Retinopatía asociada a inhibidor de la proteinquinasa de activación mitogénica (MEKAR). A propósito de un caso / Mitogen-activated protein kinase inhibitor-associated retinopathy (MEKAR). A clinical case

Los inhibidores de la proteína quinasa de activación mitogénica (MEK) son fármacos utilizados para el tratamiento de neoplasias tales como el melanoma metastásico. Su introducción ha mejorado el pronóstico de estas enfermedades, pero su uso no está exento de complicaciones oculares. Se ha descrito una retinopatía asociada a estos fármacos (MEKAR) consistente en la aparición de desprendimientos neurosensoriales (DNS), generalmente bilaterales y múltiples similares a los que aparecen en la coriorretinopatía serosa central (CSC). En la mayoría de los casos la tomografía de coherencia óptica es suficiente para diferenciar esta entidad de una CSC. Presentamos el caso de una paciente de 55 años que, en este contexto, desarrolló DNS bilaterales que asociaron disminución de agudeza visual y que se resolvieron cuando se suspendió la terapia por progresión tumoral (AU)

Mitogen-activated protein kinase kinase (MEK) inhibitors have significantly improved the prognosis of various types of cancer such as metastatic melanoma. However, their use is usually associated with ocular side effects. A retinopathy associated with these agents (MEKAR) has been described, consisting of the development of neurosensory detachments, generally bilateral and multiple, similar to those that appear in the central serous chorioretinopathy (CSC). Generally, optical coherence tomography allows us to differentiate the two conditions. We present the case of a 55-year-old woman in treatment with a MEK inhibitor, who developed bilateral neurosensory detachments and blurred vision, which resolved with the discontinuance of the treatment due to tumour progression (AU)

Calphostin C as a rapid and strong inducer of apoptosis in human coronary artery smooth muscle cells.

Vascular smooth muscle cells (VSMCs) play a major role in the development of atherosclerotic and restenotic lesions. The apoptotic process has been implicated in the development of this pathology. In this study, we characterized the induction of apoptosis by calphostin C (CC), a protein kinase C (PKC) inhibitor, in primary human coronary artery smooth muscle cells in the presence and absence of insulin-like growth factor-I (IGF-I). Additionally, we investigated the signal transduction pathways important for IGF-I mediated protection. Calphostin C induced apoptosis, as measured by terminal deoxy-UTP nick-end labeling (TUNEL), in a time- and dose-dependent manner, approaching 20% within 6 h of 50 nM calphostin C treatment. The amount of apoptosis increased to 44.58+/-8.08%, 47.54+/-1.66% and 78.1+/-11.9% after 8, 10 and 12 h of treatment, respectively (p<0.01 vs. control). IGF-I offered significant protection (p<0.05) at 8 and 10 h of treatment (60.6% and 52.5% protection, respectively). DNA ELISA confirmed the apoptotic effect of calphostin C and the protective effect of IGF-I. After 6 h of calphostin C treatment, DNA ELISA revealed 11.20+/-1.53 fold greater apoptosis as compared to baseline values. IGF-I treatment offered a level of protection of 46.6% as measured by DNA ELISA (p=0.06). Apoptosis was further qualitatively confirmed by time-lapse video microscopy and scanning electron microscopy. Interestingly, inhibitors of phosphatidylinositol-3-kinase (PI-3-K), p38 and extracellular regulated kinase (ERK) activation significantly (p<0.05 vs. calphostin C only treatment) increased apoptosis when used in conjunction with calphostin C. Inhibitors of phospatidylinositol-3-kinase and ERK activation reversed IGF-I protection. However, the p38 inhibitor SB203580 failed to reverse IGF-I protection. This study characterized an apoptotic system for human coronary artery smooth muscle cells offering a rapid and strong induction of programmed cell death (PCD) that remains responsive to the survival effects of IGF-I. Studies utilizing this system may prove useful in understanding the apoptotic response of VSMCs in the arterial wall.

Contribution of 5- and 12-lipoxygenase products to mechanical hyperalgesia induced by prostaglandin E(2) and epinephrine in the rat.

We evaluated the role of lipoxygenase products of arachidonic acid metabolism in mechanical hyperalgesia induced by epinephrine, an agent that directly sensitizes nociceptors to produce mechanical hyperalgesia via three second messenger signaling pathways, protein kinase A (PKA), protein kinase C epsilon (PKCepsilon), and mitogen activated protein kinase (MAPK). Epinephrine hyperalgesia and that induced by a selective activator of PKCepsilon, psiepsilonRACK, were inhibited by nordihydroguaretic acid (NDGA, non-selective lipoxygenase inhibitor), baicalein (BAIC, 12-lipoxygenase inhibitor) and 5, 6-dehydroarachidonic acid (5, 6-dhAA, 5-lipoxygenase inhibitor). NDGA and 5, 6-dhAA inhibited the hyperalgesia associated with activation of the protein kinase A pathway, elicited by the direct-acting hyperalgesic agent prostaglandin E(2) or by the catalytic subunit of protein kinase A. The hyperalgesia produced by active MAPK was not blocked by any of the lipoxygenase inhibitors. Injection of 5- and 12-lipoxygenase produced hyperalgesia that was not antagonized by inhibitors of PKA, PKCepsilon or MAPK. These findings suggest that: (1). lipoxygenase products of arachidonic acid function as second messengers in the peripheral hyperalgesia induced by agents that act directly on primary afferent nociceptors (epinephrine and prostaglandin E(2)), (2). products of the 5-lipoxygenase and 12-lipoxygenase pathway are involved in this function, and (3). these lipoxygenase products contribute to hyperalgesia at or downstream of protein kinase A and PKCepsilon.