Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: Discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole

In this work we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and platelet anti-aggregating properties of new 3-(arylideneamino)-2-methyl-6,7-methylenedioxy-quinazolin-4 (3H)-one derivatives (3a-j), designed as conformationally constrained analogues of analgesic 1,3- benzodioxolyl-N- acylhydrazones (1) previously developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (2) as starting material. The pharmacological assays lead us to identify compounds LASSBio-1240 (3b) and LASSBio-1272 (3d) as new analgesic prototypes, presenting an antinociceptive pro. le more potent and effective than dipyrone and indomethacin used, respectively, as standards in AcOH-induced abdominal constrictions assay and in the formalin test. These results confirmed the success in the exploitation of conformation restriction strategy for identification of novel cyclic N-acylhydrazone analogues with optimized analgesic profile (C) 2009 Elsevier Ltd. All rights reserved.

Postoperative analgesic effects of epidural administration of neostigmine alone or in combination with morphine in ovariohysterectomized dogs

Objective-To evaluate analgesic effects of epidurally administered neostigmine alone or in combination with morphine in dogs after ovariohysterectomy.Animals-40 healthy bitches.Procedures-After acepromazine premedication, anesthesia was induced. Dogs randomly received 1 of the following 4 epidural treatments 30 minutes before ovariohysterectomy (n = 10/group): saline (0.9% NaCl) solution (control), morphine (0.1 mg/kg), neostigmine (10 pg/kg), or morphine-neostigmine (0.1 mg/kg and 10 pg/kg, respectively). Analgesia was assessed for 24 hours after surgery by use of a visual analogue.scale (VAS; scale of 0 to 10) or numeric descriptive scale (NDS; scale of 0 to 24) and by the need for supplemental analgesia (morphine [0.5 mg/kg, IM] administered when VAS was >= 4 or NDS was >= 8).Results-Significantly more control dogs (n = 8) received supplemental analgesia, compared with the number of neostigmine-treated dogs (1); no dogs in the remaining groups received supplemental analgesia. Compared with values for the control dogs, the NDS scores were lower for morphine-neostigmine-treated dogs (from 2 to 6 hours and at 12 hours) and for morphine-treated dogs (all time points). The NDS scores were lower for morphine-treated dogs at 3, 12, and 24 hours, compared with values for neostigmine-treated dogs. The VAS was less sensitive than the NDS for detecting differences among groups.Conclusions and Clinical Relevance-Epidurally administered neostigmine reduced the use of supplemental analgesia after ovariohysterectorny in dogs. However, analgesic effects were less pronounced than for epidurally administered morphine or morphine-neostigmine. Adding neostigmine to epidurally administered morphine did not potentiate opioid-induced analgesia.

Critical analysis of the international classification of headache disorders diagnostic criteria (ICHD I-1988) and (ICHD II-2004), for migraine in children and adolescents

The present study analyzed the (ICHD I-1988) and ( ICHD II-2004) diagnostic criteria in children and adolescents. Our population consisted of 496 patients of the Headache Outpatient Ward for Children and Adolescents retrospectively studied from 1992 to 2002. Individuals were classified according to three diagnostic groups: Intuitive Clinical Diagnosis ( Gold Standard), ICHD I-1988 and ICHD II-2004. They were statistically compared using the variables: Sensitivity ( S), Specificity (Sp), Positive Predictive Value (PPV), Negative Predictive Value (NPV). When ICHD I-1988 was used, the sensitivity of migraine without and with aura was 21% and 27%, respectively, whereas in ICHD II-2004 it changed to 53% and 71% without affecting specificity. As a conclusion, the current classification criteria ( ICHD II-2004) showed greater sensitivity and high specificity for migraine than ICHD I-1988, although it improved migraine diagnosis in children and adolescents, the sensitivity remains poor.

Post-operative analgesic effects of butorphanol or firocoxib administered to dogs undergoing elective ovariohysterectomy

ObjectiveTo compare the post-operative analgesic effects of butorphanol or firocoxib in dogs undergoing ovariohysterectomy.Study designProspective, randomized, blinded, clinical trial.AnimalsTwenty-five dogs > 1 year of age.MethodsDogs received acepromazine intramuscularly (IM), 0.05 mg kg-1 and either butorphanol IM, 0.2 mg kg-1 (BG, n = 12) or firocoxib orally (PO), 5 mg kg-1 (FG, n = 13), approximately 30 minutes before induction of anesthesia with propofol. Anesthesia was maintained with isoflurane. Ovariohysterectomy was performed by the same surgeon. Pain scores using the dynamic and interactive visual analog scale (DIVAS) were performed before and at 1, 2, 3, 4, 6, 8 and 20 hours after the end of surgery by one observer, blinded to the treatment. Rescue analgesia was provided with morphine (0.5 mg kg-1) IM and firocoxib, 5 mg kg-1 (BG only) PO if DIVAS > 50. Groups were compared using paired t-tests and Fisher's exact test (p < 0.05). Data are presented as mean +/- SD.ResultsThe BG required significantly less propofol (BG: 2.6 +/- 0.59 mg kg-1; FG: 5.39 +/- 0.7 mg kg-1) (p < 0.05) but the anesthesia time was longer (BG: 14 +/- 6, FG: 10 +/- 4 minutes). There were no differences for body weight (BG: 7.9 +/- 5.0, FG: 11.5 +/- 4.6 kg), sedation scores, and surgery and extubation times (BG: 10 +/- 2, 8 +/- 5 minutes; FG: 9 +/- 3, 8 +/- 4 minutes, respectively) (p > 0.05). The FG had significantly lower pain scores than the BG at 1, 2 and 3 hours following surgery (p < 0.05). Rescue analgesia was administered to 11/12 (92%) and 2/13 (15%) dogs in the BG and FG, respectively (p < 0.05).Conclusion and clinical relevanceFirocoxib produced better post-operative analgesia than butorphanol. Firocoxib may be used as part of a multimodal analgesia protocol but may not be effective as a sole analgesic.

Postoperative analgesic effects of intravenous, intramuscular, subcutaneous or oral transmucosal buprenorphine administered to cats undergoing ovariohysterectomy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analgesic efficacy of perioperative use of vedaprofen, tramadol or their combination in cats undergoing ovariohysterectomy

The analgesic efficacy of tramadol and/or vedaprofen was evaluated in cats submitted for elective ovariohysterectomy, using a randomised double blind placebo controlled design. Forty adult female cats (3.0 +/- 0.32 kg; 1.8 +/- 0.7 years) were distributed into four groups. Vedaprofen PO (0.5 mg/kg), tramadol SC (2 mg/kg), both, or placebo was administered 1 h before surgery and every 24 and 8 h, respectively, for 72 h after surgery. Pain score evaluated by interactive visual analogue and composite pain score and hyperalgesia by the von Frey filament test were recorded at 1, 2, 4, 6, 8, 12, 24, 28, 32, 48, 52, 56, 72, 96 h and on the 7th day after surgery. Animals treated with combined vedaprofen and tramadol treatment did not need rescue analgesia, did not develop hyperalgesia, and their serum cortisol concentrations and pain scores were lower than placebo until 24 and 72 h after surgery, respectively. Combined vedaprofen and tramadol treatment provided more effective postoperative analgesia and prevented hyperalgesia than when used on their own. Multimodal technique is a superior method of treating pain after feline ovariohysterectomy. This work also provides evidence for the benefits of analgesia for up to 3 days following ovariohysterectomy. (C) 2008 ESFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Cardiopulmonary and analgesic effects of caudal epidurally administered ropivacaine in cattle

Objective To assess cardiopulmonary and analgesic effects after administration of ropivacaine into the caudal epidural space of cattle.Study design Prospective, single-dose trial.Animals Eight healthy mixed breed cows aged 8 +/- 5 years and weighing 507 +/- 112 kg.Methods Caudal epidural anesthesia was produced in cows with 0.75% ropivacaine (0.11 mg kg(-1)). Onset time, duration and cranial spread of analgesia were recorded. Heart rate (HR), respiratory rate (f(R)), rectal temperature (RT), and mean arterial blood pressure (MAP) were measured prior to epidural administration (T-0) and at 15, 30, 60, 120, 180 and 240 minutes after epidural administration (T-15, T-30, T-60, T-120, T-180 and T-240). Arterial blood acid-base balance (pH, standard bicarbonate and base excess), gas tension (PaO2, PaCO2, SaO(2)) and electrolytes (Na+, K+, iCa(2+), Cl-) were recorded at T-0, T-30, T-60, T-120, T-180 and T-240. Ataxia was evaluated at T-0, T-30, T-60, T-120, T-180 and T-240 and at 1 hour intervals thereafter until analgesia was no longer present in each animal.Results Epidurally administered ropivacaine induced variable analgesia extending bilaterally from the coccyx to S3. Time to onset of analgesia and mean duration in the perineal area were 15 +/- 4 and 359 +/- 90 minutes, respectively. Respiratory rate and RT increased from T-120 to T-240 when compared to the value at T-0. Ionized calcium and chloride concentrations increased at T-180 and T-240 when compared to T-0. The other variables were not significantly different from baseline values (p > 0.05). Four animals were mildly ataxic.Conclusion and clinical relevance Ropivacaine (0.75%, 0.11 mg kg(-1)) can be administered by caudal epidural injection to produce prolonged bilateral perineal analgesia with minimal ataxia and cardiopulmonary changes in standing cattle.

Headache and Symptoms of Temporomandibular Disorder: An Epidemiological Study

Objectives.-A population-based cross-sectional study was conducted to estimate the prevalence of migraine, episodic tension-type headaches (ETTH), and chronic daily headaches (CDH), as well as the presence of symptoms of temporomandibular disorders (TMD) in the adult population.Background.-The potential comorbidity of headache syndromes and TMD has been established mostly based on clinic-based studies.Methods.-A representative sample of 1230 inhabitants (51.5% women) was interviewed by a validated phone survey. TMD symptoms were assessed through 5 questions, as recommended by the American Academy of Orofacial Pain, in an attempt to classify possible TMD. Primary headaches were diagnosed based on the International Classification of Headache Disorders.Results.-When at least 1 TMD symptom was reported, any headache happened in 56.5% vs 31.9% (P < .0001) in those with no symptoms. For 2 symptoms, figures were 65.1% vs 36.3% (P < .0001); for 3 or more symptoms, the difference was even more pronounced: 72.8% vs 37.9%. (P < .0001). Taking individuals without headache as the reference, the prevalence of at least 1 TMD symptom was increased in ETTH (prevalence ratio = 1.48, 95% confidence interval = 1.20-1.79), migraine (2.10, 1.80-2.47) and CDH (2.41, 1.84-3.17). At least 2 TMD symptoms also happened more frequently in migraine (4.4, 3.0-6.3), CDH (3.4; 1.5-7.6), and ETTH (2.1; 1.3-3.2), relative to individuals with no headaches. Finally, 3 or more TMD symptoms were also more common in migraine (6.2; 3.8-10.2) than in no headaches. Differences were significant for ETTH (2.7 1.5-4.8), and were numerically but not significant for CDH (2.3; 0.66-8.04).Conclusions.-Temporomandibular disorder symptoms are more common in migraine, ETTH, and CDH relative to individuals without headache. Magnitude of association is higher for migraine. Future studies should clarify the nature of the relationship.

Migraine is the Most Prevalent Primary Headache in Individuals with Temporomandibular Disorders

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Temporomandibular Disorders Are Differentially Associated With Headache Diagnoses A Controlled Study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)