Andrew T. Hasegawa

Study of a rat model for calcium oxalate crystal formation without severe renal damage in selected conditions

Abstract  Background:  Although nephrotoxic in high doses, ethylene glycol (EG) has been used with ammonium chloride (NH4Cl) or vitamin D3 to study calcium oxalate stone formation in rat models. In the present study we used EG alone or with NH4Cl to study hyperoxaluria, crystaluria, and crystal attachment to renal epithelial cells in rats with minimal renal damage.

Effect of chloroquine and phenobarbital on morphine glucuronidation and biliary excretion in the rat

Abstract The relationship between morphine glucuronidation and biliary excretion was studied in rats pretreated with saline (control), chloroquine (CQ) or phenobarbital (PB) by determining the conversion of morphine to morphine-3-glucuronide (MG) in vitro and the biliary excretion of intravenously administered morphine and MG in vivo . For the biliary excretion studies. 14 C-morphine or 14 C-MG was administered intravenously and excretion measured in anesthetized renal-ligated rats in which the common bile ducts were cannulated. The effect of PB treatment on the biliary excretion of morphine and MG was complex and it was found that: (1) PB pretretment did not alter the proportions of morphine and MG in bile; (2) the rate of biliary excretion of morphine (as MG) was decreased in PB-pretreated rats even though MG formation was increased in vitro ; (3) the plasma disappearance of 14 C after 14 C-morphine administration was also decreased by PB pretreatment; (4) the biliary excretion of administered MG was significantly decreased by PB pretreatment; and (5) the 14 C plasma disappearance after 14 C-MG administration was not changed by PB pretreatment. Several interpretations can be derived from these results. One possibility is that MG formation is not a rate-limiting step in the biliary excretion of morphine. An alternate interpretation would be that PB pretreatment may have an inhibitory effect on the biliary excretion of morphine and MG that is unrelated to metabolism. Chloroquine pretreatment produced only a slight effect on the biliary excretion of morphine and no effect on the biliary excretion of administered MG. Using studies in vitro , we could not demonstrate that CQ induced an increase in MG formation.

Reserpine and alpha-methyldopa in the treatment of tardive dyskinesia

Thirty inpatients with evidence of tardive dyskinesia secondary to antipsychotic medications participated in this double-blind, controlled, randomized study comparing reserpine, α-methyldopa and placebo. Reserpine at doses of 0.75–1.5 mg daily, or α-methyldopa at doses of 750–1,500 mg daily, produced a statistically significant improvement in tardive dyskinesia symptomatology compared to the results obtained with placebo.

Occurrence of corneal opacities in rats after acute administration of l-α-acetylmethadol

Abstract The ability of l-α-acetylmethadol (LAAM) to induce ocular opacities was studied in rats. Between the third and fifth days after subcutaneous or oral administration of a single dose of LAAM, a dose-dependent incidence of opacification of the anterior segments of rat eyes was observed. Observation of the eyes of LAAM-treated rats, using a dissection microscope and a slit beam biomicroscope, indicated that the opacities were localized to the cornea and the depth of corneal involvement varied from patches of grayish epithelium to full-thickness involvement. Light microscopy of eye sections from rats given LAAM, 20 mg/kg orally, revealed corneal changes ranging from thickening and loss of regularity of epithelial cell layers to stromal vascularization and spindle cell infiltration. The sc and oral ED-50 for LAAM-induced corneal opacities was found to be 4.7 (4.2–5.3) and 12.6 (9.8–16.1) mg/kg, respectively. This is similar to or lower than the ED-50 for pharmacological effects of LAAM such as analgesia and mydriasis. The mechanism(s) by which LAAM initiates the corneal opacities is unknown. However, in rats made tolerant to morphine by implantation of a morphine pellet, we observed a threefold tolerance to LAAM-induced corneal opacities, suggesting a central nervous system mechanism in the development of the observed corneal changes.

The effect of some urinary stone inhibitors on membrane interaction potentials of stone crystals.

The effect of stone growth inhibitors (citrate, pyrophosphate, ethane diphosphonate, methane diphosphonate, chondroitin sulfate A, chondroitin sulfate C, heparin and ribonucleic acid) on crystal-membrane interactions of whewellite, weddellite, apatite, brushite, struvite, uric acid, monosodium urate and quartz (control) stones was quantitated. As a model for the initial retention of microcrystals by kidney epithelial membranes, crystal-induced membranolysis of red blood cells served as a measure of crystal-membrane interactions. The inhibitors induced changes in hemolytic potential from approximately 320 per cent enhancement to 80 per cent inhibition. No inhibitor behaved the same way for all crystals studied. However, some crystals showed consistent trends in altered hemolytic potential in the presence of inhibitors. These crystals included weddellite and sodium urate, which were inhibited consistently, and apatite and quartz, which were enhanced consistently. Whewellite, uric acid, brushite and struvite exhibited mixed patterns in the altered hemolytic potentials owing to the inhibitors.

Effect of phenobarbital pretreatment on the metabolism and biliary excretion of methadone.

Abstract The effect of phenobarbital (PB) pretreatment on the biliary excretion of methadone in rats was studied. Possible mechanisms by which PB pretreatment altered the biliary excretion of methadone were considered and studies in vitro on the metabolism of methadone were correlated with findings in vivo . For the biliary excretion studies, 14 C-methadone was administered intravenously and biliary excretion measured in anesthetized renal-ligated rats in which the common bile duct was cannulated. PB pretreatment increased the biliary excretion of 14 C after 14 C-methadone administration. The different metabolites of methadone formed in vivo and excreted into bile were separated by thin-layer chromatography and quantitated. The biliary excretion of the metabolite which results from N -demethylation and cyclization of methadone was not altered by PB pretreatment. However, the biliary excretion of metabolites which result from further N -demethylation, hydroxylation and glucuronidation was increased by PB pretreatment. Several determinants of biliary excretion (i.e. bile flow, hepatic blood flow and metabolism). which are enhanced by PB pretreatment, could cause the observed increase in the biliary excretion of methadone. Of these possibilities, we feel the data best support the suggestion that enhancement of methadone metabolism by PB pretreatment is responsible for the increased biliary excretion of methadone in PB-pretreated rats. Furthermore, metabolism studies in vitro , using microsomes from PB-treated rats, support the suggestion that PB pretreatment enhances the metabolism of methadone in vivo .

Calcium oxalate monohydrate crystal binding substance produced from Madin-Darby canine kidney cells

Abstract Background: The interaction between kidney urothelium and crystals is a critical event in the growth of renal calculi. When studying calcium oxalate monohydrate (COM) crystal binding to Madin‐Darby canine kidney (MDCK) cells in culture, we observed that crystals also attached to areas on the coverslips devoid of cells. This phenomenon could be the result of substances produced by the cells that adhere to the glass and subsequently bind COM crystals. We investigated the characteristics of this COM binding substance.

Comparative protection by a combination treatment in mice irradiated with fission neutrons or x-rays.

A triple treatment, including (1) preirradiation protection by a chemical mixture (7 μmoles of AET, 25 μmoles of MEA, and 2 μmoles of serotonin, injected intraperitoneally, 0.4 ml/mouse), (2) posti...

Value of Chemical Mixture in Multiple Supralethal X-Irradiation of Mice

A chemical mixture containing 25 Amoles of MEA, 7 pmoles of AET, and 2 micromoles of 5-HT was found to be of significant value in protecting mice against repeated exposures of 800 R, 1100 R, or 1400 R given at intervals of 28 days. Dose-reduction factors of 2.17, 2.18, 1.95, 2.14, and 1.58 were obtained for the first five exposures. Following the first exposure there was no chemical mortality. The beneficial value of this mixture, however, was limited by the incidence of chemical toxicity which was more prevalent in mice with higher cumulative doses of radiation.

Cardiovascular responses to radioprotective compounds in rats.

Heart rate and blood pressure were measured in anesthetized rats after the intraperitoneal administration of radioprotective doses of 5-hydroxytryptamine (5-HT), 2-mercaptoethylamine (MEA), 2-aminoethylisothiouronium (AET), and their mixtures. All of the chemicals produced a slowing of the heart rate in most of the animals. Both doses of 5-HT (7 and 14 mg/kg) consistently elicited a marked depressor response. While a low dose of AET (100 mg/kg) had little effect, higher doses (175 and 250 mg/kg) tended to increase blood pressure. On the other hand, low doses of MEA (60 and 120 mg/kg) tended to lower blood pressure, while a high dose (165 mg/kg) produced no significant change. The blood pressure response after the administration of the mixtures of the chemicals appeared to be the resultant effect of the action of each component. The mixture of all three chemicals (7 mg/kg 5-HT, 100 mg/kg AET, 60 mg/kg MEA) elicited the most consistent response in all animals, slowing the heart rate by 20% and decreasing th...