RESUMO
1. This study aimed to evaluate the effects of phosphodiesterase (PDE) inhibitors and currently prescribed anti-asthma drugs for their ability to inhibit inflammatory cell activation in vitro. 2. Alveolar macrophages and eosinophils were isolated from the bronchoalveolar lavage (BAL) fluid of ovalbumin (Ovalb)-sensitized guinea-pigs. Opsonized zymosan (OZ) and PAF stimulated leukotriene B4 (LTB4) release from eosinophils was measured by radioimmunoassay. Ovalb-induced superoxide generation was measured by reduction of cytochrome C. 3. Monocytes were separated from human peripheral venous blood and mast cells were dispersed from human lung fragments. Lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) release from monocytes was measured by ELISA and anti-IgE stimulated histamine release from mast cells was measured by a radioenzymatic method. 4. The beta 2 agonist, salbutamol inhibited TNF-alpha release from monocytes and histamine release from mast cells whilst having no effect on eosinophil-derived LTB4 release or macrophage superoxide generation. 5. The PDE 3 inhibitor, milrinone produced a concentration-related inhibition of TNF-alpha release from monocytes which achieved statistical significance at 10(-5) M but inhibited LTB4 release from eosinophils and superoxide generation from macrophages only at the highest concentration (10(-3) M) examined. Milrinone had no effect on histamine release from mast cells. 6. The selective PDE 4 inhibitors, denbufylline and rolipram and the corticosteroid, beclomethasone produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes and superoxide generation from alveolar macrophages whilst having no effect on histamine release from mast cells. 7. The mixed PDE 3/4 inhibitor, benzafentrine produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes, superoxide generation from alveolar macrophages and histamine release from mast cells. 8. In conclusion these data clearly show that both established anti-asthma medication as well as PDE inhibitors have the potential to inhibit inflammatory cell activation in vitro but that the anti-secretory actions of beta 2 agonists, corticosteroids and PDE inhibitors are distinct.
Assuntos
Antiasmáticos/farmacologia , Isoenzimas/antagonistas & inibidores , Inibidores de Fosfodiesterase/farmacologia , Animais , Plaquetas/enzimologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Feminino , Cobaias , Liberação de Histamina , Humanos , Isoenzimas/análise , Leucotrieno B4/biossíntese , Macrófagos Alveolares/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Monócitos/efeitos dos fármacos , Neutrófilos/enzimologia , Diester Fosfórico Hidrolases/análise , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The spiropiperidylrifamycin LM 427 (4-deoxo-3,4-[2-spiro-N-isobutyl-4-piperidyl]-(1H)-imidazo-(2,5-dihydro) rifamycin S) displays a broad spectrum of potent antibacterial activity in vitro. In vivo it is particularly effective in the therapy of experimental tubercular infections of mice. Three schedules of treatment were employed and the best results were obtained when intermittent administrations were used (ED50 of LM 427; 7 times lower than rifampicin). LM 427 is well distributed in tissues of mice and rats, with lung concentrations 10 to 20 times higher than plasma levels.
Assuntos
Rifamicinas/toxicidade , Animais , Bactérias/efeitos dos fármacos , Feminino , Cinética , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Rifabutina , Rifampina/toxicidade , Rifamicinas/metabolismo , Especificidade da Espécie , Distribuição TecidualRESUMO
The biological properties of spiro-piperidyl-rifamycins, a new class of rifamycin antibiotics, are described. In these derivatives the positions 3 and 4 have been incorporated into an imidazolyl ring bearing a spiro-piperidyl group N substituted with linear and branched aliphatic chains. The in vitro antibacterial activity against Staphylococcus aureus and Mycobacterium tuberculosis increases with the number of the carbon atoms in the linera side chain, whereas the inhibitory effect on Escherichia coli is lowered. The antibacterial activity is only marginally affected by branching of the side chain. In vivo (experimental infections of mice) the optimal therapeutic activity against M. tuberculosis is shown by compounds bearing 3 approximately 5 carbon atoms as a linear or branched side chain; in comparison with rifampicin, the potency of these derivatives is 2 approximately 3 times higher. The finding is in a good agreement with the exceptional tissue tropism, which seems to be a favourable property of this group of derivatives.
Assuntos
Rifamicinas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Feminino , Cinética , Camundongos , Rifabutina , Rifamicinas/metabolismo , Distribuição TecidualRESUMO
A number of semisynthetic rifamycin derivatives modified at positions 3 and/or 4, belonging to general structures 3, 5, and 6 (see Scheme 1), have been prepared. The synthesis, structure and antimicrobial evaluation of the new compounds are described. All the derivatives have "in vitro" antibacterial activities well comparable with that of rifampicin.
Assuntos
Rifamicinas/síntese química , Bactérias/efeitos dos fármacos , Fenômenos Químicos , Química , Rifamicinas/farmacologiaAssuntos
Antibacterianos/farmacologia , Embrião de Galinha , Chlamydia/efeitos dos fármacos , Técnicas de Cultura , Eritromicina/farmacologia , Penicilinas/farmacologia , Sulfonamidas/farmacologia , Tetraciclina/farmacologia , Animais , Fenômenos Químicos , Química , Células HeLa , Modelos Teóricos , Tracoma/tratamento farmacológicoAssuntos
Ampicilina/metabolismo , Oxazóis/metabolismo , Penicilinas/metabolismo , Administração Oral , Adulto , Ampicilina/administração & dosagem , Ampicilina/sangue , Ampicilina/urina , Dicloxacilina/administração & dosagem , Dicloxacilina/sangue , Dicloxacilina/metabolismo , Dicloxacilina/urina , Sinergismo Farmacológico , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Oxazóis/urina , Penicilinas/urina , Staphylococcus/efeitos dos fármacosAssuntos
Leucomicinas/administração & dosagem , Absorção , Adulto , Idoso , Bordetella pertussis/efeitos dos fármacos , Ensaios Clínicos como Assunto , Estudos de Avaliação como Assunto , Feminino , Haemophilus influenzae/efeitos dos fármacos , Humanos , Injeções Intramusculares , Klebsiella/efeitos dos fármacos , Leucomicinas/sangue , Leucomicinas/farmacologia , Leucomicinas/urina , Masculino , Pessoa de Meia-Idade , Proteus/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Shigella/efeitos dos fármacosRESUMO
We report the levels of concentration of ampicillin, dicloxacillin, and carbenicillin reached in the blood and in the expectoration following the administration of these drugs by rapid venous infusion, once every 24 h. The concentration of ampicillin in the blood serum varied from 150 to 180 micrograms/ml at the end of the infusion and from 30 to 3 micrograms/ml 4 afterwards and the dicloxacillin concentration from 150 to 120 micrograms/ml, and from 24 to 6 micrograms/ml. The concentration of ampicillin in purulent expectoration was 5-7 micrograms/ml and that of dicloxacillin 2.5-4 micrograms/ml. The concentration of carbenicillin in the plasma varied from 1,040 to 130 micrograms/ml, and in the expectoration it was around 15 micrograms/ml. Several cases of acute and chronic lung and bronchial diseases caused by bacteria have been treated by means of venous infusion once every 24 h and results were excellent.
Assuntos
Ampicilina/sangue , Broncopatias/sangue , Carbenicilina/sangue , Dicloxacilina/sangue , Pneumopatias/sangue , Muco/análise , Ampicilina/administração & dosagem , Broncopatias/tratamento farmacológico , Carbenicilina/administração & dosagem , Dicloxacilina/administração & dosagem , Humanos , Infusões Parenterais , Pneumopatias/tratamento farmacológicoRESUMO
Intercalation, insertion of a conjugated polycyclic aromatic ligand between stacked bases of helical DNA, is a common means of binding for a number of agents. This mode of binding generally accounts directly for a number of effects which are broadly uniform for most cells under appropriate conditions. Intercalating agents bind to plasma and intracellular membranes and interact with phospholipids to varying degrees. Biotransformation and activation may also occur at the membrane sites. Besides effects attributable to DNA binding, many of the therapeutic and cytotoxic effects that are characteristic of these agents may be a function of binding and activation in membranes, appearing to be independent of intercalation in some cases but also enhancing DNA-related actions in others. The range of differential effects of intercalating drugs stemming from binding at DNA and membranal sites seems sufficiently diverse to explain selectivity which is expressed in cell- and organ-specific changes, individual and species variability, and numerous drug actions apparently unrelated to intercalation alone.
Assuntos
Antineoplásicos/metabolismo , DNA/metabolismo , Animais , Antineoplásicos/farmacologia , Sítios de Ligação , Humanos , Técnicas In Vitro , Ligantes , Lipídeos de Membrana/metabolismo , Membranas/metabolismo , Conformação de Ácido Nucleico/efeitos dos fármacos , Fosfolipídeos/metabolismoRESUMO
Thiamphenicol glycinate acetylcysteinate (TGA, CAS 20192-91-0) is a water soluble ester of thiamphenicol (TAP) that allows a rapid utilization by the systemic route but also a direct local action when used as aerosol. To assess the efficacy of aerosolized TGA in the treatment of experimental pneumonia in mice, we compared its in vivo activity with that of thiamphenicol glycinate hydrochloride (TG), erythromycin (ERT) and amoxicillin (AMX), the last two compounds being more active in vitro than TAP. TGA, administered by aerosol route, showed better efficacy than the aerosolized TG, particularly as far as survival rate is concerned, and was significantly more potent than ERT and similar to AMX either administered by oral route. No significantly different therapeutic efficacy was observed when TGA was parenterally administered. The rapid release, at the site of infection, of TAP and N-acetylcysteine and the favourable pharmacokinetic properties of TGA accounted in large part for its high therapeutic efficacy against Streptococcus pyogenes pneumonia.
Assuntos
Acetilcisteína/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes , Tianfenicol/análogos & derivados , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Aerossóis , Amoxicilina/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Combinação de Medicamentos , Eritromicina/uso terapêutico , Feminino , Pulmão/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Penicilinas/uso terapêutico , Pneumonia Bacteriana/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/efeitos dos fármacos , Tianfenicol/administração & dosagem , Tianfenicol/farmacologia , Tianfenicol/uso terapêuticoRESUMO
After 30 years of therapeutic use, thiamphenicol glycinate acetylcysteinate (CAS 20192-91-0) is still widely employed in the treatment of upper and lower respiratory tract infections. This is due to its particular characteristic to exert at pulmonary level, either the antibacterial activity of thiamphenicol (CAS 15318-45-3) and the mucolytic activity of N-acetylcysteine (CAS 616-91-1). The aim of this study was to evaluate the present pattern of susceptibility of several clinical isolates to thiamphenicol and the interference of N-acetylcysteine on this parameter. The studies have been performed in vitro. Equimolar concentrations of N-acetylcysteine and even higher concentrations did not interfere with the antibacterial activity of thiamphenicol against Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae. The spectrum of activity of thiamphenicol was similar to that observed in the past and was superior to that of erythromycin and amoxicillin. The activity of thiamphenicol was greater than that of erythromycin against H. influenzae and streptococci and equivalent versus Branhamella catarrhalis. In comparison with amoxicillin the activity of thiamphenicol was higher against H. influenzae and B. catarrhalis and slightly lower against streptococci. The results demonstrate that thiamphenicol maintains its therapeutic value confirming the importance of thiamphenicol glycinate acetylcysteinate in the treatment of respiratory tract infections.
Assuntos
Acetilcisteína/farmacologia , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Respiratórias/microbiologia , Tianfenicol/análogos & derivados , Amoxicilina/farmacologia , Cloranfenicol/farmacologia , Combinação de Medicamentos , Eritromicina/farmacologia , Testes de Sensibilidade Microbiana , Penicilinas/farmacologia , Tianfenicol/farmacologiaRESUMO
The mechanism of the interference of the antiviral antibiotic distamycin A with the bacterial cell has been investigated. Labelled distamycin A is firmly bound by E. coli cells and the binding process does not require metabolic energy as indicated by the use of inhibitors. The antibiotic does not induce gross alteration in the cell membrane but inhibits cyclic AMP accumulation in the cells exposed to a glucose-free medium. This inhibition is concomitant with that exerted on the synthesis of an inducible enzyme such as beta-galactosidase. By the method of pulse induction it appears that distamycin A exterts its inhibiting effect on inducible synthesis at the level of transcription. This effect is probably related to an interference with the positive control of enzyme synthesis performed via the system represented by cyclic AMP and the CRP protein.
Assuntos
Distamicinas/farmacologia , Indução Enzimática/efeitos dos fármacos , Escherichia coli/enzimologia , Pirróis/farmacologia , Sítios de Ligação , AMP Cíclico/metabolismo , Galactosidases/metabolismo , Salmonella typhimurium/enzimologiaRESUMO
A number of semisynthetic rifamycin derivatives, modified at position 3, belonging to general structures (II), (III), (IV), (V), (VI), (VII) and (VIII) (see Scheme), have been prepared. The synthesis, structure, and antimicrobial evaluation of the new compounds are described. All the derivatives have in vitro antibacterial activities comparable with that of rifampicin.
Assuntos
Bactérias/efeitos dos fármacos , Rifamicinas/síntese química , Fenômenos Químicos , Química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Rifamicinas/farmacologiaRESUMO
A new type of hydrolyzable ester of penicillin G, benzamidomethyl benzylpenicillinate (FI 7303), was studied for the antibacterial activity and kinetics of absorption in comparison with DBED-penicillin G. FI 7303 resulted to be a good repository form of penicillin G, slowly eliminated in mouse, dog and man. It exerted a remarkable therapeutic activity in mice infected with Staphylococcus aureus even when administered 26 h before infection. The protective effect in mice was more prolonged than that of DBED-penicillin G, in agreement with the longer persistence of significant blood levels.
Assuntos
Bactérias/efeitos dos fármacos , Penicilina G/análogos & derivados , Infecções Estafilocócicas/tratamento farmacológico , Absorção , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Penicilina G/metabolismo , Penicilina G/farmacologia , Penicilina G/uso terapêutico , Penicilina G Benzatina/metabolismo , Penicilina G Benzatina/farmacologia , Penicilina G Benzatina/uso terapêutico , Resistência às Penicilinas , Staphylococcus aureusRESUMO
Reactive oxygen intermediates (ROI) and cytokines, particularly tumor necrosis factor (TNF) have been implicated in the pathogenesis of influenza. Using a murine model of influenza, we have studied the levels of TNF, interleukin 6 (IL-6) and of superoxide-generating xanthine oxidase (XO). Mice infected intranasally with influenza virus APR/8 had high levels of XO, TNF and IL-6 in the broncoalveolar lavage, as early as 3 d after infection. XO was elevated also in serum and lung tissue. Administration of the antioxidant N-acetylcysteine (NAC,1 g/kg per day, orally) significantly decreased the mortality in infected mice, indicating a role for RO1 in the lethality associated with influenza infection.
RESUMO
The in vitro effect of different doses of alpha, beta and gamma human interferons and their interaction on the proliferation rate of human erythroleukemic cell line (K-562) and other cell lines has been evaluated. The results show that the stronger activity is exerted by beta HIF in comparison with alpha HIF. The action is selective and species-specific. beta HIF never elicited an "enhancing" effect on cell proliferation; on the contrary this phenomenon has been observed to occur with alpha and gamma HIF. In our cell system, the interaction between beta and gamma HIF gave a synergistic effect; on the contrary, no interaction has been observed to take place when beta HIF and directly cytotoxic mycotoxins extracted from A. terreus are associated.