Development and validation of a liquid chromatographic method for Casiopeina IIIi in rat plasma (original) (raw)
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Genotoxicity of Casiopeina III-Ea in mouse bone marrow cells
Drug and Chemical Toxicology, 2016
Casiopeina III-Ea Õ (Cas III-Ea Õ) is a chelated copper complex with antineoplastic activity that is capable of reducing tumor size and inducing antiproliferative and apoptotic effects. However, little is known about its in vivo genotoxic effects. Therefore, this study evaluated two cytogenetic and two proliferative parameters 24 h after the administration of Casiopeina III-Ea Õ to male CD-1 mice. Three doses of Cas III-Ea Õ were administered by intraperitoneal injections of 1.69, 3.39 and 6.76 mg/kg (corresponding to 1/8, 1/4 and 1/2 of LD 50 , respectively). A reduction in the mitotic index (MI) and an increased numbers of cells with structural chromosomal aberrations (SCA) were detected. Additionally, a low but significant increase in the frequency of sister chromatid exchange (SCE) was observed at the highest dose. Changes in the DNA replication index (RI) were not observed. These results indicate that Casiopeina III-Ea Õ shows cytotoxic and clastogenic activity in bone marrow cells from treated mice.
2021
Abstract. In the present work, the physicochemical (pka, intrinsic solubility, Log D distribution coefficient) and biopharmaceutical characterization (IC50 studies in MDCK cells) of Casiopeina III-Ea, a Cu (II) mixed chelate compound, was carried out. These parameters will tell us about the behaviour of Casiopeina III-Ea, as a new antineoplastic agent, in physiological media. This basic research of the Faculty of Chemistry of the UNAM, is directed towards the maturation of a technology, which consists of the pharmaceutical development of an antineoplastic copper coordination compound Casiopeina III-Ea. Resumen. En el presente trabajo se realizó la caracterización fisicoquímica (pka, solubilidad intrínseca, coeficiente de distribución Log D) y biofarmacéutica (estudios IC50 en células MDCK) de Casiopeina III-Ea, un nuevo compuesto quelato mixto de cobre (II). Estos parámetros nos dirán mucho sobre el comportamiento de Casiopeina III-Ea, como un nuevo agente antineoplásico, en medio...
Antimicrobial Agents and Chemotherapy, 2010
A rapid, precise, and sensitive liquid chromatography/mass spectrometry (LC/MS) method to quantify the caspofungin concentration in human aqueous humor was developed and validated. Sample preparation involved simple dilution of aqueous humor samples with acetonitrile. Azithromycin was the internal standard. Good linearity over 10 to 5,000 ng/ml was observed. The lower limit of quantification was 10 ng/ml. The intra-and interday accuracies (percent bias) were within 11%, while the intra-and interday precisions were within 6%.
Journal of the Mexican Chemical Society
Casiopeína IIgly is a mixed chelate coordination compound with copper (II) core that has shown important antineoplastic activity, even in some resistant cellular lines to Cisplatin. In this work, preclinical studies as blood to plasma ratio, plasma protein binding, short-term stability in blood and pharmacokinetics of this coordination complex are reported. The results indicate that Casiopeína IIgly is stable in blood at least for 6 hours at 37 °C. Also, this compound exhibits an important accumulation in whole blood rather than plasma fluid, a high plasma protein binding (>90%) as well as short half-life (47 min).
Recently, the use of capillary electrophoresis (CE) methods in pharmaceutical practice has gradually increased. Moreover, measurement uncertainty has been used to guarantee the traceability and the reliability of analytical results obtained. The aim of this work was to develop and validate a CE method for the quantification of caspofungin in lyophilised powder for injection, as well as to study the main sources of uncertainty associated with the method proposed and establish a procedure to estimate uncertainty in routine analysis. The results obtained during the validation procedure were statistically evaluated and demonstrate the specificity, robustness, linearity (r = 0.9999; y= 7.9014x-0.0107, concentration range: 20 to 300 g/ml), precision (repeatability, RSD: 0.40%; intermediate precision, RSD: 0.54%) and accuracy (recovery range: 95.80 to 100.45%). Without using internal standard correction, almost all uncertainty is associated to repeatability of sample and standard peak areas (more than 90%). On the other hand, using internal standard reduced variability significantly. The results allow us to affirm that EC method is suitable for analysis of caspofungin and it may be applied in routine quality control laboratories. In addition, this study confirmed that the equations proposed in the paper may be used for the measurement of uncertainty estimation in routine analysis.
Assessment of Acute Respiratory and Cardiovascular Toxicity of Casiopeinas in Anaesthetized Dogs
Basic & Clinical Pharmacology & Toxicology, 2007
Abstract: The 99 lethal dose in an acute toxicity study of two anticancer novel molecules named casiopeinas® in dogs was calculated to be 200 mg/m2 for casiopeina III-ia and 160 mg/m2 for casiopeina IIgly. Considering therapeutic dose ranges from 3.6 to 18 mg/m2 for the former and 1.2 to 3 mg/m2 for the latter, true therapeutic margin of safety varies from 4.7 to 23.6 mg/m2 and from 20 to 50 mg/m2, respectively. For both casiopeinas intravenous administration of the corresponding lethal dose in 100 ml of 5% dextrose solution in a time period of 30 min. induced death after an almost uneventful latency time period of 30–50 min. Then, after an apparently sudden onset, changes in blood gases indicated respiratory distress (PO2 from 82.5% to 26.5% for casiopeina III-ia and from 88.6% to 37.5% for casiopeina IIgly; end-tidal CO2 from 38 to 8.1 mmHg for the first and from 35.1 to 11.2 mmHg for the second, this was almost simultaneously confirmed by the onset of tachypnoea (from 16 to almost 60 breaths/min. for both casiopeinas) and by a drop in arterial blood pressure (from 117 to 51 mmHg for casiopeina III-ia and from 108 to 49 mmHg for casiopeina IIgly). Reflex tachycardia occurs at the beginning of intravenous administration followed by bradycardia a few minutes later (from 158 to 63 beats/min. for casiopeina III-ia and from 148 to 56 beats/min. for casiopeina IIgly). Finally, cardiac arrest occurred no later than 25 min. towards the end of these events lung oedema appeared as fluid dripping from the endotracheal tube. Death occurred in a mean of 15 ± 5 min. S.D. from the beginning of the end of the latency period. For both casiopeina's data allow the speculation that lung oedema is caused by a joined toxicity to the lung capillary bed, and particularly to the heart. Carvedilol premedication for 8 days delayed the outcome of lung oedema by approximately 8 hr but could not prevent it.
Comparison of immunoturbidimetric and immunonephelometric assays for specific proteins
Clinical Biochemistry, 2009
Immunoturbidimetric assays for specific proteins are available on "open system" clinical chemistry analyzers. The analytical performance of nine immunoturbidimetric specific protein assays (C3, C4, CRP, Haptoglobin, IgA, IgG, IgM, RF, and Transferrin) was compared to immunonephelometry. Testing was performed on the Abbott ARCHITECT ci8200 and the Dade Behring BNII nephelometer and evaluated for precision, linearity, limit of detection, prozone phenomenon, method comparison, workflow, and proficiency testing survey comparison. Immunoturbidimetric assays performance was satisfactory for total precision, linearity, limit of detection and the prozone effect was not observed. Method comparison was acceptable for the immunoglobulins, CRP and transferrin but less favorable for the other assays, likely due to methodology and antibody specificity differences. Immunourbidimetric specific protein assays allow for efficient test consolidation on a general purpose clinical chemistry analyzer.
PLoS ONE, 2013
Biotherapeutics are often produced in non-human host cells like Escherichia coli, yeast, and various mammalian cell lines. A major focus of any therapeutic protein purification process is to reduce host cell proteins to an acceptable low level. In this study, various E. coli host cell proteins were identified at different purifications steps by HPLC fractionation, SDS-PAGE analysis, and tryptic peptide mapping combined with online liquid chromatography mass spectrometry (LC-MS). However, no host cell proteins could be verified by direct LC-MS analysis of final drug substance material. In contrast, the application of affinity enrichment chromatography prior to comprehensive LC-MS was adequate to identify several low abundant host cell proteins at the final drug substance level. Bacterial alkaline phosphatase (BAP) was identified as being the most abundant host cell protein at several purification steps. Thus, we firstly established two different assays for enzymatic and immunological BAP monitoring using the cobas® technology. By using this strategy we were able to demonstrate an almost complete removal of BAP enzymatic activity by the established therapeutic protein purification process. In summary, the impact of fermentation, purification, and formulation conditions on host cell protein removal and biological activity can be conducted by monitoring process-specific host cell proteins in a GMP-compatible and high-throughput (> 1000 samples/day) manner.