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Biomedical subjects

L Shargel

Publications and source records attributed to L Shargel.

18 recordsLinked to original sources
PubMed1992

Distribution of etanidazole into human brain tumors: implications for treating high grade gliomas.

Etanidazole was developed as an oxygen-mimetic radiosensitizer less lipophilic than misonidazole. Sensitization depends on an adequate concentration of drug in the tumor at the time of irradiation. Therefore, due to the presence of the blood-brain barrier, brain tumors may theoretically be difficult to radiosensitize due to the hydrophilic characteristics of etanidazole. Based on previous reports of loss of BBB integrity in brain tumors, we investigated the ability of etanidazole to penetrate into malignant gliomas of patients receiving etanidazole as part of a Phase I continuous infusion protocol. The patients had completed previous external beam irradiation. Twenty-two patients were studied and their etanidazole plasma and biopsy data were compared to the 2-compartment model derived from a second group of 19 patients with bolus etanidazole. Etanidazole concentration in brain tumor biopsies varied widely and appeared to be clustered into a higher and a lower pharmacokinetic group having mean tumor to well-perfused second compartment ratios of 1 and 0.25, respectively. Both high and low etanidazole concentrations were evident in different biopsies obtained from the same patient. Correlations between histology and tissue concentrations suggested that the higher level correspond to malignant tissue. These data indicate that the blood brain barrier is disrupted to varying degrees by the brain tumor and/or prior irradiation and that etanidazole penetrates into brain tumors.

Brain Neoplasms↗
PubMed1990

Bioavailability and cardiovascular safety of Dexatrim (phenylpropanolamine hydrochloride) from a controlled-release caplet.

The bioavailability and pharmacokinetics of phenylpropanolamine hydrochloride (PPA HCl) from a Dexatrim controlled-release (CR) caplet and solution was studied. Each subject (n = 12) received either a 75 mg PPA HCl CR caplet once daily or a 25 mg PPA HCl solution given three times a day. All subjects received the medication for 4 consecutive days. On Day 1, the mean +/- SEM, AUC, tmax, and Cmax values were 1651 +/- 127 ng x h ml-1, 4.5 +/- 0.26 h and 143 +/- 13.5 ng ml-1, respectively, for the CR caplet and 1716 +/- 90.3 ng x h ml-1, 1.25 +/- 0.08 h and 126 +/- 5.8 ng ml-1 for the solution, respectively. At steady state (Day 4), the mean +/- SEM, AUC, tmax, and Cmax values were 1832 +/- 101 ng x h ml-1, 4.17 +/- 0.17 h and 151 +/- 6.5 ng ml-1, respectively, for the CR caplet and 2014 +/- 116 ng x h ml-1, 1.33 +/- 0.09 h and 143 +/- 8.7 ng ml-1, respectively, for the solution. The data from Day 1 were fitted to an oral one compartment model with a first order absorption rate constant, kA, first order elimination rate constant, k and lag time. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the CR caplet were 0.488 +/- 0.182 ng h ml-1, 5.84 +/- 1.66 h and 0.394 +/- 0.224 h, respectively. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the solution were 2.87 +/- 1.51 ng x h ml-1, 3.73 +/- 1.21 h, and 0.325 +/- 0.101 h, respectively. The smaller apparent kA and longer elimination half-life for PPA HCl from the CR caplet is due to the slow release of PPA HCl, thereby slowing its absorption producing sustained plasma drug concentrations. Blood pressures (supine and sitting) and heart rates measured at the time of blood sampling after the administration of the PPA HCl dosage forms demonstrated no clinically significant relationship between cardiovascular response and PPA HCl plasma concentration. These data demonstrate the bioavailability and pharmacokinetics of PPA HCl from a CR caplet and an immediate release solution.

Administration, Oral↗
PubMed1989

A simple and rapid liquid chromatographic method for the determination of major metabolites of sulfasalazine in biological fluids.

A simple and rapid assay for quantitation of sulfasalazine metabolites in rat urine and plasma was developed using high-performance liquid chromatography (HPLC). The method involves dilution of urine or plasma samples (0.1 mL) with methanol for protein precipitation, followed by mixing and centrifugation at 10,000 x g. Chromatography was accomplished with a reversed-phase ODS C-18 column (5 mu; 4.6 x 250 mm). The mobile phase consisted of 20% methanol in 5.0 mM phosphate buffer (pH 6.0), with 0.5 mM tetrabutylammonium chloride as an ion-pairing agent. The flow rate was 1.7 mL/min. An injection volume of 30 microL was used and the metabolites were quantitated by an ultraviolet detector at 254 nm. Benzamide was used as the internal standard. This method is linear in the range of 0.5 to 25 micrograms/mL for 5-aminosalicylic acid (5-ASA), acetylsulfapyridine (Ac-SP), and acetyl-5-aminosalicylic acid (Ac-5-ASA), and from 0.25 to 25 micrograms/mL for sulfapyridine (SP). The percent relative standard deviation ranged from 1 to 7.9% for the metabolite standard curves and precision studies. The limit of detection for 5-ASA, Ac-SP, and Ac-5-ASA is 100 ng/mL, and for SP is 50 ng/mL, in both urine and plasma. This method is rapid, precise, and accurate, and has been used to determine sulfasalazine metabolites in individual rat plasma and urine samples following an oral dose of 60 mg/kg of sulfasalazine.

Administration, Oral↗
PubMed1989

Pharmacokinetics of sulfasalazine metabolites in rats following concomitant oral administration of riboflavin.

Sulfasalazine, 60 mg/kg, was administered orally to groups of rats (n = 4) along with 1, 5, or 10 mg/kg of riboflavin. Plasma and urine were assayed for 5-aminosalicylic acid, acetyl-5-aminosalicylic acid, sulfapyridine, and acetyl-sulfapyridine using an HPLC method. The mean percent of dose recovered as total metabolites in urine was significantly greater (alpha = 0.01) for the group receiving 10 mg/kg riboflavin compared to the controls or the group receiving 1 mg/kg riboflavin. Plasma AUC and Cmax values were also significantly greater (alpha = 0.05) for the 10 mg/kg riboflavin group. These results suggest that at higher doses, a significant fraction of riboflavin reaches the colon intact and stimulates more efficient reduction of the azo bond in sulfasalazine. Since the concentrations of 5-ASA achieved in the colon may be directly related to the efficacy of sulfasalazine in treating inflammatory bowel disease, concomitant administration of riboflavin may enhance sulfasalazine's efficacy in humans.

Administration, Oral↗
PubMed1988

Cefamandole pharmacokinetics during standard and pulsatile cardiopulmonary bypass.

The pharmacokinetics of cefamandole during standard or pulsatile cardiopulmonary bypass were studied in 13 adult cardiac surgery patients. All patients received 20 mg/kg of cefamandole intravenously at midnight before surgery, 6 AM on the morning of surgery and just prior to the initiation of cardiopulmonary bypass (CPB) surgery. Serum, skeletal muscle, and fat samples were taken at the beginning of CPB and at 30-minute intervals thereafter and assayed for cefamandole concentration. The average elimination rate constant and elimination half-life for cefamandole in patients undergoing standard CPB were 0.73 +/- 0.09 hour-1 and 0.94 +/- 0.11 hour, respectively. In contrast patients undergoing pulsatile CPB had significantly slower elimination rate constants (0.50 +/- 0.1 hour-1 and 1.4 +/- 0.28 hours, respectively; P less than or equal to .05). Area under the curve (AUC) values for cefamandole in fat and muscle tissue were higher in patients undergoing pulsatile CPB, but the differences were not statistically significant. Prolonged elimination from the serum, skeletal muscle, and adipose tissue, as compared with normal subjects, is seen with both pulsatile and standard CPB but is greater for the pulsatile method. Intraoperative dosing of cefamandole is required to maintain adequate serum and tissue levels for operations lasting longer than 4 or 6 hours in which standard or pulsatile CPB, respectively, are used.

Adipose Tissue↗
PubMed1988

Comparison of excretion of nicotinuric acid after ingestion of two controlled release nicotinic acid preparations in man.

We tested an inexpensive controlled-release nicotinic acid product (Bronson Pharmaceuticals, LaCanada, CA) and compared it with the standard, more expensive, controlled release product, Nicobid (Rorer Pharmaceuticals), by measuring the 24 hour urinary recovery of nicotinic and nicotinuric acids from ten subjects following 500 mg oral ingestion of each product. Nicotinuric acid is the major detoxification product of nicotinic acid and may serve as a simple quantitative index of hepatic biotransformation of nicotinic acid. Although both products demonstrated controlled release profiles, the rate of appearance of nicotinic and nicotinuric acid in the urine as well as the rate of in vitro drug dissolution of the Bronson product were more rapid compared with Nicobid. Moreover, the total amounts of nicotinic acid and nicotinuric acid recovered in the urine after 24 hours were greater for the Bronson product (P less than .05). Since sustained presentation of nicotinic acid to the liver may correlate with clinical antihyperlipidemic effects, our results suggest that the Bronson product may prove to be a clinically useful preparation.

Adult↗
PubMed1986

Conversion from intravenous to sustained-release oral theophylline in pediatric patients with asthma.

A method for converting pediatric patients from intravenous aminophylline to sustained-release oral theophylline was evaluated in eight asthmatic children. The administration of Theo-Dur tablets two hours before discontinuation of a continuous intravenous aminophylline infusion resulted in a peak rise of 5.6 +/- 3.0 micrograms/ml over steady-state serum theophylline concentrations. This method of conversion is acceptable in children with equivalent oral and intravenous doses of theophylline and serum theophylline concentrations less than 15 micrograms/ml. Children with steady-state theophylline concentrations greater than 15 micrograms/ml are likely to develop concentrations exceeding the therapeutic range using this conversion method.

Adolescent↗
PubMed1985

Effect of phenobarbital pretreatment on the plasma and urinary levels of (-)-alpha-acetylmethadol and its metabolites.

The effect of phenobarbital (PB), an inducer of the hepatic microsomal enzyme system, on the plasma levels and urinary elimination of (-)-alpha-acetylmethadol 1 and its metabolites have been examined in the rat. [3H]1 was administered to saline control and PB-pretreated rats at doses of 5 mg/kg ip (55 muCi/kg). The concentration of 1 and its metabolites noracetylmethadol 2, dinoracetylmethadol 3, methadol 4, normethadol 5, and N-acetylnormethadol 6 were quantitated in plasma and urine over 48 h by TLC and liquid scintillation counting. PB pretreatment significantly decreased the plasma total radioactivity and the levels of 1 and its five metabolites over the 48-h period investigated. Urinary total radioactivity and elimination of 1 and its five metabolites were also reduced in PB-pretreated rats. The results indicated that PB pretreatment markedly affects the in vivo transformation and elimination of 1 and its metabolites. The decrease in the levels observed for 1 and its metabolites in the plasma and urine can be due either to an increase in the metabolism of 1 via a different pathway than the formation of the biologically active metabolites 2, 3, 4, and 5, or it may be that PB is enhancing the further metabolism of these compounds to more polar water-soluble products which are mainly excreted through the bile.

Animals↗
PubMed1979

High-pressure liquid chromatographic analysis of antipyrine in small plasma samples.

A high-pressure liquid chromatographic (HPLC) method was developed for the assay of antipyrine in small (0.1-ml) plasma samples using aminopyrine as the internal standard and a reversed-phase microparticulate column. The assay sensitivity (1 microgram/ml) permits development of a plasma level--time curve using a single rat. The mean (+/- SE) plasma elmination half-life in rats was 1.28 +/- 0.14 hr. A comparison of the spectrophotometric method with the HPLC method yielded a correlation coefficient of 0.98. The HPLC assay for antipyrine is rapid and precise and can be used for hepatic drug metabolism study in a single animal.

Animals↗
PubMed1976

Rapid procedure for assessment of compounds that modify uptake and release of tritiated norepinephrine.

A rapid procedure to estimate tritiated norepinephrine (levarterenol) in a single mouse heart is described. The method is based upon oxidation of the tritium in the tissue to tritiated water, which is then determined by liquid scintillation spectroscopy. Large numbers of samples can be assayed with great facility. The effects of standard compounds that modify the uptake and release of 3H-norepinephrine in heart tissue were determined with this system, and a procedure for studying their interactions is described.

Animals↗
PubMed1975

Cardiovascular effects and blood concentrations of ajmaline and its 17-monochloroacetate ester in cats.

The antiarrhythmic drugs ajmaline and its 17-monochloroacetate ester (MCAA; Rtimos-Elle) were studied in cats. MCAA was less than half as toxic as ajmaline. Non-lethal doses of MCAA decreased blood pressure before heart rate, whereas ajmaline initially decreased heart rate. Both drugs prolonged the PR, QRS and QT intervals of the EKG. Recovery of these effects was within one hr. MCAA (10 mg/kg) and ajmaline (4.05 mg/kg) were studied separately by a one and 10 min infusion in the same cat. The dose of MCAA was ten times the usual dose in man and that of ajmaline four times the usual clinical dose. More marked effects were observed with the one min infusion. Arrhythmias were usually observed with ajmaline, but not with MCAA, even though it was rapidly converted to ajmaline. Maximal cardiovascular effects of MCAA and ajmaline were observed within 3 min of the end of infusion, which was also the time of peak blood levels. The elimination of MCAA resembled the kinetics of a multi-compartment system after a one min infusion. Peak blood levels declined by one-half in 3 min. Ajmaline blood levels declined linearly, with a half-life of 100 min, after a one min infusion. The peak blood level of MCAA after an intraduodenal dose of 25 mg/kg occurred at 20 min, whereas the peak blood level of the ajmaline formed occurred at 4 hr. In conclusion, MCAA has some different pharmacological properties and different kinetics of elimination than ajmaline.

Acetates↗
PubMedDate not supplied

Effect of cimetidine or ranitidine pretreatment on hepatic mixed function oxidase activity in the rat.

This study compared the effect of single equimolar oral doses of cimetidine (100 mg/kg) or ranitidine (139 mg/kg) on rat hepatic mixed function oxidases. Cimetidine significantly (p less than 0.05) increased hexobarbital sleeping time and prolonged aminopyrine and theophylline elimination. In contrast, ranitidine did not significantly affect hexobarbital sleeping time and theophylline elimination but significantly (p less than 0.025) increased aminopyrine elimination. Aminopyrine N-demethylase activity in vitro was significantly (p less than 0.05) inhibited by cimetidine pretreatment but significantly (p less than 0.025) increased by ranitidine pretreatment. The direct addition of cimetidine or SKF 525A to the 10,000g supernatant fraction from controlled liver homogenates decreased aminopyrine N-demethylase activity, whereas the direct addition of ranitidine tended to increase aminopyrine N-demethylase activity. A significant correlation (r = 0.65, p less than or equal to 0.005) was observed between hexobarbital sleeping time in vivo and aminopyrine N-demethylase activity in vitro in the same rat. The results of this study showed that cimetidine inhibited mixed function oxidases, whereas ranitidine had no effect or tended to stimulate mixed function oxidases.

Aminopyrine↗
PubMedDate not supplied

Physiological disposition and metabolism of N-t-butylarterenol and its di-p-toluate ester (bitolterol) in the rat.

The metabolism and disposition of the bronchodilator, N-t-butylarterenol (tBA) and its di-p-toluate ester (bitolterol) were compared in the rat. Radioactivity was preferentially retained in lungs of rats compared with heart and blood after iv medication with tritium-labeled bitolterol, but was not retained in tissues after iv medication with [3H]tBA. After oral and iv medication with [3H]bitolterol, fecal radioactivity accounted for 24% of the dose and 65 and 79% of the radioactivity, respectively, was excreted in urine (0-72 hr). In comparison, urine radioactivity after oral and iv medication with [3H]tBA was 43 and 83% of the dose, respectively, and fecal radioactivity accounted for 43 or 23% of the dose, respectively (0-72 hr). Bitolterol was hydrolyzed in vitro to tBA by esterases found in various tissues including small intestine, liver, and plasma. Moreover, tBA was a substrate for catecholamine O-methyltransferase but not for monoamine oxidase. Similar metabolites were observed in urine samples of rats given either [3H]tBA or [3H]bitolterol. Urine metabolites were identified as free and conjugated forms of both tBA and 3-O-methyl-tBA.

Animals↗
PubMedDate not supplied

Physiological disposition and metabolism of (3H)bitolterol in man and dog.

The metabolism and disposition of bitolterol, the di-p-toluate ester of N-t-butylarterenol (tBA) was studied in man after a single oral dose and in dog after intraduodenal, iv, or oral administration. The mean (+/- SE) peak plasma radioactivity in man (dose, 70 mug/kg) was 180 +/- 18 ng equivalents of [3H]bitolterol per ml or approximately 11% of the dose, whereas peak plasma radioactivity in dog (dose, 200 mug/kg) was 144 +/- 23 ng equivalents per ml or approximately 4% of the dose. For both man and dog, the time for maximum plasma level of radioactivity varied from 0.5 to 2 hr. In man, only 1% of the plasma radioactivity represented intact [3H]bitolterol 1.0 hr after medication. In the dog, radioactivity was concentrated in lung tissue after iv administration of [3H]bitolterol. Recovery of intact [3H]bitolterol in lung at 4.5 hr ranged from 26 to 46% of total tissue radioactivity after iv dosage and from 4 to 14% total tissue radioactivity after intraduodenal administration. Radioactivity recovered in human urine and feces (0-72 hr) accounted for 86 and 8.1% of the dose, respectively. Recovery of radioactivity in dog urine and feces accounted for 58 and 23% of the dose, respectively, in the same time period. Radiochromatograms of urine samples from man and dog revealed similar patterns of metabolites including free and conjugated forms of both tBA and the 3-O-methyl metabolite, N-t-butylmetarterenol. The major radioactive components of the feces were bitolterol and tBA. The results indicate that bitolterol is absorbed orally and retained as the intact ester in lung. The prolonged bronchodilator activity of bitolterol is due to the slow release of the ester from lung and hydrolysis to tBA, an active beta2-adrenoceptor agonist. Pharmacological activity is terminated by metabolism of tBA via conjugation or 3-O-methylation.

Animals↗