CEDIA dau Benzodiazepine screening assay: a reformulation.

The CEDIA dau Benzodiazepine assay has been reformulated to include online hydrolysis of urinary benzodiazepine glucuronide conjugates. The new antibody possesses enhanced cross-reactivities toward the low-dose benzodiazepines, which are excreted at low urinary drug-metabolite concentrations. The screening method was evaluated using lorazepam as the probe benzodiazepine. Four subjects each consumed a 1-mg lorazepam tablet. Sequential urine voids over the same time intervals were collected for the next 48 h. Twelve postdose urine samples were collected from each subject. Positive results were obtained from 5-24 h to 2-35 h using a 200-ng/mL nitrazepam calibration cutoff. There was no practical difference between hydrolyzing online with the supplied E. coli beta-glucuronidase or offline with Helix pomatia beta-glucuronidase purchased separately. Without hydrolysis, all urine samples tested negative. The cross-reactivities of lorazepam in terms of nitrazepam calibration equivalents, varied from 108 to 178% for lorazepam concentrations between 50 and 2500 ng/mL. Lorazepam glucuronide gave cross-reactivities (expressed as lorazepam base) between 72 and 136% using the online hydrolysis procedure with E. coli beta-glucuronidase. Offline hydrolysis with Helix pomatia gave cross-reactivities between 84 and 134%. Without hydrolysis, lorazepam glucuronide gave less than 4% cross-reactivity in the assay.

Zopiclone fatality in a hospitalized patient.

The death of a 72-year-old man is described who overdosed himself while in hospital. The man was being treated for lung cancer and ingested 90 mg of zopiclone in a suicide attempt. He died between 4 and 10 h after the ingestion. Zopiclone, quantitated by GC-MS in the femoral blood, cardiac blood, vitreous humor, urine and bile was found to be 254, 408, 94, 7,330, and 114,700 ng/mL, respectively. Considering the man's weakened physical condition, 90 mg could represent a minimum lethal zopiclone dose.

High urinary cannabinoids from a hashish body packer.

A body packer swallowed 39 condoms containing a total of 518 g hashish oil. He was arrested on entry into Canada. Two days later, a urine sample was obtained. Total cannabinoid concentrations by TDx and Emit II were 10,200 ng/mL and 11,400 ng/mL, respectively. The concentration of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid by gas chromatography/mass spectrometry was 1140 ng/mL.

Lack of in vitro inactivation of tobramycin by imipenem/cilastatin.

OBJECTIVE: Inactivation of aminoglycosides by beta-lactam antimicrobials both in vitro and in vivo has been documented. Such an interaction has not previously been documented between carbapenems and aminoglycosides. Examination of serum concentrations of tobramycin in a patient receiving both agents suggested that this interaction might exist. The purpose of this study was to look at this question in an in vitro model. METHODS: Low concentrations of tobramycin (10 micrograms/mL) were incubated with imipenem/cilastatin (concentrations of 10, 20, and 40 micrograms/mL) in human serum at 37 degrees C. Aliquots of these solutions were withdrawn at 0, 6, 24, 72, and 120 hours and assayed for tobramycin concentrations using a fluorescence polarization immunoassay. Aliquots of tobramycin 10 micrograms/mL and carbenicillin 200 micrograms/mL were analyzed in the same manner, as a positive control. High concentrations of tobramycin (800 micrograms/mL) and imipenem (5000 micrograms/mL)/cilastatin were incubated together at 21 degrees C and sampled at 0, 6, 24, and 72 hours for tobramycin concentrations. RESULTS: The degradation rates for low-concentration tobramycin and the various concentrations of imipenem/cilastatin were not statistically different from those of the controlled incubations. In contrast, carbenicillin significantly enhanced the degradation rate of tobramycin at this concentration (half-life 72 hours and a 34 percent loss at 24 hours, p = 0.0028). Higher in vitro concentrations of imipenem (5000 micrograms/mL)/cilastatin and tobramycin (800 micrograms/mL) resulted in significant, but moderate degradation over controlled incubations (half-life 80 hours and 10 percent loss at 12 hours, p = 0.0031). CONCLUSIONS: These results suggest that inactivation of tobramycin is not a problem at common clinically achievable imipenem serum concentrations in patients.

Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy.

We retrospectively reviewed our 10-year experience with the management of sulfonylurea overdose. There were 40 overdoses in 37 patients aged 1 to 78 years, with two deaths and one patient being left in a chronic vegetative state. Blood sugar levels ranged from normal to severe recalcitrant hypoglycemia. Maximal duration of recurrent hypoglycemia was 82 hours. In 21 of 31 patients with hypoglycemia, response to hypertonic glucose therapy was poor, resulting in recurrent hypoglycemia. Six of these patients were treated with intravenous diazoxide and had prompt correction. Overdose of sulfonylurea drugs may produce severe, protracted hypoglycemia poorly responsive to hypertonic glucose therapy. Treatment with diazoxide is rational and effective and may be lifesaving.

A sensitive thin-layer chromatographic procedure for the detection of urinary 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid.

A sensitive high-performance thin-layer chromatographic (HPTLC) procedure for the detection of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), the major urinary metabolite of delta 9-tetrahydrocannabinol (THC), is described. After alkaline hydrolysis, the THC-COOH is extracted from acidified urine into hexane. The hexane is evaporated and the residue spotted onto an HPTLC plate. Chromatography time is 11 min with heptane/butanol/acetic acid (90:9:1) as mobile phase. The cannabinoids are visualized by sequentially dipping the thin-layer plate in diethylamine then in 0.1% Fast Blue BB. The limit of detection for THC-COOH is 5 ng/mL when 2 mL of urine is used. Extraction efficiencies averaged 71% over the 10-400 ng/mL range. No drugs, drug metabolites, or endogenous urinary substances interfere with the procedure.

Premedication and high-dose fentanyl anesthesia for myocardial revascularization: a comparison of lorazepam versus morphine-scopolamine.

Using a randomized double-blind placebo-controlled experimental protocol, the authors compared two premedication regimens in 42 patients undergoing elective myocardial revascularization. Group L patients (n = 23) received lorazepam 0.06 mg/kg po 90 min preoperatively, while group M patients (n = 19) received morphine 0.1 mg/kg im, plus scopolamine 0.006 mg/kg im 60 min preoperatively. Anesthesia was induced with fentanyl 100 micrograms/kg and atracurium 0.50 mg/kg administered over 10 min. The treatment groups did not differ significantly with respect to the degree of sedation or anxiolysis achieved, or the rapidity of induction with fentanyl. Premedication significantly influenced the hemodynamic response to anesthetic induction. Hemodynamics were stable post-induction in group M, but cardiovascular depression was noted in group L. Control heart rate (HR) was lower in group L. The HR, arterial pressure, and cardiac index were significantly lower, following both induction and intubation, in group L. Following sternotomy hemodynamics were identical in both groups. Serum fentanyl concentration was significantly higher during intubation in group L, probably secondary to the pharmacokinetic consequences of a decreased CI. New electrocardiographic evidence of myocardial ischemia did not occur in either group. Based on their findings with fentanyl-at-racurium, and their review of the literature, the authors speculate that premedication exerts a significant hemodynamic effect during induction with other narcotic-relaxant combinations.

The effect of excessive ethanol ingestion on sleep in severe chronic obstructive pulmonary disease.

The effect of a moderately intoxicating dose of ethanol on sleep was evaluated in five patients with severe emphysematous chronic obstructive pulmonary disease (COPD) (mean FEV1 0.83 L, PaO2 75 mm Hg). Mean serum ethanol before sleep was 129 mg/dl. With alcohol, total sleep time per night decreased from a mean of 293 to 238 min. Relative sleep time per stage also changed; NREM time increased, and REM time decreased greater than 50%. Alcohol caused significant O2 desaturation; group mean sleep arterial oxygen saturation (SaO2) decreased from 90.6 to 87.7% with alcohol. Although the decrease in SaO2 was not uniform across all sleep stages, no individual sleep stage accounted for the desaturation. The fall in SaO2 with alcohol was not explained by increasing apneas or hypopneas. Mean heart rate increased significantly from 71.8 to 77.1 with alcohol, with premature ventricular contractions increasing in two subjects. Excessive alcohol ingestion in severe COPD alters total sleep time and stage distribution, decreases SaO2 without significant change in apneas, and increases heart rate. Prior to sleep, patients with severe COPD should strictly limit ingestion of alcohol.

A randomized double-blind comparison of fentanyl and sufentanil anaesthesia for coronary artery surgery.

Using a randomized double-blind protocol the authors compared two narcotic anaesthetic regimens in 33 patients with good ventricular function undergoing coronary artery surgery. After premedication with morphine and scopolamine, patients received either fentanyl 100 micrograms X kg-1 (n = 16), or sufentanil 15 micrograms X kg-1 (n = 17), intravenously (IV) over 10 min to induce anaesthesia. Metocurine 0.42 mg X kg-1 provided muscle relaxation. No further IV anaesthetic agents were given. The haemodynamic response to induction, intubation, and surgery, differed minimally between agents. The degree of rigidity on induction was identical with both agents, as were the intervals following induction at which patients lost consciousness, regained consciousness, or met criteria for extubation. However, the interval until extubation criteria were met did correlate with the duration of cardiopulmonary bypass. Sufentanil 15 micrograms X kg-1, was clinically indistinguishable from fentanyl 100 micrograms X kg-1, when used as the primary anaesthetic agent for coronary surgery.

Pharmacokinetics of cefixime (CL 284,635; FK 027) in healthy subjects and patients with renal insufficiency.

The pharmacokinetics of the extended-half-life, broad-spectrum oral cephalosporin cefixime (CL 284,635; FK 027) were studied in 7 healthy volunteers and 35 patients with various degrees of renal insufficiency, including patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis. Apparent total body, renal, and apparent nondialysis-nonrenal clearances and protein binding declined and elimination half-life increased with decreasing creatinine clearance. All of these alterations became statistically significant as the creatinine clearance fell below 20 ml/min per 1.73 m2. Cefixime concentrations in urine exceeded the MICs for most urinary tract pathogens for up to 24 h postdose, even in patients with severe renal insufficiency. CAPD removed an insignificant fraction of cefixime body burden over the 72-h study period (1.57 +/- 0.60% [mean +/- the standard error of the mean]). Area under the curve data suggested that hemodialysis similarly removed an insignificant fraction of the cefixime body burden. Volume of distribution at steady state was not altered significantly by renal insufficiency. It is recommended that standard doses of cefixime be administered at extended intervals, especially in patients with creatinine clearances less than 20 ml/min per 1.73 m2. In addition, supplemental doses are not necessary during CAPD and at the end of hemodialysis.

Pharmacokinetics of fentanyl in patients undergoing abdominal aortic surgery.

The authors determined the pharmacokinetics of fentanyl 100 micrograms X kg-1 iv in patients undergoing elective abdominal aortic surgery. The mean (+/- SD) age of the ten patients was 67.2 +/- 8.7 yr; their mean weight was 78.5 +/- 13.7 kg. Seven patients had aortic aneurysm repair, and the other three patients had aortobifemoral grafts. Serum fentanyl concentrations were determined from samples drawn at increasing intervals over a 24-h period. A three-compartment pharmacokinetic model was fit to the concentration versus time data. Total drug clearance was 9.8 +/- 1.8 ml X min-1 X kg-1. The volume of distribution at steady-state (Vdss) was 5.4 +/- 1.9 X 1 kg-1. Elimination half-time was 8.7 +/- 2.5 h. There were no significant correlations between these pharmacokinetic parameters and patient's age, duration of aortic cross-clamping, duration of surgery, intraoperative blood loss, or volume of iv fluids given intraoperatively. In healthy volunteers or patients undergoing general surgery, other investigators report mean elimination half-times for fentanyl ranging from 1.7 to 4.4 h. The prolonged elimination half-time in patients having abdominal aortic surgery has important clinical implications. In particular, recovery from large doses will take much longer than would have been anticipated from previously published fentanyl pharmacokinetic data.

Effects of upper or lower airway anesthesia on hypercapnic ventilation in humans.

To evaluate the contribution of vagal airway receptors to ventilatory control during hypercapnia, we studied 11 normal humans. Airway receptor block was induced by inhaling an aerosol of lidocaine; a preferential upper oropharyngeal block was also induced in a subgroup by gargling a solution of the anesthetic. Inhalation of lidocaine aerosol adequate to increase cough threshold, as measured by citric acid, did not change the ventilatory response to CO2, ratio of the change in minute ventilation to change in alveolar PCO2 (delta VI/delta PACO2), compared with saline control. Breathing pattern at mean CO2-stimulated ventilation of 25 l/min showed significantly decreased respiratory frequency, increased tidal volume, and prolonged inspiratory time compared with saline. Resting breathing pattern also showed significantly increased tidal volume and inspiratory time. In nine of the same subjects gargling a lidocaine solution adequate to extinguish gag response without altering cough threshold did not change delta VI/delta PACO2 or ventilatory pattern during CO2-stimulated or resting ventilation compared with saline. These results suggest that lower but not upper oropharyngeal vagal airway receptors modulate breathing pattern during hypercapnic as well as resting ventilation but do not affect delta VI/delta PACO2.

Ranitidine does not alter pethidine disposition in man.

The effect of concurrent ranitidine administration on the disposition of pethidine was investigated in eight healthy male volunteers (19-33 years). The subjects received 70 mg i.v. pethidine HCl doses before and during ranitidine treatment (150 mg p.o. twice daily). Ranitidine therapy was not associated with significant alterations in pethidine elimination rate constant, volume of distribution at steady state, total body clearance, and 24 h urinary excretion. No alteration in pethidine oxidation to norpethidine was noted, as suggested by nonsignificant changes in lag time to appearance of quantifiable norpethidine in serum, time to peak concentration, peak concentration, area under the curve from time 0.24 h, and 24 h urinary excretion. It would appear that, unlike cimetidine, ranitidine does not interact pharmacokinetically with pethidine. Further studies are necessary to evaluate the potential clinical advantages of ranitidine vs cimetidine therapy in patients also receiving pethidine.

Analysis of meperidine and normeperidine in serum and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method is described for the simultaneous analysis of meperidine and normeperidine in serum and urine. A 1-ml sample aliquot is extracted into hexane, then back-extracted into a small volume of dilute acid which is injected onto a cyanopropyl analytical column. Absorbance of the column effluent is monitored at 205 nm. Two internal standards are employed, diphenhydramine for meperidine and nordiphenhydramine for normeperidine. Chromatography of the four compounds takes 4 min. Serum concentration--time curves of meperidine and normeperidine are presented for eight healthy subjects following single 70-mg bolus injections of meperidine.

Cimetidine alters pethidine disposition in man.

The effect of concurrent cimetidine administration on the disposition of pethidine was investigated in eight healthy male volunteers (18-31 years). The subjects received 70 mg i.v. pethidine HCl doses before and during cimetidine treatment (1200 mg/day p.o.). During cimetidine treatment, pethidine total body clearance (CL) decreased by 22% (0.611 +/- 0.101 [mean +/- s.d.] to 0.474 +/- 0.098 1 kg-1 h, P less than 0.05) and pethidine volume of distribution at steady state (Vss) decreased by 13% (4.79 +/- 0.82 to 4.16 +/- 0.75 l/kg, P less than 0.05). A cimetidine-induced reduction in pethidine oxidation to norpethidine was suggested by a 23% reduction in norpethidine area under the curve from 0 to 24 h (472 +/- 93 to 362 +/- 38 ng ml-1 h, P less than 0.05) and a 29% reduction in peak norpethidine concentration (26.7 +/- 5.3 to 18.9 +/- 1.9 ng/ml, P less than 0.05). There were no significant linear correlations of serum trough cimetidine concentration with percentage reductions in pethidine CL, pethidine Vss, norpethidine AUC (24), or norpethidine peak concentrations. It would appear that the cimetidine-pethidine kinetic interaction may be of sufficient magnitude to be clinically significant. Caution is advised when patients are treated concurrently with these two agents.

Activated charcoal adsorption of diphenhydramine.

The adsorption of the antihistamine diphenhydramine (D) by activated charcoal (AC) was assessed in vitro and in vivo in six healthy volunteers in order to assess the utility of AC as an adjunct in the treatment of antihistamine overdose. Results of greater than 85% adsorption with AC:D weight ratios of 10:1 or greater in the in vitro studies led to a three-way crossover trial in six volunteers. Fifty mg D was administered alone (control), with 50 g AC within 5 minutes of D (D + C5) and with 50 g AC 60 minutes after D (D + C60). Mean reductions in peak serum D concentrations of 94.8% (D + C5) and 12.3% (D + C60), AUC 0-24 h of 96.9% (D + C5) and 20.4% (D + C60), and AUC 0-omega of greater than 90% (D + C5) and 24.0% (D + C60) were noted, although only the comparison of D with D + C5 reached statistical significance due to wide interpatient variation. A positive correlation of time to peak concentration of drug in serum in the control group with percentage reduction in AUC in the D + C60 group further indicate the potential for positive therapeutic benefit of AC in antihistamine overdose. This is because lag time and time to peak concentration may be excessively prolonged in overdose due to anticholinergic-induced alterations in G.I. motility. Maximal and multiple doses of AC are recommended for adjunctive treatment of antihistamine overdose.

Isothermal gas chromatographic analysis of diphenhydramine after direct injection onto a fused-silica capillary column.

The packed column injector of a gas chromatograph was modified to accommodate direct injection by syringe onto a wide-bore fused-silica capillary column. No changes were made to the nitrogen-phosphorus detector. The resultant configuration combines fast separations with precise quantitations. The analysis of diphenhydramine in serum is presented as an application. Chromatographic separation of diphenhydramine and orphenadrine (internal standard) from caffeine and other endogenous material takes 2 min. Serum diphenhydramine concentrations are presented for six volunteers following a 50-mg oral dose.

Pharmacokinetics of metronidazole in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of metronidazole, its biologically active alcohol metabolite, and its inactive acid metabolite were studied in five noninfected patients undergoing continuous ambulatory peritoneal dialysis and five patients undergoing hemodialysis. The latter were studied on off-dialysis days as a control group. Peritoneal dialysis caused insignificant changes in the apparent volume of distribution, elimination half-life, and total body clearance of metronidazole. Peritoneal dialysis clearance (4.49 +/- 0.88 ml/kg per h [mean +/- standard deviation]) accounted for only 8.9% of total body clearance (50.17 +/- 18.64 ml/kg per h). Analysis of the 24-h area under the serum concentration versus time curves and peritoneal dialysis clearance data for the two metabolites suggested a similar insignificant effect of peritoneal dialysis on their elimination. Metronidazole dialysate concentrations in the first 6-h exchange ranged from 7.6 to 11.7 micrograms/ml. This would suggest that cumulative penetration of metronidazole from the systemic circulation into the peritoneal cavity with dosing every 8 h should lead to adequate concentrations for the treatment of anaerobic peritonitis. For the treatment of systemic anaerobic infections, it would appear at present that metronidazole dosage adjustments are not necessary in patients undergoing continuous ambulatory peritoneal dialysis. The potential for metabolite accumulation was noted in this study. If further studies confirm that excessive serum metabolite concentrations are toxic, dosage reduction in this group of patients may be warranted.