A lack of pharmacokinetic interaction between ranitidine and piroxicam.

The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng.ml-1 for ranitidine alone and 466 ng.ml-1 in the presence of piroxicam: mean area under the plasma concentration vs time curve (AUC) was 2460 h.ng ml-1 and 2551 h.ng ml-1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 micrograms.ml-1 in the presence of placebo and 2.0 micrograms.ml-1 in the presence of ranitidine respectively; mean AUC was 133 h.microgram ml-1 and 137 h.microgram ml-1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.

C-reactive protein in the serial assessment of disease activity in rheumatoid arthritis.

C-reactive protein (CRP) levels were measured in 105 patients with rheumatoid arthritis (RA) during treatment with slow-acting anti-rheumatoid drugs D-penicillamine, alclofenac, hydroxychloroquine, gold, sulphasalazine and azathioprine. A control group treated with aspirin alone was also included. Patients were assessed clinically (pain score, articular index and summated change score) and in terms of acute-phase reactants (CRP, haptoglobin, fibrinogen, ESR and plasma viscosity) at eight separate clinic visits during the 6-month treatment period. The estimation of CRP was found to be more useful than haptoglobin, fibrinogen or ESR as an index of disease activity.

Serum biochemistry in relation to the action of azathioprine in rheumatoid arthritis.

In a long-term study we have been comparing biochemical changes in the blood of patients with classical or definite rheumatoid arthritis (RA) when groups of patients are treated for the first time with specific anti-rheumatoid drugs for a six-month period. One such group was treated for 26 weeks with azathioprine. Biochemical and clinical assessments were made at each of 10 clinic visits during the treatment period. Side-effects prevented six patients completing the study. Clinical improvement in the remaining patients was accompanied by a reduction in acute phase proteins, increases in total serum sulphydryl and serum histidine, but little or no change in immunological variables. Comparison of correlation matrices constructed between clinical and laboratory variables for azathioprine and drugs previously tested suggests that azathioprine is more effective than a control group on aspirin alone and in some ways comparable with D-penicillamine.

A clinical and biochemical evaluation of Clozic, a novel disease modifying drug in rheumatoid arthritis.

We have compared two dose levels of Clozic, a novel agent with potential anti-rheumatoid activity, to D-penicillamine and aspirin in an observer blind randomised parallel group study of 56 patients with active rheumatoid arthritis. Eight clinical assessments and 26 laboratory assessments were performed on each patient at each visit over a six month period. Results were analysed by conventional methods and also by correlation matrices constructed between clinical and laboratory variables. Patients treated with D-penicillamine (500 mg/day) responded adequately and the control group on aspirin (up to 3.6 g of enteric coated formulation/day) performed well, though the withdrawal rate from this latter group was high, predominantly because of continued disease activity. Patients receiving Clozic (100 mg/day or 300 mg/day) improved more than patients receiving penicillamine, particularly at the higher dose. Comparison of methods of analysis validates the use of correlation matrices both for detecting anti-rheumatoid activity and for determining the optimum dose of a novel compound. This trial illustrates the problems of a study of this nature, with the powerful effect on patients of being enrolled in such a closely monitored investigation. It emphasises the greater value of biochemical changes in following disease changes.

Gastro-intestinal blood loss with high dose tilcotil (Ro 12-0068) and aspirin: an open crossover clinical trial and pharmacokinetic assessment in normal volunteers.

An open crossover study was carried out in 8 normal volunteer subjects to compare faecal blood loss resulting from tilcotil (Ro12-0068), a new anti-inflammatory agent, and from enteric-coated aspirin. After a 1-week run-in period, subjects were allocated at random to receive treatment for 2 weeks with either 40 mg tilcotil as a single dose per day or aspirin, 900 mg 4-times daily, reduced if necessary to a maximum tolerated dose. Subjects were then crossed over to the alternative treatment for a further 2 weeks. The results showed that tilcotil produced less blood loss, assessed by a radioactive labelling method, and was better tolerated than aspirin. Plasma concentrations of tilcotil showed that the drug's half-life was approximately 50 hours, compatible with once daily dosage, and steady state concentrations on multiple dosing were reached after 10 to 12 days.

The effect of drugs on serum histidine levels in rheumatoid arthritis.

Groups of 15 patients with active rheumatoid arthritis were treated for 24 weeks with zinc sulphate, trien, captopril, clozic in two doses or a combination of D-penicillamine and hydroxychloroquine. Serum histidine levels were monitored along with measures of disease activity including C-reactive protein, plasma viscosity, articular index, grip strength and early morning stiffness. Zinc sulphate and trien were found to be ineffective while the other drugs all showed evidence of second-line action. Serum histidine was found to improve during successful therapy. The possible cause of low serum histidine and its response to therapy is discussed.

A pharmacological and clinical comparison of prednisolone and betamethasone in rheumatoid arthritis.

1. Two oral corticosteroids, prednisolone (8 mg/day) and betamethasone (1 mg/day) have been compared in terms of efficacy and adrenal suppressive activity when used in chronic oral dosage in rheumatoid arthritis. 2. 20 patients were entered to a single blind crossover study receiving each drug for a two-week period. Clinical and laboratory assessments were performed. 3. At this dosage there was no significant difference between any of the clinical parameters assessed for either drug though patient preference was 13 for prednisolone and 7 for betamethasone. 4. At this dosage adrenal suppression was not equivalent, being significantly more marked with betamethasone. 5. The results suggest that prednisolone is the drug of choice for chronic dosage.

The effect of ibuprofen on the excretion of steroid metabolites.

An inexpensive gas chromatographic method is described that allows simultaneous measurement in urine of androsterone (A), aetiocholanolone (E), 11-hydroxyandrosterone (11-OA), 11-hydroxyaetiocholanolone (11-OE), pregnanediol (PD), pregnanetriol (PT), tetrahydrocortisone (THE) and tetrahydrocortisol (THF). Dehydroepiandrosterone was also resolved by the column. Ibuprofen was administered to five healthy normal males at a dose used therapeutically in rheumatoid arthritis (RA). The above urinary steroids were measured weekly during a control period, during a four week period of drug treatment and for four weeks after drug treatment had ceased. The excretion of A fell to a mean of 63% of the control value (p less than 0.02) and returned to the control value within two weeks. 11-OA, which showed a greater variability than A, fell to the same extent (p less than 0.1). No other steroid measured showed a change that could be related to the drug. This relatively limited effect of ibuprofen on steroid metabolism makes it a suitable drug for maintaining patients with RA during studies of their steroid metabolism.

A comparison between gastrointestinal blood loss caused by tilcotil (Ro 12-0068) and aspirin in normal volunteers.

An open crossover study was carried out in 6 normal volunteers to measure faecal blood loss caused by tilcotil (Ro 12-0068), a new anti-inflammatory drug, compared with that caused by enteric-coated aspirin. Subjects were allocated at random to receive either single doses of 20 mg tilcotil daily or 900 mg aspirin 4-times daily, reducing to a maximum tolerated dose, over a period of 2 weeks before being crossed over to the alternative medication for a further 2 weeks. Faecal specimens passed during 4 consecutive days in a run-in-period of 1 week, in each treatment period, and in the 2 weeks after the finish of drug therapy were analyzed for blood using a radioactive labelling method. The results showed that faecal blood loss was lower and it did not produce any haematological or biochemical abnormalities or any increase in urinary N-acetyl-beta-glucosaminidase activity indicative of renal damage. It is suggested that the method described provides a simple and reliable means of comparing faecal blood loss with different anti-inflammatory drugs.

Biochemical indices of response to hydroxychloroquine and sodium aurothiomalate in rheumatoid arthritis.

Biochemical and clinical changes have been monitored in 30 patients with rheumatoid arthritis treated with either hydroxychloroquine or sodium aurothiomalate over a period of 6 months. Acute-phase reactants improved in both treatment groups, while serum sulphydryl and serum histidine improved only in the gold-treated patients. Correlation matrices were constructed from mean clinical and biochemical data at successive clinic visits. Correlations obtained with gold were more frequent and of a higher level of significance than those obtained with hydroxychloroquine at the doses we studied. This lends support to the use of correlation matrices as a screening test for potential long-term antirheumatoid activity of drugs in man.

A pharmacokinetic and tolerance study of Ro13-9904, a new cephalosporin antibiotic.

1 Six healthy male volunteers received a total of 2500 mg of a new cephalosporin antibiotic Ro13-9904 by intramuscular injection in five divided doses at intervals of 12 h. 2 No significant systemic side-effects were observed and this was confirmed haematologically and biochemically. 3 The drug was distributed following intramuscular injection reaching a mean peak plasma concentration of 55 micrograms ml-1 (range 46-66) 1 to 2 h after the first injection. 4 Monoexponential elimination of drug was demonstrated. No significant difference was recorded in the plasma half-life after the initial dose (mean 6.7 h) and at steady state (mean 6.7 h). The half-life is long compared with other cephalosporin antibiotics. 5 On the basis of the observed half-life, steady state should be reached within 48 h. A mean peak plasma concentration of 74 micrograms ml-1 (range 65-87) was recorded at steady state. Steady state plasma concentrations of Ro13-9904 with a dose of 500 mg every 13 h may be predicted from the pharmacokinetics of a single dose.

Plasma viscosity--a new appraisal of its use as an index of disease activity in rheumatoid arthritis.

The suitability of the plasma viscosity (PV) test has been examined in relation to the more commonly used erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) estimations as a diagnostic aid in 120 outpatients with rheumatoid arthritis (RA) and as an index of improvement during subsequent specific antirheumatic drug treatment (60 outpatients). Correlation data based on 7 clinical variables suggest that PV estimations are at least as reliable as ESR and CRP in terms of diagnosis and as indices of improvement. The methodological advantages offered by the PV test lend support to its application in RA.

Bioavailability of aspirin in the presence of dextropropoxyphene/paracetamol combination.

The effect of 2 doses of a combination analgesic preparation (each dose containing 65 mg dextropropoxyphene hydrochloride and 650 mg paracetamol) upon plasma salicylate concentration after a single dose of soluble aspirin (1.2 g) or enteric-coated aspirin (1.2 g) was examined in 6 normal volunteers and compared with the effect of placebo. The dextropropoxyphene/paracetamol caused no reduction in the plasma salicylate level after absorption of soluble aspirin compared with placebo and, although a reduction in plasma salicylate was seen after enteric-coated aspirin in a single subject, this may reflect erratic absorption rather than a drug interaction.

Discriminatory indices of response of patients with rheumatoid arthritis treated with D-penicillamine.

A long-term study is being undertaken to classify drugs used as specific agents in the treatment of rheumatoid arthritis in terms of their effects on biochemical and clinical characteristics of the disease. In particular is hoped to establish those indices which are most relevant to the response of RA to treatment. Fifteen patients were treated with D-penicillamine after an initial period of 2 weeks on aspirin alone, when the baseline investigations were made. The dose of penicillamine was increased gradually to a maximum of 500 mg a day over the period of 6 months, and changes in 8 clinical and 25 laboratory indices were measured on 8 separate occasions in the 6-month period. Marked clinical improvement took place, and this was mirrored by changes in a wide range of biochemical parametaers. ESR and C-reactive protein were shown to be the most suitable indices of disease improvement with penicillamine treatment.

A biochemical comparison of alclofenac and D-penicillamine in rheumatoid arthritis.

In view of the claim that alclofenac has a specific antirheumatoid action a detailed biochemical study has been made over a 6-month period of 2 groups of patients with rheumatoid arthritis receiving either alclofenac or D-penicillamine for the first time. We found no biochemical evidence and little clinical evidence that alclofenac had a 'penicillamine-like' effect in rheumatoid arthritis.