RESUMEN
Combined administration of the amphetamine analogs phentermine and fenfluramine (PHEN/FEN) has been used in the treatment of obesity. While these medications are thought to modulate monoamine transmission, the precise neurochemical effects of the PHEN/FEN mixture have not been extensively studied. To assess the mechanism of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus accumbens of conscious freely moving rats. A series of amphetamine derivatives including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM) or injected systemically (1 mg/kg, ip). Dialysate samples were assayed for dopamine (DA) and serotonin (5-HT) by high-performance liquid chromatography with electrochemical detection. When infused locally, phentermine preferentially increased extracellular DA, whereas fenfluramine selectively increased extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN mixture caused parallel elevations of both transmitters. Analogous results were obtained when the drugs were injected systemically. Phentermine stimulated robust locomotor activity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect at the highest dose. Accumulating evidence suggests that chronic drug and alcohol abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine releasing agents may be an effective treatment strategy for substance use disorders, as well as for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.
Asunto(s)
Dopamina/metabolismo , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Fenfluramina/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Fentermina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Simpatomiméticos/farmacología , Anfetamina/farmacología , Animales , Clorfentermina/farmacología , Cocaína/análogos & derivados , Cocaína/farmacología , Técnicas In Vitro , Radioisótopos de Yodo , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Núcleo Accumbens/citología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-DawleyRESUMEN
A possible mechanism for fenfluramine-induced pulmonary hypertension has been investigated. Fenfluramine, like chlorphentermine, may inhibit the pulmonary uptake and/or metabolism of 5-hydroxytryptamine (5-HT). This allows more 5-HT to remain in the pulmonary circulation, where it may exert a greater vasoconstrictor action resulting in pulmonary hypertension. Chlorphentermine has been shown to inhibit the uptake and metabolism of 5-HT. The effect of fenfluramine on the pulmonary disposition of [14C]5-HT has been investigated, in comparison with chlorphentermine, using a recirculating isolated perfused rat lung system. The pulmonary disposition of [14C]5-HT was assessed by measuring the change in [14C]5-HT concentration in the perfusion medium during the experiment and at the end, and the concentration in the lung at the end of the experiment. The concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, was measured in perfusate and lung samples. Mean pulmonary clearance of 5-HT for the control lung and lungs challenged with either fenfluramine (2.5 microM) or chlorphentermine (25 microM) was 4.514, 1.316 and 1.007 mL min(-1), respectively (n = 5). The concentration of 5-HT found in the lungs at the end of the experiment for the control and the lungs preloaded with fenfluramine or chlorphentermine was 695.05+/-9.69, 638.65+/-10.27 and 617.3+/-14.38 ng g(-1), respectively. Fenfluramine, like chlorphentermine, inhibited the pulmonary disposition of 5-HT resulting in an elevated perfusate level of 5-HT. This is a possible contributing mechanism for fenfluramine-induced pulmonary hypertension. The effect of fenfluramine was less pronounced than chlorphentermine.
Asunto(s)
Clorfentermina/farmacología , Fenfluramina/farmacología , Depuradores de Radicales Libres/metabolismo , Pulmón/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Simpatomiméticos/farmacología , Animales , Cromatografía Liquida , Femenino , Depuradores de Radicales Libres/análisis , Ácido Hidroxiindolacético/análisis , Ácido Hidroxiindolacético/metabolismo , Pulmón/metabolismo , Tasa de Depuración Metabólica/efectos de los fármacos , Perfusión , Ratas , Serotonina/análisisRESUMEN
BACKGROUND: The amphiphilic drugs chloroquine and chlorphentermine are known to cause lipidosis in the human and rat retina. METHODS: We treated femal albino Wistar rats orally with chloroquine for 12 weeks, followed by a period of 4 months with normal feed and another group with chlorphentermine for 4-16 weeks. The animals were submitted to electroretinography, and the retinae were prepared for histological investigations. RESULTS: Chloroquine caused severe lipidosis in the neuroretina and slight photoreceptor cell degeneration after 12 weeks of treatment. The b-wave was reduced to 30% of initial values. After withdrawal the lipidosis remitted, but the degeneration of the photoreceptor cell layer continued to progress. The a-wave and b-wave amplitudes were reduced to 25% and 16% of initial values, respectively. Chlorphentermine caused pronounced lipidosis in the pigment epithelium and less numerous in the neuroretina after 16 weeks; no photoreceptor cell degeneration was found. The b-wave was reduced to 80% of initial values, the a-wave appeared unaffected. CONCLUSION: Whether lipidosis is the primary cause of changes in the electroretinogram and of receptor cell degeneration is doubtful. Excessive lipid storage may be the cause of secondary changes. It is unlikely that lipidosis in pigment epithelium played a role.
Asunto(s)
Cloroquina/farmacología , Clorfentermina/farmacología , Lipidosis/inducido químicamente , Retina/efectos de los fármacos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Electrorretinografía , Femenino , Ratas , Ratas Wistar , Retina/patología , Células Fotorreceptoras Retinianas Conos/efectos de los fármacos , Células Fotorreceptoras Retinianas Conos/patología , Factores de TiempoRESUMEN
Cationic amphiphilic drugs (CADs) are structurally characterized by hydrophobic ring structures and hydrophilic side chains. Studies have demonstrated that repeated administration of CADs to experimental animals and humans may induce phospholipid (PL) accumulation within the cells of various tissues. The immunomodulatory azaspiranes are novel CADs with beneficial effects in a number of animal models of autoimmune disease and transplantation. Although the mechanism of action of these compounds is unclear, efficacy in all of the disease models is accompanied by the generation of suppressor cell (SC) activity in various lymphoid organs. SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine+ ++ hydrochloride) and two analogs, SK&F 106615 and SK&F 103811, were compared with chlorphentermine and chloroquine for their ability to induce PL accumulation and SC activity. Oral administration of SK&F 105685 and SK&F 106615 caused PL accumulation in bronchoalveolar lavage macrophages (AM) but to a far lesser extent (three- to fivefold) than chlorphentermine. Neither the immunologically unreactive azaspirane SK&F 103811 nor chloroquine affected PL levels. AM from rats treated with SK&F 105685 or SK&F 106615 expressed more potent SC activity than chlorphentermine. Thus, SC activity did not correlate with the extent of PL accumulation. Neither SK&F 103811 nor chloroquine induced SC activity. AM from SK&F 105685-treated rats had an enhanced ability to kill the opportunistic pathogen Candida albicans in vitro indicating that there was no impairment of macrophage-dependent host defense mechanisms.
Asunto(s)
Bronquios/metabolismo , Macrófagos Alveolares/metabolismo , Fosfolípidos/metabolismo , Compuestos de Espiro/farmacología , Animales , Bronquios/efectos de los fármacos , Candida albicans/efectos de los fármacos , Cloroquina/farmacología , Clorfentermina/farmacología , Inmunosupresores/farmacología , Cuerpos de Inclusión/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Masculino , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/metabolismo , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismoRESUMEN
When administered to humans and animals, the iodine-containing drug amiodarone can cause pulmonary toxicity. As part of the pulmonary response to amiodarone, the drug and its principal metabolite, desethylamiodarone, accumulate in alveolar macrophages. Little is known about the susceptibility of lungs with preexisting damage to amiodarone administration. A number of chemicals can cause pulmonary phospholipidosis in humans and animals. To study the effect of a preexisting phospholipidosis on the intracellular accumulation of amiodarone and desethylamiodarone, rats were treated with chlorphentermine to induce a phospholipidosis in alveolar macrophages. The cells were recovered from the lungs by pulmonary lavage and placed in cell culture. They were then exposed to the same concentration of either amiodarone or desethylamiodarone. The intracellular distribution of each drug was quantified by measuring the associated iodine signal using X-ray microanalysis of freeze-dried cryosections of cells. Both drugs accumulated in lipid-rich amorphous bodies which correspond to lysosomally derived lamellar structures observed in conventional plastic sections. The level of desethylamiodarone exceeded that of amiodarone in the amorphous bodies. With both drugs, a higher concentration of iodine was present at the outer edges of the amorphous bodies compared to that in the center core. This suggests that the drugs are unable to freely penetrate the performed structures. By monitoring the concentrations of sodium and potassium ions within the nucleus, it was determined that chlorphentermine treatment disrupted the ionic distribution in the cells. Exposure to amiodarone, but not desethylamiodarone, resulted in further changes in sodium and potassium levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Lipidosis/metabolismo , Lipidosis/patología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Fosfolípidos/metabolismo , Amiodarona/análogos & derivados , Amiodarona/análisis , Amiodarona/metabolismo , Amiodarona/farmacología , Animales , Núcleo Celular/química , Núcleo Celular/metabolismo , Núcleo Celular/ultraestructura , Células Cultivadas , Clorfentermina/farmacología , Microanálisis por Sonda Electrónica , Liofilización , Secciones por Congelación , Cuerpos de Inclusión/química , Cuerpos de Inclusión/ultraestructura , Macrófagos Alveolares/química , Masculino , Potasio/análisis , Potasio/metabolismo , Ratas , Ratas Endogámicas F344 , Sodio/análisis , Sodio/metabolismoRESUMEN
In these studies we examined the kinetics of amiodarone (Am) uptake and efflux in/from the lung, and the influence of other amphiphilics on these processes. We used single-pass perfused isolated lungs from rats. Medium containing Am (30 microM + 1 microCi of [14C]Am) was perfused through the lung for 20 min (uptake), followed by 20 min of perfusion with drug-free medium (efflux). Lack of metabolism enabled us to follow Am by measuring the amount of radioactivity in perfusate and lung. Other concentrations of Am (3, 60 and 120 microM; n = 2-4 each) were also examined. Inhibited uptake and accelerated efflux of Am were attempted with the pneumophilic amphiphilics chlorimipramine, chlorphentermine, chlorpromazine, verapamil and with the main metabolite of Am: desethylamiodarone (60 and/or 240 microM; n = 3-4 lungs each). Lung extracted Am extensively during uptake. The amount of Am accumulated at 20 min (inflowing concentration: 30 microM) averaged 1307 +/- 109 (S.E.) nmol/g, corresponding to a tissue to medium ratio of 43.3 +/- 1.6. Spontaneous efflux of Am was incomplete. At 40 min, 862 +/- 105 nmol of Am remained bound per g of lung, suggesting sequestration of Am in a slowly effluxable pool in which calculations show that more than 50% of the drug will ultimately persist. Uptake and efflux rates obey biexponential kinetics, indicating storage into two pools. Uptake rate and the amount of Am accumulated in lung at 20 min increased in proportion to inflowing concentration up to 60 microM. At 120 microM the increase was less. Neither amphiphilic was capable of inhibiting Am uptake, whereas only chlorphentermine significantly accelerated Am efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Amiodarona/farmacocinética , Pulmón/metabolismo , Animales , Clorfentermina/farmacología , Clomipramina/farmacología , Técnicas In Vitro , Masculino , Perfusión , Ratas , Ratas Endogámicas F344RESUMEN
Among the surfactant-associated proteins (SP-A) characterized so far, there is a group of glycoproteins 26 to 34 kDa that features collagenlike sequences near their N-terminal end. We herein report the cross-reactivity of a rabbit polyclonal antibody to EHS tumor-derived type IV collagen towards rat SP-A. Rat lung tissues were processed for the localization of both type IV collagen and SP-A by high-resolution immunocytochemistry, applying the protein A-gold technique with specific antibodies. In addition to the various basal laminae of the pulmonary tissue, the antitype IV collagen antibody labeled the surfactant material found in alveolar spaces and macrophages, as well as in type II pneumocytes. The surfactant nature of the alveolar material labeled by the antiserum to type IV collagen was confirmed by the positive labeling obtained using an antibody to SP-A. This antibody labeled specifically the alveolar surfactant material, without binding any basal laminae. Several control experiments demonstrated the specificity of each labeling. These results were further supported by immunoblot experiments on nitrocellulose membrane. These findings thus provide further support to the existence of collagenlike sequences on SP-A, and further demonstrate that this structural similarity with collagens can lead to some cross-antigenicity.
Asunto(s)
Colágeno/análisis , Epítopos/análisis , Glicoproteínas/análisis , Proteolípidos/análisis , Surfactantes Pulmonares/análisis , Animales , Clorfentermina/farmacología , Colágeno/farmacocinética , Glicoproteínas/farmacocinética , Immunoblotting , Inmunohistoquímica , Pulmón/análisis , Pulmón/ultraestructura , Masculino , Microscopía Electrónica , Fosfolípidos/análisis , Proteolípidos/farmacocinética , Proteína A Asociada a Surfactante Pulmonar , Proteínas Asociadas a Surfactante Pulmonar , Surfactantes Pulmonares/farmacocinética , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Membrana Celular/metabolismo , Clorfentermina/farmacología , Lipidosis/metabolismo , Lípidos de la Membrana/metabolismo , Fentermina/análogos & derivados , Fosfolípidos/metabolismo , Animales , Oro , Histocitoquímica/métodos , Riñón/efectos de los fármacos , Riñón/metabolismo , Lipidosis/inducido químicamente , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Microscopía Electrónica , RatasRESUMEN
Over 30 drugs of differing pharmacologic action are capable of inducing lamellar bodies of lysosomal origin in cells of animals and humans. The structures develop because of a drug-induced impairment in lysosomal phospholipid catabolism. Toxicity frequently accompanies the induction of these bodies. However, little information exists as to whether their development or presence is causally linked to the cellular or tissue dysfunction. This review examines the biological aspects of the induction of lysosomal lamellar bodies by drugs and considers the toxicologic implications of their presence in cells.
Asunto(s)
Lisosomas/efectos de los fármacos , Lípidos de la Membrana/metabolismo , Toxicología/métodos , Animales , Células Cultivadas/efectos de los fármacos , Cloroquina/farmacología , Clorfentermina/farmacología , Gentamicinas/farmacología , Humanos , Lisosomas/ultraestructura , Microscopía Electrónica , Fosfolípidos/metabolismoRESUMEN
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.
Asunto(s)
Clorfentermina/farmacología , Generalización del Estimulo , Fentermina/análogos & derivados , Animales , Condicionamiento Operante/efectos de los fármacos , Dextroanfetamina/farmacología , Aprendizaje Discriminativo , Fenfluramina/farmacología , Masculino , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Clorfentermina/farmacología , Activación de Linfocitos , Linfocitos/metabolismo , Fentermina/análogos & derivados , Fosfatidilinositoles/biosíntesis , Animales , Concanavalina A , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos , Bazo , Fosfolipasas de Tipo C/metabolismoRESUMEN
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.
Asunto(s)
Clorfentermina/farmacología , Macrófagos/fisiología , Dióxido de Nitrógeno/farmacología , Fentermina/análogos & derivados , 5'-Nucleotidasa , Animales , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Nitroazul de Tetrazolio , Nucleotidasas/metabolismo , Fagocitosis/efectos de los fármacos , Valores de ReferenciaRESUMEN
The present study was designed to investigate whether lungs can utilize 5-hydroxytryptophan (5-HTP), formed elsewhere and transported, for the synthesis of 5-hydroxytryptamine (5-HT). [14C]5-HTP uptake was 7.7 +/- 1.1 and 3.9 +/- 0.2% by rabbit and rat lungs, respectively, after 1 h of perfusion with 10 microM [14C]5-HTP. There was an increase in the lung uptake of [14C]5-HTP when the lungs were preperfused with 0.5 mM chlorphentermine (CP) and the uptake was low when the lungs were preperfused with 0.1 mM hydroxybenzylhydrazine dihydrochloride (HBH). The perfusate concentration of 5-hydroxyindole acetic acid (5-HIAA) increased significantly (3-4 micrograms/100 mL) during rabbit lung perfusion with 10 microM [14C]5-HTP and this did not change significantly when the lungs were preperfused with 0.5 mM CP. However, 5-HT increased with time in the perfusate. 5-HT, but not 5-HIAA, was detected in the perfusate and increased with time of perfusion when the rat lungs were perfused either with 10 microM 5-HTP or with 0.5 mM CP and 10 microM 5-HTP. However, no metabolites were detected in either the rabbit lung or rat lung perfusates when they were preperfused with 0.1 mM HBH. Lung contents of 5-HT and 5-HIAA were significantly higher in the rat lungs and only 5-HIAA increased in rabbit lungs after 1 h of perfusion with 10 microM 5-HTP. Preperfusion with 0.5 mM CP resulted in a greater increase in the 5-HT content of both rabbit and rat lungs.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
5-Hidroxitriptófano/farmacocinética , Pulmón/metabolismo , Serotonina/biosíntesis , Animales , Clorfentermina/farmacología , Hidrazinas/farmacología , Ácido Hidroxiindolacético/metabolismo , Pulmón/efectos de los fármacos , Perfusión , Conejos , RatasRESUMEN
Four pigeons were trained to discriminate injections of d-amphetamine (AMPH; 2.0 mg/kg i.m.) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. When drugs used therapeutically as anorectics were tested, they consistently produced greater than 80% of AMPH-appropriate responding. The order of potency for substituting for AMPH was: mazindol greater than AMPH = phenmetrazine = phentermine greater than chlorphentermine = phendimetrazine = diethylpropion greater than clortermine = mefenorex. Other anorectics such as phenylpropanolamine (0.3-30.0 mg/kg) and fenfluramine (1.0-17.0 mg/kg) only substituted partially for AMPH whereas benzphetamine (1.0-100.0 mg/kg) resulted primarily in saline-appropriate responding. Compounds related to AMPH in biochemical mechanism of action or psychomotor stimulant activity also were tested. Methylphenidate (0.1-3.0 mg/kg), piribedil (0.3-17.0 mg/kg) and nisoxetine (0.03-1.0 mg/kg) shared discriminative stimulus properties with AMPH whereas bupropion (1.0-30.0 mg/kg) and propylhexedrine (10.0-100.0 mg/kg) substituted for AMPH in two of three pigeons tested. In contrast, caffeine and fenetylline resulted principally in saline-appropriate responding. Compounds from pharmacological classes not related to AMPH, such as morphine, diazepam and phencyclidine, failed to substitute for AMPH. In general, compounds with anorectic and/or stimulant properties shared discriminative stimulus properties with AMPH.
Asunto(s)
Depresores del Apetito/farmacología , Dextroanfetamina/farmacología , Anfetaminas/farmacología , Animales , Bupropión , Cafeína/farmacología , Clorfentermina/farmacología , Columbidae , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fenfluramina/farmacología , Mazindol/farmacología , Propiofenonas/farmacología , Propilaminas/farmacología , Teofilina/análogos & derivados , Teofilina/farmacologíaRESUMEN
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.
Asunto(s)
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Cloroquina/farmacología , Clorfentermina/farmacología , Imipramina/farmacología , Liposomas , Fentermina/análogos & derivados , Fosfolipasas A/metabolismo , Fosfolipasas/metabolismo , Venenos de Abeja , Hidrólisis , Cinética , Fosfolipasas A2 , TermodinámicaRESUMEN
The effects of chlorphentermine on the bioenergetics and activity of monoamine oxidase in mitochondria from the brain of the rat were examined. Oxidation rates of glutamate and succinate were investigated in the presence of chlorphentermine (0.1-5.0 mM). In small concentrations (0.1-1.0 mM), chlorphentermine decreased the respiratory control ratio and the adenosine diphosphate oxygen (ADP/O) ratio, and stimulated state four respiration. State three respiration and the uncoupled state were also decreased, but to a lesser degree. In the presence of larger concentrations of chlorphentermine (1.0-5.0 mM), the respiration in states four, three, and in the uncoupled state, as well as the respiratory control ratio and ADP/O ratio, were decreased significantly. These data indicate that chlorphentermine functions as an uncoupler of oxidative phosphorylation. Oxidation of norepinephrine, serotonin, octopamine, tyramine and dopamine by monoamine oxidase (MAO), an enzyme marker of the outer mitochondrial membrane, was inhibited in the presence of 0.01 to 0.1 mM of chlorphentermine. Oxidation of tryptamine and benzylamine was unaffected. A kinetic study of the oxidation of serotonin in the absence and presence of chlorphentermine (0.025-0.1 mM) indicated that both the Vmax and Km were affected. This drug is an inhibitor of monoamine oxidase of mitochondria of the brain with mixed type inhibition. These combined data show that chlorphentermine affects biochemical processes in both inner and outer mitochondrial membranes.
Asunto(s)
Encéfalo/efectos de los fármacos , Clorfentermina/farmacología , Membranas Intracelulares/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Fentermina/análogos & derivados , Animales , Metabolismo Energético/efectos de los fármacos , Técnicas In Vitro , Masculino , Monoaminooxidasa/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , RatasRESUMEN
Chlorphentermine is a cationic amphiphilic drug which produces a phospholipid storage disorder in rat lungs. Experiments were carried out to characterize changes in the composition of acellular alveolar lavage materials and to study possible mechanisms by which pulmonary surfactant phospholipidosis is produced by administration of the drug. Following ten daily injections of chlorphentermine (25 mg/kg body weight), there are 12.2- and 13.6-fold increases of pulmonary lavage total phospholipids and disaturated phosphatidylcholines (disaturated PC), respectively. In addition, there is a 2.8-fold increase in total protein and a 12.7-fold increase in the surfactant apoprotein group with molecular weights from 28,000 to 32,000. We measured incorporation of labeled palmitate, choline and glycerol into disaturated PC in type II cells and alveolar macrophages isolated from control and chlorphentermine-treated animals. The drug does not affect the incorporation of labeled substrates into disaturated PC in either cell type. However, in alveolar macrophages there is a decrease in the rate of intracellular degradation of recently synthesized disaturated PC in chlorphentermine-treated animals. The drug also inhibits the phospholipase-induced catabolism of rat surfactant disaturated PC which occurs during incubation of alveolar lavage fluid in vitro at 37 degrees C. When the lavage fluid is divided into subfractions by differential centrifugation, a larger percentage of the phospholipid is distributed in the less sedimentable subfractions in chlorphentermine-treated animals relative to controls, suggesting the accumulation of older surfactant materials. These results suggest that chlorphentermine-induced phospholipidosis of pulmonary surfactant materials is due to decreased rates of phospholipid degradation.
Asunto(s)
Clorfentermina/farmacología , Fentermina/análogos & derivados , Fosfolípidos/metabolismo , Proteínas/metabolismo , Alveolos Pulmonares/efectos de los fármacos , Surfactantes Pulmonares/metabolismo , Animales , Colina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Electroforesis en Gel de Poliacrilamida , Glicerol/metabolismo , Inmunoelectroforesis , Masculino , Microscopía Electrónica , Ácido Palmítico , Ácidos Palmíticos/metabolismo , Fosfatidilcolinas/metabolismo , Alveolos Pulmonares/metabolismo , Ratas , Ratas EndogámicasRESUMEN
The effect of chlorphentermine (CP) treatment (50 mg/kg/day, per os [po]) on the incorporation of [14C]choline into rat lung phospholipid was studied. Total phospholipid content was increased 2.0-fold and 1.7-fold after seven and 14 days, respectively, compared with the pair-fed rats. The incorporation of [14C]choline into phosphatidylcholine (PC) was significantly inhibited by either seven or 14 days of CP treatment. Nevertheless, the PC content was significantly increased by day 7 and stayed elevated at day 14 of CP treatment. Choline and phosphorylcholine contents were significantly decreased by the CP treatment. These results suggest that the higher accumulation of PC is due to inhibition of enzymes involved in the hydrolysis of phospholipids rather than to a stimulation of the phospholipid synthesis.
Asunto(s)
Clorfentermina/farmacología , Colina/metabolismo , Pulmón/metabolismo , Fentermina/análogos & derivados , Fosfolípidos/biosíntesis , Animales , Peso Corporal/efectos de los fármacos , Radioisótopos de Carbono , Cinética , Pulmón/anatomía & histología , Pulmón/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
In this study we have shown that the alveolar macrophage (AM) plays a major role in the induction of phospholipidosis in rat lung by chlorphentermine (CP). Rats were administered CP (30 mg/kg i.p., 5 days/week) for 1, 4 and 8 weeks and the levels of CP and total phospholipid were measured in whole lungs and in the AM fraction recovered from the lungs by pulmonary lavage. Lungs accumulate CP to a much greater extent than liver or kidney and show a marked increase in phospholipid content by 8 weeks. Drug treatment is accompanied by the recovery of an elevated number of AMs at all time points. The CP and phospholipid levels in AMs reach a peak at 4 weeks with little change beyond that time. Initially the phospholipidosis is localized largely in the AMs with the disorder developing in other compartments of the lungs with increasing treatment time. The AMs contribute 3% of the total pulmonary phospholipid in control rats. After 1 week of CP, 34% of the pulmonary phospholipid is in the AM fraction with this value being 21% after 8 weeks. The CP to phospholipid molar ratio is higher in AMs than whole lung at all three time points.