No abstract

To compare efficacy, toxicity, and the pharmacokinetics of the combination of sulphasalazine (SASP) and methotrexate (MTX) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial. Forty RA patients with active arthritis despite adequate SASP therapy, were allocated randomly to regimes of either SASP+MTX or MTX alone. The patients were evaluated openly by a single observer for 24 weeks. In the first 15 patients using the combination, pharmacokinetics of MTX without and with SASP were studied. Thirty-eight patients completed the trial. The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group (-2.6 vs -1.3 respectively). The same pattern was seen concerning the other efficacy variables. There was no difference in the occurrence of toxicity. SASP had no influence on the pharmacokinetics of MTX. In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone, the toxicity of both therapies was similar. This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration.

Pharmacokinetic data were obtained from four healthy volunteers after oral administration of a single 400 or 600 mg dose of enoxacin. Enoxacin was absorbed quickly and absorption was increased when enoxacin was ingested after a meal. Renal clearance of enoxacin and 4-oxo-enoxacin decreased after simultaneous administration of probenecid. In addition, pharmacokinetic parameters of enoxacin and its 4-oxo metabolite were determined for plasma and sputum from 19 patients treated with enoxacin, 400 or 600 mg bd, for a respiratory tract infection. The half-life of both enoxacin and 4-oxo-enoxacin was 5-6 h; during treatment with 400 and 600 mg bd, the plasma concentrations exceeded MIC values for most bacteria isolated in respiratory tract infections, including most Pseudomonas aeruginosa strains; Streptococcus pneumoniae was an exception. Diffusion from plasma to sputum was approximately 100%. Of an ingested dose, 60-65% was recovered in the urine in 24 h. In a third study, a single 600 mg dose of enoxacin was given to 15 patients undergoing thoracotomy. Subsequent lung tissue concentrations of enoxacin were significantly higher than plasma concentrations at the same time after ingestion.

No abstract

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, the t1/2 increased from 3 to 6 h. The Cmax was 14 micrograms/ml with a dosage of 250 mg, 31 micrograms/ml with 500 mg, 70 micrograms/ml with 1,000 mg and 120 micrograms/ml with 1,500 mg. The tmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6-0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34-59%). The protein binding of probenecid glucuronide in vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate--time profile of probenecid glucuronide shows a plateau value of approximately 700 micrograms/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects its Vmax of formation.

The pharmacokinetics of alfentanil under the conditions of an empirically derived 1-h continuous infusion of 3 micrograms kg-1 min-1, with a bolus of 80 micrograms kg-1, both i.v., were determined in five patients. The distribution half-life (mean +/- SD) (7.4 +/- 3.1 min), elimination half-life (86.7 +/- 15.8 min), apparent volume of distribution, Varea (0.44 +/- 0.15 litre kg-1) and elimination clearance (3.33 +/- 0.75 ml kg-1 min-1) were similar to those previously reported for a single bolus of alfentanil. These values for apparent volume of distribution and clearance can be used to calculate correct bolus and infusion doses to maintain any desired steady state plasma concentration using standard formulae: for example, to maintain a steady state plasma concentration of 400 ng ml-1, a bolus dose of 176 micrograms kg-1 and an infusion of 1.3 micrograms kg-1 min1 would be required.

No abstract

SUMMARYEighty per cent of codeine is conjugated with glucuronic acid to codeine‐6‐glucuronide. Only 5% of the dose is O‐demethylated to morphine, which in turn is immediately glucuronidated at the 3‐ and 6‐ position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the μ‐receptor to result in analgesia, codeine‐6‐glucuronide in analogy to morphine‐6‐glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O‐demethylation to morphine, experience analgesia from codeine‐6‐glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype. (Int J Clin Pract 2000; 54(6): 395‐398)