Ewa Bałkowiec-Iskra

Tumor necrosis factor inhibitors – state of knowledge

Tumor necrosis factor (TNF) is considered a major proinflammatory cytokine, affecting various aspects of the immune reaction. All five TNF inhibitors currently available on the market (i.e., etanercept, infliximab, adalimumab, certolizumab and golimumab) are top sellers, although indicated only in autoimmune diseases, including rheumatoid arthritis, Crohns disease and psoriasis. This article briefly discusses the background and place for TNF inhibitors in modern therapy. The main safety aspects of TNF inhibitor administration are described in particular, with special consideration of the available meta-analyses. Finally, perspectives on the next-generation TNF inhibitors and their use in the clinic are given.

TNF inhibitors – Mechanisms of action, approved and off-label indications

Tumor necrosis factor inhibitors (TNFi) belong to the group of biologic drugs, holding presently top positions on lists of most profitable products for pharmaceutical companies. Although current indications for TNFi include only selected diseases with an established role of immune dysfunction in their pathogenesis, studies on new indications are being carried out all over the world. The most important aspect of TNFi therapy is a targeted therapeutic approach, allowing to avoid a wide range of side effects associated with treatment with nonspecific immunosuppressive agents. Results of the trials on TNFi in the approved indications are widely accessible and analyzed elsewhere, both in primary publications as well as in systematic reviews and meta-analyses. Here we aim to discuss their mechanisms of action, and approved, as well as off-label indications of TNFi. In addition, we present comprehensive evidence on TNFi in treatment of rheumatoid arthritis (RA); the first authorized and probably most extensively developed indication for the majority of TNFi.

Targeting of calcitonin gene-related peptide action as a new strategy for migraine treatment

Migraine is a chronic, recurrent disorder, characterized by attacks of severe pain, affecting around 1% of adult population. Many studies suggest, that trigeminovascular system plays a key role in pathogenesis of migraine and other primary headaches. Calcitonin gene-related peptide (CGRP) is an endogenous substance, which is regarded a key mediator released from trigeminovascular system after stimulation of sensory nerve endings, responsible for dilatation of peripheral vessels and sensory transmission. CGRP is and extensively studied peptide as one of the most promising targets in migraine drug research. In the article we focus on the role of CGRP in the pathophysiology of migraine and present current data on CGRP antagonists and CGRP monoclonal antibodies.

Regulatory and clinical aspects of psychotropic medicinal products bioequivalence

Introduction of generic medicinal products to the market has increased access to modern therapies but also enabled significant reduction in their cost, leading to containment of public expenditures on medicinal products reimbursement. The critical assessment of bioequivalence of any reference medicinal product and its counterpart is based on comparison of their rate and extent of absorption. It is assumed that two medicinal products are bioequivalent when their rate and extent of absorption do not show significant differences when administered at the same dose under similar experimental conditions. Bioequivalent medicinal products are declared to be also therapeutically equivalent and can be used interchangeably. However, despite regulatory declaration, switching from reference to generic drugs is often associated with concerns of healthcare providers about decreased treatment effectiveness or occurrence of adverse drug reactions. The aim of this article is to provide a description of rules that guide registration of generic medicinal products in the European Union and to analyze specific examples from the scientific literature concerning therapeutic equivalence of reference and generic antidepressant and antipsychotic medicinal products.

The Role of Monoamine Oxidase in Humans and Its Metabolism

PSYCHIATRIC ANNALS • Vol. 44, No. 11, 2014 495 ABSTRACT Monoamine oxidase (MAO) isoenzymes A and B are mitochondrial-bound proteins that catalyze the oxidative deamination of dietary amines and monoamine transmitters. Others include: serotonin, epinephrine, 2-phenylethylamine, and dopamine. MAOs can potentially modulate all the processes involving bioactive amines, including regulation of mood, emotional behavior, and other brain function. MAO enzymatic activity plays a role in the pathophysiology of a wide range of mental and neurodegenerative disorders, including personality disorders, depressive syndromes, and Parkinson’s disease. Similarly, the byproducts of MAO-mediated reactions include some chemical species that can cause mitochondrial damage leading to neurotoxicity, and can affect the function of other organs such as the heart. In this article, genetic variations, anatomical distribution, and physiological functions of MAO-A and MAO-B are described. [Psychiatr Ann. 2014;44(11):495-501.]

Bioequivalence and therapeutic equivalence of psychotropic drugs

Introduction to the market of generic drugs has increased access to modern therapies and enabled significant reduction of their cost, leading to containment of public expenditures on drug reimbursement. The assessment of bioequivalence of reference and generic drugs is based on the assumption that two different drug products are equivalent when their rate and extent of absorption do not show significant differences when administered at the same dose under similar experimental conditions. However, despite regulatory declaration, switching from reference to generic drugs is often associated with concerns of healthcare providers about decreased treatment effectiveness or occurrence of adverse drug reactions. The aim of the present research was to retrospectively study therapeutic equivalence of selected reference and generic psychotropic drugs. In our preliminary data we show, that no significant differences in clinical outcome was observed in patients after the switch. It indicates, that bioequivalent drugs are also therapeutically equivalent and can be used interchangeably.

Inhibition of TNF reduces mechanical orofacial hyperalgesia induced by Complete Freund’s Adjuvant by a TRPV1-dependent mechanism in mice

BACKGROUND Inflammation in the orofacial region results in pain and is associated with many pathological states, including migraine, neuralgias and temporomandibular disorder. Although extensively studied, the mechanisms responsible for these conditions are not known and effective treatments are lacking. We reported earlier that the proinflammatory cytokine tumor necrosis factor (TNF) plays an important role in regulation of trigeminal ganglion (TG) neuron function in vitro. In the present study we investigated the role of TNF in mechanical hypersensitivity in mice. METHODS We employed the Complete Freunds Adjuvant (CFA)-induced model of orofacial pain and evaluated the effect of blocking of soluble TNF activity by peripheral administration of the novel dominant negative TNF biologic, XPro1595. RESULTS We show that CFA administration into the lower lip causes hyperalgesia and an increase in both expression of transient receptor potential vanilloid subfamily member 1 (TRPV1) mRNA and in the average intensity of TRPV1 protein immunoreactivity in TG neurons. We also show that intraperitoneal administration of XPro1595 prevents both CFA-induced mechanical hypersensitivity and, as shown in immunohistochemical staining - upregulation of TRPV1 protein expression in TG neurons. CONCLUSIONS We conclude that one of the possible regulatory mechanisms of TNF in pain involves upregulation of the nociceptor TRPV1, and that peripheral treatment with a selective anti-soluble TNF biologic can prevent hyperalgesia caused by inflammation in the orofacial region. Therefore, these new findings suggest that XPro1595 may serve as a novel treatment for orofacial pain disorders.

Effect of antidepressants use in pregnancy on foetus development and adverse effects in newborns

Over the last few years, several reports on the safety of antidepressants use in pregnancy have been published. Studies concerning the adverse effects of exposure to selective serotonin reuptake inhibitors (SSRI) during pregnancy on the developing foetus have indicated an increased risk of various congenital malformations and untoward effects such as poor neonatal adaptation syndrome or persistent pulmonary hypertension, but there still remain inconsistencies between various study results. This paper aims at reviewing the literature on the risks of exposure to antidepressants during pregnancy. SSRIs are generally considered as first-line antidepressant treatment in pregnancy, as they are generally safe and effective. To minimize the teratogenic risks, pregnant women should receive the minimal effective dose of the medication. Depression during pregnancy must not be left untreated, and it should also be remembered that the condition may extend into the postpartum period.

Review/Praca poglądowaBioequivalence and therapeutic equivalence of psychotropic drugsRównoważność biologiczna i terapeutyczna leków psychotropowych

Objective It is the objective of this paper to discuss the requirements that must be met by generic drugs and explain basic concepts relating to bioequivalence. The authors have also included two tables listing the trading names of antidepressants and antipsychotics, with a valid authorization for marketing in Poland, which might prove helpful in daily psychiatric practice.

Assessment of Generic Psychotropic Drugs Therapy Costs in Poland

Provision of cost-effective drug treatment is of particular importance in patients with psychiatric diseases. Most of the therapies in question requires life-long treatment and consists of more than one medicine. Introduction of generic drugs is one of the major strategies for reducing contribution of costs of medications to total healthcare costs. The primary evidence required both by FDA and EMA for marketing approval of a new generic drug is acceptable bioequivalence between the generic drug product and its corresponding reference product. The price of the generic drug is estimated to be 25% lower comparing with the reference product. In the present study a comprehensive cost analysis of a two-year psychotropic drug treatment in one of high reference Polish psychiatric hospitals has been performed. The total real costs have been compared with predictable costs of treatment with reference products if used instead of the available generic drugs. Our study due to the comprehensive analysis of both the availability and costs of psychotropic medicinal products in Poland.