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Biomedical subjects

L J Fischer

Publications and source records attributed to L J Fischer.

At least 37 records · Page 2Linked to original sources
PubMed1990

Cyproheptadine-induced alterations in clonal insulin-producing cell lines.

Cyproheptadine (CPH) inhibits glucose-stimulated insulin synthesis and secretion, and reversibly depletes pancreatic insulin content in the rat. To examine whether the inhibitory actions of CPH on insulin cell function are linked to the ability of glucose to stimulate insulin synthesis and secretion, studies were performed in two different insulin-producing cell lines. CPH effects were compared in HIT-T15 cells, which respond to glucose with increased insulin synthesis and secretion, and in glucose-unresponsive RINm5F cells. CPH produced similar alterations in both cells lines. After a 48-hr culture period in the presence of 0, 0.1, 1.0 or 10.0 microM CPH, cellular insulin stores and media insulin levels were decreased in a concentration-dependent manner. At 10.0 microM CPH, RIN and HIT cell insulin content declined to 34 and 33% of controls respectively. Cellular insulin returned to control levels 48 hr after removal of CPH. In experiments designed to test a direct inhibitory effect on stimulated insulin secretion, 1 and 10.0 microM concentrations of CPH were found to inhibit glucose-stimulated insulin release from HIT cells, and K+, alanine and glyceraldehyde-stimulated release from RIN cells. CPH was also shown to inhibit insulin biosynthesis in both cell lines at concentrations that did not alter the synthesis of total cellular proteins. All of these alterations in cellular function were shown to occur at CPH concentrations that did not affect cell growth or viability. The results show that the actions of CPH do not appear to be dependent upon the existence of operational glucose signalling mechanisms for insulin synthesis and secretion.

Animals↗
PubMed1990

Metabolites of methohexitone do not contribute to its prolonged action on the central nervous system.

Methohexitone has been reported to have a prolonged action on the central nervous system (CNS) despite its relatively short elimination half-life. A hydroxy metabolite of methohexitone was identified, purified and isolated from the urine collected from eight surgical patients and five mongrel dogs anaesthetized with methohexitone. Using a rotarod device, the CNS-activity of the human and canine metabolites was tested in mice and compared to that of methohexitone. In this test, the metabolites showed CNS-depressant activity, but the ED50 (dose needed to affect 50% of the animals) of the metabolites was ten times higher than the ED50 of the parent drug. Because in patients, no traces of the hydroxy metabolite could be found in blood, and in dogs the plasma concentration of the metabolite was about two-thirds of that of the parent compound, it is unlikely that the residual CNS-effects of methohexitone are due to its major metabolite, hydroxymethohexitone.

Animals↗
PubMed1989

Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets.

The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic beta-cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals.

Animals↗
PubMed1988

Age-related susceptibility to the insulin-depleting action of 4-diphenylmethylpiperidine in young rats.

Studies were undertaken to investigate age-related changes in the ability of 4-diphenylmethylpiperidine (4-DPMP) to reduce levels of pancreatic insulin in young rats. Oral doses of 4-DPMP (5.0 or 10.0 mg/kg) were given once daily for two days to 9-, 15- and 21-day-old rats. Twenty-four hours after the last dose, pancreatic insulin content, non-fasting serum glucose, and the amount of unchanged 4-DPMP present in the whole body were estimated. 4-DPMP treatment produced a decline in pancreatic insulin and the extent of this action was greater in younger animals. The observed changes in pancreatic insulin were not reflected in altered serum glucose levels, showing this parameter is a relatively poor indicator of pancreatic insulin loss. Younger animals had a larger fraction of the total dose of 4-DPMP in the body at the end of the experimental period when compared to the fraction retained by older rats. The age-related susceptibility of young rats to the diabetogenic action of 4-DPMP may be related to the differences in the rate of elimination of the chemical at different ages.

Aging↗
PubMed1988

Evidence that drug metabolites are involved in cyproheptadine-induced loss of pancreatic insulin.

The effects of pretreatment with inhibitors of drug metabolism on the biotransformation of cyproheptadine (CPH) and the ability of the drug to deplete pancreatic insulin were investigated. CPH (45 mg/kg p.o.) or water was given once daily for 2 days to rats. SKF-525A (beta-diethylaminoethyl-2,2-diphenylpentanoate) (40 mg/kg i.p.) or water was administered 0.5 hr before the CPH treatment, and the animals were sacrificed 6 hr after the second dose of CPH. The pancreatic insulin concentration was determined, and the levels of CPH and its metabolites in pancreas, liver and lung were measured. It was found that SKF-525A pretreatment significantly protected rats from the insulin loss induced by CPH; SKF-525A alone had no effect on pancreatic insulin. The tissues from animals pretreated with SKF-525A, when compared with those of the control, had 10-fold higher levels of CPH, significantly lower concentrations of the metabolite desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) and no change in the levels of desmethylcyproheptadine (DMCPH). The in vivo N-demethylation of N-[methyl-14C]CPH, as measured by the excretion rate of 14CO2, also was inhibited by SKF-525A pretreatment. Similar experiments were performed with another inhibitor of drug metabolism, 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine (DDEP, 50 mg/kg i.p.); and the same results were obtained. In other experiments using DMCPH as the insulin-depleting compound, SKF-525A or DDEP pretreatment also afforded significant protection against chemical-induced insulin loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Susceptibility of fetal rat endocrine pancreas to the diabetogenic action of cyproheptadine.

The susceptibility of fetal endocrine pancreas to the diabetogenic action of cyproheptadine was investigated. Cyproheptadine (5 or 11 mg/kg) or water (control) was given orally once daily to pregnant rats on Days 13.5-20.5 or on Days 19.5-20.5 of gestation. Fetuses were obtained by cesarean section 24 hr after the last dose. Serum and pancreatic immunoreactive insulin and serum glucose from maternal and fetal animals were measured. Differences in maternal pancreatic insulin, serum insulin, and glucose between control and treated groups were not detected. In contrast, fetal pancreatic and serum insulin concentrations in animals exposed to 2 or 8 doses of cyproheptadine were less than 50% those of control. Drug treatment did not alter fetal pancreatic glucagon, pancreatic somatostatin, serum glucose, pancreas weight, or body weight. The drug-related depletion of fetal pancreatic insulin was reversible; the level returned to normal 3 days after cessation of the drug treatment. A similar depletion of fetal insulin was observed after 8 oral doses (11 mg/kg) of desmethylcyproheptadine, a metabolite which lacks the antiserotonin-antihistaminic properties of the parent compound. In vitro experiments showed that cyproheptadine inhibited the biosynthesis and release of insulin in fetal rat pancreas. These results indicate that cyproheptadine, when given to pregnant rats using a dose which produces no apparent effects in the maternal endocrine pancreas, causes abnormalities in the function of the insulin-secreting B cells in the fetal endocrine pancreas.

Administration, Oral↗
PubMed1986

Phenytoin metabolism in infants following intravenous and oral administration.

The disposition of phenytoin was examined in 7 infants with a mean age of 22 days and a mean weight of 3,756 g. Multiple doses of phenytoin were administered intravenously and/or orally as a part of required medical care. Gas chromatography/mass spectrometry was employed for analyses of phenytoin and three metabolites - 5-(4-hydroxyphenyl)-5-phenylhydantoin, methylated 3,4-catechol, and 3,4-dihydrodiol - in blood, urine, and feces. Data from identical studies previously conducted in adults were utilized for comparison with the infants. The mean phenytoin dose (+/- SD) in infants was 8.1 +/- 4.4 mg/kg/day, and the mean serum concentration (+/- SD) was 4.8 +/- 4.6 micrograms/ml. In adults, the mean dose was 5.3 +/- 0.6 mg/kg/day, and the mean serum concentration was 12.0 +/- 1.9 micrograms/ml. No significant differences were found between infants and adults in the pattern of urinary metabolites or in the total recovery of phenytoin and metabolites in 24-hour urine samples. These results indicate that pathways for phenytoin metabolism are the same in infants and adults. Absorption of an oral dose of phenytoin in infants appeared to be completely based on recoveries of drug and metabolites in urine and on the fact that less than 3% of an oral dose could be found in stools. The results of these studies indicate that the low blood concentrations of phenytoin resulting from the relatively high daily dosage of phenytoin in infants, when compared to adults, cannot be explained on the basis of poor oral absorption of phenytoin. These age-related differences must be due to a relatively high metabolic clearance of the drug in infants.

Administration, Oral↗
PubMed1985

Lack of effect of oral activated charcoal on imipramine clearance.

The effect of oral activated charcoal on the pharmacokinetics of intravenous imipramine was studied in a randomized, crossover trial. Four normal men received intravenous imipramine (12.5 mg/70 kg) on two separate occasions, followed by either water or water plus high-surface-area activated charcoal (180 gm) in divided doses over 24 hours. Serum imipramine concentrations were measured from 0 to 24 hours after the imipramine infusion. There was no difference in the mean (+/- SE) t1/2 (9.0 +/- 0.8 vs. 10.9 +/- 1.6 hours), apparent volume of distribution (11.2 +/- 2.1 vs. 12.4 +/- 2.1 L/kg), or systemic clearance (992.2 +/- 138.3 vs. 930.3 +/- 101.9 ml/min/70 kg) of imipramine after dosing without and with oral activated charcoal, respectively (P greater than 0.05; paired t test). These results suggest that multiple oral doses of activated charcoal do not increase the clearance of imipramine in man.

Absorption↗
PubMed1985

Effects of metyrapone on the pharmacological activity, plasma levels and urinary excretion of the dopamine receptor agonist DK-118.

Possible metabolic activation of the dopamine receptor agonist DK-118 (5-hydroxy-6-methyl-N,N-di-n-propyl-2-aminotetralin) was investigated in cats. Metyrapone, an inhibitor of oxidative drug metabolism, was given to cats before DK-118 and the pharmacologic effects of the dopamine agonist were compared to those observed in nonpretreated animals. A sensitive high-performance liquid chromatography assay using electrochemical detection was developed to monitor urine and plasma concentrations of DK-118 in metyrapone-pretreated and control animals. The DK-118-mediated inhibition of cardioaccelerator nerve stimulation-induced tachycardia was reduced markedly in cats pretreated with metyrapone but the pretreatment had no effect on the hypotension or bradycardia produced by DK-118. In a separate group of cats, the tachycardia inhibitory effect of a nonbioactivated dopamine agonist, dipropyldopamine, was unaffected by metyrapone pretreatment, confirming that the inhibitor of drug metabolism does not interfere with this dopamine receptor-mediated effect. Pretreatment with metyrapone before a 0.14-mumol/kg i.v. dose of DK-118 increased the half-life, reduced total drug clearance and increased urinary excretion of unchanged DK-118. All of the changes are consistent with a metyrapone-related inhibition of DK-118 metabolism. The results of this study show that inhibition of DK-118 metabolism reduces certain of its pharmacologic actions, indicating that one or more of the metabolites of the drug may contribute to its effects.

Animals↗
PubMed1984

Hepatotoxicity of acetaminophen in neonatal and young rats. I. Age-related changes in susceptibility.

The susceptibility of neonatal (11 days) and young rats (19 and 33 days) to acetaminophen-induced hepatic necrosis was examined. Acetaminophen-induced lethality (LD50) was slightly lower in 19-day-old animals (840 mg/kg) compared to 11- and 33-day-old animals (1220 and 1580 mg/kg, respectively). A toxic dose of the drug ( LD20 ) produced elevated serum glutamate-pyruvate transaminase and lactate dehydrogenase activities 20-24 hr after drug administration only in 19- and 33-day-old animals. Serum enzyme elevation was not observed after a toxic dose of acetaminophen ( LD20 or LD50) in 11-day-old rats. Histological evaluation showed that both 19- and 33-day-old rats developed extensive hepatic centrilobular damage, whereas morphological parameters in 11-day-old animals given acetaminophen were not different from controls. It appears that high doses of acetaminophen are lethal to young rats, but that 11-day-old animals are different from 19-day-old and older rats in that the neonatal animals lack susceptibility to the hepatotoxic effects of the drug. Lower susceptibility of the neonatal rat liver to the hepatic effects of two other hepatotoxicants (bromobenzene and tannic acid) was also observed.

Acetaminophen↗
PubMed1984

Hepatotoxicity of acetaminophen in neonatal and young rats. II. Metabolic aspects.

The effects of a toxic dose of acetaminophen on levels of hepatic glutathione and [14C]acetaminophen-derived metabolites covalently bound to tissue macromolecules were investigated in 11- (1000 mg/kg), 19- (750 mg/kg), and 33-day-old (1250 mg/kg) rats. Although hepatic glutathione levels are lower in untreated 11- and 19-day-old rats compared to 33-day-old animals, a toxic dose of acetaminophen produced similar maximal depletion in all ages (to 0.5 mg/g). Covalent binding of [14C]acetaminophen to hepatic and renal macromolecules was higher in the younger animals. Glutathione-derived conjugates of APAP were present in the liver and kidney of neonatal and young rats given a toxic dose of the drug. In addition, age-related differences in the levels of the sulfate and glucuronide conjugates of the drug in these tissues were observed. The data presented suggest that neonatal rats, while less susceptible than older rats to the hepatic necrosis produced by the drug, are more able to metabolically activate a toxic dose of acetaminophen.

Acetaminophen↗
PubMed1984

Alterations in rat pancreatic B-cell function induced by prenatal exposure to cyproheptadine.

Treatment of pregnant rats with cyproheptadine during the last 8 days of gestation produced alterations in the function of the endocrine pancreas in the offspring. The abnormalities exhibited by 50-day-old progeny of drug-treated dams included glucose intolerance, a two-fold increase in levels of insulin in the pancreas, and an accentuated response to the insulin-lowering action of cyproheptadine in the endocrine pancreas. The alterations observed in these animals were limited to the insulin-containing cells, and no change was found in the pancreatic concentrations of glucagon and somatostatin. The results are the first to demonstrate that postnatal pancreatic B-cell function can be selectively altered by prenatal exposure to an exogenous chemical.

Animals↗
PubMed1984

Inhibition of insulin release from rat pancreatic islets by drugs that are analogues of dopamine.

Various synthetic dopamine (DA) analogues have been shown to produce glucose intolerance and inhibit the compensatory increase in serum insulin during an oral glucose tolerance test (OGTT). To investigate the possibility that there is a direct action of dopamine analogues to inhibit glucose-stimulated insulin release from the endocrine pancreas, the following compounds were compared with the effects of epinephrine (EPI) on isolated rat pancreatic islets: apomorphine (APO), pergolide, lergotrile, TL-99 (2-dimethylamino-6,7-dihydroxytetralin), and RDS-127 (2-di-n-propyl-amino-4,7-dimethoxyindane). EPI, TL-99, and pergolide inhibited insulin release in a concentration-dependent fashion (10(-7)-10(-5) M), whereas lergotrile inhibited at 10(-5) M but not at 10(-6) M. RDS-127 and APO were ineffective at 10(-5) M, but produced a greater than 50% inhibition at 2 X 10(-4) M. The potencies of the DA analogues fell into two groups: compounds that are approximately as active as EPI (e.g., TL-99 and pergolide) or compounds that are relatively inactive (e.g., APO, lergotrile, and RDS-127). The inhibitory actions of EPI, TL-99, and pergolide were blocked by the alpha 2-adrenergic receptor antagonist yohimbine, whereas the DA receptor antagonist, sulpiride, had no effect, suggesting an action initiated at alpha 2-adrenergic receptors. Drugs from both groups produced marked glucose intolerance and inhibited the compensatory increase in insulin during an OGTT. Adrenodemedullation blocked the glucose intolerance and inhibition of insulin release caused by RDS-127, whereas these effects of TL-99 were not attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1984

Dopamine analog-induced hyperglycemia in rats: involvement of the adrenal medulla and the endocrine pancreas.

The following synthetic, structural analogs of dopamine (DA) were examined for their ability to produce hyperglycemia in conscious unrestrained rats: APO (apomorphine), RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane), di-n-propyldopamine, 2-di-n-propylamino-5,6-dihydroxytetralin, 2-dimethylamino-6,7-dihydroxytetralin, lergotrile, pergolide, bromocriptine and d-amphetamine. All the compounds demonstrated dose- and time-dependent hyperglycemic actions. The most potent DA analog to induce hyperglycemia was 2-di-n-propylamino-5,6-dihydroxytetralin (0.18 mumol/kg) and, at the doses used, 2-dimethylamino-6,7-dihydroxytetralin produced the greatest elevation in blood glucose (227% control). APO and RDS-127 were used in experiments designed to provide additional mechanistic information concerning their hyperglycemic action. The hyperglycemia produced by APO or RDS-127 was blocked by adrenalectomy, adrenodemedullation or prior administration of pimozide, a DA receptor antagonist. Phentolamine, an alpha adrenergic receptor antagonist had no effect on the hyperglycemia induced by APO or RDS-127. Oral glucose tolerance tests indicated that APO and RDS-127 caused abnormal glucose tolerance and inhibited the compensatory increase in serum immunoreactive insulin. These effects were prevented by pimozide or phentolamine pretreatment. The potencies of the compounds to produce increases in serum glucose concentrations (SG), inhibit the accumulation of DOPA using the in vivo gamma-butyrolactone procedure (DOPA) and inhibit food intake (FI) were subjected to correlation analysis. Positive correlations were found for FI vs. DOPA, r = 0.96; SG vs. decreases DOPA, r = 0.98 and SG vs. FI, r = 0.98.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1984

Evidence that central dopamine receptors modulate sympathetic neuronal activity to the adrenal medulla to alter glucoregulatory mechanisms.

Previous reports suggest that analogs of dopamine (DA) can produce hyperglycemia in rats by interacting with DA receptors. Experiments reported here indicate the site of action and describe the metabolic sequalae associated with the hyperglycemic effect of apomorphine (APO), produced in conscious unrestrained rats. Apomorphine was more potent when administered by intracerebroventricular (i.c.v.) injection than when given subcutaneously (s.c.). Very small doses of the DA receptor antagonist pimozide, given intraventricularly, blocked the hyperglycemic effect of apomorphine administered subcutaneously. Sectioning of the spinal cord at thoracic vertebra T1-2 or sectioning the greater splanchnic nerve blocked apomorphine-induced hyperglycemia; whereas section of the superior colliculus or section at T5-6 had no effect. A dose of apomorphine or epinephrine (EPI) producing a similar degree of hyperglycemia elevated the concentration of EPI in serum to a similar degree, and the increase in EPI in serum preceded the increase in glucose in serum. Fasting animals for 2 or 18 hr had no significant effect on EPI- or apomorphine-induced hyperglycemia despite a reduction (91-93%) of the glycogen content of liver and skeletal muscle during the 18 hr fast. 5-Methoxyindole-2-carboxylic acid (MICA), an inhibitor of gluconeogenesis, blocked EPI- and apomorphine-induced hyperglycemia in rats fasted for 18 hr. However, 5-methoxyindole-2-carboxylic acid was ineffective in blocking hyperglycemia in animals fasted for 2 hr. Changes in insulin or glucagon in serum alone cannot account for the hyperglycemic action of apomorphine. These data demonstrate that apomorphine interacts with central DA receptors located in the hindbrain to activate sympathetic neuronal activity to the adrenal gland which subsequently releases epinephrine to alter homeostasis of glucose. Epinephrine may then, depending on the nutritional status, facilitate glycogenolytic or gluconeogenic processes to produce hyperglycemia.

Adrenal Medulla↗
PubMed1983

Hamster hepatocytes in culture as a model for acetaminophen toxicity studies with inhibitors of drug metabolism.

A hamster hepatocyte system was developed for use in studying the toxicity of acetaminophen (APAP). The cells were isolated and placed in culture conditions in petri dishes containing a film of collagen. Hepatocytes, after attachment to collagen, were exposed for various periods of time to different concentrations of APAP. Hepatocytes exposed to APAP exhibited concentration- and time-dependent GSH depletion followed by cytoplasmic enzyme leakage and an increase in malondialdehyde content (TBA-reactive material). These effects were reduced by the drug metabolism inhibitors metyrapone, piperonyl butoxide, and dithiocarb. Removal of APAP and its unbound metabolites from cells prior to 1.5 hr followed by culture in drug-free medium resulted in no observable damage to the cells over a 24-hr period. Removal of drug after longer exposure times followed by culture in fresh medium resulted in eventual cell damage. This finding showed that deleterious changes caused by APAP occurred over a 1.5-hr period after which eventual hepatocyte damage could not be reversed by removal of the drug. Further experiments showed that metyrapone and dithiocarb had some protective effect when added after APAP had been completely removed from damaged cells. This result indicates that these agents have a protective action separate from, and in addition to, their ability to inhibit APAP oxidation via cytochromes P-450.

Acetaminophen↗
PubMed1983

Characteristics of nicotinamide and N1-methylnicotinamide protection from alloxan diabetes in mice.

Comparisons were made of the dose-response and time-course characteristics of nicotinamide (NIC) and its metabolite, N1-methylnicotinamide (MNIC), protection from alloxan-induced diabetes in mice. A significant reduction in the permanent hyperglycemia caused by alloxan (50 mg/kg, iv) was observed when NIC or MNIC was given iv at a dose of 800 mg/kg 2 hr before alloxan. Complete protection was provided by pretreatment with 1200 mg/kg of either agent. There was a linear increase in 2-hr serum levels of NIC or MNIC after increasing doses of each protective agent. Protection after a 1200 mg/kg dose of NIC was of a shorter duration (6 hr) than after a corresponding dose of MNIC (greater than 24 hr). This longer protective action of the metabolite was accompanied by correspondingly higher serum levels of MNIC when compared to levels of NIC after an identical dose. No protective effects of NIC or MNIC were apparent when the agents were added to isolated mouse pancreatic islets prior to alloxan exposure in vitro. The results indicate that both NIC and its metabolite, when given in high doses before alloxan, are capable of protecting mice from alloxan diabetes. The protective action of NIC and MNIC appears to be an indirect one because the agents were ineffective as protectants in an in vitro system.

Alloxan↗