RESUMEN
Clinical and animal studies indicate that increased fatty acid delivery to lean tissues induces cardiac electrical remodeling and alterations of cellular calcium homeostasis. Since this may represent a mechanism initiating cardiac dysfunction during establishment of insulin resistance and diabetes or anaerobic cardiac metabolism (ischemia), we sought to determine if short-term exposure to high plasma concentration of fatty acid in vivo was sufficient to alter the cardiac sodium current (INa) in dog ventricular myocytes. Our results show that delivery of triglycerides and nonesterified fatty acids by infusion of Intralipid + heparin (IH) for 8 h increased the amplitude of INa by 43% and shifted its activation threshold by -5 mV, closer to the resting membrane potential. Steady-state inactivation (availability) of the channels was reduced by IH with no changes in recovery from inactivation. As a consequence, INa "window" current, a strong determinant of intracellular Na+ and Ca2+ concentrations, was significantly increased. The results indicate that increased circulating fatty acids alter INa gating in manners consistent with an increased cardiac excitability and augmentation of intracellular calcium. Moreover, these changes could still be measured after the dogs were left to recover for 12 h after IH perfusion, suggesting lasting changes in INa. Our results indicate that fatty acids rapidly induce cardiac remodeling and suggest that this process may be involved in the development of cardiac dysfunctions associated to insulin resistance and diabetes.
Asunto(s)
Potenciales de Acción , Hiperlipidemias/metabolismo , Remodelación Ventricular , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Calcio/metabolismo , Perros , Ácidos Grasos/sangre , Ácidos Grasos/metabolismo , Femenino , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/metabolismo , Hiperlipidemias/fisiopatología , Miocitos Cardíacos/metabolismo , Sodio/metabolismo , Triglicéridos/metabolismoRESUMEN
Considering that adrenal glands possess a variety of purinoceptors associated with various cell types and that some of these cells (chromaffin cells) secrete large amounts of adenine nucleotides, it was of interest to localize nucleoside triphosphate diphosphohydrolase (NTPDase) in these glands and to define the biochemical characteristics of this ectonucleotidase. Immunolocalization produced a moderate reaction in capsula and medulla, with no signal in zona glomerulosa and zona reticularis. In contrast, a very strong reaction was found in zona fasciculata. Biochemical analysis of particulate fractions isolated from whole glands revealed high levels of ATPase and ADPase activities. This appeared to be attributable to the NTPDase since the level of ADPase was as high as ATPase. Both ATPase and ADPase activities were similarly inhibited by sodium azide. Additionally electrophoretograms with these two substrates showed comparable patterns. Western blots with 'Ringo', an antibody that recognizes the different isoforms of mammalian NTPDases, showed the presence of isoforms of NTPDases at 54 and 78 kDa, respectively. Interestingly, the 54 kDa isoform remains in the supernatant of a chromaffin granule lysate after ultracentrifugation. Up until now little interest has been given to the relationship between adrenal medulla and cortex. Presence of purinoceptors and ectonucleotidases in both these regions together with the effects of ATP in vivo and in vitro in different species indicate that purines play a significant role in adrenal glands.
Asunto(s)
Ácido Anhídrido Hidrolasas/metabolismo , Glándulas Suprarrenales/enzimología , Corteza Suprarrenal/enzimología , Médula Suprarrenal/enzimología , Animales , Fraccionamiento Celular , Cromatografía en Gel , Electroforesis en Gel de Poliacrilamida , Inmunohistoquímica , Isoenzimas/metabolismo , Nucleósido-Trifosfatasa , PorcinosRESUMEN
The implication of protein kinase C in the phenomenon of pancreatic acinar cell desensitization to carbamylcholine, caerulein and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated using a potent PKC inhibitor, staurosporine. At a concentration of 1 microM, staurosporine caused a maximum 64% inhibition of amylase release from rat pancreatic acini stimulated by 100 nM TPA. At 100 nM, staurosporine reduced by 50 to 55% amylase secretion elicited by maximal concentrations of carbamylcholine or caerulein without affecting their potency. Staurosporine was also able to prevent completely desensitization by TPA of the subsequent secretory response to carbamylcholine and caerulein. Furthermore, staurosporine also totally prevented desensitization by caerulein of the subsequent secretory response to caerulein. In contrast, staurosporine only partially prevented desensitization by carbamylcholine of the subsequent secretory response to carbamylcholine. These results indicate that staurosporine is a potent inhibitor of protein kinase C as it inhibited the secretory response to carbamylcholine, caerulein and TPA. They also suggest that desensitization of the secretory response induced by TPA and caerulein used a common pathway involving protein kinase C activation. Finally, desensitization by carbamylcholine is more complex as it is only partially prevented at staurosporine; therefore, protein kinase C activation seems to be one of the factors involved.
Asunto(s)
Alcaloides/farmacología , Carbacol/farmacología , Ceruletida/farmacología , Páncreas/efectos de los fármacos , Proteína Quinasa C/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/farmacología , Amilasas/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Activación Enzimática , Masculino , Páncreas/enzimología , Proteína Quinasa C/metabolismo , Ratas , Ratas Endogámicas , EstaurosporinaRESUMEN
The dog is a widely-used model for conducting metabolic studies. This is mainly due to its large size and its physiology which is relatively similar to that of humans. Here, we attempted to optimize a postprandial metabolic study protocol used in dogs. Following acclimatization, female mongrel dogs underwent 9 h profiling for time-course baseline plasma data on triglyceride, adrenocorticotropic hormone (ACTH) and cortisol levels. One week later, carotid and jugular catheters were surgically inserted for sampling and infusions. Initial post-operative care, based on the literature (Protocol 1), consisted of analgesia (buprenorphine every 8-12 h and 2-3 doses/day of acepromazine), restriction by Pavlov harness within cages, and a two- to three-day recovery period. Throughout the experiment, dogs received a lipid tracer diluted in 5% bovine serum albumin (BSA). Compared with baseline, animals vomited (n = 6/6) and exhibited high ACTH + cortisol levels (stress biomarkers), resulting in blunted triglyceride peak levels. To avoid these undesirable effects, post-operative care was modified (Protocol 2) as follows: animals (n = 19) were given a single dose of buprenorphine and no acepromazine, were unrestrained and free to move within cages, the recovery period was extended to seven days, and the lipid tracer was diluted in 0.002% versus 5% BSA. Using this modified protocol, postprandial plasma-triglyceride and ACTH/cortisol patterns were similar to baseline values. Controlling for stressors, as well as for factors which may alter proper digestion, is critical for all postprandial metabolic studies. Our results show that an optimized postprandial metabolic protocol used in dogs reduces experimental variability, while improving animal care and comfort.
Asunto(s)
Perros/fisiología , Ayuno , Ácidos Grasos/metabolismo , Modelos Animales , Periodo Posprandial , Analgésicos/administración & dosificación , Analgésicos/metabolismo , Animales , Femenino , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/metabolismo , Albúmina Sérica Bovina/administración & dosificación , Albúmina Sérica Bovina/metabolismo , Estrés FisiológicoRESUMEN
Interest for extracellular nucleotides has increased since the pioneer work of Burnstock in the early seventies. Research on cellular functions modulated by purines and pyrimidines has led to the identification and characterization of the different components of purine signaling, namely purinoceptors and ecto-nucleotidases. Receptors for tri- and diphosphonucleosides, known as P2 nucleotide receptors, are designated either P2Y receptors, for those coupled to G-proteins, or P2X for those which are ligand gated-ion channels. Ecto-nucleoside triphosphate diphosphohydrolase (NTPDase; EC 3.6.1.5), previously identified as ecto-ATPase, ecto-ATPDase or CD39, is now considered as the main ecto-nucleotidase responsible for the sequential hydrolysis of beta and gamma phosphates of tri- and diphosphonucleosides. More recently, research has been focused on the development of specific agonists and antagonists to P2 purinoceptors. The need to develop specific inhibitors for NTPDase to understand the role of this enzyme has clearly emerged. This paper covers the development of specific molecules targeting purinergic signaling, more specifically the inhibition of NTPDase and their impact on the different physiological systems.
Asunto(s)
Apirasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Purinas/farmacología , Transducción de Señal , Animales , Inhibidores Enzimáticos/química , Humanos , Agonistas del Receptor Purinérgico P2 , Antagonistas del Receptor Purinérgico P2 , Purinas/química , Relación Estructura-ActividadRESUMEN
The role of ornithine decarboxylase and of polyamines was investigated on caerulein-induced pancreatic growth through the use of alpha-difluoromethylornithine (DFMO) and putrescine. Caerulein, the cholecystokinin analog, given at a dose of 1 microgram . kg-1 three times a day was associated with pancreatic hyperplasia and hypertrophy after 2 and 4 days of treatment. The present study shows that putrescine, given once daily i.p. at a dose of 300 mumol . kg-1, can reverse the previously observed DFMO inhibition on pancreatic DNA content increments stimulated by caerulein. It was also observed that putrescine inhibits severely the 2-day caerulein-induced pancreatic hypertrophy, yet interferes only moderately with 4 days of caerulein treatment. These data lend further support to the involvement of ornithine decarboxylase and polyamines in induced pancreatic growth.
Asunto(s)
Ceruletida/farmacología , Inhibidores de la Ornitina Descarboxilasa , Ornitina/análogos & derivados , Páncreas/anatomía & histología , Putrescina/farmacología , Animales , Peso Corporal/efectos de los fármacos , ADN/aislamiento & purificación , Replicación del ADN/efectos de los fármacos , Eflornitina , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ornitina/antagonistas & inhibidores , Ornitina/farmacología , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Ratas , Ratas EndogámicasRESUMEN
The role of ornithine decarboxylase and of polyamines was investigated on caerulein-induced pancreatic growth by the use of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase. By itself, DFMO did not affect the pancreatic gland at all but when combined with caerulein, it reduced the increases in DNA synthesis and DNA content initiated by the cholecystokinin analog. The general hypertrophic action of caerulein was not affected by DFMO but specific increases in amylase and chymotrypsin concentrations were observed after 2 days of caerulein. The effect on amylase concentration was further increased after 4 days but that on chymotrypsin was reversed, showing a significant decrease. These data suggest that the polyamines might be involved in pancreatic growth that is stimulated by caerulein and that their action could be mainly oriented towards cellularity. The specific decreases obtained in DNA synthesis and content brought about by DFMO support this observation.
Asunto(s)
Ceruletida/farmacología , Inhibidores de la Ornitina Descarboxilasa , Ornitina/análogos & derivados , Páncreas/fisiología , Amilasas/metabolismo , Animales , ADN/análisis , Replicación del ADN/efectos de los fármacos , Interacciones Farmacológicas , Eflornitina , Cinética , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ornitina/farmacología , Páncreas/anatomía & histología , Páncreas/efectos de los fármacos , ARN/análisis , Ratas , Ratas EndogámicasRESUMEN
Chronic reserpine treatment of animals, an experimental model for cystic fibrosis (CF), results in generalized exocrinopathy, impaired secretion, and decreased pancreatic content of amylase. However, the mechanisms of altered acinar pancreatic function in both CF patients and reserpine-treated rats are still unknown. The present study was designed to investigate the secretory response of the rat pancreas after reserpine treatment. Rats were given reserpine (1 mg kg-1 day-1 ip) or vehicle, and killed 2, 4, or 7 days later. To distinguish between specific effects of reserpine and those related to secondary malnutrition caused by the drug, secretory response of a group of pair-fed animals to reserpine was also investigated. During reserpine treatment, body weight and food intake were significantly reduced from the 2nd day on. Amylase release from dispersed pancreatic acini, prepared from control pair-fed and from reserpine-treated rats were used to evaluate functional secretory capacity. After 7 days, both chronic reserpine and pair-feeding significantly decreased pancreatic amylase concentration to 75 and 50% of controls, respectively. Reserpine caused desensitization of the pancreatic acini secretory response to carbamylcholine, without altering maximal amylase release. Desensitization occurred gradually and reached a maximum after 7 days. Secretory responses to caerulein and to the phorbol ester 12.0-tetradecanoyl phorbol-13 acetate (TPA) were not altered. These findings indicate that desensitization of amylase release after reserpine was specific to this muscarinic agonist. It may result from increased endogenous acetylcholine release in the course of treatment.
Asunto(s)
Acetilcolina/fisiología , Amilasas/metabolismo , Páncreas/efectos de los fármacos , Reserpina/toxicidad , Acetilcolina/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Carbacol/farmacología , Ceruletida/farmacología , Fibrosis Quística/inducido químicamente , Fibrosis Quística/fisiopatología , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Masculino , Páncreas/enzimología , Páncreas/metabolismo , Ratas , Ratas Endogámicas , Acetato de Tetradecanoilforbol/farmacología , Factores de TiempoRESUMEN
Activation of polyamine metabolism may be important to initiation of pancreatic cell growth. We are reporting that such activation did occur during pancreatic growth initiation by caerulein, a cholecystokinin analog. Maximal increases in total putrescine (319%), spermidine (63%) and spermine (50%) were observed 12, 96 and 96 hr respectively after the beginning of the caerulein treatment. This time period coincides with pancreatic hypertrophy and hyperplasia as characterized by increased cell mass and DNA content. Rates of pancreatic weight and DNA content increases were significantly correlated with total spermidine and spermine contents. These data suggest that polyamine biosynthesis is closely associated with pancreatic growth.
Asunto(s)
Ceruletida/farmacología , Páncreas/crecimiento & desarrollo , Putrescina/metabolismo , Espermidina/metabolismo , Espermina/metabolismo , Animales , ADN/análisis , Eflornitina , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ornitina/análogos & derivados , Ornitina/farmacología , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Complementary antitumor treatments are required to increase the cure rate achieved by surgery and/or radiotherapy by avoiding future recurrences and metastases. The growth of most solid tumors, particularly carcinomas, depends upon the simultaneous development of internal tumor vasculature to allow the proliferation of tumor cells. Inhibition of tumor vascularization is an indirect means of limiting tumor expansion. Daily administration of cortisone and maltose tetrapalmitate (MTP) abolished growth of implanted syngeneic C3HBA mammary tumor. Gross and macroscopic examination of these tumors revealed that tumor growth was prevented. Histological examination demonstrated lack of vascularization within the neoplastic tissue. We believe that this combination in an appropriate form could provide a prophylactic treatment regimen after conventional antitumor treatments in humans.
Asunto(s)
Antineoplásicos/uso terapéutico , Cortisona/uso terapéutico , Glucolípidos/uso terapéutico , Neoplasias Mamarias Experimentales/irrigación sanguínea , Neovascularización Patológica , Animales , Femenino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C3HRESUMEN
Sixty CDl mice received dimethylhydrazine 20 mg/kg s.c. once weekly for 26 weeks to induce colorectal cancer. At this time the animals harbored frank colorectal cancer and early epidermoid cancer. The animals were divided into six groups that were subjected to the following treatments: none, MTP immunotherapy (MTP) alone, radiotherapy (R) alone, difluoromethylornithine (DFMO) chemotherapy alone and combinations of R+DFMO and R+DFMO+MTP. Criteria of evaluation of treatment efficacy were: number of colorectal tumor lesion and their staging at death, the incidence and size of anal cancer at death and survival time. Radiotherapy alone was marginally effective and MTP treatment was moderately effective in preventing anal cancer and reducing the number of colorectal tumors as well as their size. DFMO was exceptional in preventing anal cancer in a majority of animals and increasing animal survival; the latter effect was due to its preventive action against pyelonephritis, the major cause for animal death. However, in DFMO treated animals, the incidence of angiosarcoma increased from 10-16% (in the absence of DFMO) to 35-50% (in the presence of DFMO). The most effective treatment of the colorectal tumor was the triple combination of R + DFMO + MTP.
Asunto(s)
Neoplasias del Ano/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Eflornitina/administración & dosificación , Hemangiosarcoma/etiología , Animales , Neoplasias del Ano/patología , Neoplasias del Ano/radioterapia , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Neoplasias del Colon/patología , Neoplasias del Colon/radioterapia , Terapia Combinada , Dimetilhidrazinas , Glucolípidos/administración & dosificación , Hemangiosarcoma/patología , Ratones , Pielonefritis/patología , Pielonefritis/prevención & controlRESUMEN
Pathological studies were undertaken in three tumor-host models which were subjected to cortisone based treatments. The first model was Fisher 344 rats with established orthotopically implanted syngeneic bladder tumor. Cortisone-herapin and cortisone-maltose tetrapalmitate (MTP) treatments induced focal areas of tumor necrosis and necrobiosis, whereas cortisone alone caused necrobiosis. The second model was C3HBA mammary tumor fragments implanted subcutaneously in syngeneic MTP responder C3H/HeN and MTP non-responder C3H/HeJ female mice. Only cortisone-MTP treatment led to an absence of capillary extension from surrounding blood vessels into the scant tumor stroma. The third model, ethyl carbamate induced primary lung cancer in AJ mice, was tested only with cortisone-herapin combination. The treatment caused central zones of necrosis.
Asunto(s)
Antineoplásicos/uso terapéutico , Cortisona/uso terapéutico , Glucolípidos/uso terapéutico , Heparina/uso terapéutico , Neoplasias Pulmonares/patología , Neoplasias Mamarias Experimentales/patología , Neoplasias de la Vejiga Urinaria/patología , Animales , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Ratones Endogámicos A , Ratones Endogámicos C3H , Necrosis , Ratas , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
C3HBA mammary tumor (H-2k) was implanted s.c. by trocar in MTP responder C3H/HeN (H-2k) and non-responder C3H/HeJ (H-2k) female mice. One half of the animals received MTP i.p. The size of the tumor was measured everyday. Tumor growth was slightly slower in the C3H/HeJ than in the C3H/HeN. MTP treatment was effective only for the tumor implanted in the C3H/HeN. Microscopic and microscopic visualization of the tumor 1, 2, 3, and 15 days after tumor implantation and MTP treatment revealed poor vascular development in the MTP-treated C3H/HeN compared to untreated controls at days 2 and 3.
Asunto(s)
Antineoplásicos/uso terapéutico , Glucolípidos/uso terapéutico , Neoplasias Mamarias Experimentales/irrigación sanguínea , Neovascularización Patológica , Animales , División Celular/efectos de los fármacos , Femenino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C3HRESUMEN
Treatment of human colonic cancer in early stages when the process is still limited to the colonic wall is primarily surgery. We wished to see if maltose tetrapalmitate (MTP) immunotherapy alone or in combination with radiotherapy (R) and cyclophosphamide (C) chemotherapy would be effective against primary colon cancer in a fashion similar to that reported by us for primary liver cancer (Anticancer Research 6: 245-250, 1986). One hundred female CD1 mice were subjected to dimethylhydrazine (DMH) treatment once a week for 26 weeks, a period one week before which, colon cancer was histologically documented in each animal of a group that was sacrificed. Surprisingly, many of the animals harboured early anal cancer as well. At 28 weeks, 85 of the available animals were divided into 6 groups that received: Gr. 1, no treatment; Gr. 2, MTP alone (M); Gr. 3, radiotherapy alone (R); Gr. 4, cyclosphophamide alone (C); Gr. 5, R + C; Gr. 6, M + R + C. Criteria of treatment efficacy were: number, size and staging of colorectal tumors and the incidence and the size of anal tumors at death. Mean survival time was also determined although it remained a questionable criterium since most animals died due to complication (hepatic toxicity, pyelonephritis, thrombose) elicited by DMH, R and C toxicities and not as a result of colonic tumor size or metastases. As a single therapy, M appeared to be superior to either R or C alone. However, R + C combination was effective and was further improved upon by its association with M. With the triple combination, (M + R + C), lesions of both cancers decreased in size and/or number and the colon cancer histologically eclipsed from 46% of the treated animals.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Neoplasias del Ano/terapia , Neoplasias del Colon/terapia , Ciclofosfamida/uso terapéutico , Glucolípidos/uso terapéutico , Animales , Neoplasias del Ano/inducido químicamente , Neoplasias del Ano/tratamiento farmacológico , Neoplasias del Ano/radioterapia , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/radioterapia , Terapia Combinada , Dimetilhidrazinas/toxicidad , Masculino , Ratones , Ratones EndogámicosRESUMEN
The antitumor activity of either cortisone-heparin or cortisone-maltose tetrapalmitate combination or both was tested against two animal tumor models. The first model was orthotopically implanted bladder tumor established in syngeneic Fisher 344 rats. Shrinkage and growth arrest of the tumors were induced by cortisone and amplified by its combination with either heparin or maltose tetrapalmitate (MTP). The second model was trocar implanted C3HBA mammary tumor piece s.c. in syngeneic LPS and MTP responder C3H/HeN and non responder C3H/HeJ mice. The tumor was sensitive to growth inhibition by cortisone-MTP in the C3H/HeN but not by cortisone alone or cortisone-heparin. Tumor implanted in C3H/HeJ was much less sensitive to cortisone-MTP. Cortisone could be replaced by 17-alpha-hydroxyprogesterone, but not by cortexolone.
Asunto(s)
Antineoplásicos/uso terapéutico , Cortisona/uso terapéutico , Glucolípidos/uso terapéutico , Heparina/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Femenino , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C3H , Ratas , Ratas Endogámicas F344 , Esteroides/uso terapéutico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in three vehicles: poly(D,L-lactic acid) (PLA) nanoparticles, polyethylene glycol (PEG)-coated nanoparticles and a Cremophor EL (CRM) oil-water emulsion. Nanoparticles were prepared by the salting-out procedure. Biodistribution of the dye was assessed by fluorescence in EMT-6 mammary tumour bearing mice after intravenous injection of 1 mumol kg-1 ZnPcF16. Plain nanoparticles were rapidly retained by the reticuloendothelial system (RES) as reflected by the low area under the blood concentration-time curve (AUC0-168, 57 micrograms h g-1). Little tumour uptake of the dye was observed with this formulation. In contrast, PEG-coated nanoparticles displayed a reduced RES uptake, leading to significantly higher blood levels over an extended period (t1/2 30 h; AUC 0-168 227 micrograms h g-1) and enhanced tumour uptake. At 48 h post injection, tumour to skin and tumour to muscle concentration ratios reached 3.5 and 10.8, respectively. Blood levels of ZnPcF16 after administration as a CRM emulsion decreased faster than with PEG-coated nanoparticles (t1/2 12 h), but since no early liver uptake was observed, the AUC0-168 and the tumour uptake were only slightly lower. However, with the CRM formulation, a late liver uptake was observed, reaching 51% of the injected dose after 7 days.
Asunto(s)
Indoles/administración & dosificación , Ácido Láctico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Compuestos Organometálicos/administración & dosificación , Fotoquimioterapia , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Animales , Coloides , Preparaciones de Acción Retardada , Emulsiones , Glicerol/análogos & derivados , Indoles/farmacología , Inyecciones Intravenosas , Lactatos , Masculino , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Endogámicos BALB C , Microesferas , Compuestos Organometálicos/farmacología , Poliésteres , Polietilenglicoles , Polímeros , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Solventes , Distribución TisularRESUMEN
A/J mice were given ethyl carbamate to accelerate and to raise to 100 percent the incidence of lung tumours at 34 weeks (day 237) of age. The animals were then divided into groups which received the following treatments: group 1, no treatment; group 2, MTP alone; group 3, radiotherapy alone; group 4, cyclophosphamide alone; group 5, radiotherapy + MTP; group 6, MTP + cyclophosphamide; group 7, radiotherapy followed by cyclophosphamide and group 8, MTP and radiotherapy together followed by MTP and cyclophosphamide. Except for radiotherapy, which was given for 5 consecutive days, MTP and cyclophosphamide were continued till the death of the animals. The treatment efficacies were evaluated by the number and size of tumour nodules, taking into consideration the survival time of the animal. Animals in groups receiving cyclophosphamide died earlier (between days 290 and 315) due to its toxic effects, and half of the radiotherapy-MTP were sacrificed at day 314 for comparison. Although cyclophosphamide alone and radiotherapy plus cyclophosphamide demonstrated antitumour activity, the number of tumour nodules and the nodule diameter were reduced most effectively in group 8 (receiving MTP, radiotherapy and cyclophosphamide). Among the animals in the non-cyclophosphamide group, radiotherapy alone was ineffective. MTP given before and after radiotherapy (group 5) kept tumour volume in control although this group died suddenly. The animals receiving only MTP died between day 430 and 470. The number of tumour nodules and the nodule diameter in the MTP group were, however, significantly reduced when compared to controls or radiotherapy group animals dying at or near the same time.
Asunto(s)
Antineoplásicos/uso terapéutico , Ciclofosfamida/uso terapéutico , Glucolípidos/uso terapéutico , Inmunoterapia , Neoplasias Pulmonares/terapia , Uretano/toxicidad , Animales , Terapia Combinada , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Ratones , Ratones Endogámicos ARESUMEN
CGS 35601 is a triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme, neutral endopeptidase, and endothelin-converting enzyme-1 with respective IC50 values of 22, 2, and 55 nM. We characterized the safety profile and toxicity of escalating doses of CGS 35601 over a 20-day period in chronically instrumented, unrestrained, conscious, male, spontaneously hypertensive rats (SHR). Once instrumented with an arterial catheter, the SHR were placed in metabolic cages allowing daily assessment of hemodynamics and blood sampling for biochemical and hematological measurements. After a 7-day stabilization period, the SHR were divided into 2 groups: Gr. 1, (n = 13 to 18) receiving CGS 35601 at 0.01, 0.1, 1 and 5 mg kg(-1) day(-1) (continuous i.a. infusion) for 5 consecutive days/dose, followed by a 5-day washout; and Gr. 2, (n = 10) receiving vehicle (saline). The highest dose of CGS 35601 dose-dependently reduced MABP from 156 +/- 4 up to 94 +/- 5 mm Hg, whereas heart rate, metabolic, electrolytic, and hematological profiles, growth, diuresis, and renal activity were unaffected, and no hepatic or liver toxicities were observed. These results suggest that this novel triple VPI presents no safety concerns at this stage and may become of interest for the treatment of hypertension and other cardiovascular disorders. Long-term chronic experiments are needed to assess possible angioedema and increases in vascular permeability.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Hipertensión/tratamiento farmacológico , Indoles/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Neprilisina/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/toxicidad , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Enzimas Convertidoras de Endotelina , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hipertensión/enzimología , Hipertensión/fisiopatología , Indoles/toxicidad , Masculino , Estructura Molecular , Ratas , Ratas Endogámicas SHRRESUMEN
Mixtures of maltose palmitates containing predominantly maltose tetrapalmitate (designated MTP) possess immune potentiating and antitumor properties. Immune potentiation derives from macrophage activation and B lymphocyte mitogenicity and antitumor action from anti-angiogenic activity. Their mode of action at the cellular level is not known. Since high performance liquid chromatography (HPLC) provided purified maltose palmitates, we tested whether they individually and as a mixture could modulate activity of protein Kinase C (PKC), an enzyme implicated in mitogenic and release reactions. MTP activated crude lymphocyte and purified brain PKC in the absence of phosphatidyl serine (PS). It also augmented labeled dibutyryl phorbol (PDBu) binding to the brain enzyme in the absence of phospholipid. HPLC purified maltose tetrapalmitates (two isomers) were insoluble in aqueous solvent, and activated PKC slightly after incorporation into PS liposomes. Purified maltose di- and tri-palmitates were inhibitory to the enzyme. The activation of PKC was, therefore, due to higher saturated maltose palmitates, well dispersed by less substituted maltose palmitates acting as emulsifiers.
Asunto(s)
Glucolípidos/farmacología , Proteína Quinasa C/metabolismo , Animales , Sitios de Unión , Encéfalo/enzimología , Activación Enzimática/efectos de los fármacos , Técnicas In Vitro , Macrófagos/enzimología , Ratones , Ratones Endogámicos C3H , Forbol 12,13-Dibutirato/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Bazo/enzimologíaRESUMEN
Reserpine treatment resulted in altered enzyme secretion from rat pancreatic acini in response to carbamylcholine and secretin (1,2). This study was undertaken: (1) To evaluate if the alterations caused by reserpine can be prevented by EGF and/or cerulein treatments; (2) To determine the time-course of secretion recovery after reserpine treatment; and (3) To establish if EGF and/or cerulein treatments can accelerate such a recovery after the reserpine treatment. Male Sprague-Dawley rats (250-265 g) were used in these experiments. In experiment I, rats divided into three groups received either reserpine (R) or the reserpine vehicle for the controls (C) and the pair-fed controls (PF) for 7 d. During treatment, PF and R rats were given SC, twice a day, saline, EGF (10 micrograms/kg), cerulein (1 microgram/kg), or both at the same dose. C rats received saline in gelatin. In experiment II, rats were treated for 7 d with reserpine or the vehicle as described in experiment I, were allowed a 30-d recovery period and then were killed. In experiment III, C, PF, and R rats were treated for 7 d as described in experiment I; on the 8th d and for the next 6 d, reserpine rats received saline (reserpine-saline), cerulein, EGF, or both cerulein +EGF at the same dose as indicated in experiment I. C and PF rats received saline in gelatin. After sacrifice, acini were prepared, and amylase dose-response curves to carbamylcholine (Cch) and secretin were established. EGF, cerulein, or their combination given to R rats did not improve the desensitized secretory response to Cch.(ABSTRACT TRUNCATED AT 250 WORDS)