ABSTRACT
Drug reaction with eosinophilia and systemic symptoms (DRESS) is an infrequent, but severe, adverse drug-induced reaction which occurs due to massive T-cell stimulation resulting in cytotoxicity and eosinophil activation and recruitment. The incidence is 0.4 cases per 100, 0000 in the general population; the mortality rate is up to 10%. Therefore, we believe that recognizing this syndrome is of particular importance. The problem we notice is that DRESS is often seen and described in patients receiving rheumatologic or anticonvulsant drugs, but very rarely in psychiatric hospitals, where Clozapine is frequently used, and that is the importance of this paper. DRESS Syndrome must be recognized promptly, and causative drugs withdrawn. Indeed, it has been reported that the earlier the drug withdrawal, the better the prognosis. In this paper, we present three cases of Clozapine-induced DRESS. All cases were recorded in the Multicenter Drug Safety Surveillance Project (AMSP).
Subject(s)
Anticonvulsants/adverse effects , Clozapine/adverse effects , Drug Hypersensitivity Syndrome/etiology , Aged , Depression/drug therapy , Female , Humans , Male , Middle AgedABSTRACT
Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.
Subject(s)
Behavior, Addictive/chemically induced , Dopamine Antagonists/adverse effects , Flupenthixol/adverse effects , Gambling/chemically induced , Adult , Behavior, Addictive/psychology , Depressive Disorder, Major/complications , Depressive Disorder, Major/drug therapy , Dopamine Antagonists/administration & dosage , Flupenthixol/administration & dosage , Gambling/psychology , Humans , Male , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/drug therapyABSTRACT
Previous studies suggested that pro-apoptotic stimuli may trigger a fatal reactivation of cell cycle elements in postmitotic neurons. Supporting this hypothesis, small molecule inhibitors of cyclin-dependent kinases (CDKs), which are known primarily as cell cycle regulators, are neuroprotective. However, available CDK inhibitors cannot discriminate between the different members of the CDK family and inhibit also CDK5, which is not involved in cell cycle control. Testing a new class of CDK inhibitors, we find that inhibitory activity against CDK5, but not cell cycle-relevant CDKs, confers neuroprotection. Moreover, we demonstrate that cleavage of the CDK5 activator protein p35 to p25 is associated with CDK5 overactivation after focal cerebral ischemia, but not in other models used in this study. We find that blocking CDK5 activity, but not caspase inhibition, protects mitochondrial integrity of lesioned neurons. Thus, in our models, CDK5, rather than cell cycle-relevant CDKs, activates neuronal cell death pathways upstream of mitochondrial dysfunction, and inhibition of CDK5 may promote functional long-term rescue of injured neurons. Moreover, we present the first CDK5-selective small molecule inhibitor, lacking unwanted cytostatic effects due to cross-inhibition of mitotic CDKs.
Subject(s)
Apoptosis/drug effects , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Mitochondria/drug effects , Neurons/drug effects , Animals , Apoptosis/physiology , Brain Ischemia/drug therapy , Brain Ischemia/enzymology , Buthionine Sulfoximine/pharmacology , Buthionine Sulfoximine/therapeutic use , Cell Death/drug effects , Cell Death/physiology , Cyclin-Dependent Kinase 5 , Cyclin-Dependent Kinases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/therapeutic use , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mitochondria/enzymology , Necrosis , Neurons/enzymology , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
Recently, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) rescues retinal ganglion cells (RGCs) from retrograde cell death in vivo after axotomy of the optic nerve. The mechanism of RGC rescue was dependent on TNF-receptor I-mediated potassium current reduction and consecutive activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. Here, we present evidence that interleukin-1 beta (IL-1 beta) also promotes RGC survival, but shows distinct differences with respect to its neuroprotective mechanisms. Using whole-cell and outside-out patch-clamp techniques, we observed that IL-1 beta decreased both inward sodium current amplitudes and outward potassium current amplitudes. Counteracting these effects by sodium or potassium channel opening inhibited the survival-promoting effects of this cytokine. IL-1 beta-induced current reduction could not be abolished by the interleukin-1 receptor antagonist, indicating that the electrophysiological effects of IL-1 beta are independent of interleukin-1 receptor I (IL-1RI) activation. Western blot analysis revealed an IL-1 beta-induced IL-1RI-dependent upregulation of phospho-Akt. Antagonism of the survival-promoting effects of IL-1 beta by PI3-K inhibition revealed the functional relevance of the PI3-K/Akt pathway in IL-1 beta-induced signal transduction in vivo.
