Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study.

OBJECTIVE: To assess the efficacy and tolerability of sulfasalazine (SSZ) in the treatment of spondylarthropathy. METHODS: We conducted a 6-month randomized, placebo-controlled, double-blind, multicenter study of patients with spondylarthropathy whose disease had remained active despite treatment with nonsteroidal antiinflammatory drugs. Patients were treated with SSZ (3 gm/day) or placebo. The primary efficacy variables were the physician's and patient's overall assessments, pain, and morning stiffness. End points were analyzed in the intent-to-treat and completer patient populations; the time course of effect was analyzed in the completer patient population. RESULTS: Of the 351 patients enrolled, 263 (75%) completed the 6-month treatment period. The withdrawal rates were 35 (20%) and 53 (30%) in the placebo and SSZ groups, respectively. In the intent-to-treat analysis of end point efficacy, the between-treatment difference reached statistical significance only for 1 of the 4 primary outcome variables, the patient's overall assessment of disease activity, for which 60% of the patients taking SSZ improved by at least 1 point on a 5-point scale, in contrast to 44% of the patients taking placebo. Laboratory markers of inflammation also showed statistically significant change in favor of SSZ. In subgroup analysis, the most impressive effects were seen in patients with psoriatic arthritis, both for the 4 primary efficacy variables and for secondary efficacy variables such as the number of inflamed joints. Adverse events were more frequent in the SSZ group than the placebo group, but all were transient or reversible after cessation of treatment. CONCLUSION: The results of this study show that SSZ had greater efficacy than placebo in the treatment of active spondylarthropathy, notably in patients with psoriatic arthritis.

The course of established ankylosing spondylitis and the effects of sulphasalazine over 3 years.

A 3-year placebo-controlled trial of sulphasalazine (SASP) in 89 patients with established AS (including radiological sacroiliitis) showed a reduced frequency of peripheral arthritis in the treated group but did not show any definite benefit in the maintenance of spinal mobility. Adverse effects causing treatment withdrawal occurred in five placebo-treated patients and eight SASP-treated patients, but 22 patients preferred to stop taking daily medication of unproven benefit for the full 3 years. The natural history of established AS suggested two groups of patients: the majority with principally spinal symptoms and infrequent peripheral arthritis or iritis, and a minority who tend to have recurrent extra-spinal problems.

Smoking in Crohn's disease: effect on localisation and clinical course.

The effects of smoking on the localisation and clinical course of Crohn's disease is evaluated in 231 patients. Heavy smokers (greater than 10 cigarettes/day) had an increased risk of operation at least once--odds ratios for heavy smokers compared with never smokers after five and 10 years were 1.14 and 1.24 respectively (p = 0.03 and p = 0.017). The risk of further operations was even higher and after 10 years the odds ratio was 1.79 (p = 0.015). The accumulated number of fistulae and/or abscesses was higher for smokers than for never smokers (p = 0.046). Patients with a high life time tobacco exposure (greater than 150 cigarette years) and heavy smokers (greater than 10 cigarettes/day) had small bowel disease more often than patients with lower life time exposure (less than or equal to 150 cigarette years) and patients smoking less than or equal to 10 cigarettes/day (p = 0.002 and p = 0.045 respectively). The course of Crohn's disease analysed in different ways was unfavourable for smokers, especially heavy smokers. Patients with Crohn's disease should be dissuaded from smoking.

The relationship of crowding and aggressive behavior on a psychiatric intensive care unit.

During a 25-week period, all incidents of aggressive behavior in a 19-bed psychiatric acute care unit were systematically recorded using the Staff Observation Aggression Scale. Forty-seven of the 163 patients admitted to the unit were aggressive on 119 occasions. Of these incidents, 100 were physical attacks on another person, and 95 were perpetrated by 23 patients. The patients were predominantly aggressive without visible provocation or were provoked by staff's denying a request. An increased number of patients on the ward significantly increased the likelihood of aggressive behavior, especially by patients with schizophrenia or schizophreniform disorder.

The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy.

Classification criteria for most of the disorders belonging to the spondylarthropathy group already exist. However, the spectrum of spondylarthropathy is wider than the sum of these disorders suggests. Seronegative oligoarthritis, dactylitis or polyarthritis of the lower extremities, heel pain due to enthesitis, and other undifferentiated cases of spondylarthropathy have been ignored in epidemiologic studies because of the inadequacy of existing criteria. In order to define classification criteria that also encompass patients with undifferentiated spondylarthropathy, we studied 403 patients with all forms of spondylarthropathy and 674 control patients with other rheumatic diseases. The diagnoses were based on the local clinical expert's opinion. The 403 patients included 168 with ankylosing spondylitis, 68 with psoriatic arthritis, 41 with reactive arthritis, 17 with inflammatory bowel disease and arthritis, and 109 with unclassified spondylarthropathy. Based on statistical analysis and clinical reasoning, we propose the following classification criteria for spondylarthropathy: inflammatory spinal pain or synovitis (asymmetric or predominantly in the lower limbs), together with at least 1 of the following: positive family history, psoriasis, inflammatory bowel disease, urethritis, or acute diarrhea, alternating buttock pain, enthesopathy, or sacroiliitis as determined from radiography of the pelvic region. These criteria resulted in a sensitivity of 87% and a specificity of 87%. The proposed classification criteria are easy to apply in clinical practice and performed well in all 7 participating centers. However, we regard them as preliminary until they have been further evaluated in other settings.

Relative bioavailability of olsalazine from tablets and capsules: a drug targeted for local effect in the colon.

The aim of this investigation was to compare two formulations of the prodrug olsalazine (OLZ) with regard to local bioavailability of 5-aminosalicylic acid (5-ASA) in the colon. Since 5-ASA can not be measured directly in the colon, the bioavailability was evaluated by studying the plasma concentration and cumulative urinary excretion (Ae) of its main metabolite N-acetyl-5-aminosalicylic acid (ac-5-ASA). The absorption of OLZ was also studied. A single dose of 1g OLZ tablets and capsules was given to nine healthy fasting volunteers in two repeated two-period cross-over studies. Blood and urine samples were collected for 72 and 96 h, respectively. AUC, Cmax and Ae data from both studies were combined for statistical analysis. Ninety per cent confidence limits for differences in mean AUC for ac-5-ASA (tablet-capsule) compared to that of capsules were -0.31 per cent and 30.8 per cent. This indicates bioequivalence if a more relaxed criterion than the conventional +/- 20 per cent is applied, which is justified in this situation. The 90 per cent confidence limits for Cmax were -10.5 per cent and 36.9 per cent while for Ae the values were -20.5 per cent and 23.7 per cent. Within and between subject variability estimates for AUC of ac-5-ASA were 24 per cent and 46 per cent, respectively.

A double-blind comparative study of remoxipride and thioridazine in the acute phase of schizophrenia.

Sixty-one patients with acute schizophrenia received either remoxipride (75-375 mg daily) or thioridazine (150-750 mg daily) for 6 weeks. There was no statistically significant between-drug difference in improvement in mental state, as measured by the Brief Psychiatric Rating Scale, although the trend favoured thioridazine; global assessment of illness severity at the last rating also favoured thioridazine. Sedation, anticholinergic effects, autonomic dysfunction, and weight gain were significantly more common in patients receiving thioridazine. Both drugs produced few extrapyramidal effects, but both were associated with cardiovascular changes in two patients; neither drug produced significant abnormalities in laboratory tests.

A double blind comparative study of remoxipride and thioridazine in the acute phase of schizophrenia.

This is the first comparative double blind study of remoxipride. Sixty-one patients with acute schizophrenia received either remoxipride (75-375 mg daily) or thioridazine (150-750 mg daily) for 6 weeks. There was no statistically significant between-drug difference in improvement in mental state, as measured by the Brief Psychiatric Rating Scale, although the trend favoured thioridazine; global assessment of illness severity at the last rating also favoured thioridazine. Sedation, anticholinergic effects, autonomic dysfunction and weight gain were significantly more common in patients receiving thioridazine. Both drugs produced few extrapyramidal effects, but both produced cardiovascular changes in two patients; neither drug produced significant abnormalities in laboratory tests.

Statistical aspects of clinical trials of antibiotics in acute infections.

Controlled clinical trials are important tools for evaluating antibiotics in acute infections. External and internal validity, definition of efficacy criteria, and size of the patient sample constitute special statistical problems in such studies. Critical issues regarding external validity pertain to the selection of patients and to the concept of consecutive patients. The internal validity of a study is influenced by the withdrawal of patients from the evaluation after randomization and the comparability of treatment groups with regard to prognostic factors. The definition of efficacy criteria on the basis of bacteriologic outcomes across control visits is not straightforward. Particularly, the evaluation of efficacy at the last follow-up visit must take into account the accumulated information rather than the cross-sectional information. The most common situation in comparative trials of antibiotics is that rather small differences in efficacy can be anticipated. Sometimes, the question at issue is the demonstration of antibiotic equivalence. For valid conclusions to be made in such situations, large samples must be used. A basic problem affecting many studies of antibiotics is that this criterion is not fulfilled.

Intra- and inter-individual variation in pharmacokinetics of intravenously infused amoxycillin and ampicillin to elderly volunteers.

The purpose of this study was to investigate the disposition of two aminopenicillins and their intra- and inter-individual variation in pharmacokinetic parameters in healthy, elderly volunteers. Two groups, each of 12 active, community-dwelling volunteers between 69 and 83 years of age participated. One group was given 500 mg of amoxycillin, the other group 500 mg of ampicillin as single i.v. infusions. Within the drug groups each volunteer was given the infusion at two different occasions separated by a time-period of 1 week. Amoxycillin and ampicillin were determined in plasma and urine by modern column liquid chromatographic methods. The mean plasma clearance was about 200 ml min-1 1.73 m-2 for both drugs and renal clearance accounted for approximately 80% of this. As expected, drug clearance was correlated to renal function as determined by 51Cr-EDTA. The volume of distribution at steady-state (Vss) was about 0.3 l kg-1 for both drugs. Compared to our previous results in younger subjects, plasma and renal clearances were essentially similar in this study, but slightly longer half-lives and higher Vss were seen for amoxycillin and ampicillin. The intra-individual variation, expressed as the error of a single determination (CV), was small, for plasma clearance 3.7% and 6.4% after amoxycillin and ampicillin. The corresponding inter-individual variation in clearance was higher, 14.4% after amoxycillin, and 11.9% after ampicillin. The results confirm a higher relative efficiency of a crossover vs a completely randomized parallel groups design in parenteral studies of these penicillins. In our elderly subjects there was only an approximately 30% decrease in renal function. This was not enough to reduce the drug clearance and offers an explanation for the similarity between our present results in the elderly and our previous results in younger subjects. Elderly volunteers may be different from patients with disease as a confounding factor. Studies on elderly active and community-dwelling volunteers, as in this study, may therefore be more representative as to the effect of age per se on drug kinetics.

Effect of beta-lactam prodrugs on human intestinal microflora.

The ampicillin prodrugs bacampicillin, pivampicillin, and talampicillin, the mecillinam prodrug pivmecillinam and the sulbactam prodrug sulbactam pivoxil all have a greatly improved oral availability compared to the parent drug. They show no antibacterial activity themselves until transformed into active drugs after absorption. This double advantage makes them less likely to influence the intestinal microbial ecosystem. Ampicillin has been reported to cause marked changes in the colon microflora, particularly as regards Enterobacter species, Klebsiella species, enterococci, lactobacilli, bacteroides, and clostridia, in contrast to pivampicillin, which did not exert much influence. Similarly, talampicillin has been reported to have less influence than ampicillin on the colon flora. Diarrhoea was more common after ampicillin and was accompanied by an overgrowth of Candida. Pivmecillinam has been reported to reduce the number of Escherichia coli and lactobacilli. No changes were seen in the colon flora of subjects receiving bacampicillin tablets. This was verified in a parallel group study, in which one group was given the combination of bacampicillin and sulbactam pivoxil, the other bacampicillin, for seven days. Of the subjects given the combination, five had a moderate and ten a considerable change in their colon microflora. The subjects were often heavily colonized by new aerobic strains such as enterococci, E. coli, Bacillus, Enterobacter, Aeromonas, and yeasts. Among the anaerobes, Veillonella, the bifidobacteria-lactobacillus group, and bacteroides decreased. Some strains of clostridia decreased but there was also a colonization with new strains. One subject was colonized with Clostridium difficile. Diarrhoea was seen only during the week of active drug administration in the group given the combination. The symptoms generally appeared on the second or third day of treatment and had, in most cases, subsided at the end of treatment. The results illustrate the correlation between disturbances in the intestinal microbial ecosystem and intestinal adverse reactions.

Correlation between the bioavailability of microencapsulated bacampicillin hydrochloride in suspension and in vitro microcapsule dissolution.

The relative bioavailability of microencapsulated bacampicillin hydrochloride in suspension was correlated with the in vitro dissolution half-lives of the microcapsules. Simultaneously, a sensory evaluation was performed to evaluate the taste acceptability of the suspension. The in vitro dissolution half-life is directly related to the coating thickness of the microcapsules. The four suspensions of bacampicillin hydrochloride, containing microcapsules with different coating thickness, were given as single 400-mg oral doses to 12 healthy volunteers after overnight fasting using a crossover design with balanced sequences. Bacampicillin is a prodrug of ampicillin, the concentration of which was determined in plasma and urine by bioassay. There were significant inverse linear relationships between the dissolution half-life and plasma peak concentration, area under the curve, and urinary recovery. The terminal exponential disposition phases of the curves were similar for all four suspensions. There was a significant direct linear relationship between the dissolution half-life and overall taste and bitterness. The results show that the mean bioavailability of bacampicillin hydrochloride from a microcapsule suspension can be predicted from an in vitro dissolution half-life. The results also suggest that bacampicillin hydrochloride can be given in a suspension with sufficient microcapsule film thickness to reduce the bitter taste of the drug and still retain adequate bioavailability.

Methods for evaluating the taste of paediatric formulations in children: a comparison between the facial hedonic method and the patients' own spontaneous verbal judgement.

The aim of the study was to evaluate two essentially different methods of assessing differences in children's taste preferences with regard to five different paediatric penicillin formulations. The study was performed with a parallel group design comparing five groups. A taste evaluation was recorded in 103 children with upper respiratory tract infections after a single therapeutic test dose. First the patient's own spontaneous verbal judgement was recorded then a judgement was arrived at using a hedonic scale of facial expressions. Both judgements were passed immediately and also 3-4 minutes after the test dose. In the children who were 6 years of age or younger, a better discrimination of taste differences between formulations was achieved by using the patients' own spontaneous verbal judgements instead of the facial hedonic method. Both methods seem appropriate in older children, but the hedonic scale is preferable since its use implies a more standardised procedure.

A double-blind evaluation of zimelidine in comparison to placebo and amitriptyline in patients with major depressive disorder.

This paper presents the results from a large multicenter study, performed at three clinical research units in the USA. Prior to a three to seven days of placebo washout period, patients were randomly assigned to zimelidine, a potent and selective 5-HT reuptake blocker, amitriptyline or placebo. The scheduled treatment period was four weeks. Dosage range was 75-300 mg/day for active medications. The rating instruments were the Hamilton Depression Scale and the Clinical Global Impression scale. The side effects were recorded by using a side effect inventory (TESS). Vital signs, laboratory work including clinical chemistry, ECG, and plasma levels of drugs, were performed. In the main efficacy evaluation there were 229 depressed outpatients included, all having completed at least two weeks of treatment after the washout period. The patients treated with zimelidine as well as those treated with amitriptyline showed a significant improvement relative to the placebo treated patients. For the safety evaluation 263 patients were included. Side effects, in particular anticholinergic effects but also drowsiness and cardiovascular effects, were much less pronounced in the zimelidine group as compared to the amitriptyline group. Only marginal differences regarding side effects were reported for zimelidine compared to those reported for placebo.

Comparison between zimeldine and amitriptyline of efficacy and adverse symptoms--a combined analysis of four British clinical trials in depression.

The similarities and differences in the clinical response and incidence of adverse symptoms between zimeldine and amitriptyline have been evaluated by use of a combined analysis of four double-blind clinical trials in depression. In total, 197 patients were included in this series of studies. The efficacy of the drugs was assessed using the Hamilton Rating Scale for Depression (HAM-D). Reports of adverse symptoms were actively elicited by use of a check-list of symptoms and rated for severity. The overall clinical efficacy of the two drugs was shown to be equivalent with a high degree of statistical confidence. However, there exist differences in the profile of action. Amitriptyline has a significant advantage in insomnia problems. In spite of this zimeldine was shown to be at least as effective as amitriptyline in reducing anxiety. Amitriptyline is associated with significantly more anticholinergic side-effects, whereas headache is more disturbing during zimeldine treatment. The combination of several independent trials based on similar protocols can be a useful tool to increase the statistical reliability of conclusions relative to that which can be achieved in standard sized, individual studies in depression.

An analgesic study with repeated doses of phenazone, phenazone plus dextropropoxyphene, and paracetamol, using a visual analogue scale.

A double blind randomized analgesic trial was carried out in patients suffering from pain after removal of an impacted lower wisdom tooth. In a repeated dose regimen, 120 patients received one of three different analgesics: phenazone, phenazone plus dextropropoxyphene, or paracetamol. The assessments of pain were made hourly on a visual analogue scale and the evaluation was carried out according to a method which considers repeated dose intake. The analgesic efficacy of 500 mg phenazone was similar to 500 mg of paracetamol. The pain reduction seemed adequate in most patients and no statistical differences were obtained between the treatment drugs. All analgesics were taken when needed, and the time interval from end of operation to first tablet intake, as well as the pain score at first tablet intake, were factors which significantly influenced the efficacy of the drugs. Therefore, these factors may be of significant importance in the evaluation of analgesics in small sample studies.

A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. I. Design and methodologic considerations.

The design and execution of the Cooperative Crohn's Disease Study in Sweden are described in this paper. A double-blind, double-dummy, crossover (2 X 4 mo) technique was used to compare the suppressive efficacy of metronidazole (0.4 g b.i.d.) and sulfasalazine (1.5 g b.i.d.). The number of randomized patients (78) presented approximately one-third of the available population. The Crohn's Disease Activity Index and the plasma level of orosomucoid were the main variables for clinical evaluation. Results were analyzed primarily in the first treatment period by ranking the clinical outcome of every patient according to a uniform and detailed scheme and applying Wilcoxon nonparametric statistics. The cross-over data only served as additional information. Thirty-six patients had had earlier and mostly positive experience with sulfasalazine. Repeated plasma drug analysis indicated good compliance. The blindness of the trial was tested and appeared satisfactory. The coordination of the trial proceeded as planned. A lack of full conformity in the electroimmunoassay of orosomucoid was taken care of satisfactorily.

A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. II. Result.

Seventy-eight patients with active Crohn's disease participated in a randomized, double-blind, cross-over trial. The study comprised two 4-mo period. The purpose was to test the efficacy of metronidazole in comparison with that of sulfasalazine. As the main evaluation criteria the Crohn's Disease Activity Index and plasma levels of orosomucoid were chosen. In the first period no difference in efficacy as measured by Crohn's Disease Activity Index was found between the treatment groups. The reduction of the plasma orosomucoid level was significantly more pronounced in the metronidazole group. The hemoglobin concentration increased more in this group than in the sulfasalazine group, possibly due to a toxic effect of sulfasalazine. The erythrocyte sedimentation rate decreased similarly with both drugs. In 15 patients who had active disease throughout the first period, Crohn's Disease Activity Index decreased significantly in the second period for those who switched to metronidazole, but not for those who switched to sulfasalazine. After crossover, no apparent further change in Crohn's Disease Activity Index occurred in either of the treatment groups among patients who had responded favorably in the first period. The plasma concentration of orosomucoid increased significantly among the patients in the sulfasalazine group but not in the metronidazole group. It is therefore concluded that metronidazole is slightly more effective than sulfasalazine in the treatment of crohn's disease. It is worthwhile switching the drug regimen from sulfasalazine, when it fails, to metronidazole, but not from metronidazole to sulfasalazine.

Placebo in clinical drug trials--a multidisciplinary review.

The use of placebo in controlled clinical trials is a very difficult matter from an ethical point of view. Scientifically it offers probably the best way of obtaining fast and valid conclusions, thus promoting medical progress for the benefit of future patients. On the other hand, some patients may stand the risk of obtaining a suboptimal therapy in a placebo-controlled trial. In general, this latter aspect must be given precedence. Therefore the use of placebo control should be minimized and other control methods encouraged. However, in certain well-defined instances the use of a placebo control can be justified, provided the ethical implications can be handled.

Antibody responses in man after single or repeated treatment with intramuscular ampicillin.

Antibody responses to the penicilloyl moiety were recorded in patients treated intramuscularly with ampicillin for respiratory infections. For practical reasons this was performed at two clinics. At each clinic, two commercially available ampicillin preparations were used in a single-blind, randomised study. One of the preparations at each clinic was of high-grade purity and the other was slightly contaminated, according to a radioimmunoassay. There was the same heterogeneity in the patient material between the two clinics. The results showed a slight but significant (p less than 0.001) increase in IgM penicilloyl antibodies in the group of patients treated with the pure penicillin but not in those treated with the contaminated penicillin. When the patients in the two studies were analysed jointly, the increase in IgM antibodies was significantly greater (p less than 0.05) in the group treated with pure penicillin than in that treated with impure penicillin. The difference in antibody formation between the patient groups treated with pure or contamined ampicillin at each clinic was not significant, however. An immunological activity of the impurities suppressing the IgM antibody response is suggested.