RESUMO
Aminophosphonates, like glyphosate (GS) or metal chelators such as ethylenediaminetetra(methylenephosphonic acid) (EDTMP), are released on a large scale worldwide. Here, we have characterized a bacterial strain capable of degrading synthetic aminophosphonates. The strain was isolated from LC/MS standard solution. Genome sequencing indicated that the strain belongs to the genus Ochrobactrum. Whole-genome classification using pyANI software to compute a pairwise ANI and other metrics between Brucella assemblies and Ochrobactrum contigs revealed that the bacterial strain is designated as Ochrobactrum sp. BTU1. Degradation batch tests with Ochrobactrum sp. BTU1 and the selected aminophosphonates GS, EDTMP, aminomethylphosphonic acid (AMPA), iminodi(methylene-phosphonic) (IDMP) and ethylaminobis(methylenephosphonic) acid (EABMP) showed that the strain can use all phosphonates as sole phosphorus source during phosphorus starvation. The highest growth rate was achieved with AMPA, while EDTMP and GS were least supportive for growth. Proteome analysis revealed that GS degradation is promoted by C-P lyase via the sarcosine pathway, i.e., initial cleavage at the C-P bond. We also identified C-P lyase to be responsible for degradation of EDTMP, EABMP, IDMP and AMPA. However, the identification of the metabolite ethylenediaminetri(methylenephosphonic acid) via LC/MS analysis in the test medium during EDTMP degradation indicates a different initial cleavage step as compared to GS. For EDTMP, it is evident that the initial cleavage occurs at the C-N bond. The detection of different key enzymes at regulated levels, form the bacterial proteoms during EDTMP exposure, further supports this finding. This study illustrates that widely used and structurally more complex aminophosphonates can be degraded by Ochrobactrum sp. BTU1 via the well-known degradation pathways but with different initial cleavage strategy compared to GS.
Assuntos
Ochrobactrum , Organofosfonatos , Fentermina/análogos & derivados , Ochrobactrum/genética , Ochrobactrum/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Biodegradação Ambiental , Glifosato , Organofosfonatos/metabolismo , Fósforo/metabolismoRESUMO
In this study representation of chemical substances in IDMP is reviewed, with an exploration of aggregation levels for substance used in the virtual drug data models of RxNorm, SNOMED-CT, ATC/INN, and the Belgian SAM database, for products with a single substance and combinations of substances. Active moiety and available solid states forms are explored for diclofenac, amoxicillin, carbamazepine, amlodipine, with regard to their representation in coding systems such as WHODrug, SMS, UNII, CAS, and SNOMED-CT. By counting the number of medicinal products in Belgium for amlodipine in each level of aggregation, concepts for grouper of substances and two levels of grouper of medicinal products are illustrated. Recommendations are made for the further development of IDMP and its link to international drug classifications.
Assuntos
RxNorm , Systematized Nomenclature of Medicine , Anlodipino , Fentermina/análogos & derivados , Vocabulário ControladoRESUMO
Nonmedical use of prescription stimulants such as phentermine (PT) has been regulated by law enforcement authorities due to its euphorigenic and relaxing effects. Due to high potential for its abuse, reliable analytical methods were required to detect and identify PT and its metabolite in biological samples. Thus a dilute and shoot liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for simultaneous determination of PT, N-hydroxyphentermine (NHOPT) and mephentermine (MPT) in urine. A 5µL aliquot of diluted urine was injected into the LC-MS/MS system. Chromatographic separation was performed by reversed-phase C18 column with gradient elution for all analytes within 5min. Identification and quantification were based on multiple reaction monitoring (MRM) detection. Linear least-squares regression with a 1/x(2) weighting factor was used to generate a calibration curve and the assay was linear from 50 to 15000ng/mL (PT and MPT) and 5 to 750ng/mL (NHOPT). The intra- and inter-day precisions were within 8.9% while the intra- and inter-day accuracies ranged from -6.2% to 11.2%. The limits of quantification were 3.5ng/mL (PT), 1.5ng/mL (NHOPT) and 1.0ng/mL (MPT). Method validation requirements for selectivity, dilution integrity, matrix effect and stability were satisfied. The applicability of the developed method was examined by analyzing urine samples from drug abusers.
Assuntos
Estimulantes do Sistema Nervoso Central/urina , Cromatografia Líquida de Alta Pressão/métodos , Mefentermina/urina , Fentermina/análogos & derivados , Fentermina/urina , Detecção do Abuso de Substâncias/métodos , Simpatomiméticos/urina , Humanos , Limite de Detecção , Espectrometria de Massas em Tandem/métodosRESUMO
We report a 72-year-old woman with complex partial status epilepticus who showed recurrent episodes of complex visual hallucinations (CVH). Brain diffusion-weighted magnetic resonance images revealed gyriform cortical hyperintensity in the right parietal, occipital and temporal lobes, and brain magnetic resonance angiograhy revealed a hyperintensity in the right dilated middle cerebral artery during ictal period. Ictal N-isopropyl-p-(iodine-123)-iodoamphetamine single photon emission computed tomography (123I-IMP-SPECT) with three-dimensional stereotactic surface projection (3D-SSP) 14 days after the onset of the first CVH revealed hyperperfusion in the right latero-inferior occipito-temporal region with relation to motion. CVH spontaneously subsided 17 days after the onset of the first CVH. CVH recurred one year after the first CVH. Ictal 123I-IMP-SPECT with 3D-SSP revealed marked hyperperfusion in the right lateral parietal region probably with relation to face and figure hallucinations. Ictal scalp EEGs revealed rhythmic polyspikes at 12â Hz with high amplitude (100-200â µV) in bilateral posterior occipital and temporal region with the right side dominance for 20 seconds and more in several occasions. Interictal 123I-IMP-SPECT with 3D-SSP 28 days after recurrence of CVH revealed marked hypoperfusion in the right lateral parietal region, and recovery of hypoperfusion in the right latero-inferior occipito-temporal region. These findings suggest that ictal CVH might be induced by the spread of epileptic discharges from the right parieto-occipito-temporal region with the old brain contusion (epileptogenic region) to the right latero-inferior occipito-temporal region and the right lateral parietal region (symptomatogenic regions).
Assuntos
Alucinações/complicações , Estado Epiléptico/fisiopatologia , Idoso , Eletroencefalografia , Feminino , Alucinações/diagnóstico , Alucinações/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Fentermina/análogos & derivados , Recidiva , Estado Epiléptico/complicações , Estado Epiléptico/diagnóstico , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
PURPOSE: We carried out differential diagnosis of brain blood flow images using single-photon emission computed tomography (SPECT) for patients with Parkinson's disease (PD) or progressive supranuclear paralysis (PSP) using statistical parametric mapping (SPM) and to whom we had applied anatomical standardization. MATERIALS AND METHODS: We studied two groups and compared brain blood flow images using SPECT (N-isopropyl-4-iodoamphetamine [(123)I] hydrochloride injection, 222 MGq dosage i.v.). A total of 27 patients were studied using SPM: 18 with PD and 9 with PSP; humming bird sign on MRI was from moderate to medium. RESULTS: The decline of brain bloodstream in the PSP group was more notable in the midbrain, near the domain where the humming bird sign was observable, than in the PD group. CONCLUSIONS: The observable differences in brain bloodstream decline in the midbrain of PSP and PD patients suggest the potential usefulness of this technique's clinical application to distinction diagnosis.
Assuntos
Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Imagem de Perfusão/métodos , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/fisiopatologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Radioisótopos do Iodo , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fentermina/análogos & derivados , Compostos RadiofarmacêuticosRESUMO
Phentermine was shown in the 1970s to inhibit the metabolism of serotonin by monoamine oxidase (MAO), but never was labeled as an MAO inhibitor; hence, it was widely used in combination with fenfluramine, and continues to be used, in violation of their labels, with other serotonin uptake blockers. We examined the effects of phentermine and several other unlabeled MAO inhibitors on MAO activities in rat lung, brain, and liver, and also the interactions of such drugs when administered together. Rat tissues were assayed for MAO-A and -B, using serotonin and beta-phenylethylamine as substrates. Phentermine inhibited serotonin-metabolizing (MAO-A) activity in all three tissues with K(i) values of 85-88 microM. These potencies were similar to those of the antidepressant MAO inhibitors iproniazid and moclobemide. When phentermine was mixed with other unlabeled reversible MAO inhibitors (e.g. pseudoephedrine, ephedrine, norephedrine; estradiol benzoate), the degree of MAO inhibition was additive. The cardiac valvular lesions and primary pulmonary hypertension that have been reported to be associated with fenfluramine-phentermine use may have resulted from the intermittent concurrent blockage of both serotonin uptake and metabolism.
Assuntos
Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fentermina/farmacologia , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Dextroanfetamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Efedrina/farmacologia , Iproniazida/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Masculino , Moclobemida/farmacologia , Monoaminoxidase/efeitos dos fármacos , Inibidores da Monoaminoxidase/química , Fentermina/análogos & derivados , Ratos , Ratos Sprague-DawleyRESUMO
A series of phentermine analogs, including the unsubstituted, the para-F, -Cl, -Br and -I, and the meta-CF3 derivatives, were labeled by [11C]methylation and evaluated in rats to determine the structure-localization relationships for this class of regional cerebral blood flow imaging agents. All the phentermines were well-localized in the brain; however, only the para-substituted agents were well-retained. Localization in the nontarget tissue was affected by the lipophilicity of the substituent. Comparison with the radioiodinated analogs showed virtually identical results, which suggests that the compounds were not significantly metabolized. The agent with the best biodistribution characteristics was the N-[11C]methyl-p-iodophentermine, with the p-bromo analog almost equivalent.
Assuntos
Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Fentermina/análogos & derivados , Animais , Encéfalo/fisiologia , Circulação Cerebrovascular/fisiologia , Marcação por Isótopo , Fentermina/farmacocinética , Cintilografia , Ratos , Ratos Endogâmicos F344 , Distribuição TecidualRESUMO
1. Metabolites of mephentermine (MP), phentermine (Ph), p-hydroxy-MP, p-hydroxy-Ph, N-hydroxy-MP and N-hydroxy-Ph on incubation with rat liver microsomal and cytosolic preparations were identified by g.l.c. and g.l.c.-mass spectrometry. 2. Identification of the metabolites indicated the following new metabolic routes of MP: NADPH-dependent microsomal formation of p-hydroxy-MP from MP, of p-hydroxy-Ph from p-hydroxy-MP, and the NADH-dependent microsomal formation of Ph from N-hydroxy-Ph.
Assuntos
Citosol/metabolismo , Fígado/metabolismo , Mefentermina/farmacocinética , Microssomos Hepáticos/metabolismo , Animais , Inativação Metabólica , Masculino , Mefentermina/análogos & derivados , Mefentermina/metabolismo , Modelos Biológicos , NAD/metabolismo , NADP/metabolismo , Fentermina/análogos & derivados , Fentermina/metabolismo , Fentermina/farmacocinética , Ratos , Ratos EndogâmicosRESUMO
1. p-Hydroxymephentermine (p-hydroxy-MP) and p-hydroxyphentermine (p-hydroxy-Ph) were isolated as hydrochlorides from urine of male Wistar rats repeatedly dosed with mephentermine (MP). In addition, p-hydroxy-Ph was isolated as the hydrochloride from urine of the rats dosed with phentermine (Ph). 2. These results substantiate previous indications that p-hydroxylation of MP and Ph was a primary metabolic reaction in the rat.
Assuntos
Compostos de Anilina/metabolismo , Mefentermina/urina , Fentermina/urina , Compostos de Anilina/farmacocinética , Compostos de Anilina/urina , Animais , Cromatografia Gasosa , Cromatografia Gasosa-Espectrometria de Massas , Hidroxilação , Espectroscopia de Ressonância Magnética , Masculino , Mefentermina/análogos & derivados , Mefentermina/isolamento & purificação , Fentermina/análogos & derivados , Fentermina/isolamento & purificação , Ratos , Ratos EndogâmicosRESUMO
Chronic administration of amphiphilic drugs to rats induces pulmonary phospholipidosis (P), a disease characterized by accumulation of phospholipids and large foamy macrophages in alveolar spaces. We investigated whether P induced by chlorphentermine (CPH) causes changes in lung volumes and mechanics in this species. Groups of rats were fed CPH (50 mg.kg-1.day-1) for 1, 2, 3, 5, 9, and 14 wk. After each treatment period, lung volumes and mechanics were studied in the anesthetized, paralyzed, supine rat. Partial pressure-volume (PV) curves were developed at 3 and 6 ml above functional residual capacity (FRC; PV3, PV6), followed by maximal [up to total lung capacity (TLC)] PV curves. FRC was determined by saline displacement. Lungs were then fixed for histopathological examination. A subgroup of animals was allowed a recovery period of 6 wk, after the 9 wk of CPH administration. Pair-fed rats served as controls (CTR) at each time point. Lung weight increased in CPH-treated (CPH-T) rats from 1.5 +/- 0.2 (SD) g at week 1 to 5.8 +/- 1.4 g at week 14, reflecting the development of P. TLC, FRC, transpulmonary pressure at FRC, the shape of maximal PV curves, and static expiratory lung compliance computed from maximal PV data points did not change in CPH-T rats. However, partial PV curves of CPH-T lungs (particularly PV3) were shifted downward and to the right of those of CTR at 2, 3, 5, and 9 wk, indicating increased recoil pressure in phospholipidotic lungs at these time points.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Clorfentermina/toxicidade , Pulmão/patologia , Fentermina/análogos & derivados , Fosfolipídeos/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Complacência Pulmonar , Medidas de Volume Pulmonar , Masculino , Tamanho do Órgão/efeitos dos fármacos , Fosfolipídeos/análise , Ratos , Ratos Endogâmicos , Valores de Referência , Testes de Função RespiratóriaRESUMO
We recently introduced a novel cytochemical approach to high-resolution cytochemistry of phospholipids in biological tissues. The technique consists of adsorption of bee venom phospholipase A2 to colloidal gold particles (PLA2-gold complex) and subsequent application of this complex for localization of the enzyme substrate, i.e., glycerophospholipids. In the present study, this technique was applied at the post-embedding level, in both light (LM) and transmission electron microscopy (TEM), to investigate drug-induced phospholipidosis, an experimental disorder in which the lysosomal catabolism of phospholipids is inhibited. Rats received one week of daily treatment (40 mg IP/kg) with chlorphentermine (CP), a cationic amphiphilic drug known to induce phospholipidosis in several tissues. Glutaraldehyde- and osmium-fixed lung and kidney tissues from both treated and control animals, were embedded in Epon and sections processed for labeling by PLA2-gold. In CP-treated specimens the presence of large osmiophilic inclusions in several cell types of lung parenchyma and kidney cortex confirmed the onset of phospholipidosis. These inclusions were densely labeled by PLA2-gold at both LM and TEM levels. Two general types of abnormal inclusions were distinguished on the basis of their ultrastructure and labeling pattern by PLA2-gold, suggesting different content or configuration of phospholipids. Moreover, quantitative evaluation of labeling density over various membrane compartments in lung alveolar cells evidenced significantly increased phospholipid content after CP treatment. In type II pneumocytes, such increases were measured in membranes of the RER, Golgi complex, outer and inner nuclear envelope, and the basolateral and apical domains of the plasma membrane. In capillary endothelial cells, the basal and luminal domains of the plasma membrane also showed an increase in labeling density. These results further demonstrate the potential usefulness of the PLA2-gold technique for in situ ultrastructural localization of phospholipids in normal and pathological tissues.
Assuntos
Membrana Celular/metabolismo , Clorfentermina/farmacologia , Lipidoses/metabolismo , Lipídeos de Membrana/metabolismo , Fentermina/análogos & derivados , Fosfolipídeos/metabolismo , Animais , Ouro , Histocitoquímica/métodos , Rim/efeitos dos fármacos , Rim/metabolismo , Lipidoses/induzido quimicamente , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Microscopia Eletrônica , RatosRESUMO
Daily, oral administration of chlorphentermine (60 mg/kg) for 5 days to rats produced a significant increase in the concentration of whole lung total phospholipid as well as sphingomyelin, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine. Similarly, a significant elevation in total and all individual phospholipid components was found in the lysosomal fraction of chlorphentermine-treated rat lung. In contrast, the activities of pulmonary Na+,K+-ATPase and alkaline phosphatase, enzymatic markers of membrane function, were not markedly affected by chlorphentermine treatment. The observed lung phospholipidosis was accompanied by inhibition of phospholipase C activity. Regardless of the phospholipid substrate, chlorphentermine significantly decreased pulmonary phospholipase C to approximately the same extent. Our data show that accumulation of phospholipid in whole lung and lysosomes is associated with an inhibition of phospholipase C activity.
Assuntos
Clorfentermina , Lipidoses/induzido quimicamente , Pneumopatias/induzido quimicamente , Fentermina , Fosfolipases Tipo C/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Clorfentermina/administração & dosagem , Lipidoses/enzimologia , Pulmão/enzimologia , Pneumopatias/enzimologia , Masculino , Fentermina/análogos & derivados , Ratos , Ratos Endogâmicos , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Administration of chlorphentermine to rats leads to an increase in the phospholipid content of pulmonary surfactant materials and alveolar macrophages. It is known that this drug binds to pure phospholipids and prevents their degradation by phospholipases. Therefore, experiments were carried out to determine if chlorphentermine binds to surfactant phospholipids in vitro and to measure the in vivo association of drug with phospholipids in alveolar lavage materials from rats injected with [14C]chlorphentermine. The presence of chlorphentermine in alveolar macrophages, type II cells and other small pneumocytes (a population of lung cells which does not include alveolar macrophages or type II cells) from treated animals was also assessed. Binding of the drug to surfactant phospholipids, as measured with the fluorescent probe, 1-anilino-8-naphthalene sulfonate, occurs in vitro and does not differ in various subfractions of alveolar lavage materials isolated by differential centrifugation. Following daily administration of chlorphentermine to rats for 3 days, the drug appears to be associated with surfactant phospholipids such that the molar ratio is 1:100 (chlorphentermine/phospholipid). Chlorphentermine is also associated with alveolar macrophages (molar ratio, 1:18) and type II cells (molar ratio, 1:33). Not much drug is associated with the population of other lung cells (molar ratio, 1:333). In alveolar macrophages, approx. 70% of the drug seems to be bound to phospholipid and/or sequestered in subcellular organelles. However, only 20% of the chlorphentermine is bound and/or sequestered in type II cells. The results of these experiments suggest that following chlorphentermine administration, the drug is associated with phospholipids in acellular pulmonary lavage materials, alveolar macrophages and type II cells. This drug-phospholipid interaction may impair phospholipid degradation and lead to a phospholipidosis in surfactant materials and alveolar macrophages.
Assuntos
Líquido da Lavagem Broncoalveolar/metabolismo , Clorfentermina/metabolismo , Pulmão/metabolismo , Macrófagos/metabolismo , Fentermina/análogos & derivados , Fosfolipídeos/metabolismo , Surfactantes Pulmonares/metabolismo , Animais , Técnicas In Vitro , Ratos , Ratos Endogâmicos , Espectrometria de FluorescênciaRESUMO
Male Swiss-Webster mice were treated daily for 14 days with either 120 mg/kg chlorphentermine (CP) to produce pulmonary lipidosis or an equal volume of water. Animals in each treatment group were then exposed by whole-body inhalation to either air or NO2 for 48 h. Immediately following exposure, alveolar macrophages (MPs) were collected from each animal by bronchoalveolar lavage. Assays performed on adherent viable MPs showed some changes in metabolic reduction, phagocytosis, and killing activity. 5'-Nucleotidase activity and yeast phagocytosis and killing assays suggested that CP elicited an increase in phagocytosis over control levels. Although the percentage metabolic reduction and microbicidal killing activities following CP were not increased when compared to controls, absolute reduction and killing (percentage values times total MPs) were significantly increased. These increased functions seemed to be highly dependent on the large increase in the total number of MPs induced by CP. It is possible that the large accumulation of MPs in the airways of the lipidotic lung may help protect the alveolar epithelium from NO2 by quenching free radicals produced during NO2-induced lipid peroxidation.
Assuntos
Clorfentermina/farmacologia , Macrófagos/fisiologia , Dióxido de Nitrogênio/farmacologia , Fentermina/análogos & derivados , 5'-Nucleotidase , Animais , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Nitroazul de Tetrazólio , Nucleotidases/metabolismo , Fagocitose/efeitos dos fármacos , Valores de ReferênciaRESUMO
We have previously demonstrated that the chlorphentermine (CP)1-induced impairment in lymphocyte blastogenesis involves drug-induced inhibition of an event which occurs very early during lymphocyte activation. An early event, which is associated with mitogen-induced lymphocyte activation, involves the hydrolysis of phosphatidylinositol by phospholipase C to yield inositol phosphates and diacylglycerol as products. Inositol phosphates and diacylglycerol then function as mediators of a trans-membrane signal for the continuation of the cellular response. It was the purpose of the present study to determine the effects of CP on this phosphatidylinositol pathway. We demonstrated that formation of inositol phosphates in lymphocytes increases progressively above control over a 2 hour period following concanavalin A (Con A)-stimulation. In contrast, lymphocytes pre-incubated with 10(-5)M CP for 60 min, then stimulated with Con A for 2 hours in the presence of 10(-5)M CP, exhibit a significantly depressed inositol phosphate formation. In addition, CP also inhibited the activity of phospholipase C (IC50 = 0.58 mM), the enzyme responsible for the formation of inositol phosphates during lymphocyte activation. Further, lymphocytes activated in a manner that bypasses the phosphatidylinositol pathway are not inhibited by 10(-7)M or 10(-9)M CP as are cells activated with Con A. These results suggest that the suppression of the phosphatidylinositol pathway may be involved in the inhibition by CP of lymphocyte blastogenesis induced by Con A.
Assuntos
Clorfentermina/farmacologia , Ativação Linfocitária , Linfócitos/metabolismo , Fentermina/análogos & derivados , Fosfatidilinositóis/biossíntese , Animais , Concanavalina A , Relação Dose-Resposta a Droga , Técnicas In Vitro , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Baço , Fosfolipases Tipo C/metabolismoRESUMO
1. Rats were trained to discriminate injections of either (+)-amphetamine (0.75 mg/kg) or (+/-)-fenfluramine (1.5 mg/kg) from saline in a two-lever drug discrimination task. 2. After stable discrimination performances were attained in each group, stimulus generalization studies were conducted with amphetamine, fenfluramine, and chlorphentermine. 3. Stimulus generalization (substitution) did not occur between amphetamine and fenfluramine when either drug was used as the training stimulus. 4. In contrast, both the amphetamine stimulus and the fenfluramine stimulus generalized completely to chlorphentermine. 5. Taken together, the results suggest that chlorphentermine may be capable of producing dual stimulus effects in animals.
Assuntos
Clorfentermina/farmacologia , Generalização do Estímulo , Fentermina/análogos & derivados , Animais , Condicionamento Operante/efeitos dos fármacos , Dextroanfetamina/farmacologia , Aprendizagem por Discriminação , Fenfluramina/farmacologia , Masculino , Ratos , Ratos EndogâmicosRESUMO
Daily subcutaneous injection of gentamicin (100 mg/kg) for 2 days produced a significant decrease in the activities of alkaline phosphatase, a brush-border membrane marker, and Na+-K+ ATPase, a basolateral membrane marker, in adult rat kidney cortex. Analysis of homogenate and lysosomal fractions revealed a significant rise in the concentration of total renal cortical phospholipid, phosphatidylserine, phosphatidylcholine, and phosphatidylinositol. In the lysosomal fraction, an increase in the levels of phosphatidylglycerol and phosphatidylethanolamine was also noted. Daily, oral chlorphentermine (60 mg/kg) administration for 5 days significantly reduced renal Na+-K+ ATPase without a marked change in alkaline phosphatase. As in the case of gentamicin, chlorphentermine produced a significant elevation in phosphatidylserine, phosphatidylcholine, and phosphatidylinositol as well as total phospholipid in both the homogenate and lysosomal fractions of kidney cortex. The observed chlorphentermine- or gentamicin-induced renal phospholipidosis was associated with a significant reduction in the activity of phosphatidylinositol-specific phospholipase C. The drug-induced inhibition of phospholipase C was quantitatively equal in the renal cortical homogenate and lysosomal fractions. In addition, gentamicin significantly inhibited the activity of phosphatidylserine-phospholipase C and phosphatidylcholine-phospholipase C in renal cortical homogenate. In contrast, only the activity of phosphatidylinositol-specific phospholipase C was decreased in chlorphentermine-treated kidneys. Evidence thus indicates that the gentamicin-induced accumulation of phospholipid in renal cortical lysosomes is associated with inhibition of various forms of phospholipase C, while in the case of chlorphentermine the inhibition of different phospholipases may be involved in phospholipid accumulation.
Assuntos
Clorfentermina/toxicidade , Gentamicinas/toxicidade , Córtex Renal/efeitos dos fármacos , Lipidoses/induzido quimicamente , Fentermina/análogos & derivados , Fosfolipídeos/metabolismo , Animais , Córtex Renal/enzimologia , Córtex Renal/metabolismo , Lipidoses/enzimologia , Lisossomos/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos , Fosfolipases Tipo C/antagonistas & inibidoresRESUMO
Chlorphentermine HCl (CP) was used to induce preexisting alveolar alterations resembling a pulmonary lipidosis in mice to study these effects on the severity and duration of nitrogen dioxide (NO2) toxicity. Results indicated that a daily dose of 120 mg/kg for 14 days produced consistent histopathologic changes characterized by an accumulation of large foamy macrophages. Male Swiss-Webster mice were divided into a control and three treatment groups. Group 1 received 120 mg/kg CP po daily for 2 weeks followed by exposure to air for 48 hr. Group 2 received 20 ppm NO2 for 48 hr via whole-body inhalation, and group 3 received 120 mg/kg CP daily for 2 weeks followed by 20 ppm NO2 for 48 hr. The fourth group served as a nontreated control and received water in place of CP and air in place of NO2. All groups were compared by morphologic evaluation of pulmonary tissues at the light and electron microscopic levels at Days 0, 1, 3, 5, and 7 after the 48-hr exposure to air or NO2. In a second experiment using the same treatment groups, thin-section light microscopy was used to count the number of type I and type II cells and macrophages. NO2 exposure alone caused deaths in 20.8 and 18.5% of the mice in the two studies, but no deaths were seen in the combination groups from both experiments. Histopathologic evaluation showed a typical cellular response to the NO2 exposure, but differences were noted between the two groups receiving NO2 on this treatment. There was increased type II cell hyperplasia and terminal bronchiolitis on Days 0 and 1 but less on Days 3 to 7 in the combination group compared to the NO2 alone group. CP treatment prior to NO2 exposure caused less terminal bronchiolar epithelial hyperplasia and less pulmonary edema than was seen in the NO2 along group. The CP treatment appeared to protect against the lethal effects of NO2 at the concentration and time of exposure used and altered the cellular repair mechanism that occurs in response to NO2 toxicity. CP treatment prior to NO2 exposure caused significantly less loss of type I cells and less increase in type II cells due to NO2 damage. The combination treatment also caused an increase in macrophages greater than that seen in either individual treatment, and this number remained increased through 5 days post-NO2 exposure, whereas the NO2 alone caused a steady increase in macrophages following the exposure until Day 3.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Clorfentermina/toxicidade , Pulmão/efeitos dos fármacos , Dióxido de Nitrogênio/toxicidade , Fentermina/análogos & derivados , Animais , Peso Corporal/efeitos dos fármacos , Contagem de Células , Hiperplasia , Lipidoses/induzido quimicamente , Pulmão/patologia , Pulmão/ultraestrutura , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Microscopia EletrônicaRESUMO
p-Iodo-phentermine (IP) and two of its derivatives, N,N,-dimethyl-p-iodo-phentermine (IDMP) and N-isopropyl-p-iodo-phentermine (IIP) were synthesized and radiolabelled with iodine by isotopic exchange. They were evaluated as potential brain imaging agents and compared to IAMP biodistribution in rats did not show any superiority to IAMP.
Assuntos
Encéfalo/diagnóstico por imagem , Radioisótopos do Iodo , Fentermina/análogos & derivados , Animais , Masculino , Cintilografia , Ratos , Ratos Endogâmicos , Distribuição TecidualRESUMO
On chronic treatment certain amphiphilic drugs induce a generalized phospholipidosis. This drug side effect has been related to an inhibition of the lysosomal phospholipases due to the interaction of the drugs with phospholipids (PL). In the present experiments, the influence of the amphiphilic drugs ambroxol, imipramine, chloroquine and chlorphentermine on the hydrolysis of dipalmitoyl-phosphatidylcholine (DPPC) unilamellar liposomes by bee venom phospholipase A2 (PLase A2) was studied. Special emphasis was laid on the initial phase and temperature dependence. The activity of PLase A2 was measured continuously with a spectrophotometric assay using cresol red as indicator. In most cases a lag-phase of different duration was observed before the enzyme exhibited its full activity. The duration of the lag-phase and the rate of hydrolysis in the second phase are inversely related. The temperature dependence of the hydrolysis reveals a maximum of activity near the phase transition of the bilayer and a gradually decreasing activity at lower and higher temperatures, respectively. The analysis of the influence of amphiphilic drugs reveals three types of interaction. Imipramine and ambroxol shift the temperature activity profile towards lower temperatures without a substantial influence on the shape of the profile and on the maximal rate of hydrolysis. Chloroquine inhibits the enzyme activity without any temperature dependence. Chlorphentermine, the classical lipidosis inducing drug, exhibits a third type of interaction which seems to be a combination of the two former types.