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D G Kaiser

Publications and source records attributed to D G Kaiser.

At least 19 recordsLinked to original sources
PubMed1995

Modelling the relative metabolic occurrence of alkyl-nitrogen bond cleavage using structure-reactivity maps.

Over a broad range of tertiary N-methyl amines, whenever alkyl-nitrogen bond cleavage was observed, N-demethylation was also observed. Alkyl-nitrogen bond cleavage in rings, alkyl-nitrogen bond cleavage if the carbon of the N-dealkylation reaction-site is in a ring and the nitrogen atom of the reaction-site is not in a ring, and dedimethylamination are not likely to occur relative to N-demethylation. Structure-reactivity relationships for other N-dealkylations, such as N-debenzylation, N-dethiophenation, and N-dedimethylaminoethylation of tertiary amines were evident from a visual inspection of the structure-reactivity map. Structure-reactivity maps proved to be a useful tool for ascertaining structural environments influencing the relative occurrence of alkyl-nitrogen bond cleavage in tertiary N-methyl amines.

Biotransformation↗
PubMed1994

An analysis of the relative occurrence of N-demethylation and N-oxidation in xenobiotic metabolism using structure-reactivity maps.

The relative occurrence of N-demethylation and N-oxidation in a structurally diverse set of N-methyl tertiary amines was examined using structure-reactivity maps. A structure-reactivity map of the data indicated important structural features useful for predicting the relative occurrence of these reactions. A steric index which describes the degree of steric hinderance at the N-methyl reaction site is defined. A QSAR between the relative occurrence of N-demethylation and N-oxidation of N-methyl tertiary amines and the steric index was developed.

Animals↗
PubMed1994

Taurine conjugation of ibuprofen in humans and in rat liver in vitro. Relationship to metabolic chiral inversion.

Following administration of a single oral dose (400 mg) or RS-ibuprofen (RS-IBP) to humans, a novel metabolite was isolated from urine and identified by tandem mass spectrometry as the taurine conjugate of IBP (IBP-Tau). The corresponding glycine conjugate was sought but was not detected in these studies. Quantitative analyses indicated that taurine conjugation represents a minor biotransformation pathway for IBP (1.52 +/- 0.43% of the dose over 24 h, n = 4), but it is nonetheless one of mechanistic significance in that it requires the prior formation of the coenzyme A thioester of IBP (IBP-CoA). The latter conjugate, which has not been detected in vivo because of its intracellular compartmentalization, plays a key role in the metabolic chiral inversion of R- to S-IBP. By means of stereoselective gas chromatography-mass spectrometry, it was found that IBP liberated from the urinary IBP-Tau under nonracemizing conditions consisted mainly (ca. 87%) of molecules of S configuration. From separate experiments with volunteers given a pseudoracemic mixture of the drug (R-IBP/S-[2H3]IBP), it was shown that the majority of the S-IBP-Tau was derived from S-IBP, rather than from R-IBP by way of chiral inversion. These findings, together with the results of in vitro experiments with rat liver mitochondrial preparations and isolated rat hepatocytes, demonstrate that although activation of IBP to its CoA thioester favors the R enantiomer over its antipode, S-IBP also participates in CoA-dependent reactions, including metabolic chiral inversion.

Adult↗
PubMed1992

The lazaroid U74006F, a 21-aminosteroid inhibitor of lipid peroxidation, attenuates myocardial injury from ischemia and reperfusion.

U74006F, a novel new 21-aminosteroid inhibitor of lipid peroxidation, has been effective in preventing free-radical-mediated injury in central nervous system models. To assess its ability to diminish myocardial injury due to ischemia and reperfusion, U74006F (n = 11) or its vehicle (n = 11) were administered intravenously to New Zealand white rabbits. After allowing for distribution, the hearts were excised and exposed to 30 min of stop-flow ischemia and 30 min of reperfusion on a nonrecirculating Langendorf apparatus. There was diminished creatine phosphokinase release; improved peak positive dP/dt, developed pressure, and peak negative dP/dt; and diminished diastolic pressure in the group treated with U74006F. Thus, pretreatment with U74006F diminished myocardial injury and enhanced systolic and diastolic functional recovery, probably by protecting the lipid component of cell membranes from peroxidation by reactive oxygen metabolites.

Animals↗
PubMed1990

The fate of soluble steroids within breast prostheses in humans.

The long-term fate of 6-alpha-methyl-methylprednisolone hemisuccinate (MPHS) placed into breast prostheses prior to implantation in humans was determined. MPHS hydrolyzes to the active form 6-alpha-methylprednisolone (MP) in water, which then diffuses out of the implant. Twenty prostheses were recovered 5.3 to 34.7 months after placement, and the solution inside was analyzed for MPHS and MP. Half-lives were calculated for the hydrolysis of MPHS to MP (3.4 +/- 0.58 months [mean +/- SEM]) and for the diffusion of MP out of the prostheses (20.63 +/- 6.10 months). The large half-lives found imply that MPHS slowly hydrolyzes to MP, and that active steroid is released for a longer time than was previously thought. This long release could be the cause of the long-term effects seen with steroids used in this manner.

Breast↗
PubMed1989

Potentiation of aspirin-induced gastric lesions by exposure to cold in rats. Role of acid secretion, mucosal blood flow, and gastric mucosal prostanoid content.

We investigated the mechanism by which exposure to cold sensitizes rats to the formation of gastric lesions after a low dose of aspirin (50 mg/kg). Six times more lesions were produced by aspirin plus cold than by aspirin alone. Three hypotheses were studied to explain the synergism of aspirin plus cold on lesion formation: gastric acid hypersecretion, reduced gastric mucosal blood flow, and decreased prostanoid synthesis by the stomach. Cold, and cold plus aspirin, stimulated gastric acid secretion (to a similar extent), whereas aspirin had no effect. Gastric mucosal blood flow, measured by the hydrogen gas clearance method, was decreased by cold, aspirin, and aspirin plus cold, and the extent of decrease was similar. Prostanoid generation [prostaglandin E2 (PGE2), PGF2 alpha, 6-keto PGF1 alpha, and thromboxane B2] by the gastric corpus mucosa was not affected by cold, but was reduced equally (by at least 90%) in animals receiving aspirin alone or aspirin plus cold. After oral administration of aspirin, the plasma contained mostly salicylic acid (98%), whereas the gastric mucosa contained mostly aspirin (80%-85%). We conclude that the synergism of aspirin plus cold on the formation of gastric lesions probably results from the combined effects of three factors: increased secretion of acid (because of exposure to cold) that is in contact with a gastric mucosa in which blood flow is reduced (because of exposure to cold or to aspirin), and in which the synthesis of cytoprotective prostaglandins is inhibited (by aspirin). Such mucosa may be particularly vulnerable to the damaging effect of hyperacidity.

Animals↗
PubMed1989

Mechanistic studies of the metabolic chiral inversion of (R)-ibuprofen in humans.

The metabolic chiral inversion of R-(-)-ibuprofen has been studied in human subjects by means of specific deuterium labeling and stereoselective gas chromatography-mass spectrometry methodology. After simultaneous p.o. administration of a mixture of R-(-)-ibuprofen (300 mg) and R-(-)-[3,3,3-2H3]ibuprofen (304 mg) to four adult male volunteers, the enantiomeric composition and deuterium content of the drug in serum, and of the drug and its principal metabolites in urine, were followed over a period of 24 hr. The results of these analyses indicated that: 1) conversion of R-(-)- to S-(+)-ibuprofen takes place with complete retention of deuterium at the beta-methyl (C-3) position; 2) chiral inversion of R-(-)-[2H3]ibuprofen is not subject to a discernible deuterium isotope effect; and 3) replacement of the beta-methyl hydrogen atoms by deuterium has no effect on any of the serum pharmacokinetic parameters for R-(-)- or S-(+)-ibuprofen. These data indicate that the process whereby R-(-)-ibuprofen undergoes metabolic inversion in human subjects does not involve 2,3-dehydroibuprofen as an intermediate, and that the underlying mechanism cannot, therefore, entail a desaturation/reduction sequence.

Adult↗
PubMed1988

Gas chromatographic determination of guanadrel in plasma and urine.

To evaluate the pharmacokinetics and drug availability from various dosage formulations, a method for the determination of guanadrel, (1,4-dioxaspiro[4,5]dec-2-ylmethyl)guanidine, in plasma and urine was required. A gas chromatographic procedure, based on formation of a hexafluoroacetylacetone derivative in a two-phase system of water and toluene, was developed. The limit of determination of the method is 5 ng/ml guanadrel in plasma and 15 ng/ml guanadrel in urine. Statistical analyses indicate average recoveries of 98.1 +/- 18.0 and 104.4 +/- 15.6% from plasma and urine, respectively. Mass spectrometric analyses, in conjunction with gas chromatography, confirmed the specificity of the method for intact drug. The procedure was applied successfully to drug absorption studies in humans.

Chemical Phenomena↗
PubMed1986

Pharmacokinetics of flurbiprofen.

Both radiolabeled and nonlabeled drug have been used to study the pharmacokinetics of flurbiprofen (Ansaid, Upjohn). Drug absorption is rapid, drug disappearance half-life is independent of oral dose, and the area under the plasma drug concentration versus time curve increases with increasing oral dose. Elimination of intact drug from the peripheral circulation is biphasic and rapid. Following a single oral dose of 100 mg of flurbiprofen, drug bioavailability is equivalent using regimens of four 25-mg tablets, two 50-mg tablets, or one 100-mg tablet once daily. Long-term administration of flurbiprofen appears neither to inhibit nor induce the drug's metabolism.

Aspirin↗
PubMed1981

Placental transfer of methylprednisolone following maternal intravenous administration.

Seven normal patients in labor at term were given 125 mg of methylprednisolone hemisuccinate intravenously shortly before delivery. Analysis of maternal and cord plasma samples indicated that both the hemisuccinate and free alcohol forms of the corticosteroid were transported in pharmacologic levels to the fetal compartment. Since methylprednisolone may have less of an infection-potentiating effect than other commonly used corticosteroids, use of it as a stimulator of fetal lung surfactant deserves further investigation.

Female↗
PubMed1980

Endogenous serum testosterone in males after different doses and routes of administration of medroxyprogesterone acetate.

The effects of different doses and routes of administration (oral and IM) of medroxyprogesterone acetate on endogenous testosterone secretion were studied in healthy male volunteers. There were three treatment groups. Serum testosterone levels, measured by radioimmunoassay before, during and after different doses of medroxyprogesterone acetate, were significantly lowered (p < 0.05) in these subjects. A tendency to return toward pretreatment values was noted within three to six weeks after the last dose of medroxyprogesterone acetate. The IM route of administration suppressed the testosterone levels for the longest period of time. No indication of drug-induced toxicity, as judged by vital signs, systemic side effects, standard laboratory evaluations and some special clinical evaluations, was found during treatment or in the period immediately following the course of therapy. No serious or untoward side effects were encountered.

Administration, Oral↗
PubMed1978

Electron-capture GLC determination of ibuprofen in serum.

To evaluate drug-protein binding, a sensitive method for the determination of ibuprofen in submilliliter amounts of serum was required. A specific and highly sensitive procedure, based on benzene extraction of the acidified specimen. TLC of the benzene extract residue, fomation of the pentafluorobenzyl esters of the materials eluted from the thin-layer chromatogram, and quantification of the pentafluorobenzyl esters by GLC, was developed. Utilizing electron-capture detection, the method is sensitive to 0.1 microgram of ibuprofen/0.1 ml of serum. Statistical analyses indicated an average recovery of 97.7% with a standard deviation of +/- 7.3%. Mass spectrometric analysis, in conjunction with GLC, confirmed the specificity of the method for the intact drug. The procedure was applied successfully to drug absorption and drug-protein binding studies in humans.

Blood Proteins↗
PubMed1978

Ventilatory response to medroxyprogesterone acetate in normal subjects: time course and mechanism.

The time course of ventilatory adaptation to medroxyprogesterone acetate (MPA) and potential mediators of this response in plasma and lumbar CSF were determined in five healthy adult males. A significant decrease in arterial PCO2 (PACO2) at rest and exercise was noted within 48 h of drug administration with the maximum effect reached within 7 days and amounting to a 5-Torr decrement in PACO2. Blood and lumbar cerebrospinal fluid pH because significantly alkaline to control as soon as the ventilatory resporse was noted and remained alkaline during the treatment period. The ventilatory and dP/dt max response to exogenous CO2 was unchanged but their response to moderate exercise was increased after MPA. MPA-rlated materials were detected in both the plasma and CSF as soon as the ventilatory response was noted. The increase in CSF MPA-related materials approximated the unbound fraction determined in plasma. We conclude that [H+] in plasma and CSF is a function rather than a cause of ventilator acclimatization to MPA. MPA-related materials are capable of crossing the blood-brain barrier and could potentially exert their ventilatory stimulant effect by some central mechanism.

Adult↗
PubMed1977

Generic propoxyphene: need for clinical bioavailability evaluation.

Plasma level data on two investigational capsule formulations of propoxyphene with similar physicochemical parameters demonstrate that the formulations have different in vivo bioavailabilities. The potential bioavailability problems with water-soluble drugs and the lack of correlation of in vitro and in vivo parameters for equivalent drug formulations are discussed.

Adult↗