Rapid development of functional tolerance to caffeine-induced seizures in rats.

The concentration and time dependence of caffeine-induced neurotoxicity was determined by infusing rats intravenously with caffeine at a rate of about 5, 12.5, and 25 mg kg-1 min-1 until the onset of generalized seizures which occurred at about 82, 28, and 11 min, respectively. The concentration of caffeine in the serum, brain, and cerebrospinal fluid at onset of seizures increased with decreasing infusion rate; the concentrations of caffeine metabolites were negligible and serum protein binding was not affected by the infusion rate.

Regional myocardial ajmaline concentration and antiarrhythmic activity for ischaemia- and reperfusion-induced arrhythmias in rats.

1. Antiarrhythmic actions of ajmaline against ischaemia (left coronary artery occlusion for 15 min) and subsequent reperfusion-induced arrhythmias were investigated in anaesthetized rats. 2.

Kinetics of drug action in disease states. XIX. Effect of experimental liver disease on the neurotoxicity of theophylline in rats.

There are pronounced interindividual differences in the neurotoxicity of theophylline in humans as reflected by the wide range of plasma theophylline concentrations associated with the occurrence of life-threatening, generalized seizures in patients treated with this widely used bronchodilator. The variability indicates that there may be a number of as yet unrecognized risk factors for theophylline neurotoxicity. After the development of an animal model of theophylline-induced seizures, renal failure was identified as one such risk factor.

Kinetics of ajmaline disposition and pharmacologic response in beagle dogs.

Pharmacokinetics and pharmacodynamics of ajmaline were studied in four healthy dogs after intravenous administration of the drug at the infusion rate of 1.0 mg/min for 45 min. Ajmaline exhibited a saturable binding to plasma protein.

Sublobular differences in hepatic microtubular changes of alcoholic liver disease: morphometrical analysis.

To clarify the cause of predominant hepatocytic changes in the centrolobular area of livers with alcoholic liver injuries, changes in hepatic microtubules at different sublobular areas of liver with alcoholic liver disease were analyzed by ultrastructural morphometry. Hepatocytic volumes in both the centrolobular and periportal areas of livers with alcoholic liver disease were significantly larger than those in the corresponding areas of livers with non-alcoholic liver disease, respectively. The volume of hepatocytes was significantly larger in the centrolobular area than in the periportal area in both alcoholic and non-alcoholic liver diseases.

Blink reflex elicited by auditory stimulation in the rabbit.

The pathway of the blink reflex, elicited by auditory stimulation, was investigated electrophysiologically. The reflex was recorded as microvibrations of the eyelid and was named the auditory-evoked eyelid microvibration (AMV). Pharmacophysiological studies suggest that AMV is closely related to the midbrain reticular formation and studies of electrical lesions in the midbrain reticular formation support this.

Degradation of acetaldehyde produced by the nonalcohol dehydrogenase pathway.

Acetaldehyde (Ac-CHO) is produced via the oxidation of ethanol by two different pathways; alcohol dehydrogenase (ADH) and non-ADH systems. However, degradation of Ac-CHO in the liver, especially with respect to the relative amounts produced by the two pathways, remains unclear. In order to clarify the metabolic fates of Ac-CHO produced by the two pathways, the ethanol metabolic rate (EMR) and hepatic Ac-CHO levels in the rats fed an alcohol-containing or control diet for 4 weeks were determined after a single administration or constant infusion of ethanol, with or without 4-methylpyrazole pretreatment.

Pharmacokinetics and antiarrhythmic activity of ajmaline in rats subjected to coronary artery occlusion.

The pharmacokinetics and the antiarrhythmic action of intravenous ajmaline were investigated in anaesthetized rats subjected to coronary artery occlusion. Ajmaline (0.125-2 mg kg-1, i.

Mechanisms of pharmacokinetic interaction between ajmaline and quinidine in rats.

In order to elucidate the mechanism of ajmaline-quinidine interaction previously observed in humans, the effects of quinidine on pharmacokinetics of ajmaline were investigated in rats. Concurrent oral administration of 10 mg/kg of quinidine markedly increased the plasma concentration of ajmaline at a dose of 2 mg/kg. On the other hand, it did not affect the pharmacokinetics of ajmaline after intravenous dose.

An analysis program MULTI(ELS) based on extended nonlinear least squares method for microcomputers.

An analysis program MULTI(ELS) was developed for population pharmacokinetics on a microcomputer. The program based on the extended least squares (ELS) is written in the Microsoft minimum BASIC command alone. ELS simultaneously estimates not only the population pharmacokinetic parameters but also the variances of inter-individual variabilities around the population parameters and of intra-individual variabilities for the plural time courses, whereas the ordinary least squares estimates the pharmacokinetic parameters of each time course.

Effect of altered plasma protein binding on pharmacokinetics and pharmacodynamics of propranolol in rats after surgery: role of alpha-1-acid glycoprotein.

The pharmacokinetics and pharmacodynamics of propranolol in rats 2 days after laparotomy were compared to control animals. The apparent volumes of distribution and the systemic clearance of propranolol were decreased to about 20 to 40 and 70% of control values, respectively. The area under the blood concentration-time curve (AUC) of propranolol after p.

Identification of the major binding protein of salmon calcitonin in the rat.

The major serum binding protein of salmon calcitonin (sCT) in the rat was identified. High-molecular-weight (HMW) forms of sCT, produced by the incubation of radioactive sCT in rat serum, were isolated by gel filtration and analysed by chromatofocusing. The major radioactive peak was eluted at the region of albumin in gel filtration, and this peak had a slightly higher pI than albumin on chromatofocusing.

Reduced hepatic uptake of propranolol in rats with acute renal failure.

The effect of acute renal failure (ARF) on the hepatic uptake and metabolism of propranolol was investigated in relation to the hepatic clearance of the drug. ARF was induced by the subcutaneous injection of uranyl nitrate to rats. The uptake rate of propranolol in the isolated perfused liver was determined by the multiple-indicator dilution method and was found to decrease from 43.

Comparison between ballooned hepatocytes occurring in human alcoholic and nonalcoholic liver diseases.

To establish clearly what the pathogenetic differences are in the hepatocytic ballooning between human alcoholic and nonalcoholic liver diseases, hepatic microtubules were examined by morphometric and biochemical methods, and staining of transferrin was carried out on liver sections immunohistochemically. Microheterogeneity of serum transferrin was also detected by immunofixation after isoelectric focusing. Hepatic microtubules were significantly decreased in alcoholic liver disease, and transferrin was clearly stained in the ballooned hepatocytes of alcoholic liver disease but not in nonalcoholic liver disease.

Influence of acute renal failure on pharmacokinetics of phenolsulfonphthalein in rats: a comparative study in vivo and in the simultaneous perfusion system of liver and kidney.

The effect of acute renal failure (ARF) on the disposition of phenolsulfonphthalein (PSP) after intravenous administration was investigated in rats. ARF was induced by the subcutaneous injection of uranyl nitrate to rats. Renal excretion of PSP decreased significantly in ARF compared to that in normal controls.

Phakomatosis pigmentovascularis type IVa.

Phakomatosis pigmentovascularis was first reported in 1947. We describe a 1-year-old Japanese girl who, since birth, has had three nevoid skin disorders: nevus flammeus, nevus spilus, and aberrant mongolian spots. No systemic disease of any kind has been present.

A nonlinear multiple regression program, MULTI2 (BAYES), based on Bayesian algorithm for microcomputers.

A nonlinear multiple regression analysis program MULTI2(BAYES) was developed for microcomputers. The Bayesian algorithm which is incorporated in MULTI2 (BAYES) combines the insufficient individual patient data (individual data) with the pharmacokinetic parameters published in literatures (population parameters) to predict the plasma time course of the patient. The program is written in the minimum Microsoft BASIC commands alone to be executable on many personal computers without any modification.

[So-called "carcinoid tumor of the breast"--a case report].

A 70-year-old woman underwent modified radical mastectomy following excisional biopsy of a right breast mass. The excised tumor was 1.4 cm in diameter.

Comparison of ballooned hepatocytes in alcoholic and non-alcoholic liver injury in rats.

Ballooned hepatocytes are commonly observed in alcoholic and sometimes in non-alcoholic liver diseases. To clarify whether pathogenesis of this change is different in alcoholic and non-alcoholic liver diseases, changes of the livers in rats fed alcohol with pyrazole for 12 weeks were compared with those of CCl4 treated rats. Both groups of rats showed marked ballooning of the hepatocytes in the centrolobular area.

High molecular weight derivative of salmon calcitonin with prolonged hypocalcemic activity.

A new method preparing a long-acting formula of salmon calcitonin, which possesses high specific activity, has been developed. This method consists of two processes: (a) preparation of a high molecular weight derivative of salmon calcitonin and (b) preparation of a zinc suspension of the derivative. The derivative was prepared by the incubation of reduced salmon calcitonin with bovine serum albumin.

Distribution of patients' test values and applicability of "average of normals" method to quality-control of radioimmunoassays.

Applicability of the Hoffmann's average of normals (Mn) method was evaluated in quality control (QC) of radioimmunoassays (RIA) for thyroxine, 3,5,3'-tri-iodothyronine, thyrotropin, and insulin--assays that are performed routinely in the authors' laboratory. In the first three RIAs, the patterns of the distributions were almost constant and Mn showed significant correlations with values of QC sera and intercepts of the dose-response curve. In insulin RIA, the patterns varied appreciably and Mn showed correlations with parameters that reflect a disturbance in the distribution.

Characterization of high molecular weight forms of peptide drugs in vivo.

Studies were undertaken to investigate the site and conversion mechanism of exogenous peptides into high molecular weight (HMW) forms when administered in vivo. Functional nephrectomy reduced the conversion of aprotinin into HMW form in circulation whereas incubation of aprotinin in kidney homogenate in vitro resulted in an increase in HMW component, indicating that the kidney participates in conversion of aprotinin into HMW form. Incubation of aprotinin in rat serum showed that HMW forms can be produced in blood.

In vivo conversion of peptide drugs into high molecular weight forms.

Following injection of 125I-porcine insulin, 125I-aprotinin, 125I-salmon calcitonin, or 125I-(Asu1,7)-eel calcitonin into rats, high molecular weight (HMW) forms of these peptides were detected in serum or plasma when analyzed by gel chromatography. The conversion into HMW forms occurred after 1) intravenous bolus injection of insulin, aprotinin, or calcitonins, 2) intravenous infusion of insulin or aprotinin, and 3) subcutaneous injection of insulin, indicating that HMW forms were produced in the general circulation not in the subcutaneous tissue. Rechromatography of HMW forms produced in vivo from insulin or aprotinin showed the release of lower molecular weight component which was eluted at the same position of parent peptide, the immunoreactivity of the released component derived from insulin was almost the same as for insulin.