Evaluation of self-swabbing coupled with a telephone health helpline as an adjunct tool for surveillance of influenza viruses in Ontario.

BACKGROUND: Calls to a telephone health helpline (THHL) have been previously evaluated for the ability to monitor specific syndromes, such as fever and influenza-like-illness or gastrointestinal illness. This method of surveillance has been shown to be highly correlated with traditional surveillance methods, and to have potential for early detection of community-based illness. Self-sampling, or having a person take his/her own nasal swab, has also proven successful as a useful method for obtaining a specimen, which may be used for respiratory virus detection. METHODS: This study describes a self-swabbing surveillance system mediated by a nurse-led THHL in Ontario whereby syndromic surveillance concepts are used to recruit and monitor participants with influenza-like illness. Once recruited, participants collect a nasal specimen obtained by self-swabbing and submit for testing and laboratory confirmation. Enumeration of weekly case counts was used to evaluate the timeliness of the self-swabbing surveillance system through comparison to other respiratory virus and influenza surveillance systems in Ontario. The operational efficiency of the system was also evaluated. RESULTS: The mean and median number of days between the day that a participant called the THHL, to the day a package was received at the laboratory for testing were approximately 10.4 and 8.6 days, respectively. The time between self-swab collection and package reception was 4.9 days on average, with a median of 4 days. The self-swabbing surveillance system adequately captured the 2014 influenza B season in a timely manner when compared to other Ontario-based sources of influenza surveillance data from the same year; however, the emergence of influenza B was not detected any earlier than with these other surveillance systems. Influenza A surveillance was also evaluated. Using the THHL self-swabbing system, a peak in the number of cases for influenza A was observed approximately one week after or during the same week as that reported by the other surveillance systems. CONCLUSION: This one-year pilot study suggests that the THHL self-swabbing surveillance system has significant potential as an adjunct tool for the surveillance of influenza viruses in Ontario. Recommendations for improving system efficacy are discussed.

No evidence of drug-induced pancreatitis in rats treated with exenatide for 13 weeks.

AIMS: The potential association of glucagon-like peptide receptor agonists (GLP-1RAs) with the development of pancreatitis or pancreatic malignancies in patients with diabetes has been suggested. This study evaluated the long-term effects of the GLP-1RA exenatide on pancreatic exocrine structure and function in the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. METHODS: Rats received subcutaneous twice-daily injections of 0 (control), 6, 40 and 250 µg/kg/day exenatide for 3 months. Clinical signs, body and pancreas weight, food consumption, HbA1c, fasting serum amylase, lipase, glucose and insulin concentrations were evaluated during treatment and after a 28-day off-drug period to assess the reversibility of any observed effects. Morphometric analysis of pancreatic ductal cell proliferation and apoptosis were performed. RESULTS: Plasma exenatide concentrations were several-fold higher than therapeutic levels observed in humans. No exenatide-related effects were observed on clinical signs, lipase concentration, pancreatic weight, pancreatic histology, ductal cell proliferation or apoptosis. Exenatide improved animal survival, physical condition, glucose concentrations and HbA1c, decreased food intake, and increased serum insulin concentration. Total amylase concentrations, although within normal ranges, were slightly higher in exenatide-treated rats; following the off-drug period, total amylase concentrations were comparable in treated and untreated rats. Exenatide-related minimal-to-moderate islet hypertrophy was observed at doses ≥6 µg/kg/day, with dose-related increases in incidence and degree. These changes were still present after the off-drug period. CONCLUSIONS: Chronic administration of exenatide in ZDF rats resulted in the expected metabolic benefits and improved animal survival, with no adverse effects noted on pancreatic exocrine structure and function.

Metabolism, sister chromatid exchanges, and DNA single-strand breaks induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and their modulation by vitamin A in vitro.

The nicotine-derived N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) is abundant in smokeless tobacco and tobacco smoke and is hepatocarcinogenic in F344 rats. We have investigated how vitamin A modulates sister chromatid exchanges and DNA single-strand breaks induced by NNK. In V79 cells, vitamin A at concentrations ranging from 34.9 to 139.6 microM inhibited sister chromatid exchange frequencies induced by 20 mM NNK activated by primary rat hepatocytes. Sister chromatid exchanges were inhibited by 24, 44, and 55% when cells were cotreated with 34.9, 69.8, and 139.6 microM vitamin A, respectively. DNA single-strand breaks induced by NNK in rat hepatocytes were also inhibited by vitamin A. After 9 h of elution, DNA single-strand breaks induced by 1, 5, and 10 mM NNK were inhibited by 13, 5, and 3.5% in the presence of 69.8 microM vitamin A, respectively. This protective effect by vitamin A was associated with a reduction of alpha-carbon hydroxylation, an activation pathway of NNK. This pathway was inhibited by 50% when cells were cotreated with 3.49 microM vitamin A. The reduction in the hepatic microsomal aminopyrine N-demethylase, aniline hydroxylase, and N,N-dimethyl aniline N-demethylase in the presence of vitamin A (0.035 to 0.35 microM) suggests that vitamin A could reduce NNK genotoxicity by inhibiting the enzymes involved in the activation process.

Biological rhythms in the absorption, distribution, metabolism and excretion of drugs.

Studies carried out in the last 20 years indicated that biological rhythms can be detected in the pharmacokinetics of most classes of drugs. These time-dependent variations could be due to parallel changes in the physiological functions and variables involved in the absorption, distribution, metabolism and excretion of drugs. A review of the data available suggests that the peak and trough values of these functions and variables do not occur at the same hour of the day in every factor involved in drug disposition. This information could be used to predict the time-dependent changes in the pharmacokinetics. The presence of circadian variations in the kinetics of drugs raise the rather old question: "When to administer drug?"

An overview of foodborne outbreaks in Canada reported through Outbreak Summaries: 2008-2014.

BACKGROUND: Enteric outbreak investigation in Canada is performed at the local, provincial/territorial (P/T) and federal levels. Historically, routine surveillance of outbreaks did not occur in all jurisdictions and so the Public Health Agency of Canada, in partnership with P/T public health authorities, developed a secure, web-based Outbreak Summaries (OS) Reporting System to address this gap. OBJECTIVE: This analysis summarizes the foodborne outbreak investigations reported to the OS Reporting System between 2008 and 2014. METHODS: Finalised reports of investigations between 2008 and 2014 for all participating jurisdictions in Canada were extracted and descriptive analysis was carried out for foodborne outbreaks on etiological agent, severity of illness, outbreak duration, exposure setting and outbreak source. RESULTS: There were 115 reported foodborne outbreaks included in the analysis. This represents 11.2% of all outbreaks reported in the enteric module of the OS Reporting System between 2008 and 2014. Salmonella was the most commonly reported cause of foodborne outbreak (40.9%) and Enteritidis was the most common serotype reported. Foodborne outbreaks accounted for 3,301 illnesses, 225 hospitalizations and 30 deaths. Overall, 38.3% of foodborne outbreaks were reported to have occurred in a community and 32.2% were associated with a food service establishment. Most foodborne outbreak investigations (63.5%) reported a specific food associated with the outbreak, most frequently meat. CONCLUSION: The OS Reporting System supports information sharing and collaboration among Canadian public health partners and offers an opportunity to obtain a national picture of foodborne outbreaks. This analysis has demonstrated the utility of the OS Reporting System data as an important and useful source of information to describe foodborne outbreak investigations in Canada.

Role of CYP2D6 in the N-hydroxylation of procainamide.

Sequential oxidations at the arylamine moiety of the procainamide molecule leading to the formation of N-hydroxyprocainamide and its nitroso derivative may be responsible for lupus erythematosus observed in patients treated with the drug. The objective of the present study was to characterize major cytochrome P450 isozyme(s) involved in the N-hydroxylation of procainamide. Firstly, incubations were performed with microsomes from either lymphoblastoid cells or yeast transfected with cDNA encoding for specific human cytochrome P450 isozymes. Experiments performed with these enzyme expression systems indicated that the highest formation rate of N-hydroxyprocainamide was observed in the presence of CYP2D6 enriched microsomes. Additional experiments demonstrated that the formation rate of N-hydroxyprocainamide by CYP2D6 enriched microsomes was decreased from 45 +/- 4% to 93 +/- 1% by quinidine at concentrations ranging from 30 nM to 100 microM (all p < 0.05 vs control) and by approximately 75% by antibodies directed against CYP2D6. Secondly, incubations were performed with microsomes prepared from 15 human liver samples. Using this approach, an excellent correlation was observed between the formation rate of N-hydroxyprocainamide and dextromethorphan O-demethylase activity (CYP2D6; r = 0.9305; p < 0.0001). In contrast, no correlation could be established between N-hydroxyprocainamide formation rate and caffeine N3-demethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), S-mephenytoin N-demethylase (CYP2B6), tolbutamide methlhydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), chlorzoxazone 6-hydroxylase (CYP2E1), dextromethorphan N-demethylase (CYP3A4), testosterone 6 beta-hydroxylase (CYP3A4/5) or lauric acid 12-hydroxylase (CYP4A11) activities. Furthermore, formation rate of N-hydroxyprocainamide was decreased in a concentration-dependent manner by quinidine (300 nM to 100 microM) and by antibodies directed against CYP2D6 but not by furafylline 20 microM (CYP1A2), ketoconazole 1 microM (CYP3A4), sulfaphenazole 10 microM (CYP2C9) or antibodies directed against CYP1A1/1A2, CYP2C, CYP2A6, CYP2E1 or CYP3A4/3A5. In conclusion, the results obtained in the present study demonstrate that CYP2D6 is the major human cytochrome P450 isozyme involved in the formation of the reactive metabolite of procainamide, namely N-hydroxyprocainamide.

Involvement of CYP2D6 activity in the N-oxidation of procainamide in man.

Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that CYP2D6 is the major cytochrome P450 isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus erythematosus syndrome observed with procainamide. In the current study, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of procainamide in man. Nineteen healthy individuals, 13 with high (extensive metabolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, once alone (period 1) and once during the concomitant administration of the selective inhibitor quinidine (50 mg four times daily; period 2). Blood and urine samples were collected over 36 h after drug administration of procainamide and analysed for procainamide and its major metabolites (N-acetylprocainamide, desethylprocainamide, N-acetyl-desethylprocainamide, p-aminobenzoic acid and its N-acetylated derivative, and nitroprocainamide). No differences were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. However, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metabolizers during both periods. Most importantly, the urinary excretion of nitroprocainamide during period 1 was measurable in 7/13 extensive metabolizers but in none of the poor metabolizers. During the concomitant administration of quinidine, nitroprocainamide could not be detected in the urine of any individuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function in man. Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide.

The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin.

BACKGROUND: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. METHODS: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity. Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. RESULTS: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p < 0.05). Norfluoxetine Cmax and AUCzero-->t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p < 0.05). No significant differences between extensive and poor metabolizers were found for sertraline and desmethylsertraline pharmacokinetics. CONCLUSION: These data indicate that poor metabolizers accumulate fluoxetine but not sertraline and that CYP2D6 plays an important role in the demethylation of fluoxetine but not of sertraline.

Metabolic synthesis of arylacetic acid antiinflammatory drugs from arylhexenoic acids. 2. Indomethacin.

Arylacetic acid antiinflammatory drugs can be metabolically produced by beta-oxidation of a 6-arylhex-5-enoic acid side chain. Such a mechanism provides for an in vivo sustained release of the active principle indomethacin from 6-[N-(p-chlorobenzoyl)-2-methylindol-3-yl]hex-5-enoic acid (7). Similarly, biphenylacetic acid was produced from both 6-(4'-biphenylyl)hex-5-enoic acid and its lower even homologue, 4-(4'-biphenylyl)but-3-enoic acid. The indole derivative produced sustained analgesia in a yeast-induced hyperalgesia model over a 12-h period. Indomethacin plasma levels of 2 micrograms/mL were observed for up to 24 h. Such levels were less than those achieved for the analogous case in which biphenylacetic acid was produced from biphenylylhex-5-enoic acid, suggesting metabolic discrimination between hex-5-enoic substrates. When indomethacin was dosed in equipotent analgesic levels, the level of circulating drug was considerably higher than that seen for metabolically derived drug. Hence 6-hex-5-enoic acid derivatives of indomethacin are metabolized to indomethacin in vivo to give sustained analgesia at low apparent circulating plasma levels of free drug. The possibility of tissue compartmentalization enhancing biological efficacy is suggested by these observations.

Development of 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (L-670,630) as a potent and orally active inhibitor of 5-lipoxygenase.

Leukotrienes are potent biological mediators of allergic and inflammatory diseases and are derived from arachidonic acid through the action of the 5-lipoxygenase. In this study, the syntheses and comparative biological activities of three series of 2,3-dihydro-2,6-disubstituted-5-benzofuranols with various substituents on position 3 are described. Compounds from each series were evaluated for their ability to inhibit the production of leukotriene B4 (LTB4) in human peripheral blood polymorphonuclear (PMN) leukocytes and the 5-lipoxygenase reaction in cell-free preparations from rat PMN leukocytes. The structure-activity relationships of each series in vitro and in vivo are presented. The bioavailability, metabolism, and toxicity profile of each series are discussed. The series with no substituent at position 3 was the most potent and among the compounds in that series 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (46, L-670,630) was chosen for further development.

Synthesis and structure-activity relationships of a novel class of 5-lipoxygenase inhibitors. 2-(Phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans: the development of L-656,224.

The synthesis of a series of 2-(phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans and their inhibitory effects against leukotriene biosynthesis and 5-lipoxygenase activity in vitro are described. Many compounds in this series were found to be potent inhibitors of LTB4 production by human polymorphonuclear leukocytes with IC50 values ranging from 7 to 100 nM. Structure-activity relationships of the series are presented. Within this series, 2-[(4'-methoxyphenyl)methyl]-4-hydroxy-3-methyl-5-propyl-7-chlorobenz ofuran (L-656,224) showed extremely potent activity, inhibiting leukotriene biosynthesis in intact human leukocytes (IC50 = 11 nM), as well as the 5-lipoxygenase reaction catalyzed by cell-free preparations from rat leukocytes (IC50 = 36 nM), human leukocytes (IC50 = 0.4 microM), and the purified enzyme from porcine leukocytes (IC50 = 0.4 microM). The compound also shows oral activity in a number of animal models in vivo.

Synthesis and orexigenic activity of some 1-methyl-4-piperidylidene-Substituted pyrrolo[2,1-g][3] benzazepine and dibenzocycloheptene derivatives.

The synthesis and orexigenic activity of some unsubstituted and Bz-carboxylic acid substituted 1-methyl-4-piperidylidenepyrrolo[2,1-b][3]benzazepine and dibenzocycloheptene derivatives are described. 10,11-Dihydro-3-carboxycyproheptadine (7c) has been selected for clinical evaluation as a orexigenic agent based on its low threshold dose for increasing food consumption in cats (0.031 mg/kg po) and its lack of undesirable central nervous system activity. The levorotatory enantiomer of 3-carboxycyproheptadine (1d) and the 9-carboxypyrrolobenzazepine derivative 4f also possess orexigenic activity, but with these compounds such activity diminishes sharply below 0.25 mg/kg po. The unsubstituted 1-methyl-4-(5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidine (4d) and its 6,11-dihydroanalogue (4a) are comparable to cyproheptadine (1a) in promoting hyperphagia in cats.

Preparation and analgesic properties of amino acid derivatives of (-)-5,9 alpha-diethyl-2'-hydroxybenzomorphan.

The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,9 alpha-diethyl-2'-hydroxybenzomorphan was prepared and evaluated for analgesic activity. In vitro activities were found to vary greatly, depending on the nature of the amino acid used. The N-arginyl derivative was found to be equipotent to (-)-5,9 alpha-diethyl-2'hydroxybenzomorphan and also to methionine-enkephaline in the naloxone binding assay.

Synthesis and receptor binding studies relevant to the neuroleptic activities of some 1-methyl-4-piperidylidene-9-substituted-pyrrolo[2,1-b][3]benzazepine derivatives.

The synthesis of a series of 1-methyl-4-(9-substituted-11H-pyrrolo[2,1-b]benzazepin-11-ylidene)piperidines (4a-f) and 1-methyl-4-(9-substituted-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidines (4g-l) is described. As with th e 3-substituted cyproheptadine compounds 1b-e, atropisomerism exists in 4b-f, but unlike the enantiomers of 1b-e, the pyrrolobenzazepine enantiomers racemize at room temperature. Thus, the bromo compound (+)-4b has a half-life of 128 +/- 1 min at 25 degrees C, while the chloro compound (-)-4c has a half-life of 114 +/- 9 min at 25 degrees C. Compounds 4a-l have been examined for receptor binding affinities in assays that have been recognized as predictive for antipsychotic activity. The displacement of specifically bound tritiated ligands, comprising the dopamine antagonist [3H]spiperone, the dopamine agonist [3H]apomorphine, the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB), the alpha-adrenergic antagonist [3H]prazosin, the alpha-adrenergic agonist [3H]clonidine, the serotonin-1 binding agent [3H]serotonin, and the mixed serotonin agonist-antagonist [3H]lysergic acid diethylamide (LSD), by 4a-l has been measured utilizing membrane preparations of mammalian brain. Certain of the features of the receptor binding of these compounds have been shown to be common to several of the receptor sites. Data from these binding studies have been compared to corresponding data previously obtained for a series of chiral 3-substituted cyproheptadine analogues, and the receptor binding data of the two classes of compounds are discussed with respect to their molecular geometries.

Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits.

1 To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3-methylcholanthrene (3MC) pre-treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73+/-0.43 to 1.48+/-0.13 ml min-1 kg-1 (P<0. 05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU) and 1,3-dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. 2 Turpentine-induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. 3 Pre-treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre-treatment with 3MC prevented the hypoxia-induced decrease in amount and activity of the P450. 4 It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre-treatment with 3MC prevents the hypoxia-induced depression of the P450.

Effects of acute exercise on the gluconeogenic capacity of periportal and perivenous hepatocytes.

The present study was conducted to examine the effect of a single bout of exercise (rodent treadmill, 60 min at 26 m/min, 0% grade) on the gluconeogenic activity of periportal hepatocytes (PP-H) and perivenous hepatocytes (PV-H) in fasted (18 h) rats. Isolated PP-H and PV-H, obtained by selective destruction following liver perfusion with digitonin and collagenase, were incubated with saturating concentrations of alanine (Ala; 20 mM) or a mixture of lactate and pyruvate (Lac+Pyr; 20:2 mM) to determine the glucose production flux (J(glucose)) in the incubation medium. Results show that, in the resting conditions, J(glucose) from all exogenous substrates was significantly higher (P < 0.01) in PP-H than in PV-H. Exercise, compared with rest, resulted in a higher J(glucose) (P < 0.01) from Lac+Pyr substrate in the PV-H but not in the PP-H, resulting in the disappearance of the difference in J(glucose) between PP-H and PV-H. Exercise, compared with rest, led to a higher J(glucose) (P < 0.01) from Ala substrate in both PP-H and PV-H. However, the exercise-induced increase in J(glucose) (gluconeogenic activity) from Ala substrate was higher in PV-H than in PP-H, resulting, as from Lac+Pyr substrate, in the disappearance (P > 0.05) of the difference of J(glucose) between PP-H and PV-H. It is concluded that exercise differentially stimulates the gluconeogenic activity of PV-H to a larger extent than PP-H, indicative of a heterogeneous metabolic response of hepatocytes to exercise.

Pharmacokinetics of nalidixic acid in old and young volunteers.

Plasma levels of active naphthyridine were measured in healthy old (mean age 77.3 years) and young (mean age 25.4 years) subjects following oral administration of 1 Gm nalidixic acid. The plasma levels of active naphthyridine, i.e., nalidixic acid and its metabolite 7-hydroxynalidixic acid, were generally higher in the old group, particularly in the elimination phase. Significant variations in the pharmacokinetic parameters were obtained between the two groups of volunteers. The plasma half-life of active naphthyridine averaged 11.5 hours in old subjects and 2.7 hours in the younger group. Diminished renal function in the geriatric group may explain the slower elimination of the drug in the old subjects. The mean values of the other parameters calculated were: apparent volume of distribution, 0.55 (old) and 0.47 (young) liter/kg body weight; area under the curve, 327.7 (old) and 156.3 (young) micrograms/ml x hr; total body clearance 2.9 (old) and 8.3 (young) liters/hr; absorption rate constant, 0.29 (old) and 0.52 (young) hr. -1

Inhibitory effect of isoniazid on antipyrine clearance in man.

The effect of both concomitant administration and pretreatment with isoniazid on the activity of the hepatic drug-metabolizing enzymes of healthy young volunteers, as indicated by the antipyrine clearance test, is reported. Concomitant administration of isoniazid with antipyrine results in a significant decrease in the hepatic clearance of the latter compound. In contrast, pretreatment for 14 days with isoniazid had no effect on antipyrine elimination kinetics. It is concluded that isoniazid depresses hepatic drug metabolism only when present in significant amounts at the hepatic site of drug oxidation.

Temporal variations in chloroform-induced hepatotoxicity in rats.

There is increasing evidence to show that drug metabolism and effects are modulated by biological rhythms; therefore the possibility that chloroform (CHCl3) induced acute hepatotoxicity may also vary as function of time of administration was investigated in male Sprague--Dawley rats. The animals were given a single intraperitoneal dose of CHCl3 or saline, 0.5 ml/kg, at 09:00 h, 13:00 h, 17:00 h, 21:00 h or 03:00 h and killed 4 h after treatment. The hepatotoxicity induced by CHCl3 was determined by the serum glutamic-pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH) activities and by the glucose-6-phosphatase (G6Pase) activity of the liver. The increases in SGPT, SGOT and LDH were minimal and maximal when the organic solvent was injected at 09:00 h and 21:00 h, respectively, whilst the activity of G6Pase was depressed significantly at 03:00 h and 13:00 h under similar conditions. Starving the rats for 16 h prior to the injection of CHCl3 at 09:00 h increased substantially the hepatotoxicity as measured by the above enzyme activities. These findings may be relevant in the toxicity of CHCl3 in industrial workers exposed to this solvent at various times of the day.

Simultaneous determinations of tolbutamide and its hydroxy and carboxy metabolites in serum and urine: application to pharmacokinetic studies of tolbutamide in the rat.

Methods of analysis of tolbutamide (1) and its hydroxylated (2) and carboxylated (3) metabolites in serum and urine based on high-performance liquid chromatography were developed. The separation was performed on a Apex ODS column in the isocratic mode using a mobile phase composed of 22.5% acetonitrile, 77.5% Sorensen phosphate buffer (pH 7.0), and 0.30 mL of tetrabutylammonium phosphate reagent (Pic A). The compounds were detected at 254 mm. The retention times of 3, 2, 1, and the internal standard chlorpropamide were 3.1, 4.1, 14.8, and 10.0 min, respectively. These conditions were suitable for the simultaneous quantitation of 1, 2, and 3 in serum or plasma samples, but not for the determination of metabolites 2 and 3 in urine. For the analysis of 2 and 3 in urine, the mobile phase was modified to 18% acetonitrile, 82% Sorensen phosphate buffer (pH 7.0), and 0.35 mL of Pic A. Under these conditions, the retention times of the carboxy and hydroxylated metabolites and the internal standard salicylic acid were 4.6, 6.7, and 8.1 min, respectively. These methods were applied to study the pharmacokinetics of 1 administered intravenously and intraperitoneally to the rat. Tolbutamide was almost completely recovered as metabolites 2 and 3 in the urine within 24 h.