Intramuscular diazepam pharmacokinetics in soman-exposed guinea pigs

Intramuscular (i.m.) diazepam is included by the US military as an anticonvulsant in the standard therapeutic regimen for organophosphorus nerve agent intoxication. In this study we investigated the pharmacokinetics of diazepam after i.m. administration while monitoring pharmacodynamic (electroencephalogram, EEG) data in soman-exposed guinea pigs. Prior to experiments the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered pyridostigmine (0.026 mg x kg(-1) i.m.) 30 min prior to soman (56 microg x kg(-1), 2 x LD50; subcutaneously, s.c.), which was followed in 1 min by atropine sulfate (2 mg x kg(-1) i.m.) and pralidoxime chloride (25 mg x kg(-1) i.m.). All animals receiving this regimen developed seizure activity. Diazepam (10 mg x kg(-1) i.m.) was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure terminated or not terminated at 30 min after diazepam. Serial blood samples were obtained from each animal. Diazepam (10 mg x kg(-1) i.m.) terminated seizure activity in 52% of the animals within 30 min. The pharmacokinetics were characterized by a one-compartment model with first-order absorption and elimination. The maximum plasma concentrations (Cmax) were 991 and 839 ng x ml(-1) for seizure terminated and not terminated, respectively. Mean plasma concentrations of diazepam were significantly different (P < 0.05) for seizure terminated vs not terminated groups at 30 min. The plasma Cmax in seizure-terminated animals in this study is similar to the minimum range of plasma diazepam (200-800 ng x ml(-1)) reported to suppress seizure activity in humans. It has been reported in an earlier study that the minimum effective i.m. dose (0.1 mg x kg(-1)) required to prevent soman-induced convulsions in Rhesus monkeys produces a mean Cmax of 50 ng x ml(-1) for diazepam. The data from our current study suggest that a higher dose (and corresponding Cmax) is necessary to terminate ongoing seizure activity.     

Imipramine treatment alters the pharmacokinetics and pharmacodynamics of diazepam

This report describes observations of the relationship between the pharmacokinetics and pharmacodynamics of diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ; 5 mg/kg) during the concomitant administration of diazepam and imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride; 20 and 50 mg/kg) to rats. We measured plasma, brain, and liver concentrations of diazepam and its metabolites in rats by high-performance liquid chromatography. The concomitant use of imipramine hydrochloride increased diazepam and desmethyldiazepam concentrations, but decreased temazepam and oxazepam concentrations in rat plasma. Diazepam plasma protein binding was unaltered. The liver concentrations of diazepam and its metabolites showed similar changes in their plasma concentrations. The concomitant use of imipramine hydrochloride increased the concentrations of diazepam and its metabolites in the brain. We also studied the effect of benzodiazepines on convulsions induced by pentylenetetrazole (6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a] azepine; 135 mg/kg) in rats. The concomitant use of imipramine hydrochloride led to an increased antipentylenetetrazole effect of diazepam. This result is in accordance with the findings on brain concentrations of diazepam and its metabolites.     

Naltrexone effects on diazepam intoxication and pharmacokinetics in humans

 The opiate antagonist naltrexone (NTX) blocks relapse drinking in alcoholics and modifies some of the subjective effects of alcohol intoxication. Benzodiazepines have demonstrated cross-dependence and cross-tolerance to alcohol. Furthermore, benzodiazepine intoxication has effects on mood and psychomotor performance that are similar to alcohol intoxication. The effects of NTX on diazepam intoxication were investigated in non-drug abusing individuals. Eighteen men and eight women were randomly assigned to receive either 50 mg NTX or placebo PO, on two different occasions in a within-subjects, cross-over, double-blind protocol. Diazepam was taken by mouth, 90 min after NTX. At −90, 45, 75, 135, 210 min, subjects were tested with repeated assessments of several mood and sensation scales and a computer-generated psychomotor test battery (CTB). Blood samples were also obtained and analyzed for serum diazepam levels. Diazepam induced several sensations and mood effects similar to those induced by alcohol. Negative mood states such as sedation, fatigue, and anxiety were higher for NTX than for placebo. Positive mood states such as friendliness, vigor, liking the effects of diazepam, and feeling high from diazepam were all lower for NTX than for placebo. There were no group differences on the CTB performance. NTX delayed the time to reach peak diazepam levels, so that peak levels occurred at 75 min for placebo compared to 135 min for NTX. A sub-analysis was conducted with 14 subjects who were FHP for alcoholism, but no differences were found on these outcome measures. Received: 31 March 1997/Final version: 10 July 1997     

Comparative pharmacokinetics and pharmacodynamics of lorazepam,alprazolam and diazepam

The contribution of differential absorption-distribution pharmacokinetics to drug activity can be partially determined by comparing simultaneous estimates of drug serum level with pharmacodynamic effects. In the present paper we have contrasted the effects of clinically equipotent doses of lorazepam, alprazolam, and diazepam on the performance of tracking and digit symbol substitution tasks. Eight young males were tested for 12 h after ingesting the drug. The three benzodiazepines and placebo were administered to each subject according to a balanced double-blind Latin square design. A model is presented that describes the relationship between drug concentration and the degree of impairment across time after the final peak effect. Exponential rate constants were determined for each drug using a Marquardt nonlinear fit of the pooled data. Basically, the constants relate offset serum drug values to the impairment curves at a time when serum-brain equilibrium is assumed to have occurred. The values indicate markedly rapid acute tolerance for alprazolam and diazepam but relatively little acute tolerance for lorazepam. Whether these constants reflect adaptation or differential association-dissociation receptor rate constants cannot be determined, but they do highlight the need to consider receptor kinetics as an important factor in benzodiazepine pharmacodynamics.     

A comparative study of diazepam with sustained-release diazepam as oral premedication in minor gynaecological surgery

Sixty patients undergoing elective minor gynaecological surgery received oral pre-operative medication with 10 mg diazepam in either conventional tablet form on the morning of operation or as the sustained-release tablet the night before. Subjective and objective assessments of the effectiveness of premedication were made. Patients receiving sustained-release diazepam on the night before surgery experienced fewer periods of wakefulness than those who received placebo. Patients who were given diazepam on the morning of surgery felt more drowsy pre-operatively than those who received sustained-release diazepam the night before.     

Comparison of the pharmacokinetics of diazepam after single and subchronic doses

Summary In seven healthy male volunteers the effects of the pattern of dosing on the pharmacokinetics of diazepam have been studied. A cross-over design was employed that consisted of three parts: a single intravenous dose (0.1 mg/kg), and oral dosing (10 mg/day) for six days followed by an intravenous bolus (0.1 mg/kg) on the seventh day, followed by re-examination of a single intravenous dose after diazepam (D) and its major metabolite desmethyldiazepam (DD) had been completely eliminated. Plasma levels of D and DD were monitored by a specific, sensitive GLC-method. In younger patients (n=5, age 29 – 35 years) the elimination half-life, T_{1/2 ()}, of D was 33.9±10.6 h (mean±S.D.) after the single dose. The control study gave an almost identical result (35.7±12.1). After subchronic dosage in all patients T_{1/2 ()} showed a modest but significant prolongation (paired t-test p<0.01) to 52.9±17.4 h. It was caused by a significant decrease (p=0.016) in total plasma clearance ( ), from 26.0±10.8 ml/min to 18.2±7.0 ml/min. Older patients (age 43–60 years) showed the same phenomenon. Blood/plasma ratios remained constant indicating no change in protein binding. Biliary excretion of D was measured in five patients with a T-tube. Only negligible amounts (0.3–0.4%) of administered D were excreted within 3 days after subchronic dosage, which demonstrates a lack of enterohepatic cycling of D. After multiple administration of D, there was accumulation of DD to levels approximately five times higher than after a single dose. The possibility that the slower elimination of D after subchronic treatment might be caused by DD was also supported by experiments in dogs and rabbits. After pretreating rabbits with DD and maintaining a high DD plasma level, there was prolongation of T_{1/2 ()} from 2.7 h to 5.2 h, with a corresponding decrease of from 101.6 ml/min to 23.4 ml/min. Similar results were obtained in dogs. It is concluded that the disposition of D is altered by subchronic use and may be regulated by the plasma DD concentration.The results were presented in part at the 6th International Congress of Pharmacology, Helsinki, 1975     

Multiple-dose pharmacokinetics of diazepam following once-daily administration of a controlled-release capsule

The study was designed to determine the steady-state pharmacokinetic profile of diazepam and desmethyldiazepam following a 15-mg controlled-release capsule dosed once daily at either 7 a.m. or 11 p.m. compared with the respective profiles of the conventional 5-mg tablet dosed three times a day at 7 a.m., 12 p.m., and 5 p.m. Plasma concentrations of diazepam and desmethyldiazepam were assayed by an electron-capture gas-liquid chromatographic method. Plasma concentrations indicated that there were no differences between the pharmacokinetic profiles following the 7 a.m. or 11 p.m. dosings of the controlled-release capsule. Steady-state concentrations of diazepam were attained between days 7 and 9 during the controlled-release dosing, and the accumulation profiles are similar to those observed for the conventional tablet given three times a day. Nearly identical areas under the diazepam plasma concentration-time curves (AUC) on day 1 and at steady state for both regimens indicate equal extents of absorption from the two formulations. In addition, the steady-state AUCs for desmethyldiazepam were independent of formulation. The data indicate that a single daily dose of the 15-mg controlled-release capsule results in accumulation and steady-state profiles comparable to those observed following a regimen of the 5-mg conventional tablet three times a day.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma

The pharmacokinetics of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) in both plasma and brain after a single 5 mg/kg IP dose of diazepam were studied in rats. Four rats were sacrificed at 5 min, 15 min, 30 min, 1 h, 1.5, 2, 3, 4, 5 and 6 h after the dose. DZ rapidly disappeared from plasma and brain in parallel, with nearly identical overall half-lives of 0.88 and 0.89 h, respectively. Apparent volume of distribution was 19.3 1/kg and the apparent total clearance was 255 ml/kg/min. Free fractions were 19.6% and 15.8% for DZ and DMDZ, respectively. DMDZ rapidly appeared in both plasma and brain. Thereafter, DMDZ was likewise eliminated in parallel from both compartments, with nearly identical half-lives of disappearance from plasma (1.11 h) and brain (1.09 h). The rapid elimination of DZ was due to its very high clearance. Brain to plasma concentration ratios did not differ significantly over time either for DZ or for DMDZ. The overall ratios (mean±SE) were 4.5±0.1 for DZ and 3.5±0.2 for DMDZ. Equilibrium was attained at no more than 5 min after dose for both DZ and DMDZ. No evidence was found for persistence or sequestration of DZ or DMDZ in brain longer than could be predicted on the basis of first-order exponential disappearance.     

The pharmacokinetics of atropine and diazepam in sheep: intramuscular co-administration

The purpose of this study was to determine whether the co-administration of atropine and diazepam affect the rate and extent of absorption of either drug. A triple crossover pharmacokinetic study using adult sheep was conducted. Each of nine animals received single injections of atropine (2 mg), diazepam (10 mg), and a combination of the two compounds weekly over a 3-week period. The combination of the drugs was injected into a single intramuscular site through a specially designed tandem syringe. Blood samples were obtained from time 0 to 300 min post-injection. Serum samples were analyzed for atropine by radioimmunoassay and for diazepam by gas chromatography/mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. The co-administration of atropine and diazepam intramuscularly in sheep caused a delay in the time to reach maximal concentration of atropine. However, at the time when a single injection of atropine reached its maximum serum concentration, 92 per cent of that concentration was reached by atropine in the presence of diazepam. Additionally, no difference was detected in the rate or extent of diazepam absorption when administered intramuscularly in combination with atropine at the same site.     

Time dependent influence of diazepam on the pharmacokinetics of ibuprofen in man

Circadian variation in the disease activity of rheumatoid arthritis has been established. Several nonsteroidal anti-inflammatory drugs have been studied for their chronokinetic behaviour. Time dependent influence of diazepam on the pharmacokinetics of diclofenac and naproxen has been reported. We report the time dependent influence of diazepam on the pharmacokinetics of ibuprofen in healthy subjects. Either ibuprofen or ibuprofen with diazepam was administered at 10.00 or 22.00 hours to eight healthy volunteers in a randomized crossover study. Serum ibuprofen levels were estimated by high performance liquid chromatography. There was a significant (p < 0.05) increase in mean elimination half life (2.39 +/- 0.42 to 3.59 +/- 0.35 h) following ibuprofen and diazepam administration compared to ibuprofen alone administered at 22.00 hours. The mean clearance of ibuprofen was therefore lowered from 62.7 +/- 8.9 to 41.7 +/- 2.6 ml/h/kg under the influence of diazepam during the night. Such a time dependent influence of diazepam on the pharmacokinetics of ibuprofen may be due to circadian variation in the pattern of protein production in the liver and/or competitive protein binding of the two drugs during the dark period.     

Factors influencing diazepam pharmacokinetics: age, sex, and liver disease

Published data on the effect of cirrhosis on diazepam pharmacokinetics were reanalyzed to determine how age, sex, and body weight might have influenced the conclusions. Diazepam elimination half-life (t1/2beta) and weight-corrected volume of distribution (Vd) were significantly larger in patients with cirrhosis (n = 9) than in controls (n = 4). Weight-corrected diazepam clearance was significantly reduced in cirrhotics as compared with controls. Multiple stepwise regression analysis, however, revealed that age and liver disease were of approximately equal importance as determinants of t1/2beta. Age, sex, and liver disease all influenced Vd, but liver disease by far was the most important determinant of diazepam clearance. Thus age, sex, and body size can have an important influence on the pharmacokinetics of drugs, and should be included as independent variables in pharmacokinetic studies.     

Halazepam and diazepam in neurotic anxiety: A double-blind study

Halazepam (160 mg/day) was compared to diazepam (20 mg/day) and to a placebo in a double-blind study with anxious neurotic outpatients from general family practice and a symptomatic volunteer clinic. One hundred twenty-five patients completed at least 4 weeks of treatment. Halazepam produced the most amount of side effects followed by diazepam, while placebo produced the least amount of side effects. Sedation was the most frequently reported side effect.No significant drug x population interaction effects were found and only very few population effects occurred indicating SVC patients to improve more than GP patients. Treatment differences indicate diazepam to be slightly more effective than halazepam, and both drugs to be superior to placebo according to several outcome criteria. At the 6-week period, diazepam, in fact, was significantly more effective than halazepam according to physician and patient questionnaire ratings. Global ratings of improvement, however, indicated both drugs to be equally effective and to produce significantly more improvement than placebo.Initial levels of anxiety and depression were found to have a differential effect on treatment outcome. Anxious patients with little secondary depression improved more than patients with more marked secondary depression regardless of treatment agent prescribed. High anxious halazepam-treated patients were found to improve significantly more than low anxious halazepam-treated patients, while initial level of anxiety showed little effect on the diazepam response. It would thus seem that in the present study diazepam (20 mg/day) was slightly more efficacious in reducing anxious symptomatology than halazepam (160 mg/day) and particularly in the only mildly anxious patient. Perhaps a daily dosage of 120 mg/day of halazepam might have been more appropriate for most anxious patients.     

Effects of thioridazine and diazepam on the pharmacokinetics of [14C]imipramine in rat: acute study.

The pharmacokinetics of [14C]imipramine (10 mg kg minus 1) were tested in male Wistar rats for interaction with thioridazine (16 mg kg minus 1) or diazepam (10 mg kg- minus 1). All drugs were administered orally with the test substances being given 40 min before [14C]imipramine dosing. Bile and urine were collected for 90 min after the radioactive drug was given. The animals were then killed and the tissues removed. Thioridazine reduced the excretion of radioactivity into the bile and urine, and increased the weight of the contents within the gastrointestinal tract. These effects were interpreted as being mainly due to a reduction in gastrointestinal motility resulting in a slower stomach emptying of [14C]imipramine. No effect on metabolism was detected. Diazepam pretreatment reduced the concentration ratio of radioactivity in the small intestinal contents to that of plasma, but did not alter the tissue distribution, metabolism or excretion of [14C]imipramine.     

A double-blind outpatient study of diazepam (Valium) and placebo

Summary Investigators reporting clinical studies of diazepam tend to be enthusiastic about its effectiveness in controlling anxiety, but two careful double-blind studies on hospitalized patients found diazepam relatively ineffective. This investigation covering an outpatient population of one hundred found that treatment with diazepam was not significantly superior to placebo. Moreover, diazepam treatment was also associated in some patients with the emergence of suicidal thoughts or tendencies and paranoid tendencies in others.This study was undertaken by the Psychopharmacology Research and Treatment Unit. It was supported in part by a grant from the U.S. Public Health Service (MH 05090).     

Relationship between cerebral pharmacokinetics and anxiolytic activity of diazepam and its active metabolites after a single intra-peritoneal administration of diazepam in mice

The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a single intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min after administration, the sedative effect interfered with the anxiolytic effect, thus the results of the anxiolytic effect were not interpretable. From 30 min to 60 min after administration, this interference disappeared, the cerebral level of benzodiazepines was stable (the brain elimination of diazepam was compensated for by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5 mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could explain this result.     

A comparative study of haloperidol and diazepam in the treatment of anxiety

Summary

In a single-blind study in general practice, 60 patients with anxiety neuroses were randomly allocated to receive either 0.5?mg haloperidol twice daily or 2?mg diazepam 3-times daily for 6 weeks. Eighteen patients (6 on haloperidol and 12 on diazepam) were excluded from the analysis of efficacy. On the Hamilton Rating Scale both haloperidol and diazepam reduced the anxiety and depression scores. The investigator's assessment of 14 anxiety symptoms and signs indicated that haloperidol produced significantly (p=0.05) greater symptomatic improvement than diazepam after 4 and 6 weeks of treatment, and the patients' overall response was also significantly (p<0.005) greater with haloperidol. After 6 weeks, 93% of patients felt ‘better’ or ‘much better’ on haloperidol, compared with 83% on diazepam. A few, minor side-effects were reported, slightly fewer on haloperidol than on diazepam. In the parameters tested in this study, haloperidol has been shown to be more effective than diazepam in the treatment of anxiety neuroses and appears to provide significantly better overall symptomatic relief and to be more acceptable to patients than diazepam.     

不同纯度高良姜素的药代动力学比较研究

目的研究不同纯度高良姜素(galangin,GL)在大鼠体内的药代动力学。方法取健康SD大鼠(240～300)g随机分组,每组6只,单次口服给药后尾静脉分时采血、处理。采用反相高效液相色谱法,以外标法测定GL在大鼠血浆中的浓度,应用DAS2.0软件计算主要药代动力学参数。结果在所建立的方法学下,GL在0.05～1.8 mg.L-1的血浆浓度范围内呈良好的线性关系,最低检测限为0.03 mg.L-1(S/N=3),在0.24、0.47、0.94 mg.L-1 3个浓度下的绝对回收率为75.5%～86.9%,相对回收率为85.8%～91.2%,日内和日间RSD均小于5.0%(n=5)。按100 mg.kg-1单次口服给药后,GL在大鼠体内的药代动力学过程均符合二室模型,主要药代动力学参数T12α、T12β、Ka、AUC、Cl/F、V1/F,90%GL分别为19.415 min、33.983 min、0.059 min-1、101.722 mg.min.L-1、0.983 L.min-1.kg-1、5.073 L.kg-1;99%GL分别为24.398 min、31.719 min、0.048 min-1、55.201 mg.min.L-1、1.812 L.min-1.kg-1、6.861 L.kg-1。结论所建立的方法简便、准确、快速,能够满足GL的药代动力学要求。GL纯度为99%时较90%吸收缓慢,消除快。     

A population study of the pharmacokinetics of felodipine.

1. The pharmacokinetics of felodipine was studied after continuous oral administration of 5 or 10 mg conventional tablets to a population of 140 male and female Caucasian subjects, of which 67 were hypertensive patients and 73 were healthy volunteers. In addition, 42 of these individuals received felodipine intravenously. 2. With increasing age the area under the felodipine plasma concentration vs time curve (AUC), the maximum plasma concentration (Cmax), and the terminal elimination half-life of felodipine increased, while the plasma clearance of felodipine decreased. The bioavailability and steady state volume of distribution and the time to Cmax were not consistently influenced by age. 3. The ratio of the AUC of the primary pyridine metabolite of felodipine and that of unchanged drug decreased with increasing age. 4. Neither Cmax, AUC nor the half-life of felodipine were related to body mass index. 5. The distribution of AUC for felodipine, as well as the ratio of the AUC of this first metabolite to that of unchanged felodipine, was unimodal. Thus, the presence of a sizable group of individuals, with a clinically significant different metabolism of 1,4-dihydropyridine due to genetic factors is unlikely. 6. The pharmacokinetics of felodipine did not seem to differ between hypertensive patients and healthy volunteers, when adjusted for age. Neither was there a difference between patients taking beta-adrenoceptor antagonists and those who did not. 7. As a group the elderly had higher total concentrations of unchanged felodipine in plasma compared with younger individuals. The variation in plasma concentrations of felodipine between individuals is, however, only partially explained by age. In clinical practice this emphasizes the need for dose titration of felodipine.