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In this paper we discuss the details, limitations, and difficulties of the implementation in hardware of a memristor-based random number generator that exhibits monofractal/multifractal behavior. To do so, the components and selection criteria of a reference memristor and one proposed by the authors, the chaotic circuit leveraging them, and the processing that is performed on the chaotic signals to achieve the random discrete sequences are described. After applying the estimation tools, findings indicate that more than 60% of the proposed combinations allow generating random discrete sequences, with long-range dependence, and that both monofractal and multifractal behaviors can also be obtained. Consequently, a hardware system was achieved that can be used as a source of entropy in future synthetic biological signal generators.
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CONTEXT: The recombinant human erythropoietin (rHuEPO) stimulates the erythropoiesis process. Because this glycoprotein has a short half-life, it needs to be administrated two to three times a week. One of the technics to solve this issue is the PEGgilation. AIMS: To evaluate the pharmacokinetics (PK) and pharmacodynamics of two new branched PEGylated erythropoietins (i.e., an asymmetric 32 kDa-PEG2-rHuEPO and a symmetric 40 kDa-PEG2-rHuEPO molecule) compared to non-PEGylated ior®EPOCIM and MIRCERA®. METHODS: Serum concentrations of both PEGylated and non-PEGylated erythropoietins were measured at various time points in order to determine PK parameters using non-compartmental analysis approach. The reticulocyte (%), erythrocyte count and hemoglobin levels were ascertained in order to compare the effect of these molecules after administrating a single intravenous dose (10 µg/kg) of each product in male New Zealand rabbits. RESULTS: Both branched PEGylated erythropoietin forms exhibited half-lives that were significantly longer than ior®EPOCIM (p<0.05), but not statistically different to MIRCERA®. The mean elimination half-life increased from 4 h (ior®EPOCIM) to 131 h for the 32 kDa-PEG2-rHuEPO and 119 h for the 40 kDa-PEG2-rHuEPO. Conversely, MIRCERA® exhibits a half-life of 64 h. Both PEGylated erythropoietin products significantly enhanced the stimulating effect on reticulocytes and erythrocytes formation, as well as on hemoglobin levels, when compared to ior®EPOCIM treatment up to 42 days post-dose. CONCLUSIONS: The PEGylation strategy employed in this study is an effective method to modify the pharmacokinetics and pharmacodynamics of rHuEPO molecule achieving higher half-lives and, therefore, longer in vivo bioactivity. Both of the branched PEGylated-EPO forms tested are promising candidates for human testing.
CONTEXTO: La eritropoyetina humana recombinante (rHuEPO) estimula la formación de eritrocitos en la medula ósea. Esta glicoproteína terapéutica presenta rápida eliminación en el organismo. Una de las estrategias tecnológicas para resolver esta problemática es la PEGgilación. OBJETIVOS: Evaluar la farmacocinética y la farmacodinámica de dos nuevas eritropoyetinas PEGiladas ramificadas (una asimétrica de 32 kDa-PEG2-rHuEPO y otra simétrica de 40 kDa-PEG2-rHuEPO) en comparación con ior®EPOCIM y el producto de referencia MIRCERA®. MÉTODOS: Se midieron las concentraciones séricas de eritropoyetina PEGilada y no PEGilada, a diferentes tiempos, para determinar los parámetros farmacocinéticos usando el método de análisis no compartimental. Se determinaron los % de reticulocitos, los niveles de eritrocitos y hemoglobina para comparar el efecto de estas moléculas después de administrar a dosis única 10 µg/kg por vía intravenosa en conejos Nueva Zelanda machos. RESULTADOS: Las eritropoyetinas PEGiladas ramificadas presentaron semividas significativamente superiores a ior®EPOCIM (p<0.05), pero no fueron estadísticamente diferentes a MIRCERA®. El t1/2 aumentó de 4 h (ior®EPOCIM) a 131 h para la 32 kDa-PEG2-rHuEPO y 119 h para la 40 kDa-PEG2-rHuEPO, respectivamente. Ambas eritropoyetinas PEGiladas mejoraron significativamente el efecto estimulante sobre la formación de reticulocitos y eritrocitos, así como los niveles de hemoglobina, en comparación con ior®EPOCIM hasta 42 días después de la dosis. CONCLUSIONES: La estrategia de PEGilación, empleada en este estudio, es un método efectivo para modificar la farmacocinética y farmacodinamia de moléculas de eritropoyetinas. Esta tecnología permitió aumentar la semivida de estas moléculas, así como prolongar su bioactividad in vivo. Ambas formas ramificadas de rHuEPO PEGiladas son candidatos prometedores para su uso clínico.
RESUMO
The author has compared the type of Gelidium filicinum Bory, 1927 with several specimens from the coasts of Chile, and he has ound that they could a different species: G. crispum Howe, 1941 (=G. lingulaltum Agartah, 1872, nee G. lin gularum Küzing, 1986) or Acropeltis chilensis Montagne, 1939. He also assue that Gelidium hovei Acleto, 1973, could be a synonymouns of G. filicinum.
De la comparación con el tipo de Gelidium filicium Bory, 1927, el autor encuentra que diversos especímenes provenientes de la costas de Chile, citadas bajo ese nombre, corresponderían a otras especies. Podría tratase de G. crispum Howe, 1914 (=G. lingulaltum Agartah, 1872, nee G. lin gularum Küzing, 1986) or Acropeltis chilensis Montagne, 1939). Por otro lado, la especie Gelidium howei Acleto, 1973 probablemente represente un sinónimo de la verdadera especie G. filicinum.