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1.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540826

RESUMEN

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.


Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Glucolípidos/uso terapéutico , Hiperalgesia/prevención & control , Queratitis/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Receptor Toll-Like 4/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Señalización del Calcio/efectos de los fármacos , Citocinas/metabolismo , Evaluación Preclínica de Medicamentos , Glucolípidos/farmacología , Células HEK293 , Humanos , Hiperalgesia/etiología , Queratitis/inducido químicamente , Queratitis/patología , Lipopolisacáridos/toxicidad , Antígeno 96 de los Linfocitos/metabolismo , Masculino , Ratones , MicroARNs/genética , Modelos Moleculares , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Conformación Proteica , Células RAW 264.7 , Distribución Aleatoria , Nervio Ciático/lesiones , Canal Catiónico TRPA1/metabolismo
2.
Molecules ; 26(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546181

RESUMEN

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. First, an antagonist in principle generally only affects one receptor. Secondly, most antagonists must have an ongoing presence on the receptor to have an effect. Capsaicin overcomes both liabilities by disrupting peripheral terminals of nociceptive fibers that express TRPV1, and thereby affects all of the potential means of activating that pain fiber (not just TRPV1 function). This disruptive effect is dependent on the dose and can occur within minutes. Thus, unlike a typical receptor antagonist, continued bioavailability at the level of the receptor is not necessary. By disrupting the entire terminal of the TRPV1-expressing nociceptive fiber, capsaicin blocks all the activation mechanisms within that fiber, and not just TRPV1 function. Topical capsaicin, an FDA approved treatment for neuropathic pain, addresses pain from abnormal nociceptor activity in the superficial layers of the skin. Effects after a single administration are evident over a period of weeks to months, but in time are fully reversible. This review focuses on the rationale for using capsaicin by injection for painful conditions such as osteoarthritis (OA) and provides an update on studies completed to date.


Asunto(s)
Capsaicina/uso terapéutico , Neuralgia/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Humanos , Neuralgia/metabolismo , Neuralgia/patología , Nociceptores/metabolismo , Nociceptores/patología , Osteoartritis/metabolismo , Osteoartritis/patología , Canales Catiónicos TRPV/metabolismo
3.
J Med Chem ; 64(3): 1685-1700, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33523678

RESUMEN

Nicotinic acetylcholine receptors (nAChRs) are pharmacological targets for the treatment of neuropathic pain, and the α6ß4 subtype has been identified as particularly promising. Rat α6ß4 nAChRs are less sensitive to some ligands than the human homologue potentially complicating the use of rodent α6ß4 receptors for screening therapeutic compounds. We used molecular dynamics simulations coupled with functional assays to study the interaction between α-conotoxin PeIA and α6ß4 nAChRs and to identify key ligand-receptor interactions that contribute to species differences in α-conotoxin potency. Our results show that human and rat α6ß4 nAChRs have distinct ligand-binding motifs and show markedly different sensitivities to α-conotoxins. These studies facilitated the creation of PeIA-5667, a peptide that shows 270-fold higher potency for rat α6ß4 nAChRs over native PeIA and similar potency for the human homologue. Our results may inform the design of therapeutic ligands that target α6ß4 nAChRs for the treatment of neuropathic pain.


Asunto(s)
Antagonistas Nicotínicos/síntesis química , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Animales , Conotoxinas/farmacología , Diseño de Fármacos , Humanos , Ligandos , Modelos Moleculares , Simulación de Dinámica Molecular , Neuralgia/tratamiento farmacológico , Oocitos/efectos de los fármacos , Péptidos/síntesis química , Péptidos/farmacología , Ratas , Receptores Nicotínicos/química , Xenopus laevis
4.
Expert Opin Investig Drugs ; 30(2): 119-130, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33423557

RESUMEN

BACKGROUND: Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN). METHODS: We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide. RESULTS: Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process. EXPERT OPINION: The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.


Asunto(s)
Neuropatías Diabéticas/tratamiento farmacológico , Desarrollo de Medicamentos , Neuralgia/tratamiento farmacológico , Fármacos del Sistema Nervioso Periférico/uso terapéutico , Animales , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/fisiopatología , Humanos , Neuralgia/diagnóstico , Neuralgia/fisiopatología , Fármacos del Sistema Nervioso Periférico/efectos adversos , Resultado del Tratamiento
5.
Cochrane Database Syst Rev ; 1: CD011352, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33427305

RESUMEN

BACKGROUND: Many women experience perineal pain after childbirth, especially after having sustained perineal trauma. Perineal pain-management strategies are an important part of postnatal care. Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly-used type of medication in the management of postpartum pain, and their effectiveness and safety should be assessed. This is an update of a review first published in 2016. OBJECTIVES: To determine the effectiveness of a single dose of an oral NSAID for relief of acute perineal pain in the early postpartum period. SEARCH METHODS: For this update, we searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (9 December 2019), OpenSIGLE and ProQuest Dissertations and Theses (28 February 2020), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing a single dose of a NSAID versus a single dose of placebo, paracetamol or another NSAID for women with perineal pain in the early postpartum period. We excluded quasi-RCTs and cross-over trials. We included papers in abstract format only if they had sufficient information to determine that they met the review's prespecified inclusion criteria. DATA COLLECTION AND ANALYSIS: Two review authors (FW and VS) independently assessed all identified papers for inclusion and risks of bias, resolving any discrepancies through discussion. Two review authors independently conducted data extraction, including calculations of pain relief scores, and checked it for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 35 studies examining 16 different NSAIDs and involving 5136 women (none were breastfeeding). Studies were published between 1967 and 2013. Risk of bias due to random sequence generation, allocation concealment and blinding of outcome assessors was generally unclearly to poorly reported, but participants and caregivers were blinded, and outcome data were generally complete. We downgraded the certainty of evidence due to risk of bias, suspected publication bias, and imprecision for small numbers of participants. NSAID versus placebo Compared to women who receive a placebo, more women who receive a single-dose NSAID may achieve adequate pain relief at four hours (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.64 to 2.23; 10 studies, 1573 women; low-certainty evidence) and at six hours (RR 1.92, 95% CI 1.69 to 2.17; 17 studies, 2079 women; very low-certainty evidence), although we are less certain about the effects at six hours. At four hours after administration, women who receive a NSAID are probably less likely to need additional analgesia compared to women who receive placebo (RR 0.39, 95% CI 0.26 to 0.58; 4 studies, 486 women; moderate-certainty evidence) and may be less likely to need additional analgesia at six hours after initial administration, although the evidence was less certain at six hours (RR 0.32, 95% CI 0.26 to 0.40; 10 studies, 1012 women; very low-certainty evidence). One study reported that no adverse events were observed at four hours post-administration (90 women). There may be little or no difference in maternal adverse effects between NSAIDs and placebo at six hours post-administration (RR 1.38, 95% CI 0.71 to 2.70; 13 studies, 1388 women; low-certainty evidence). Fourteen maternal adverse effects were reported in the NSAID group (drowsiness (5), abdominal discomfort (2), weakness (1), dizziness (2), headache (2), moderate epigastralgia (1), not specified (1)) and eight in the placebo group (drowsiness (2), light-headedness (1), nausea (1), backache (1), dizziness (1), epigastric pain (1), not specified (1)), although not all studies assessed adverse effects. Neonatal adverse effects were not assessed in any of the studies. NSAID versus paracetamol NSAIDs may lead to more women achieving adequate pain relief at four hours, compared with paracetamol (RR 1.54, 95% CI 1.07 to 2.22; 3 studies, 342 women; low-certainty evidence). We are uncertain if there is any difference in adequate pain relief between NSAIDs and paracetamol at six hours post-administration (RR 1.82, 95% CI 0.61 to 5.47; 2 studies, 99 women; very low-certainty evidence) or in the need for additional analgesia at four hours (RR 0.55, 95% CI 0.27 to 1.13; 1 study, 73 women; very low-certainty evidence). NSAIDs may reduce the risk of requiring additional analgesia at six hours compared with paracetamol (RR 0.28, 95% CI 0.12 to 0.67; 1 study, 59 women; low-certainty evidence). One study reported that no maternal adverse effects were observed at four hours post-administration (210 women). Six hours post-administration, we are uncertain if there is any difference between groups in the number of maternal adverse effects (RR 0.74, 95% CI 0.27 to 2.08; 3 studies, 300 women; very low-certainty evidence), with one case of pruritis in the NSAID group and one case of sleepiness in the paracetamol group. Neonatal adverse effects were not assessed in any of the included studies. Comparisons of different NSAIDs or doses did not demonstrate any differences in effectiveness for any primary outcome measures; however, few data were available on some NSAIDs. None of the included studies reported on any of this review's secondary outcomes. AUTHORS' CONCLUSIONS: In women who are not breastfeeding and who sustained perineal trauma, NSAIDs (compared to placebo or paracetamol) may provide greater pain relief for acute postpartum perineal pain and fewer women need additional analgesia, but uncertainty remains, as the evidence is rated as low- or very low-certainty. The risk of bias was unclear for many studies, adverse effects were often not assessed and breastfeeding women were not included. While this review provides some indication of the likely effect, there is uncertainty in our conclusions. The main reasons for downgrading were the inclusion of studies at high risk of bias and inconsistency in the findings of individual studies. Future studies could examine NSAIDs' adverse effects, including neonatal effects and the compatibility of NSAIDs with breastfeeding, and could assess other secondary outcomes. Future research could consider women with and without perineal trauma, including perineal tears. High-quality studies could be conducted to further assess the efficacy of NSAIDs versus paracetamol and the efficacy of multimodal treatments.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Neuralgia/tratamiento farmacológico , Perineo/lesiones , Periodo Posparto , Acetaminofén/administración & dosificación , Administración Oral , Analgesia , Analgésicos no Narcóticos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Femenino , Humanos , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo
6.
Postgrad Med ; 133(1): 1-9, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33423590

RESUMEN

Pregabalin is one of the first-line treatments approved for the management of neuropathic pain (NeP). While many patients benefit from treatment with pregabalin, they are often treated with suboptimal doses, possibly due to unfamiliarity around prescribing the drug and/or side effects that can occur with up-titration. This narrative review discusses key aspects of initiating, titrating, and managing patients prescribed pregabalin therapy, and addresses concerns around driving and the potential for abuse, as well as when to seek specialist opinion. To ensure that patients derive maximum therapeutic benefit from the drug, we suggest a 'low and slow' dosing approach to limit common side effects and optimize tolerability alongside patients' expectations. When requiring titration to higher doses, we recommend initiating 'asymmetric dosing,' with the larger dose in the evening. Fully engaging patients in order for them to understand the expected timeline for efficacy and side effects (including their resolution), can also help determine the optimal titration tempo for each individual patient. The 'low and slow' approach also recognizes that patients with NeP are heterogeneous in terms of their optimal therapeutic dose of pregabalin. Hence, it is recommended that general practitioners closely monitor patients and up-titrate according to pain relief and side effects to limit suboptimal dosing or premature discontinuation.


Asunto(s)
Analgésicos/administración & dosificación , Neuralgia/tratamiento farmacológico , Pregabalina/administración & dosificación , Pregabalina/efectos adversos , Factores de Edad , Analgésicos/uso terapéutico , Conducción de Automóvil , Comorbilidad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Cumplimiento de la Medicación , Dimensión del Dolor , Educación del Paciente como Asunto , Pregabalina/uso terapéutico , Factores Sexuales , Trastornos Relacionados con Sustancias/prevención & control
7.
Psychopharmacology (Berl) ; 238(3): 877-886, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33404738

RESUMEN

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.


Asunto(s)
Analgésicos/uso terapéutico , Curcumina/uso terapéutico , Hipocampo/efectos de los fármacos , Interleucina-1beta/metabolismo , Neuralgia/tratamiento farmacológico , Memoria Espacial/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Conducta Animal/efectos de los fármacos , Constricción , Curcumina/administración & dosificación , Curcumina/química , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Nanopartículas/administración & dosificación , Nanopartículas/química , Neuralgia/complicaciones , Neuralgia/metabolismo , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones
8.
Molecules ; 26(1)2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33401491

RESUMEN

7ß-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid obtained from a natural source has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose-dependent manner. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor-alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing the caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed a protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, the anti-neuropathic potential of ECN might be due to the inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Neuralgia , Estrés Oxidativo/efectos de los fármacos , Nervio Ciático , Sesquiterpenos , Animales , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Neuralgia/patología , Nervio Ciático/metabolismo , Nervio Ciático/patología , Sesquiterpenos/química , Sesquiterpenos/farmacología
9.
J Ethnopharmacol ; 265: 113338, 2021 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-32920137

RESUMEN

Medicinal plants remain an invaluable source for therapeutics of diseases that affect humanity. Sideritis bilgeriana (Lamiaceae) is medicinal plant used in Turkey folk medicine to reduce inflammation and pain, but few studies scientific corroborates its medicinal use so creating a gap between popular use and scientific evidence. Thus, we aimed to evaluate the pharmacological effects of the methanolic extract of S. bilgeriana (MESB) in rodents nociception models and also performed its phytochemical analysis. Firstly, a screening was carried out that enabled the identification of the presence of phenolic compounds and flavonoids. In view of this, a chromatographic method by HPLC-DAD-UV was developed that made it possible to identify chlorogenic acid and its quantification in MESB. MESB-treated mice (MESB 50, 100 and 200 mg/kg, p.o.) reduced mechanical hyperalgesia and myeloperoxidase activity (p < 0.01), and also showed a reduced pain behavior in capsaicin test. In the carrageenan-induced pleurisy test, MESB (100 mg/kg p.o.) significantly reduced the leukocyte (polymorphonuclear) count in the pleural cavity and equally decreased the TNF-α and IL-1ß levels (p < 0.001). In the PSNL model, mechanical hyperalgesia was reduced on the first evaluation day and during the 7 days of evaluation compared to the vehicle group (p < 0.001). Thermal hyperalgesia was also reduced 1 h after treatment compared to the vehicle group (p < 0.001) and reversed the loss of force initially displayed by the animals, thus inferring an analgesic effect in the muscle strength test. Analysis of the marrow of these animals showed a decrease in the level of pro-inflammatory cytokine IL-6 (p < 0.001) and factor NF-κB, in relation to the control group (p < 0.05). Moreover, the MESB treatment produced no noticeable side effects, no disturb in motor performance and no signs of gastric or hepatic injury. Together, the results suggests that MESB could be useful to management of inflammation and neuropathic pain mainly by the management of pro-inflammatory mediators (NF-κB, TNF-α, IL-1ß and IL-6), so reinforcing its use in popular medicine and corroborating the need for further chemical and pharmacological studies for the species.


Asunto(s)
Antiinflamatorios/farmacología , Extractos Vegetales/farmacología , Sideritis/química , Analgésicos/aislamiento & purificación , Analgésicos/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Mediadores de Inflamación/metabolismo , Ratones , Neuralgia/tratamiento farmacológico , Extractos Vegetales/análisis
10.
J Med Chem ; 64(1): 890-904, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33372782

RESUMEN

The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.


Asunto(s)
Manejo del Dolor/métodos , Receptores sigma/antagonistas & inhibidores , Triazoles/química , Animales , Sitios de Unión , Barrera Hematoencefálica/metabolismo , Diseño de Fármacos , Cobayas , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Ratas , Receptores sigma/metabolismo , Triazoles/metabolismo , Triazoles/uso terapéutico
11.
Z Rheumatol ; 80(3): 226-233, 2021 Apr.
Artículo en Alemán | MEDLINE | ID: mdl-33355701

RESUMEN

Pain is a leading symptom in inflammatory rheumatic diseases. For a long time it has been assumed that this pain is of nociceptive origin; however, in about one fifth of all patients the pain remains despite successful anti-inflammatory treatment and is not typically described as nociceptive by those affected. Recent studies indicate that some patients with rheumatoid arthritis (RA) experience pain with a neuropathic pain component. The treatment of neuropathic pain with damage to the somatosensory system differs markedly from the treatment of nociceptive pain in which the pain processing system is intact. Thus, the recognition and, above all, the more precise differentiation of the pain symptoms of affected patients make a decisive contribution to a successful treatment. With the help of a few points in the history and a physical examination, the assumption of the diagnosis neuropathic pain can often be rejected or substantiated. Pain with a neuropathic component does not adequately respond to typical analgesics. Instead, the high efficacy of co-analgesics, such as anticonvulsants and antidepressants, has been repeatedly proven.


Asunto(s)
Neuralgia , Enfermedades Reumáticas , Analgésicos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Humanos , Neuralgia/diagnóstico , Neuralgia/tratamiento farmacológico , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/diagnóstico , Enfermedades Reumáticas/tratamiento farmacológico
12.
Arq Neuropsiquiatr ; 78(11): 741-752, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33331468

RESUMEN

BACKGROUND: Central neuropathic pain (CNP) is often refractory to available therapeutic strategies and there are few evidence-based treatment options. Many patients with neuropathic pain are not diagnosed or treated properly. Thus, consensus-based recommendations, adapted to the available drugs in the country, are necessary to guide clinical decisions. OBJECTIVE: To develop recommendations for the treatment of CNP in Brazil. METHODS: Systematic review, meta-analysis, and specialists opinions considering efficacy, adverse events profile, cost, and drug availability in public health. RESULTS: Forty-four studies on CNP treatment were found, 20 were included in the qualitative analysis, and 15 in the quantitative analysis. Medications were classified as first-, second-, and third-line treatment based on systematic review, meta-analysis, and expert opinion. As first-line treatment, gabapentin, duloxetine, and tricyclic antidepressants were included. As second-line, venlafaxine, pregabalin for CND secondary to spinal cord injury, lamotrigine for CNP after stroke, and, in association with first-line drugs, weak opioids, in particular tramadol. For refractory patients, strong opioids (methadone and oxycodone), cannabidiol/delta-9-tetrahydrocannabinol, were classified as third-line of treatment, in combination with first or second-line drugs and, for central nervous system (CNS) in multiple sclerosis, dronabinol. CONCLUSIONS: Studies that address the treatment of CNS are scarce and heterogeneous, and a significant part of the recommendations is based on experts opinions. The CNP approach must be individualized, taking into account the availability of medication, the profile of adverse effects, including addiction risk, and patients' comorbidities.


Asunto(s)
Neuralgia , Neurología , Analgésicos Opioides , Brasil , Consenso , Humanos , Neuralgia/tratamiento farmacológico
13.
An Acad Bras Cienc ; 92(4): e20191155, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33331440

RESUMEN

Gabapentin has antihyperalgesic action, decreasing central sensitization in neuropathic pain models; this effect depends on the mobilization of endogenous pain control pathways. This study aims to investigate the contribution of the endocannabinoid system to the antihyperalgesic action of gabapentin. Mus musculus Swiss, male, were submitted to PSL. On the 7th and 14th days post PSL, different groups were treated with CB1 receptor antagonist, AM281 via i.t. (2 µg/5 µl) or i.pl. (10 µg/20 µl) or CB2, AM630 via i.t. (5 µL i.t.) or (20 µL i.p.) and 15 min after gabapentin (30 mg / kg orally). Mechanical hyperalgesia was measured by the frequency of paw removal by the von Frey monofilament. Gabapentin demonstrated antihypernociceptive action, which was attenuated in animals pretreated with AM281 in both the i.t. and i.pl routes on the 7th and 14th days, differently from animals pretreated with AM630 that did not achieve a significant reduction with administration i.t. only on the 14th day with administration i.pl. The results show that endocannabinoid system contributes to the antihyperalgesic action of gabapetin in neuropathic pain by PSL, suggesting participation in the medullary and peripheral levels of CB1 receptors, and the peripheral performance of CB2 receptors.


Asunto(s)
Endocannabinoides , Neuralgia , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Gabapentina , Hiperalgesia/tratamiento farmacológico , Masculino , Ratones , Neuralgia/tratamiento farmacológico , Nervio Ciático
14.
Neurología (Barc., Ed. impr.) ; 35(9): 628-632, nov.-dic. 2020. tab
Artículo en Español | IBECS | ID: ibc-192758

RESUMEN

INTRODUCCIÓN: En los últimos meses han surgido dudas por parte de pacientes, médicos de familia y neurólogos sobre la posibilidad de que algunos de los fármacos que habitualmente se utilizan en cefaleas y neuralgias puedan facilitar o complicar la infección por el SARS-CoV-2. MATERIAL Y MÉTODOS: Hemos recabado información sobre el posicionamiento de sociedades científicas, así como de las distintas Agencias de Medicamentos (americana, europea y española) para poder esclarecer dudas respecto al uso de fármacos como lisinopril, candesartán, ibuprofeno, corticoides, carbamazepina, anticuerpos monoclonales contra el péptido relacionado con el gen de la calcitonina (CGRP) durante la pandemia por COVID-19. RESULTADOS: Planteamos recomendaciones acerca del uso de fármacos habituales en el tratamiento de las cefaleas en el contexto de la pandemia por COVID-19, basándonos en las evidencias de las que disponemos en el momento actual. CONCLUSIONES: Actualmente no existe ningún argumento científico robusto para contraindicar formalmente ninguno de los tratamientos que se emplean en cefaleas y neuralgias


INTRODUCTION: In recent months, doubts have arisen among patients, general practitioners, and neurologists as to whether some drugs commonly used in patients with headaches and neuralgia may favour or complicate the disease caused by SARS-CoV-2. MATERIAL AND METHODS: We collected information on the opinions of scientific societies and medicines agencies (American, European, and Spanish) to clarify doubts regarding the use of drugs such as lisinopril, candesartan, ibuprofen, corticosteroids, carbamazepine, and monoclonal antibodies targeting the calcitonin generelated peptide in the context of the COVID-19 pandemic. RESULTS: We make recommendations about the use of standard headache treatments in the context of the COVID-19 pandemic, based on the current scientific evidence. CONCLUSIONS: At present, there is no robust scientific argument to formally contraindicate any of the standard treatments employed for headaches and neuralgias


Asunto(s)
Humanos , Sociedades Médicas , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico , Pandemias , Cefalea/tratamiento farmacológico , Cefalea/virología , Neuralgia/tratamiento farmacológico , Neuralgia/virología , España , Interacciones Farmacológicas
16.
BMJ Case Rep ; 13(12)2020 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-33334741

RESUMEN

A 23-year-old woman diagnosed with type 1 diabetes mellitus in 2011 came to our outpatient office because of an inability to walk correctly. She was under a basal bolus insulin regimen. In the summer of 2016, she experienced a rapid improvement in her glycaemic control. A few weeks later, she started to complain of a severe burning pain in the soles of her feet (pain score 10/10). Neither macrovascular nor microvascular complications were detected. The patient was forced to walk barefoot due to an intense pain using shoes or socks and used to soak her feet in water for several hours daily. She also developed severe intolerance to environmental heat, both indoors and outdoors. A diagnosis of treatment-induced diabetic neuropathy was made. The patient was admitted to a general ward to start pain therapy. After a 6-month course of different neuropathic pain drugs, the patient was able to walk autonomously again.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Neuropatías Diabéticas/diagnóstico , Insulina/efectos adversos , Neuralgia/diagnóstico , Diabetes Mellitus Tipo 1/complicaciones , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/tratamiento farmacológico , Dibenzazepinas/administración & dosificación , Quimioterapia Combinada/métodos , Electromiografía , Femenino , Pie , Gabapentina/administración & dosificación , Humanos , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Tramadol/administración & dosificación , Resultado del Tratamiento , Prueba de Paso , Adulto Joven
17.
Arq. neuropsiquiatr ; 78(11): 741-752, Nov. 2020. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1142359

RESUMEN

ABSTRACT Background: Central neuropathic pain (CNP) is often refractory to available therapeutic strategies and there are few evidence-based treatment options. Many patients with neuropathic pain are not diagnosed or treated properly. Thus, consensus-based recommendations, adapted to the available drugs in the country, are necessary to guide clinical decisions. Objective: To develop recommendations for the treatment of CNP in Brazil. Methods: Systematic review, meta-analysis, and specialists opinions considering efficacy, adverse events profile, cost, and drug availability in public health. Results: Forty-four studies on CNP treatment were found, 20 were included in the qualitative analysis, and 15 in the quantitative analysis. Medications were classified as first-, second-, and third-line treatment based on systematic review, meta-analysis, and expert opinion. As first-line treatment, gabapentin, duloxetine, and tricyclic antidepressants were included. As second-line, venlafaxine, pregabalin for CND secondary to spinal cord injury, lamotrigine for CNP after stroke, and, in association with first-line drugs, weak opioids, in particular tramadol. For refractory patients, strong opioids (methadone and oxycodone), cannabidiol/delta-9-tetrahydrocannabinol, were classified as third-line of treatment, in combination with first or second-line drugs and, for central nervous system (CNS) in multiple sclerosis, dronabinol. Conclusions: Studies that address the treatment of CNS are scarce and heterogeneous, and a significant part of the recommendations is based on experts opinions. The CNP approach must be individualized, taking into account the availability of medication, the profile of adverse effects, including addiction risk, and patients' comorbidities.


RESUMO Introdução: A dor neuropática central (DNC) é frequentemente refratária às estratégias terapêuticas disponíveis e há poucas opções de tratamento baseado em evidência. Muitos pacientes com dor neuropática não são diagnosticados ou tratados adequadamente. Desse modo, recomendações baseadas em consenso, adaptadas à disponibilidade de medicamentos no país, são necessárias para guiar decisões clínicas. Objetivo: Desenvolver recomendações para o tratamento da DNC no Brasil. Métodos: Revisão sistemática, metanálise e discussão dos resultados entre especialistas e pesquisadores da área, considerando eficácia, perfil de eventos adversos, custo e disponibilidade do fármaco na saúde pública. Resultados: Foram encontrados 44 estudos sobre tratamento da DNC, dos quais 20 foram incluídos na análise qualitativa e 15, na quantitativa. Classificaram-se as medicações em primeira, segunda e terceira linhas de tratamento, baseando-se em revisão sistemática, meta-análise e opinião de especialistas. Como primeira linha, foram incluídos gabapentina, duloxetina e antidepressivos tricíclicos. Como segunda, venlafaxina, pregabalina para DNC secundária à lesão medular, lamotrigina para DNC pós-acidente vascular cerebral e, em associação aos fármacos de primeira linha, opioides fracos, em particular tramadol. Para os pacientes refratários, opioides fortes (metadona e oxicodona) e canabidiol/delta-9-tetrahidrocanabinol foram classificados como terceira linha de tratamento, em associação com drogas de primeira ou segunda linha, e, para DNC na esclerose múltipla, dronabinol. Conclusões: Os estudos que abordam o tratamento da DNC são escassos e heterogêneos, e parte significativa das recomendações é baseada em opiniões de especialistas. A abordagem da DNC deve ser individualizada, levando em conta a disponibilidade de medicação, o perfil de efeitos adversos, incluindo risco de dependência e as comorbidades do paciente.


Asunto(s)
Humanos , Neuralgia/tratamiento farmacológico , Neurología , Brasil , Consenso , Analgésicos Opioides
18.
Neurologia ; 35(9): 628-632, 2020.
Artículo en Inglés, Español | MEDLINE | ID: mdl-32896463

RESUMEN

INTRODUCTION: In recent months, doubts have arisen among patients, general practitioners, and neurologists as to whether some drugs commonly used in patients with headaches and neuralgia may favour or complicate the disease caused by SARS-CoV-2. MATERIAL AND METHODS: We collected information on the opinions of scientific societies and medicines agencies (American, European, and Spanish) to clarify doubts regarding the use of drugs such as lisinopril, candesartan, ibuprofen, corticosteroids, carbamazepine, and monoclonal antibodies targeting the calcitonin gene-related peptide in the context of the COVID-19 pandemic. RESULTS: We make recommendations about the use of standard headache treatments in the context of the COVID-19 pandemic, based on the current scientific evidence. CONCLUSIONS: At present, there is no robust scientific argument to formally contraindicate any of the standard treatments employed for headaches and neuralgias.


Asunto(s)
Analgésicos/efectos adversos , Infecciones por Coronavirus/complicaciones , Cefalea/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Neumonía Viral/complicaciones , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Antivirales/farmacología , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Betacoronavirus , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Carbamazepina/efectos adversos , Carbamazepina/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Susceptibilidad a Enfermedades/inducido químicamente , Interacciones Farmacológicas , Inducción Enzimática/efectos de los fármacos , Cefalea/complicaciones , Cefalea/prevención & control , Humanos , Ibuprofeno/efectos adversos , Ibuprofeno/farmacología , Ibuprofeno/uso terapéutico , Lisinopril/efectos adversos , Lisinopril/uso terapéutico , Neuralgia/complicaciones , Pandemias , Peptidil-Dipeptidasa A/biosíntesis , Peptidil-Dipeptidasa A/genética , Receptores Virales/biosíntesis , Receptores Virales/genética , Factores de Riesgo , Tetrazoles/efectos adversos , Tetrazoles/uso terapéutico
19.
Anesthesiology ; 133(3): 611-627, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32788559

RESUMEN

BACKGROUND: Voltage-gated sodium channel Nav1.7 has been validated as a perspective target for selective inhibitors with analgesic and anti-itch activity. The objective of this study was to discover new candidate compounds with Nav1.7 inhibitor properties. The authors hypothesized that their approach would yield at least one new compound that inhibits sodium currents in vitro and exerts analgesic and anti-itch effects in mice. METHODS: In silico structure-based similarity search of 1.5 million compounds followed by docking to the Nav1.7 voltage sensor of Domain 4 and molecular dynamics simulation was performed. Patch clamp experiments in Nav1.7-expressing human embryonic kidney 293 cells and in mouse and human dorsal root ganglion neurons were conducted to test sodium current inhibition. Formalin-induced inflammatory pain model, paclitaxel-induced neuropathic pain model, histamine-induced itch model, and mouse lymphoma model of chronic itch were used to confirm in vivo activity of the selected compound. RESULTS: After in silico screening, nine compounds were selected for experimental assessment in vitro. Of those, four compounds inhibited sodium currents in Nav1.7-expressing human embryonic kidney 293 cells by 29% or greater (P < 0.05). Compound 9 (3-(1-benzyl-1H-indol-3-yl)-3-(3-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)propanamide, referred to as DA-0218) reduced sodium current by 80% with a 50% inhibition concentration of 0.74 µM (95% CI, 0.35 to 1.56 µM), but had no effects on Nav1.5-expressing human embryonic kidney 293 cells. In mouse and human dorsal root ganglion neurons, DA-0218 reduced sodium currents by 17% (95% CI, 6 to 28%) and 22% (95% CI, 9 to 35%), respectively. The inhibition was greatly potentiated in paclitaxel-treated mouse neurons. Intraperitoneal and intrathecal administration of the compound reduced formalin-induced phase II inflammatory pain behavior in mice by 76% (95% CI, 48 to 100%) and 80% (95% CI, 68 to 92%), respectively. Intrathecal administration of DA-0218 produced acute reduction in paclitaxel-induced mechanical allodynia, and inhibited histamine-induced acute itch and lymphoma-induced chronic itch. CONCLUSIONS: This study's computer-aided drug discovery approach yielded a new Nav1.7 inhibitor that shows analgesic and anti-pruritic activity in mouse models.


Asunto(s)
Analgésicos/uso terapéutico , Diseño de Fármacos , Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Prurito/tratamiento farmacológico , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL
20.
Pain Res Manag ; 2020: 6042941, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32774567

RESUMEN

Objective: Current recommendations controversially discuss local infiltration techniques as specific treatment for refractory pain syndromes. Evidence of effectiveness remains inconclusive and local infiltration series are discussed as a therapeutic option in patients not responding to standard therapy. The aim of this study was to investigate the effectiveness of infiltration series with techniques such as sphenopalatine ganglion (SPG) block and ganglionic local opioid analgesia (GLOA) for the treatment of neuropathic pain in the head and neck area in a selected patient group. Methods: In a retrospective clinical study, 4960 cases presenting to our university hospital outpatient pain clinic between 2009 and 2016 were screened. Altogether, 83 patients with neuropathic pain syndromes receiving local infiltration series were included. Numeric rating scale (NRS) scores before, during, and after infiltration series, comorbidity, and psychological assessment were evaluated. Results: Maximum NRS before infiltration series was median 9 (IQR 8-10). During infiltration series, maximum NRS was reduced by mean 3.2 points (SD 3.3, p < 0.001) equaling a pain reduction of 41.0% (SD 40.4%). With infiltration series, mean pain reduction of at least 30% or 50% NRS was achieved in 54.2% or 44.6% of cases, respectively. In six percent of patients, increased pain intensity was noted. Initial improvement after the first infiltration was strongly associated with overall improvement throughout the series. Conclusion: This study suggests a beneficial effect of local infiltration series as a treatment option for refractory neuropathic pain syndromes in the context of a multimodal approach. This effect is both significant and clinically relevant and therefore highlights the need for further randomized controlled trials.


Asunto(s)
Bloqueo Nervioso/métodos , Neuralgia/tratamiento farmacológico , Manejo del Dolor/métodos , Anciano , Dolor Crónico/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
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