Quaternary ammonium salt derivatives of allylphenols with peripheral analgesic effect

Ammonium salt derivatives of natural allylphenols were synthesized with the purpose of obtaining potential peripheral analgesics. These drugs, by virtue of their physicochemical properties, would not be able to cross the blood brain barrier. Their inability to enter into the central nervous system (CNS) should prevent several adverse effects observed with classical opiate analgesics (Ferreira et al., 1984). Eugenol (1) O-methyleugenol (5) and safrole (9) were submitted to nitration, reduction and permethylation, leading to the ammonium salts 4, 8 and 12. Another strategy applied to eugenol (1), consisting in its conversion to a glycidic ether (13), opening the epoxide ring with secondary amines and methylation, led to the ammonium salts 16 and 17. All these ammonium salts showed significant peripheral analgesic action, in modified version of the Randall-Sellito test (Ferreira et al. 1978), at non-lethal doses. The ammonium salt 8 showed an activity comparable to that of methylnalorphinium, the prototype of an ideal peripheral analgesic (Ferreira et al., 1984).

A química medicinal de N-acilidrazonas: novos compostos-protótipos de fármacos analgésicos, antiinflamatórios e anti-trombóticos

In this article are described new bioactive N-acylhydrazone (NAH) derivatives, structurally designed as optimization of aryl hydrazones precursors planned by molecular hybridization of two 5-lipoxigenase inhibitors, e.g. CBS-1108 and BW-755c. The analgesic, antiedematogenic and anti-platelet aggregating profile of several isosteric compounds was investigated by using classic pharmacological assays in vivo and ex-vivo, allowing to identify new potent peripheric analgesic lead, a new anti-inflammatory and an antithrombotic agent. During this study was discovered dozen of active NAH compounds clarifying the structure-activity relationship for this series of NAH derivatives, indicating the pharmacophore character of the N-acylhydrazone functionality.

The Analgesic Effect Of Dipyrone In Peripheral Tissue Involves Two Different Mechanisms: Neuronal K(atp) Channel Opening And Cb(1) Receptor Activation.

Dipyrone (metamizole) is an analgesic pro-drug used to control moderate pain. It is metabolized in two major bioactive metabolites: 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA). The aim of this study was to investigate the participation of peripheral CB1 and CB2 cannabinoid receptors activation in the anti-hyperalgesic effect of dipyrone, 4-MAA or 4-AA. PGE2 (100ng/50µL/paw) was locally administered in the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test, before and 3h after its injection. Dipyrone, 4-MAA or 4-AA was administered 30min before the von Frey test. The selective CB1 receptor antagonist AM251, CB2 receptor antagonist AM630, cGMP inhibitor ODQ or KATP channel blocker glibenclamide were administered 30min before dipyrone, 4-MAA or 4-AA. The antisense-ODN against CB1 receptor expression was intrathecally administered once a day during four consecutive days. PGE2-induced mechanical hyperalgesia was inhibited by dipyrone, 4-MAA, and 4-AA in a dose-response manner. AM251 or ODN anti-sense against neuronal CB1 receptor, but not AM630, reversed the anti-hyperalgesic effect mediated by 4-AA, but not by dipyrone or 4-MAA. On the other hand, the anti-hyperalgesic effect of dipyrone or 4-MAA was reversed by glibenclamide or ODQ. These results suggest that the activation of neuronal CB1, but not CB2 receptor, in peripheral tissue is involved in the anti-hyperalgesic effect of 4-aminoantipyrine. In addition, 4-methylaminoantipyrine mediates the anti-hyperalgesic effect by cGMP activation and KATP opening.

Analgesic and Anti-Inflammatory Activities of Salicylaldehyde 2-Chlorobenzoyl Hydrazone (H(2)LASSBio-466), Salicylaldehyde 4-Chlorobenzoyl Hydrazone (H(2)LASSBio-1064) and Their Zinc(II) Complexes

Salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their complexes [Zn(LASSBio-466) H(2)O](2) (1) and [Zn(HLASSBio-1064) Cl](2) (2) were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acid-induced writhing response. Upon coordination the anti-nociceptive activity was favored in the complex 1. H(2)LASSBio-466 inhibited only the first phase of the formalin test, while 1 was active in the second phase, like indomethacin, indicating its ability to inhibit nociception associated with the inflammatory response. Hence coordination to zinc(II) altered the pharmacological profile of H(2)LASSBio-466. H(2)LASSBio-1064 inhibited both phases but this effect was not improved by coordination. The studied compounds did not increase the latency of response in the hot plate model, indicating their lack of central anti-nociceptive activity. All compounds showed levels of inhibition of zymosan-induced peritonitis comparable or superior to indomethacin, indicating an expressive anti-inflammatory profile.

Analgesic Effects of Sweet-Tasting Solutions for Infants: Current State of Equipoise

OBJECTIVE: The goal was to review published studies of analgesic effects of sweet solutions, to ascertain areas with sufficient evidence of effectiveness and areas of uncertainty. METHODS: Databases searched included Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature database, and PsycINFO, using the terms pain*, infant*, neonat*, newborn*, sucrose, glucose, and alternative sugars. Publications were sorted according to type, year, painful procedure studied, placebo/no-treatment groups, population studied, and country of publication. RESULTS: A total of 298 relevant unique publications involving human infants were identified; 125 (42%) were primary research studies, of which 116 (93%) were randomized controlled trials. Healthy preterm or term newborns were included in 82 studies (65%), and sick or very low birth weight infants were included in 22 (18%). Most studies included single episodes of painful procedures, with only 3 (2%) conducted over long periods. Procedures investigated most frequently were heel lance (49%), venipuncture (14%), and intramuscular injection (14%). Placebo or no-treatment groups were included in 111 studies (89%); in 103 (93%) of those studies, sweet solutions reduced behavioral responses, compared with placebo/no treatment. CONCLUSION: Clinical equipoise relating to analgesic effects of sweet solutions no longer exists for single episodes of procedures for healthy preterm and term newborn infants. Uncertainties include outcomes after prolonged use of sweet solutions, concomitant use of other analgesics, and effectiveness beyond the newborn period. Future research should focus on addressing these knowledge and research gaps. Pediatrics 2010;126:894-902

A chemometric study on the analgesic activity of cannabinoid compounds using SDA, KNN and SIMCA methods

The supervised pattern recognition methods K-Nearest Neighbors (KNN), stepwise discriminant analysis (SDA), and soft independent modelling of class analogy (SIMCA) were employed in this work with the aim to investigate the relationship between the molecular structure of 27 cannabinoid compounds and their analgesic activity. Previous analyses using two unsupervised pattern recognition methods (PCA-principal component analysis and HCA-hierarchical cluster analysis) were performed and five descriptors were selected as the most relevants for the analgesic activity of the compounds studied: R (3) (charge density on substituent at position C(3)), Q (1) (charge on atom C(1)), A (surface area), log P (logarithm of the partition coefficient) and MR (molecular refractivity). The supervised pattern recognition methods (SDA, KNN, and SIMCA) were employed in order to construct a reliable model that can be able to predict the analgesic activity of new cannabinoid compounds and to validate our previous study. The results obtained using the SDA, KNN, and SIMCA methods agree perfectly with our previous model. Comparing the SDA, KNN, and SIMCA results with the PCA and HCA ones we could notice that all multivariate statistical methods classified the cannabinoid compounds studied in three groups exactly in the same way: active, moderately active, and inactive.

Ester prodrugs of a potent analgesic, morphine-6-sulfate: syntheses, spectroscopic and physicochemical properties

The aim of this work is to develop 3-acyl prodrugs of the potent analgesic morphine-6-sulfate (M6S). These are expected to have higher potency and/or exhibit longer duration of analgesic action than the parent compound. M6S and the prodrugs were synthesized, then purified either by recrystallization or by semi-preparative HPLC and the structures confirmed by mass spectrometry, IR spectrophotometry and by detailed 1- and 2-D NMR studies. The lipophilicities of the compounds were assessed by a combination of shake-flask, group contribution and HPLC retention methods. The octanol-buffer partition coefficient could only be obtained directly for 3-heptanoylmorphine-6-sulfate, using the shake-flask method. The partition coefficients (P) for the remaining prodrugs were estimated from known methylene group contributions. A good linear relationship between log P and the HPLC log capacity factors was demonstrated. Hydrolysis of the 3-acetyl prodrug, as a representative of the group, was found to occur relatively slowly in buffers (pH range 6.15-8.01), with a small buffer catalysis contribution. The rates of enzymatic hydrolysis of the 3-acyl group in 10% rat blood and in 10% rat brain homogenate were investigated. The prodrugs followed apparent first order hydrolysis kinetics, with a significantly faster hydrolysis rate found in 10% rat brain homogenate than in 10% rat blood for all compounds. (C) 1998 Elsevier Science B.V. All rights reserved.

Comparative Study of Analgesic Effectiveness Using Three Different Anesthetic Techniques for Intravitreal Injection of Bevacizumab

BACKGROUND AND OBJECTIVE: To compare the analgesic effectiveness and aesthetic appearance associated with topical, subconjunctival, and peribulbar anesthesia for intravitreal bevacizumab injection. PATIENTS AND METHODS: Sixty consecutive patients undergoing their first intravitreal bevacizumab injection were randomized to receive one of three forms of anesthesia: proxymetacaine eye drops, subconjunctival injection of 2% xylocaine, and peribulbar injection of 2% xylocaine. Pain associated with the intravitreal injection and with the entire procedure (including anesthesia administration) was recorded using a Visual Analog Scale 15 minutes after intravitreal injection. Anterior segment evaluation was performed 24 hours after injection to measure the number of clock hours of subconjunctival hemorrhage. RESULTS: Median injection-related pain score was significantly lower in the peribulbar group compared with the topical and subconjunctival groups (P < .05). Median entire procedure pain score was significantly higher In the peribulbar group compared with the topical and subconjunctival groups (P < .05). The median extent of subconjunctival hemorrhage was significantly lower in the topical group compared with the other groups (P < .05). CONCLUSION: Among the three anesthetic techniques, peribulbar anesthesia was associated with greater effectiveness in controlling injection-related pain but was least effective in controlling entire procedure pain. There was no significant difference in pain scores between the topical and subconjunctival groups, and topical anesthesia was associated with less subconjunctival hemorrhage.

Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia

We assessed for the first time the long-term maintenance of repetitive transcranial magnetic stimulation (rTMS)-induced analgesia in patients with chronic widespread pain due to fibromyalgia. Forty consecutive patients were randomly assigned, in a double-blind fashion, to 2 groups: one receiving active rTMS (n = 20) and the other, sham stimulation (n = 20), applied to the left primary motor cortex. The stimulation protocol consisted of 14 sessions: an ""induction phase"" of 5 daily sessions followed by a ""maintenance phase"" of 3 sessions a week apart, 3 sessions a fortnight apart, and 3 sessions a month apart. The primary outcome was average pain intensity over the last 24 hours, measured before each stimulation from day 1 to week 21 and at week 25 (1 month after the last stimulation). Other outcomes measured included quality of life, mood and anxiety, and several parameters of motor cortical excitability. Thirty patients completed the study (14 in the sham stimulation group and 16 in the active stimulation group). Active rTMS significantly reduced pain intensity from day 5 to week 25. These analgesic effects were associated with a long-term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new therapeutic option in patients with fibromyalgia. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers

We investigated the analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in two models of experimental pain in healthy volunteers. Two studies were carried out in parallel in two groups of 26 paid healthy volunteers. The effects of active or sham rTMS (frequency, 10 Hz; intensity, 80% resting motor threshold) applied to the right M1 or DLPFC were compared in a double-blind randomized cross-over design. In the first series of experiments, we analyzed the effects of rTMS on thermal (heat and cold) detection and pain thresholds measured on both hands and the left foot, by standardized quantitative sensory testing methods. In the second series of experiments, we measured the effects of M1 or DLPFC rTMS on the threshold and recruitment curves of the RIII nociceptive reflex evoked by ipsilateral electrical stimulation of the sural nerve and recorded on the biceps femoris of both lower limbs. In both studies, measurements were taken before and up to 60 min after the end of rTMS. Active rTMS of both M1 and DLPFC significantly increased the thermal pain thresholds, measured for both hands and the left foot, this effect being most marked for cold pain. These effects, which lasted at least 1 h after rTMS, were selective because they were not associated with changes in non-painful thermal sensations. By contrast, the second study showed that rTMS of M1 or DLPFC had no significant effect on the threshold or recruitment curve of the nociceptive flexion RIII reflex. Our findings demonstrate that unilateral rTMS of M1 or DLPFC induces diffuse and selective analgesic effects in healthy volunteers. The lack of effect on the RIII reflex suggests that such analgesic effects may not depend on the activation of descending inhibitory systems. (C) 2009 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

Lectin extracted from Canavalia grandiflora seeds presents potential anti-inflammatory and analgesic effects

Neutrophil migration is responsible for tissue damage observed in inflammatory diseases and is also implicated in inflammatory nociception. The use of lectins has been demonstrated to be effective in different activities including anti-inflammatory, antimicrobial, and in cancer therapy. In this study, we addressed the potential use of a lectin from Canavalia grandiflora seeds (ConGF) to control neutrophil migration and inflammatory hypernociception. Pretreatment of the animals intravenously (15 min before) with ConGF inhibited neutrophil migration to the peritoneal cavity in a dose-dependent fashion confirmed by an inhibition of rolling and adhesion of leukocytes by intravital microscopy. Another set of experiments showed that pretreatment of the animals with ConGF inhibited the mechanical hypernociception in mice induced by the i.pl. injection of carrageenan or formalin. This anti-nociceptive effect correlated with an effective blockade of neutrophil influx, as assessed by the hind paw tissue myeloperoxidase levels. Furthermore, ConGF had important inhibitory effects on the mouse carrageenan-induced paw edema. In addition, animals treated with ConGF showed inhibition of cytokines release. In conclusion, we demonstrated that the lectin ConGF inhibits neutrophil migration and mechanical inflammatory hypernociception.

Assessment of non-steroidal anti-inflammatory and analgesic pharmaceuticals in seawaters of North of Portugal: Occurrence and environmental risk

The occurrence of seven pharmaceuticals and two metabolites belonging to non-steroidal anti-inflammatory drugs and analgesics therapeutic classes was studied in seawaters. A total of 101 samples covering fourteen beaches and five cities were evaluated in order to assess the spatial distribution of pharmaceuticals among north Portuguese coast. Seawaters were selected in order to embrace different bathing water quality (excellent, good and sufficient). Acetaminophen, ketoprofen and the metabolite hydroxyibuprofen were detected in all the seawater samples at maximum concentrations of 584, 89.7 and 287 ng L− 1, respectively. Carboxyibuprofen had the highest seawater concentration (1227 ng L− 1). The temporal distribution of the selected pharmaceuticals during the bathing season showed that, in general, higher concentrations were detected in August and September. The environmental risk posed by the pharmaceuticals detected in seawaters towards different trophic levels (fish, daphnids and algae) was also assessed. Only diclofenac showed hazard quotients above one for fish, representing a potential risk for aquatic organisms. These results were observed in seawaters classified as excellent bathing water. Additional data is needed in order to support the identification and prioritization of risks posed by pharmaceuticals in marine environment.

Effects of Local Anesthetic on the Time Between Analgesic Boluses and the Duration of Labor in Patient-Controlled Epidural Analgesia: Prospective Study of Two Ultra-Low Dose Regimens of Ropivacaine and Sufentanil

BACKGROUND: Patient-controlled epidural analgesia with low concentrations of anesthetics is effective in reducing labor pain. The aim of this study was to assess and compare two ultra-low dose regimens of ropivacaine and sufentanil (0.1% ropivacaine plus 0.5 μg.ml-1 sufentanil vs. 0.06% ropivacaine plus 0.5 μg.ml-1 sufentanil) on the intervals between boluses and the duration of labor. MATERIAL AND METHODS: In this non-randomized prospective study, conducted between January and July 2010, two groups of parturients received patient-controlled epidural analgesia: Group I (n = 58; 1 mg.ml-1 ropivacaine + 0.5 μg.ml-1 sufentanil) and Group II (n = 57; 0.6 mg.ml-1 ropivacaine + 0.5 μg.ml-1 sufentanil). Rescue doses of ropivacaine at the concentration of the assigned group without sufentanil were administered as necessary. Pain, local anesthetic requirements, neuraxial blockade characteristics, labor and neonatal outcomes, and maternal satisfaction were recorded. RESULTS: The ropivacaine dose was greater in Group I (9.5 [7.7-12.7] mg.h-1 vs. 6.1 [5.1-9.8 mg.h-1], p < 0.001). A time increase between each bolus was observed in Group I (beta = 32.61 min, 95% CI [25.39; 39.82], p < 0.001), whereas a time decrease was observed in Group II (beta = -1.40 min, 95% CI [-2.44; -0.36], p = 0.009). The duration of the second stage of labor in Group I was significantly longer than that in Group II (78 min vs. 65 min, p < 0.001). CONCLUSIONS: Parturients receiving 0.06% ropivacaine exhibited less evidence of cumulative effects and exhibited faster second stage progression than those who received 0.1% ropivacaine.