Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells.

Spinal glial activation contributes to the development and maintenance of chronic pain states, including neuropathic pain of diverse etiologies. Cannabinoid compounds have shown antinociceptive properties in a variety of neuropathic pain models and are emerging as a promising class of drugs to treat neuropathic pain. Thus, the effects of repeated treatment with WIN 55,212-2, a synthetic cannabinoid agonist, were examined throughout the development of paclitaxel-induced peripheral neuropathy. Painful neuropathy was induced in male Wistar rats by intraperitoneal (i.p.) administration of paclitaxel (1mg/kg) on four alternate days. Paclitaxel-treated animals received WIN 55,212-2 (1mg/kg, i.p.) or minocycline (15 mg/kg, i.p.), a microglial inhibitor, daily for 14 days, simultaneous with the antineoplastic. The development of hypersensitive behaviors was assessed on days 1, 7, 14, 21 and 28 following the initial administration of drugs. Both the activation of glial cells (microglia and astrocytes) at day 29 and the time course of proinflammatory cytokine release within the spinal cord were also determined. Similar to minocycline, repeated administration of WIN 55,212-2 prevented the development of thermal hyperalgesia and mechanical allodynia in paclitaxel-treated rats. WIN 55,212-2 treatment also prevented spinal microglial and astrocytic activation evoked by paclitaxel at day 29 and attenuated the early production of spinal proinflammatory cytokines (interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α). Our results confirm changes in the reactivity of glial cells during the development of peripheral neuropathy induced by paclitaxel and support a preventive effect of WIN 55,212-2, probably via glial cells reactivity inactivation, on the development of this neuropathy.

Antinociceptive effect of three common analgesic drugs on peripheral neuropathy induced by paclitaxel in rats.

Nowadays, there are no validated drugs to control the neuropathic pain induced by paclitaxel, one of the most effective antineoplastic drugs. The aim was to study the involvement of opioid and NMDA receptor on established paclitaxel-induced pain, testing three common analgesics drugs morphine, ketamine and methadone. Animals received four intraperitoneal (i.p.) injections on alternate days of paclitaxel (1mg/kg). Three weeks later, animals showed a mechanical and heat allodynia/hyperalgesia. Morphine (1, 2.5, 5 and 10mg/kg) abolished the reduction in the mechanical and thermal withdrawal thresholds in a dose dependent manner. This effect was blocked by naloxone. Only highest dose of ketamine (50mg/kg) was able to increase the mechanical and thermal threshold and returned to basal values. Subanalgesic doses of morphine (1mg/kg) and ketamine (12.5mg/kg) produced an additive effect on heat hyperalgesia reaching an antinociceptive effect. This combination did not induce any change on tactile allodynia. Methadone (2.5 and 5mg/kg) produced an analgesic effect that was completely antagonized by naloxone in both tests. Our results confirm that: the activation of opioids receptor produced analgesia; the blockade of NMDA receptors produce antinociception but at high doses with motor impairments and low doses of ketamine enhancing the effect of opioids.

Antinociceptive effect of the cannabinoid agonist, WIN 55,212-2, in the orofacial and temporomandibular formalin tests.

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is not always adequately resolved. Cannabinoids have demonstrated their analgesic effect in several pain conditions, both in animal models and in clinical situations. The aim of the present study was to evaluate the cannabinoid-mediated antinociception in two inflammatory models of orofacial pain (orofacial and temporomandibular joint (TMJ) formalin test) and to compare it with a spinal inflammatory model (paw formalin test). WIN 55,212-2 (0.5, 1mg/kg), a synthetic cannabinoid agonist, was intraperitoneally (i.p.) administered prior to formalin and significantly reduced the nociceptive behavioural responses in these inflammatory tests. To elucidate which subtype of receptor could be involved in such effect, two selective cannabinoid antagonists were administered prior to WIN. SR141716A (1mg/kg i.p.), the CB1 receptor-selective antagonist, was able to prevent the cannabinoid-induced analgesia in all three models, whereas SR144528 (1mg/kg i.p.), the CB2 receptor-selective antagonist, only prevented it in the paw formalin test. A comparison with the antinociceptive effects of morphine (2.5, 5, 10mg/kg, i.p.), indomethacin (2.5, 5mg/kg, i.p.) and ketamine (25, 50mg/kg, i.p.) was also performed. Morphine displayed a dose-dependent reduction of acute and inflammatory pain in all three models, whereas indomethacin and ketamine only attenuated inflammatory pain at the highest tested doses. These results indicate that the cannabinoid-induced antinociception in the orofacial region is mediated by activation of CB1 cannabinoid receptor. Moreover WIN was as effective as morphine and more effective than indomethacin and ketamine, in oral inflammatory pain.

Cytokine polymorphisms in patients with pemphigus.

The aim of this study was to assess whether tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta1 (TGF-beta1) and interleukin-10 (IL-10) polymorphisms are among the factors influencing the development of pemphigus. Whole blood from 20 patients with pemphigus and 24 control subjects was taken. Genomic DNA was obtained and cytokine genotyping for IL-10 (-1082 G/A; -819 C/T), TGFB1 (codon 10 C/T, codon 25 G/C) and TNFA (-308 G/A) was performed using the ARMS-PCR method. The distribution of IL-10 (-819) alleles was significantly different between the pemphigus and control groups (P=0.009). In particular, allele T was associated with the disease (OR 3.291, 95% CI 1.350-8.020). Similar results were observed when only pemphigus vulgaris (PV) patients were analyzed (P=0.012, OR 3.410, 95% CI 1.346-8.639). An increased frequency of the low producer IL-10 haplotype (-1082/-819 A/T) in patients with pemphigus compared with controls was observed (OR 2.714, 95% CI 1.102-6.685) and this association was also significant when only PV patients were considered (OR 2.667, 95% CI 1.043-6.816). There were no differences between patients and controls in the frequency of any other gene polymorphism analyzed. The increased frequency of the low producer IL-10 haplotype (-1082 /-819 A/T) suggest that the carriage of this haplotype might predispose to pemphigus or the high and intermediate producer haplotypes may be protective factors. The prevalence of the allele IL-10 (-819 T) in pemphigus patients cannot be explained by the current hypothesis, according to which a particular allele of the gene is associated with a different level of cytokine production and therefore affects the predisposition to a particular disease. However, this cytokine polymorphism might be linked to an unknown susceptibility factor.

Ulcera de Marjolin / Ulcer of Marjolin

Se presentan 4 pacientes que, sobre cicatrices de quemaduras previas, desarrollaron carcinomas espinocelulares después de un tiempo suficientemente prolongado de hasta 50 años. Se realizan consideraciones terapéuticas sobre la oportunidad del uso de injerto en las secuelas de quemaduras de 3§ grado.

PENFIGO: agrupamiento y seguimiento clínico de pacientes tratados con gammaglobulina sérica humana como tratamiento adyuvante, 1987-1997

El Pénfigo es el prototipo de enfermedad autoinmune órgano-dirigida, caracterizada por una dermatosis ampollar adquirida, siendo a Acantólisis su sustrato fundamental.Pese a su rareza, se conoce de la época hipocrática. Más aún, por su expresión clínica, altera severamente la calidad de vida de los pacientes; y sin tratamiento es letal. La aparición de los corticoides en el arsenal terapeutico en 1950, salvó o prolongó la vida de estos pacientes a un alto precio: los graves efectos colaterales a largo plazo que originaron: El aumento de la morbi-mortalidad en los años siguientes se vinculó con esta terapéutica. Desde 1970 primó en nuestra Cátedra la idea de no utilizar esquemas rígidos y considerar la utilización de las terapéuticas adyuvantes no corticoideas que ofrecían una esperanza de mejor calidad de vida a nuestros pacientes.Se estudiaron 34 pacientes afectados de Pénfigo, que fueron atendidos en la Primera Cátedra de Dermatología y en el Servicio de Dermatología Clínica del Hospital Nacional de Clínicas de Córdoba, Argentina, durante un período de 10 años.El propósito del presente trabajo fue el de agrupar las distintas formas clínicas y determinar aquellas correspondientes a la fase de mantenimiento o remisión, como asimismo la mortalidad. Para ello se tuvieron en cuenta parámetros clínicos, de laboratorio y anatomopatológicos. Se concedió especial importancia a la evaluación del tratamiento, consistente en Corticosteroides y Gammaglobulina Sérica Humana, por vía intramuscular. A este respecto, se realizaron análisis estadísticos. Se consideraron de especial interés la Remisión (61) de estos casos, con el fin de evaluar esta variante terápeutica. Se considera que estos resultados son alentadores, puesto que ofrecen la posiblidad de un autentico ahorro corticoideo, con dosis menores a las descriptas en la literatura actual.

Esclerodermia-polimiositis - enfermedad de Charcot-Marie-Tooth / Scleroderma-polymiositis - Charcot-Marie-Tooth syndrome

Presentamos una paciente de sexo femenino de 42 años afectada de enfermedad de Charcot-Marie-Tooth. Hace dos años a nuestra paciente se le añade un cuadro de esclerodermia sistémica con insuficiencia pulmonar severa y síntomas típicamente dermatológicos. Los anticuerpos anti Scl 70 y anticentrómero fueron positivos. La anatomía patológica mostró además miositis y las características típicas de la esclerodermia. El tratamiento con corticoides, lidocaína y vasodilatadores periféricos no fue efectivo y nuestra paciente falleció