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Resumen La hemofilia B es un trastorno hemorrágico hereditario, ligado al cromosoma X, que se caracteriza por el déficit del factor IX (FIX) de la coagulación. Para mejorar la calidad de vida de los pacientes y la adherencia al tratamiento se han desarrollado concentrados de factores recombinantes modificados para extender su vida media, denominados factores de vida media extendida (EHL: extended half life concentrates). El nonacog beta pegol (N9-GP) es una molécula de FIX humano recombinante glicopegilada que tiene una vida media de 93 h con una sola dosis y ha mostrado un porcentaje de recuperación mayor que otras moléculas. Para diagnosticar y monitorear el tratamiento del paciente hemofílico se determina la actividad del FIX con el ensayo coagulable en una etapa (OSA: one stage assay) y/o en el ensayo cromogénico. El objetivo de este trabajo, realizado en tres centros, fue medir la recuperación de N9-GP con 10 reactivos de APTT diferentes en tres plataformas, en muestras deficientes en FIX adicionadas in vitro con N9-GP, en cuatro niveles de concentración diferentes. Los resultados muestran una heterogeneidad en la actividad de N9-GP medidos por OSA con los diferentes reactivos de APTT cuando se realizaron las calibraciones con el estándar específico de cada coagulómetro. Se obtuvo un porcentaje de recuperación mayor de 92% con Cephascreen, Actin FSL y APTTest elágico en las tres plataformas evaluadas. Estos reactivos serían los únicos apropiados cuando se usa el OSA calibrado con plasma comercial para monitorear el tratamiento de los pacientes que reciben N9-GP.
Abstract Hemophilia B (HB) is an X-linked hereditary bleeding disorder characterised by coagulation factor IX (FIX) deficiency. To improve the quality of life of patients and adherence to treatment, recombinant factor concentrates glicomodified to extend their half-life have been developed. These are called extended half-life factors (EHL: extended half-life concentrates). Nonacog beta pegol (N9-GP) is a glycopegylated recombinant human FIX molecule that has a half-life of 93 h with a single dose and has shown a higher recovery percentage than other molecules. For diagnosis and monitoring the treatment of hemophiliac patients, FIX activity is determined with the One Stage Clotting Assay (OSA) and/or the chromogenic assay. The objective of this work, carried out in three centres, was to measure the recovery of N9-GP with 10 different APTT reagents on three platforms, in FIX deficient samples spiked in vitro with N9-GP, at four different concentration levels. The results show a heterogeneity in the activity of N9-GP measured by OSA with the different APTT reagents when the calibrations were performed with the specific standard of each coagulometer. A recovery percentage greater than 92% was obtained with Cephascreen, Actin FSL and APTTest ellagic in the three platforms evaluated. These reagents would be the only ones appropriate when using the commercial plasma-calibrated OSA to monitor the treatment of patients treated with N9-GP.
Resumo A hemofilia B é uma doença hemorrágica hereditária ligada ao cromossomo X caracterizada pela deficiência do fator de coagulação IX (FIX). Para melhorar a qualidade de vida dos pacientes e a adesão ao tratamento, foram desenvolvidos concentrados de fatores recombinantes modificados para prolongar sua meia-vida, chamados de fatores de meia-vida estendida (EHL: extended half life concentrates). Nonacog beta pegol (N9-GP) é uma molécula de FIX humano recombinante glicopeguilada que tem meia-vida de 93 h com uma dose única e mostrou uma porcentagem de recuperação maior do que outras moléculas. Para diagnosticar e monitorar o tratamento de pacientes hemofílicos, a atividade do FIX é determinada com o ensaio coagulável em um estágio (OSA: One Stage Assay) e/ou o ensaio cromogênico. O objetivo deste trabalho, realizado em três centros, foi medir a recuperação de N9-GP com 10 reagentes de APTT diferentes em três plataformas, em amostras deficiente de fator IX adicionadas in vitro com N9-GP, em quatro níveis de concentração diferentes. Os resultados mostram uma heterogeneidade na atividade de N9-GP medidos por OSA com os diferentes reagentes de APTT quando as calibragens foram realizadas com o padrão específico de cada coagulômetro. Uma porcentagem de recuperação superior a 92% foi obtida com Cephascreen, Actin FSL e APTTest elágico nas três plataformas avaliadas. Esses reagentes seriam os únicos apropriados ao usar o OSA calibrado com plasma comercial para monitorar o tratamento de pacientes tratados com N9-GP.
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@#During chemotherapy of malignant tumors,neutropenia is the most important adverse event caused by myelosuppressive chemotherapeutics,of which the degree and duration are closely related to the risk of infection and even death.Granulocyte-colony stimulating factor(G-CSF) is an endogenous hematopoietic growth factor that can stimulate the proliferation and differentiation of neutrophil precursors,and increase the survival rate and activity of mature neutrophils.Recombinant human granulocyte-colony stimulating factor(rhG-CSF) is an artificially synthesized cytokine with G-CSF biological activity.It is used clinically for the prevention and treatment of neutropenia after treatment with cytotoxic chemotherapeutics,requiring multiple medications and repeated injections during application for its short half-life.Pegylated recombinant human granulocyte-colony stimulating factor(PEG-rhG-CSF) is its long-acting dosage form,and patients only need to be administered once per cycle of chemotherapy,which has been widely used in clinical practice because of its stability and convenience.This paper systematically described the clinical application value of PEG-rhG-CSF in neutropenia after chemotherapy,aiming to provide a reference for its further clinical application.
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Objective:To evaluate the effects of pegylated interferon (Peg-IFN) alfa-2b combined with nucleotide analogues (NAs) on the recurrence of hepatitis B-related liver cancer after resection, and to explore the changes of HBsAg and HBV DNA in patients with chronic hepatitis B liver cancer during postoperative treatment.Methods:The prospective study was conducted. Clinical data of 43 patients with hepatitis B-related liver cancer who underwent radical resection treated in 900th Hospital of People′s Liberation Army were prospectively analyzed from January 2020 to December 2021. Among 43 patients, there were 39 males and 4 females, the age was 30-76 years. According to different treatment methods they were divided into two groups, the patients treated by Peg-IFN alfa-2b combined with NAs were devided into the IFN group( n=10), and those treated by NAs alone into the NAs group( n=33). Two-pair semi-quantitative were collected every 3 months after operation. The recurrence-free survival rate, recurrence time after 2 years in the two groups, the clearance rate and the negative rate of HBsAg and HBV DNA in the two groups. Peg-IFN alfa-2b was evaluated in improving the prognosis of hepatitis B-related liver cancer. The measurement data of normal distribution were expressed by mean±standard deviation ( ± s), and t-test was used for comparison between the two groups. Chi-square test was used for comparison between the two groups of count data. Repeated analysis of measurement variance was used for analysis HBsAg and HBV DNA changes of the interferon group overall survival time and recurrence-free surrival time of patients was estimated using Kaplan-Meier method and the difference between groups was assessed using Log-rank test. Results:HBsAg and HBV DNA: The HBsAg clearance rate at 24 weeks and that at 48 weeks in the IFN group were 24.6% and 59.0% respectively. The HBsAg negative rate at 48 weeks was 16.7%. The HBV DNA clearance rate at 24 weeks and that at 48 weeks were 33.9% and 53.8% respectively. The HBV DNA negative rate was 0 at 48 weeks. The levels of HBsAg and HBV DNA in the IFN group decreased gradually with time. There were statistically differences between the levels of HBsAg and HBV DNA at 0 weeks, 24 weeks and 48 weeks( P<0.05). The 2-year overall survival rates of IFN group and NAs group were 100% and 90.9% respectively. The 2-year recurrence-free survival rates were 90.0% and 63.6% respectively. There were no significant statistical differences in the overall survival rate and recurrence-free survival rate between the groups ( P>0.05). The postoperative recurrence time of the IFN group and the NAs group were (15.00±7.07) months and (5.78±3.39) months respectively. The difference between the two groups was statistically significant ( t=3.160, P<0.01). Conclusion:Long-term antiviral therapy of Peg-IFN alfa-2b combined with NAs can prolong the recurrence time of liver cancer, reduce the levels of HBsAg and HBV DNA in serum, and potentially improve the survival rate of the patients compared with therapy of NAs alone.
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AIM: To evaluate the clinical efficacy and safety of pegylated interferon-alpha (Peg-IFN-α) in the treatment of essential thrombocythemia (ET). METHODS: A total of 50 ET patients were treated with Peg-IFN-α for more than 12 months. 180 μg was injected subcutaneously once every two weeks as the initial dose, and then the treatment interval was adjusted according to blood routine. The clinical efficacy and adverse reactions were analyzed. RESULTS: The hematologic response of ET patients treated with Peg-IFN-α occurred quickly, and the platelet decreased significantly after 3 months (508.56±120.75 vs. 931.44±209.13, P=0.000). Hematologic complete remission rate and overall remission rate at 12 months were 70% and 98%, respectively. The JAK2-V617F mutation burden of ET patients treated with Peg-IFN-α was significantly lower at 6 months of treatment than at initial diagnosis (0.254 1±0.122 8 vs. 0.315 3±0.133 2, P 0.05). Hematological adverse reactions were rare, and all of them were grade 1-2 adverse reactions. Non-hematological adverse reactions were mainly influenza-like symptoms. Most of the patients were grade 1-2, and occasionally had grade ≥3 adverse reactions. All adverse reactions could be tolerated after extending medication interval or symptomatic treatment, and no patient terminated treatment because of adverse reactions. CONCLUSION: Peg-IFN-α is effective and safe in the treatment of ET.
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Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]3) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3‒x (x = 1,2) and PEG-[linker] during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.
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ObjectiveTo establish an early predictive model using serological markers based on LASSO regression for predicting the possibility of HBsAg clearance in HBeAg-negative chronic hepatitis B （CHB） patients treated with pegylated interferon α-2b （PEG-IFNα-2b）， and to investigate the diagnostic value of the model. MethodsA total of 136 HBeAg-negative CHB patients who received PEG-IFNα-2b treatment in the Affiliated Hospital of Xuzhou Medical University from April 2020 to October 2021 were enrolled， among whom 47 received PEG-IFNα-2b for the first time （previously untreated） and 89 received PEG-IFNα-2b after 48 weeks of treatment with nucleos（t）ide analogues （treatment-experienced）. The patients were randomly assigned to a training set with 95 patients and a validation set with 41 patients at a ratio of 7∶3， and related data were collected for both groups， including virological markers， routine blood test results， and liver function at baseline and week 12 of treatment. According to HBsAg status at week 48 of treatment， the patients were divided into seroconversion group with 38 patients and non-seroconversion group with 98 patients. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical variables between two groups. The LASSO regression analysis and univariate and multivariate logistic regression analyses were used to establish a nomogram model； the receiver operating characteristic （ROC） curve was used to assess its predictive ability， and the area under the ROC curve （AUC） was used for comparison of predictive value. ResultsIn the training set， 95 HBeAg-negative CHB patients were treated with PEG-IFNα-2b for 48 weeks， among whom there were 27 patients in the seroconversion group and 68 in the non-seroconversion group. The univariate Logistic regression analysis， with P<0.2 as the criterion for screening， showed that 9 indicators were included in the LASSO regression analysis， i.e.， sex， baseline HBV DNA level， the reduction in HBV DNA in 0 — 12 weeks， baseline HBsAg level， the reduction in HBsAg in 0 — 12 weeks， baseline aspartate aminotransferase （AST） level， the reduction in AST in 0 — 12 weeks， baseline alanine aminotransferase （ALT） level， and the reduction in ALT in 0 — 12 weeks. The LASSO regression analysis showed that sex， baseline HBsAg level， the reduction in HBsAg in 0 — 12 weeks， and the reduction in ALT in 0 — 12 weeks were non-zero variables and were included in the multivariate Logistic regression analysis. The multivariate Logistic regression analysis obtained 4 independent predictive factors， i.e.， sex （odds ratio ［OR］=5.38， 95% confidence interval ［CI］： 1.11 — 34.21， P=0.049）， baseline HBsAg level （OR=0.12， 95%CI： 0.04 — 0.26， P<0.001）， the reduction in HBsAg in 0 — 12 weeks （OR=5.54， 95%CI： 1.97 — 19.18， P=0.003）， and the reduction in ALT in 0 — 12 weeks （OR=0.99， 95%CI： 0.97 — 1.00， P=0.039）. A nomogram model was established based on the results of the multivariate Logistic regression analysis， and the ROC curve was used to assess the predictive value of this nomogram model. This nomogram model had an AUC of 0.934 （95%CI： 0.886 — 0.981） in the training set and an AUC of 0.921 （95%CI： 0.838 — 1.000） in the validation set. In addition， the results of calibration curve and decision curve analyses showed that the model had good consistency and accuracy. ConclusionBased on general information and serological markers， the LASSO regression analysis is used to establish a nomogram model using sex， baseline HBsAg level， the reduction in HBsAg in 0 — 12 weeks， and the reduction in ALT in 0 — 12 weeks， and this model can be used to predict the probability of achieving HBsAg clearance in HBeAg-negative CHB patients treated with PEG-IFNα-2b， which provides important reference and theoretical support for the clinical treatment of patients.
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Antiviral therapy for chronic hepatitis C virus (HCV) infection has entered the era of direct antiviral agent (DAA), and up to 95% of patients could be clinically cured. Under this circumstance, HCV infection has gradually changed from relative contraindication to surgical indication for kidney transplantation. However, at present, the number of kidney transplantation from HCV-infected donors or recipients has been rarely reported in China. The short-term follow-up data of HCV-negative recipients undergoing kidney transplantation from HCV-positive renal allografts in other countries have confirmed that DAA yields high cure rate and safety in the treatment of HCV infection, and recipients could obtain favorable short-term survival and allograft outcome. However, the long-term safety of HCV-infected kidney transplantation remains to be validated by clinical trials with large sample size and long-term follow-up. In this article, the virological clearance, allograft outcome and safety of DAA use in HCV-negative recipients undergoing kidney transplantation from HCV-positive renal allografts under the intervention of DAA were investigated, aiming to evaluate clinical safety and efficacy of this pattern of kidney transplantation and deepen the understanding of safe use of HCV-positive organs.
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Objective:To compare the efficacy and safety of pegylated liposomal Doxorubicin(PLD)and Epirubicin(EPI)as first-line chemotherapy for diffuse large B-cell lymphoma(DLBCL).Methods:Clinical data of DLBCL patients treated at Zhejiang Cancer Hospital from March 2013 to April 2018 were retrospectively collected.A total of 411 patients who had received first-line chemotherapy were included.Based on age, sex, Ann Arbor staging and other parameters and using the PSM method for 1∶1 matching, 151 patients were assigned into each of the PLD group and the EPI group.Efficacy and adverse events were compared between the PLD group and the EPI group.All patients were followed up for 3 years after treatment to monitor survival.Results:The complete response(CR)rate in the PLD group was 81.5%, and the CR rate in the EPI group was 72.2%.The objective response rate(ORR)of the PLD group was 98%, and the ORR of the EPI group was 96.7%.There was no significant difference in CR rate( χ2=0.478, P=0.489)or ORR between the two groups( χ2=0.007, P=0.934). In the PLD group, myelosuppression occurred in 25 cases(16.6%)and cardiotoxicity-related events in 21 cases(13.9%); in the EPI group, there were 24 cases(15.9%)of myelosuppression and the same number of cases of cardiotoxicity-related events, and there were no significant differences in myelosuppression( χ2=0.018, P=0.895)or cardiotoxicity( χ2=0.174, P=0.677)between the two groups.During the 3-year follow-up, the progression free survival(PFS)rates of the PLD group and the EPI group were 79.1% and 69.6%, respectively, with a statistically significant difference between the two groups( χ2=3.930, P=0.047). Both the PLD group and the EPI group had a 3-year OS rate of 85.2%, with no statistically significant difference between the two groups( χ2=0.402, P=0.538). Conclusions:The 3-year progression-free survival of DLBCL patients with PLD as first-line chemotherapy is significantly better than with EPI, and the 3-year overall survival, short-term efficacy and myelosuppression are comparable to those with EPI.
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Visceral leishmaniasis (VL), also known as Kala-azar, is caused by Leishmania (L.) donovani complex, which includes L. donovani and L. infantum and is associated with a high death rate as compared to the cutaneous and subcutaneous form. Treatment of VL includes chemotherapeutic agents which are associated with some major hurdles like toxicities, parenteral administration, high cost, parasite resistance and stability. Hence, there is an urgent requirement to develop novel chemotherapeutic agents or repurposing of existing drugs against VL. Developing formulation of new chemical entity for the treatment of VL is laborious, time consuming and associated with huge financial burden. However, screening of existing chemotherapeutic agents is a good alternative to avail cost-effective treatment option for VL. Non-PEGylated liposome encapsulated doxorubicin (Myocet ®) is proposed as an alternative treatment option for VL in this review article. Here, we covered the fundamental aspects of VL, loophole associated with available current treatment strategies and non-PEGylated liposome encapsulated doxorubicin as a novel alternative formulation for treating VL, as this liposomal delivery system of doxorubicin might passively target the intra- cellular regions of macrophage.
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A Leucemia Linfoide Aguda (LLA) é um câncer de maior incidência em crianças, e tem a Lasparaginase (ASNase) como fármaco amplamente utilizado no tratamento dos afetados. A ASNase catalisa a hidrólise do aminoácido L-asparagina (Asn), presente na corrente sanguínea, a ausência do aminoácido no meio extracelular leva à morte células leucêmicas, que necessitam deste aminoácido para as funções celulares. Fatores envolvendo a eficiência do tratamento com ASNase como reações adversas e curta meia-vida, principalmente devido ao reconhecimento pelo sistema imune e degradação por proteases, limitam a sua eficácia. A encapsulação da enzima em lipossomas pode conferir proteção à degradação, melhorar seu perfil farmacocinético e diminuir os efeitos adversos, de forma a melhorar o tratamento da LLA sendo este o objetivo desse trabalho. Lipossomas de DOPC (1,2-dioleoil-sn-glicero-3-fosfocolina) e DMPC (1,2-dimiristoil-snglicero-3-fosfocolina) foram desenvolvidos empregando-se o método de hidratação do filme lipídico e diferentes protocolos de preparo contendo ou não diferentes concentrações de 18:0 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polietilenogicol)-2000] (DSPE-PEG). Os lipossomas produzidos foram utilizados para encapsular a ASNase e os sistemas contendo ou não ASNase encapsulada foram caracterizados por espalhamento de luz dinâmico (DLS), potencial zeta, microscopia eletrônica de transmissão (MET) e criomicroscopia de transmissão. Adicionalmente, foram avaliados a taxa de encapsulação e o perfil de permeabilidade das vesículas à L-asparagina. As análises de DLS mostraram que as nanoestruturas formadas empregando-se agitação magnética a partir de sistemas contendo 10% e 20% de DSPE-PEG possuem diâmetro hidrodinâmico menor (~ 25 nm a 60 nm) que os mesmos sistemas sem o fosfolipídio peguilado (~190 nm a 222 nm), demonstrando a relação entre a diminuição do tamanho e o aumento da quantidade de fosfolipídio peguilado e possível formação de estruturas micelares ou bicelares. O emprego de agitação em vórtex para hidratação do filme lipídico, adição do antioxidante -tocoferol e redução da concentração de DSPE-PEG (5% e 10%) levou à formação de sistemas com diâmetro hidrodinâmico maior, sendo esse protocolo e concentrações de PEG definidos como padrão. As análises de MET comprovaram a formação de lipossomas com diâmetro hidrodinâmico semelhante ao observado por DLS; com a utilização da criomicroscopia foi possível observar os lipossomas sem deformações. Os lipossomas de DMPC/DSPE-PEG 10% apresentaram maior permeabilidade à L-asparagina ao longo do tempo e, portanto, poderiam funcionar como nanoreatores, depletando o aminoácido da circulação. Estudos in vitro com células tumorais devem ser realizados e em seguida estudos in vivo, para confirmar este potencial
L-asparaginase (ASNase) is a first-choice drug, combined with other drugs, in therapeutic schemes to treat Acute Lymphoblastic Leukemia (ALL) in children and adolescents. ASNase catalyzes the hydrolysis of L-asparagine (Asn) in the bloodstream; since ALL cells cannot synthesize this amino acid, protein synthesis is impaired leading to leukemic cells death by apoptosis. In spite of its therapeutic importance, treatment with ASNase is associated to side effects, mainly hypersensitivity and immunogenicity. Another drawback refers to degradation by plasma proteases that altogether with immunogenicity shortens the enzyme half-life. Encapsulation of ASNase in liposomes, vesicular nanostructures formed by the self-aggregation of phospholipids, is an attractive alternative that possibly will protect the enzyme from plasma proteases, resulting on better pharmacokinetics profile. In this work, we prepared by thin film hydration liposomal formulations of the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 1,2-dimyristoyl-sn-glycero-3- phosphocholine (DMPC) containing or not different concentrations of 18:0 1,2-distearoyl-snglycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG), and encapsulated ASNase by electroporation. The systems containing or not ASNase were analyzed by Dynamic Light Scattering, zeta potential and Electron Microscopy. The encapsulation efficiency and vesicles permeability were also evaluated. According to the DLS analysis, the nanostructures formed by film hydration under magnetic stirring employing 10% or 20% DSPE-PEG presented smaller hydrodynamic diameter (~ 25 nm to 60 nm) than the same systems without the pegylated phospholipid (~ 190 nm to 222 nm), demonstrating the relation between size and the amount of pegylated phospholipid that results in formation of micellar or bicellar structures. The protocol was stabilize by hydration of the lipid film under vortex agitation, addition of the antioxidant - tocopherol and reduction of the concentration of DSPE-PEG (5% and 10%), what altogether led to the formation of nanostructures of higher hydrodynamic diameter and monodisperse systems. TEM analyzes confirmed the formation of liposomes with hydrodynamic diameter similar to that observed by DLS; with the use of cryomicroscopy it was possible to observe the liposomes without deformations. Liposomes of DMPC/DSPE-PEG 10% showed permeability to L-asparagine over time and, therefore, could function as nanoreactors, depleting the circulating amino acid
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Asparaginasa/farmacología , Liposomas/análisis , Asparagina/antagonistas & inhibidores , Técnicas In Vitro/instrumentación , Preparaciones Farmacéuticas/análisis , Microscopía Electrónica/métodos , Microscopía Electrónica de Transmisión/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Antioxidantes/efectos adversosRESUMEN
BACKGROUND PEGylation, defined as the covalent attachment of polyethylene glycol, allows the synthesis of PEGylated therapeutic proteins with enhanced physicochemical properties. Traditional alkylating Nterminal PEGylation reactions on amine groups involve the use of modified linear mono-methoxy polyethylene glycol (mPEG) molecules looking for the synthesis of mono-PEGylated products. However, this approach requires different purification steps since inevitably undesired cross-linked products are synthesized. Herein, we propose the use of reactive aqueous two-phase systems (ATPS) to produce and purify PEGylated therapeutic conjugates using Ribonuclease A (RNase A) as a model protein. RESULTS: Selected linear 5 kDa and 20 kDa mPEG potassium phosphate systems were produced according to equilibrium data obtained from constructed binodal curves. All reactive systems were able to generate biphasic systems and to PEGylate RNase A. Two 5 kDa and two 20 kDa systems were selected based on the reaction yield percentage and the feasibility of purifying the mono-PEGylated RNase A from the diPEGylated and native RNase A by contrasting the differences in their partition behaviors. The remnant biological activity was of 94% and of 100% for the mono-PEGylated RNase A purified from the 5 kDa and 20 kDa mPEG systems when compared to the mono-PEGylated conjugate obtained by standard procurement methods.
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Polietilenglicoles/química , Proteínas/aislamiento & purificación , Proteínas/químicaRESUMEN
Purpose: Recently, drug delivery system with controlled and targeted drug release at the tumor sites emerged as an attractive option for improving anticancer therapeutics. Advanced Nano therapeutics must not be limited to nano scale but should find their way to target the solid tumor via direct or indirect way. Pegylation on the surface of liposome helps to become liposome as long circulating and indirect or passive targeting to tumor. Purpose of this study is to develop and optimize the critical process parameters which plays important role in the quality pegylated liposome. Design of experiment (DOE) was used to study the impact of critical process variables like hydration temperature, extrusion process temperature, ethanol concentration, drug loading temperature and drug loading time.
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OBJECTIVE: To evaluate the efficacy and safety profile of first-line R-CDOP(rituximab, cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone) like regimen in diffuse large B-cell lymphoma (DLBCL) with cardiovascular diseases or risk factors. METHODS: DLBCL Patients who were diagnosed with at least one cardiovascular disease/risk factor and received first-line R-CDOPlike chemotherapy in our institute between January 2010 and November 2016 were collected. Cardiovascular diseases/risk factors were referred as:coronary heart disease, hypertension, age ≥60, hyperlipidemia, diabetes mellitus, obesity, history of smoking, and hypothyroidism/hyperthyroidism. Chemotherapy in our institute were retrospectively reviewed. RESULTS: A total of 94 DLBCL patients were recruited. All enrolled patients had history of a cardiovascular disease or presented a high-risk group of developing cardiovascular diseases:coronary heart disease 10 cases, hypertension 33 cases, hyperlipidemia 44 cases, diabetes mellitus 23 cases, obesity 15 cases, history of smoking 25 cases, hypothyroidism/hyperthyroidism 3 cases. A total of 74 patients had more than one cardiovascular disease or risk factors. A total of 34 patients were germinal center B-cell subtype(GCB) and 60 were non-germinal center B-cell subtype(non-GCB). First-line R-CDOP like chemotherapy was given at a median cycle of 4.5 (range, 2-8). Overall response rate(ORR) and complete response rate (CRR) were 92.6%(87/94) and 70.2%(66/94) for the whole group. 5-Year progression-free survival (PFS) and overall survival(OS) rates were 71.3% and 76.9% for overall. For GCB subtype and non-GCB subtype, 5-year PFS rates were 84.6% and 63.9% respectively(P<0.05), and 5-year OS rates were 80.6% and 74.6%, respectively(P=0.407). Grade III/ neutropenia and thrombocytopenia were documented in 53.2%(50/94) and 3.2% (3/94) of patients. 19 (20.2%) patients developed grade /Ⅱ cardiotoxicity. There was no grade III/ cardiac event causing chemotherapy delay or break off. No further cardiotoxicity occurred neither during follow-up. CONCLUSION: PLD-containing first-line R-CDOP like regimen is demonstrated as a highly effective and much tolerable alternative for DLBCL patients with cardiovascular diseases/risk factors.
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As a new type of anthracyclines, pegylated liposomal doxorubicin (PLD) is widely used in the treatment of a variety of malignant tumors, including soft tissue sarcoma, ovarian cancer, breast cancer, multiple myeloma, and so on. Compared with traditional anthracyclines, PLD can significantly decrease the incidences of adverse events such as cardiac toxicity and alopecia. However, the use of PLD will be accompanied with toxic side effects such as hand-foot syndrome, oral mucositis, and infusion reaction. This consensus will mainly focus on the mechanism, prevention and treatment of adverse events of PLD, in order to improve the therapeutic efficacy of PLD and life quality of patients.
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Femenino , Humanos , Antibióticos Antineoplásicos , Usos Terapéuticos , Consenso , Doxorrubicina , Usos Terapéuticos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Síndrome Mano-Pie , Neoplasias , Quimioterapia , Polietilenglicoles , Usos Terapéuticos , Guías de Práctica Clínica como Asunto , EstomatitisRESUMEN
Context: In platinum-resistant ovarian cancer, single-agent chemotherapy is recommended for the reduction of adverse events. However, in clinical practice, some patients can tolerate drug-specific adverse events. Aims: We assessed the safety of pegylated liposomal doxorubicin (PEG-LD) and docetaxel regimen in the first cycle of ovarian cancer. Settings and Design: We performed a phase I study to evaluate the combination therapy of PEG-LD and docetaxel. Materials and Methods: We recruited five patients with recurrent ovarian cancer within 12 months of first-line platinum-based chemotherapy. All patients had measurable disease severity. PEG-LD and docetaxel were intravenously administered on day 1 and every 21 days using three dose levels: 25 mg/m2 PEG-LD and 50 mg/m2 docetaxel; 30 mg/m2 PEG-LD and 50 mg/m2 docetaxel; and 30 mg/m2 PEG-LD and 60 mg/m2 docetaxel. Statistical Analysis Used: We defined the maximum tolerated dose of the combination therapy based on the modified Fibonacci method. Results: Five patients were enrolled in this study. The median treatment-free interval was 5.5 months. Two dose-limiting toxicities (Grade 4 neutropenia) were observed in two patients. One complete response, one partial response, one stable disease, and two progressive disease cases were observed. The overall response rate was 2/5, and the disease control rate was 3/5. The median overall survival was 7.4 months. Conclusions: We determined that 25 mg/m2 of PEG-LD and 50 mg/m2 of docetaxel were safe and effective doses. This preliminary efficacy and safety data should be further investigated in a Phase II trial.
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Brown adipose tissue (BAT) is responsible for adaptive thermogenesis. We previously showed that genetic deficiency ofreceptor for advanced glycation end products (RAGE) prevented the effects of high-fat diet (HFD). This study was tocompare BAT activity in RAGE knock out (Ager-/-, RKO) and wild-type (WT) mice after treated with HFD or LFD.[18F]FDG PET-CT imaging under identical cold-stimulated conditions and mean standard uptake values (SUVmean), ratio ofSUViBAT/SUVmuscle (SUVR, muscle as the reference region) and %ID/g were used for BAT quantification. The resultsshowed that [18F]FDG uptake (e.g., SUVR) in WT-HFD mice was significantly reduced (three-fold) as compared to that inWT-LFD (1.40 ± 0.07 and 4.03 ± 0.38; P = 0.004). In contrast, BAT activity in RKO mice was not significantly affectedby HFD, with SUVRRKO-LFD: 2.14 ± 0.10 and SUVRRKO-LFD: 1.52 ± 0.13 (P = 0.3). The uptake in WT-LFD was almostdouble of that in RKO-LFD (P = 0.004); however, there was no significant difference between RKO-HFD and WT-HFDmice (P = 0.3). These results, corroborating our previous findings on the measurement of mRNA transcripts for UCP1 inthe BAT, suggest that RAGE may contribute to altered energy expenditure and provide a protective effect against HFD byAger deletion (Ager -/-).
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Cancer persists to be a major cause of hospitalization and death every year. With the passage of time, new formulations of anticancer drugs are being introduced to the market and are drawing the concern of healthcare professionals in terms of the superiority, toxicology, and cost-effectiveness of the new formulations in comparison to the conventional formulation of the same drugs. Doxorubicin, a highly potent chemotherapeutic agent, it comes with three formulations (pegylated liposomal, nonpegylated liposomal and non-liposomal conventional formulations). English-language literature of the three formulations of Doxorubicin has been reviewed to inform the healthcare professionals regarding the differences between these formulations. Liposomal Doxorubicin promotes better toxicology profile than non-liposomal conventional Doxorubicin with an increased cost. Due to very limited studies, the cost-effectiveness of liposomal Doxorubicin is not well defined. Apart from that, this review highlights the inter patient variability in regard to the clearance and volume of distribution following the administration of liposomal Doxorubicin. In conclusion, further studies regarding the superiority of liposomal formulation of Doxorubicin , efficacy and dose standardization of liposomal Doxorubicin should be sought in the near future in a more better way.
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This study aimed to investigate relationship of the HCV genome structure and treatment with Pegylated Interferonα/Ribavirin (peg-IFNα/RBV) Egyptian patient. Mutations in two sites of HCV genome; the internal ribosome entry site(IRES) and the interferon sensitivity determining region (ISDR) of HCV genotype 4a were studied in details including DNAsequences and mutations detection in response to treatment. Ninety patients, responders and non-responders, to treatmentwith peg-IFN α /RBV were included in this study. IRES and ISDR regions were amplified by RT-PCR using specific designedprimers, and amplified regions were sequenced. The data obtained were aligned with published sequences in GenBank usingBLAST program. Results of this study have revealed that there are different mutations in the studied sequences in both ISDRand IRES regions. The predicted amino acids sequences in the ISDR region showed significant differences ranging from oneup to more than eight mutations in the HCV Genome sequences. Although there was a significant difference betweensequences of HCV RNA isolated from responders and non-responders, these data were not able to give an absolute answerwhether response to interferon therapy is directly/relates to the structure of the HCV genome
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Objective: To evaluate the efficacy and safety of PEG-rhG-CSF therapy in the primary and secondary prevention of chemo-therapy-induced neutropenia . Methods: This single-center, one-arm, and open-label clinical study involved 217 patients with non-my-eloid malignant tumors. These patients included 18 gynecologic oncology (3 endometrial and 15 ovarian cancer), 50 breast cancer, 30 bone tumor, and 119 lymphoma patients who underwent a total of 774 cycles of chemotherapy, comprising 146 primary and 71 sec-ondary prevention patients. The patients ≥45 kg and those <45 kg received a single subcutaneous injection of 6 mg and 3 mg PEG-rhG-CSF, respectively, 24-48 h after the chemotherapy was completed. All patients received only one dose of PEG-rhG-CSF admin-istration per chemotherapy cycle. Results: The overall incidence of febrile neutropenia (FN) was found to be 5.7%, with rates of 4.9% and 7.2% in the primary and secondary prevention groups, respectively. Univariate and multivariate Logistic regression analyses re-vealed that the longer PEG-rhG-CSF was sustained in the treatment cycle, the lower the incidence of FN was. The incidence of FN was significantly lower in the second cycle of the treatment than in the first in both the primary and secondary prevention groups (cycle 1 vs. cycle 2: 11.6% vs. 4.4%, respectively, P=0.039, in the primary group; 16.9% vs. 5.6%, respectively, P=0.034, in the secondary group). The overall incidence of gradeⅣneutropenia was 10.3% (80/774), with rates of 6.7% (34/510) and 17.4% (46/264) in the primary and secondary prevention groups, respectively (P<0.001). The incidence of gradeⅣneutropenia was significantly lower in the second cy-cle of the treatment than in the first (cycle 1 vs. cycle 2: 17.1% vs. 5.3%, respectively, P=0.004, in the primary group; 46.5% vs. 11.3%, respectively, P<0.001, in the secondary group). The treatment-induced toxicity mainly involved bone pain, with 3.7% (8/217) and 1.8% (4/217) incidence rates for grade 1-2 and 3-4 bone pain, respectively. Conclusions: PEG-rhG-CSF administration can effectively reduce the incidence of FN (5.7%) when prophylactically applied to patients with non-myeloid malignant tumors. Primary prevention can sig- nificantly reduce the risk of grade IV neutropenia in all chemotherapy cycles relative to the secondary prevention.
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Objective@#Hepatitis B surface antigen (HBsAg) loss is seldom achieved with nucleos(t)ide analog (NA) therapy in chronic hepatitis B patients but may be enhanced by switching to finite pegylated-interferon (Peg-IFN) alfa-2a. We assessed HBsAg loss with 48- and 96-week Peg-IFN alfa-2a in chronic hepatitis B patients with partial response to a previous NA.@*Methods@#Hepatitis B e antigen (HBeAg)-positive patients who achieved HBeAg loss and hepatitis B virus DNA < 200 IU/mL with previous adefovir, lamivudine or entecavir treatment were randomized 1:1 to receive Peg-IFN alfa-2a for 48 (n = 153) or 96 weeks (n = 150). The primary endpoint of this study was HBsAg loss at end of treatment. The ClinicalTrials.gov identifier is NCT01464281.@*Results@#At the end of 48 and 96 weeks' treatment, 14.4% (22/153) and 20.7% (31/150) of patients, respectively, who switched from NA to Peg-IFN alfa-2a cleared HBsAg. Rates were similar irrespective of prior NA or baseline HBeAg seroconversion. Among those who cleared HBsAg by the end of 48 and 96 weeks' treatment, 77.8% (14/18) and 71.4% (20/28), respectively, sustained HBsAg loss for a further 48 weeks. Baseline HBsAg < 1 500 IU/mL and week 24 HBsAg < 200 IU/mL were associated with the highest rates of HBsAg loss at the end of both 48- and 96-week treatment (51.4% and 58.7%, respectively). Importantly, extending treatment from 48 to 96 weeks enabled 48.3% (14/29) more patients to achieve HBsAg loss.@*Conclusion@#Patients on long-term NA who are unlikely to meet therapeutic goals can achieve high rates of HBsAg loss by switching to Peg-IFN alfa-2a. HBsAg loss rates may be improved for some patients by extending treatment from 48 to 96 weeks, although the differences in our study cohort were not statistically significant. Baseline and on-treatment HBsAg may predict HBsAg loss with Peg-IFN alfa-2a.