Canales iónicos Receptores de Potencial Transitorio y su papel protagónico en la terapia analgésica / Transient receptor potential ion channels and their leading role in analgesic therapy

En la búsqueda de nuevas opciones terapéuticas para el tratamiento del dolor, se ha llegado al descubrimiento de canales iónicos que actúan como receptores y están presentes en neuronas nociceptoras aferentes primarias. Entre estos receptores, se encuentran los canales iónicos receptores de potencial transitorio que regulan las vías involucradas en el dolor y la nocicepción. Se realizó una revisión actualizada de los principales canales iónicos receptores de potencial transitorio implicados en la fisiopatología del dolor. Se hace una reseña histórica del descubrimiento de estas moléculas y sus estudios avanzados. A continuación se revisan las diferentes familias de estos canales con su clasificación, nomenclatura, estructura y funciones celulares. También se hace un recuento de la relación de estos canales con la analgesia, así como el mecanismo de acción de algunos analgésicos que actúan sobre ellos. Finalmente, se detallan importantes consideraciones a tomar en cuenta, que pudieran influir sobre la utilización de estos medicamentos en la clínica. Por tal motivo, el trabajo procura ser una revisión que abarque el rol de los canales TRP como nuevas dianas farmacológicas en el tratamiento del dolor.

In the search for new therapeutic options for pain treatment, new ion channels have been discovered, which act as receptors and are present in primary afferent nociceptor neurons. Some of them are the transient receptor potential ion channels that regulate the pathways involved in pain and nociception. An updated review of the main transient potential receptors ion channels involved in pain physiopathology and a historical review of the discovery of these molecules and advanced studies on them were also made. Then the different families of these channels with their classification, nomenclature, structure and cell functions were also examined. An account of the relationships of these channels with analgesia as well as the mechanism of action of some analgesics acting upon them was also presented. Finally, important considerations were given, which should be taken into account since they might influence on the clinical use of these drugs. For these reasons, the paper intends to be a review covering the role of the transient receptor potential channels as new pharmacological targets in the pain treatment.

Tuberculosis in renal transplant patients: The experience of a single center in Medellín-Colombia, 2005-2013 / Tuberculose em pacientes transplantados renais: experiência de um único centro em Medellín-Colômbia, 2005-2013

Introduction: Tuberculosis is a common opportunistic infection in renal transplant patients. Objective: To obtain a clinical and laboratory description of transplant patients diagnosed with tuberculosis and their response to treatment during a period ranging from 2005 to 2013 at the Pablo Tobón Uribe Hospital. Methods: Retrospective and descriptive study. Results: In 641 renal transplants, tuberculosis was confirmed in 12 cases. Of these, 25% had a history of acute rejection, and 50% had creatinine levels greater than 1.5 mg/dl prior to infection. The disease typically presented as pulmonary (50%) and disseminated (33.3%). The first phase of treatment consisted of 3 months of HZRE (isoniazid, pyrazinamide, rifampicin and ethambutol) in 75% of the cases and HZME (isoniazid, pyrazinamide, moxifloxacin and ethambutol) in 25% of the cases. During the second phase of the treatment, 75% of the cases received isoniazid and rifampicin, and 25% of the cases received isoniazid and ethambutol. The length of treatment varied between 6 and 18 months. In 41.7% of patients, hepatotoxicity was associated with the beginning of anti-tuberculosis therapy. During a year-long follow-up, renal function remained stable, and the mortality rate was 16.7%. Conclusion: Tuberculosis in the renal transplant population studied caused diverse nonspecific symptoms. Pulmonary and disseminated tuberculosis were the most frequent forms and required prolonged treatment. Antituberculosis medications had a high toxicity and mortality. This infection must be considered when patients present with a febrile syndrome of unknown origin, especially during the first year after renal transplant. .

Introdução: A tuberculose é uma infecção oportunista comum em pacientes transplantados renais. Objetivo: Oferecer uma descrição clínica e laboratorial de pacientes transplantados com diagnóstico de tuberculose e sua resposta ao tratamento durante o período entre 2005 e 2013 no Hospital Pablo Tobón Uribe. Métodos: Estudo retrospectivo descritivo. Resultados: Em 641 transplantes renais, a tuberculose foi confirmada em 12 pacientes. Destes, 25% tinham histórico de rejeição aguda e 50% apresentaram níveis de creatinina superiores a 1,5 mg/dl antes da infecção. A patologia geralmente se apresentava como pulmonar (50%) e disseminada (33,3%). A primeira fase do tratamento consistiu de três meses de HZRE (isoniazida, pirazinamida, rifampicina e etambutol) em 75% dos casos e HZME (isoniazida, pirazinamida, moxifloxacina e etambutol) em 25% dos pacientes. Durante a segunda fase do tratamento, 75% dos pacientes receberam isoniazida e rifampicina e 25% isoniazida e etambutol. A duração do tratamento variou entre seis e 18 meses. Em 41,7% dos pacientes, hepatotoxicidade foi associada ao início do tratamento da tuberculose. Durante o seguimento de um ano a função renal manteve-se estável e a taxa de mortalidade foi de 16,7%. Conclusão: A tuberculose foi responsável por diversos sintomas inespecíficos na população de transplantados renais estudada. Tuberculose pulmonar e disseminada foram as formas mais frequentes de acometimento e necessitaram de tratamento prolongado. Medicamentos contra a tuberculose apresentaram alta toxicidade e mortalidade. Esta infecção deve ser considerada quando o paciente apresenta síndrome febril de origem desconhecida, especialmente durante o primeiro ano após o transplante renal. .

Potassium channel openers exhibit cross-tolerance with morphine in two experimental models of pain / Los abridores de canales de potasio exhiben tolerancia cruzada con la morfina en dos modelos experimentales de dolor

OBJECTIVE: The study was performed to assess the effect of potassium channel openers on morphine tolerance and vice-versa. METHODS: Swiss albino mice of either gender weighing between 25-30 g were used for the study. The study assesses the effect of potassium channel openers (cromakalim, diazoxide and minoxidil) on morphine tolerance and vice-versa, using formalin and tail-flick tests. RESULTS: The antinociceptive effect of cromakalim and minoxidil was significantly reduced when administered to morphine-tolerant mice, in both the behavioural tests. However, reduced analgesic effect of diazoxide was observed on morphine-tolerance in the formalin test but not in the tail-flick test. Tolerance was observed when morphine was administered to animals chronically treated with any of the potassium channel openers. The same effect was observed when morphine was injected into a group treated with a combination of morphine and any of the potassium channel openers. CONCLUSIONS: This study, therefore, suggests that both morphine and potassium channel openers are cross-tolerant. However, such interaction occurs at the level of potassium channels rather than at the level of receptors.

OBJETIVO: El estudio fue realizado para evaluar el efecto de los abridores de canales de potasio en la tolerancia a la morfina, y viceversa. MÉTODOS: Para el estudio, se usaron ratones albinos suizos de ambos sexos que pesaban entre 25-30 g. El estudio evalúa el efecto de los abridores de canales de potasio (cromacalina, diazóxido y minoxidil) en la tolerancia a la morfina, y viceversa, usando la prueba de la sacudida de la cola y la prueba de la formalina. RESULTADOS: El efecto antinociceptivo de la cromacalina y el minoxidil fue significativamente reducido cuando se le administró a los ratones tolerantes a la morfina, en ambas pruebas conductuales. Sin embargo, se observó un efecto analgésico reducido de diazóxido sobre la tolerancia a la morfina en la prueba de la formalina, pero no en la prueba de la sacudida de la cola. Se observó tolerancia al administrar morfina a animales crónicamente tratados con cualquiera de los abridores de canales de potasio. El mismo efecto fue observado cuando se inyectó la morfina al grupo tratado con una combinación de morfina y cualquiera de los abridores de canales de potasio. CONCLUSIONES: Por consiguiente, este estudio sugiere que tanto la morfina como los abridores de canales de potasio son tolerantes cruzados. Sin embargo, tal interacción ocurre a nivel de los canales de potasio más bien que a nivel de los receptores.

Noncompetitive inhibitors of the acetylcholine receptor help paint a picture of its ion channel

This review describes and analyzes the evidence from studies using noncompetitive inhibitors of the nicotinic acetylcholine receptor that the receptor's ion channel is formed by the second transmembrane segment of all five receptor subunits. Inconsistencies in this generally accepted model are also presented and discussed

Potassium channel opening drugs and the airways

1. Potassium channel opening drugs (KCOs) include benzopyrans such as cromakalim, cyanoguanidines such as pinacidil and tetrahydrothiopyrans such as RP 49356. 2. While clinical trials have indicated that cromakalim may be of benefit in the treatment of nocturnal asthma, it remains to be determined whether KCOs will find a place in our armamentarium of clinically useful anti-asthma agents. 3. KCOs inhibit the spontaneous tone of airways smooth muscle in vitro, an action associated with membrane hyperpolarization towards the potassium equilibrium potential and with the promotion of 86Rb+ or 42K+ efflux from the muscle cells. KCOs suppress spasm of airways smooth muscle evoked by low (< 40 mM) but not high (> 40 mM) concentrations of KCl. Their relaxant effects in airways smooth muscle can be attenuated by a variety of agents (including sulphonylureas) known to inhibit the opening of plasmalemmal K(+)-channels. 4. The KCOs open an ATP-sensitive K(+)-channel (KATP) in the plasmalemma. KATP is not open under normal circumstances and does not play an important role in determining the strong outward rectifying behavior of the cell membrane. The biochemical mechanisms by which the KCOs promote the opening of KATP remain to be elucidated but probably do not involve channel phosphorylation consequent to the intracellular accumulation of cAMP. 5. By causing hyperpolarization of the plasmalemma, the KCOs inhibit the cellular influx of Ca2+ through voltage-dependent channels. Relaxation follows both as a direct consequence of the fall in cytosolic free Ca2+ and also as a consequence of reduced production of phosphoinositide second messengers. The KCOs may also inhibit Ca2+ uptake by, and hence Ca2+ release from, the sarcoplasmic reticulum. 6. KCOs can inhibit cholinergic and non-adrenergic, non-cholinergic (NANC) excitatory neuroeffector transmission in the airways by glibenclamide-sensitive mechanisms which may involve inhibition of neurotransmitter release. The KCOs do not attenuate NANC inhibitory neuroeffector transmission, suggesting that KATP may not be expressed in neurones of this type. 7. The active enantiomer of cromakalim has been found to be effective in alleviating nocturnal asthma at plasma concentrations just threshold for relaxing human airways smooth muscle in vitro. The clinical efficacy of cromakalim may therefore depend on an action other than the direct relaxation of airways smooth muscle. Animal studies indicate that KCOs can reduce airway hyper-reactivity at sub-bronchodilator doses. The mechanism of this effect remains to be elucidated and may not crucially depend upon inhibition of neurotransmitter release within the lung

Benzodiazepine receptor ligand influences on learning: an endogenous modulatory mechanism mediated by benzodiazepines possibly of alimentary origin

In rats pre-but not post-training ip administration of either flumazenil, a central benzodiazepine (BSD) receptor antagonist, or of n-butyl-B-carboline-carboxylate (BCCB), an inverse agonist, enhanced retention of inhibitory avoidance learning. Flumazenil vlocked the enhancing effect of BCCB, and the inhibitory effect of the BZD agonists clonazepam and diazepam also given pre-training. Post-training administration of these drugs had no effects. The peripheral BZD receptor agonist/chloride channel blocker Ro5-4864 had no effect on the inhibitory avoidance task when given ip prior to training, buth it caused enhancement when given immediately post-training either ip or icv. This effect was blocked by PK11195, a competitive antagonist of Ro5-4864. These results suggest that ther is an endogenous mechanism mediated by BZD agonists, which is sensitive to inverse agonists and that normally down-regulates the formation of memories through a mechanism involving GABA-A receptors and the corresponding chloride channels. The most likely agonists for the endogenous mechanism suggested are the diazepam-like BZDs found in brain whose origin is possibly alimentary. Levels of these BZDs in the cortex were found to sharply decrease after inhibitory acoidance training or mere exposure to the training apparatus.