Alprazolam abuse and methadone maintenance.
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Alprazolam↗
Biomedical subjects
A D Fraser
Publications and source records attributed to A D Fraser.
Clinical valproate toxicity induced by acetylsalicylic acid.
We report three patients with serious clinical valproate (VPA) toxicity induced by interaction with acetylsalicylic acid (ASA). Two patients had a documented rise in VPA free level, and the third showed only clinical signs of toxicity. Symptoms resolved in all three when the ASA was stopped. This interaction has been previously documented under experimental conditions, and is due to displacement of VPA from plasma protein binding sites and a probable interference in metabolism. This is the first report of the clinical significance of this interaction.
Adolescent↗
Analysis of 2-hydroxyimipramine in an imipramine-related fatality.
A fatality following ingestion of the tricyclic antidepressant imipramine (Novopramine), acetaminophen, and ethyl alcohol is described. Imipramine, desipramine, acetaminophen, and 2-hydroxyimipramine were quantitated by high performance liquid chromatography, and ethyl alcohol by gas liquid chromatography. Concentrations of imipramine, desipramine, 2-hydroxyimipramine, and acetaminophen were: in blood--9.0, 1.1, 3.9, and 11 mg/L; in urine--92, 14, and 42 mg/L (acetaminophen not quantitated in urine). Ethyl alcohol concentration in blood was less than 10 mg/dL and 105 mg/dL in the urine by headspace gas chromatography. These findings are compared to previous reports of imipramine-related fatalities. To our knowledge, this is the first fatality reported involving imipramine where analysis included quantitation of 2-hydroxyimipramine in blood and urine.
Acetaminophen↗
A carpipramine related fatality.
A fatality following ingestion of the tricyclic antidepressant carpipramine (Prazinil) and ethyl alcohol is described. Carpipramine was quantitated by high performance liquid chromatography. The concentration of carpipramine was 2.0 mg/L in blood and 0.44 mg/L in urine. Ethyl alcohol was measured by headspace gas chromatography and found to be 105 mg/dL in blood and 55 mg/dL in the urine. Quantitative analysis of stomach contents was positive for carpipramine by thin-layer chromatography. To our knowledge, this is the first reported fatality involving carpipramine.
Alcohol Drinking↗
A fatality involving clomipramine.
A fatality following ingestion of the tricyclic antidepressant clomipramine (Anafranil), alprazolam (Xanax), and ethyl alcohol is described. Clomipramine and N-desmethylclomipramine were quantitated by high performance liquid chromatography and alprazolam by gas liquid chromatography. Concentrations of clomipramine and N-desmethylclomipramine were: in blood--0.84 and 1.4 mg/L; in urine--0.56 and 0.62 mg/L. Alprazolam concentration in blood was 0.069 mg/L. Ethyl alcohol was measured by headspace gas chromatography and found to be 375, 385, and 435 mg/dL in blood, urine, and vitreous humor, respectively. These findings are compared to previous reports of clomipramine related fatalities and alprazolam toxicity combined with ethyl alcohol.
Alcohol Drinking↗
Experience with a specific request form for antidepressant drug monitoring.
With the introduction of an antidepressant drug monitoring service in this hospital, it became necessary to have a completed request form prior to analysis. The importance of ordering these tests selectively and of basic pharmacokinetics for antidepressants was stressed through special lectures and a newsletter. This study was undertaken to assess whether the use of this form assisted in optimizing drug monitoring of antidepressants. Information provided on the form was used to assist in interpretative reporting and to improve clinical use of the results. Requested information included the name, age, sex, height, and weight of the patient; time of last dose; date therapy started at present dose; reason for the request; and a list of concurrent medications. Results obtained for 600 specimens in 18 months showed that the form was completed fully, sampling time was appropriate, and drug concentration was at steady state 82, 73, and 95% of the time, respectively. Major reasons for requesting analysis were suspicion of subtherapeutic (52%), uncertain (20%), above therapeutic (15%), and toxic (10%) ranges. The most popular monitoring requests were for imipramine (40%), doxepin (28%), amitriptyline (14%), and desipramine (11%). Clinical impression of efficacy in the treatment of endogenous depression agreed with plasma levels 60% of the time in the subtherapeutic range, but agreement was only 32% above the therapeutic range. It was concluded that a special request form helps to assure appropriate sampling, explain observed drug interactions, and facilitate interpretative reporting for the medical and nursing staff.
Antidepressive Agents↗
The black-and-white positive line slide: a modern approach.
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Medical Illustration↗
Toxicologic studies in a fatal overdose of 2,4-D, mecoprop, and dicamba.
A suicidal poisoning committed by a 61-year-old woman, who ingested an unknown quantity of Killex, containing in aqueous solution 100 g/L of (2,4-dichlorophenox)acetic acid (2,4-D), 50 g/L of mecoprop, and 9 g/L of dicamba as amine salts is described. Quantitation of chlorophenoxy acids was performed by extraction from an acidified mixture and concentration before high performance liquid chromatography analysis. All three herbicides were separated in a phosphate buffer/acetonitrile mixture at 280 nm on a RP-8 column. Concentrations of herbicides found were: in blood--520-mg/L 2,4-D, 530-mg/L mecoprop, and 170-mg/L dicamba; in urine--670-mg/L 2,4-D and 520-mg/L mecoprop; in bile--340-mg/L 2,4-D, 530-mg/L mecoprop, and 140-mg/L dicamba; and in liver--540-mg/Kg 2,4-D, 500-mg/Kg mecoprop, and less than 100-mg/Kg dicamba. Liquid chromatography was found to be a reliable method for herbicide quantitation in biological tissues and fluids. The technique offered definite advantages over ultraviolet spectrophotometry and avoids the derivatization requirement for gas chromatography.
2,4-Dichlorophenoxyacetic Acid↗
Liquid chromatographic determination of piroxicam in serum.
A sensitive method for monitoring serum piroxicam (Feldene) is described. The assay requires 1.0 ml of specimen and involves chloroform extraction from an acidified mixture followed by concentration and injection into a liquid chromatograph. Column effluent is monitored at 330 nm. Retention times of piroxicam and the internal standard (naproxen) are 6.6 and 11.0 min, respectively. The lower limit of detection in serum is 0.5 mg/L. Within-day precision (coefficient of variation, CV) of piroxicam in serum (5-13 mg/L range) varied from 3.6 to 6.3%; between-day CV at concentrations of 5 to 20 mg/L varied from 6.5 to 9.8%. Analytical recovery of piroxicam at 20 mg/L was 88%. Several other drugs were analyzed but none interfered with the assay. Serum concentrations found in 28 patients on a 20-30 mg/day dose ranged from 1.5 to 15.2 mg/L.
Anti-Inflammatory Agents↗
Clinical evaluation of the EMIT salicylic acid assay.
Salicylic acid was measured by a homogeneous enzyme immunoassay technique (EMIT). Replicate analyses of samples in the therapeutic range gave a within-day coefficient of variation (CV) of 5.1% and day-to-day CV of less than 5.0%. Quantitative results obtained by immunoassay on serum samples from patients receiving acetylsalicylic acid were compared with the results obtained by the colorimetric procedure of Trinder. Regression analysis of 100 specimens analyzed by immunoassay (y) and the reference procedure (x) gave the equation y = 0.99x - 1.18 (r = 0.995, Sy.x = 1.23). Clinical evaluation of the results indicates that the enzyme immunoassay procedure is highly sensitive and specific for salicylic acid.
Antibody Specificity↗
Characterization of an Escherichia coli mutant which utilizes glycerol in the absence of cyclic adenosine monophosphate.
The aerobic catabolism of glycerol depends on the expression of the glpK operon specifying a glycerol kinase and the glpD operon specifying an sn-glycerol-3-phosphate (G3P) dehydrogenase. It has not been clearly established how the expression of these operons is dependent on adenosine 3',5'-cyclic monophosphate (cAMP). We have isolated a promoterlike mutant (CA8306B) which, owing to a mutation in the glpK operon, can utilize glycerol in the absence of cAMP. Glycerol kinase and G3P dehydrogenase are inducible in CA8306B and its wild-type parent CA8000. The induced level of glycerol kinase in CA8306B is 30% that of CA8000 and this level is increased fivefold by the addition of cAMP. However, the induced level of G3P dehydrogenase in CA8306B is similar to that of CA8000 and is unaffected by cAMP addition. These results suggest that the promotion of the glpK operon requires cAMP whereas the promotion of the glpD operon does not.
Cyclic AMP↗
Mannose utilization in Escherichia coli requires cyclic AMP but not an exogenous inducer.
It has been clarified whether the utilization of mannose by Escherichia coli requires adenosine 3',5'-cyclic monophosphate (cyclic AMP). Using an adenylyl cyclase deficient mutant (CA8306B) and a cyclic AMP receptor protein (CRP) deficient mutant (5333B) we have shown that the utilization of mannose is dependent on the cyclic AMP - CRP complex. 2-Deoxyglucose (DG) is a nonmetabolizable glucose analog specific for the phosphotransferase system (PTS) which transports mannose (termed here PTSM). Growth of CA8306B on glycerol is unaffected by addition of the analog, whereas growth of the strain on glycerol plus cyclic AMP ceases immediately upon addition of DG. These results suggest that the formation of PTSM is dependent on cyclic AMP. In addition, CA8306B grown on glycerol plus cyclic AMP can immediately utilize mannose when transferred to a medium containing mannose as a sole carbon source, whereas the same strain grown on glycerol without cyclic AMP cannot utilize mannose when so transferred. The results suggest that the formation of PTSM does not require an exogenous inducer.
Cyclic AMP↗
Chemotherapy as a cause of low serum creatine kinase activity.
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Creatine Kinase↗
Effect of carbon sources on the rates of cyclic AMP synthesis, excretion, and degradation, and the ability to produce beta-galactosidase in Escherichia coli.
We have determined the rates of adenosine 3',5'-cyclic monophosphate (cAMP) synthesis, excretion, and degradation, and the cAMP pool size in Escherichia coli grown on various carbon sources. We have found that the cAMP pool size increases in approximate proportion to increases in the cAMP synthetic rate. Although the combined rate of excretion and degradation of cAMP is in approximate proportion to the cAMP pool size, no such regular relationship is seen between the cAMP pool size and either the excretion rate or the degradation rate. Using a method which we have developed for determining the cellular efficiency of enzyme production (termed 'cellular' rate), we have reexamined the relationship between cAMP pool size and the rate of beta-galactosidase production. Although there exists an overall trend of increasing rate of beta-galactosidase production with increasing cAMP pool size, large variations in the rates of beta-galactosidase production are seen even under culture conditions which yield similar cAMP pool sizes. This suggests that the intracellular level of cAMP cannot be the unique regulator of beta-galactosidase production.
Culture Media↗
In vivo preparation of [32P]cAMP and thin-layer chromatography of cAMP-related compounds.
A simple and rapid method for preparing [32P]adenosine 3'5'-cyclic monophosphate (cAMP) is described. A culture of an Escherichia coli mutant which excretes cAMP about 150 times faster than does a wild-type strain was incubated overnight with [32P]orthophosphate of high specific activity (e.g., 4000 Ci/mol (1 Ci = 37 GBq). The [32P]cAMP which accumulated extracellularly was then purified to 99.9% radiochemical purity in less than 4 h by adsorption to charcoal and alumina column chromatography. A two-dimensional chromatography system using a PEI-cellulose plate is also described which should prove useful for studying cAMP metabolism with 32P- or 3H-labeled cAMP or ATP.
Chromatography, Thin Layer↗
Bilirubin inhibition of gamma-glutamyltransferase on the DuPont aca.
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Autoanalysis↗
Modification of the DuPont aca as exemplified by a new procedure for neonatal total bilirubin.
Hemoglobin interferes with determination of total bilirubin by the diazo procedure with the DuPont aca. We compared results by that procedure with those by a manual direct spectrophotometric two-wavelength method. Because the manual method was not inhibited by hemolysis as was the DuPont aca diazo procedure, we reprogrammed our DuPont aca to measure the absorbance of diluted serum samples at 452 and 577 nm with use of DuPont absorbance packs as the sample pack and cuvette. Results correlated well with those by the manual spectrophotometric method, and hemolysis no longer interfered. The method is primarily intended for use with serum from neonates.
Autoanalysis↗
Determination of the rates of synthesis and degradation of adenosine 3',5'-cyclic monophosphate in Escherichia coli CRP- and CRP+ strains.
We have developed a method for estimating the rates of synthesis and degradation of adenosine 3',5'-cyclic monophosphate (cAMP) in Escherichia coli during balanced growth. Applying this method, we have found that an E. coli CRP- mutant 5333 (deficient for cAMP receptor protein) synthesizes cAMP about 25 times faster than does its CRP+ parent 1100. This accounts for the abnormally high intracellular and extracellular cAMP accumulation in 5333.
Cyclic AMP↗