[Spirapril in patients with hypertension: clinical experience in Germany]. / Primenenie spiraprila u patsientov s arterial'noi gipertoniei - klinicheskii opyt v Germanii.

AIM: To examine efficacy and tolerability of a single daily dose of 6 mg quadropril (spirapril). MATERIAL AND METHODS: An open multicenter study enrolled 5000 out-door patients with hypertension. All the patients received an ACE inhibitor quadropril for 3 months with four control visits (on week 0, 4, 8 and 12). RESULTS: Quadropril caused a marked decrease in systolic and diastolic blood pressure. At the end of the study 89.4% of patients had a systolic blood pressure reduction of at least 15 mm Hg and 85.4% had a diastolic blood pressure reduction of at least 10 mm Hg. There were no clinically significant heart rate changes. The overall tolerability of the drug was estimated as good or very good in 95.3% of patients. Only 2.9% of patients had side effects during treatment with once daily dose of 6 mg quadropril. No serious side effects were observed. CONCLUSION: 6 mg daily dose of quadropril is an effective and safe therapy for arterial hypertension.

Efficacy and safety of spirapril in mild-to-moderate hypertension.

Spirapril is a new angiotensin-converting enzyme (ACE) inhibitor. It is a prodrug with a resorption of about 50%. The active metabolite spiraprilat reaches maximal plasma concentration within 2-3 h after oral administration. Spirapril can be administered once daily because of its long duration of action caused by an elimination half-life of about 40 h. It undergoes renal and hepatic elimination. In contrast to other ACE inhibitors it has a narrow dose range; therefore, the recommended dose is 6 mg for most patients without the need for dose titration. Spirapril has no relevant drug interactions. In several studies, spirapril was given to patients with mild-to-moderate essential hypertension at doses of 1-24 mg/day. There was an identical blood pressure lowering effect at doses of 6-24 mg/day; doses of 1-3 mg/day were less effective. Twenty-four-hour blood pressure monitoring showed a trough:peak ratio up to 0.84. In studies comparing the effect of spirapril with enalapril, lisinopril, trandolapril or captopril, spirapril was at least as effective as the other substances. Besides treating uncomplicated mild-to-moderate essential hypertension, spirapril can be used in patients with diseases accompanying hypertension such as heart and renal diseases, diabetes mellitus, and lipid disturbances. Possible advantages of spirapril compared to other ACE inhibitors are the dual mechanism of elimination, the lack of need for dose titration and a low incidence of cough.

Clinical experience with spirapril in human hypertension.

The efficacy and tolerability of spirapril were evaluated in a prospective, multicentre, post-marketing surveillance study on the treatment of arterial hypertension in 5000 patients, most of whom had received a single daily dose of 6 mg spirapril. The study was carried out by internists and general practitioners. In accordance with placebo-controlled clinical trials, spirapril was proven to be a very effective antihypertensive drug, in respect of both the mean reduction in systolic and diastolic blood pressure achieved as well as the responder rate of 89.4% and 85.4% for systolic and diastolic blood pressure, respectively. Efficacy was equally good in single drug treatment and combination treatment. Differentiated evaluation of blood pressure values in respect of the severity of hypertension on the basis of the World Health Organization classification showed a clear relationship between the baseline blood pressure and the reduction in blood pressure. The higher the baseline blood pressure, the more pronounced was the antihypertensive efficacy; a particular reduction in diastolic blood pressure being observed. Tolerability was also good, with an incidence of side effects of only 2.9%. Coughing was observed in only 0.88% of patients. Thus spirapril is seen to be an effective and well-tolerated antihypertensive drug whose efficacy is clearly related to baseline blood pressure and thus is also very effective in the treatment of severe forms of hypertension.

Nilvadipine in hypertension--experience in ambulatory treatment.

To investigate the 24-hour efficacy of nilvadipine (8 and 16 mg)in patients with mild to moderate essential hypertension, a double-blind, randomized, placebo-controlled, multicenter study with 3 parallel medication groups (placebo, 8, and 16 mg nilvadipine) was performed. Included in the study were 172 outpatients of both sexes with a mean age of 56 years. The primary target variable for the evaluation of efficacy was the difference in sitting diastolic blood pressure 24 hours after administration of the trial medication, in mmHg, achieved by the different doses after 8 weeks of therapy compared to baseline. This difference was -6.8 in the placebo group (n = 59), -10.4 in the nilvadipine 8 mg group (n = 60), and -11.0 in the nilvadipine 16 mg group (n = 49). Paired comparison showed a significant and clinically relevant difference between placebo and both nilvadipine doses. There were no serious adverse events reported. Nonserious adverse events were reported in 40.1% of all patients. Most frequently reported adverse drug reactions were flushing, headache, edema, and tachycardia. The adverse events occurred dose-dependently. As the dose-response relationship shows clinical saturation at a daily dose of 16 mg, the recommended dose is 8 mg taken once daily.

Immunohistochemical properties of dipyrone-induced cytochromes P450 in rats.

1. Rat hepatic cytochrome P450s induced by dipyrone were studied enzymatically, immunochemically and immunohistochemically. 2. Dipyrone administered to male Wistar rats increased pentoxyresorufin O-depentylation (PROD), ethoxyresorufin O-deethylation (EROD) and 7-ethoxycoumarin O-deethylation (ECOD) activities up to 44-, 1.9-, and 2.6-fold, respectively. Aryl hydrocarbon hydroxylase (AHH) activity was not affected. 3. Immunoinhibition with the monoclonal antibody (Mab) 2-66-3 (to CYP2B1/2) markedly decreased PROD and EROD activities, but not AHH activity. The Mab 1-7-1 (to CYP1A1/2) was without effect. 4. Histochemically, the Mab 2-66-3 gave a strong and uniform staining in livers from dipyrone-treated rats, whereas the Mab 1-7-1 gave a positive reaction in a narrow perivenous strip. 5. The induction pattern as well as inhibition by the Mabs convincingly demonstrate the predominant production of CYP2B1/2 in the induction spectrum of dipyrone. The increase in enzyme activities other than PROD may be due to the overlapping substrate specificity of CYP2B1/2 enzymes. The immunohistochemical analysis also indicated the participation of CYP1A1/2.

Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects.

The objective of the presented two-way randomized crossover study was to investigate whether repeated doses of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h) enhanced bioavailability of diltiazem (120 mg, orally) in nine healthy male subjects. Grapefruit juice did not alter AUC or cmax of diltiazem, whereas the half life experienced a slight, but statistically significant, increase (4.1 +/- = 1.2 vs 5.1 +/- 0.7 h). The N-demethyldiltiazem/diltiazem and deacetyldiltiazem/diltiazem ratios were not affected by grapefruit juice intake, which indicates that these metabolic pathways are not inhibited. Whereas bioavailability of some calcium channel antagonists of the dihydropyridine type metabolized via the same cytochrome P450 has been shown to be dramatically increased by grapefruit juice intake, the bioavailability of the benzothiazepine calcium channel antagonist diltiazem remained unchanged. This suggests that factors other than biotransformation may contribute to the clear effect of grapefruit juice on the bioavailability of those substances.

Interindividual variability of coumarin 7-hydroxylation in healthy volunteers.

A test designed to estimate the extent and rate of formation of 7-hydroxycoumarin by measuring the urinary excretion of the metabolite in humans after administering 5 mg coumarin was developed. Coumarin was rapidly metabolized after oral administration and more than 95% of the 7OHC formed was excreted in 4 h. The total amount of 7OHC formed was 64 +/- 15% (mean +/- SD, variation 20-100%) of the dose given. The percentage of 7OHC excreted in 2 h, as compared with the 7OHC excretion in 4 h, was found to be a constant and stable individual characteristic for the rate of the formation of 7OHC ('2 h coumarin test'). In 110 volunteers, there was a great interindividual variability in the extent and rate of 7OHC formation. Four individuals had relatively 'slow' coumarin test values (50-60%), but much larger populations would be needed for the demonstration of polymorphism.

Lack of effect of diacetyl-splenopentin (Berlopentin) on the pharmacokinetics of caffeine.

The influence of Berlopentin on caffeine clearance was measured after a 6 week i.v. treatment or a 4 week s.c. administration within a phase I trial. It was demonstrated that therapy with Berlopentin did not affect significantly caffeine elimination. Thus, clearance of drugs which are biotransformed by hepatic microsomal oxidation are unlikely to be affected by the coadministration of Berlopentin.

Nephrotoxic effects of diethylene glycol (DEG) in rats.

Diethylene glycol (DEG) is a widely used substance with various risks of intoxication. In adult rats influences of DEG on functional parameters are characterized, indicating early signs of nephrotoxicity. A dose dependent proteinuria, an oliguric effect, an increased excretion of free hydrogen ions and a compensated impairment of renal tubular transport processes can be stated (0.25, 0.5 and 0.75 ml DEG/100 g b.m. i.p.). Following a single dose of 0.5 ml DEG/100 g b.m. i.p. the maximally expressed nephrotoxic effect is measurable 4 to 8 days after administration.

The cerium-induced liver injury and oxidative drug metabolism in DBA/2 and C57BL/6 mice.

The influence of the known hepatotoxic agent, cerium (Ce) on the activity of liver microsomal monoxygenases, especially coumarin 7-hydroxylase (COH) was investigated in two inbred strains of male mice, DBA/2N and C57BL/6N. Ce was injected intravenously in three doses (0.5, 1.0 and 2.0 mg/kg body wt) and the animals were killed 24 or 72 h later. On the basis of histological assessment of the liver, C57BL/6N mice are apparently more resistant to the hepatotoxic effect of Ce. At 24 h, COH activity was increased in a dose-dependent manner in DBA/2 animals, whereas no change was seen in C57BL/6N animals. A significant increase in all other enzymes studied, cytochrome P-450 (P450), ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase, was seen in DBA/2 mice injected with the highest dose of Ce. At 72 h Ce increased CON activity, as well as other enzymes, in C57BL/6N mice in a dose-dependent manner, whereas in DBA/2 mice the increase was only seen after the two lower doses, the highest dose causing severe morphological changes in the liver structure and a clear decrease in COH and other activities. The distribution studies with Ce-141 showed that C57BL/6N livers contained more Ce than DBA/2 livers after the highest dose.

[7-ethoxycoumarin o-deethylase and fibrosis in chronic liver diseases]. / Die 7-Ethoxycoumarin O-Deethylase und der fibrosierende Prozess bei chronischen Lebererkrankungen.

In the liver biopsy of 100 patients with chronic liver diseases, the activity of 7-ethoxycoumarin O-deethylase (ECOD) was determined as a parameter of hepatic monooxygenase system and was compared with some markers of fibrosis e.g. collagen peptidase and hydroxyproline. ECOD was significantly different in healthy liver, fatty liver, chronic active hepatitis (CAH) and cirrhosis. The importance of the fibrotic process was shown by the significant correlations between ECOD and the signs of fibrosis in the liver biopsy. A connection between ECOD and the markers of fibrosis was not found. Further research is necessary to clarify this difference.

Comparison of in vitro and in vivo biotransformation in patients with liver disease of differing severity.

The activity of 7-ethoxycoumarin O-deethylase (ECOD) has been measured in liver biopsy samples from 23 patients (smokers and non-smokers) with different degrees of structural liver damage. The results, which reflect in vitro cytochrome P450-dependent biotransformation, were correlated with various measures of the P450-dependent in vivo elimination of caffeine and metamizol. The relatively non-specific, low affinity component of ECOD activity was significantly correlated with the kinetics of metamizol (mean residence time, apparent clearance, half-life, area under the concentration-time curve, and metabolite excretion in the urine). Thus, metamizol elimination, which is mainly due to P450 IIB, and the low affinity component of ECOD both reflect, at least in part, the activity of the same form of P450. In contrast, caffeine biotransformation, which is via P450 IA, was not correlated with ECOD activity. There was no relation between the kinetics of metamizol and caffeine, perhaps because of the inducing effect that smoking has on caffeine elimination. In patients with liver disease, smoking appears to alter the elimination of caffeine more than the degree of liver disease.

[Comparison of ICG elimination with biotransformation of model substances and histological features of liver biopsy in liver diseases]. / Vergleich der ICG-Elimination mit der Biotransformation von Modellsubstanzen und mit histologischen Merkmalen im Leberbioptat bei Lebererkrankungen.

The elimination of indocyanine green (ICG) was measured in 45 patients with histologically proved liver disease to evaluate liver blood flow. Furthermore, the elimination of caffeine and metamizol was determined in serum as a parameter of in vivo biotransformation. In a further step the activity of 7-ethoxycoumarin O-deethylation was measured in liver biopsy samples of 30 out of 45 patients (in vitro parameter of biotransformation). The half-life of ICG was compared with the data of biotransformation by means of the calculation of correlations with special consideration of histological findings in liver biopsy samples (monocellular necrosis, intra-acinar fibrosis, structural transformation). Results demonstrate that ICG-elimination is a nonsufficient criterion of liver blood flow in patients with liver disease, because of considerable variation and many influencing factors including the function of the liver cells. Therefore, it is difficult to evaluate results.

[Effect of 3 months of thioacetamide treatment on liver biotransformation in vivo and in vitro (various times after discontinuation)]. / Der Einfluss einer dreimonatigen Thioazetamidbehandlung auf die Biotransformation der Leber in vivo und in vitro (unterschiedliche Karenzzeiten).

Female Uje: WIST rats received thioacetamide (TAA) in the tap water (0.3 g/l) from the 4th to 6th months of life to produce experimental liver cirrhosis. Immediately, 2 and 7 days after TAA cessation it was investigated by means of in vivo (caffeine and metamizol elimination) and vitro methods (cytochrome P-450, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation), whether this animal model represents the restricted cytochrome P-450-dependent biotransformation comparable to human liver cirrhosis. The total capacity of the liver was diminished immediately and 2 days after TAA cessation. After 7 days the capacity was unchanged compared to the controls or partly even enhanced. Therefore, this animal model reflects rather a short time than a stable alteration of biotransformation after TAA cessation comparable to human liver cirrhosis.

[Simultaneous administration of various model substances for characterizing in vivo biotransformation in chronic liver diseases]. / Die simultane Gabe verschiedener Modellsubstanzen zur Charakterisierung der in-vivo Biotransformation bei chronischen Lebererkrankungen.

16 patients with different chronic liver diseases were given single doses of the model substances caffeine, metamizol, sufamethacine and debrisoquine. This was followed by the simultaneous administration of all these substances as a "cocktail". A comparison between the single and the "cocktail" dosage did not reveal any significant differences in the pharmacokinetic parameters. So the "cocktail" administration is even possible in chronic liver diseases. Requiring relatively little time, it makes statements possible concerning various cytochrome P450 enzymes including the types of hydroxylation and acetylation. Intraindividual variations can be ruled out.

Studies on the in-vitro biotransformation in patients with liver diseases.

The activity of 7-ethoxycoumarin O-deethylase (ECOD) was determined in the human liver bioptate of 53 patients with chronic liver diseases. Remarkable are the lower values of ECOD in the hepatoses, chronic hepatitis and cirrhosis as compared to patients with normal histology or residual hepatitis. The decline in the activity of ECOD in the patients with chronic hepatitis and cirrhosis has to be seen in connection with parenchymatous necrosis, nodular liver transformation and intracinar fibrosis. For the time being it is not possible to give a satisfactory explanation of the decrease in the ECOD activity of the hepatoses.

Cytochrome P-450-dependent biotransformation in Uje:WIST rats with chronic liver injury induced by thioacetamide.

In female Uje:WIST rats micronodular liver cirrhosis was produced by thioacetamide (TAA) given in the drinking water (0.3 g/l) from the 4th to 6th months of life. 14 d after TAA cessation it was examined, whether this animal model reflects the restricted cytochrome P-450-dependent biotransformation in severe stages of human liver cirrhosis by in vivo (caffeine and metamizol elimination) and in vitro methods (cytochrome P-450, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation, ethylmorphine N-demethylation). The total biotransformation capacity was unchanged in TAA rats, partly even enhanced. Only several in vitro parameters reflect diminished cytochrome P-450-dependent biotransformation calculated per weight unit comparable to severe stages of human liver cirrhosis. Therefore, the chosen experimental conditions are suitable for conclusions concerning cytochrome P-450-dependent biotransformation in early rather than in severe stages of human liver cirrhosis.