[Controlled clinical studies of tolerance development and dosing problems in nitrate therapy]. / Kontrollierte klinische Studien zur Toleranzentwicklung und Dosierungsprobleme der Nitrattherapie.

The phenomenon of development of tolerance to nitroglycerine as well as avoidance of this through a nitrate-free interval was known 100 years ago. Concerning the haemodynamic and anti-ischaemic effect of organic nitrates in therapy, the development of a tolerance is a clinical problem that is much discussed. Conducive to tolerance are obviously continuous application, short dosing intervals and high-dosage level so that an anti-ischaemic protection or rather, for heart insufficiency a haemodynamic relief, cannot be achieved by using organic nitrates around the clock. On the contrary, keeping a nitrate-free interval of 12 to 18 hours allows proof of the effect of at least 12 hours under IS-5-MN as is also the case under s.r. ISDN or 8 hours under nitroglycerine-patches. In this case, a lack of anti-ischaemic protection in the interval, particularly in the early morning hours, has to be accepted.

Pharmacokinetics of isosorbide mononitrate.

Pharmacokinetic studies show that isosorbide mononitrate is rapidly absorbed after oral administration, reaches peak concentrations within an hour, undergoes no significant first-pass metabolism, and is virtually 100% bioavailable. The half-life is approximately 5 hours, the volume of distribution is 0.62 liter/kg, and the systemic clearance is 115 mL/min. Only 1-2% of an orally administered dose is excreted unchanged in the urine, with the remainder being eliminated as inactive metabolites. Isosorbide mononitrate follows dose-linear kinetics after single and multiple doses. Its pharmacokinetic profile is consistent and highly reproducible and is unchanged in the elderly and in patients with coronary artery disease, renal failure, or liver cirrhosis. An asymmetrical dosage regimen of isosorbide mononitrate has been shown to provide antianginal efficacy for at least 12 hours. Because asymmetrical dosing creates irregular, sawtooth-like changes in plasma concentrations and a fall below a critical threshold level during the night, tolerance does not develop.

A new molecule with vasodilating and beta-adrenoceptor blocking properties.

Carvedilol is a new substance displaying beta-sympatholytic and vasodilating activities in the same dose range. Data obtained from a considerable number of animal experiments show that the beta-blocking properties of carvedilol resemble those of propranolol. However, in contrast to propranolol the arterial blood pressure decreases dose dependently after single doses of carvedilol due to a reduced total peripheral resistance. The vasodilating activity of carvedilol can be demonstrated in a variety of experimental models. According to the present state of knowledge neither alpha-blockade, nor Ca antagonism, serotonin antagonism, prostaglandin-mediated vasorelaxation, or endothelial-derived relaxing factor (EDRF)-dependent activity are responsible for the antihypertensive effect. Thus, although the mechanism of vasodilation has still not been completely clarified, a postreceptor mechanism seems likely. The acute vasodilating properties in humans have been shown as a dose-dependent increase of the finger pulse amplitude in healthy subjects after both intravenous and oral administration, and as a decrease of the regional resistances and an increase of regional blood flow. The pharmacokinetics of carvedilol are dose linear and peak concentrations are reached within 1-1.5 h after oral administration. The elimination half-life after single oral doses varies from 6-7 h. The renal clearance of 4 ml/min is negligible in comparison with the total body clearance of 590 ml/min. Therefore, the absolute bioavailability of 24% indicates some degree of first-pass extraction. The highly lipophilic drug is extensively distributed to the tissues, as shown by the distribution volume of 132 l. In patients with hypertension, single doses of carvedilol (25-50 mg) decrease systolic and diastolic blood pressure for more than 10 h, whereas heart rate is only slightly decreased. In hypertensive patients treated from 7 days up to 1 year, carvedilol proved to be an effective and safe antihypertensive drug. In contrast to conventional beta-blockers, the reduced vascular resistance, in particular of the renal circulation, observed after both acute and chronic administration of carvedilol, indicated the useful hemodynamic profile of this compound. In addition, patients not sufficiently controlled with conventional beta-blockers responded promptly to carvedilol. At the same time left ventricular performance is not depressed. In a 1-year open clinical trial with hypertensives WHO I and II, the responder rate was about 85% with carvedilol as monotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Lipid lowering treatment with bezafibrate in patients on chronic haemodialysis: pharmacokinetics and effects.

Hyperlipidaemia may contribute to the high rate of cardiovascular complications in patients on chronic haemodialysis (CHD). However, possibilities of lipid lowering therapy in CHD are still limited. The applicability of bezafibrate (BF), a recently developed clofibrate analogue, was investigated in patients on CHD with triglyceride and/or total cholesterol levels above 300 mg/dl. The lipid lowering effect was studied in a placebo-controlled trial over 6 months in 19 patients. Long-term effect was followed in six patients over a mean period of 29 months. Elimination half-life and mean therapeutic serum concentration were calculated by 72-h BF serum profiles, obtained after the first drug administration of a single 200-mg dose and during steady state after 12 weeks of treatment. Elimination half-lives were 17 h at start and 22 h after 12 weeks compared with 2 h in subjects with normal renal function. Dose reduction to 200 mg every 3rd day was necessary and resulted in a mean therapeutic serum concentration of 3.4 mg/l, which was similar to 3.0 mg/l of normal subjects, who received the dose optimal for lowering of lipids (200 mg 3 X/day). The protein-bound serum fraction of BF was decreased to 8% in CHD patients, compared with 95% found in normal subjects. BF therapy resulted in a marked reduction of serum triglycerides from 478 mg/dl by 31% and total cholesterol levels from 311 mg/dl by 19% as well as beta-Lp-cholesterol from 178 mg/dl by 17%, whereas the initially low alpha-Lp-cholesterol increased significantly from 18.3 mg/dl by 58%.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacologic investigations with carvedilol, a new beta-blocker with direct vasodilator activity.

Carvedilol (BM 14.190) has been shown to have beta-adrenergic blocking and vasodilating activity. By means of digital plethysmography, the threshold for vasodilation was ascertained at a dose of 2.6 mg iv infused over 1 hour. The oral threshold dose was established at about 15 mg, with a linear increase in response (r = 0.78) up to 76.5 mg. This dose increased blood flow to the forearm by reduction of arterial resistance. Although venous capacity was not changed, postural symptoms in three subjects could also be indicative of venous involvement. Carvedilol, 50 mg, reduced exercise heart rate for about 10 hours.

Haemodynamic abnormalities in hypertensive patients: a review of the influence of vasodilating drugs.

Mean arterial pressure is determined primarily by cardiac output and total peripheral resistance, in addition to blood volume and compliance of the arterial system. The regulation of these determinants occurs via reflex neurogenic mechanisms and metabolic or humoral mechanisms. The haemodynamic situation in the early stages of arterial hypertension is characterized by a slight hypercirculatory state due to a moderate increase in heart rate and cardiac output, whereas the total peripheral resistance is increased only moderately, if at all. In later stages, however, a progressive increase in total peripheral resistance prevails, accompanied by a decrease in left ventricular performance due to the development of left ventricular hypertrophy, changes in ventricle geometry and coronary heart disease. A pharmacologically-induced decrease of total peripheral resistance by means of vasodilators, therefore, represents a logical approach to therapy, at least of advanced hypertension. Vasodilators can be classified into three categories: those with preferential activity on the arterial resistance vessels, eg hydralazine, diazoxide, minoxidil; those with preferential activity on venous capacitance vessels, eg organic nitrates; and those with activities on both branches, eg sodium nitroprusside, urapidil, prazosin and other a-blockers. Brief reference is made to new and possibly more acceptable vasodilators--in particular carvedilol and prizidilol.

[Immunopharmacologic treatment of 9 digitalis poisonings in children with sheep antidigoxin Fab]. / Immunopharmakologische Behandlung von 9 Digitalisvergiftungen bei Kindern mit Schaf-Antidigoxin Fab.

A report is presented of the clinical experience in the treatment of severe digitalis poisoning in nine young children aged 1 month to 4 years with digitalis antibody fragments (Fab). In 8 cases, accidental poisoning was involved, and in one case there was overdosage during the course of treatment. Digoxin preparations had been taken by 8 of the cases, 6 times in liquid form, and in one case digitoxin. Reliable signs for the ingestion of digitalis with high concentrations in the serum and the appearance of life-threatening disorders of rhythm or conduction were taken as the indication for the use of Fab. The Fab dose was 80 to 480 mg per case treated and was adjusted according to the quantity of glycoside ingested. All of the children recovered completely. Regression of the arrhythmias and improvement of the clinical condition were seen during or shortly after administration of the Fab infusion. In the serum there was a rapid fall in the level of free digoxin and a simultaneous marked rise in that of bound inactive digoxin. The digoxin was excreted in the urine in the bound form. Tolerance was good. No allergic reactions to foreign protein or later reactions in the form of serum sickness were observed.

Absolute bioavailability and bioequivalence of glibenclamide (Semi-Euglucon N).

The absolute bioavailability of HB 420 (a new pharmaceutical form of glibenclamide) was investigated in comparison with an i.v. infusion of glibenclamide and also in comparison with HB 419 (Semi-Euglucon) on a group of 10 healthy volunteers with the aid of a highly specific bioanalytical detection method. A comparison of the dose-corrected areas under the concentration-time curves yielded an absolute bioavailability of 102% for HB 420. The relative bioavailability of HB 419 to HB 420 was 73%. This resulted in a bioequivalent dosage relationship of 2.5 mg HB 419 to 1.75 mg HB 420. It could be experimentally confirmed on further 10 healthy volunteers that 1.75 mg HB 420 (identical with Semi-Euglucon N) and Semi-Euglucon (containing 2.5 mg HB 419) are bioequivalent with respect to the absorbed quantity of active agents. The differences in absorption rate between the new and the old form did not lead to relevant differences in the glucose profile and the release of insulin, so that the two forms can be regarded as being pharmacodynamically equivalent. The median for the terminal elimination half-life for glibenclamide was 1.38 hours (min. 0.65, max. 4.64 hours), the total clearance was 100 ml/min and the steady-state distribution volume was 7.3 l (0.1 l/kg). On the basis of half-life, it can be expected that the elimination of the unchanged substance will be virtually complete within 10-12 hours. During long-term therapy, however, it cannot be ruled out that in some diabetics cumulation could occur, the cause of which cannot be explained by the data presented.

Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration.

The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KIN-PAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.71/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmogenic dose of acetylstrophanthidin unchanged by beta-sympathomimetics in conscious dogs.

The enhanced arrhythmogenic risk of combined treatment with cardiac glycosides and beta-sympathomimetics is referred in some textbooks, but only a few detailed studies on in vivo models are available. We therefore investigated this problem in conscious dogs in an intraindividual study. We determined the dose of acetylstrophanthidin (intravenous infusion of 5 mcg/kg per min), which provoked ventricular premature beats with and without concomitant treatment with the partial beta-agonistic compounds doxaminol (3 mg/kg p.o.), prenalterol (0.4 or 1.0 mg/kg p.o.) or isoprenaline (0.31 +/- 0.100 mcg/kg per min). In some dogs a coronary artery was narrowed in order to reduce the coronary blood supply. The arrhythmogenic dose of acetylstrophanthidin was nearly the same in all the groups investigated (range from 52.1 +/- 5.66 to 59.9 +/- 3.23 mcg/kg). Whereas the arrhythmogenic dose of acetylstrophanthidin was unchanged by beta-sympathomimetics, the combination of the glycoside and each of the beta-agonistic drugs increased the contractile force more than did either single compound. We therefore conclude that the arrhythmogenic risk of the combination of glycosides and beta-sympathomimetics may be--at least in experimental models--less than has been suggested in the past.

The influence of age and multimorbidity on the pharmacokinetics and metabolism of spironolactone.

The pharmacokinetics of the metabolites of spironolactone (canrenone and fluorigenic metabolites) were investigated in 10 geriatric female patients with multimorbidity after a multiple daily oral administration of 100 mg spironolactone under steady state conditions. The concentration determinations were carried out simultaneously with a specific HPLC method and a less specific fluorimetric method. On comparison of the pharmacokinetic parameters with the respective values of a control group of younger healthy female subjects, the serum concentrations in the elderly patients were found to be twice as high. In addition, a statistically significant positive correlation with age was found in the patients for the kinetic parameters investigated. A positive correlation existed between erythrocyte count and the pharmacokinetic parameters of canrenone, especially with the area under the concentration/time curve. No such association was detectable, however, for the total fraction of fluorigenic metabolites (including canrenone). The results of our investigation indicate that, in addition to the known high binding of canrenone to plasma proteins, there is also possibly a (restrictive) binding to erythrocytes.

[Report of experiences in the treatment of 16 cases of severe glycoside poisoning with digitalis antibody fragments (Fab)]. / Erfahrungsbericht über die Behandlung von 16 schweren Glykosidvergiftungen mit Digitalis-Antikörper-Fragmenten (Fab).

To date, 16 patients with severe glycoside poisoning have been treated with Fab as part of the clinical trial for efficacy and tolerance. The ages of the patients ranged from 4 to 77 years. In 13 cases, the substance was taken with suicidal intent. The following were considered to be indications for the use of Fab: the appearance of life-threatening arrhythmias as high-grade atrioventricular conduction disorders, multifocal ectopic beats, ventricular tachycardia, and relapsing ventricular fibrillation in 5 cases. Serum digoxin concentrations were between 3.8 and 78 ng/ml before the start of treatment. The amount of Fab administered was 240-800 mg, in the majority of cases 480 mg. Regression of the arrhythmias was seen in all patients during or shortly after the Fab infusion. There was a rapid fall in the free digoxin in the serum to levels that were no longer measurable and a marked rise in bound digoxin with a simultaneous intensive excretion of bound digoxin in the urine. Fab therapy is considered to be a major advance in the treatment of severe, previously fatal, glycoside poisoning. No notable side effects were observed, nor were there any allergic reactions to foreign protein.

Investigations into the development of tolerance to organic nitrates in conscious dogs.

The role of doses and dose intervals in the development of tolerance towards organic nitrates was investigated. It was studied whether the decrease in systolic blood pressure (SBP) induced by i.v. injection of 30 micrograms/kg glyceryl trinitrate (GTN) is influenced by the simultaneous i.v. infusion of GTN or isosorbide-5-mononitrate (IS-5-MN) - two dose levels each - at doses that lower the SBP by 20-35 mmHg. Although infusion of the lower dose of IS-5-MN caused a constant plasma concentration that was about 100 times more than that required for the anti-anginal effects, the acute GTN response was not reduced. However, the acute response was diminished at the other groups. In additional investigations incremental doses of IS-5-MN were injected i.v. at different dose intervals. It was observed that the responsiveness was nearly identical at dose intervals of 24, 4 and 2 h (= 1.3 half-lives in the dog, which is equivalent to a t.i.d. dose schedule in man), whereas it was markedly reduced at intervals of 10 min.

An open, long-term, multi-centre study of the anti-anginal efficacy and safety of isosorbide 5-mononitrate at low doses in patients with coronary heart disease.

A total of 250 patients with coronary heart disease diagnosed clinically, by ECG and in some cases by coronary angiography, was treated with isosorbide 5-mononitrate, 221 of the patients being treated for up to 6 months. In 181 patients previously treated with isosorbide dinitrate (ISDN)-retard, the mean daily dosage of nitrate was reduced from 77 mg (200 mg maximum) ISDN to 45 mg (120 mg maximum) isosorbide 5-mononitrate in long-term treatment. During previous treatment with ISDN-retard (with high doses in some cases: 80 to 200 mg daily in 48.6% of patients and 40 mg or less daily in only 33.1%), 4.5% of the patients were totally free of angina pectoris attacks. In the same patients, this proportion was 53.6% after administration of isosorbide 5-mononitrate for 6 months (dosage 40 mg daily or less in 67.4% of patients, 80 mg or more in 8.8% of patients). A substantial increase in subjective exercise tolerance and the reduction in incidence of angina pectoris was associated with a marked reduction in nitrate consumption for acute attacks. Isosorbide 5-mononitrate lowered slightly the blood pressure and heart rate. Treatment with isosorbide 5-mononitrate was withdrawn in 22 (8.8%) patients due to nitrate intolerance (headache in 7.6%) and in a further 7 (2.8%) patients for other reasons. Of patients completing 6-months' treatment, 9.9% reported one or more reversible undesirable reactions typical of nitrates at the start of the trial (compared with 6.8% in the pre-trial period). The incidence of such effects decreased to 1.4% after 6 months. The incidence of tolerable headache was 7.7% during the first week on isosorbide 5-mononitrate, decreasing to 0.9% after 24 weeks (5.9% in the pre-trial period). The laboratory parameters and subjective tolerability data confirmed the therapeutic safety of isosorbide 5-mononitrate.

[Pharmacokinetics of the beta-receptor blocker metipranolol in patients with liver cirrhosis (author's transl)]. / Pharmakokinetik des beta-Rezeptorenblockers Metipranolol bei Patienten mit Leberzirrhose.

The pharmacokinetics after oral administration of the beta-blocker metipranolol (Disorat) were investigated in 20 patients with liver cirrhosis, 8 of them with portocaval shunt. Twenty healthy persons were used as controls. Kinetic data in patients were not notably different from the normal group, in particular there was no significant difference in the mean serum concentration over 24 hours. In patients with advanced disease the only noteworthy difference was an increase of the linear rate of increase of serum concentrations. Maximal serum concentrations were found with a median of only 0,37 and 0,59 hours after intake, and in controls 0,76 hours after intake. It appears that metipranolol has no hepatic first-pass-effect and that its total clearance remains largely uninfluenced even in severe liver damage. A reduction of dosage in these diseases is thus not required from the pharmacological point of view.

Pharmacokinetics of metipranolol in normal man.

The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6-25mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of beta-blocking agents.