The EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With at Least Two Tyrosine Kinase Inhibitors

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P=.029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence≥5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.</p

Supramolecular interactions between tolfenamic acid and various cyclodextrins: Effects of complexation on physicochemical and spectroscopic data

Tolfenamic acid is a non-steroidal inflammatory drug with associated gastrointestinal side-effects and problems with bioavailability. Furthermore, it is extremely insoluble in water. Tolfenamic acid was complexed with various cyclodextrins (β-CyD, HP-β-CyD, methyl-β-CyD) in order to circumvent some of these problems. During the characterization of the inclusion complexes with spectroscopic methods, significant variations in the UV and NMR spectra were observed and attributed to the supramolecular interactions between the guest and host molecules. A validated HPLC method was applied to obtain accurate measurements. The complexation process was further examined; the time needed for the completion of the complexation was determined, the binding constants of the complexes were calculated and the energetics of the system were evaluated. The solubility of tolfenamic acid was 30-fold in the presence of HP-β-CyD and twofold in the presence of methyl-β-CyD

Study of structural features and thermodynamic parameters, determining the chromatographic behaviour of drug-cyclodextrin complexes

The chromatographic behaviour of host-guest inclusion complexes was studied, in order to predict the optimal conditions for their accurate analysis and overcome the significant analytical errors generated by the presence of cyclodextrins. Complexes of tolfenamic acid and ketoprofen with β-cyclodextrtin (βCD), 2-hydroxypropyl-βCD (HPβCD) and methyl-βCD (MeβCD) prepared in different molar ratios, were studied. Since the drug release from cyclodextrins&apos; complexes is a prerequisite for its accurate quantitation, several parameters affecting the dissociation during the analysis were evaluated. In an attempt to explain the drug release mechanism from cyclodextrins, during HPLC analysis, the possible correlation of the NMR structural findings with the binding constants and the thermodynamic quantities of complexation were examined, in relation to their chromatographic behaviour. Finally, the presence of the solvation spheres around the supramolecules, which affect the complex stability, is suggested to be crucial for our chromatographic findings. Particularly, entropy change in the system is considered the most critical factor, determining the time required for dissociation of drug-cyclodextrin complexes, during drug quantitation. © 2005 Elsevier B.V. All rights reserved

Competitive complexation and SPE techniques combined with liquid chromatography for the separation and determination of cyclodextrin encapsulated drug substances

A new onalytical procedure, combining sample pretreatment with solid phase extroction ond high performonce liquid chromatography, was developed and opplied to ketoprofen:cyclodextrin (CD) complexes. The significont differences in molar absorptivity between free and CD bound drugs leod to analytical errors up to 30%. Procedures routinely used to remove most of the common excipients proved to be inadequate, creating the necessity of more specific (HPLC) onalytical methods including the step of dissociotion ond separation of drugs from CDs before the quontitation by UV detector. In the case of complexes such as Ketoprofen: CDs, strong binding to CDs inhibits the dissociation. Prior to the anolysis, the addition of molecules competing the binding in the CD cavity fairly decreased the strength of the complexation. When molecules, competing the binding to CD such os 1-odomantanol, were added to the samples the results were improved. The extent of the selective binding and the drug displocement were monitored with 1H-NMR spectroscopy and it was revealed that only partial dissociation of the complexes was obtained. The combination of the sample pre-treatment with a solid phase extraction technique was proved to be inevitable for the dissociation of the complex. When analyzing supramolecules spectral changes, arising from intramolecular and/or intermolecular interactions, are expected. Cansequently, analytical methods utilized should be carefully revised

Improved photostability indicating ion-pair chromatography method for pergolide analysis in tablets and in the presence of cyclodextrins

Pergolide (PG) a semi-synthetic ergot alkaloid derivative used mainly for the treatment of Parkinson&apos;s disease is known to be a photosensitive drug substance. The major photodegradation products are PG sulphoxide (SX) and PG sulphone (SN), which are also the main impurities of the bulk drug substance. It is widely metabolized to more than 10 metabolites including SX and SN. In this work an improved photostability indicating ion-pair chromatography method for PG mesilate was developed. The method can be applied in the determination of PG and impurities in aqueous solutions and in tablets for routine analysis. This new method is appropriate for the quantitative determination of PG in the presence of its impurities and photodegradation products and can also be used for PG complexes with cyclodextrins (commonly used as photostabilizing agents). Furthermore it is suitable for the quantitation of its impurities and its thermal or photo-induced decomposition products. Separation was achieved on a ThermoQuest C18 BDS column and Sodium octanosulphonate was used as ion-pairing agent. Analysis was performed at 223 nm. Validation parameters included: specificity, linearity, precision and accuracy, limit of quantitation and suitability. The method was found to be specific and linear for PG, as well as for SX and, SN impurities. The recovery was 100.83 ± 0.46% for PG, 99.86 ± 0.33% for SX and 99.77 ± 1.84% for SN. Finally the photodegradation profile of PG mesilate was studied in different initial sample concentration. The obtained result revealed that: PG photolysis is catalyzed by its degradation products and that decrease of initial sample concentration reduces the rate of PG photoinduced degradation. © 2006 Elsevier B.V. All rights reserved

Covid-19 pandemic and bats: a lucky symbol of evil fortune.

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The effect of β-cyclodextrin on tenoxicam photostability, studied by a new liquid chromatography method; the dependence on drug dimerisation

Tenoxicam (TXM) is an effective anti-inflammatory and analgesic drug, which presents fast photochemical decomposition. In this work in an attempt to investigate the potential β-CD photostabilizing effect on TXM, the photodegradation rate of β-CD complexed drug was monitored under simulated solar irradiation from Xenon arc lamp. The photodegradation was studied at pH 7.5. A new stability indicating Liquid Chromatography method, for TXM in the presence of β-CD was used. According to the obtained results, in the case of free molecules increasing the concentration the photostability is enhanced. The effect of complexation with CDs on the photodegradation rate seems to vary depending on TXM initial concentration. At low TXM concentrations photodecomposition is retarded upon CD complexation, while at high concentrations the process is accelerated. Molecular dimerisation was studied by 1H(1D) NMR and 2D NOESY experiments. 2D ROESY spectra of complexed molecule were evaluated in order to confirm the complexation. TXM dimers could be considered as a critical parameter affecting oxicams photostability, in combination with the already described ESIPT phenomenon. © 2007 Springer Science+Business Media, Inc

Theophrastus Bombastus Von Hohenheim: Theological Reformer, Philosopher and Physician

Theophrastus Bombastus Von Hohenheim (1493–1541), known as Paracelsus, was a German-Swiss Renaissance man. His interests included alchemy and medicine. During the early 1500s, he worked as a physician, introducing mineral-based therapies to treat ailments. He is credited with developing the first recipe for laudanum, a powerful opium-based pain medication. He had radical beliefs, claiming that supreme knowledge could be reached by observing nature, not by reading books. He expressed rebellious opinions on religious topics and, though devoted Christian, criticized the Catholic Church, preaching that the spirit of Christianity dwells in the human soul and not within the church walls. Paracelsus’ efforts to “renovate” the expression of the Christian faith by limiting the ritual and augmenting the spirituality among believers are presented. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature

Photostabilization of oxolinic acid in hydroxypropyl-β-cyclodextrins; implications for the effect of molecular self-assembly phenomena

Oxolinic acid (OXA) is a first-generation quinolone antibacterial agent, known to cause drug induced photosensitivity. In the present work its photoinduced degradation was monitored under simulated solar irradiation. The effect of photoprotecting agents on OXA stability was also assessed by drug complexation with hydroxypropyl-β-cyclodextrin (HPβCD). The complex was studied by UV-Vis and 1H (2D) NMR Spectroscopy. A photostability indicating chromatographic method was developed and validated. Because OXA is insoluble in acidic solutions, and because an acidic solvent is necessary for successful chromatographic separation, a procedure was developed to pre-treat the sample. This method is suitable for the separation of degradation products from OXA and from each other. The method was also evaluated in the presence of HPβCD, in order to ensure that inclusion complexation did not generate inaccuracies. Investigation of OXA photodegradation profiles confirms first order kinetics and acceleration at higher initial sample concentrations. A 94% photostabilization upon complexation with HPβCD was achieved. Furthermore, molecular self association phenomena were determined by self titration experiments, using 1H NMR Spectroscopy and suggestions were made for the photostabilization mechanism of cyclodextrins. © Springer Science+Business Media B.V. 2009