2,263 research outputs found
Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders
No full textThe discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with bipolar disorder and after five decades, lithium continues to be the mainstay of treatment for bipolar disorder. Recent research on the molecular mechanism underlying the therapeutic effect of lithium has focused on how it changes the activities of cellular signal transduction systems, especially the cyclic AMP and phosphomositide second-messenger systems. Considerable data suggest that carbamazepine and valproate (VPA) are an alternative or adjunctive treatment to lithium. VPA, despite being dissimilar structurally to lithium, shares most of the effects of lithium at the level of protein kinase C (PKC). Like lithium, VPA reduces the activity of PKC and reduces the protein levels of different PKC isoforms, however the effects of VPA appear to be largely independent of inositol. The ton-term efficacy of VPA and lithium in bipolar disorder suggested that modulation of gene expression might be an important target for these drugs. Both VPA and lithium altered the expression of the early inducible genes for c-fos and cjun thus promoting the expression of specific proteins. The genes known to be regulated by the AP-1 family of transcription factors include genes for various neuropeptides, neurotrophins, receptors, transcription factors, enzymes, proteins that bind to cytoskeletal elements, and cytoprotective proteins such as bcl-2. In conclusion chronic treatment with lithium and other mood stabilizers, by regulating transcriptional factors, may modulate the expression of a variety of genes that compensate for aberrant signalling associated with the pathophysiology of bipolar disorder
Tumors in invertebrates
No full textTumors are ectopic masses of tissue formed by due to an abnormal cell proliferation. In this review tumors of several invertebrate species are examined. The description of tumors in invertebrates may be a difficult task, because the pathologists are usually inexperienced with invertebrate tissues, and the experts in invertebrate biology are not familiar with the description of tumors. As a consequence, the terminology used in defining the tumor type is related to that used in mammalian pathology, which can create misunderstandings in some occasions
Biologically active peptides in molluscs
No full textThe immune and neuroendocrine systems of invertebrates, as well as vertebrates, share a common
pool of molecules that have been conserved throughout evolution. Now we add a new interface to this
bidirectional interaction, demonstrating the involvement of the gut system, showing that these three
systems use the same biologically active peptides
P.2.a.012 Co-administration of fluoxetine with acetylsalicylic acid, but not flurbiprofen or celecoxib, for one week shows an antidepressant-like effect
No full textIncreasing evidence is now demonstrating the involvement of the immune system and in particular of their effectors, cytokines, in the development and progression of depression. In particular, it is worth underlying how pro-inflammatory cytokines appear to be increased in blood or brain of patients with major depression (MD) and that pharmacological use of pro-inflammatory cytokines (i.e. interferon alpha) may induce MD. These data suggest a role for inflammation in the pathogenesis of depression and that anti-inflammatory drugs may be used as an adjunctive therapy in the treatment of MD. However, some studies reported contradictory results and suggest that adverse effects may contraindicate the use of anti-inflammatory agents in the treatment of depression. Nevertheless, non-steroidal anti-inflammatory drugs (NSAIDs) can have different mechanisms of action also depending on the dose. This is true for the therapeutic effects as well as for the unwanted side effects.
On this basis, the present study aimed at evaluating the behavioural effect of the co-administration of fluoxetine (FLX, 5 mg/kg i.p.) with different NSAIDs in the chronic escape model of depression (CED). The CED model of depression possesses face, construct and pharmacological validity and is based on the induction, and maintenance, of an escape deficit upon exposing rats to unavoidable stressors. We previously demonstrated that, in this model, the stress-induced impaired behaviour can be resolved by one week of treatment with the co-administration of FLX (5 mg/kg/i.p.) plus acetylsalicylic acid (ASA, 45 mg/kg i.p.) but not FLX alone [1]. Here we evaluated the effect of the co-administration of FLX and flurbiprofen (FLB, an inhibitor of Cox-1 and Cox-2, 5 mg/kg, p.o.) or celecoxib (CLX, a selective COX2 inhibitor, 5 mg/kg, p.o.) in the CED model after 7 days of treatment. The co-administration FLX plus ASA (45mg/kg i.p.) was used as a positive control. Morever we tested the behavioral effect of different doses (45, 22.5 and 11.25 mg/Kg i.p.) of ASA as potentiating agent of the effect of fluoxetine.
Our study shows that only the co-administration of ASA with FLX reverted the stress-induced condition of escape deficit after 7 days of treatment. Moreover, the amplitude of the antidepressant-like effect was dose dependent. The percentage of the antidepressant response was about 90%, 60% and 40% for animals receiving FLX (5 mg/kg/i.p.) plus ASA at the dose of 45, 22.5 or 11.25 mg/Kg i.p. respectively. Both flurbiprofen and celecoxib, when administered together with FLX for 7 days, failed to induce an antidepressant-like effects in the CED model. Higher dose of FLB (50 mg/Kg p.o.) and CLX (20 mg/Kg p.o.) were also tested, but they were associated to high mortality rate (80% and 25% respectively).
These data demonstrated that neither all NSAIDs, nor all doses, may be useful in the treatment of depression while adverse effects can be potentiated or induced by the co-administration with antidepressants. Unraveling the cellular and molecular mechanisms behind the dissimilar behavioral response elicited by different anti-inflammatory drugs can contribute to understand the role of inflammation in the etiopathogensis of MD and to improve patient care.
[1] Brunello, N., Alboni, S., Capone, G., Benatti, C., Blom, J.M., Tascedda, F., Kriwin, P., Mendlewicz, J., 2006 Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 21:227-31
Psicofarmacologia clinica
No full textIl volume raccoglie le acquisizioni più recenti sull'utilizzo clinico delle principali classi di psicofarmaci impiegati nella terapia delle patologie psichiatriche di più rilevante intersse sociale. Si divide in due sezioni principali: le classi di farmaci psichiatrici e i trattamenti psicofarmacologici. Nella Sezione I, per ogni molecola all'interno di una specifica classe, sono commentati i dati di studi preclinici e in fase clinica; inoltre, sono illustrati gli aspetti farmacodinamici e farmacocinetici, le indicazioni terapeutiche, i dosaggi, gli effetti collaterali e le interazioni con altri farmaci, psichiatrici e non psichiatrici. La Sezione II presenta lo stato dell'arte della terapia farmacologica nelle principali malattie psichiatriche. Gli autori descrivono, inoltre, la farmacoterapia in speciali popolazioni, come i bambini e gli adolescenti, i pazienti affetti da malattie sistemiche e gli anziani. Alcuni capitoli son infine dedicati alla psicofarmacoterapia in situazioni particolari, quali la gravidanza, l'allattamento e le emergenze. Particolare cura è stata posta nelladattare la descrizione delle singole molecole alla realtà italiana: sono stati inseriti alcini farmaci non in commercio negli Stati Uniti ma venduti in Italia; inoltre, laddove la legislazione del nostro Paese differisce da quella americana, si è provveduto a fornire indicazioni di sicuro riferimento per lo specialista italiano. Questo volume è una preziosa fonte di informazioni per psichatri, psicofarmacologi, neurologi, geriatri e specializzandi, nonché un valido strumento di approfondimento per gli studenti delle Facoltà di Medicina e Farmacia
Neither all anti-inflammatory drugs nor all doses are effective in accelerating the antidepressant-like effect of fluoxetine in an animal model of depression
No full textIntroduction: Non-steroidal anti-inflammatory drugs (NSAIDs) have been studied as possible adjunctive therapy in the treatment of depression. However, administering NSAIDs to increase the effectiveness of antidepressant has yielded inconsistent results. Methods: We evaluated the effect of the co-administration of fluoxetine (5 mg/kg) and flurbiprofen (5 mg/kg) or fluoxetine (5 mg/kg) and celecoxib (5 mg/kg) in the chronic escape deficit (CED) model of depression after 7 days of treatment. The co-administration of fluoxetine plus acetylsalicylic acid (ASA, 45 mg/kg i.p.) was used as a positive control. Moreover, we tested the behavioral effect of different doses (45, 22.5, and 11.25 mg/Kg i.p.) of ASA as potentiating agent of the effect of fluoxetine in the same paradigm. Results: Our study showed that only the co-administration of ASA with fluoxetine was able to revert the stress-induced condition of escape deficit after 7 days of treatment, and that the amplitude of the antidepressant-like effect of ASA was dose dependent. In the same experimental conditions, celecoxib with fluoxetine only partially resolved the stress-induced impaired behavior while flurbiprofen/fluoxetine cotreatment was ineffective. Limitations: Our study is still exploratory, more doses, longer treatment regimens, and different behavioral outcomes must be investigated to draw a clear conclusion. Conclusion: Our results further stress the importance of the type and dose when NSAIDs are associated with antidepressants to ameliorate a clinical response
Chronic antidepressant treatments resulted in altered expression of genes involved in inflammation in the rat hypothalamus
No full textTo gain insight into the possible immune targets of antidepressant, we evaluated the expression of several inflammatory mediators in the hypothalamus of rats chronically (28 days) treated with the serotonin selective reuptake inhibitor fluoxetine (5mg/kg, i.p.) or the tricyclic compound imipramine (15 mg/kg, i.p.). We focused our attention on the hypothalamus as it plays a key role in determining many of the somatic symptoms experienced by depressed patients. This brain region, critical also for expression of motivated behaviours, participates in the control of the hypothalamic-pituitary-adrenal axis activity and in stress response as well as coordinates physiological functions such as sleep and food intake that have been found altered in a high percentage of depressed patients. Notably, hypothalamus is a key structure for brain cytokine expression and function as it integrates signals from the neuro, immune, endocrine systems. By means of quantitative Real Time PCR experiments we demonstrated that a chronic treatment with either fluoxetine or imipramine resulted in a reduction of IL-6 and IFN-γ mRNAs and increased IL-4 mRNA expression in the rat hypothalamus. Moreover, we demonstrated that hypothalamic expression of members of IL-18 system was differentially affected by chronic antidepressant treatments. Chronically administered fluoxetine decreased IL-8 and CX3CL1 hypothalamic expression, while a chronic treatment with imipramine decreased p11 mRNA. Our data suggest that a shift in the balance of the inflammation toward an anti-inflammatory state in the hypothalamus may represent a common mechanism of action of both the chronic treatments with fluoxetine and imipramine
Regulation of NMDA receptor subunit mRNA expression in the rat brain during postnatal development
No full textDifferent NMDA receptor subunits have been recently cloned. The present paper describes the developmental profile of expression of the NR-1 subunit and three NR-2 subunits (A, B, C) in the rat central nervous system. A sensitive RNase protection assay was employed to determine simultaneously the mRNA levels of these receptor subunits. We found low levels of NR-1 mRNA (comprising all different splicing isoforms) in newborn rats with a progressive increase of its expression in the following 2–3 weeks. NR-2 subunits can be regarded as ‘modulatory’ since their expression can produce differences in the properties of NMDA receptors. More than one NR-2 subunits can be expressed in the same brain region. NR-2A and NR-2C are concomitantly expressed in the cerebellum and during development their mRNAs increase with a similar profile from low levels in P-8 rats to maximal expression in P-21 animals. NR-2A and NR-2B are concomitantly expressed in several brain regions with a different ontogenetic profile. In the hippocampus NR-2B mRNA increases rapidly during the first week of life as compared to the NR-2A subunits which at this time is expressed to low levels indicating that NR-2B will probably be dominant in determining the NMDA properties during the first period of life. Our data can provide a molecular correlate with properties of NMDA receptors such as voltage dependent Mg2+ block and deactivation kinetics which undergo significant changes during development and have been shown to depend upon the NR-2 subunit co-expressed with the common NR-1 subunit in various brain regions
Embracing the Healthcare Digital Revolution: pioneering an Ethical and Legal framework for Individual Participant Clinical Data Return
No full textThe exponential growth of qualitative and quantitative health data presents both unprecedented opportunities and challenges in pharmacology and clinical research. Within the realm of P4 medicine—embracing predictive, preventive, personalized, and participatory approaches—the healthcare digital revolution demands a trusted ethical, legal, and regulatory ecosystem for clinical trial data governance. Moreover, technological solutions are essential to support ethical data sharing and reuse.
Central to this revolution is the empowerment of patients, who need to play an active role in shaping the strategy and design of clinical trials, with newfound rights and responsibilities in clinical studies and drug development. Establishing a social alliance (Blom et al., 2023) among all study participants—patients, healthcare professionals, regulators, and pharmaceutical companies—is thus a primary objective in clinical research. In response to this need, the Innovative Medicine Initiative (IMI), launched the FACILITATE project two years ago, to establish a transparent and accountable framework for data sharing in clinical research across European Member States.
By fostering integrity, trustworthiness, inclusivity, and reciprocity, FACILITATE endeavors to ensure ethical, person-centered clinical research and navigate the complexities of building a robust social alliance during the digital healthcare revolution. Recognizing that the future of participatory clinical research hinges on cultivating and sustaining social alliances, and co-creation FACILITATE engages a multidisciplinary team from diverse sectors—including industry, academia, advocacy groups, non-profit organizations, and regulatory agencies. Through the creation of a roadmap that integrates legal, ethical, and technological considerations, FACILITATE is developing a social alliance adaptable to the evolving landscape of clinical research.
This initiative is responsive to the imperative for more efficient and ethical strategies for data sharing and participant protection. By putting patient participation at the center of the development of health research and giving them the confidence to shift from passive receivers of care to active, responsible, and conscious drivers of their own health, FACILITATE offers a concrete opportunity to modify the current healthcare paradigm and clinical and pharmacological research.
Due to the challenges posed by differing regulations across countries, the involvement of the pharmaceutical industry is essential to create a standardized approach that ensures that the return of individual participants' data and the reuse of data for future research is incorporated from the onset of the development of clinical studies and clearly communicated while guaranteeing privacy, security, and data integrity
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