Local Anesthetic Drug Lidocaine Research Articles

1,3,5‐Triazinanes as Formaldimine Surrogates in the Ugi Reaction

In the present study, a new synthetic strategy towards N‐acylated glycinamides was developed by the use of 1,3,5‐triazinanes as formaldimine surrogates in the Ugi reaction. The targeted products were obtained in a combinatorial, diversity‐oriented fashion in good yields. Further modifications allowed us to adapt this procedure for the one‐pot two‐step syntheses of a local anesthetic druglidocaine and several unsymmetrically substituted diketopiperazines.

Thermal baths as sources of pharmaceutical and illicit drug contamination

Despite the fact that there are tens of thousands of thermal baths in existence, knowledge about the occurrence of pharmaceutically active compounds (PhACs) in untreated thermal wastewater is very limited. Because used thermal water is typically legally discharged into surface waters without any treatment, the effluent poses environmental risks for the receiving water bodies. The aim of this study was to show the occurrence patterns and spatiotemporal characteristics of 111 PhACs in thermal wastewater. Six thermal water outflows of different thermal baths were tested in different seasons in the Budapest metropolitan region (Hungary), and diurnal analysis was performed. After solid-phase extraction, the samples were analysed and quantified by coupling supercritical fluid chromatography and mass spectrometry to perform simultaneous multi-residue drug analysis. The results confirm that water discharge pipes directly transport pharmaceuticals into surface water bodies; 34 PhACs were measured to be over the limit of quantification at least once, and 21 of them were found in more than one water sample. The local anaesthetic drug lidocaine, antiepileptic carbamazepine, analgesic derivative tramadol and illicit drug cocaine were detected in more than half of the samples. Caffeine, metoprolol and bisoprolol (cardiovascular drugs), benzoylecgonine (cocaine metabolite), diclofenac (NSAID), citalopram (antidepressant) and certain types of hormones also have a significant frequency of 30-50%. However, the occurrence and concentrations of PhACs vary according to the season and number/types of visitors. As demonstrated by the diurnal fluctuation, drug contamination of thermal waters can significantly vary, even for similar types of baths; furthermore, the quantity and types of some pollutants rapidly change in the discharged thermal wastewater.

A 3D printed chitosan-pectin hydrogel wound dressing for lidocaine hydrochloride delivery.

A chitosan-pectin (CS-PEC) biopolymeric hydrogel wound dressing was investigated for lidocaine delivery. Here we demonstrate for the first time the feasibility of three-dimensional (3D) printed CS-PEC hydrogel incorporating the local anaesthetic drug lidocaine hydrochloride (LDC) as a potential wound dressing candidate. The hydrogels were prepared by physical crosslinking of CS and PEC polysaccharides. The scaffolds were printed using an extrusion-based 3D printer using a mechanical positive displacement dispensing system followed by lyophilisation. The 3D printed hydrogels showed good printability, dimensional integrity and self-adhesion to skin. The high swelling ratio and water absorption of 3D printed hydrogels indicated suitability for absorbing exudates and maintaining a moist wound healing environment. Fourier transform infrared (FTIR) spectroscopy results indicated that the CS-PEC hydrogel was formed by hydrogen bonds. Incorporation of LDC in the hydrogel did not interfere with its functional stability. In vitro drug release studies of LDC over 6 h fitted the Korsmeyer-Peppas model. This work demonstrates the possibility of a 3D printed hydrogel as a suitable candidate for wound dressings.

A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel.

Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated to the activated state. The crystal structures of several bacterial NaVs have captured the voltage sensor module (VSM) in an activated state, but structure of the deactivated voltage sensor remains elusive. In this study, we sought to identify peptide toxins stabilizing the deactivated VSM of bacterial NaVs. We screened fractions from several venoms and characterized a cystine knot toxin called JZTx-27 from the venom of tarantula Chilobrachys jingzhao as a high-affinity antagonist of the prokaryotic NaVs NsVBa (nonselective voltage-gated Bacillus alcalophilus) and NaChBac (bacterial sodium channel from Bacillus halodurans) (IC50 = 112 nM and 30 nM, respectively). JZTx-27 was more efficacious at weaker depolarizing voltages and significantly slowed the activation but accelerated the deactivation of NsVBa, whereas the local anesthetic drug lidocaine was shown to antagonize NsVBa without affecting channel gating. Mutation analysis confirmed that JZTx-27 bound to S3-4 linker of NsVBa, with F98 being the critical residue in determining toxin affinity. All electrophysiological data and in silico analysis suggested that JZTx-27 trapped VSM of NsVBa in one of the deactivated states. In mammalian NaVs, JZTx-27 preferably inhibited the inactivation of NaV1.5 by targeting the fourth transmembrane domain. To our knowledge, this is the first report of peptide antagonist for prokaryotic NaVs. More important, we proposed that JZTx-27 stabilized the NsVBa VSM in the deactivated state and may be used as a probe to determine the structure of the deactivated VSM of NaVs.-Tang, C., Zhou, X., Nguyen, P. T., Zhang, Y., Hu, Z., Zhang, C., Yarov-Yarovoy, V., DeCaen, P. G., Liang, S., Liu, Z. A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel.

The molecular structure and vibrational, 1H and 13C NMR spectra of lidocaine hydrochloride monohydrate

The structure, vibrational and NMR spectra of the local anesthetic drug lidocaine hydrochloride monohydrate salt were investigated by B3LYP/6-311G∗∗ calculations. The lidocaine·HCl·H2O salt is predicted to have the gauche structure as the predominant form at ambient temperature with NCCN and CNCC torsional angles of 110° and −123° as compared to 10° and −64°, respectively in the base lidocaine. The repulsive interaction between the two N–H bonds destabilized the gauche structure of lidocaine·HCl·H2O salt. The analysis of the observed vibrational spectra is consistent with the presence of the lidocaine salt in only one gauche conformation at room temperature. The 1H and 13C NMR spectra of lidocaine·HCl·H2O were interpreted by experimental and DFT calculated chemical shifts of the lidocaine salt. The RMSD between experimental and theoretical 1H and 13C chemical shifts for lidocaine·HCl·H2O is 2.32 and 8.21ppm, respectively.

The conformational stability, solvation and the assignments of the experimental infrared, Raman, 1H and 13C NMR spectra of the local anesthetic drug lidocaine

The structure, vibrational and 1H and 13C NMR spectra of the local anesthetic drug lidocaine were investigated by the B3LYP/6-311G∗∗ calculations. The molecule was predicted to have the non-planar cis (NCCN∼0°) structures being about 2–6kcal/mol lower in energy than the corresponding trans (NCCN∼180°) forms. The calculated NCCN (9.6°) and CNCC (−132.2°) torsional angles were in a good qualitative agreement with the reported X-ray angles (3.1 and 13.0°, −102.67 and −77.9°, respectively, for H-bonded dimers). The Gibbs energy of solution of lidocaine in formamide, water, dimethylsulfoxide, acetonitrile, methanol, ethanol and chloroform solutions was estimated at the B3LYP level. The predicted affinity of lidocaine toward the alcohols, acetonitrile and chloroform solutions was in excellent agreement with the reported experimental solubility of the drug in organic solvents. The analysis of the observed vibrational spectra is consistent with the presence of lidocaine in only one conformation at room temperature. The 1H and 13C NMR spectra of lidocaine were interpreted by experimental and DFT calculated chemical shifts of the drug. The RMSD between experimental and theoretical 1H and 13C chemical shifts for lidocaine is 0.47 and 8.26ppm, respectively.

Investigations into distribution of lidocaine in human autopsy material.

With screening methods in the legal medicine drugs were often detected in autopsy material. In this study the antiarrhythmic and the local anesthetic drug lidocaine could be proved in fifty-one cases and determined in different autopsy materials. For the first time the comparison of so many distribution patterns of lidocaine in human compartments was possible. A liquid-liquid extraction procedure, a standard addition method and LC/MS/MS were used for analytics. The measured concentrations in blood were in the therapeutic range or lower. The time between lidocaine application and death was given in twenty-nine cases. These data were very helpful to estimate and interpret the distribution process of lidocaine between application and death. This time exerted a crucial influence on the distribution of lidocaine in the compartments. Most of the intravenous applicated lidocaine was found in heart blood after a very short time of distribution. Afterwards the highest concentrations were measured in brain. Later the highest concentration was found in the kidney samples or in urine. If the time between lidocaine application and death is known, the results of this study can be used to deepen the knowledge of its pharmacokinetics. If this time is unknown, the circumstances and the causes of death can be better explained.

A Molecular Switch between the Outer and the Inner Vestibules of the Voltage-gated Na+ Channel

Voltage-gated ion channels are transmembrane proteins that undergo complex conformational changes during their gating transitions. Both functional and structural data from K+ channels suggest that extracellular and intracellular parts of the pore communicate with each other via a trajectory of interacting amino acids. No crystal structures are available for voltage-gated Na+ channels, but functional data suggest a similar intramolecular communication involving the inner and outer vestibules. However, the mechanism of such communication is unknown. Here, we report that amino acid Ile-1575 in the middle of transmembrane segment 6 of domain IV (DIV-S6) in the adult rat skeletal muscle isoform of the voltage-gated sodium channel (rNaV1.4) may act as molecular switch allowing for interaction between outer and inner vestibules. Cysteine scanning mutagenesis of the internal part of DIV-S6 revealed that only mutations at site 1575 rescued the channel from a unique kinetic state (“ultra-slow inactivation,” IUS) produced by the mutation K1237E in the selectivity filter. A similar effect was seen with I1575A. Previously, we reported that conformational changes of both the internal and the external vestibule are involved in the generation of IUS. The fact that mutations at site 1575 modulate IUS produced by K1237E strongly suggests an interaction between these sites. Our data confirm a previously published molecular model in which Ile-1575 of DIV-S6 is in close proximity to Lys-1237 of the selectivity filter. Furthermore, these functional data define the position of the selectivity filter relative to the adjacent DIV-S6 segment within the ionic permeation pathway.

Influence of non-volatile anesthetics on the migration behavior of the human breast cancer cell line MDA-MB-468.

Anesthetic agents are known to influence functions of the immune system. Anesthetic drugs also support cancer progression by suppressing the activity of immune cells. In breast carcinoma an increase in expression of peripheral-type benzodiazepine receptors (PBR) and the gamma aminobutyl acid (GABA) level has been discovered. Therefore, an investigation of a direct influence of GABA-A agonist propofol, GABA-A and PBR-agonist etomidate, and the local anesthetic drug lidocaine, which can also bind to the GABA-A receptor and PBR, on migration of breast carcinoma cells was performed. MDA-MB-468 cells were incubated with anesthetic agents using clinically relevant concentrations (propofol 3, 6, 9 mg/l, etomidate 2, 3, 4 mg/l, and lidocaine 1.25, 2.5, 5 mg/l). Locomotion was investigated in a three-dimensional collagen matrix using time-lapse video microscopy and computer-assisted cell-tracking. The percentage of migrating cells (57.4+/-1.9) as well as the velocity (0.22+/-0.09 microm/min) and distance migrated (89.4+/-66.8 microm/10 h) increased in the presence of propofol in a dose-dependent manner (up to 74.4+/-7.5, 0.30+/-0.09, 143.8+/-89.1, respectively) compared with the long chain triglyceride (LCT) control. In contrast, no influence of etomidate on the number of migrating cells could be observed. The velocity and distance migrated at 3 and 4 mg/l were found to be statistically significantly enhanced. Treatment with lidocaine caused an increase in the percentage of migrating cells (up to 75.0+/-5.6) in velocity dose dependently (up to 0.33+/-0.06) and in distance migrated (up to 151.5+/-92.9). These results show that different anesthetic drugs are able to modulate the migratory machinery of human breast carcinoma cells in vitro.

Lidocaine and soyasterole-PEG-16-ether ? investigations on the interaction between an amphiphilic drug and a nonionic surfactant in aqueous solution

In order to study the interactions between the surface active local anaesthetic drug lidocaine and the nonionic surfactant soyasterole-PEG-16-ether firstly the self association of the drug in aqueous solution was investigated by different methods. Transmission electron microscopy hinted at micellization and surface tension measurements resulted in a CMC of 12.9% (salt form) and 0.08% (base form), respectively, whereas solubilization experiments, NMR spectroscopy and osmotic pressure measurements obviously disproved the existence of drug micelles. The detected CMC only meant a surface saturation and the TEM pictures probably showed artifacts. In diluted systems containing both drug and surfactant no formation of mixed micelles took place, as pointed out by the tensiometric determination of the CMC of the mixtures showing no minimum in the CMC/% drug-curve. Also, gel permeation chromatography clearly separated surfactant micelles and drug molecules. In contrast to this, evident interactions between the base form of the drug and the surfactant occurred when the drug concentration was increased: the dynamic viscosity of the systems rose distinctly, probably caused by growth of the surfactant associates to a more rodlike form. The salt form had nearly no influence on the viscosity of the preparations.

The contribution of neurogenic reflexes to hypertonic saline-induced bronchoconstriction in asthma

Background: Hypertonic saline induces bronchoconstriction in most patients with asthma; however, the mechanisms involved are not clearly understood. We have investigated the role of neurogenic mechanisms in hypertonic saline-induced bronchoconstriction. Methods: The effect of pretreatment with the anticholinergic drugs atropine and ipratropium bromide and the local anesthetic drug lidocaine on hypertonic saline responsiveness was studied in 11 subjects with asthma. Ultrasonically nebulized hypertonic saline challenge was given in a dose-response manner to determine the provocative dose of hypertonic saline-laden air required to produce a fall in forced expiratory volume in 1 second (FEV 1) of 20% or greater (PD 20HS). A control PD 20HS with no pretreatment was measured before randomization, and on the next three visits PD 20HS was determined after pretreatment with each of the following: intramuscularly administered atropine, inhaled ipratropium bromide, and inhaled lidocaine. Results: The baseline mean FEV 1 values increased by 3.5% and 4% 30 minutes after administration of atropine and ipratropium bromide, respectively, and decreased by 5.8% at 10 minutes after inhalation of lidocaine. These changes in the baseline FEV 1 were not significant and did not have any effect on the PD 20HS response. Premedication with atropine, ipratropium bromide, and lidocaine resulted in increases of 2.5, 2.0, and 2.6 times in mean PD 20HS, respectively. Conclusions: The protection afforded by the drugs was variable in the individual subjects and not related to age, sex, baseline FEV 1, provocative concentration of histamine causing a 20% fall in FEV 1 or use of the inhaled corticosteroids. The protection afforded by anticholinergic and local anesthetic drugs suggests the contribution of neurogenic reflexes in the pathogenesis of hypertonic saline-induced bronchoconstriction in asthma.

Metabolism of lidocaine in human liver in vitro.

We have incubated the local anaesthetic drug lidocaine with microsomes from human adult livers. The metabolites deethylated lidocaine (MEGX) and aromatically hydroxylated lidocaine (3-hydroxylidocaine) were isolated by high performance liquid chromatography and quantitated by the liquid scintillation counting technique. The deethylation rate markedly exceeded the hydroxylation rate also at very low lidocaine concentrations. This pattern differs from that detected earlier with rat liver microsomes where aromatic hydroxylation is significant at low lidocaine concentrations, but it is similar to that in female guinea pig microsomes. These findings show the importance of performing this type of experiments also with human materials.

Evidence for two catalytically different binding sites of liver microsomal cytochrome P-450: importance for species and sex differences in oxidation pattern of lidocaine.

When the local anaesthetic drug lidocaine is added to liver microsomes biphasic type I spectral change titration curves can be observed. A high-affinity and a low-affinity phase is observed. In the present study we have found that microsomes from female rats have a dominant high-affinity phase, which can hardly be observed within microsomes from female guinea pigs. Male rats showed an intermediate phase. On incubation of lidocaine at concentrations of 1 micron or less with female rat liver microsomes a larger fraction of the drug was aromatically hydroxylated than deethylated. The opposite was true for guinea pig liver microsomes, and microsomes from male rats were intermediate. The ratio between the formation of deethylated and hydroxylated metabolites increased with the lidocaine concentration and at a lidocaine concentration of 10(-4)M deethylation was the dominant oxidation type in all microsomes. The data suggest that the two spectral phases represent two binding sites of cytochrome P-450 each having a certain "catalytic specificity" - the high affinity catalyzing aromatic hydroxylation and the "low-affinity site" deethylation. This hypothesis is further supported by the observed differential effects of pH and MgCl2 concentration on the two types of oxidation.

Effects of dibenzepine and imipramine on the isolated rat heart

The tricyclic antidepressants, imipramine and dibenzapine and the local anaesthetic drug lidocaine were added to the recirculating perfusate in a rat heart perfusion apparatus. Each drug produced the following effects: (a) A dose-dependent decrease in impulse generation and impulse conduction velocity. (b) A dose-dependent decrease in cardiac contractile force. (c) A dose-dependent decrease in coronary flow preceded by an increase at lower concentrations. (d) A dose-dependent decrease in potassium loss from the heart. (e) Potentiation of the imipramine-induced decrease in contractile force and coronary flow in the presence of lidocaine. Further, in the concentration range in wich the antidepressants produced their cardiac effects, they stabilized eryhrocytes against hypotonic lysis. The antidepressants and the local anaesthetic share this effect and the cardiac effects with a variety of drugs commonly referred to as membrane stabilizers. It is concluded that the membrane stabilizers probably change the properties of biomembranes in a common way, and that the cardiac effects are secondary to these changes.

Cardiac effects of antiparkinson drugs, local anesthetics, and tranquilizers

The antiparkinson drugs, etybenztropine, prophenamine and benzhexole, the local anesthetic drug lidocaine, and the tranquilizing drug chlorpromazine were added to the recirculating medium in a rat heart perfusion apparatus. All the drugs caused the following effects: (a) A dose-dependent decrease in impulse generation and impulse conducting velocity. (b) A dose-dependent decrease in cardiac contractility. (c) A dose-dependent decrease in coronary flow preceded by an increase at lower concentrations. (d) A dose-dependent decrease in potassium loss from the hearts, followed by an increase at higher concentrations. An additive effect of chlorpromazine and etybenztropine on cardiac contractility was found. It is concluded that the changes in ECG cardiac contractility and coronary flow in the isolated perfused rat heart induced by antiparkinson drugs and local anesthetics are similar to those produced by tranquilizing phenothiazine derivatives. It is further suggested that the effects can be explained as secondary to a decrease in cell membrane permeability.