Добірка наукової літератури з теми "Local anesthetics of amide and ether groups"

Background Human ether-a-go-go-related gene (HERG) potassium channels constitute a potential target involved in cardiotoxic side effects of amino-amide local anesthetics. The molecular interaction site of these low-affinity blockers with HERG channels is currently unknown. The aim of this study was to determine the effect of the mutations Y652A and F656A in the putative drug binding region of HERG on the inhibition by bupivacaine, ropivacaine, and mepivacaine. Methods The authors examined the inhibition of wild-type and mutant HERG channels, transiently expressed in Chinese hamster ovary cells by bupivacaine, ropivacaine, and mepivacaine. Whole cell patch clamp recordings were performed at room temperature. Results Inhibition of HERG wild-type and mutant channels by the different local anesthetics was concentration dependent, stereoselective, and reversible. The sensitivity decreased in the order bupivacaine > ropivacaine > mepivacaine for wild-type and mutant channels. The mutant channels were approximately 4-30 times less sensitive to the inhibitory action of the different local anesthetics than the wild-type channel. The concentration-response data were described by Hill functions (bupivacaine: wild-type IC50 = 22 +/- 2 microm, n = 38; Y652A IC50 = 95 +/- 5 microm, n = 31). The mutations resulted in a change of the stereoselectivity of HERG channel block by ropivacaine. The potency of the local anesthetics to inhibit wild-type and mutant channels correlated with the lipophilicity of the drug (r > 0.9). Conclusions These results indicate that local anesthetics specifically but not exclusively interact with the aromatic residues Y652 and F656 in S6 of HERG channels.

Background This study's aim was to investigate the interaction of amino-amide local anesthetics with human Kv1.1 potassium channels. These channels were chosen because of their proven physiologic role. By using a homolog series of local anesthetics with different lengths of the N-substituent, it was intended to elucidate the role of lipophilic interactions with Kv1.1. The use of stereoisomers allowed testing of the role of polar drug actions. Methods Human Kv1.1 channels were measured with the patch clamp technique. Concentration-response data were described by Hill functions. Gating changes were described by Boltzmann functions. Results Inhibition of Kv1.1 channels by dextrobupivacaine, bupivacaine, levobupivacaine, dextroropivacaine, levoropivacaine, and mepivacaine was concentration dependent, reversible, stereoselective, voltage dependent, and frequency independent. The IC(50) values were (mean +/- SEM) 41 +/- 3 microm (n = 20), 56 +/- 3 microm (n = 26), 76 +/- 8 microm (n = 24), 135 +/- 29 microm (n = 23), 313 +/- 32 microm (n = 25), and 1,451 +/- 351 microm (n = 23), respectively. The midpoint of current activation was shifted into the hyperpolarizing direction. The inhibitory potency as well as the potency to induce gating changes correlated with the number of CH(2) groups in the side chain of the drugs (r > 0.9, P < 0.05). Conclusions Kv1.1 channels constitute an important biophysical model for elucidating molecular mechanisms underlying local anesthetic drug effects. Inhibition likely results from an open state-dependent blocking mechanism. Interaction of local anesthetics with the ion channel protein is determined by lipophilic drug properties.

ABSTRACT. The problem of the development of adverse reactions as a result of the use of diagnostic and medicinal products (drugs) in medicine is becoming increasingly important. Patients more often note reactions to local anesthetics (LA) – 43.2 %, antibiotics – 18.8 %, nonsteroidal anti-inflammatory drugs – 9.7 %, other drugs – 28.4 %. LA include two chemical groups: esters of benzoic acid (Ester-type anesthetics), which are potentially allergens, and amides (Amide-type anesthetics), which have virtually no allergenic potential. Based on the history for doctor is often difficult to assess the risk of allergic reactions, so if in the past the patient had a side effect of LA, then these drugs should be skin and provocative tests, having obtained the informed consent of the subject to conduct them. Skin prick tests are used for initial diagnosis in patients with suspected LA allergy. If the results of the pre-test and intradermal test are negative, a subcutaneous challenge test with LA is performed. Skin testing for suspected hypersensitivity (НS) of the delayed type begins with application (patch) tests and only with a negative result using an intradermal test with LA. Laboratory methods for diagnosing НS to LA are used much less often than skin and provocative tests, because for many drugs the appropriate methods have not been developed, as well as because it is a time-consuming and expensive method of diagnosis. Therapeutic tactics in the event of НS to LA include providing patients with emergency care in the development of anaphylaxis and treatment of other clinical manifestations of HS reactions in accordance with existing international and domestic protocols. Epinephrine, oxygen therapy, colloid/crystalloid infusions, antihistamines, systemic and topical corticosteroids, protease inhibitors, inhaled β2-agonists, leukotriene receptor antagonists, etc. are most commonly used for this purpose.

Background: Pain is a common complaint of patients after surgery. Different techniques or medications including local anesthetics infiltration, non-steroidal anti-inflammatory drugs or opioids have been used for postoperative analgesia. Lidocaine is an amide local anesthetic agent that works by influencing the complex phenomenon of pain. Aim: To compare the mean pain score with intraoperative lidocaine versus control in patients undergoing laparoscopic cholecystectomy under general anesthesia. Methods: 350 patients aged 20-60 years of either sex scheduled for laparoscopic cholecystectomy were included in the study. Patients with allergy to lidocaine; patients with neuromuscular disease, endocrine or metabolic disorder and pregnant patients were excluded from study. Patients were randomly divided in two groups by using lottery method after taking informed consent. On arrival to the operating room, monitor was attached to display continuous ECG, mean arterial blood pressure, and arterial oxygen saturation. Results: In lidocaine group, the mean age of patients was 39.93±11.56years. In control group, the mean age of patients was 37.93±11.83years. In lidocaine group, there were 91 (52%) males and 84 (48%) females. In control group, there were 77 (44%) males and 98 (56%) females. In lidocaine group, the mean BMI of patients was 26.66±4.81kg/m2. In control group, the mean BMI of patients was 26.77±4.76kg/m2. In lidocaine group, the mean pain score of patients was 1.00±0.84. In control group, the mean pain score of patients was 2.39±1.10. The difference was significant (p<0.05). Conclusion: Thus lidocaine is found to be more effective in reducing postoperative pain than control. Keywords: General anesthesia, laparoscopic cholecystectomy, lidocaine, postoperative pain.

Background Ropivacaine is a new amide local anesthetic, having therapeutic properties similar to those of bupivacaine but with a wider margin of safety. Bupivacaine is probably the most commonly used drug in obstetric epidural analgesia, even though laboratory studies have suggested that pregnancy increases the cardiotoxicity of bupivacaine but not of other local anesthetics. The current study was designed to reevaluate, in a random and blinded fashion, the systemic toxicity of bupivacaine and ropivacaine in nonpregnant and pregnant sheep. Methods Chronically prepared nonpregnant and pregnant ewes were randomized to receive an intravenous infusion of ropivacaine or bupivacaine at a constant rate of 0.5 mg.kg-1.min-1 until circulatory collapse. The investigators were blinded to the identity of local anesthetic. Heart rate, arterial blood pressure, and cardiac rhythm were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations, which appeared in the following sequence: convulsions, hypotension, apnea, and circulatory collapse. Serum drug concentrations and protein binding were determined. Blood pH and gas tensions were measured. Results There were no significant differences between non-pregnant and pregnant animals in the doses or serum concentrations of either drug required to elicit toxic manifestations. In nonpregnant animals, similar doses and serum concentrations of ropivacaine and bupivacaine were associated with the onset of convulsions and circulatory collapse. In pregnant ewes, greater doses of ropivacaine as compared to bupivacaine were required to produce convulsions (7.5 +/- 0.5 vs. 5.0 +/- 0.6 mg.kg-1) and circulatory collapse (12.9 +/- 0.8 vs. 8.5 +/- 1.2 mg.kg-1). The corresponding serum concentrations of ropivacaine were similar to those of bupivacaine. Pregnancy did not affect the serum protein binding of either drug. The proportion of animals manifesting a malignant ventricular arrhythmia as the terminal event was similar among all groups. Conclusions The systemic toxicity of ropivacaine or bupivacaine is not enhanced by gestation in sheep. This is in contrast to an earlier study in which the cardiotoxicity of bupivacaine was enhanced during ovine pregnancy. Greater doses of ropivacaine, as compared to bupivacaine, are needed to produce toxic manifestations in pregnant animals.

Background: A variety of medications are administered to the intra-articular space for the relief of joint pain. While amide-type local anesthetics have been extensively studied, there is minimal information regarding the potential chondrotoxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid medications. Purpose: To investigate the in vitro chondrotoxicity of single-dose equivalent concentrations of ketorolac, morphine, meperidine, and fentanyl on human chondrocytes. Study Design: Controlled laboratory study. Methods: Human cartilage was arthroscopically harvested from the intercondylar notch and expanded in vitro. Gene expression of cultured chondrocytes before treatment was performed with quantitative polymerase chain reaction for type I collagen, type II collagen, aggrecan, and SOX9. Chondrocytes were then exposed to 0.01%, 0.02%, and 0.04% morphine sulfate; 0.3% and 0.6% ketorolac tromethamine; 0.5%, 1.0%, and 1.5% meperidine hydrochloride; 0.0005% and 0.001% fentanyl citrate; and saline. A custom bioreactor was used to constantly deliver medications, with the dosage of each medication and the duration of exposure based on standard dose equivalents, medication half-lives, and differences in the surface area between the 6-well plates and the native joint surface. After treatment, a live/dead assay was used to assess chondrocyte viability and if minimal cell death was detected. A subset of samples after treatment was maintained to analyze for possible delayed cell death. Results: All tested concentrations of ketorolac and meperidine caused significantly increased cell death versus the saline control, demonstrating a dose-response relationship. The morphine and fentanyl groups did not show increased chondrotoxicity compared with the saline group, even after 2 weeks of additional culture. Conclusion: In vitro exposure of chondrocytes to single-dose equivalent concentrations of either ketorolac or meperidine demonstrated significant chondrotoxicity, while exposure to morphine or fentanyl did not lead to increased cell death.

The possibility of creating polymers with fluorescence, derivatives of poly (3-aminopropene) (PAP) by alkylation of amino groups with aromatic or heterocyclic aldehydes by Leykart-Wallach reaction with own fluorescence was investigated. Synthesis of N-alkylated PAP derivatives was performed by sequential conversion: acrylamide → PAA (Mν = 100 kDa) → PAP → alkylated PAP. Due to the impossibility of using LiAlH4 to reduce the amide groups of polyacrylamide to amine due to the low solubility of PAA in the non-aqueous (diethyl ether, tetrahydrofuran, etc.) solvents, the reduction of PAA by other reducing agents was optimized. It was found that the best conditions for the reduction of amide groups of PAA to amine - acetic acid - dioxane as a solvent and NaBH4 (suspended in anhydrous 1,4-dioxane) as a reducing agent. According to IR spectroscopy, the products obtained are copolymers of 3-aminopropene (the main amount of elementary units), acrylamide and acrylic acid. To modify the structure of the obtained polymer, the Leuckart-Wallach reaction was used, where the following aldehydes having luminescence were selected: pyrene-3-aldehyde, 2-hydroxy-1-naphthaldehyde, anthracene-9-carbaldehyde, and 3.5 phenyl-1-(4-formylphenyl)-2-pyrazoline. To obtain N-Ar/Het-methylene derivatives, a mixture of PAP, aldehyde and 98% formic acid was heated under harsh conditions (6 hours, glycerol bath), isolated and purified. The obtained modified samples of polymers are intensely fluorescent both in the solid state and in the form of solutions, which indicates the successful passage of the Leykart-Wallach reaction. Spectral characteristics were obtained for solutions in a mixed solvent – ethyl acetate – formic acid (9 : 1). For both the original aldehydes and the copolymers in the mixed solvent used, the spectral fluorescence curves lose their oscillatory structure, probably due to the specific effect of the mixed solvent on the phosphor molecules (for the original aldehydes) and the side methylamino-N-arylmethylene - […СН2-СН(СН2-NH-CH2-Ar)- …] and methylamino-N-getarylmethylene […-СН2-СН(СН2-NH-CH2-Het)-…] groups both in the ground and in the excited state, and for polymers of inhomogeneity of the medium with local polarity zones.

The work presents results of experimental investigations of erythrocytes’ permittivity to the influence of local anesthetics amide and ether groups, since unclarity of the mechanisms of action of these drugs on molecular and cellular level remain and also serious allergic reactions in dentistry are observed. EHF-dielectrometry (K-band, 37,5 GHz) in contrast to traditional biochemical and immunoenzyme test-systems ensures rapid analysis of real part of erythrocytes’ permittivity () which determine of definite molecules’ polarizability in external alternating electric field. In our experiment we observe the decrease  in erythrocytes’ suspension at action procaine (c=500mcg/ml) concerning control samples. The lidocaine’s action (c=500mcg/ml) results in more marked decrease  in erythrocytes’ structures concerning procaine’s action possibly due to additional hydrating of organic molecule with amide bond.