Biomedical subjects

H Iven

Publications and source records attributed to H Iven.

At least 37 records · Page 2Linked to original sources

PubMed1991

Plasma concentrations and organ distribution of thiopurines after oral application of azathioprine in mice.

The plasma concentrations and tissue distribution of thiopurines were studied in mice after oral administration of 50 mg/kg azathioprine (AZA) using HPLC analysis. Peak concentrations of AZA and three other thiopurine metabolites in plasma [thiouric acid (TUA) greater than 6-mercaptopurine (6-MP) greater than AZA greater than 8-hydroxy-AZA] were observed as early as 10 min after drug application, thus indicating fast absorption and extensive metabolism of AZA, and were followed by a rapid decline. The extraction of thiopurines from organs (intestinal mucosa, liver, kidney, testes, spleen, and bone marrow) and from red blood cells (RBCs) was preceded by an acid hydrolysis procedure resulting in the release of thiopurine bases from their corresponding ribonucleotides. 6-MP, 6-thioxanthene (6-TX), 6-thioguanine (6-TG), TUA, and 8-hydroxy-6-MP (8-OH-6-MP) were extracted from the organs, whereas only 6-MP and 8-OH-6-MP were found in the processed RBCs. Initially, high concentrations of TUA, the endpoint of metabolic AZA degradation, were detected in the intestinal mucosa and in the liver. This provides evidence for a first-pass metabolism of AZA in these two organs. The initial concentrations of 6-MP extracted from the organs were about 10-fold those found in plasma. This indicates rapid cellular uptake of 6-MP and an accumulation of 6-MP derivatives that can be explained by formation of the 6-MP ribonucleotide thioinosine monophosphate (TIMP). With the exception of plasma and RBCs, 6-TG, which may originate from intracellular 6-thioguanosine nucleotides (TGNs), was extracted from all organs examined in the study. From the sequence of appearance of 6-MP, 6-TX, and 6-TG extracted from spleen and bone marrow homogenates, it can be assumed that formation of TGN occurs via the nucleotide interconversion pathway TIMP----6-thioxanthosine monophosphate----6-thioguanosine monophosphate. The highest concentrations of 6-TG derivatives were found in the spleen and bone marrow. This correlates with the clinical and experimental observation that AZA cytotoxicity mainly affects bone-marrow stem cells and lymphocytes and supports the hypothesis (derived from in vitro experiments) that the incorporation of TGN into DNA is the cytotoxic mechanism of AZA and 6-MP.

Administration, Oral↗

PubMed1991

Inotropic and electrophysiological effects of BDF 9148, a congener of DPI 201-106, in guinea-pig atria and papillary muscles.

1. BDF 9148 is a newly synthesized congener of DPI 201-106 in which the piperazidinyl moiety has been replaced by an azetidine-3-oxy-moiety. The inotropic effect of both drugs was studied as well as their influence on the action potential, by use of standard microelectrode techniques. 2. BDF 9148 increased the contractile force of guinea-pig atria and papillary muscles. The EC50 was 1.32 X 10(-7) mol l-1 and 0.7 X 10(-6) mol l-1 respectively. DPI 201-106 was effective in a similar concentration-range, the EC50 being 2.6 X 10(-7) mol l-1 for atria and 2.8 X 10(-7) mol l-1 for papillary muscles. 3. Both drugs caused a concentration-dependent prolongation of the relaxation time of the isometric contraction curve. With 10(-6) mol l-1 BDF 9148, the mean increase was 39.1 +/- 4.4 ms in atria and 39.4 +/- 7.5 ms in papillary muscles while 10(-6) mol l-1 DPI 201-106 caused increases of 56.7 +/- 2.5 ms and 79.3 +/- 11.7 ms, respectively. The effect of BDF 9148 was not prevented by propranolol, but was reversed by 3 X 10(-6) mol l-1 tetrodotoxin. Pretreatment of atria with 3 X 10(-8) mol l-1 BDF shifted the concentration-response curve of ouabain to the left and reduced the EC50 of the glycoside from 3.21 X 10(-7) mol l-1 to 2 X 10(-7) mol l-1. 4. BDF 9148 and DPI 201-106 concentration-dependently increased the action potential duration of papillary muscles and their functional refractory period. The drugs did not modify the resting potential, the action potential amplitude or the maximum depolarization velocity.5. All effects of BDF 9148 persisted after washout. The lipophilic drug accumulated in the tissues and the tissue drug concentration was little reduced by washout of BDF 9148 from the organ bath.6. In contrast to DPI 201-106, which had a prominent negative chronotropic effect in right atria, BDF 9148 caused only a slight reduction of the beating frequency with the largest (3 x 10 5mol 11) concentration.7. The results are consistent with BDF 9148 being a sodium channel activator with much weaker influence on the beating frequency than the parent compound DPI 201-106.

Action Potentials↗

PubMed1990

Cephalosporins increase the renal clearance of methotrexate and 7-hydroxymethotrexate in rabbits.

Anaesthetized rabbits were infused with methotrexate (MTX; 30 micrograms x kg-1 x min-1) for 4 h. Constant plasma concentrations of MTX and its main metabolite 7-hydroxymethotrexate (7-OH-MTX) were achieved 40-60 min after the start of the infusion. In all, 50% of the infused MTX was eliminated by the kidney; another 15%-30% was hydroxylated and excreted as 7-OH-MTX in the urine. A concomitant infusion of penicillin G (3.96 mg x kg-1 x min-1) decreased the renal clearance of MTX and 7-OH-MTX, probably by competitive antagonism at the common tubular secretion site. In contrast, the four cephalosporins ceftriaxone, ceftazidime, ceftizoxime and cefoperazone all increased the renal clearance of MTX and 7-OH-MTX. At similar plasma concentrations, ceftriaxone and ceftazidime were almost equipotent, ceftizoxime was less effective and cefoperazone seemed to have a biphasic effect, depressing the clearance of MTX and 7-OH-MTX at higher drug concentrations. The effects are best explained by an inhibition of the tubular reabsorption of the cytostatic and its metabolite. The results suggest that cephalosporins are a better choice than penicillin for antibiotic treatment during MTX therapy.

Animals↗

PubMed1990

Influence of N-ethylmaleimide on action potential and force of contraction of guinea-pig papillary muscles.

1. Standard microelectrode techniques were used to investigate the influence of N-ethylmaleimide on the action potential, slow response action potential and force of contraction of guinea-pig papillary muscles. 2. N-ethylmaleimide, 3 x 10(-5) to 10(-4) mol l-1, concentration-dependently increased the force of contraction. The positive inotropic effect developed quickly and, with the largest drug concentration, was followed by a progressive decline of the contractile force. The action potential duration was progressively shortened by N-ethylmaleimide. 3. The effects of N-ethylmaleimide were not prevented in the presence of tetrodotoxin 3 x 10(-8) mol l-1 and propranolol 4 x 10(-6) mol l-1 or by a reduction of the Na(+)-concentration to 70 mmol l-1. 4. Verapamil, 10(-6) mol l-1, reduced the positive inotropic, but not the action potential shortening effect of N-ethylmaleimide. 5. In K(+)-depolarized muscles in the presence of propranolol and tetrodotoxin, N-ethylmaleimide 10(-4) mol l-1 increased the maximum depolarization velocity and the duration of the slow response action potential. The latter effect was transient and was followed by a progressive reduction of the action potential duration. 6. The most likely explanation for the action potential shortening effect of N-ethylmaleimide seems to be an increase of an outward potassium current while the transient inotropic effect of the drug may be caused, at least in part, by an increase of the slow inward calcium current.

Action Potentials↗

PubMed1989

No influence of enzyme inhibitors on the hydroxylation of methotrexate in rats.

In anaesthetized rats 50% of an infused dose of methotrexate (MTX) was excreted into the bile. About 3% was metabolized to 7-hydroxymethotrexate (7-OH-MTX), which appeared also in the bile. Pretreatment with allopurinol had no influence on the elimination of MTX or the production of 7-OH-MTX during a 3-h infusion of MTX. Cyanamide decreased the total MTX clearance, but increased the biliary elimination of 7-OH-MTX. Phorone decreased the biliary MTX-clearance, but not the biliary secretion of 7-OH-MTX. The results show that neither aldehyde oxidase nor xanthine oxidase is the predominant hydroxylating enzyme for MTX in the rat.

Aldehyde Oxidase↗

PubMed1989

Pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in rats and evidence for the metabolism of MTX to 7-OH-MTX.

In pentobarbital anesthetized rats that received 4 mg/kg i.v. methotrexate (MTX) or 7-hydroxymethotrexate (7-OH-MTX), the pharmacokinetics of the two drugs were similar. Plasma concentrations of both drugs declined biexponentially, with terminal half-lives of 90.6 min for MTX and 97.2 min for 7-OH-MTX. The total clearance values were 9.2 and 9.6 ml x kg-1 x min-1, respectively. With MTX, 48.2% of the dose was excreted in the urine within 200 min and another 31.6% was recovered from the bile; 5.8% was metabolized to 7-OH-MTX and appeared in the bile. Plasma concentrations of the metabolite 7-OH-MTX after MTX administration were below the detection limit. Injected 7-OH-MTX was predominantly excreted into the bile (72.8% of the dose); only 11.2% could be recovered from the urine. Differences between the physicochemical properties of MTX and 7-OH-MTX or different affinities for active transport systems may account for the unequal importance of these two excretion pathways for the two compounds.

Animals↗

PubMed1988

The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits.

In anesthetized rabbits, continuous infusion of methotrexate (MTX; 30 micrograms kg-1 min-1) established steady-state plasma concentrations for MTX and the metabolite 7-hydroxymethotrexate (7-OH-MTX) within 40 min. Fifty percent of the infused dose was eliminated unchanged by the kidneys and the renal MTX clearance was slightly higher than the inulin clearance. Another 15%-30% was metabolized and excreted as 7-OH-MTX in the urine. Infusions of 7-OH-MTX, furosemide or benzarone had no influence on the clearance of MTX or 7-OH-MTX. Infusions of probenecid or piperacillin decreased the renal clearance of MTX and 7-OH-MTX mainly by reducing the tubular secretion of both compounds. In contrast, infusions of the antibiotics ceftriaxone and sulfamethoxazole increased the renal elimination of MTX and 7-OH-MTX. An increase was also observed during the infusion of the uricosuric drugs sulfinpyrazone and benzbromarone. These results are consistent with competition for tubular reabsorption between MTX, ceftriaxone and sulfamethoxazole. The pharmacokinetic drug interactions observed occurred with therapeutic drug concentrations and thus may be clinically relevant.

Animals↗

PubMed1988

Electrophysiologic effects of saterinone and milrinone in the isolated guinea pig myocardium.

The positive inotropic agent milrinone and the newly synthesized compound saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) dose-dependently increased the contractile force of guinea pig left atria. During a 90-min exposure, 10(-4) mol/l saterinone caused a continuous increase of the functional refractory period (FRP), while the initial positive inotropic effect faded gradually. No change of the FRP was observed with milrinone. Saterinone (10(-4) mol/l) also increased the action potential duration and the FRP of guinea pig papillary muscles, while milrinone had no influence on either parameter. Both milrinone and saterinone increased the amplitude, depolarization velocity and duration of slow response action potentials in K+-depolarized muscles. These effects appeared in the presence of tetrodotoxin or propranolol and could be reversed by carbachol. It is concluded that saterinone increases the force of contraction and the slow inward current by inhibiting cardiac phosphodiesterase. The increase of the FRP may be attributed to a decrease of the membrane K+ conductance.

Action Potentials↗

PubMed1986

Influence of the antibiotics piperacillin, doxycycline, and tobramycin on the pharmacokinetics of methotrexate in rabbits.

In rabbits methotrexate (MTX) plasma concentrations showed a triexponential decline after short-term infusion (12 mg/kg in 10 min). Probenecid (50 mg/kg PO 1 h before MTX) and piperacillin (100 mg/kg SC 10 min before MTX plus 50 mg/kg SC 4 h later) increased the plasma concentrations of MTX and its metabolite 7-hydroxy-methotrexate (7-OH-MTX) 40 min to 6 h after the end of MTX infusion. The total body clearance of MTX was reduced, while the elimination half-life and the drug distribution to the peripheral body compartments were unchanged. Doxycycline (5 mg/kg PO 30 min before MTX) had no influence on the pharmacokinetics of MTX. Tobramycin was ineffective when given either only on the day of MTX infusion (2 mg/kg SC, 5 min before MTX and 2 mg/kg SC 4 h later) or as a 5-day pretreatment (2 X 2 mg/kg SC daily). The influence of probenecid and piperacillin can be explained by a reduction of the renal elimination of MTX via the tubular transport mechanism for organic acids. This interaction occurred with therapeutic drug concentrations and thus may be clinically relevant.

Animals↗

PubMed1985

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits.

In rabbits the IV kinetics of MTX (1.33, 4 and 12 mg/kg) could be described by a linear three-compartment model with a terminal half-life between 2.4 and 3.6 h. During 8 h 50% of the dose was excreted into urine in unchanged form and 15% as the metabolite 7-OH-MTX. These fractions remained constant with increasing dose. In continuous infusion experiments (9-900 micrograms/kg X min MTX IV) a decrease of the renal MTX clearance with increasing plasma concentration was observed. This effect was nearly compensated by an increase of the extrarenal MTX clearance. After short-term infusion of 7-OH-MTX (4 mg/kg) a biexponential decline of 7-OH-MTX plasma concentrations was observed with a terminal half-life of 0.45 h. About 80% of the dose was regained from urine during 5 h. From the combined pharmacokinetic data a linear model was constructed for the calculation of 7-OH-MTX plasma concentrations after short-term MTX infusion. For the first 4 h after MTX application the predicted values were in good accordance with the 7-OH-MTX concentrations actually measured.

Animals↗

PubMed1984

Influence of Tris (hydroxymethyl) aminomethane on plasma insulin and glucose concentration of normal and streptozotocin-diabetic rats.

The influence of Tris buffer on plasma glucose and insulin concentrations was investigated in pentobarbital-anesthetized (60 mg/kg i.p.) Wistar rats. A bolus injection of neutralized Tris (5 mmol/kg; pH 7.4) caused a transient increase of plasma insulin concentration (+ 130 +/- 20 microU/ml; means +/- S means, n = 6) but did not change the glucose concentration. A continuous infusion of Tris (0.5 mmol/kg X min for 90 min) reduced the plasma glucose concentration from 8.7 +/- 0.42 to 5.1 +/- 0.33 mmol/l after 30 min. The plasma insulin concentration was elevated during the first 20 min (maximum +122 +/- 21 microU/ml after 10 min). In streptozotocin-diabetic rats (75 mg/kg i.v., 48 h prior to the experiments) an infusion of Tris changed neither glucose nor insulin concentration in plasma. The results indicate that in the rat Tris-induced hypoglycemia is always associated with a transient stimulation of insulin secretion.

Animals↗

PubMed1983

Pharmacokinetics of phenobarbital and propylhexedrine after administration of barbexaclone in the mouse.

The antiepileptic barbexaclone is the salt of the base propylhexedrine (indirect sympathomimetic) and phenylethylbituric acid. After i.v. and oral administration of 66 mg/kg barbexaclone to mice the time course of propylhexedrine and phenobarbital concentrations was studied in plasma, brain, lung, liver, kidney, spleen, heart, and skeletal muscle. Furthermore, the kinetics of phenobarbital were studied after treatment with an equimolar dose of phenobarbital-Na (40 mg/kg). In contrast to the i.v. bolus of phenobarbital-Na, barbexaclone was non-lethal only when infused over a period of 3 min. After the i.v. administration of either salt, phenobarbital plasma levels declined monoexponentially with a half-life of 7.5 h; the volume of distribution was 0.78 l/kg. After oral application absorption of phenobarbital was complete with both salts, though it was delayed after barbexaclone. The latter was the result of a delayed gastro-intestinal passage. Brain uptake of phenobarbital was a slow process, equilibrium with plasma concentrations being reached only 30 min after injection. Propylhexedrine reduced phenobarbital concentrations in brain as evident from steady state tissue-plasma ratios. This was observed after i.v. as well as after oral application. After i.v. application of barbexaclone the following pharmacokinetic parameters for propylhexedrine were determined: t0.5 alpha 0.31 h, t0.5 beta 2.5 h, Vd beta 19.3 l/kg; bioavailability (AUC oral/AUC i.v.) 0.37. Propylhexedrine penetrated the blood-brain barrier rapidly. High but unequal tissue accumulation was observed: lung = kidney greater than liver = brain greater than spleen greater than heart greater than skeletal muscle.

Animals↗

PubMed1982

Pharmacokinetics of TRIS (hydroxymethyl-)aminomethane in healthy subjects and in patients with metabolic acidosis.

To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg = 1 mmol/kg;pH 7.4) and to 20 patients suffering from metabolic acidosis (109--376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,beta = 5.6 h) and patients with intact renal function (t0.5,beta = 16.3--45.6 h). The final volume of distribution (V beta) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.

Acidosis↗

PubMed1982

The pathophysiological profile of the acute cardiovascular toxicity of sodium fluoride.

The intravenous infusion of sodium fluoride (2 mg/kg X min) into anesthetized rats caused a progressive fall in arterial blood pressure, cardiac output, heart rate and peripheral resistance. Respiratory rate increased during the first 20 min of infusion resulting in increased oxygen and decreased carbon dioxide blood concentrations. Total body oxygen consumption decreased after 30 min of NaF infusion by 29%, whereas the respiratory quotient (RQ) increased from 0.8 to 1.06. Death occurred after a mean dose of 79.6 +/- 4.6 mg/kg NaF. The terminal cardiac event before death was atrioventricular block followed immediately by asystole. Artificial ventilation did not influence the cardiovascular and the lethal effects of fluoride infusion. The plasma concentrations of total and ionized calcium decreased upon NaF infusion. The infusion of extra calcium did not prevent NaF-induced cardiovascular failure but decreased plasma fluoride levels and increased the lethal dose of NaF by 17% (not significant). In isolated atria and perfused hearts in vitro, NaF decreased the force of contraction in a dose-dependent manner. In conclusion, cardiovascular failure resulting from the direct cardiodepressive and vasodilatating effects of fluoride (and not from respiratory depression or hypocalcemia) accounts for the lethal outcome of fluoride intoxication.

Animals↗

PubMed1982

[Influence of (+)-Catechin and Dithiocarb on the Pharmacokinetics of Phenprocoumon, Tolbutamide and Three Inhalation Anesthetics in rats].

Pretreatment with (+)-catechin ((+)-cyanidanol-3, Catergen) (200 mg/kg p.o.) did not alter the elimination of intravenously injected phenprocoumon (0.6 mg/kg) or tolbutamide (100 mg/kg) in rats, while dithiocarb (Sodium diethyl-dithiocarbamate) (200 mg/kg p.o.) prolonged only the elimination half-life of phenprocoumon to a small extent. The metabolism of halothane (100 ppm), enflurane (100 ppm) or methoxyflurane (300 ppm) was studied by measuring the disappearance of the compounds from the atmosphere of a closed exposure system. Pretreatment with (+)-catechin did not impair the metabolic removal of all three anesthetics; in the case of enflurane (+)-catechin caused a small, but significant shortening of the elimination half-life, for enflurane and methoxyflurane the uptake of the compounds into the rats seemed to be impaired under the influence of (+)-catechin. Dithiocarb strongly impaired the in vivo metabolism of halothane and methoxyflurane, whereas that of enflurane remained unaffected.

4-Hydroxycoumarins↗

PubMed1981

Pharmacokinetics and organ distribution of methotrexate in the rat.

After intravenous injection of 31 mg/kg methotrexate (MTX), its concentrations were determined in plasma, liver, kidney, bone marrow, stomach, duodenum, jejunum, colon and muscle up to 23 days, using an enzymatic assay. Plasma pharmacokinetics were described by a triexponential function, with a terminal half-life of 4.2 h. Up to 1.5 h after injection, the initial rapid decline of MTX concentrations in bone marrow, kidney, and liver roughly paralleled that in plasma. The terminal half-life of MTX in bone marrow was greatly prolonged (37 h), while MTX remained nearly constant in liver (0.57 microgram/ml) and kidney (0.53 microgram/ml) from 6 h to 23 days. In the intestines, luminal as well as tissue MTX concentrations were determined. The stomach showed a triexponential decay of tissue MTX and low luminal concentrations throughout. In the duodenum, the middle of jejunum, and the colon tissue MTX seemed to follow a bi- or triexponential function. However, high luminal concentrations due to MTX biliary excretion, when reaching a given intestinal portion, increased the MTX tissue concentration in this segment.

Animals↗

PubMed1981

Pharmacokinetics of TRIS (hydroxymethyl-)aminomethane in the rabbit.

Pharmacokinetics of TRIS were investigated in rabbits after infusion of 1 mmol/kg. The drug exhibited three-compartment characteristics with long terminal half-life (13 hr). The final volume of distribution V beta (3700 ml/kg) indicated drug accumulation inside cells, but equilibration between compartments was slow compared to drug elimination. From these data is seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis.

Acidosis↗

PubMed1980

Field-stimulus response of guinea-pig atria as influenced by the peptides angiotensin, bradykinin, and substance P.

Field stimulation produced in isolated guinea-pig left atria a positive inotropic response, which was highly sensitive to the inhibitory actions of lidocaine, tetrodotoxin, and of pindolol. The field-stimulus effect was enhanced by angiotensin and by bradykinin, but not by substance P. Only bradykinin exerted also a direct positive inotropic effect (in the absence of field stimulation). It is concluded that the intramural adrenergic neurons of the guinea-pig atrium have receptors for both angiotensin and bradykinin, but not for substance P.

Angiotensin II↗