The urinary elimination profiles of diazepam and its metabolites, nordiazepam, temazepam, and oxazepam, in the equine after a 10-mg intramuscular dose.
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A method for the extraction of diazepam and its metabolites (nordiazepam, temazepam, and oxazepam) from equine urine and serum and their quantitation and confirmation by liquid chromatography-tandem mass spectrometry is presented. Valium, a formulation of diazepam, was administered at a dose of 10 mg intramuscularly to four standard-bred mares. Diazepam is extensively metabolized in the horse to nordiazepam, temazepam, and oxazepam. Diazepam urinary concentrations were found to be less than 6 ng/mL. Nordiazepam was found to be mainly in its glucuronide-conjugated form and was measured out to a collection time of 53-55 h. Oxazepam and temazepam were entirely conjugated, and their urinary concentrations were measured out to collection times of 121 h and 77-79 h, respectively. Diazepam and nordiazepam were measured in equine postadministration serum out to collection times of 6 and 54 h, respectively. Oxazepam and temazepam were not detected in postadministration serum. (+info)
Sigmoidal kinetic model for two co-operative substrate-binding sites in a cytochrome P450 3A4 active site: an example of the metabolism of diazepam and its derivatives.
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Cytochrome P450 3A4 (CYP3A4) plays a prominent role in the metabolism of a vast array of drugs and xenobiotics and exhibits broad substrate specificities. Most cytochrome P450-mediated reactions follow simple Michaelis-Menten kinetics. These parameters are widely accepted to predict pharmacokinetic and pharmacodynamic consequences in vivo caused by exposure to one or multiple drugs. However, CYP3A4 in many cases exhibits allosteric (sigmoidal) characteristics that make the Michaelis constants difficult to estimate. In the present study, diazepam, temazepam and nordiazepam were employed as substrates of CYP3A4 to propose a kinetic model. The model hypothesized that CYP3A4 contains two substrate-binding sites in a single active site that are both distinct and co-operative, and the resulting velocity equation had a good fit with the sigmoidal kinetic observations. Therefore, four pairs of the kinetic estimates (KS1, kalpha, KS2, kbeta, KS3, kdelta, KS4 and kgamma) were resolved to interpret the features of binding affinity and catalytic ability of CYP3A4. Dissociation constants KS1 and KS2 for two single-substrate-bound enzyme molecules (SE and ES) were 3-50-fold greater than KS3 and KS4 for a two-substrate-bound enzyme (SES), while respective rate constants kdelta and kgamma were 3-218-fold greater than kalpha and kbeta, implying that access and binding of the first molecule to either site in an active pocket of CYP3A4 can enhance the binding affinity and reaction rate of the vacant site for the second substrate. Thus our results provide some new insights into the co-operative binding of two substrates in the inner portions of an allosteric CYP3A4 active site. (+info)
Prescribing and dispensing for drug misusers in primary care: current practice in Scotland.
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BACKGROUND: Substitute prescribing has increased in Scotland, as in the rest of the UK. Both GPs and pharmacists are becoming increasingly involved in service provision for drug misusers, but anecdotal evidence has suggested considerable variation in prescribing and dispensing practice. OBJECTIVE: We aimed to gain baseline data on (i) current prescribing practice by medical practitioners and drug agencies, (ii) dispensing practice by community pharmacists across Scotland for the management of drug misuse and (iii) variations in practice between health boards. METHODS: A structured questionnaire was posted to all community pharmacies in Scotland (n = 1142), in order to gather information on prescribing from prescriptions held at the time of the survey and information on current dispensing practice in managing drug misusers. RESULTS: The response rate was 79%. Sixty-one per cent of pharmacists were currently dispensing drugs for the management of drug misuse. The most frequently prescribed drug was methadone, dispensed by 46% of pharmacists, followed by diazepam (37%), dihydrocodeine (26%) and temazepam (25%). Sixty-five per cent of methadone prescriptions were dispensed daily on request from the prescriber. Of the 3387 people receiving a methadone prescription, 32.9% had to consume their daily dose on the pharmacy premises under a pharmacist's supervision. Nineteen per cent of pharmacies currently provided a service to supervise the consumption of methadone by clients and a further 14% were prepared to but had no current demand. The proportion of prescriptions requiring supervision of methadone consumption varied considerably between health board areas. CONCLUSIONS: Methadone is the most widely prescribed drug for drug misuse across Scotland, but there is considerable variation between health board areas in how prescribing is managed. Prescribing practice should be revised locally, in a process involving GPs and pharmacists. Pharmacists have an important role in preventing drug misuse in primary care, but need further support to optimize good practice. (+info)
Closed-loop control of propofol anaesthesia.
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We describe the use of a closed-loop system to control depth of propofol anaesthesia automatically. We used the auditory evoked potential index (AEPindex) as the input signal of this system to validate it as a true measure of depth of anaesthesia. Auditory evoked potentials were acquired and processed in real time to provide the AEPindex. The AEPindex was used in a proportional integral (PI) controller to determine the target blood concentration of propofol required to induce and maintain general anaesthesia automatically. We studied 100 spontaneously breathing patients. The mean AEPindex before induction of anaesthesia was 73.5 (SD 17.6), during surgical anaesthesia 37.8 (4.5) and at recovery of consciousness 89.7 (17.9). Twenty-two patients required assisted ventilation before incision. After incision, ventilation was assisted in four of these 22 patients for more than 5 min. There was no incidence of intraoperative awareness and all patients were prepared to have the same anaesthetic in future. Movement interfering with surgery was minimal. Cardiovascular stability and overall control of anaesthesia were satisfactory. (+info)
Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse.
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Rhabdomyolysis is a common cause of acute renal failure (ARF) associated with drug misuse. Abuse of the gel formulation of temazepam has been a particular problem in the West of Scotland. We performed a retrospective review of dialysis-dependent ARF from rhabdomyolysis and drug misuse in the West of Scotland, 1986-1997. We identified 76 patients, of whom 87% were male. Seventeen cases occurred in the first 6 years, compared with 59 in the subsequent 6 years. Median age was 32. Thirty cases followed intravenous drug misuse, 46 followed oral drug misuse. The substances most frequently misused were alcohol (54%), heroin (24%) and parenteral temazepam (17%). The temazepam cases all followed the introduction of the gel formulation. Three out of 4 patients requiring limb amputation had injected temazepam. Of intravenous drug misusers tested, 72% were hepatitis-C-positive. Some 43% of patients had deprivation scores in the worst category. ARF due to rhabdomyolysis from substance misuse is increasing in our area. Alcohol is frequently responsible. The introduction of the gel formulation of temazepam has contributed to the increase. Those at risk in this study were young, male, had a high incidence of hepatitis C and lived in the most deprived areas. (+info)
Gastric decontamination performed 5 min after the ingestion of temazepam, verapamil and moclobemide: charcoal is superior to lavage.
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AIMS: The aim was to study the efficacy of gastric lavage and activated charcoal in preventing the absorption of temazepam, verapamil and moclobemide when gastric decontamination was performed immediately after ingestion of the drugs. METHODS: Nine healthy volunteers took part in a randomized cross-over study with three phases. The subjects were administered single oral doses of 10 mg temazepam, 80 mg verapamil and 150 mg moclobemide. Five minutes later, they were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal as a suspension in 200 ml water or gastric lavage. Plasma concentrations and the cumulative excretion into urine of the three drugs were determined up to 24 h. RESULTS: The mean AUC(0,24 h) of temazepam, verapamil and moclobemide was reduced by 95.2% (P < 0.01), 92.8% (P < 0.01) and 99. 7% (P < 0.01), respectively, by activated charcoal compared with control. Gastric lavage did not reduce significantly the AUC(0,24 h) of these drugs. The 24 h cumulative excretion of temazepam, verapamil and moclobemide into urine was reduced significantly (P < 0.05) by charcoal but not by gastric lavage. Charcoal reduced the AUC(0,24 h), Cmax and urinary excretion of all three drugs significantly more than lavage. CONCLUSIONS: Activated charcoal is very effective and gastric lavage can be rather ineffective in preventing the absorption of temazepam, verapamil and moclobemide when the treatment is given very rapidly after ingestion of the drugs, before tablet disintegration has occurred. (+info)
Neurobehavioural performance effects of daytime melatonin and temazepam administration.
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Exogenous melatonin is a potential treatment for circadian disruption and insomnia. Hence, it is important to determine and quantify neurobehavioural performance effects associated with its use. The present study compared neurobehavioural performance following administration of melatonin and the benzodiazepine temazepam, using a within-subjects design. Following a training day, 16 healthy, young subjects (six males, 10 females; mean age +/- SEM, 21.4 +/- 6 years) participated in a 3-day protocol. After sleeping overnight in the laboratory, subjects completed a battery of tests at hourly intervals between 08:00 and 11:00 hours and at two hourly intervals between 13:00 and 17:00 hours. The neurobehavioural performance tasks included: unpredictable tracking, spatial memory, vigilance and logical reasoning. Subjective sleepiness was measured at hourly intervals using a visual analogue scale. At 12:00 h subjects were administered a capsule containing 5 mg melatonin, 10 mg temazepam or placebo, in a randomized, double-blind crossover fashion. A significant drug x time interaction was evident on the unpredictable tracking, spatial memory and vigilance tasks (P < 0.05). Greater changes in performance were evident following temazepam administration than melatonin administration, relative to placebo. Administration of melatonin or temazepam significantly elevated subjective sleepiness levels, relative to placebo (P +info)
The influence of particle size on the bioavailability of inhaled temazepam.
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1. Temazepam was administered by aerosol using a standard protocol to healthy volunteers. Two studies are reported in which different dosage formulations were used: a) 30 mg of the 5 mu diameter particle (n = 6); b) 10 mg of the 2 mu diameter particle (n = 6). 2. An open crossover design was followed in each study. On one occasion in both studies subjects used a gargling procedure to remove drug which had been deposited in the mouth and oropharynx. 3. Serial venous blood samples were drawn for a period of 24 h. The mean total AUC of the 5 mu preparation was significantly reduced by gargling (3153 ng ml-1 h to 1066 ng ml-1 h) (F = 0.32). Gargling also had a significant effect on the mean AUC(0-1 h). 4. In contrast gargling had no significant effect on the mean AUC associated with the smaller diameter particle preparation (630 ng ml-1 h) vs 397 ng ml-1 h (F = 0.74). 5. These findings also indicate that temazepam deposition in the pulmonary tree is enhanced by the use of a 2 mu rather than a 5 mu diameter particle. However, the plasma drug concentrations achieved are unlikely to produce a sufficiently marked sedative effect for endoscopic investigations such as gastroscopy. (+info)