Role of ß-Caryophyllene in the Antinociceptive and Anti-Inflammatory Effects of Tagetes lucida Cav. Essential Oil.

Tagetes lucida Cav. (Asteraceae) is an ancient medicinal plant commonly used to alleviate pain. Nevertheless, scientific studies validating this property are lacking in the literature. Animal models of pain were used to evaluate the antinociceptive and anti-inflammatory activities of T. lucida essential oil (TLEO) and a bioactive metabolite. The chemical constitution and possible toxicity of the extract and the mechanism of action of ß-caryophyllene were also explored. Temporal course curves and dose-response graphics were generated using TLEO (0.1-10 mg/kg or 3.16-31.62 mg/kg) and ß-caryophyllene (3.16-10 mg/kg). Metamizole (80 mg/kg) and indomethacin (20 mg/kg) were used as reference drugs in the formalin assay and writhing test in rats and mice, respectively. The ß-caryophyllene mechanism of action was explored in the presence of naloxone (1 mg/kg), flumazenil (10 mg/kg), WAY100635 (0.16 mg/kg), or nitro-l-arginine methyl ester (L-NAME) (20 mg/kg) in the formalin test in rats. GC/MS analysis demonstrated the presence of geranyl acetate (49.89%), geraniol (7.92%), and ß-caryophyllene (6.27%). Significant and dose-dependent antinociceptive response was produced by TLEO and ß-caryophyllene without the presence of gastric damage. In conclusion, ß-caryophyllene was confirmed as a bioactive compound in the T. lucida analgesic properties by involving the participation of receptors like opioids, benzodiazepines, and Serotonin 1A receptor (5-HT1A), as well as nitric oxide.

Broccoli sprouts produce abdominal antinociception but not spasmolytic effects like its bioactive metabolite sulforaphane.

Abdominal pain is a common health problem that requires efficacious and safe therapy. Broccoli is a rich source of health-promoting bioactive compounds with potential for pain therapy. However, there is a lack of scientific pharmacological evidence to support this. Our aim was to investigate the antinociceptive and spasmolytic activities of broccoli aqueous extracts from seeds, sprouts, and inflorescence, as well as some metabolites. Experiments were done using enteral and parenteral administration in an in vivo model of pain accompanied with an in vitro assay. Data established that sprouts (100 mg/kg, i.p. and 1000 mg/kg, p.o.) produced significant and major antinociceptive effect at similar or even lower doses in comparison to the seeds (125 mg/kg, i.p. and 1000 mg/kg, p.o.) and broccoli heads (250 mg/kg, i.p. and 1000 mg/kg, p.o.). These results resembled the analgesic response observed with the reference drug metamizole (80 mg/kg, i.p.). Chlorogenic acid (CA, 3, 10, 30, and 100 mg/kg, i.p.) and SFN (0.1, 1 and 10 mg/kg, i.p.) were partial responsible antinociceptive metabolites of broccoli. SFN effects involved participation of endogenous opioids, since they were inhibited in the presence of naltrexone (5 mg/kg, s.c.). In the in vitro assay, a significant 80% spasmolytic-like response was reached with SFN alone in comparison to 20% obtained with aqueous extracts of sprouts and seeds. Participation of calcium channels was a mechanism involved in the in vitro response of SFN. In conclusion, broccoli sprouts, SFN and CA are potential nutraceuticals for abdominal pain therapy.

Antinociceptive effect of systemically administered dipyrone (metamizol), magnesium chloride or both in a murine model of cancer.

BACKGROUND: Opioid effectiveness to treat cancer pain is often compromised by the development of tolerance and the occurrence of undesirable side effects, particularly during long-term treatment. Hence, the search for more efficient analgesics remains a necessity. The main goal of this study was to relieve neuropathic symptoms associated with tumour growth by administering the non-opioid analgesic dipyrone (DIP) alone or in combination with magnesium chloride (MgCl2 ), an adjuvant that blocks the NMDA receptor channel. METHODS: Mice were inoculated with a melanoma cell line (B16-BL6) in the left thigh and two protocols were used to evaluate the effect of DIP (270 mg/kg), MgCl2 (200 mg/kg), or the combination DIP-MgCl2 . In the therapeutic protocol the drugs, alone or combined, were administered once tumour had promoted increased nociception. In the preventive protocol, drugs were administered prior to the appearance of the primary tumour. Tumour growth was assessed with a caliper and nociception was determined using behavioural tests. RESULTS: DIP promoted antinociception only at the beginning of both protocols due to the development of tolerance. The combination DIP-MgCl2 improved the antinociceptive effect, avoiding tolerance and reducing tumour growth in the preventive treatment, more efficiently than each compound alone. CONCLUSIONS: These results suggest that DIP-MgCl2 may represent a safe, affordable and accessible option to reduce tumour growth and to treat cancer pain avoiding the risk of tolerance, without the typical complications of opioids agents, particularly when long-term treatment is required. SIGNIFICANCE: This study shows a non-opioid analgesic combined with an adjuvant as a therapeutic option to treat cancer pain. The avoidance of antinociceptive tolerance when repeated administration is required, as well as tumor growth reduction, are additional advantages to be considered.

Metamizol Relieves Pain Without Interfering With Cerulein-Induced Acute Pancreatitis in Mice.

OBJECTIVES: Animal models are essential to understand the pathogenesis of acute pancreatitis (AP) and to develop new therapeutic strategies. Although it has been shown that cerulein-induced AP is associated with pain in experimental animals, most experiments are carried out without any pain-relieving treatment because researchers are apprehensive of an interference of the analgetic agent with AP-associated inflammation. In light of the growing ethical concerns and the legal tightening regarding animal welfare during experiments, this attitude should be changed. METHODS: Acute pancreatitis was induced by cerulein in the C57BL/6J and FVB/N mouse inbred strains. One group received vehicle only, and the other was treated with metamizol as analgetic agent. Pain sensation and parameters of AP were analyzed as well as the effect of metamizol in the pancreas and its actions in the brain. RESULTS: We report that oral administration of metamizol protects cerulein-treated mice from abdominal pain without influencing the clinical and histopathological course of the disease. In addition, it could be shown that metamizol reduces the central pain response. CONCLUSIONS: This study reveals that oral administered metamizol has no influence on the cerulein-induced AP and can be given as an analgesic to increase animal welfare in experiments with induced AP.

A Comparative Investigation of the Analgesic Effects of Metamizole and Paracetamol in Rats.

BACKGROUND: This study investigated the effects of metamizole and paracetamol on pain and oxidative stress induced by scalpel incision and carrageenan in rats. MATERIALS AND METHODS: Total of 144 rats were divided into groups of 12 animals. Six groups each were used for scalpel incision and carrageenan tests. Pain was inflicted by applying a scalpel incision or carrageenan. Pain-created groups by scalpel incision received metamizole (SIM) or paracetamol (SIP) at doses of 250 or 500 mg/kg. Pain-created groups by carrageenan received metamizole (CAM) or paracetamol (CAP) at doses of 250 or 500 mg/kg. Analgesic activity was determined by Basile Algesimeter. The COX-2 and MPO gene expressions were determined, and malondialdehyde and tGSH were measured in rat paws. RESULTS: In the scalpel incision test, pain was reduced in groups of SIM-250 and SIM-500 in the first hour by 65.2% and 91.3%, respectively, and in the third hour by 51.9% and 77.8%, respectively, compared with the SIC group. In SIP-250 and SIP-500 groups, pain was reduced in the first hour by 43% and 74%, respectively, and by 33.4% and 59.3%, respectively, in the third hour compared with the SIC group. In the carrageenan test, in groups CAM-250 and CAM-500, pain was reduced in the first hour by 72.3% and 86.1%, respectively, and by 65.8% and 71.4%, respectively, in the third hour compared with the CCG group. In groups CAP-250 and CAP-500, pain was reduced in the first hour by 52.8% and 69.4%, respectively, and by 28.6% and 25.8%, respectively, in the third hour compared with the CCG group. Metamizole inhibited COX-2 gene expression at a dose of 500 mg/kg in the carrageenan test. At doses of 250 and 500 mg/kg, metamizole reduced COX-2 and MPO gene expressions and oxidative stress induced by scalpel incision or carrageenan. But both doses of paracetamol were unable to suppress that parameters. CONCLUSIONS: Our results show that metamizole is more effective than paracetamol for treating surgical trauma-related pain, inflammation, and oxidative stress and hence may be a preferential drug to paracetamol.

Analgesic activity of diterpene alkaloids from Aconitum baikalensis.

We compared analgesic activities of individual alkaloids extracted from Baikal aconite (Aconitum baikalensis): napelline, hypaconitine, songorine, mesaconitine, 12-epinapelline N-oxide. The detected analgesic activity was comparable to that of sodium metamizole. The mechanisms of analgesia were different in diterpene alkaloids of different structure. The antinociceptive effect of atisine alkaloids (12-epinapelline N-oxide, songorine) was naloxonedependent and realized via opioid receptor modulation.

Dipyrone metabolite 4-MAA induces hypothermia and inhibits PGE2 -dependent and -independent fever while 4-AA only blocks PGE2 -dependent fever.

BACKGROUND AND PURPOSE: The antipyretic and hypothermic prodrug dipyrone prevents PGE2 -dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects. EXPERIMENTAL APPROACH: Male Wistar rats were treated i.p. with indomethacin (2 mg·kg(-1) ), dipyrone, 4-methylaminoantipyrine (4-MAA), 4-aminoantipyrine (4-AA) (60-360 mg·kg(-1) ), 4-formylaminoantipyrine, 4-acethylaminoantipyrine (120-360 mg·kg(-1) ) or vehicle 30 min before i.p. injection of LPS (50 µg·kg(-1) ), Tsv (150 µg·kg(-1) ) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE2 concentrations were determined in the CSF and hypothalamus by elisa. KEY RESULTS: In contrast to LPS, Tsv-induced fever was not followed by increased PGE2 in the CSF or hypothalamus. The antipyretic time-course of 4-MAA and 4-AA on LPS-induced fever overlapped with the period of the highest concentrations of 4-MAA and 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE2 increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia. CONCLUSIONS AND IMPLICATIONS: The presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE2 -independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone.

Effects of intravenous metamizole on ongoing and evoked activity of dura-sensitive thalamic neurons in rats.

Migraine and tension-type headache (TTH) are the most common forms of primary headaches. A general key mechanism underlying development of both the diseases is the trigeminal system activation associated with the ascending nociceptive transmission via the trigemino-thalamo-cortical pathway. The ventroposteromedial (VPM) nucleus is a key thalamic structure, receiving afferent inflow from the craniofacial region; it holds the third-order neurons responsible for conveying sensory information from the extra- and intracranial nociceptors to the cortex. The VPM is currently seen as a therapeutic target for various antimigraine medications, which is shown to reduce the VPM neuronal excitability. A non-opioid analgesic metamizole is widely used in some countries for acute treatment of migraine or TTH. However, the precise mechanisms underlying anticephalgic action of metamizole remain unclear. The objective of our study performed in the rat model of trigemino-durovascular nociception was to evaluate the effects of intravenously administered metamizole on ongoing and evoked firing of the dura-sensitive VPM neurons. The experiments were carried out on rats under urethane-chloralose anesthesia. Cumulative administration of metamizole (thrice-repeated intravenous infusion of 150 mg/kg performed 30 min apart) in 56% of cases produced a suppression of both the ongoing activity of the thalamic VPM neurons and their responses to dural electrical stimulation. Although the inhibitory effect was prevailing, a number of VPM neurons were indifferent to the administration of metamizole. These data suggest that one of the main components of neural mechanism underlying anticephalgic action of metamizole is suppression of the thalamo-cortical nociceptive transmission associated with trigemino-vascular activation.

Synergistic effects of celecoxib and bupropion in a model of chronic inflammation-related depression in mice.

This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund's Adjuvant (CFA). Male Swiss mice received an intraplantar (i.pl.) injection of CFA (50 µl/paw) or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks), and different pharmacological tools were tested. The brain levels of IL-1ß and BDNF, or COX-2 expression were also determined. CFA elicited a time-dependent edema formation and mechanical allodynia, which was accompanied by a significant increase in the immobility time in the tail suspension (TST) or forced-swimming (FST) depression tests. Repeated administration of the antidepressants imipramine (10 mg/kg), fluoxetine (20 mg/kg) and bupropion (30 mg/kg) significantly reversed depression-like behaviour induced by CFA. Predictably, the anti-inflammatory drugs dexamethasone (0.5 mg/kg), indomethacin (10 mg/kg) and celecoxib (30 mg/kg) markedly reduced CFA-induced edema. The oral treatment with the analgesic drugs dipyrone (30 and 300 mg/kg) or pregabalin (30 mg/kg) significantly reversed the mechanical allodyinia induced by CFA. Otherwise, either dipyrone or pregabalin (both 30 mg/kg) did not significantly affect the paw edema or the depressive-like behaviour induced by CFA, whereas the oral treatment with dipyrone (300 mg/kg) was able to reduce the immobility time in TST. Noteworthy, CFA-induced edema was reduced by bupropion (30 mg/kg), and depression behaviour was prevented by celecoxib (30 mg/kg). The co-treatment with bupropion and celecoxib (3 mg/kg each) significantly inhibited both inflammation and depression elicited by CFA. The same combined treatment reduced the brain levels of IL-1ß, as well as COX-2 immunopositivity, whilst it failed to affect the reduction of BDNF levels. We provide novel evidence on the relationship between chronic inflammation and depression, suggesting that combination of antidepressant and anti-inflammatory agents bupropion and celecoxib might represent an attractive therapeutic strategy for depression.

Antinociceptive and anti-inflammatory activities of crude methanolic extract of red alga Bryothamnion triquetrum.

The marine environment is an extraordinary reservoir of bioactive natural products, many of which exhibit chemical and structural features not found in terrestrial natural products. In this regard, the aim of this study was to investigate the possible antinociceptive and anti-inflammatory activities of a crude methanolic extract of the red alga Bryothamnion triquetrum (BT-MeOH) in murine models. Groups of Swiss mice of both sexes (25-30 g) were used throughout the experiments. The potential antinociceptive of BT-MeOH was evaluated by means of the following tests: acetic acid-induced writhing, hot-plate test and glutamate- and formalin-induced nociception. The anti-inflammatory activity of BT-MeOH was investigated using the zymosan A-induced peritonitis test. The tests were conducted using 100 mg/kg (p.o.) BT-MeOH, 33.3 mg/kg (p.o.) dipyrone, 35.7 mg/kg (p.o.) indomethacin and 5.7 mg/kg (s.c.) morphine. The extract and all standard drugs were administered 40 min before the nociceptive/inflammatory stimulus. In the acetic acid-induced writhing test, BT-MeOH and dipyrone inhibited the nociceptive response by 55.9% (22.2 ± 2.0 writhings; p < 0.01) and 80.9% (9.6 ± 2.1 writhings; p < 0.01). In the hot-plate test, BT-MeOH did not increase the latency time of the animals in the time evaluated. In addition, BT-MeOH inhibited glutamate-induced nociception by 50.1%. While BT-MeOH did not inhibit the neurogenic phase in formalin-induced nociception, the inflammatory phase was inhibited by 53.1% (66.8 ± 14.2 s; p < 0.01). Indomethacin inhibited the inflammatory phase by 60.2% (56.8 ± 8.7 s; p < 0.01). In the zymosan-induced peritonitis test, BT-MeOH inhibited 55.6% (6.6 ± 0.2 × 10(6) leukocytes/mL; p < 0.01) of leukocyte migration, while indomethacin inhibited 78.1% (3.2 ± 0.1 × 10(6) leukocytes/mL; p < 0.01). Based on the results obtained in this study, we conclude that BT-MeOH has peripheral antinociceptive and anti-inflammatory activities. However, more studies need to be conducted to confirm these properties.

Involvement of PGE2 and RANTES in Staphylococcus aureus-induced fever in rats.

This study investigated the involvement of prostaglandins and regulated on activation, normal T cell expressed and secreted (RANTES), in fever induced by live Staphylococcus aureus (no. 25923, American Type Culture Collection) injection in rats. S. aureus was injected intraperitoneally at 10(9), 10(10), and 2 × 10(10) colony-forming units (CFU)/cavity, and body temperature (T(b)) was measured by radiotelemetry. The lowest dose of S. aureus induced a modest transient increase in T(b), whereas the two higher doses promoted similar long-lasting and sustained T(b) increases. Thus, the 10(10) CFU/cavity dose was chosen for the remaining experiments. The T(b) increase induced by S. aureus was accompanied by significant decreases in tail skin temperature and increases in PGE(2) levels in the cerebrospinal fluid (CSF) and hypothalamus but not in the venous plasma. Celecoxib (selective cyclooxygenase-2 inhibitor, 2.5 mg/kg po) inhibited the fever and the increases in PGE(2) concentration in the CSF and hypothalamus induced by S. aureus. Dipyrone (120 mg/kg ip) reduced the fever from 2.5 to 4 h and the PGE(2) increase in the CSF but not in the hypothalamus. S. aureus increased RANTES in the peritoneal exudate but not in the CSF or hypothalamus. Met-RANTES (100 µg/kg iv), a chemokine (C-C motif) receptor (CCR)1/CCR5 antagonist, reduced the first 6 h of fever induced by S. aureus. This study suggests that peripheral (local) RANTES and central PGE(2) production are key events in the febrile response to live S. aureus injection. As dipyrone does not reduce PGE(2) synthesis in the hypothalamus, it is plausible that S. aureus induces fever, in part, via a dipyrone-sensitive PGE(2)-independent pathway.

Myometrial response to neurotropic and musculotropic spasmolytic drugs in an extracorporeal perfusion model of swine uteri.

To compare the effects of neurotropic and musculotropic spasmolytic drugs in isolated swine uterus specimens, 80 swine uteri were perfused using an established model for preserving a viable organ that responds to oxytocic hormones and spasmolytic drugs. An intrauterine catheter was used to record pressure changes. Following initiation of rhythmic uterine contractions and recording of spontaneous rhythmic contractions, spasmolytic drugs (butylscopolamine, atropine, denaverine, morphine, metamizole, pethidine and celandine) were administered at various concentrations. The musculotropic relaxant denaverine in particular showed significant results (P ≤ 0.05) for all dosages and parameters investigated. In terms of muscle physiology, musculotropic agents (denaverine and celandine) have clear advantages in comparison with neurotropic (butylscopolamine and atropine) or musculoneurotropic (morphine, metamizole and pethidine) spasmolytic drugs for inhibiting contractions. Experiments with pethidine (Dolantin) also showed promising results; with celandine (Paverysat), an initial increase in contractions was observed that may suggest ways of promoting rapid directed sperm transport. Denaverine and pethidine in particular may in the future be able to play an important role in improving the pregnancy rate after IVF.

The antipyretic effect of dipyrone is unrelated to inhibition of PGE(2) synthesis in the hypothalamus.

BACKGROUND AND PURPOSE: Bacterial lipopolysaccharide (LPS) induces fever through two parallel pathways; one, prostaglandin (PG)-dependent and the other, PG-independent and involving endothelin-1 (ET-1). For a better understanding of the mechanisms by which dipyrone exerts antipyresis, we have investigated its effects on fever and changes in PGE(2) content in plasma, CSF and hypothalamus induced by either LPS or ET-1. EXPERIMENTAL APPROACH: Rats were given (i.p.) dipyrone (120 mg·kg(-1)) or indomethacin (2 mg·kg(-1)) 30 min before injection of LPS (5 µg·kg(-1), i.v.) or ET-1 (1 pmol, i.c.v.). Rectal temperature was measured by tele-thermometry. PGE(2) levels were determined in the plasma, CSF and hypothalamus by elisa. KEY RESULTS: LPS or ET-1 induced fever and increased CSF and hypothalamic PGE(2) levels. Two hours after LPS, indomethacin reduced CSF and hypothalamic PGE(2) but did not inhibit fever, while at 3 h it reduced all three parameters. Three hours after ET-1, indomethacin inhibited the increase in CSF and hypothalamic PGE(2) levels but did not affect fever. Dipyrone abolished both the fever and the increased CSF PGE(2) levels induced by LPS or ET-1 but did not affect the increased hypothalamic PGE(2) levels. Dipyrone also reduced the increase in the venous plasma PGE(2) concentration induced by LPS. CONCLUSIONS AND IMPLICATIONS: These findings confirm that PGE(2) does not play a relevant role in ET-1-induced fever. They also demonstrate for the first time that the antipyretic effect of dipyrone was not mechanistically linked to the inhibition of hypothalamic PGE(2) synthesis.

Antinociceptive effect of methanol extract of Capparis ovata in mice.

CONTEXT: Capparis ovata Desf. (Capparaceae) grows widely in Turkey. Flower buds and fruits of the plant are used in folk medicine for their analgesic, antirheumatismal, and diuretic effects. OBJECTIVE: This study evaluated the possible antinociceptive effect of the methanol extract of C. ovata (CME) in mice. MATERIALS: The antinociceptive effect of methanol extract, prepared with the C. ovata flower buds, was studied at the doses of 50, 100, and 200 mg/kg (i.p.) using tail-immersion, hot-plate, and writhing tests in mice. Morphine sulfate (5 mg/kg; i.p.) and dipyrone (100 mg/kg; i.p.) were used as reference analgesic agents. Naloxone (5 mg/kg; i.p.) was also tested. RESULTS: It was observed that the C. ovata extract had a significant antinociceptive effect in these tests. In the hot-plate and tail-immersion test results, the doses of 50, 100, and 200 mg/kg increased the percentage of the maximum possible effect (MPE%) value for nociception significantly according to the control value (P < 0.001). All doses of the extract decreased the number of acetic acid-induced abdominal constrictions in mice when compared with control group (P < 0.001). These effects were inhibited by pretreatment with naloxone. DISCUSSION AND CONCLUSION: Based on the results obtained, it can be concluded that CME is a potentially antinociceptive agent which acts as both at the peripheral and central levels.

Analgesic and antiinflammatory activity of Morinda citrifolia L. (Noni) fruit.

M. citrifolia is a tropical plant with a long tradition of medicinal use in Polynesia and tropical parts of eastern Asia and Australia. One of its favorite uses is the treatment of painful inflammatory conditions, such as arthritis. The analgesic activity of Noni fruit puree on mice was investigated using the hot plate test. A 10% solution of freeze concentrated Noni fruit puree in the drinking water of mice reduced the pain sensitivity comparably to the central analgesic drug tramadol. This effect was only partly reversed by the application of the morphine antagonist naloxone. An alcohol extract of noni fruit puree also caused an inhibition of MMP-9 release from human monocytes after stimulation with LPS. This effect was comparable to hydrocortisone (10(-5) m). The findings suggest that preparations of noni fruits are effective in decreasing pain and joint destruction caused by arthritis.

Potenciais interações medicamentosas em prescrições de um hospital-escola de Porto Alegre / Potential drug interactions among prescriptions of a teaching hospital in Porto Alegre

Introdução: Relatos das prevalências de interações medicamentosas em hospitais brasileiros são escassos. Objetivos: Descrever a prevalência de interações medicamentosas potenciais entre os fármacos prescritos nas enfermarias clínicas e cirúrgicas de um hospital-escola. secundariamente, descrever as características dessas interações e relacionar a sua ocorrência com o número de medicamentos prescritos e a idade dos pacientes. Pacientes e Métodos: Os dados foram coletados durante uma semana de out/2007, de 2a a 6a feira, a partir da última ficha de prescrição encontrada nos prontuários, envolvendo 128 fichas de prescrição com 10,5±4,1 fármacos. Os pacientes tinham 58,6±16,9 anos e 51,2% eram homens. A doença cardiovascular foi a enfermidade principal (23,4%) e a comorbidade (42,5%) mais frequentemente encontrada. A análise das interações foi feita através de consulta a um sistema interativo (Micromedex®). Resultados: 485 interações foram encontradas, estando presentes em 79,7% (IC95%: 72,6-86,8) das fichas de prescrição (média 3,8). A interação mais frequente foi captopril/dipirona (9,7%), seguida por dipirona/furosemida (4,5%), e os fármacos mais envolvidos foram dipirona (29,3%) e captopril (21,2%). A maioria das interações tinha mecanismo farmacodinâmico (65,5%), gravidade moderada (55,5%), começo tardio (61,3%) e bom embasamento científico (71,1%). A prevalência de interações esteve associada fortemente com o número de fármacos prescritos (r=0,65, p<0,001) e fracamente com a idade do paciente.

Introduction: Reports of the prevalence of drug interactions in Brazilian hospitals are scarce. Aims: To describe the prevalence of potential drug interactions among the medical drugs prescribed in the clinical and surgical units of a teaching hospital. Secondarily, to describe the characteristics of drug interactions and relate their occurrence to the number of prescribed medications and patient age. Patients and Methods: The data were collected from Monday to Friday of a week in Oct 2007, starting from the last prescription form found in the medical charts, and involved 128 prescription forms with 10.5±4.1 drugs. The patients’ mean age was 58.6±16.9 years and 51.2% were males. Cardiovascular disease was the main disease (23.4%) and the most frequently found comorbidity (42.5%). The analysis of interactions was done through consultation with an interactive system (Micromedex®). Results: 485 cases of drug interactions were found, being present in 79.7% (CI95%: 72.686.8) of the prescription forms (mean 3.8). The most frequent interaction was captopril/dipyrone (9.7%), followed by ipyrone/furosemide (4,5%), and the most frequently involved drugs were dipyrone (29.3%) and captopril (21.2%). Most of the interactions had a pharmacodynamic mechanism (65.5%), moderate severity (55.5%), late onset (61.3%), and a good scientific basis (71.1%). The prevalence of interactions was strongly associated with the number of drugs prescribed (r=0.65, p<0.001) and weakly associated with patient age.

Characterization and pharmacological evaluation of febrile response on zymosan-induced arthritis in rats.

The present study investigated the febrile response in zymosan-induced arthritis, as well as the increase in PGE(2) concentration in the cerebrospinal fluid (CSF), along with the effects of antipyretic drugs on these responses in rats. Zymosan intra-articularly injected at the dose of 0.5 mg did not affect the body core temperature (Tc) compared with saline (control), whereas at doses of 1 and 2 mg, zymosan promoted a flattened increase in Tc and declined thereafter. The dose of 4 mg of zymosan was selected for further experiments because it elicited a marked and long-lasting Tc elevation starting at 3 1/2 h, peaking at 5 1/2 h, and remaining until 10 h. This temperature increase was preceded by a decrease in the tail skin temperature, as well as hyperalgesia and edema in the knee joint. No febrile response was observed in the following days. In addition, zymosan-induced fever was not modified by the sciatic nerve excision. Zymosan increased PGE(2) concentration in the CSF but not in the plasma. Oral pretreatment with ibuprofen (5-20 mg/kg), celecoxib (1-10 mg/kg), dipyrone (60-240 mg/kg), and paracetamol (100-200 mg/kg) or subcutaneous injection of dexamethasone (0.25-1.0 mg/kg) dose-dependently reduced or prevented the fever during the zymosan-induced arthritis. Celecoxib (5 mg/kg), paracetamol (150 mg/kg), and dipyrone (120 mg/kg) decreased CSF PGE(2) concentration and fever during zymosan-induced arthritis, suggesting the involvement of PGE(2) in this response.

Nociceptive behavior induced by mustard oil injection into the temporomandibular joint is blocked by a peripheral non-opioid analgesic and a central opioid analgesic.

The aim of this study was to improve the mustard oil (MO) induced temporomandibular joint (TMJ) nociception model and to investigate the potential analgesic activity of systemic dipyrone and tramadol on the nociceptive behavioral responses induced by injection of low concentrations of the MO into the rat TMJ region. TMJ injection of 2.5% MO produced a significant nociceptive behavior expressed by head flinching and orofacial rubbing. This activity was related to the MO injection since mineral oil (vehicle) did not elicit response. Local application of the lidocaine N-ethyl bromide quaternary salt, QX-314 (2%) and systemic administration of morphine (4 mg/kg) significantly reduced the MO-induced nociceptive responses, validating the nociceptive character of the behaviors. The pretreatment with systemic dipyrone (19, 57 or 95 mg/kg) as well as tramadol (5, 7.5 or 10 mg/kg) was effective in decreasing the nociceptive behavioral responses induced by the injection of MO into the rat TMJ. In conclusion, TMJ injection of low concentrations of MO in rats produces well defined and quantifiable nociceptive behaviors constituting a reliable behavioral model for studying TMJ pain mechanisms and testing analgesic drugs. The results also suggest that dipyrone and tramadol could be effective analgesic options in the management of TMJ pain.

Antinociceptive properties of ethanolic extract and fractions of Pterodon pubescens Benth. seeds.

We have previously demonstrated that the hydroalcoholic extract from Pterodon pubescens Benth. seeds (sucupira branca, Leguminosae) exhibits anti-arthritic activity and that its oleaginous extract (OEP) and PF1 fraction exhibit acute and topic anti-edematogenic activities. In this work, we studied the antinociceptive activity of OEP and its fractions on the acetic acid-induced abdominal constriction and formalin assays in SW male mice. OEP was obtained by ethanol extraction and its four fractions by sequential liquid-liquid extraction. PF2 GC/MS profile indicated it contains furane diterpenes derivatives of vouacapan and non-vouacapan compounds. The antinociceptive properties were demonstrated to OEP and predominantly to PF1 and PF2 by the writhing test. In the formalin assay, PF1 inhibited both phases and PF2 inhibited mainly the late one. Then, PF1 and PF2 seemed to present antinociceptive effects by different mechanisms, peripheral and/or central inhibitory ones, and showed maximum antinociceptive properties with very low doses, providing a rationale for its popular use in pain disorders.