Cell-based medicinal products approved in the European Union: current evidence and perspectives

Advanced Therapy Medicinal Products (ATMPs) are innovative clinical treatments exploiting the pharmacological, immunological, or metabolic properties of cells and/or gene(s) with the aim to restore, correct, or modify a biological function in the recipient. ATMPs are heterogeneous medicinal products, developed mainly as individualized and patient-specific treatments, and represent new opportunities for diseases characterized by a high-unmet medical need, including rare, genetic and neurodegenerative disorders, haematological malignancies, cancer, autoimmune, inflammatory and orthopaedic conditions. Into the European Union (EU) market, the first ATMP has been launched in 2009 and, to date, a total of 24 ATMPs have been approved. This review aims at reporting on current evidence of cell-based therapies authorized in the EU, including Somatic Cell Therapies, Tissue Engineering Products, and Cell-based Gene Therapy Products as Chimeric Antigen Receptor (CAR) T-cells, focusing on the evaluation of efficacy and safety in clinical trials and real-world settings. Despite cell-based therapy representing a substantial promise for patients with very limited treatment options, some limitations for its widespread use in the clinical setting remain, including restricted indications, highly complex manufacturing processes, elevated production costs, the lability of cellular products over time, and the potential safety concerns related to the intrinsic characteristics of living cells, including the risk of severe or life-threatening toxicities, such as CAR-T induced neurotoxicity and cytokine release syndrome (CRS). Although encouraging findings support the clinical use of ATMPs, additional data, comparative studies with a long-term follow-up, and wider real-world evidences are needed to provide further insights into their efficacy and safety profiles

Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood

Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes 9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21 deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous 9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands

Aspetti regolatori dello sviluppo clinico di un nuovo prodotto medicinale

Il seminario è stato promosso da Fase 1 e Sardegna Ricerche, fa parte di una serie di incontri volti a dare un quadro generale sulle principali tematiche inerenti lo sviluppo preclinico e clinico di nuovi farmaci. In particolare, questa seconda sessione ha visto la partecipazione di esperti dell'ISS per gli aspetti normativi dello sviluppo preclinico e una lezione di approfondimento sui requisiti necessari all’avvio della sperimentazione clinica nel campo della nutraceutica e degli alimenti a fini medici speciali.Lezione tenuta nell'ambito del seminario 'Aspetti regolatori nello sviluppo preclinico', si è incentrata sugli aspetti normativi dello sviluppo preclinico.2011-12-16Sardegna Ricerche, Edificio 2, Località Piscinamanna 09010 Pula (CA) - ItaliaAspetti regolatori nello sviluppo preclinico: dal candidato farmaco alla first in ma

A new iridoid diglycoside from Sambucus ebulus L

The phytochemical examination of the polar constituents of Sambucus ebulus L. leaves led to the identification of patrinoside (1) and of a new diglycoside iridoid, patrinoside-aglycone-11-O-[b-D-glucopyranosyl-(1!6)-20-deoxy-b-D-glucopyranoside] (trivially named as sambuloside) (2). Both of these structures have been assigned by spectroscopic means (NMR and MS)

In vitro relaxant and spasmolytic effects of constituents from Viburnum prunifolium and HPLC quantification of the bioactive isolated iridoids

Ethnopharmacological relevance: Viburnum prunifolium is a North America shrub used in ethnomedicine because of its spasmolytic, sedative, and anti-asthmatic properties. Aim of the study: Contrasting results were reported in past literature about the active principles of this plant. Our aim was to clarify this matter by evaluating the relaxant and spasmolytic activities of the main constituents obtained from the drug. Materials and methods: The pharmacological assays were carried out on rabbit jejunum spontaneous contractions and on guinea-pig carbachol-precontracted trachea. Results: Cumulative concentration (1-100 μg/ml) of Viburnum prunifolium methanolic extract (MeOH extract), its purified fractions soluble in ethylacetate (EtOAc fraction) and in n-butanol (BuOH fraction), and the iridoid glucosides (2 × 10-5 to 4 × 10-4 M): 2′-O-acetyldihydropenstemide (1), 2′-O-trans-p-coumaroyldihydropenstemide (2), 2′-O-acetylpatrinoside (3), and patrinoside (4), isolated from EtOAc fraction (1 and 2) and BuOH fraction (3 and 4), induced both relaxant effect of rabbit jejunum spontaneous contractions and spasmolytic effect on guinea-pig carbachol (5.5 × 10-7 M)-precontracted trachea. Propranolol (10-6 M) antagonised all Viburnum prunifolium tested components relaxant and spasmolytic effects. At non-relaxing concentrations (0.5 μg/ml), MeOH extract and its fractions induced a potentiating effect of isoprenaline cumulative concentrations also in both isolated tissues. Conclusion: In both tissues, the order of potency was EtOAc fraction > BuOH fraction > MeOH extract and 1 > 2 > 3 > 4 suggesting that the major iridoids of EtOAc fraction may be considered among the most active compounds. HPLC analysis of the bioactive iridoids indicates that 1 and 2 are present for 7.38% and 14.90% in EtOAc fraction, and 3 and 4 for 18.47% and 8.86% in BuOH fraction. By comparing the values of EC50 of the fractions and compounds isolated from them, we may assume that the iridoids play a significant role in the biological activity of the corresponding fractions. © 2009 Elsevier Ireland Ltd. All rights reserved

Relaxant effects of Hydrastis canadensis L. and its major alkaloids on guinea pig isolated trachea

Hydrastis or goldenseal, one of the most popular medicinal herbs in the U.S.A., is used in mild pathological conditions Like cold and flu, based on the pharmacological properties of its active components, berberine (anticholinergic, antisecretory, and antimicrobial) and Beta-hydrastine (astringent). We previously reported the relaxant effect of a total ethanolic extract of hydrastis on carbachol precontracted isolated guinea pig trachea, and with the present study, using the same experimental model, we aimed at evaluating the contribution of its major alkaloids, berberine, Beta-hydrastine, canadine and; canadaline to the total effect. Furthermore, using specific pharmacological tools, like timolol and xanthine amine congener, we attempted to elucidate its mechanism of action. The ECS, of berberine, beta -hydrastine, canadine and canadaline, went 34.2+/-0.6, 72.8+/-0.6, 11.9+/-1.2 and 2.4+/-0.8 mug/ml, respectively. Timolol effectively antagonized the effect of canadine (EC50=19.7+/-3.0 mug/ml) and canadaline (EC50=17.1+/-1.2 mug/ml) but not that of berberine and Beta-hydrastine, while xanthine amine congener antagonized the effect of beta -hydrastine (EC50=149.9+/-35.3 mug/ml) and canadaline (EC50=26.1+/-3.0 mug/ml) but not that of berberine and canadine. Besides, the hydrastis extract, at concentrations between 0.01 and 0.1 mug/ml, potentiated the relaxant effect of isoprenaline on carbachol-precontracted isolated guinea pig trachea. These data, which are insufficient to draw definite mechanistic conclusions, indicate that the aforementioned alkaloids may act by interacting with adrenergic and adenosinic receptors

A new iridoid diglucoside from Antirrhinum siculum

A new iridoid diglucoside has been isolated from an ethanolic extract of Antirrhinum siculum, together with five-known compounds. Its structure has been assigned as 5-O-glucopyranosyl-7-hydroxyharpagide by spectroscopic means

Phytochemical analysis of Viburnum davidii Franch. and cholinesterase inhibitory activity of its dihydrochalcones

One flavonoid (quercetin, 1) and three dihydrochalcones (6’’-O-phydroxybenzoyl-davidioside, 2, 4’-O-methyl-davidioside, 3, and davidioside, 4) were isolated from the leaves and young branches of Viburnum davidii Franch. All the structures were identified by comparison of their spectroscopic data (NMR and MS) with those present in literature. In addition, compounds 2–4 were evaluated for their cholinesterase inhibitory (ChEI) activity, for the first time. Accordingly, compounds 2 and 4 showed significant inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values equal to 36.883 and 39.274 mM, respectively for the former and 39.504 and 43.101 mM, respectively for the latter

New cholinesterase inhibiting bisbenzylisoquinoline alkaloids from Abuta grandifolia

The phytochemical study of the stem bark and wood of Abuta grandifolia (Mart.) Sandwith led to the identification of four bisbenzylisoquinoline alkaloids (BBIQs), namely (R,S)-2 N-norberbamunine (1), (R,R)-isochondodendrine (2), (S-S)-O4 ''-methyl, Nb-nor-O6 '-demethyl-(+)-curine (3), and (S-S)-O4 ''-methyl, O6 '-demethyl-(+)-curine (4), together with the aporphine alkaloid R-nomuciferine (5), all obtained by countercurrent distribution separation (CCD) and identified on the basis of their spectroscopic data. Alkaloids 3 and 4 were new. All the isolated compounds were tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. 1 was the most active against AChE, whereas 3 and 4 were the most potent against BChE. interestingly, all tested alkaloids are more potent against BChE than against AChE. This selectivity of cholinesterase (ChE) inhibition could be important in order to speculate on their potential therapeutic relevance. (C) 2012 Elsevier B.V. All rights reserved