RESUMO
In the present study we evaluated two commonly used iodinated contrast agents, iohexol and iodixanol, as potential markers of impaired renal function. A reversed phase LC-MS method has been developed in order to separate and quantify the two substances. The assay was linear between 0.02 and 9.7 micromol/L for iohexol and between 0.4 and 49.3 micromol/L for iodixanol (r(2) > 0.998). The recovery during sample preparation ranged from 89.1 to 112.4%. The intra- and inter-assay RSD values were 3.06-13.6% for iohexol and 4.32-12.7% for iodixanol. The validated method was subsequently applied to 17 patients scheduled for angiographic procedure displaying normal and impaired renal function. A mixture of iohexol and iodixanol was intra-arterially injected and their corresponding plasma levels were determined periodically over a 24h period following administration. The elimination of both contrast agents followed by the LC-MS approach allowed us to discriminate between patients with normal and impaired renal function at 4, 8 and 24h after administration. Our preliminary results support the predictive value of iohexol and/or iodixanol clearance in a clinical environment to screen and identify patients at risk of developing CIN.
Assuntos
Cromatografia Líquida/métodos , Meios de Contraste/análise , Taxa de Filtração Glomerular , Testes de Função Renal/métodos , Espectrometria de Massas/métodos , Meios de Contraste/química , Humanos , Iohexol/análise , Iohexol/química , Estrutura Molecular , Reprodutibilidade dos Testes , Ácidos Tri-Iodobenzoicos/análise , Ácidos Tri-Iodobenzoicos/químicaRESUMO
Glucocorticoids have deleterious effects on glucose and protein metabolism. RU 486 is an antiprogestin with antiglucocorticoid activity, which could be used to prevent the undesirable metabolic effects of glucocorticoids. A randomized, controlled, double blind study was performed in eight healthy male volunteers who were tested four times: during the iv infusion of cortisol (2 micrograms/kg.min for 5 h) after the oral ingestion of RU 486 (600 mg) or a placebo, and during the infusion of a normal saline solution with placebo or RU 486 ingestion. During each test, a primed continuous iv infusion of D-[6,6-2H]glucose and [1-13C-]leucine was given for the calculation of hepatic glucose production and plasma leucine appearance rate. 13CO2 enrichment in breath was measured for the calculation of leucine oxidation. Plasma concentrations of cortisol, ACTH, insulin, C-peptide, glucagon, and GH were measured at regular intervals. Compared to saline, cortisol infusion increased plasma glucose 5.5 +/- 0.6 vs. 4.7 +/- 0.4 mmol/L; P < 0.01) and leucine (179 +/- 35 vs. 155 +/- 35 mumol/L; P < 0.01) concentrations as well as the leucine appearance rate (2.24 +/- 0.3 vs. 2.0 +/- 0.28 mumol/kg.min; P < 0.05) and oxidation (0.51 +/- 0.22 vs. 0.39 +/- 0.06 mumol/kg.min; P < 0.01), and there was no change in hepatic glucose production. None of the metabolic changes induced by cortisol were seen when cortisol was administered after the ingestion of RU 486. When RU 486 was given before normal saline infusion, plasma glucose concentrations were transiently lower than those after placebo ingestion, as was the hepatic glucose production. No change in insulin, C-peptide, or glucagon was seen between tests. GH concentrations were higher during cortisol infusion, but not when cortisol was administered after the ingestion of RU 486. The following conclusions were reached. 1) RU 486 can suppress the effects of acute hypercortisolemia on glucose and protein metabolism and GH secretion in man. Long term studies are warranted to explore the potential of antiglucocorticoid molecules as preventive agents of the deleterious effects of chronic glucocorticoid administration. 2) RU 486 is useful molecule for studying the metabolic effects of cortisol in man.
PIP: In Montreal, Quebec, a randomized, double blind study was conducted in eight healthy men at Hotel-Dieu Hospital during administration of cortisol (2 mcg/kg per minute for 5 h) with RU-486 (600 mg), during cortisol administration with a placebo, during 0.9% saline administration with RU-486, and during normal saline administration with a placebo. Clinicians administered a primed continuous infusion of D-[6,6-2H]glucose and [1-13C-]leucine during each test to determine hepatic glucose production and plasma leucine appearance rate. Continuous infusion of labeled bicarbonate in four men was also conducted to calculate the recovery factor of carbon dioxide in their breath. Researchers wanted to examine glucose and protein metabolism during hypercortisolemia with or without RU-486 and the effects of RU-486 on the metabolic effects of acute cortisol deficiency. Among men receiving the placebo, plasma glucose levels were higher during cortisol infusion than saline infusion (5.5 vs. 4.7 mmol/l; p 0.01). The leucine appearance rate was also higher during cortisol infusion than saline infusion (2.24 vs. 2 mcmol/kg per min; p 0.05) as well as leucine oxidation (0.51 vs. 0.31 mcmol/kg; p 0.01). Hepatic glucose production did not change in either placebo group. Cortisol did not induce the same metabolic changes when it was administered after RU-486. Normal saline infusion after RU-486 induced a short-term lower plasma glucose level and hepatic glucose production. Insulin, C-peptide, or glucagon did not change. Cortisol induced increased growth hormone (GH) levels (e.g., at 240 min, 5.9 vs. 1.7 mcg/l; p 0.01) while GH levels did not change when cortisol was administered after RU-486. These findings show that RU-486 suppresses the effects of acute hypercortisolemia on glucose and protein metabolism and GH secretion in males. Long-term studies could reveal the potential of RU-486 to prevent the adverse effects of chronic glucocorticoid administration. RU-486 allows researchers to study the metabolic effects of cortisol in males.
Assuntos
Glucose/metabolismo , Hidrocortisona/farmacologia , Leucina/metabolismo , Mifepristona/farmacologia , Hormônio Adrenocorticotrópico/sangue , Adulto , Glicemia/metabolismo , Método Duplo-Cego , Hormônios/sangue , Humanos , Hidrocortisona/sangue , Cinética , Masculino , Oxirredução , Troca Gasosa Pulmonar/efeitos dos fármacos , Fatores de TempoRESUMO
Intracisternal injection of the TRH analog RX 77368 (p-Glu-His-(3,3'-dimethyl)-Pro NH2) increased gastric acid and pepsin output in conscious pylorus-ligated rats. In urethane-anesthetized, gastric fistula rats, intracisternal RX 77368 or TRH induced stimulation of gastric acid output which was rapid in onset, long lasting, and dose-dependent, in doses ranging from 3 to 100 ng/rat for RX 77368, and 0.1 to 1 micrograms/rat for TRH. Vagotomy or atropine pretreatment reversed RX 77368 gastric secretory response. The analog was less effective when infused intravenously (1-10 micrograms X kg-1 X h-1) and 22 times more potent than TRH when given intracisternally. These results demonstrated the ability of RX 77368 to act within the rat brain to enhance gastric secretion (acid and pepsin) through vagus cholinergic dependent mechanisms. The enhanced potency and extended duration of action of RX 77368 over TRH, could make intracisternal injection of this peptide a useful test to induce centrally mediated vagal dependent stimulation of gastric secretion in rats.
Assuntos
Suco Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Hormônio Liberador de Tireotropina/análogos & derivados , Animais , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Injeções Espinhais , Masculino , Pepsina A/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ratos , Ratos Endogâmicos , Estimulação Química , Hormônio Liberador de Tireotropina/administração & dosagem , Hormônio Liberador de Tireotropina/farmacologia , Uretana/farmacologia , Nervo Vago/fisiologiaRESUMO
Intracisternal injection of the TRH analogs, MK 771 (0.01-1 micrograms) or A 3475 [pGlu-His-(1,3'-dicarboxymethyl)-Pro-NH2] (0.1-1 micrograms), dose-dependently stimulated gastric acid secretion in pylorus-ligated rats although A 43475 was devoid of TSH-releasing activity by cultured anterior pituitary cells. Depletion of brain catecholamine by combined administration of the neurotoxic agent, 6-hydroxydopamine, and the catecholamine synthesis inhibitor, alpha-methyl-ptyrosine, completely abolished intracisternal TRH-induced stimulation of gastric secretion. Blockade of dopamine receptors by intracisternal haloperidol, peripheral depletion of catecholamine by chronic treatment with guanethidine combined with acute adrenalectomy or cervical cord transection at C5 level, did not modify gastric response to TRH. These results suggested that the stimulation of gastric secretion by intracisternal TRH is unrelated to its hypophysiotropic activity and required the integrity of central but not peripheral catecholaminergic system.
Assuntos
Encéfalo/efeitos dos fármacos , Catecolaminas/fisiologia , Ácido Gástrico/metabolismo , Hormônio Liberador de Tireotropina/farmacologia , Animais , Cisterna Magna , Ciproeptadina/análogos & derivados , Ciproeptadina/farmacologia , Masculino , Ratos , Ratos Endogâmicos , Sistema Nervoso Simpático/efeitos dos fármacos , Tireotropina/metabolismo , Nervo Vago/efeitos dos fármacosRESUMO
Possible humoral and neural components mediating intracisternal bombesin (500 ng)-induced inhibition of gastric secretion were studied in rats. Intracisternal bombesin induced a marked rise in gastric pH from 2.0 +/- 0.5 up to 6.5 +/- 0.6 whereas gastric secretion in parabiotic saline-treated partners was not modified. Bombesin inhibited pentagastrin-stimulated gastric acid output by 88 +/- 5% in intact rats and 71 +/- 7% in vagotomized animals. Spinal cord transection at the level of the 5th or 7th cervical but not the 8th or 13th thoracic vertebrae significantly reversed the rise in pH and the decrease in acid concentration induced by bombesin and abolished the hyperglycemic effect of the peptide. These results suggest that bombesin inhibitory action on gastric secretion is not mediated through humoral factors but through neural pathways in part related to the sympathetic nervous system along the spinal cord, whereas the parasympathetic outflow from the vagus or the sacral spinal nerves does not seem to play an important role.
Assuntos
Bombesina/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Animais , Glicemia/metabolismo , Bombesina/administração & dosagem , Bombesina/metabolismo , Cisterna Magna , Determinação da Acidez Gástrica , Mucosa Gástrica/inervação , Mucosa Gástrica/metabolismo , Injeções , Masculino , Vias Neurais/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Medula Espinal/fisiologia , VagotomiaRESUMO
BACKGROUND: Patients with a mutation in the LDL receptor gene (familial hypercholesterolemia, or FH) are characterized by substantial elevations in plasma LDL cholesterol and are at higher risk of developing coronary artery disease (CAD). Correlates of abdominal obesity may also contribute to the risk of ischemic cardiac events. Whether the hyperinsulinemic-insulin-resistant state of abdominal obesity affects coronary atherosclerosis among FH patients has not been determined. METHODS AND RESULTS: The relation of abdominal adiposity and hyperinsulinemia to angiographically assessed CAD was evaluated in a sample of 120 French Canadian men aged <60 years who were heterozygotes for FH and in a group of 280 men without FH. In the present study, the risk of CAD associated with abdominal obesity, as estimated by the waist circumference, was largely dependent on the concomitant variation in plasma lipoprotein and insulin concentrations. In contrast, the association between fasting insulin and CAD was independent of variations in waist girth, triglyceride, HDL, and apolipoprotein B concentrations (odds ratio, 1.86; P=.0005). However, the most substantial increase in the risk of CAD was observed among abdominally obese (waist circumference >95 cm) and hyperinsulinemic FH patients (odds ratio, 12.9; P=.0009). This increase in risk remained significant even after adjustment for LDL cholesterol or apolipoprotein B concentrations. CONCLUSIONS: Results of the present study provide support for the notion that the hyperinsulinemic-insulin-resistant state of abdominal obesity is a powerful predictor of CAD in men, even in a group of patients with raised LDL cholesterol concentrations due to FH.
Assuntos
Doença das Coronárias/etiologia , Hiperinsulinismo/complicações , Hiperlipoproteinemia Tipo II/complicações , Obesidade/complicações , Constituição Corporal , Estudos de Casos e Controles , Angiografia Coronária , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico por imagem , Humanos , Hiperlipoproteinemia Tipo II/sangue , Insulina/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Receptores de LDL/genética , Fatores de RiscoRESUMO
The aim of this study was to compare the age at first elective coronary angiogram and the age at first revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) in 102 patients without familial hypercholesterolaemia (FH), who were matched for age and sex with 76 heterozygous FH patients carrying a defective allele at the low-density lipoprotein (LDL) receptor gene (LDL-R) and 26 heterozygous FH patients bearing a null mutation at the LDL-R. The prevalence of diabetes was significantly higher in the non-FH group than in the two FH groups (P < 0.05). Furthermore, mean body mass index (BMI) and waist circumference values were also higher in the non-FH group than in the two FH heterozygous groups (P < 0.005). However, FH patients who were null allele carriers had the highest plasma total and LDL-cholesterol levels and the highest cholesterol/HDL-cholesterol ratio, whereas the defective allele carriers group had intermediate levels between null allele carriers and non-FH patients. Comparison of the age at first coronary angiography revealed that the null allele carriers group were younger at first angiogram than the non-FH patients (P < 0.005). In addition, a trend was observed for a younger age at first angiogram in FH heterozygotes bearing a null allele than in carriers of a defective allele (P = 0.06). Moreover, null allele carriers were younger at first revascularization than defective allele carriers (P < 0.005) or non-FH patients (P < 0.005). Finally, the mean number of diseased vessels with > 50% stenosis was higher in null allele carriers than in non-FH patients and tended to be higher than among defective allele carriers (P < 0.01). Although no difference in plasma Lp(a) levels were noted between null allele carrier and non-FH patients, plasma Lp(a) concentrations were higher in the defective allele group than in the other two groups. In summary, the development of coronary artery disease as estimated by the age at first elective coronary angiography or at first revascularization is premature in FH patients carrying a null mutation compared with defective allele carriers or with non-FH patients. Moreover, the higher number of stenosed vessels among null allele carriers suggests that coronary artery disease was more severe in FH subjects with a null allele at the LDL-R locus.