Antinociceptive activity of 3ß-6ß-16ß-trihydroxylup-20 (29)-ene triterpene isolated from Combretum leprosum leaves in adult zebrafish (Danio rerio).

Drugs used to treat pain are associated with adverse effects, increasing the search for new drugs as an alternative treatment for pain. Therefore, we evaluated the antinociceptive behavior and possible neuromodulation mechanisms of triterpene 3ß, 6ß, 16ß-trihydroxylup-20(29)-ene (CLF-1) isolated from Combretum leprosum leaves in zebrafish. Zebrafish (n = 6/group) were pretreated with CLF-1 (0.1 or 0.3 or 1.0 mg/mL; i.p.) and underwent nociception behavior tests. The antinociceptive effect of CFL-1 was tested for modulation by opioid (naloxone), nitrergic (L-NAME), nitric oxide and guanylate cyclase synthesis inhibitor (methylene blue), NMDA (Ketamine), TRPV1 (ruthenium red), TRPA1 (camphor), or ASIC (amiloride) antagonists. The corneal antinociceptive effect of CFL-1 was tested for modulation by TRPV1 (capsazepine). The effect of CFL-1 on zebrafish locomotor behavior was evaluated with the open field test. The acute toxicity study was conducted. CLF-1 reduced nociceptive behavior and corneal in zebrafish without mortalities and without altering the animals' locomotion. Thus, CFL-1 presenting pharmacological potential for the treatment of acute pain and corneal pain, and this effect is modulated by the opioids, nitrergic system, NMDA receptors and TRP and ASIC channels.

ENLIST 1: An International Multi-centre Cross-sectional Study of the Clinical Features of Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL) is a severe multisystem immune mediated complication of borderline lepromatous leprosy and lepromatous leprosy. ENL is associated with skin lesions, neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis and nephritis. The treatment of ENL requires immunosuppression, which is often required for prolonged periods of time and may lead to serious adverse effects. ENL and its treatment is associated with increased mortality and economic hardship. Improved, evidence-based treatments for ENL are needed; however, defining the severity of ENL and outcome measures for treatment studies is difficult because of the multiple organ systems involved. A cross-sectional study was performed, by the members of the Erythema Nodosum Leprosum International STudy (ENLIST) Group, of patients with ENL attending seven leprosy referral centres in Brazil, Ethiopia, India, Nepal, the Philippines and the United Kingdom. We systematically documented the clinical features and type of ENL, its severity and the drugs used to treat it. Patients with chronic ENL were more likely to be assessed as having severe ENL. Pain, the most frequent symptom, assessed using a semi-quantitative scale was significantly worse in individuals with "severe" ENL. Our findings will determine the items to be included in a severity scale of ENL which we are developing and validating. The study also provides data on the clinical features of ENL, which can be incorporated into a definition of ENL and used for outcome measures in treatment studies.

Anti-inflammatory effect of triterpene 3ß, 6ß, 16ß-trihydroxylup-20(29)-ene obtained from Combretum leprosum Mart & Eich in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The 3ß, 6ß, 16ß-trihydroxylup-20(29)-ene (TTHL) is a pentacyclic triterpene obtained from a medicinal plant named Combretum leprosum. In folk medicine, this plant is used to treat several diseases associated with inflammation and pain. We previously demonstrated that TTHL presents a significant antinociceptive effect, suggesting the involvement of the glutamatergic system. AIM OF THE STUDY: This study was designed to investigate the effect of TTHL on nociception and vascular permeability induced by acetic acid. We also evaluated the effect of TTHL on carrageenan-induced peritonitis and the levels of cytokines (interleukin 1-ß [IL-1ß], tumor necrosis factor α [TNF-α] and interleukin 10 [IL-10]) on peritoneal fluid. MATERIALS AND METHODS: TTHL was administered orally by intra-gastric gavage (i.g.) 60 min prior to experimentation. Abdominal contractions and vascular permeability were induced by an intraperitoneal (i.p.) injection of acetic acid (0.6%). We also investigated whether TTHL decreases carrageenan-induced peritonitis (750 µg/cavity) by measuring leukocyte migration and vascular permeability. In addition, we evaluated the effects of TTHL on TNF-α, IL-1ß and IL-10 release induced by carrageenan on peritoneal fluid. The levels of these cytokines were measured by ELISA. RESULTS: TTHL (0.01-10 mg/kg) administered by intra-gastric (i.g.) gavage inhibited (69±3%) acetic acid-induced abdominal constrictions, with an ID50 of 0.15 (0.03-0.8) mg/kg. TTHL (10mg/kg) also reduced the leukocyte infiltration induced by acetic acid, with an inhibition of 59±9 but had no effect on abdominal vascular permeability. In addition, indomethacin (10 mg/kg, i.p.) reduced the nociceptive behavior (92±1%), total leukocyte migration (29±3%) and capillary permeability (71±3%) induced by acetic acid. While the glucocorticoid dexamethasone (2 mg/kg, s.c.) reduced partially but significantly the nociception (31±1%), besides to promote a marked reduction on total leukocyte migration (60±2%) to the peritoneal cavity caused by acetic acid. In a model of peritonitis induced by carrageenan, TTHL also reduced total leukocyte migration, mainly neutrophils (inhibition of 84±3% and 85±2% at 30 mg/kg and 100 mg/kg, respectively). Likewise, dexamethasone (0.5 mg/kg, i.p.) resulted in an inhibition of 93±3%. Nevertheless, carrageenan-induced abdominal vascular permeability was reduced by dexamethasone but was not altered by TTHL. Furthermore, dexamethasone and TTHL significantly reduced the TNF-α and IL-1ß levels in peritoneal fluid, whereas the IL-10 levels were unchanged. CONCLUSIONS: Altogether, our data confirm the antinociceptive effect of TTHL and demonstrate its effect in inflammatory animal models, providing novel data about this compound, which could be useful as an anti-inflammatory drug.

Tactile threshold detection in leprosy patients with an electronic algometer.

OBJECTIVE: To propose an electronic method for sensitivity evaluation in leprosy and to compare it to the Semmes-Weinstein monofilaments. METHODS: Thirty patients attending the Dermatology outpatient clinic of HCFMRP-USP were consecutively evaluated by both the electronic aesthesiometer and Semmes-Weinstein monofilaments on hand and foot test points. The intraclass correlation coefficient (ICC) was calculated to determine the variability of the electronic measures and the Kappa coefficient was calculated to determine the agreement between methods according to their categories (altered and non-altered tactile sensitivity). RESULTS: The ICC was approximately 1, demonstrating repeatability. The Kappa coefficient showed more than 75 and 63% agreement on the hand and foot points, respectively. The mean agreement between the 2 methods for the 7 points of the right and left hand was 77.14 and 75.71%, respectively. The mean agreement for all 10 points was 74.33 and 63.66% on the right and left foot, respectively. In cases of disagreement the detection of altered tactile sensitivity by the electronic esthesiometer on the right and left foot was 90.91 and 84.25%, respectively, with no detection by the monofilaments. CONCLUSION: The results suggest that the electronic esthesiometer is a reliable and easy application, capable of evaluating alterations of tactile sensitivity in leprosy patients.

Recent advances in the neurophysiology of chronic pain.

UNLABELLED: The chronic pain syndrome patient has become the 'leper' of emergency medicine. There are no emergency medicine guidelines and minimal research into managing this challenging group of patients. OBJECTIVE: To summarize the recent advances in laboratory research into the development of chronic pain that have relevance to emergency management. When the level of supporting evidence is low, it is imperative that emergency physicians understand the physiology that underpins those expert opinions upon which they base their treatment strategies. METHODS: Literature was searched via Medline, Cochrane, Cinahl, and PsycINFO from 1996 to 2004, under 'chronic pain and emergency management'. Medline from 1996 was searched for 'chronic pain and prevention', 'chronic pain and emergency' and 'chronic pain'. Bibliographies were manually searched for older keynote articles. RESULTS: Advances in understanding the biochemical changes of chronic pain are paralleled by lesser known advances in delineation of the corticol processing. CONCLUSIONS: Drug manipulation causes complex action and reaction in chronic pain. Emergency physicians must also optimize cognitive and behavioural aspects of treatment to successfully manage this systemic disease.

Near-nerve potential in lepromatous leprosy.

In leprosy, sensory action potentials (SAPs) may be normal in spite of clinical sensory loss. This may result from the early involvement of small nerve fibers, which have potentials that are not detected in routine studies. To evaluate this possibility, we used a near-nerve recording technique that records potentials from nerve fibers as small as 4-6 microm in diameter. We hypothesized that this technique might increase the sensitivity of nerve conduction studies in detecting leprosy neuropathy. We found the technique to be useful for recording conduction abnormalities in recently diagnosed patients, including those with preserved sensation, suggesting that axonal loss may be the underlying mechanism. Contrary to our hypothesis, however, recording the late SAP components did not improve the sensitivity of nerve conduction studies. We suggest that the late components having normal conduction velocities may be generated by either regenerating or remyelinating abnormal fibers, which have an electrophysiological behavior similar to that of normal 4-6-microm-diameter fibers.

Enfermedad de Hansen: dolor y sus rutas nerviosas

Este trabajo conjunto de "Dolor", sus Rutas Nerviosas y todos los Aspectos Psicológicos muestran los determinantes desde los receptores, sus vías, estaciones terminales y los correspondientes compromisos biológicos y psico - emocionales; así como su relación de los procesos físicos y psíquicos que se encuentran en personas afectadas con la Enfermedad de Hansen (Lepra).Los dos trabajos, "Dolor": Sus Rutas Nerviosas y Aspectos Psicológicos del Dolor, se complementan para explicar qué pasa en el individuo cuando percibe la sensación de "dolor" ya sea físico y/o psico-emocional, especialmente en indivi duos afectados de Lepra, adonde el compromiso nervioso periférico es un dramático signo de la enfermedad (AU)

Dor central encefálica / Encefalica central pain

Foram analisados 123 pacientes portadoresde dor central por lesoes encefalicas. A mediana de idade foi 55 anos (limites 87-21 anos). Na maioria dos casos, a lesao foi de origem vascular isquemica. Houve casos de lesao hemorragica, traumatismo cranio-encefalico, meningiomas parietais e casos em que a etiologia nao pode ser determinadas com recisao. A topografia das lesoes, diagnosticadas pelo exame clinico, pela TC e RNM, foi dividida em 3 regioes principais: tronco encefalico, talamo e estruturas supratentoriais extra-talamicas. Na maioria dos pacientes, a dor se instalou ao mesmo tempo da lesao ou nas primeiras semanas apos esta. Raramente a dor se manifestou apos o segundo ano de instalacao da doenca. A maioria dos pacientes, apresentava dor permanente e diaria, raramente com periodos de remissao. Estes, quando presentes, foram de curta duracao (minutos ou horas). A dor, em geral, foi de grande intensidade (media 8 numa escala de 0 a 10). O principal descritor da dor foi a sensacao de queimor e laceracao. Foram comuns varios padroes de dor no mesmo paciente. Muitos doentes pioravam com a movimentacao e com a emocao. Todos apresentaram algum tipo de deficit neurologico nao sensitivo, sendo os mais comuns a paresia e a ataxia, e deficit sensitivo no lado afetado, sendo o mais comum a hipoestesia termica. Cinquenta e nove por cento dos pacientes beneficiaram-se do tratamento com drogas antidepressivas triciclicas e fenotiazinas. Apenas 15 dos 123 apresentaram alivio completo da dor. Foram realizados bloqueio da cadeia neurovegetativa simpatica em 5 doentes, talamotomia dos nucleos CM, Pf, Pu talamicos em 3, talamotomia e mesencefalotomia em 1, talamotomia e lesao da Zi em 3, talamotomia e cingulotomia em 3. A estimulacao dos nucleos do complexo ventro-basal e capsula interna foi realizada em 8 doentes. A talamotomia proporcionou alivio satisfatorio a longo prazo em 50 por cento dos doentes, a cingulotomia em 66,6 por cento e a estimulacao encefalica em 12,5 por cento. Os movimentos anormais apresentaram melhora significativa nos casos em que a subtalamotomia foi realizada,. Os bloqueios simpaticos nao proporcionaram resultados satisfatorios. O autor concluiu que, embora os mecanismos neurofisiologicos de geracao da dor central de origem encefalica sejam hoje melhor conhecidos, o tratamento eficaz para seu controle constitui ainda um grande desafio.

Ankle fractures treated with a stabilizing shoe.

Twenty-four patients with a Lauge-Hansen Stage II supination-eversion fracture of the lateral malleolus were treated with a stabilizing shoe, which prevents supination and eversion of the foot, but allows a tibiotalar motion. In 23 patients the result was excellent, without secondary dislocation during healing. We therefore conclude that this fracture type can be treated functionally.

Autonomic neuropathy in leprosy.

21 patients of borderline lepromatous and lepromatous leprosy of both sexes were taken for study after exclusion of autonomic disorders. Autonomic functions pertaining to cardiovascular and genital system were carried out. Five healthy volunteers served as controls. Autonomic function tests indicate definite involvement of cardiovascular and genital system. The incidence of autonomic neuropathy in 21 patients studied was ranging from 14.3 to 57% for various tests. There is involvement of parasympathetic system (vagus nerve) which occurred early and more common than sympathetic. The sympathetic damage is always associated with parasympathetic damage. The severity of automatic neuropathy is found to be high in leprosy of longer duration. Autonomic neuropathy widely occurs in leprosy as in diabetes mellitus.

Objective grading of the loss of pain and touch sensations in leprosy patients.

Two new instruments named Pain/Touch Sensation Testing and Grading devices, which provide standardized and graded stimuli of pain and touch, respectively, were employed to grade the sensory loss at the center of 110 lesions in 97 patients. The grades of sensory loss for pain were 0 (no sensory loss) in 8 lesions, 1 in 6 lesions, 2 in 14 lesions, 3 in 26 lesions, 4 in 19 lesions, and 5 (complete loss) in 37 lesions (total 110 lesions). Grades of sensory loss for touch were 0 in 12 lesions, 1 in 3 lesions, 2 in 5 lesions, 3 in 9 lesions, 4 in 15 lesions, and 5 in 22 lesions (total 66 lesions). Reevaluation done after 2-40 weeks in 46 of these lesions revealed that the grade for pain had decreased in 17 lesions, increased in 4, and remained the same in 25. The grade for loss of touch sensation had decreased in 10, increased in 1, and remained the same in 35. Grading of the sensory loss in most of the 1-cm-square areas of the entire lesion, done in 19 patients (26 lesions), revealed that the sensory loss was not uniform all over the lesion and it was also not maximum at the center of the lesion, though generally it was less at the margin in comparison with the central area. Follow up of 11 of these lesions revealed a decrease in the grades in 7 lesions for both pain and touch sensations, while 2 lesions showed a decrease in the grades for touch sensation only.(ABSTRACT TRUNCATED AT 250 WORDS)

An attempt to reduce the loss of pain and touch sensations in leprosy patients.

An attempt was made to improve the perception of pain and touch sensations at the leprosy lesions. The loss of pain and touch sensations in a lesion was graded using Pain/Touch-Sensation-Testing-and-Grading devices. Application of a solution containing 1 mg of histamine per ml of DMSO, at the affected area decreased the grades of the loss of pain sensation in 11 (31.4%) patients and of touch sensation in 8 (22.8%) patients, out of the 35 patients tested, indicating an improvement in the perception at the lesion. This effect, however, did not persist even for 5 minutes. A higher concentration (2 mg/ml) of histamine produced reduction in the sensory loss in a larger percentage (47% for pain and 35.3% for touch) of patients, though the duration of this effect was still not prolonged.

A new approach in the relief of pain of leprous neuritis.

Transcutaneous Nerve Stimulation (TNS) has been known since the last several decades to relieve pain in many conditions. For the first time it was used in the treatment of the severe and agonizing pain caused by leprous neuritis with highly beneficial results without producing any side effects. This study was made on 40 patients, and in the majority of the cases there was total relief of pain with one application of a few hours duration. This encouraging result has led the authors to the conclusion that TNS could be a useful tool in a hospital where leprosy patients are treated.