The polysomnographic effects of clonidine on sleep disorders in posttraumatic stress disorder: a pilot study with Cambodian patients.
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Adult↗
Biomedical subjects
C M Riley
Publications and source records attributed to C M Riley.
A liquid chromatographic method for the determination of the enantiomeric purity of the anticancer drug, 9-amino-20(S)-camptothecin.
A method was developed for determining the enantiomeric purity of 9-amino-20(S)-camptothecin (9-A-20(S)-CAM). The chiral derivatizing reagent, 1-(1-naphthyl)ethyl isocyanate (NEI) was used to derivatize the enantiomers of 9-A-CAM, and 1H-NMR, LC-MS, and LC-UV were used to identify and quantitate the two diastereomers produced. During the first 24 h, derivatization was exclusively at the 9-amino nitrogen. The much slower reaction involving reaction of NEI with the 20-hydroxy oxygen could be prevented by quenching the reaction within the first 24 h with methanol. NMR analysis provided useful information about the site of derivatization; however, the partial separation of the signals was insufficient for quantitative analysis of the two diastereomers. Whereas baseline resolution of the two diastereomers was achieved by reversed-phase LC, the reproducibilities of the resolution and the peak area ratios were dependent on the nature and composition of the mobile phase, the flow rate, the column temperature, sample concentration and sample preparation.
Antineoplastic Agents↗
A stability-indicating assay and the preformulation characteristics of the radiosensitizer, 1,2,4-benzotriazin-3-amine 1,4-dioxide.
A stability-indicating LC assay was developed for the analysis of 1,2,4-benzotriazin-3-amine 1,4-dioxide and applied to the preformulation characterization of the drug. The dissociation constants of the drug were determined using UV-vis spectrophotometry. The LC method was used to determine the aqueous stability of the drug under a variety of accelerated conditions, its solubility in a variety of pharmaceutical solvents and its octan-1-ol-water partition coefficient. The preformulation data were used to develop three prototype aqueous formulations of the drug at a concentration of 0.5 mg ml-1 in 5% Dextrose Injection USP, phosphate buffer (pH 7.4) and phosphate buffered mannitol. The 3-month stability of those formulations at room temperature was demonstrated.
Buffers↗
Characterization of the complexation of fluoroquinolone antimicrobials with metal ions by nuclear magnetic resonance spectroscopy.
The complexation of the fluoroquinolone antimicrobials is important because it has been implicated in reduced oral bioavailability and reduced antimicrobial activity when the drugs are co-administered with antacids or multi-vitamin preparations containing iron. The complexation of two model compounds, lomefloxacin and norflaxacin was studied using NMR. With aluminum ions, exchange between free and bound drug molecules was slow on the NMR time-scale. Two complexes, proposed to have stoichiometries of 2:1 and 3:1 (drug:metal) based on peak widths and variable temperature studies, were observed. The crystal structure of lomefloxacin, which shows intermolecular self association previously reported to be crucial to the drug's mode of action, is also reported. Because the metal ion complexes could not be crystallized, the crystal structure of uncomplexed lomefloxacin together with the NMR data on the aluminum complexes were used in the molecular modelling of the lomefloxacin-aluminum complexes.
Anti-Infective Agents↗
Electrochemical characteristics of amino acids and peptides derivatized with naphthalene-2,3-dicarboxaldehyde: pH effects and differences in oxidation potentials.
The electrochemical oxidations of the cyanobenz[f]isoindole (CBI) derivatives of 18 amino acids and 15 peptides, including enkephalins and several enkephalin fragments, were studied. Cyclic voltammetry indicated that the oxidation potentials of derivatized amino acids were virtually independent of pH. The utility of this pH-independence was demonstrated by controlling, through varying the pH, the selectivity with which CBI derivatives could be detected in the presence of phenolic compounds. In addition, hydrodynamic voltammograms of derivatized amino acids and peptides were constructed from chromatographic data and compared. The E1/2 values among the derivatized amino acids covered a range of 215 mV, with the derivatives of the basic amino acids being the easiest to oxidize and those of the acidic amino acids being the most difficult to oxidize. The E1/2 values of the derivatized peptides examined varied by 270 mV, with minor variations in structure capable of producing marked changes in oxidation potential. These results indicate that voltammetry can aid in identification or selective detection of CBI derivatives of amino acids or peptides.
Amino Acid Sequence↗
Reversed-phase liquid chromatography of the opioid peptides--2. Quantitative structure-retention relationships and isocratic retention prediction.
The ability of Snyder's theory of linear gradient elution to predict the starting isocratic reversed-phase LC conditions (k' = 4-10) for the opioid peptides was investigated. The errors in predicting the concentration of acetonitrile (phi) required to elute the peptides with a k' value of 4 were high, ranging from 13.5 to 38.1%. At k' = 10 the errors were generally reduced to less than 20%. This analysis was repeated with the same peptides after conversion to their fluorescent 1-cyanobenz[f]isoindoles (CBIs) by reaction with naphthalene-2,3-dicarboxaldehyde/cyanide. For the CBI derivatives, the errors in predicting the required concentration of acetonitrile for isocratic elution were markedly reduced and ranged from 0 to 14.3 for k' = 4 and 0 to 11.9% for k' = 10. The errors in the model in predicting the required isocratic mobile phase accurately were attributed to a mixed mechanism of retention involving solvophobic and silanophilic interactions and leading to non-linear relationships between log k' and phi. Even when the errors in predicting the required value of phi were relatively high, the Snyder approach was found to be very useful in predicting the initial starting conditions for the reversed-phase LC of the native opioid peptides as well as their fluorescence CBI derivatives.
Algorithms↗
Degradation of dacarbazine in aqueous solution.
The effects of initial concentration (0.05-5.0 mg ml-1, 2.5 x 10(-4)-0.025 M) (pH 1-13), buffer concentration (0.01-0.075 M), light, antioxidants and co-solvents on the degradation of dacarbazine in aqueous solution were investigated at 37 degrees C. Liquid chromatography was used to monitor the degradation of dacarbazine as well as the appearance of degradation products. The kinetics of hydrolysis of dacarbazine in the dark were pseudo first-order and independent of the initial concentration of the drug. The degradation of dacarbazine was accelerated by light and at low concentration proceeded by pseudo zero-order kinetics. The pH-rate profiles showed that both the photolytic and the hydrolytic reactions were dependent on the ionization state of the molecule. The main degradation product of both hydrolysis and photolysis was detected by liquid chromatography and confirmed by mass spectrometry to be 2-azahypoxanthine.
Buffers↗
Microdialysis sampling for the investigation of dermal drug transport.
Microdialysis perfusion in vivo has the potential to be a powerful sampling technique in dermal and transdermal drug delivery studies. Characterization of a commercially available microdialysis probe in vitro considering relevant physiological parameters is a vital first step in the evaluation of microdialysis as a dermal sampling technique. In previous microdialysis studies, analyte concentration and neutrality have been implicated in altering microdialysis recovery. The recovery of a model compound 5-fluorouracil (5-FU) was investigated at several pH values and donor concentrations. The relative recovery of 5-FU by the microdialysis probe was affected by pH but not by donor concentration. To confirm further that the changing concentration and pH profile presented by the flux of 5-FU was not significantly altering microdialysis recovery, an experiment comparing direct and microdialysis sampling of a Franz diffusion cell receptor compartment was performed. Although the 5-FU concentration (0-686 ng/ml) and pH (7.40-7.24) changed substantially, the recovery of 5-FU was not adversely affected. To demonstrate the feasibility of dermal microdialysis, the flux of a commercial preparation of 5-fluorouracil was monitored utilizing a microdialysis probe implanted in excised rat skin in vitro. The results from the dermally implanted probe demonstrate the potential of the technique while establishing the limitations of the current microdialysis system.
Animals↗
Clinical pharmacology of deoxyspergualin in patients with advanced cancer.
Pharmacokinetic studies were carried out in 25 patients with advanced cancer receiving deoxyspergualin (DSG), a candidate anticancer agent, in a dose-finding Phase I study. The dosage range explored was 80 to 2160 mg/m2/day for 5 days by continuous i.v. infusion. The drug levels in plasma and urine were measured by high-performance liquid chromatography with postcolumn derivatization and fluorescence detection. One drug metabolite was demonstrated in plasma and urine of treated patients. This metabolite was extracted from urine and purified to homogeneity; thereafter, it was examined by high-performance liquid chromatography, nuclear magnetic resonance, and fragmentation mass spectrometry and was demonstrated to be identical to chemically synthesized desaminopropyl-DSG. The mean steady state plasma concentrations of DSG ranged from 0.28 to 11.1 microM at, respectively, the 80- and 2160-mg/m2 dosage levels. The plasma concentration at steady state and the area under the plasma concentration versus time curve of DSG were proportional to dose (r = 0.97). Following discontinuance of the infusion, DSG was cleared from the plasma in a biexponential fashion. The mean total body clearance was 364 +/- 78 ml/min/m2. Desaminopropyl-DSG was formed extensively at all dosage levels; mean steady state plasma levels of this metabolite reached a plateau 2.65 microM at a dose of 720 mg/m2/day and did not rise with further dose increments. The urinary content of DSG was examined in 20 patients over the dosage range from 160 to 960 mg/m2/day; in this group less than 10% of the administered dose was excreted as DSG. In four patients at the 720- and 960-mg/m2/day dosage levels, the total DSG plus metabolite excretion ranged from 7 to 18% of the administered dose, with comparable quantities occurring as the parent drug and desaminopropyl-DSG.
Animals↗
Reversed-phase ion-pair liquid chromatography of the angiotensins.
The isocratic reversed-phase liquid chromatography of the angiotensins and a number of their synthetic analogues is described. Complete separation of 10 out of 12 peptides was achieved through a solvent optimization strategy with a total analysis time of about 20 min. The retention behavior of the angiotensins studied was described in terms of the hydrophobic contribution of their amino acid residues; there was good correlation between predicted and experimental retention for those peptides that were retained by a common mechanism. However, because ion-pair chromatography was required for good peak symmetry, retention was substantially modulated by the presence of acidic and basic residues. The limit of detection of these peptides was 3-5 pmol by UV absorbance at 214 nm. For those peptides containing a primary amino group the detection limit was improved by two orders of magnitude by fluorogenic derivatization with naphthalene-2,3-dicarboxaldehyde/cyanide to the corresponding N-substituted 1-cyanobenz[f]isoindole (CBI) derivatives. The contribution of the CBI ring system to retention was also investigated.
Amino Acid Sequence↗
Stability of amrinone and digoxin, procainamide hydrochloride, propranolol hydrochloride, sodium bicarbonate, potassium chloride, or verapamil hydrochloride in intravenous admixtures.
The stability of amrinone and digoxin, procainamide hydrochloride, propranolol hydrochloride, sodium bicarbonate, potassium chloride, or verapamil hydrochloride in intravenous admixtures was studied. Admixtures of amrinone and digoxin were studied at one concentration. Amrinone admixtures with propranolol hydrochloride, sodium bicarbonate, potassium chloride, and verapamil hydrochloride were studied at two concentrations. In general, 0.45% sodium chloride injection was used as the diluent; 5% dextrose injection was also used for the procainamide hydrochloride experiments. Duplicate solutions of each test admixture and single-drug control admixture were prepared and stored for four hours at 22-23 degrees C under fluorescent light. Samples were analyzed by visual inspection, tested for pH, and assayed by high-performance liquid chromatography. Admixtures containing amrinone 1.25 or 2.5 mg/mL (as the lactate salt) and sodium bicarbonate 37.5 mg/mL precipitated immediately or within 10 minutes. No changes in pH or visual appearance were noted for amrinone admixtures with procainamide hydrochloride, digoxin, propranolol hydrochloride, potassium chloride, and verapamil hydrochloride. Appreciable degradation of both amrinone and procainamide was observed after four hours when the two were mixed in 5% dextrose. No degradation of amrinone or procainamide was seen when the 5% dextrose was replaced by 0.45% sodium chloride. Amrinone and sodium bicarbonate were incompatible in intravenous admixtures. Amrinone was compatible with digoxin, propranolol hydrochloride, potassium chloride, and verapamil hydrochloride. Amrinone and procainamide were compatible in 0.45% sodium chloride injection but not in 5% dextrose injection.
Amrinone↗
Irreversibility of procainamide-dextrose complex in plasma in vitro.
The extent to which the procainamide-dextrose complex reverts to free procainamide hydrochloride in plasma was studied in vitro. The procainamide-dextrose species was formed, isolated using preparative liquid chromatography, and then added to six different lots of pooled plasma that were maintained at physiological temperature (37 +/- 0.1 degrees C). At zero, four, and eight hours after preparation of the samples, 1-mL portions were removed from each sample, extracted, and assayed for procainamide hydrochloride using high-performance liquid chromatography. The mean procainamide hydrochloride concentrations at zero, four, and eight hours after preparation were 2.67, 4.81, and 1.38 g/mL, respectively. Each lot of pooled plasma was statistically analyzed to determine if a significant amount of procainamide hydrochloride reappeared. Analysis of variance showed significant difference between the concentrations of free procainamide hydrochloride in the samples at zero, four, and eight hours (p less than 0.02). Follow-up with Duncan's multiple comparisons test determined that the mean procainamide hydrochloride concentrations immediately after preparation were not significantly different from those at eight hours, but the mean procainamide hydrochloride concentrations at four hours were significantly different from those at eight hours (p less than 0.01). A paired Student's t test comparing the data from zero and eight hours showed a significant reduction in mean procainamide hydrochloride concentrations with time (p less than 0.05). The procainamide-dextrose complex in vitro does not revert to free procainamide hydrochloride in plasma at physiological temperature during the first eight hours.
Drug Compounding↗
Chromatographic methods for the bioanalysis of antiviral agents.
The present review has concentrated on chromatographic techniques for the quantitative determination of antiviral drugs in biological samples. Special attention has been paid to the elements of chromatographic assays that are essential to ensure selectivity, sensitivity, accuracy and precision of the various methods. Wherever possible, attempts have been made to determine the suitability of the methods for application to investigations in pharmacokinetics in man and experimental animals, biopharmaceutics, therapeutic drug monitoring, metabolism and pharmacology. Because of the serious consequences of infection from material contaminated with viruses, special consideration has been given to the handling of contaminated samples. It was convenient to divide the antiviral drugs for the purpose of this review into two groups, the nucleoside and the non-nucleoside antiviral drugs. The nucleosides discussed are vidarabine, cytarabine, ribavirin, riboxamide, acyclovir, ganciclovir, desciclovir, carbovir, 2',3'-dideoxyadenosine, 2',3'-dideoxycytidine, zidovudine, 2',3'-dideoxyinosine, 2',3'-didehydro-3'-deoxythymidine, idoxuridine, 5-(2-bromovinyl)-2'-deoxyuridine, 2'-fluoro-5-iodoaracytidine and 5-iodo-2'-deoxycytidine. The non-nucleoside antiviral drugs discussed are arildone, amantidine, rimantidine, moroxydine, enviroxime, foscarnet and ampligen.
Antiviral Agents↗
Stereoselective pharmacokinetics and metabolism of the enantiomers of cyclophosphamide. Preliminary results in humans and rabbits.
[R(+),S(-)]-Cyclophosphamide [(R,S)-CP] is an anticancer drug, containing a chiral phosphorous atom, which is prepared and used clinically as the racemic mixture. A new high-performance liquid chromatographic assay suitable for pharmacokinetic studies of CP enantiomers in plasma has been reported recently by this laboratory (Reid et al., Anal Chem 61: 441-446, 1989). Briefly, the assay involves ethyl acetate extraction of CP enantiomers from plasma followed by derivatization to diastereomers in a two-step process utilizing chloral and (+)-naproxen acid chloride. Chromatographic analysis was performed on a reversed phase (ODS) column with detection at 232 nm. In the present study, preliminary results on the applicability of this assay to pharmacokinetic studies are presented. Several rabbits were used to compare the influence of i.p., i.v., and oral routes of administration on the stereoselective disposition of (R,S)-CP. Following i.p. administration, S-CP was cleared faster than R-CP. Following oral administration, only R-CP was detectable in plasma, while i.v. administration resulted in minor or no stereoselective disposition. These results indicated that there was a marked stereoselective metabolism of the S-CP enantiomer, with the i.p. and oral routes producing the greatest differences due to first-pass metabolism. Incubation of rabbit-liver microsomes with (R,S)-CP demonstrated that the monooxygenase system can exhibit marked stereoselectivity in its metabolism of CP. The ratio of R-CP to S-CP in the incubation medium increased during the incubation period from 1:1 initially to 4.5:1 after 60 min. The results from the experiments with rabbits indicate that the first-pass metabolism of this drug is highly stereoselective; in contrast, cancer patients who had received (R,S)-CP as an i.v. infusion showed no stereoselectivity in the elimination of the enantiomers. Pharmacokinetic studies with cancer patients, receiving (R,S)-CP as an oral dose, are in progress in order to determine if stereoselective first-pass metabolism of this drug also occurs in humans.
Administration, Oral↗
Determination of the anticancer drug, 15-deoxyspergualin, in plasma ultrafiltrate by liquid chromatography and precolumn derivatization with naphthalene-2,3-dicarboxaldehyde/cyanide.
An alternative analytical method for the determination of 15-deoxyspergualin in plasma is described. The drug was initially separated from the plasma matrix by ultrafiltration and a precolumn derivatization step was performed with naphthalene-2,3-dicarboxaldehyde in the presence of sodium cyanide to yield the fluorescent N-substituted 1-cyanobenz[f]isoindole (CBI) derivative. The CBI derivative was separated and quantitated by reversed-phase chromatography using an ODS Hypersil column and mobile phase of KH2PO4 (0.1 M)-H3PO4-acetonitrile (48:0.8:52, v/v/v) containing dodecyl sodium sulphate (18 mM). The excitation and emission wavelengths for the fluorescence detector were 420 and 490 nm, respectively. The peak height was linearly related to drug concentration over the range from 5 ng ml-1 (10 nM) to 10 micrograms ml-1 (20 microM) in phosphate buffer (0.1 M, pH 7.0), spiked plasma ultrafiltrate and ultrafiltrate obtained from spiked plasma. Measurements could be made with a relative standard deviation of 4.5% or less in phosphate buffer (0.1 M, pH 7.0), 6.1% or less in spiked plasma ultrafiltrate and 12% or less in ultrafiltrate obtained from spiked plasma.
Antibiotics, Antineoplastic↗
Improved preparation and structural conformation of the fluorescence labelling reagents 1,2-diamino-4,5-dimethoxybenzene and 3,4-dihydro-6,7-dimethoxy-4-methyl-3-oxo-quinoxaline-2-carbonyl chloride.
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Fluorescence↗
Chemiluminescence: a sensitive and versatile method for analyte detection.
The generation of light from the oxidation of oxalic esters with hydrogen peroxide has been applied to the detection of luminescent materials. In order to improve the efficiency of this method, which is less than 0.1%, and to enhance the selectivity for target analytes, an in-depth investigation of the oxalate ester-hydrogen peroxide reaction has been conducted. A kinetic model has been developed based on the effects of catalysts, reagents and reaction conditions for maximum light production. Application of the model to liquid chromatography through the "time-dependent emission window" concept affords a predictable maximum sensitivity for selected analytes. Application to the detection and quantitation of met- and leu-enkephalins which have been labelled with naphthalene-2,3-dicarboxyaldehyde/cyanide provides support for this methodology. Other bioanalytical applications are presented.
Humans↗
Fluorogenic derivatization of peptides with naphthalene-2,3-dicarboxaldehyde/cyanide: optimization of yield and application in the determination of leucine-enkephalin spiked human plasma samples.
Initial attempts to derivatize the alpha-amino site of several tripeptides with naphthalene-2,3-dicarboxaldehyde/cyanide (NDA/CN) resulted in poor yields of the expected N-substituted 1-cyanobenz[f]isoindole (CBI) products. Examination of the CBI-formation mechanism, in conjunction with knowledge of the general structure-reactivity properties of the tripeptides, led to the recognition of a competing non-productive reaction pathway. Through the use of model reactions and the isolation and structural elucidation of a predicted side-product the viability of the competing pathway was confirmed. From an understanding of the key features of both the productive and non-productive reaction pathways, a rational approach for the optimization of CBI-derivative yield was proposed and confirmed experimentally. This information led, in turn, to the development of HPLC methodology suitable for the determination of leu-enkephalin spiked into human plasma; fluorescence detection was used in conjunction with leu-enkephalin amide as the internal standard. The method enabled leu-enkephalin to be determined at a concentration of 0.31 nmol ml-1 with an error of less than 4% for 25 pmol injected.
Chemical Phenomena↗