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Abstract |
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We investigated the effectiveness for cutaneous analgesia of bupivacaine (Bup) stereoisomers in male rats. As a model of infiltration anesthesia, inhibition of a nocifensive reflex by subcutaneous injection of 0.6 mL of different concentrations of R-, S-, and racemic-Bup was evaluated quantitatively by the fraction of times a pinprick failed to evoke a nocifensive motor response. R-Bup was more potent in the extent of block; however, S-Bup had a longer-lasting action at smaller doses. This significant difference was apparent when R-Bup and S-Bup were administered in equipotent doses of 0.06% and 0.075%, respectively. Co-injection of epinephrine (Epi) with these equipotent doses enhanced and prolonged the blocking effects of both Bup stereoisomers, although at dilutions of 1:100,000 to 1:1,000,000 Epi itself induced partial, transient analgesia. At 1:2,000,000 dilution, Epi alone had no analgesic effect; however, when co-injected with the shorter-acting R-Bup (0.06%), Epi prolonged its blocking effect to equal the duration of block evoked by equipotent S-Bup (0.075%). We conclude R-Bup is more potent for cutaneous analgesia and that the longer duration of block by S-Bup probably originates from vasoconstrictor activity.
Implications: Here we show that the more potent optical R-isomer of bupivacaine (Bup) can be used at a smaller dose (80%) than the S-isomer of Bup to give equal pain relief of a skin prick. Although the analgesia from R-Bup is briefer than that from equipotent S-Bup solutions, the durations become equal when a very dilute solution of the vasoconstrictor epinephrine is mixed with the R-isomer. The resulting vasoconstriction thus reduces vascular drug uptake and peak blood levels of systemic drug, reducing potential toxicity.
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Introduction |
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Stereoisomers of local anesthetics show differences in analgesic potency in both in vitro and in vivo investigations. According to in vitro studies (1–4), the R-isomers of many local anesthetics are more potent than S-isomers for the inhibition of normal Na+ currents and the competitive antagonism of Na+ channel activators. Analysis of use-dependent (phasic) inhibition of neuronal Na+ current (2), that develops under rapid stimulation, showed that binding of bupivacaine (Bup) to activated channels was faster for the R- (or "+") isomer whereas dissociation from closed channels was approximately 2.5 times slower for R-Bup than for S- (or "-") Bup (5). Similar differences were reported for Bup in cardiac muscle (6). By using the sucrose-gap method, the effects of Bup stereoisomers were tested on desheathed frog sciatic nerves (4). There the R-enantiomers of Bup, and of three other chiral local anesthetics (1), RAC 109, HS 37, and HS 38, were all found to be more potent than the corresponding S-enantiomers for tonic depression of compound action potentials, measured at low stimulation frequencies (e.g., one per minute) and for phasic depression during trains of stimulation at 5–20 Hz (4).
In contrast to a lower in vitro potency, S-Bup was essentially equipotent to R-Bup for sciatic nerve block by percutaneous injection in the rat (7). Furthermore, experiments on topical anesthesia showed that the S-Bup isomer in vivo acted for a longer time than its R-enantiomorph and with a higher activity in intradermal anesthesia in guinea-pigs although no differences were found for corneal anesthesia (8). The differences in duration were greater when the isomers were tested by intradermal injection than by spinal administration. In contrast, Aberg and Wahlstrom (9,10) found no significant difference between Bup stereoisomers in modifying contraction of the rat portal vein, whereas the S(+)-isomer of mepivacaine had a more marked effect than the R(-)-isomer. Aberg (11) found a much longer duration of infiltration anesthesia in intradermal wheal tests on guinea pigs with S-Bup and attributed this to a difference in tissue penetrability between Bup isomers, because in their previous work, they showed only a negligible difference between Bup enantiomers in directly assayed vascular effects (10).
Based on data showing both different in vivo potency of local anesthetic stereoisomers and different concentration-dependent vasoactive effects (12,13), Aps and Reynolds (14) examined the local anesthetic and vascular activity and duration of action of S- and R-Bup given intradermally to humans. They found a correlation between a longer duration of analgesic action of S-Bup over R-Bup and the greater vasoconstrictor effect shown by the S-enantiomer in the same range of concentrations (between 0.48 and 3.84 mmol/L, equal to 0.016% to 0.124% Bup/HCl solution). However, these authors also noted that it was impossible to separate differences in intrinsic analgesic potency from those due exclusively to differences in duration of action by using the intradermal technique, because variations in rates of vascular resorption from the tissues could not be eliminated and, at the smaller concentrations of Bup, removal from the site of injection would rapidly reduce the concentration of local anesthetic to below the fully effective anesthetic concentrations.
To assess the relative potencies of Bup stereoisomers, without differences in vascular removal rates, we used the model of subcutaneous infiltration anesthesia on conscious, unanesthetized rats and combined the administration of Bup enantiomers with epinephrine (Epi) in an attempt to equalize cutaneous blood flow and thus control local anesthetic uptake by the systemic circulation.
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Methods |
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We investigated cutaneous analgesia from Bup stereoisomers in conscious, unanesthetized Sprague-Dawley male rats (weight 300–350 g). All experiments were performed by using protocols approved by the Harvard Medical Area Committee on Animals. All rats were housed on a 12-h light/dark cycle with food and water ad libitum.
The experiments were done on handled animals (daily, over 10–12 days) familiarized with the behavioral experimenter, the experimental environment, and the specific experimental procedures. Criteria for sufficient handling were an absence of behavioral signs of stress (e.g., immobilization and lack of exploratory behavior in an open field environment, frequent defecation) and an extinction of the initially present dorsal contractile response to the nonnoxious stroking of the area to be tested (accommodated by the completion of the handling period), followed by a robust, distinctive response to noxious stimulation. The cutaneus trunci muscle reflex (CTMR), which is characterized by reflex movement of the skin over the back produced by twitches of lateral thoracispinal muscles in response to local dorsal cutaneous stimulation, was studied as a reaction to noxious pinprick (15). Because reactions to nonnoxious stroking were intentionally extinguished by repeated handling (previously mentioned), responses to stimuli after drug injection were due exclusively to noxious stimulation. As a model of infiltration anesthesia, inhibition of CTMR by subcutaneous injection of the given concentration of anesthetic in 0.6 mL solution was used. The injections were done under the dorsal surface of the thoracolumbar region, from which hair was mechanically clipped 24 h beforehand. The small degree of local irritation produced by clipping preceding the experiment disappeared overnight. The injections caused a circular raising of the skin, a wheal, of approximately 2 cm in diameter that was marked with ink within a few minutes after the injection. After observing an animal’s normal reaction to pinpricks applied outside the wheal and on the contralateral side, we applied six pinpricks inside the wheal and scored the number to which the rat failed to react. Six pricks per test were sufficient to obtain reproducible results among different rats in a group, but few enough to produce no sensitization (redness, swelling) of the skin during repeated tests of one skin patch. The local anesthetic effect was quantitatively evaluated by the number of times the pinprick failed to elicit a response; the complete absence of six responses was defined as 100% CTMR block (100% of maximum possible effect [MPE]), absence of three responses was scored as 50% MPE, etc. The test of six pinpricks was applied every 5–10 min until full CTMR recovery from block was achieved. Each dose of Bup stereoisomers (alone or together with Epi) or Epi itself was always administered over a naive part of the rat’s clipped back. The back was subdivided into four areas, and each animal was injected 2–4 times, separated by an interval not <48 h.
All drugs were prepared and diluted in a solution containing 0.15 M NaCl and 5 mM piperazine-N,N'-bis-[2-ethenesulfonic acid] (PIPES) buffer, pH adjusted (twice, before and after a dilution) to 6.82–6.86. Bup hydrochloride enantiomers, R, (batch #GF-272–301-9), and S, (lot #22801), were supplied by Chiroscience, Cambridge, UK. Racemic Bup (Rac-Bup) hydrochloride was used as a mixture of these R- and S-isomers (1:1 w/w). PIPES was obtained from Sigma Chemical (St. Louis, MO), sodium chloride from Fisher Scientific (Fairlawn, NJ), and Epi from American Regent Laboratories, (Shirley, NY) as a solution (1:1000) for injections.
Data were reported as mean ± SEM. To establish significant differences between values for two stereoisomers, a two-tailed Student’s t-test or 
2 test, where appropriate, was applied, with P < 0.05 considered significant.
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Results |
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The different Bup formulations were differentially capable of providing complete cutaneous analgesia in a varying fraction of the tested population, and of producing different degrees of block when averaged over all animals tested. At the concentration of 0.0375% (1.16 mM), R-Bup induced complete analgesia in 33.3% (4 of 12) rats, Rac-Bup in 62.5% (5 of 8) rats (P > 0.10,
2 test), and S-Bup in 7.1% (1 of 14) rats (P < 0.05). When the analgesia was calculated as a graded value (percentage of MPE, Fig. 1A), the peak effects of R-Bup and Rac-Bup were similar (74.9 ± 7.3%, n = 12 and 87.5 ± 5.7%, n = 8, respectively, P > 0.10, Student’s t-test), whereas that of S-Bup was significantly lower (32.4 ± 8.5%, n = 14, P < 0.001). The duration of partial analgesia (from block onset to full recovery) was greater for the S-enantiomer than the R-enantiomer, whereas for the racemic mixture, block was as slow to regress as it was for S-Bup.
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, R-Bup, n = 11; 
, S-Bup, n = 14; 
, and racemic Bup, n = 8) and B, 0.075% (The integrated analgesia for these separate formulations can be quantitated by the relative areas under the curve (AUC) for the graphs in Figure 1A. This value is 2.00 ± 0.40 x 103% x min for R-Bup; 1.66 ± 0.70 x 103% x min for S-Bup; and 4.00 ± 0.86 x 103% x min for the racemate (P < 0.05 for R-Bup versus Rac-Bup; P < 0.05 for Rac-Bup versus S-Bup; P > 0.05 for S-Bup versus R-Bup). In total, the order of analgesic effectiveness at this small concentration (0.0375%) is Rac-Bup > R-Bup > S-Bup, which is distinctly different than what is predicted by classic pharmacodynamics from binding to a single receptor, where the racemate has a potency between that of the two enantiomers.
At twice the concentration (0.075%) of Bup, enantioselectivity was absent when percentage of MPE was calculated, with all three drugs yielding 90% to 100% analgesia (Fig. 1B). However, on the basis of fraction of animals blocked, R-Bup was more potent than S-Bup; i.e., 100% were blocked by R-Bup (11 of 11) at 15–20 min, and only 63.6% (7 of 11) by S-Bup (P < 0.05, 2 test). Rac-Bup at this concentration also induced a complete block in all of the rats injected (7 of 7; compared with S-Bup, P < 0.1, 2 test). No significant differences were found between the duration of complete block by the different enantiomers, with full recovery occurring at 110–120 min (see Fig. 1B).
Analysis of AUC at this concentration also showed identical effects of the three drugs: 6.91 ± 0.75 x 103% x min R-Bup; 6.66 ± 0.64 x 103% x min S-Bup; and 6.70 ± 0.75 x 103%/min Rac-Bup.
Comparing the effects of the separate formulations between the two concentrations shows a supralinear concentration dependence for R-Bup (threefold higher incidence of complete block, 3.5-fold larger AUC) and for S-Bup (ninefold higher incidence of complete block, fourfold larger AUC) but an approximately proportional concentration dependence for Rac-Bup (1.6-fold higher incidence of complete block, 1.7-fold larger AUC). This comparison implies that Rac-Bup is nearer than the two enantiomers to its limiting effectiveness at the smaller concentration (closer to saturation) and thus, in terms of the listed assays, is the most potent formulation.
Epi (1:100,000; 54.6 µM) dramatically enhanced and prolonged the blocking effects of both Bup stereoisomers. At the small anesthetic concentration (0.0375%) in the presence of Epi, both R-Bup and S-Bup induced a complete CTMR block in 100% of rats (four of four and three of three, respectively). The duration of full block for R-Bup was 137.5 ± 10.3 min (n = 4), compared with 11.0 ± 2.5 min for the four rats with complete analgesia of the 12 rats injected without Epi; for S-Bup, complete analgesia lasted 126.6 ± 6.7 min (n = 3), compared with one rat completely blocked without Epi (n = 14). Cutaneous nociception fully recovered at 3.0–3.5 h for S-Bup + Epi, and at 4 h for R-Bup + Epi.
When 0.075% Bup enantiomers were co-injected with Epi, complete analgesia occurred in 100% of rats for both R-Bup (11 of 11) and S-Bup (7 of 7). The time course of analgesia, assayed as percentage of MPE, is shown in Figure 2A for Epi at 1:100,000. Epi significantly prolonged the complete block of CTMR by S-Bup to 145 ± 8 min (n = 7) (from 44 ± 8 min, for the seven rats with complete analgesia of 11 rats injected without Epi); complete block by 0.075% R-Bup + Epi continued for 192 ± 6 min (n = 11) (compared with 49 ± 5 min, n = 11 without Epi). Thus, full block of nociception produced by R-Bup in the presence of 1:100,000 Epi outlasted full block induced by S-Bup at the same concentration (P < 0.001) (Fig. 2A).
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, 0.075% R-Bup + Epi, n = 11; and 
, 0.075% S-Bup + Epi, n = 7; P < 0.001 at 160 min and 210–230 min; P < 0.01 at 175–200 min); and B, 1:400,000 Epi (When Epi was used at a smaller concentration (1:400,000) with the separate enantiomers, a similar complete block duration occurred (R-Bup, 187 ± 12 min, n = 6 and S-Bup, 164 ± 8 min, n = 7; P > 0.05), and at no time during the block was the analgesia from the two drugs significantly different (Fig. 2B). Also, the durations of complete block were only slightly less than those when 1:100,000 Epi was used (Fig. 2A), raising the question about whether Epi’s direct actions were extending into the 3- to 4-h period when block regressed and, indeed, whether Epi’s actions in this assay were purely vascular in origin. Therefore, experiments were conducted with Epi alone.
Control experiments with Epi showed that the catecholamine itself at 1:100,000 induced an unexpected, transient, partial block of CTMR. Complete analgesia occurred only in one of six rats for approximately 5 min. Maximal CTMR block, as seen in Figure 3A, produced by 1:100,000 Epi was 78.2 ± 3.8%. Onset of significant partial CTMR block was observed at 15.0 ± 1.6 min and full recovery at 91.0 ± 8.9 min (n = 5). To decrease Epi’s analgesic effect, we decreased the concentration at a constant volume (0.6 mL). At 1:400,000 dilution, complete analgesia was not observed in any rats and the maximal percentage of MPE for block of CTMR decreased to 57.8 ± 6.0 (n = 5, data not shown). Further dilution of Epi to 1:1,000,000; 1:2,000,000 and 1:5,000,000 (5.5–1.1 µM) led to attenuation of Epi-induced analgesia, with the most dilute solution producing no significant analgesia (Fig. 3A). Dilute Epi was then combined with the Bup enantiomers in tests of CTMR-assayed analgesia.
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, 1:1000,000 Epi, n = 6; *1:2,000,000 Epi, n = 6; and x, 1:5,000,000 Epi, n = 6); and B, effect of Epi (1:2,000,000) on the inhibition of cutaneous trunci muscle reflex induced by R-bupivacaine (R-Bup) (
, 0.06% R-Bup + Epi, n = 6) compared with S-bupivacaine (S-Bup) in equipotent dose (Because R-Bup enantiomer is known to be more potent than S-Bup for blocking neuronal Na+ channels and action potentials at the resting potential (1,4,5) we chose concentrations of these stereoisomers that are equipotent in vitro to compare their effectiveness for cutaneous analgesia in vivo. These concentrations, confirmed by pilot CTMR experiments (not shown), were found to be 0.06% R-Bup and 0.075% S-Bup. However, despite the nearly identical maximum degree of analgesia induced by these two formulations (three of seven rats with complete block for R-Bup versus two of six rats for S-Bup, P > 0.10), the full recovery from S-Bup induced analgesia took considerably longer, as seen in Figure 3B (101 ± 4.4 min, n = 6 vs 69 ± 2.8 min, n = 6; P < 0.05 between percentage of MPEs from R-Bup and S-Bup measured at 45–100 min after injection). Assuming that this difference arose from a greater vasoconstrictive activity of S-Bup, we sought to approach equivalent vascular flows by administering Epi in the small doses that have no analgesic effect per se, together with the shorter acting R-enantiomer. Although at 1:5,000,000 Epi failed to prolong the block by R-Bup, at 1:2,000,000 Epi significantly increased block duration. Addition of the catecholamine increased the fraction of animals having complete block from three of seven (43%) rats to four of six (67%) rats and extended the duration of complete block from 25 ± 7 min to 47 ± 9 min (P < 0.05). Also, the time when peak analgesia (as percentage of MPE) had regressed halfway to the baseline was doubled by adding Epi, from 45 ± 6 min to 91 ± 8 min (P < 0.01). As a result, the entire time course of CTMR block from 0.06% R-Bup (plus Epi) became indistinguishable from that from 0.075% S-Bup. Importantly, the period when R-Bup block was increased to significance because of Epi inclusion, 75–100 min (Fig. 3B), was far beyond the 30–40 min time postinjection when this dilution of Epi showed any analgesic activity, (Fig. 3A).
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Discussion |
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The results of this study indicate that the overall profile of cutaneous analgesia from Bup depends on pharmacodynamic and pharmacokinetic factors. Whereas R-Bup is intrinsically more potent for impulse blockade in vitro than S-Bup (1,4,5), it may have less vasoconstrictive activity. When a less concentrated solution of R-Bup was combined with a nonanalgesic concentration of Epi, the resulting cutaneous analgesia had the same course as from more concentrated S-Bup alone. The experimental findings support the earlier suggestion (8,14) that the longer duration of cutaneous block by S-Bup originates from its greater vasoconstrictor activity. Remarkably, the combined neural and vascular actions of the separate enantiomers appears to provide an overall advantage in potency for the racemic drug at small concentrations.
Regional anesthesia in vivo may show enantioselective actions for both pharmacodynamic and pharmacokinetic reasons. Pharmacodynamically, the relative potencies of R-Bup and S-Bup will depend on the test conditions. Voltage-clamp studies of neuronal and cardiac Na+ channels show that in depolarized membranes R-Bup is substantially more potent than S-Bup, however, at the resting potential Na+ blockade is equal for the two enantiomers (5,7). This voltage-dependent action explains why R-Bup’s greater potency may influence cardiac action potentials to have 150–250 ms depolarizations, and is consistent with its more potent cardiac action and related toxicity in vitro and in vivo (6,16). The stereoselective actions we detect here for infiltration analgesia may reflect a somewhat depolarized cutaneous nerve ending compared with the axon membranes that bind drugs during the nonstereoselective in vivo sciatic nerve block (7).
The vascular actions of local anesthetics that influence their local disposition are varied. Both vasoconstriction and vasodilation have been reported and net vascular effects are dependent on the local anesthetic species, its concentration, and the particular vascular bed under study. Spinal cord blood flow was decreased by Rac-Bup (20 mg, 0.4% solution), and addition of Epi, which prevented the vasodilation produced by tetracaine and lidocaine, had no effect on the decrease in blood flow produced by Bup (17). Although increasing the smaller concentrations of Rac-Bup up to 0.01% resulted in progressively greater vasoconstriction, even larger concentrations (0.1% to 0.25%) resulted in vasodilation of precapillary arterioles in the rat cremaster muscle in vivo (18). Similarly, skin capillary blood flow in humans was decreased after subcutaneous injections of 0.2 mL 0.025% Rac-Bup but increased at concentrations of 0.25% to 0.75%.1 By comparison, dilute Rac-Bup (0.025%) reduced skin capillary blood flow only one-half as much as saline plus 1:200,000 (5 µg/mL) Epi.1
The direct topical application of local anesthetics to rat sciatic nerve also demonstrated Rac-Bup’s inversely dose-dependent reductions in nerve blood flow, with the lowest concentrations (0.25%) producing the greatest reduction and the largest concentrations (0.75%) producing the least (19). This contrasts with the actions of lidocaine in which increasing concentrations of anesthetic resulted in greater reductions in nerve blood flow (19,20).
Taken together, these observations show that Rac-Bup is intrinsically vasoconstrictive at the lowest concentrations (<0.025%; 0.8 mM) but that larger concentrations produce a dominating vasodilatory action. A similar pattern occurring with the nonchiral drug lidocaine (18,19) challenges the notion that the separate enantiomers of Bup are responsible for these opposing vascular responses. Vasoconstriction may result from a direct action of anesthetics on vascular smooth muscle, such as an elevation of [Ca2+]in (Wingrove D, Weiss E, Strichartz G, 1992, unpublished data; cf. Johnson M, Uhl CB2), whereas vasodilation may follow the presynaptic inhibition of tonically active sympathetic efferents, because it can be antagonized by, ostensibly, postjunctionally acting Epi. Our findings may be interpreted as showing that the first action is predominant for S-Bup and the second action is predominant for R-Bup, as suggested originally by Luduena et al. (8), although we have no direct evidence this is so.
The use of Epi in concentrations from 1:200,000 to 1:3,200,000 is recommended for prolongation of analgesia after local infiltration (21). Larrabee et al. (22), using the laser Doppler method for quantification of blood flow changes in pig skin, found no significant differences in the reduction of flow between subcutaneous Epi at concentrations of 1:50,000 (80% reduction), 1:100,000 (80% reduction), and 1:200,000 (55% reduction), although there was a significant (P = 0.0001) difference in flow between Epi at 1:400,000 (25% reduction) and all others. If rat and pig skin have a similar vascular sensitivity to Epi, then, the small concentration used here to enhance the duration of analgesia from R-Bup (1:2,000,000) is approximately 0.1 of the 50% effective dose for vasoconstriction and should cause only a minor decrease in blood flow. That we observed a doubling in the duration of R-Bup-induced analgesia under these conditions raises an apparent discrepancy that might have three explanations: (a) sympathetic control of vascular tone differs between the rat and pig, (b) Epi has vascular effects that are altered by Bup, and (c) the block-extending effects of Epi at 1:2,000,000 are not because of vascular actions.
The second possibility is consistent with the previously mentioned speculation that vasoconstriction by dilute Bup (especially R-Bup) results from mild elevation of intracellular Ca2+ of smooth muscle and a synergistic action with Epi’s facilitation of myogenic tension. Alternatively, vasoconstriction by Epi could result in a transient neural ischemia that directly depolarizes nerve fibers and selectively potentiates the block by R-Bup (5). Such an ischemia-induced nerve block may account for the transient, partial analgesia so apparent after injection of Epi alone at 1:000,000 (55 µM) down to 1:1,000,000 (5.5 µM). The latency for this action, 15–20 min (Fig. 3A), was distinctly longer than that for almost immediate-acting Bup (Fig. 1A, e.g., R-Bup), consistent with an accumulating reaction to ischemia or to a receptor-second messenger-mediated effect in neurons, rather than a direct local anesthetic action (23). Because under normal conditions, primary afferent neurons and their sensory endings do not show catecholamine sensitivity (24), any direct neuronal action of Epi on nociceptors is surprising. Moreover, other studies report that 
1-agonists (norepinephrine and phenylephrine) injected intradermally may induce thermal hyperalgesia in humans (25), and that Epi can produce mechanical hyperalgesia in rats (26). Our observations of acute analgesia are inconsistent with those reports, and we can only speculate that Epi has other activities, mediated by vascular and neural targets, in the hairy skin of the rat.
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Acknowledgments |
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Supported, in part, by a grant from Chiroscience, Ltd., UK, the United States Public Health Service, and the National Institutes of Health Grant GM35647.
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Footnotes |
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1Carpenter RL, Morell RC. Bupivacaine and lidocaine are more potent vasodilators than mepivacaine: Effects determined by anesthetic concentration [abstract]. Anesthesiology 1988;69:A873
2Johnson ME, Uhl CB. Lidocaine elevates cytoplasmic calcium to toxic levels in a neuronal cell line [abstract]. Anesthesiology 1996;85:A649.
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  Y. S. Choi, Y. S. Jeong, S.-H. Ok, I.-W. Shin, S. H. Lee, J.-Y. Park, E. M. Hwang, Y.-S. Hah, and J.-T. Sohn The Direct Effect of Levobupivacaine in Isolated Rat Aorta Involves Lipoxygenase Pathway Activation and Endothelial Nitric Oxide Release Anesth. Analg., February 1, 2010; 110(2): 341 - 349. [Abstract] [Full Text] [PDF]
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C.-F. Wang, P. Gerner, B. Schmidt, Z. Z. Xu, C. Nau, S.-Y. Wang, R.-R. Ji, and G. K. Wang Use of Bulleyaconitine A as an Adjuvant for Prolonged Cutaneous Analgesia in the Rat Anesth. Analg., October 1, 2008; 107(4): 1397 - 1405. [Abstract] [Full Text] [PDF]
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A. Haderer, P. Gerner, G. Kao, V. Srinivasa, and G. K. Wang Cutaneous Analgesia After Transdermal Application of Amitriptyline Versus Lidocaine in Rats Anesth. Analg., June 1, 2003; 96(6): 1707 - 1710. [Abstract] [Full Text] [PDF]
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