RESUMEN
The formulation of the antituberculosis drug rifampicin embedded into 20-30 nm nanoparticles from soy phosphatidylcholine and sodium oleate, is characterized by greater bioavailability as compared with free drug substance. In this study higher antituberculosis activity of this formulation was shown. Rifampicin in nanoparticles demonstrated more effective inhibition of M. tuberculosis H37Rv growth: minimal inhibiting concentration (MIC) was twice smaller than for free rifampicin. Administration of this preparation to mice with tuberculosis induced by M. tuberculosis Erdman revealed that after 6 weeks of oral administration the CUF value in lung was 22 times smaller for rifampicin in nanoparticles than for free drug (1.7 un. vs. 37.4 un.). The LD50 value in mice was two fold higher for rifampicin in nanoformulation.
Asunto(s)
Antituberculosos/farmacología , Portadores de Fármacos , Nanopartículas , Ácido Oléico , Rifampin/farmacología , Animales , Ratones , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
The specific activity of drug formulation of doxorubicin embedded into phospholipid nanoparticles with diameter less than 30 nm ("Doxolip") was studied in mice LLC carcinoma. Doxolip was prepared according to technology that was elaborated in Institute earlier. Doxorubicin tumor accumulation after intraperitoneal administration (at 4 h) was 4.5 times higher for Doxolip, than for free doxorubicin. The study of doxorubicin antitumor activity in developing tumor after single intravenous administration, 48 h after inoculation, showed, that: 1) tumor growth inhibition of Doxolip was observed at 6th day, while it was only at 11th day for free doxorubicin and revealed in less extent; 2) there was no antitumor effect of free doxorubicin at 8 days after administration of doses 2 and 4 mg/kg, but it was observed for Doxolip in dose-dependent manner, 10% and 30% correspondently. In experiment with developed tumor weekly Doxolip intraperitoneal administration (5 mg/kg, 3 weeks beginning from 7 days after inoculation) resulted in 56% decrease of tumor volume as compared with control. This parameter for free doxorubicin was 2.8 times lower. The obtained data indicate, that incorporation of doxorubicin into phospholipid nanoparticles with size up to 30 nm as delivery system increases its tumor accumulation and results to increase of specific activity both in intraperitoneal and in intravenous administration.
Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Portadores de Fármacos , Nanopartículas/administración & dosificación , Fosfolípidos/química , Animales , Antibióticos Antineoplásicos/farmacología , Carcinoma Pulmonar de Lewis/patología , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Miembro Posterior , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Inyecciones Subcutáneas , Ratones , Nanopartículas/química , Tamaño de la Partícula , Distribución Tisular , Carga Tumoral/efectos de los fármacosRESUMEN
It is known that disorders in the cell functioning of the organs/tissues is accompanied by increased expression of certain receptors. A modern approach to improve the specificity of the drug accumulation in the affected area is to construct the delivery nanosystems with the address fragments. Active tagged transport may help to reduce the dose of the drug, minimizing the impact on healthy cells and organs (reduced adverse events). This approach is particularly important in oncology because of the high toxicity of the drugs used. In this work we have obtained and characterized the pharmaceutical composition of doxorubicin and chlorine e6 into colloidal nanoparticles with synthesized previously targeted conjugates based on folic acid and biotin. On the cell culture Hep G2 it was shown an increase in the internalization of drugs when they were introduced in the incubation medium in the form of drug compositions with transport nanosystems and targeted fragments.
Asunto(s)
Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Endocitosis , Nanopartículas/metabolismo , Antineoplásicos/química , Biotina/química , Clorofilidas , Doxorrubicina/química , Ácido Fólico/química , Células Hep G2 , Humanos , Nanopartículas/química , Porfirinas/químicaRESUMEN
The use of targeted transport systems for drug delivery is a promising approach to improve pharmacokinetics of drug substances, accumulation in the lesion. In this study we have obtained and characterized the pharmaceutical composition of doxorubicin in colloidal nanoparticles equipped with targeted conjugates based on folic acid and biotin with dodecylamine. The inclusion of the address fragments into colloidal nanopartical was carried out without surface and drug substance modification The accumulation of anthracycline antibiotic doxorubicin in tumor tissue was compared in Lewis lung carcinoma mouse models after intravenous administration of the composition of colloidal nanoparticles with targeted conjugates biotin-dodecylamine and folic acid-dodecylamine or free doxorubicin. It was shown that the doxorubicin accumulation in tumor tissue when administered in drug compositions with targeted fragments are 2 times higher for the folic acid-dodecylamine conjugate and 1.4 times higher for the biotin-dodecylamine conjugate.
Asunto(s)
Doxorrubicina/química , Doxorrubicina/farmacocinética , Nanopartículas/química , Aminas/química , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Biotina/química , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Coloides/administración & dosificación , Coloides/química , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Ácido Fólico/química , Masculino , Ratones Endogámicos , Nanopartículas/administración & dosificación , Distribución TisularRESUMEN
An enzyme of cephalosporin-acid synthetase produced by the E. coli strain VKPM B-10182 has specificity for the synthesis of ß-lactam antibiotics of the cephalosporin acids class (cefazolin, cefalotin, cefezole etc.). A comparison of the previously determined genomic sequence of E. coli VKPM B-10182 with a genome of the parent E. coli strain ATCC 9637 was performed. Multiple mutations indicating the long selection history of the strain were detected, including mutations in the genes of RNase and ß-lactamases that could enhance the level of enzyme synthesis and reduce the degree of degradation of the synthesized cephalosporin acids. The CASA gene--a direct homolog of the penicillin G-acylase gene--was identified by bioinformatics methods. The homology of the gene was confirmed by gene cloning and the expression and determination of its enzymatic activity in the reaction of cefazolin synthesis. The CASA gene was isolated and cloned into the original expression vector, resulting in an effective E. coli BL2l(DE3) pMD0107 strain producing CASA.
Asunto(s)
Cefalosporinas/metabolismo , Escherichia coli/enzimología , Ligasas/genética , Clonación Molecular , Escherichia coli/genética , Genoma Bacteriano , Ligasas/aislamiento & purificación , Ligasas/metabolismo , Penicilina Amidasa/genética , Penicilina Amidasa/metabolismo , beta-Lactamasas/genética , beta-Lactamasas/metabolismoRESUMEN
The effects of natural polyphenols, resveratrol (RES) and dihydroquercetin (DHQ), included in phospholipid nanoparticles, have been compared with free substances of RES and DHQ in in vitro and in vivo experiments. Preincubation of healthy donor plasma low density lipoproteins (LDL) with RES or DHQ included in phospholipid nanoparticles caused a more pronounced decrease in Cu2+ induced lipid oxidation compared with the free substances, and reduced the formation of lipid peroxides products. Bioavailabilities of RES and DHQ in phospholipid formulations after oral administration in rats were increased by 1.5-2 times. In an acute hypoxia model in mice prophylactic two-week administration of RES or DHQ phospholipid formulations resulted in 25% increase in survival and 1.5-fold increase in catalase activity in brain homogenates compared to free substances. Using the model of endothelial dysfunction in rats induced by L-NAME it was shown, that RES markedly attenuated the inhibition effect of L-NAME on NO synthesis. RES in phospholipid nanoparticles had the same action at a dose 10 times lower compared to free RES. Load test with resistance (clamping of the ascending aorta for 30 sec) showed that phospholipid formulation of RES possessed more pronounced protective effect due to the stimulation of endothelial NO-synthase.
Asunto(s)
Antioxidantes/farmacología , Nanopartículas/química , Fosfolípidos/química , Quercetina/análogos & derivados , Estilbenos/farmacología , Alquenos/antagonistas & inhibidores , Alquenos/metabolismo , Animales , Antioxidantes/química , Antioxidantes/farmacocinética , Portadores de Fármacos , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas LDL/química , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Quercetina/química , Quercetina/farmacocinética , Quercetina/farmacología , Ratas , Ratas Wistar , Resveratrol , Estilbenos/química , Estilbenos/farmacocinéticaRESUMEN
Cephalosporin acid synthetase (CASA) is responsible for specific to synthesis of cephalosporin-acids, its expression in Escherichia coli cells is accompanied by accumulation of unprocessed insoluble precursor. In order to optimize conditions of recombinant CASA production we have studied the effects of several parameters of strain cultivation, including growth media composition, temperature, and inoculation dose. Also plasmids for production of CASA variants with the signal sequence of Erwinia carotovora L-asparaginase (ansCASA) and "leaderless" CASA were created in search of more efficient expression constructs. Removal of the N-terminal secretion signal sequence reduced the production of functionally active CASA more than 10-fold and inhibited strain growth. Insertion of the L-asparaginase signal sequence increased the specific enzyme activity in the resultant recombinant strain. The ansCASA producing strain was used to develop the method of immobilization of the recombinant enzyme on an epoxy-activated macroporous acrylic support. The resultant biocatalyst performed effective synthesis of cefazolin from 3-[(5-methyl-1,3,4-thiadiazol-2-il)-thiomethyl]-7- aminocephalosporanic acid (MMTD-7-ACA) and methyl ester of 1(H)-tetrazolilacetic acid (ÐETzAA), under mild conditions a transformation level of MMTD-7-ACA to cefazolin of 95% is reached.
Asunto(s)
Asparaginasa/metabolismo , Proteínas Bacterianas/metabolismo , Cefazolina/metabolismo , Proteínas Inmovilizadas/metabolismo , Complejos Multienzimáticos/metabolismo , Acrilatos/química , Asparaginasa/genética , Proteínas Bacterianas/genética , Biocatálisis , Clonación Molecular , Medios de Cultivo/química , Escherichia coli/enzimología , Escherichia coli/genética , Expresión Génica , Ingeniería Genética , Proteínas Inmovilizadas/genética , Complejos Multienzimáticos/genética , Pectobacterium carotovorum/química , Pectobacterium carotovorum/enzimología , Plásmidos/química , Plásmidos/metabolismo , Señales de Clasificación de Proteína , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
A new generation of plant phosphatidylcholine (PC)-based pharmacological agents has been developed under academician A.I. Archakov leadership at the Institute of Biomedical Chemistry (IBMC). For their production a unique technology allowing to obtain dry lyophilized phospholipid nanoparticles of 30 nm was elaborated. The successful practical application of PC nanoparticles as a drug agent may be illustrated by Phosphogliv (oral and injection formulations). Being developed at IBMC for the treatment of liver diseases, including viral hepatitis, Phosphogliv (currently marketed by the "Pharmstandard" company) is approved for clinical application in 2000, and is widely used in medical practice. Based on the developed and scaled in IBMC technology of prerparation of ultra small size phospholipid nanoparticles without the use of detergents/surfactants and stabilizers another drug preparation, Phospholipovit, exhibiting pronounced hypolipidemic properties has been obtained. Recently completed preclinical studies have shown that PC nanoparticles of 20-30 nm activate reverse cholesterol transport (RCT) and in this context it is more active than well known foreign preparation Essentiale. Phospholipovit is now at the stage of clinical trials (phase 1 completed). PC was also used as a basis for the development of a transport nanosystem with a particles size of 20-25 nm in diameter and incorporation of various drug substances from various therapeutic groups. Using several drugs substances as an example, increased bioavailability and specific activity were demonstrated for the formulations equipped with such transport nanosystem. Formulations equipped with the transport nanosystems have been developed for such pharmacological agents as doxorubicin, rifampin, budesonide, chlorin E6, prednisone, and others.
Asunto(s)
Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Ácido Glicirrínico/farmacología , Nanoestructuras/química , Fosfatidilcolinas/farmacología , Fosfolípidos/química , Animales , Disponibilidad Biológica , Colesterol/metabolismo , Doxorrubicina/administración & dosificación , Portadores de Fármacos , Combinación de Medicamentos , Ácido Glicirrínico/química , Humanos , Nanopartículas/química , Tamaño de la Partícula , Fosfatidilcolinas/química , Rifampin/administración & dosificaciónRESUMEN
A new method for the analysis of blood lipid based on direct mass spectrometry of lipophilic low molecular weight fraction of blood plasma has been considered. Such technique allows quantification of hundreds of various types of lipids and this changes existing concepts on diagnostics of lipid disorders and related diseases. The versatility and quickness of the method significantly simplify its wide use. This method is applicable for diagnostics of atherosclerosis, diabetes, cancer and other diseases. Detalization of plasma lipid composition at the molecular level by means of mass spectrometry allows to assess the effectiveness of therapy and to optimize the drug treatment of cardiovascular diseases by phospholipid preparations.
Asunto(s)
Análisis Químico de la Sangre/métodos , Lípidos/sangre , Espectrometría de Masas/métodos , Humanos , Sensibilidad y EspecificidadRESUMEN
Cryptococcus neoformans is a common agent of fungal meningoencephalitis in immunocompromised patients. Cerebral salt-wasting syndrome is one of the rare causes of severe hyponatremia in patients with CNS diseases. The paper describes the first clinical case of a patient, whose onset of chronic lymphocytic leukemia was complicated by cryptococcal meningoencephalitis presenting with mental disorders and severe electrolytic imbalance. Antifungal treatment with amphotericin B and fluconazole could alleviate an infectious process and metabolic disturbances.
Asunto(s)
Antifúngicos/uso terapéutico , Hiponatremia , Leucemia Linfocítica Crónica de Células B , Meningitis Criptocócica/tratamiento farmacológico , Anciano , Anfotericina B/uso terapéutico , Comorbilidad , Fluconazol/uso terapéutico , Humanos , Hiponatremia/epidemiología , Leucemia Linfocítica Crónica de Células B/epidemiología , Masculino , Meningitis Criptocócica/epidemiología , SíndromeRESUMEN
The drug formulations of antituberculous remedy rifampicin in nanoparticles less than 30 nm based on soy phosphatidylcholine and sodium oleate was elaborated in Institute of Biomedical Chemistry. The distribution of rifampicin in blood plasma fractions after incubation with this formulation and with free rifampicin was studied. This goal was stimulated by the literature data about activation of macrophages LDL receptors in cases of M. tuberculosis infection. Plasma was incubated 30 min with free rifampicin or rifampicin encapsulated into the nanoformulation followed by ultracentrifugation and subsequent rifampicin determination by HPLC in lipoprotein fractions. In the case of free rifampicin it appeared mainly in the plasma protein fraction and in HDL (41% and 38%, correspondentely). But after incubation of rifampicin in nanoparticles the drug redistribution was observed. Its proportion in these factions decreased 2-3-fold, and it was found mainly in LDL (60% as compared with 21% for free rifampicin). The increased association of rifampicin encapsulated into phospholipid nanoparticles with LDL is considered as facilitating factor for macrophages delivery and thus for antituberculosis efficiency as well.
Asunto(s)
Antibióticos Antituberculosos/química , Lipoproteínas HDL/química , Lipoproteínas LDL/química , Nanopartículas/química , Rifampin/química , Antibióticos Antituberculosos/sangre , Centrifugación por Gradiente de Densidad , Fraccionamiento Químico , Humanos , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Ácido Oléico/química , Fosfatidilcolinas/química , Unión Proteica , Rifampin/sangreRESUMEN
One of the main ways to increase the effectiveness of well-known medical formulations well-established in clinical medicine - development of delivery systems using new technological approaches and nanomaterials. Currently, much attention is given to targeted delivery systems. At the same time drug carrier has in addition to medication the so-called vector/address with a high affinity for binding to specific receptors on cells/tissue target. In this paper it is described the method for producing of address conjugates to over-expressed receptors on the tumor cells. As address fragment it was folic acid and as a linker was dodecylamine, causing inclusion the conjugate into lipid nanoparticles.
Asunto(s)
Aminas/química , Portadores de Fármacos/síntesis química , Ácido Fólico/química , Nanopartículas/química , Transporte Biológico , Etildimetilaminopropil Carbodiimida/química , Células Hep G2 , HumanosRESUMEN
The increase of tuberculosis incidence in last decade stimulated elaboration of both new antituberculous drugs and also searches ofoptimiting delivery systems for existing drugs. It is determined by their side effects and low bioavailability of effective first line drug rifampicin. Various nanosystems for transport of antituberculous drugs are considered on the basis of various polymers, liposomes, lipid nanoparticles, nanoemulsios, nanosuspensions, dendrimers, cyclodextrines. Influence of drug incorporation into nanoparticles, most often for rifampicin, on pharmacokinetics and efficiency in tuberculosis models is discussed. The most of works are devoted to polymer nanoparticles for oral administration where increased circulation time and efficiency were shown. The best results were observed after drug inclusion into solid lipid nanoparticles. The liposomes formulations were investigated mostly for inhalation and injection administrations. Positive results were also observed. Authors underline the viability of incorporation of antituberculous drugs into phospholipid nanoparticles that may increase intestinal absorption and bioavailability. It is confirmed by authors' own data that showed increase of rifampicin efficiency after their incorporation into such nanoparticles.
Asunto(s)
Antituberculosos/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Tuberculosis/tratamiento farmacológico , Administración Oral , HumanosRESUMEN
Low bioavailability of rifampicin, one of the main antituberculous drug, stimulates searches of its new optimized formulations. The present study has showen possibility of rifampicin embedding into nanoparticles from plant phosphatidylcholine (diameter of 20-30 nm). Addition of sodium oleate to the phospholipid system caused a 2-fold increase of the percent of rifampicin incorporation. After oral administration to rats, the maximal drug observed in plasma one hour after was 0.5 and 4.2 mkg/ml for free rifampicin for rifampicin in phospholipids-oleate nanoparticles, respectively. These levels were maintained for more than two hours of the experiment. High rifampicin bioavailability in the oleate containing phospholipid nanosystem suggests prospectivity of its pharmaceutical elaboration.
Asunto(s)
Antibióticos Antituberculosos , Nanopartículas/química , Ácido Oléico , Fosfolípidos , Rifampin , Animales , Antibióticos Antituberculosos/química , Antibióticos Antituberculosos/farmacocinética , Antibióticos Antituberculosos/farmacología , Sistemas de Liberación de Medicamentos , Masculino , Nanopartículas/ultraestructura , Ácido Oléico/química , Ácido Oléico/farmacocinética , Ácido Oléico/farmacología , Tamaño de la Partícula , Fosfolípidos/química , Fosfolípidos/farmacocinética , Fosfolípidos/farmacología , Ratas , Ratas Wistar , Rifampin/química , Rifampin/farmacocinética , Rifampin/farmacologíaRESUMEN
Thirty four patients with mucormycosis in 10 hospitals of St. Petersburg were observed in 2004-2013. The most frequent underlying diseases of mucormycosis were acute leukoses (64%). In 100% of the patients mucormycosis developed as a nosocomial infection. The risk factors, etiology, basic clinical signs and strategy in the treatment of mucormycosis were analyzed.
Asunto(s)
Antifúngicos/uso terapéutico , Infección Hospitalaria/microbiología , Leucemia Linfocítica Crónica de Células B/microbiología , Leucemia Mieloide Aguda/microbiología , Mucormicosis/microbiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Infección Hospitalaria/complicaciones , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/mortalidad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mucormicosis/complicaciones , Mucormicosis/tratamiento farmacológico , Mucormicosis/mortalidad , Estudios Prospectivos , Rhizopus/efectos de los fármacos , Rhizopus/crecimiento & desarrollo , Rhizopus/aislamiento & purificación , Factores de Riesgo , Federación de Rusia , Análisis de SupervivenciaRESUMEN
Increasing distance between practical public health services and collecting of theoretical information in the field of biomedical researches reflects the necessity of professional contact between clinicians and scientists in many areas associated with medicine for active carrying over ("translation") of the modern basic researches in which mechanisms of basic metabolic processes and possibilities of their correction are detected, to effective medical help to individual patient, i.e., personified medicine. Such approach was called transmitting medicine. Examples of the personified medicine in which biomedical researches together with the anamnesis morbi of individual patient that are responsible for treatment strategy including doses and regimens are discussed.
Asunto(s)
Salud Pública , Investigación Biomédica Traslacional/tendencias , Investigación Biomédica , Humanos , Medicina de PrecisiónRESUMEN
Glycyrrhizic acid (GL)--one of the active components of the Russian drug formulation "Phosphogliv" possesses extremely low bioavailability. A sensitive method for GL determination in blood using high performance liquid chromatography coupled with mass-spectrometry (HPLC-MS) has been developed in order to investigate absorption characteristics of glycyrrhizic acid after peroral administration of "Phosphogliv" and GL sodium salt. Separation of blood components was achieved on the analytical reverse-phase column C18 "EcoNova" ProntoSIL, using a gradient mode. Detection of GL and an internal standard (IS) (glycyrrhetic acid) was performed using electrospray ionization with the selected ion monitoring in negative mode (SIM) using target ions at m/z 821.3 for GL and 469.3 for IS. The calibration curve was linear over the range of 50-5000 ng/ml (the correlation coefficient was 0.995). The detection limit for GL in blood was 25 ng/ml and the lower limit of quantification was 50 ng/ml. The developed method has been applied to compare absorption efficiency of glycyrrhizic acid as the component of "Phosphogliv" composition and solution of GL sodium salt during first two hours after their single peroral administration to rats at the dose of 8.5 mg/kg. It was shown that GL absorption occurs several minutes after peroral administration. Moreover, GL bioavailability after administration of drug "Phosphogliv" was higher than after administration of GL sodium salt. This difference may be attributed to incorporation of glycyrrhizic acid in the phospholipid nanoparticles structure.
Asunto(s)
Antiinflamatorios/farmacocinética , Ácido Glicirrínico/farmacocinética , Fosfatidilcolinas/farmacocinética , Administración Oral , Animales , Antiinflamatorios/farmacología , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Ácido Glicirrínico/farmacología , Espectrometría de Masas , Fosfatidilcolinas/farmacología , RatasRESUMEN
AIM: The new formulation of doxorubicin on the base of phospholipid nanoparticles (particle size <30 nm) is elaborated in the Institute of Biomedical Chemistry (Russian Academy of Medical Sciences) on the base of plant phospholipids. The aim of study is to investigate an antitumor effect of this nanoformulation in mice with two cancer models with various sensitivity to chemotherapy lymphoid malignancy P-388 and Lewis lung carcinoma (LLC). METHODS: Nanophospholipid (NPh) formulation of doxorubicin was prepared by homogenization of soybean phosphatidylcholine and doxorubicin hydrochloride. The effect of this formulation was studied in experiments with single or threefold drug administration. Percents of tumor growth inhibition in mice under influence of free or NPh doxorubicin forms were compared. RESULTS: Single administration of both free and NPh doxorubicin in mice with P-388 resulted in the same quick severe inhibition of tumor growth (6090% depending from dose), with further gradual decrease of inhibition degree. However for more resistant tumor, LLC, the obvious advantage of NPh doxorubicin form was shown. The little effect of free doxorubicin began to reveal only after 11 days, but NPh formulation induced significant inhibition of tumor growth (40%) from the first experimental point (6 days after administration). The advantages of NPh doxorubicin was manifested particularly in low drug doses, 2 and 4 mg/kg. In other experiment design in mice with LLC, with threefold weekly drug administration, NPh doxorubicin appeared to be 2.5 times more active than free drug. The reason of the same actions of free and NPh doxorubicin form in P-388 is suggested the high drug sensitivity of this model, that gives quick high drug response for any doxorubicin form. CONCLUSION: Doxorubicin in phospholipids nanoformulation revealed higher antitumor efficiency as compared with free doxorubicin in mice with LLC carcinoma. The mechanism of such changes is supposed to be caused by increase of doxorubicin availability for cancer cells.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias Experimentales/tratamiento farmacológico , Fosfolípidos , Animales , Química Farmacéutica , Ratones , Ratones Endogámicos BALB CRESUMEN
The drug composition based on the plant phospholipids and the antitumor drug doxorubicin (particle size <30 nm) was obtained using original technology elaborated in the Institute of Biomedical Chemistry (Russian Academy of Medical Sciences). In in vitro experiments demonstrated decreased drug association with blood cells for this nanophospholipid form as compared with free doxorubicin. This was accompanied by a with corresponding increase in its plasma level ans also by drug redistribution from plasma protein fraction to high density lipoproteins. Significance of these changes for doxorubicin biodistributon and antitumor activity is discussed.
Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Nanopartículas , Fosfolípidos/farmacocinética , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/química , Doxorrubicina/farmacología , Eritrocitos/metabolismo , Lipoproteínas HDL/metabolismo , Masculino , Fosfolípidos/química , Fosfolípidos/farmacología , Ratas , Ratas WistarRESUMEN
The ultrafine formulation on the base of plant phosphatidylcholine and antiinflammatory remedy indomethacin with nanoparticles less than 50 nm was obtained. Drug bioavailability after its peroral administration to rats was more than 2 fold higher as compared with free indomethacin. Increased antiinflammatory activity of indomethacin in phospholipids nanoparticles as compared with its free form was shown in two models of inflammation - adjuvant arthritis in rats and conconavalin A induced edema in mice. The increased bioavailability of indomethacin after administration of its phospholipid formulation allows to decrease a dose for achievement of therapeutic effect, that reduces risks of occurrence of collateral displays.