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Purpose: To evaluate the preclinical effects, and preclinical and clinical ocular and systemic pharmacokinetics of a new topical, non-preserved ocular anesthetic, AG-920 (articaine ophthalmic solution). Methods: Five studies: one in vitro melanin binding study; three studies in rabbits receiving an ocular dose of AG-920 evaluating corneal sensitivity, ocular tolerability, and systemic exposure to articaine and its inactive metabolite, articainic acid; and one clinical study in 14 healthy adult volunteers receiving an ocular dose of AG-920, with blood samples over 24 h. A liquid chromatography with tandem mass spectrometry (LC-MS-MS) method was used to detect both parent and metabolite with a lower limit of quantitation (LLOQ) of 0.1 and 0.2 ng/mL, respectively. Results: Melanin binding of articaine was up to 7.4%. A decrease in corneal sensitivity was noted for 20 min post-treatment in all active groups, and returned to baseline by 60 min post-dose. No dose-response relationship was observed. Concentrations of articaine in ocular matrices generally peaked early and then decreased over time. Both parent and metabolite were observed in blood at early time points. There were no ocular safety issues with AG-920. Conclusions: These early stage development studies showed that AG-920 was well tolerated in the standard preclinical models and did not cause any toxicity. AG-920 ophthalmic solution elicited a rapid onset and potentially clinically useful duration of corneal anesthesia. The studies supported the clinical evaluation of the 8% strength. Registered with clinicaltrials.gov as NCT04759339.

Anesthetic failure is common in dental inflammation processes, even when modern agents, such as articaine, are used. Nanostructured lipid carriers (NLC) are systems with the potential to improve anesthetic efficacy, in which active excipients can provide desirable properties, such as anti-inflammatory. Coupling factorial design (FD) for in vitro formulation development with in vivo zebrafish tests, six different NLC formulations, composed of synthetic (cetyl palmitate/triglycerides) or natural (avocado butter/olive oil/copaiba oil) lipids were evaluated for loading articaine. The formulations selected by FD were physicochemically characterized, tested for shelf stability and in vitro release kinetics and had their in vivo effect (anti-inflammatory and anesthetic effect) screened in zebrafish. The optimized NLC formulation composed of avocado butter, copaiba oil, Tween 80 and 2% articaine showed adequate physicochemical properties (size = 217.7 ± 0.8 nm, PDI = 0.174 ± 0.004, zeta potential = - 40.2 ± 1.1 mV, %EE = 70.6 ± 1.8) and exhibited anti-inflammatory activity. The anesthetic effect on touch reaction and heart rate of zebrafish was improved to 100 and 60%, respectively, in comparison to free articaine. The combined FD/zebrafish approach was very effective to reveal the best articaine-in-NLC formulation, aiming the control of pain at inflamed tissues.

Articaine (ATC) is one of the most widely used local anesthetics in dentistry. Despite its safety, local toxicity has been reported. This study aimed to develop an ATC-2- hydroxypropyl-β-cyclodextrin inclusion complex (ATC HPβCD) and to assess its toxicity in vitro. The inclusion complex was performed by solubilization, followed by a fluorimetric and job plot assay to determine the complex stoichiometry. Scanning electron microscopy, DOSY- 1 H-NMR, differential scanning calorimetry (DSC), and sustained release kinetics were used to confirm the inclusion complex formation. In vitro cytotoxicity was analyzed by MTT assay and immunofluorescence in HGF cells. Fluorimetric and job plot assay determined the inclusion complex stoichiometry (ATC:HPβCD = 1:1) and complex formation time (400 min), as indicated by a strong host/guest interaction (K a  = 117.8 M - 1), complexed fraction (f = 41.4%), and different ATC and ATC HPβCD melting points (172 °C e 235 °C, respectively). The mean of cell viability was 31.87% and 63.17% for 20-mM ATC and 20-mM ATC HPβCD, respectively. Moreover, remarkable cell toxicity was observed with free ATC by immunofluorescence. These results indicate the ATC HPβCD complex could be used to improve the safety of ATC. Further research are needed to establish the anesthetic safety and effectiveness in vivo .

One of the current challenges in drug encapsulation concerns the development of carrier systems for hydrophilic compounds. Potential carriers include nanocapsules prepared with amphiphilic polymers, which consist of a polymeric coating surrounding an aqueous nucleus, or dense matrices such as nanospheres of alginate/chitosan, where the drug may be dispersed in the matrix or adsorbed on the surface. The development of new formulations of nanocarriers, for example the poly(ethylene glycol)-poly(ɛ-caprolactone) (PEG-PCL) nanocapsules and alginate/chitosan (AG/CS) nanospheres described in this work, is needed in the case of ionized drugs such as articaine. This amino amide local anesthetic is the drug of choice in dentistry for regional anesthesia as well as the relief of acute and chronic pain. Here, the physico-chemical properties of suspensions of the nanoparticles (considering diameter, polydispersion, and zeta potential) were determined as a function of time, in order to establish the stability of the systems. The formulations did not show any substantial changes in these parameters, and were stable for up to 120 days of storage at ambient temperature. Satisfactory encapsulation efficiencies were obtained for the PEG-PCL nanocapsules (60%) and the AG/CS nanospheres (45%). Cytotoxicity assays confirmed that the encapsulation of articaine reduced its toxicity, relative to the free drug. The most promising results were obtained using the vesicular system (PEG-PCL nanocapsules), which not only altered the release profile of the drug, but also resulted in the lowest toxicity. This carrier system therefore holds promise for use in future practical applications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Along with the brief history of amide local anesthetics development, their most important properties (from the viewpoint of use in clinical dental practice), are also reviewed. In particular, some properties of most commonly used local anesthetics, such as lidocaine, mepivacaine, prilocaine, bupivacaine and articaine are analysed. The most important data concerning pharmacological mechanisms of mentioned anesthetics' action, that cause certain features and peculiarities of their clinical application are given in condensed form. Besides, some precaution measures that must be taken into account in specific clinical cases together with the history and current status of each patient are mentioned as well.

Articaine, as a local anesthetic drug has been simulated in neutral and charged forms, and its interaction with the dimyristoylphosphatidylcholine (DMPC) lipid bilayer membrane is investigated by molecular dynamics simulation using GROMACS software. In order to obtain the optimum location of the drug molecules, as they penetrate into the membrane, umbrella sampling is applied and the free energy is calculated. The effect of protein binding to DMPC membrane on the process of drug diffusion through the membrane is considered. Five simulation systems are designed and by applying the potential of mean force, the molecular dynamics simulation on the system is performed. In light of the obtained results, the electrostatic potential, variation of lipid bilayer's order parameter and the diffusion coefficient of drug are discussed.

Background: Lidocaine has been considered the gold standard for local analgesia agents in dentistry for years. Articaine is now widely used but there has been a reluctance to use it in children., Review: Compared with lidocaine, articaine is 1.5 times as potent and only 0.6 times as toxic and has been shown to be superior in achieving successful anaesthesia following infiltration. The use of inferior alveolar nerve blocks (IANB) can be almost eliminated in children by using articaine due to its ability to effectively anaesthetic teeth up to the first permanent molar region. In addition, diffusion of the anaesthetic agent onto the palatal surface may also eliminate the discomfort of palatal infiltration. Soft tissue analgesia may be prolonged, but the risk of other adverse reactions is similar to other local anaesthetic agents., Conclusion: The use of articaine achieves successful pain control while reducing the volume administered and is advocated as a safe and effective alternative to lidocaine for use in children.

The interactions of the racemic mixture of articaine as well as pure (R)-articaine and pure (S)-articaine with monolayers of glycerophospholipids and brain lipids have been studied using the Langmuir monolayer technique. Articaine was added to the glycerophospholipids dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylserine (DPPS), 1-palmitoyl-2-oleoylphosphatidylserine (POPS) and total lipid extract from pig brain (TLPB). The amount of articaine in the monolayers was 30 mol%. The intercalation of each of the two enantiomers of articaine into a glycerophospholipid/brain lipid monolayers composed of chiral phospholipids will be diastereoisomeric in nature, hence different intercalation pattern for the two enantiomers can be expected. All the articaine species are found to intercalate into the DPPC monolayer and to increase the monolayer stability, this is most pronounced for the (R)-enantiomer. Intercalation of the articaine species into the DPPS monolayer increases the MMA and hardly affects the stability of the DPPS monolayer. In this monolayer, the articaine species intercalates into the head group region of the small and negatively charged serine head group, this is pronounced for the (R)-enantiomer. Our results indicate that by introducing an unsaturated acyl chain in the monolayer as in POPS, the monolayer discriminates between the articaine species. The (R)-enantiomer is located deep in the acyl chain region, whereas the (S)-enantiomer is found at or close to the head group. The data also might indicate that the (R)-enantiomer in the racemic mixture forms dimers in the POPS monolayer. Both articaine species as well as the racemic mixture intercalate into the monolayer of TLPB. Intercalation into this monolayer did not show any distinct difference in intercalation mode of the articaine species, probably due to camouflaging effect of large head groups like gangliosides and/or formation of lipid rafts in the monolayer. However, the (R)-enantiomer appears to intercalate better into the TLPB monolayer than the (S)-enantiomer. With proper standardization the Langmuir monolayer technique is a powerful method to discriminate between (R)- and (S)-enantiomer articaine interaction with model membranes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Local anesthetics (LAs) are drugs that cause reversible loss of nociception during surgical procedures. Articaine is a commonly used LA in dentistry that has proven to be exceptionally effective in penetrating bone tissue and induce anesthesia on posterior teeth in maxilla and mandibula. In the present study, our aim was to gain a deeper understanding of the penetration of articaine through biological membranes by studying the interactions of articaine with a phospholipid membrane. Our approach involves Langmuir monolayer experiments combined with molecular dynamics simulations. Membrane permeability of LAs can be modulated by pH due to a titratable amine group with a pKa value close to physiological pH. A change in protonation state is thus known to act as a lipophilicity switch in LAs. Our study shows that articaine has an additional unique lipophilicity switch in its ability to form an intramolecular hydrogen bond. We suggest this intramolecular hydrogen bond as a novel and additional solvent-dependent mechanism for modulation of lipophilicity of articaine which may enhance its diffusion through membranes and connective tissue., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Local anesthesia forms the foundation of pain control techniques in clinical dentistry. Within the rich local anesthetic drugs available in dentistry for the prevention and management of pain 4% articaine solutions achieve highest level of anesthetic potency and lowest systemic toxicity in all clinical situations, prior to its superlative physicochemical characteristics and the pharmacological profile. These are - low lipid solubility, high plasma protein binding rate, fast metabolization, fast elimination half time; low blood level. Articaine inactivates in both ways: in the liver and the blood serum. It has good spreading through tissues. Thus, articaine seems to be the local anesthetic of first choice in tissues with suppurative inflammation, for adults, children (over 4), elderly, pregnant women, breastfeeding women, patients suffering from hepatic disorders and renal function impairment. In Articaine solutions (1: 200,000) epinephrine is in low concentration, thus in patients at high risk adverse responses are maximally decreased. In these patients articaine should be used with careful consideration of risk/benefit ratio. Articaine solutions must not be used in persons who are allergic or hypersensitive to sulphite, due to content of Sodium metabisulfite as vasoconstrictor's antioxidant in it. Incidence of serious adverse effects related to dental anesthesia with articaine is very low. Toxic reactions are usually due to an inadvertent intravascular injection or use of excessive dose. To avoid overdoses maximum recommendation dose (MRD) must not be exceeded and aspiration test always performed prior all LA injections. In these article we introduce new graphs providing a quick and effect way to determine maximum LA dose. If the overdose reactions develop, adherence to the basic step of emergency management with end to a successful outcome in virtually all cases.

In order to investigate structural and dynamical properties of local anesthetic articaine in a model lipid bilayer, a series of molecular dynamics simulations have been performed. Simulations were carried out for neutral and charged (protonated) forms of articaine inserted in fully hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer. For comparison purpose, a fully hydrated DMPC bilayer without articaine was also simulated. The length of each simulation was 200ns. Various properties of the lipid bilayer systems in the presence of both charged and uncharged forms of articaine taken at two different concentrations have been examined: membrane area per lipid, mass density distributions, order parameters, radial distribution functions, head group tilt, diffusion coefficients, electrostatic potential, etc, and compared with results of previous simulations of DMPC bilayer in the presence of lidocaine. It was shown that addition of both charged and neutral forms of articaine causes increase of the dipole electrostatic potential in the membrane interior., (Copyright © 2010 Elsevier B.V. All rights reserved.)

In 2000, the US Food and Drug Administration (FDA) approved the use of 4% articaine with epinephrine 1:100,000, and with epinephrine 1:200,000 in 2006. Articaine has been commonly compared with its predecessor, lidocaine hydrochloride. Since its introduction in 1948, lidocaine has maintained a status as the most widely used local dental anesthetic in most countries. Proven efficacy with low allergenicity and toxicity over long-term clinical use and research have confirmed the value and safety of this drug. Thus, it became the gold standard to which all new local anesthetics are compared. Despite the gold standard status of lidocaine, numerous reports and editorials have supported and recognized the use of articaine., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In this paper I have explored four areas of current interest to pain control in dentistry. Articaine HCl, the most recent addition to the dental LA armamentarium, has become a favoured drug in many, if not most, countries in which it is available. Rapid onset and improved hard- and soft-tissue penetration enable articaine HCl to be administered with great success as a mandibular infiltration, precluding the need, in most situations, to employ it by inferior alveolar nerve block. The 'question' about an increased risk of paresthesia following articaine administration via IANB has been answered by careful evaluation of case reports. C-CLAD systems have enabled the administration of LA to become much more comfortable, especially in the palate, and with accessory techniques such as the periodontal ligament injection (PDL, ILI). Two highly successful techniques, the AMSA and P-ASA, have been developed as a result of C-CLAD systems. Phentolamine mesylate (OraVerse) allows for the reversal of residual soft-tissue anaesthesia, decreasing its duration by approximately 50%. Reversal enables patients to 'feel normal' more quickly after dental treatment and should decrease the risk of traumatic injury to soft tissues. Knowledge of the maximum dosages of LAs to be administered to all patients, but to younger, lighter-weight patients in particular, is essential to safety. The prevention of LA overdose is more gratifying than managing this fear-inducing medical emergency. When used properly, local anaesthetics represent the safest and most effective drugs in all of medicine for the prevention and management of pain.

Objective: Local anesthetics are the most commonly used drugs in dentistry, with a wide range of effects, including antimicrobial activity. High antimicrobial effects have recently been reported on oral microbes from articaine hydrochloride, revealed by the minimum inhibitory concentration and minimal bactericidal concentration. Additionally, articaine has recently been used as an alkaline component in endodontic materials with a proposed antibacterial activity. However, the detailed mechanisms of action have not been discussed., Material and Methods: We determined the Langmuir surface pressure/molecular area isotherms of prokaryotic lipid monolayers, as well as the phospholipid phase transitions, by employing differential scanning calorimetry on unilamellar prokaryotic liposomes (bilayers)., Results: Articaine hydrochloride was found to interact with the prokaryotic membrane lipids in both monolayers and bilayers. An increase of the phospholipid molecular area of acidic glycerophospholipids as well as a decrease in phase transition temperature and enthalpy were found with increasing articaine hydrochloride concentration. The thermodynamic changes by adding articaine hydrochloride to prokaryotic membrane lipids are potentially related to the effects observed from antimicrobial peptides resulting from membrane insertion, aggregate composition, pore formation, and lysis., Conclusion: Interaction of articaine hydrochloride with prokaryotic membrane lipids is indicated. Hence, further research is necessary to gain insight into where these compounds exert their effects at the molecular level.

Articaine hydrochloride, 4-methyl-3-(2-[propylamino]propionamido)-2-thiophenecarboxylic acid, methyl ester hydrochloride, is a local anaesthetic commonly used in dentistry, and is classified as an amide local anaesthetic. Solid-state (13)C and (31)P NMR were used to investigate the uncharged articaine species (sample pH 10.0) when interacting with distearoylphosphatidylcholine (DSPC) model membranes. The DSPC phospholipid bilayer was studied at four different molar ratios of articaine, 10, 25, 40, and 55 mol%, respectively. The articaine concentration-dependent decrease in the DSPC bilayer gel-to-liquid-crystalline phase-transition temperature demonstrates substantial articaine interaction with this bilayer. A DSPC bilayer contains a large hydrophobic core and the (13)C and (31)P NMR spectra of the 40 mol% articaine-containing sample demonstrate a disturbance in the molecular packing of the polar bilayer region that extends into the hydrophobic region, evidenced by carbon 2 and 3 of the stearoyl acyl chains. Observed (31)P and (13)C NMR spectral changes when articaine is increased from 40 to 55 mol%, suggest formation of articaine aggregates and decrease in DSPC bilayer perturbation at the latter articaine level.

Background: Articaine is a unique amide anesthetic that contains a thiophene ring and an additional ester group. The rapid diffusion and enhanced tissue-penetrating properties of articaine enable its use for infiltrative anesthesia., Objective: To describe the effective use of articaine as an adjuvant local anesthetic for surgical excisions requiring dissection at the level of the muscular fascia., Methods and Materials: We discuss the successful adjunctive use of articaine to provide effective infiltrative anesthesia of muscular fascia. We review the composition, the pharmacologic properties, and the safety profile of articaine., Results: Adjuvant local anesthesia using articaine results in painless surgery at the level of the muscular fascia without any perioperative complications., Conclusion: Articaine is not only well tolerated but also rapidly effective for anesthesia in the fascial plane of the trunk and extremities. We recommend it be considered as an adjunctive local anesthetic for consistently painless cutaneous surgery near the muscular fascia.

We report the case of a 51-year-old woman who had an immediate skin reaction after subcutaneous administration of a local anesthetic (LA) composed of articaine and epinephrine before a dental procedure. The patient subsequently underwent further dental procedures without LA. Skin prick tests performed with commercial LAs (lidocaine, mepivacaine, bupivacaine and articaine) were negative with epinephrine and all LAs except articaine. In 10 healthy controls, skin prick tests with articaine were negative. Subcutaneous challenge test with mepivacaine (0.3 and 0.5 ml) was negative. Provocations with the remaining anesthetics of the amide group were not carried out due to the patient's refusal.

The main known benefit of calcium hydroxide as an intracanal medicament lies in the bactericidal effect conferred by its pH. The objective of this work was to determine the influence of the vehicle on the pH of calcium hydroxide pastes after usage in patients and in vitro. The incisor root canals of 180 patients were instrumented and filled with calcium hydroxide pastes containing distilled water, chlorhexidine, propylene glycol, anesthetic solution, camphorated p-monochlorophenol and camphorated p-monochlorophenol-propylene glycol. The pH of the paste in the patients' root canals was measured at 7, 14 and 21 days. Similarly, pH was measured in vitro up to 21 days. The pH of all the pastes remained constant throughout the time periods assessed. The calcium hydroxide-water combination showed significantly higher pH values than the other pastes in clinical use. Comparative analysis showed that the pH values of the anesthetic solution, camphorated p-monochlorophenol and camphorated p-monochlorophenol-propylene glycol were significantly higher in vitro. The type of vehicle was shown to influence the final pH of the pastes. However, the alkalinity of all pastes was maintained over time under the experimental conditions.

Objective: Calcium hydroxide, Ca(OH)(2), is a common intracanal medicament. Ca(OH)(2) powder can be mixed with different vehicles and used as a paste for temporary intracanal treatment. The vehicle may influence the dissociation of calcium hydroxide into ions. We sought to evaluate the level of pH and to quantitatively estimate the release of proteins, hydroxyproline, and phosphorus from pieces of radicular dentin kept in different Ca(OH)(2) solutions., Study Design: Twenty-eight extracted incisors were maintained for 35 days in Ca(OH)(2) aqueous solutions prepared in chlorhexidine digluconate, propylene glycol (PG), anesthetic solution, camphorated monochlorophenol (CMCP), and CMCP-PG. The control solution contained Ca(OH)(2) without vehicle., Results: The pH values changed little during the experiment. The concentrations of proteins, hydroxyproline, and phosphorus rose for all the solutions under study. Statistical analysis of the data from the control and the experimental groups revealed an increase in the concentration of proteins when chlorhexidine, anesthetic solution, and PG were used; a rise in hydroxyproline levels when CMCP-PG, CMCP, and PG solutions were used; and an increase in phosphorus when PG and chlorhexidine vehicles were used., Conclusion: The test solutions with the root dentin remained alkaline. A release of proteins, hydroxyproline, and phosphorus was observed.

The aim of this study was to evaluate the surface tension values of established and potential endodontic irrigants to which a surface active agent had not been added. Additionally, Cetredixine, a surfactant-containing 0.2% chlorhexidine gluconate solution, was included in the measurements. Surface tension measurements were performed using the ring method on a DuNouy tensiometer at a standard room temperature. Ringer's solution, saline solution, and distilled water had the highest surface tension values, whereas those of NaOCl (2.5% and 5%) and 17% EDTA were relatively low. Two anesthetic solutions, Ultracaine and Citanest, demonstrated values similar to NaOCl and EDTA, although a statistically significant difference was found between all solutions tested. Cetredixin displayed the lowest surface tension. A low surface tension agent should penetrate tubules better.

Purpose: Three identical single-dose, randomized, double-blind, parallel-group, active-controlled multicenter studies were conducted to compare the safety and efficacy of articaine HCl (4% with epinephrine 1:100,000) to that of lidocaine HCl (2% with epinephrine 1:100,000) in patients aged 4 years to 79 years, with subgroup analysis on subjects 4 to < 13 years., Methods: Fifty subjects under the age of 13 years were treated in the articaine group and 20 subjects under the age of 13 were treated with lidocaine. Subjects were randomized in a 2:1 ratio to receive articaine or lidocaine. Efficacy was determined on a gross scale immediately following the procedure by having both the subject and investigator rate the pain experienced by the subject during the procedure using a visual analog scale (VAS). Safety was evaluated by measuring vital signs before and after administration of anesthetic (1 and 5 minutes post-medication and at the end of the procedure) and by assessing adverse events throughout the study. Adverse events were elicited during telephone follow-up at 24 hours and 7 days after the procedure., Results: Pediatric patients received equal volumes, but higher mg/kg doses, of articaine than lidocaine during both simple and complex dental procedures. Pain ratings: Articaine: VAS (Visual Analogue Scale) scores (from 0 to 10 cm) by patients 4 to < 13 years of age were 0.5 for simple procedures and 1.1 for complex procedures, and average investigator scores were 0.4 and 0.6 for simple and complex procedures, respectively. Lidocaine: patients 0.7 (simple) and 2.3 (complex); investigators 0.3 (simple) and 2.8 (complex). Adverse events: No serious adverse events related to the articaine occurred. The only adverse event considered related to articaine was accidental lip injury in one patient., Conclusions: VAS scores indicate that articaine is an effective local anesthetic in children and that articaine is as effective as lidocaine when measured on this gross scale. Articaine 4% with epinephrine 1:100,000 is a safe and effective local anesthetic for use in pediatric dentistry. Time to onset and duration of anesthesia are appropriate for clinical use and are comparable to those observed for other commercially available local anesthetics.

Since the introduction of cocaine local analgesia in 1886, and the subsequent development of procaine (1904) and other closely related ester-type compounds, dentistry has prided itself on being as close to 'painless' as possible. In the late 1940s the newest group of the local anesthetic compounds, the amides, was introduced. The initial amide local analgesic, lignocaine (Xylocaine), revolutionised pain control in dentistry worldwide. In succeeding years other amide-type local anesthetics, mepivacaine, prilocaine, bupivacaine and etidocaine, were introduced. They gave the dental practitioner a local anesthetic armamentarium which provided pulpal analgesia for periods of from 20 minutes (mepivacaine) to as long as three hours (bupivacaine and etidocaine with adrenaline). In addition these popular drugs proved to be more rapid-acting than the older ester-type drug and, at least from the perspective of allergenicity, more safe. In 1976, in Germany, the newest amide local analgesic, carticaine HCl was introduced into dentistry. Articaine (the generic name was changed) possesses properties similar to lignocaine but has additional properties which made the drug quite attractive to the general dental practitioner. In 1986 articaine was introduced in North America (Canada) where it has become the most used local anesthetic, supplanting lignocaine. Articaine has been approved for use in the United Kingdom. In this introductory discussion we review the development of articaine and discuss its place in the dental local analgesic armamentarium.

A series of ethyl 2-substituted amino-cyclopenteno[b]thiophen-3-carboxylates was synthesized as a carticaine analogues and evaluated for their local anesthetic and antiarrhythmic activity. Compounds ethyl 2-[1-oxo-2-(ethylamino)ethylamino]-(4a), ethyl 2-[1-oxo-2-(n-propylamino)-ethylamino]-(4c), ethyl 2-[1-oxo-2-(4-methylpiperazino)ethylamino]-(4e), ethyl 2-[1-oxo-2-(ethylamino)propylamino]-(5a) and ethyl 2-[1-oxo-2-(n-propylamino)propylamino]cyclopenteno[b]thiophen++ +-3-carboxylate (5c) proved to possess local anesthetic and antiarrhythmic activity comparable to carticaine and lidocaine. The active compounds exert their antiarrhythmic potency via blocking Na+ channels as in case of 5c or blocking Ca+2 channels as in case of 4a, 4c and 5c. Compound 4e exhibited a dual mechanism by blocking both Na+ and Ca+2 channels.

Articaine is the most widely used local anaesthetic agent in dentistry in a number of European countries. The amide structure of articaine is similar to that of other local anaesthetics, but it contains an additional ester group which is quickly hydrolysed by esterases. High performance liquid chromatography has been used to determine the concentrations of articaine and its metabolite articainic acid in serum. Rapid sample preparation is critical in the accurate determination of articaine serum concentrations, since blood and serum are the sites of metabolism. The time to maximum drug concentrations of articaine occurs about 10 to 15 minutes after submucosal injection of articaine 4% 80 mg, irrespective of epinephrine (adrenaline). The mean maximum plasma drug concentration is about 400 micrograms/L for articaine with epinephrine 1:200,000 and 580 micrograms/L for articaine without epinephrine. The elimination half-time of articaine is about 20 minutes. The rapid breakdown of articaine to the inactive metabolite articainic acid is related to a very low systemic toxicity and consequently to the possibility of repeated injections. Equal analgesic efficacy along with lower systemic toxicity (i.e. a wide therapeutic range) permits the use of articaine in higher concentrations than other amide-type local anaesthetics. Complete anaesthesia can be observed in nearly 90% of all cases, using articaine 4% 60 to 80 mg with epinephrine 1:200,000. Articaine is better able to diffuse through soft tissue and bone than other local anaesthetics. The concentration of articaine in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. The plasma protein binding rate of articaine and articainic acid is 70%. It has been concluded that an unintentional intravascular injection of articaine 80 mg does not cause toxic effects in healthy individuals.

Background and Objectives: The amide-type local anesthetic articaine is unique in that hydrolysis to articainic acid by serum esterases is its main metabolic pathway. The purpose of the present investigation was to study the concentration dependence of this pathway in vitro., Methods: To unbuffered (pH 8.2) as well as phosphate-buffered (pH 7.4) heated serum samples were added various amounts of articaine in the range 10-300 micrograms/mL. Concentrations of articaine and articainic acid were measured by high-performance liquid chromatography after incubating the samples at 37 degrees C for intervals ranging from 5 minutes to 6 hours after addition of articaine., Results: The in vitro metabolism of articaine was shown to undergo pH-dependent Michaelis-Menten kinetics, indicating saturation at higher substrate concentrations. The Michaelis constant K(m) was determined as 175 micrograms/mL and 22.1 micrograms/mL and the maximum reaction rate Vmax as 2.1 micrograms/mL/min and 0.17 microgram/mL/min at pH 8.2 and pH 7.2, respectively. These results support previous in vivo observations that suggest saturable articaine metabolism, indicated by higher articaine/articainic acid metabolic ratio with higher articaine concentrations in alveolar blood after dental extraction., Conclusion: Local saturation of the serum esterases may contribute to the advantageous relationship between persistence of the local anesthetic effect and low systemic toxicity caused by the last systemic elimination of articaine (ie, its wide toxic therapeutic ratio).