Cardiac safety of second-generation H1 -antihistamines when updosed in chronic spontaneous urticaria

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism

Management of epilepsy in elderly

The prevalence of seizures and epilepsy in the elderly is generally underestimated. Epileptic seizures are not a rare occurrence in the elderly and their prevalence increases with age. The clinical manifestations of seizures, the aetiology, the treatment and the psychosocial impact of the epilepsy diagnosis may differ in the elderly. Differential diagnosis with episodes of unconsciousness and/or fall or other non-epileptic manifestations is often difficult. The presence of comorbidities, the polypharmatherapy and the age-related pharmacokinetic changes can represent a problem for the treatment of epilepsy in the elderly, with a higher risk of adverse effects and potentially inappropriate drug interactions. Epileptic seizures in the elderly can have semiological characteristics similar to those of other age groups. On the other hand, the richness of the electroclinical syndromes of childhood and adolescence is not found in the elderly, and, in particular, idiopathic generalized epilepsies are rarely expressed at this age. Symptomatic seizures related to acute structural injury or metabolic causes are particularly frequent. Therapy management of the elderly with an epileptic seizure should concern not only neurologists, but also general practitioners, geriatricians, and cardiologists, therefore involving a wide range of clinical specialties. This review aims to summarize the management of epilepsy in the elderly, reporting also differences in epidemiology, electroclinical features, aetiology and diagnostic procedures

Marine pharmacology in 2009-2011: marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action.

The peer-reviewed marine pharmacology literature from 2009 to 2011 is presented in this review, following the format used in the 1998–2008 reviews of this series. The pharmacology of structurally-characterized compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities were reported for 102 marine natural products. Additionally, 60 marine compounds were observed to affect the immune and nervous system as well as possess antidiabetic and anti-inflammatory effects. Finally, 68 marine metabolites were shown to interact with a variety of receptors and molecular targets, and thus will probably contribute to multiple pharmacological classes upon further mechanism of action studies. Marine pharmacology during 2009–2011 remained a global enterprise, with researchers from 35 countries, and the United States, contributing to the preclinical pharmacology of 262 marine compounds which are part of the preclinical pharmaceutical pipeline. Continued pharmacological research with marine natural products will contribute to enhance the marine pharmaceutical clinical pipeline, which in 2013 consisted of 17 marine natural products, analogs or derivatives targeting a limited number of disease categories

Changes in Frontoparietotemporal Connectivity following Do-As-I-Do Imitation Training in Chimpanzees (Pan troglodytes)

Human imitation is supported by an underlying ‘mirror system’ principally composed of inferior frontal (IF), inferior parietal (IP), and superior temporal (ST) cortical regions. Across primate species, differences in fronto-parieto-temporal connectivity have been hypothesized to explain phylogenetic variation in imitative abilities. However, if and to what extent these regions are involved in imitation in non-human primates is unknown. We hypothesized that ‘Do As I Do’ (DAID) imitation training would enhance white matter integrity within and between fronto-parieto temporal regions. To this end, four captive chimpanzees (Pan troglodytes) were trained to reproduce 23 demonstrated actions, while four age/sex-matched controls were trained to produce basic husbandry behaviors in response to manual cues. Diffusion tensor images were acquired before and after 600 minutes of training over an average of 112 days. Bilateral and asymmetrical changes in fronto-parieto-temporal white matter integrity were compared between DAID trained subjects and controls. We found that imitation trained subjects exhibited leftward shifts in both mean fractional anisotropy and tract strength asymmetry measures in brain regions within the mirror system. This is the first report of training-induced changes in white matter integrity in chimpanzees and suggests that fronto-parieto-temporal connectivity, particularly in the left hemisphere, may have facilitated the emergence of increasingly complex imitation learning abilities

Signaling pathways mediating a selective induction of nitric oxide synthase II by tumor necrosis factor alpha in nerve growth factor-responsive cells

BACKGROUND: Inflammation and oxidative stress play a critical role in neurodegeneration associated with acute and chronic insults of the nervous system. Notably, affected neurons are often responsive to and dependent on trophic factors such as nerve growth factor (NGF). We previously showed in NGF-responsive PC12 cells that tumor necrosis factor alpha (TNFα) and NGF synergistically induce the expression of the free-radical producing enzyme inducible nitric oxide synthase (iNOS). We proposed that NGF-responsive neurons might be selectively exposed to iNOS-mediated oxidative damage as a consequence of elevated TNFα levels. With the aim of identifying possible therapeutic targets, in the present study we investigated the signaling pathways involved in NGF/TNFα-promoted iNOS induction. METHODS: Western blotting, RT-PCR, transcription factor-specific reporter gene systems, mutant cells lacking the low affinity p75NTR NGF receptor and transfections of TNFα/NGF chimeric receptors were used to investigate signalling events associated with NGF/TNFα-promoted iNOS induction in PC12 cells. RESULTS: Our results show that iNOS expression resulting from NGF/TNFα combined treatment can be elicited in PC12 cells. Mutant PC12 cells lacking p75NTR did not respond, suggesting that p75NTR is required to mediate iNOS expression. Furthermore, cells transfected with chimeric TNFα/NGF receptors demonstrated that the simultaneous presence of both p75NTR and TrkA signaling is necessary to synergize with TNFα to mediate iNOS expression. Lastly, our data show that NGF/TNFα-promoted iNOS induction requires activation of the transcription factor nuclear factor kappa B (NF-κB). CONCLUSION: Collectively, our in vitro model suggests that cells bearing both the high and low affinity NGF receptors may display increased sensitivity to TNFα in terms of iNOS expression and therefore be selectively at risk during acute (e.g. neurotrauma) or chronic (e.g. neurodegenerative diseases) conditions where high levels of pro-inflammatory cytokines in the nervous system occur pathologically. Our results also suggest that modulation of NFκB-promoted transcription of selective genes could serve as a potential therapeutic target to prevent neuroinflammation-induced neuronal damage

Minor Phytocannabinoids: A Misleading Name but a Promising Opportunity for Biomedical Research

Despite the very large number of phytocannabinoids isolated from Cannabis (Cannabis sativa L.), bioactivity studies have long remained focused on the so called "Big Four" [Δ9-THC (1), CBD (2), CBG (3) and CBC (4)] because of their earlier characterization and relatively easy availability via isolation and/or synthesis. Bioactivity information on the chemical space associated with the remaining part of the cannabinome, a set of ca 150 compounds traditionally referred to as "minor phytocannabinoids", is scarce and patchy, yet promising in terms of pharmacological potential. According to their advancement stage, we sorted the bioactivity data available on these compounds, better referred to as the "dark cannabinome", into categories: discovery (in vitro phenotypical and biochemical assays), preclinical (animal models), and clinical. Strategies to overcome the availability issues associated with minor phytocannabinoids are discussed, as well as the still unmet challenges facing their development as mainstream drugs

A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability

Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early-onset epilepsies with wide phenotypic expression, ranging from Benign Familial Neonatal Seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic EEG and neuroradiological features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early-onset epilepsy and neurocognitive deficits segregated with a novel mutations in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity

Activation of Kv7 potassium channels inhibits intracellular Ca2+ increases triggered by TRPV1-mediated pain-inducing stimuli in F11 immortalized sensory neurons

Kv7.2-Kv7.5 channels mediate the M-current (IKM), a K+-selective current regulating neuronal excitability and representing an attractive target for pharmacological therapy against hyperexcitability diseases such as pain. Kv7 channels interact functionally with transient receptor potential vanilloid 1 (TRPV1) channels activated by endogenous and/or exogenous pain-inducing substances, such as bradykinin (BK) or capsaicin (CAP), respectively; however, whether Kv7 channels of specific molecular composition provide a dominant contribution in BK- or CAP-evoked responses is yet unknown. To this aim, Kv7 transcripts expression and function were assessed in F11 immortalized sensorial neurons, a cellular model widely used to assess nociceptive molecular mechanisms. In these cells, the effects of the pan-Kv7 activator retigabine were investigated, as well as the effects of ICA-27243 and (S)-1, two Kv7 activators acting preferentially on Kv7.2/Kv7.3 and Kv7.4/Kv7.5 channels, respectively, on BK- and CAP-induced changes in intracellular Ca2+ concentrations ([Ca2+]i). The results obtained revealed the expression of transcripts of all Kv7 genes, leading to an IKM-like current. Moreover, all tested Kv7 openers inhibited BK- and CAP-induced responses by a similar extent (~60%); at least for BK-induced Ca2+ responses, the potency of retigabine (IC50~1 µM) was higher than that of ICA-27243 (IC50~5 µM) and (S)-1 (IC50~7 µM). Altogether, these results suggest that IKM activation effectively counteracts the cellular processes triggered by TRPV1-mediated pain-inducing stimuli, and highlight a possible critical contribution of Kv7.4 subunits