Early Nonclinical and Clinical Development of AG-920, a Repurposed Topical Ocular Anesthetic.

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.

Articaine in functional NLC show improved anesthesia and anti-inflammatory activity in zebrafish.

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.

Physicochemical characterization and cytotoxicity of articaine-2-hydroxypropyl-ß-cyclodextrin inclusion complex.

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-ß-cyclodextrin inclusion complex (ATC HPßCD) 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:HPßCD = 1:1) and complex formation time (400 min), as indicated by a strong host/guest interaction (Ka = 117.8 M - 1), complexed fraction (f = 41.4%), and different ATC and ATC HPßCD 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 HPßCD, respectively. Moreover, remarkable cell toxicity was observed with free ATC by immunofluorescence. These results indicate the ATC HPßCD complex could be used to improve the safety of ATC. Further research are needed to establish the anesthetic safety and effectiveness in vivo .

Development of hydrophilic nanocarriers for the charged form of the local anesthetic articaine.

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.

[Pharmakological characteristic of some amide local anesthetics, currently used in dental clinics].

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.

Effects of protein binding on a lipid bilayer containing local anesthetic articaine, and the potential of mean force calculation: a molecular dynamics simulation approach.

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.

Articaine use in children: a review.

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.

Interaction of local anaesthetic articaine enantiomers with brain lipids: a Langmuir monolayer study.

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.

Articaine - the best choice of local anesthetic in contemporary dentistry.

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.

Intramolecular hydrogen bonding in articaine can be related to superior bone tissue penetration: a molecular dynamics study.

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.

Molecular dynamics simulations of local anesthetic articaine in a lipid bilayer.

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.

Efficacy of articaine formulations: quantitative reviews.

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.

What's new in local anaesthesia?

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.

Interaction of articaine hydrochloride with prokaryotic membrane lipids.

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 interaction with DSPC bilayer: a 13C and 31P solid-state NMR study.

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.

Articaine: an effective adjunctive local anesthetic for painless surgery at the depth of the muscular fascia.

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.