Current treatment goals are achieved by the majority of patients with atopic dermatitis treated with tralokinumab: results from a multicentric, multinational, retrospective, cohort study.

BACKGROUND: Tralokinumab is a human monoclonal antibody targeting interleukin-13 that is approved for the treatment of moderate-severe atopic dermatitis. Studies analyzing the efficacy and safety of tralokinumab in a real-world setting are scarce. RESEARCH DESIGN AND METHODS: A European, multicentric, real-world, retrospective cohort study was defined to assess the effectiveness and safeness profile of tralokinumab, investigating the achievement of pre-specified treatment goals; and to detect potential differences in terms of effectiveness and safeness across some selected patient subcohorts. RESULTS: A total of 194 adult patients were included in this study. A significant improvement in physician-assessed disease severity was detected at each follow-up visit as compared with baseline and similar trend was observed for patient-reported outcomes and quality of life. No meaningful difference in effectiveness was found when considering patient age (<65 versus ≥65 years), neither dissecting patient cohort in dupilumab-naive vs dupilumab-treated subjects. Among tralokinumab-treated patients, 88% achieved at least one currently identified real-world therapeutic goal at week 16. CONCLUSIONS: This retrospective multicenter study confirmed the effectiveness and safeness of tralokinumab throughout 32 weeks of observation, showing the achievement of therapeutic goals identified in both trial and real-world settings in a large proportion of tralokinumab-treated patients.

Dupilumab-associated ocular adverse events are predicted by low tear break-up time and correlate with high IL-33 tear concentrations in patients with atopic dermatitis.

Dupilumab, blocking IL-4 and IL-13 signals, improves atopic dermatitis and Quality of Life but might be also associated with the occurrence of ocular adverse events (OAEs). The main objective of our prospective study was to characterize the cytokine and chemokine profile in the tear fluid of dupilumab-treated patients with moderate-to- severe atopic dermatitis and to identify biomarkers predicting the occurrence of ocular adverse events. Patients with moderate-to-severe AD underwent dermatological and ophthalmological evaluation at the baseline (T0) and week 16 or at the time of an eventual ocular adverse events (T1). A multiplex immunoassay measuring multiple cytokines and chemokines in the tear fluid extracted during ocular examination at both T0 and T1 was performed. Thirty-nine patients with moderate-to-severe AD and treated with dupilumab were included in the study. Baseline tear fluid levels revealed a significantly higher concentration of type 2 cytokines and chemokines in AD patients than healthy controls. The occurrence of ocular adverse events during dupilumab therapy was associated with a significant increase of IL-33 tear fluid levels and a significantly lower tear break-up time, this latter also identified as predictive factor. Our findings suggest that the ophthalmological examination should be considered a valid support to identify patients at risk of developing OAEs and to provide their appropriate management.

Behavioural and electrocortical changes induced by paraquat after injection in specific areas of the brain of the rat.

The behavioural and electrocortical effects of paraquat were studied after its administration into the substantia nigra, pars compacta, an area where dopamine-(DA) containing cell bodies are present, into the caudate nucleus, where DA-containing nerve endings of the DA nigro-striatal system project, into the locus coeruleus, an area containing noradrenaline cell-bodies and into the n. raphe dorsalis or into the n. raphe medianus, two nuclei containing serotonin (5-HT) cell bodies. The intraventricular administration of paraquat (10 and 50 micrograms) produced an intense pattern of behavioural stimulation and an increase in locomotor activity, circling and the wet-dog syndrome. This symptomatology was accompanied by desynchronization of the electrocorticogram (ECoG) and the appearance of bilateral high voltage epileptogenic spikes, culminating in clonic convulsions. The infusion of paraquat into the s. nigra produced contralateral head and neck deviation, behavioural and motor stimulation, these effects being observed also with smaller doses (1 and 5 micrograms), than those used intraventricularly. The ECoG activity was desynchronized and characterized by high voltage spike discharges. A similar behavioural, postural and ECoG pattern was also observed after infusion of paraquat into the caudate nucleus (10, 25 and 50 micrograms). In addition, paraquat, infused into the locus coeruleus or into the raphe nuclei (5 and 10 micrograms), produced circling, escape responses, jumping and clonic convulsions accompanied by ECoG desynchronization and epileptic phenomena. In conclusion, the present experiments showed that paraquat was able to produce central neurotoxicological effects which did not seem to be specific, at least for the doses used, for the DA nigro-striatal system.

Replacement therapy against increased hydroxyurea toxicity in pituitary or adrenal ablated rats.

The main rat adrenocortical hormone, corticosterone, the mineralocorticoid, 11-deoxycorticosterone (DCA) acetate given alone or together (2:1 ratio) twice daily at doses of 2-4 and 1-8 mg/kg, DCA enanthate given in a single injection of 20 mg/kg 0-3 days before the beginning of the experiments and a highly-concentrated injectable extract of the adrenal cortex (4 mg/kg as hydrocortisone twice a day) given by the intramuscular route, delay and partially protect against the increased toxicity following administration of the anticancer drug, hydroxyurea (800 mg/kg/day for 5 days) in adrenalectomized or hypophysectomized animals (80-100% lethality; in control non ablated rats 0-10% lethality). ACTH1-24 (tetracosactide) also proved effective in pituitary ablated rats. The best protection was afforded with the joint administration of corticosterone and DCA (2-4 and 1-2 mg/kg twice a day) or with corticosterone alone at doses (4 mg/kg twice a day) capable of giving plasma levels, six hours after administration on the third day, similar to those observed in non ablated rats receiving HYD in the morning. The adrenocortical hormones may replace a possible unique defense mechanism against drug toxicity, which is lacking in pituitary or adrenal ablated rats.

Long-lasting hypothermic effects of vincristine in rats.

The effects of vincristine given intravenously on deep and superficial body temperature were assessed in rats kept at ambient temperature within the thermoneutral range. Vincristine (0.5 and 1 mg/kg i.v.) produced a gradual but marked hypothermic response which was dose-dependent, reached its maximum after approximately 3 h and lasting approximately 48 h. Vincristine induced a decrease in deep body temperature which was accompanied by piloerection and a decrease in skin temperature. Pretreatment with phentolamine, an alpha-adrenoceptor blocking agent (0.5 mg/kg i.v. 15 min before) prevented the hypothermic effects induced by subsequent administration of vincristine (0.5 mg/kg i.v.). These experiments showed that vincristine produced a marked hypothermic response in rats. However, the precise site of action remains to be established.

Optic tectum adenylate cyclase activity from goldfish (Carassius auratus) as a model to assess dopamine receptor agonists and antagonists.

The distribution of adenylate cyclase activity in several discrete areas of brain in the goldfish (Carassius auratus) and the responsiveness of this activity in the optic tectum to various neurotransmitters were studied. Adenylate cyclase activity was found to have an uneven distribution in the brain, the highest concentrations occurring in the telencephalon. A dopamine-sensitive adenylate cyclase was found in the optic tectum. The increase in cAMP formation induced by dopamine was selectively prevented by antagonists at post-synaptic dopamine receptors linked to adenylate cyclase.

Comparative effects of indoprofen and indomethacin on rat hypothalamic prostaglandin-synthetase activity.

The inhibiting effects of indoprofen were compared with those of indomethacin on prostaglandin-synthetase activity in rat hypothalamus. A dose-dependent inhibition of PG-synthetase activity was obtained after intramuscular administration of both antiphlogistic agents; however, indoprofen was found more powerful. In conclusion, the present experiments provide additional evidence against the idea that pyrogen fever is due to the release of PG's of the E type within the hypothalamus since when comparing results obtained with the two antiphlogistic drugs used, no correlation exists between potency in inhibiting PG's synthesis and antipyretic activity.