Original biotechnology medicines and biosimilars - what one should know to provide safety of treatment?

Leki wytwarzane metodami biotechnologicznymi odgrywają obecnie główną rolę w farmakoterapii wielu chorób, zwłaszcza tych, w których tradycyjne leki chemiczne były dotychczas nieskuteczne. Onkologia stanowi jedną z głównych dziedzin, w których stosuje się biofarmaceutyki. Obecnie dostępne leki biotechnologiczne uważa się za bezpieczne i bardzo dobrze tolerowane, a typowe dla tej grupy preparatów zawierających białka i polipeptydy reakcje immunologiczne są rzadkie. W związku z wygasaniem w ostatnich latach ochrony patentowej leków biotechnologicznych pierwszej generacji (w tym wielu czynników wzrostu) należy oczekiwać stopniowego pojawiania się w lecznictwie leków biotechnologicznych naśladujących leki oryginalne. Określa się je nazwą leków biopodobnych (lub biofarmaceutyków naśladowczych). Wymagania w procesie rejestracji leków biopodobnych zostały już wstępnie określone przez dyrektywę Komisji Europejskiej i wytyczne Europejskiej Agencji ds. Oceny Produktów Medycznych (EMEA), jednak obecnie brakuje podobnych uregulowań prawnych na szczeblu krajowym zarówno w krajach europejskich (poza Francją), jak i w Stanach Zjednoczonych. Niniejsze wprowadzenie do problematyki leków biopodobnych przeznaczone jest dla praktykujących lekarzy, którzy niedługo staną przed wyborem oryginalnego bioleku i leku biopodobnego. W pracy podkreślono ważne i mające praktyczne znaczenie różnice pomiędzy preparatami biopodobnymi i tradycyjnymi lekami generycznymi oraz podano kryteria bezpieczeństwa terapii, zasady śledzenia działań niepożądanych, możliwości automatycznej zamiany leków zachodzącej na poziomie aptek, zasady nazewnictwa i oznaczania leków uzyskiwanych metodami biotechnologicznymi i ich preparatów naśladowczych.Biotechnology medicines play a major role in modern pharmacotherapy. They have already helped to fight many diseases which were recognized as incurable in the previous era of conventional chemical drugs. Oncology remains one of the leading areas for the current and future clinical application of biotechnology medicines. Biotech drugs are generally safe and well-tolerated and adverse reactions typical for biological products such as immunogenicity are rare. Recently, the expiry of patent protection for many original biotech drugs (including most recombinant growth factors) has led to the development of products known as biosimilars or follow-on-biologics. Detailed regulations for the approval of biosimilar products have been recently introduced by the European Medicines Agency (EMEA, in full name: European Agency for the Evaluation of Medicinal Products ) but all European countries, except France and the US, lack the national approval pathways on this new kind of biomedicines. This review provides an introduction to the issue of biosimilars revealing the differences between biosimilars and traditional chemical generics as well as potential problems including safety, pharmacovigilance, automatic substitution, naming, labeling and prescription rules

BcsA and BcsB form the catalytically active core of bacterial cellulose synthase sufficient for in vitro cellulose synthesis

[EN] Cellulose is a linear extracellular polysaccharide. It is synthesized by membrane-embedded glycosyltransferases that processively polymerize UDP-activated glucose. Polymer synthesis is coupled to membrane translocation through a channel formed by the cellulose synthase. Although eukaryotic cellulose synthases function in macromolecular complexes containing several different enzyme isoforms, prokaryotic synthases associate with additional subunits to bridge the periplasm and the outer membrane. In bacteria, cellulose synthesis and translocation is catalyzed by the inner membrane-associated bacterial cellulose synthase (Bcs)A and BcsB subunits. Similar to alginate and poly-β-1,6 N-acetylglucosamine, bacterial cellulose is implicated in the formation of sessile bacterial communities, termed biofilms, and its synthesis is likewise stimulated by cyclic-di-GMP. Biochemical studies of exopolysaccharide synthesis are hampered by difficulties in purifying and reconstituting functional enzymes. We demonstrate robust in vitro cellulose synthesis reconstituted from purified BcsA and BcsB proteins from Rhodobacter sphaeroides. Although BcsA is the catalytically active subunit, the membrane-anchored BcsB subunit is essential for catalysis. The purified BcsA-B complex produces cellulose chains of a degree of polymerization in the range 200–300. Catalytic activity critically depends on the presence of the allosteric activator cyclicdi- GMP, but is independent of lipid-linked reactants. Our data reveal feedback inhibition of cellulose synthase by UDP but not by the accumulating cellulose polymer and highlight the strict substrate specificity of cellulose synthase for UDP-glucose. A truncation analysis of BcsB localizes the region required for activity of BcsA within its C-terminal membrane-associated domain. The reconstituted reaction provides a foundation for the synthesis of biofilm exopolysaccharides, as well as its activation by cyclic-di-GMP.SIThis work was primarily supported by The Center for LignoCellulose Structure and Formation, Energy Frontier Research Center, US Department of Energy, Office of Science, Grant DE-SC0001090 and in part (BcsB truncation studies) by NIH Grant 1R01GM101001 (awarded to J.Z.). V.B. and H.M. were supported by the Royal Institute of Technology (KTH) Advanced Carbohydrate Materials Consortium (CarboMat) funded by the Swedish Research Council Formas

Two- and three-dimensional transvaginal ultrasound in assessment of the impact of selected obstetric risk factors on cesarean scar niche formation: the case-controlled study

Objectives: Incomplete healing of the uterine scar after cesarean section may result in formation of a niche. The aim of this study is to identify the potential risk factors for the improper uterine healing after cesarean section in women with single layer, full thickness uterine closure with the use of two- and three-dimensional transvaginal ultrasonography.Material and methods: 204 women with a history of at least one low transverse cesarean section (CS) with a single layer uterine closure participated in the study. Residual myometrial thickness (RMT), adjacent myometrial thickness (AMT), width (W), depth (D) and volume of the niche, RMT/AMT, RMT/D, RMT/W ratio and clinical characteristics were analyzed.Results: A niche after cesarean section was found in 153 cases. However only five patients had a RMT < 2.2 mm, and 35 had an RMT/AMT ratio ≤ 0.5. The RMT and RMT/AMT ratio among women who had undergone more than one cesarean section was lower than among women who underwent the first cesarean section. No statistically significant relationship was found between the incidence of niche, its parameters and cervical dilation, uterine contractions, cesarean section in the second stage of labor, type of uterus incision expansion and flexion, operator’s experience.Conclusion: Healing of the uterine cesarean section scar in women with single-layer continuous suture covering the entire thickness of the myometrium, excluding the decidua is not affected by the mode of caesarean section, type of uterine incision expansion and flexion, operator’s experience, stage of labor at the time of caesarean section

The analgesic efficiency of transversus abdominis plane (TAP) block after caesarean delivery

Objectives: The ultrasound-guided transversus abdominis plane (TAP) block is a supporting method of pain relief after different types of surgical and gynecological procedures. The aim of the present study was to evaluate the analgesic effects of the TAP-block in patients undergoing caesarean section. Material and methods: 88 women undergoing elective caesarean section under spinal anaesthesia were prospectively randomized into two groups. In the first group, an ultrasound-guided bilateral TAP block was performed using 40 mL 0.25% bupivacaine, while the second group was treated without a regional nerve block. Both groups received a standard analgesia protocol with intravenous paracetamol administered every 6 hours and intravenous tramadol on-demand, delivered using the Patient Controlled Analgesia (PCA) method. Pain intensity was assessed according to the visual analogue scale (VAS) directly after the TAP block and at 3, 6 and 12 hours postoperatively. Any patient complaints and side-effects during the postoperative period were recorded. Results: The TAP block resulted in a significant reduction of pain intensity using the visual analogue scale after 3, 6 and 12 hours (p < 0.05) and a significant decrease in tramadol administration (p < 0.05) during the first 12 hours postoperatively. No significant differences in the heart rate and blood pressure were noted between groups (p > 0.05). There were no complications related to the TAP block. Conclusions: The TAP block is a safe and effective adjunctive method of pain relief after caesarean delivery

The role of crisis management in organisations functioning in COVID-19 pandemic conditions

The purpose of the paper is to analyse the influence of crisis management on job performance as well as indicate a mechanism, which supports such influence. The theoretical model was proposed based on a literature review, showing the role of organisational trust, organisational communication, knowledge sharing, job security and openness to change in shaping job performance by crisis management among organisations operating under COVID-19 pandemic conditions. The model was empirically verified based on a sample of 1,160 organisations operating in Poland, Italy and the USA during an active wave of the pandemic in 2021. The obtained results allow to confirm that crisis management significantly positively influences the job performance of employees in organisations operating under the dynamic and turbulent COVID-19 pandemic conditions. Moreover, such influence was proven to be mediated by organisational trust, organisational communication, knowledge sharing, job security and finally – openness to change. The performed analysis fills in the existing research gap and constitutes and important contribution to the field of crisis management. The results show that in order for crisis management to bring benefits to the entire organisation, employees need to go beyond the routines of their behavior and efficiently adapt to the changed conditions of the organisation. The openness to change becomes a de facto enabler of that. The obtained results also have practical implications, showing the mechanism through which crisis management impacts individual employees, allowing organisations to stimulate each factor and contributing to the possibility of ensuring more benefits coming from implementing crisis management

Influence of Intra-Organizational Trust on Organizational Outcomes

Nowadays, trust is perceived as one of the key factors that can build an organization's competitive advantage, increase the efficiency of its functioning and ability to develop. It can be expected that shaping trust in an organisation will lead to improvements in various aspects of its functioning, especially effectiveness. This issue has not yet been the object of comprehensive scientific research. Hence, this study tackles the issue of the impact of trust on an organization's outcomes. At the same time, two basic categories of trust are distinguished: global (attitudinal/affective) trust (regarding the belief that people in general are trustworthy) and specific (situational/cognitive) trust (modified by an individual's experience). In the latter category, we may distinguish between vertical trust (concerning superior-subordinate relations) and lateral trust (concerning relations between co-workers). The relation between the level of trust and organizational outcomes is examined for each of these categories of trust. The research covers organisations functioning in Poland and is based on a questionnaire. (original abstract

Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity

Microglia, the resident immune cells of the brain, play important roles in defending the brain against pathogens and supporting neuronal circuit plasticity. Chronic or excessive pro-inflammatory responses of microglia damage neurons, therefore their activity is tightly regulated. Pharmacological and genetic studies revealed that cannabinoid type 1 (CB1) receptor activity influences microglial activity, although microglial CB1 receptor expression is very low and activity-dependent. The CB1 receptor is mainly expressed on neurons in the central nervous system (CNS)—with an especially high level on GABAergic interneurons. Here, we determined whether CB1 signaling on this neuronal cell type plays a role in regulating microglial activity. We compared microglia density, morphology and cytokine expression in wild-type (WT) and GABAergic neuron-specific CB1 knockout mice (GABA/CB1−/−) under control conditions (saline-treatment) and after 3 h, 24 h or repeated lipopolysaccharide (LPS)-treatment. Our results revealed that hippocampal microglia from saline-treated GABA/CB1−/− mice resembled those of LPS-treated WT mice: enhanced density and larger cell bodies, while the size and complexity of their processes was reduced. No further reduction in the size or complexity of microglia branching was detected after LPS-treatment in GABA/CB1−/− mice, suggesting that microglia in naïve GABA/CB1−/− mice were already in an activated state. This result was further supported by correlating the level of microglial tumor necrosis factor α (TNFα) with their size. Acute LPS-treatment elicited in both genotypes similar changes in the expression of pro-inflammatory cytokines (TNFα, interleukin-6 (IL-6) and interleukin 1β (IL-1β)). However, TNFα expression was still significantly elevated after repeated LPS-treatment in WT, but not in GABA/CB1−/− mice, indicating a faster development of tolerance to LPS. We also tested the possibility that the altered microglia activity in GABA/CB1−/− mice was due to an altered expression of neuron-glia interaction proteins. Indeed, the level of fractalkine (CX3CL1), a neuronal protein involved in the regulation of microglia, was reduced in hippocampal GABAergic neurons in GABA/CB1−/− mice, suggesting a disturbed neuronal control of microglial activity. Our result suggests that CB1 receptor agonists can modulate microglial activity indirectly, through CB1 receptors on GABAergic neurons. Altogether, we demonstrated that GABAergic neurons, despite their relatively low density in the hippocampus, have a specific role in the regulation of microglial activity and cannabinoid signaling plays an important role in this arrangement

Usunięcie jajników podczas zabiegu histerektomii z przyczyn nieonkologicznych – bilans korzyści i strat

Usunięcie macicy to jedna z najczęstszych interwencji chirurgicznych w ginekologii. Zazwyczaj wskazaniami dozabiegu są schorzenia łagodne. Podczas każdego zabiegu histerektomii chirurg staje przed decyzją co do losujajników — w wielu przypadkach są one usuwane jednocześnie w ramach profilaktyki raka jajnika. W piśmiennictwiemożna znaleźć argumenty wskazujące na istotność tej decyzji wobec dowodów na hormonalną aktywnośćgonad także po menopauzie, niskie ryzyko rozwoju procesu złośliwego w populacji ogólnej i możliwe konsekwencjeustania czynności hormonalnej jajników w wyniku interwencji chirurgicznej. Z drugiej strony grupa pacjentekz podwyższonym ryzykiem raka jajnika, jajowodu i otrzewnej może odnieść niewątpliwą korzyść z wycięcia gonadpodczas zabiegu histerektomii

Ultrasonographic analysis of cesarean scars features in nonpregnant uterus

Abstract Objectives: To define and assess the new ultrasonographic parameters of cesarean hysterotomy scars and to analyze their variation depending on the number of cesarean sections. Material and methods: Transvaginal ultrasound was carried out among 109 patients after cesarean section in the lower uterine segment with single-layer uterine closure. The following cesarean hysterectomy scar parameters were assessed: angle of the apex (K), basis (P) and height (W) of the anechoic triangle, the thickness of the knit tissue scar segment (G), G/P index and G/W index. Results: Transvaginal ultrasound detected the cesarean hysterectomy scar in 100% of the examined woman. In 5,5% of cases the completely knit hysterectomy scar tissue was identified. All patients from this group underwent a single cesarean section. In the remaining 94,5% of women, the ultrasound detected a presence of the anechoic triangle, defined as scar defect. No difference of statistical importance considering assessed scar parameters was observed between the groups of patients after one and two cesarean sections. The decrease of the thickness of the knit tissue scar segment (G) in the group of patients after three cesarean, sections in comparison to the group of patients after single (1,3 mm vs 6,7 mm, p=0,0134) and two (1,3 mm vs 7,4 mm, p=0,0366) abdominal deliveries, was found, as well as statistically important decrease in G/P index value in the group of patients after three cesarean sections in comparison to the patients after one (0,3 vs 1,3, p=0,0263) and two cesarean sections (0,3 vs 1,2, p=0,0138). Conclusions: The new ultrasonographic parameters to assess the cesarean hysterectomy scar in nonpregnant uterus were introduced. Statistically important decrease in the thickness of the knit tissue scar segment (G) and G/P index value in the group of patients after three cesarean sections in comparison to the group of patients after single and two abdominal deliveries was revealed