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Effekt av soppmedisinen Nystatin hos pasienter med diffuse symptomer.

En randomisert, dobbeltblind studie med Nystatin versus placebo i allmennpraksis.

 Heiko Santelmann, Even Lærum, Jørgen Rønnevig^a, og Hans E Fagertun^b, 

Institutt for allmenn- og samfunnsmedisin, Universitet i Oslo, 0317 Oslo,
^a Alpharma AS, 0212 Oslo
^b Parexel Medstat AS, 2001 Lillestrøm, Norway. 

Korrespondanse til: Dr. Heiko Santelmann, Holmenveien 1, N-0374 Oslo, E-mail: drheiko@online.no 

Bakgrunn. Det har blitt hevdet at en behandling mot sopper er effektiv for pasienter med diffuse symptomer fra forskjellige organer og til og med vel definerte sykdommer som tradisjonelt ikke settes i sammenheng med sopper. Det har blitt antatt at dette kunne skyldes overfølsomhet mot soppenes proteiner og toksiner. 

Metoder. Vi gjennomførte en fireukers randomisert, dobbeltblind, placebo-kontrollert studie på 116 personer, selektert ved et spørreskjema med syv spørsmål for å finne ut om kapsler med antisoppmiddelet Nystatin var bedre enn placebo. Ved starten av studien kunne forsøkspersonene selv velge mellom sitt vanlige kosthold eller en diett fri for sukker og gjær. Slik fikk vi fire forskjellige undergrupper: Nystatin + diett (ND); placebo + diett (PD); Nystatin (N) og placebo (P).

Resultater. Nystatin var signifikant bedre enn placebo til å redusere den totale symptom score (p < 0.003). Bedringen var signifikant på seks av de 45 individuell rapporterte symptomer (p < 0.01). Alle tre grupper med aktiv behandling reduserte sine totale symptom score signifikant ( p < 0.0001), mens placebo-behandlingen ikke hadde noen effekt (p < 0.83). Effekten av dietten var signifikant, både i Nystatin- (ND>N) og placebo-gruppene (PD>P).

Konklusjon. Nystatin reduserer lokale og systemiske symptomer hos personer med mistenkt soppoverfølsomhet (Fungus-Related Desease, FRD), som ble selektert ved hjelp av et spørreskjema (FRDQ-7) bedre enn placebo. Denne positive effekten blir sannsynligvis ytterligere forsterket av en sukker- og gjærfri diett. 

Family Practice Vol. 18, No. 3, 258-265 © Oxford University Press 2001 

Effectiveness of nystatin in polysymptomatic patients.

A randomised, double-blind trial with nystatin versus placebo in general practice. 

Heiko Santelmann, Even Lærum, Jørgen Rønnevig^a, and Hans E Fagertun^b,

Department of General Practice and Community Medicine, University of Oslo, 0317 Oslo,
^a Alpharma AS, 0212 Oslo and ^b Parexel Medstat AS, 2001 Lillestrøm, Norway. 

Correspondence to: Dr. H. Santelmann, Holmenveien 1, 0374 Oslo, Norway. E-mail: drheiko@online.no  

Santelmann H, Lærum E, Rønnevig J and Fagertun HE. Effectiveness of nystatin in polysymptomatic patients. A randomised, double-blind trial with nystatin versus placebo in general practice. Family Practice 2001; 18: 258–265. 

Received 15 October 1999; Revised 10 October 2000; Accepted 8 January 2001.  

Abstract  

 
Background. Antifungal therapy has been claimed to be effective in polysymptomatic patients with diffuse symptoms from multiple body systems and even well defined diseases, traditionally not related to fungi. Hypersensitivity to fungus proteins and mycotoxins has been proposed as the cause.

Methods. We conducted a 4-week randomised, double-blind, placebo-controlled study in 116 individuals selected by a 7-item questionnaire to determine whether the antifungal agent nystatin given orally was superior to placebo. At the onset of the study, the patients were free to select either their regular diet or a sugar- and yeast-free diet, which resulted in four different subgroups: nystatin + diet (ND); placebo + diet (PD); nystatin (N); and placebo (P).

Results. Nystatin was significantly better than placebo in reduction of the overall symptom score (P < 0.003). In six of the 45 individually recorded symptoms, the improvement was significant (P < 0.01). All three active treatment groups reduced their overall symptom scores significantly (P < 0.0001), while the placebo regimen had no effect (P = 0.83). The benefit of diet was significant within both the nystatin (ND > N) and the placebo groups (PD > P).

Conclusions. Nystatin is superior to placebo in reducing localised and systemic symptoms in individuals with presumed fungus hypersensitivity as selected by a 7-item questionnaire. This superiority is probably enhanced even further by a sugar- and yeast-free diet.

Keywords. Candida albicans, general practice, nystatin, polysymptomatic, yeast. 

Introduction  

 
It is generally known by primary care physicians that about half of the medical evaluations of out-patient polysymptomatic patients fail to elucidate a specific causative disease. The symptom patterns often suggest the possibility of a systemic disease process involving multiple body systems. The patient may complain of chronic fatigue, poor concentration, impaired memory, respiratory tract symptoms, gastrointestinal distress, pains in muscles and joints, skin problems, recurrent infections, urogenital problems, etc. All too often, the diagnosis given to the patient is in terms such as ‘stress’, ‘psychosomatic symptoms’ or an assurance that ‘there is nothing physically wrong’.

A number of these patients have been reported to have had an unexpected marked improvement in their symptoms when antifungal drugs were administered to treat various fungal infections. In addition, there are increasing numbers of reports that drugs possessing antifungal activity have been remarkably effective in a number of well-defined diseases.¹ There are also reports of cures of chronic fatigue, allergic conditions including bronchial asthma, pre-menstrual distress, multiple sclerosis and autism² with a regimen of diet free from yeasts, moulds and sugars,^3,4 antifungal medication and sometimes desensitisation by Candida extract.⁵ An immunological response to fungal antigens or a reaction to fungal toxins (mycotoxins), yeast-produced alcohols and other metabolic products have all been suggested as an explanation for these phenomena.^3,6

Many of the reported benefits have occurred with the use of nystatin, an antifungal agent usually prescribed for the treatment of Candida albicans infections, the most common pathogenic fungus in humans. This has led to a belief that C.albicans must be the cause of the underlying disorder, a conclusion which has ignored the fact that nystatin is actually a broad spectrum antifungal antibiotic effective against many different species of fungi.

The proponents in the USA for a C.albicans aetiology of the involved symptoms and/or diseases have called the phenomena ‘The yeast connection’, ‘Candidiasis hypersensitivity syndrome’ and, most recently, ‘Candida-related complex’ (CRC). In the UK, the entity is often referred to as ‘The gut fermentation syndrome’.

The Candida hypothesis lacks a specific diagnostic test to support the validity of the concept. The diagnostic methods are limited to a combination of patient history, questionnaires, provocative challenge to yeast antigens and response to a broad treatment programme. There are no published controlled studies supporting a positive effect of antifungal medication or antifungal diet alone on patients thought to have CRC.^7–9  

In this study, we use the term ‘fungus-related disease’ (FRD) for a condition showing improvement with antifungal treatment. It was not the purpose of this study to identify the specific fungal species that may be playing an etiological role. Rather, the objectives of our study were to determine whether the antifungal agent nystatin, administered orally to patients with presumed FRD, was superior to placebo as assessed by change in overall symptom score and in specific symptoms from baseline, and to evaluate the influence of diet on the outcome. We believe that our research has provided results which are consistent with the stated objectives of this study. 

Methods 

 
The study took place at an urban (Oslo) and a suburban (Mandal) centre. Volunteers were invited through the press from all parts of Norway. FRD was verified by using the questionnaire FRDQ-7 (Table 1). This questionnaire was developed to identify responders to nystatin and/or antifungal diet in an open study based on a historic group of 380 patients previously selected by symptoms and a CRC questionnaire⁴ to classify the clinical diagnosis of FRD according to a sustained beneficial effect of nystatin and/or a sugar- and yeast-free diet. In order to determine the relevance of individual items of the CRC scheme, a gradual statistical discrimination analysis was carried out and resulted in the 7-item questionnaire (FRDQ-7) characterising the historic patient population (H Santelmann, E Lærum and J Rønnevig, unpublished). 

TABLE 1
Questionnaire FRDQ-7

Selection criteria
Within 3 months, 1620 persons volunteered. Of these, 954 were excluded due to being aged under 18 or over 75 years or because they were pregnant or lactating, dependent on a diet, or taking antibiotics, corticosteroids or other immunosuppressive agents orally or systemically during the 2 weeks prior to the start of the study. They were also excluded if they were receiving oral antimycotics and/or a sugar- and yeast-free diet 2 months prior to assessment of eligibility, or if they were unable to attend for two control evaluations. Five hundred and forty-six volunteers were excluded due to a low FRDQ-7 score (<10 out of 21). Among the 120 persons enrolled, 103 were women and 17 were men, with a mean age of 39 years (range 22–69). 

Study design
The study was carried out as a double-blind, randomised placebo-controlled, multicentre trial with block design and diet as block factor. Patients were randomly assigned to receive either nystatin or placebo for a period of 4 weeks (Fig. 1). This part of the study was double-blind and the codes were stored sealed until all data from all patients were delivered to an independent statistical institute for evaluation. 

FIGURE 1
Study design

 
Treatment regimens
Two hundred milligrams of nystatin powder (1 112 000 IU) or cornflour were packaged in transparent gelatine capsules. Blinded observers could not detect any difference between the two types of capsules. Patients were instructed to swallow one capsule unopened, three times a day, after meals, with a non-alcoholic liquid for 4 weeks. In cases of adverse effects, the patients were instructed to decrease the dose to one capsule daily, increase to three capsules within 1 week and continue for 4 weeks altogether. 

At the start of the study, patients were free to choose between a modified sugar- and yeast-free diet, in compliance with a food list, or their regular diet for the period of the study. We used this approach because a double-blind diet regimen appeared to be extremely difficult to manage and exceeded the capacity of our study. We chose voluntary selection of diet to enhance compliance. By this means, we obtained four subgroups: nystatin plus sugar- and yeast-free diet (ND), placebo plus sugar- and yeast-free diet (PD), nystatin (N) and placebo (P). 

Patients in the diet groups obtained a list of foods to avoid, those containing sugars, yeasts or moulds, i.e. honey, jam, sweets, ice cream, lemonade, fruit juices (except freshly prepared), alcohol, cheese, and breads and pastries containing yeast. Additionally, they were asked not to consume more than half a glass of milk or yoghurt daily. Artificial sweeteners such as aspartame, saccharin and xylitol, and bread made with baking powder were allowed. 

Evaluation
Upon entry to the study and 4 weeks after starting the capsules, the patients filled in a questionnaire referring to 45 different symptoms derived from the 70 questions in the CRC questionnaire which were related to localised and systemic symptoms (Table 3). The scores ranged from 0 to 3 (absent, mild, moderate or severe). Improvement in individual symptoms was noted on the basis of a decline in the severity grade. The overall symptom score was calculated as the sum of the severity grades of all 45 symptoms. Since deterioration resulted in a higher score after treatment, it was conceivable that patients could achieve negative symptom scores.