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Biomedical subjects

F J Vajda

Publications and source records attributed to F J Vajda.

69 records · Page 4Linked to original sources
PubMedDate not supplied

H2-receptor antagonists and hepatic drug disposition.

The effect of four H2-receptor antagonists (cimetidine, burimamide, oxmetidine, and ranitidine) on antipyrine elimination was studied in the isolated perfused rat liver. The first three drugs are substituted imidazoles, whereas ranitidine contains a furanyl nucleus. Isolated livers were perfused using a 100-ml, recycling, constant flow circuit for 4 hr. Antipyrine elimination was studied with or without an H2-receptor antagonist present. In all experiments, antipyrine concentrations declined monoexponentially. In control experiments (no other drug present), antipyrine clearance was 32.5 +/- 0.9 ml per hr. This was greatly reduced in the presence of cimetidine (clearance = 10.1 +/- 0.8 and 5.8 +/- 1.5 ml per hr after 1 and 5 mg doses, p less than 0.01) and burimamide (4.5 +/- 0.6 and 3.0 +/- 1.7 ml per hr, p less than 0.001). By contrast, neither oxmetidine nor ranitidine significantly altered antipyrine pharmacokinetics. These results indicate that the inhibitory effect on hepatic mixed-function oxidases is rapid in onset, independent of H2-receptor antagonist activity, and is not an inevitable consequence of the presence of an imidazole nucleus.

Animals↗
PubMedDate not supplied

Gas chromatographic measurement of plasma levels of sodium valproate: tentative therapeutic range of a new anticonvulsant in the treatment of refractory epileptics.

1. A precise and rapid gas chromatographic method for the measurement of plasma sodium valproate concentrations is presented. 2. The extraction is a single step procedure, and is reproducible and linear throughout the concentration range encountered. 3. Clinical evaluation of the drug is presented in eighteen epileptics on the basis of the percentage of days on which subjects had seizures before and after sodium valproate therapy. 4. A tentative therapeutic range for sodium valproate is presented on the basis of plasma levels and therapeutic effect.

Chromatography, Gas↗
PubMedDate not supplied

Bioavailability of valproate after gastric and direct intestinal administration in rats.

1. The chemical characteristics of sodium valproate suggest that it might be absorbed from stomach as well as from intestine. 2. Absorption from these sites was assessed in rats by measuring plasma drug levels after administering [14C]-valproate or unlabelled valproate separately into (a) intact animals (by gavage), (b) ligated intestine, or (c) ligated stomach. 3. After gastric administration, mean plasma valproate at 1 h, and the mean area under the 0-3 h plasma radioactivity-time curves were 53% and 64% respectively, of the corresponding values after intestinal administration. 4. It is concluded that sodium valproate is absorbed from rat stomach, although at a slower rate than from the whole intestine.

Absorption↗
PubMedDate not supplied

Effect of increased bile flow and bile acid secretion on the hepatic elimination of sodium valproate in the cat.

The effect of increased bile flow and hepatic bile acid flux on the systemic clearance and hepatic elimination of intravenously administered sodium valproate was studied in the bile fistula cat. Taurochenodeoxycholic acid (TCDC), tauro-3 alpha, 7 beta-dihydroxy-12-keto-5 beta-cholanoic acid (T12K), SC-2644, and secretin were infused intravenously to vary bile flow and biliary bile acid secretion. Control animals were infused with 0.15 mol/l NaCl. Less than 1% of the drug administered to controls appeared as unchanged valproate in the bile over 6 h. Although SC-2644, T12K, and secretin significantly increased biliary excretion of valproate, it did not exceed 2% of the intravenous dose. Biliary clearance was directly related to the rate of bile flow, but not to the bile acid flux. By contrast, 18-19% of the dose appeared in bile as metabolite in controls, and none of the choleretic agents significantly increased this percentage. As a result, systemic clearance of valproate was unaltered. We conclude that the movement of unchanged valproate into bile is consistent with a process of simple diffusion. The fact that choleretic agents do not increase metabolite excretion into bile suggests that metabolite formation may be the rate-limiting step in the hepatic elimination of valproate, rather than transport and excretion of metabolites into bile.

Animals↗
PubMedDate not supplied

Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration.

The pharmacokinetics of fluorouracil after oral, intravenous and rectal administration were compared in 12 patients with colorectal cancers. Oral administration of 10 to 15 mg/kg gave variable plasma levels (0 to 10.5 microgram/ml) and bioavailability (0 to 74%; mean 28%). Bioavailability increased markedly with increases in dose, suggesting saturation of the 'first pass' hepatic metabolism of the drug. Differences in bioavailability could not be related to standard liver function tests or the presence of metastatic deposits in the liver. Plasma levels were not detectable after rectal administration in the 4 patients studied and were very low (0 to 8 microgram/ml) during high dose (20 to 30 mg/kg/24h) slow intravenous infusion in 6 patients. These findings indicate that different dose schedules and routes of administration produce markedly different plasma levels. They suggest that the rate of degradation of fluorouracil by the liver is quite variable and may become saturated with increasing dose. For these reasons monitoring of plasma levels of the drug in individual patients may be useful.

Administration, Oral↗
PubMedDate not supplied

Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis.

OBJECTIVES: To measure MTX polyglutamates in circulating erythrocytes (E-MTX), mononuclear cells (MNC-MTX) and polymorphs (PMN-MTX) in rheumatoid arthritis (RA) patients and to see whether these correlated with clinical efficacy and side effects. METHODS: Sixty-five patients (40F, 25M; mean age 57 yrs.) with RA (ARA revised criteria) who had been on weekly pulse MTX (2.5-37.5 mg) for at least 2 months were entered into this study. The patients were classified as responders (R), partial responders (PR) or non-responders (NR) when blood was sampled for the MTX determination. Side effects since the initiation of MTX were also recorded. MTX-polyglutamates were measured (blinded to clinical details) using an enzymatic assay. RESULTS: E-MTX in responders and partial responders were significantly higher (p < 0.001) than in non-responders. Similarly, PMN-MTX were also higher, but the difference was only significant for the R group (p = 0.0019). The differences in concentrations could not be explained on the basis of the dose, which tended to be higher in NR than in R (p = 0.085). The concommitant prednisolone dose was significantly lower in R than in NR (p = 0.001), as were the ESR and CRP (p = 0.007, and p = 0.05 respectively), but the MCV was higher (p = 0.047). E-MTX tended to be higher in patients with side effects, but this difference did not reach statistical significance (p = 0.15). CONCLUSION: The results suggest that circulating intracellular levels of MTX polyglutamates in RBC and PMN correlate with clinical efficacy but not with toxicity in patients with RA.

Adult↗
PubMedDate not supplied

Effects of non-steroidal anti-inflammatory drugs (NSAIDs) on human polymorphonuclear leucocyte function in buffer and plasma.

OBJECTIVE: To elucidate the mechanism of action of a wide range of non-steroidal anti-inflammatory drugs (NSAIDs) on the respiratory burst of isolated normal PMNs in buffered saline and plasma. METHODS: The oxidative burst of PMN was assessed by luminol enhanced chemiluminescence and myeloperoxidase-mediated iodination. Cells were stimulated by the synthetic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), serum coated zymosan or the phorbol ester phorbol myristate acetate (PMA). RESULTS: When using buffered saline as the suspending medium, tenoxicam, piroxicam, ibuprofen, ketoprofen and diclofenac, at concentrations achieved clinically, inhibited both PMA- and FMLP-induced luminol chemiluminescence. Tenoxicam and piroxicam in buffered saline also inhibited the iodination reaction. However, in plasma, which mimics the in vivo situation more closely, the inhibitory effect was markedly reduced. Only tenoxicam and piroxicam were found to cause the inhibition of luminol chemiluminescence at concentrations achieved clinically. CONCLUSION: If these study conditions are representative of the in vivo pathological state, the results suggest that only tenoxicam, piroxicam and possibly diclofenac sodium are likely to possess anti-inflammatory properties which are independent from effects on cyclooxygenase.

Anti-Inflammatory Agents, Non-Steroidal↗