In vitro assessment of interaction between lidocaine hydrochloride and irrigating solutions on root canal dentin: a scanning electron microscope study / Evaluación in vitro de la interacción entre el clorhidrato de lidocaína y las soluciones de irrigación en la dentina del conducto radicular: un estudio con microscopio electrónico de barrid

Aim: To investigate the precipitate formed from the interaction between 2% lidocaine hydrochloride with adrenaline (LA) with 2.5% sodium hypochlorite (NaOCl) and 0.2% chitosan nanoparticles on root canal dentin, using scanning electron microscopy (SEM). Material and Methods: Sixty mandibular premolars were decoronated, and the root length standardised. The specimens were randomly distributed into the following groups: Group 1 (control): 2% LA mixed with sterile water without root canal instrumentation, Group 2: 2% LA with 2.5% NaOCl in water without root canal instrumentation, and Group 3: 2% LA with 0.2% chitosan nanoparticles in water without root canal instrumentation. Teeth specimens were split and subjected to SEM analysis at cervical, middle, and apical root thirds. On observing precipitate formation in Group 2, 10 premolars were decoronated and treated with 2% LA and 2.5% NaOCl and subjected to root canal instrumentation. Results: Group 1 and Group 3 showed patent dentinal tubules and no precipitate formation. Group 2 showed precipitate blocking dentinal tubules in all the three sections, and the precipitate could not be removed completely after cleaning and shaping. Conclusion: NaOCl forms an insoluble precipitate on interaction with local anaesthetic solution that cannot be removed after chemo-mechanical preparation. Chitosan nanoparticles do not form any such precipitate and show patent dentinal tubules. Hence, chitosan can be used as a flushing irrigant.

Objetivo: Investigar el precipitado formado a partir de la interacción entre el clorhidrato de lidocaína al 2% con adrenalina (LA), el hipoclorito de sodio al 2,5% (NaOCl) y nanopartículas de quitosano al 0,2% en la dentina del conducto radicular, mediante microscopía electrónica de barrido (SEM). Material y Métodos: Se decoraron 60 premolares mandibulares y se estandarizó la longitud de la raíz. Los especímenes se distribuyeron aleatoriamente en los siguientes grupos: Grupo 1 (control): 2% la que fue mezclado con agua estéril sin instrumentación del conducto radicular, Grupo 2: 2% LA con 2,5% de NaOCl sin instrumentación del conducto radicular y Grupo 3: 2 % LA con 0,2% de nanopartículas de quitosano sin instrumentación del conducto radicular. Las muestras de dientes se dividieron y se sometieron a análisis SEM en los tercios radiculares cervical, medio y apical. Al observar la formación de precipitado en el Grupo 2, 10 premolares fueron decorados y tratados con LA al 2% y NaOCl al 2,5% y sometidos a instrumentación de conductos radiculares. Resultado: El Grupo 1 y el Grupo 3 mostraron túbulos dentinarios permeables y sin formación de precipitados. El grupo 2 mostró precipitado que bloqueaba los túbulos dentinarios en las tres secciones, y el precipitado no se pudo eliminar por completo después de limpieza y conformación. Conclusión: el NaOCl forma un precipitado insoluble al interactuar con la solución anestésica local que no se puede eliminar después de la preparación quimiomecánica. Las nanopartículas de quitosano no forman ningún precipitado de este tipo y muestran túbulos dentinarios permeables. Por lo tanto, el quitosano se puede utilizar como irrigante para el lavado.

Impact of Different Mixing Methods on the Performance of Suspension-Based Transdermal Delivery Systems.

Suspension-based matrix transdermal delivery systems (TDSs) are specialized systems that maintain a continuous driving force for drug delivery over prolonged wear. The pressure-sensitive adhesive (PSA) is the most critical constituent of such systems. Our study aimed to determine the effect of different mixing methods on the performance of silicone PSA-based suspension TDSs. Lidocaine suspension TDSs were prepared using conventional slow rotary mixing, high-speed homogenization, bead-mill homogenization, vortex shaking, and by an unguator. Resultant TDSs were tested for tack, shear, and peel properties and correlated to coat weight, content uniformity, microstructure, and in vitro permeation across dermatomed human skin. Every mixing method tested caused a significant reduction in peel. However, bead-mill homogenization resulted in significant loss of all adhesive properties tested, while unguator-mixed TDSs retained most properties. Good linear correlation (R2 = 1.000) between the shear properties of the TDSs with the average cumulative amount of lidocaine permeated after 24 h was observed, with no significant difference between percutaneous delivery from slow rotary-mixed systems (1334 ± 59.21 µg/cm2) and unguator-mixed systems (1147 ± 108.3 µg/cm2). However, significantly lower delivery from bead-mill homogenized systems (821.1 ± 28.00 µg/cm2) was noted. While many factors affect TDS performance, careful consideration must also be given to the processing parameters during development as they have been shown to affect the resultant system's therapeutic efficacy. Extensive mixing with bead-mill homogenization demonstrated crystallization of drug, loss in adhesive properties, coat weight, and film thickness, with reduced transdermal delivery of lidocaine from the prepared system.

In vitro and in vivo studies of micro-depots using tailored microemulsion for sustained local anaesthesia.

In clinical practice, lidocaine is used as local anesthetic for the management of post-operative pain. The commercial formulation including gels, injections and ointments showed short duration of action (1 to 2 h). In this paper, the efforts have being made to develop tailored lidocaine-microemulsion (o/w), which on penetration in the skin layer cause micro-depots formation due to destabilization of the microemulsion system. To identify the microemulsion region, pseudo ternary diagrams were constructed using Capmul MCM as oil, Pluronic F68 as tri-block surfactant, polyethylene glycol 200 as co-surfactant at 1:4 and 1:6 ratios (S:Co-S). The selected 5%w/v lidocaine loaded microemulsion [Ld-ME-2(1:4)] was stable in thermodynamic test and during shelf life period (3 months). In ex vivo permeability study, the lidocaine release from Ld-ME-2(1:4) microemulsion was sustained in comparison to the marketed lidocaine ointment. The skin irritation study confirmed the safety of lidocaine loaded microemulsion. Tail flick test showed improved and sustain local anaesthetic effect in comparison to the market ointment. The improved efficacy of microemulsion system, was due to high penetration in the skin layer due to local precipitation of lidocaine from microemulsion. The findings suggest that the tailored microemulsion could be a potential strategy to prolong the local anaesthesia.

Work overload is related to increased risk of error during chemotherapy preparation.

PURPOSE: Chemotherapy preparation units face peaks in activity leading to high workloads and increased stress. The present study evaluated the impact of work overloads on the safety and accuracy of manual preparations. METHOD: Simulating overwork, operators were asked to produce increasing numbers of syringes (8, 16, and 24), with markers (phenylephrine or lidocaine), within 1 h, in an isolator, under aseptic conditions. Results were analyzed using qualitative and quantitative criteria. Concentration deviations of < 5%, 5%-10%, 10%-30%, and >30% from the expected concentration were considered as accurate, weakly accurate, inaccurate, and wrong concentrations, respectively. RESULTS: Twenty-one pharmacy technicians and pharmacists carried out 63 preparation sessions (n = 1007 syringes). A statistically significant decrease in the manufacturing time for one syringe was observed when workload increased (p < 0.0001). Thirty-nine preparation errors were recorded: 30 wrong concentrations (deviation > 30%), 6 mislabeling, 2 wrong diluents, and 1 wrong drug. There was no statistically significant difference in the mean concentration accuracy of final preparations across the three workloads. The overall error rate increased with the number of preparations made in 1 h: 1.8% for 8 preparations, 2.7% for 16 preparations, and 5.4% for 24 preparations (p < 0.05). CONCLUSION: Although pharmacy technicians and pharmacists were able to increase production speeds with no effect on mean concentration accuracy under stressful conditions, there were greater probability errors being made. These results should encourage actions to spread workloads out over the day to avoid peaks in activity.

Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server.

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.

A Novel, Optimized Method to Accelerate the Preparation of Injectable Poly-L-Lactic Acid by Sonication.

Current consensus for preparing injectable poly-L-lactic acid (PLLA) suggests adequate hydration (less than equal to 2-24 hours of reconstitution) of the lyophilized particles before injection, but the volume of reconstitution and the duration of hydration time varies. This study established a method to evaluate the distribution of PLLA particles after hydration and found that longer hydration time increased the effective portion (particles less than 60 µm) of PLLA products. Further investigation of the feasibility of reconstitution with sonication revealed that 2-hour hydration of PLLA powders with additional 5-minute-sonication could yield a comparable particle distribution with 48-hour-hydration of PLLA. Moreover, adding lidocaine into the diluent did not alter the distribution of PLLA particles. We proposed a new, feasible and efficient method of preparing PLLA injectable products: 2-hour hydration of the powders, sonication of the bottle or vial containing PLLA products for at least 5 minutes, and finalization with 1-2 mL of lidocaine immediately before injection. J Drugs Dermatol. 2018;17(8):894-898.

Cytotoxicity and cellular response mechanisms of water-soluble platinum(II) complexes of lidocaine and phenylcyanamide derivatives.

Three new platinum(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pt(3,5-(NO2)2pcyd)2(LC)], 1, K[Pt(3,5-(CF3)2pcyd)2(LC)], 2, K[Pt(3,5-Cl2pcyd)2(LC)], 3 (LC: lidocaine, 3,5-(NO2)2pcyd: 3,5-dinitro phenylcyanamide, 3,5-(CF3)2pcyd: 3,5-bis(trifluoromethyl) phenylcyanamide, 3,5-Cl2pcyd: 3,5-dichloro phenylcyanamide) have been synthesized and fully characterized. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. The complexes 1-3 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell lines. All the complexes are more active than cisplatin and follow the trend 1 > 2 > 3. Mechanistic studies showed that the trend in cytotoxicity of the Pt(II) complexes is mainly consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which consequently results in the loss of mitochondrial membrane potential and apoptosis induction. The complex 1 caused to approximately 80-fold higher DNA platination level with respect to cisplatin. The complexes 1-3 can considerably stimulate the production of hydrogen peroxide in a time-dependent manner. Also, the complexes 1-3 induced an increase in reactive oxygen species (ROS) production that was superior to that induced by antimycin. The complex 1 had the most effect on ROS production in comparison with other complexes.

Synthesis and Analgesic Properties of Lidocaine Derivatives with Substituted Aminobenzothiazoles.

Local anesthetics are the most widely consumed drugs in the practice of medicine which provide a loss of sensation in a certain body part without loss of consciousness or impairment of central control of essential functions. Lidocaine (I) is the most commonly local anaesthetic drug which is widely used in all species due to its fabulous diffusing and penetrating properties as well as prompt onset of surgical analgesia. In this study, new aminobenzothiazole (with many useful biological and pharmacological properties) analogues were synthesized by changing of amine moiety of I. Both acute and chronic pain properties of new compounds (II-VI) were studied by using the tail immersion and formalin tests on mice and the outcomes were compared with control and lidocaine groups. According to the results, aminobenzothiazole derivatives are better candidates than diethylamine group for replacement on amine moiety of I. Also, derivatives with electron-withdrawing groups on this amine (V and VI) could decrease pain better than electron-donating ones (II and III) (specially on position 6 of this amine, II and V) which may be of concern for blockade of specific sodium channels by these new compounds.

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine.

Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80 seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines.

Synthesis of ¹³C-lidocaine as a probe of breath test for the evaluation of cytochrome P450 activity.

(13)C-Labeled lidocaine, 2-di[1-(13)C]ethylamino-N-(2,6-dimethylphenyl)acetamide (1), was synthesized from [1-(13)C]acetic acid in six steps, as a probe for a breath test to evaluate in vivo cytochrome P450 activity. The measurement of (13)CO2 in breath was successfully performed following oral administration of (13)C-lidocaine 1 to mice.

Formulation, in vitro and in vivo evaluation of lidocaine HCl ocular inserts for topical ocular anesthesia.

Topical anesthesia is a safe and cost-effective method considered as the first-choice in many procedures. The objective of the present study was to develop ocular inserts as a new form of lidocaine HCl to give a sufficient level of anesthetic. Ocuserts were prepared using HPMC and PVA in different ratios with lidocaine HCl alone and lidocaine HCl ß-cyclodextrins complex. Drug polymer interactions were studied by Fourier transform infrared spectroscopic studies. The prepared ocular inserts were characterized by means of ocusert thickness, weight variation, folding endurance, surface pH, moisture absorption, drug content and in-vitro drug release. Stability study was conducted on selected formulations, and in vivo evaluation of lidocaine HCl was also carried out. The results revealed that F7 formulations containing drug ß-cyclodextrins with 4 % HPMC and 2 % PVA were found to have good physical characteristics and appropriate flexibility. In addition to the highest initial and cumulative percentage of drug released in vitro. The selected F7 ocuserts retained their characteristics during the stability study. The results of in vivo study showed that the addition of ß-cyclodextrins in F7 significantly increase the drug content in the aqueous humor when compared with F3 ocuserts containing lidocaine HCl alone.

Lidocaine-derivative JMF2-1 prevents ovalbumin-induced airway inflammation by regulating the function and survival of T cells.

BACKGROUND: Inhalation of the local anaesthetic lidocaine has been suggested to be beneficial for asthmatics, but airway anaesthesia is unpleasant and may exacerbate bronchoconstriction. Our previous study showed that inhalation of the lidocaine analogue JMF2-1 can elicit the anti-inflammatory properties of lidocaine without anaesthesia. This prompted further research on the mechanism of action and putative therapeutic application of JMF2-1. OBJECTIVE: We tested the hypothesis that JMF2-1 would prevent allergen-induced lung inflammation and airway hyperresponsiveness (AHR) by modulating T cell function in vivo and in vitro. Methods Local and systemic changes in leucocyte levels, cytokine production and lung mechanics were examined in a murine model of lung inflammation. JMF2-1 (0.05-2%) or saline was aerosolized twice a day during the ovalbumin (OVA)-provocation period (19-21 days post-sensitization). Analyses were performed 24 h after the final challenge. Primary cultured lymph node cells were used to assess the effects of JMF2-1 (100-600 µm) at the cellular level. RESULTS: OVA challenge resulted in lung recruitment of CD4(+) T cells and eosinophils, increased generation of inflammatory cytokines and AHR to inhaled methacholine within 24 h. These changes were prevented by JMF2-1 nebulization, and occurred in parallel with an increase in the number of apoptotic cells in the lung. JMF2-1 treatment did not alter levels of CD4(+) or CD8(+) T cells in the thymus or lymph nodes of naïve mice, although it inhibited OVA-induced IL-13 production and the lymphocyte proliferative response in vitro. It also induced apoptosis of OVA-activated lymphocytes in a mechanism sensitive to z-VAD, indicating that JMF2-1 mediates caspase-dependent apoptosis. CONCLUSION: Inhalation of JMF2-1 prevents the cardinal features of asthma by reducing T(H) 2 cytokine generation and lung eosinophilic inflammatory infiltrates via local inhibition of T cell function and survival. JMF2-1 may represent a novel therapeutic alternative for asthma control with distinct advantages over local anaesthetics.

Synthesis of lidocaine-loaded PLGA microparticles by flow focusing. Effects on drug loading and release properties.

In the present work, two methods for the preparation of lidocaine-loaded PLGA microparticles are compared. The differences between the polymeric particles obtained by solvent evaporation (SEVM) or flow focusing (FF) were studied by means of scanning electron microscopy and surface thermodynamics determinations. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The physical state of the drug in the polymeric particles and the existence of interactions between both entities were studied by differential scanning calorimetry. The main factors determining the lidocaine incorporation and the release kinetics were the synthesis procedure followed, the amount of drug dissolved in the organic phase during the synthesis routine, the type of polymer (molecular weight and end chemical groups) and the size and the hydrophobic/hydrophilic properties of the particles. The FF technology allowed higher drug incorporations and slower release kinetics. The release studies showed a biphasic profile probably due to diffusion-cum-degradation mediated processes.

Synthesis and antispasmodic activity of lidocaine derivatives endowed with reduced local anesthetic action.

The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.

Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine--synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid.

Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml-1 corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1-9.8 (37 degrees C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (approximately 80%) and an unknown compound X (approximately 20%) was observed. LC-MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37 degrees C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pKa values below approximately 6 and intrinsic solubilities in the low microM range.

Characterization of cellulosic hot-melt extruded films containing lidocaine.

Hot-melt extrusion technology was used to produce thin films containing a model drug, lidocaine, and the cellulosic polymers hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC). Two film formulations were extruded and compared, one containing only HPC and the other containing HPC:HPMC (80:20). Thermal analysis of the films using differential scanning calorimetry (DSC) suggested that the drug existed in the amorphous condition, which was confirmed by wide angle X-ray diffractometry. Sustained release of the drug was observed from both of the polymer matrices. Dissolution profiles suggested that HPMC retarded the drug release from HPC:HPMC (80:20) films. However, the mechanism of drug release from both of the films was predominantly diffusion of the drug through the polymer matrices. Incorporation of HPMC also increased both adhesive strength and work of adhesion as compared to the HPC-only films.

Efeitos da lidocaína hiperbárica em concentrações crescentes, administrada no espaço subaracnóideo, sobre a medula e meninges: estudo experimental no cão / Effect of the hyperbaric lidocaína in increasing concentrations, managed in the subaracnóideo space, on the marrow and meninges: experimental study in the dog

Em estudo experimental em ratos, a injeçao de lidocaina subaracnoidea a partir da concentraçao de 7,5 porcento, resultou em mudanças neurofuncionais e histopatologicas. O proposito deste estudo foi investigar, em animais vivos as possiveis alteraçoes clinicas e histologicas desencadeadas por injeçoes de lidocaina hiperbarica nas concentraçoes de 5 porcento, 7,5 porcento e 10 porcento, administradasno espaço subaracnoideo de caes. Quarenta animais foram randomizados em quatro grupos que receberam por via subaracnoidea: G1 glicose a 7,5 porcento e 10 porcento, administradas no espaço subaracnoideo de caes. Quarenta animais foram randomizados em quatro grupos que receberam por via subaracnoidea: G1 glioce a 7,5 porcento, G2 lidocaina hiperbarica a 5 porcento, G3 lidocaina hiperbarica a 7,5porcento e G4 lidocaina hiperbarica a 10 porcento. A punçao subaracnoidea foi realizada no espaço intervetebral L6-L7. O volume da solução injetada foi de 1 ml. Os animais foram sacrificados apos sete dias de observaçao em cativeiro.As porçoes lombar e sacral da medula foram removidas para exame histologico, por microscopia optica. Os caes pertencentes aos grupos G1 e G2, ao apresentaram alteraçoes clinicas e histologicas na medula e meninges. Foi observado tres casos em G3, de necrose em focosno tecido medular mas, necrose abrangendo toda a superficie da medula em somente um dos animais e, a despeito dos achados histologicos, um destes caes permaneceu clinicamente normal. No G4, sete caes apresentaram alteraçoes clinicas e histologicas. As mudanças histologicas encontradas variaram de areas de necrose restritas a algumas regioes da medula a necrose em faixa abrangendo toda a superficie medular. Observamos diminuiçao de força muscular nas patas posteriores em seis animais, sendo que em tres deles houve associação em relaxamento de esfincter anal, e em um dos animais, a diminiçao do tonus esfincteriano foi a unica alteraçao clinica obervada. A neurotoxicidade da lidocaina hiperbarica espinhal em concentraçoes supra-clinicas determinou alteraçoes histopatologicas, restritas ao tecido nervoso da medula espinhal. A extensão e gravidade das lesoes foram intimamente relacionadas com a concentração da lidocaina. Lesoes brandas causadas por concentraçoes mais baixas de lidocaina podem nao manifestar alteraçoes clinicas.

Synthesis, structure and pharmacology of acyl-2,6-xylidines.

L-2-perhydroheterocyclicalkyl acids were condensed with 2,6-xylidine. 8 new optically active acyl-2,6-xylidines were obtained. Absolute configuration of acyl-2,6-xylidines were selected for pharmacological examinations.

Solid-phase synthesis of lidocaine and procainamide analogues using backbone amide linker (BAL) anchoring.

New solid-phase strategies have been developed for the synthesis of lidocaine (1) and procainamide (2) analogues, using backbone amide linker (BAL) anchoring. Both sets were prepared starting from a common resin-bound intermediate, followed by four general steps: (i) attachment of a primary aliphatic or aromatic amine to the solid support via reductive amination (as monitored by a novel test involving reaction of 2,4-dinitrophenylhydrazine with residual aldehyde groups); (ii) acylation of the resultant secondary amine; (iii) displacement of halide with an amine; and (iv) trifluoroacetic acid-mediated release from the support. A manual parallel strategy was followed to provide 60 novel compounds, of which two dozen have not been previously described. In most cases, initial crude purities were >80%, and overall isolated yields were in the 40-88% range.