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Biomedical subjects

S Schenker

Publications and source records attributed to S Schenker.

At least 91 records · Page 5Linked to original sources
PubMed1989

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

Exposure of the fetal rat hepatocyte to ethanol in vitro blocks epidermal growth factor (EGF)-dependent cell replication. To define possible mechanisms for this growth arrest, we determined the effects of ethanol on EGF binding and EGF receptor (EGF-R) levels. During a 24-h exposure to ethanol (1.7 mg/ml, 31 mM), cell replication was completely blocked while EGF binding per cell doubled. This effect was no specific for EGF, with variable degrees of increased binding noted for insulin, transferrin, and glucagon. Significantly increased EGF binding was seen after 6 h of ethanol exposure, and both growth arrest and enhanced EGF binding were reversed within 12 h of ethanol withdrawal. Increases in both "high" and "low" affinity sites were seen, with no changes in the apparent Kd's. Total RNA, beta-actin mRNA, and EGF-R mRNA were increased 50-70% in ethanol exposed cells. However, direct measurements of EGF-R synthesis rates by [35S]methionine incorporation revealed no differences between control and ethanol exposed cells. Internalization of EGF-R was significantly altered by ethanol exposure. A 2-h incubation resulted in the internalization of 57% of the ligand in control cells, while only 31% of bound EGF was internalized in the ethanol exposed cells. Thus, the enhanced EGF binding may be due to decreased efficiency of internalization.

Animals↗
PubMed1988

Effect of aging on hepatic elimination of cimetidine and subsequent interaction of aging and cimetidine on aminopyrine metabolism.

Aging and cimetidine may each impair hepatic microsomal drug metabolism. To test if and by what mechanisms advanced age may increase sensitivity to the inhibitory effects of cimetidine, the interaction of these two factors with aminopyrine metabolism in the rat was studied using a correlative approach. Initial studies using the aminopyrine breath test indicated that a 40 mg/kg dose of cimetidine, i.p., impaired the 14CO2 exhaled by up to 76% more in aged (26-month) than in young (3- to 4-month-old) rats. Using an isolated liver perfusion to dissect out hepatic components of this phenomenon, it was found that various doses of cimetidine impaired aminopyrine clearance to a greater degree (P less than 0.05) in aged than in young livers. However, cimetidine metabolism in this system ranged from 36 to 78% less in aged versus young livers (P less than 0.05). Subsequent in vitro studies indicated that microsomes isolated from aged livers also averaged a 76% lower rate of cimetidine metabolism (P less than 0.05). A fixed cimetidine concentration, however, inhibited aminopyrine demethylation to the same degree in aged versus young rats (P less than 0.05). In vivo pharmacokinetics showed an age-related decrease in both aminopyrine and cimetidine systemic clearance. In the young rat the liver contributed about 30% to total systemic clearance of cimetidine. In the aged rat, all clearance was renal. Despite a decrease in glomerular filtration rate, net tubular cimetidine secretion was well-maintained. Despite this, absence of the hepatic component resulted in decreased overall systemic clearance of the drug in aged rats. It is concluded that (1) the aged rat liver exhibits impaired cimetidine metabolism, resulting in decreased overall systemic clearance of the drug despite normal net renal tubular secretion, (2) there is no age-related enhanced sensitivity to cimetidine of the hepatic microsomal oxidizing system using aminopyrine as the probe drug, and (3) the larger inhibition of aminopyrine metabolism in aged rats following various doses of cimetidine is due to decreased overall cimetidine clearance, resulting in higher concentrations of the inhibitor in the liver of aged rats.

Aging↗
PubMed1988

Fluoxetine disposition and elimination in cirrhosis.

Fluoxetine is a specific and potent inhibitor of presynaptic serotonin reuptake and has been shown to be a clinically effective antidepressant. Elimination of the drug depends primarily on hepatic metabolism, with formation of a pharmacologically active demethylated product, norfluoxetine. The present study assesses for the first time the effect of chronic liver disease on these processes. Our data show that in stable alcoholic cirrhosis, the elimination of fluoxetine is significantly reduced. The mean t1/2 was 6.6 vs. 2.2 days and plasma clearance was 4.2 vs. 9.6 ml/min/kg for patients with cirrhosis vs. normal volunteers, respectively. In addition, the formation of norfluoxetine was decreased and its clearance was also reduced. Thus, at steady state both fluoxetine and norfluoxetine concentrations will be higher in patients with cirrhosis, unless the dosage is reduced. Conventional liver tests and indocyanine green clearance in cirrhosis did not correlate in a predictive manner with individual patients' elimination of fluoxetine.

Adult↗
PubMed1988

A comparative evaluation of the transport of H2-receptor antagonists by the human and baboon placenta.

Using a single cotyledon perfusion model, the placental transport of four H2-receptor antagonists, cimetidine, famotidine, nizatidine, and ranitidine, was determined and compared using normal term human and normal preterm baboon placentas. In both the human and baboon placentas, the transport of each agent was similar whether administered singly or in combination with the other drugs. Drug transport was the same in both directions, maternal-to-fetal and vice versa, indicating a lack of preferential transfer. The H2-receptor antagonists were transported at about 40% the rate of the freely diffusable reference compound, antipyrine. There were no significant differences between the human and baboon in any of the parameters of placental function evaluated. Placental glucose and oxygen consumptions, and lactate production were comparable in the human and baboon preparations. The transport and clearance of each of the H2-antagonists were similar in each species.

Adolescent↗
PubMed1987

Human placental transport of cimetidine.

This study addresses the mechanism of transport of the H2-receptor antagonist, cimetidine, by the human placenta. A 4-h recycling perfusion of a single placental cotyledon of normal, term, human placenta was used. At a maternal concentration of 1 microgram/ml, cimetidine clearance from the maternal circulation was 0.58 +/- 0.16 ml/min per g placenta, a rate about one third that of antipyrine. There was no evidence of cimetidine metabolism by the placenta. Transfer of cimetidine from maternal to fetal compartments showed no saturation kinetics and was not inhibited by putative carrier competitors. Cimetidine did not accumulate against a drug concentration gradient. Fetal clearance of cimetidine was similar to maternal clearance. Studies with placental apical vesicles confirmed lack of saturability of cimetidine transport and of its concentration within vesicles. Thus, (a) cimetidine is transported across the human placenta bidirectionally at a rate about one third that of antipyrine, (b) the drug is not metabolized by the placenta, and (c) the transport is a passive one.

Adolescent↗
PubMed1987

United Sciences of America, Incorporated: an "optimal" diet?

The diet plan marketed by the United Sciences of America, Incorporated (USAI) claims to offer "optimal nutrition" for the health of Americans. This claim raises the question, what is an "optimal" diet? Analyses of the four diet products--a fiber energy bar, an omega-3 fatty-acid concentrate, a calorie-control formula, and a master formula of mixed ingredients--raise questions regarding safety and efficacy of this plan. Still further questions focus on endorsement of the USAI diet plan and the relation of endorsement to receiving "grants" from the producer.

Advertising↗
PubMed1986

Hepatic oxidative drug metabolism and the microsomal milieu in a rat model of congenital hyperbilirubinemia.

The aims of this study were to evaluate the hypothesis that impaired glucuronidation of bilirubin and possibly of drug oxidation in the liver of homozygous (jj) Gunn rats may be due to an altered microsomal milieu. Accordingly, we investigated and compared in vivo and in vitro demethylation of aminopyrine, hepatic cytochrome P-450 levels, microsomal lipid composition, and microsomal membrane fluidity in icteric, homozygous (jj) Gunn rats and in their anicteric heterozygous (jJ) littermates. In both males and females, [14C]aminopyrine demethylation in vivo, using the 14CO2 breath test, was unimpaired in the icteric animals. Likewise, cytochrome P-450 levels in the icteric and nonicteric groups were similar, and aminopyrine kinetics in vitro in the females were comparable in icteric and nonicteric littermates. The main lipid classes were also similar in the homozygous and heterozygous female Gunn rats, whereas only minor changes were seen in the phospholipid fatty acyl composition with a small, but significant, increase in the unsaturated index in the icteric group. Despite this, there was no apparent effect on hepatic microsomal membrane fluidity as measured by the order parameter of I[12,3] and the rotational correlation time of I[1,14] in either female or male sets of homozygous and heterozygous Gunn rats. Our data, therefore, do not support an alteration of composition or fluidity of the microsomal milieu as a mechanism of impaired bilirubin glucuronidation and possibly of oxidation in these animals. They also absolve long-term unconjugated hyperbilirubinemia as a mechanism of hepatic microsomal dysfunction. Our study, therefore, indirectly suggests that abnormal glucuronidation of bilirubin and some other aglycones in homozygous Gunn rats is due to genetic abnormalities involving the enzyme(s) itself.

Aminopyrine↗
PubMed1986

Effects of age, sex, and cimetidine on acute ethanol-induced inhibition of the hepatic monooxygenase systems.

Our aim was to investigate the possible interaction of acute ethanol (E) with the metabolism of other drugs by microsomes isolated from immature and mature rat livers and placenta. The effects of acute in vitro E exposure on the N-demethylation of [14C]aminopyrine and [1-14C]methylcaffeine by these tissues were determined. In addition, the effects of ethanol on these two enzyme systems from male and female livers were compared along with an analysis of ethanol and cimetidine inhibitory interactions. The degree (percentage) of inhibition by acute E (1-3 mg/ml) varied with both age and sex. Aminopyrine demethylase activity was inhibited by E to a greater degree (p less than 0.05) in the adult female than the male. However, when inhibition was expressed in absolute terms (control minus inhibited activity), these inhibitory values varied in direct proportion to initial (control) enzyme activity. Thus, E reduced aminopyrine demethylase from adult male microsomes by 4 times that in the female and in excess of 1000 times the absolute inhibition observed in fetal liver regardless of E concentration. A similar pattern of sex and age differences in caffeine demethylase response to E was observed except that absolute differences in inhibition were less due to smaller variation in control values. In addition, placental caffeine demethylase was highly sensitive to E inhibition (51% at 3 mg/nl) but not to the extent of caffeine demethylase from fetal liver (75% at 3 mg/nl). Finally, it was demonstrated that E interacts with cimetidine in a manner that may be additive.

Age Factors↗
PubMed1986

Effects of age and sex on the hepatic monoxygenase system: a correlative approach.

The following studies compare developmental patterns of a hepatic monoxygenase system using (1) the aminopyrine (Ap) breath test, (2) in vivo Ap pharmacokinetics (clearances) and (3) in vitro Ap demethylation by hepatic microsomes. Together, the three methodological approaches indicate that hepatic metabolism of Ap increases from the fetal stage through 70 days of age with the male showing a significantly greater drug metabolizing capacity than the female. However, sex and developmental patterns derived by the three methodologies do not necessarily correlate quantitatively, due to a number of complex variables (i.e., liver size, drug volume of distribution, etc.) less likely encountered in the adult of fixed age and mature sexual development.

Aging↗
PubMed1986

Effect of H2-receptor antagonists on steady-state extraction of indocyanine green and lidocaine by the perfused rat liver.

Variable effects of cimetidine on the clearance in humans of the high-clearance compounds lidocaine and indocyanine green have been reported, some investigators finding a reduction and others no change. We measured the extraction of indocyanine green, which is not metabolized and of lidocaine, which is metabolized by the perfused rat liver, in an open system with a fixed flow rate. The extraction ratios of both indocyanine green (ERICG) and lidocaine (ERL) were determined under control conditions and during continuous infusion of cimetidine and other H2-receptor antagonists (ranitidine, nizatidine, and ICI 125,211) on separate occasions. The effects of increasing concentrations of cimetidine and ranitidine were measured, and single concentrations of nizatidine and ICI 125,211 were used. Indocyanine green was measured spectrophotometrically or by high-performance liquid chromatography (HPLC). Lidocaine concentrations in perfusate were measured by gas chromatography, and H2-receptor antagonist levels in perfusate and in liver by HPLC. The perfused rat liver extracted indocyanine green (ERICG = 0.43 +/- 0.04) and lidocaine (ERL = 0.78 +/- 0.01) with steady state being reached within 5 minutes. Neither cimetidine nor ranitidine altered steady-state indocyanine green extraction. In contrast, ERL was decreased by all four H2-receptor antagonists but with differing potencies. In this system, cimetidine was the most potent agent, reducing ERL by 28.5% at a cimetidine concentration of 56 mumol/L. The other H2-receptor antagonists also decreased ERL:ICI 125,211 by 20% (49 mumol/L), ranitidine by 13% (38 mumol/L), and nizatidine by 9% (43 mumol/L). A dose-response relationship for cimetidine and ranitidine was developed, confirming the greater potency of cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Pancreatic phlegmon. Clinical features and course.

The clinical course of 19 patients with pancreatic phlegmon, as diagnosed by computed tomography (CT) and clinical criteria, was assessed retrospectively and compared to that of eight patients with pancreatic abscess diagnosed either at surgery or with percutaneous aspiration. Controls consisted of 55 patients with uncomplicated acute pancreatitis without CT scans and 11 patients with acute pancreatitis in whom CT scans were negative or only consistent with acute pancreatitis (no phlegmon). The age, sex, and presumed etiology of the pancreatitis were not significantly different in the four groups. Patients with phlegmon had a higher incidence of severe pancreatitis as defined by Ranson's criteria, presence of an abdominal mass, as well as a longer duration of fever, abdominal pain and leukocytosis than controls without CT scans. With the exception of a palpable abdominal mass and fever lasting over five days, the results were similar when comparing the phlegmon group and controls with CT scans, although the severity of the disease and prolonged abdominal pain tended to be increased in the former patients. There was no statistically significant difference in clinical or laboratory criteria between the phlegmon and abscess groups, although the latter group had longer hospital stays and periods with no oral intake (npo). Management of patients with phlegmon tended to include TPN, longer npo periods, antibiotics, and longer hospital stay than in controls without CT scans. Controls with CT scans were managed similarly to the phlegmon group because of prolonged amylase elevation and abdominal pain. Percutaneous aspiration was successful in differentiating abscess from phlegmon in five of six cases. Major complications were rare in the phlegmon group and spontaneous resolution was the rule. Pancreatic phlegmon is a distinct clinical/radiologic entity which may be very difficult to differentiate clinically from pancreatic abscess. Early percutaneous thin-needle aspiration of the inflammatory mass (under CT guidance) seems to be the diagnostic procedure of choice. Management is nonsurgical unless complications arise. The role of TPN and antibiotics is unknown, and controlled studies of these therapeutic approaches in pancreatic phlegmon are needed.

Abscess↗
PubMed1985

Nizatidine, a new histamine H2-receptor antagonist, and hepatic oxidative drug metabolism in the rat: a comparison with structurally related compounds.

The effects of nizatidine (a new H2-receptor antagonist) and of related compounds were studied on oxidative drug metabolism in the rat both in vivo and in vitro. Nizatidine is a structural analog of the H2-receptor antagonists ICI 125,211 (Tiotidine) and ranitidine (Zantac). Nizatidine (120 mg/kg, ip) had no effect on the [14C]aminopyrine (ABT) or [14C]caffeine breath (CBT) tests, nor on the clearance from plasma of aminopyrine despite high tissue and plasma concentrations of nizatidine. Binding of nizatidine (1 mM) to rat hepatic microsomal P-450 determined by spectral analysis was not observed. In vitro aminopyrine demethylation was inhibited by nizatidine only at high concentrations (Ki = 92 mM). Cimetidine, ICI 125,211, and imidazole bind avidly to rat hepatic microsomal cytochrome P-450 and are potent inhibitors of aminopyrine demethylation in vitro. Imidazole inhibited the aminopyrine breath test, while imidazole, ranitidine, and ICI 125,211 inhibited the caffeine breath in vivo. These data indicate that nizatidine has no acute inhibitory effect on hepatic oxidative drug metabolism in the rat, both in vitro and in vivo. The composite structural-activity data suggest that inhibition of in vivo oxidative drug metabolism by H2-antagonists may not depend primarily on either the imidazole ring side chain or the thiazole ring per se. Furthermore, the in vivo inhibition may not correlate with in vitro data.

Aminopyrine↗
PubMed1985

Effects of influenza virus vaccine on hepatic drug metabolism.

Experimental and more limited clinical studies have suggested that influenza vaccination may depress the oxidative hepatic metabolism of various drugs and lead to drug toxicity. The alleged mechanism is the formation of interferon and the resulting decrease in cytochrome P-450 available for drug oxidation. Because of the clinical and basic science implications of these reports, we undertook to study the effects of influenza vaccine on the metabolism of three commonly used drugs: chlordiazepoxide, theophylline, and lorazepam. Our healthy male subjects were studied just before and 1 and 7 days after vaccination. As expected, lorazepam metabolism, which proceeds by glucuronidation and not oxidation, was not altered by vaccination. Surprisingly, however, the oxidation of chlordiazepoxide was also not depressed by the vaccine. Theophylline oxidation, which proceeds primarily by microsomal oxidation (demethylation), was significantly decreased 1 day, but not 7 days, after vaccination. Serum alpha-interferon levels rose after vaccination for only about 8 hours, and levels of gamma-interferon rose to about 500 IU/ml at 24 hours, peaked at 72 hours, and returned to normal by 100 hours after dosing. It appeared that the higher the theophylline clearance before vaccination, the greater the degree of clearance depression after vaccination. Thus the inhibition of drug oxidation after influenza vaccination is selective and each drug should be studied individually. The degree of depression of theophylline clearance is small and transient and appears to be greater in subjects with higher prevaccination clearance.

Adult↗
PubMed1985

Lack of effect of nizatidine on hepatic drug metabolism in man.

The effect of nizatidine, a new H2-receptor antagonist, on the hepatic metabolism of three probe drugs was studied in normal volunteers. The drugs studied were chlordiazepoxide and theophylline which are metabolized in part by N-demethylation by the hepatic microsomal cytochrome P-450 system and lorazepam which is conjugated to lorazepam glucuronide. A 7 day course of nizatidine did not interfere with the disposition of any of these therapeutic agents in man.

Adult↗