Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

Social instability in female rats: the relationship between stress-related and anxiety-like consequences.

It is generally believed that anxiety and depression develop in response to stressful events that chronically increase glucocorticoid production (which in turn affects various neurotransmitter systems). In contrast to depression, however, the relationship between chronic stress and anxiety is less clear, as anxiety patients often show normal glucocorticoid levels and respond normally to dexamethasone challenge. Here we report on the interaction between symptoms of chronic stress and anxiety in female rats by making use of the social instability model of anxiety. Subjects were exposed to alternating 24 h periods of isolation and moderate crowding for 14 days. Symptoms of chronic stress and anxiety-like behaviour in the social interaction test were evaluated on the 15th day, i.e. 1 day after the last crowding phase. Social instability resulted in decreased weight gain, and chronically elevated plasma glucocorticoid levels only in rats that showed high aggressiveness during the crowding phases. In contrast, anxiety-like behaviour was increased irrespective to crowding-related aggressiveness. Thus, the development of chronic stress symptoms and anxiety-like behaviour dissociated: the former was bound to crowding-induced aggressiveness (i.e. to a higher stress load), whereas the latter occurred also when such aggressiveness was low, and symptoms of chronic stress did not develop. This finding is consistent with human data, and suggests that stressful events lead to anxiety in both cases: when stressors do or do not lead to chronic stress responses. Studying the distinctive features of anxieties associated or not with chronic endocrine stress responses would enhance our understanding of this disorder.

Stress-induced social avoidance: a new model of stress-induced anxiety?

We have studied the long-term behavioral effects of a single stressor in male rats by using an approach/avoidance situation as the behavioral endpoint. A single exposure to social defeat or electric shocks was used as stressors. Behavioral testing was performed in a two-compartment cage divided by an opaque wall and connected by a short tunnel. The larger compartment contained an unfamiliar male rat that was separated from the rest of the compartment by a transparent, perforated Plexiglas wall. The subject was placed in the small compartment and allowed to explore the cage for 5 min. The test was performed on Days 1, 5, or 10 after stress application. Unstressed rats spent 90% of time in the large compartment that contained the unfamiliar male. Social defeat dramatically reduced the exploration of the large compartment, without time-related changes in this response. A mild electric shock had a similar effect that lasted more than 5 days but less than 10 days. The exploration of an empty cage was significantly less inhibited by stress than the exploration of a cage that contained the stimulus rat. The test could be applied repeatedly in the same rat, without major changes in the response. Chlordiazepoxide applied 1 h before behavioral testing abolished completely the stress-induced behavioral deficit. We suggest that the model can be used for studying the effects of various compounds on stress-induced anxiety.

[Second generation non-sedative antihistaminics]. / Második generációs, nonszedatív antihisztaminok.

In the 1980's a new group of antihistamines was developed, which has got, besides its increased efficiency, fewer by effects. Considering their pharmacokinetic characteristics and effects, the requirements the modern second generation antihistamine should meet, can be summarized as follows: the modern antihistamine should be selective, peripheral H1 receptor antagonist, should have a low affinity to the H1 receptors of the brain, be void of antikolinerg and antiserotonin effect, should stabilize the membrane of the mastocytes and/or have an impeding effect on eosinophil accommodation. The introduction of modern, second generation antihistamines was started by terfenadin in 1985, and was followed by astemizole, loratadine and cetirizine in 1988. The author gives a thorough survey of the pharmacokinetic characteristics of the second generation antihistamines and their clinical importance.

[Immunopathologic disorders in atopic dermatitis]. / Immunpatológiai eltérések atópiás dermatitisben.

The atopic dermatitis is a multifactorial inheritable disease, in which pathogenesis in addition to environmental factors (climate, allergens, clothing) genetically determined multiplex metabolic differences (arachidonic acids, essential fatty acids) and immunologic alterations play an important role. Within immunologic findings the disturbances of balance in Th1 and Th2 subclasses, the increased degranulation activity of mast cells and the increased antigen presentation activity of Langerhans cells can be stressed. The clinical immunological alterations shown in the diseases, the increased production of IgE and so the type I. allergic reactions (urticaria, gastrointestinal manifestation of food allergy, allergic rhinitis, asthma bronchiale), the difference of cellular immunity of the skin can be explained by the above mentioned main immunological changes. In understanding of immunological origin of atopic dermatitis the IgE receptors expressed on the surface of Langerhans cells (connecting the immediate and delayed type of immune response) mean significant help.

[Treatment of atopic dermatitis]. / Az atopiás dermatitis terápiája.

The authors give a survey of the treatment of atopic dermatitis with respect to its extent and severity. Our knowledge about the immunopathology of the disease altered during the past years and thus it was possible to use new medicines. The most important one among them is Cyclosporin A, which is a selective immunosuppressive drug. It effectively decreases the symptoms of atopic dermatitis by blocking T cells which were already activated. Because of the serious side-effects of Cyclosporin A (nephrotoxicity, hypertension) it can only be applied when no other local or systemic treatment proves to be effective. Even a short application of the medicine improves not only the quality of patient's life but also the long-term outcome of the disease.

[Cross reactivities between food antigens of plant or animal origin]. / Növényi és állati eredetú táplálékok közötti allergiás keresztreakciók.

Knowledge about cross reactivities among food proteins of plant or animal origin is getting more and more important. Cross reaction provoking often clinical symptoms may be based on close taxonomical relations or on the presence of "archaic", ubiquiter protein structures preserved during phylogenesis. The most significant cross reactivities characterized by increasing incidence are between pollens and foods of plant origin and between latex and fruits.

[Immunologic studies in chronic urticaria]. / Immunológiai vizsgálatok chronicus urticariában.

Chronic urticaria is considered to be a heterogeneous disease, which can be divided into several subclasses. The authors investigated 126 patients suffering from chronic urticaria with 41 of unknown origin. The aim of the present study was to work out a strategy for the complete investigation of patients with chronic urticaria. The findings of the immunological study modified the results obtained by medical assessment of the 126 chronic urticaria cases, diminished the number of the patient with chronic urticaria unknown etiology.

[Chronic urticaria]. / A chronicus urticaria vizsgálata.

66 patients with chronic urticaria were examined using a three-stage examination protocol. Stage I. consisted of case history, general dermatological and internal physical examination and routine laboratory tests. Stage II. comprised investigation for focal infections (dental, oto-laryngeal, gynecological, bile culture), determination of AST, acidity tests of the stomach and aimed radiological examinations. Stage III. consisted of immunological laboratory tests (immune complex, Igs, IgE, special IgE determination) and allergological examinations (epicutaneous, intracutaneous probes, Prick test).

Stress, social avoidance and anxiolytics: a potential model of stress-induced anxiety.

We investigated the social behavioural effects of a single exposure to either social defeat or electric shocks, using the recently developed social avoidance test in rats. The testing apparatus consisted of two connected chambers, one of which contained an unfamiliar male confined in a sub-chamber by a perforated Plexiglas wall. The subjects were placed in the empty chamber and, after 3 min of habituation, were allowed to explore the apparatus for 5 min. The latency, frequency and duration of visits made to the opponent-containing chamber were recorded. Both stressors reduced the exploration of the opponent-containing chamber for more than 5 days. The effects of electric shocks were not affected by housing conditions, whereas group housing protected rats from the long-term effects of defeat. In addition, the effects of social defeat in isolated rats lasted longer than the effects of electric shocks. These differences suggest that the two stressors have qualitatively different effects and may model different behavioural states in humans. In a second experiment, social avoidance induced by electric shocks was readily abolished by both chlordiazepoxide and buspirone. We suggest that the shock-induced social avoidance paradigm may become a useful model of stress-induced anxiety.

High prevalence of IgG and IgA antibodies to 19-kDa Helicobacter pylori-associated lipoprotein in chronic urticaria.

BACKGROUND: Chronic urticaria has been described in patients with Helicobacter pylori infection. We studied the titer of IgG and IgA type antibodies against H. pylori in patients with and without urticaria of unknown etiology. We also investigated the prevalence of antibodies against H. pylori-associated lipoprotein 20 (lpp20) in patients with and without chronic urticaria. METHODS: The concentration of anti-H. pylori antibodies (IgG and IgA) was determined by the RIDA test. The level of anti-lpp20 antibodies was determined by Western blot using various H. pylori antigens (from 19 to 120 kDa). RESULTS: Patients with chronic urticaria and H. pylori infection (subgroup 1, n = 33) had high IgG and IgA titers whereas all patients with chronic urticaria and without H. pylori infection (subgroup 2, n = 23) were seronegative (P = 0.0128 for IgG and P = 0.003 for IgA). Titers in subgroup 1 did not differ significantly from a control group (n = 33) with severe H. pylori-associated gastritis without urticaria. The prevalence of the anti-lpp20 antibodies was significantly higher in subgroup 1 compared to the control group (93.9 vs 21.2%, P < 0.0001 for IgG, and 46.1 vs 6.3%, P < 0.0029 for IgA). CONCLUSIONS: We suggest that IgG and IgA antibodies to H. pylori-associated lpp20 may play role in the pathogenesis of chronic urticaria.

The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety.

The aim of this study was to compare the effects of the genetic and pharmacological disruption of CB1 cannabinoid receptors on the elevated plus-maze test of anxiety. In the first experiment, the behaviour of CB1-knockout mice and wild-type mice was compared. In the second experiment, the cannabinoid antagonist SR141716A (0, 1, and 3 mg/kg) was administered to both CB1-knockout and wild type mice. Untreated CB1-knockout mice showed a reduced exploration of the open arms of the plus-maze apparatus, thus appearing more anxious than the wild-type animals, however no changes in locomotion were noticed. The vehicle-injected CB1-knockout mice from the second experiment also showed increased anxiety as compared with wild types. Surprisingly, the cannabinoid antagonist SR141716A reduced anxiety in both wild type and CB1 knockout mice. Locomotor behaviour was only marginally affected. Recent evidence suggests the existence of a novel cannabinoid receptor in the brain. It has also been shown that SR141716A binds to both the CB1 and the putative novel receptor. The data presented here supports these findings, as the cannabinoid receptor antagonist affected anxiety in both wild type and CB1-knockout mice. Tentatively, it may be suggested that the discrepancy between the effects of the genetic and pharmacological blockade of the CB1 receptor suggests that the novel receptor plays a role in anxiety.