A preliminary ecotoxicity study of pharmaceuticals in the marine environment.

Environmental fates and effects of pharmaceuticals in the aquatic environment have been the focus of recent research in environmental ecotoxicology. Worldwide studies of common over-the-counter pharmaceuticals have reported detectable levels in the aquatic environment, but there are few studies examining impacts on marine habitats. These drugs can affect the functions of various vertebrates and invertebrates. The stability of two pharmaceuticals, cyclizine (CYC) and prochlorperazine (PCZ), in seawater was examined under light and dark conditions, as well as the toxicity of these compounds to larvae of the barnacle Balanus amphitrite, which is a cosmopolitan marine organism found in most of the world's oceans. CYC was very stable under all the tested conditions. On the other hand, PCZ degraded in light but not in the dark, and was more stable in seawater than fresh water. For the barnacle larvae, the LC50 of prochlorperazine was 0.93 microg/ml and the LC50 for CYC was approximately 0.04 microg/ml.

Mechanistic investigation of N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide-induced insulin depletion in the rat and RINm5F cells.

These studies describe the effect of N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide (AR-M100390), a delta-opioid agonist, on the pancreas and its mechanisms for pancreatic toxicity. Rats were treated with 5, 100, and 600 micromol/kg of AR-M100390 for 3 and/or 7 days; another group of rats treated with 600 micromol/kg of compound were allowed to recover for 14 days. AR-M100390 (600 micromol/kg) caused vacuolation in the beta-cell of the rat pancreas that was associated with depletion of insulin and hyperglycemia after 7 days of dosing. The loss of insulin by AR-M100390 was due to specific inhibition of rat insulin2 mRNA transcription in vivo. Insulin depletion and hyperglycemia were reversible. The effects of AR-M100390 in rats were reproduced in the rat pancreatic beta-cell line RINm5F, where it inhibited intracellular insulin content and secretion without affecting cell survival. Loss of insulin in vitro was also a result of specific inhibition of insulin2 mRNA transcription and was reversible. Pretreatment of cells with the delta-opioid antagonist naltrindole or pertussis toxin did not reverse loss of insulin in AR-M100390-treated cells suggesting that the effects were not mediated by the delta-opioid receptor. AR-M100390 inhibited KCl-mediated calcium mobilization in RINm5F cells, suggesting that L-type calcium channels found in these cells and in pancreatic beta-cells may partially play a role in the inhibition of insulin secretion by this compound. In summary, the in vitro and in vivo studies suggest that inhibition of insulin by AR-M100390 is due to a combination of inhibition of insulin synthesis and/or release.

Stress modification of the toxicity of antimotion sickness drugs and aspirin.

The effect of environmental temperature on the toxicity of cyclizine, trimethobenzamide, and Aspirin were studied in mice. LD50s were compared at 30 degrees C (warm), 22 degrees C (normal), and 15 degrees C (cool). At 30 degrees C the toxicity of all three drugs increased, with that to aspirin being affected most. Cooling decreased the toxicity of cyclizine and had no significant effect on that of trimethobenzamide or Aspirin. These findings indicate that alterations in environmental temperature markedly affect drug toxicity. They emphasize that such alterations, and particularly increases in temperature, do not have to be particularly drastic, but that "mild' variations in the environment are effective in altering an animal's sensitivity to a drug.

Morphological and immunocytochemical study of rat pancreatic beta cell changes induced by cyclizine.

Wistar rats were treated daily with cyclizine (50-75 mg kg-1) and autopsied every week until the eighth week of the treatment. Although no evident change could be detected by either serum analysis or by light microscopy from the first week to the fourth week, electron microscopy revealed that beta cells showed depletion of secretory granules and cystic dilation of the rough endoplasmic reticulum from the first week. A significantly higher level of plasma glucose and a lower level of plasma insulin than those of untreated rats were recognized from the fifth week. A diabetic pattern was also observed in the glucose tolerance test which was conducted at the seventh week. From the sixth week, large cytoplasmic vacuoles were observed light microscopically in islet cells. Electron microscopic examination revealed that the vacuoles originated from the rough endoplasmic reticulum in beta cells, while no prominent change was found on the Golgi apparatus. In addition to the above findings, immunocytochemical study with anti-insulin serum demonstrated that the staining intensity of the beta cell cytoplasm became weaker (as judged by light microscopy) from the fifth week, but large cytoplasmic vacuoles were stained positively under both the light microscope (PAP method) and the electron microscope (enzyme-labelled antibody method). These findings suggested that the depletion of secretory granules and accumulation of insulin or its precursor in the rough endoplasmic reticulum occurred in beta cells. The diabetogenic effect of cyclizine on rats is discussed with reference to the immunocytochemical findings.