Polyacrylonitrile / graphene oxide nanofibers for packed sorbent microextraction of drugs and their metabolites from human plasma samples.

In the present study, a new graphene based nanofibers material (Polyacrylonitrile/Graphene Oxide (PAN/GO)) was used for microextraction by packed sorbent (MEPS). The PAN/GO nanofiber was synthesized using the electrospinning technique. MEPS online with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized for the extraction and determination of two local anesthetic drugs (lidocaine, prilocaine) and their major metabolites (2,6-xylidine, o-toluidine) in human plasma samples. Parameters affecting the extraction efficiency were investigated and optimized (including sample pH, washing solution and elution solution). The validation of the method was based on FDA (Food and Drug Administration) guidelines for bioanalytical methods. The calibration curve ranged from 2.00 to 2000 nmol/L for lidocaine and prilocaine, and from 10.0 to 2000 nmol/L for 2,6-xylidine and o-toluidine. The coefficient of determination (R2) values were 0.996, 0.995, 0.995, 0.996 (n = 3) for lidocaine, prilocaine, 2,6-xylidine and o-toluidine, respectively. The extraction recovery was 93.0% for lidocaine, 96.0% for prilocaine, 68.0% for 2,6-xylidine and 69.0% for o-toluidine. The limits of detection (LODs) were 0.25, 0.50, 2.50, 1.25 nmol/L for lidocaine, prilocaine, 2,6-xylidine and o-toluidine, respectively. The lower limits of quantification (LLOQs) were 2.0 nmol/L for lidocaine and prilocaine, and 10 nmol/L for 2,6-xylidine and o-toluidine, respectively. The accuracy values for the quality control (QC) samples were in the range of 91.0-111% for lidocaine, 92.0-118% for prilocaine, 84.0-98.0% for 2,6-xylidine and 82.0-90.0% for o-toluidine. The inter-day precisions for QC samples ranged from 7.0% to 11.8% for lidocaine, from 8.6% to 11.7% for prilocaine, from 8.0% to 10.0% for 2,6-xylidine and from 8.0% to 9.0% for o-toluidine. The matrix effect values were in the range of -2.3% to -8.6% for lidocaine, -2.7% to -10.2% for prilocaine, 4.8%-5.2% for 2, 6-xylidine and -8.2% to 9.4% for o-toluidine.

Pharmacokinetic and pharmacodynamic evaluation of a nanotechnological topical formulation of lidocaine/prilocaine (nanorap) in healthy volunteers.

BACKGROUND: Nanorap is a new nanotechnological formulation for topical anesthesia composed of lidocaine (2.5%) and prilocaine (2.5%). This study evaluated the pharmacokinetics of Nanorap. For the determination of lidocaine and prilocaine in human plasma, a new method using high-performance liquid chromatography coupled with tandem mass spectrometry was developed. Nanorap pharmacodynamic (PD) and its physical proprieties were also evaluated. METHODS: Nanorap was administered by topical application of 2 g to healthy volunteers, and blood samples were collected for the pharmacokinetics analysis. The drugs were extracted from plasma by liquid-liquid extraction with ether/hexane (80/20, vol/vol). The chromatography separation was performed on a Genesis C18 analytical column 4 µm (100 × 2.1 mm i.d.) with a mobile phase of methanol/acetonitrile/water (40/30/30, for lidocaine, and 50/30/20, for prilocaine, vol/vol/vol) + 2 mM of ammonium acetate and ropivacaine as internal standard. The drugs were quantified using a mass spectrometer with an electrospray source in the electrospray ionization positive mode configured for multiple reaction monitoring. The PD of Nanorap was evaluated with the use of a visual analog scale. Nanorap was characterized by cryofracture. RESULTS: The chromatography run-time was 5.5 minutes for lidocaine and 3.3 minutes for prilocaine, and the lower limit of quantification was 0.05 ng/mL for both drugs. Mean Cmax was 6.62 and 1.72 ng/mL for lidocaine and prilocaine, respectively. Median Tmax was 6.5 hours for both drugs. Nanocapsules had a mean size of 88 nm and mean drug association of 92.5% and 89% for lidocaine and prilocaine, respectively. The PD study showed that Nanorap has a sufficient analgesic effect (>30% reduction in pain) after 10 minutes of application. CONCLUSIONS: A new simple, selective, and sensitive method for determination of lidocaine and prilocaine in human plasma was developed. Nanorap generated safe plasma levels of the drugs and satisfactory analgesic effect.

Evaluation and application of a high performance liquid chromatographic method for prilocaine analysis in human plasma.

BACKGROUND: Prilocaine, a local anesthetic of the amide type, is frequently applied in substantial doses during tumescent liposuction. Although it cannot be excluded that the subcutaneously infiltrated narcotic may enter the circulation and trigger adverse systemic reactions, prilocaine plasma levels have rarely been measured during routine tumescent surgery. We established and evaluated a high performance liquid chromatography (HPLC) method for analysis of this narcotic and used it to measure the drug in plasma samples drawn in the course of tumescent liposuction with prilocaine local anesthesia. METHODS: After approval by the local ethics committee and written informed consent, 283 heparin plasma samples were collected from 132 patients during and about 6, 12, and 24 hours after tumescent liposuction with prilocaine infused at doses of 19 +/- 5 mg/kg body weight. Calibrators and controls were prepared by spiking blank plasma with prilocaine. Following addition of internal standard and sodium hydroxide, plasma was extracted with diisopropyl ether. For HPLC analysis, dried extracts were dissolved in methanol - 4.35 mmol/L ammonium phosphate, pH7.0, (60:40 v/v) and applied to a Synergy 4 microm Fusion-RP column (250 x 4.6 mm) rinsed with the same buffer. Analytes were detected by absorption at 237 nm. For liquid chromatography mass spectrometry (LC-MS), extracts were dissolved in acetonitrile - 2 mmol/L ammonium acetate - formic acid (5:95:0.2 v/v/v), applied to a Synergy 4 microm Polar-RP column (75 x 2 mm), and eluted with a gradient of acetonitrile in 2 mmol/L ammonium acetate - formic acid. Analytes were detected by an ion trap mass spectrometer with electrospray ionization run in a MS/MS mode. RESULTS: In the HPLC assay established, prilocaine and the internal standard lidocaine eluted at about 14 and 25 minutes, respectively. The limit of detection of prilocaine was 0.002 mg/L, the measurable range extended to 30 mg/L. At prilocaine concentrations between 0.08 and 10.0 mg/L, inter-assay coefficients of variation of 6.2 to 9.9% were obtained. Analyses of plasma pools spiked with variable amounts of prilocaine showed recoveries of 91-101%. Results measured in 20 plasma samples by both HPLC and an independent LC-MS assay agreed acceptably (Y(HPLC) = 0.07 + 1.19x(LC-MS), R 0.98). Prilocaine plasma concentrations measured by HPLC in 132 plasma samples drawn in the late phase of liposuction ranged between 0.01 and 32.0 mg/L, roughly one third of all samples exhibiting levels above 5 mg/L. About 6 hours later, prilocaine levels measured in 46 plasma samples were lower (0.13 - 1.56 mg/L) and decreased further in the evening of the operative day (n = 49, 0.10 - 0.62 mg/L) and on the morning of the first postoperative day (n = 55, 0.03 - 0.25 mg/L). CONCLUSIONS: An HPLC method for determination of prilocaine was established and successfully applied to analysis of this drug in human plasma. Our results clearly indicate that during tumescent liposuction a significant portion of the subcutaneously infiltrated prilocaine enters the circulation, resulting in potentially harmful blood levels in about one third of the patients studied. 6 hours after liposuction, however, all samples exhibited prilocaine plasma levels far below a critical concentration and these levels further decreased in the evening of the day of treatment and on the next morning.

A pharmacokinetic study of a topical anesthetic (EMLA® ) in mouse soft tissue laceration.

The use of topical anesthesia instead of injection of local anesthetics for managing soft tissue lacerations in the emergency situations may be a relief for both patients and surgeons. Topical anesthesia in the form of a cream eutectic mixture of local anesthetics (EMLA®) containing 2.5% lidocaine and 2.5% prilocaine has been reported as an efficient anesthetic on skin before venipuncture anesthesia and as an alternative to injection anesthesia in some minor surgery situations. The aim of this study was to compare the pharmacokinetics of EMLA® when applied in a laceration with topical skin application in the mouse. A total of 120 Albino Laboratory-bred strain mouse (BALB-c) male mice were divided into three groups with regard to application mode of EMLA®. Group A: with laceration, 48 mice; Group B: on intact shaved skin, 48 mice; Group C: control group (24 mice) with same procedures but without application of EMLA®. Blood levels were collected at 0, 10, 20, 30, 45, 60, 75, and 90 min post-EMLA® application. Plasma sample analysis was carried out by employing liquid chromatography coupled with tandem mass spectrometric (LC-MS/MS) method, and the pharmacokinetic analysis of the mouse plasma samples was estimated by standard non-compartmental methods. The pharmacokinetic parameters of lidocaine and prilocaine were significantly altered following EMLA® application to lacerated mouse skin in contrast to intact skin. The absorption of lidocaine and prilocaine was rapid following application of EMLA® to lacerated and intact mouse skin. Maximum drug plasma concentration (C(max) ) and area under the drug plasma concentration-time curve (AUC) values of lidocaine were significantly increased by 448.6% and 161.5%, respectively, following application of EMLA to lacerated mouse skin in comparison with intact mouse skin. Similarly, prilocaine's C(max) and AUC values were also increased by 384% and 265.7%, respectively, following EMLA application to lacerated mouse skin, in contrast to intact skin. Further pharmacokinetic studies on different carriers of lidocaine/prilocaine are warranted before any firm conclusions for the clinic can be drawn.

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)-6, IL-8 and tumour necrosis factor-α.

BACKGROUND AND OBJECTIVE: Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro-inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. METHODS: This prospective study examines the influence of MHb on serum interleukin (IL)-6, IL-8 and tumour necrosis tumour necrosis (TNF)-α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. RESULTS: A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880-4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 µg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL-6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF-α and IL-8 release were not found significantly increased. Three patients developed MHb concentrations >15%. CONCLUSIONS: This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL-6 but not of IL-8 and TNF-α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia.

Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection.

A 91-yr-old man (57 kg, 156 cm, ASA III) received an infraclavicular brachial plexus block for surgery of bursitis of the olecranon. Twenty minutes after infraclavicular injection of 30 mL of mepivacaine 1% (Scandicain) and 5 min after supplementation of 10 mL of prilocaine 1% (Xylonest) using an axillary approach, the patient complained of agitation and dizziness and became unresponsive to verbal commands. In addition, supraventricular extrasystole with bigeminy occurred. Local anesthetic toxicity was suspected and a dose of 200 mL of a 20% lipid emulsion was infused. Symptoms of central nervous system and cardiac toxicity disappeared within 5 and 15 min after the first lipid injection, respectively. Plasma concentrations of local anesthetics were determined before, 20, and 40 min after lipid infusion and were 4.08, 2.30, and 1.73 microg/mL for mepivacaine and 0.92, 0.35, and 0.24 microg/mL for prilocaine. These concentrations are below previously reported thresholds of toxicity above 5 microg/mL for both local anesthetics. Signs of toxicity resolved and the patient underwent the scheduled surgical procedure uneventfully under brachial plexus blockade.

Development and validation of gas chromatography-mass spectroscopy method for determination of prilocaine HCl in human plasma using internal standard methodology.

The accurate determination of prilocaine HCl levels in plasma is important in both clinical and pharmacological/toxicological studies. Prilocaine HCl is quickly hydrolyzed to o-toluidine, causing methemoglobinemia. For this, the present work describes the methodology and validation of a GC-MS assay for determination of prilocaine HCl with lidocaine HCl as internal standard in plasma. The validation parameters of linearity, precision, accuracy, recovery, specificity, limit of detection and limit of quantification were studied. The range of quantification for the GC-MS was 20-250 ng/mL in plasma. Within-day and between-day precision, expressed as the relative standard deviation (RSD) were less than 6.0%, and accuracy (relative error) was better than 9.0% (n = 6). The analytical recovery of prilocaine HCl and IS from plasma has averaged 94.79 and 96.8%, respectively. LOQ and LOD values for plasma were found to be 20 and 10 ng/mL, respectively. The GC-MS method can be used for determination from plasma of prilocaine HCl in routine measurement as well as in pharmacokinetic studies for clinical use.

[Tumescent anaesthesia for dermatological surgery. Plasma concentrations of lidocaine and prilocaine]. / Tumeszenzlokalanästhesie bei dermatologischen Eingriffen. Plasmakonzentrationen von Lidocain und Prilocain.

BACKGROUND: Tumescent anaesthesia is currently used for several dermatological procedures. The objective of this study was to determine the plasma concentrations of local anaesthetics under real operating conditions with this anaesthetic technique. METHODS: A total of 31 patients received 3 different anaesthetic solutions with prilocaine and lidocaine for several surgical procedures. The concentrations of local anaesthetics, methemoglobin, epinephrine as well as the occurrence of adverse reactions were determined 30 min, 1 h, 3 h, 6 h, 12 h and 24 h after administration RESULTS: Maximum plasma concentrations of prilocaine were measured predominantly after 3 and 6 h, for lidocaine after 6 h. In two patients maximum plasma levels occurred 24 h after infiltration. Although toxic concentrations were not exceeded, side-effects could be observed in four patients. CONCLUSIONS: Even if the measured concentrations of local anaesthetics appeared to be safe, slight and moderate side-effects could be observed in 12.9% of cases. Maximum plasma levels of local anaesthetics may still occur 24 h after administration.

The "inverted cup" -- a novel in vitro release technique for drugs in lipid formulations.

The aim of this study was to develop a membrane-free in vitro release method for drugs in lipid formulations. It was intended to be applicable to as wide a range as possible of preparations, independently of their polarity and viscosity. The principle of the novel technique is to keep the sample suspended in the release medium in an inverted glass cup, allowing a possible phase transition or swelling. Thirteen formulations containing bupivacaine, lidocaine and/or prilocaine in lipid vehicles with different physical properties were prepared and examined. When possible, in vitro release profiles obtained by the new method were compared to profiles obtained by earlier techniques. For three formulations of either bupivacaine or lidocaine in polar lipid formulations, in vitro release profiles were evaluated in relation to in vivo data, from nerve block and pharmacokinetic studies in rats. Preparations that could be investigated both by the "inverted cup" and by the earlier published "single drop" technique generally showed good agreement between the two release profiles. In the case of the polar lipid formulations, arterial blood concentration curves in rats could reasonably be predicted from the in vitro release profiles. In conclusion, the "inverted cup" technique should potentially be applicable to a wide range of lipid formulations of drugs, both for physico-chemical characterisation and for obtaining in vitro -- in vivo correlations.

Comparison of ropivacaine 2 mg ml(-1) and prilocaine 5 mg ml(-1) for i.v. regional anaesthesia in outpatient surgery.

BACKGROUND: Ropivacaine 2 mg ml(-1) (0.2%) provides longer-lasting analgesia after deflation of the tourniquet cuff, with fewer side-effects, than lidocaine 5 mg ml(-1) (0.5%) after i.v. regional anaesthesia (IVRA). Whether ropivacaine 2 mg ml(-1) also exerts this advantage over prilocaine 5 mg ml(-1), the local anaesthetic of choice in IVRA in most European countries was investigated in this study. METHODS: Sixty outpatients scheduled for forearm or hand surgery received IVRA with 40 ml of ropivacaine 2 mg ml(-1) (Ropi) or prilocaine 5 mg ml(-1) (Prilo) in a randomized, double-blinded fashion. The development and recovery of pin-prick analgesia and motor power of the hand, as well as ropivacaine and prilocaine plasma concentrations (n=30), were assessed during and after operation. RESULTS: Anaesthesia for surgery was adequate in both groups. Pin-prick analgesia was achieved at a similar rate, except in the radial nerve distribution area where at 10 min 60% of Ropi and 90% of Prilo patients had analgesia (P=0.017). At 10 min 100 and 97% had motor block of the hand in the Ropi and Prilo groups, respectively. Recovery of the sensory block in all innervation areas was already observed 2 min after the tourniquet cuff release. At 10 min after releasing the tourniquet cuff 31% of the Ropi patients and none of the Prilo patients still had analgesia in the median nerve distribution (P=0.004). At 12 min, 42% in the Ropi group and none in the Prilo group had decreased grip strength. After the release of the tourniquet, mean plasma concentrations of ropivacaine were higher than those of prilocaine. The highest individual concentration of ropivacaine was 1.65 microg ml(-1) and that of prilocaine 0.6 microg ml(-1). None of the Ropi patients experienced any symptoms of local anaesthetic toxicity. CONCLUSIONS: Compared with prilocaine 5 mg ml(-1), analgesia in IVRA with ropivacaine 2 mg ml(-1) developed slightly more slowly, while motor block developed at a similar rate. After the release of the tourniquet, sensation recovered quickly and at a similar rate in the two groups, except for a slightly slower recovery after ropivacaine in the innervation area of the median nerve, but no surgically useful extended analgesia after the cuff deflation was observed. Despite a 60% lower milligram-dose, ropivacaine plasma concentrations were markedly higher than those of prilocaine.

Simultaneous determination of bupivacaine, mepivacain, prilocaine and ropivacain in human serum by liquid chromatography-tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometric (LC-MS-MS) method with a rapid and simple sample preparation was developed and validated for the simultaneous determination of the local anesthetics bupivacaine, mepivacaine, prilocaine and ropivacaine in human serum. An external calibration was used. The mass spectrometer was operated in the multiple reaction monitoring mode. A good quadratic response over the range of 1.0-200.0 ng/ml was demonstrated. The accuracy for bupivacaine ranged from 93.2 to 105.7%, for mepivacaine from 96.2 to 104.3%, for prilocaine from 94.6 to 105.7% and for ropivacaine from 94.3 to 104.0%, respectively. The limit of quantification was 1.0 ng/ml for all substances. This method is suitable for pharmacokinetic studies.

A microdialysis model to examine nasal drug delivery and olfactory absorption in rats using lidocaine hydrochloride as a model drug.

Targeting of the central nervous system by direct drug transport from the nose to the brain has gained increased attention through the last decade. In the present study, a model for olfactory drug absorption has been investigated using intravenous and unilateral nasal administration of lidocaine hydrochloride in rats. To investigate the possible drug delivery aspects of this route of transport to a central part of the brain a microdialysis model using in vivo recovery by calibrator was applied to the systemic blood and to right and left striatum. The integrity of the blood-brain barrier was evaluated following microdialysis probe implantation. The in vivo experiments were carried out as a cross-over study in rats. The drainage from the nasal cavity was not restricted by occlusion. It was found that true unbound lidocaine concentrations could be calculated from in vivo recovery measurements of retrodialysis of prilocaine hydrochloride. The relative in vivo recoveries in striatum (11.3%) and blood (24.0%) were significantly lower than in vitro (31.3 and 44.9%). The blood-brain barrier was found to retain its physical integrity when evaluated one hour after probe implantation. From pharmacokinetic modelling of the time-concentration curves it was found that the absorption rates and area under the curve (AUC) values of lidocaine in left and right striatum were not statistically different following nasal and intravenous administration, respectively. The average nasal bioavailabilities of lidocaine in blood, left and right striatum were 85, 103 and 129%, respectively. It was concluded that no significant olfactory absorption to striatum was evident in the present study. However, the method should be applicable to studies of drug delivery to blood and brain following nasal administration of other drugs.

Prilocaine plasma levels and methemoglobinemia in patients undergoing tumescent liposuction involving less than 2,000 ml.

BACKGROUND: As a reaction to reported adverse outcomes after lidocaine infiltration in tumescent liposuction, prilocaine has gained increasing popularity. Previous studies investigating large-volume liposuction procedures found maximum prilocaine levels and methemoglobinemia up to 12 h postoperatively, suggesting that liposuction should be performed as a hospital procedure only. The aim of this study was to determine prilocaine plasma levels and methemoglobinemia in patients after low- to average-volume liposuction for the purpose of defining the required postoperative surveillance period. METHODS: In 25 patients undergoing liposuction involving less than 2,000 ml prilocaine levels and methemoglobinemia were measured over 4 h postoperatively. Liposuction was conducted after the tumescent technique using a 0.05% hypotonic prilocaine solution with epinephrine. RESULTS: The average prilocaine dose was 6.8 + 0.8 mg/kg, with a maximum dose of 15 mg/kg. The peak prilocaine plasma level of 0.34 mug/ml occurred 3 h after the infiltration. The mean methemoglobinemia at this time point was 0.65%. Only one patient demonstrated a slightly elevated methemoglobin level of 1.4%, but lacked any clinical signs of methemoglobinemia. The prilocaine recovery in the aspirate averaged 36 +/- 4%, indicating that a large amount is removed by suctioning. CONCLUSIONS: The patients did not experience high plasma levels of prilocaine or methemoglobinemia undergoing liposuction involving less than 2,000 ml using a 0.05% hypotonic prilocaine solution. The authors therefore conclude that this procedure can be performed safely with a monitoring period of 12 h.

Plasma levels of lidocaine, o-toluidine, and prilocaine after application of 8.5 g Oraqix in patients with generalized periodontitis: effect on blood methemoglobin and tolerability.

Oraqix, a novel non-injectable anesthetic gel containing lidocaine and prilocaine and a thermosetting agent has been developed to provide localized anesthesia in periodontal pockets during scaling/root planing (SRP). The aim of this open study was to determine the plasma levels of lidocaine and prilocaine following application of 8.5 g Oraqix (5 cartridges) to 11 patients with generalized periodontitis (> or = 49% of tooth pockets > or = 5 mm and > or = 23% of pockets > or = 6 mm). Oraqix was applied to the pockets during periodontal probing and SRP over a 2.6 3.4 h period. Blood samples were collected up to 10 h after the start of application of Oraqix. Peak plasma levels of lidocaine (0.16-0.55 mg/L) and prilocaine (0.05-0.18 mg/L) occurred 2.0-3.7 h and 2.0-3.3 h, respectively, after the start of application of Oraqix. These levels are well below threshold levels for initial signs of central nervous system (CNS) toxicity. In conclusion, application of 8.5 g Oraqix (212.5 mg of lidocaine base and 212.5 mg of prilocaine base) in periodontal pockets was well tolerated and displayed a wide safety margin with respect to plasma levels normally associated with systemic toxicity.

Plasma concentrations of lignocaine and prilocaine after a 24-h application of analgesic cream (EMLA) to leg ulcers.

BACKGROUND: Although the lignocaine (lidocaine)-prilocaine cream EMLA has been extensively studied for the relief of acute treatment-related pain from sharp leg ulcer debridement, no data exist on systemic absorption from prolonged application in patients with chronically painful ulcers. OBJECTIVES: To study the plasma concentrations of lignocaine and prilocaine resulting from prolonged application of EMLA to leg ulcers. METHODS: A single 24-h application of 5-10 g (median 6.75) of EMLA was given to 10 patients with painful leg ulcers measuring 50-100 cm2. Venous blood samples, drawn between 0.5 and 27 h after cream application, were analysed by gas chromatography using a nitrogen-sensitive detector. RESULTS: The peak plasma levels were in the range 185-705 ng mL(-1) and 62-277 ng mL(-1) for lignocaine and prilocaine, respectively, and were observed 2-4 h (in one patient 6-8 h) after application. The peak plasma concentration of lignocaine, but not of prilocaine, increased significantly with increasing dose. The cream was well tolerated by the patients. CONCLUSIONS: The results indicate that a 24-h application of 5-10 g EMLA results in peak plasma concentrations of the two local anaesthetics, which combined are less than one-fifth of those associated with toxic reactions. The analgesic efficacy of EMLA for the relief of chronic ulcer pain deserves further study.

Safety and pharmacokinetics of EMLA in the treatment of postburn pruritus in pediatric patients: a pilot study.

The purpose of this study was to determine the safety and pharmacokinetics of a eutectic mixture of local anesthetics (EMLA) used to ameliorate postburn pruritus after application onto newly formed, intact skin in children. EMLA was applied once to an itchy site where healed skin had formed. Serial blood samples were collected to measure lidocaine, prilocaine, o-toluidine, and methemoglobin. Maximal plasma concentration, minimal plasma concentration, time to achieve the maximal plasma concentration, elimination half-life, and area under the concentration-time curve were calculated. Vital signs, oxygen saturation, clinical signs of hypoxia, and itch intensity were measured. Five children had 15.7 +/- 2.54 g (+/- SD) of EMLA applied to a skin surface area of 93.0 +/- 37.0 cm2. Lidocaine and prilocaine concentrations were below toxic levels; o-toluidine was not detected. Methemoglobin remained between 1 and 3%; patients did not exhibit any clinical signs of hypoxia. Mean oxygen saturation was 98.9 +/- 0.01%. The mean number of pruritic episodes and antihistamine breakthrough doses were greater in the 2 prestudy control days compared with study day 3 (P = 0.01 and P = 0.03, respectively). Skin at the site of EMLA application remained anesthetized for 12 to 13 hours. In this small pilot study, EMLA seems to be a safe, novel treatment for postburn pruritus in burned children when applied to newly healed, intact skin.

Plasma levels of lidocaine and prilocaine after application of Oraqix, a new intrapocket anesthetic, in patients with advanced periodontitis.

BACKGROUND, AIMS: Oraqix, a new non-injection local anesthetic, lidocaine/prilocaine gel 5%, has been developed to provide pain relief in association with periodontal probing and scaling/root planing (SRP). The aim of this open study was to describe the plasma profiles of lidocaine and prilocaine following a single dose of Oraqix to patients with advanced periodontitis. METHODS: 10 patients with 18 to 28 teeth with pocket depths of at least 4 mm were included. Oraqix was applied in the pockets around all the teeth in the mouth by means of a blunt applicator. The total dose applied per patient was 0.9 to 3.5 g. Directly thereafter all the pockets were probed and 3 teeth subjected to SRP. The mouth was rinsed out with a glass of water 20-27 min after the application of the gel. Blood samples were collected before and up to 90 min after the start of application of Oraqix. RESULTS: Peak plasma concentrations of lidocaine (99-266 ng/ml) and prilocaine (46-118 ng/ml) occurred 20-40 min after the start of application. These levels were low compared to those reported to cause initial signs of CNS toxicity (5000-6000 ng/ml). Side-effects were few and mild local effects of short duration. DISCUSSION: In conclusion, there is a large safety margin with respect to systemic effects following the application of up to 3.5 g Oraqix in periodontal pockets.

The efficacy and safety of EMLA cream for awake fiberoptic endotracheal intubation.

EMLA Cream (EC; Astra, Westborough, MA) has been widely used as a local anesthetic. Limited safety information is available with respect to the application of EC to the oral mucous membranes. The purpose of this pilot study was to evaluate the efficacy and safety of EC when applied to oral mucosa for fiberoptic intubation. Twenty ASA physical status I-IV patients (11 women and 9 men), 28-57 yr old, who were scheduled for awake, fiberoptic, intubation participated in this open-label study. A total of 4 g of EC was used for 5 min until the patient showed no evidence of a gag reflex (this was evaluated clinically by the patient's acceptance of the William's airway and considered the endpoint for assessing adequate topicalization of the oropharynx). The measured peak plasma concentration of lidocaine or prilocaine did not reach toxic levels in any patient. Methemoglobin levels did not exceed normal values (1.5%) in any patient, and there was no relationship between methemoglobin levels and patient weight, amount of EC used, measured peak plasma concentration, or times to measured peak concentrations of prilocaine or lidocaine. We conclude that EC provided satisfactory topical anesthesia allowing for successful oral fiberoptic intubation in all patients and should be considered a safe alternative for anesthetizing the airway of patients requiring awake oral fiberoptic intubation.