Efficacy of canakinumab in patients with Still's disease across different lines of biologic therapy: real-life data from the International AIDA Network Registry for Still's Disease

Introduction: The effectiveness of canakinumab may change according to the different times it is used after Still's disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment.Methods: Patients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still's disease. Seventy-seven (51 females and 26 males) patients with Still's disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent.Results: No statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response (p =0.62), partial response (p =0.61), treatment failure (p >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy (p =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use (p =0.34), daily glucocorticoid dosage (p =0.47), or concomitant methotrexate dosage (p =0.43) at the last assessment during CAN treatment.Conclusion: Canakinumab has proved to be effective in patients with Still's disease, regardless of its line of biologic treatment

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies

Inhibitory action of neuroleptic drugs and serotonin on dopamine autoxidation and lipid peroxidation

1. Dopamine, like other catecholamines, is normally metabolized by the enzymes monoamino oxidase and catechol-ortho-methyl transferase but it can also undergo oxidation to potentially toxic products, that, in turn, can generate free radicals. 2. In the present paper the effect of neuroleptic drugs (chlorpromazine, trifluoperazine and clozapine) and serotonin on the in vitro oxidation of dopamine and on lipid peroxidation was examined. Serotonin, clozapine, chlorpromazine and trifluoperazine inhibit autoxidation of dopamine both at pH 7.4 and pH 8.5. Trifluoperazine appears more efficient than chlorpromazine while serotonin shows an inhibitory effect intermediate between those of trifluoperazine and chlorpromazine; clozapine has only a moderate effect. 3. The catalytic effect of trace metal seems irrelevant since chelating agents do not show any significant inhibition. 4. All the substances used show a strong antiperoxidative activity. 5. It is concluded that the molecular and biochemical properties of serotonin and neuroleptic drugs on brain dopamine autoxidation and lipid peroxidation could be related to their physiological and clinical effects on mental illness in general and schizophrenia in particular

Antioxidant properties of clozapine and related neuroleptics

The antioxidant properties of clozapine and other related molecules were evaluated with the crocin bleaching test both in aqueous and non-aqueous environment. The tests of microsomal lipid peroxidation and carbonyl formation were also used. In aqueous solution, chlorpromazine and trifluoperazine appear particularly effective in the bleaching of crocin, while serotonin has an efficacy intermediate between those of phenothiazines and clozapine. The latter drug, on the other hand, in a non-aqueous medium shows an antioxidant power comparable to that of butylated hydroxytoluene, indicating that its antioxidant properties are better expressed in a hydrophobic environment of the type present in a biological membrane. In fact, in lipid peroxidation induced in microsomal membranes, clozapine, chlorpromazine, trifluoperazine and serotonin act as very good antioxidants; at low concentrations, clozapine appears to be the most efficient after butylated hydroxytoluene. Similarly, all these compounds markedly inhibit protein carbonyl formation, clozapine being one of the most efficient. Thus, under different in vitro experimental conditions, the neuroleptic drugs chlorpromazine and trifluoperazine and the antipsychotic substance clozapine act as very effective antioxidants; this property might, at least in part, be responsible for the physiological and clinical effects observed in vivo

DECREASE OF SERUM MALONDIALDEHYDE IN PATIENTS TREATED WITH CHLORPROMAZINE

Malondialdehyde determination in serum from schizophrenic patients before and after treatment with chlorpromazine showed that, after treatment, patients had significantly lower values than before. The antioxidant properties of chlorpromazine can be related to its effect on the level of serum lipid peroxides and possibly to its neuroleptic action

Thioredoxin reductase: a target for gold compounds acting as a potential anticancer drugs.

The thioredoxin system plays a key role in regulating the overall intracellular redox balance. It basically comprises the small redox protein thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate, in its reduced form (NADPH), and thioredoxin reductase (TrxR), a large homodimeric selenzoenzyme controlling the redox state of thioredoxin. Details of the thioredoxin system are provided herein, particular emphasis being given to the protein chemistry of thioredoxin reductases. Several lines of evidence point out today that the thioredoxin system represents an effective "druggable" target for the development of new anticancer agents. Accordingly, a number of established anticancer agents were retrospectively found to be potent inhibitors of thioredoxin reductases and to induce severe oxidative stress. During the last decade a variety of gold compounds, either gold(I) or gold(III), were reported to manifest outstanding antitumor properties, forming a promising class of experimental anticancer agents. In turn, recent studies have revealed that several cytotoxic gold Compounds, either gold(I) or gold(III), are potent TrxR inhibitors. Details of their mechanism of selenoenzyme inhibition are currently under investigation, in our laboratory, and some new results will be anticipated here; notably, preferential gold targeting of active site selenolate could be experimentally supported. Based on the numerous experimental evidences now available, both at the molecular and cellular level, we propose that the relevant cytotoxic actions produced by gold compounds are mainly the result of potent inhibition of thioredoxin reductase; the alterations of mitochondrial functions, elicited by profound TrxR inhibition, would eventually lead to cell apoptosis. A general and unitary framework is thus offered to interpret the mode of action of cytotoxic gold compounds, according to which they should be primarily considered as antimitochondrial drugs. The peculiar properties of gold compounds highlighted in this review might be further exploited for the obtainment of newer and selective anticancer agents

Mitochondrial permeability transition and release of cytochrome c induced by retinoic acids.

Retinoic acids, structurally related to vitamin A, inhibit the in vitro proliferation of different types of normal and neoplastic cells. The effects of all-trans, 9-cis, and 13-cis retinoic acids were tested on mitochondria isolated from rat liver. All the compounds were able to induce the membrane permeability transition observed as swelling and decrease in membrane potential, but 13-cis retinoic acid appeared to be the most effective. The latter was also shown to stimulate the release of cytochrome c from mitochondria, suggesting a potential target of retinoids in the induction of cell apoptosis. Interestingly, EGTA and cyclosporin A, which strongly inhibit the permeability transition induced by 13-cis retinoic acid, were without effect on the release of cytochrome c from the mitochondrial intermembrane space

Effect of the intravenous anesthetic 2,6-diisopropylphenol on respiration and energy production by rat brain synaptosomes.

The sensitivity of the mitochondrial energy production system to propofol (DPP) has been investigated in rat brain synaptosomes. DPP at 0.8 mM concentration produced a partial inhibition of coupled respiration, an apparent decrease of the oxygen uptake stimulation induced by CCCP and a full inhibition of the mitochondrial ATP production by synaptosomes. Higher concentrations of DPP (1 mM) fully abolish uncoupler-dependent stimulation and at 1.3 mM DPP also coupled respiration is completely blocked. Similar results were obtained when dinitrophenol replaced CCCP and phenol or propylbenzene replaced DPP. The presence of the alkyl residues seems critical for the DPP effect. In the presence of 30 mM glutamate both respiration and ATP production are enhanced but DPP effects are similar to those obtained in the absence of glutamate

Correlation between fluidising effects on phospholipid membranes and mitochondrial respiration of propofol and p-nitrosophenols homologues

Nitrosopropofol (2-6-diisopropyl-4-nitrosophenol) has dramatic consequences for respiration, ATP synthesis and the transmembrane potential of isolated rat liver mitochondria at concentrations at which propofol (2-6-diisopropylphenol) does not cause any apparent effects. These results correlate well with the observation that nitrosopropofol is also a stronger perturbing agent of phospholipid membranes. In this paper we verify the possible biological activity of different phenols and nitrosophenols on mitochondrial respiration. We then discuss their interactions with phospholipid liposomes, studied with differential scanning calorimetry, spin labelling techniques and UV-Vis spectrophotometry, in order to obtain information on drug distribution and the modifications they impose on lipid bilayer. The results of the experiments performed on mitochondria and model membranes prove an interesting correlation between the effects of the molecules on both systems