Endorphins in psychiatry: an overview and a hypothesis.

This article presents an overview of the biochemistry, pharmacology, and physiology of endogenous opioid peptides (endorphins). Clinical psychopharmacology of exogenous opiate agonists and antagonists is reviewed. The evidence presented in the review is compatible with a hypothesis that the level of functional endorphins may be related to psychological events, with a normal level needed for psychological homeostasis. One corollary of this hypothesis is that the level of opioids in the brains of the mentally ill may be disturbed. Therapeutic implications of this hypothesis are considered.

Loss of the cortisol response to naltrexone in Alzheimer's disease.

The administration of a single dose of the opiate antagonist naltrexone (NT) was accompanied by significant elevations in plasma cortisol in normal elderly subjects; in contrast, the cortisol response to NT was absent in individuals of comparable age with Alzheimer's disease (AD). The differential effect of AD on the cortisol response was not accompanied by a significant group difference in plasma prolactin in response to NT administration. Furthermore, this differential cortisol response to NT was not associated with any evident differences in age, sex ratio, plasma levels of naltrexone or its major metabolite beta-naltrexol, or with differences in measures of nonspecific stress, such as plasma free MHPG, pulse, or blood pressure, between the two groups. The absence of the well-characterized cortisol response to NT in AD, together with other reports of abnormal responses to other pharmacological challenges, suggests that neuroendocrine abnormalities might be an important concomitant and possibly a central contributor to the pathophysiology of Alzheimer's disease.

Naltrexone: disposition, metabolism, and effects after acute and chronic dosing.

The disposition of naltrexone during acute and chronic administration of 100-mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 +/- 29.9 ng/ml at 1 hr and for the major biotransformation product, beta-naltrexol, was 87.2 +/- 25.0 ng/ml at 2 hr. Twenty-four hours after the dose the X levels of naltrexone and beta-naltrexol declined to 2.1 +/- 0.47 and 17.6 +/- 5.0 ng/ml, respectively. Following chronic administration and X peak plasma levels of naltrexone and beta-naltrexol rose to 46.4 +/- 18.5 and 158.4 +/- 89.9 ng/ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and beta-naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady-state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and beta-naltrexol in the first 24 hr. The half-life of naltrexone and beta-naltrexol decreased slightly from the acute to thechronic study from 10.3 +/- 3.3 to 9.7 +/- 1.1 hr and from 12.7 +/- 2.6 to 11.4 +/- 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half-life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6% while urinary excretion was 38% and 70% of the dose in a 24-hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half-life of naltrexone and opiate antagonism it was 0.99.

Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene.

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130-mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and in former heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first-pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, "maintenance" patients exhibited steady-state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 2210 ml/min, P half-life (t 1/2) increased from 3.3 to 11.8 hr, NP t 1/2 increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single-dose kinetic profile. Changes in the extent of first-pass elimination of P result in variability in plasma P and NP that may contribute to P-induced toxicity.

Phencyclidine-induced stereotype in rats: effects of methadone, apomorphine, and naloxone.

Phencyclidine (PCP) given to male Wistar rats produced hyperactivity and various stereotypic motor behaviors. Methadone, apomorphine, and naloxone were tested for their effects on PCP-induced stereotypy. Methadone (0.5 mg/kg) had no effect on the hyperactivity produced by PCP, but significantly attenuated PCP-induced stereotypy when given both before and after PCP. Low doses of apomorphine were equally effective as methadone in attenuating PCP-induced stereotypy. However, when naloxone was given after methadone or apomorphine to PCP-treated rats, the full PCP-induced stereotypy was again observed. Naloxone pretreatment on doses up to 20 mg/kg was not effective in antagonizing PCP-induced behavioral effects. Methadone and apomorphine antagonism of PCP-induced stereotypy may be mediated by opiate receptors. The results of this study and observations from human studies collectively suggest the possible effectiveness of opiates in treating PCP-induced and functional psychoses.

Confirmation of EMIT benzodiazepine assay with GLC/NPD.

A simple, rapid, and reliable gas-liquid chromatographic (GLC) confirmation procedure was developed for urine samples found positive by the EMIT-dau benzodiazepine metabolite assay. The procedure involves acid hydrolysis, organic extraction, and identification using GLC-nitrogen-phosphorus detection (NPD). The method was validated in three subjects who took 10 mg diazepam daily for five days. Urinary excretion of the diazepam related substances was monitored quantitatively for 12 days. Considerable differences in diazepam metabolism was observed, despite the small number of subjects used. The data further indicated that both the physical characteristics and the metabolic profile of each individual may determine whether or not their occasional benzodiazepine use would be detected by the EMIT procedure. In some individuals taking daily diazepam, 48 to 72 hours may be required before sufficient metabolites accumulate in the urine to give a positive EMIT reaction.

Rapid, sensitive micro blood lead analysis: a mass screening technique for lead poisoning.

A rapid micro blood lead method is described. Analyses were performed on 20-microL blood samples spotted on filter paper, collected in graduated heparinized capillary glass tubes following finger pricks. The samples were air dried on filter paper and mailed to the laboratory in glassine envelopes. These samples stored on filter paper are stable for at least six months. The blood spots were punched out with a 1/4-in. diameter hole punch and placed in Delves cups for insertion into the flame atomic absorption spectrometer. The innovation of this method is that an ashing step precedes sample introduction into the flame. In phase 1, the Delves cup with the blood sample is pushed 1 cm from the flame. The heat is sufficient for the filter paper to ignite and burn to completion in seconds. After the smoke dissipates, the samples are introduced into the flame for lead analysis, reading the signal at 283.3 nm. The entire analysis time is 15 s per sample. The limit of quantitation is 4 micrograms/dL of lead. Standard curves were linear from 4-42 micrograms/dL. The average CV for this range is 8.2%. The comparative study between the MIBK extraction method and this method yielded a correlation coefficient r = .99 (n = 55). The method is fast, practical, economical, and easily adaptable to screen large numbers of micro lead samples.

A rapid, quantitative GLC method for the simultaneous determination of nicotine and cotinine.

Published gas-liquid chromatographic (GLC) methods for the determination of nicotine and cotinine have proved impractical for the analysis of a large number of clinical samples. Significant improvements over other methods have been achieved, being low sample volume (0.5 mL plasma), rapid two-step extraction from plasma, no evaporation step, and good separation. The lower limits of sensitivity for nicotine and cotinine were 1 and 5 ng/mL, respectively. The method was validated by the analysis of plasma samples from cigarette-smoking volunteers. The method described permits the quick, routine determination of nicotine and cotinine in a large number of samples.

Quantitative determination of 2-hydroxy-3-methoxy-6 beta-naltrexol (HMN), naltrexone, and 6 beta-naltrexol in human plasma, red blood cells, saliva, and urine by gas liquid chromatography.

Two gas liquid chromatographic methods differing mainly in sensitivity are described for the quantitative determination of 2-hydroxy-3-methoxy-6 beta-naltrexol (HMN), a minor metabolite of naltrexone (NT), in human body-fluids. The methods also incorporate simultaneous determinations of naltrexone and its major human metabolite, 6 beta-naltrexol (beta-OL), in urine, serum (or plasma), red blood cells (RBC), and saliva. Flame ionization detection of the bis-(trimethylsylil) trifluoroacetamide (BSTFA) derivatives provided sufficient sensitivity for quantitation of the bases in urine. However, lower levels in serum, RBC and saliva necessitated the use of more sensitive electron capture detection of the pentafluoropropionate (PFPA) derivatives of the bases. Because HMN and 6 beta-naltrexol PFPA derivatives have nearly identical gas chromatographic retention times, their separation was achieved by differential extraction, based on their different partition characteristics between aqueous and organic solvents. In the plasma of 4 subjects, 16 and 24 hrs. after 2 X 200 mg NT doses, the relative percentages were 23.1% HMN, 3.4% NT and 73.5% beta-OL. In urine samples collected at the same time as the blood samples the relative percentages were 14.4% HMN, 9.0% NT and 76.6% beta-OL. The nonpolar nature of HMN and the greater polarity of beta-OL may have influenced their differential distribution into RBCs and saliva. In the RBCs, 96.1% HMN and no significant amount of beta-OL was found, in saliva, 92.3% of beta-OL and no HMN was found.

Rapid confirmation of enzyme multiplied immunoassay technique (EMIT) cocaine positive urine samples by capillary gas-liquid chromatography/nitrogen phosphorus detection (GLC/NPD).

A rapid gas-liquid chromatographic (GLC) method was developed for the confirmation of benzoylecgonine (BE) positive urine samples screened by the enzyme multiplied immunoassay technique (EMIT) assay. The procedure is performed by solvent extraction of BE from 0.1 or 0.2 mL of urine, followed by an aqueous wash of the solvent and evaporation. The dried residue was derivatized with 50 microL of pentafluoropropionic anhydride and 25 microL of pentafluoropropropanol at 90 degrees C for 15 min. The derivatizing reagents were evaporated to dryness, and the derivatized BE, and cocaine if present, were reconstituted and injected into the gas chromatograph. The column was a 15-m by 0.2-mm fused silica capillary column, coated with 0.25 micron of DB-1, terminating in a nitrogen phosphorus detector (NPD). Cocaine and the pentafluoro BE derivatives retention times were 3.2 and 2.6 min, respectively. Nalorphine was used as reference or internal standard with a retention time of 4.78 min. The complete procedure can be performed in approximately 1.5 h. The EMIT cutoff between positive and negative urine samples is 300 ng/mL of BE. The lower limit of sensitivity of this method is 25 ng of BE extracted from urine. Validation studies resulted in confirmation of 101 out of 121 EMIT cocaine positive urine samples that could not be confirmed by thin-layer chromatography (TLC). This represents 84% confirmation efficiency.

Capillary gas-liquid chromatography separation of phenethylamines in amphetamine-positive urine samples.

Good gas chromatography (GC) separation of molecules is essential for clean gas chromatography/mass spectrometry (GC/MS) confirmation of compounds. The trifluoro derivatives of ephedrine (E) and methamphetamine (MA) coelute on dimethyl silicone capillary columns, such as DB-1, which are most commonly used by chromatographers. Methods are described to separate E and MA to aid GC/MS confirmations of methamphetamine, ephedrine, or both E and MA together, whichever may be present in Enzyme Immunoassay (EIA)-analyzed amphetamine-positive urine samples. The use of the heptafluoro derivatives of E and MA on a DB-1 column, or the trifluoro derivatives of E and MA on a DB-17 column, is suggested for good gas chromatographic separation.

Simultaneous determination of nicotine and cotinine in human plasma by nitrogen detection gas-liquid chromatography.

Human plasma levels of nicotine and its principal metabolite, cotinine, were simultaneously quantitated by gas-liquid chromatography combined with nitrogen selective detection. Nicotine, cotinine, and the added internal standard ketamine are extracted from plasma at basic pH into methylene chloride, back-extracted into acid, and then re-extracted into methylene chloride. Analysis is carried out on a packed glass column of 3% SE-30 while column temperature is programmed from 150 to 200 degrees C. Detector response is linea over the range of 2 to 50 ng/mL nicotine and 50 to 500 ng/mL cotinine. The method was validated on 150 plasma samples obtained from habitual smokers. Mean levels of 19.5 and 219 ng/mL were found for nicotine and cotinine, respectively. Both the mean and the range of the levels were in agreement with previously reported plasma levels for nicotine and cotinine.

The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics.

The time-action of opiate antagonist activity of naltrexone was evaluated in detoxified ex-opiate addicts, using 25 mg intravenous heroin challenges. A 100 mg naltrexone dose provided 96% blockade at 24 hr, 86.5% blockade at 48 hr and 46.6% blockade at 72 hr. Following oral administration, naltrexone was rapidly and completely absorbed. Peak levels of naltrexone and its major metabolite 6 beta-naltrexol were reached 1 hr after the dose. The high 6 beta-naltrexol plasma concentrations only 1 hr after drug administration indicate a rapid biotransformation process, converting a large fraction of the dose to less active metabolites. Over 70% of the dose was excreted in the 24 hr urine and less than 0.5% in the feces. No change was observed in the rate of naltrexone disposition during chronic dosing vs. the acute study, indicating no metabolic induction. The rapid achievement of steady state naltrexone plasma levels eliminates the need of stepwise induction at the beginning of naltrexone treatment.

Quantitative determination of naltrexone, 6 beta-naltrexol and 2-hydroxy-3-methoxy-6 beta-naltrexol (HMN) in human plasma, red blood cells, saliva and urine by gas liquid chromatography.

Two gas liquid chromatographic methods differing mainly in sensitivity are described for the quantitative determination of naltrexone (NT) and its metabolites in human biofluids. Flame ionization detection of the N,O-bis-(trimethylsilyl) trifluoroacetamide (BSTFA) derivatives provided sufficient separation and sensitivity for quantitative of the bases in urine. However, the thousand times lower levels in serum, red blood cells (RBC) and saliva necessitated the use of more sensitive electron capture detection methods of the pentafluoro derivatives of NT and its metabolites. The 2-hydroxy-3-methoxy-6 beta-naltrexol (HMN) and 6 beta-naltrexol (beta-OL) pentafluoro derivatives had nearly identical gas liquid chromatographic retention times in a number of stationary liquid phases. Thus, their separation had to be achieved prior to chromatography. Differential extraction was based on the different partition characteristics of HMN and 6 beta-naltrexol between aqueous and organic solvents. Applicability of the methods was tested using the biofluids of four subjects taking 2 x 200 mg naltrexone per day chronically. Blood, saliva and urine samples were collected at the same time (prior to drug administration), which was 16 and 24 hours after the doses. In the plasma the relative percentages of the bases were 73.5 beta-OL; 23.1 HMN and 3.4 NT. The same in the urine were 76.6 beta-OL, 14.4 HMN and 9.0 NT. The lipophilic nature of HMN and the hydrophilic property of beta-OL may have influenced their distribution into RBC and saliva. In the RBC 96.1% HMN and only trace amounts of beta-OL distributed and in saliva 92.3% of beta-OL and no HMN was found; the difference in both cases was made up by naltrexone to 100%.

Interaction of d-propoxyphene and diphenylhydantoin in rat liver microsomal preparation.

Inhibition of diphenylhydantoin biotransformation by d-propoxyphene and the ihibition of d-propoxyphene metabolism by diphenylhydantoin was studied in rat liver microsomal 9000 x g supernatant preparations. The parahydroxylation of diphenylhydantoin was inhibited 98% by 5 x 10(-4)M concentration of d-propoxyphene in a noncompetitive manner with a Kj of 3.2 +/- 1.6 x 10(-5)M. Only 18% inhibition of the N-demethylation of d-propoxyphene was observed at clinically unrealistic diphenylhydantoin concentrations of 10(-3)M. The in vitro studies suggest that the inhibition of diphenylhydantoin metabolism by d-propoxyphene may result in toxicity when the two drugs are chronically administered together.

Quantitative determination of haloperidol in human plasma by high-performance liquid chromatography.

We present a method for the quantitative determination of haloperidol in human plasma. The high-performance liquid chromatographic method of analysis is a significant advancement in terms of ease and speed of haloperidol determination. The drug and the internal standard, chlorohaloperidol, are extracted from 2.0 ml of serum or plasma, back-extracted into the aqueous mobile phase, separated on a C-18 reversed-phase column, and monitored at 254 nm. The potential interference by other drugs was evaluated and was found to be negative. The method is sensitive to at least 5 ng/ml of extracted material and is suitable for drug measurement in the therapeutic range (5-20 ng/ml) and in the toxic range (greater than 50 ng/ml).

Methadone dose, plasma level, and cross-tolerance to heroin in man.

The development of cross-tolerance between methadone and heroin was studied in postaddict volunteers who had been drug-free for at least 6 weeks. Two methadone dose schedules were used; each was employed in six subjects. One schedule brought the subjects to a dose of 40 mg, while the other brought them to 80 mg of methadone a day. Subjects received injections of heroin (0.214 mg/kg) and placebo at various times before and during methadone treatment. Pupillary and subjective effects of injections were measured. Plasma levels of methadone were determined concurrently. Subjects on both treatment schedules developed an incomplete cross-tolerance to this dose of heroin. As the dose and plasma level of methadone increased with time, the cross-tolerance to all heroin effects increased. Plasma levels did not affect the development of cross-tolerance independently of methadone dose. The most important contribution to the cross-tolerance to pupillary effects was made by the duration of methadone treatment. Furthermore, the cross-tolerance to the subjective effects of heroin developed earlier than that to the pupil effect.

Estimation of the systemic availability and other pharmacokinetic parameters of naltrexone in man after acute and chronic oral administration.

First pass metabolism, metabolic clearance, volume of distribution and steady state plasma levels were estimated in man following acute and chronic 100 mg oral doses of naltrexone. Essentially no statistical differences was observed in these values between the acute and chronic physiologic state. The values for the first pass effect were 79.6 +/- 4.6% and 78.0 +/- 3.0% for acute and chronic treatment respectively. From our pharmacokinetic data an apparent chronic release rate (ACRR) for a sustained release preparation of naltrexone was calculated as 11.8 microgram/kg/hr. In practice a release rate of one half the ACRR should be sufficient to provide continuous antagonism of 25 mg i.v. heroin. In conclusion our data clearly indicate that naltrexone is an effective and safe narcotic antagonist in man.