RESUMO
In this study, we have prepared PLGA (poly-D,L-lactide-co-glycolide) nanospheres loaded with biocompatible magnetic fluid and anticancer drug taxol by a modified nanoprecipitation technique and investigated their magnetic properties. A magnetic fluid, MF-PEG, with a biocompatible layer of polyethylene glycol (PEG), was chosen as a magnetic carrier. The PLGA, whose copolymer ratio of D,L-lactide to glycolide is 85:15, was utilized as a capsulation material. Taxol, as an important anticancer drug, was chosen for its significant role against a wide range of tumours. The morphology and particle size distributions of the prepared nanospheres were investigated by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed a spherical shape of prepared nanospheres with size 250 nm. Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetry (TGA) analysis confirmed incorporation of magnetic particles and taxol into the PLGA polymer. The results showed good encapsulation with magnetite content 21.5 wt% and taxol 0.5 wt%. Magnetic properties of magnetic fluids and taxol within the PLGA polymer matrix were investigated by SQUID magnetometry from 4.2 to 300 K. The SQUID measurements showed superparamagnetism of prepared nanospheres with a blocking temperature of 160 K and saturation magnetization 1.4 mT.
RESUMO
Quinazolines - 1,3-benzodiazines are biological active compounds, and some of them act as anticancer drugs. We evaluated cytotoxic/antiproliferative activity of new synthetically prepared [1,2,4]triazolo[4,3-c]quinazolines using tumor cell lines HeLa and B16. The in vitro cytotoxic studies of the most active derivative 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin- 4-yl[1,2,4]triazolo[4,3-c]quinazoline (NTCHMTQ) were complemented by cell cycle analysis, and determination of apoptotic DNA fragmentation. Possible direct interaction of NTCHMTQ with calf thymus DNA was tested by the DNA-modified screen-printed electrode. Five quinazoline derivatives tested acted cytotoxically on both tumor cell lines. The melanoma cells B16 were more sensitive to quinazolines treatment than HeLa cells. The most effective derivative was NTCHMTQ which manifested significant in vitro cytotoxic/antiproliferative effect. NTCHMTQ at micromolar concentrations induced morphological changes and necrosis of B16 cells. NTCHMTQ at concentrations tested did not cause changes in cell cycle, did not induce apoptotic cell death in the B16 cells and did not even behave as a typical intercalating agent.
Assuntos
Antineoplásicos/farmacologia , Melanoma Experimental/tratamento farmacológico , Quinazolinas/farmacologia , Triazóis/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Melanoma Experimental/patologia , CamundongosRESUMO
The antifungal activity of 6-amino-2-n-pentylthiobenzothiazole (APB) against 26 strains of the genus Candida in vitro was studied. Susceptibility of 17 strains was IC(50) = 40 mumol/ml, of 7 strains IC(50) = 40-80 mumol/ml and of 2 strains IC(50) = 80-200 mumol/ml. Generalized candidosis of mice was treated with APB (doses 50, 100, 250 mg/kg) and ketoconazole (KET, 50 mg/kg of body weight). The optimal dose of APB was shown to be 100 mg/kg; 25% of mice survived after 14 days as compared to control animals. C. albicans was not found in the kidney of the sacrificed mice. 80% of mice survived after KET therapy. However, C. albicans was present in the kidney in an amount of 10(5)-10(6) CFU/g of tissue. C. albicans did not reappear in the kidney 7 days after the discontinuation of APB treatment, but it was found there after KET therapy.
RESUMO
Vermiculine, a macrocyclic aglycosidic dilactone isolated from Penicillium vermiculatum, has been shown to have immunomodulatory properties. Here, we tested the effects of vermiculine on selected parameters of cell-mediated immunity in vitro and on skin allograft survival in vivo. Vermiculine inhibited in a dose-dependent manner the proliferation of mouse spleen cells stimulated with Concanavalin A ((Con A), i.e. T-cell mitogen), bacterial lipopolysaccharide ((LPS), B-cell mitogen) or with irradiated allogeneic cells. In addition, vermiculine dose-dependently inhibited the production of Thl (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokines and suppressed the production of nitric oxide (NO) by activated macrophages. When compared with cyclosporine (CsA), vermiculine was less inhibitory for IL-2 gene expression and IL-2 synthesis, comparably suppressive on IL-10 production and even more inhibitory for NO synthesis. These observations suggest that vermiculine and CsA inhibit immune reactions by different mechanisms. Treatment of graft recipients with vermiculine or CsA prolonged survival of skin allografts in a mouse model. The combination of both drugs enhanced the survival of allografts significantly more than either drug alone. The results thus suggest that vermiculine is a potential immunosuppressive drug acting by a mechanism distinct from that of CsA, and thus it may be used alone or in combination with other drugs for immunoregulatory purposes.
Assuntos
Imunossupressores/farmacologia , Lactonas/farmacologia , Imunologia de Transplantes/efeitos dos fármacos , Transplante Homólogo/imunologia , Animais , Divisão Celular/efeitos dos fármacos , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Interleucina-2/biossíntese , Interleucina-2/genética , Teste de Cultura Mista de Linfócitos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitógenos/farmacologia , Óxido Nítrico/biossíntese , Transplante de Pele/imunologia , Baço/citologia , Baço/efeitos dos fármacosRESUMO
The tolerance of the new calcium antagonist VULM 993 was investigated in a series of toxicological studies. The following results were obtained: the maximum tolerated oral dose in acute toxicity was 10,000 mg/kg for mice and 6600 mg/kg for rats, for venous administration it was 26.1 mg/kg in mice and 32.2 mg/kg in rats. In subacute oral toxicity test in rats, VULM 993 showed no toxic effect up to 300 mg/kg/d. The drug was not teratogenic in rats (5, 50 or 250 mg/kg/d, p.o.). VULM 993 did not show any positive response in tests for genotoxicity in vitro. Transplacental study of VULM 993 in rabbits indicated active placental barrier function in the late stage of pregnancy. The toxicological profile of VULM 993 is characterised by a high tolerance in all relevant species of experimental animals, and no biologically significant mutagenic potential was recorded.
Assuntos
Bloqueadores dos Canais de Cálcio/toxicidade , Troca Materno-Fetal , Piridinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Administração Oral , Animais , Biotransformação , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Linhagem Celular , Feminino , Injeções Intravenosas , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Testes de Mutagenicidade , Placenta/fisiologia , Gravidez , Piridinas/administração & dosagem , Piridinas/farmacocinética , Coelhos , Ratos , Ratos Wistar , Salmonella typhimurium/efeitos dos fármacos , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacocinética , TeratogênicosRESUMO
The induction of mutations at the HPRT locus and cytotoxicities of 4 vermiculin derivatives 2-4 and 6 were examined in V79 Chinese hamster cells and compared with those of the parent compound vermiculin (1). Derivatives prepared by hydrogenation were less toxic and mutagenic or non toxic and non mutagenic. The substitution at position 13 affected the evaluated biological effects. The results suggest that in vitro metabolism of vermiculin resulted in decreased cytotoxicity and mutagenicity.
Assuntos
Antibióticos Antineoplásicos/síntese química , Mutagênicos/síntese química , Animais , Antibióticos Antineoplásicos/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Hipoxantina Fosforribosiltransferase/genética , Lactonas/síntese química , Lactonas/toxicidade , Masculino , Testes de Mutagenicidade , Mutagênicos/toxicidade , Ratos , Ratos WistarRESUMO
Hydrogenation of the macrodiolide antibiotic vermiculin (1) over Adams catalyst afforded [8S, 16S]-8,16-bis(2'-oxopropyl)-1,9- dioxyacyclohexadeca-2,5,10,13-tetrone (2), [8S, 16S]-8,16-bis(2'-oxopropyl)-13-hydroxy-1,9-dioxacyclohexadeca- 2,5,10-trione (3), [8S,16S]-8,16-bis(2' oxopropyl)-1,9- dioxacyclohexadeca-2,5,10-trione (4) together with [7S]-4,9-dioxo-7-(4',9'-dioxodecanoyloxy)decanoic acid (5). Hydrogenation of diolide 1 over Pd/C gave tetrahydrovermiculin (2) only. The prepared compounds showed lower antibacterial and cytotoxic activities than vermiculin (1).
Assuntos
Antibióticos Antineoplásicos/síntese química , Animais , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Arthrobacter/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Hidrogenação , Lactonas/síntese química , Lactonas/farmacologia , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The effect of the combination of sulbactam, cephalothin, and cephazolin was studied in vitro on 88 strains of E. coli and 11 strains of P. mirabilis producing beta-lactamases. Quantitative susceptibility of the tested strains to cephalothin was examined by the disk dilution method and the effect of the combinations with sulbactam by the micromethod. The production of beta-lactamases was determined by the qualitative test with the chromogenic substrate PODAC. Of the total number of 160 E. coli strains beta-lactamases were established in 53.3% of the strains. Of the 47 P. mirabilis strains 23.4% were found to produce beta-lactamases. The effect of the combinations with sulbactam was assessed as synergistic, additive, indifferent or antagonistic. In the combination of sulbactam in the concentration of 16.0 mg/l with cephalothin and cephazolin a higher rate of synergistic and additive effect was recorded on both strains. In none of the combinations did sulbactam exert an antagonistic effect.
Assuntos
Cefazolina/farmacologia , Cefalotina/farmacologia , Escherichia coli/efeitos dos fármacos , Proteus mirabilis/efeitos dos fármacos , Sulbactam/farmacologia , beta-Lactamases/biossíntese , Cefazolina/administração & dosagem , Cefalotina/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Escherichia coli/enzimologia , Testes de Sensibilidade Microbiana , Proteus mirabilis/enzimologia , Sulbactam/administração & dosagemAssuntos
Aleitamento Materno , Promoção da Saúde , Tchecoslováquia , Feminino , História do Século XX , Humanos , Recém-NascidoAssuntos
Aleitamento Materno , Tchecoslováquia , Feminino , Humanos , Lactente , Alimentos Infantis , Recém-Nascido , Fatores de TempoRESUMO
4-Chloro-2-methylphenoxyacetic acid (MCPA) is an aryloxyacetic acid derivative categorised as a plant hormone herbicide. The aim of the study was to evaluate the effect of MCPA on pregnant females and the prenatal development of rabbits. The substance tested was administered orally to pregnant New Zealand White rabbits from day 6 to day 27 of gestation at doses of 5, 10 and 25 mg kg(-1) day(-1). The animals were killed on day 28 of gestation and live fetuses were examined for gross, skeletal and visceral anomalies. Administration of MPCA did not induce any signs of maternal toxicity. There was a significant decrease of fetal and placental weight compared with controls at the highest dose of MPCA. No adverse effect of the substance tested was seen on uterine content variables, e.g. corpora lutea, pre-implantation and post-implantation loss, early, late resorptions, live and dead fetuses and sex ratio. Rabbit fetuses treated with the middle and highest doses of MPCA had a significantly elevated incidence of skull and pelvic bone delays. In conclusion, prenatal administration of MCPA did not exhibit a teratogenic effect on rabbit fetus development.
Assuntos
Ácido 2-Metil-4-clorofenoxiacético/toxicidade , Anormalidades Induzidas por Medicamentos , Feto/efeitos dos fármacos , Herbicidas/toxicidade , Ossos Pélvicos/anormalidades , Crânio/anormalidades , Ácido 2-Metil-4-clorofenoxiacético/administração & dosagem , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Peso Fetal , Idade Gestacional , Herbicidas/administração & dosagem , Tamanho do Órgão , Placenta/efeitos dos fármacos , Placentação , Gravidez , CoelhosRESUMO
In vitro and in vivo antifungal activities of synthetically parepared 6-amino-2-n-pentylthiobenzothiazole (APB) against Trichophyton strains were studied. APB inhibited the growth of 3 Trichophyton strains at 65 micrograms/ml. 2-Mercaptobenzothiazole was not effective at 125 micrograms/ml and ketoconazole inhibited the growth at 20-30 micrograms/ml. Treatment of experimental dermatophytosis in guinea pigs using 2.5% APB cream was studied in comparison to Canesten cream (1% clotrimazole). Dermatophytosis was considerably reduced after both APB and Canesten therapies.