An open-label study of the safety and tolerability of converting stable liver transplant recipients to neoral

STUDY OBJECTIVES: (1) To compare the dose-response relations of rocuronium and vecuronium in healthy adult patients anesthetized with nitrous oxide-oxygen-fentanyl-thiopental; and (2) to evaluate the time-course of action of two drugs following equipotent doses. DESIGN: Prospective, randomized, clinical comparison. SETTING: Operating room, Plastic Surgery Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College. PATIENTS: 60 ASA physical status I patients, aged 17-51 years, scheduled for elective plastic surgery. INTERVENTIONS: All patients were randomly assigned to either the rocuronium or vecuronium group. General anesthesia was induced with thiopental 4 to 6 mg/kg and fentanyl 2 to 4 micrograms/kg intravenously (i.v.), and maintained with 60% nitrous oxide (N2O) in oxygen. Further increments of thiopental or fentanyl were given as required. The dose-response relations of rocuronium and vecuronium were determined by the cumulative dose-response technique. MEASUREMENTS AND MAIN RESULTS: Neuromuscular function was assessed mechanomyographically with train-of-four (TOF) stimulation at the wrist every 12 seconds. The percentage depression of first twitch (T1) was used as the study parameter. The cumulative dose-response curve of vecuronium was shifted to the left in a parallel fashion compared with that of rocuronium. As assessed by linear regression, the potency ratio of vecuronium: rocuronium was 1:7.2. There were significant differences in the ED50, ED90, and ED95 between the two drugs. After i.v. administration of equipotent doses of both drugs (2 x ED90), the duration of peak effect, clinical duration, recovery index, and total duration were not significantly different between the two drugs. CONCLUSIONS: Compared with vecuronium, rocuronium is a low-potency, nondepolarizing relaxant, and its neuromuscular blocking potency is approximately 15% that of vecuronium in adult patients anesthetized with N2O and fentanyl. Following equipotent doses, the time-course of recovery for rocuronium is similar to that of vecuronium.     

Dose-response relationships for edrophonium and neostigmine antagonism of rocuronium bromide (ORG 9426)-induced neuromuscular blockade

BACKGROUND: Rocuronium bromide (ORG 9426) is a new nondepolarizing muscle relaxant with a rapid onset but an intermediate duration of action. The dose-response relationships for neostigmine and edrophonium were studied during antagonism of neuromuscular block induced by rocuronium bromide. METHODS: Sixty-four ASA physical status 1 or 2 adults were given 0.6 mg/kg rocuronium bromide during thiopental-fentanyl-nitrous oxide-isoflurane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 10% of its initial control value, edrophonium (0.1, 0.2, 0.4, or 1 mg/kg) or neostigmine (0.005, 0.01, 0.02, or 0.05 mg/kg) was administered by random allocation. Neuromuscular function in another eight subjects was allowed to recover spontaneously. Assisted recovery was defined as actual recovery minus mean spontaneous recovery in patients who were not given antagonists. RESULTS: The dose-response curves for neostigmine- and edrophonium-assisted antagonism of rocuronium bromide neuromuscular blockade for the single twitch and TOF ratio were not parallel. The doses of neostigmine required to achieve 50% and 80% recovery (ED50 and ED80, respectively) of the first twitch after 10 min were 0.017 (0.001) and 0.033 (0.001) mg/kg (mean (standard error of estimate for the mean)), respectively. Corresponding ED50 and ED80 values for edrophonium were 0.161 (0.001) and 0.690 (0.001) mg/kg, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 9.5 (0.56) and 21 (0.67) for first twitch ED50 and ED80 height, respectively. The calculated doses producing ED50 of the TOF ratio at 10 min were 0.017 (0.001) and 0.469 (0.001) mg/kg for neostigmine and edrophonium, respectively. These values corresponded to a potency ratio of 27.5 (1.66). CONCLUSIONS: Under the conditions described in this study, if reversal was attempted at 10% first twitch recovery, edrophonium was less capable than neostigmine of reversing fade (potency ratio of 19.2 and 27.5 at 5 and 10 min, respectively) than first twitch (potency ratio of 6.7 and 9.5 at 5 and 10 min, respectively) during antagonism of rocuronium bromide-induced blockade. Edrophonium was found to be less effective than neostigmine at reversing rocuronium bromide-induced TOF fade.     

Neuromuscular interaction between cisatracurium and mivacurium, atracurium, vecuronium or rocuronium administered in combination

We compared the dose-response relationships of cisatracurium, mivacurium, atracurium, vecuronium and rocuronium and examined the interactions of cisatracurium with mivacurium, atracurium, vecuronium and rocuronium in humans by isobolographic and fractional analyses. We studied 180 adult patients during nitrous oxide-fentanyl-propofol anaesthesia. Neuromuscular block was monitored using mechanomyography to detect the twitch response of the ulnar nerve at the wrist. The dose-response curves were determined by probit analysis. The calculated ED50 values and their 95% confidence intervals were 40.9 (38.1-43.7), 49.8 (47.0-52.6), 187.2 (175.1-199.3), 36.6 (34.7-38.5) and 136.4 (129.2-143.6) micrograms.kg-1 for cisatracurium, mivacurium, atracurium, vecuronium and rocuronium, respectively. Corresponding ED95 values were 57.6 (53.5-61.7), 91.8 (88.1-95.5), 253.1 (238.9-267.3), 52.9 (49.1-56.7) and 288.7 (276.2-301.2) micrograms.kg-1, respectively. The interaction between cisatracurium and mivacurium, vecuronium or rocuronium was found to be synergistic, but the interaction between cisatracurium and atracurium was found to be additive. Synergy between cisatracurium and vecuronium or rocuronium was greater than between cisatracurium and mivacurium.     

Ranitidine reverses gallamine paralysis in rats

The effect of ranitidine on gallamine-induced depression of twitch tension was evaluated in urethane-anaesthetized and mechanically ventilated male Sprague-Dawley rats. Gallamine was administered as an intravenous (IV) bolus and constant rate infusion in 15 rats to maintain 89 +/- 7% (SE) depression of twitch tension induced by electrical stimulation of a sciatic nerve. Ranitidine, IV at either 0.5, 1, 2.5, 5, or 10 mg/kg, was then administered into groups of three rats. Ranitidine produced an immediate dose- and serum concentration-dependent reversal (antagonism) of the twitch tension depression induced with gallamine. The reversal was observed within approximately 30 s and was maintained for 3-26 (12 +/- 2) min. The dose of ranitidine that produced 50% reversal was 2.9 +/- 0.1 mg/kg, and this reversal was associated with a ranitidine serum concentration of 5.2 +/- 0.3 micrograms/mL. Ranitidine administered alone (and without gallamine) did not alter twitch tension at either 2.5 or 20 mg/kg. In addition, ranitidine did not alter either the gallamine neuromuscular blocking concentration in serum or the serum clearance of gallamine. Ranitidine reverses the neuromuscular action of gallamine, and this effect of ranitidine is not due to a pharmacokinetic interaction between ranitidine and gallamine.     

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.     

Resistance to atracurium in rats with experimental inflammation: role of protein binding

The influence of altered protein binding on the neuromuscular effect of atracurium has been studied in rats with experimental inflammation induced by subcutaneous injection of turpentine oil. Doses of atracurium ranging from 0.45 to 1.5 mg.kg-1 were administered to control (n = 30) and to experimental inflammation induced rats (n = 30). Neuromuscular transmission was monitored by recording the twitch tension of the tibialis-anterior muscle elicited by stimulation of the sciatic nerve. Three effect parameters were recorded: (i) intensity of the effect, measured as percentage depression of baseline twitch tension, (ii) duration of drug action (min) and (iii) recovery time (min). The dose-intensity of the effect relationship was modelled using a sigmoid Emax model. The ED50 (effective dose eliciting 50% of the maximum effect) was significantly increased (P < 0.01) in the inflammation group as compared to the control group (0.94 vs. 0.68 mg.kg-1). This change was reflected in a shift of the dose-response curve to the right in the pretreated rats. For equipotent doses ED95 (defined as the effective dose eliciting 95% of maximum effect), no differences were found in recovery time and duration of action between the two groups of rats. Mucoproteins levels (index of alpha 1-acid glycoprotein (AAG) and protein binding were significantly increased in rats with experimental inflammation as compared to control rats. Based on these results, altered serum protein binding of atracurium appears to be responsible, at least in part, for the resistance to atracurium.     

Isobolographic and dose-response analysis of the interaction between pipecuronium and vecuronium

We have studied the neuromuscular effects of pipecuronium, vecuronium and their combination in 130 ASA group I or II patients. Patients were anaesthetized with 0.8% halothane and 60% nitrous oxide in oxygen. Neuromuscular block was recorded as the evoked thenar mechanomyographic response to train-of-four stimulation of the ulnar nerve (2 Hz at 10-s intervals). The dose-response curves were determined by probit analysis. The calculated doses producing 50% depression of the first twitch height were 15.6, 16.9 and 15.0 micrograms kg-1 for the pipecuronium, vecuronium and pipecuronium-vecuronium combination groups, respectively. Isobolographic and algebraic (fractional) analyses were used to assess quantitatively the combined neuromuscular effect of pipecuronium and vecuronium and to define the type of interaction between these drugs. The interaction between pipecuronium and vecuronium was found to be additive.     

The acute effect of minocycline on the pericardium: experimental and clinical findings

To evaluate the influence of acute isovolemic hemodilution on the dose-response and time course of action of vecuronium, we studied 60 adult patients with and without hemodilution during surgery. The patients with hemodilution underwent major elective plastic surgery with an anticipated surgical loss of more than 600 mL. Anesthesia was induced with thiopental 4-6 mg/kg and fentanyl 2-4 microg/kg i.v. and was maintained with 60% nitrous oxide in oxygen. Further increments of thiopental 2 mg/kg or fentanyl 2 microg/kg were given as required. Acute isovolemic hemodilution in the hemodilution group was induced by drainage of venous blood and an i.v. infusion of lactated Ringer's solution and 6% dextran, during which hematocrit and hemoglobin decreased from 45.7% to 26.2% and from 148.5 g/L to 90.2 g/L, respectively. Neuromuscular function was assessed mechanomyographically with train-of-four stimulation at the wrist every 12 s, and the percent depression of T1 response was used as the study parameter. The dose-response relationships of vecuronium in the two groups were determined by using the cumulative dose-response technique. The results showed that during hemodilution, the dose-response curve of vecuronium was shifted to the left in a parallel fashion, and the potency of vecuronium was increased. There were significant differences in the 50%, 90%, and 95% effective doses between the two groups. After the i.v. administration of vecuronium 80 microg/kg, vecuronium-induced neuromuscular block was significantly longer in the patients with hemodilution than in the control patients. The duration of peak effect, clinical duration, recovery index, and total duration in the hemodilution patients were significantly different from those in the control patients. We conclude that hemodilution induces significant changes in the pharmacodynamics of vecuronium. Implications: We found that patients with hemodilution were 20% more sensitive to vecuronium and had a longer duration of action after the administration of the same dose than the controls. This should be taken into account when vecuronium is used as a muscle relaxant during acute hemodilution.     

Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT1A agonists

Previous studies [Meller et al. (1990) Mol. Pharmacol., 37:231-237] have shown that a large receptor reserve exists for the inhibition of serotonin synthesis in rat cortex and hippocampus by the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), whereas little or no reserve exists for the lower efficacy agonists ipsapirone and BMY 7378. The current studies were undertaken to determine if the above drugs exhibit similar relative efficacies and receptor reserves in an electrophysiological model of 5-HT1A receptor activation, i.e., the inhibition of dorsal raphe cell firing. Intravenous dose-response curves were constructed in untreated control rats, or in rats which received an injection of the irreversible receptor inactivator N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 6 mg/kg, s.c.) 24 hours before recording. All three drugs fully inhibited dorsal raphe cell firing in control rats (ED50's: 1.5 micrograms/kg, 8-OH-DPAT; 30.0 micrograms/kg, ipsapirone; 17.5 micrograms/kg, BMY 7378). However, unlike effects on serotonin synthesis, EEDQ treatments caused no depression of the maximal inhibitory response for any of the agonists, although all dose-response curves were shifted to the right (ED50's: 10.1 micrograms/kg, 6.7-fold shift, 8-OH-DPAT; 139.9 micrograms/kg, 4.7-fold shift, ipsapirone; 53.8 micrograms/kg, 3.1-fold shift, BMY 7378). Although the order of agonist efficacies was similar for both inhibition of serotonin synthesis and dorsal raphe cell firing (8-OH-DPAT > ipsapirone > BMY 7378), a large (> 50%) receptor reserve was estimated for all three drugs in this electrophysiological system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of 5-HT1A receptors potentiates the clonidine inhibitory effect in the locus coeruleus

Using in vivo extracellular recordings, we have examined the effect of the application of the prototypical 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), on the firing rate of locus coeruleus neurons. 8-OH-DPAT (1 microgram/kg, i.v.) did not modify the basal activity of the locus coeruleus but shifted to the left the dose-response curve for the clonidine induced inhibition of firing rate and reduced the corresponding ED50 by 77%. 2-[2-[4-(o-methoxyphenyl)piperazin-1-yl]ethyl]-4,4-dimethyl-1,3(2H ,4H)-isoquinolinedione (ARC 239; 75 micrograms/kg, i.v.), and chlorpromazine (75 micrograms/kg, i.v.) also shifted to the left the dose-response curve for clonidine and reduced by 38 and 46%, respectively, the ED50, while slightly increasing the basal firing rate. The results indicated that 5-HT1A receptors may modulate the responses mediated by alpha 2A-adrenoceptors in the locus coeruleus.     

In vitro metabolic N- and C-oxidation of phenanthridine

In order to compare an acceleromyograph (TOF-Guard) with a mechanomyograph (Grass FT03), the dose-response relationship of rocuronium was simultaneously determined in both arms of 15 children aged 3-11 years during anaesthesia with thiopentone, alfentanil and nitrous oxide. Three subgroups of five children received rocuronium 120, 180 or 240 micrograms.kg-1 randomly. The effective doses to produce 50% and 95% depression of the first twitch of the train-of-four determined by acceleromyography were 206 and 337 micrograms.kg-1, respectively, while these values determined by mechanomyography were 151 and 331 micrograms.kg-1, respectively. The dose-response curve obtained by acceleromyography was steeper and shifted to the right compared with that obtained by mechanomyography (p < 0.0001). The difference between the effective dose producing 50% twitch depression determined by the two devices was highly significant (p < 0.0001). In 13 out of 15 children, the acceleromyograph control train-of-four ratio was significantly greater than unity. Although there was a good correlation (r = 0.85) between simultaneous pairs of measurements of neuromuscular block, the acceleromyograph exhibited a bias of -25% relative to the mechanomyograph with wide limits of agreement (-62 to +12%). We conclude that acceleromyographic and mechanomyographic measurements should not be used interchangeably when determining the potency of muscle relaxants.     

The haemodynamic effects of rocuronium and vecuronium are different under balanced anaesthesia

BACKGROUND: Rocuronium has been reported to have minimal haemodynamic effects. However, this conclusion has been drawn primarily from investigations conducted under narcotic-based anaesthesia. This study was designed to evaluate the cardiovascular effects of rocuronium under isoflurane/N2O/fentanyl anaesthesia and to compare rocuronium's haemodynamic effects to those of vecuronium and pancuronium. METHODS: Anaesthesia was induced with fentanyl 2 micrograms/kg, thiopentone 4 mg/kg, and suxamethonium 0.5 mg/kg in 75 ASA I or II patients. After tracheal intubation, anaesthesia was maintained with isoflurane 0.5% and N2O 50% in oxygen. Five min after intubation (baseline), patients randomly received either vecuronium 100 micrograms/kg, rocuronium 600 micrograms/kg, rocuronium 900 micrograms/kg, rocuronium 1200 micrograms/kg, or pancuronium 140 micrograms/kg. One min after administration of muscle relaxant, mean arterial pressure (MAP) and heart rate (HR) were recorded and were subsequently measured at 1-min intervals for the next 4 min. RESULTS: HR decreased significantly (P < 0.05) at all times compared to baseline in patients receiving vecuronium. HR significantly (P < 0.05) increased in those receiving rocuronium 1200 micrograms/kg or pancuronium. Patients who received vecuronium had a significant (P < 0.05) decrease in MAP at all times compared to baseline. Comparing results between groups, patients who received rocuronium or pancuronium had significantly (P < 0.05) higher MAP compared to those administered vecuronium. CONCLUSION: The haemodynamic effects of rocuronium and vecuronium are different under balanced anaesthesia. Rocuronium may attenuate the fall in MAP that often occurs under balanced anaesthesia without surgical stimulation.     

Peripheral morphine analgesia: synergy with central sites and a target of morphine tolerance

Morphine injected s.c. in the tail is a potent analgesic in the tail-flick assay when the radiant heat source is focused directly over the injection site (ED50, 4.5 micrograms), but not if the radiant heat source is moved 1 cm proximally or distally to the injection site. Naloxone given systemically reverses this peripheral analgesia. Antisense oligodeoxynucleotides directed against exons 1 and 4 of MOR-1, a cloned mu opioid receptor, administered intrathecally (i.t.) block the local analgesic effect of morphine in the tail, indicating that the local response is mediated through mu receptors located on the terminals of sensory neurons from the dorsal root ganglia. Combinations of morphine given locally in the tail and spinally (i.t.) are synergistic. Spinal morphine also synergizes with systemic morphine in analgesia assays. Supraspinal morphine enhances systemic morphine analgesia, but less dramatically. We also examined tolerance on these analgesic systems by using a daily morphine injection paradigm which shifts the dose-response curve for systemic morphine approximately 2-fold after 5 days. In this paradigm, morphine's analgesic potency after either supraspinal or spinal administration alone does not change. However, the dose-response curve for local morphine in the tail is shifted by over 19-fold. The analgesic activity of the combination of supraspinal and systemic morphine is lowered approximately 2-fold and the combination of i.t. and systemic morphine by 12-fold. These studies confirm the presence of a peripheral mechanism for morphine analgesia mediated by mu receptors located on sensory neurons from the dorsal root ganglia, which is extremely sensitive to chronic morphine dosing.     

Labelled decamethonium in cat muscle

1 Tritium-labelled decamethonium was infused intravenously in 12 cats at final rates of 1.3-4.2 nmol kg-1 min-1 to produce a steady plasma concentration which ranged between 0.21-1.3 mumol/l in different experiments. Muscle contractions were elicited by nerve stimulation and the potential at the end-plate regions of superficial fibres was recorded by extracellular electrodes. 2 Under these conditions, it was not possible to obtain a steady degree of neuromuscular block. The initial decrease in muscle contractions was followed by recovery towards the original value although the concentration of decamethonium in the plasma remained constant, or in some cases rose. The initial depolarization of the end-plate region also waned during the constant infusion of the drug. 3 Once the twitch tension had returned to control values during infusion of the drug, prolongation of the infusion for a total of four hours did not produce a secondary neuromuscular block. 4 Scintillation counting showed that during infusion of labelled decamethonium the radioactivity of the muscles increased progressively with time. The uptake was less in the soleus muscle than in the fast-contracting flexor longus digitorum and extensor longus digitorum muscles. Muscles which had been denervated 12-13 days previously showed a greater uptake of labelled drug than control muscles from the contralateral limb. 5 The labelled drug was localized by autoradiography of frozen sections of leg muscles following intra-arterial injection of decamethonium. Grain counts in individual fibres showed that small amounts of decamethonium had entered the muscle fibres along their entire length, and there was increased uptake of the drug into the cell in the region of the end-plate. 6 The mechanisms underlying the waning of the pharmacological response during constant application of depolarizing drugs are discussed.     

Benzydamine protection in a mouse model of endotoxemia

OBJECTIVE: Previous studies have shown that benzydamine (40 mg/kg s.c.) is able to inhibit tumor necrosis factor (TNF) production and to reduce mouse lethality when administered before or concomitantly with LPS. The present study was designed to further investigate benzydamine activity against LPS-induced toxicity in terms of potency and therapeutic effects. METHODS: Female Balb/c mice were used. A dose-response curve of animal lethality versus endotoxin dose was performed (LD50 = 45 micrograms/mouse). Therapeutic effects were studied selecting the dose of LPS to achieve an LD100 (160 micrograms/mouse). Mortality was assessed daily and mice were followed for 8 days. The potential mode of action of therapeutically administered benzydamine was also investigated. TNF alpha and IL-1 beta levels were measured, at 5 h after LPS injection, both in sera and in lungs. Moreover, the drug was assayed in a TNF-dependent cytoxicity test. RESULTS: Benzydamine, administered at 20 mg/kg s.c. simultaneously with the endotoxin, significantly increased LPS LD50 up to 230 micrograms/mouse (p < 0.05). Moreover, the drug significantly protected mice against LPS-induced lethality when administered either 30 min or 4 h after endotoxin injection (p < 0.001). Benzydamine, therapeutically administered at 20 mg/kg s.c., significantly reduced TNF alpha and IL-1 beta production induced by LPS both in serum and lungs and it was shown to inhibit TNF-dependent cytoxicity on L929 cells. CONCLUSIONS: These results clearly demonstrate the therapeutic activity of benzydamine in a simple model of endotoxic shock. Available data confirm the potential role of benzydamine as an anti-cytokine agent and provide suggestions for novel therapeutic applications of this anti-inflammatory drug.     

Primate performance decrements following acute soman exposure: failure of chemical countermeasures

Three experiments are reported: 1) a feasibility study on using laboratory primates repeatedly in behavioral toxicity studies of organophosphate (OP) agents or of chemical countermeasures against OPs; 2) a study of the efficacy of pyridostigmine pretreatment and 2-PAM therapy; and 3) a study to determine the effects of these treatments on soman-induced cholinesterase (ChE) inhibition and its recovery. In rhesus monkeys, three repeated acute low-dose (2.1 to 2.8 micrograms/kg) soman exposures, separated by intervals > 5 weeks, did not change baseline compensatory tracking performance or the soman ED50. Atropine therapy (97 micrograms/kg) alone had no effect on soman ED50. Addition of pyridostigmine pretreatment (150 micrograms/kg) and 2-PAM therapy (17 mg/kg) to atropine therapy increased the soman ED50 for a performance decrement from 2.27 micrograms/kg to 2.58 micrograms/kg, an insignificant protective effect. At the soman ED50 for behavioral decrements, pyridostigmine pretreatment increased the inhibition of serum ChE observed immediately after soman exposure, but reduced the extent of permanent inhibition. The 2-PAM therapy reduced serum ChE inhibition from about 80% to less than 70%. These effects on the time course of ChE inhibition following soman exposure appear to combine additively. These chemical countermeasures do not prevent soman-induced performance decrements, even though they are effective in protecting lives after much higher doses. The soman doses used produce only small, transient performance decrements; animals so exposed can, thus, be used repeatedly in such studies.     

Electrophysiological comparison of 5-Hydroxytryptamine1A receptor antagonists on dorsal raphe cell firing

Single-unit recording studies were undertaken in chloral hydrate-anesthetized rats to compare the effects on dorsal raphe cell firing of several putative 5-hydroxytryptamine (HT)1A receptor antagonists, including WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide), p-MPPI (4-(2-methoxyphenyl)1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido]ethyl] pip erazine), and two newly described 5-HT1A receptor antagonists, NDL-249 [(R)-3-(N-propylamino)-8-fluoro-3, 4-dihydro-2H-1-benzopyran-5-carboxamide] and NAD-299 [(R)-3-N, N-dicyclobutylamino-8-fluoro-3, 4-dihydro-2H-1-benzopyran-5-carboxamide]. Consistent with a 5-HT1A receptor antagonist profile, pretreatment with an approximately equimolar (0.02-0.03 micromol/kg) i.v. dose of each compound caused a significant rightward shift in the dose-response curve for 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin]. Antagonist potency was clearly highest for NAD-299 and WAY 100635, which caused shifts roughly 3 times greater than those for either p-MPPI or NDL-249 (ED50 for 8-OH-DPAT, 1.3 +/- 0.3 microg/kg; after NAD-299, 18.2 +/- 1.0 microg/kg; after WAY 100635, 16.9 +/- 2.9 microg/kg; after NDL-249, 6.0 +/- 1.2 microg/kg; after p-MPPI, 4.7 +/- 1.1 microg/kg). In separate studies, each of the antagonists was administered alone in increasing cumulative doses to evaluate whether they possessed intrinsic agonist activity in this system. At doses below 0.01 micromol/kg, none of the drugs altered firing by more than +/-20% basal rates. At higher doses (>0.1 micromol/kg), WAY 100635, NDL-249, and NAD-299 caused a dose-dependent suppression of dorsal raphe cell firing (ED50 = 0.6 +/- 0.2, 0.7 +/- 0.3, and 0. 9 +/- 0.4 micromol/kg, respectively). However, the ED50 values for inhibition by these drugs were roughly 30 times higher than the doses that antagonized effects of 8-OH-DPAT. Moreover, the inhibition by all three antagonists (but not 8-OH-DPAT) was readily reversed by d-amphetamine (3.2 mg/kg i.v.), a releaser of norepinephrine, suggesting that these effects were likely due to alpha adrenergic receptor blockade rather than to 5-HT1A receptor agonism. Thus, it was concluded that WAY 100635, NAD-299, NDL-249, and p-MPPI all fulfill criteria as 5-HT1A receptor antagonists lacking intrinsic efficacy in the dorsal raphe system. The newly described compound NAD-299 exhibits antagonist potency comparable to that of WAY 100635 in this electrophysiological assay.     

Daily dietary intake of manganese by several population groups in Belgium: preliminary reports

STUDY OBJECTIVES: To compare succinylcholine (S) and rocuronium (R) used for endotracheal intubation, and to assess the possible action of S on subsequently administered R. DESIGN: Double-blind, randomized, phase III study. SETTING: University Medical Center. PATIENTS: 24 ASA physical status I and II patients, ages 28 to 65, undergoing general anesthesia for abdominal procedures. INTERVENTION: Double-blind administration of R 600 mcg/kg (Group A) or S 1 mg/kg was achieved with open label R 150 mcg/kg. Standardized general anesthetic technique with sodium thiopental, fentanyl, and nitrous oxide in oxygen was administered. MEASUREMENTS AND MAIN RESULTS: Neuromuscular junction was tested by ulnar nerve stimulation and mechanomyograph. Intubation was attempted at 80% first twitch depression of train-of-four. Heart rate and blood pressure were recorded throughout. Onset times were 74 +/- 37 seconds for S and 130 +/- 46 seconds for R. Intubation times were 76 +/- 29 seconds for S and 85 +/- 23 seconds for R (no significant difference). Good to excellent intubation conditions were achieved in both groups. S given prior to R decreased onset time and increased duration of R, when compared with R given alone. No drug related cardiovascular events were noted. CONCLUSION: Rapid intubation conditions can be obtained after both S and R. Given its overall safety profile, R can be used when S is contraindicated, or in healthy patients with no apparent difficult airway, when procedures are expected to last more than 25 minutes.     

8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine antagonist in vitro and in vivo

An adenosine antagonist, 8-(3-chlorostyryl)caffeine (CSC), was shown previously to be 520-fold selective for A2a-adenosine receptors in radioligand binding assays in the rat brain. In reversing agonist effects on adenylate cyclase, CSC was 22-fold selective for A2a receptors in rat phenochromocytoma cells (Kb 60 nM) vs. A1 receptors in rat adipocytes (Kb 1.3 microM). Administered i.p. in NIH mice at a dose of 1 mg/kg, CSC shifted the curve for locomotor depression elicited by the A2a-selective agonist APEC to the right (ED50 value for APEC shifted from 20 micrograms/kg i.p. to 190 micrograms/kg). CSC had no effect on locomotor depression elicited by an ED50 dose of the A1-selective agonist CHA. CSC alone at a dose of 5 mg/kg stimulated locomotor activity by 22% over control values. Coadministration of CSC and the A1-selective antagonist CPX, both at non-stimulatory doses, increased activity by 37% (P < 0.001) over CSC alone, suggesting a behavioral synergism of A1- and A2-antagonist effects in the CNS.     

Acute cytotoxicity testing with cultured human lung and dermal cells

STUDY OBJECTIVE: To determine if 450 micrograms/kg (1.5 times the ED95) of rocuronium would result in a comparable onset with a shorter duration of action when compared with 600 micrograms/kg (2 times the ED95). DESIGN: Randomized, single-blind study. SETTING: Teaching hospital. PATIENTS: 85 ASA physical status I and II children ages 2 through 12, undergoing elective surgery with an inhalation induction using halothane. INTERVENTIONS: Group 1 received 600 micrograms/kg rocuronium, and Group 2 received 450 micrograms/kg rocuronium. MEASUREMENTS AND MAIN RESULTS: The two groups were compared using a Student's t-test, with p < 0.05 significant. The time of onset, or time to 95% suppression of neuromuscular twitch with standard errors, was 140 +/- 13 seconds (range 46 to 365 sec) in Group 1 and 148 +/- 13 seconds (range 82 to 345 sec) in Group 2 (NS = not significant). The times to 25% return of twitch from baseline (T25) in Groups 1 and 2 were 28 +/- 1.5 minutes (range 14 to 45 min) and 26 +/- 1.6 minutes (range 10 to 55 min), respectively (NS). The differences between these two doses in onset of, and recovery from, block were not found to be statistically significant. The results, however, excluded 5% of the higher dose group and 31% of the lower dose group who did not achieve 95% suppression of twitch. Time to maximal suppression of neuromuscular blockade, however, was not statistically significant for the 85 patients with a time of 270 +/- 28 seconds (range 91 to 605 sec) with a mean maximal suppression of 98.7% in Group 1 and 313 +/- 25 seconds (range 91 to 899 sec) with a mean maximal suppression of 93.1% in Group 2. CONCLUSION: The two doses of rocuronium did not differ statistically in onset or duration. Rocuronium at 600 micrograms/kg offers more reliability than 450 micrograms/kg in achieving adequate muscle relaxation, and the lower dose may result in a significantly large number of patients who may have inadequate intubating conditions.