Topical ophthalmic atropine in horses, pharmacokinetics and effect on intestinal motility.

BACKGROUND: Topical ophthalmic atropine sulfate is an important part of the treatment protocol in equine uveitis. Frequent administration of topical atropine may cause decreased intestinal motility and colic in horses due to systemic exposure. Atropine pharmacokinetics are unknown in horses and this knowledge gap could impede the use of atropine because of the presumed risk of unwanted effects. Additional information could therefore increase safety in atropine treatment. RESULTS: Atropine sulfate (1 mg) was administered in two experiments: In part I, atropine sulfate was administered intravenously and topically (manually as eye drops and through a subpalpebral lavage system) to six horses to document atropine disposition. Blood-samples were collected regularly and plasma was analyzed for atropine using UHPLC-MS/MS. Atropine plasma concentration was below lower limit of quantification (0.05 µg/L) within five hours, after both topical and IV administration. Atropine data were analyzed by means of population compartmental modeling and pharmacokinetic parameters estimated. The typical value was 1.7 L/kg for the steady-state volume of distribution. Total plasma clearance was 1.9 L/h‧kg. The bioavailability after administration of an ophthalmic preparation as an eye drop or topical infusion were 69 and 68%, respectively. The terminal half-life was short (0.8 h). In part II, topical ophthalmic atropine sulfate and control treatment was administered to four horses in two dosing regimens to assess the effect on gastro-intestinal motility. Borborygmi-frequency monitored by auscultation was used for estimation of gut motility. A statistically significant decrease in intestinal motility was observed after administration of 1 mg topical ophthalmic atropine sulfate every three hours compared to control, but not after administration every six hours. Clinical signs of colic were not observed under any of the treatment protocols. CONCLUSIONS: Taking the plasma exposure after topical administration into consideration, data and simulations indicate that eye drops administrated at a one and three hour interval will lead to atropine accumulation in plasma over 24 h but that a six hour interval allows total washout of atropine between two topical administrations. If constant corneal and conjunctival atropine exposure is required, a topical constant rate infusion at 5 µg/kg/24 h offers a safe alternative.

Pharmacokinetics after a single dose of naloxone administered as a nasal spray in healthy volunteers.

BACKGROUND: There is increasing interest in the use of intranasal naloxone to reverse adverse opioid effects during management of procedural pain in children and in adults after overdose. There are limited data on the pharmacokinetics of intranasal naloxone so in this study we aimed to detail the pharmacokinetic profile of the commercially marketed injectable solution of naloxone 0.4 mg/ml when administered as an intranasal spray. METHODS: Twenty healthy volunteers received naloxone as an intranasal spray at a dose of 10 µg/kg. Venous blood sampling was carried out for 90 min after administration to determine the time profile of the plasma concentrations of using tandem mass spectrometry. Pharmacokinetic parameters were calculated using a one-compartment model. RESULTS: Median time to maximum naloxone concentration (Tmax) was 14.5 (95% CI: 9.0-16.5) min, mean maximum naloxone concentration (Cmax) was 1.09 ± 0.56 ng/ml and mean AUC0-90 min was 37.1 ± 15.0 ng*min/ml. Elimination half-life estimated from the median concentration data was 28.2 min. CONCLUSION: Our results show a faster uptake of intranasal naloxone to maximum concentration compared with previous studies although with a marked variation in maximum concentration. The findings are consistent with our clinical experience of the time profile for reversing the effects of sufentanil sedation in children.

Nickel in equine sports drug testing - pilot study results on urinary nickel concentrations.

RATIONALE: The issue of illicit performance enhancement spans human and animal sport in presumably equal measure, with prohibited substances and methods of doping conveying both ways. Due to the proven capability of unbound ionic cobalt (Co(2) (+) ) to stimulate erythropoiesis in humans, both human and equine anti-doping regulations have listed cobalt as a banned substance, and in particular in horse drug testing, thresholds for cobalt concentrations applying to plasma and urine have been suggested or established. Recent reports about the finding of substantial amounts of undeclared nickel in arguably licit performance- and recovery-supporting products raised the question whether the ionic species of this transition metal (Ni(2) (+) ), which exhibits similar prolyl hydroxylase inhibiting properties to Co(2) (+) , has been considered as a substitute for cobalt in doping regimens. METHODS: Therefore, a pilot study with 200 routine post-competition doping control horse urine samples collected from animals participating in equestrian, gallop, and trotting in Europe was conducted to provide a first dataset on equine urinary Ni(2) (+) concentrations. All specimens were analyzed by conventional inductively coupled plasma mass spectrometry (ICP-MS) to yield quantitative data for soluble nickel. RESULTS: Concentrations ranging from below the assay's limit of quantification (LOQ, 0.5 ng/mL) up to 33.4 ng/mL with a mean value (± standard deviation) of 6.1 (±5.1) ng/mL were determined for the total nickel content. CONCLUSIONS: In horses, nickel is considered a micronutrient and feed supplements containing nickel are available; hence, follow-up studies are deemed warranted to consolidate potential future threshold levels concerning urine and blood nickel concentrations in horses using larger sets of samples for both matrices and to provide in-depth insights by conducting elimination studies with soluble Ni(2) (+) -salt species. Copyright © 2016 John Wiley & Sons, Ltd.

A quantitative approach to analysing cortisol response in the horse.

The cortisol response to glucocorticoid intervention has, in spite of several studies in horses, not been fully characterized with regard to the determinants of onset, intensity and duration of response. Therefore, dexamethasone and cortisol response data were collected in a study applying a constant rate infusion regimen of dexamethasone (0.17, 1.7 and 17 µg/kg) to six Standardbreds. Plasma was analysed for dexamethasone and cortisol concentrations using UHPLC-MS/MS. Dexamethasone displayed linear kinetics within the concentration range studied. A turnover model of oscillatory behaviour accurately mimicked cortisol data. The mean baseline concentration range was 34-57 µg/L, the fractional turnover rate 0.47-1.5 1/h, the amplitude parameter 6.8-24 µg/L, the maximum inhibitory capacity 0.77-0.97, the drug potency 6-65 ng/L and the sigmoidicity factor 0.7-30. This analysis provided a better understanding of the time course of the cortisol response in horses. This includes baseline variability within and between horses and determinants of the equilibrium concentration-response relationship. The analysis also challenged a protocol for a dexamethasone suppression test design and indicated future improvement to increase the predictability of the test.

Plasma concentration-dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone-21-isonicotinate.

Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03 mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 ± 2.9 days (LLOQ: 0.025 µg/L) and in urine for 9.8 ± 3.1 days (LLOQ: 0.15 µg/L). Maximum observed dexamethasone concentration in plasma was 0.61 ± 0.12 µg/L and in urine 4.2 ± 0.9 µg/L. Terminal plasma half-life was 38.7 ± 19 h. Hydrocortisone was significantly suppressed for 140 h. The plasma half-life of hydrocortisone was 2.7 ± 1.3 h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 ± 0.04 µg/L, 0.95 ± 0.04 and 6.2 ± 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.

Synthesis, characterization, and detection of new oxandrolone metabolites as long-term markers in sports drug testing.

The discovery and implementation of the long-term metabolite of metandienone, namely 17ß-hydroxymethyl-17α-methyl-18-norandrost-1,4,13-trien-3-one, to doping control resulted in hundreds of positive metandienone findings worldwide and impressively demonstrated that prolonged detection periods significantly increase the effectiveness of sports drug testing. For oxandrolone and other 17-methyl steroids, analogs of this metabolite have already been described, but comprehensive characterization and pharmacokinetic data are still missing. In this report, the synthesis of the two epimeric oxandrolone metabolites-17ß-hydroxymethyl-17α-methyl-18-nor-2-oxa-5α-androsta-13-en-3-one and 17α-hydroxymethyl-17ß-methyl-18-nor-2-oxa-5α-androsta-13-en-3-one-using a fungus (Cunninghamella elegans) based protocol is presented. The reference material was fully characterized by liquid chromatography nuclear magnetic resonance spectroscopy and high resolution/high accuracy mass spectrometry. To ensure a specific and sensitive detection in athlete's urine, different analytical approaches were followed, such as liquid chromatography-tandem mass spectrometry (QqQ and Q-Orbitrap) and gas chromatography-tandem mass spectrometry, in order to detect and identify the new target analytes. The applied methods have demonstrated good specificity and no significant matrix interferences. Linearity (R(2) > 0.99) was tested, and precise results were obtained for the detection of the analytes (coefficient of variation <20%). Limits of detection (S/N) for confirmatory and screening analysis were estimated at 1 and 2 ng/mL of urine, respectively. The assay was applied to oxandrolone post-administration samples to obtain data on the excretion of the different oxandrolone metabolites. The studied specimens demonstrated significantly longer detection periods (up to 18 days) for the new oxandrolone metabolites compared to commonly targeted metabolites such as epioxandrolone or 18-nor-oxandrolone, presenting a promising approach to improve the fight against doping.

High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension.

PURPOSE: To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). METHODS: Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. RESULTS: The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C(max)) was 21.4 ± 1.7 µg/L, (2) the normalized C(max) (C(max, norm)) 79.1 ± 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 ± 1.6 µg · h/L and (4) the normalized AUC (AUC(norm)) 261.6 ± 1.7 g · h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C(max), C(max, norm), AUC and AUC(norm). CONCLUSION: The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.

Pharmacokinetics of meloxicam in adult goats and its analgesic effect in disbudded kids.

The pharmacokinetics and analgesic effect of the nonsteroidal anti-inflammatory drug meloxicam (0.5 mg/kg) in goats were investigated. In a randomized, cross-over design the pharmacokinetic parameters were investigated in adult goats (n = 8) after single intravenous and oral administration. The analgesic effect was evaluated in kids using a randomized, placebo controlled and blinded protocol. Kids received meloxicam (n = 6) once daily and their siblings (n = 5) got isotonic NaCl intramuscularly while still anaesthetized after cautery disbudding and injections were repeated on three consecutive days. In the adult goats after intravenous administration the terminal half-life was 10.9 ± 1.7 h, steady-state volume of distribution was 0.245 ± 0.06 L/kg, and total body clearance was 17.9 ± 4.3 mL/h/kg. After oral administration bioavailability was 79 ± 19%, C(max) was 736 ± 184 ng/mL, T(max) was 15 ±5 h, although the terminal half-life was similar to the intravenous value, 11.8 ± 1.7 h. Signs of pain using a visual analogue scale were smaller in kids treated with meloxicam compared with kids treated with placebo on the first day after disbudding, but subsequently no difference in pain was noticeable. Plasma cortisol and glucose concentrations did not differ between the two groups.

The effect of acute administration of rifampicin and imatinib on the enterohepatic transport of rosuvastatin in vivo.

Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts. This study aimed at investigating the contribution of sinusoidal versus canalicular transport on the pharmacokinetics of an intrajejunal dose of 80 mg rosuvastatin in pigs (control group, n = 2 + 6). The transport inhibitors, rifampicin (20 mg/kg, n = 6) and imatinib (14 mg/kg, n = 6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5 h along with bile sample collection. Rifampicin reduced the hepatic extraction of rosuvastatin by 35% and the area under the curve in the hepatic vein compartment increased by a factor of 6.3 (95% confidence intervals (CI): 3.1-32, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.1-3.8, P value <0.05), suggesting that the inhibition was predominantly located in the liver rather than in the intestine and suggesting inhibition if sinusoidal transport. In contrast, no effect on the pharmacokinetics of rosuvastatin was observed following concomitant administration with imatinib possibly due to insufficient concentration of the inhibitor inside the hepatocyte. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.

Effect of erythromycin on the absorption of fexofenadine in the jejunum, ileum and colon determined using local intubation in healthy volunteers.

OBJECTIVE: To investigate the in vivo intestinal absorption mechanism(s) and systemic availability of fexofenadine in the jejunum, ileum and colon in humans. METHOD: A single dose of fexofenadine hydrochloride (60 mg as solution) was applied under fasting conditions, either alone or directly after a solution of erythromycin lactobionate (corresponding to a dose of 250 mg erythromycin), to the jejunum, ileum and colon in 6 healthy volunteers (3 male and 3 female) using a regional intubation dosing technology (Bioperm AB, Lund, Sweden). A total of 36 fexofenadine administrations were performed. The administration of fexofenadine to the specified location either alone or in combination with erythromycin was conducted in a randomized manner on 2 consecutive days with a 5-day washout period between doses. RESULTS: The plasma AUC for fexofenadine (mean +/- SEM) was higher (2.7-to 2.3-fold, p < 0.001) after application to the jejunum (1090 +/- 134 h x ng/ml) than to the ileum (404 +/- 102 h x ng/ml) or colon (476 +/- 212 h x ng/ml). No significant differences were found between application to the ileum and colon. The administration of erythromycin affected the absorption rate after jejunal application with a prolonged tmax from a median of 40 min (range 10-90 min) to a median of 3 hours (range 10-180 min) (p = 0.009). A change in tmax was not observed with application to the ileum and colon. The concomitant administration of erythromycin in the jejunum tended to increase the plasma AUC of fexofenadine from 1090 +/- 134 to 1750 +/- 305 h x ng/ml (p = 0.069). CONCLUSIONS: The systemic availability of fexofenadine was significantly higher after jejunal administration in accordance with a low permeability compound. The effects of erythromycin suggest that absorption of fexofenadine involves an uptake transport in addition to passive diffusion in the jejunum and predominantly passive diffusion in the ileum and colon.

Clinical Research Abstracts of the British Equine Veterinary Association Congress 2015.

REASONS FOR PERFORMING STUDY: Hypoglycin A (HG) appears to cause atypical myopathy (AM), but to our knowledge, detection of HG in affected and unaffected horses and concurrently in plants that they were exposed to has not previously been reported. OBJECTIVES: To investigate HG in samples from horses exposed to Acer pseudoplatanus (European sycamore maple) and in such plant material, at the time of clinical cases of AM in the herd. STUDY DESIGN: Cross-sectional study. METHODS: Blood was collected from 2 horses with AM and 22 clinically healthy co-grazing horses in 2 Swedish farms within one week of onset of signs (May 2014) and one month later, after horses were moved to other pastures. Ten healthy control horses from unaffected farms were sampled once. Samaras, seedlings, flowers and leaves from Acer pseudoplatanus and from Acer platanoides L (Norway maple) were collected from affected pastures. Hypoglycin A was analysed using chemical derivatisation with dansyl chloride (DNS) and ultra high performance liquid chromatography-tandem mass spectrometry. Hypoglycin A was detected as derivatised compound HG-DNS [M+H]+ with selected reaction monitoring. RESULTS: Hypoglycin A was detected in the horses affected with AM, and also in 20 out of 22 co-grazing horses. One month later, a surviving case horse and 9/20 co-grazing horses were still positive for HG. Controls from other farms were negative for HG. Hypoglycin A was detected in plant material from Acer pseudoplatanus, but not from Acer platanoides L. CONCLUSIONS: Horses grazing in pastures with HG-containing Acer pseudoplatanus were positive for HG in blood, and some showed severe signs of myopathy. Ethical animal research: Ethical consent for blood sampling was granted (C113/11) and horse owners gave their informed consent to inclusion of horses in the study. SOURCE OF FUNDING: National Veterinary Institute, Sweden. Competing interests: None declared.

Selective effects of somatostatin analogs on human drug-metabolizing enzymes.

Pharmacologic or surgical manipulation with growth hormone secretion or with the physiologic release of somatostatin and growth hormone-releasing hormone affects some rat liver enzymes, especially the sex-differentiated ones. We investigated the effects of two somatostatin analogs on several enzyme functions in six patients with carcinoid syndrome, using codeine as a probe drug. Codeine was given intravenously and its N- and O-demethylation, as well as 6-glucuronidation catalyzed by CYP3A, CYP2D6, and uridine diphosphate-glucuronosyltransferase, respectively, were studied before and during treatment with somatostatins. After 3 days of treatment with somatostatins the partial metabolic clearance of codeine by N-demethylation decreased by 21% to 64% in all patients (mean change, 44%; p < 0.05), and the clearance by O-demethylation was decreased by 20% to 69% in five of the patients (mean change in all patients, 35%; p < 0.05). In contrast, the partial clearance by 6-glucuronidation and the total systemic clearance of codeine were unchanged. Our results may be caused by the inhibition of growth hormone secretion induced by the somatostatins, inasmuch as direct metabolic interactions with these peptide drugs are improbable. The decline in CYP3A4 and CYP2D6 activity might have clinical implications when substrates of these enzymes with low therapeutic indices are combined with somatostatin analogs. Because the formation of morphine from codeine was altered, the analgesic effect of this drug may be reduced during concomitant treatment with somatostatins.

Patient-controlled analgesic therapy, Part III: pharmacokinetics and analgesic plasma concentrations of ketobemidone.

The effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vd(area) was 5.9 +/- 2.6L/kg and the terminal half-life was 3.9 +/- 1.7 h. In the postoperative period Vd(area) decreased to 3.7 +/- 0.4L/kg and the terminal half-life to 2.1 +/- 0.4 h. Plasma clearance (Clp) did not change significantly, peroperative Clp being 18 +/- 4.3 ml/min/kg and postoperative Clp being 22 +/- 7.5 ml/min/kg. The pharmacokinetics of ketobemidone were not influenced by the addition of a spasmolytic agent in the commercial combination ketobemidone preparation 'Ketogin'. Postoperative pain was relieved in 15 patients by patient-controlled intravenous administration of ketobemidone by means of a programmable drug injector. The mean ketobemidone consumption was 2.3 +/- 0.8 mg/h, which produced a mean plasma concentration of 28 +/- 11 mg/ml. Pseudosteady-state plasma concentrations of ketobemidone were established with a mean minimum effective concentration (MEC) of 25 +/- 11 ng/ml. Ketobemidone 'plain' and 'Ketogin' did not differ significantly in these respects. Analgesia was considered by all patients to be satisfactory.

Transplacental passage of isradipine in the treatment of pregnancy-induced hypertension.

The aim of this study was to assess the concentration of isradipine in maternal and fetal plasma, and in amniotic fluid under steady-state conditions. Eight women were treated with 5-mg isradipine tablets twice daily and eight women were given slow-release isradipine capsules (SRO) twice daily for hypertension in pregnancy. Blood and amniotic fluid sampling for analysis of drug concentration was performed at delivery. In the isradipine tablet group, maternal and fetal plasma levels were 788 +/- 701 pg/mL (mean +/- SD) and 270 +/- 90 pg/mL, respectively. The corresponding levels in the SRO-treated group were 463 +/- 217 pg/mL and 185 +/- 95 pg/mL, respectively. In the amniotic fluid, the concentration was 74 +/- 42 pg/mL in the tablet group and 45 +/- 14 pg/mL in the SRO group. Therefore, isradipine passes the placental barrier, but its concentration is considerably lower in the fetal compartments.

Determination of clozapine and its N-demethylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection.

A gas chromatographic-mass spectrometric method with single ion detection has been developed for determination of clozapine and its N-demethylated metabolite norclozapine in plasma. Propylnorclozapine was used as internal standard and the mass spectrometer was adjusted to record the ion m/z 373 for the compounds analyzed. The precision of the method was found to be high, with a relative standard deviation of 6% or less for replicated samples. The limit of determination was 1.0 ng/ml for clozapine and 5.0 ng/ml norclozapine. A significant correlation was obtained between the daily oral dose of clozapine within the dose interval 100-800 mg/day and the plasma level of clozapine in 22 chronic schizophrenic patients. The plasma levels of clozapine and norclozapine were also significantly correlated. The quotient norclozapine/clozapine showed great interindividual variation and was not correlated to the daily dose of clozapine. The method is rapid and sensitive to allow evaluation of the pharmacokinetic properties of clozapine in the treatment of schizophrenic patients.

CSF and serum concentrations of clozapine and its demethyl metabolite: a pilot study.

With the aim of exploring putative correlations between serum and CSF levels of clozapine and its demethyl metabolite, lumbar puncture was performed on four male and five female schizophrenic patients during long-term treatment with clozapine. Three consecutive 6-ml fractions were collected after at least 8 h of bedrest and fasting. On comparing serum and CSF levels, a correlation was found for norclozapine in the third (13-18 ml) CSF fraction. Norclozapine in the first (0-6 ml) CSF correlated significantly with height. The CSF/serum ratio of clozapine in the first fraction was correlated significantly with body weight. No correlations were found between serum levels of clozapine and norclozapine, or between the serum and CSF levels of clozapine. The study suffers from a small number of patients (for ethical reasons), but the present results might be explicable if the first (0-6 ml) CSF fraction represents a cul-du-sac of the CSF, mirroring the previous day's drug levels. The second fraction, then, will represent the CSF level in the steady state during the night.

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET).

By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5-12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.

Pharmacokinetics of haloperidol in psychotic patients.

Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5-5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79 +/- 0.03. The blood clearance was then calculated to be 550 +/- 133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9 +/- 2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60 +/- 0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3 +/- 1.1 h and a longer absorption half-life (1.9 +/- 1.4 h) was found in the patients compared with healthy volunteers.

Effects of buprenorphine in heroin addicts.

Twelve heroin addicts on the 8th day after withdrawal, and 8 healthy volunteers were given a single i.m. injection of buprenorphine 0.6 mg and their subjective response rated on 10 psychological variables. Pre-injection rating differed significantly between addicts and controls on 7 variables out of 10. Following buprenorphine more subjective changes were noted in the control group which became more calm, depressed, more aware of the environment, sleepy, tired, intoxicated, dizzy and nauseated. The drug addicts reported changes only in 2 variables (less tense and dysphoric) but otherwise showed no significant changes. These findings support the notion that buprenorphine induces low or normalizing effects in heroin addicts. This drug might thus be suitable for maintenance therapy in opiate addiction.

Distribution of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in experimental animals studied by postiron emission tomography and whole body autoradiography.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective potent neurotoxin which has induced a syndrome similar to parkinsonism both in man and in monkeys. At autopsy degeneration of pigmented nerve cells in the pars compacta of the substantia nigra has been confirmed. The regional distribution of intravenously administered 1-(11C-methyl)-4-phenyl-1,2,3,6-tetrahydropyridine (11C-MPTP) in the brain of Rhesus monkeys was studied by positron emission tomography and the whole body distribution in mice was documented by autoradiography and by impulse counting of selected tissues. A very rapid and high uptake of 11C-MPTP derived radioactivity was seen in areas corresponding to striatum and midbrain, including the substantia nigra area. No elimination from these regions was seen during the study period of 2 h. The uptake was in the order of 7-8 times the homogenous distribution of the radioactivity in the monkey. The uptake was generally high also in other regions of the brain, but there some elimination could be distinguished. Pretreatment of the monkey with spiperone, a selective dopamine receptor antagonist, did not alter uptake nor the kinetics of the 11C-MPTP derived radioactivity. Thus 11C-MPTP does not have a high affinity for postsynaptic dopamine receptors. A remarkably high uptake of 11C-MPTP derived radioactivity was seen in the eye of the monkey. The selective uptake of radioactivity in the eye was also confirmed in pigmented but not in albino mice. The melanin affinity of MPTP may cause high intracellular concentrations of the compound or its metabolites in the melanin containing nerve cells in substantia nigra, which may explain the serious vulnerability of these neurons to MPTP.