The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of lidocaine

Injection of lidocaine into the subcutaneous tissues by the tumescent technique results in a delayed absorption of the local anesthetic and has allowed clinicians to exceed the maximum recommended dose of lidocaine without reported complications. However, little knowledge exists about the mechanisms that permit such high doses of lidocaine to be used safely with this technique. The presence of low concentration epinephrine and the increased tissue pressure resulting from the tumescent injection have both been implicated as important factors, but neither has been studied in patients whose results were not altered by the variability of the suction procedure. The purpose of this work was to determine the effect of tissue pressure during tumescent injection and presence of low concentration epinephrine on the absorption of lidocaine from subcutaneous tissues in human volunteers. Twenty healthy female human volunteers were randomized into four study groups. After body fat measurements, all subjects received an injection of 7 mg/kg of lidocaine into the subcutaneous tissues of both lateral thighs. The injected solution consisted of 0.1% lidocaine and 12.5 meq/liter sodium bicarbonate in normal saline with or without 1:1,000,000 epinephrine. Tissue pressure was recorded during injection using a specially designed double-barreled needle. The time required for injection was also recorded. Subjects in group 1 received lidocaine with epinephrine injected by a high-pressure technique. Group 2 subjects received lidocaine with epinephrine injected by a low-pressure technique. Group 3 subjects received lidocaine without epinephrine injected under high pressure. Group 4 subjects received lidocaine without epinephrine injected under low pressure. Following injection, sequential blood samples were drawn over a 14-hour period, and plasma lidocaine concentrations were determined by gas chromatography. No suction lipectomy was performed. Maximum tissue pressure during injection was 339 +/- 63 mmHg and 27 +/- 9 mmHg using high- and low-pressure techniques, respectively. Addition of 1:1,000,000 epinephrine, regardless of the pressure of injected fluid, significantly delayed the time to peak plasma concentration by over 7 hours. There was no significant difference in the peak plasma concentration of lidocaine among the four groups. Peak plasma concentrations greater than 1 mcg/ml were seen in 11 subjects. Epinephrine (1:1,000,000) significantly delays the absorption of lidocaine administered by the tumescent technique. High pressure generated in the subcutaneous tissues during injection of the solution does not affect lidocaine absorption. The delay in absorption may allow time for some lidocaine to be removed from the tissues by suction lipectomy. In addition, the slow rise to peak lidocaine concentration in the epinephrine groups may allow the development of systemic tolerance to high lidocaine plasma levels.     

Kinetics of local anesthetic inhibition of neuronal sodium currents. pH and hydrophobicity dependence.

This study assesses the importance of local anesthetic charge and hydrophobicity in determining the rates of binding to and dissociation from neuronal Na channels. Five amide-linked local anesthetics, paired either by similar pKa or hydrophobicity, were chosen for study: lidocaine, two tertiary amine lidocaine homologs, a neutral lidocaine homolog, and bupivacaine. Voltage-clamped nodes of Ranvier from the sciatic nerve of Bufo marinus were exposed to anesthetic externally, and use-dependent ("phasic") block of Na current was observed. Kinetic analysis of binding (blocking) rates was performed using a three parameter, piecewise-exponential binding model. Changes in extracellular pH (pHo) were used to assess the role of drug protonation in determining the rate of onset of, and recovery from, phasic block. For those drugs with pKa's in the range of pHo tested (6.2-10.4), the forward binding rate during a depolarizing pulse increased at higher pH, consistent with an increase in either intracellular or intramembrane concentration of drug. The rate for unbinding during depolarization was independent of pHo. The dissociation rate between pulses also increased at higher pHo. The pHo dependence of the dissociation rate was not consistent with a model in which the cation is trapped relentlessly within a closed channel. Quantitative estimates of dissociation rates show that the cationic form of lidocaine dissociates at a rate of 0.1 s-1 (at 13 degrees C); for neutral lidocaine, the dissociation rate is 7.0 s-1. Furthermore, the apparent pKa of bound local anesthetic was found to be close to the pKa in aqueous solution, but different than the pKa for "free" local anesthetic accessible to the depolarized channel.     

Plasma concentrations of monoethylglycinexylidide during and after breast augmentation

MEGX (monoethylglycinexylidide) is the main metabolite of lidocaine and is 83 percent as potent as an antiarrhythmic drug and with the same toxicity as lidocaine. In this study, plasma levels of MEGX were measured in 10 other wise healthy women during and after breast augmentation. A total dose of 825 to 1,280 mg of lidocaine of 0.2% and 0.5% lidocaine with epinephrine corresponding to 16.3 to 21.8 mg/kg (mean, 18.2 mg/kg) was injected in the spatium between the pectoralis muscle and the mammary gland. The peak plasma concentrations of MEGX varied between 0.40 and 0.99 microg/ml (mean, 0.49 microg/ml) and occurred between 8 and 12 hours (mean, 9.1 hours), postoperatively. In three patients, the concentration of MEGX was still increasing after 12 hours. In comparison, the peak plasma concentrations of lidocaine varied between 0.96 and 3.12 microg/ml (mean, 1.49 microg/ml) and occurred between 4 and 12 hours (mean, 7.3 hours) after the end of the injection. The peak lidocaine + MEGX concentrations varied between 1.45 and 3.58 microg/ml (mean, 2.02 microg/ml) and occurred between 5 and 12 hours (mean, 8.5 hours), postoperatively. These data suggest that MEGX might contribute to lidocaine toxicity when high doses of lidocaine are injected. The substantial interindividual variation strongly indicates that recommendations about maximum safe doses of lidocaine should be made with caution.     

A new system of infiltration anesthesia and sedation for plastic surgery

This technique produces patient cooperation during the phase of local anesthetic injection by judicious use of intravenous ketamine. The addition of diazepam and a narcotic drug to low-dose ketamine may account for a low incidence of hallucinations and psychic sensations. The use of a dilute solution of lidocaine and a very low concentration of epinephrine allows large areas to be anesthetized. The ultralow concentration of epinephrine provides effective vasoconstriction. The result is good patient acceptance, a stable blood pressure and heart rate, and a low incidence of complications classically associated with local anesthetic toxicity.     

Pharmacokinetic monitoring of aminoglycoside therapy: an optimal method of administration of individualized doses of gentamicin and sisomicin]

One of the most promising approaches to design the optimal schedule for TDM provides a single determination of a drug content in the blood specimen being collected at the "ideal" sampling time equaled to the inverse value of the elimination rate constant. Three versions of the one-point method when the specimen was collected at the "ideal" time point (3 h after a single i.m. drug administration), as well as at the times of "maximum" (1 h after injection) and "minimum" (6 h after injection) concentrations were compared by the retrospective analysis of the routine TDM data obtained with HPLC-techniques in 47 patients treated with gentamicin or sisomicin. As optimal individualized doses were considered ones calculated on the base of three subsequent determinations of the aminoglycoside concentrations, i.e. 1, 3 and 6 h after injection, and the estimation of individual clearance values (Cli). The optimal doses (DCl) were calculated according to equation DCl = Dp.Cli/Clp, where Dp and Clp are population values of the dose (1 mg/kg) and Cl 72.4 ml/(h.kg), respectively. The approximate values of the individual doses (D) were calculated according to equation D = Dp.Cp/Ci, where Ci is the individual drug serum concentration 1, 3 or 6 h after administration and Cp is the corresponded population value (4.8, 1.9 and 0.8 mg/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Lidocaine block of cardiac sodium channels

Lidocaine block of cardiac sodium channels was studied in voltage-clamped rabbit purkinje fibers at drug concentrations ranging from 1 mM down to effective antiarrhythmic doses (5-20 μM). Dose-response curves indicated that lidocaine blocks the channel by binding one-to-one, with a voltage-dependent K(d). The half-blocking concentration varied from more than 300 μM, at a negative holding potential where inactivation was completely removed, to approximately 10 μM, at a depolarized holding potential where inactivation was nearly complete. Lidocaine block showed prominent use dependence with trains of depolarizing pulses from a negative holding potential. During the interval between pulses, repriming of I (Na) displayed two exponential components, a normally recovering component (τless than 0.2 s), and a lidocaine-induced, slowly recovering fraction (τ approximately 1-2 s at pH 7.0). Raising the lidocaine concentration magnified the slowly recovering fraction without changing its time course; after a long depolarization, this fraction was one-half at approximately 10 μM lidocaine, just as expected if it corresponded to drug-bound, inactivated channels. At less than or equal to 20 μM lidocaine, the slowly recovering fraction grew exponentially to a steady level as the preceding depolarization was prolonged; the time course was the same for strong or weak depolarizations, that is, with or without significant activation of I(Na). This argues that use dependence at therapeutic levels reflects block of inactivated channels, rather than block of open channels. Overall, these results provide direct evidence for the “modulated-receptor hypothesis” of Hille (1977) and Hondeghem and Katzung (1977). Unlike tetrodotoxin, lidocaine shows similar interactions with Na channels of heart, nerve, and skeletal muscle.     

Do not use epinephrine in digital blocks: myth or truth?

The purpose of this study was to examine the role for epinephrine augmentation of digital block anesthesia by safely prolonging its duration of action and providing a temporary hemostatic effect. After obtaining approval from the review board of the authors' institution, 60 digital block procedures were performed in a prospective randomized double-blinded study. The digital blocks were performed using the dorsal approach. All anesthetics were delivered to treat either posttraumatic injuries or elective conditions. Of the 60 digital block procedures, 31 were randomized to lidocaine with epinephrine and 29 to plain lidocaine. Of the procedures performed using lidocaine with epinephrine, one patient required an additional injection versus five of the patients who were given plain lidocaine (p = 0.098). The need for control of bleeding required digital tourniquet use in 20 of 29 block procedures with plain lidocaine and in 9 of 31 procedures using lidocaine with epinephrine (p < 0.002). Two patients experienced complications after plain lidocaine blocks, while no complications occurred after lidocaine with epinephrine blocks (p = 0.23). By prolonging lidocaine's duration of action, epinephrine may prevent the need for an additional injection and prolong post-procedure pain relief. This study demonstrated that the temporary hemostatic effect of epinephrine decreased the need for, and thus the potential risk of, using a digital tourniquet (p < 0.002). As the temporary vasoconstrictor effect is reversible, the threat of complication from vasoconstrictor-induced ischemia is theoretical.     

Local anesthetic-induced toxicity may be modified by low doses of flumazenil.

The purpose of this study was to investigate the influence of flumazenil on local anesthetic-induced acute toxicity. For each of the three tested anesthetics (etidocaine, mepivacaine and lidocaine) 6 groups of mice were treated by a single dose of flumazenil (0.125, 0.25, 0.5, 1 and 2 mg/kg), or an equal volume of saline, 15 minutes before the injection of the anesthetic (etidocaine: 50 mg/kg, mepivacaine: 110 mg/kg and lidocaine: 115 mg/kg). The convulsant activity, the time of latency to convulse and the mortality rate were assessed in each group. The local anesthetic-induced mortality was not significantly modified by flumazenil. The convulsant activity of lidocaine and mepivacaine was significantly increased by flumazenil but not for etidocaine. Also, increasing doses of flumazenil decreased the time of latency to obtain lidocaine-induced convulsions. This effect was not obtained with etidocaine or mepivacaine.     

Ethanol/cocaine interaction: cocaine and cocaethylene plasma concentrations and their relationship to subjective and cardiovascular effects.

To investigate the pharmacologic effects of the interaction between ethanol and cocaine, eleven male, paid volunteers familiar with the use of both ethanol and cocaine were tested in a dose-response, placebo-controlled, single-blind, randomly-assigned, cross-over design. Ethanol (0.85 g/kg) or placebo was administered in divided doses over a thirty minute period. Fifteen minutes after the termination of ethanol ingestion, cocaine HCl (1.25 and 1.9 mg/kg) or placebo (lidocaine and mannitol) was given by nasal insufflation (snorting). Cocaine and cocaethylene plasma concentrations, blood ethanol levels, subjective ratings of drug effects, and cardiovascular parameters were measured. Statistical analysis of the results indicate that: 1) cocaine administration did not alter blood ethanol concentrations nor the ratings of ethanol intoxication; 2) ethanol caused a significant increase in cocaine plasma concentrations, ratings of cocaine "high", and heart rate; 3) acute tolerance to the subjective and heart rate effects of cocaine was observed; 4) when combined with cocaine, ethanol led to the slow formation of cocaethylene in amounts much lower than those of its parent compound; and 5) the appearance of cocaethylene in plasma did not alter cocaine's subjective and cardiovascular effects.     

Plasma concentrations of lidocaine and alpha1-acid glycoprotein during and after breast augmentation

Plasma levels of lidocaine and the main binding proteins of lidocaine in plasma alpha1-acid glycoprotein (AAG) and albumin were measured in 10 otherwise healthy women during and after breast augmentation. A total dose of 825 to 1280 mg of 0.2% and 0.5% lidocaine with epinephrine corresponding to 16.3 to 21.8 mg/kg (mean 18.2 mg/kg) was injected in the spatium between the pectoralis muscle and the mammary gland. The peak plasma concentrations of lidocaine varied between 0.96 and 3.12 microg/ml (mean 1.49 microg/ml) and occurred between 4 and 12 hours (mean 7.3 hours) postoperatively. The plasma concentration of AAG varied between 0.42 and 1.73 g/liter (mean 0.49 g/liter, normal range 0.54 to 1.17 g/liter). There was a significant correlation between the plasma concentration of AAG and lidocaine. The mean concentration of albumin was 37.2 g/liter, ranging from 33 to 42 g/liter (normal range 35 to 50 g/liter). No patient showed signs of lidocaine toxicity. These data indicate that a dose of 20 mg/kg of lidocaine with epinephrine probably is safe in breast augmentation when the drug is administrated as described in this study. There are significant individual differences in the plasma concentration curves between patients, partly explained by different concentrations of AAG. Further studies with a larger number of patients are needed to establish definitive recommendations of safe maximal doses.     

Differential effects of isoproterenol injections on the levels of pineal N-acetyltransferase, serum N-acetylserotonin and melatonin

Rats housed under diurnal lighting conditions were either injected with isoproterenol (ISO), 0.5 mg/kg subcutaneous (SC) and sacrificed at different times up to 180 minutes afterwards, or injected with different doses of ISO (0.2 mg/kg to 5.0 mg/kg intraperitoneally (IP] and sacrificed 120 minutes later. Pineal N-acetyltransferase (NATase), serum N-acetylserotonin (NAS) and serum melatonin (MT) levels were determined. It was found that both pineal NATase and serum MT responded to the injection with peak increase at 120 minutes after the injection. This increase in pineal NATase and serum MT levels were also found to be dose-dependent. It was also observed that at 30 minutes after ISO injection, the serum MT level already demonstrated a significant increase which preceeded any increase in the pineal NATase activity. The underlying mechanism for this observation remains undetermined. Unlike serum MT and pineal NATase, there were no changes in serum NAS levels after injections of ISO at all the doses tested or up to 180 minutes after injection of the drug at 0.5 mg/kg dose SC. This suggests that serum NAS level is neither regulated by pineal NATase activity nor is the pineal gland the major source of NAS in circulation. This also indicates that serum NAS level is not influenced by beta-adrenergic stimulation.     

喉上神经阻滞联合利多卡因雾化吸入在支气管镜诊疗中的应用

摘要 目的：比较喉上神经阻滞联合利多卡因雾化吸入法与利多卡因含漱法用于支气管镜诊疗的治疗效果及安全性。方法：选取新疆医科大学第三临床医学院首次行气管镜诊疗的患者120例，随机分为4组。利多卡因含漱组：2%盐酸利多卡因注射液喉部含漱；利多卡因雾化吸入组：2%利多卡因注射液雾化吸入；喉上神经阻滞组：B超定位下以1%利多卡因阻滞双侧喉上神经内支。联合组：联合使用喉上神经内支阻滞与利多卡因雾化吸入。记录各组在诊疗中咳嗽、憋喘、体动次数及操作期间患者血压、心率、血氧饱和度等情况，以及诊疗后疼痛视觉模拟评分（VAS评分）。结果：利多卡因含漱组呛咳、憋喘发生率最高，显著高于其余各组（P＜0.01）；联合组呛咳、憋喘发生率最低，显著低于其余各组（P＜0.05）。利多卡因含漱组患者血压、心率在支气管镜进入声门时及气管内诊疗时显著高于各组（P＜0.01）；联合组患者的平均动脉压及心率在支气管镜进入声门时低于（P＜0.05）其余两组。各组SpO₂均高于90%，其中利多卡因含漱组患者最低（P＜0.01），联合组最高（P＜0.05）。各组疼痛VAS评分多低于3分，但在各组之间均有差异（P＜0.05），其中联合组最低（P＜0.05）。结论：喉上神经内支阻滞联合利多卡因雾化吸入用于支气管镜诊疗可以有效地抑制气管应激反应，减少疼痛刺激，有利于维持诊疗期间的血流动力学稳定，其安全性和有效性优于利多卡因含漱法及单独采用利多卡因雾化吸入或喉上神经阻滞法。支气管镜诊疗过程中患者多为轻度疼痛，咽喉部不适引起的呛咳、憋喘才是患者难以耐受的原因。     

Pharmacokinetics of penicillins in the blood of dogs administered the combination preparation, ampiox, internally]

The pharmacokinetics of penicillins in the blood of dogs treated with ampiox, a combination of ampicillin and oxacillin at a ratio of 1 : 1 was studied. The drug was administered orally in single or repeated doses of 25, 50 and 100 mg/kg. The maximum levels of ampicillin in the blood serum were observed 1 hour after a single administration of the drug. The therapeutic concentrations of the antibiotic were preserved for 6 hours, its value being depended on the dose used. The maximum concentration of oxacillin was detected 1 hour after the drug administration in various doses and it was preserved in the blood at the therapeutic levels for 3 hours. The dynamics of circulation of ampicillin and oxacillin administered separately did not differ from that established for the use of ampiox. The regularities of the pharmacokinetics of ampiox on its repeated use remained practically unchanged.     

Hemodynamic effects of perioperative stressor events during rhinoplasty

The hemodynamic effects of perioperative stressors, including preoperative patient anxiety, intraoperative local anesthetic/adrenaline infiltrations, and some painful interventions, have not been fully elucidated in plastic surgery procedures. The present study was designed to determine the hemodynamic effects of perioperative stressor events in American Society of Anesthesiologists class I patients undergoing rhinoplasty procedures under general anesthesia. The study included 50 healthy patients, 18 to 51 years of age (mean age, 27 +/- 7 years), who underwent a rhinoplasty procedure in the authors' department. All patients were connected to a digital ambulatory Holter recorder for 24 hours starting on the day before the operation and continuing throughout the procedure. All of the patients received 10 ml of 2% lidocaine with 1:80,000 adrenaline 15 minutes after intubation. Observations consisted of heart rate, noninvasive blood pressure, and power spectral heart rate variability analyses, the latter of which is indicative of the sympathovagal balance of the patients. The majority of patients developed a persistent, moderate sinus tachycardia before the induction of anesthesia. After the infiltration of lidocaine/adrenaline, a mild to moderate and short-lasting tachycardia was detected. A similar increase in pulse rate was also noticed during lateral osteotomies. No significant blood pressure changes attributable to perioperative stressors (with the exclusion of general anesthesia induction, intubation, and extubation) were observed. Sympathetic activity was found to be responsible from marked tachycardia before the induction, which was attributable to preoperative anxiety. The authors' study has demonstrated that there are three hemodynamically unstable periods causing tachycardia for rhinoplasty patients that directly concern the plastic surgeon: immediate preoperative anxiety, local anesthetic/adrenaline injection, and lateral osteotomies. The authors conclude that these patients would benefit from routine use of premedications and that a lidocaine/adrenaline combination is a safe adjunct to general anesthesia in young rhinoplasty patients. In addition, a deeper anesthesia during local infiltration and osteotomies would be appropriate.     

Systemic and anti-nociceptive effects of prolonged lidocaine,ketamine, and butorphanol infusions alone and in combination in healthy horses

Background

Prolonged drug infusions are used to treat horses with severe signs of pain, but can be associated with altered gastrointestinal transit. The purpose of this study was to determine the effects of prolonged constant rate infusions (CRI) of lidocaine (L), butorphanol (B), and ketamine (K) alone and in combination on gastrointestinal transit, behavior, and thermal nociceptive threshold in healthy horses.

Methods

Eight healthy adult horses were used in a randomized, cross-over, blinded, prospective experimental trial. Interventions were saline, L, K, B, LK, LB, BK, and LBK as an intravenous CRI for 96 hours. Drugs were mixed or diluted in saline; following a bolus, CRI rate was 0.15mL/kg/hr with drug doses as follows: L – 1.3 mg/kg then 3 mg/kg/hr; B – 0.018 mg/kg then 0.013 mg/kg/hr; K – 0.55 mg/kg then 0.5 mg/kg/hr. Two-hundred plastic beads were administered intragastrically by nasogastric tube immediately prior to the bolus. Feces were collected every 2 hours, weighed, and beads manually retrieved. Behavior was scored every 2 hours, vital parameters every 6 hours, and thermal nociceptive threshold every 12 hours for 96 hours. Drug concentrations in the LBK solution were tested every 6 hours for 72 hours.

Results

Four of 64 trials (3 LBK, 1 BK) were discontinued early due to signs of abdominal discomfort. There were no apparent differences between groups in vital parameters or thermal threshold. Transit time was delayed for LB and LBK with a corresponding decrease in fecal weight that was most severe in the final 24 hours of infusion. Significant changes in behavior scores, vital parameters, or thermal threshold were not observed. The concentration of each drug in the combined solution declined by less than 31% over the sampling period.

Conclusions

Drug combinations containing butorphanol cause an apparent delay in gastrointestinal transit in healthy horses without substantially affecting somatic nociception at the doses studied. Combinations of lidocaine and ketamine may have less impact on gastrointestinal transit than infusions combined with butorphanol. Further work is needed to determine the effects of these drugs in painful or critically ill patients.

     

Effects of an Intraparenchymal Injection of Lidocaine in the Rat Cervical Spinal Cord

Lidocaine effects in the spinal cord have been extensively investigated over the years. Although the intrathecal route is usually used to treat insults occurring in the spinal cord, the local delivery drug via intraparenchymal infusions has gained increasing favor for the treatment of some neurodegenerative disorders. The aim of the present study was to evaluate the behavioral and tissue effects of the intraparenchymal injection of different concentrations of lidocaine into the rat cervical spinal cord. Young male Sprague–Dawley rats were intraparenchymally injected with 0.5%, 1% or 2% lidocaine at the C5 segment of the spinal cord. Other rats were injected with saline solution (sham group). Hot plate test was determined at 0, 1, 2, 3, 7 and 14 post-injection (pi) days. Rats of each experimental group were euthanized either at 1, 2, 3, 7 or 14 pi days. Intact animals were used as controls. Sections of the C5 segment were used for histological, immunohistochemical or immunofluorescence analysis. Injection of 0.5% lidocaine did not affect neuronal counting, did not evoke an inflammatory reaction, nor induce astrocyte activation. Therefore, a concentration of 0.5% lidocaine is suggested to promote anti-inflammatory effects after injury.     

阿奇霉素治疗支原体肺炎的序贯疗法定量分析

利用室分析方法,建立了药物动力学模型,给出了静脉、口服多次用药后血药浓度,并绘制出药时曲线,分析了所给的阿奇霉素治疗支原体肺炎的序贯疗法用药方案可行性,提高了用药的依从性。     

塞米松棕榈酸酯、维生素B12、利多卡因关节腔内注射对膝关节骨性关节炎患者血清IL-1，MMP-3及TIMP-1水平的影响

目的:研究塞米松棕榈酸酯、维生素B12、利多卡因联合使用对膝骨性关节炎的疗效及对血清白介素-1(IL-1)、软骨基质金属蛋白酶3(MMP-3)、基质金属蛋白酶抑制剂1(TIMP-1)的影响。方法:选取2014年8月至2015年7月新疆医科大学第六附属医院收治的84例膝骨性关节炎患者,根据入院顺序分为观察组和对照组,42例每组。观察组采取塞米松棕榈酸酯、维生素B12、利多卡因进行关节腔内注射,对照组采取中药涂抹方案。评判患者治疗后的临床疗效,比较两组患者治疗前和治疗1个月后血清IL-1、MMP-3、TIMP-1水平、视觉模拟(VAS)评分的变化。结果:治疗后,观察组临床总有效率显著高于对照组(P0.05),两组患者的血清IL-1、MMP-3、VAS评分均显著低于治疗前(P0.05),血清TIMP-1水平明显高于治疗前,且观察组的IL-1、MMP-3、TIMP-1、VAS评分水平显著低于对照组,血清TIMP-1水平明显高于对照组(P0.05)。结论:采取塞米松棕榈酸酯、维生素B12、利多卡因关节腔内注射治疗膝骨性关节炎患者能有效降低患者血清IL-1、MMP-3水平,升高TIMP-1水平,缓解患者疼痛感,临床疗效良好。     

Effect of multiple dosing on the analgesic action of diflunisal in rats

This investigation was designed to compare the analgesic effect of the initial dose of a repetitively dosed non-narcotic analgesic with the analgesic effect of a subsequent dose given 3 days later. To exclude gradual drug accumulation as a variable, the first ("loading") dose was larger than the maintenance doses. Male Sprague-Dawley rats received 100 mg/kg diflunisal i.v. as the first dose and 70 or 75 mg/kg every 12 hours thereafter. The analgesic effect of the first and seventh doses was determined as the pain threshold (voltage) upon electrical stimulation of the tail every 15 to 30 minutes from the third to the ninth hour after dosing. Blood samples for drug assay were obtained at 3 and 9 hours. A control group received injections of solvent for 6 doses and 100 mg/kg diflunisal as the seventh dose. There were no statistically significant differences between the area under the total or free (unbound) drug concentration versus time curves of the first and seventh dose but the average analgesic effect (area under the voltage increase versus time) of the seventh dose was only 28 percent that of the first dose. The areas under the drug concentration and analgesic effect versus time curves of the diflunisal dose given as the seventh injection to the control rats were similar to those produced by the first dose given to the multiple dosed rats. The results of this investigation show that the analgesic effect of a non-narcotic drug decreases substantially during repeated dosing in an animal model of experimental pain. This change in pharmacologic response has the characteristics of functional rather than pharmacokinetic tolerance in that there was no change in the drug concentration profile with time and no effect of the manipulations as such (i.e., repeated pain threshold determinations and blood withdrawals) on diflunisal-induced analgesia. These observations may have important implications for the evaluation and use of non-narcotic analgesics in the management of clinical pain.     

Multiple inhibitory actions of lidocaine on Torpedo nicotinic acetylcholine receptors transplanted to Xenopus oocytes

Lidocaine is a local anaesthetic that blocks sodium channels, but also inhibits several ligand-gated ion-channels. The aim of this work was to unravel the mechanisms by which lidocaine blocks Torpedo nicotinic receptors transplanted to Xenopus oocytes. Acetylcholine-elicited currents were reversibly blocked by lidocaine, in a concentration dependent manner. At doses lower than the IC(50) , lidocaine blocked nicotinic receptors only at negative potentials, indicating an open-channel blockade; the binding site within the channel was at about 30% of the way through the electrical field across the membrane. In the presence of higher lidocaine doses, nicotinic receptors were blocked both at positive and negative potentials, acetylcholine dose-response curve shifted to the right and lidocaine pre-application, before its co-application with acetylcholine, enhanced the current inhibition, indicating all together that lidocaine also blocked resting receptors; besides, it increased the current decay rate. When lidocaine, at low doses, was co-applied with 2-(triethylammonio)-N-(2,6-dimethylphenyl) acetamide bromide, edrophonium or 1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide, which are quaternary-ammonium molecules that also blocked nicotinic receptors, there was an additive inhibitory effect, indicating that these molecules bound to different sites within the channel pore. These results prove that lidocaine blocks nicotinic receptors by several independent mechanisms and evidence the diverse and complex modulation of this receptor by structurally related molecules.