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Biomedical subjects

M W Lo

Publications and source records attributed to M W Lo.

35 records · Page 2Linked to original sources
PubMed1995

Effects of cimetidine on pharmacokinetics and pharmacodynamics of losartan, an AT1-selective non-peptide angiotensin II receptor antagonist.

This was a 2-period randomized, crossover study in 8 healthy males to determine the effects of cimetidine (400 mg q.i.d. for 6 days) on the pharmacokinetics and pharmacodynamic effects of the angiotensin II receptor antagonist, losartan (100 mg). Cimetidine increased the AUC for losartan 18% without affecting the AUC for E-3174, the active metabolite of losartan. The increase in plasma renin activity following losartan was not affected by cimetidine (maximum mean increases 12.6 and 12.1 ng Ang I.ml-1.h-1 without and with cimetidine, respectively). These results indicate that cimetidine does not appear to alter the pharmacokinetics or pharmacodynamics of losartan to a clinically significant extent.

Adult↗
PubMed1995

Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans.

The pharmacokinetics of the angiotensin II receptor antagonist losartan potassium and its active carboxylic acid metabolite EXP3174 were characterized in 18 healthy male subjects after administration of intravenous losartan, intravenous EXP3174, and oral losartan. In these subjects, the average plasma clearance of losartan was 610 ml/min, and the volume of distribution was 34 L. Renal clearance (70 ml/min) accounted for 12% of plasma clearance. Terminal half-life was 2.1 hours. In contrast, the average plasma clearance of EXP3174 was 47 ml/min, and its volume of distribution was 10 L. Renal clearance was 26 ml/min, which accounted for 55% of plasma clearance; terminal half-life was 6.3 hours. After oral administration of losartan, peak concentrations of losartan were reached in 1 hour. Peak concentrations of EXP3174 were reached in 3 1/2 hours. The area under the plasma concentration-time curve of EXP3174 was about four times that of losartan. The oral bioavailability of losartan tablets was 33%. The low bioavailability was mainly attributable to first-pass metabolism. After intravenous or oral administration of losartan the conversion of losartan to the metabolite EXP3174 was 14%.

Administration, Oral↗
PubMed1993

Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers.

Losartan is an orally active, nonpeptide angiotensin II (Ang II) (site-1) receptor antagonist. We conducted a multiple-dose study in healthy male volunteers to investigate the tolerability, blood pressure effects, and changes in plasma renin activity (PRA) and plasma Ang II concentration associated with once-daily administration of 100 mg losartan for a week. Subjects were studied on a standardized sodium diet (24-hour urinary sodium excretion, 98 +/- 37 [SD] mEq per 24 hours on the placebo run-in day). Measurements of blood pressure, heart rate, PRA, Ang II, and aldosterone were taken during a placebo run-in day and after single and multiple (7 days) daily doses of losartan (100 mg, n = 10) or placebo (n = 4). Ang II was measured specifically by high performance liquid chromatography coupled with radioimmunoassay. In subjects given losartan, respective decreases (systolic/diastolic) from run-in in supine blood pressure 6 hours after dosing were (mean +/- SD), compared with the placebo run-in day, first dose: -8.8 +/- 9.6/-6.8 +/- 5.0, last dose: -11.6 +/- 8.9/-7.0 +/- 4.8 mm Hg (p < 0.05 for all changes). At this 6-hour time point, corresponding increases from run-in in PRA were from 1.2 +/- 0.6 to 12.0 +/- 6.3 (first dose) and 9.6 +/- 4.9 (last dose) ng angiotensin I per milliliter per hour and in Ang II were from 4.3 +/- 1.7 to 72.4 +/- 33.3 and 45.7 +/- 14.1 pg/mL. All changes in PRA and Ang II were statistically significant within the losartan-treated group, and the biochemical changes were significantly greater than those in the placebo-treated group. The increment in Ang II was less after the last dose than after the first (p < 0.05). The drug was well tolerated by all subjects. These data indicate that, under the conditions of this study, losartan administration (100 mg/day for eight doses over 9 days) results in treatment-related decreases in blood pressure and increases in PRA and Ang II octapeptide.

Adolescent↗
PubMed1992

Determination of remoxipride in human plasma and urine by reversed-phase ion-pair high-performance liquid chromatography.

A sensitive method is described for the measurement of remoxipride in human plasma and urine. Remoxipride and its internal standard are extracted from plasma or urine at pH 12 with a mixture of hexane and methyl tert.-butyl ether. After washing the organic phase with base, the compounds are extracted into acid and analyzed on a C18 column with ultraviolet detection at 214 nm. The mobile phase is composed of acetonitrile and aqueous buffer (sodium perchlorate and phosphoric acid, pH 1.7). The limits of reliable quantitation for remoxipride are 12.5 and 50 ng/ml for plasma and urine, respectively. The run times are 6 min for plasma and 3 min for urine. The method has been successfully used to assay remoxipride clinical study samples. This mobile phase has also been successfully applied to the analysis of other basic drugs such as cimetidine, codeine, diltiazem and quinidine with minor modifications.

Chromatography, High Pressure Liquid↗
PubMed1992

High-performance liquid chromatographic determination of angiotensin II receptor antagonists in human plasma and urine. I. DuP 532 (L-694,492).

A sensitive reversed-phase high-performance liquid chromatographic method with ultraviolet detection was developed for the analysis of a new angiotensin II receptor antagonist, DuP 532 (L-694,492), in human plasma and urine. The analyte and internal standard are extracted from plasma and urine at a pH between 3.3 to 3.6 by liquid-liquid extraction and analyzed on a C6 column with ultraviolet detection at 254 nm. The mobile phase is composed of acetonitrile and phosphate buffer at pH 2.5. The limits of quantification are 6 and 7.5 ng/ml for plasma and urine, respectively.

Angiotensin Receptor Antagonists↗
PubMed1992

Simultaneous determination of a novel angiotensin II receptor blocking agent, losartan, and its metabolite in human plasma and urine by high-performance liquid chromatography.

A sensitive and selective high-performance liquid chromatographic method for the simultaneous determination of a new angiotensin II receptor blocking agent, losartan (DuP 753, MK-954, I), and its active metabolite, EXP3174 (II), in human plasma or urine is described. The two analytes and internal standard are extracted from plasma and urine at pH 2.5 by liquid-liquid extraction and analyzed on a cyano column with ultraviolet detection at 254 nm. The mobile phase is composed of acetonitrile and phosphate buffer at pH 2.5. The limit of quantification for both compounds in plasma is 5 ng/ml. The limit in urine is 20 and 10 ng/ml for I and II, respectively. The assay described has been successfully applied to samples from pharmacokinetic studies.

Angiotensin II↗
PubMed1987

The disposition and bioavailability of intravenous and oral nalbuphine in healthy volunteers.

The pharmacokinetics of intravenous and oral nalbuphine were studied in 24 healthy male volunteers ranging in age from 21 to 30 years. On separate test days over a five-week period, subjects received single doses of each of four different formulations of nalbuphine, with a one-week washout period between treatments: 10 mg intravenously administered over two minutes, 45 mg orally given as a solution, and 45 mg orally administered in two tablet formulations (formulation A and formulation B). Blood samples were collected over 48 hours postadministration, and plasma nalbuphine concentrations were determined by reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection. The mean nalbuphine plasma concentration five minutes after 10 mg intravenously was 53 ng/mL, and the half-life of nalbuphine with this route of administration was 2.3 hours. In contrast, mean maximum nalbuphine concentrations (Cmax) after the three orally administered preparations ranged from 14.4 to 15.5 ng/mL, and occurred 0.9 to 1.2 hours after dose administration. Mean elimination half-lives after administration of the three nalbuphine oral formulations were essentially identical, ranging from 6.9 to 7.7 hours. Nalbuphine plasma concentration curves decayed biexponentially regardless of route of administration or type of formulation. Absolute bioavailability of the orally administered forms of nalbuphine ranged from 16.4 to 17.4% and Cmax and AUC data further established the bioequivalence of the three oral formulations. The low absolute bioavailability and prolonged elimination half-life of nalbuphine associated with oral administration are likely due to extensive first-pass metabolism and enterohepatic circulation, respectively.

Administration, Oral↗
PubMed1987

The pharmacokinetics of intravenous, intramuscular, and subcutaneous nalbuphine in healthy subjects.

The pharmacokinetics of intravenously, intramuscularly, and subcutaneously administered nalbuphine were studied in three parallel groups of 12 healthy volunteers each. The subjects received single doses of 10 mg and 20 mg of nalbuphine separated by a one week washout period. Blood specimens were obtained up to 15 h after dosing for determination of nalbuphine. Mean plasma nalbuphine concentrations 5 min after intravenous administration of 10 or 20 mg were 39 and 73 ng/ml, respectively. The mean maximum plasma concentrations (Cmax) after intramuscular or subcutaneous administration of nalbuphine 10 mg were 29 and 31 ng/ml, respectively. Mean Cmax values after 20 mg doses were 60 and 56 ng/ml. Mean Cmax occurred 30 to 40 min after nalbuphine administration. The mean elimination half-lives of parenterally administered nalbuphine ranged between 2.2 and 2.6 h, regardless of dose given or route administered. The mean absolute bioavailability was 81% and 83% for the 10 and 20 mg intramuscular doses, respectively, and 79% and 76% following 10 and 20 mg of subcutaneous nalbuphine. The mean volumes of distribution (Vss) of the intravenously administered drug were 290 and 274 l and the mean systemic clearances were 1.6 and 1.5 l/min following administration of 10 and 20 mg doses, respectively. Intramuscular and subcutaneous nalbuphine appear to be interchangeable based on the similarities in Cmax, mean times until maximum concentration, mean AUC data, and absolute bioavailabilities.

Adult↗
PubMed1986

A dosing nomogram for continuous infusion intravenous naloxone.

Naloxone hydrochloride is extremely valuable for diagnosing and managing the opioid overdose. Due to naloxone's short half life and a long duration of action of most opioids, repeated naloxone dosing often is required to prevent the recurrence of respiratory depression. An alternative to repeated bolus administration is a continuous IV infusion. We conducted a two-phase study to determine the pharmacokinetics of naloxone and to develop a continuous dosing nomogram. In the first phase seven patients were given an IV bolus dose alone and serial plasma naloxone levels were determined. Naloxone elimination was found to be biexponential with the mean beta half life equal to 0.023 +/- 0.002 reciprocal minutes in two patients and 0.015 +/- 0.02 reciprocal minutes in five patients. In the second phase ten volunteers were given either a 2-mg or a 4-mg bolus dose followed by a 1.5-mg/hr or a 3-mg/hr continuous infusion. The mean volume of distribution of the central compartment was found to be 0.806 +/- 0.408 L/kg. The mean beta rate constant of elimination was found to be 0.036 +/- 0.027 reciprocal minutes. A computer simulation of the pharmacokinetic parameters determined in our study found that a continuous infusion of two-thirds of the bolus dose that resulted in reversal each hour will maintain the plasma naloxone levels equal to or greater than the naloxone levels that would have existed 30 minutes following the bolus dose.

Adult↗
PubMed1984

Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions.

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.3 mg/min. In all dogs the formation of 4-hydroxypropranolol, alpha-naphthoxylactic acid, and propranolol glycol was saturable. Vmax and Km values were determined at steady state by relating the rate of excretion of each metabolite into bile and urine to the blood concentration of propranolol. The formation of propranolol glucuronide was a first order process. The use of a dog with a portacaval transposition has permitted development of a method to estimate, in vivo, the kinetic properties of enzymes responsible for hepatic first-pass metabolism of drugs.

Animals↗
PubMed1984

Bioequivalence, dose-proportionality, and pharmacokinetics of naltrexone after oral administration.

Healthy male volunteers (N = 24) participated in a four-way crossover study to compare the rate and extent of absorption of naltrexone after administration of 50 mg tablets as 50, 100, and 200 mg doses and a 10 mg/ml reference syrup. A high-performance liquid chromatographic method was employed to measure naltrexone and 6-beta-naltrexol in plasma and urine. Compared to the syrup, the 50 mg tablets were absorbed more slowly but equally well. There was excellent linearity between the administered dose and the area under the plasma concentration-time profile, as well as total urinary recovery of both drug and metabolite. The mean half-lives for naltrexone and beta-naltrexol were approximately 4 and 12 hours, respectively. The fraction of drug reaching the systemic circulation was estimated to be 5% of the administered dose because of extensive first-pass metabolism. Less than 1% of the dose was excreted in the urine as naltrexone after 48 hours, while 25% was recovered as unconjugated beta-naltrexol. The renal clearance of naltrexone and beta-naltrexol was approximately 127 ml/min and 283 ml/min, respectively. The total systemic clearance for naltrexone was approximately 94 L/hr.

Administration, Oral↗
PubMed1984

Determination of nalbuphine in human plasma by automated high-performance liquid chromatography with electrochemical detection.

A sensitive plasma assay for the agonist/antagonist analgesic nalbuphine utilizing reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection is described. It involves extracting nalbuphine from plasma at pH 9 into an ethyl acetate/toluene/isopropanol mixture and then back extracting it into aqueous phosphoric acid. The extract is injected onto an octyl column using a solvent mixture of acetonitrile and phosphoric acid. Intra-day assay coefficients of variation (CV) ranged from 0.2 to 4.2% over a concentration range from 0.21 to 42 ng/ml. Nalbuphine extraction recovery exceeded 90% using 1 or 3 ml of plasma. No degradation of the drug in frozen plasma was observed after 18 weeks. The limit of detection is 0.1 ng/ml using 3 ml of plasma.

Chromatography, High Pressure Liquid↗
PubMed1982

An automated HPLC method for the assay of propranolol and its basic metabolites in plasma and urine.

An automated HPLC method is described for the simultaneous determination of propranolol, 4-hydroxypropranolol, and N-desisopropylpropranolol in plasma and urine before and after beta-glucuronidase/aryl sulfatase treatment. It involves extraction with ether at pH 10 in the presence of ascorbic acid, added to prevent oxidation of 4-hydroxypropranolol. The compounds are then back extracted into dilute acid and assayed on an HPLC using a fluorescence detector. Three HPLC columns have been used (a phenyl, an octyl, and an octadecyl column). The last column was found to be most reproducible with minimal intercolumn variation. The solvent system includes a combination of acetonitrile, methanol, and phosphoric acid. Concentrations as low as 0.2, 1.0, and 0.2 ng/ml of propranolol, 4-hydroxypropranolol, and N-desisopropylpropranolol, respectively, can be measured using 1 ml of plasma.

Chromatography, High Pressure Liquid↗
PubMed1982

A technique to study hepatic and intestinal drug metabolism separately in the dog.

A model to study hepatic and intestinal drug metabolism in the dog has been evaluated. The model is made by performing a portacaval transposition, cholecystectomy and inserting a Thomas cannula into the duodenum. The result is a healthy animal in which drugs can be infused either in a normal i.v. (forelimb) fashion, directly into the liver (hindlimb) or given orally. Blood can be sampled from a peripheral vein, peripheral artery or hepatic vein. Bile and urine can be collected continuously. Pharmacokinetics can be studied in awake, unmedicated animals. The model can be used to assess oral, i.v. or hepatic infusion of drugs and their hepatic, intestinal or pulmonary metabolism.

Animals↗
PubMed1982

Lack of gastrointestinal metabolism of propranolol in dogs after portacaval transposition.

We studied whether or not propranolol underwent presystemic metabolism in the gastrointestinal wall in five dogs. The dogs were studied before and four weeks after creation of a portacaval transposition. Before surgery, systemic bioavailability of the oral dose was 8 +/- 8% (mean +/- S.D.), whereas after transposition the bioavailability was 102 +/- 9%. The systemic plasma clearance increased from 766 +/- 192 to 976 +/- 280 ml/min. The terminal half life and apparent volume of distribution after transposition were not significantly different from those obtained preoperatively. Our results indicate that there is complete absorption but no metabolism of propranolol by the gastrointestinal wall.

Administration, Oral↗
PubMedDate not supplied

Innovations in mission architectures for exploration beyond low Earth orbit.

Through the application of advanced technologies and mission concepts, architectures for missions beyond Earth orbit have been dramatically simplified. These concepts enable a stepping stone approach to science driven; technology enabled human and robotic exploration. Numbers and masses of vehicles required are greatly reduced, yet the pursuit of a broader range of science objectives is enabled. The scope of human missions considered range from the assembly and maintenance of large aperture telescopes for emplacement at the Sun-Earth libration point L2, to human missions to asteroids, the moon and Mars. The vehicle designs are developed for proof of concept, to validate mission approaches and understand the value of new technologies. The stepping stone approach employs an incremental buildup of capabilities, which allows for future decision points on exploration objectives. It enables testing of technologies to achieve greater reliability and understanding of costs for the next steps in exploration.

Astronomy↗