and blood pressure at rest or during exercise and was well tolerated by the subjects. These data suggest a high inter-individual variability in PK 11195 disposition with extensive metabolism in normal exercising volunteers.

Clinical pharmacology of hydroxy-3(S)-dihydroquinidine in healthy volunteers following oral administration.

Pharmacokinetics and effects of oral hydroxy-3(S)-dihydroquinidine (3-OH-HQ) on heart rate (HR), blood pressure (BP), and ECG intervals were studied in 12 healthy volunteers. Three oral single doses of 3-OH-HQ (225, 450, and 900 mg) and placebo were randomly administered to each subject at one week intervals. Pharmacokinetics of 3-OH-HQ was linear in the range of administered doses, with rapid absorption (tmax 0.5-2.5 h) and distribution (t1/2 alpha 0.8-1.2 h) phases. Elimination half-lives did not significantly change with the three doses (15 +/- 4.3, 13.7 +/- 3.9, and 13 +/- 2.2 h). Unchanged 3-OH-HQ was partially eliminated by urine (mean renal clearance 0.24 +/- 0.02 L h-1 kg-1). 3-OH-HQ significantly increased HR after the three doses as compared to placebo. PR interval was not significantly modified but QRS duration significantly increased from 91 +/- 7 to 108 +/- 11 ms (p less than 0.001) 2 h after the 900 mg dose. QTc interval was significantly prolonged from 0.5 to 8 h after the highest dose (14.4 +/- 8.7% 1 h after dosing). Heart rate QRS, and QTc variations were significantly correlated to 3-OH-HQ plasma levels.

Pharmacokinetics of hydroxy-3(S)-dihydroquinidine in healthy volunteers after intravenous and oral administration.

The pharmacokinetics of hydroxy-3(S)-dihydroquinidine (HDHQ) were studied in 6 healthy volunteers following a 15 min intravenous infusion of a 300 or 400 mg dose, a 300 mg oral dose in solution and a 300 mg tablet administration on three separate occasions (random order) with at least one week intervals. Using a specific HPLC assay for HDHQ, the post-infusion and post-absorption plasma HDHQ concentrations declined bi-exponentially. Both oral forms of HDHQ were absorbed rapidly (tmax 1 h-1.2 h) with an absolute bioavailability of the oral solution (F = 0.54 to 0.93) which was not significantly different from that of the tablet (F = 0.66 to 0.90). HDHQ was rapidly and extensively distributed to the tissues with a high steady-state volume of distribution (6.82 +/- 1.85 l X kg-1). Mean elimination half-life was 6.7 +/- 1.4 h after IV infusion, 8.4 +/- 1.7 h after the oral solution and 11.3 +/- 4.4 h after the tablet administration. HDHQ was partially eliminated from the body in the unchanged non-conjugated form by the urine and renal clearance represented approximately 50% of the total body clearance. These results show that HDHQ is rapidly and almost completely absorbed and has potential for a twice daily administration regimen for the treatment of cardiac arrhythmias.