International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes.

Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.

Comparative local anesthetic efficacy and pharmacokinetics of epidurally administered ropivacaine and bupivacaine in the sheep.

BACKGROUND AND OBJECTIVES: Ropivacaine is the S(-) propyl homolog of bupivacaine and mepivacaine. Studies in humans have confirmed the results of studies in laboratory animals that ropivacaine is a long-acting local anesthetic with an anesthetic profile similar to bupivacaine. Acute, intravenous systemic toxicity studies have been conducted in sheep and dogs. Local anesthetic efficacy has been studied after epidural administration in the dog. This study was initiated to determine the local anesthetic efficacy and pharmacokinetics of ropivacaine and bupivacaine after epidural administration in an experimental sheep model and to evaluate the sheep model as a model of experimental epidural anesthesia. METHODS: Twelve adult nonpregnant ewes were prepared with chronically implanted lumbar epidural catheters and arterial lines. Each sheep received injections of 5.0 mL ropivacaine and bupivacaine (0.5% and 0.75%) in a blinded, random, cross-over fashion. Onset and duration of sensory and motor blockade were evaluated. Arterial blood samples were drawn for serum drug concentration determinations and pharmacokinetic analysis. RESULTS: Onset and duration of motor blockade were similar for comparable concentrations of both drugs. Both concentrations of ropivacaine and bupivacaine 0.5% demonstrated differential neural blockade. The peak serum concentrations generally occurred within 8 minutes after administration. The terminal elimination half-life in serum was about 3.5-4.0 hours and 6 hours for ropivacaine and bupivacaine, respectively. No signs of systemic toxicity were observed. Results of sensory and motor blockade were consistent with previous studies in laboratory animals and humans. CONCLUSIONS: Ropivacaine produces sensory and motor blockade which is similar to that produced by equal concentrations of bupivacaine after epidural administration in the sheep. Peak serum concentrations produced no signs of systemic toxicity. The results of this study are consistent with previously published data from studies in laboratory animals and humans. The sheep model of experimental epidural anesthesia appears to be a clinically relevant method to evaluate experimental local anesthetics.

Neurophysiologic actions and neurological consequences of veratridine on the rat sciatic nerve.

BACKGROUND: The quest for a drug that would provide analgesia with minimal motor deficiency, through the selective inhibition of impulses in small-diameter fibers, was brightened by a previous report of veratridine's C-fiber-selective actions on the isolated rabbit vagus nerve. The goal of the present research was to demonstrate the same actions on rat sciatic nerve in vitro and to observe the functionally differential blockade in the rat in vivo. METHODS: Sciatic nerves were removed from rats, mounted in a recording chamber, wherein a 1-cm length of the ensheathed nerve was superfused with the plant alkaloid veratridine (2 microM) in bicarbonate-buffered Liley's solution, and the compound action potential (CAP) was stimulated supramaximally to give A- and C-fiber elevations. Onset, steady-state, and recovery from veratridine effects were assayed for a range of stimulus frequencies. Open-field behavior and quantitative neurological assessments of proprioception, motor function, and nociception were tested in 15 trained rats after injection near the sciatic nerve of 0.1 ml veratridine at 0.5, 0.7, and 1.0 mM each plus epinephrine (1:200,000). RESULTS: Veratridine inhibited the C-fiber component of the CAP in a frequency-dependent manner. At 0.1 Hz the CAP was 65% of the control amplitude, 50% at 0.5 Hz, and 40% at 5 Hz. A-fiber elevations were unattenuated at stimulus frequencies as high as 50 Hz. Steady-state inhibition was reached 5 min after drug administration, and recovery from the effects was 30% complete by 15 min of drug washout. Proprioception, measured as a "hopping" or "placing" reaction, was inhibited dose dependently by maximum degree and for durations of, respectively, 0.5 mM, 61%, 180 min; 0.7 mM, 100%, 360 min; and 1 mM, 100%, 420 min. Extensor postural thrust, as a measure of motor function, was inhibited by and for 0.5 mM, 77%, 240 min; 0.7 mM, 99%, 390 min; and 1 mM, 100%, 420 min. Analgesia, as a prolonged withdrawal latency to a noxious thermal stimulus, had the following profile: 0.5 mM, 10%, 30 min; 0.7 mM, 52%, 150 min; and 1 mM, 66%, 150 min. CONCLUSIONS: Despite the fact that veratridine gave a C-fiber preferential blockade in the isolated sciatic nerve, heightened analgesia over motor block was not achieved in vivo. Indeed, just the opposite occurred. If preferential C-fiber blockade also occurs in vivo, then its traditionally expected correlation with analgesia must be re-examined.

Regional distribution of 11C-labeled lidocaine, bupivacaine, and ropivacaine in the heart, lungs, and skeletal muscle of pigs studied with positron emission tomography.

The regional myocardial uptake and kinetics of 11C-lidocaine, 11C-bupivacaine, and 11C-ropivacaine were examined in the pig, utilizing positron emission tomography to determine whether disproportionate distribution exists among these agents. The three drugs were rapidly distributed to the myocardium and lung with mean peak radioactivities occurring between 0.35 and 0.48 min post-injection in myocardium and 0.35 and 0.65 min in lung. Radioactivities peaked later in skeletal muscle than in the myocardium and lung, occurring between 1.1 and 2.7 min post-end injection. Blood radioactivities for bupivacaine and ropivacaine were significantly higher than those of lidocaine, whereas myocardial, lung, and muscle uptakes for the three agents were not significantly different. Myocardium-blood partition coefficients were similar for bupivacaine and ropivacaine (0.55 and 0.49 respectively), while it was three times higher for lidocaine (1.4). A similar relationship existed for skeletal muscle- and lung-blood partition coefficients. Bupivacaine and ropivacaine t1/2z in skeletal muscle were significantly longer than those of lidocaine. The results of this study indicate that the increased cardiotoxicity associated with bupivacaine does not appear to be related to disproportionate distribution in the myocardium when compared to lidocaine and ropivacaine.

Antinociceptive and motor-blocking efficacy of ropivacaine and bupivacaine after epidural administration in the dog.

BACKGROUND AND OBJECTIVES: This study was initiated to evaluate the antinociceptive and motor blocking capabilities of epidurally administered 0.5% and 0.75% ropivacaine and bupivacaine using a blinded, random crossover design in the dog. Additionally, serum drug concentrations and serum protein binding were determined. METHODS: Twelve male beagles were prepared with chronic epidural and arterial catheters under sterile conditions. The epidural space was identified by a loss-of-resistance technique using an 18-gauge thin-wall Crawford needle via the midline approach. The catheter was attached to a Schraeder-type Teflon valve sutured subcutaneously. Local anesthetic drugs were administered into the lumbar epidural space in a constant volume of 3.0 mL. Evaluation of antinociceptive and motor blocking qualities were evaluated at regular intervals. Arterial blood samples were drawn during the 15 minutes following local anesthetic injection for drug concentration and pharmacokinetic analysis. RESULTS: Onset time of motor block in the ropivacaine 0.5% group was longer than in other groups but not significantly different. Duration of motor and sensory block demonstrated a dose-dependent relationship of both drugs. Bupivacaine 0.5% and 0.75% produced motor block (81 +/- 42 minutes and 198 +/- 44 minutes [mean +/- SD], respectively) of significantly longer duration than corresponding concentrations of ropivacaine (69 +/- 35 minutes and 133 +/- 32 minutes, respectively). The onset times for sensory block of the vertebral dermatomes were not different between groups. No difference was found in duration of dermatomal sensory block between the 0.5% solutions. However, the duration of dermatomal sensory block was significantly longer in the bupivacaine 0.75% group than in any other group. Peak arterial serum drug concentrations were not different between drugs at equal concentrations and were reached between 2 and 6 minutes in all animals. Both drugs were highly bound to serum proteins (> 98%). No severe adverse effects or sequelae were observed. CONCLUSIONS: The 0.5% solutions produced similar sensory block of the vertebral dermatomes. Duration of dermatomal block with 0.75% bupivacaine was longer than with the corresponding ropivacaine concentration. Ropivacaine produced motor block of shorter duration as compared with bupivacaine. Serum concentrations of the two drugs were similar after injection of the same doses. In this animal model, ropivacaine produced shorter durations of sensory and motor block than corresponding concentrations of bupivacaine. These data are consistent with previously published data in animals and humans.

Chronotropic and inotropic effects of ropivacaine, bupivacaine, and lidocaine in the spontaneously beating and electrically paced isolated, perfused rabbit heart.

BACKGROUND AND OBJECTIVES: The purpose of this study was to compare the inotropic and chronotropic effects of ropivacaine, bupivacaine, and lidocaine in an isolated, spontaneously beating rabbit heart preparation. The ability to electrically pace the heart in the presence of local anesthetic also was examined. METHODS: Hearts were perfused with Krebs-Henseleit solution, then exposed to ropivacaine or bupivacaine at 1, 6, or 13 micrograms/ml or lidocaine at 6, 20, or 40 micrograms/ml (n = 6, each concentration). Left ventricular pressure, left ventricular dP/dt (rate of change derivation from analog waveform of the left ventricular pressure wave), pulmonary artery flow, oxygen consumption, and electrocardiogram were monitored throughout the studies. Drug exposure was for 30 minutes or until a 75% decrease in left ventricular pressure occurred. RESULTS: All preparations were exposed to 1 microgram/ml bupivacaine or ropivacaine and 6 micrograms/ml lidocaine for the full 30 minutes. At the intermediate concentrations, only one of six bupivacaine preparations (6 micrograms/ml) survived the full 30-minute exposure period, compared to six of six preparations for both ropivacaine (6 micrograms/ml) and lidocaine (20 micrograms/ml; p less than 0.05). Similar results were found with exposure to the highest concentrations of these local anesthetics. No electrocardiogram changes were observed with any of the three lidocaine concentrations or with the lowest ropivacaine and bupivacaine concentration. At the intermediate concentration, atrioventricular conduction changes were seen with bupivacaine in five of six preparations, compared to one of six ropivacaine preparations (p less than 0.05). With the high concentration, ventricular tachycardia occurred in four of six bupivacaine preparations, compared to zero of six with ropivacaine (p less than 0.05). In general, left ventricular systolic pressure, dP/dt, heart rate, and oxygen consumption were reduced during exposure to all concentrations of the three local anesthetics. The most profound effects (greater than 75% reduction) were seen with 13 micrograms/ml bupivacaine. All local anesthetics caused an increase in the voltage required to pace the hearts via the atria. With 6 micrograms/ml bupivacaine and 13 micrograms/ml ropivacaine, 50% of the preparations could not be paced via the atria; and with 13 micrograms/ml bupivacaine, none of the preparations could be paced via the atria. The depressant effects of 6 micrograms/ml bupivacaine approximated those seen with 13 micrograms/ml ropivacaine. The reductions in oxygen consumption and pulmonary artery flow were not significantly different between treatment groups. CONCLUSION: The results of this study indicate that bupivacaine is more cardiodepressant and arrhythmogenic than either ropivacaine or lidocaine.

The effects of epinephrine on the anesthetic and hemodynamic properties of ropivacaine and bupivacaine after epidural administration in the dog.

Ropivacaine is a new local anesthetic that is chemically related to mepivacaine and bupivacaine. Previous laboratory studies have demonstrated that ropivacaine possesses an anesthetic profile similar to that of bupivacaine and has less arrhythmogenic potential. The current study was initiated to compare the hemodynamic and anesthetic effects of epidurally administered 0.75% bupivacaine and 1% ropivacaine, with and without epinephrine (1:200,000), in the dog. Two groups of six dogs were randomly assigned to the ropivacaine or bupivacaine treatment groups. Administration of 0.75% bupivacaine and 1% ropivacaine with and without epinephrine was randomized. Volumes of 3 ml of each solution were injected in a blinded manner via an indwelling lumbar epidural catheter with 48 hours between injections. No statistically significant difference existed between the four treatment groups with regard to onset and duration of sensory or motor block. Hemodynamic changes were, for the most part, not different between drugs. Significant decreases were seen in mean arterial blood pressure and cardiac output in all test groups. No difference in the degree of cardiovascular depression was observed. The addition of epinephrine did not alter onset or duration of sensory or motor block in this animal model. Epinephrine reduced the average anesthetic blood concentration observed in both treatment groups at the various time intervals, but not the time to achieve the mean maximum blood level. No residual adverse effects were observed in any animal.

Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog.

Two groups of six beagle dogs received rapid intravenous (IV) injections of ropivacaine or bupivacaine on two occasions in a blinded random fashion. Initially, a dose sufficient to cause convulsions (CD) was given followed by twice the CD (2 x CD), which was administered 48 h later. The CD of bupivacaine (4.3 mg/kg) and ropivacaine (4.9 mg/kg) caused significant (P less than 0.05) increases in heart rate and mean arterial blood pressure. There was no difference between drug groups. Seizures were abolished by 10 mg/kg of intravenous thiamylal. Endotracheal intubation and controlled respiration with O2-enriched air with no other treatment resulted in rapid and complete recovery in all dogs. All dogs receiving 2 x CD of bupivacaine (8.6 mg/kg) or ropivacaine (9.8 mg/kg) were initially treated with thiamylal and mechanical ventilation. Two dogs in the bupivacaine group developed hypotension, respiratory arrest, ventricular tachycardia, and ventricular fibrillation, which were resistant to closed chest cardiac massage, treatment with epinephrine, bretylium, and atropine, and direct current cardioversion. The four remaining dogs in the infusion group were successfully resuscitated. All of the animals in the ropivacaine-treated group survived the administration of the 2 x CD dose. Mild hypotension developed in one dog and was treated with intravenous epinephrine (0.75 mg). This resulted in nodal tachycardia, which was abolished after treatment with bretylium. Another dog had two 1-s bursts of premature ventricular contractions requiring no treatment. The rapid treatment of convulsions and cardiovascular toxicity resulted in a decreased number of deaths in both groups when compared with dogs from a previously published study in which no therapy was instituted. Thus, early aggressive treatment of central nervous system and cardiovascular system toxicity is capable of reducing the incidence of mortality associated with the rapid intravenous administration of excessive doses of local anesthetics.

Lipopolysaccharide-induced myocardial depression is not mediated by cyclooxygenase products.

BACKGROUND AND METHODS: We tested the hypothesis that a sublethal dose of lipopolysaccharide in vivo induces in vitro atrial depression in rats via release of cyclooxygenase products. Male Sprague-Dawley rats (mean weight 366 +/- 9 [SE] g) were injected iv at time 0 with Escherichia coli lipopolysaccharide (1 mg/kg, n = 22) or saline (2.5 mL, n = 11). Some animals injected with lipopolysaccharide were pretreated 30 mins before with ibuprofen (15 mg/kg, n = 7). At time 2 hrs, the hearts were harvested and the atria were immersed in tissue baths and attached to force displacement transducers. Blood was collected for measurement of thromboxane B2 (TxB2) by radioimmunoassay. Force of contraction and rate in response to four different preloads were measured. Afterward, the preload was changed to 1 g, and force of contraction and rate were evaluated in response to graded doses of isoproterenol. RESULTS: Force of contraction was significantly (p less than .05) lower at all preloads in animals given lipopolysaccharide. Pretreatment with ibuprofen did not prevent the depression in force of contraction but prevented the increase in TxB2 seen after lipopolysaccharide injection (p less than .05). The force of contraction and rate response to isoproterenol were similar across groups. CONCLUSIONS: These data suggest that cyclooxygenase products do not mediate lipopolysaccharide-induced cardiac dysfunction in the rat.

Endotoxin-induced myocardial depression in rats: effect of ibuprofen and SDZ 64-688, a platelet activating factor receptor antagonist.

We tested the hypothesis that lipopolysaccharide (LPS)-induced myocardial dysfunction is mediated by cyclooxygenase-derived metabolites of arachidonic acid or platelet activating factor (PAF). Ether-anesthetized rats were injected iv with normal saline (NS; 2.5 ml/kg), ibuprofen (cyclooxygenase inhibitor; 15 mg/kg), or SDZ 64-688 (PAF receptor antagonist; 5 mg/kg). Thirty minutes later, the rats were injected iv with NS (5 ml/kg) or Escherichia coli 0111:B4 LPS (20 mg/kg). Two hours later, atria were harvested, connected to an isometric force transducer-amplifier-recorder apparatus, and maintained in vitro in oxygenated 37.5 degrees C Krebs--Henseleit buffer. Force of contraction indexed to body weight (FOCI; g/kg) was significantly (P less than 0.05) lower in the NS/LPS group (N = 7) than in the NS/NS group (N = 7). Pretreatment with ibuprofen (ibuprofen/LPS group; N = 8) did not affect the adverse effect of LPS on atrial FOCI. In contrast, pretreatment with SDZ 64-688 (64-688/LPS group; N = 8) ameliorated (P less than 0.05) the deleterious effect of LPS on contractility. The PAF antagonist did not manifest intrinsic positive inotropic activity (64-688/NS group; N = 8). These results support the notion that LPS-induced myocardial dysfunction in the rat is mediated, at least in part, by PAF.

Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog.

This study evaluated the systemic toxicity, arrhythmogenicity, and mode of death of convulsant and supraconvulsant doses of lidocaine, bupivacaine, and ropivacaine. Experiments in awake dogs were designed to mimic the clinical situation of an accidental intravenous (IV) injection of local anesthetics. On the first experimental day, lidocaine (8 mg.kg-1.min-1), bupivacaine (2 mg.kg-1.min-1), and ropivacaine (2 mg.kg-1.min-1) were infused intravenously until seizures occurred (n = 6 for each group). The average dose and arterial plasma concentration at seizure onset was 20.8 +/- 4.0 mg/kg and 47.2 +/- 5.4 micrograms/mL for lidocaine, 4.31 +/- 0.36 mg/kg and 18.0 +/- 2.7 micrograms/mL for bupivacaine, and 4.88 +/- 0.47 mg/kg and 11.4 +/- 0.9 micrograms/mL for ropivacaine. The margin of safety between the convulsive and lethal doses was determined by administering two times the convulsive dose 24 h later. Two dogs given lidocaine died because of progressive hypotension, respiratory arrest, and finally cardiovascular collapse with an average peak plasma concentration (Cmax) of 469 micrograms/mL. No ventricular arrhythmias were observed in this group. Ventricular arrhythmias occurred in five of six dogs receiving bupivacaine. Four animals died because of hypotension, respiratory arrest, and cardiovascular collapse. One additional animal died because of ventricular fibrillation. The Cmax for bupivacaine was 70.1 +/- 14.6 micrograms/mL in nonsurvivors. In the ropivacaine group one animal died because of hypotension, respiratory arrest, and cardiovascular collapse (Cmax = 72.4 micrograms/mL). A surviving dog had transient premature ventricular contractions. Twenty-four hours later three times the convulsive dose was administered to the survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative motor-blocking effects of bupivacaine and ropivacaine, a new amino amide local anesthetic, in the rat and dog.

Ropivacaine (S-(-)-1-propyl-2',6'-pipecoloxylidide) is a new local anesthetic that is structurally related to mepivacaine and bupivacaine. The comparative effects of ropivacaine and bupivacaine on motor function were assessed in the laboratory rat and dog. (It was not possible to accurately evaluate sensory blockade in these models.) Several concentrations of both agents were injected in the region of the sciatic nerve of the rat and into the lumbar epidural or subarachoid space in the dog. Epidural blockade was also performed utilizing solutions of ropivacaine and bupivacaine which contained epinephrine (1:200,000). The rat sciatic block studies indicate that at concentrations of 0.5 and 0.75%, ropivacaine had a slightly shorter time of onset and duration of motor blockade than did bupivacaine. In the epidural and spinal studies in the dog, ropivacaine was less potent and had a shorter duration of motor blockade than did bupivacaine at equal drug concentrations. A 1.0% solution of ropivacaine produced epidural motor blockade similar in onset and duration to that achieved with a 0.75% solution of bupivacaine. Epinephrine did not significantly prolong the duration of motor blockade of either agent after epidural administration.

Comparative pharmacokinetics of bupivacaine and ropivacaine, a new amide local anesthetic.

The pharmacokinetics of ropivacaine, a new amide local anesthetic, and bupivacaine were determined in dogs after IV and epidural administration. After 15-minute IV infusions of 3.0 mg/kg ropivacaine (n = 6) and 3.4 mg/kg bupivacaine (n = 4), the maximum arterial concentrations (Cmax) of ropivacaine averaged 2.41 +/- 0.52 micrograms/ml compared with 3.35 +/- 0.16 micrograms/ml of bupivacaine. The elimination half life (t 1/2 beta) of ropivacaine (25.9 +/- 1.7 min) was significantly shorter than for bupivacaine (39.1 +/- 13.3 min) after IV infusion. This was reflected by mean clearance values (Cl) for ropivacaine of 41.1 +/- 8.2 ml.min-1.kg-1 compared with 32.3 +/- 4.8 ml.min-1.kg-1 for bupivacaine, although the difference was not statistically significant. After epidural injections (ropivacaine n = 6; bupivacaine n = 5), a dose-related increase in Cmax was observed with both drugs. Although Cmax tended to be higher for ropivacaine, a significant difference was only attained when comparing Cmax after administration of 0.25% plain solutions of both agents. The addition of epinephrine did not consistently decrease the Cmax of either agent. The apparent t 1/2 beta of both agents was significantly longer after epidural administration than after IV infusion. No differences existed between t 1/2 beta values for ropivacaine and bupivacaine after epidural administration. Total body clearance of both agents tended to be lower after epidural administration, particularly when epinephrine-containing solutions were employed. Little difference existed between the two drugs when equivalent solutions were administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in the pharmacokinetic properties of amide local anaesthetics following local anaesthetic induced convulsions.

The comparative pharmacokinetic properties of lidocaine, bupivacaine, etidocaine and mepivacaine were investigated in convulsing and non-convulsing dogs. The same dose of a given local anaesthetic was administered as either a 30-s intravenous (IV) bolus to produce convulsions or as a 15-min IV infusion producing no convulsions. Derived pharmacokinetic data were found to be different in convulsing and non-convulsing animals. Total body clearance was found to be significantly reduced for lidocaine (29%, P less than 0.05), bupivacaine (31%, P less than 0.05), etidocaine (60%, P less than 0.01) and mepivacaine (68%, P less than 0.01) in convulsing animals. Increases in elimination half-life only achieved statistical significance in mepivacaine-treated animals (non-convulsing 45.2 min, convulsing 105.4 min, P less than 0.01). Overall, the most profound effects of convulsions on pharmacokinetic data were seen with mepivacaine. Convulsions were associated with increases in heart rate ranging from 117% (lidocaine, P less than 0.05) to 129% (mepivacaine, P less than 0.05), increases in cardiac output ranging from 78% (mepivacaine) to 232% (bupivacaine, P less than 0.05) and increases in mean arterial pressure ranging from 45% (lidocaine, P less than 0.05) to 80% (bupivacaine, P less than 0.05). The results suggest that when local anaesthetic-induced seizures occur in man, it cannot be assumed that these drugs will be distributed and eliminated as predicted by intravenous infusion of non-toxic doses.

Bupivacaine for intercostal nerve blocks in children: blood concentrations and pharmacokinetics.

A pharmacokinetic evaluation of bupivacaine was carried out after intercostal nerve blocks performed on 28 occasions in 27 children varying in age from 3 months to 16 yr. Bupivacaine HCl, 0.5%, with epinephrine 1:200,000 was employed. Doses of 2 mg/kg, 3 mg/kg, and 4 mg/kg resulted in peak whole blood arterial bupivacaine (base) concentrations (mean +/- SD) of 0.77 +/- 0.25 microgram/ml, 1.37 +/- 0.23 microgram/ml, and 1.87 +/- 0.53 microgram/ml, respectively. Calculated pharmacokinetic parameters (mean +/- SD) were the following: apparent volume of distribution (VD beta), 2.8 +/- 0.8 L/kg; steady-state volume of distribution (VDss), 2.7 +/- 0.7 L/kg; elimination half-life (t1/2 beta), 147 +/- 80 min; and total body clearance (Cl), 16.0 +/- 7.4 ml X min-1 X kg-1, or 382 +/- 201 ml X min-1 X m-2. Compared with data reported for adult patients, our data indicate that the volume of distribution is greater and clearance is more rapid in children than in adults. The absorption of local anesthetic from the intercostal space appears to be more rapid in children than adults. In an additional group of 11 children, the relationship of the bupivacaine blood:plasma concentration ratio (lambda) to hematocrit was investigated. Hematocrit in this group ranged from 30 to 59, and lambda varied from 0.47 to 0.82. There was a significant relationship between lambda and hematocrit defined by the equation lambda = -0.0079 Hct + 1.028 (r = 0.72, P less than 0.05). Reporting bupivacaine concentration in terms of plasma concentration may introduce an artifact that is dependent on the hematocrit, and we therefore suggest that whole blood concentration values be reported by investigators in the future.

Bupivacaine toxicity in pregnant and nonpregnant ewes.

The relative central nervous system and cardiovascular toxicity of bupivacaine was compared in pregnant and nonpregnant ewes during continuous infusion of bupivacaine into the jugular vein at the rate of 0.5 mg X kg-1 X min-1. In all animals, identical symptoms of toxicity occurred in the following order: convulsions, hypotension, respiratory arrest, and circulatory collapse. The dose of bupivacaine required to produce central nervous system (CNS) toxicity in the pregnant ewe tended to be lower than in the nonpregnant animal, although the difference was not statistically significant (P less than 0.1). However, the mean dose of bupivacaine resulting in cardiovascular collapse was significantly lower in pregnant ewes (5.1 +/- 0.7 mg/kg) than in nonpregnant animals (8.9 +/- 0.9 mg/kg). Similarly, bupivacaine blood concentrations at the onset of respiratory arrest and circulatory collapse were lower in the pregnant group, being 5.2 +/- 0.7 micrograms/ml and 5.5 +/- 0.8 micrograms/ml, respectively, versus 7.5 +/- 1.0 microgram/ml and 8.0 +/- 0.9 micrograms/ml, respectively, in the nonpregnant group (P less than 0.05). The concentration of bupivacaine in the brain of pregnant ewes at the time of cardiovascular collapse was significantly lower (P less than 0.01) than in the nonpregnant group (7.5 +/- 1.5 vs. 16.3 +/- 1.7 micrograms/g). The myocardial tissue concentration of bupivacaine also tended to be lower in the pregnant group, although the differences were not statistically significant (P less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of lidocaine and bupivacaine on isolated guinea pig atria in the presence of acidosis and hypoxia.

In an isolated guinea pig atrial preparation, the bathing solution pH, PO2, and PCO2 were manipulated to mimic normal, acidotic, and hypoxic conditions. The effect of lidocaine and bupivacaine on spontaneous heart rate (HR) and contractile force (CF) was determined for 60 min under conditions of normal pH, PO2, and PCO2. Lidocaine (50 micrograms/ml) reduced HR by a maximum of 34.2 +/- 1.5% and CF by 38.9 +/- 8.1% (mean +/- SEM). Bupivacaine (5 micrograms/ml) reduced HR by a maximum of 30.1 +/- 1.9% and CF by 48.0 +/- 6.5%. Bupivacaine (10 micrograms/ml) caused a maximum HR reduction of 61.7 +/- 9.5% and CF reduction of 66.0 +/- 8.6%. Hypoxia or metabolic or respiratory acidosis did not further enhance the local anesthetic induced atrial depression. However, conditions of combined acidosis/hypoxia, while not significantly altering the HR and CF depression caused by lidocaine, did enhance bupivacaine-induced depression of HR and CF (93.6 +/- 6.3% and 95.2 +/- 4.8%, respectively). The effect of a protein-free bathing solution on the relative toxicities of lidocaine and bupivacaine is discussed.

Comparative CNS toxicity of lidocaine, etidocaine, bupivacaine, and tetracaine in awake dogs following rapid intravenous administration.

The comparative central nervous system (CNS) toxicity of serially administered intravenous doses of lidocaine, bupivacaine, etidocaine, and tetracaine was investigated in awake dogs. The mean cumulative dose required for convulsive activity was 4.0 mg/kg tetracaine, 5.0 mg/kg bupivacaine, 8.0 mg/kg etidocaine, and 22.0 mg/kg lidocaine. The cumulative convulsive dose of lidocaine was significantly greater than that of the other three agents (P less than 0.01). A comparison of the in vivo anesthetic potency and the acute CNS toxicity of these various agents suggests little difference in the therapeutic ratio between less potent anesthetics such as lidocaine and more potent drugs, i.e., tetracaine, bupivacaine, and etidocaine. The relative CNS toxicity of the different agents as determined in awake dogs in this study was compared with their relative cardiovascular toxicity previously evaluated in a series of ventilated dogs anesthetized with pentobarbital. The dose of lidocaine, etidocaine, tetracaine, and bupivacaine required to produce irreversible cardiovascular depression was 3.5-6.7 times greater than that which produced convulsions. These results suggest that the CNS is the primary target organ for the toxic effects of both highly lipid-soluble and highly protein-bound local anesthetics (i.e., bupivacaine, etidocaine, and tetracaine) and less lipid-soluble and less protein-bound drugs (i.e., lidocaine) following rapid intravenous administration.

Etidocaine toxicity in the adult, newborn, and fetal sheep.

The systemic toxicity of etidocaine was compared in adult, newborn, and fetal sheep during continuous infusion of the drug into the jugular vein at the rate of 0.5 mg X kg-1 X min-1. All recipients exhibited symptoms of toxicity in the following order: convulsions, hypotension, respiratory arrest, and circulatory collapse. The dose of etidocaine required to produce CNS and cardiovascular toxicity was significantly different among the three age groups, being the highest in the fetus and the lowest in the adult. In contrast, no significant difference in etidocaine blood concentrations at the onset of each toxic symptom was observed among the groups except that convulsions and hypotension occurred at lower blood levels in the fetus as compared with the newborn and adult. Comparisons of etidocaine blood concentrations associated with the onset of convulsions and circulatory collapse (CC/CNS ratio) with those of lidocaine reported previously indicate that a narrower margin exists in adults and newborn following administration of etidocaine.

Loxapine succinate as initial treatment of hostile and aggressive schizophrenic criminal offenders.

The efficacy and safety of loxapine were evaluated in 18 acutely ill schizophrenic criminal offenders in the Essex County Jail. The offender patients were treated for three days with intramuscular loxapine (25 mg three or four times a day), followed by seven days of oral concentrate (up to 150 mg/day in three or four divided doses). Psychiatric status was determined with the Brief Psychiatric Rating and the Clinical Global impression scales at the time of admission, after 8, 24, 48, and 72 hours, amd on days 7 and 10 of medication. Three patients did not complete treatment: one was released on bail after 24 hours of therapy, and the other two had adverse reactions (tongue swelling and muscle spasms, each in one patient) which required cessation of treatment. Statistically significant improvement in both rating scale results was evident as early as 8 hours after treatment began. By day 10, all Brief Psychiatric Rating Scale items and factors and the Clinical Global impression results were statistically improved over baseline measurements. At the end of the study, 87 per cent (13/15) of the patients were well enough to cooperate with their attorneys and understand the procedures of the court. Adverse effects (generally extrapyramidal) appeared in four of 18 patients during parenteral administration and in two of 15 patients during oral therapy.