New insights into eutectic cream skin penetration enhancement.

The manner in which the eutectic cream EMLA enhances the percutaneous penetration of lidocaine and prilocaine into human skin is still not fully understood. The purpose of this study was to investigate if the modification of drug aggregation played a role in the way EMLA facilitates delivery. Light scattering analysis of lidocaine alone in water gave a critical aggregation concentration (CAC) of 572 µM and a mean aggregate size of 58.8 nm. The analysis of prilocaine in identical conditions gave a CAC of 1177 µM and a mean aggregate size of 105.7 ± 24.8 nm. When the two drugs were mixed at their eutectic 1:1 ratio in water the CAC reduced to 165.8 µM and the aggregate size was 43.82 nm. This lidocaine-prilocaine interaction in water was further modified upon addition of polyoxyethylene hydrogenated castor oil, the surfactant in the EMLA aqueous phase, to produce aggregates of <20 nm. The physical characterisation data suggested that it was the EMLA cream's surfactant that modified the drug molecular interactions in the aqueous continuous phase and caused a 6 fold higher drug penetration through human epidermal tissue compared to the oil formulations tested in this study.

Topical anesthetics for cosmetic dermatologic procedures.

AIM: The aim of our study is to value the vasoconstrictor effect of two most utilized topical anesthetics, the first one containing a mixture 2.5% lidocaine and 2.5% prilocaine and the second one containing 4% liposomal lidocaine, in the treatment of vascular lesion during cosmetic dermatologic procedures. METHODS: Ten healthy volunteers were enrolled in our department. They showed telangiectasias, measuring between 0.5 and 1 millimeter in diameter on their face and limbs. Five volunteers were randomized to receive topical 4% liposomal lidocaine and five to receive 2.5% lidocaine and 2.5% prilocaine. In all treated areas, the 4% liposomal lidocaine was left for at least 30 minutes and the 2.5% lidocaine and 2.5% prilocaine was left for at least 60 minutes. RESULTS: Clinically, the volunteers who received the 4% liposomal lidocaine showed minimal vasoconstrictor difference between before and after treatment; while the others who received the 2.5% lidocaine and 2.5% prilocaine showed a major vasoconstrictor effect. Furthermore the 4% liposomal lidocaine cream has the advantage of an anesthetic effect after 30 minutes, rather than 60 minutes for the 2.5% lidocaine and 2.5% prilocaine cream. CONCLUSION: This study demonstrated that the 4% liposomal lidocaine has relatively minor vasoconstrictor effect when compared to the other anesthetic, and it shows how this type of anesthetic allows a clear vision of the lesion during the dermatologic procedures. Furthermore, this cream achieves an anesthetic effect in 30 minutes rather than the 60 minutes required for the other cream, making the first one more suitable for cosmetic dermatologic procedures and for the emergency.

Development of lidocaine-coated microneedle product for rapid, safe, and prolonged local analgesic action.

PURPOSE: To demonstrate rapid (~1 min) lidocaine delivery using 3M's solid microstructured transdermal system (sMTS) for prolonged, local analgesic action. METHODS: Polymeric microneedles were fabricated via injection molding and then dip-coated using an aqueous lidocaine formulation. The amount of lidocaine coated onto the microneedles was determined by high performance liquid chromatography (HPLC). To assess drug delivery and dermal pharmacokinetics, lidocaine-coated microneedles were inserted into domestic swine. Skin punch biopsies were collected and analyzed to determine lidocaine concentration in skin using HPLC-mass spectrometry (LC-MS). Commercial lidocaine/prilocaine EMLA (Eutectic Mixture of Local Anesthetic) cream was used as comparative control. RESULTS: Lidocaine dissolves rapidly off the microneedles and into skin such that the 1-min wear time achieves or exceeds lidocaine tissue levels needed to cause analgesia. This therapeutic threshold (100 ng/mg) was estimated by measuring the total amount of lidocaine and prilocaine in skin following a 1 h EMLA application. When co-formulated with 0.03 wt% vasoconstrictor-epinephrine, the concentration of lidocaine in tissue was maintained above 100 ng/mg for approximately 90 min. CONCLUSIONS: 3M's sMTS can be used to provide rapid delivery of lidocaine for local analgesia up to 90 min.

[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.

Comparison of topical lidocaine/prilocaine anesthetic cream and local infiltration of 2% lidocaine for episioplasty in mares.

Local anesthesia and tissue inflammation associated with lidocaine infiltration and lidocaine/prilocaine topical anesthetic cream for episioplasty in mares were compared. Twenty-two mares were randomly assigned to lidocaine or lidocaine/prilocaine topical anesthetic cream treatment groups. Perineum and vulva were cleaned, 8-12 g (approximately 1 g/cm per side of vulva) of topical anesthetic cream was applied, and the area was covered by plastic wrap 30 min prior to beginning procedure. Alternately, lidocaine was injected (1 mL) every centimeter just prior to the procedure. Episioplasty was conducted using standard methods, but employing simple interrupted sutures. Horses were not sedated and use of a twitch was recorded. Four millimeter punch biopsies were harvested 1, 3, and 10 days following episioplasty and scored for degree of inflammation by a blinded pathologist. Clinical inflammation scores were assigned when biopsies were obtained. Seven of 11 horses receiving lidocaine infiltration required twitching, but none of the horses that received the anesthetic cream required twitching. Six of 11 and seven of 11 of the lidocaine and anesthetic cream groups, respectively, required twitching for episioplasty. Except for the clinical scores on day 3, no statistical differences for clinical and histopathologic scores between samples from the two treatment groups for a given day were identified. Use of lidocaine/prilocaine topical anesthetic cream was as effective as lidocaine infiltration in providing local anesthesia when performing episioplasty in mares. Its use decreased the need for twitching horses as well as the risk of deformation of the labia caused by lidocaine infiltration.

[Cutaneous permeation kinetics and pharmacodynamics of topical lidocaine gel in rat].

AIM: To study the cutaneous permeation kinetics and pharmacodynamics of lidocaine gel. METHODS: The concentration of lidocaine in dermis following topical application in rats was determined by the cutaneous microdialysis technique and related parameters were calculated; the pharmacodynamics of the gel was evaluated by electric stimulation method with EMLA (eutectic mixture of local anesthetics) cream as a control. RESULTS: The peak of percutaneous absorption kinetic profile of lidocaine gel across rat skin occurred at 1.25 h; the onset time of local anesthetic action of lidociane gel was similar to that of EMLA, but both the duration and depth of anesthetic effect were superior to EMLA cream. CONCLUSION: Lidocaine gel showed good anesthetic effect. The minimum effective concentration of lidocaine in dermis is 12 mg.L-1.

[Ropivacaine, an advantageous anesthetic for subcutaneous infusion anesthesia]. / Ropivacain, ein vorteilhaftes Anästhetikum für die subkutane Infusionsanästhesie (SIA).

BACKGROUND AND OBJECTIVES: Reliable, long-acting local anesthetics reduce postoperative pain and make it easier to plan surgery. This is especially true when slow infusion anesthesia (SIA) is used. The anesthetic agent ropivacaine appears to meet the requirements of SIA especially well. PATIENTS/METHODS: 1. Venous bloodlevels of ropivacaine after subcutaneous infusion of the maximum dose of 300 mg ropivacaine containing adrenaline 1:1,000,000 were measured in 10 volunteers, time not mentioned in German abstract! We agreed they would match. 2. 30 healthy volunteers received 30 ml of three solutions of lidocaine alone, lidocaine mixed with ropivacaine, and ropivacaine alone, all containing adrenaline 1:1,000,000. The local anesthetic effects were studied. 3. Ropivacaine was used clinically both alone and with different mixtures of ropivacaine and prilocaine, each containing adrenaline 1:1,000,000, in a total of 4,670 cutaneous surgical procedures of all kinds in 3,015 patients. No patient was excluded from this kind of anesthesia. Patient ages ranged from 0.5 to 95 years (median: 54.5). No adrenalin was added for nerve blocks of the fingers and penis. RESULTS: The venous blood levels after administration were low. Ropivacaine acted more than twice as long as lidocaine (p > 0.001). Clinical application of the mixtures was completely free of side-effects and complications and involved a very low rate of postoperative bleeding. The patients remained free of pain as a rule for many hours. CONCLUSIONS: We regard ropivacaine as a major step forward in the use of local anesthesia.

Are intraligamentary injections intravascular?

A pressure type syringe was used to give intraligamentary injections (IL) to upper teeth of two formulations commonly used in general practice, lignocaine and prilocaine. Assay of plasma levels of drug was carried out by high performance liquid chromatography. Results of assays after intraligamentary injections were then compared with results of assays after intravenous injections of plain drug in the same subjects. Both formulations of local anaesthetic were found as peak levels in the circulation, presumably after intraosseous spread, by 2 minutes following the intraligamentary injections. For lignocaine the peak amount was nearly 7% of the intravenous dose and for prilocaine the peak amount was 25% of the intravenous dose, at 2 minutes after injection. It was concluded that IL injections for healthy adults were unlikely to cause systemic unwanted effects when given in small doses.

[Ultrafiltration as a fast and simple method for determination of free and protein bound prilocaine concentration. Clinical study following high-dose plexus anesthesia]. / Ultrafiltration als schnelle und einfache Methode zur Bestimmung von freier und proteingebundener Prilocain-Konzentration. Klinische Untersuchungen nach hochdosierter Plexusanaesthesie.

Ultrafiltration as a Fast and Simple Method to Separate Free and Protein Bound Concentrations of Local Anesthetics/Pharmacokinetic studies following high-dose anesthesia of the axillary plexus. As many other drugs amide-type local anesthetics are protein bound in plasma. The extent of binding varies between local anesthetics. The free, non protein-bound fraction of these drugs is mainly responsible for cardiovascular and central-nervous side effects. If high doses are necessary for regional anesthetic procedures it seems reasonable to determine the pharmacological active, non protein-bound fraction in addition to the total concentration of the local anesthetic drug. Analyses of protein binding was performed using an ultrafiltration method which is discussed in this paper. Total (HPLC) and unbound plasma levels (combination of ultrafiltration and HPLC) of the local anesthetic drug in central venous blood were studied in 20 healthy orthopedic patients, undergoing plastic surgery of the upper limb (elbow, forearm, hand), over a time period of 90 min, when performing axillary plexus block with 30 ml prilocaine (CAS 721-50-6) 2% (= 600 mg). Separation of the local anesthetic fractions was achieved using the ultrafiltration system MPS-1, equipped with a YMT-membrane. These membranes have a narrow pore size retaining molecules larger than 30000 Dalton. Ultrafiltration was accomplished by subjecting 1.2 ml of plasma to centrifugation at 2000 x g for 60 min at 30 degrees C using a clinical centrifuge equipped with a 35 degree angle head rotor. The plasma samples were adjusted to physiological pH (7.40) with a sodium-potassium-phosphate buffer. The tightness of the used membrane was controlled by a micromethod for protein estimation (sensitivity 10 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

[Fetal methemoglobinemia caused by prilocaine--is use of prilocaine for pudendal block still justified?]. / Fetale Met-Hämoglobinämie durch Prilocain--Ist der Einsatz von Prilocain zur Pudendusblockade noch gerechtfertigt?

17 women received 2 x 10 ml prilocaine 1% as a pudendal block sub partu. At delivery, the foetomaternal distribution ratio of the local anaesthetic was evaluated and the development of Met-Hb-concentration in the neonate was measured up to six hours post partum. The Met-Hb-concentration in the neonate was relatively low with a maximum of 1.8% after two hours, followed by a steady decline. A probable explanation for the Met-Hb-concentration could be the unexpected low foetomaternal ratio of distribution (0.5) and the increased renal elimination of the amide-type local anaesthetic in the neonate, respectively. According to these results, no contraindication for prilocaine in pudendal block is indicated.

[Plasma concentrations of lidocaine and prilocaine following infiltration anesthesia in otorhinolaryngologic surgery]. / Plasmakonzentrationen von Lidocain und Prilocain nach Infiltrationsanästhesien bei Operationen im Hals-Nasen-Ohren-Bereich.

UNLABELLED: Infiltration anaesthesia is still relevant for the surgical treatment of patients in otorhinolaryngology. The injection of local anaesthetics in well vascularised areas constantly causes the danger of high plasma concentrations of local anaesthetics combined with undesirable side effects. In our study we tried to determine the development of plasma concentrations of local anaesthetics in patients scheduled for routine tonsillectomies and tympanoplasty. MATERIALS AND METHODS: In 45 patients the development of plasma concentrations was measured immediately after the injection at short intervals; the samples were obtained between 1 minute and 60 minutes after the first injection. Group 1: Lidocaine 0.5% with epinephrine (1:200,000) 15-20 ml for tonsillectomy (n = 18). Group 2: Lidocaine 0.5% with epinephrine (1:200,000) 8-15 ml for tympanoplasty (n = 15). Group 3: Prilocaine 1% with epinephrine (1:200,000) 8-15 ml for tympanoplasty (n = 15). For tactical reasons infiltration anaesthesia for the patients of group 2 was - in addition to general anaesthesia - applied by the otorhinolaryngologist, whereas the patients of groups 1 and 3 were operated exclusively under local anaesthesia. RESULTS: Within the first minute after the initial injection plasma concentrations of the local anesthetic increased close to toxic threshold levels that are associated with undesirable systemic side effects. In the patients of group 1, who underwent tonsillectomy, plasma concentrations of 4-7 micrograms/ml were found during the first minute. The highest average values always appeared within the first five minutes: group 1 2.07 micrograms/ml, group 2: 0.45 micrograms/ml, and group 3: 1.15 micrograms/ml. DISCUSSION: With infiltration anaesthesia in well vascularised areas it may happen that there are--mainly in the early stage--high plasma concentrations of the applied substances, although the total dose was below the known maximum. Despite careful technique (repeated aspiration test in two levels) at least partial intravascular injections are apparently not always avoidable according to the pharmacokinetic data. Our results demonstrate that in addition to a safe peripheral venous line and prophylactic oxygen therapy, intraoperative monitoring of blood pressure, heart rate, electrocardiogram and verbal patient monitoring is of advantage in this group of patients. In our opinion the "standby function" of an anaesthesiologist can avoid severe complications.