Cephalosporin clinical concentration-time profile modelling and in-vitro bactericidal effects on Escherichia coli.

We assessed the cephalosporin concentration-time curve area (AUC), peak concentration, maintained concentration and duration of exposure on in-vitro bactericidal effects on Escherichia coli NCTC 10418, using exposures modelling cephazolin clinical profiles after 1 g and 2 g i.m. injection, equal AUC exposures (288 mg x h/L, 576 mg x h/L; 48 h) and constant exposures to 6, 12 and 24 mg/L. Cephalosporin dosage exposures based on maintenance of concentrations at multiples (6-24 times) of the MIC were not as effective in early or sustained (24 h) bactericidal effect as exposures modelling im injection profiles with equal or lower AUC (P<0.05, ANOVA). Similar results applied to i.m. comparisons with equal AUC exposures modelling extremes of concentration and time exposures. These results indicate a need for intermittent dosage to produce optimally effective profiles, and raise the possibility that these optimum dosing profiles may allow an extension of minimum interdose intervals beyond 8 h.

The effect of tenoxicam on tolbutamide pharmacokinetics and glucose concentrations in healthy volunteers.

There was no significant difference in the pharmacokinetic parameters of tolbutamide (500 mg) determined before and after 14 days treatment with tenoxicam (20 mg/day) in 7 healthy volunteers (6 male, 1 female). In addition, co-administration of tenoxicam did not alter blood glucose concentrations.

Factors affecting the hepatic elimination of oxidized and of glucoronidated high clearance drugs following acute administration of carbon tetrachloride.

The factors affecting drug elimination following acute administration of carbon tetrachloride (CCl4) were investigated using a perfused rat liver system. Morphine and pethidine were used as markers of hepatic glucuronidation and oxidation, respectively. Hepatoxicity of CCl4 was indicated by widespread cellular necrosis and raised serum asparatate aminotransferase levels. At a perfusion rate of 10 ml/min, the extraction ratio of morphine in the normal liver was 0.67 +/- 0.18 and fell to 0.48 +/- 0.03 (p < 0.001) in the acutely damaged livers. The hepatic clearance of morphine fell from 6.7 +/- 0.2 ml/min in controls to 4.7 +/- 0.3 (p < 0.005) in the treated livers. Similar changes were seen at perfusion rates of 7 and 12 ml/min. Intrinsic clearances calculated according to both the venous equilibrium and the undistributed sinusoidal models were independent of perfusion rate and were also lower in the damaged livers. Perfusion rate was a dominant factor in determining morphine elimination in control livers. However, in the damaged livers, the fall in intrinsic clearance resulted in the elimination of morphine being mixed, i.e. both capacity and flow limited. At a perfusion rate of 10 ml/min, the extraction ratio of pethidine was 0.97 +/- 0.01 in control livers and was reduced to 0.91 +/- 0.02 (p < 0.005) in damaged livers. The hepatic clearance also fell at each perfusion rate in the damaged livers. As for morphine, the intrinsic clearances of pethidine calculated by both venous equilibrium and undistributed sinusoidal models gave qualitatively similar results and were lower in the damaged livers than controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Neither cimetidine nor probenecid affect the pharmacokinetics of tenoxicam in normal volunteers.

The effect of pretreatment with cimetidine (1 g day-1, 7 days) and of probenecid (1 g twice daily, 4 days) on the pharmacokinetics of tenoxicam (single oral dose, 20 mg) was studied in six healthy volunteers. Cmax was increased significantly when tenoxicam was given with probenecid (2.8 micrograms ml-1 alone, 3.5 micrograms ml-1 after probenecid; P < 0.005). No other pharmacokinetic parameters were altered significantly by either drug. It is concluded that neither cimetidine nor probenecid affects the pharmacokinetics of tenoxicam in a clinically important way.

Hepatic enzyme activity is the major factor determining elimination rate of high-clearance drugs in cirrhosis.

The relative importance of alterations in hepatic enzyme activity, blood flow and drug binding to drug elimination in patients with liver disease remains controversial. In addition, liver disease appears to selectively impair drug oxidation pathways while leaving glucuronidation preserved. These studies using isolated perfused rat livers were designed to examine the effects of liver disease on the hepatic extraction and clearance and intrinsic clearance of morphine, a glucuronidated drug, and meperidine, an oxidized drug, under controlled blood flow and drug-binding conditions. We chose chronic carbon tetrachloride-induced cirrhosis as the liver disease. At a flow rate of 12 ml/min, the extraction of meperidine was reduced from 0.91 +/- 0.02 ml/min in controls to 0.76 +/- 0.04 ml/min (p < 0.05) in cirrhosis, hepatic clearance was reduced from 10.9 +/- 0.3 ml/min in controls to 9.15 +/- 0.48 ml/min (p < 0.05) in cirrhosis and intrinsic hepatic clearance was reduced from 179 +/- 35 ml/min in controls to 69 +/- 14 ml/min (p < 0.05) in cirrhosis. In contrast, for morphine we saw no significant changes: extraction ratio, 0.59 +/- 0.02 in controls and 0.49 +/- 0.04 in cirrhosis; hepatic clearance, 7.02 +/- 0.26 ml/min in controls and 6.04 +/- 0.42 ml/min in cirrhosis; and hepatic intrinsic clearance, 15.4 +/- 1.2 ml/min in controls and 13.9 +/- 2.3 ml/min in cirrhosis. Regression analysis of hepatic clearance vs. hepatic blood flow and hepatic clearance vs. hepatic intrinsic clearance demonstrate that in normal livers the elimination of both morphine and meperidine is mainly dependent on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Covert self poisoning with brodifacoum, a 'superwarfarin'.

The clinical course of a patient poisoned with the 'superwarfarin' brodifacoum and a method for estimation of plasma levels is described. It was characterised by prolonged depression of Vitamin K-dependent clotting factors poorly responsive to Vitamin K administration.

The effect of concurrent aspirin upon plasma concentrations of tenoxicam.

1. The effect of chronic, high-dose aspirin therapy upon the disposition of a single dose and multiple doses of tenoxicam was examined in normal volunteers. 2. Aspirin caused a 24% drop in the t1/2 (P less than 0.005), a 49% rise in the volume of distribution (P less than 0.0003) and a 98% increase in the clearance (P less than 0.0001) of tenoxicam after a single dose of the tenoxicam. 3. Steady-state concentrations of tenoxicam decreased significantly from 10.4 +/- 1.5 to 4.5 +/- 1.6 micrograms ml-1 in the presence of chronic, high-dose aspirin treatment. 4. Tenoxicam percentage free measured in plasma from a normal volunteer was 0.56 +/- 0.05% over the tenoxicam concentration range 1-20 micrograms ml-1 and rose to 1.24 +/- 0.07% in the presence of aspirin 150 micrograms ml-1. 5. The effect of aspirin upon the disposition of tenoxicam was consistent with a competitive protein binding interaction.

Effect of food and various antacids on the absorption of tenoxicam.

1 Twelve healthy volunteers received a single oral dose of tenoxicam 20 mg on six occasions separated by 3 weeks. 2 The six occasions were: fasted overnight; postprandial; fasting and 15 ml aluminium hydroxide gel; postprandial and 15 ml aluminium hydroxide gel; fasting and 15 ml aluminium and magnesium hydroxide gel; postprandial and 15 ml aluminium and magnesium hydroxide gel. 3 Twenty plasma samples were collected over 15 days following dosing with tenoxicam. 4 The following kinetic parameters for plasma tenoxicam were compared: peak concentrations, time taken to reach peak concentrations, area under the plasma concentration-time curve (AUC) and half-life of elimination. 5 Food lengthened the time taken to reach peak tenoxicam concentrations (5.82 +/- 4.6 vs 1.84 +/- 1.0 h in the fasting state; P less than 0.02) and marginally reduced the peak concentrations achieved. AUC was not affected by any of the different regimens. 6 These effects of food on tenoxicam bioavailability are unlikely to be of clinical significance during chronic dosing with the drug.

Evidence that alpha-methyl-p-tyramine is implicated in behavioural augmentation to amphetamine.

Behavioural studies showed that administration of alpha-methyl-p-tyramine (AMT; 10 mg/kg i.p.) to rats 24 hr before treatment with d-amphetamine (AMPHET; 4 mg/kg i.p.) resulted in augmentation of AMPHET-induced stereotype activity. Parallel experiments involving electro-chemical estimation of dopamine metabolites in the striatum showed that the decrease in the concentration of homovanillic acid (HVA) produced by AMPHET (4 mg/kg) was enhanced in AMT (10 mg/kg) pretreated animals. These findings suggest that AMT derived from previous doses of AMPHET may play a role in the phenomena of behavioural augmentation observed after chronic administration of AMPHET.

Gastric emptying rate and the systemic availability of levodopa in the elderly parkinsonian patient.

The gastric emptying rate and systemic availability of levodopa, administered as a single oral dose, was studied in six elderly parkinsonian patients, five elderly nonparkinsonian subjects, and six young healthy volunteers. In both elderly groups, gastric emptying was slowed relative to the young healthy volunteers. The lack of significant differences in the plasma elimination half-life of levodopa among the three groups was accompanied by increased absorption of the drug in the elderly patient groups. These findings are discussed in relation to a possible age-related alteration in the activity of peripheral dopa decarboxylase in the elderly parkinsonian patients.

The effects of enteric coating of aspirin tablets on occult gastrointestinal blood loss.

The effect of enteric coating of aspirin tablets on the gastrointestinal blood loss associated with high dose aspirin therapy was investigated in 12 patients with rheumatoid arthritis. Occult blood loss was measured after labelling the patients' red blood cells with Cr51. Three salicylate preparations were used: enteric coated tablets of aspirin ("Rhusal", G.P. Laboratories, 7 x 650 mg per day), uncoated tablet cores of aspirin from the same batch (7 x 650 mg per day) and enteric coated tablets of sodium salicylate (7 x 600 mg and 1 x 300 mg per day). Daily blood loss during a salicylate-free period was (0.7 +/- 0.15 ml, mean +/- SE). Blood loss was significantly increased during dosage with all three salicylate preparations. Daily blood loss during dosage with the uncoated tablets of aspirin (5.3 +/- 0.3 ml) was significantly greater than during dosage with the enteric coated tablets of aspirin (2.3 +/- 0.3 ml) and enteric coated tablets of sodium salicylate (2.1 +/- 0.4 ml). The bioavailability of the salicylate preparations was studied in seven of the 12 patients. Mean plasma salicylate concentration two hours after the second daily dose during dosage with the enteric coated tablets of aspirin was 118 +/- 15 microgram/ml compared to 131 +/- 16 microgram/ml during dosage with the uncoated tablets. Urinary recoveries of the daily dosage of aspirin in the two formulations were also similar.

The measurement of histamine release from suspensions of rat peritoneal cells rich in mast cells.

Histamine released from the mast cells in unfractionated rat peritoneal cell suspensions could be quickly and conveniently measured by an automated chemical method. There were no substances in the unfractionated peritoneal cells that interfered with the chemical histamine measurement. Organic extraction of histamine and deproteinization of samples were not necessary using the automated method. The amount of histamine released from preparations of peritoneal cells by a fixed concentration of compound 48/80 decreased with the time of preincubation of the cells but this varied between preparations. Phagocytic activity directed against the mast cells probably explained these observations. The state of nutrition of the rats and the presence or absence and/or glucose in the medium all influenced the rate of decline of viability of the mast cells.

Patterns of plasma concentrations and urinary excretion of salicylate in rheumatoid arthritis.

Intersubject differences in the volume of distribution, whole body clearance, and steady-state plasma concentrations of salicylic acid (SA) were studied in a series of patients with rheumatoid arthritis and healthy control subjects. The measurement of the plasma concentration of SA 12 hr after an oral dose of 1.2 gm aspirin appears predictive of the success of long-term dosage of aspirin. Concentrations below 5 microgram/ml in this single-dose test were associated with failure to achieve therapeutic plasma concentrations of SA (above 150 microgram/ml during long-term therapy with approximately 4.8 gm aspirin per day. Conversely, plasma concentrations above 10 microgram/ml in the single-dose test were associated with levels above 150 microgram/ml during long-term therapy. The volume of distribution of SA correlated poorly with body weight (r = 0.51, p less than 0.01) and did not correlate significantly with plasma albumin levels. Corticosteroids appear to induce the metabolism of SA and most subjects dosed with oral corticosteroids and aspirin 4.8 gm/day did not attain plasma levels of SA above 150 microgram/ml. The clearance of SA was greater in male than in female patients. The difference appears to be of clinical significance since fewer men than women achieved therapeutic plasma concentrations of SA.

Single-dose evaluation of a new enteric-coated aspirin preparation.

The bioavailability of a new enteric-coated tablet of aspirin (Ecotrin, Smith, Kline and French) was evaluated after single doses to eight volunteers. One tablet was administered to each subject on four occasions--twice after a light breakfast, once after a heavy breakfast and once after pretreatment with metoclopramide. The study utilized non-invasive techniques. The rate of absorption of aspirin was estimated by the time course of concentrations of salicylate in saliva, while the total bioavailability was determined by the recovery of total salicylate in urine. The urinary recovery of aspirin from all 32 trials was 575 +/- 25 mg (mean +/- standard error), representing 89% +/- 4% of the administered dose. The different treatments did not significantly alter the urinary recovery. The absorption of aspirin from the enteric-coated tablets was delayed and slow. Absorption was retarded by a heavy meal and hastened by pretreatment with metoclopramide. The effect of metoclopramide is consistent with the release of aspirin in the small intestine. Overall, the single-dose tests indicated satisfactory functioning of the enteric coating.

Evaluation of an enteric coated aspirin preparation.

The bioavailability and gastrointestinal site of release of enteric coated aspirin tablets ("Rhusal", G.P. Laboratories) were investigated following dosage with single tablets. A delay of one to more than eight hours was observed between dosage and the appearance of salicylate in plasma or saliva. This delay was decreased by pretreatment with metoclopramide. No aspirin or salicylate was detected in gastric aspirates. The mean urinary recovery of salicylate was equivalent to 92% of the administered dose. All these tests were consistent with the designed function of the enteric coating. The time course of concentrations of salicylate in saliva rather than in plasma was confirmed as a useful technique for the evaluation of different formulations of aspirin. The acceleration of gastric emptying by metoclopramide is a useful technique for the evaluation of enteric coated tablets.