|
Klikk
her for å åpne
artikkelen i
Adobe PDF-format
(Engelsk).
|
Effekt av soppmedisinen Nystatin
hos pasienter med diffuse symptomer.
En randomisert, dobbeltblind
studie med Nystatin versus placebo i allmennpraksis.
Heiko
Santelmann, Even Lærum, Jørgen Rønneviga, og Hans E Fagertunb,
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
Rønneviga,
and Hans
E Fagertunb,
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).
|
1
|
Have
you, at any time in your life, taken "broad spectrum"
antibiotics ?
|
0
|
3
|
|
2
|
Have
you taken tetracycline or other broad spectrum
antibiotics for one month or longer ?
|
0
|
3
|
|
3
|
Are
your symptoms worse on damp, muggy days or in mouldy places?
|
0
|
3
|
|
4
|
Do
you crave sugar ?
|
0
|
3
|
|
5
|
Do
you have a feeling of being "drained" ?
|
0
|
|
|
|
- occasional or mild
|
|
1
|
|
|
-
frequent or moderately severe
|
|
2
|
|
|
- severe or disabling
|
|
3
|
|
6
|
Are
you bothered with vaginal burning, itching or discharge (do you have similar symptoms from the penis) ?
|
0
|
|
|
|
- occasional or mild
|
|
1
|
|
|
- frequent or moderately severe
|
|
2
|
|
|
- severe or disabling
|
|
3
|
|
7
|
Are
you bothered by burning, itching or tearing of eyes ?
|
0
|
|
|
|
- occasional or mild
|
|
1
|
|
|
- frequent or moderately severe
|
|
2
|
|
|
- severe or disabling
|
|
3
|
|
|
|
|
|
|
|
total
score :
|
|
|
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.
|
SYMPTOM
|
Treatment
groups with mean proportional improvement
|
|
|
ND+N
|
PD+P
|
|
FATIGUE
OR LETHARGY
|
21
|
13
|
|
|
FEELING
OF BEING "DRAINED"
|
22
|
16
|
|
|
DEPRESSION
|
16
|
4
|
|
|
POOR
MEMORY
|
10
|
8
|
|
|
FEELING
"SPACEY" OR "UNREAL"
|
23
|
14
|
|
|
INABILITY
TO MAKE DECISIONS
|
20
|
16
|
|
|
NCOORDINATION
|
19
|
5
|
|
|
DIZZINESS
/ LOSS OF BALANCE
|
26
|
6
|
*
|
|
INABILITY
TO CONCENTRATE
|
15
|
0
|
|
|
IRRITABILITY
OR JITTERINESS
|
14
|
7
|
|
|
FREQUENT
MOOD SWINGS
|
15
|
2
|
|
|
ATTACKS
OF ANXIETY OR CRYING
|
27
|
6
|
*
|
|
INSOMNIA
|
17
|
15
|
|
|
SHAKING
OR IRRITABLE WHEN HUNGRY
|
26
|
0
|
*
|
|
HEADACHE
|
12
|
0
|
|
|
PRESSURE
ABOVE EARS
|
19
|
8
|
|
|
BURNING
OR TEARING OF EYES
|
26
|
-3
|
*
|
|
SPOTS
IN FRONT OF EYES OR ERRATIC VISION
|
22
|
8
|
|
|
NASAL
CONGESTION OR POST NASAL DRIP
|
14
|
7
|
|
|
NASAL
ITCHING
|
9
|
13
|
|
|
DRY
MOUTH OR THROAT
|
10
|
4
|
|
|
RASH
OR BLISTERS IN MOUTH
|
14
|
13
|
|
|
SORE
THROAT
|
11
|
20
|
|
|
LARYNGITIS,
LOSS OF VOICE
|
14
|
13
|
|
|
COUGH
OR RECURRENT BRONCHITIS
|
11
|
15
|
|
|
PAIN
OR TIGHTNESS IN CHEST
|
13
|
14
|
|
|
BAD
BREATH
|
4
|
16
|
|
|
INDIGESTION
OR HEARTBURN
|
10
|
11
|
|
|
ABDOMINAL
PAIN
|
15
|
-2
|
|
|
CONSTIPATION
AND / OR DIARRHEA
|
19
|
3
|
*
|
|
MUCUS
IN STOOLS
|
16
|
6
|
|
|
RECTAL
ITCHING
|
17
|
13
|
|
|
BLOATING,
BELCHING
OR
INTESTINAL
GAS
|
17
|
4
|
|
|
FOOD
SENSITIVITY OR
INTOLERANCE
|
7
|
-9
|
|
|
CHRONIC
RASHES OR
ITCHING
|
25
|
8
|
*
|
|
NUMBNESS,
BURNING OR
TINGLING
|
26
|
17
|
|
|
FOOT,
HAIR OR BODY ODOR NOT RELIEVED BY WASHING
|
1
|
16
|
|
|
MUSCLE
ACHES
|
20
|
6
|
|
|
MUSCLE
WEAKNESS OR
PARALYSIS
|
17
|
14
|
|
|
PAIN
AND / OR SWELLING IN JOINTS
|
12
|
18
|
|
|
VAGINAL
BURNING, ITCHING
OR DISCHARGE
|
31
|
15
|
|
|
LOSS
OF SEXUAL
DESIRE OR
FEELING
|
11
|
11
|
|
|
URINARY
FREQUENCY OR
URGENCY
|
22
|
6
|
|
|
BURNING
ON URINATION
|
24
|
11
|
| |