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Biomedical subjects

A H Scaf

Publications and source records attributed to A H Scaf.

At least 37 records · Page 2Linked to original sources
PubMed1986

Hepatobiliary disposition of vecuronium bromide in man.

The plasma and bile concentrations, the biliary excretion and the neuromuscular blocking effect of vecuronium bromide were studied during surgery in 13 patients who had received 150 micrograms kg-1 i.v. The amount of vecuronium in liver biopsies taken after i.v injection was measured in a separate group of six patients. Vecuronium appeared early in the bile, in concentrations that were 30-50 times greater than those in the plasma. On the basis of the measured amount of vecuronium excreted in the bile, together with the accepted average daily bile flow, it was estimated that more than 40% of vecuronium was excreted in the bile in 24 h. Liver biopsies indicated that the liver may contain more than 50% of the i.v. dose 30 min after injection. The large distribution of vecuronium into the liver may account for the initial rapid decline in vecuronium plasma concentration and its relatively short duration of action. In this study, neuromuscular blockade was prolonged, possibly as a result of interference, by surgical manipulation, with the rapid hepatic uptake of vecuronium.

Adult↗
PubMed1986

Comparative pharmacokinetics and dynamics of vecuronium and pancuronium in anesthetized patients.

Plasma concentrations and the degree of neuromuscular blockade after a 2-min infusion of 0.1 mg/kg of vecuronium bromide or pancuronium bromide (equipotent doses) were studied in 12 gynecologic patients. The plasma concentrations of both drugs declined in a triphasic manner. The difference between the intercepts and rate constants of the two drugs was not significant. Vecuronium was removed faster from the plasma than pancuronium; this was reflected in a significantly larger plasma clearance rate for vecuronium (4 ml X min-1 X kg-1 vs 1.1 ml X min-1 X kg-1 for pancuronium). The effective plasma concentrations at 50% recovery of the twitch height were 0.11 +/- 0.02 (vecuronium) and 0.2 +/- 0.03 microgram/ml (pancuronium). The disposition kinetics were adequately described by a three-compartment model. An effect compartment was added to the model to correlate the neuromuscular effects and plasma concentrations of both drugs. The ratio between concentrations of vecuronium and pancuronium in the effect compartment at 50% twitch height was 0.83. In spite of its greater potency, vecuronium has a shorter duration of action than pancuronium.

Adult↗
PubMed1986

Disposition and urinary excretion of vecuronium bromide in anesthetized patients with normal renal function or renal failure.

The effect and plasma concentrations of vecuronium bromide were measured in normal patients after an intravenous dose of 50, 100, or 150 micrograms/kg and in patients with renal failure after 50 or 100 micrograms/kg. Urinary excretion of vecuronium was studied in normal patients after the 150 micrograms/kg dose. Pharmacokinetic parameters of patients with or without renal failure were similar. No metabolites of vecuronium were found in the plasma. Twenty percent of vecuronium was excreted unchanged in the urine; 5% as the 3-hydroxy derivative. No other metabolites of vecuronium were found in the urine. Increasing doses of vecuronium shortened the onset, but prolonged the duration of action and the recovery rate, to a similar extent in patients with or without renal failure. It was concluded that the disposition of vecuronium was best described by a three compartment model. Both the disposition and the effect of vecuronium are only marginally disturbed by renal failure.

Adult↗
PubMed1985

Disposition of vecuronium bromide in the cat.

The disposition of vecuronium bromide has been investigated in six normal cats (group I) and in six cats with ligated renal pedicles (group II). A combined fluorimetric and chromatographic technique was used to determine the concentrations of vecuronium and its metabolites in biological material. After i.v. injection of 0.6 mg kg-1, vecuronium disappeared rapidly from the plasma of the normal cat. Concentrations decreased bi-exponentially with half-lives of 4.6 and 31 min, respectively. The steady state volume of distribution was 0.23 litre kg-1 and the clearance 11 ml min-1 kg-1. Seventy percent of an i.v. dose of vecuronium (or its metabolites) was recovered: 15% in the urine, 40% in the bile and 15% in the liver. Only 3.8% of this consisted of the 3-hydroxy metabolite. There were no significant differences in pharmacokinetic data or in the amounts of vecuronium and its metabolites recovered in cats with ligated renal pedicles. The 15% of vecuronium normally excreted by the kidney was compensated for by increased hepatic and biliary concentration of vecuronium.

Animals↗
PubMed1983

Clinical pharmacokinetics of (NPAz2)2NSOAz: 'SOAz'.

Pharmacokinetic studies of 1,3,3,5,5 pentakis (aziridino)-1 lambda 6,2,4,6,3 lambda 5,5 lambda 5 thiatriazadiphosphorine-1-oxide ('SOAz'), a new antineoplastic agent containing an inorganic ring system and five aziridino groups, were performed in six patients who took part in a phase I clinical trial of the agent. The drug was administered as a rapid IV infusion. Serum decay curves could be fitted to an open two-compartment model of drug disappearance. After a short initial phase with a t 1/2 (+/- SD) of 7.8 +/- 4.2 min a terminal phase with a dose-independent half-life of 203 +/- 17 min occurred. The coefficient of apparent distribution was 0.71 +/- 0.13. The renal clearance was 75 +/- 11 ml/min and the total body clearance 162 +/- 23 ml/min. A percentage of 46.5 +/- 6.6 of the administered drug could be recovered unchanged in the urine within 24 h. It is concluded that in view of concentrations known to be effective in vitro, administration in large single doses may be advantageous. Dose adjustments should be made for patients with impaired renal function.

Adult↗
PubMed1982

Hepatic drug transport in the rat. A comparison between isolated hepatocytes, the isolated perfused liver and the liver in vivo.

The hepatic transport of three different drugs, the organic anion dibromosulphophthalein, the organic cation d-tubocurarine and the uncharged compound ouabain was studied in vivo in the isolated perfused rat liver and isolated hepatocytes. The respective clearances by uptake were determined for the various substrates and corrected for differences in hepatic blood flow and extracellular protein binding in the three liver preparations. The corrected uptake values in the intact organ, in vivo and in the isolated perfused liver were highly comparable; for dibromosulphophthalein a clearance of 2.1 ml/min per 10(6) hepatocytes was found in vivo, whereas in perfusion a value of 2.4 ml/min per 10(6) cells was calculated. For d-tubocurarine, the values were 34 x 10 (-4) and 55 x 10(-4) ml/min per 10(6) cells obtained in vivo and in the isolated perfused organ, respectively. With ouabain as the substrate, the in vivo clearance amounted to 5.1 x 10(-2), whereas in the isolated perfused liver a value of 4.8 x 10(-2) ml/min per 10(6) cells was calculated. The clearance by uptake obtained for dibromosulphophthalein was ouabain in the isolated hepatocytes appeared to be a factor of 2-3 lower than in the intact organ. In the case of d-tubocurarine however the clearance was identical to that in vivo and the isolated perfused liver. The rate of secretion from isolated hepatocytes was, for dibromosulphophthalein identical to, and for d-tubocurarine and ouabain lower than that in the intact organ, especially as compared with the in vivo preparation. It is concluded that transport function is well preserved in the isolated perfused liver and isolated hepatocytes. For certain substrates freshly isolated hepatocytes may exhibit a somewhat lower uptake and/or secretion rate, in spite of a good cell quality as judged by generally accepted criteria for cell viability. Whether this is due to changes in membrane composition (not detected by our viability tests) or a selection of a subpopulation of hepatocytes, is discussed.U

Animals↗
PubMed1982

4-Aminopyridine kinetics.

Nine healthy subjects (7 men; 2 women) received single 20-mg IV injections of 4-aminopyridine (4-AP). Six of the subjects received the same dose in the form of enteric-coated tablets and four the same dose in uncoated tablets; treatments were at least 2 wk apart. Blood, saliva, and urine were assayed for 4-AP using a high-performance liquid chromatography. Kinetic analysis of serum concentrations after intravenous dosing resulted in the best fitting of a triexponential model in five and a biexponential model in four subjects. The apparent volume of distribution (V) was 2.6 +/- 0.9 (mean +/- SD) 1 kg-1, the terminal half-life (t 1/2) 3.6 +/- 0.9 hr, and the total serum clearance 0.61 +/- 0.14 1 hr-1 kg-1. Saliva concentrations were higher than those in serum after 5 min, with a mean correlation coefficient of 0.989 (n = 5). The t 1/2 and V calculated from serum and saliva concentrations were of the same order. The total urinary excretion of unchanged 4-AP was 90.6 +/- 7.8% after intravenous doses and 88.5 +/- 4.8% after oral doses of enteric-coated tablets. The bioavailability of the enteric-coated tablets calculated from the area under the serum concentration curve (95 +/- 29%) did not differ from that calculated from urinary excretion (98 +/- 8%). Protein binding of 4-AP was found to be negligible. Biotransformation is unlikely.

4-Aminopyridine↗
PubMed1981

Hepatic and renal disposition of pancuronium and gallamine in patients with extrahepatic cholestasis.

The plasma clearance of pancuronium in patients with extrahepatic cholestasis was 16% lower than in a control group (1.47 +/- 0.11 ml min-1 kg-1 v. 1.76 +/- 0.21 ml min-1 kg-1), but the difference was not significant. A significant increase in the elimination half-life T 1/2 beta of pancuronium (from 141 to 224 min) and a significant increase in the volume of the peripheral compartment (V2) was found in patients with extrahepatic cholestasis when compared with control patients. There was a significantly lower cumulative biliary excretion of pancuronium (0.3 +/- 0.3% v. 10.9 +/- 3.2% in the controls) during the 48-h period of observation. The biotransformation and cumulative urinary excretion patterns of pancuronium revealed no significant differences between the two groups of patients. The increase of T 1/2 beta pancuronium in patients with extrahepatic cholestasis was mainly a consequence of the increase in the volume of distribution. No significant differences in the plasma clearance, T 1/2 beta or in the volume of distribution were observed with gallamine in the patients with extrahepatic cholestasis when compared with the control group. The cumulative urinary excretion of gallamine during 48 h in both groups of patients was approximately 100%. We concluded that in patients with cholestasis and normal glomerular filtration, gallamine is probably more reliable than pancuronium for neuromuscular blockade.

Adult↗
PubMed1980

Effect of experimental cholestasis on neuromuscular blocking drugs in cats.

Pancuronium, Org 6368 and gallamine were compared in control cats and in cats with experimental cholestasis. A decrease in the plasma clearance and a prolongation of neuromuscular blockade with Org 6368 and pancuronium were found in the latter; no significant difference was detected in the biotransformation pattern of Org 6368 and pancuronium compared with controls. Inhibition of hepatic uptake of Org 6368 and pancuronium in extrahepatic cholestasis might explain the significant alterations in the pharmacokinetics of the two steroid neuromuscular blocking drugs. The pharmacokinetics of gallamine were normal during cholestasis. The results suggest that, under pathological conditions involving increased plasma concentrations of bile salts, neuromuscular blocking agents that are cleared from the plasma by the liver may have an impaired hepatic uptake and consequently a prolonged duration of action.

Animals↗
PubMed1979

The effect of dantrolene sodium on rat skeletal muscle in relation to the plasma concentration.

Dantrolene sodium is a muscle relaxant used in the treatment of spasticity. It has been shown to interfere with calcium release from the sarcoplasmic reticulum and thus to inhibit excitation--contraction coupling. The effect of dantrolene sodium on the twitch tension of the tibialis anterior muscle of the rat was measured after 2 mg/kg i.v. or 25 mg/kg orally. Plasma concentrations were estimated at maximum twitch depression and during recovery from the block. In a separate series of experiments the half-life of labelled dantrolene sodium was measured in blood plasma, skeletal muscle and heart muscle of rats. Dantrolene sodium 2 mg/kg i.v. gave a maximal block of approximately 47%, the mean dantrolene sodium concentration was then 5.8 microgram/ml. A half-life for distribution of 1.1 min and an elimination half-life of 31 min after intravenous administration were observed, elimination rate constants in skeletal and heart muscle were comparable. Recovery from the block went much slower, the half-time of the process being approximately 80 min. Dantrolene sodium 25 mg/kg orally gave a maximal block of approximately 38% at a mean plasma concentration of 3.6 microgram/ml after 14 min. The recovery was again very slow. These experiments demonstrated that dantrolene sodium acts according to a two-compartment pharmacokinetic model. There was a discrepancy between duration of effect and plasma concentration of dantrolene sodium in the rat. This suggests that the receptor for dantrolene sodium is not located in the central compartment.

Animals↗
PubMed1979

Comparative pharmacokinetics of d-tubocurarine and metocurine in man.

To compare the pharmacokinetics of d-tubocurarine and metocurine in man, concentrations of 3H-d-tubocurarine and 14C-metocurine (0,0,N-trimethyl-tubocurarine) in plasma, urine and bile were determined after intravenous administration of d-tubocurarine, 0.15 mg/kg (five patients), and metocurine, 0.05 mg/kg (five patients), in patients anesthetized with thiopental and nitrous oxide for cholecystectomy. Plasma disappearances of both drugs were triexponential, with mean terminal half-lives of 346 and 217 min for d-tubocurarine and metocurine, respectively. By ion-pair thin-layer chromatography, no metabolite of either compound was found in urine or bile. Renal excretions 48 hours after injection ranged from 46 to 95 per cent of the dose for d-tubocurarine and from 46 to 58 per cent for metocurine. Mean total-body clearances were 56 and 96 ml/min for d-tubocurarine and metocurine, respectively. Biliary elimination of d-tubocurarine was greater than that of metocurine: within 48 hours 11.8 and 2.1 per cent of the doses were excreted in bile, respectively. The observed differences in total-body clearances and volumes of distribution (V1) may be partly explained by greater protein binding of d-tubocurarine. The results indicate that biliary excretion is an alternative route of elimination for d-tubocurarine only. Also, d-tubocurarine is less dependent on renal excretion for its elimination, and probably is preferable to metocurine for use in patients with renal failure.

Adult↗
PubMed1979

Influence of bile salts on hepatic transport of dibromosulphthalein.

The influence of bile salts on hepatic transport of the organic anion dibromosulphthalein (DBSP) was investigated in rats. Bile salts influence the hepatic uptake, intracellular binding, and biliary excretion of DBSP. The overall effect depends on the administered dose of bile salts and DBSP. High doses of bile salts inhibited hepatic uptake of DBSP, whereas low doses of bile salts stimulated bile flow and simultaneously increased maximal biliary excretion of DBSP. The uncharged nonbile salt choleretic ouabain also stimulated biliary DBSP excretion. In contrast, the anionic nonbile salt choleretics, ethacrynic acid and theophylline, did not stimulate biliary excretion of DBSP. Because DBSP inhibited biliary excretion of ethacrynic acid and its metabolites, the lack of a stimulatory effect of ethacrynic acid choleresis might be explained by concomitant inhibition of biliary excretion of DBSP, masking the stimulatory effect of ethacrynic acid. Biliary transport maximum of DBSP was highly correlated with bile flow. The biliary clearance (Vmax/Km) was only moderately changed by bile salt administration, whereas the increase in the maximal biliary excretion rate was more pronounced, implying that the apparent Km for biliary excretion of DBSP was also increased by the bile salts. It is inferred that the stimulation of net biliary excretion of DBSP by bile salts may be due to a diminished transport from bile into the hepatocytes as the consequence of the decreased biliary concentration caused by the choleresis.

Animals↗
PubMed1978

A preliminary investigation of the renal and hepatic excretion of gallamine triethiodide in man.

The fate of gallamine triethiodide has been investigated in patients undergoing cholecystectomy with choledochostomy (group I), pelvic operations (group II) and orthopaedic operations (group III). Following a single i.v. injection of gallamine 2.5 mg kg(-1) the disappearance of the drug from the serum occurred in three phases with half-lives of less than 5, 30, 138 min, less than 5, 39, 141 and less than 5, 48, 144 min in the respective groups. Twenty-four hours after injection the renal excretion of the unchanged drug was 53% (15-100%) of the administered dose in group I, 67% (40-90%) in group II and 95% (89-100%) in group III. The biliary excretion of gallamine appeared to be negligible in man. The relationship between renal excretion and duration of action of gallamine, and the influence of some intraoperative factors on drug disposition, are discussed.

Adult↗
PubMed1977

Human experience of cetiedil, a new vasodilator with anticholinergic properties.

Cetiedil, a new vasodilating drug with anticholinergic properties, was shown to be metabolised very rapidly in man after intravenous and oral administration of the 14C-compound. Higher concentrations of labelled compound after oral than after intravenous administration at the same sampling time, and proportional differences in urinary excretion, suggest that metabolic handling of the drug differs depending on the route of administration. Experiments in which inhibition of saliva secretion was measured indicated that (an) active metabolite(s) probably was (were) responsible for the action of the drug. As an anticholinergic drug, cetiedil is at least 400 times weaker than atropine.

Administration, Oral↗
PubMed1977

Relationship of the serum concentration of pancuronium to its neuromuscular activity in man.

The relationship between the time course of the decay of serum concentrations of pancuronium and its neuromuscular blocking effect has been investigated after the intravenous administration of 50, 80 and 100 microgram/kg doses to anesthetized patients. Following administration of these doses, maximal neuromuscular block in the adductor pollicis muscle developed in about 7, 2.5, and 2 minutes and lasted about 20, 40, and 60 minutes, respectively. The times from start of recovery to return of twitch tension to 25, 50, and 75 per cent of control were similar in the different dosage groups, but occurred progressively later with increasing doses. At times of 25, 50, and 75 per cent recovery mean serum concentrations (pooled values) were 0.13 +/- 0.01,0.11 +/- 0.01, and 0.10 +/- 0.01 microgram/ml (+/- SEM), respectively. Neuromuscular transmission to the adductor pollicis muscle started to recover at a mean serum pancuronium concentration of 0.21 +/- 0.03 microgram/ml. The data obtained in this study are in agreement with the experimental and clinical findings of similar studies with d-tubocurarine, and indicate that there is a correlation between the serum concentrations of muscle relaxants and the intensity of their neuromuscular activities.

Adolescent↗
PubMed1977

The relationship between disposition and duration of action of congeneric series of steroidal neuromuscular blocking agents.

The renal and hepatic elimination and biotransformation, as well as the relation between disposition and duration of action of pancuronium and two of its analogues, dacuronium and ORG.6368, have been investigated in the cat. In pharmacokinetic studies, appreciable amounts of the latter two compounds were found in the urine, bile and liver 8 h after their intravenous administration. Various proportions of the injected dose of the respective drugs were metabolized. In another series of experiments it was shown that the early hepatic uptake (during the first 3 min after the injection) of ORG.6368 was significantly greater than that of dacuronium and pancuronium. The intensity and duration of action of the neuromuscular blocking effect of the three compounds were studied after intravenous and "close" intraarterial injection. On the basis of these pharmacokinetic and neuromuscular studies, it was concluded that the short duration of action of ORG.6368 is due primarily to its early hepatic uptake. The possibility cannot be excluded, however, that differences in the kinetics of the drug action of ORG.6368 and the other two compounds also contributed significantly to the differences seen in the duration of action of these compounds.

Animals↗
PubMed1977

The desensitizing interaction of hexafluorenium with the cholinergic receptor in the diaphragm of the rat.

1. The interaction of hexafluorenium with acetylcholine, carbachol and suxamethonium with regard to the depolarization of the end-plate of rat diaphragm was studied. The depolarization was measured with the moving meniscus technique of Fatt. The competitive antagonist d-tubocurarine was included in the studies. 2. Hexafluorenium inhibited acetylcholinesterase in the end-plate. 3. The receptors in the end-plate were desensitized by carbachol and suxamethonium. Hexafluorenium enhanced the desensitization by suxamethonium. d-Tubocurarine had no direct influence on desensitization 4. The desensitization of the receptors in rat diaphragm is compatible with a cyclic model of desensitization. 5. The desensitizing interaction of hexafluorenium with the receptors may explain the non-competitive antagonism with depolarizing drugs with regard to the depolarization of the end-plate and the synergism with these drugs with regard to the paralysis of the indirectly stimulated muscle reported earlier. 6. The affinities of carbachol, suxamethonium and d-tubocurarine to the sensitive receptors are 4.9, 5.2 and 6.8, respectively.

Acetylcholine↗