Physicochemical Modification of Lidocaine Uptake in Rat Lung Tissue

Abstract The uptake of lidocaine, methyllidocaine, bupivacaine, etidocaine was studied in rat lung slices at different pH-values. The accumulation of the quaternary analogue, methyllidocaine, was not changed in the pH interval 7.0-8.0. The uptake of the three other substances was about 3-4 times lower at pH 7.0 than at pH 8.0. The rank order of distribution at a fixed catiodbase ratio was bupivacaine>etidocaine>lidocaine. Interactions between lidocaine and other substances were studied in lung slices and in isolated perfused lungs. Bupivacaine and nortriptyline counteracted the accumulation of ¹⁴C-lidocaine in lung slices in a dose-dependent manner. Nortriptyline was more effective than bupivacaine. In isolated perfused lung, bolus injections of nortriptyline and lidocaine rapidly displaced ¹⁴C-lidocaine from the tissue. In this study we suggest that the base form of local anaesthetics accumulate in the lung tissue, while the cationic form binds to accessible binding sites in the cell membranes.     

Transport and binding of lidocaine by lung slices and perfused lung of rats

The accumulation of radioisotopically labelled lidocaine was investigated in lung slices and perfused lungs of rats. Lidocaine was taken up by rat lung slices incubated in an oxygenated physiological solution (pH 7.4) at 37 degrees. 14C-lidocaine accumulated in lung slices to a much greater extent than did 3H-sucrose, and the lidocaine space was approximately 7 times that of the extracellular space. No metabolism of lidocaine took place during the incubation period. The accumulation of lidocaine was inhibited by low temperature, while anaerobic conditions had no inhibitor effect. The uptake of lidocaine (0.028 mM) was slightly antagonized by high concentrations of Ca2+ (10 mM). The isolated perfused lung model was used for studying the pulmonary absorption of lidocaine from the vascular bed. Lidocaine was rapidly extracted from the perfusion solution and the drug appeared to accumulate in at least two compartments. It seems that in the rat lung a portion of the lidocaine taken up had accumulated within the cells, while some of it may be fixed to the cell surfaces.     

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 t_1/2z 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. © 1997 by John Wiley & Sons, Ltd.     

Pharmacological profile of RWJ 20085: A new,potent, long-acting local anesthetic

RWJ 20085 is a potent, long-acting local anesthetic that has been studied in vivo and in vitro relative to several clinically active agents. In mice, RWJ 20085 [ED₅₀ = 0.0078% (0.0053–0.011%)] was more potent by perineural infiltration than bupivacaine [ED₅₀ = 0.035% (0.026–0.046%)], etidocaine [ED₅₀ = 0.025% (0.016–0.035%)], or lidocaine [ED₅₀ = 0.18% (0.13–0.26%)]. The onset of action of each compound was 5 minutes, and the duration was 90 minutes for RWJ 20085 and 30 minutes for bupivacaine or etidocaine while lidocaine was active for only 15 minutes. In the rabbit corneal assay, RWJ 20085 [ED₅₀ = 0.012% (0.0049–0.023%)] was more potent than bupivacaine [ED₅₀ = 1.4% (0.47–3.05%)]. The lowest topical local anesthetic ED₅₀ of each agent was observed within 5 or 15 minutes after administration, and RWJ 20085 was active for 300 minutes, whereas bupivacaine and etidocaine were active for 90 or 45 minutes, respectively. In the guinea pig intradermal assay RWJ 20085 [ED50 = 0.017% (0.0094–0.028%)], bupivacaine [ED₅₀ = 0.016% (0.0078–0.028%)], and etidocaine [ED₅₀ = 0.02% (0.0093–0.042%)] were equipotent while lidocaine [ED₅₀ = 0.072% (0.040–0.12%)] was less potent. The onset of action of each compound was 5 minutes. The duration of action of RWJ 20085 and etidocaine was 60 minutes, whereas bupivacaine and lidocaine were active for 45 and 15 minutes, respectively. In the frog isolated-sciatic nerve preparation, similar concentrations of RWJ 20085 (2.5 × 10^?3M) and lidocaine (5.0 × 10^?3M) produced a 50% reduction of the amplitude of the pretreatment action potential; however, bupivacaine and etidocaine were each effective at a lower concentration (5.0 × 10^?4M). When their intramuscular therapeutic ratios (TR = lethal dose LD₅₀/local anesthetic ED₅₀) were calculated in mice, the therapeutic ratio of RWJ 20085 (82) was less than that of etidocaine (103) but was larger than that of either lidocaine (36) or bupivacaine (29). Calculation of the therapeutic ratios by using the intravenous LD₅₀ values suggests that lidocaine would have the smallest margin of safety if inadvertently administered by the intravenous route. The therapeutic ratios of the other agents were larger than that of lidocaine; however, there was little difference among them. RWJ 20085 has a low potential for dermal irritation as shown in rabbits and has no liability for contact sensitization as shown in guinea pigs. RWJ 20085 may have clinical utility as an injectable and/or topical local anesthetic.     

The uptake of bupivacaine in an in situ isolated perfused rabbit lung preparation.

A double indicator technique has been used in an in situ isolated perfused rabbit lung model to examine the first pass effect of the lung on systemic bupivacaine concentrations. Bupivacaine (0.5 mg/kg) was given in two consecutive boluses to six in situ isolated perfused New Zealand White rabbit lung preparations. The mean recovery (first bolus) of bupivacaine was 62.6% +/- 6.3 (S.E.M.), and 63.7% +/- 10.2 (second bolus), suggesting bupivacaine accumulation in the lung. The average mean transit time for bupivacaine was 280.5% +/- 24.1 and 264.8% +/- 36.7 longer than ICG (Indocyanine Green) following the first and second boluses respectively (P less than 0.01). There were no differences in the first pass effect of the lung between the first and second boluses of bupivacaine. The profiles of the bupivacaine concentrations suggest that uptake is followed by accumulation and later back diffusion. This has implications for conditions that decrease the uptake and therefore increase the risk of systemic toxicity.     

The Uptake of Bupivacaine in an in situ Isolated Perfused Rabbit Lung Preparation

Abstract: A double indicator technique has been used in an in situ isolated perfused rabbit lung model to examine the first pass effect of the lung on systemic bupivacaine concentrations. Bupivacaine (0.5 mg/kg) was given in two consecutive boluses to six in situ isolated perfused New Zealand White rabbit lung preparations. The mean recovery (first bolus) of bupivacaine was 62.6% ± 6.3 (S.E.M.), and 63.7% ± 10.2 (second bolus), suggesting bupivacaine accumulation in the lung. The average mean transit time for bupivacaine was 280.5% ± 24.1 and 264.8% ± 36.7 longer than ICG (Indocyanine Green) following the first and second boluses respectively (P < 0.01). There were no differences in the first pass effect of the lung between the first and second boluses of bupivacaine. The profiles of the bupivacaine concentrations suggest that uptake is followed by accumulation and later back diffusion. This has implications for conditions that decrease the uptake and therefore increase the risk of systemic toxicity.     

Uptake and disposition of putrescine, spermidine, and spermine by rabbit lungs

The pulmonary uptake and accumulation of the three polyamines in intact, ventilated, and perfused rabbit lungs was investigated. Lungs were perfused using Krebs-Ringer bicarbonate buffer with albumin in which putrescine, spermidine, or spermine were included at an initial concentration of 10(-3), 10(-2), 10(-1), 5, 10, or 20 mM. At a 5 mM concentration of spermidine and spermine, the uptake by isolated lungs reached a steady state equilibrium in 20-30 min of perfusion. This did not occur for putrescine, which showed linear uptake throughout the entire period of the 60-min perfusion. The lung uptake of putrescine for all perfusate concentrations was greater than that of spermidine or spermine, but all three showed concentration-dependent linear uptake. In the presence of harmaline (1 mM) and ouabain (1 mM), isolated perfused rabbit lungs showed a decrease in uptake of putrescine although no effect was seen for spermidine and spermine. Perfusate containing decreased sodium showed no effect on putrescine uptake by isolated rabbit lungs, but there was a significant increase in the uptake of spermidine and spermine. Significant uptake of all three polyamines was also observed when incubated separately with rabbit lung slices for 60 min. HPLC analysis of lung, the perfusate samples, lung slices, and the incubation medium after a 60-min incubation did not indicate the presence of metabolites of these polyamines. Likewise, the analysis of the lung homogenate incubated with polyamines did not show any metabolites confirming the absence of detectable pulmonary metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Concentration of (+/-)-propranolol in isolated, perfused lungs of rat.

1 The metabolism and the accumulation of (+/-)-propranolol have been studied in isolated lungs of the rat, perfused with an artificial medium. 2 Little or no metabolism took place during the perfusion periods (up to 10 minutes). 3 Accumulation was observed with high tissue/medium ratios for substrate concentrations of 0.2 muM to 1 mM; there was evidence for saturability, but no real plateau could be seen. The presence of two binding sites with different affinities was established. 4 Cold greatly inhibited the accumulation process at low substrate concentrations, but had no effect at 1 mM propranolol. 5 Inhibition of accumulation was measured in the presence of imipramine, desmethylimipramine, nortryptiline, chlorpromazine and of Na+-free medium. Cocaine, 5-hydroxytryptamine and noradrenaline had no effect. Lidocaine enhanced the accumulation process. Release of previously bound propranolol was accelerated in the presence of propranolol and imipramine, unaffected by a Na+-free medium and decreased by cold and by lidocaine. 6 Experiments on lung tissue slices yielded qualitatively similar results to those obtained with perfused lungs. Ouabain and KCN had no or little effect on propranolol accumulation.     

Displacement of lidocaine from serumα 1-acid glycoprotein binding sites by basic drugs

Since little is known of the number and types of binding sites on alpha 1-acid glycoprotein (AAG) and because drug-drug protein binding interactions often fail to fit a simple model, a study of the effect of 9 known AAG binding drugs on lidocaine free fraction (LFF) was performed. Serum was obtained from 10 healthy males, pooled and various concentrations (from 0.15 to 1000 micrograms/ml) of amitriptyline, bupivacaine, chlorpromazine, disopyramide, imipramine, meperidine, nortriptyline, propranolol and quinidine were added. LFF was determined by equilibrium dialysis at an initial lidocaine concentration of 2.0 micrograms/ml. LFF increased from 0.30 +/- 0.019 (mean +/- SD) in the absence of displacing agents to maximum values ranging from 0.59 (nortriptyline) to 0.73 (bupivacaine). Plots of LFF vs. the logarithm of displacing drug concentration yielded simple sigmoidal curves in all cases. LFF was increased 50% by an initial bupivacaine concentration of 6.0 micrograms/ml with all other drugs requiring more than 10 micrograms/ml to increase LFF to that extent. Lidocaine binding in a 4.5 g/dl albumin solution was unaffected by concentrations of quinidine, meperidine, nortriptyline and bupivacaine up to 200 micrograms/ml. Addition of AAG to serum reduced LFF as expected. A plot of the reciprocal of bound drug concentration vs. the reciprocal of free drug concentration in the presence and absence of quinidine suggested a competitive binding interaction. These data indicate that the binding interactions between lidocaine and the various displacing compounds are not significantly complicated by cooperative effects and that, with the possible exception of bupivacaine, displacement of lidocaine by any of these drugs is likely to be of clinical significance.     

Transfer of Lidocaine and Bupivacaine Across the Isolated Perfused Human Placenta *

Abstract: Drug permeability and pharmacokinetics through the placenta are important factors determining foetal drug exposure. The purpose of the present study was to establish a perfused human placental cotyledon system to assess the placental transfer of lidocaine and bupivacaine, widely used local anaesthetics in obstetric anaesthesia. Term placentas were obtained immediately after delivery with maternal consent and a two-hour recycling perfusion of a single placental cotyledon was performed. Bupivacaine or lidocaine with antipyrine as a reference compound were added to the maternal reservoir and their disappearance from the maternal circulation and appearance to the foetal circulation were followed in five experiments for each drug. Drug concentrations were measured by gas chromatography. Bupivacaine disappeared more rapidly from the maternal circulation than lidocaine. At 2 hr, bupivacaine foetal:maternal concentration ratio was 0.56±0.12 and 14.6%±2.99 of the total circulating amount was found in the foetal circulation. Lidocaine concentration increased more in the foetal circulation and the foetal: maternal concentration ratio at 2 hr was 0.90±0.09 (P<0.01), and 22.1%±2.21 (P<0.01) was found in the foetal circulation. The maternal to foetal transfer of bupivacaine and lidocaine were 67.2%±0.153 and 98.9%+0.07 (P<0.05) of that of freely diffusable antipyrine, respectively. Both amide local anaesthetics crossed the dually perfused human placenta rapidly. Bupivacaine disappeared faster than lidocaine from the maternal circulation but less was transferred to foetal circulation. This difference is probably explained by the greater lipophil-icity of bupivacaine and hence higher placental binding. These results suggest less foetal drug exposure with bupivacaine than lidocaine.     

Structure-activity correlations of amines inhibiting active uptake of paraquat (Methyl viologen) into rat lung slices

Analysis of amine structure with respect to inhibitory potency utilized a new method for determining equipotent inhibitor concentrations of paraquat uptake by lung slices. Fifteen N-alkyl homologues of paraquat (viologens) were tested and inhibition of lung uptake of paraquat was found to be a function of the inductive effect and steric bulk of groups attached to the nitrogens of 4,4′-bipyridyl. Several classes of amine inhibitors were examined. Polyamines were generally more potent than compounds containing only one quaternizable nitrogen at pH 7.4. α, ω-Diaminoalkanes were the most potent inhibitors of paraquat accumulation by lung slices.     

Effect of pH on the myocardial uptake and pharmacodynamics of propafenone in the isolated rabbit heart

The influence of pH on the myocardial disposition of propafenone was studied in isolated perfused rabbit hearts. Five pH groups were evaluated: pH 7.0, 7.2, 7.4, 7.6, and 7.8. Hearts were perfused with a modified Krebs-Henseleit buffer containing approximately 100 ng/ml propafenone. Myocardial propafenone accumulation was determined from differences in the aortic perfusate and coronary sinus effluent propafenone concentrations. The myocardial accumulation of propafenone was significantly pH dependent. The steady-state propafenone concentration increased from 5.9 +/- 1.3 micrograms/g at pH 7.0 to 13.2 +/- 3.8 micrograms/g at pH 7.4 and 24.2 +/- 3.5 micrograms/g at pH 7.6. The time to reach steady-state myocardial propafenone levels increased proportionately with the increased propafenone levels. Steady-state was not reached by 150 min at pH of 7.6 or 7.8. Percent change in QRS duration was measured to monitor the electrophysiologic effect of propafenone. The relationship between the myocardial drug concentration and the measured changes in QRS also was evaluated. The myocardial concentration-effect relationships were linear over the observed myocardial concentration range. The slopes of these concentration-effect relationships were similar for three groups (pH 7.0, 7.2, and 7.4). Over the pH range 7.0-7.4, the steady-state effect increased as a function of pH and correlated with the differences in propafenone steady-state myocardial concentrations. However, at alkalotic pH, the concentration-effect relationship was shifted to the right; less effect was observed than might be predicted for the myocardial propafenone concentration. Thus, small changes in pH may significantly alter the myocardial distribution and pharmacodynamics of propafenone.     

精密肺切片方法学的建立及中性红比色法检测肺切片活力的有效性

目的　建立精密肺切片方法学,探讨中性红比色法检测肺切片活力的有效性。方法　 1%低熔琼脂糖充盈肺组织,振荡切片机切片,厚度分别为 400、500、600、700μm, 培养液pH分别为 6 8、7 0、7 2、7 4,预培养 1h,于 24孔培养板持续浸润培养 0、2、4、6h,以中性红比色法,MTT比色法乳酸脱氢酶漏出率,超氧化物歧化酶活力为检测手段确定肺切片最适制备培养条件。结果　肺切片厚 600μm,培养液pH7 0时,活力保持最佳,可稳定维持 6h;不同厚度肺切片中性红摄取率与MTT还原量呈正相关 (r1 = 0 91,P0 05),不同pH培养液培养的肺切片中性红摄取率与MT还原量呈正相关(r2 =0 98,P<0 01 )。结论　精密肺切片是简便可行、有待发展的新型体外模型,中性红比色法操作简便,结果稳定,灵敏准确,可作为肺切片活力判定指标。     

Dependence of Lung Uptake of Lidocaine in Vivo on Blood pH

Abstract: Lung uptake of lidocaine was studied in anaesthetized Swedish landrace pigs using the double indicator dilution method with indocyanine green dye as i ntravascular marker. The pigs were given infusions of sodium bicarbonate or hydrochloric acid to arterial blood pH in the range 7 to 8. Lung uptake of lidocaine was found to correlate statistically significant (P < 0.05) with pH. Lung uptake in the first injection before the infusion of acid or base, was 42 ± 4 (X? ± S.E.M.)%. The uptake was not found to correlate to cardiac output. The conclusion from this work is therefore that lung uptake of xenobiotic amines in part is dependent on blood pH.     

Pulmonary uptake of bupivacaine in isolated perfused rat lung

The ability of rat lung to remove the local anaesthetic drug bupivacaine from the blood was studied in isolated organs which were perfused either in an open (single-pass mode) or in a closed system (recirculating medium).Isolated perfused rat lungs exhibited a very low capacity to metabolize bupivacaine within 3 h during which the drug circulated continuously through the organ. The clearance values differed only by 0.2 ml/min from the control parameters in sham perfusions. The calculated extraction ratio was 0.2% and the elimination half-life was about 210 min. The volume of distribution of bupivacaine was 133 ml which remarkably surmounted the reference values obtained for sham perfusions.The distribution of bupivacaine into the pulmonary tissue was investigated applying the multiple indicator dilution technique to isolated lungs perfused in the single-pass mode. The mean elimination time of model compounds for distribution into the intravascular space, ¹⁴C-inulin, and the total water space, ³H-water, were 68 and 75 s at a flow rate of 6 ml/min. The volume of distribution was 5.9 ml for inulin and 6.5 ml for water. The mean transit time for concomitantly injected bupivacaine was 221 s and the volume of distribution was 14.4 ml. The respective parameters of sham perfusions performed without an isolated organ were substantially lower, i.e. mean elimination time 50, 50 and 61 s and distribution volume 4.9, 5.0 and 6.1 ml for inulin, water and bupivacaine.The volume of distribution during single-pass contact of bupivacaine to lung was not substantially influenced by an increase of the flow rate from 6 to 9 and 12 ml/min whereas the mean transit time dropped from 221 to 121 and 108 s, respectively. These results support the assumption that bupivacaine is extensively retained by the pulmonary tissue and that elimination of bupivacaine by metabolism can be neglegted for lung.The hemodynamic parameters of bronchiolar perfusion in the artificially perfused lung were determined using two fluorochrome-labeled macromolecular proteins, i.e. fluorescein-isothiocyanate (FITC)- and lissamine-rhodamine-B 200 (RB 200)-labeled globulin. After 10 min of perfusion at a flow rate of 12 ml/min in the closed system an area of 10.8070 of the peribronchiolar tissue area contained the dye-label FITC. A very similar index (10.1%) of dye-coloured capillaries was obtained when the lungs of anaesthetized rats were examined 10 min after intravenous injection of the fluorochrome into the pulmonary artery in vivo. In isolated perfused rat lungs receiving both FITC and RB 200 59.5% of FITC-labeled capillaries were reached by the second fluorochrome within 2 s. This fraction accounted for 93.3% after 10 s of circulation time. This proves that isolated rat lungs were well perfused in vitro.     

Simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone

A gas-liquid chromatographic method for the simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone in serum is described. The drugs and the internal standard, prilocaine, are extracted from 1 ml of serum. The procedure involves a two-step extraction and injection of the extract into a gas chromatograph equipped with a 10-ft OV-11 glass column and a nitrogen-phosphorus detector. The temperature gradient program results in a run time of 16 min and retention times for meperidine, prilocaine (internal standard), lidocaine, etidocaine, mepivacaine, methadone, and bupivacaine of 3.8, 5.4, 6.0, 8.7, 11.0, 11.7, and 14.8 min, respectively. Standard curves for all drugs were linear over the 80 to 2,000-ng/ml range and recovery of all components averaged 97 +/- 2% with the lowest detection limit of 10 ng/ml for all drugs except meperidine and methadone, which were 20 ng/ml. The within-day coefficients of variation ranged from 12 to 8% at 500 ng/ml. The day-to-day coefficients of variation of the slope and intercept values ranged from 2 to 0% and 130 to 3%, respectively. Response factors of the nitrogen-specific collector varied with the drug analyzed and resulted in peak area variation at constant offset and attenuation of 30%. This method is intended and adequate for therapeutic monitoring of chronically treated pain patients who are being given various combinations of local anesthetic and/or narcotic agents.     

Comparison of pulmonary accumulation of pyrilamine and pyrilamine N-oxide

Our previous studies have indicated that a phenothiazine drug, chlorpromazine, and a tricyclic antidepressant, imipramine, are metabolized by the isolated perfused rat lungs via N-oxidation from whence their N-oxides are released into the circulation. This work was undertaken to compare the pulmonary accumulation of another pneumophilic tertiary amine drug, pyrilamine, with that of its N-oxide. Approximately 10-fold greater accumulation of pyrilamine than that of its N-oxide was observed in the mouse lung after a single pass perfusion with 40 microM of the drug for a 3 min period. The largest difference between accumulation of pyrilamine and its N-oxide was noted in the lung among the various tissue slices tested, suggesting the tissue specificity of affinity.     

Tricyclic Antidepressant Agents. I. Comparison of the Inhibition of the Uptake of 3H-Noradrenaline and 14C-5-Hydroxytryptamine in Slices and Crude Synaptosome Preparations of the Midbrain-Hypothalamus Region of the Rat Brain

Abstract: The simultaneous uptake of ³H-I-noradrenaline (NA) and ¹⁴C-5-hydroxytryptamine (5-HT) in slices from the midbrain-hypothalamus region of the rat brain was compared with the corresponding uptake in crude synaptosome preparations of the same brain region. In both preparations the uptake of the two amines was selective at the concentration used (1 x 10^-7 M or lower). The K_M values for the amines (NA: 2 x 10^-7 M in synaptosomes and 5 x 10^-7 M in slices; 5-HT: 8 x 10^-8 M in synaptosomes and 6 x 10^-7 M in slices) and the inhibitory concentrations (IC₅₀) of the antidepressant agents were lower in the synaptosome experiments than in the slices experiments. Moreover the order of the inhibitory activities differed between the two preparations. In the slices experiments the NA uptake was inhibited most markedly by desipramine followed by imipramine > chlorimipramine = nortriptyline ≥ amitriptyline ≥ chlordesipramine whereas in the synaptosome experiments the order was desipramine > nortriptyline ≥ chlordesipramine ≥ imipramine > amitriptyline ≥ chlorimipramine. For the 5-HT uptake in slices the order of activity was: chlorimipramine > imipramine ≥ amitriptyline ≥ chlordesipramine = desipramine ≥ nortriptyline whereas in the synaptosome preparations the order was: chlorimipramine > imipramine ≥ amitriptyline ≥ chlordesipramine > nortriptyline = desipramine. The role of protein binding and diffusion barriers in the causation of the difference in the results obtained with the two preparations is discussed.     

Effect of tricyclic antidepressants on the uptake of noradrenaline and 5-hydroxytryptamine by rat brain slices incubated in buffer or human plasma

Summary A method is described for measuring the inhibition of transmitter uptake into noradrenaline (NA) and 5-hydroxytryptamine (5-HT) neurons incubated in plasma from patients receiving tricyclic antidepressants. The potency was determined of the tricyclic antidepressants nortriptyline and chlorimipramine in inhibiting NA and 5-HT uptake by rat brain slices incubated in buffer or human plasma. As expected, nortriptyline produced greater inhibition of NA than of 5-HT uptake, and chlorimipramine had more effect on 5-HT uptake. These drugs caused 10 to 100 times more inhibition of monoamine uptake from buffer than from plasma, probably because they were bound to plasma proteins. Plasma from patients taking nortriptyline inhibited NA uptake by brain slices 35—55% of the value found in each subject in a pretreatment sample. During long term therapy the concentration of a drug in plasma should be in equilibrium with its concentration at central receptor sites. Thus, it seems likely that the present results reflect the inhibition of uptake by the central monoaminergic neurons of patients taking tricyclic antidepressants. The method also permits evaluation of inter-individual differences in the effects of various antidepressants on NA and 5-HT nerve terminals. It can also be used to evaluate the relative effects of various antidepressants on these two monoaminergic systems.     

Actions of three local anaesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax)

The new local anaesthetic ropivacaine (LEA 103) like lidocaine and bupivacaine used as references, blocked cardiac sodium channels in a use-dependent fashion. At equimolar concentrations lidocaine had the lowest efficacy and bupivacaine the highest. The action potential was shortened and the plateau was depressed at high concentrations of each drug. Pacing a papillary muscle at 3.3 Hz in the presence of all three drugs resulted in a marked use-dependent accumulation of block (P less than 0.01). The accumulated block slowly dissipated after rest. At -90 mV holding (= resting) potential, and at a concentration of 10 microM, the time constant for recovery from block was 186 msec. in lidocaine (n = 4), 1.4 sec. in ropivacaine (n = 7), and 2.1 sec. in bupivacaine (n = 7). Lidocaine decreased Vmax progressively at high rates of stimulation, but not significantly at rates below 2 Hz. Ropivacaine progressively decreased Vmax significantly at rates above 1 Hz, but to a lesser degree than bupivacaine. The use-dependent action of the drugs was increased at more depolarized (less negative) holding potentials, whereas at more hyperpolarized potentials the block was diminished. Lidocaine and ropivacaine could be readily dissociated from the receptors at more hyperpolarized membrane potentials (-100 to -120 mV), whereas bupivacaine bound much harder. All three drugs blocked sodium channels more effectively after a long single conditioning pulse. Bupivacaine had the most prominent effect, and lidocaine was least effective. Bupivacaine and ropivacaine seem to interact with the inactivated state of the sodium channels, whereas lidocaine acted on both the open and on the inactivated state of the channels.(ABSTRACT TRUNCATED AT 250 WORDS)