[Combination therapy in chronic heart failure. Hemodynamic effects with a calcium antagonist-diuretic combination]. / Kombinationstherapie bei chronischer Herzinsuffizienz. Hämodynamische Wirkungen unter einer Kalziumantagonist-Diuretikum-Kombination.

In twelve patients with chronic cardiac insufficiency (NYHA II-III), the effect of a fixed combination of drugs (160 mg verapamil/50 mg triamterene/25 mg hydrochlorothiazide) on cardiac hemodynamics was studied over a period of four weeks. During the course of treatment, the arterial blood pressure decreased from 145 +/- 16/93 +/- 9 mmHg to 133 +/- 18/86 +/- 14 mmHg, and the heart rate from 79 +/- 13 to 75 +/- 12 beats/min. Exercise blood pressure (900 watts) decreased from 180 +/- 22/104 +/- 14 mmHg to 158 +/- 25/96 +/- 17 mmHg and the heart rate from 104 +/- 14 to 100 +/- 16 beats per min. After treatment, a decrease in pulmonary arterial pressure and resting pulmonary capillary wedge pressure (PPA:-2.3 mmHg, PPC:-1.4 mmHg) and in exercise pressure (PPA:-8.5 mmHg, PPC:-6.6 mmHg) was established. Clinically relevant changes in cardiac output and cardiac index were not observed. The subjective symptoms (NYHA stage) were improved in eight patients. Combination treatment would appear suitable for patients with mild-to-moderate cardiac insufficiency.

[Animal experimental and human pharmacologic studies with phase-II metabolites of triamterene]. / Tierexperimentelle und humanpharmakologische Untersuchungen mit dem Phase-II-Metaboliten von Triamteren.

Animal Experiments and Human Studies with the Phase-II Metabolite of Triamterene The described animal experiments as well as the pharmacological investigations in man show the diuretic efficacy of the phase-II metabolite of triamterene (CAS 396-01-0), OH-TA-ester. As demonstrated in the present investigation, a phase-II metabolite can not be considered only as an ineffective conjugation product, formed to accomplish the excretion of a foreign compound, but also it must be considered as an important factor in the therapy, if its pharmacologic efficacy has been established, moreover if as a result of disease-related alterations in the pharmacokinetics the phase-II metabolite cumulates.

[Pharmacokinetics of triamterene in healthy subjects and patients with liver and kidney function disorders]. / Pharmakokinetik von Triamteren bei Probanden und Patienten mit Leber- und Nierenfunktionsstörungen.

The knowledge about the pharmacokinetics of triamterene (TA) was limited until recently. The metabolic pathway of TA is the formation of p-hydroxytriamterene (OH-TA), which is subsequently conjugated with active sulfate to form p-hydroxytriamterene sulfuric acid ester (OH-TA-ester). The phase-II-metabolite is surprisingly pharmacologically active. TA and its metabolites were measured concomitantly by a specific and sensitive tlc-method. The i.v. kinetics of TA were determined after application of a newly developed lactic acid solution of the drug. Comparing these data with results after oral application of TA the bioavailability of TA was 52% and the extent of absorption 83%. The bioavailability of different dosage forms was correlated with in vitro-tests. In liver disease the pharmacokinetics of TA are markedly altered. While in cirrhosis the hydroxylation of TA was decreased, the biliary excretion of this agent was strongly reduced in hepatitis. In renal disease the excretion of TA and OH-TA-ester was reduced proportional to the reduction of endogenous creatinine clearance. In older patients the elimination of TA was impaired.

Pharmacokinetics of triamterene after i.v. administration to man: determination of bioavailability.

With a new formulation, which made intravenous infusion of triamterene (TA) possible, plasma levels and urinary excretion rates of TA and its main metabolite (OH-TA-ester) were measured in a randomized, cross-over trial in 6 healthy volunteers given triamterene 10 mg i.v. and 50 mg p.o. TA and OH-TA-ester were determined by densitometric measurement of native fluorescence after thin layer chromatography. Distribution volumes of the central compartment of TA and OH-TA-ester were 1.49 l/kg and 0.11 l/kg, respectively. Terminal half-lives were 255 min for TA and 188 min for OH-TA-ester after i.v. administration. For TA total plasma clearance was 4.5 l/min and renal plasma clearance 0.22 l/kg. The formation of OH-TA-ester was very rapid and the concentration of the metabolite exceeded that of TA at all times. After i.v. administration the urinary recovery of TA and OH-TA-ester was 4.4% and 50.9%, respectively. The bioavailability of TA was 52%, corresponding to absorption of 83%. TA is partly eliminated by a first-pass-effect. The main metabolite of TA is OH-TA-ester, which is pharmacologically active.

Pharmacokinetics of triamterene.

The knowledge about the pharmacokinetics of triamterene (TA) was limited until recently. The metabolic pathway of TA is the formation of p-hydroxytriamterene (OH-TA), which is subsequently conjugated with active sulfate to form p-hydroxytriamterene sulfuric acid ester (OH-TA-ester). The phase-II-metabolite is surprisingly pharmacologically active. TA and its metabolites were measured by a specific and sensitive tlc-method concomitantly. The i.v. kinetics of TA were determined after application of a newly developed lactic acid solution of the drug. Comparing these data with results after oral application of TA the bioavailability of TA was 52% and the extent of absorption 83%. The bioavailability of different dosage forms was correlated with in vitro tests. In liver disease the pharmacokinetics of TA are markedly altered. While in cirrhosis the hydroxylation of TA was decreased, the biliary excretion of this agent was strongly reduced in hepatitis. In renal disease the excretion of TA and OH-TA-ester was reduced according to endogenous creatinine clearance. In older patients the elimination of TA was impaired.

Effects of triamterene and its phase I and phase II metabolities on sodium transport of the isolated frog skin.

We studied the effects of triamterene (TA) on its phase I and phase II metabolites, p-hydroxytriamterene (OH-TA) and p-hydroxytriamterene sulfuric acid ester (OH-TA ester), on sodium transport in the isolated frog skin. While TA applied to the inside (corial side) surface had no effects on potential difference (PD) and short-circuit current (SCC), TA, OH-TA, and OH-TA ester at a concentration of 10(-5) mol/l significantly decreased SCC by 19, 24 and 16%, respectively, when added to the solution bathing the outside (epithelial side) surface of the skin. In vasopressin-treated skins TA was more effective than OH-TA or OH-TA ester. In aldosterone-treated skins all compounds significantly suppressed SCC, the strongest effect was again exerted by TA. Only minor and transient changes in PD were noted. Inhibition of sodium transport was rapidly reversible when skins were washed with fresh Ringer solution. Thus, OH-TA and OH-TA ester possess qualitatively similar pharmacological activity as TA. The quantitatively smaller effects of OH-TA and OH-TA ester in the hormone-stimulated skin as compared to TA agrees well with their relative natriuretic potency observed in vivo.

[On the diuretic and saluretic activity of p-hydroxytriamterene and methoxytriamterene (author's transl)]. / Uber die diuretische und saluretische Aktivität von p-Hydroxytriamteren und Methoxytriamteren.

Applying i.v. the phase-I-metabolite of 2,4,7-triamino-6-phenylpteridine (triamterene), p-hydroxytriamterene, to rats, we found a strong natriuresis. This contradicts the investigation of a previous study which stated that p-hydroxytriamterene is essentially inactive. We think, these different results depend on the fact that probably oral application was employed without testing the absorption concerned.

[On the bioavailability of hydrochlorothiazide and triamterene from commercial drugs (author's transl)]. / Zur bioverfügbarkeit von Hydrochlorothiazid und Triamteren aus Fertigarzneimitteln.

In a study on the bioavailability of triamterene and hydrochlorothiazide from 3 diuretics, preparation A (25 mg hydrochlorothiazide), preparation B (50 mg triamterene) and preparation C (combination of hydrochlorothiazide and triamterene), the data for tmax, Cmax, AUC and the cumulative urine excretion were determined in 7 healthy volunteers. The different formulations of the diuretics influenced the kinetics of the agents. The in vivo data agreed well with those obtained in vitro. Plasma levels of triamterene and its active metabolite from preparation C were reached more rapidly than from preparation B. However, the bioavailability of the agents was not significant different in the two diuretics when given immediately after breakfast. The AUC-data of hydrochlorothiazide determined after administration of preparation A or C do not differ significantly, only the comulative excretion of hydrochlorothiazide in urine is greater after application of preparation A than after application of preparation C.

Influence of triamterene and hydroxytriamterene sulfuric acid ester on diuresis and saluresis in rats after oral and intravenous application.

Previous transport measurements on the submaxillary duct of the rat, the model epithelium for the distal nephron, showed that even the phase-II metabolite of triamterene (TA), hydroxytriamterene sulfuric acid ester (OH-TA-ester), has a diuretic effect. The present studies were aimed at answering the question whether or not this finding was also valid in vivo. Clearance measurements in the rat after i.v. injection of OH-TA-ester did result in an increased diuresis and natriuresis. In comparison with the native triamterene the phase -II metabolite caused only a relative potassium retention. The ester was inactive when administered orally. The potassium loss after administration of furosemide could be prevented by simultaneous i.v. administration of the OH-TA-ester.

[Pharmacological effects of phase-I- and phase-II-metabolites of triamterene (author's transl)]. / Pharmakologische Wirksamkeit von Phase-I- und Phase-II-Metaboliten des Triamteren.

Since triamterene (TA) is rapidly metabolized to hydroxytriamterene (OH-TA) and then to its sulfuric acid ester (OH-TA-ester) the question arose whether the metabolites are still effective on ion transport as is triamterene. The effect of the metabolites was studied in microperfusion experiments on the rat submaxillary duct, which resembles the distal nephron and is considered the site of action of triamterene. Added to the lumen the phase-I- as well as the phase-II-metabolites decreased reabsorption of Na+, secretion of K+, and yielded an accumulation of HCO3-. These effects of the metabolites were produced by equimolar concentrations and are almost identical to those of native triamterene. In conclusion, the phase-II-metabolite must be considered to be essentially responsible for the natriuresis and antikaliuresis observed after oral administration of triamterene.

[Pharmacokinetics of triamterene and its active metabolites in renal insufficiency (author's transl)]. / Zur Pharmakokinetik zon Triamteren und seinen wirksamen Metaboliten bei eingeschränkter Nierenfunktion.

1. After one oral dose of 100 mg triamterene plasma levels of triamterene (TA) and its metabolites hydroxytriamterene (OH-TA) and hydroxytriamterene sulfuric acid ester (OH-TA-ester) were studied in patients with normal and impaired renal function and in patients submitted to hemodialysis. Triamterene and its metabolites were also determined in the urine and the dialysate, respectively. 2. Hydroxytriamterene sulfuric acid ester (OH-TA-ester) representing a phase-II-metabolite of triamterene was found to yield plasma concentrations which were always higher than those of native TA. 3. In decreased renal function the elimination half-lives (t 1/2) of TA and OH-TA-ester were increased yielding elevated plasma levels of TA and its metabolites. The data of t 1/2 for TA and OH-TA-ester correlated with the creatinine clearance in an almost hyperbolic fashion. 4. Dialysance values of about 2 to 4 ml/min were determined for TA and OH-TA-ester.

The influence of triamterene on isoproterenol-induced and spontaneous myocardial calcium uptake in cardiomyopathic hamsters.

In this study the influence of 2,4,7-triamino-6-phenylpteridine (triamterene) on isoproterenol-induced myocardial accumulation of calcium in cardiomyopathic hamsters in the prenecrotic phase of their disease was investigated (acute experiments). When triamterene is administered in increasing doses simultaneously with the standard dose of 1 mg/kg isoproterenol, a dose-dependent decrease in the isoproterenol-induced calcium accumulation can be observed. A dose of 60 mg/kg triamterene is fully effective in preventing the isoproterenol-provoked myocardial calcium accumulation. In addition under the influence of isoproterenol the myocardial magnesium and potassium contents drop. This decrease can be also avoided when triamterene is administered simultaneously. The action of triamterene on spontaneous myocardial calcium accumulation was also studied in the cardiomyopathic hamsters, which beginning on their 30th day of life chronically received triamterene over a period of 27 days (twice daily 60 mg/kg p.o.). Usually the spontaneous calcium accumulation runs in parallel with progressive myocardial necrotization starting about the 40th day of life. The chronic experiment was unsuccessful; the myocardial calcium content was even higher in the triamterene-treated animals than in the controls. The failure of the long-term experiment seems to result from uremia due to high doses of triamterene with metabolic alterations that have not yet been clarified. Neverthless, triamterene seems to possess a cardioprotective effect against myocardial calcium overload. As the substance could also maintain normal intracellular potassium and magnesium contents in the acute isoproterenol experiments a combined application of triamterene and calcium antagonistic drugs is suggested. By this combination not only transmembrane calcium conductivity is reduced but also intracellular calcium binding sites might be blocked by normalized intracellular magnesium and potassium contents.