RESUMEN
Fluconazole administered at 150 mg/week for 1-5 weeks is effective orally against dermatophytes and yeast in stratum corneum. Clinical and mycological cure rates approach 90%, but the precise distribution of the drug within various layers of skin is uncertain. We administered fluconazole at 150 mg/week for 2 weeks to 5 volunteers. Distribution of fluconazole in biopsies of skin was imaged by energy dispersive analysis of X-rays (EDX) and transmission electron microscopy, and in cells by electron energy-loss spectroscopy (EELS). Eight hours after a second dose, EDX showed fluconazole highest and homogeneously distributed in stratum corneum, lower in the rest of the epidermis, and lowest in dermis. The highest fluconazole levels detected by EELS were in cytoplasmic inclusions of sweat and sebaceous glands and less in keratinocytes and dermal collagen. We conclude that fluconazole delivered to stratum corneum by direct diffusion from capillaries and in sweat is also in all likelihood transported in sebum.
Asunto(s)
Antifúngicos/farmacocinética , Epidermis/metabolismo , Fluconazol/farmacocinética , Piel/metabolismo , Administración Oral , Adulto , Antifúngicos/administración & dosificación , Antifúngicos/análisis , Biopsia , Capilares/metabolismo , Colágeno/metabolismo , Microanálisis por Sonda Electrónica , Epidermis/anatomía & histología , Epidermis/química , Fluconazol/administración & dosificación , Fluconazol/análisis , Humanos , Cuerpos de Inclusión/química , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/ultraestructura , Queratinocitos/química , Queratinocitos/citología , Queratinocitos/metabolismo , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Glándulas Sebáceas/anatomía & histología , Glándulas Sebáceas/química , Glándulas Sebáceas/metabolismo , Sebo/metabolismo , Piel/anatomía & histología , Piel/química , Análisis Espectral , Sudor/metabolismo , Glándulas Sudoríparas/anatomía & histología , Glándulas Sudoríparas/química , Glándulas Sudoríparas/metabolismoRESUMEN
Candida albicans is an opportunistic pathogen of human mucosal surfaces. Colonization of oral and vaginal mucosa by this yeast is antagonized by the resident normal bacterial population. However, antibacterial therapy can alter the normal flora to allow fungal cells to attach, grow and invade host tissues. We studied the antimicrobic activity of fluconazole against clinical isolates of oral and vaginal bacteria and Candida albicans in vitro and in vivo by scanning and transmission electron microscopy; we also compared the bactericidal activity of fluconazole with clotrimazole in vitro by microbiologic assay. Fluconazole lysed fungi but did not change the ultrastructure of bacteria. Clotrimazole, but not fluconazole, was bactericidal against lactobacillus and streptococcus, the principal species of the oral and vaginal cavities. We conclude that Candida albicans, but not oral and vaginal bacteria, is susceptible to fluconazole. These observations help explain the antimycotic specificity of fluconazole and its efficacy against candidiasis in humans.
Asunto(s)
Candida albicans/efectos de los fármacos , Fluconazol/farmacología , Candida albicans/ultraestructura , Clotrimazol/farmacología , Femenino , Humanos , Lactobacillus/efectos de los fármacos , Microscopía Electrónica , Microscopía Electrónica de Rastreo , Mucosa Bucal/microbiología , Membrana Mucosa/microbiología , Especificidad de la Especie , Streptococcus/efectos de los fármacos , Vagina/microbiologíaRESUMEN
The economic consequences of antibiotic prophylaxis and therapy for bacterial infections in humans are profound. The reduction in real-dollar terms in the amount of illness and disability resulting from the use of developed and marketed antibiotics far outweighs costs of adverse effects, including resistance. Although bacterial infections continue to cause substantial mortality and morbidity worldwide, standard criteria for assessing the relation of infection to death or the contribution of resistance to mortality and morbidity do not exist. While local outbreaks of resistance may have serious consequences, bacterial susceptibility to antimicrobial therapy has remained virtually unchanged nationally where studied. Nevertheless, discriminating use of antimicrobial agents is held widely to be the keystone for minimizing resistance. It is not clear whether risk of selecting resistance is lowered by current community or clinical practices. Some analysts concentrate on the "problem" and "cost" of resistance and forget the benefits of the use of antibiotics. Development of resistance is a natural consequence of antibiotic use, but further quantification of this relation is required. Reports that resistance is increasing worldwide have presented a scientific challenge and economic opportunity to the pharmaceutical industry for the development of new antimicrobial agents. However, if a reasonable rate of return cannot be foreseen, capital for research and development is likely to be invested in areas that appear more financially attractive.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Bacterianas/economía , Industria Farmacéutica/economía , Infecciones Bacterianas/tratamiento farmacológico , Costos y Análisis de Costo , Farmacorresistencia Microbiana , Utilización de Medicamentos/economía , Humanos , Legislación de Medicamentos , Comercialización de los Servicios de SaludRESUMEN
The authors have developed a primate model for evaluating cytoprotection against alcohol-induced injury in gastric mucosa pretreated with antiulcer agents. In the present study, groups of squirrel monkeys received either a single oral dose of misoprostol (500 or 200 micrograms/kg), cimetidine (3 or 6 mg/kg), placebo, or no treatment. After 30 min, 1 ml of 50% ethanol was administered to all animals, except for one of two untreated controls. At 90 min, stomachs from lethally anesthetized primates were processed for scanning electron and quantitative stereoscopic microscopy. Fifty percent ethanol alone damaged epithelial cells and produced submucosal hemorrhagic lesions. Pretreatment with misoprostol limited alcohol-induced injury to superficial erosion of epithelial cells. Cimetidine did not protect the mucosa against ethanol-induced injury. We conclude that misoprostol-conferred cytoprotection in primate gastric mucosa correlates with the endoscopic findings by others that misoprostol, but not cimetidine, protected human stomach against alcohol-induced injury.
Asunto(s)
Alprostadil/análogos & derivados , Antiulcerosos/farmacología , Cimetidina/farmacología , Etanol/toxicidad , Mucosa Gástrica/efectos de los fármacos , Alprostadil/farmacología , Animales , Membrana Basal/efectos de los fármacos , Membrana Basal/ultraestructura , Femenino , Mucosa Gástrica/patología , Mucosa Gástrica/ultraestructura , Microscopía Electrónica de Rastreo , Misoprostol , Placebos , SaimiriRESUMEN
A fast semi-automated method is described for labeling the antibiotic, erythromycin A (1), with the short-lived positron-emitting radionuclide, 11C (t 1/2 = 20.4 min), in order to permit the non-invasive study of its tissue uptake in vivo. Labelling was achieved by the fast reductive methylation of N-demethylerythromycin A (2) with [11C]formaldehyde, itself prepared from cyclotron-produced [11C]-carbon dioxide. Rapid chemical and radiochemical purification of the [N-methyl-11C]erythromycin A (3) were achieved by HPLC and verified by TLC with autoradiography. The purified material was formulated for human i.v. injection as a sterile apyrogenic solution of the lactobionate salt. The preparation takes 42 min from the end of radionuclide production and from [11C]carbon dioxide produces [N-methyl-C11]erythromycin A lactobionate in 1-12% radiochemical yield, corrected for radioactive decay.
Asunto(s)
Radioisótopos de Carbono , Eritromicina/análogos & derivados , Claritromicina , Marcaje Isotópico/métodosRESUMEN
The distribution of orally administered nitrofurantoin macrocrystals in the urinary tract was studied by whole body radioautography in female squirrel monkeys and by bioautography of excised human kidney. The drug was rapidly absorbed and widely distributed throughout the simian urinary tract and human kidney. Concentrations of 14C drug in simian renal cortex and renal pelvis were up to 5 times plasma levels. Nitrofurantoin-derived antibacterial activity was observed by bioautography throughout sections of human kidney at concentrations that killed susceptible human urinary tract pathogens.
Asunto(s)
Nitrofurantoína/metabolismo , Infecciones Urinarias/tratamiento farmacológico , Animales , Autorradiografía , Radioisótopos de Carbono , Femenino , Humanos , Riñón/metabolismo , Nitrofurantoína/uso terapéutico , Pielonefritis/tratamiento farmacológico , Saimiri , Distribución Tisular , Sistema Urinario/metabolismoRESUMEN
The concentration achieved in the infected tissue is of fundamental importance in the use of antibiotics. Erythromycin labelled with the positron-emitting nuclide carbon-11 and positron tomography were used to compare local concentrations of this antibiotic in the pneumonic and unaffected lungs of five patients with lobar pneumonia. The time course of uptake of erythromycin into the extravascular compartment (i.e., the intracellular, interstitial, and alveolar compartments) of the pneumonic lung was measured. The mean extravascular concentrations obtained during the first hour after an intravenous injection of 270 mg erythromycin lactobionate were similar in the pneumonic lung and the unaffected lung (5.5 +/- 2.2 and 6.6 +/- 2.2 micrograms/g, respectively). An effective concentration of erythromycin was reached in the pneumonic lung within 10 min of the injection and was maintained throughout the period of measurement (60 min).
Asunto(s)
Eritromicina/análogos & derivados , Pulmón/metabolismo , Neumonía Neumocócica/metabolismo , Tomografía Computarizada de Emisión , Enfermedad Aguda , Anciano , Eritromicina/administración & dosificación , Eritromicina/metabolismo , Eritromicina/uso terapéutico , Femenino , Humanos , Inyecciones Intravenosas , Pulmón/diagnóstico por imagen , Pulmón/microbiología , Masculino , Persona de Mediana Edad , Neumonía Neumocócica/tratamiento farmacológico , Neumonía Neumocócica/microbiología , Alveolos Pulmonares/metabolismoRESUMEN
The physiological disposition of N-(phosphonacetyl)-L-aspartate (NSC 224131; PALA), a potent inhibitor of aspartate transcarbamylase, has been studied in mouse, rat, dog, and monkey after administration of [14C]PALA at 120 mg/sq m i.v. or p.o. Concentrations of PALA equivalents in plasma, urine, and feces were determined radiochemically, and urine was analyzed chromatographically for PALA. The disposition of PALA equivalents in mouse tissues was determined radioautographically. After i.v. administration, PALA was rapidly (half-time, approximately 1 hr) and extensively (up to 80% of the dose) excreted in the urine of all species. Less than 5% was excreted in the feces. Only PALA was found in the urine of all four species, indicating that the metabolism of PALA, if it occurs at all, is insignificant. PALA equivalents were poorly taken up by mouse tumors and tissues, except kidney, bone, and to a lesser extent, skin and lung, and were rapidly and extensively cleared from all except bone. No differences were apparent in the uptake of PALA equivalents by Lewis lung carcinoma (sensitive to PALA treatment) and L1210 lymphocytic leukemia (insensitive). The pharmacokinetics of PALA in the plasma of rat, dog, and monkey, as well as mouse, were inconsistent with deposition of PALA in tissues and more consistent with the probable distribution of PALA into extracellular water. PALA equivalents were eliminate from all species at a rate (half-time, 1 to 1.5 hr) reflecting the rate of urinary excretion of the drug and at a secondary slower rate probably reflecting the rate of release of bound PALA from sites such as aspartate transcarbamylase. PALA was poorly absorbed into the systemic circulation when administered p.o., in that mouse, rat, and monkey excreted less than 5% of the dose in the urine after p.o. administration. These data on the physiological disposition of PALA explain why high doses of the drug have to be administered to achieve therapeutic and toxic effects, despite the inhibitory potency of the drug on aspartate transcarbamylase. They indicate that PALA will be ineffective administered p.o. and might be contraindicated in patients with impaired renal function and that the kinetics of aspartate transcarbamylase-bound drug is probably more important in determining dose scheduling than the kinetics of free PALA.
Asunto(s)
Ácido Aspártico/análogos & derivados , Compuestos Organofosforados/metabolismo , Ácido Fosfonoacético/metabolismo , Administración Oral , Animales , Aspartato Carbamoiltransferasa/metabolismo , Ácido Aspártico/sangre , Ácido Aspártico/metabolismo , Ácido Aspártico/orina , Autorradiografía , Disponibilidad Biológica , Perros , Heces/análisis , Femenino , Semivida , Inyecciones Intravenosas , Cinética , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos , Ácido Fosfonoacético/análogos & derivados , Ácido Fosfonoacético/sangre , Ácido Fosfonoacético/orina , Ratas , Ratas Endogámicas , Distribución TisularRESUMEN
Ethambutol (EMB) concentrations that kill Mycobacterium tuberculosis in vitro accumulated in squirrel monkey tissues and cells known to be sites of tubercular infections. After oral administration of a clinically relevant 25 mg/kg dose, the whole-body distribution and intracellular localization of EMB were studied by radioautography. Tissue concentrations of drug were assayed by radiochemical and microbiological methods. The EMB was distributed rapidly and widely to most body tissues including lung and localized within pulmonary alveolar and axillary lymph node macrophages. The EMB in lung at 2 and 5 h after drug administration was markedly higher than the corresponding plasma concentrations and exceeded concentrations that are bactericidal in vitro for tubercle bacilli. These observations may help explain the early bactericidal activity of EMB in humans. Similarities in plasma and tissue concentrations of the drug in both species suggest the usefulness of the squirrel monkey as a model for the use of EMB in humans.
Asunto(s)
Etambutol/metabolismo , Administración Oral , Animales , Autorradiografía , Etambutol/sangre , Humanos , Pulmón/citología , Macrófagos/fisiología , Microscopía Electrónica , Modelos Biológicos , Mycobacterium tuberculosis/patogenicidad , Alveolos Pulmonares/citología , Alveolos Pulmonares/ultraestructura , Saimiri , Distribución TisularRESUMEN
Investigations to develop an implantable assist pump for prolonged circulatory support have been impeded by accumulation of friable thrombus on the prosthetic interface, with subsequent embolization. To circumvent this problem, the textured, fibril surface of a polyurethane pump chamber (mat thickness 430 microns) was inoculated with cultured bovine fetal fibroblasts (labelled with thymidine-14C) prior to animal implantation. The pneumatically actuated device (stroke volume 75 ml), maintained a pulsatile blood flow throughout each study. In 20 calf experiments, extending up to 335 days, 30 X 10(6) fibroblasts (in 50 ml media) derived from a single Holstein fetus were distributed on the urethane surface (360 +/- 50 cells/mm2) by rotation of a sealed device for three hours (12 revolutions/hour). Following connection to the circulation, cell washout was minimal. Resultant biologic linings, examined after animal sacrifice, were densely adherent to the underlying polymer matrix, and varied in thickness from 250 micron-1.5 mm. Microscopically, fibroblasts were identified from the surface to base, accompanied by numerous collagen bundles and abundant ground substance. Amino acid analysis in 10/20 pumps implanted for 31--335 days, revealed 50 +/- 5 Hydroxyproline residues/1000 residues (50% collagen) and scant elastin. Donor fibroblasts were identified by radioautography and karyotyping. Lack of immunologic response in 12 Hereford pump recipients as confirmed by serial fibroblast cytotoxicity assays. In conclusion, an induced collagenous-blood interface permitted prolonged mechanical circulatory support in animals without thromboembolic complications.
Asunto(s)
Circulación Asistida/instrumentación , Colágeno , Técnicas de Cultivo/métodos , Fibroblastos/citología , Poliuretanos , Trombosis/prevención & control , Animales , Autorradiografía , Prótesis Vascular , Bovinos , Cariotipificación , Prueba de Cultivo Mixto de Linfocitos , Microscopía Electrónica de RastreoRESUMEN
An in vitro test system was used to compare the antimicrobial activity of erythromycin, amoxicillin and ampicillin against respiratory tract pathogens isolated from man. The minimum inhibitory concentrations (MICs) of fresh clinical isolates of Streptoccus pyogenes, Streptocuccus pneumoniae, Staphylococcus aureus and Haemophilus influenzae to the macrolide and penicillins ranged between 0.01 and 0.9 microgram/ml. The microbes were exposed to each antibiotic for approximately 3 h at 1x,2x and 5x the relevant MIC. Irreversible surface defects and intracellular lesions were resolved by scanning and transmission electron microscopy in all antibiotic-treated bacterial species, irrespective of the antimicrobial used. In each case, inhibition of growth was recorded by turbometric assay; no significant difference was observed among the declining slopes of post-dosing growth curves for either erythromycin-, amoxicillin- or ampicillin-treated pathogens. The experimental observations show that the onset of antimicrobial activity and the bactericidal effectiveness of equipotent concentrations of erythromycin, amoxicillin and ampicillin were comparable in this study. The results complement previous clinical, bacteriologic and ultrastructure studies in vivo and demonstrate the contribution of the combined in vivo/in vitro study design for better understanding of antimicrobial activity in human respiratory tract infections.
Asunto(s)
Amoxicilina/farmacología , Ampicilina/farmacología , Bacterias/efectos de los fármacos , Eritromicina/farmacología , Sistema Respiratorio/microbiología , Bacterias/ultraestructura , Pared Celular/ultraestructura , Haemophilus influenzae/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacosRESUMEN
Mechanical circulatory support was accomplished in 20 calves (mean, 140 days) and in 5 patients following operation for acquired heart disease (range, 1 hour to 8 days) employing a pneumatically actuated xenograft-valved assist pump interposed between the left ventricular apex and aorta. Following pump implantation in calves, hematocrit and platelets decreased transiently and returned to normal within 14 days. Plasma hemoglobin and erythrocyte mechanical fragility values were elevated for 48 hours. Platelet survival was slightly reduced, but erythrocyte survival values were similar to controls. In patients who received assist pumps, plasma hemoglobin and erythrocyte mechanical fragility were transiently elevated, but rapidly decreased to normal. Thrombocytopenia occurred only in the presence of bleeding and renal failure requiring hemodialysis. Pump flow of the left ventricular assist device was maintained above 2.0 L/min/m2 despite serious arrhythmias. Postmortem examination revealed no evidence of thromboemboli in the clinical patients although anticoagulant agents were not administered.
Asunto(s)
Circulación Asistida/efectos adversos , Procedimientos Quirúrgicos Cardíacos , Hemólisis , Adulto , Anciano , Animales , Circulación Asistida/instrumentación , Circulación Asistida/métodos , Recuento de Células Sanguíneas , Plaquetas , Gasto Cardíaco , Bovinos , Estudios de Evaluación como Asunto , Femenino , Fibrinógeno/análisis , Hematócrito , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Fragilidad Osmótica , Complicaciones Posoperatorias/terapia , Resucitación , Reticulocitos , Factores de TiempoRESUMEN
The antitumor antibiotic, adriamycin, induces severe cardiac toxicity associated with peroxidation of cardiac lipids in mice. Both this lipid peroxidation and cardiac toxicity of adriamycin are reduced by prior treatment of the animals with the free radical scavenger tocopherol. Such treatment with tocopherol does not, however, alter the magnitude or duration of the adriamycin-induced suppression of DNA synthesis in P388 ascites tumor, nor does it diminish the antitumor responsiveness of P388 ascites tumor. These results suggest that adriamycin has at least two mechanisms of tissue damage: one, which involves lipid peroxidation, is blocked by tocopherol and results in cardiac toxicity; the other, which involves binding to DNA, is not antagonized by tocopherol and is responsible for tumor response.
Asunto(s)
Doxorrubicina/toxicidad , Corazón/efectos de los fármacos , Metabolismo de los Lípidos , Neoplasias Experimentales/tratamiento farmacológico , Vitamina E/farmacología , Animales , ADN de Neoplasias/biosíntesis , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/uso terapéutico , Quimioterapia Combinada , Masculino , Ratones , Miocardio/metabolismo , Neoplasias Experimentales/metabolismo , Peróxidos/metabolismo , Vitamina E/uso terapéuticoRESUMEN
The effects of cytosine arabinoside (ara-C), cyclocytidine (cyclo-C), and anhydro-ara-5-fluorocytidine (AAFC) on the ultrastructure of the serous and mucous cells of the submaxillary salivary glands were evaluated in normal BDF1 mice. Rapid loss of zymogen granules from serous cells and a discharge of mucous cell contents were observed within the first hour after administration of a single iv dose of cyclo-C. Serous cells were essentially devoid of granules (1-3 mum) within 3 hours; regranulation observed initially at 6 hours produced a population of microgranules (approximately 0.8 mum) by 24 hours; most serous cells contained a reduced complement of small granules through 96 hours after cyclo-C. Mucous cells recovered secretory content within 3-6 hours after drug administration. Neither ara-C nor AAFC produced zymogen-granule or mucous discharge or other cytopathologic effects in the murine submaxillary salivary glands. Thus, it can be postulated that cyclo-C itself is the secretogogue. The ultrastructural changes observed in this study provide a cytopathologic correlate of the salivary gland dysfunctions reported to follow the administration of cyclo-C to man.
Asunto(s)
Ancitabina/farmacología , Citarabina/análogos & derivados , Citarabina/farmacología , Glándula Submandibular/efectos de los fármacos , Animales , Citoplasma/efectos de los fármacos , Ratones , Membrana Mucosa/efectos de los fármacos , Membrana Serosa/efectos de los fármacos , Glándula Submandibular/ultraestructuraRESUMEN
The distribution of cyclocytidine and cytosine arabinoside has been studied in normal BDF mice and in mice bearing 6-day solid L1210 lymphocytic leukemia by whole-body radioautography, bioassay, and radiochemical techniques. Radioactivity was widely distributed throughout the tissues between 15 minutes and 12 hours after a single intravenous dose of either cyclocytidine-2-14C or cytosine arabinoside-2-14C. Whole-body radioautograms demonstrated that for most tissues, cytosine arabinoside-derived 14C was uniformly excreted by 48 hours; cyclocytidine-derived 14C, however, was localized in certain tissues as early as 15 minutes after drug administration and was retained in these sites for 48 hours. Depot loci of 14C included salivary and adrenal glands, fat, cardiac muscle, gastrointestinal tract, and L1210 tumor. The distribution and persistence of cyclocytidine-derived radioactivity is consistent with other reports of toxicity induced by the drug in these tissues. Radiochromatography and bioassay data from BDF mice dosed intraperitoneally with cyclocytidine demonstrated that 65%-95% of the 14C-radioactivity in a number of tissues was the parent compound itself. Thus, cyclocytidine contributed in large measur to the generation of the radioautograms. This study demonstrates that the retention of cyclocytidine in body tissues may serve to effect the sustained release of the deaminase-resistant chemotherapeutic drug from these depot sites and thus prolong cytotoxic levels of drug in tumor tissue.
Asunto(s)
Citarabina/análogos & derivados , Citarabina/metabolismo , Leucemia L1210/metabolismo , Tejido Adiposo/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Autorradiografía , Encéfalo/metabolismo , Citarabina/sangre , Citarabina/orina , Sistema Digestivo/metabolismo , Femenino , Cobayas , Riñón/metabolismo , Sistema Linfático/metabolismo , Músculos/metabolismo , Páncreas/metabolismo , Sistema Respiratorio/metabolismo , Glándulas Salivales/metabolismo , Médula Espinal/metabolismo , Factores de Tiempo , Vejiga Urinaria/metabolismoRESUMEN
The two studies which are reviewed in this paper demonstrate the value of fluorescent microscopic observations in the studying of the distribution of antibiotics in lung tissue and in sinus secretions. In the lung tissue study, the standard microbiologic assay data on doxycycline concentrations in respiratory tissue take on greater meaning when one is able to visualize the relative distribution of doxycycline-derived fluorescence among bronchiolar, vascular and parenchymal sites. In the sinus secretions study, doxycycline was shown to pass into the sinus secretions in concentrations, in most instances, which are significantly greater than the relevant MICs. These therapeutic levels were achieved and assayed in sinus secretions, even though a corresponding fluorescence was not always demonstrated. When fluorescence was shown, the wide homogeneous distribution of doxycycline throughout the aspirate of purulent maxillary sinus mucus was striking. Fluorescent microscopy can provide a dynamic visualization of doxycycline's presence in human tissue and secretions. Fluorescent microscopy, together with standard microbiological assay methods, affords both qualitative and quantitive data on the drug's biologic activity.