Self-administration of 3alpha-androstanediol increases locomotion and analgesia and decreases aggressive behavior of male hamsters.

Androgens, such as testosterone (T), can have reinforcing effect, which may be due in part to actions of T's metabolite, 3alpha-androstanediol (3alpha-diol). To investigate rewarding effects of 3alpha-diol, gonadally intact adult male hamsters were given a two-bottle choice test to determine the amount of 3alpha-diol that would be self-administered over 4 days of exposure. After 2 days of habituation and 4 days of monitoring of consumption, hamsters were tested in an activity monitor and the open field (locomotion/exploration), paw lick (analgesia) and resident-intruder (aggression) tasks. Hamsters consumed significantly more 3alpha-diol than vehicle in the two-bottle choice test. Hamsters that were allowed to self-administer 3alpha-diol made significantly more beam breaks and total entries in the open field had increased latencies to pawlick, and engaged in significantly fewer attacks, than did hamsters with access to vehicle alone. Hamsters that self-administered 3alpha-diol had higher levels of 3alpha-diol in serum, hippocampus, prefrontal cortex, striatum and midbrain than did hamsters with access to vehicle alone. Together, these data suggest that 3alpha-diol may have rewarding effects.

The nucleus accumbens as a site of action for rewarding properties of testosterone and its 5alpha-reduced metabolites.

Testosterone (T)'s positive hedonic effects may be mediated by actions of its metabolites, dihydrotestosterone (DHT) or 3alpha-androstanediol (3alpha-diol), in the nucleus accumbens (NA). In Experiment 1, adult, intact, male rats were systemically administered 1 mg of T, DHT, 3alpha-diol or vehicle, at different time points to examine concentrations of androgens in the NA. Rats administered 3alpha-diol had significantly increased concentrations of 3alpha-diol in the region of the brain encompassing the NA. These data are consistent with previous data from our laboratory demonstrating that 3alpha-diol elicits a conditioned place preference (CPP) more effectively than either T or DHT, when administered systemically. In Experiment 2, rats received implants of T, DHT or 3alpha-diol to the NA immediately prior to placement in the CPP apparatus on conditioning days. Implants of T, DHT or 3alpha-diol, but not vehicle, significantly increased time spent on the non-preferred side of the chamber on the test day. This effect was only produced by androgenic stimulation of the shell of the NA and not the core of the NA. Thus, androgen regimens we have previously found to enhance CPP produced the greatest increases in 3alpha-diol concentrations in the NA region and direct implants of T, DHT or 3alpha-diol to the shell, but not the core, of the NA enhanced CPP. These data are consistent with the hypothesis that the hedonic effects of T may be due to actions of its metabolites in the NA.

Evidence for significant differences in microsomal drug glucuronidation by canine and human liver and kidney.

The in vitro glucuronidation of a range of structurally diverse chemicals has been studied in hepatic and renal microsomes from human donors and the beagle dog. These studies were undertaken to improve on the limited knowledge of glucuronidation by the dog and to assess its suitability as a model species for pharmacokinetic studies. In general, the compounds studied were glucuronidated severalfold more rapidly (based on intrinsic clearance estimates) by DLM than by HLM. Intrinsic clearance values for human UGT1A1 and UGT2B7 substrates were an order of magnitude higher in DLM than in HLM (e.g., gemfibrozil: 31 microl/min/mg versus 3.0 microl/min/mg; ketoprofen: 2.4 microl/min/mg versus 0.2 microl/min/mg). There were also drug-specific differences. HLM readily glucuronidated propofol (2.4 microl/min/mg) whereas DLM appeared unable to glucuronidate this drug directly. Regioselective differences in morphine glucuronidation were also apparent. Human kidney microsomes catalyzed the glucuronidation of many xenobiotics, although glucuronidation of the endobiotic bilirubin was not detectable in this tissue. In direct contrast, dog kidney microsomes glucuronidated bilirubin only (no glucuronidation of all other xenobiotics was detected). These preliminary studies indicated significant differences in the glucuronidation of xenobiotics by microsomes from the livers and kidneys of human and dog and should be confirmed using a larger panel of tissues from individual dogs. Early knowledge of the relative rates of in vitro glucuronidation, the UGTs responsible for drug glucuronidation, and their tissue distribution in different species could assist the design and analysis of preclinical pharmacokinetic and safety evaluation studies.

Newer neuromuscular blocking drugs. An overview of their clinical pharmacology and therapeutic use.

Four new nondepolarising muscle relaxants, pipecuronium bromide, doxacurium chloride, mivacurium chloride and Org 9426 (rocuronium) offer alternatives to the established agents atracurium besilate and vecuronium bromide. Pipecuronium and Org 9426 are steroidal compounds, the latter being a monoquaternary agent, whereas doxacurium and mivacurium are bisquaternary benzylisoquinolinium compounds. Pipecuronium and doxacurium have a relatively slow onset and a long duration of action. Pipecuronium produces maximum block in 3 to 6 min when given in a dose of 45 to 80 micrograms/kg, and a duration of clinical relaxation of between 40 and 110 min. Doxacurium is more potent, but is the least rapid and the longest acting relaxant currently available. When administered in doses of 37 to 80 micrograms/kg, it produces maximum block within 3.5 to 10 min, with a duration of clinical relaxation of 77 to 164 min. The advantage of both pipecuronium and doxacurium is their cardiovascular stability. Both agents are primarily eliminated via the kidneys and both have now been licensed for use in the US. Mivacurium is a muscle relaxant with a short duration of action. When administered in doses of 0.1 to 0.25 mg/kg it produces maximum block in 2 to 4 min, but the duration of clinical relaxation is less than 20 min. Higher doses which could induce a faster neuromuscular block are unfortunately associated with some histamine liberation. The drug is metabolised by plasma cholinesterase. Mivacurium has also been licensed for use in the US. Org 9426 is an agent with a rapid onset but an intermediate duration of action. A dose of 0.5 to 0.6 mg/kg induces maximum block in about 1.5 min and has a duration of clinical relaxation of about 30 min. The rapid onset of effect could be useful for early intubation as an alternative to suxamethonium chloride. However, much more clinical experience is needed with this agent, particularly with regard to duration of action of larger doses and occurrence of side effects. The drug is mainly eliminated via the liver.

Pharmacokinetics and pharmacodynamics of pipecuronium bromide (Arduan) in elderly surgical patients.

The neuromuscular response to pipecuronium bromide (Arduan), 70 micrograms/kg, was studied in 20 elderly (greater than 70 yr) and 10 younger patients (less than 60 yr) during nitrous oxide, fentanyl, and droperidol anesthesia. The adductor pollicis response to single 0.2-ms supramaximal pulses was recorded. Although all younger patients were completely paralyzed, 2 of 20 elderly patients did not attain 90% paralysis. Onset time in the elderly was prolonged (6.9 +/- 2.6 vs 4.3 +/- 1.5 min, P less than 0.02). Spontaneous recovery was similar in both groups, with 75% recovery occurring at 133 +/- 52 min in the elderly and 146 +/- 46 min in the younger patients. The pharmacokinetic variables were similar for the two groups, and pharmacodynamic analysis revealed a similar sensitivity at the neuromuscular junction. The pharmacologic actions of pipecuronium in otherwise healthy patients do not differ between young and elderly adults.

[Pharmacokinetics and metabolism of pipecuronium bromide (Arduan)]. / A pipecuronium bromid (Arduan) farmakokinetikája és metabolizmusa.

The pharmacokinetics of pipecuronium bromide (Arduan) studied in animals (rat, dog, cat) and in humans can be described by a two-compartment open model. The elimination half-life in animals was found to be around 40 min, in humans between 44-137 min. The main route of elimination is the excretion of the unchanged molecule in urine. In kidney patients the elimination becomes longer. The metabolism in the elimination is less important, in rats 3-hydroxy-, 17-hydroxy and 3,17-dihydroxy metabolites have been identified.

The pharmacokinetics, urinary and biliary excretion of pipecuronium bromide.

The pharmacodynamics and -kinetics of pipecuronium were studied in 12 patients, six of whom received 100 micrograms kg-1 for laryngectomy (Group L), and six who underwent choledochotomy after insertion of the T-drain and were given 50 micrograms kg-1 (Group C). Onset time and clinical duration were 2.3 and 109 min and 2.8 and 39 min in Groups L and C, respectively. All patients could be sufficiently reversed with neostigmine. Terminal half-lives were 101.5 min (Group L) and 179 min (Group C) in a three-exponent decay; the distribution volumes at steady state 0.339 l kg-1 (Group L) and 0.506 l kg-1 (Group C); the plasma clearance 3.4 ml kg-1 min-1 (Group L) and 2.5 ml kg-1 min-1 (Group C). Within 24 h, 38.6% and 37% were excreted unchanged in the urine and 4.4% and 1% as 3-desacetyl pipecuronium in Groups L and C, respectively. Within 24 h only 2% was excreted into the bile in Group C. Distribution volume and terminal half-life in Group C were positively correlated with pre-operative serum aminotransferase levels (P less than 0.005).

[Comparative pharmacokinetics of pipecuronium bromide, pancuronium bromide and vecuronium bromide in anesthetized man].

The pharmacokinetics of pipecuronium bromide was studied in 9 male patients (ASA class 1-2, 20-65 years of age). Following a single intravenous dose of pipecuronium 0.08 mg.kg-1, plasma levels were measured by capillary gas chromatography. Plasma concentration-time curves were evaluated by fitting the data to a bi-exponential equation. The pharmacokinetic parameters of pipecuronium were compared with those of pancuronium (0.08 mg.kg-1) and vecuronium (0.08 mg.kg-1) previously obtained under the same anesthesia (66% N2O, 33% O2 and 1% halothane). With pipecuronium, following pharmacokinetic parameters were obtained; distribution half-life; T1/2 alpha = 3.9 +/- 0.7 min (mean +/- SEM), elimination half-life; T1/2 beta = 102 +/- 12 min, volume of the central compartment; V1 = 95 +/- 13 ml.kg-1, volume of distribution at steady state; Vdss = 264 +/- 41 ml.kg-1, clearance; Cl = 1.8 +/- 0.2 ml.min-1.kg-1. Microconstants of two-compartment open models (k12, k21, k10) were also calculated. Using Mann-Whitney's U-test, these parameters of pipecuronium were compared with those of pancuronium (n = 3) and vecuronium (n = 4). V1 and Vdss of pipecuronium were significantly larger than those of pancuronium (V1; 38 +/- 12 ml.kg-1 and Vdss; 120 +/- 4 ml.kg-1) (both P less than 0.10). Reflecting the larger central volume of pipecuronium, pipecuronium tended to have a larger clearance than that of pancuroniumu (Cl; 1.1 +/- 0.2 ml.min-1.kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and cardiovascular dynamics of pipecuronium bromide during coronary artery surgery.

The haemodynamic effects of 200 micrograms.kg-1 pipecuronium and pancuronium were compared under etomidate/piritramide anaesthesia in 20 patients scheduled for elective coronary artery surgery. Following the completion of the haemodynamic measurements (ten minutes), anaesthesia was maintained by etomidate/sufentanil infusion. The mean changes in cardiac output were approximately -19 and -2 per cent and in heart rate -1 and +26 per cent for pipecuronium and pancuronium respectively. Plasma and urine concentrations of pipecuronium were also measured and the pharmacokinetic variables obtained indicated rapid initial decrease in plasma concentration (t1/2 = 7.6 minutes) followed by a longer terminal phase (t1/2 = 161 minutes). The central compartment volume was 102 +/- 24 ml.kg-1 and plasma clearance was 1.8 +/- 0.4 ml.kg-1 min-1. Approximately 56 per cent of the dose was recovered from the urine within 24 hours of administration and about 25 per cent of this was the metabolite, 3-desacetyl pipecuronium. High-dose pipecuronium administration under the anaesthetic regimen employed did not produce deleterious haemodynamic effects. The pharmacokinetic variables after bolus injection of pipecuronium did not deviate from those reported under normothermic conditions.

Pharmacokinetics and disposition of pipecuronium bromide in dogs with and without ligated renal pedicles.

The pharmacokinetics of pipecuronium bromide have been studied in anesthetized beagle dogs with and without ligated renal pedicles. A gas chromatographic assay was used to measure the plasma, urine, bile concentrations, and liver content of pipecuronium, the later of which was obtained 8 h after injection. Following an iv bolus injection of 0.1 mg/kg, pipecuronium disappeared from the plasma exponentially with distribution half-lives of 3.9 +/- 1.1 min and 12.7 +/- 9.5 min (mean +/- SD), and elimination half-lives of 44.8 +/- 2.6 min and 196.7 +/- 102.0 min in animals with and without renal pedicle ligation, respectively. Except for the volume of central compartment, all other pharmacokinetic variables differed significantly between the two experimental groups. The elimination half-life was longer (196.7 +/- 102 (SD) vs. 44.8 +/- 2.6 min), plasma clearance slower (5.9 +/- 0.8 ml.kg-1.min-1 vs. 0.9 +/- 0.1 ml.kg-1.min-1) and mean residence time longer (221 +/- 73 vs. 51.1 +/- 1.8 min) in dogs with ligated renal pedicles. Eight hours after injection, the recovery of the parent form of pipecuronium approximated 77% of the administered dose in the urine, 4.5% in the bile, and 3.3% in the liver of normal animals. In animals with ligated renal pedicles 16% of the unchanged pipecuronium was excreted into the bile and 10% of the administered dose was recovered from the liver. Since the total recovery of unaltered pipecuronium approximated 85% of the administered dose in the intact animals, biotransformation seems to play an insignificant role in disposition of this new neuromuscular blocking drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative potency of pipecuronium bromide and pancuronium bromide.

Cumulative dose-response curves were constructed to determine the comparative potency of pipecuronium and pancuronium. From these, the ED50 and ED95 values were calculated. These were 24.96 micrograms kg-1 and 44.96 micrograms kg-1, respectively, for pipecuronium and 30.42 micrograms kg-1 and 61.12 micrograms kg-1, respectively, for pancuronium.

The influence of renal failure on the pharmacokinetics and duration of action of pipecuronium bromide in patients anesthetized with halothane and nitrous oxide.

The authors determined the pharmacokinetics and duration of action of a bolus dose of pipecuronium bromide (0.07 mg.kg-1) in 40 patients anesthetized with halothane and nitrous oxide. Twenty were patients with normal renal function, undergoing a variety of surgical procedures, and 20 were undergoing cadaver renal transplantation because of end-stage renal disease. Plasma concentrations of pipecuronium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by nonlinear regression and fit to a two-compartment or three-compartment model; in addition, the data were analyzed by a non-compartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The pharmacokinetic parameters derived by compartmental modelling were (normal vs. renal failure, respectively): volume of distribution at steady state (309 +/- 103 vs. 442 +/- 158 ml.kg-1, mean +/- SD), plasma clearance, (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (140 +/- 63 vs. 329 +/- 198 min), and elimination half-life (137 +/- 68 vs. 263 +/- 168 min). The same parameters as derived by the non-compartmental method were (normal vs. renal failure, respectively): volume of distribution at steady state (307 +/- 80 vs. 426 +/- 119 ml.kg-1, mean +/- SD), plasma clearance (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (134 +/- 41 vs. 323 +/- 228 min), and elimination half-life (118 +/- 35 vs. 247 +/- 168 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Pipecuronium and pancuronium: comparison of pharmacokinetics and duration of action.

The pharmacokinetics of pipecuronium 0.07 mg kg-1 and pancuronium 0.1 mg kg-1 were compared in 39 ASA class I or II patients. Plasma concentrations of these agents were measured for 6 h following administration, using a sensitive and specific capillary gas chromatographic assay. Concentration v. time data were analysed by non-linear regression and fitted to a two- or three-compartment model as appropriate. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. Pipecuronium had a larger steady-state volume of distribution (Vss) (309 (SD 103) ml kg-1) and greater plasma clearance (Cl) (2.4 (0.6) ml kg-1 min-1) than pancuronium (199 (54) ml kg-1 and 1.5 (0.4) ml kg-1 min-1, respectively). The volumes of the central compartment, distribution and elimination half-lives and mean residence times were similar for both agents and within the range expected for drugs of this type. The durations of action (injection to 25% recovery of twitch tension) of pipecuronium and pancuronium were similar: 98.0 (36.1) min and 117.2 (35.8) min, respectively. We conclude that the time courses of neuromuscular blockade following pipecuronium and pancuronium are similar, despite the differences in Vss and Cl.

Pharmacokinetics and disposition of pipecuronium bromide in the cat.

The pharmacokinetics and hepatic disposition of pipecuronium have been investigated in cats with normal and absent renal function. A combined fluorimetric and chromatographic technique was used to determine the concentrations of pipecuronium and its metabolites in the samples. Following intravenous injection of 150 micrograms kg-1, pipecuronium disappeared from the plasma bi-exponentially with half-lives of 9.8 +/- 5.4, 77.7 +/- 9.7 min and 7.2 +/- 5.0, 100, 6 +/- 23.7 min; the Vd was 362.3 +/- 74.9 ml kg-1 and 123.7 +/- 14.6 ml kg-1 and the clearance was 5.0 +/- 0.9 ml min-1 kg-1 and 1.0 +/- 0.1 ml min-1 in the animals with and without renal function, respectively. In the animals with normal kidney function 53%, 12% and 8% of the administered dose of pipecuronium were recovered within 8 h in the urine, bile and liver, respectively. In 'nephrectomized' cats the lack of renal elimination was to a great extent compensated for by increased hepato-biliary elimination. Absence of renal function significantly altered the pharmacokinetic parameters and prolonged the time-course of the neuromuscular blocking effects of pipecuronium. Neither temporary hepatic exclusion nor intraportal administration of pipecuronium indicated any significant role of the liver in handling pipecuronium. Renal excretion seems to be the predominant route of elimination. No metabolites were found in this study.