The onset of rocuronium, but not of vecuronium or mivacurium, is modified by tourniquet inflation

A previous investigation showed that inflation of a tourniquet did not interrupt onset of vecuronium neuromuscular block. To test the hypothesis that this effect depended on potency, twitch tension was measured in an arm with a tourniquet inflated during onset and compared with a control arm in 30 patients under fentanyl-thiopental-nitrous oxide-isoflurane anesthesia. Patients were randomly allocated to receive either vecuronium 0.1 mg/kg (n = 10), rocuronium 0.6 mg/kg (n = 10), or mivacurium 0.2 mg/kg (n = 10). The electromyographic response of the first dorsal interosseus to single twitch stimulation of the ulnar nerve every 10 s was recorded in both arms. When neuromuscular block was 20% (i.e., twitch tension was 80% of control), the tourniquet was inflated to a pressure of 300 mm Hg. It was deflated 5 min later. In the vecuronium and mivacurium groups, the tourniquet did not influence onset of block. In the rocuronium group, maximum neuromuscular block was (mean +/- SD) 79% +/- 10% in the tourniquet arm, compared with 96% +/- 4% in the perfused arm (P < 0.05). The maximum rate of onset was half that of the perfused arm. The difference in maximum neuromuscular block between arms was 17% +/- 7%, 5% +/- 5%, and 0% +/- 2% in the rocuronium, vecuronium, and mivacurium groups (P < 0.05). To explain that onset of block continues in spite of interruption of blood flow, drug molecules must gain access to the neuromuscular junction via routes other than the circulation. The results of this investigation are consistent with the hypothesis that there is redistribution of drug from extrajunctional to junctional areas during onset of action of muscle relaxants and this process is more important for the more potent drugs (vecuronium and mivacurium) than for rocuronium.     

Perinatal cocaine decreases the expression of prodynorphin mRNA in nucleus accumbens shell in the adult rat

Postpartum patients have decreased plasma cholinesterase activity, which may slow the metabolism of mivacurium. We compared the duration of a mivacurium neuromuscular block in 11 women undergoing postpartum tubal ligation 36-99 h after delivery with that in 11 control women undergoing gynecological surgery. Anesthesia was induced with propofol and fentanyl and maintained with propofol and nitrous oxide. Neuromuscular block was monitored by electromyography, and the ulnar nerve was stimulated transcutaneously using a train-of-four pattern. Patients received a bolus dose of mivacurium 0.15 mg/kg. The median (range) duration of neuromuscular block until 25% recovery of the first twitch response was longer in the postpartum group, 19.4 (15.6-25.2) min, compared with the control group, 16.3 (11.0-23.4) min (P = 0.04). The median (range) plasma cholinesterase activity was decreased in the postpartum group, 4.0 (0.1-5.5) kU/L, compared with the control group, 7.1 (6.2-10.0) kU/L (P < 0.001). The duration of neuromuscular block was inversely correlated with cholinesterase activity (Kendall rank correlation tau = -0.43, P = 0.005). The slight prolongation of neuromuscular block should not be significant clinically. Implications: Postpartum patients have decreased amounts of the plasma cholinesterase enzyme. This would slow the metabolism of the muscle relaxant mivacurium. However, the duration of muscle paralysis is only prolonged by approximately 3 min, which would not normally cause any significant problems.     

The stethoscope. A potential source of nosocomial infection?

OBJECTIVE: To determine the relation between epidural injectate volume (ml/kg of body weight) and its craniad migration in calves and pigs. ANIMALS: 23 neonatal calves and 26 feeder pigs. PROCEDURE: Animals were randomly assigned to receive different volumes of new methylene blue (NMB, 1.2 mg/ml in 0.9% saline solution). Injections were made into the sacrococcygeal intervertebral space in calves and the lumbosacral intervertebral space in pigs, immediately after euthanasia. Sagittal sections of the spine were made at necropsy, and craniad migration of NMB was determined and rounded to the nearest intervertebral space. RESULTS: In calves treated with 0.05, 0.1, or 0.15 ml of NMB/kg, mean +/- SEM number of stained spinal segments was 5 +/- 0.3, 8 +/- 0.6, and 8 +/- 0.6, respectively. Craniad migration of NMB was significantly greater for 0.15 and 0.1 ml/kg volumes versus 0.05 ml/kg. In pigs treated with 0.05, 0.1, 0.2, of 0.3 ml of NMB/kg, mean number of stained spinal segments was 8 +/- 1.1, 8 +/- 0.9, 10 +/- 1.2, and 18 +/- 2.0. Craniad dye migration was significantly greater in the 0.3 ml/kg group versus the 3 lower volume groups. Linear regression performed on both sets of data after logarithmic transformation of spaces migrated to correct for non-normality was significant (P < 0.05), and R2 values of 0.49 and 0.55 were obtained for calves and pigs, respectively. CONCLUSIONS: There is a significant correlation between volume (ml/kg) of NMB injected in the epidural space and its craniad migration in calves and pigs. CLINICAL RELEVANCE: Results provide a basis for determination of volume of injectate to be given to reach a minimal desired level and should be a useful baseline for future investigations of epidural drug administration.     

Gastric and biliary excretion of meperidine in man

The role and importance of enterogastric secretion in the disposition and elimination of the weak base, meperidine (pKa 8.63), was studied after intravenous administration (50 mg) of the drug to 6 normal volunteers. Continuous collection of the gastric fluid over a 4-hr period demonstrated the establishment of high gastric fluid/plasma concentration ratios for meperidine (mean about 50, range, 10 to 200). However, the total amount of drug recovered, even after correction for incomplete collection, was only a small percentage of the administered dose. Under basal conditions a mean +/- SE of 1.9 +/- 0.3 mg, equivalent to 3.7% of the administered dose, was found in the total gastric aspirate. Stimulation of gastric secretion by subcutaneous injection of betazole (1.5 mg/kg) increased this recovery to 3.6 +/- 0.3 mg (7.2%) primarily due to the increase in gastric volumen output. Aspiration of the gastric fluid in either the basal or stimulated situation had no observable effect upon the plasma concentration/time profile of meperidine whether assessed by the terminal half-life, t 1/2 beta, or the plasma clearance; control values were 3.8 +/- hr and 1,190 +/- 130 ml/min, respectively. In 2 subjects "bile fluid" was also collected for 2.5 hr and found to contain less than 0.2% of the administered dose. Enterosystemic recycling is therefore of minor importance in the disposition and elimination of meperidine in man.     

Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus

The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (FTC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (mean +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h/kg, and the oral bioavailability was 90% +/- 8%. The volume of distribution at steady state (Vss) was 1.5 +/- 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowered the Vss to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavailability to 65% +/- 15%. FTC in the brains of rats was initially less than 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.     

Temporal and environmental effects on quinpirole-induced biphasic locomotion in rats

The dopamine D2/D3 agonist quinpirole induces suppression of locomotor activity at low doses, and suppression followed by activation at high doses when given to rats of 30 days of age and older that are immediately placed in activity monitors. The duration of suppression is longer and the level of activation is lower at 60 than at 30 days of age, suggesting that the mechanism responsible for the suppression may play a role in the lesser activation in the older rats. However, habituation limits the ability to measure the duration of locomotor suppression. Therefore, 0, 0.2, or 0.2 mg/kg quinpirole was injected S.C. either 30, 60, or 120 min before placing male or female rats of 30 or 60 days of age in activity monitors for 30 min. At both ages, both doses of quinpirole suppressed activity when the animal was placed in the monitor 30 or 60 min after injection; at 60 days the drug also suppressed activity at 120 min after injection. Previously, 0.2 mg/kg quinpirole elicited locomotor activity 60 min after injection in rats placed immediately in activity monitors at both ages. Thus, not only time after injection but novelty of the environment are critical factors in the expression of locomotor suppression or activation in response to quinpirole.     

Comparison of [123I]beta-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates

The aim of our randomized controlled study was to compare the neuromuscular characteristics of mivacurium and atracurium by evaluating the intubation conditions, intubation times, onset times and the duration of action of these two muscle relaxants using two different dosing principles. Forty-eight patients were included in this study. All patients were premedicated orally with 0.2 mg/kg diazepam. Anaesthesia was induced with 2.0 mg/kg propofol and 0.02 mg/kg alfentanil and maintained with 6 mg/kg/h propofol and 60% nitrous oxide in oxygen. Neuromuscular monitoring was carried out with supramaximal TOF-stimulation (2 HZ) of the ulnar nerve every 10 seconds and recording of the mechanomyogram (MMG) (Myograph 2000, Biometer) at the adductor pollicis muscle. The patients of group 1 (n = 12) received an intubation dose of 0.15 mg/kg mivacurium (2 x ED95) and the patients of group 2 (n = 12) received a priming dose of 0.015 mg/kg mivacurium (20% of ED95) followed by an intubation dose of only 0.07 mg/kg mivacurium (ED95) two minutes later. The patients of group 3 (n = 12) were intubated with 0.46 mg/kg atracurium (2 x ED95) and the patients of group 4 (n = 12) received a priming dose of 0.046 mg/kg atracurium (20% of ED95) and an intubation dose of 0.23 mg/kg atracurium (ED95) four minutes later. The patients were intubated under normocapnic conditions and following stabilisation of the palmar skin temperature after a 90% neuromuscular block (T1) had occurred. The intubation conditions were measured semiquantitatively using an intubation score.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protection afforded by a novel K channel opener (Y-26763), against glycerol-induced acute renal failure (ARF) in rats

Y-26763, a benzopyran derivative, is a newly developed ATp-sensitive K channel opener and has been reported to protect against ischemic acute renal failure (ARF). We examined the effects of Y-26763 on glycerol-induced myoglobinuric ARF in the rats. ARf was induced in 28 adult male Sprague-Dawley rats by hind-limb intramuscular injection of 50% glycerol (5 ml/kg) after 18 hrs of water deprivation. Y-26763, 7 micrograms/kg (GY group, n = 10) of vehicle (G group, n = 12) was given intravenously 15 min before glycerol injection. Glibenclamide (20 mg/kg), a K channel blocker was given prior to Y-26763 injection to see of the effects was due to the K-channel opener (GYG group, n = 6). Animals were sacrificed 24 or 96 hrs after glycerol injection. Y-26763 partially, but significantly, restored renal dysfunction 24 hrs after ARF. Pcr (mg/dl) and Ccr (ml/min), respectively were as follows: G group, 5.7 +/- 0.4, 0.015 +/- 0.006; GY group, 4.1 +/- 0.4, 0.061 +/- 0.027 (p < 0.05). These favorable effects were antagonized by glibenclamide (Pcr in GYG group, 5.4 +/- 0.3 mg/dl, p < 0.05). Renal calcium content was not statistically significant (3.5 +/- 1.2 vs. 3.4 +/- 1.2 micrograms/mg dry weight). Histological examinations revealed that extensive tubular necrosis and cast formation seen in the G group were reduced in the GY group. At the recovery phase, 96 hrs after glycerol injection, Y-26763 accelerated the recovery from ARF as shown in Pcr (mg/dl) and Ccr (ml/min): 4.3 +/- 0.2, 0.05 +/- 0.01 in the G group, 2.8 +/- 0.2, 0.13 +/- 0.02) in the GY group (p < 0.01). In conclusion, Y-26763 partially protected against glycerol-induced ARF.     

Nicotine absorption after pulmonary instillation

Levels of nicotine in plasma were determined by gas chromatography in eight mongrel dogs after instillation of 0.5 mg of nicotine in 100 microL of normal saline at three levels of the tracheobronchial tree: the trachea, a subsegmental bronchus of the right middle lobe, and a subpleural location of the right middle lobe ("distal"). An equivalent dose was given intravenously (iv). Peak of nicotine concentrations in plasma were significantly lower after instillation at the trachea (11.5 +/- 4.4 ng/mL) and the subsegmental bronchus (18.2 +/- 5.0 ng/mL) than after an iv dose (30.3 +/- 10.7 ng/mL); p < 0.05 for each comparison. In addition, the peak concentration after instillation at the trachea was significantly lower than that after instillation at the distal site (22.1 +/- 6.2 ng/mL, p < 0.05). Time to peak concentration was significantly longer after tracheal instillation (5.3 +/- 3.0 min) than after subsegmental instillation (2.0 +/- 0.0 min) or iv infusion (2.0 +/- 0.0 min); p < 0.05 for each comparison. Total drug absorbed, half-life, and clearance were equivalent from all four sites. This study demonstrated that quantitative absorption of nicotine from the described lung sites is equivalent to that after an iv dose, with slower absorption and lower peak concentrations from the tracheal site.     

cAMP analogues downregulate the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in human bone marrow stromal cells in vitro

STUDY OBJECTIVE: To determine the neuromuscular blocking effect and recovery profile of cisatracurium besylate in children after administration of a bolus dose that was twice the estimated dose required to produce 95% of the maximum effect (2 x ED95; 0.08 mg/kg) followed by an infusion during halothane-nitrous oxide anesthesia. STUDY DESIGN: Open-label study. SETTING: Teaching hospital. PATIENTS: 30 male and female (ASA physical status I and II) patients, 2 to 10 years of age, scheduled for elective surgery of low to moderate risk. INTERVENTIONS: After induction of general anesthesia, patients received cisatracurium 0.08 mg/kg administered over 5 to 10 seconds. For surgical procedures requiring neuromuscular block for at least 60 minutes, a second bolus dose of cisatracurium 0.02 mg/kg was administered after the first response to a train-of-four stimuli (T1) recovered to 25% of baseline. When T1 was 5% of baseline after the second dose, a 3 microg/kg/min infusion of cisatracurium was initiated and titrated to maintain 89% to 99% block for the duration of the surgery. For procedures requiring neuromuscular block of less than 60 minutes, one or more maintenance doses of 0.02 mg/kg cisatracurium were administered when T1 was 25% of baseline after the preceding dose. In 10 patients, recovery was facilitated with edrophonium 1.0 mg/kg administered when T1 was 26% to 48% of the final baseline. MEASUREMENTS AND MAIN RESULTS: Evoked muscular response at the adductor pollicis was measured by electromyography. With 0.08 mg/kg, onset time (mean +/- SEM) was 4.1 +/- 0.4 minutes, and clinically effective duration was 27.3 +/- 0.9 minutes. Mean 5% to 95% and 25% to 75% recovery indices were 28.4 +/- 2. 7 minutes and 11.2 +/- 0.8 minutes, respectively. The mean infusion rate necessary to maintain 89% to 99% T1 suppression for 17 to 145 minutes was 1.7 microg/kg/min. After termination of infusion, the mean 5% to 95% and 25% to 75% recovery indices were similar to those after a single bolus dose, and time to 95% recovery was 30.4 +/- 3.0 minutes. After administration of edrophonium, full recovery (T4:T1 > or = 70%) occurred in 1.5 +/- 0.4 minutes. No clinically significant changes in heart rate or blood pressure were noted during the first 5 minutes after administration of cisatracurium 0.08 mg/kg. CONCLUSIONS: Cisatracurium provided maximal neuromuscular block, cardiovascular stability, and predictable recovery at the doses tested. In view of this finding, cisatracurium should be a useful intermediate-duration neuromuscular blocking drug for children during general anesthesia.     

Measuring muscle relaxation with mivacurium in comparison with mechano- and electromyography

Based on survey of the literature, methodological problems of electromyographic and mechanomyographic neuromuscular monitoring are presented. Often mechanomyography (MMG) is accompanied by mechanical problems during the registration of the contractions in the operating theatre. In contrast to mechanomyography the registration of electromyographic signals is easier whereas the processing of electromyographic signals is more difficult. In the operating theatre, registration problems can also occur with electromyography (EMG) from artefacts arising from stimulation impulses, high frequency apparatus and alternating current. During neuromuscular monitoring using MMG, a positive drift of the amplitudes of the contractions can be observed, whereas EMG leads to a negative drift of the amplitudes of the action potentials. Both observations can lead to misinterpretation of the degree of neuromuscular block measured by single twitch stimulation during the recovery period. Both the positive and negative drifts can be prevented by single twitch stimulation lasting for up to 10 minutes before the start of the neuromuscular monitoring of the effect of a given dose of a muscle relaxant. Finally, a clinical study of simultaneous registration of the MMG at the M. adductor pollicis and of the EMG at the M. interosseus dorsalis DI under total intravenous anaesthesia using propofol and alfentanil and muscle relaxation with a bolus dose of 75 mg/kg mivacurium is described. During the mechanomyographic studies, a decrease in the preload by an average of 1.2 Newton (N) with a maximum level of 4.0 N occurred. The decrease in preload was less than 25%. The mechanomyographically measured onset time of an ED95 of mivacurium amounted to 3.5 +/- 1.2 minutes on average and the degree of maximum neuromuscular block on average (95.1 +/- 5.6%) tallied very well with the expected value of 95.0%. The electromyographically measured onset time of an ED95 of mivacurium amounted to 4.3 +/- 1.2 minutes on average and the degree of maximum neuromuscular block amounted to only 91.3 +/- 8.1% on average. A comparison of the mechanomyographic values and the electromyographic values leads to the following results: the MMG showed a significantly shorter onset time (p < 0.0001) and a significantly deeper maximum neuromuscular block (p = 0.0004) than the EMG. There were also significant differences between mechanomyographically and electromyographically measured recovery values regarding T1(75) (p = 0.0007), T1(90) (p < 0.0001), TOF0.8 (p = 0.0386) and T1(25-75) (p < 0.0001). On average, an ED95 of mivacurium showed a significantly slower recovery in the mechanomyogram than in the electromyogram.     

An infant with 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase deficiency presenting with typical neonatal hepatitis syndrome: the first Japanese case

We investigated the in vivo effects of thalidomide on the production of tumor necrosis factor-alpha (TNF-alpha). An in vivo systemic release of TNF-alpha occurred after the injection of lipopolysaccharide (LPS) in male ddY mice, and the TNF-alpha serum levels reached 652.2 +/- 75.7 pg/ml 90 min after the injection of LPS (0.3 mg/kg, i. p.). When thalidomide (1, 3, or 6 mg/kg) was administered intraperitoneally 3 h before the injection of LPS (0.3 mg/kg, i. p.), thalidomide markedly enhanced LPS-induced TNF-alpha release in a dose-dependent manner. The TNF-alpha serum levels at 90 min were 640 +/- 58.6, 1985 +/- 132.6, and 2795 +/- 203.5 pg/ml, respectively, compared to 628.6 +/- 64.4 pg/ml in mice treated with LPS-alone. Pretreatment with a single injection of thalidomide (1, 3, or 6 mg/kg, i. p.) dose-dependently increased the subsequent mortality caused by a challenge with LPS (15 mg/kg, i. p.), a dose that caused death in 10% of the control mice. We conclude that thalidomide enhances in vivo TNF-alpha secretion and the lethality of LPS in mice.     

Pharmacokinetics and pharmacodynamics of mivacurium stereoisomers in beagle dogs using twitch height and train-of-four response

Mivacurium, a non-depolarizing neuromuscular blocking agent, consists of three isomers; trans-trans (57%), cis-trans (36%) and cis-cis (7%). The purpose of this study was to characterize the pharmacokinetics and pharmacodynamics of mivacurium after various inputs. Four beagle dogs weighing between 7.95 and 9.89 kg were anesthetized with isofluorane (5%) and received a bolus dose (0.010-0.020 mg kg(-1)) and two constant rate infusions (1.0-1.5 microg kg(-1) min(-1)) of mivacurium via the saphenous vein. Single twitch height (TH) and train-of-four (TOF) were evaluated every 15 and 30 s, respectively. Arterial blood samples were collected, processed and analysed for mivacurium using a stereospecific HPLC-fluorescence method. The disposition of mivacurium isomers was best described by a two compartment model. Mean Cl for the cis-trans, trans-trans and cis-cis isomers were 19.98, 13.53 and 3.47 mL min(-1) kg(-1) respectively and the corresponding mean Vdss were 0.29, 0.24 and 1.00 L kg(-1). The measurement of onset showed dose dependence as evidenced by a rapid onset at the higher doses. TOF measurements were more sensitive to the onset of action and required a longer period of time to recover to baseline values as compared with TH measurements.     

Use of a new Russian antihypertensive drug dilazin in surgery of the coronary arteries and abdominal aorta

Dilazin in a dose of 0.2 mg/kg/min (n = 20) and 0.4 mg/kg/min (n = 20) was used to normalize arterial blood pressure during and after surgery. Intravenous infusion of the drug decreased the arterial pressure to baseline values within 2-3 min by reducing the elevated systemic vascular resistance. Dilazin did not affect the heart rate, mean pulmonary capillary wedge pressure, or central venous pressure. The drug brought about a marked increase of cardiac output and cardiac index. Prompt effect and easy control, when dilazin is infused in a dose of 0.2 to 0.4 mg/kg/min, recommend it as an alternative antihypertensive agent to be used during various procedures.     

Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus

(2'R,5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/- 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 mg/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33% +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% +/- 7% of the radiolable in the )- to 48-h urine. Small amounts of the 3' -sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.     

Pharmacokinetics of mivacurium isomers and their metabolites in healthy volunteers after intravenous bolus administration

BACKGROUND: Previous studies report the pharmacokinetics of mivacurium isomers after an infusion using venous blood sampling. Although the extent of the mivacurium arterial-venous gradient is not known, the sampling site is likely to influence mivacurium pharmacokinetic parameters because the drug is rapidly metabolized as it traverses the circulation. The objectives of this study were (1) to determine the pharmacokinetics of mivacurium isomers in healthy persons after intravenous bolus administration using intensive arterial blood sampling, and (2) to characterize the formation and elimination of mivacurium metabolites in human plasma. METHODS: Eight persons classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled to undergo elective surgery under balanced anesthesia received 0.15 mg/kg mivacurium chloride as an intravenous bolus. Arterial blood samples were collected every 10 s during the first 2 min and at frequent intervals for 4 h thereafter. Plasma concentrations of mivacurium isomers and their metabolites were determined by two stereoselective high-performance liquid chromatographic methods coupled with fluorometric detection and noncompartmental pharmacokinetic parameters. RESULTS: Mean elimination half-lives of the trans-trans, cis-trans, and cis-cis isomers were 2.4, 2, and 28.5 min, respectively, with corresponding mean plasma clearances of 29.2, 45.7, and 6.7 ml.min 1.kg-1. The volumes of distribution at steady state of the trans-trans, cis-trans, and cis-cis isomers were 0.047, 0.054, and 0.189 l/kg, respectively. Plasma concentrations of monoester and alcohol metabolites peaked 25 s (median) after mivacurium injection, with half-lives in the range of 90 min, except for the cis alcohol metabolite, which was only negligibly and transiently formed. CONCLUSIONS: Substantial hydrolysis of mivacurium isomers by cholinesterases was confirmed by the rapid appearance of mivacurium metabolites in plasma. The intensive arterial sampling proved to be critical for the trans-trans and cis-trans isomers because the area under the curve between 0 and 2 min accounted for 75% and 86% of the total, respectively.     

MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias

We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.     

Plasma clearance of cholyl-lysyl-fluorescein: a pilot study in humans

BACKGROUND/AIMS: Cholyl-lysyl-fluorescein is a fluorescent analogue of the natural bile acid, cholyl glycine. In vivo and in vitro studies showed that this analogue has many biological characteristics similar to cholyl glycine. In this study we analysed cholyl-lysyl-fluorescein plasma clearance in six healthy volunteers as a potential quantitative liver function test. METHODS: The compound in water for injection was administered as an i.v. bolus in the dose of 0.02 mg/kg b.w. RESULTS: The plasma elimination curve showed rapid, intermediate and slow phases of clearance. Half-life (T1/2 time) for the first (t1/2 1st phase), second (t1/2 2nd phase) and third (t1/2 3rd phase) phases of elimination was 1.7+/-0.9 min, 6.7+/-1.6 min and 68+/-17 min, respectively. Ninety-minute plasma retention (% dose/l plasma) was 2.2%. Cholyl-lysyl-fluorescein volume of distribution and residual fluorescence after 60 min were similar to the data obtained by others for natural or radiolabelled bile acids. In five out of six healthy volunteers a 25-fold higher dose of cholyl-lysyl-fluorescein (0.5 mg/kg b.w.) was injected to estimate the safety margins of the compound. This dose was eliminated at a disappearance rate similar to that of the dose of 0.02 mg/kg b.w. and did not cause any adverse reactions. Serum liver tests measured before and after injection did not change significantly. CONCLUSIONS: This study showed that cholyl-lysyl-fluorescein clearance is similar to the clearance of endogenous natural bile acids and may potentially offer a new, dynamic test of liver function.     

Potentiation of mivacurium by rocuronium is age- and time-dependent: a study in children, adolescents, and young and elderly adults

Potentiation occurs when the steroidal muscle relaxant, rocuronium, is coadministered with the benzylisoquinolinium relaxant, mivacurium. The effect of time and age on this interaction was evaluated in four predetermined groups: children, adolescents, young adults, and elderly adults (15 per group) by monitoring the ulnar nerve-evoked force of contraction of the adductor pollicis (twitch response). During recovery from paralysis induced by 800 micrograms/kg of rocuronium, an infusion of mivacurium was started and maintained for at least 90 minutes to retain the twitch response at 1% to 9% of baseline tension (95 +/- 4% paralysis). Rocuronium at 600 micrograms/kg induced greater than 95% paralysis in 57 of the 60 patients within 2.2 +/- 0.4 (mean +/- SE) minutes. The period of recovery from rocuronium-induced paralysis to 5% of baseline twitch height was longest in the elderly (30.1 +/- 2.9 minutes) and shortest in the adolescents (16.5 +/- 2.4 minutes). The mivacurium infusion requirements to maintain 95 +/- 4% paralysis was highest in children and progressively increased with time. In young and elderly adults, the infusion rates remained lower than that of children and did not change with time. The incidence of satisfactory spontaneous recovery within 20 minutes (train-of-four ratio > 75%) was the highest in children, followed by adolescents and young adults, and was least in the elderly. The residual neuromuscular effect of rocuronium on the subsequent mivacurium infusion was most pronounced in the elderly, followed by young adults, then adolescents, and was least in children.     

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.