Simvastatin,an HMG-CoA reductase inhibitor,induces the synthesis and secretion of apolipoprotein AI in HepG2 cells and primary hamster hepatocytes

Clinical studies have recently suggested that statin treatment may beneficially elevate plasma concentrations of high density lipoprotein (HDL)-cholesterol in patients with hyperlipidemia. Here, we have investigated the effect of a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on the synthesis and secretion of apolipoprotein AI (apoAI) in two model systems, HepG2 cells and primary hamster hepatocytes. Cultured cells were incubated with different doses of simvastatin (0.1-10 microM) for a period of 18 h. A dose-dependent increase in synthesis and secretion of apoAI was observed in both cell types. There was a significant increase in the synthesis of apoAI in HepG2 cells (44.3+/-12.1%), and hamster hepatocytes (212+/-2%) after treatment with 10 microM of the statin. The increase in apoAI synthesis appeared to result in a higher level of apoAI secreted into the culture media in both cell types (49.2+/-7.8% in HepG2, 197+/-0.2% in hamster hepatocytes). ApoAI mRNA levels were also significantly increased in both cell types in response to statin treatment. Control experiments with transferrin confirmed specificity of the effect on apoAI secretion. Analysis of a density fraction containing HDL particles in culture media revealed an increase in HDL-associated apoAI of 94.3+/-2.1% in HepG2 cells and 27.0+/-0.03% in hamster hepatocytes following 10 microM simvastatin-treatment. Comparative studies of simvastatin and lovastatin indicated a differential ability to induce apoAI synthesis and secretion, with simvastatin having a more significant effect. Thus, acute statin treatment of cultured hepatocytes (transformed as well as primary) resulted in a significant upregulation of apoAI mRNA and apoAI synthesis, causing oversecretion of apoAI and HDL extracellularly. The stimulatory effect on apoAI synthesis and secretion may thus explain the clinical observation of an elevated plasma HDL-cholesterol level in hyperlipidemic patients treated with certain statins.     

Bioequivalence of a sustained-release isosorbide dinitrate formulation at steady-state

Isosorbide 2,5-dinitrate and its pharmacologically active metabolites, isosorbide 2-nitrate and isosorbide 5-nitrate, in plasma accumulated to the predicted steady-state after five consecutive oral doses of sustained-release tablets containing 40 mg isosorbide dinitrate at 12-h intervals and after five consecutive oral doses of reference standard-release tablets containing 20 mg at 6-h intervals to 12 subjects in a crossover study. The comparative bioavailability of isosorbide dinitrate, isosorbide 2-nitrate and isosorbide 5-nitrate from the sustained-release tablet was 110 per cent (p greater than 0.05), 89 per cent (p greater than 0.05), and 89 per cent (p less than 0.05), respectively, of that from the reference standard-release tablet. The isosorbide dinitrate plasma level data were the more variable, as expected for a drug of low systemic availability subject to extensive first-pass elimination. The posterior probability that the true bioavailability of isosorbide dinitrate was included within the usually accepted limits of 80-120 per cent was 0.74, a value which is probably insufficient to justify claims of bioequivalence with the reference formulation in respect of extent of availability. In contrast, the posterior probability that the bioavailability of the metabolites isosorbide 2- and 5-nitrate was included within these limits was 0.90 and 0.98, respectively. On the basis of the mononitrate data, these two formulations may be judged bioequivalent in respect of extent of availability despite a formal statistically significant formulation-related effect in the analysis of variance of the isosorbide 5-nitrate bioavailability data. Claims of bioequivalence of isosorbide dinitrate sustained-release formulations may be more economically justified by analysis of the mononitrate plasma concentrations, although concentrations of the formulated parent dinitrate should also be known.     

Measles control in developing and developed countries: the case for a two-dose policy.

Despite major reductions in the incidence of measles and its complications, measles control with a single dose of the currently used. Schwarz strain vaccine has failed to eradicate the disease in the developed countries. In developing countries an enormous toll of measles deaths and disability continues, despite considerable efforts and increasing immunization coverage. Empirical evidence from a number of countries suggests that a two-dose measles vaccination programme, by improving individual protection and heard immunity can make a major contribution to measles control and elimination of local circulation of the disease. Cost-benefit analysis also supports the two-dose schedule in terms of savings in health costs, and total costs to society. A two-dose measles vaccination programme is therefore an essential component of preventive health care in developing, as well as developed countries for the 1990s.     

Selective arterial stimulation of secretin in localization of gastrinomas

In two patients with malignant gastrinoma and the Zollinger-Ellison syndrome, we were able to use selective arterial stimulation with secretin as a technique to localize the lesions accurately, allowing resection. The technique of selected arterial secretin stimulation is one of measuring variations in gastrin levels in both the hepatic vein and a peripheral artery at specified times after injection of secretin into a specific artery. When the criteria for localization have been met, one can plot the presence of the gastrinoma within the blood supply of the injected artery and, using angiograms, thus accurately localize the lesion. This method promises to be a valuable additional tumor-localizing procedure, particularly when gastrinomas are extrapancreatic.     

SRIF-like immunoreactivity in the brain and pituitary of Tinca tinca (Cyprinidae, Teleostei)

SRIF-immunoreactive perikarya occurred in the nucleus entopeduncularis, the nucleus praeopticus and praeopticus periventricularis, in the nucleus lateralis tuberis pars anterior, the nucleus ventromedialis, and in the nucleus posterior periventricularis. Additionally, SRIF-containing neurons were located in the nucleus dorsomedialis and dorsolateralis thalami. Weaklyimmunoreactive perikarya were found medially to the nucleus diffusus tori lateralis and in the rostral rhombencephalon, laterally to the fasciculus longitudinalis medialis, and dorsally to the fasciculus longitudinalis lateralis. SRIF-positive fibres could be found in the lateral and dorsal telencephalon, below most of the diencephalic nuclei, in the pituitary, the tectum opticum, the torus semicircularis, and in the lateral medulla oblongata.