[Combined 3-in-1 sciatic block. Prilocaine 500 mg vs. 650 mg]. / Kombinierter Ischiadikus/3-in-1-Block. Prilocain 500 mg vs. 650 mg.

The objective of the study was to investigate the clinical effectiveness of increasing the dosage of prilocaine for a combined 3-in-1/sciatic nerve block from 500 to 650 mg (open study with 29 patients compared with 30 patients from a former study) and to validate these findings in a second stage (randomised study comparing two groups of 30 patients each). Not only was clinical effectiveness improved by increasing the dose to 650 mg, but methaemoglobinaemia and toxicity were not relevant problems. With the higher dosage, development of the block was slightly faster (onset and completion); there were fewer unsatisfactory blocks; and clinically relevant plasma levels of methaemoglobin did not occur.

A three year comparative study of auranofin and gold sodium thiomalate in rheumatoid arthritis.

UNLABELLED: One hundred twenty-one patients with active RA were randomly assigned to receive 6 mg auranofin (AF)/day (60 patients) or 50 mg gold sodium thiomalate (GST)/week (62 patients) in a double-blind fashion. There were no intergroup differences with respect to sex, age, duration (median 2 years), stage and activity of the disease. In the case of "striking improvement" after 24 weeks a dose reduction to 50 mg GST/month or 4 mg AF/day was allowed and carried out in all GST patients and no AF patient. The serum gold levels were 5 times higher with weekly GST, they approached those of the AF group with monthly GST injections. The clinical parameters--number of swollen joints, activity index, articular index, grip strength, ESR--improved significantly in both groups, but grip strength, articular index and ESR improved more pronounced in the GST group. The X-ray progression (hands and forefeet) was significantly greater in the AF group. Forty-eight AF patients (80%) and 39 GST patients (36%) completed the first year. Thereafter the study was continued as an open study but the patients were allowed to switch from GST to AF. After the first and second year 14/7 GST patients switched to AF. The second/third year was completed by 37/22 AF pat. (62%/37%) and by 15/8 GST pat. (24%/13%). Skin reactions were more common with GST (41.9%/26.7%), diarrhoea was more common with AF (36.7%/19.4%), proteinuria occurred in 10% in both groups, leucopenia and thrombocytopenia were rare in both groups (1.7%). The withdrawal rate due to adverse events was 10%/26% in the AF/GST group during the first year (p less than 0.05) and 25%/32% over the three year period (n.s.). CONCLUSION: Both AF and GST are effective in the long-term treatment of RA, but GST is more so in radiological progression and ESR.

Longterm results of auranofin therapy.

The results of longterm therapy with the oral gold preparation auranofin in patients with rheumatoid arthritis (RA) were evaluated based on the following data: 1) Two multicenter open uncontrolled studies (MTC06) and (162EMUA-RA), 2) the reevaluation of these data for the MTC06 study after 4 years from the beginning of the study and 3) the results of a postmarketing surveillance program (PMSP) of patients on auranofin therapy. The specific rheumatologic documentation and information system (IKR inhaltkodierte rheumatologic) serves as the basis of the follow-up studies and longterm observations. The first year data on 207 patients (MTC06) indicating that duration of the disease less than 2 years was the only discriminating factor regarding a positive treatment outcome were confirmed by the two-year (151 patients). Patients, who responded favourably to Auranofin did usually well for the four-year or longer observation period. The data base of these two studies and the PMSP failed to outline any new severe or threatening side effects. Diarrhea and loose stools were more common at the beginning of the treatment. The overall withdrawal for untoward events was 11.2%. Patients who did or did not respond to previous DIMARD therapy either on i.m. gold, D-Penicillamine or Chloroquine, did usually well when treated with Auranofin, even if severe side effects leading to withdrawal had occurred on previous therapy. The favourable safety profile was confirmed by the PMSP data.

Auranofin: first choice for remission-inducing drug (RID) therapy in rheumatoid arthritis?

Numerous studies have demonstrated that auranofin (AF) causes less severe side effects than other disease-modifying antirheumatic drugs (DMARDs) such as injectable gold (IG) and D-penicillamine (DPA). As the efficacy of AF appears comparable to that of IG, AF could be the first choice for early and long-term therapy for rheumatoid arthritis (RA). A total of 444 patients were enrolled in 2 uncontrolled, open, multicenter studies in Germany, Austria, and Switzerland; data were evaluated from 300 patients with RA treated for 12 months and 179 patients treated for 24 months. Patients with disease duration of 1 year or less had greater improvement in grip strength, joint index, morning stiffness, and activity index when compared with patients whose disease duration was more than 2 years. Drug treatment prior to AF included IG in 46, DPA in 36, chloroquine in 57, and antineoplastic agents in 5. Within this group, subpopulations were isolated who were withdrawn from prior DMARD therapy due to lack of efficacy or adverse events, and the results of subsequent AF therapy evaluated. Adverse events observed with previous DMARDs, particularly proteinuria, did not necessarily recur with AF. The data from these 2 studies suggest that auranofin can be initiated early in the course of RA and can be used successfully in patients who have experienced lack of efficacy or adverse events with other DMARDs.

Postmarketing experience with auranofin in the Federal Republic of Germany.

Data about adverse events can be particularly useful when assessing newly marketed drugs. However, spontaneous reporting of adverse events does not generally provide sufficient or highly accurate data on incidence and prevalence. In order to provide the most complete and accurate data, a postmarketing surveillance program (PMSP) for auranofin (AF) oral gold therapy for rheumatoid arthritis (RA) was conducted in the Federal Republic of Germany (FRG) from December 1982 through December 1985. The objectives of the program were to observe a large population treated with AF for more than a year; to compare the safety profile of AF with experience from clinical trials; and to register rare or previously unknown adverse events. The program included 2,777 patients with RA from 928 test centers. Disease duration was less than 2 years in 29%. 2-5 in 23.2%, 5-10 in 32.5%, and more than 10 in 13.3% (no data for 2%); disease was mild or moderate in 67.4% and severe in 29.9% (no data for 2.7%). Auranofin was given 6 mg/day as either two 3-mg tablets at breakfast or 1 tablet at breakfast and 1 at the evening meal. Laboratory studies and efficacy, as indicated by increase in grip strength and decrease in number of tender and swollen joints, were monitored regularly. A total of 1,595 patients completed 1 year of treatment with AF. Withdrawals included 12.9% for adverse events, 4.2% for insufficient therapeutic effect, and 33.1% for a variety of administrative or technical reasons. The most common adverse event was alteration in stool pattern, which occurred in 22.5% of patients, compared with 46.6% in worldwide AF clinical trials. Other gastrointestinal symptoms occurred in 17.4%, compared with 22.4% worldwide. The occurrence of most adverse events in the PMSP was much less than in worldwide studies, for example: skin rash 7.3% vs. 24.2% worldwide, pruritus 4.2% vs. 16.6%, proteinuria 1.0% vs. 5.0%, and leukopenia 0.7% vs. 1.9%. These discrepancies may be explained by the method of monitoring employed in the postmarketing study, which favored the reporting of only clinically relevant adverse events. The pattern of occurrence of adverse events was similar to that seen during other AF trials, indicating that any intolerance to AF occurs primarily within the first 6 months of treatment. However, hematologic or nephrologic adverse events appear to be independent of time on therapy, with a constant monthly prevalence of about 0.1-0.2%.(ABSTRACT TRUNCATED AT 400 WORDS)

[Multiple-dose pharmacokinetics of paracetamol and salicylamide in man after combined rectal application (author's transl)]. / Humanpharmakokinetik von Paracetamol und Salicylamid nach kombinierter rektaler Mehrfachverabreichung.

The pharmacokinetic behaviour of paracetamol (300 mg) and salicylamide (200 mg) in the course of combined repetitive (three times tau = 4 h) administration of suppositories was investigated in 10 healthy, male volunteers. The estimation of the pharmacokinetic constants was performed by a simultaneous curve fitting from all single values with a direct search procedure, based on an open two-compartment model and the multiple-dose equation. Both drugs showed a pharmacokinetic behaviour which was conformable to the literature data for single dose and mono substance applications. The dynamics of the absorption kinetics was decreased, as is generally seen after the application of suppositories. In spite of this both substances reached a steady state after the 3rd application. A calculation of collapse coefficients showed for paracetamol as well as for salicylamide a pharmacokinetic distribution behaviour deviating from an open one-compartment model. Due to the good conformity of the parameters, which causes the synchronism of the time-concentration curves after multiple dose application, paracetamol and salicylamide are suited combination partners as seen from a pharmacokinetic point of view.

Single-dose pharmacokinetics of macrocrystalline nitrofurantoin formulations.

The pharmacokinetics of macrocrystalline formulations of nitrofurantoin (50 mg and 150 mg) were studied after single dose administration in 10 healthy male volunteers, using a cross-over study design. The total estimation of the pharmacokinetic data was calculated simultaneously from all of the single values, using a direct search procedure based on an open two-compartment-model (with additional 2 first-order input steps for one of the 150 mg formulations). Analysis showed that the relevant pharmacokinetic parameters for the formulations studied were in comparable ranges; however, the terminal elimination half-lives, 1.2 h and 1.7 h, were 3 to 4 times longer in comparison to those currently reported in the literature. The marked discrepancy in these findings is discussed and a review of the current data on the elimination kinetics of nitrofurantoin is recommended.