Local Anesthetic Activity Research Articles

A review and new insights to antimicrobial action of local anesthetics.

Local anesthetics (LAs) are medications which can provide analgesia in distinct body regions through the blockade of voltage-gated sodium channels. Besides pain management, the supplemental role of LAs as antimicrobial agents has been documented in several studies. Different databases including PubMed, Scopus, and Web of Science with the name of different local anesthetics and related names for antimicrobial keywords were searched without time limitation. This review summarized different in vitro and in vivo studies regarding antimicrobial effects of different LAs with focuses on antimicrobial applications of most studied LAs, interaction with different agents which combined with LAs, and mechanisms of action and structural dependence of LAs antibacterial effects. Among different LAs, lidocaine is the most studied preparation. Reduction of the incidence of endophthalmitis after intravitreal injection, prophylaxis for surgical wound infections, prevention of the incidence of catheter-associated infections, oral biofilm reduction on the buccal mucosa, and prevention against bacteria that produced nosocomial infection are some examples of lidocaine antimicrobial application. Studies showed that different factors including structure, concentration, duration of exposure, type of microorganism tested, and temperature affect the degree of LA antimicrobial activity. In addition, various agents such as antibiotics, preservatives, opioids, epinephrine, and propofol can combine with LAs and affect their antimicrobial properties through synergistic or antagonistic action. Due to antibacterial activities, LAs could be applied in a clinic for prophylaxis of surgical site infection. In the application of LAs prior to diagnostic procedures caution should be needed; otherwise, when culturing the specimen, they could lead to false negative results.

Are drug-related dental management cautions in Lexicomp Online for Dentistry evidence-based? A systematic review of the literature.

Drug reference databases provide information on potential drug-related medical complications in a dental patient. It is important that database entries and recommendations are supported by evidence-based original studies focused on drug-related dental management complications. The aim of this study was to review and identify database drug categories associated with evidence-based drug-related medical complications during dental treatment. Relevant publications on adverse drug reactions and dental management complications were thoroughly reviewed from the literature published between July 1975 and July 2019. The drug reference database "Lexicomp Online for Dentistry" was reviewed to identify medications associated with the highest propensity to trigger drug-related dental management complications, and these were correlated with published original studies in PubMed, Embase, and Scopus databases that associated drug actions with dental treatment complications. Fifty-four publications (1.2% of all full-text articles) reported original studies that directly tested drug associations with dental management complications. The cautions in the drug reference database on drug-related dental treatment mainly focused on local anesthetic precaution (P < .001), xerostomia (P < .001), bleeding (P < .001), and a combination of xerostomia and bleeding (P < .001). Antipsychotics/antidepressants were mostly associated with local anesthetic complications (80.95%), xerostomia (81.93%), and a combination of xerostomia and bleeding (22.89%). Bleeding complication was associated with anticoagulants (80.00%) and cancer chemotherapeutic agents (59.21%). Similarities exist within and across different drug categories in the database entries on drug-related medical complications in a dental patient. There were a relatively limited number of publications that directly tested the association between drug-related medical complications and dental therapies. The most common drug cautions during dental treatment reported in Lexicomp Online for Dentistry were limited to drug-drug interactions with local anesthetic actions, excessive bleeding, xerostomia, or a combination of any of these. These recommendations were supported by limited evidence-based studies.

Efficacy of nalbuphine as an adjuvant to 0.5% ropivacaine for ultrasound-guided supraclavicular brachial plexus block in upper limb surgeries: A prospective randomized double-blind study

Background: The benefit of postoperative analgesia in regional block is short lived due to limited duration of action of local anesthetics. Various adjuvants have been tried to enhance the duration of analgesia. The aim of this study was to evaluate the analgesic efficacy and safety of nalbuphine as an adjuvant to 0.5% ropivacaine for ultrasound-guided supraclavicular brachial plexus block. Methods: A prospective, randomized, double-blind study was conducted on 100 patients of American Society of Anesthesiologists physical status I/II aged 18–70 years scheduled for upper limb surgeries under USG supraclavicular brachial plexus block. The patients were randomly allocated into two groups of 50 each to receive either 20 ml of 0.5% ropivacaine with 1 ml of normal saline (Group A) or 20 ml of 0.5% ropivacaine with 1 ml (10 mg) of nalbuphine (Group B). The onset and duration of sensory and motor block, duration of analgesia, and side effects were noted. Results: There was no significant difference in mean onset of sensory and motor blocks between the two groups; but in Group B, there was significantly longer duration of sensory block (401.20 ± 19.963 vs. 387.60 ± 29.731 min, P = 0.009), longer duration of motor block (333.20 ± 20.941 vs. 323.00 ± 26.283 min, P = 0.03), and prolonged duration of analgesia (502.60 ± 22.751 vs. 441.20 ± 30.815 min, P 0.05). Conclusion: Nalbuphine (10 mg) used as an adjuvant to 0.5% ropivacaine for supraclavicular brachial plexus block prolonged the duration of both sensory and motor blockade along with the duration of postoperative analgesia without any increase in side effects.

Synthesis and biological activities of local anesthetics.

Local anesthetics are mainly used in stomatology, ophthalmology, gynecology and surgery to temporarily relieve pain. Local anesthetics act on nerve endings or around nerve trunks, and are combined with specific sodium ion (Na+) channel sites on the nerve membrane. They can affect the membrane potential by reducing Na+ passage through sodium ion channels, thus blocking the generation and conduction of nerve impulses, reversibly blocking the generation and conduction of sensory nerve impulses. Local anesthetics are used for convenience in local surgical operations and treatments. Herein, we mainly review the research progress on local anesthetics and discuss the important aspects of design, synthesis and biological activity of various new compounds.

On mechanism of reduction on DME of some compounds with local anesthetic activity N-oxides containing tertiary amine

It has been shown for the first time the obtaining of N-oxides of dymedrol (DMD) and bupivacaine (BVK). Bupivacaine is a local anesthetic of amide group. Dymedrol (diphenhydramine hydrochloride) is an antihistamine that reduces the effects of natural chemical histamine in the body. The N-oxides of DMD and BVK are formed during chemical oxidation with potassium peroxymonosulfate (KPMS). The first step was investigation of the optimal conditions for oxidation reaction to reach the maximum yield of final products (N-oxides). The investigated conditions were pH, time of oxidation and ratio of reagents. The needed time for oxidation of DMD and BVK is 10 min. At least two-fold excess of KPMS must be in the solution in recount to analyte concentration, but not higher than 10 -4 M. The maximum concentration of BVK and DMD N-oxides was obtained in weakly basic medium (pH 8.5–9.3). The second step was optimization of conditions for polarographic reduction of BVK and DMD N-oxides on the dropping mercury electrode (DME). The best medium for electrochemical reduction was the medium of phosphate buffer solution with pH in the range 5–6. On polarogramms it was observed only one irreversible peak in full pH range studied. The rate of electrochemical reaction is diffusion-controlled with weak adsorption of BVK, other local anesthetics (LA) (lidocaine, mepivacaine and trimecaine) and DMD N-oxides on DME surface confirmed by studying of effect of scan rates on polarogramms characteristics. The reduction potentials of peak linearly depend on solution pH. Thus, the electrochemical reduction of LA and DMD N-oxides includes protonation reaction stage. Based on literature survey and our calculations it was suggested that reduction mechanism of BVK and DMD N-oxides consist in monoelectron transfer resulting in anion-radical formation proceeding one proton adjunction. Keywords : polarography, N-oxides, local anesthetics, dymedrol, bupivacaine.

Effect of Local Anesthetics on the Organization and Dynamics of Hippocampal Membranes: A Fluorescence Approach.

Understanding the mechanism of action of local anesthetics has been challenging. We previously showed that the local anesthetic phenylethanol (PEtOH) inhibits the function of serotonin1A receptor, which is a member of the G protein-coupled receptor family and a neurotransmitter receptor. With the objective of gaining insight into the molecular mechanism underlying the anesthetic (PEtOH) action, we monitored the organization and dynamics of hippocampal membranes using multiple fluorescent reporters, which include a molecular rotor (BODIPY-C12) and a voltage-sensitive probe (4-(2-(6-(dioctylamino)-2-naphthalenyl)ethenyl)-1-(3-sulfopropyl)-pyridinium inner salt) (di-8-ANEPPS), besides pyrene. These interfacial membrane probes were chosen because membrane partitioning of PEtOH would be reflected in the membrane interfacial environment. Taken together, we report a reduction in dipole potential and microviscosity of hippocampal membranes, with a concomitant increase in lateral diffusion in the presence of PEtOH. The reduction in membrane dipole potential induced by PEtOH constitutes one of the first experimental demonstrations on the modulation of membrane dipole potential by local anesthetics. Our results assume significance in view of previous reports that correlate membrane-perturbing effects of local anesthetics to their anesthetic action. We envision that insights into the interaction of local anesthetics with membranes could serve as a crucial link in developing a comprehensive understanding of the molecular mechanisms involved in anesthesia.

On local anesthetic action of some dimethylacetamide compounds

The study aim was to explore local anesthetic properties of some tertiary and quaternary derivatives of dimethylacetamide. Materials and methods. The study was performed on white laboratory mice and rats of both sexes, male Agouti guinea pigs, and isolated sciatic nerves of lake frog. In the focus of the study there were two quaternary and eight tertiary compounds of dimethylacetamide with substituted anion with some amino and carbonic acids residue. A local anesthetic property was predicted by computational analysis. Acute toxicity of the most promising substances was studied in mice through subcutaneous route. Local anesthetic activity of tertiary compounds LKhT-3-00, LKhT-4-00 and quaternary LKhT-12-02 was studied on models of terminal, infiltration and conduction anesthesia. The influence of substances on mixed nerve conduction was investigated on lake frog’s isolated sciatic nerves. Results and discussion. The greatest probability of the local anesthetic activity during computational analysis was estimated for the tertiary derivatives of dimethylacetamide LKhT-3-00 and LKhT-4-00 and for the quaternary compound LKhT-12-02. According to their toxicological profile, the compounds belong to moderately toxic substances (class 3). On the model of terminal and infiltration anesthesia, substances LKhT-3-00 and LKhT-4-00 at concentrations of 0.5-1% rapidly cause deep and prolonged anesthesia. On the models of conduction anesthesia, the quaternary derivative of dimethylacetamide LKhT-12-02 has the greatest analgesic effect. The duration of the effect of the substance is over 3 hours. All the investigated compounds block sciatic nerve conduction. The longest effect is registered for LKhT-12-02. Conclusions. Dimethylacetamide derivatives at concentrations of 0.5-1.0% exhibit a local anesthetic activity, and are effective for terminal, conduction and infiltration anesthesia. Their effect is due to blockade of nerve conduction.

Efficacy and Safety of Dexamethasone as an Adjuvant With Bupivacaine and Lignocaine in Supraclavicular Brachial Plexus Block

Background: Perineural injection of corticosteroid has been successfully used to prolong the local anesthetic action. The aim of this study was to evaluation the efficacy and safety of dexamethasone as an adjuvant with bupivacaine-lignocaine in supraclavicular block. Material and methods: This analytical study was carried out in the Department of Anesthesiology in Chittagong Medical College Hospital in collaboration with the Department of Orthopedic Surgery over a period of 22 months starting from January 2012 to December 2014. A total 130 adult patients of either sex with American Society of Anesthesiology (ASA) health status I-II were selected for upper limb surgery under supraclavicular brachial plexus block was randomly allocated in to two groups of 65 patients in each. Group- D was received dexamethasone 2ml (10mg) and Group-C (Control) was received distilled water 2ml in 38ml of bupivacaine and lignocaine with adrenaline (total volume of 40ml). Results: The mean onset of sensory &amp; motor block was 7.72±1.949min &amp; 8.75±2.008min in group-D and 10.49±0.75min &amp; 9.41±0.76 min in group-C. The duration of analgesia in group-D was 11.40±0.844hrs and in group-C was 3.81±0.88hrs. Conclusion: There was significantly prolonged duration of analgesia and better onset of sensory and motor block in dexamethasone group without any unwanted effects.&#x0D; JCMCTA 2018 ; 29 (1) : 47-52

Blocking ion channels induced by antifungal lipopeptide syringomycin E with amide-linked local anesthetics

The effects of the amide-linked (lidocaine (LDC), mepivacaine (MPV), prilocaine (PLC)) and ester-bound local anesthetics (benzocaine (BZC), procaine (PRC), and tetracaine (TTC)) on the pore-forming activity of the antifungal lipopeptide syringomycin E (SRE) in lipid bilayers were studied. Independently on electrolyte concentration in the membrane bathing solution the observed changes in conductance of SRE channels agreed with the altered membrane dipole potential under the action of ester-bound local anesthetics. Effects of aminoamides in diluted and concentrated solutions were completely different. At 0.1 M KCl (pH 7.4) the effects of amide-linked anesthetics were in accordance with changes in the membrane surface potential, while at 2 M KCl aminoamides blocked ion passage through the SRE channels, leading to sharp reductions in pore conductance at negative voltages and 100-fold decreases in the channel lifetimes. The effects were not practically influenced by the membrane lipid composition. The interaction cooperativity implied the existence of specific binding sites for amide-bound anesthetics in SRE channels.

Pharmacological and toxicological activity of RSD921, a novel sodium channel blocker

BackgroundRSD921, the R,R enantiomer of the kappa (k) agonist PD117,302, lacks significant activity on opioid receptors. MethodsThe pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity. ResultsIn rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (ito) and sustained (IKsus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized. ConclusionsRSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity.

Büchi's model based analysis of local anesthetic action in procaine hydrochloride: Vibrational spectroscopic approach

The drug action of ester type local anesthetic (LA) procaine hydrochloride (PRC HCl) is activated by blocking Na+ ion flow when it binds to the ion channel in the ligand gated sodium ion channel protein. Büchi's model, explains binding action of ester type LA drug with receptor in terms of charge transfer, dipole-dipole, hydrogen bonding and van der Waals interactions through lipophilic, ester and hydrophilic moieties. The present work investigates molecular structural and vibrational spectral features of para amino benzoate group, ester part and tertiary amino group respectively belonging to lipophilic, ester and hydrophilic moieties, accountable for the binding of drug to sodium channel. The electron transport mechanism through the ring responsible for structural deviation from benzenoid to quinonoid form and consequent dipolar nature of carbonyl group have been investigated, based on the analysis of XRD, DFT computed molecular structure, 8a ring mode and NBO charges. The characteristic UV absorption peaks and vibrational marker bands of LA drugs have been identified and the charge transfer interaction responsible for lipophilic binding has been investigated. The blocking of Na+ in the ion channel has been probed using attractive and repulsive energy profile. The molecular polarizability has been computed to substantiate the correlation between the structure activity relationship of LA drug molecule and molecular polarizability. The low toxicity of PRC HCl was evaluated using in vitro cytotoxicity study, confirming it as a potential short acting local anesthetic.

Epinephrine-Induced Acute Pulmonary Edema during Septoplasty

Epinephrine is used with lidocaine to provide bloodless surgical field and to prolong the action of local anesthetics. But epinephrine also has many adverse reactions, such as agitation, restlessness, headache, tachycardia, hypertension, and some significantly more dangerous conditions including myocardial ischemia, ventricular arrhythmia, cerebral hemorrhage and pulmonary edema, cardiac arrest, etc. We have experienced epinephrine-induced acute pulmonary edema due to submucosal intranasal application of epinephrine soaked gauze during septoplasty. The patient was successfully treated in intensive care unit with positive pressure ventilation, diuretics, and inotropic support. He was extubated after 5 hours and discharged after 7 days without any complications. Key words: Epinephrine; Pulmonary edema; Septoplasty

Amide-linked local anesthetics preferentially target leukemia stem cell through inhibition of Wnt/β-catenin

The anti-cancer activities of amide-linked local anesthetics have been demonstrated in various types of bulky/differentiated cancer cells. However, whether these anesthetics also affect biological functions of cancer stem cells is largely unknown. In this study, we systematically investigated the effects of three commonly used amide-linked local anesthetics (ropivacaine, lidocaine and bupivacaine) on leukemia stem cell (LSC) derived from two different leukemia diseases (acute myeloid leukemia, n = 8 and chronic myeloid leukemia, n = 8) as well as normal hematopoietic stem cell (HSC) derived from cord blood donors (n = 8) as comparison. We show that all three local anesthetics at clinically achievable concentrations significantly inhibit colony formation and serial replating of LSC in a dose-dependent manner, suggesting their inhibitory effects on LSC differentiation, proliferation and self-renewal. In addition, lidocaine and bupivacaine are more potent than ropivacaine. However, local anesthetics at the same concentrations do not affect LSC and HSC survival, demonstrating the differentiation and self-renewal as the primary effects of local anesthetics on LSC and HSC. Interestingly, local anesthetics display certain selectivity between LSC and HSC by having higher efficacy on LSC than HSC. Mechanism studies using both pharmacological and genetic approaches demonstrate that these local anesthetics target LSC via inhibiting Wnt/β-catenin but not Hedgehog or NF-ĸB signaling. Our work is the first to demonstrate the possible influence of amide-linked local anesthetics on cancer as well as normal stem cells via inhibiting Wnt/β-catenin signaling. Our findings contribute to the comprehensive understanding of potential implication of amide-linked local aesthesis in tumor biology.

Impact of dexmedetomidine on the tissue distribution, anesthetic action, and hemodynamic effects of mepivacaine.

The present study investigated the regional blood flow, tissue distribution, local anesthetic action, and hemodynamic effects of mepivacaine containing dexmedetomidine hydrochloride (DEX) in rats. Blood flow was measured after injection of 0.5% mepivacaine (M group), 12.5µg/ml DEX (D group), or 0.5% mepivacaine containing 12.5µg/ml DEX (DM group) into the upper lip. Mepivacaine distribution was autoradiographically observed in maxillary bone resected after injection of 0.5% 3H-mepivacaine (HM group) or 0.5% 3H-mepivacaine containing 12.5µg/ml DEX (DHM group) into the palatal mucosa adjacent to the right maxillary first molar. Radioactivity was also measured using a liquid scintillation counter. SEP were measured to analyze anesthetic action. Blood pressure and heart rate were measured to compare hemodynamic effect. The addition of DEX significantly decreased blood flow compared to M group from 10 to 60min after injection. The addition of DEX significantly increased the amount of radioactivity compared to HM group in the palatal mucosa from 5 to 60min after injection and in the body of the maxilla from 2 to 60min after injection. Maximum blood radioactivity was measured at 5min after injection in HM group and 50min after injection in DHM group. The addition of DEX significantly decreased peak-to-peak amplitudes compared to M group until 60min after injection. No significant hemodynamic differences were observed. DEX enhances the action of mepivacaine in reducing regional blood flow prolongs its tissue retention, and increases the local anesthetic action without affecting hemodynamics on local administration.

Adjunct medications for peripheral and neuraxial anesthesia.

Regional and neuraxial anesthesia can provide a safer perioperative experience, greater satisfaction, reduced opioid consumption, and reduction of pain, while minimizing side effects. Ultrasound technology has aided clinicians in depositing local anesthetic medication in precise proximity to targeted peripheral nerves. There are a plethora of adjuvants that have been utilized to prolong local anesthetic actions and enhance effects in peripheral nerve blocks. This manuscript describes the current state of the use of adjuncts, e.g., dexmedetomidine, dexamethasone, clonidine, epinephrine, etc., in regional anesthesia. Additionally, evidence behind dosing and block prolongation is summarized along with patient outcomes, adverse effects, and future directions.

The history and progress of local anesthesia: multiple approaches to elongate the action.

Analgesia and temporary inhibition of motor activity without interfering with central nervous function have been the essential merits of local anesthesia. Local anesthetics originated from cocaine have played a major role in local analgesia. However, the relatively short duration of action of local anesthetics has been a concern in intra- and post-operative analgesia. From the early age of modern local anesthesia, physicians and medical scientists had been struggling to control the active duration of local anesthetics. Such approach includes: development of long-acting local anesthetics, with physical tourniquet techniques, co-administration of other medicines such as vaso-constrictive agents or analgesics, development of mechanical devices to continuously or intermittently administer local anesthetics, and utilization of pharmaceutical drug delivery systems. In this review, the historical sequence of studies that have been performed in an effort to elongate the action of local anesthetics is presented, referring to epoch-making medical and scientific studies.

The Science of Local Anesthesia: Basic Research, Clinical Application, and Future Directions.

Local anesthetics have been used clinically for more than a century, but new insights into their mechanisms of action and their interaction with biological systems continue to surprise researchers and clinicians alike. Next to their classic action on voltage-gated sodium channels, local anesthetics interact with calcium, potassium, and hyperpolarization-gated ion channels, ligand-gated channels, and G protein-coupled receptors. They activate numerous downstream pathways in neurons, and affect the structure and function of many types of membranes. Local anesthetics must traverse several tissue barriers to reach their site of action on neuronal membranes. In particular, the perineurium is a major rate-limiting step. Allergy to local anesthetics is rare, while the variation in individual patient's response to local anesthetics is probably larger than previously assumed. Several adjuncts are available to prolong sensory block, but these typically also prolong motor block. The 2 main research avenues being followed to improve action of local anesthetics are to prolong duration of block, by slow-release formulations and on-demand release, and to develop compounds and combinations that elicit a nociception-selective blockade.

Lipid-mediated mode of action of local anesthetics on lipid pores induced by polyenes, peptides and lipopeptides.

The effects of local anesthetics (LAs), namely, lidocaine (LDC), prilocaine (PLC), mepivacaine (MPV), bupivacaine (BPV), procaine (PC), and tetracaine (TTC), on the steady-state transmembrane conductance induced by the cis-side addition of the antifungal polyene macrolide antibiotic, nystatin (NYS), in planar lipid bilayers were studied. The addition of TTC to model membranes comprising DOPC and cholesterol (33 mol%) led to a nearly twenty-fold increase in the steady-state NYS-induced membrane conductance. BPV slightly enhanced the channel-forming activity of polyene. LDC, PLC, MPV, and PC did not affect the NYS-induced transmembrane current. We concluded that the effects of LAs on the channel-forming activity of NYS were in agreement with their effects on the elastic properties of model membranes. The ability of aminoamide LAs to promote calcein leakage from large unilamellar DOPC-vesicles was decreased in the following order: BPV >> LDC ≈ PLC ≈ MPV. LDC, PLC, and MPV produced a graded leakage of fluorescent marker from liposomes, up to 10-13%. A initial sharp jump in fluorescence after the introduction of BPV was attributed to the solubilization of liposomes and the formation of mixed DOPC:BPV-micelles. Differential scanning microcalorimetry (DSC) of large unilamellar DPPC-vesicles showed that the main transition temperature (Tm) is continuously decreased upon increasing concentrations of TTC. A sharp drop in the enthalpy of the transition at higher TTC concentrations indicated a formation of anesthetic/lipid mixed micelles. In contrast to TTC, PC slightly decreased Tm, broadened the DSC signal and did not provoke vesicle-to-micelle transition. Both the calcein leakage and DSC data together with the results of measurements of threshold voltages that are required to cause the lipid bilayer breakdown might indicate an alteration in the curvature lipid packing stress, induced by BPV and TTC. The data presented here lend support to a lipid-mediated mode of LAs action on NYS pores via an alteration in curvature stress near the trans-mouth. Similar results were obtained for several lipid pores, formed by polyene amphotericin B, lipopeptide syringomycin E, and the peptides magainin and melittin. This finding further developed the concept of non-specific regulation of lipid pores by LAs. In conclusion, the combination of nystatin with LAs could be a novel treatment for efficient therapy of superficial and mucosal candidiasis.

Factors predictive of the onset and duration of action of local anesthesia in mandibular third-molar surgery: a prospective study.

The aim of this study was to assess the influence of patients' and surgical variables on the onset and duration of action of local anesthesia (LA) in mandibular third-molar (M3) surgery. Patients scheduled for mandibular M3 surgery were considered for inclusion in this prospective cohort study. Patients' and surgical variables were recorded. Two per cent (2%) lidocaine with 1:100,000 epinephrine was used to block the nerves for extraction of mandibular M3. Then, the onset of action and duration of LA were monitored. Univariate analysis and multivariate regression analysis were used to analyze the data. The final cohort included 88 subjects (32 men and 56 women; mean age ± SD = 29.3 ± 12.3 yr). With univariate analysis, age, gender, body mass index (BMI), smoking quantity and duration, operation time, and 'volume of local anesthetic needed' significantly influenced the onset of action and duration of LA. Multivariate regression revealed that age and smoking quantity were the only statistically significant predictors of the onset of action of LA, whereas age, smoking quantity, and 'volume of local anesthetic needed' were the only statistically significant predictors of duration of LA. Further studies are recommended to uncover other predictors of the onset of action and duration of LA.

A Computational Model of the Cardiac Sodium Channel DIII Voltage Sensor: Connecting Molecular Movements to Tissue Dynamics

The cardiac Na+ channel is a macromolecular protein complex consisting of 4 domains, each composed of 6 transmembrane subunits. The voltage sensing domains (VSD) on DI - DIV, and in particular the DIII VSD has been shown to be critical in activation, inactivation, channel opening, and local anesthetic antiarrhythmic drug action. To date, computational models of the cardiac Na+ channel only account for current kinetics, which limits their ability to predict how perturbations by mutations and drugs at the molecular level may affect higher dimensional properties in the heart. We began by expanding a computational model of the cardiac Na+ channel, and incorporated voltage clamp fluorometry data on DIII VSD movement; this technique allows one to fluorescently track VSD conformation and correlate VSD kinetics with ionic currents. Our expanded 12-state Markov model of the Na+ channel recapitulates a wide range of current kinetics including steady state availability, steady state activation, deactivation, recovery from inactivation, and mean open time, as well as DIII fluorescent activation and deactivation. Next, we examined two LQT3 mutations, R1626P, and M1652R, which have opposing effects on DIII and have differing sensitivities to the Na+ channel blocker mexelitine. We built computational models of each, and their unique interaction with mexelitine. Our results show that a hyperpolarizing shift in DIII can account for the increased sensitivity of R1626P to mexelitine, and the depolarization seen with M1652R renders it mexelitine insensitive. Our computational models were then used to characterize and track these differential effects on DIII movement on the action potential and coupled virtual tissue. We conclude that DIII represents a novel molecular target and plays a primary role in determining differential sensitivity of certain LQT3 mutations to the local anesthetic mexelitine.