Biomedical subjects

D D Shen

Publications and source records attributed to D D Shen.

At least 73 records · Page 4Linked to original sources

PubMed1993

Insulin resistance, glucose intolerance, and hyperinsulinemia. Hypertriglyceridemia versus hypercholesterolemia.

Plasma glucose and insulin responses to oral glucose and mixed meals and the ability of insulin to stimulate glucose disposal were quantified in normal volunteer subjects and patients with types IIA, IIB, and IV hyperlipoproteinemia (HLP). The results indicated that patients with either type IIB or IV HLP had higher plasma glucose (p < 0.05-< 0.001) and insulin (p < 0.001) responses to both oral glucose and mixed meals compared with the normal subjects and patients with type IIA HLP. Steady-state plasma glucose concentrations (mmol/L) were also higher (p < 0.001) in patients with types IIB (13.3 +/- 0.6) and IV (12.8 +/- 1.2) HLP during a continuous infusion of somatostatin, glucose, and insulin than either the control group (volunteer subjects) (6.2 +/- 0.9) or patients with type IIA HLP (5.6 +/- 1.0). Because the steady-state plasma insulin concentrations were similar in all four groups, patients with either type IIB or IV HLP were resistant to insulin-mediated glucose uptake. These data indicate that patients with hypertriglyceridemia are insulin resistant, glucose intolerant, and hyperinsulinemic, irrespective of the plasma cholesterol concentration. The results further demonstrate that hypercholesterolemic patients with normal triglyceride concentrations do not have any abnormalities of glucose and insulin metabolism.

Adult↗

PubMed1992

Comparative anticonvulsant potency and pharmacokinetics of (+)-and (-)-enantiomers of stiripentol.

The anticonvulsant potency and pharmacokinetics of the enantiomers of stiripentol were compared using the intravenous pentylenetetrazol infusion seizure model in the rat. Enantioselectivity was observed with respect to both the anticonvulsant activity and elimination kinetics of this compound. (+)-Stiripentol was 2.4 times more potent than its antipode against pentylenetetrazol-induced clonic seizure (brain EC50 of 15.2 micrograms/ml versus 36.1 micrograms/ml). The (+)-enantiomer was eliminated more rapidly than the (-)-enantiomer, as reflected in a higher plasma clearance (1.64 l/h/kg versus 0.557 l/h/kg) and a shorter half-life (2.83 h versus 6.50 h). Parallel studies with the racemate of stiripentol indicated that the anticonvulsant potency of the racemate was between the potency of the two enantiomers, suggesting that the combined activity reflects the additive action of (+)- and (-)-stiripentol. However, a marked metabolic interaction between enantiomers was evident after racemate administration. These results point to the need for information on the differential pharmacokinetics of stiripentol enantiomers following racemic drug administration.

Animals↗

PubMed1992

Insulin resistance and abnormal electrocardiograms in patients with high blood pressure.

Plasma glucose and insulin responses to an oral glucose challenge and fasting plasma lipid and lipoprotein concentration were compared in 25 normal individuals and 53 patients with high blood pressure. Patients with hypertension were further subdivided into two groups--normal electrocardiogram (EKG) (n = 24) or abnormal EKG (n = 29)--using the Minnesota code criteria. Patients with hypertension and an abnormal EKG had significantly higher plasma glucose and insulin concentrations following oral glucose than did the control population. Furthermore, plasma triglyceride (TG) concentration was higher and high density lipoprotein cholesterol concentration lower then normal in hypertensive patients with an abnormal EKG, and the ratio of total to HDL cholesterol was higher in this subgroup. Values for patients with high blood pressure and a normal EKG were intermediate. Insulin-mediated glucose uptake was also measured in a subset of patients with hypertension and either a normal (n = 18) or abnormal (n = 17) EKG. When these two subgroups were compared, those with high blood pressure and an abnormal EKG were significantly more insulin resistant than patients with hypertension and a normal EKG. In addition, they also had higher plasma glucose and insulin responses to oral glucose, higher fasting plasma triglyceride and cholesterol concentrations, and an increase in the ratio of total to HDL cholesterol. Thus, patients with high blood pressure have abnormalities of glucose, insulin, and lipid metabolism when compared to a nonhypertensive control group, and the magnitude of these metabolic defects is significantly greater in patients with high blood pressure who have EKG evidence of coronary heart disease.

Administration, Oral↗

PubMed1992

Improvement in metabolic risk factors for coronary heart disease associated with cilazapril treatment.

Patients with hypertension tend to be glucose intolerant, hyperinsulinemic, and dyslipedemic. Since all of these changes increase risk of coronary heart disease (CHD), it is important to know what effect antihypertensive treatment has on these variables. The current open-labelled, uncontrolled study was initiated in order to extend our understanding of these issues. This study was performed in 19 patients with hypertension who were started on an angiotensin converting enzyme (ACE)-inhibitor, cilazapril, with hydrochlorothiazide (HC) added if needed to control blood pressure. Plasma glucose and insulin responses to oral glucose and lipid concentrations were measured before, 26, and 52 weeks after starting treatment. Patients treated with either cilazapril (n = 9) or cilazapril+HC (n = 10) did not differ in terms of original (mean +/- SEM) blood pressure (159 +/- 5/101 +/- 1 v 156 +/- 4/103 +/- 2 mm Hg), age (53 +/- 2 v 54 +/- 2 years), sex distribution (5M:4F v 7M:3F), or body mass index (24.4 +/- 0.5 v 24.2 +/- 0.9 kg/m2). Blood pressure was also similar after 26 (137 +/- 4/88 +/- 1 v 133 +/- 3/90 +/- 1 mm Hg) and 52 (137 +/- 4/87 +/- 1 v 134 +/- 4/89 +/- 2 mm Hg) weeks of treatment. Plasma glucose and insulin responses decreased by 8 +/- 3% (P less than .05) and 25 +/- 9% (P less than .002), respectively, in cilazapril-treated patients, but did not change in those treated with cilazapril plus HC.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1992

Low and variable presence of valproic acid in human brain.

We studied the distribution of valproic acid (VPA) between brain (gray matter) and serum in 13 patients receiving chronic VPA therapy who underwent cortical resections for intractable seizures. Valproate concentration in cerebral cortex was remarkably low compared with either total or unbound valproate concentration in serum. The respective brain-to-serum partition ratios based on total and free drug in serum were 0.111 +/- 0.051 and 0.544 +/- 0.175. In comparison with other commonly used antiepileptic drugs, valproate has the distinction of exhibiting the lowest brain-to-blood partitioning. Moreover, the brain-to-serum concentration ratio varied over a four-fold range between patients. Some of this variability was related to variation in serum protein binding, as indicated by a modest correlation between the partition ratio and serum free fraction (r = +0.687). However, the brain-to-unbound concentration ratio still showed a three-fold variation. The variability in distribution of VPA between brain and blood is probably one of the underlying factors for the lack of a clearly definable therapeutic range of serum VPA concentration in epileptic patient populations.

Adolescent↗

PubMed1991

Effect of serum protein binding on the entry of lidocaine into brain and cerebrospinal fluid in dogs.

To test the hypothesis that lidocaine passage into the central nervous system is a function of free rather than total lidocaine concentration, we examined the effect of serum protein binding on the distribution of lidocaine into brain and cerebrospinal fluid (CSF) in dogs. Six of the 13 dogs studied were pretreated with rifampin to induce a 4-fold increase (P = 0.019) in serum concentration of alpha 1-acid glycoprotein, which is a major binding protein for lidocaine. The dogs were anesthetized and prepared surgically to obtain samples of cortical brain tissue or CSF from the cisterna magna. Lidocaine at a dose of 3 mg/kg was infused intravenously over 15 s. Arterial blood and brain cortex or CSF were sampled serially during a 60-min interval and analyzed for lidocaine content. Unbound or free fraction of lidocaine in serum was measured by equilibrium dialysis. Rifampin pretreatment led to a significant decrease in average serum free fraction of lidocaine, from 0.24 +/- 0.08 to 0.080 +/- 0.030 (P less than 0.001). Total lidocaine concentration in serum was higher, but free lidocaine concentration was lower in the rifampin group. Equilibration of lidocaine between serum and brain or CSF was reached by 10 min after lidocaine administration. Rifampin-pretreated dogs had consistently lower partition ratios of lidocaine between brain and serum or between CSF and serum. A strong and positive correlation between time-averaged brain to serum or CSF to serum ratios and serum free fractions were observed (r = 0.92, P less than 0.001 for brain; r = 0.90, P less than 0.01 for CSF).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Nonlinear binding of valproic acid (VPA) and E-delta 2-valproic acid to rat plasma proteins.

The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-delta 2-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-delta 2-VPA than with VPA (10(4)-10(6) versus 10(3) M-1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-delta 2-VPA compared with VPA (much less than 10 versus greater than 20% at total concentrations of less than 100 micrograms/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin.

Animals↗

PubMed1989

Stereoselective high-performance liquid chromatographic assay for propranolol enantiomers in serum.

A simple and sensitive stereoselective high-performance liquid chromatographic assay for the quantitation of propranolol enantiomers in serum is described. The method involves conversion of the propranolol enantiomers to diastereomeric urea derivatives by reaction with the clinical reagent (+)-phenylethylisocyanate, followed by chromatographic separation of the diastereomeric products. Conditions of the derivatization reaction were optimized to achieve rapid and quantitative yield with either of the enantiomers. Baseline resolution of the diastereomers was achieved on a reversed phase C8 column with an isocratic mobile phase. Fluorescence detection afforded an absolute on-column detection limit of 100 pg. The assay has been applied to pharmacokinetic studies in humans and small laboratory animals.

Animals↗

PubMed1989

Contribution of metabolites to the route- and time-dependent hepatic effects of di-(2-ethylhexyl)phthalate in the rat.

The effects of exposure to the plasticizer di-(2-ethyl-hexyl)phthalate (DEHP) and its two primary products of presystemic de-esterification, mono-(2-ethylhexyl)phthalate and 2-ethyl-hexanol, on hepatic microsomal oxidation were investigated in rats. The metabolic clearance of antipyrine was utilized as an in vivo measure of the activity of the hepatic microsomal oxidative enzyme system. Subchronic (7 days) p.o. treatment of rats with DEHP, mono-(2-ethylhexyl)phthalate or 2-ethylhexanol produced a substantial increase in both wet liver weight and antipyrine clearance relative to corn oil-treated controls. In contrast, i.p. administration of DEHP resulted in a minor but statistically significant stimulation of liver growth and antipyrine metabolism. Whereas chronic administration of the plasticizer or its metabolites produced apparent induction of hepatic microsomal oxidative enzymes, administration of a single dose of each compound was associated with immediate inhibition of the metabolism of antipyrine. The present data suggest that the products of deesterification of DEHP are primarily responsible for the stimulation of hepatic metabolism observed after long-term exposure to the plasticizer, whereas the parent compound and both metabolites have the potential to produce acute inhibition of hepatic microsomal oxidation in vivo.

Animals↗

PubMed1988

Capillary gas chromatographic assay for valproic acid and its 2-desaturated metabolite in brain and plasma.

A capillary gas chromatographic method has been developed for quantitating the antiepileptic drug valproic acid and its pharmacologically active metabolite, E-delta 2-valproic acid, in brain and plasma. The method was designed to cover large concentration ranges of both valproic acid and E-delta 2-valproic acid for pharmacokinetic and pharmacodynamic studies in laboratory animals and human subjects. Careful optimization of the extraction and chromatographic procedures was needed to resolve the analytes from a variety of endogenous constituents and other known metabolites of valproic acid. A sensitivity limit of 0.10 micrograms/g for 300 mg of brain tissue or 0.20 micrograms/ml for 150 microliters of plasma was achieved using flame ionization detection. The within-batch coefficients of variation for both analytes were less than 8%. Reproducible calibration data were observed over a period of three to eleven months.

Animals↗

PubMed1988

Alteration in the disposition and metabolism of S(-)-propranolol in rats with active respiratory viral infection.

Viral illness elicited marked changes in the disposition and metabolism of S(-)-propranolol in rats during the course of a recent viral outbreak in our rodent colony. A slower rate of gastrointestinal absorption and a much higher clearance of orally-administered S(-)-propranolol were observed. The apparent increase in metabolic clearance is partly attributed to a decrease in the serum protein binding of S(-)-propranolol. A direct stimulation of microsomal oxidative metabolism was also suggested by an increase in urinary recovery of the monohydroxyl metabolites of S(-)-propranolol. In addition, a greater portion of the phenolic metabolites were present in urine as the glucuronic acid conjugates, which may be explained by a concomitant stimulation in conjugative reaction. These observations are unusual in that existing reports indicate that viral illness in man and animals generally leads to an inhibition of oxidative drug metabolism.

Administration, Oral↗

PubMed1987

Versatile isocratic high-performance liquid chromatographic assay for propranolol and its basic, neutral and acidic metabolites in biological fluids.

A comprehensive high-performance liquid chromatographic method was developed for quantitating propranolol and its known metabolites in serum, bile and urine. Analysis was performed before and after incubation of the samples with beta-glucuronidase-arylsulfatase to quantitate both free and conjugate forms of the oxidative metabolites. Fractionation of the basic, neutral and acidic metabolites was achieved by differential pH solvent extraction. The basic and neutral metabolites were extracted from the biological samples at pH 10.5 with 2% n-butanol in dichloromethane. Additional clean-up of the basic fraction by back-extraction into dilute acid was needed for those samples that were subjected to enzymatic hydrolysis. The original aqueous sample was titrated with acid to pH 1, followed by extraction of the remaining acidic metabolites into either n-butanol-dichloromethane (with unhydrolyzed serum) or carbon tetrachloride (with all other samples). Chromatographic separation of the metabolites in the different extracts was achieved on a reversed-phase C18 column, using a single isocratic mobile phase consisting of 0.044 M pH 2.7 phosphate buffer, tetrahydrofuran, methanol and acetonitrile, with the addition of n-butylamine as a competing base to control retention volume and peak shape. Detection and quantitation of propranolol and its metabolites in the low nanogram to sub-nanogram range was afforded by fluorescence at a low UV excitation wavelength. The coefficients of variation for replicate assay of spiked samples were uniformly less than 6% for all the analytes.

Animals↗

PubMed1987

Altered S(--)-propranolol disposition in bilateral ureter-ligated rats.

Previous clinical studies indicate that the metabolic clearance of oral (+/-)-propranolol is reduced in end-stage renal failure patients. Animal models are needed to explore the mechanism(s) underlying the observed metabolic inhibition in man. The disposition kinetics of S(-)-propranolol were characterized after intravenous and peroral administration in rats with acute renal failure induced by bilateral ureteral ligation (BUL). No alteration in either the systemic clearance or the apparent volumes of distribution of S(-)-propranolol was observed in renal failure animals after a single intravenous dose of 1.5 mg/kg. In contrast, acute uremia did elicit a change in the bioavailability of orally administered S(-)-propranolol. At 36 h after ureteral ligation, the area under the serum concentration-time curve after a 6 mg/kg oral dose of S(-)-propranolol was significantly elevated in renal failure animals, which corresponded to an approximate two fold increase in its systemic availability (from 7.7 to 20.5%). Such an effect could not be demonstrated at times earlier than 36 h after ureteral ligation. Additional experiments were performed to evaluate whether concomitant changes in gastrointestinal absorption or serum protein binding of S(-)-propranolol could have contributed to the apparent increase in oral availability. The results lead to the hypothesis of an inhibited first-pass hepatic metabolism of S(-)-propranolol in acute renal failure and suggest a significant time delay in the onset of inhibition.

Acute Kidney Injury↗

PubMed1985

Effects of route of administration and repetitive dosing on the disposition kinetics of di(2-ethylhexyl) phthalate and its mono-de-esterified metabolite in rats.

The disposition kinetics of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and its biologically active metabolite mono(2-ethylhexyl) phthalate (MEHP) were studied in rats following single or multiple administration of DEHP by various routes. Following a single intraarterial (ia) injection, a large apparent volume of distribution (5390 ml/kg) and a high rate of clearance (21.5 ml/min/kg) were observed for DEHP. The systemic availability of DEHP was low following both single po (13.6%) and ip (5.2%) administration. A marked route-dependency in the formation of MEHP from DEHP was observed. The circulating concentrations of MEHP were substantially higher than those of DEHP (i.e., area under the blood concentration-time curve (AUC) ratio of approximately 7) after po administration, whereas concentrations of the mono-de-esterified metabolite were much lower relative to the parent diester concentration after ia or ip administration (i.e., AUC ratio less than 0.4). Pharmacokinetic calculations revealed that approximately 80% of a po dose of DEHP undergoes mono-de-esterification, as compared to only about 1% of the dose following either ia or ip administration. Hence, the low po systemic availability of DEHP may be largely attributed to presystemic hydrolysis of DEHP to MEHP in the gut, whereas slow and/or incomplete absorption is the likely cause of the poor bioavailability of DEHP after ip administration. No significant accumulation in the circulating concentrations of DEHP or derived MEHP were observed following 7 days of repetitive administration of DEHP. However, multiple ip injections resulted in an apparent decrease in the rate and/or extent of DEHP absorption from the peritoneal cavity, while no significant change in the po absorption of the diester was observed. The striking difference in the MEHP to DEHP AUC ratio between po and ip routes was still evident after multiple dosing. These data suggest that previously reported differences in the biologic effects of DEHP in rodents following different routes of administration may be due to route dependency in the mono-de-esterification of the diester.

Administration, Oral↗

PubMed1985

Circulating concentrations of di(2-ethylhexyl) phthalate and its de-esterified phthalic acid products following plasticizer exposure in patients receiving hemodialysis.

The degree of exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) was assessed in 11 patients undergoing maintenance hemodialysis for the treatment of renal failure. The amount of DEHP leached from the dialyzer during a 4-hr dialysis session was estimated by monitoring the DEHP blood concentration gradient across the dialyzer. Circulating concentrations of the biologically active products of DEHP de-esterification, viz., mono(2-ethylhexyl) phthalate (MEHP) and phthalic acid, were also determined during the dialysis session. On the average, an estimated 105 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 23.8 to 360 mg. The rate of extraction of DEHP from the dialyzer was correlated with serum lipid content as expressed by the sum of serum cholesterol and triglyceride concentrations (r = +0.65, p less than 0.05). Time-averaged circulating concentrations of MEHP during dialysis (1.33 +/- 0.58 micrograms/ml) were similar to those of DEHP (1.91 +/- 2.11 micrograms/ml). Blood concentrations of phthalic acid (5.22 +/- 3.94 micrograms/ml) were higher than those of the esters. The length of time patients had been receiving regular dialysis treatment was not a determinant of circulating concentrations of DEHP or MEHP. In contrast, time-averaged circulating concentrations of phthalic acid correlated strongly with the duration (in years) of dialysis treatment (r = +0.92, p less than 0.001). The results indicated substantial exposure to DEHP during hemodialysis and that the de-esterified products of DEHP are present in significant concentrations in the systemic circulation. Further study is needed to assess the contribution of these metabolites to the biological actions of DEHP in man.

Adult↗

PubMed1985

A timed intravenous pentylenetetrazol infusion seizure model for quantitating the anticonvulsant effect of valproic acid in the rat.

A convulsive seizure model that utilizes timed intravenous infusions of pentylenetetrazol (PTZ) was developed to quantitate the magnitude of anticonvulsant effect in individual rats. PTZ was infused through an indwelling jugular vein catheter, and the threshold dose of PTZ was calculated from the time needed to produce clonic convulsions, the body weight of the animal, and the rate of infusion of the convulsant. The threshold dose of PTZ was determined in all animals 48 hr before and 15 min after anticonvulsant treatment. From theoretical considerations, the magnitude of anticonvulsant effect was defined as the logarithm of the posttreatment to pretreatment PTZ threshold dose ratio (log DR). The PTZ threshold was found to be insensitive to the rate of PTZ infusion and the body weight of the animal. Furthermore, the PTZ pretest did not influence the results of the posttest in animals treated with saline, and the interanimal variability in the PTZ threshold was found to be low (coefficient of variation of 12.2%). The PTZ infusion model was tested in a preliminary dose-response study of the anticonvulsant valproic acid (VPA). The ED50 for VPA determined with PTZ infusion technique (76.1 +/- 9.0 mg/kg) was in good agreement with a previous study that used the classical subcutaneous PTZ test. Since anticonvulsant effect is measured in individual, as opposed to groups, of animals, the PTZ infusion procedure may offer distinct advantages in the study of the pharmacodynamics of anticonvulsant compounds.

Animals↗

PubMed1985

Reduced extraction of I-propranolol by perfused rat liver in the presence of uremic blood.

Previous in vivo studies have shown that the presystemic clearance of p.o.-administered levo-isomer of propranolol is inhibited in rats with uranyl nitrate-induced acute renal failure. A series of steady-state single-pass rat liver perfusion studies were performed to explore the probable mechanism of the observed metabolic inhibition. When livers from normal rats were perfused with blood perfusate prepared from normal donor animals, a high extraction ratio (Eh) of 0.974 +/- 0.005 (mean +/- S.D.) was observed at an influent I-propranolol concentration of 400 ng/ml, i.e., only 2.6% of drug entering the liver escaped single-pass extraction. The extraction of I-propranolol was significantly lower (i.e., Eh = 0.906 +/- 0.017) when livers isolated from uranyl nitrate-induced renal failure rats were perfused with uremic blood; such that there was an approximate 3-fold increase in the amount of drug escaping single-pass extraction (i.e., from 2.6 to 9.4%). This difference in hepatic extraction is quantitatively consistent with the increase in p.o. systemic availability of I-propranolol observed in our previous in vivo study with the uranyl nitrate-induced renal failure rat model. When livers from normal rats were cross-perfused with uremic blood, extraction of I-propranolol was depressed to almost the same level (i.e., Eh = 0.927 +/- 0.009) as when livers from renal failure animals were perfused with uremic blood. In contrast, livers from renal failure rats cross-perfused with normal blood exhibited comparable extraction for I-propranolol (Eh = 0.970 +/- 0.010) as normal livers perfused with normal blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

PubMed1984

High-performance liquid chromatographic procedure for the determination of di-(2-ethylhexyl)phthalate in human blood specimens. Problems of variable-extraction yield and the use of standard addition for calibration.

A high-performance liquid chromatographic procedure was developed for the determination of di-(2-ethylhexyl)phthalate (DEHP) concentrations in human whole blood samples. The solvent extraction of DEHP was found to be highly variable between samples obtained from different subjects (coefficient of variation of 30.4%). The recovery of DEHP following extraction with ethyl acetate was negatively correlated with serum lipid content, as expressed by the sum of serum cholesterol and triglyceride concentrations (r = -0.864). The technique of standard addition of DEHP allowed a single-point calibration of DEHP extractability in individual blood samples, and provided an accurate estimation of DEHP concentration (coefficient of variation of approximately 6% in replicate samples). The potential for intersample variability in the solvent extraction of other highly lipid-soluble compounds should be considered.

Chromatography, High Pressure Liquid↗