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We report on the use of a new orally active fungicidal agent, terbinafine (SF 86-327, Lamisil) in the treatment of patients with dermatophyte onychomycosis. Twenty patients with toe-nail, and 10 with finger-nail infection received 250 mg of terbinafine daily: finger-nail infections were treated for 6 months and toe-nail infections for 12 months. All 24 patients who completed the course of therapy achieved mycological cure, as did two subjects who dropped out of the trial. All but two patients had clinically normal nails at the end of the study period. The mean time for mycological cure was 12.5 weeks for finger-nail infection, and 24 weeks for toe-nail infections. The time for a clinical cure with normal nails was 20.5 weeks for finger-nail infection, and 44 weeks for toe-nail infection. An exacerbation of pre-existing dyspepsia occurred in three of the six patients who did not complete the trial but there were no other significant adverse reactions.

An endoscopic study of 34 patients with rheumatic diseases taking nonsteroidal anti-inflammatory drugs (NSAIDs) was undertaken to evaluate whether dyspepsia was associated with Campylobacter pyloridis. Twenty-two patients had an indication for upper gastrointestinal endoscopy and 12 patients were asymptomatic volunteers. Dyspepsia did not correlate with the macroscopic findings at endoscopy, the presence of histological gastritis or the presence of C. pyloridis. However, this study did demonstrate that macroscopic mucosal changes, histological gastritis and the presence of C. pyloridis have an equal prevalence in asymptomatic volunteers and symptomatic patients.

Doses of 600 mg and 1200 mg of D(-)penicillamine daily were superior to a standard regimen of therapy in rheumatoid arthritis. The higher dose did not produce significantly greater therapeutic benefit in the group of patients so treated, although individual patients sometimes improved more. The frequency of rashes, blood dyscrasias, and withdrawals from the trial increased withe dosage. It is concluded that D(-)penicillamine is a useful treatment that the daily dose should be as low as possible, and that it should be increased at infrequent intervals only, with due regard to the likelihood of further improvement in relation to an increased risk of adverse reactions.

Some of the factors influencing the likelihood of the appearance of adverse drug reactions in patients are identified and discussed. Ways of quantifying some of the risks of adverse reactions in different patients are demonstrated. It is pointed out that adverse reaction data can give valuable guidance for both day-to-day patient management and for the initiation or guidance of research projects. In this latter connection, this study highlights the difference in time of onset between aplastic anaemia and agranulocytosis, suggesting different mechanisms of reaction. The majority of adverse reactions occur during the first three weeks of treatment and it is during this time that patients must be most carefully supervised. The old patients should be watched with particular care. It is concluded that age, sex, disease being treated, length of treatment and even the geographical location where the patient lives, can affect the time, type, frequency and outcome of an adverse drug reaction.

The paper discusses of the results of treatment with preparations of phenylethylbiguanide (dibotin, meltrol, dipar, dibophen-retard), of butylbiguanide (silubin-retard, buforming-retard) and of dimethyl-biguanide (glucophage-retard). All these preparations were of prolonged action. The treatment was carried out in 242 patients. The saccharolytic action of the active agent contained in one tablet of each type of biguanide was approximately the same. Biguanides of prolonged action were highly effective in obese patients with diabetes mellitus of moderate severity. The best results were obtained in complex treatment with biguanides of prolonged action together with sulfonylurea preparations of the second generation. There were noted almost no toxic reactions from the use of biguanides up to 2 tablets a day.

419 patients with uncomplicated gonorrhoea were treated with sulphamethoxazole 4 g. combined with trimethoprim 0-8 g. divided into two doses with an 8-hr interval. The failure rate was 1-9 per cent. Parallel with this trial, 319 patients received pivampicillin 1-4 g. combined with probenecid 1 g,; the failure rate was 0-9 per cent. Side-effects were few, four patients in the first group and one in the second group developing a rash. No recurrences were noted in nine patients treated for tonsillar gonorrhoea with the trimethoprim-sulphamethoxazole schedule, while two recurrences were found in thirteen patients treated with pivampicillin-probenecid. The frequency of post-gonococcal urethritis was 7-7 per cent. in the pivampicillin-pro-benecid group against 3-4 per cent. in the trimethoprim-sulphamethoxazole group, a difference which was not statistically significant.

In reviewing the literature we discussed the problem, whether there is a correspondence between the morphological picture of acute gastritis and the clinical expression including a complex of symptoms "acute gastritis", which should better be called acute dyspepsia. There is no good accord.--The histological main features of acute gastritis are infiltration of mucosa by neutrophils and the leucodiapedesis. this acute gastritis is very seldom the cause of clinical symptoms of acute dyspepsia. Alcohol, spices or drugs may produce a "toxic damage" of the mucosa, but they do not cause an acute gastritis, just as little as some viral diseases or staphylococcal toxins.

Twenty-three patients with the chronic progressive or intermittent relapsing form of multiple sclerosis (MS) were treated with d-penicillamine over a period from 6 weeks to 12 months. Clinical effect was evaluated using Kurtzke's disability status scale with follow-up lasting from 7 weeks to 15 months. Fifteen patients remained unchanged, 7 became worse and 1 improved after the treatment. Administration of penicillamine to patients with MS resulted in an insignificant lowering of serum IgA, IgG and IgM levels. It is concluded that penicillamine neither prevented the occurrence of relapses nor slowed down the chronic progressive course of multiple sclerosis.

In a single centre double-blind crossover study in eighteen patients with established rheumatoid disease, a new slow release aspirin ("slow aspirin") was compared with plain aspirin with respect to patient tolerability and gastric mucosal damage as observed at gastroscopy. "Slow aspirin" was significantly better than plain aspirin with regard to gastroscopic findings. With "slow aspirin", the gastric mucosal appearances were definitely better in eight patients, worse in two, and eight showed no difference. There was a high incidence of gastric ulceration or erosions in the groups as a whole (39%) but few patients complained of dyspepsia. There was little difference in the ability of both plain and "slow aspirin" in controlling the patients' joint symptoms. Evidence has been provided to suggest that "slow aspirin" is less injurious to the gastric mucosa. In an attempt to reduce gastric mucosal damage due to prolonged aspirin treatment it is therefore concluded that "slow aspirin" merits consideration in the management of chronic rheumatoid disease.

Gastroduodenal intolerance is one of the major factors limiting the use of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) in patients with rheumatic diseases. We previously demonstrated that dyspepsia was not a marker for ulcer in NSAID users. We have now evaluated dyspeptic symptoms in 245 arthritic patients (receiving 13 different NSAIDs) from the practices of two rheumatologists. Fifty-seven patients (23%) gave a history of previous peptic ulcers. Heartburn, indigestion, or sour stomach at least once within the past year was present in 62.5%; 36.7% had experienced these symptoms within the previous 2 months and 28.6% within the previous week. Only 39 patients (15.9%) had experienced dyspepsia more than once daily within the previous month, and 8 (3.3%) had dyspepsia greater than 5 times/day. Thirty-four of the 39 patients with daily dyspepsia claimed to obtain relief with cimetidine or antacids (34 patients) or food (2 patients), whereas 3 had not discovered anything that provided relief. Women smokers were more likely than nonsmokers to experience dyspepsia (p less than 0.001). Neither men smokers nor those with a history of previous ulcer were more likely to have dyspepsia than nonsmokers or those without a history of ulcer (p greater than 0.5). We were not able to find a statistical association between any NSAID, or combination of NSAIDs, and the frequency of dyspepsia.

The therapeutic as well as the unwanted effects, in rheumatoid arthritis patients, of once weekly administration of 150 mg levamisole were compared, under double-blind conditions, with 3 50-mg daily doses of levamisole for 3 consecutive days weekly and placebo. The applied minimization method was used to assign patients to treatment groups so that all groups were comparable at the start of the trial. All patients were evaluated monthly, for 26 weeks. Three patients on the levamisole 3-day-weekly dosage interrupted their treatment because of side-effects. Except for the unwanted effects, the differences in the therapeutic efficacy in the 2 levamisole groups were not statistically significant. Twenty-one patients (3 in the levamisole once weekly administration group and 18 in the placebo group) interrupted their treatment because of inefficacy. Placebo was statistically less effective than the active drug. It is concluded that once weekly is as effective as 3-day-weekly administration of levamisole, but has fewer side-effects.

Sulfasalazine is of proven therapeutic value in chronic inflammatory bowel diseases (ulcerative colitis and Crohn's disease in the colon) of mild and moderate degrees. However, owing to adverse effects (allergy, dyspepsia), this drug often has to be withdrawn. The present work analyzes, in 704 patients with chronic inflammatory bowel disease, the frequency of such side effects that over a 15-year period necessitated withdrawal of sulfasalazine (Salazopyrin). A total of 17% of the patients developed dyspeptic manifestations, whereas extraintestinal manifestations, mainly exanthema and fever, occurred in 13%. Out of 121 patients with dyspeptic troubles, 107 had Salazopyrin replaced by EN Salazopyrin (dragées), and in 102 of them dyspepsia did not recur. Salazosulfadimidine (Azudimidine) was given to 48 patients who had developed extraintestinal manifestations when receiving sulfasalazine. Only 29% of these patients developed intolerance to this drug too. Generally, dyspepsia occurred within the first days after institution of treatment, extraintestinal manifestations after 1 to 3 weeks.

52 outpatients with rheumatoid arthritis or osteoarthritis were given benorylate (as the 40% suspension) in doses of up to 8 g daily. Peroids of medication were varied but some patients were given the drug for nearly 2 years. Assessments of clinical progress were made at regular intervals by recording both subjective and objective measurements including duration of morning stiffness, grip strength, joint size. Laboratory investigations include renal function tests, liver function tests, blood picture and occult blood. No serious side effect, attributable to benorylate was reported and it was concluded that the drug is satisfactory for the long term treatment of rheumatic diseases.

In 24 subjects without upper gastrointestinal lesions, gastric pH was measured from 30 min before until 90 min after the administration of diclofenac sodium (50 mg), piroxicam (20 mg), or 500 mg acetylsalicylic acid. In all these cases a drop of gastric pH was recorded, which started with all the drugs 15 min after their administration and lasted throughout the recording. Pre-treatment with rosaprostol (2 g given 30 min before the start of the trial) prevented the drop in pH. Twenty subjects with chronic joint diseases were divided into two groups in a cross-over double-blind randomized experimental design. One group received piroxicam (20 mg) + rosaprostol (2 g) daily; the other group was treated with piroxicam 20 mg + placebo. The patients were clinically reviewed every week in a month and questioned about their symptoms. Statistical analysis demonstrated that patients with articular diseases treated with NSAIDs + rosaprostol exhibited a frequency and severity of symptoms lower than those recorded in subjects receiving NSAIDs + placebo. Rosaprostol was found to be capable of antagonizing the variations of gastric acid output induced by the oral administration of NSAIDs, and to prevent and treat the occurrence of digestive disorders when given in combination with NSAIDs. These effects result from the action of rosaprostol on the mucosal barrier, and this cytoprotective action is confirmed by the present study with continuous measurements of gastric pH.

The long term efficacy and tolerability of sulphasalazine (SASP) in the treatment of 21 patients with active classical or definite rheumatoid arthritis (RA) were examined and compared with the effects of penicillamine in a similarly active group of RA patients. Nineteen of the 21 patients treated with SASP improved during the first 6 months as shown by significant changes in the clinical and laboratory variables. Clinical improvement was maintained for the remainder of the year. Improvement in laboratory variables was maintained at 9 months but showed some deterioration at 1 year. Six patients went into remission by the ARA criteria, and 16 were able to continue the drug at the end of 1 year. In addition SASP had a steroid-sparing effect in 4 of the patients on systemic steroids. No potentially dangerous side effects were encountered by the end of the first year, although 5 patients were withdrawn. Dyspepsia, nausea and abdominal discomfort were the most common side-effects, although rashes (3) and macrocytosis (2) also occurred. Eighteen of the 21 patients treated with penicillamine improved during 9 months, although there was some deterioration at 1 year. Eight patients were withdrawn because of side-effects - thrombocytopenia (5), nephrotic syndrome (1) and proteinuria (2). This study suggests that SASP has a disease modifying action maintained over a year and associated with low toxicity. It is a useful addition to the small number of second-line drugs with a possibly different mode of action.

Twenty-six patients with migraine attacks were treated for 3 to 16 months with flufenamic acid (125 mg four to six times per attack), an inhibitor of prostaglandin synthesis and action. In 25 patients the drug afforded symptomatic relief in 195 of 200 treated attacks. Side effects observed were mild dyspepsia (eight patients) and severe upper gastrointestinal symptoms (two patients). None of the eight patients treated with placebo reported any relief (20 attacks). The "common" antimigraine drugs afforded symptomatic relief in 12 of the patients, partial relief in seven, and no relief in seven. Treatment with flufenamic acid was based on the hypothesis that prostaglandins are involved in migraine attack and that the drug relieves migraine by inhibition of the vasoactivity of prostaglandins.

The elderly rheumatic patients and 7 healthy young persons received naproxen (Naprosyn, Syntex) 500 mg orally twice a day for 4 weeks. The serum concentrations were determined using mass fragmentography. After an initial 1,000-mg dose, no significant differences were found between the two groups in peak serum concentration, time to peak serum concentration, area below the serum concentration-time curve, volume of distribution, elimination half-life, or total body clearance of naproxen. At steady state, the median total through naproxen concentration was 50.5 mg/l in the elderly and 62.7 in the young (p = 0.08); the unbound concentration was 58 micrograms/l and 44 micrograms/l, respectively (p = 0.06). There was a significant inverse correlation between serum albumin and the free fraction of naproxen (R = -0.58, p = 0.01). The hepatic extraction ratio of naproxen is relatively low and it is suggested that the reduced protein binding in the elderly may conceal the age-related reduction in cellular activity. An estimated value of intrinsic clearance was reduced by 37% in the elderly patients. It is suggested to start naproxen at the lower end of its dose range in the elderly.

Some forms of arthritis cause few symptoms and little or no disability, while others cause severe pain, deformity and loss of function, and may even be fatal. Management must vary accordingly between the simple and the complex, the latter necessitating the use of potentially toxic agents. This article highlights some therapeutic approaches and emphasises the factors that influence the decision making process. Some areas of difficulty are discussed, particularly the treatment of dyspepsia in chronic arthritis.

Dyspeptic symptoms, gastrointestinal bleeding, or the development of anaemia without dyspepsia in patients treated with indomethacin may be manifestations of peptic ulceration. Such manifestations occur with suppositories as well as with capsules. The ulcers in the present series tended to be prepyloric, and often aroused the suspicion of malignancy. Symptoms were promptly relieved and radiological healing occurred rapidly after withdrawal of the drug.