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Korean Journal of Family Medicine Sep 2019It has been reported that in 62.5% of cases of incurable cancer pain, the complaint is due to myofascial pain syndrome. Trigger point injections using dibucaine...
BACKGROUND
It has been reported that in 62.5% of cases of incurable cancer pain, the complaint is due to myofascial pain syndrome. Trigger point injections using dibucaine hydrochloride help patients with such cancer pain. This study evaluated the efficacy of trigger point injections for alleviating pain in patients with advanced cancer.
METHODS
Twenty patients with advanced cancer who had a life expectancy of 6 months or less and had been diagnosed with myofascial pain syndrome were treated with trigger point injections. Prior to treatment, a Visual Analog Scale (VAS) was used to measure the resting pain level and discomfort upon application of pressure on the site of pain. These values were compared with last treatment measurements.
RESULTS
The mean pre-treatment VAS scores for pain at rest and upon application of pressure on the pain site were 7.3 and 9.0, respectively. These scores decreased significantly to 1.95 and 3.2, respectively, after the treatment (P<0.05).
CONCLUSION
Trigger point injection is an alternative and effective pain control modality for advanced cancer patients with myofascial pain syndrome.
PubMed: 31487973
DOI: 10.4082/kjfm.18.0065 -
Biochimica Et Biophysica Acta. General... Sep 2019Because ordered membrane domains, called lipid rafts, regulate activation of ion channels related to the nerve pulse, lipids rafts are thought to be a possible target...
BACKGROUND
Because ordered membrane domains, called lipid rafts, regulate activation of ion channels related to the nerve pulse, lipids rafts are thought to be a possible target for anesthetic molecules. To understand the mechanism of anesthetic action, we examined influence of representative local anesthetics (LAs); dibucaine, tetracaine, and lidocaine, on raft-like liquid-ordered (L)/non-raft-like liquid-disordered (L) phase separation.
METHODS
Impact of LAs on the phase separation was observed by fluorescent microscopy. LA-induced perturbation of the L and L membranes was examined by DPH anisotropy measurements. Incorporation of LAs to the membranes was examined by fluorescent anisotropy of LAs. The biding location of the LAs was indicated by small angle x-ray diffraction (SAXD).
RESULTS
Fluorescent experiments showed that dibucaine eliminated the phase separation the most effectively, followed by tetracaine and lidocaine. The disruption of the phase separation can be explained by their disordering effects on the L membrane. SAXD and other experiments further suggested that dibucaine's most potent perturbation of the L membrane is attributable to its deeper immersion and bulky molecular structure. Tetracaine, albeit immersed in the L membrane as deeply as dibucaine, less perturbs the L membrane probably because of its smaller bulkiness. Lidocaine hardly reaches the hydrophobic region, resulting in the weakest L membrane perturbation.
CONCLUSION
Dibcaine perturbs the L membrane the most effectively, followed by tetracaine and lidocaine. This ranking correlates with their anesthetic potency.
GENERAL SIGNIFICANCE
This study suggests a possible mechanistic link between anesthetic action and perturbation of lipid rafts.
Topics: Anesthetics, Local; Fluorescence Polarization; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers; Membrane Microdomains
PubMed: 31207252
DOI: 10.1016/j.bbagen.2019.06.008 -
Anesthesia and Analgesia Jun 2019The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction...
BACKGROUND
The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture.
METHODS
We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug-drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine.
RESULTS
We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007-0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435-0.560] μmol) (P < .01), while there were no significant differences between dibucaine and bupivacaine (mean, 0.450 [95% CI, 0.400-0.505] μmol). On the equipotent basis (75% effective dose, median effective dose, and 25% effective dose), sensory block duration provoked by epinephrine was greater (P < .01) than that provoked by dibucaine or bupivacaine. Coadministration of dibucaine with epinephrine produced a synergistic nociceptive block, whereas phentolamine blocked that synergistic block.
CONCLUSIONS
The preclinical data indicated that there is no statistically significant difference between the potency and duration of dibucaine and bupivacaine in this model. Epinephrine synergistically enhances the effects of dibucaine, while phentolamine partially blocked those effects. α-Adrenergic receptors play an important role in controlling synergistic analgesic effect of dibucaine combined with epinephrine.
Topics: Adrenergic alpha-Antagonists; Analgesia; Analgesics; Anesthetics, Local; Animals; Area Under Curve; Bupivacaine; Dibucaine; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Epinephrine; Injections, Subcutaneous; Male; Pain; Phentolamine; Rats; Rats, Sprague-Dawley; Skin
PubMed: 31094809
DOI: 10.1213/ANE.0000000000003421 -
Contact Dermatitis Oct 2019
Topics: Adrenal Cortex Hormones; Anesthetics, Local; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dibucaine; Female; Humans; Middle Aged; Patch Tests; Phenylephrine
PubMed: 30977131
DOI: 10.1111/cod.13290 -
Journal of Medicinal Chemistry Apr 2019Enterovirus D68 (EV-D68) is an atypical nonpolio enterovirus that mainly infects the respiratory system of humans, leading to moderate-to-severe respiratory diseases. In...
Enterovirus D68 (EV-D68) is an atypical nonpolio enterovirus that mainly infects the respiratory system of humans, leading to moderate-to-severe respiratory diseases. In rare cases, EV-D68 can spread to the central nervous system and cause paralysis in infected patients, especially young children and immunocompromised individuals. There is currently no approved vaccine or antiviral available for the prevention and treatment of EV-D68. In this study, we aimed to improve the antiviral potency and selectivity of a previously reported EV-D68 inhibitor, dibucaine, through structure-activity relationship studies. In total, 60 compounds were synthesized and tested against EV-D68 using the viral cytopathic effect assay. Three compounds 10a, 12a, and 12c were identified to have significantly improved potency (EC < 1 μM) and a high selectivity index (>180) compared with dibucaine against five different strains of EV-D68 viruses. These compounds also showed potent antiviral activity in neuronal cells, such as A172 and SH-SY5Y cells, suggesting they might be further developed for the treatment of both respiratory infection as well as neuronal infection.
Topics: Antiviral Agents; Cell Line, Tumor; Cell Survival; Dibucaine; Drug Design; Enterovirus D, Human; Humans; Quinolines; Structure-Activity Relationship
PubMed: 30912944
DOI: 10.1021/acs.jmedchem.9b00115 -
Biochimica Et Biophysica Acta.... Jun 2019Mitochondrial membranes are pointed out as the site of cardiotoxic action of local anaesthetics. Its three main phospholipids components are phosphatidylcholine,...
Mitochondrial membranes are pointed out as the site of cardiotoxic action of local anaesthetics. Its three main phospholipids components are phosphatidylcholine, phosphatidylethanolamine and cardiolipin. Cardiolipins, in eukaryotes, are only found in mitochondria and are essential for the maintenance of its integrity and dynamics. Fluorescence and nuclear magnetic resonance spectroscopy were used to study the interactions of a local anaesthetics, Dibucaine (DBC), with different mitochondrial membrane models constituted by combinations of its three main lipid components in which cardiolipin was a natural extract (CL). Both CL presence/absence and its percentage in the model membranes were evaluated. Fluorescence spectroscopy showed that DBC lowered the transition temperature of all membrane models understudy. DBC partition showed to be dependent of CL presence and phosphatidylethanolamine:CL ratio. Furthermore, the maximum emission wavelength (λ) exhibited a notorious decreased with increasing phospholipid to DBC ratio, in all the membrane models containing CL. Nevertheless, it remained approximately the same in the membrane without CL. This indicates a differential membrane localization of the anaesthetics, dependent on the membrane models used. NMR results showed that DBC interaction and location in the membrane models is mainly influenced by CL presence, and DBC can significant alter lipid systems properties e.g. percentage and type of lipid phase present. Taken all together it was shown that DBC interaction and location are largely dependent on the membrane model system. Furthermore, DBC is able to produce significant changes in the lipidic systems which might help to explain its high toxicity.
Topics: Anesthetics, Local; Binding Sites; Cardiolipins; Dibucaine; Mitochondrial Membranes; Models, Biological; Phosphatidylethanolamines; Temperature
PubMed: 30840858
DOI: 10.1016/j.bbamem.2019.02.011 -
Pharmaceutics Nov 2018Dibucaine (DBC) is among the more potent long-acting local anesthetics (LA), and it is also one of the most toxic. Over the last decades, solid lipid nanoparticles (SLN)...
Dibucaine (DBC) is among the more potent long-acting local anesthetics (LA), and it is also one of the most toxic. Over the last decades, solid lipid nanoparticles (SLN) have been developed as promising carriers for drug delivery. In this study, SLN formulations were prepared with the aim of prolonging DBC release and reducing its toxicity. To this end, SLN composed of two different lipid matrices and prepared by two different hot-emulsion techniques (high-pressure procedure and sonication) were compared. The colloidal stability of the SLN formulations was tracked in terms of particle size (nm), polydispersity index (PDI), and zeta potential (mV) for 240 days at 4 °C; the DBC encapsulation efficiency was determined by the ultrafiltration/centrifugation method. The formulations were characterized by differential scanning calorimetry (DSC), electron paramagnetic resonance (EPR), and release kinetic experiments. Finally, the in vitro cytotoxicity against 3T3 fibroblast and HaCaT cells was determined, and the in vivo analgesic action was assessed using the test in rats. Both of the homogenization procedures were found suitable to produce particles in the 200 nm range, with good shelf stability (240 days) and high DBC encapsulation efficiency (~72⁻89%). DSC results disclosed structural information on the nanoparticles, such as the lower crystallinity of the lipid core vs. the bulk lipid. EPR measurements provided evidence of DBC partitioning in both SLNs. In vitro (cytotoxicity) and in vivo () experiments revealed that the encapsulation of DBC into nanoparticles reduces its intrinsic cytotoxicity and prolongs the anesthetic effect, respectively. These results show that the SLNs produced are safe and have great potential to extend the applications of dibucaine by enhancing its bioavailability.
PubMed: 30441802
DOI: 10.3390/pharmaceutics10040231 -
Langmuir : the ACS Journal of Surfaces... Nov 2018Dibucaine (DBC) is one of the most potent long-acting local anesthetics, but it also has significant toxic side effects and low water solubility. Solid lipid...
Electron Paramagnetic Resonance and Small-Angle X-ray Scattering Characterization of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Dibucaine Encapsulation.
Dibucaine (DBC) is one of the most potent long-acting local anesthetics, but it also has significant toxic side effects and low water solubility. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have been proposed as drug-delivery systems to increase the bioavailability of local anesthetics. The purpose of the present study was to characterize SLNs and NLCs composed of cetyl palmitate or myristyl myristate, a mixture of capric and caprylic acids (for NLCs only) plus Pluronic F68 prepared for the encapsulation of DBC. We intended to provide a careful structural characterization of the nanoparticles to identify the relevant architectural parameters that lead to the desirable biological response. Initially, SLNs and NLCs were assessed in terms of their size distribution, morphology, surface charge, and drug loading. Spectroscopic techniques (infrared spectroscopy and electron paramagnetic resonance, EPR) plus small-angle X-ray scattering (SAXS) provided information on the interactions between nanoparticle components and their structural organization. The sizes of nanoparticles were in the 180 nm range with low polydispersity and negative zeta values (-25 to -46 mV). The partition coefficient of DBC between nanoparticles and water at pH 8.2 was very high (>10). EPR (with doxyl-stearate spin labels) data revealed the existence of lamellar arrangements inside the lipid nanoparticles, which was also confirmed by SAXS experiments. Moreover, the addition of DBC increased the molecular packing of both SLN and NLC lipids, indicative of DBC insertion between the lipids, in the milieu assessed by spin labels. Such structural information brings insights into understanding the molecular organization of these versatile drug-delivery systems which have already demonstrated their potential for therapeutic applications in pain control.
Topics: Anesthetics, Local; Dibucaine; Drug Carriers; Electron Spin Resonance Spectroscopy; Myristates; Nanoparticles; Palmitates; Particle Size; Poloxamer; Scattering, Small Angle; X-Ray Diffraction
PubMed: 30299102
DOI: 10.1021/acs.langmuir.8b02559 -
Journal of Pharmaceutical Sciences Sep 2018Administration of local anesthetics is one of the most effective pain control techniques for postoperative analgesia. However, anesthetic agents easily diffuse into the...
Administration of local anesthetics is one of the most effective pain control techniques for postoperative analgesia. However, anesthetic agents easily diffuse into the injection site, limiting the time of anesthesia. One approach to prolong analgesia is to entrap local anesthetic agents in nanostructured carriers (e.g., liposomes). Here, we report that using an ammonium sulphate gradient was the best strategy to improve the encapsulation (62.6%) of dibucaine (DBC) into liposomes. Light scattering and nanotracking analyses were used to characterize vesicle properties, such as, size, polydispersity, zeta potentials, and number. In vitro kinetic experiments revealed the sustained release of DBC (50% in 7 h) from the liposomes. In addition, in vitro (3T3 cells in culture) and in vivo (zebrafish) toxicity assays revealed that ionic-gradient liposomes were able to reduce DBC cyto/cardiotoxicity and morphological changes in zebrafish larvae. Moreover, the anesthesia time attained after infiltrative administration in mice was longer with encapsulated DBC (27 h) than that with free DBC (11 h), at 320 μM (0.012%), confirming it as a promising long-acting liposome formulation for parenteral drug administration of DBC.
Topics: Anesthetics, Local; Animals; BALB 3T3 Cells; Cell Survival; Dibucaine; Drug Liberation; Liposomes; Male; Mice; Motor Activity; Pain Measurement; Phosphatidylcholines; Zebrafish
PubMed: 29802933
DOI: 10.1016/j.xphs.2018.05.010 -
Journal of Integrative Neuroscience 2018To investigate the relationship between acetyl cholinesterase associated collagen gene (COLQ) mutation in patients with acetyl cholinesterase deficiency and its clinical...
To investigate the relationship between acetyl cholinesterase associated collagen gene (COLQ) mutation in patients with acetyl cholinesterase deficiency and its clinical characteristics. Serum and red blood cell acetyl cholinesterase from patients with acetyl cholinesterase deficiency (n=6) and normal controls (n=20) were measured by butyryl thiocholine substrate. COLQ gene variations were detected by sequencing. And the cholinesterase (ChE) genotypes were measured by dibucaine inhibition in vitro. The distributions of ChE surrounded the blood vessels and nerve fibers in lung or pancreas tissues were detected by immunohistochemical staining and indirect immunofluorescence. Serum lactic acid, ammonia and other clinical data were analyzed. Serum ChE in patients with acetyl cholinesterase deficiency were only 1/50 to 1/1000 fold of normal controls. Comparing to controls, dibucaine inhibition values of patients were significantly lower, while there were no differences in red blood cells acetyl cholinesterase. Serum lactic acid and ammonia in patients were significantly higher than controls. Inser 1281-1282 GC of COLQ gene was found in 2 patients, while IVS 6 + 21 T > A, IVS 6 + 30 G > T, IVS 6 + 34 T > C and IVS66 + 12 inser T mutations were found in the other 4 patients, respectively. In addition, the patients with COLQ gene mutation were resistant to regular doses of anesthetics. COLQ gene mutation may be an important reason for the lack of serum ChE in patients with acetyl cholinesterase deficiency.
Topics: Acetylcholinesterase; Collagen; Humans; Lung; Metabolism, Inborn Errors; Muscle Proteins; Mutation; Pancreas
PubMed: 29630557
DOI: 10.3233/JIN-180080