Plasma nitrendipine concentrations in elderly hypertensive patients after single and multiple dosing.

Twenty-three elderly hypertensive subjects received nitrendipine 10mg daily by mouth for 8 days. Plasma nitrendipine concentrations were measured after the first and last dose. There was no significant difference in plasma concentrations at any time point between the two days nor in derived pharmacokinetic measurements. Drug accumulation was not observed.     

Plasma nitrendipine concentrations in elderly normotensive volunteers after single and multiple dosing

An acute and chronic dosing pharmacokinetic study of the calcium antagonist nitrendipine was carried out in 8 normotensive volunteers (mean age 80.1 +/- 3.4 years) to investigate if drug accumulation occurred in the elderly. Subjects received 10 mg nitrendipine once daily by mouth for 8 days. Plasma nitrendipine concentrations before administration and at 0.5, 1, 2, 4, 6 and 8 hours after dosing were measured after the first and last dose. Comparison of the pharmacokinetic data from Days 1 and 8 failed to show any evidence of nitrendipine accumulation in these elderly subjects.     

Alternate-day buprenorphine dosing is preferred to daily dosing by opioid-dependent humans

Alternate-day buprenorphine dosing was compared to daily dosing in opioid-dependent outpatients and choice of alternate-day versus daily dosing was assessed. Four dosing schedules were presented in random order under blind and open dosing conditions. Subjects received two exposures to each dosing schedule. During daily dosing, subjects received maintenance doses every 24 h. During blind alternate-day dosing, subjects received double maintenance doses every 48 h; placebo was interposed on intervening days. During open alternate-day dosing, subjects received twice their maintenance dose on Monday, Wednesday and Friday and maintenance doses on Sunday. After completing two exposures to each dosing schedule, subjects chose either daily or alternate-day schedules each week for 1 month. Study participation was contingent on daily attendance and opioid abstinence. Ten subjects were exposed to the four conditions once. Seven subjects repeated these conditions and participated in the choice phase. The effects of daily versus alternate-day dosing were not influenced by blind or open dosing conditions. Subjects’ ratings of withdrawal, “sick” and sedation were lower during daily than during alternate-day dosing, but the difference between treatments was small. Nonetheless, subjects still chose alternate-day dosing on 96% of occasions, suggesting that the subject-rated differences between dosing schedules were not influential. These results extend prior findings to open-dosing conditions, and replicate the safety and acceptability of alternate-day buprenorphine treatment. Choice of alternate-day buprenorphine administration underscores the procedure’s clinical utility and potential use as a positive reinforcer to enhance opioid treatment. Received: 1 August 1996/Final version: 11 September 1997     

Cannabinoid concentrations in spot serum samples 24-48 hours after discontinuation of cannabis smoking

A blood concentration of tetrahydrocannabinol (THC) in the low nanograms-per-milliliter range is often claimed to result from drug use more than 24-48 h previously. The present investigation determined concentrations of cannabinoids in blood collected at least 24 h from smoking in an in-patient setting. During sampling, distinctive effects due to drug use could not be observed. The randomly collected samples from heavy (n = 16, > 1 joint/day), moderate (n = 15, < or = 1 joint/day), and light (n = 6, < 1 joint/week) users of cannabis were analyzed for THC, 11-hydroxy-THC (OH-THC), and free 11-nor-9-carboxy-THC (THCCOOH) by gas chromatography-mass spectrometry as well as for glucuronidated THCCOOH by liquid chromatography-tandem mass spectrometry. THC was detectable in 9, 6, and 1 samples from heavy, moderate, and light users, respectively. Although cannabinoid concentrations were overlapping between groups, there was a trend towards higher concentrations of both conjugated and free THCCOOH in regular users compared to occasional users. The present findings appear to indicate that low levels of THC, or of THC along with OH-THC, may not unequivocally prove a very recent use of cannabis.     

Opioid effects and opioid withdrawal during a 24 h dosing interval in patients maintained on buprenorphine

In maintenance patients methadone has been shown to produce considerable changes in opioid effects and withdrawal over the dosing interval. As a partial agonist buprenorphine may be expected to produce smaller changes, but the nature and magnitude of these changes have only been described for single doses. In the present study opioid effects and withdrawal were described in patients maintained on buprenorphine. Twenty four opioid dependent subjects were administered 16 mg buprenorphine tablets sublingually for 10 days. On day 10 plasma samples were collected and physiological, subjective and observer-rated measures collected pre-dose and at 14 time points during the dosing interval. No significant respiratory depression was observed. Consistent with the partial agonist properties of buprenorphine, other physiological and subjective changes were also of small magnitude. However, even at a once daily dose of 16 mg some patients experienced significant opioid withdrawal that was maximal at the end of the dosing interval. Buprenorphine maintenance should be associated with a high level of safety and a low level of disruption caused by changing opioid effects over the dosing interval, but some patients may require high doses or other strategies to completely suppress withdrawal.     

Plasma and urinary concentrations of methamphetamine after oral administration of famprofazone to man.

1. To obtain further evidence for the metabolic formation of methamphetamine from famprofazone in man, concentrations of methamphetamine in plasma, as well as in urine, were measured by g.l.c. In addition, intact famprofazone and famprofazone N-oxide were analysed in the urine. 2. Methamphetamine appeared in plasma 1 h after a single 100 mg dose of the drug to two male subjects, and the concentration maintained between 24 and 44 ng/ml over 2-12 h, declining to 10 ng/ml and an undetectable level respectively after 24 h. 3. Total urinary excretion of methamphetamine over 72 h was 1.9 mg for a 25 mg dose and 2.2 mg for a 50 mg dose. After a 100 mg dose, 4.6 mg of methamphetamine was excreted over 36 h. Neither intact famprofazone nor famprofazone N-oxide were detected when the urine samples after the 100 mg dose were examined. 4. The results provide further evidence that methamphetamine is a bona fide human metabolite of famprofazone and suggest that at least 20% dose may be broken down via the pathways leading to the formation of methamphetamine. This could have significant clinical implications as the result of pharmacological activity of this metabolite.     

Plasma protein-binding and CSF concentrations of valproic acid in man following acute oral dosing

Simultaneous cerebrospinal fluid (CSF), total and free plasma valproic acid (VPA) concentrations were measured in 17 patients receiving two weight-adjusted VPA doses as seizure prophylaxis prior to diagnostic myelography or cisternography. Free drug concentrations were similar when measured by equilibrium dialysis (ED) at 37 degrees C for 24 h (Dianorm) or by a novel ultrafiltration (UF) method (EMIT freelevel system 1, SYVA) (ED:2.3-35.5 mg-1; UF:1.3-33.6 mg-1; r = 0.78, P less than 0.002). There was wide variation in total VPA concentration (39-154 mg-1) and in free fraction (ED: 3.3-25.6%; UF: 5.9-24%). Concentration dependent protein binding was not demonstrated. CSF VPA varied between 4.2 and 25.6 mg-1 and was accurately reflected by free plasma VPA concentrations (ED: r = 0.75, P less than 0.005: UF: r = 0.93, P less than 0.001). CSF concentration also correlated with the total plasma VPA (r = 0.76, P less than 0.005). The Emit freelevel system 1 provides a rapid measure of unbound VPA in the plasma which may be suitable for routine clinical use.     

Plasma concentrations of benzodiazepines.

1. Twenty anxious patients were treated with medazepam, diazepam, chlordiazepoxide, amylobarbitone and placebo, each given in flexible dosage for 2-4 weeks. 2. At the end of each treatment, a series of clinical, physiological and behavioural variables were measured and plasma samples were taken for estimation of the appropriate drug and metabolite concentrations. 3. Nordiazepam was shown to be an important metabolite of both medazepam and diazepam: the ratio of medazepam to noradiazepam was 0.14 and the ratio of diazepam to nordiazepam following diazepam administration was 0.72. 4. No significant correlations were found between the plasma concentrations of any of the treatments and the clinical ratings or behavioural measures. 5. Some relationship was shown between levels of medazepam and its physiological effects.     

Relative bioavailability of different buprenorphine formulations under chronic dosing conditions

BACKGROUND: Buprenorphine is an approved medication for the treatment of opioid dependence. Three sublingual formulations have been used at various times during its development-a solution containing alcohol, tablets containing buprenorphine alone, and tablets containing buprenorphine plus naloxone. This study compared the relative buprenorphine bioavailability of these different formulations. METHODS: Outpatient volunteers (N = 10) were maintained for 14 days of daily administration on each formulation; the dose of buprenorphine (8 mg) was constant across formulations. Blood samples were collected and tested for buprenorphine and norbuprenorphine concentrations after 7 and 14 days maintenance on each formulation. Serial samples were collected before and for 6 h after a daily dose of each formulation. RESULTS: Peak buprenorphine concentrations (C(max)) and area under the curve (AUC) for the 6h interval (AUC(0-6)) were highest for the solution and lowest for buprenorphine alone tablets; values for combination tablets were more similar to those for solution. Differences between formulations were less pronounced at day 14 than day 7. There was considerable between-subject variability in concentrations produced. CONCLUSIONS: These results suggest there may be greater bioavailability of buprenorphine/naloxone versus buprenorphine alone tablets, and that the bioavailability of buprenorphine from the former is very similar to that seen with solution after 2 weeks of stabilization on each formulation.     

Opioid detoxification using high doses of buprenorphine in 24 hours: a randomized, double blind, controlled clinical trial

In recent years, interest in shortening of opioid detoxification has increased with the rising demands to find more cost-effective approaches for treatment of opioid dependence. This study was designed to evaluate the efficacy of administration of high doses of buprenorphine during 24 h in the management of acute opioid withdrawal. A total of 40 treatment-seeking opioid dependents were admitted and randomly assigned to two groups in a double blind, parallel trial. Buprenorphine was administered intramuscularly. Twenty patients received 12 mg buprenorphine in 24 h and the remaining 20 patients treated with conventional doses of buprenorphine tapered down over 5 days. Variables that were assessed included retention in treatment, rates of successful detoxification, the Subjective Opiate Withdrawal Scale (OOWS) scores, the Objective Opiate Withdrawal Scale (SOWS) scores, intensity of craving, drug side effects, and levels of hepatic enzymes (ALT and AST). There was no significant difference between the two groups on most variables. The main difference was in the time that maximal withdrawal symptoms occurred, which in the experimental protocol group appeared early while in the conventional protocol group appeared later during the detoxification period. Moreover, the experimental protocol was not only tolerated well but also accompanied with significantly less elevation in the ALT levels compared to the conventional treatment. However, patients in this group used more indomethacin and trazodone for symptom palliation. This study suggests that administration of high doses of buprenorphine in 24 h may be a reasonable approach for shortening of opioid detoxification. However, a larger study to confirm our results is warranted.     

Plasma metronidazole concentrations after single and repeated vaginal pessary administration.

Metronidazole concentrations in plasma were measured by h.p.l.c. in 12 healthy female volunteers after single and repeated vaginal administration of 500 mg metronidazole pessaries. The area under the plasma concentration-time curve (AUC(0,12 h) was 8.4 +/- 3.9 micrograms ml-1 h (mean +/- s.d.) on day 1 and 20.6 +/- 7.1 micrograms ml-1 h (mean +/- s.d.) on day 5. The peak plasma drug concentration on day 1 was 1.2 +/- 0.6 micrograms ml-1 (mean +/- s.d.) and on day 5 it was 2.0 +/- 0.7 micrograms ml-1 (mean +/- s.d.). The plasma concentration of metronidazole at steady state was above the minimum inhibitory concentration (MIC) for anaerobic Streptococci and Clostridium tetani. These results demonstrate much lower systemic exposure than after oral administration.     

Plasma concentrations and electrocardiographic alterations after repetitive administration of propoxyphene to dogs

Propoxyphene hydrochloride was administered orally to four dogs every 8 hr for 19 days. Initial doses of 20 mg/kg were increased to 60 mg/kg in 5 to 15 mg/kg increments every 3 to 4 days. At the conclusion of the experiments animals were ambulatory although signs of toxicity including anorexia, sedation, tremors, and emesis were noted periodically throughout the study. Slight elevations in alkaline phosphatase and serum glutamate pyruvate transaminase values were also observed. Plasma concentrations of propoxyphene (P) (2.3±0.5 μg/ml) and norpropoxyphene (NP) (18.4±4.7 μg/ml), its major metabolite, were markedly elevated over those observed with a single near-lethal dose administered to naive dogs (P, 0.83 μg/ml; NP, 2.56 μg/ml). Tissue concentrations of P and NP were in excess of plasma concentrations showing marked tissue accumulation of both compounds. Electrocardiograms (ECG) showed an increase in PR interval after the first dose of propoxyphene. Doses from 20 to 45 mg/kg produced no further lengthening of the PR interval. Only when dogs were receiving 60 mg/kg (three times daily) were further changes in this interval observed, along with alterations in the QRS complex and T wave portions of the ECG. The average heart rate of these dogs was not significantly altered during the course of the study. At necropsy, mild superficial focal erosions in the mucosa of the stomach and upper small intestine were noted. No other histological changes were observed. These results demonstrated that in the dog, high plasma and tissue concentrations of P and NP can occur without causing significant toxic or lethal effects.     

Plasma and CSF morphine concentrations after i.m. and epidural administration

Morphine concentrations in plasma and CSF after i.m. and epidural morphine administration were assayed in patients undergoing surgery of the low abdomen. Morphine concentration in CSF after i.m. administration of this drug is remarkably lower than morphine concentration in plasma. The highest value is attained in CSF after about 90' and is followed by a slow downsloping to lowest values, which were observed 4 hours after drug administration. Kinetics of morphine passage into plasma after epidural administration is similar to that found after i.m. administration. In the latter experimental condition (epidural administration), concentrations of morphine in CSF 30' after administration are markedly lower than those found in plasma. However, 60 min. after epidural administration plasma and CSF morphine concentrations are similar, in particular CSF concentrations are 4 to 8 times higher than those obtained after i.m. administration. Such high levels persist for a long time.     

Pharmacokinetics of oltipraz after intravenous and oral administration in rats with dehydration for 72 hours

Pharmacokinetic parameters of oltipraz were compared after intravenous and oral administration at a dose of 30 mg/kg to control rats and rats with water deprivation for 72 h (rats with dehydration). The plasma protein binding of oltipraz was measured in both groups of rats using an equilibrium dialysis technique. The concentrations of oltipraz were measured by the reported HPLC analysis. After intravenous administration, the total area under the plasma concentration-time curve from time zero to time infinity (AUC), terminal half-life, time-averaged total body and nonrenal clearances, and apparent volume of distribution at steady state were not significantly different between the two groups of rats. However, after oral administration to rats with dehydration, the AUC was significantly smaller than that in control rats (180 versus 316 microg min/ml) mainly due to decrease in absorption. In rats with dehydration, plasma protein binding was significantly greater than that in control rats (91.5 +/- 0.309 versus 81.3 +/- 2.79%).     

Turnover and metabolism of norepinephrine in rat brain after 72 hours on a D-deprivation island

The changes in norepinephrine turnover and metabolism in brain were examined in rats maintained for 72 h on small square islands of the size shown to produce D-deprivation. The utilization of norepinephrine in brain (as reflected by the rate of disappearance of intracisternally administered norepinephrine-H³ from brain) and the apparent rate of synthesis of norepinephrine were increased after 72 h on the islands. Within 120 min after animals were removed from the islands and placed in recovery chambers, the rate of disappearance of norepinephrine-H³ from brain returned to approximately control values; but the apparent increase in norepinephrine synthesis persisted somewhat longer. Since many physiological alterations may have occurred under the stressful conditions of these experiments, it is not possible, on the basis of the present data, to relate (either as a specific cause or effect) the changes in norepinephrine turnover to particular alterations in the sleep cycle.