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Biomedical subjects

R L Foltz

Publications and source records attributed to R L Foltz.

At least 37 records · Page 2Linked to original sources
PubMed1995

Determination of ibogaine and 12-hydroxy-ibogamine in plasma by gas chromatography-positive ion chemical ionization-mass spectrometry.

Ibogaine, an indolamine derivative, is currently being investigated as a potential agent in the treatment of stimulant and opiate addiction. We developed a rapid, sensitive, and specific method for the analysis of ibogaine and its putative active metabolite, 12-hydroxy-ibogamine (12-OH-ibogamine). This assay employs a one-step basic extraction with n-butyl chloride-acetonitrile (4:1), followed by derivatization of the metabolite using N-methyl-N-(tert-butyldimethylsilyl)-trifluoroacetamide. The derivatized extracts were analyzed by capillary gas chromatography-positive ion chemical ionization-mass spectrometry. The ions monitored were at m/z 311, 314, and 411, which correspond to the protonated molecules (MH+) for ibogaine, ibogaine-d3, and 12-OH-ibogamine.tert-butyldimethylsilyl, respectively. Linear standard curves were obtained over the concentration range of 1 0-1 000 ng/mL (average r2, 0.995 for ibogaine and 0.992 for 12-OH-ibogamine; n = 3). Limits of quantitation were 10 ng/mL. The interrun and intrarun coefficients of variation for the assay of ibogaine at 25, 100, and 300 ng/mL ranged from 2.9 to 8.8%. We also established the extraction and chromatographic conditions to monitor the 12-hydroxylated metabolite. A suitable internal standard was not yet obtained so the method could only provide semiquantitative information for 12-OH-ibogamine. Chemical stability studies of these analytes indicated that ibogaine and 12-OH-ibogamine were stable in a human plasma matrix at room temperature for a period of at least 1 week.

Acetamides↗
PubMed1994

Naltrexone plasma levels, clinical response and effect on weight in autistic children.

This research measured naltrexone levels in plasma, to assess the relationship between behavioral response to naltrexone and plasma levels, and the effects of naltrexone on weight in hospitalized autistic children (n = 41). A double-blind, placebo-controlled, parallel groups design with fixed dose was used, with random assignment to naltrexone or placebo. Drug plasma levels were analyzed by gas chromatography/mass spectrometry, and weights were obtained weekly. Naltrexone levels measured in 17 children ranged from 0.12 to 5.60 ng/mL (mean = 0.71, standard error of the mean = 0.32). There was no relationship between plasma levels and age, level of intellectual functioning, scores on the 14 selected Children's Psychiatric Rating Scale (CPRS) items, Clinical Global Impressions, Global Clinical Consensus, and the CPRS hyperactivity factor. There was a trend (p = .06) for children receiving naltrexone in the highest weight percentile (> or = 90th) to lose weight (mean = -0.42 kg) but this was not the case for those in the lower weight percentiles (mean = +0.03 kg).

Autistic Disorder↗
PubMed1993

Stereoselective disposition: enantioselective quantitation of 3,4-(methylenedioxy) methamphetamine and three of its metabolites by gas chromatography/electron capture negative ion chemical ionization mass spectrometry.

A new chiral assay for 3,4-(methylenedioxy)methamphetamine (MDMA) and three of its metabolites in biological specimens is based on direct aqueous derivatization with N-heptafluorobutyryl-S-prolyl chloride, followed by capillary chromatographic separation of the diastereomeric derivatives and detection by a mass spectrometer operated in the electron capture negative ion chemical ionization mode. The assay is linear from 5 to 1000 ng ml-1 for each enantiomer and allows simultaneous quantitation of MDMA and three of its metabolites in biological specimens. Investigation of the disposition of racemic MDMA in rats and mice revealed quantitative differences in the disposition of the enantiomers of MDMA in these species; the most noteworthy result was a two-fold greater urinary excretion of the neurotoxic S-(+)-MDMA by mice. Only MDMA and 3,4-(methylenedioxy)amphetamine (MDA) enantiomers were detected at measurable concentrations in the frontal cortices and hippocampis from rats dosed with 10 mg kg-1 of racemic MDMA; in this species the enantiomeric profiles of these two compounds were similar in brain and urine.

3,4-Methylenedioxyamphetamine↗
PubMed1993

Gas chromatography/tandem mass spectrometry measurement of delta 9-tetrahydrocannabinol, naltrexone, and their active metabolites in plasma.

The combination of gas chromatography and mass spectrometry (GC/MS) is generally recognized as offering the best sensitivity and specificity for the detection and measurement of drugs and their metabolites in biological specimens. This finding has resulted in the widespread use of GC/MS in many areas of pharmacology and toxicology. However, a GC/MS assay can be performed in many ways, depending upon the specific requirements of the analytical tasks. For example, pharmacokinetic studies generally employ chemical ionization and single-ion monitoring to obtain optimum sensitivity, whereas GC/MS methods for confirmation of the presence of drugs of abuse in urine most often use electron ionization and multiple-ion monitoring to obtain conclusive results. Another example is the increasing use of the combination of gas chromatography and tandem mass spectrometry (GC/MS/MS) for analyses requiring sensitivities better than nanograms per milliliter. Examples of the application of GC/MS and GC/MS/MS methods for the detection of delta 9-tetrahydrocannabinol, naltrexone, and their active metabolites are described and compared in terms of sensitivity, specificity, and unique features.

Dronabinol↗
PubMed1993

Short-term effects of 2,4,5-trihydroxyamphetamine, 2,4,5-trihydroxymethamphetamine and 3,4-dihydroxymethamphetamine on central tryptophan hydroxylase activity.

In previous studies, we have reported the long-term effects of several metabolites of 3,4-methylenedioxymethamphetamine (MDMA) on tryptophan hydroxylase (TPH) activity. In this study, the short-term effects of three metabolites of MDMA. 2,4,5-trihydroxyamphetamine (THA), 2,4,5-trihydroxymethamphetamine (THM) and 3,4-dihydroxymethamphetamine, and the in vitro effect of THA on TPH activity are reported. After short-term treatment, hippocampal TPH activity was decreased to 8 and 54% of control in response to THA and THM, respectively, but was unaltered after 3,4-dihydroxymethamphetamine. Incubating TPH from THM-treated rats with dithiothreitol under nitrogen failed to reverse the decrease in enzyme activity induced by THM treatment. THA also decreased tyrosine hydroxylase activity to 75% of control, whereas the enzyme activity remained unaltered by THM. The structural analog of THA, 6-hydroxydopamine, failed to reproduce the effect of THA on TPH activity; however, 5,6-dihydroxytryptamine decreased hippocampal TPH activity to 18% of control. In the in vitro study, the hippocampus and the striatum were incubated in varying concentrations of THA. After a 1-h incubation at 37 degrees C, hippocampal TPH activity was decreased to 83, 71, 68, 47 and 3% of control after exposure to 0.001, 0.01, 0.1, 0.5 or 5.0 mM THA, respectively; striatal TPH activity was reduced to 98, 95, 70, 54 and 17% of control, respectively. Incubating the enzyme under reducing conditions failed to restore the enzyme activity to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

5,6-Dihydroxytryptamine↗
PubMed1992

Long-term alteration in the central monoaminergic systems of the rat by 2,4,5-trihydroxyamphetamine but not by 2-hydroxy-4,5-methylenedioxymethamphetamine or 2-hydroxy-4,5-methylenedioxyamphetamine.

The long-term effects of three metabolites of 3,4-methylenedioxymethamphetamine (MDMA) on the central monoaminergic systems of the rat were examined. Seven days after the intracerebroventricular administration of 0.25 and 0.5 mumol 2,4,5-trihydroxyamphetamine, hippocampal tryptophan hydroxylase (TPH) activity was reduced to 5 and 1% of control, respectively, while norepinephrine (NE) concentration was depressed to 10 and 18% of control. These two respective dosages also decreased striatal tyrosine hydroxylase (TH) activity to 67 and 10% of control, respectively, while nigral TH activity was reduced to 59 and 20% of control. Striatal TPH activity was reduced to 74 and 81% of control, respectively, while the activity in the dorsal and median raphe remained unaltered. The intracerebroventricular administration of 1 mumol 2-hydroxy-4,5-methylenedioxymethamphetamine (6-OH-MDMA) failed to alter TPH activity, TH activity or NE concentration after 14 days. In contrast, 1 mumol of 2-hydroxy-4,5-methylenedioxyamphetamine (6-OH-MDA) induced a 30% increase in striatal TPH activity and a 50% increase in nigral TH activity. The study of the formation of 2,4,5-trihydroxyamphetamine after MDMA treatment may provide insight as to how MDMA destroys serotonergic nerve terminals.

3,4-Methylenedioxyamphetamine↗
PubMed1992

Chromatographic and mass spectrometric methods for determination of lysergic acid diethylamide (LSD) and metabolites in body fluids.

Continued illicit use of the potent psychedelic drug lysergic acid diethylamide (LSD) has stimulated efforts to develop effective analytical methods for detection of the drug and its metabolites in body fluids from suspected LSD users. Recently reported methods based on gas and liquid chromatography, combined with single- and multiple-stage mass spectral analysis, now permit accurate detection and quantitation of LSD at sub-nanogram/milliliter concentrations.

Body Fluids↗
PubMed1992

Determination of lysergic acid diethylamide (LSD), iso-LSD, and N-demethyl-LSD in body fluids by gas chromatography/tandem mass spectrometry.

Procedures for detection and quantitation of lysergic acid diethylamide (LSD), iso-LSD, and N-demethyl-LSD by capillary chromatography/tandem mass spectrometry (GC/MS/MS) are presented. Several methods for derivatization, sample introduction, and ionization, in combination with mass spectrometry/mass spectrometry (MS/MS), have been evaluated for overall ionization efficiency and product-ion sensitivity and specificity. Fragmentation pathways derived from low-energy collision-induced dissociation (CID) spectra of protonated LSD, and the protonated trimethylsllyl derivatives of LSD (LSD-TMS) and deuterium-labeled analogs of LSD, have been proposed. Principal dissociations primarily involve the amide and piperidine-ring moieties in which losses of CH3 radical, CH3NH2, CH3NCH2, diethylamine, diethylformamide, and N,N-diethylpropenamide from MH+ are observed. Positive-ion ammonia chemical ionization and subsequent MS/MS analysis of the protonated molecules (MH+) of the trimethylsilyl (TMS) derivatives of LSD, iso-LSD, and N-demethyl-LSD provide a high degree of specificity for identification of these compounds in urine or blood at low-pg/mL concentrations. Negative-ion chemical ionization and GC/MS/MS analysis of the molecular anion (M-) of the trifluoroacetyl (TFA) derivative is well suited for trace-level identification of N-demethyl-LSD, a metabolite of LSD.

Body Fluids↗
PubMed1992

Comparative investigation of disposition of 3,4-(methylenedioxy)methamphetamine (MDMA) in the rat and the mouse by a capillary gas chromatography-mass spectrometry assay based on perfluorotributylamine-enhanced ammonia positive ion chemical ionization.

A gas chromatography-mass spectrometry assay based on perfluorotributylamine-enhanced ammonia positive ion chemical ionization has been developed for MDMA and three of its primary metabolites in biological specimens; the assay is linear from 2 to 1000 ng ml-1. Quantitatively, more of an administered dose of 10 mg kg-1 MDMA was excreted by the mouse (72%) than by the rat (35%); most in both species was excreted in urine and within 24 h. The difference in per cent excretion is entirely due to proportionally greater excretion of the parent drug by the mouse. 4-Hydroxy-3-methoxymethamphetamine (HMM) is the major urinary metabolite in both species. HMM and another primary metabolite, 4-hydroxy-3-methoxyamphetamine (HMA), were excreted mainly as glucuronide and sulphate conjugates (> 85%).

3,4-Methylenedioxyamphetamine↗
PubMed1992

Effects of 3,4-dihydroxymethamphetamine and 2,4,5-trihydroxymethamphetamine, two metabolites of 3,4-methylenedioxymethamphetamine, on central serotonergic and dopaminergic systems.

The effects of 3,4-dihydroxymethamphetamine (DHM) and 2,4,5-trihydroxymethamphetamine (THM) on central serotonergic and dopaminergic systems were investigated to determine if these metabolites share the neurochemical properties of 3,4-methylenedioxymethamphetamine. THM (50-200 micrograms) or DHM (135 micrograms) was administered i.c.v. to rats; 5 days later, cortical, striatal and hippocampal tryptophan hydroxylase (TPH) activity were decreased by THM in a dose-dependent manner, whereas DHM was without effect in these brain structures. The concentration of serotonin in the brain structures contralateral to the side of THM injection was also decreased, but to a lesser degree. THM (100 and 200 micrograms) increased TPH activity to 155% of control in the dorsal raphe, whereas a dose of 50 micrograms increased TPH activity to 132% of control in the median raphe nucleus. THM also markedly reduced striatal tyrosine hydroxylase activity, but did not alter enzyme activity in the substantia nigra; DHM increased striatal tyrosine hydroxylase activity to 115% of control. These results suggest that THM, but not DHM, is toxic to both dopaminergic and serotonergic nerve terminals. Although THM could not be established as the neurotoxic metabolite explaining 3,4-methylenedioxymethamphetamine (MDMA) toxicity, its properties may prove useful in elucidating amphetamine toxicity.

3,4-Methylenedioxyamphetamine↗
PubMed1991

In vivo formation of aromatic hydroxylated metabolites of 3,4-(methylenedioxy)methamphetamine in the rat: identification by ion trap tandem mass spectrometric (MS/MS and MS/MS/MS) techniques.

Aromatic hydroxylation has been established as a pathway for the in vivo metabolism of 3,4-(methylenedioxy)methamphetamine (MDMA) in the rat. Hydroxylation occurred at positions 2, 5 and 6 of the 3,4-methylenedioxyphenyl ring, but is favored at the 6 position. All three regioisomers of both hydroxy-MDMA and hydroxy-3,4-(methylenedioxy)amphetamine (hydroxy-MDA) were detected in the rat liver when 20 mg kg-1 of MDMA was administered. However, 6-hydroxy-MDMA and 6-hydroxy-MDA were the only hydroxylated metabolites detected in the rat brain and plasma and no hydroxylated metabolites were detected in the urine. The hydroxylated metabolites were identified by co-injection of synthetic reference compounds and comparison of the mass spectra of the trifluoroacetyl derivatives of the metabolites with the synthesized reference compounds. The regioisomers of both hydroxy-MDMA and hydroxy-MDA could not be distinguished by either single-stage or two-stage mass analysis. However, employment of a third stage of mass analysis produced distinctly different mass spectra for each of the three regioisomers.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Naltrexone in autistic children: an acute open dose range tolerance trial.

The safety and efficacy of naltrexone was explored in an open acute dose range tolerance trial in 10 hospitalized autistic children, ages 3.42 to 6.50 years (mean, 5.04). Naltrexone was given in ascending doses: 0.5, 1.0, and 2.0 mg/kg/day. Behavioral side effects were observed as early as 1/2 hour after dosing. Ratings on the Children's Psychiatric Rating Scale showed that withdrawal was reduced across all three dose levels; administration of 0.5 mg/kg/day dose resulted in increased verbal production; and the 2.0 mg/kg/day dose resulted in reduction of sterotypies. Mild sedation of brief duration was the only side effect. Electrocardiogram, liver function tests, and all other laboratory studies remained unchanged throughout the study. These preliminary findings require replication in a larger sample of patients under double-blind and placebo controlled condition.

Autistic Disorder↗
PubMed1985

Clinical evaluation of a naltrexone sustained-release preparation.

A clinical evaluation of the naltrexone bead, a biodegradable sustained-release dosage form of 3.0 mg in weight containing 70% naltrexone in a copolymer of lactic and glycolic acids, was carried out in 4 healthy normal males. Subjects were given an intravenous dose of 10 mg naltrexone and approx. 1 week later a 63-mg dose of naltrexone by subcutaneous administration of the beads. Challenge doses of 15 mg morphine were given to each subject during the study for the assessment of narcotic blockade effects of naltrexone. For a 2-4-week period after bead administration, relatively constant plasma levels were maintained at 0.30-0.46 ng/ml for naltrexone and were 0.64-1.07 ng/ml for naltrexol. Urine levels for unchanged and conjugated naltrexone were 79-215 ng/ml and for naltrexol were 315-500 ng/ml. From kinetic analysis, an average of 2.4-2.7% of implanted dose was absorbed each day from the administration of the beads. Opiate effects of morphine challenges were mitigated during the 2-4-week period after administration of naltrexone beads.

Delayed-Action Preparations↗
PubMed1985

Pharmacokinetic interaction of propoxyphene with ethanol.

In order to study the effects of ethanol on the pharmacokinetics of propoxyphene, six healthy male volunteers were each given (1) propoxyphene 65 mg p.o. preceded by 1 h by ethanol 0.9 g/kg lean body weight and followed for 7.5 h by ethanol dosed to maintain breath ethanol at 800-1000 mg/l; and (2) propoxyphene 65 mg p.o. with orange juice in the same volume and frequency as ethanol. Ethanol did not induce any significant changes in apparent t 1/2 or Cmax of propoxyphene or norpropoxyphene. The average norpropoxyphene/propoxyphene ratio decreased by a mean 36%.

Adult↗