RESUMO
OBJECTIVE: To evaluate 13C-NMR spectroscopy as a method for fat quantitation in human feces without time consuming or unpleasant preparation steps. DESIGN AND METHODS: Stool samples of seven healthy subjects were collected for 18 days before and during oral intake of the inhibitor of gastrointestinal lipases Orlistat. Fecal lipid content was determined first using 13C-NMR, then by conventional gravimetry after homogenization and Bligh & Dyer lipid extraction. RESULTS: The correlation between gravimetry and 13C-NMR was excellent (R2 = 0.91). In repeated measurements, the mean percentage error was 2.8%. On average, 13C-NMR yielded 1.27 g less fat than gravimetry. Orlistat efficacy for fat excretion assessed by 13C-NMR and by gravimetry was 34.3% and 33.9%, respectively. CONCLUSIONS: With a total measurement time of three minutes, 13C-NMR spectroscopy of unprocessed whole stool provides an accurate alternative to gravimetry for assessing total fecal fat excretion. 13C-NMR is superior with regard to practicability and speed.
Assuntos
Gorduras/análise , Fezes/química , Calibragem , Isótopos de Carbono , Humanos , Espectroscopia de Ressonância Magnética , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
BACKGROUND: Modern medical imaging modalities can trace labelled oral drug dosage forms in the gastrointestinal tract, and thus represent important tools for the evaluation of their in vivo performance. The application of gastric-retentive drug delivery systems to improve bioavailability and to avoid unwanted plasma peak concentrations of orally administered drugs is of special interest in clinical and pharmaceutical research. AIM: To determine the influence of meal composition and timing of tablet administration on the intragastric performance of a gastric-retentive floating tablet using magnetic resonance imaging in the sitting position. METHODS: A tablet formulation was labelled with iron oxide particles as negative magnetic resonance contrast marker to allow the monitoring of the tablet position in the food-filled human stomach. Labelled tablet was administered, together with three different solid meals, to volunteers seated in a 0.5-T open-configuration magnetic resonance system. Volunteers were followed over a 4-h period. RESULTS: Labelled tablet was detectable in all subjects throughout the entire study. The tablet showed persistent good intragastric floating performance independent of meal composition. Unfavourable timing of tablet administration had a minor effect on the intragastric tablet residence time and floating performance. CONCLUSION: Magnetic resonance imaging can reliably monitor and analyse the in vivo performance of labelled gastric-retentive tablets in the human stomach.
Assuntos
Alimentos , Esvaziamento Gástrico/fisiologia , Estômago/fisiologia , Comprimidos/farmacocinética , Adulto , Meia-Vida , Humanos , Imageamento por Ressonância Magnética/normas , Masculino , Sensibilidade e Especificidade , Fatores de TempoRESUMO
BACKGROUND: Controlled delivery of drugs to the small intestine in relation to emptying of an ingested meal is important in various pathophysiological conditions. We investigated the effects of different food consistencies and the amount of co-ingested liquid on the intragastric distribution of a contrast marker. METHODS: Five healthy subjects received four meals (each 650 kcal: A, mashed potato with 100 mL water; B, rice with 100 mL water; C, hamburger meal with 100 mL water; D, hamburger meal with 300 mL water). A capsule filled with gadolinium tetra-azacyclododecane tetra-acetic acid solution (as contrast marker) was ingested following meal termination, and its intragastric distribution was assessed by magnetic resonance imaging. RESULTS: Initially, marker distribution was confined to the fundus, and subsequently extended along the inner curvature of the stomach. The maximum distribution volume of the marker was lower in meal A than in meal B (P < 0.05). No differences in marker distribution were observed when the hamburger meal was given with 100 or 300 mL water. CONCLUSIONS: The intragastric distribution kinetics of the marker gadolinium tetra-azacyclododecane tetra-acetic acid appeared to depend on meal consistency, but not on the amount of water co-ingested. Three-dimensional magnetic resonance imaging allows detailed analysis of the intragastric distribution of a drug model in relation to meal emptying and intragastric meal distribution.
Assuntos
Meios de Contraste/farmacocinética , Alimentos , Mucosa Gástrica/metabolismo , Compostos Heterocíclicos/farmacocinética , Imageamento por Ressonância Magnética , Compostos Organometálicos/farmacocinética , Adulto , Esvaziamento Gástrico , Humanos , Masculino , Modelos Biológicos , Distribuição TecidualRESUMO
PURPOSE: Monitoring the distribution of drugs or drug delivery systems in the human gastrointestinal tract is an important prerequisite for the design of orally administered drugs. We investigated the intragastric distribution of a colloidal drug delivery system (liposomes containing the contrast agent Gd-DOTA) by magnetic resonance imaging. METHODS: Following ingestion of a liquid or a solid meal, gastric distribution of liposomes released from a capsule and the fat component of the solid meal were tracked in 7 healthy subjects for 90 min. Liposomes were identified in gastric content by the increased signal intensity provided by the encapsulated Gd-DOTA. RESULTS: With the liquid meal, liposomes initially formed a layer on the surface before distributing in 86 +/- 2% of gastric content (maximum distribution volume) within 42 +/- 6 min. With the solid meal, maximum distribution (7 +/- 1%, reached within 24 +/- 6 min) was confined to a small volume in the fundus without forming a layer, suggesting that distribution was related to the accessible liquid compartment. Fat distribution was inhomogeneous and concentrated in the fundus. CONCLUSIONS: Intragastric distribution of a colloidal drug carrier model, such as Gd-DOTA-filled liposomes, varies between meals of different composition. These differences can be monitored in three dimensions in humans by MRI.
Assuntos
Sistema Digestório/metabolismo , Portadores de Fármacos/farmacocinética , Monitoramento de Medicamentos/métodos , Lipossomos/farmacocinética , Imageamento por Ressonância Magnética/métodos , Adulto , Coloides , Gorduras na Dieta/farmacocinética , Feminino , Interações Alimento-Droga/fisiologia , Humanos , Masculino , Estatísticas não ParamétricasRESUMO
The surface behaviour of two bile salts, sodium deoxycholate (NaDC) and sodium taurodeoxycholate (NaTDC), as well as that of tetrahydrolipstatin (THL), a potent gastrointestinal lipase inhibitor, was studied at air/water and oil/water interfaces, using interfacial tensiometry methods. The surface behaviour of NaDC and NaTDC was comparable at both oil/water and air/water interfaces. A fairly compact interfacial monolayer of bile salts is formed well below the critical micellar concentration (CMC) and can help to explain the well-known effects of bile salts on the kinetic behaviour of pancreatic lipases. Using the Wilhelmy plate technique, the surface pressure-molecular area curves recorded with THL at the air/water interface showed a collapse point at a surface pressure of 24.5 mN.m(-1), corresponding to a molecular area of 70 A(2). Surprisingly, using the oil drop method, a limiting molecular area of 160 A(2) was found to exist at the oil/water interface. On the basis of the above data, space-filling models were proposed for bile salts and THL at air/water and oil/water interfaces.
Assuntos
Ácidos e Sais Biliares/química , Lactonas/química , Lipase/antagonistas & inibidores , Ar , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , Micelas , Óleos , Orlistate , Propriedades de Superfície , ÁguaRESUMO
The inhibition of digestive lipases by the antiobesity drug Orlistat along with lipolysis levels and fecal fat excretion were measured in healthy humans. Orlistat was found to be a powerful gastric lipase inhibitor, achieving 46.6--91.4% enzyme inhibition and thus greatly reducing gastric lipolysis of solid and liquid meals (11--33% of respective controls). Gastric lipase inhibition by Orlistat was extremely fast (half-inhibition time < 1 min). Duodenal lipolysis was reduced significantly by Orlistat given with the solid meal (32.6--37.6% of controls) but was only slightly reduced by Orlistat given with the liquid meal (74.5--100% of controls). Human pancreatic lipase (HPL) inhibition was found to be high (51.2--82.6%), however, regardless of the meal. These paradoxical results were explained when in vitro lipolysis experiments were performed. The rates of HPL inhibition by Orlistat were found to be similar with both types of meals (half-inhibition time 5--6 min), but the preemulsified triglycerides of the liquid meal were rapidly hydrolyzed by HPL before the enzyme was significantly inhibited by Orlistat. With the solid meal, the rate of hydrolysis of the meal triglycerides by HPL was slower than the rate of HPL inhibition by Orlistat. As predicted from the previous results, the effects of Orlistat on fat excretion levels were found to be much greater with the solid (40.5--57.4% of ingested fat) than with the liquid (4.2--18.8%) test meal.
Assuntos
Fármacos Antiobesidade/administração & dosagem , Lactonas/administração & dosagem , Lipase/antagonistas & inibidores , Lipólise/efeitos dos fármacos , Adulto , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacocinética , Refluxo Duodenogástrico/metabolismo , Duodeno/metabolismo , Feminino , Suco Gástrico , Mucosa Gástrica/metabolismo , Humanos , Técnicas In Vitro , Intubação Gastrointestinal , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Orlistate , Pâncreas/metabolismo , Suco PancreáticoRESUMO
BACKGROUND & AIMS: The lipolytic potential of digestive lipases in vivo has always been deduced so far from their in vitro activities under nonphysiologic conditions. In the present study, the specific activities of human gastric lipase (HGL) and pancreatic lipase (HPL) were measured on dietary triglycerides (TGs) during test meal lipolysis. METHODS: Healthy human volunteers ingested a liquid or solid meal. The specific activities of HGL and HPL were estimated from the lipase and free fatty acid (FFA) outputs at the postpyloric and duodenal levels, respectively. Based on the in vivo data, lipolysis was also performed in vitro by mixing the meal either with gastric juice and subsequently with pancreatic juice and bile or with purified HGL and HPL. FFAs were measured by thin-layer chromatography, and the specific activities of HGL and HPL were expressed as micromoles of FFA per minute per milligram of lipase. RESULTS: In vitro, the specific activities on the liquid meal TGs were 32 (gastric juice) and 34 (pure lipase) micromol x min(-1) x mg(-1) with HGL and 47 (pancreatic juice) and 43 (pure lipase) micromol x min(-1). mg(-1) with HPL. The specific activities on the solid meal TGs were 33 (gastric juice) and 32 (pure lipase) micromol x min(-1) x mg(-1) with HGL and 12 (pancreatic juice) and 15 (pure lipase) micromol x min(-1) x mg(-1) with HPL. The in vivo values obtained were in the same range. The secretory lipase outputs were 21.6+/-14.5 mg HGL and 253.5+/-95.5 mg HPL with the liquid test meal and 15.2+/-5.1 mg HGL and 202.9+/-96.1 mg HPL with the solid test meal. CONCLUSIONS: The specific activities of HGL and HPL on meal TGs were much lower than those measured in vitro under optimized assay conditions (1300-8000). However, these low specific activities are enough for the meal TGs to be completely lipolysed, given the amounts of HGL and HPL secreted during a meal.
Assuntos
Gorduras na Dieta/metabolismo , Suco Gástrico/enzimologia , Lipase/metabolismo , Lipólise , Suco Pancreático/enzimologia , Triglicerídeos/metabolismo , Adulto , Colipases/isolamento & purificação , Colipases/metabolismo , Ácidos Graxos não Esterificados/análise , Feminino , Humanos , Intubação Gastrointestinal , Cinética , Lipase/isolamento & purificação , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND & AIMS: The hypothesis that cholecystokinin release requires adequate dietary fat digestion in the small intestine was investigated in 10 healthy volunteers, and the consequences of reduced fat hydrolysis on pancreaticobiliary secretions were assessed. METHODS: Fat hydrolysis was inhibited by intraduodenal perfusion of tetrahydrolipstatin, an irreversible lipase inhibitor. An oil emulsion containing 0, 30, 60, or 120 mg tetrahydrolipstatin was perfused. After a 40-minute basal period, a test meal was eaten to stimulate cholecystokinin release and pancreaticobiliary responses. RESULTS: In the control without tetrahydrolipstatin, lipase output increased threefold with meal ingestion and remained doubled for 4 hours. At the ligament of Treitz, free fatty acid concentration averaged 60% of total fatty acids. Increasing doses of tetrahydrolipstatin induced a dose-dependent inhibition of duodenal lipase activity (P < 0.01); 120 mg tetrahydrolipstatin eliminated the postprandial lipase peak activity, free fatty acid levels decreased to < 5% of total fatty acids, and plasma cholecystokinin levels were suppressed by 77% (P < 0.01). Amylase and trypsin outputs were reduced by 77% and 59%, respectively, and bilirubin secretion was virtually abolished (P < 0.01). CONCLUSIONS: These findings show that tetrahydrolipstatin prevents triglyceride hydrolysis and that plasma cholecystokinin release, gallbladder emptying, and pancreatic enzyme secretion require adequate triglyceride digestion. These data also support the concept of negative feedback regulation of cholecystokinin secretion.
Assuntos
Colecistocinina/metabolismo , Gorduras na Dieta/metabolismo , Intestino Delgado/metabolismo , Lipase/metabolismo , Adulto , Gorduras na Dieta/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/enzimologiaRESUMO
2,3-Oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique target for a cholesterol lowering drug. Partial inhibition of OSC should reduce synthesis of lanosterol and subsequent sterols, and also stimulate the production of epoxysterols that repress HMG-CoA reductase expression, generating a synergistic, self-limited negative regulatory loop. Hence, the pharmacological properties of Ro 48-8.071, a new OSC inhibitor, were compared to that of an HMG-CoA reductase inhibitor, simvastatin. Ro 48-8.071 blocked human liver OSC and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it triggered the production of monooxidosqualene, dioxidosqualene, and epoxycholesterol. It was safe in hamsters, squirrel monkeys and Göttingen minipigs at pharmacologically active doses, lowering LDL approximately 60% in hamsters, and at least 30% in the two other species, being at least as efficacious as safe doses of simvastatin. The latter was hepatotoxic in hamsters at doses > 30 mumol/kg/day limiting its window of efficacy. Hepatic monooxidosqualene increased dose-dependently after treatment with Ro 48-8.071, up to approximately 20 micrograms/g wet liver or less than 1% of hepatic cholesterol, and it was inversely correlated with LDL levels. Ro 48-8.071 did not reduce coenzyme Q10 levels in liver and heart of hamsters, and importantly did not trigger an overexpression of hepatic HMG-CoA reductase, squalene synthase, and OSC itself. In strong contrast, simvastatin stimulated these enzymes dramatically, and reduced coenzyme Q10 levels in liver and heart. Altogether these findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.
Assuntos
Benzofenonas/farmacologia , Colesterol/análise , Colesterol/sangue , Inibidores Enzimáticos/farmacologia , Transferases Intramoleculares/antagonistas & inibidores , Lovastatina/análogos & derivados , Esqualeno/análogos & derivados , Acetatos/análise , Acetatos/metabolismo , Animais , Apolipoproteínas/sangue , Apolipoproteínas/efeitos dos fármacos , Benzofenonas/síntese química , Colesterol/biossíntese , Colesterol/metabolismo , Cricetinae , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Humanos , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/metabolismo , Lanosterol/análise , Lanosterol/metabolismo , Lipoproteínas/sangue , Lipoproteínas/efeitos dos fármacos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Lovastatina/farmacologia , Miocárdio/enzimologia , Concentração Osmolar , Saimiri , Sinvastatina , Esqualeno/administração & dosagem , Esqualeno/análise , Esqualeno/metabolismo , Suínos , Porco Miniatura , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Células Tumorais Cultivadas , Ubiquinona/análiseAssuntos
Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Animais , Sítios de Ligação , Dissulfetos/farmacologia , Inibidores Enzimáticos/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Humanos , Cinética , Lactonas/farmacologia , Lipase/química , Lipase/metabolismo , Modelos Moleculares , Estrutura Molecular , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Orlistate , Pâncreas/enzimologia , Paraoxon/farmacologia , Conformação Proteica , Coelhos , Estômago/enzimologia , Compostos de Sulfidrila/farmacologia , SuínosRESUMO
The effects of high blood pressure on atherosclerosis were examined in the Watanabe heritable hyperlipidemic (WHHL) rabbit. For this purpose, the subdiaphragmatic aorta of rabbits was partially ligated (coarctation) to increase blood pressure. Atherosclerosis was assessed 4 months later by morphometric analyses and quantitation of arterial lipids. Results were compared to control WHHL rabbits with matched plasma triglycerides and cholesterol levels. A marked increase in atherosclerotic lesions was observed in the thoracic aorta of the hypertensive rabbits without qualitative changes in its morphometric features. The cross sectional area of the atherosclerotic plaques of the ascending and descending aorta in the hypertensive rabbits was two- and six-times larger than in normotensive rabbits, respectively. Lesions represented 12.0% +/- 3.5% of the total medial cross sectional area of the descending aorta of normotensive rabbits, versus 45.0% +/- 5.7% in hypertensive rabbits. No lesions were observed downstream of the coarctation in hypertensive rabbits, nor in the normotensive rabbits. Accumulation of cholesterol and choline-containing phospholipids in the descending aorta of hypertensive rabbits was increased 3.2- and 1.5-fold, respectively, when compared to normotensive rabbits. Hypertension did not change the unesterified cholesterol/total cholesterol and sphingomyelin/lecithin + lysolecithin molar ratios. In conclusion, chronic coarctation enhances the atherosclerotic response in WHHL rabbits in the high blood pressure compartment, and reduces the variability of this response.
Assuntos
Coartação Aórtica/complicações , Artérias/metabolismo , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Hiperlipidemias/complicações , Metabolismo dos Lipídeos , Animais , Artérias/patologia , Arteriosclerose/complicações , Colesterol/sangue , Doença Crônica , Feminino , Hiperlipidemias/genética , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , CoelhosRESUMO
Tetrahydrolipstatin inhibits pancreatic lipase from several species, including man, with comparable potency. The lipase is progressively inactivated through the formation of a long-lived covalent intermediate, probably with a 1:1 stoichiometry. The lipase substrate triolein and also a boronic acid derivative, which is presumed to be a transition-state-form inhibitor, retard the rate of inactivation. Therefore, in all probability, tetrahydrolipstatin reacts with pancreatic lipase at, or near, the substrate binding or active site. Tetrahydrolipstatin is a selective inhibitor of lipase; other hydrolases tested were at least a thousand times less potently inhibited.
Assuntos
Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , Lipase/antagonistas & inibidores , Pâncreas/enzimologia , Animais , Hidrolases/antagonistas & inibidores , Lipólise/efeitos dos fármacos , Ácidos Oleicos/metabolismo , Orlistate , Suínos , Fatores de Tempo , Trioleína/metabolismoRESUMO
Watanabe heritable hyperlipidemic (WHHL) rabbits have severe hypercholesterolemia due to a genetic defect in their low density lipoprotein receptors. Therefore, they develop severe premature atherosclerosis of the large arteries including the coronary arteries. In the present study, we measured the coronary vascular reserve of these rabbits to evaluate the total cross-sectional coronary surface area. This method allowed us to quantify the functional consequences of the coronary atherosclerotic lesions. To evaluate coronary vascular reserve, we measured coronary blood flow with the radioactive microsphere technique before and after induction of maximal coronary vasodilation by an intravenous dose of 9 mg/kg of carbocromen. A group of pure-bred WHHL rabbits was compared to a group of normal Burgundy rabbits at ages of 100 and 300 days. At 100 days, there was no difference in coronary vascular reserve between the two groups. However, at 300 days, the coronary vascular reserve in WHHL rabbits was 48% smaller than in the normal Burgundy rabbits (p less than 0.001). In addition, by making corrosion casts and morphological studies, we were able to show that at 300 days nearly all the WHHL rabbits had severe coronary atherosclerotic lesions located mainly at the origin of the large coronary arteries. We conclude that WHHL rabbits at 300 days have a severe impairment of their coronary vascular reserve due to proximal atherosclerotic lesions in the coronary arteries.
Assuntos
Circulação Coronária , Hiperlipidemias/fisiopatologia , Animais , Cromonar/farmacologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/patologia , Corrosão , Técnicas Histológicas , Hiperlipidemias/genética , Coelhos , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Lipstatin, a new and very potent inhibitor of pancreatic lipase (the key enzyme of intestinal fat digestion) was isolated from Streptomyces toxytricini. Lipstatin contains a beta-lactone structure that probably accounts for the irreversible lipase inhibition. The IC50 of lipstatin for pancreatic lipase is 0.14 microM. In mice triolein absorption was dose-dependently inhibited by lipstatin, whereas oleic acid was absorbed normally. Other pancreatic enzymes, such as phospholipase A2 and trypsin, were not inhibited even at an inhibitor concentration of 200 microM.
Assuntos
Inibidores Enzimáticos/biossíntese , Lactonas/biossíntese , Lipase/antagonistas & inibidores , Streptomyces/análise , Animais , Gorduras na Dieta/metabolismo , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Fermentação , Absorção Intestinal/efeitos dos fármacos , Lactonas/isolamento & purificação , Lactonas/farmacologia , Camundongos , Streptomyces/metabolismo , Triglicerídeos/metabolismoRESUMO
In summary, THL is a potent inhibitor of pancreatic lipase, which is both selective and irreversible in its action in vitro. It is also likely that THL inhibits pancreatic lipase in vivo, since its acute administration to mice and squirrel monkeys suppresses absorption of dietary triglycerides, without an apparent alteration in the absorption of fatty acids. The marked loss in body weight and carcass fat of DIO rats with subchronic administration of THL strongly suggests that inhibition of pancreatic lipase is a feasible strategy for the treatment of obesity. Whether obese humans will overeat in response to a reduction in body energy stores is not known. However, it is probable that compliance to a therapy which maintains the present level of food intake while inducing excretion of dietary fat, will be greater than a reducing diet alone or conjunction with the currently available antiobesity drugs.
Assuntos
Lactonas/farmacologia , Lipase/antagonistas & inibidores , Obesidade/tratamento farmacológico , Pâncreas/enzimologia , Animais , Gorduras na Dieta/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Macaca mulatta , Camundongos , Orlistate , Ratos , Ratos EndogâmicosRESUMO
The effect of the imidazole oxiconazole and the morpholine derivative Ro 14-4767/002 on the sterol metabolism of Candida albicans was investigated at different periods of growth. Ergosterol, representing the main sterol component of control cells, was markedly reduced in oxiconazole-treated and Ro 14-4767/002-treated cells. However, the total sterol content of the cells treated with both drugs was increased due to accumulation of other sterols not present in control cells: in oxiconazole-treated cells 24-methenedihydrolanosterol, 4,14-dimethylfecosterol and 14-methylfecosterol accumulated, indicating an inhibition of C14-demethylation. This is in agreement with the mode of action described for other azoles in various pathogen fungi. In Ro 14-4767/002-treated cells the main sterol accumulated was ignosterol, indicating an inhibition of delta 14-sterol reductase and delta 8-delta 7-isomerase. This inhibition has not been described before in human pathogens although it has been previously found in plant pathogenic fungi treated with fenpropimorph.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Imidazóis/farmacologia , Morfolinas/farmacologia , Esteróis/metabolismo , Acetatos/metabolismo , Candida albicans/metabolismo , Metabolismo dos LipídeosRESUMO
The spreading of Hodgkin's disease in the bone marrow is of primary diagnostic significance in respect of its quantity as well as its quality, and therefore has to be taken into account from the initial staging procedure. The iliac crest is the most suitable site of the biopsy, the diagnostic significance of which depends on the adequate size of the specimen and on the technical standard of the histologic embedding with methacrylate, affording perfect semithin sections without decalcification. The prognostic value of the statement of Hodgkin's disease spreading in the marrow deserves further careful evaluation. A nonspecific reaction of the marrow against extramedullary lymphogranulomatosis closely resembling to the so-called tumor myeopathy has to be distinguished from the localized marrow changes due to the tumor itself. The former is depending primarily of the progress of the disease, the latter of its type as well. The well-known histologic classification covers the changes of the bone marrow due to Hodgkin's disease also. The different histologic types however exhibit a varying tendency of expansion within the bone. Generally the marrow involvement is accompanied with more severe clinical and hematological symptoms. The bone is altered mostly in the very region of the infiltration. This is not the consequence of direct tumorous destruction but of stimulation of environmental mesenchymal activities. Parenchymal and mesenchymal changes of the bone marrow, either directly or indirectly connected with the lymphogranulomatosis, are considered primarily as sequelae of the basic disease. The very close structural relationship between the original lymphogranulomatosus growth and these changes is one of the characteristics of Hodgkin's disease. As yet, there is no unequivocal pointer to structural characteristics whose appearance can exert an obstructive or stimulating effect on the lymphogranuloma tissue, apart from the number of lymphocytes and normal histiocytes in the specific infiltrate itself. Our observations of a special role of megakaryocytes in this connection deserve further attention.