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Biomedical subjects

D J Edwards

Publications and source records attributed to D J Edwards.

At least 91 records · Page 5Linked to original sources
PubMed1988

Decreases in tyrosine and p-hydroxyphenylglycol caused by various antidepressants.

The effects of eleven different antidepressant drugs on brain p-hydroxyphenylglycol (pHPG) and on brain and plasma tyrosine concentrations were investigated in rats. Imipramine, amitriptyline, amoxapine, desmethylimipramine and iprindole (20 mg/kg each) and bupropion (50 mg/kg) decreased brain pHPG levels 4.5 or 6 hr after injection. Each of these drugs also significantly reduced plasma tyrosine levels 1.5 hr after injection. In contrast, zimelidine, amitriptylinoxide, trimipramine and trazodone had no significant effect on either brain pHPG or plasma tyrosine. Mianserin significantly lowered plasma tyrosine but produced a nonsignificant decrease in brain pHPG. The decreases in brain pHPG caused by the various drugs were significantly correlated with 3,4-dihydroxyphenylethyleneglycol. Moreover, decreases in brain pHPG and brain and plasma tyrosine concentrations were correlated with the potencies of these drugs to inhibit in vitro norepinephrine uptake. These results suggest the possibility that noradrenergic (or similar) mechanisms regulate both pHPG and tyrosine levels. However, the decreases in pHPG cannot be explained entirely by a deficiency in tyrosine, since the depletions in pHPG were much larger and longer lasting than those of tyrosine.

Animals↗
PubMed1988

One stressful event blocks multiple actions of diazepam for up to at least a month.

Based on recent findings of this laboratory, the hypothesis was tested that a single stressful encounter might have a persistent antidiazepam influence. Our results indicate that one exposure to a brief stressful event up to at least one month earlier prevented completely the effect of diazepam on pentylenetetrazole-induced changes in dopamine in the rat frontal cortex, elevations of plasma corticosterone levels and seizures.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Effects of imipramine on tyrosine and tryptophan are mediated by beta-adrenoceptor stimulation.

Imipramine (IMI; 20 mg/kg) in rats decreased the plasma tyrosine concentration by 21% (90 min), whereas norepinephrine (NE; 1.25 mg/kg) raised it by 72% (40 min). Since NE raised plasma tyrosine by stimulating alpha-adrenoceptors, as shown by phenoxybenzamine (PB) completely abolishing this increase, an experiment was done to find out whether IMI lowered plasma tyrosine by blocking alpha-adrenoceptors. In contrast to PB, IMI pretreatment failed to alter the NE-induced elevation in plasma tyrosine, suggesting that at this dose IMI is not an effective alpha-adrenergic antagonist in vivo. Thus, IMI would not appear to reduce plasma tyrosine by blocking alpha-adrenoceptors. In a separate experiment, propranolol blocked the ability of IMI to lower plasma tyrosine. Propranolol also prevented a 17% elevation in brain tryptophan levels induced by IMI but did not alter the 29% decrease in plasma tryptophan. PB by itself decreased plasma tyrosine, but this decrease was not greater by additionally treating with IMI. Salbutamol (10 mg/kg), a beta 2 agonist, lowered plasma tyrosine to 76% and raised brain tryptophan to 143% of control. These results suggest that IMI decreases tyrosine concentrations in plasma and raises tryptophan in brain by stimulating beta-adrenoceptors.

Animals↗
PubMed1988

Protein binding of cocaine in human serum.

The protein binding characteristics of cocaine have not been extensively studied. Since cocaine is related to other local anesthetic compounds which are highly protein bound, we examined the binding of cocaine in human serum using an ultrafiltration method. The free fraction averaged 0.083 +/- 0.018 in the serum of 12 healthy volunteers. Binding was studied at concentrations ranging from 0.1 to 500 micrograms/ml and was concentration dependent, with increases being most pronounced at concentrations above 5 micrograms/ml. Two classes of binding sites were identified with affinity and capacity constants consistent with binding to alpha-1-acid glycoprotein (AAG) and albumin. The addition of AAG to serum resulted in a decrease in the free fraction from 0.079 to 0.041, while tris(butoxyethyl)phosphate increased the free fraction to 0.233. The binding ratio was found to be highly correlated with the AAG concentration (r = 0.89). In addition, the predicted free fraction in the absence of AAG (0.67) was in good agreement with the observed value of 0.647 in a solution of human serum albumin (4.5 g/dl). Of the metabolites of cocaine, only norcocaine displaced the parent drug from serum binding sites. These results indicate that cocaine is highly bound to serum proteins, primarily albumin and AAG. The significance of concentration-dependent binding to cocaine toxicity remains to be established.

Blood Proteins↗
PubMed1988

Some aspects of the epidemiology of equine salmonellosis.

A survey of 2 horse populations was done to detect the number of asymptomatic faecal excretors of Salmonella sp. 1201 faecal samples from 250 horses hospitalised at the University of Sydney were cultured. Three serotypes, S. typhimurium (4 horses), S. anatum (2) and S. tennessee (1) were isolated from 7 horses (2.8%). None was detected in 75 mares similarly examined at a thoroughbred stud farm. In retrospect, S. typhimurium was also the most common (70%) of the 19 serotypes recovered from 171 horses with clinical salmonellosis seen at Camden, 1969 to 1986. Forty cases occurring since 1983 were reviewed in detail; the mortality rate was high (60%) and an increased proportion was due to S. bovis-morbificans. Five horses developed salmonellosis while hospitalised and it was usually impossible to be certain whether these cases developed from the carrier state into overt disease or resulted from infections acquired in hospital.

Animals↗
PubMed1988

Effect of norfloxacin on theophylline pharmacokinetics at steady state.

Norfloxacin is a currently marketed fluoroquinolone antibiotic. Other quinolones which are structurally similar to norfloxacin, particularly enoxacin, inhibit theophylline clearance. Since norfloxacin may be administered to patients also receiving theophylline, we studied the effect of norfloxacin on the pharmacokinetics of theophylline in 10 healthy male volunteers. A randomized, crossover study design with a 2-week washout period between treatments was used. Subjects received oral theophylline (200 mg of aminophylline [theophylline ethylenediamine]) three times daily for 4 days either alone or with 400 mg of norfloxacin (orally) twice daily for the same period. Theophylline concentrations in serum were significantly higher (P less than 0.05) at 0, 3, 4, 10, and 12 h following the final dose in the norfloxacin treatment group than in the group receiving only theophylline. However, mean theophylline oral clearance was not significantly different between the two treatments (2.85 +/- 0.68 liters/h without norfloxacin versus 2.56 +/- 0.53 liters/h with norfloxacin [P = 0.08]). Similarly, no significant differences were observed in theophylline half-life (P = 0.11). We conclude that norfloxacin is unlikely to have a clinically significant effect on theophylline disposition in most patients.

Administration, Oral↗
PubMed1988

Inhibition of drug metabolism by quinolone antibiotics.

A number of quinolone antibiotics have been found to reduce the hepatic clearance of coadministered drugs such as theophylline. Enoxacin appears to be the most potent inhibitor, consistently decreasing theophylline clearance by more than 50%, while a single study suggests a similar degree of inhibition with pipemidic acid. Ciprofloxacin and pefloxacin reduce theophylline clearance to a smaller extent (approximately 20 to 30%). However, with ciprofloxacin, larger changes and theophylline toxicity have been reported in some subjects. Norfloxacin, ofloxacin and nalidixic acid appear to have minimal effects on theophylline clearance. Enoxacin and ciprofloxacin have also been found to reduce the clearance of caffeine, while ofloxacin has no effect. Few other substrates have been studied. Enoxacin decreases the clearance of R-warfarin with no effect on S-warfarin. In addition, enoxacin has been reported to reduce the clearance of antipyrine, with no effect on chlorpropamide, glibenclamide (glyburide) or phenytoin. The mechanism of these interactions is largely unexplored. It has been suggested that inhibition may be related to the production of 4-oxoquinolone metabolites; however, this hypothesis has not been confirmed. No unique structural feature has been identified to date which explains differences between these compounds in their propensity to affect drug metabolism. Further studies are needed to evaluate the effects of these drugs on other substrates not yet examined and to assess whether or not inhibition is dose related. Clinically, caution is advised when using a quinolone, particularly enoxacin, pipemidic acid, ciprofloxacin or pefloxacin, in combination with theophylline. Close monitoring of theophylline concentrations is recommended in any patient receiving these drugs. The clinical significance of inhibited metabolism of other substrates remains unclear at present. Until further data are available, clinicians should be aware of the possibility of reduced drug clearance resulting in adverse effects whenever the fluoroquinolones are coadministered with drugs that depend on hepatic metabolism for their elimination.

4-Quinolones↗
PubMed1988

Differential effects of yohimbine and phenoxybenzamine on norepinephrine metabolites in rat brain.

The effects of yohimbine (YOH) and phenoxybenzamine (PB) on the concentrations of norepinephrine (NE) metabolites were compared. In contrast to the large effects of YOH, PB caused only small, nonsignificant increases in brain 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG). The effects of YOH were unaltered when rats were pretreated with PB. Tyrosine failed to enhance the effect of either YOH or PB except for somewhat augmenting the increase in DHPG induced by YOH. The results rule out the possibility that the small effect of PB on MHPG levels is due to inhibition of NE metabolism, postsynaptic alpha-receptor blockade or to a deficiency in the amino acid precursor tyrosine. Rather, the large effect of YOH is likely due only partly to blockade of presynaptic autoreceptors and partly to another, reserpine-like action. It is also possible that the presynaptic receptors are incompletely blocked by even high doses of PB.

Animals↗
PubMed1988

Monthly variations in the pharmacokinetics of antipyrine in the rat: circannual rhythm or random variation?

We examined the pharmacokinetics of antipyrine in the rat over an 18 month period to determine whether or not the variations in pharmacokinetic parameters previously reported exhibited a circannual rhythm. While the clearance of antipyrine varied over the study period, no discernible rhythmic pattern was found. Comparing this data with previously published work also failed to demonstrate a rhythmic pattern of variability. Unlike previous investigations, we found only relatively small variations in antipyrine volume of distribution and half-life from month to month. These data indicate that the monthly variability in the pharmacokinetics of antipyrine in the rat are random and do not exhibit a circannual rhythm.

Animals↗
PubMed1987

The effect of a single oral dose of ethanol on hepatic blood flow in man.

The magnitude and time course of changes in hepatic blood flow following oral ingestion of a single (0.6 g/kg) dose of ethanol was studied using the model compound indocyanine green (ICG). Hepatic blood flow was not significantly different at 40, 90, 150 and 210 minutes following ethanol as compared to baseline values measured 20 and 70 min prior to alcohol ingestion. These results suggest that ethanol, at concentrations commonly associated with social drinking, has minimal effects on liver blood flow and would be expected to contribute little to changes in either the bioavailability or clearance of drugs highly extracted by the liver.

Administration, Oral↗
PubMed1987

The effect of coadministration of verapamil on the pharmacokinetics and metabolism of quinidine.

We have previously found that verapamil pretreatment significantly inhibits the metabolism of antipyrine. To assess more fully the implications of this observation, we examined the effect of verapamil on the pharmacokinetics and metabolism of quinidine. Pretreatment with verapamil, 80 mg and 120 mg (every 8 hours for 3 days), reduced the oral clearance of quinidine from 17.0 L/hr to 11.6 and 11.3 L/hr, respectively (P less than 0.01). The half-life of quinidine was also significantly prolonged by verapamil. The formation clearance of 3-hydroxyquinidine was reduced by 61.2% and 70.6% after verapamil pretreatment (80 and 120 mg, respectively) (P less than 0.01), whereas the renal clearance of unchanged quinidine was not affected. These results indicate that verapamil impairs the metabolism of quinidine to 3-hydroxyquinidine and reduces the oral clearance of quinidine to a degree that could be of clinical significance given the narrow therapeutic index of this drug.

Adult↗
PubMed1987

Lack of effect of smoking on the metabolism and pharmacokinetics of quinidine in patients.

The urinary metabolite profile of quinidine and the oral clearance of this drug were studied under steady state conditions in five smoking and nine non-smoking patients. No significant differences were observed in the urinary recovery of unchanged quinidine, 3S-3-hydroxyquinidine, 2'-oxoquinidinone or quinidine-N-oxide between smokers and non-smokers. In addition, the plasma clearance of quinidine was not affected by the smoking status of subjects. These results suggest that cigarette smoke does not induce any of the main pathways for quinidine metabolism in a typical patient population and that the consideration of smoking status is of little utility in aiding in the selection of initial dosage regimens for this drug.

Aged↗
PubMed1987

Disopyramide pharmacokinetics and metabolism: effect of inducers.

1. The disposition of orally administered disopyramide was studied in a population of smokers (n = 6) and non-smokers (n = 8) before and during phenobarbitone treatment (100 mg daily for 21 days; Cp 21st day = 13.9 +/- 2.0 micrograms ml-1). The comparative inducibility of these populations by phenobarbitone was assessed as was the inductive effect of cigarette smoking, per se. Furthermore, the determinants of the intensity of the inductive effect were examined, as well as the effect of the barbiturate on the binding of disopyramide to alpha 1-acid glycoprotein (AGP). 2. Smokers and non-smokers exhibited similar half-lives (6.48 +/- 1.49 vs 6.66 +/- 1.02 h), apparent total body clearances (0.100 +/- 0.020 vs 0.117 +/- 0.034 l h-1 kg-1), mean renal clearances (0.043 +/- 0.0093 vs 0.057 +/- 0.013 l h-1 kg-1) and apparent intrinsic metabolic clearances (0.057 +/- 0.015 vs 0.060 +/- 0.024 l h-1 kg-1) before phenobarbitone treatment. 3. Both populations responded comparably to barbiturate exposure in that apparent intrinsic metabolic clearance more than doubled. Interestingly, the magnitude of this increase was highly dependent on the observed baseline apparent intrinsic metabolic clearance, (r' = 0.81; P less than 0.001). 4. Phenobarbitone treatment of non-smokers resulted in an increase in the AUC of the active metabolite N-despropyl disopyramide (MND), but not significantly (3.8 +/- 1.6 vs 4.1 +/- 2.3 micrograms ml-1 h). Similar results were observed in smokers (3.5 +/- 1.4 vs 3.9 +/- 2.0 micrograms ml-1 h, respectively). 5. The percent of administered dose recovered in urine as disopyramide in non-smokers was significantly decreased upon phenobarbitone treatment (43 +/- 6% vs 25 +/- 5%), whereas the percent of dose recovered as MND increased significantly in this group (25 +/- 6% vs 31 +/- 5%). The population of smokers responded similarly. 6. At doses typically used to achieve hepatic microsomal enzyme induction in man, phenobarbitone treatment caused no significant change or trend towards a change in serum AGP concentrations as measured using the radial immunodiffusion method in nonsmokers (67.4 +/- 19.9 mg dl-1 vs 68.0 +/- 40.7 mg dl-1) or smokers (64.5 +/- 15.7 vs 67.9 +/- 14.9). Similarly, when AGP concentration was estimated in serum from non-smokers using a nephelometric method no effect attributable to phenobarbitone was observed (47.9 +/- 1.3 vs 47.9 +/- 16.8 mg dl-1). Consistent with this observation, disopyramide free fraction was not affected by barbiturate treatment.

Adult↗
PubMed1987

Alanine aminopeptidase and beta 2-microglobulin excretion in patients receiving vancomycin and gentamicin.

The effects of vancomycin, gentamicin, and combination vancomycin-gentamicin treatments on alanine aminopeptidase (AAP) and beta 2-microglobulin (beta 2M) elimination in 30 hospitalized patients were assessed and compared with elimination in a control group. Twenty-four-hour urine excretion values for AAP and beta 2M were determined on treatment day 1 and day 5 for patients receiving the three treatment regimens and for the control group. AAP excretion values for the vancomycin-treated group were not found to be statistically different from those of the control group. Both the gentamicin and the vancomycin-gentamicin groups had statistically higher AAP excretion values on treatment day 1 as well as on treatment day 5 when compared with the vancomycin and control groups. AAP excretion on day 5 of treatment was highest for the vancomycin-gentamicin group. Overall, beta 2M elimination was variable in all treatment groups. Although the beta 2M values were elevated as early as day 1 in all treatment groups, they were significantly elevated only in the vancomycin-gentamicin group on day 1 and only in the gentamicin group on day 5 compared with the vancomycin and the control groups. AAP appears to be a sensitive indicator of renal tubular damage. The combination of vancomycin and gentamicin results in greater AAP excretion than does either agent alone.

Adolescent↗
PubMed1987

Increased theophylline concentrations secondary to ciprofloxacin.

An 82-year-old man with a history of myasthenia gravis and heart failure was admitted to the hospital with respiratory failure. Aminophylline and eventually theophylline therapy were initiated to improve respiratory status. During the hospital stay, the patient developed a resistant pseudomonal pneumonia. After failure with conventional antibiotics, ciprofloxacin was initiated because of favorable sensitivity and the planned avoidance of aminoglycoside therapy. Seventy-two hours after initiation of ciprofloxacin, the patient's theophylline level rose from a steady-state baseline of 9.8 micrograms/ml to 34.7 micrograms/ml. After the theophylline dose was reduced by approximately 67 percent, the patient's theophylline serum concentration returned to baseline (10 micrograms/ml). Until more data concerning the interaction of theophylline and ciprofloxacin are available, we recommend close monitoring of theophylline serum concentrations in patients receiving concomitant ciprofloxacin.

Aged↗