- Email: [email protected]
Efficacy and tolerability of potato juice in dyspeptic patients: A pilot study
ARTICLE IN PRESS
Phytomedicine 13 (2006) 11–15 www.elsevier.de/phymed
Efficacy and tolerability of potato juice in dyspeptic patients: A pilot study S. Chrubasika,b,, C. Chrubasika, T. Tordac, A. Madischd a
Department of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany Herbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, NSW 2006 c School of Medical Sciences, University of New South Wales, Sydney, Australia d Medical Department I, Technical University Hospital, Dresden, Mommsenstr. 7, 01062 Dresden, Germany b
Received 8 February 2005; accepted 2 March 2005
Abstract In Europe, use of potatoes (Solani tuberosi tuberecens) is a traditional remedy for stomach complaints. We performed a pilot study on the effectiveness and tolerability of freshly squeezed potato juice in patients suffering from dyspeptic symptoms. After informed written consent, 441 patients with various dyspeptic symptoms were enrolled, to drink for 1 week twice daily 100 ml or more of potato juice (Biottas), if complaints persisted, a further 100 ml was recommended. Validated outcome measures included the gastrointestinal symptom (GIS) profile, a disease-specific health assessment questionnaire (QOLRAD) and self-rated treatment success (efficacy, a 5-point Likert Scale). The study was completed by 42 patients. The GIS and QOLRAD scores improved significantly by 41.9740.8% (p ¼ 0:001) and 50.7736.1% (po0:001), respectively (ITT); the absolute values changed from 11.575.1 to 6.375.3 (GIS) and 62.0725.7 to 32.0728.8 (QORAD). Sixteen, 18 and 26 patients, respectively, rated the effectiveness of the treatment as very good or good on the GIS, QOLRAD (improvements 460%) and on efficacy, respectively. Poor treatment success was achieved in 13 (GIS), 11 (QOLRAD) and 10 (Efficacy), not necessarily by the same patients. Since about two-thirds of the patients benefited to some extent from the treatment, potato juice in its present formulation may be useful for self-treatment. However, placebo-controlled studies with a longer treatment period are needed to confirm this. r 2005 Elsevier GmbH. All rights reserved. Keywords: Solanum tuberosum (potato) juice; Dyspeptic patients; Efficacy; Tolerability
Corresponding author. Department of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany. Tel.: +49 761 2036853; fax: +49 761 2036858. E-mail address: [email protected] (S. Chrubasik). 1 Forty-five subjects were originally enrolled. One patient withdrew consent after completing the study and was treated as if she had not been enrolled.
0944-7113/$ - see front matter r 2005 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2005.03.005
Introduction Dyspepsia, defined as pain and/or discomfort centered in the upper abdomen, is remarkably common, occurring in 20–40% of the Western population (NN., 1998; Jones et al., 1990; Talley et al., 1992). Physicians in
ARTICLE IN PRESS 12
S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
primary care and managed care organizations are increasingly confronted with the problem of managing dyspepsia and repeated consultations, investigations, courses of antisecretory agents, and time lost from work (Armstrong, 1996) cause a significant drain on our health system. Although dyspeptic symptoms are mainly treated with synthetic medications, freshly squeezed potato juice is used as traditional medicine for hyperacidic stomach complaints in Germany and Switzerland, because of supposed antispasmodic and antacid effects (NN, 1993). Main known active constituents include two steroid alkaloid glycosides (e.g. a-chaconine und a-solanine) which in properly stored potatoes do not reach concentrations of more than 10 mg/100 g. They can be used as marker substances for the HPLC-fingerprint analysis of the potato juice. Whether they contribute, however, to the antidyspeptic activity of the juice, is not clear. Higher steroid alkaloid concentrations, which may cause toxic, even fatal events are not found in marketed potatoes, after conventional harvest and storage (NN, 1993). Our objective was to gather preliminary data on the effectiveness and tolerability of a juice prepared from organically cultivated potatoes, in an observational study that was in conformity with the Regulatory Requirements in Switzerland.
mAU 14
Methods Patients suffering from dyspeptic symptoms that had lasted more than 12 weeks in the preceding year were recruited from the outpatient clinic of one of the authors (SC). They were given an information leaflet and were invited to participate in a 1 week study on the effectiveness and tolerability of a juice prepared from potatoes. Exclusion criteria comprised current or recent participation in a clinical study, serious concurrent illness, a history of drug or alcohol abuse, pregnancy or lactation, known allergy to potatoes and anticipated difficulties with language or co-operation. The juice was produced by Biotta AG, Ta¨gerwilen/ Switzerland from Solani tuberosi tuber recens harvested in the area of Ta¨gewilen and the south of Germany close to the Swiss border. The potatoes were cleaned of soil, washed, selected, mashed and squeezed, and then treated with amylases (to initiate metabolism into polysasacharides and to improve the taste) and lactic acid (acidifier, to decrease the pH and to allow pasteurization instead of sterilization). After further treatment with amylases, it was therefore pasteurized (89 1C) and immediately bottled (Fig. 1). The first 45 patients who gave written consent were enrolled. Once their baseline characteristics had been
DAD1 B, Sig=202,8 Ref=260,40 (05-02-04.B\004-0201.D)
9.859 ------- a-solanine
10 8
4.192
6 4
11.495 ------- a-chaconine
12
2 0 2
4
6
8
Fig. 1. HPLC-fingerprint of the proprietary potato juice. Column: LiChrospher RP 8, endcapped, 5 mm 125 4 mm (Merck) Solvent A: 0.02 M Phosphatebuffer pH 7.0 Solvent B: Acetonitril HPLC gradient grade (Promochem No. 9128) Mobile phase: Solvent A/Solvent B 70:30 (V/V) Temperature: 40 1C Flow rate: 1.0 ml/min, Injection volume: 20 ml, Detection: 202 nm UV a-Solanine: (No. 85472), a-Chaconine (No. 22455), Fluka AG CH-9471 Buchs
10
12
14 min
ARTICLE IN PRESS S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
recorded, they were given 4 500 ml of fresh potato juice and were recommended to drink 100 ml in the morning half an hour before breakfast and at night before going to bed. They were advised to continue their current dyspepsia medication if they took any. If symptoms bothered them during the day, patients were advised to have one or more 100 ml cups of additional juice. Three outcome measures were recorded, the gastrointestinal symptom (GIS) profile (Holtmann et al., 2004), a 10 symptom profile, each symptom scored 0–4 (max score 40); and a recently validated disease-specific quality of life measure (QOLRAD, Madisch et al., 2003), a 25 item questionnaire, each item scored 0–7 (max. 175) and, self-rated treatment success (Efficacy) on a 0–4 Likert scale (0 best, 4 worst). Statistical analyses were carried out using SPSS (SPSS Inc., Chicago ILL. 60611). One patient withdrew consent and was not included in the analysis. All variables were tested for normal distribution by the Kolmogorov–Smirnof test. If the distribution differed significantly from normal, only non-parametric tests were applied. Where scores on a 5-point scale were used, again non-parametric tests were employed. Correlations of parametric variables were tested using Pearson’s product moment correlation and those of non-parametrics by Kendall’s t-b. The before and after QOLRAD and GIS were converted to a percent change scale, (value beforevalue after/value before)100. Drop-outs were included in the analyses with their initial values used for after treatment outcomes (for ‘‘intention-totreat’’, ITT analysis). Per protocol (PP) data for the 42 patients were also included. Changes in GIS or QOLRAD were tested against individual symptoms, diurnal distribution of the symptoms, the presence or absence of reflux, reflux medications, other GI medications, other synthetic medications as a collective group, family history of GI disease, Helicobacter infection, concurrent disease or irritants (alcohol, tobacco or spices). Treatment success was defined as ‘‘very good’’, ‘‘good’’, ‘‘moderate’’, ‘‘slight’’ and ‘‘poor’’ by using 480%, 60–79.99%, 40–59.99%, 20–39.99 and o19.99% for the % change in the outcomes. In the categorical classification of outcomes the drop-outs were included in the ‘poor’ group. The confidence level for rejecting null hypotheses was taken as 95% (po0:05).
13
by 42 patients. Two patients dropped out because of insufficient relief of complaints (one suffered from intolerable heartburn after consumption of the juice). The baseline characteristics of the 44 patients (10 men, 34 women) who entered the study are summarized in Table 1 together with the duration of their symptoms. Forty-two patients suffered from concomitant reflux symptoms such as retrosternal discomfort and regurgitation but not dominating the clinical picture. Thirteen patients received acid suppressive therapy (proton pump
Table 1.
Baseline characteristics of the 44 patients
a
Age (years) Weighta (kg) Sizea (cm)
64711 70712 16879
Duration (months) of: Chronic diseasea Acute exacerbationa
1567142 22729
Diurnal distribution of symtoms Morningb Noonb Afternoonb Eveningb At nightb Continuous complaintsb Intermittant complaintsb
10 28 4 19 12 5 40
Risk factors Regular alcohol consumptionb Regular nicotine consumptionb Regular consumption of spicesb Use of synthetic medicationsb Intercurrent diseasesb 11 relative GI complaintsb Family history of stomach Cab Family history of colon/rectum Cab
11 7 2 18 34 15 9 4
a
Mean7SD. Number of patients.
b
Total Score
GIS
QOLRAD
75 62 60
± 25.7
45 32 30
Results
15
11.5 ± 5.1
0
One patient withdrew her permission to use the data after successful treatment on her family doctor advice. This patient was excluded from all results and treated as if she had not been enrolled. The study was completed
± 28.8
Baseline
6.3 ± 5.3 Day 7
Fig. 2. The total GIS and QOLRAD scores before and after 7 days potato juice therapy, mean7SD. The absolute values decreased significantly (both po0:001).
ARTICLE IN PRESS 14
Table 2.
S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
Frequency distribution of outcome classes for all three outcome variables (GIS, QOLRAD % change and efficacy) GIS group
Very good Good Moderate Slight Poor Total
QOLRAD group
Number
%
8 8 8 7 13 (11) 44 (42)
18 18 18 16 30 —
(19) (19) (19) (38) (31)
Efficacy
Number
%
12 6 6 9 11 (9) 44 (42)
27 14 14 20 25 —
(29) (14) (14) (21) (21)
Number
%
9 17 6 2 10 (8) 44 (42)
20 39 14 5 23 —
(21) (40) (14) (5) (24)
Percent changes in GIS and QOLRAD are classed as poor: 0–19.99, slight: 20–39.99, moderate: 40–59.99, good: 60–79.99, and very good: 80–100%. Self-rated efficacy was rated on a very good ¼ 0 to poor ¼ 4, scale. The two subjects who dropped out are classed as ‘poor’ responders on all scales (ITT). Forty-four subjects are included. The numbers in brackets refer to the same data, but on a ‘Per Protocol’ treatment of 42 subjects.
inhibitors n ¼ 10 (one took in addition an antacid, one a prokinetic), antacids n ¼ 2, H2-blocker n ¼ 1). Contrary to instructions, seven patients discontinued their current dyspepsia medication. In five of these patients, symptoms had improved on treatment with potato juice. One of the two patients who consumed only one cup of juice per day instead of two or more cups was satisfied with the treatment. The GIS and QOLRAD scores improved significantly by 41.9740.8% or 44.0740.7% (mean7SD; CI95 31.2–56.5) and 50.7736.1% or 53.1735.1% (CI95 41.9–63.9), respectively (ITT or PP, both po0:001). The absolute changes are shown in Fig. 2. Concomitant reflux symptoms had improved in 19 of the 41 patients. The frequency distributions of the outcome classes are listed in Table 2: 16, 18 and 26 patients rated the effectiveness of the treatment as very good or good on the GIS, QOLRAD (improvements 460%) and on the self-rated efficacy, respectively. Poor treatment success was reported by 13 (GIS), 11 (QOLRAD) and 10 (efficacy) patients, not necessarily in the same subjects. In the poor outcome class, 4 subjects had greater GIS and 4 greater QOLRAD scores after treatment than before and, 3 (GIS) and 1 (QOLRAD) subjects had no change in the scores. None of the individual GIS symptoms showed significantly greater improvement than others; of the irritants, alcohol and tobacco did not affect the outcome variables significantly. Only the use of spices (regularly used by two patients) had a significant effect, affecting the % change in QOLRAD significantly (po0:02; the % change in GIS was not significant ðp ¼ 0:168Þ.2
2 Because only two subjects used spices regularly, this ‘significant’ result must be treated cautiously. By testing for 40 possible differences, the probability of rejecting once a true null hypothesis is about 0.81. This problem of multiple tests is well recognized when performing ANOVA’s, but it also applies here.
Table 3. Correlations of the outcome variables (GIS, QOLRAD % change and efficacy) and the variables, efficacy, taste and tolerability)
(a) GIS QOLRAD Efficacy
GIS
QOLRAD
Efficacy
— o0.001 o0.001
0.626 — o0.001
0.623 0.702 —
Efficacy
Tolerability
Taste
— 0.001 0.001
0.493 — o0.001
0.498 0.630 —
(b) Efficacy Tolerability Taste
The data shown in the ‘‘north–east’ triangle are the Kendall’s correlation coefficients while those in the south–west are their significance. The fraction of the variance explained by the correlation is equal to the square of the correlation coefficient.
Efficacy self-rating scores correlated poorly with objective symptom scores or QOLRAD or with tolerability or taste. Not surprisingly, the taste and tolerability of the juice correlated a little better (Table 3). All these correlations were significant po0:01. The various cross tabulations of self-rated efficacy, tolerability and taste and further details are placed on the webpage http://remed-chrubasik.uniklinik-freiburg.de. The reports of the adverse reactions were scrutinized by an independent investigator. Eight patients suffered from adverse events, which were possibly related to the potato juice. One complained of intolerable heartburn, three of meteorism one of whom also developed diarrhea and one complained of increased mucus production. Three patients suffered from upper respiratory tract infections during the study.
ARTICLE IN PRESS S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
15
Discussion
References
Alternative health care use is common in patients suffering from dyspeptic symptoms (Koloski et al., 2003). Our results provide some evidence that potato juice may help to alleviate dyspeptic complaints and to improve the quality of life. Based on our data – % change in GIS or QOLRAD, or the absolute changes in scores – 16 (GIS), 18 (QOLRAD) and 26 (self-rated efficacy) of the subjects had very good or good improvement. Two-thirds of the patients experienced at least some improvement and about half benefited considerably. Potato juice in its present formulation may therefore have a place in self-treatment of dyspeptic symptoms, before starting synthetic medication; this is especially important to patients who prefer a natural product to a synthetic one. However, since complete relief of complaints was achieved in only 20% of the patients, greater concentration of the active principle of the potato juice for a proprietary preparation may be desirable and produce a product that might compete with synthetic medication. Although two-thirds of the patients rated taste as excellent (n ¼ 12) or good (n ¼ 20) and the taste of the juice had no statistical impact on its effectiveness, improvement in taste of the juice may increase its acceptability to patients (see webpage). A number of clinical trials indicate that herbal medicinal products do play a role in the treatment of non-ulcer dyspepsia, e.g. combination preparations containing peppermint and caraway (Thompson and Ernst, 2002). A meta-analysis on a proprietary product composed of fresh plant extract of Iberis amara and of eight other herbal extracts demonstrated a highly significant overall therapeutic effect in functional dyspepsia (Gundermann et al., 2003; Madisch et al., 2004). Artichoke leaf extract may be another alternative as shown by Holtmann et al. (2003). The fact that seven of the 15 patients on reflux medications discontinued the synthetics on their own may indicate that there is still a need for effective dyspepsia phytomedicines. Dyspepsia has shown to impair health-related quality of life compared with the general healthy population (Chang 2004). Since the different dyspepsia outcome measures (GIS, QOLRAD and self-rated efficacy) reflect different dimensions of the complaints, all three measures and in particular a quality of life measure, should be included when evaluating the effectiveness of phytomedicines for upper gastrointestinal complaints.
Armstrong, D., 1996. Helicobacter pylori infection and dyspepsia. Scand. J. Gastroenterol. 31 (Suppl. 215), 38–47. Chang, L., 2004. Review article: epidemiology and quality of life in functional gastrointestinal disorders. Aliment. Pharmacol. Ther. 20 (Suppl. 7), 31–39. Gundermann, K.J., Godehardt, E., Ulbrich, M., 2003. Efficacy of a herbal preparation in patients with functional dyspepsia: a meta-analysis of double-blind, randomized, clinical trials. Adv. Ther. 20, 43–49. Holtmann, G., Adam, B., Haag, S., Collet, W., Grunewald, E., Windeck, T., 2003. Efficacy of artichoke leaf extract in the treatment of patients with functional dyspepsia: a six-week placebo-controlled, double-blind, multicentre trial. Aliment. Pharmacol. Ther. 18, 1099–1105. Holtmann, G., Adam, B., Frote, E., Saadat-Gilani, K., Vinson, B., 2004. Validation of the gastrointestinal symptom score (GIS) in patients with functional dyspepsia. Z. Gastroenterol. 42, T1179. Jones, R.H., Lydeard, S.E., Hobbs, F.D., Kenkre, J.E., Williams, E.I., Jones, S.J., Repper, J.A., Caldow, J.L., Dunwoodie, W.M., Bottomley, J.M., 1990. Dyspepsia in England and Scotland. Gut 31, 401–405. Koloski, N.A., Talley, N.J., Huskic, S.S., Boyce, P.M., 2003. Predictors of conventional and alternative health care seeking for irritable bowel syndrome and functional dyspepsia. Aliment. Pharmacol. Ther. 17, 841–851. Madisch, A., Kulich, K.R., Malfertheimer, P., Ziegle, K., Bayerdo¨rffer, E., Miehlke, S., Labenz, J., Carlsson, J., Wiklund, I.K., 2003. Impact of reflux disease on general and disease-related quality of life – evidence from a recent comparative methodological study in Germany. Z. Gastroenterol. 41, 1137–1143. Madisch, A., Holtmann, G., Mayr, G., Vinson, B., Hotz, J., 2004. Treatment of functional dyspepsia with a herbal preparation. A double-blind, randomized, placebo-controlled, multicenter trial. Digestion 69, 45–52. NN, 1993. Solani tuberosi tuber recens (Kartoffelknolle). In: Ha¨nsel, R., Keller, K., Rimpler, H., Schneider, G. (Eds.), Handbuch der Pharmazeutischen Praxis. Band 6, Drogen P-Z, pp. 749–750. NN, 1998. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 114, 579–581. Talley, N.J., Zinsmeister, A.R., Schleck, C.D., Melton, L.J., 1992. Dyspepsia and dyspepsia subgroups: a populationbased study. Gastroenterology 10, 1259–1268. Thompson, C.J., Ernst, E., 2002. Systematic review: herbal medicinal products for non-ulcer dyspepsia. Aliment. Pharmacol. Ther. 16, 1688–1699.
Phytomedicine 13 (2006) 11–15 www.elsevier.de/phymed
Efficacy and tolerability of potato juice in dyspeptic patients: A pilot study S. Chrubasika,b,, C. Chrubasika, T. Tordac, A. Madischd a
Department of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany Herbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, NSW 2006 c School of Medical Sciences, University of New South Wales, Sydney, Australia d Medical Department I, Technical University Hospital, Dresden, Mommsenstr. 7, 01062 Dresden, Germany b
Received 8 February 2005; accepted 2 March 2005
Abstract In Europe, use of potatoes (Solani tuberosi tuberecens) is a traditional remedy for stomach complaints. We performed a pilot study on the effectiveness and tolerability of freshly squeezed potato juice in patients suffering from dyspeptic symptoms. After informed written consent, 441 patients with various dyspeptic symptoms were enrolled, to drink for 1 week twice daily 100 ml or more of potato juice (Biottas), if complaints persisted, a further 100 ml was recommended. Validated outcome measures included the gastrointestinal symptom (GIS) profile, a disease-specific health assessment questionnaire (QOLRAD) and self-rated treatment success (efficacy, a 5-point Likert Scale). The study was completed by 42 patients. The GIS and QOLRAD scores improved significantly by 41.9740.8% (p ¼ 0:001) and 50.7736.1% (po0:001), respectively (ITT); the absolute values changed from 11.575.1 to 6.375.3 (GIS) and 62.0725.7 to 32.0728.8 (QORAD). Sixteen, 18 and 26 patients, respectively, rated the effectiveness of the treatment as very good or good on the GIS, QOLRAD (improvements 460%) and on efficacy, respectively. Poor treatment success was achieved in 13 (GIS), 11 (QOLRAD) and 10 (Efficacy), not necessarily by the same patients. Since about two-thirds of the patients benefited to some extent from the treatment, potato juice in its present formulation may be useful for self-treatment. However, placebo-controlled studies with a longer treatment period are needed to confirm this. r 2005 Elsevier GmbH. All rights reserved. Keywords: Solanum tuberosum (potato) juice; Dyspeptic patients; Efficacy; Tolerability
Corresponding author. Department of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany. Tel.: +49 761 2036853; fax: +49 761 2036858. E-mail address: [email protected] (S. Chrubasik). 1 Forty-five subjects were originally enrolled. One patient withdrew consent after completing the study and was treated as if she had not been enrolled.
0944-7113/$ - see front matter r 2005 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2005.03.005
Introduction Dyspepsia, defined as pain and/or discomfort centered in the upper abdomen, is remarkably common, occurring in 20–40% of the Western population (NN., 1998; Jones et al., 1990; Talley et al., 1992). Physicians in
ARTICLE IN PRESS 12
S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
primary care and managed care organizations are increasingly confronted with the problem of managing dyspepsia and repeated consultations, investigations, courses of antisecretory agents, and time lost from work (Armstrong, 1996) cause a significant drain on our health system. Although dyspeptic symptoms are mainly treated with synthetic medications, freshly squeezed potato juice is used as traditional medicine for hyperacidic stomach complaints in Germany and Switzerland, because of supposed antispasmodic and antacid effects (NN, 1993). Main known active constituents include two steroid alkaloid glycosides (e.g. a-chaconine und a-solanine) which in properly stored potatoes do not reach concentrations of more than 10 mg/100 g. They can be used as marker substances for the HPLC-fingerprint analysis of the potato juice. Whether they contribute, however, to the antidyspeptic activity of the juice, is not clear. Higher steroid alkaloid concentrations, which may cause toxic, even fatal events are not found in marketed potatoes, after conventional harvest and storage (NN, 1993). Our objective was to gather preliminary data on the effectiveness and tolerability of a juice prepared from organically cultivated potatoes, in an observational study that was in conformity with the Regulatory Requirements in Switzerland.
mAU 14
Methods Patients suffering from dyspeptic symptoms that had lasted more than 12 weeks in the preceding year were recruited from the outpatient clinic of one of the authors (SC). They were given an information leaflet and were invited to participate in a 1 week study on the effectiveness and tolerability of a juice prepared from potatoes. Exclusion criteria comprised current or recent participation in a clinical study, serious concurrent illness, a history of drug or alcohol abuse, pregnancy or lactation, known allergy to potatoes and anticipated difficulties with language or co-operation. The juice was produced by Biotta AG, Ta¨gerwilen/ Switzerland from Solani tuberosi tuber recens harvested in the area of Ta¨gewilen and the south of Germany close to the Swiss border. The potatoes were cleaned of soil, washed, selected, mashed and squeezed, and then treated with amylases (to initiate metabolism into polysasacharides and to improve the taste) and lactic acid (acidifier, to decrease the pH and to allow pasteurization instead of sterilization). After further treatment with amylases, it was therefore pasteurized (89 1C) and immediately bottled (Fig. 1). The first 45 patients who gave written consent were enrolled. Once their baseline characteristics had been
DAD1 B, Sig=202,8 Ref=260,40 (05-02-04.B\004-0201.D)
9.859 ------- a-solanine
10 8
4.192
6 4
11.495 ------- a-chaconine
12
2 0 2
4
6
8
Fig. 1. HPLC-fingerprint of the proprietary potato juice. Column: LiChrospher RP 8, endcapped, 5 mm 125 4 mm (Merck) Solvent A: 0.02 M Phosphatebuffer pH 7.0 Solvent B: Acetonitril HPLC gradient grade (Promochem No. 9128) Mobile phase: Solvent A/Solvent B 70:30 (V/V) Temperature: 40 1C Flow rate: 1.0 ml/min, Injection volume: 20 ml, Detection: 202 nm UV a-Solanine: (No. 85472), a-Chaconine (No. 22455), Fluka AG CH-9471 Buchs
10
12
14 min
ARTICLE IN PRESS S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
recorded, they were given 4 500 ml of fresh potato juice and were recommended to drink 100 ml in the morning half an hour before breakfast and at night before going to bed. They were advised to continue their current dyspepsia medication if they took any. If symptoms bothered them during the day, patients were advised to have one or more 100 ml cups of additional juice. Three outcome measures were recorded, the gastrointestinal symptom (GIS) profile (Holtmann et al., 2004), a 10 symptom profile, each symptom scored 0–4 (max score 40); and a recently validated disease-specific quality of life measure (QOLRAD, Madisch et al., 2003), a 25 item questionnaire, each item scored 0–7 (max. 175) and, self-rated treatment success (Efficacy) on a 0–4 Likert scale (0 best, 4 worst). Statistical analyses were carried out using SPSS (SPSS Inc., Chicago ILL. 60611). One patient withdrew consent and was not included in the analysis. All variables were tested for normal distribution by the Kolmogorov–Smirnof test. If the distribution differed significantly from normal, only non-parametric tests were applied. Where scores on a 5-point scale were used, again non-parametric tests were employed. Correlations of parametric variables were tested using Pearson’s product moment correlation and those of non-parametrics by Kendall’s t-b. The before and after QOLRAD and GIS were converted to a percent change scale, (value beforevalue after/value before)100. Drop-outs were included in the analyses with their initial values used for after treatment outcomes (for ‘‘intention-totreat’’, ITT analysis). Per protocol (PP) data for the 42 patients were also included. Changes in GIS or QOLRAD were tested against individual symptoms, diurnal distribution of the symptoms, the presence or absence of reflux, reflux medications, other GI medications, other synthetic medications as a collective group, family history of GI disease, Helicobacter infection, concurrent disease or irritants (alcohol, tobacco or spices). Treatment success was defined as ‘‘very good’’, ‘‘good’’, ‘‘moderate’’, ‘‘slight’’ and ‘‘poor’’ by using 480%, 60–79.99%, 40–59.99%, 20–39.99 and o19.99% for the % change in the outcomes. In the categorical classification of outcomes the drop-outs were included in the ‘poor’ group. The confidence level for rejecting null hypotheses was taken as 95% (po0:05).
13
by 42 patients. Two patients dropped out because of insufficient relief of complaints (one suffered from intolerable heartburn after consumption of the juice). The baseline characteristics of the 44 patients (10 men, 34 women) who entered the study are summarized in Table 1 together with the duration of their symptoms. Forty-two patients suffered from concomitant reflux symptoms such as retrosternal discomfort and regurgitation but not dominating the clinical picture. Thirteen patients received acid suppressive therapy (proton pump
Table 1.
Baseline characteristics of the 44 patients
a
Age (years) Weighta (kg) Sizea (cm)
64711 70712 16879
Duration (months) of: Chronic diseasea Acute exacerbationa
1567142 22729
Diurnal distribution of symtoms Morningb Noonb Afternoonb Eveningb At nightb Continuous complaintsb Intermittant complaintsb
10 28 4 19 12 5 40
Risk factors Regular alcohol consumptionb Regular nicotine consumptionb Regular consumption of spicesb Use of synthetic medicationsb Intercurrent diseasesb 11 relative GI complaintsb Family history of stomach Cab Family history of colon/rectum Cab
11 7 2 18 34 15 9 4
a
Mean7SD. Number of patients.
b
Total Score
GIS
QOLRAD
75 62 60
± 25.7
45 32 30
Results
15
11.5 ± 5.1
0
One patient withdrew her permission to use the data after successful treatment on her family doctor advice. This patient was excluded from all results and treated as if she had not been enrolled. The study was completed
± 28.8
Baseline
6.3 ± 5.3 Day 7
Fig. 2. The total GIS and QOLRAD scores before and after 7 days potato juice therapy, mean7SD. The absolute values decreased significantly (both po0:001).
ARTICLE IN PRESS 14
Table 2.
S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
Frequency distribution of outcome classes for all three outcome variables (GIS, QOLRAD % change and efficacy) GIS group
Very good Good Moderate Slight Poor Total
QOLRAD group
Number
%
8 8 8 7 13 (11) 44 (42)
18 18 18 16 30 —
(19) (19) (19) (38) (31)
Efficacy
Number
%
12 6 6 9 11 (9) 44 (42)
27 14 14 20 25 —
(29) (14) (14) (21) (21)
Number
%
9 17 6 2 10 (8) 44 (42)
20 39 14 5 23 —
(21) (40) (14) (5) (24)
Percent changes in GIS and QOLRAD are classed as poor: 0–19.99, slight: 20–39.99, moderate: 40–59.99, good: 60–79.99, and very good: 80–100%. Self-rated efficacy was rated on a very good ¼ 0 to poor ¼ 4, scale. The two subjects who dropped out are classed as ‘poor’ responders on all scales (ITT). Forty-four subjects are included. The numbers in brackets refer to the same data, but on a ‘Per Protocol’ treatment of 42 subjects.
inhibitors n ¼ 10 (one took in addition an antacid, one a prokinetic), antacids n ¼ 2, H2-blocker n ¼ 1). Contrary to instructions, seven patients discontinued their current dyspepsia medication. In five of these patients, symptoms had improved on treatment with potato juice. One of the two patients who consumed only one cup of juice per day instead of two or more cups was satisfied with the treatment. The GIS and QOLRAD scores improved significantly by 41.9740.8% or 44.0740.7% (mean7SD; CI95 31.2–56.5) and 50.7736.1% or 53.1735.1% (CI95 41.9–63.9), respectively (ITT or PP, both po0:001). The absolute changes are shown in Fig. 2. Concomitant reflux symptoms had improved in 19 of the 41 patients. The frequency distributions of the outcome classes are listed in Table 2: 16, 18 and 26 patients rated the effectiveness of the treatment as very good or good on the GIS, QOLRAD (improvements 460%) and on the self-rated efficacy, respectively. Poor treatment success was reported by 13 (GIS), 11 (QOLRAD) and 10 (efficacy) patients, not necessarily in the same subjects. In the poor outcome class, 4 subjects had greater GIS and 4 greater QOLRAD scores after treatment than before and, 3 (GIS) and 1 (QOLRAD) subjects had no change in the scores. None of the individual GIS symptoms showed significantly greater improvement than others; of the irritants, alcohol and tobacco did not affect the outcome variables significantly. Only the use of spices (regularly used by two patients) had a significant effect, affecting the % change in QOLRAD significantly (po0:02; the % change in GIS was not significant ðp ¼ 0:168Þ.2
2 Because only two subjects used spices regularly, this ‘significant’ result must be treated cautiously. By testing for 40 possible differences, the probability of rejecting once a true null hypothesis is about 0.81. This problem of multiple tests is well recognized when performing ANOVA’s, but it also applies here.
Table 3. Correlations of the outcome variables (GIS, QOLRAD % change and efficacy) and the variables, efficacy, taste and tolerability)
(a) GIS QOLRAD Efficacy
GIS
QOLRAD
Efficacy
— o0.001 o0.001
0.626 — o0.001
0.623 0.702 —
Efficacy
Tolerability
Taste
— 0.001 0.001
0.493 — o0.001
0.498 0.630 —
(b) Efficacy Tolerability Taste
The data shown in the ‘‘north–east’ triangle are the Kendall’s correlation coefficients while those in the south–west are their significance. The fraction of the variance explained by the correlation is equal to the square of the correlation coefficient.
Efficacy self-rating scores correlated poorly with objective symptom scores or QOLRAD or with tolerability or taste. Not surprisingly, the taste and tolerability of the juice correlated a little better (Table 3). All these correlations were significant po0:01. The various cross tabulations of self-rated efficacy, tolerability and taste and further details are placed on the webpage http://remed-chrubasik.uniklinik-freiburg.de. The reports of the adverse reactions were scrutinized by an independent investigator. Eight patients suffered from adverse events, which were possibly related to the potato juice. One complained of intolerable heartburn, three of meteorism one of whom also developed diarrhea and one complained of increased mucus production. Three patients suffered from upper respiratory tract infections during the study.
ARTICLE IN PRESS S. Chrubasik et al. / Phytomedicine 13 (2006) 11–15
15
Discussion
References
Alternative health care use is common in patients suffering from dyspeptic symptoms (Koloski et al., 2003). Our results provide some evidence that potato juice may help to alleviate dyspeptic complaints and to improve the quality of life. Based on our data – % change in GIS or QOLRAD, or the absolute changes in scores – 16 (GIS), 18 (QOLRAD) and 26 (self-rated efficacy) of the subjects had very good or good improvement. Two-thirds of the patients experienced at least some improvement and about half benefited considerably. Potato juice in its present formulation may therefore have a place in self-treatment of dyspeptic symptoms, before starting synthetic medication; this is especially important to patients who prefer a natural product to a synthetic one. However, since complete relief of complaints was achieved in only 20% of the patients, greater concentration of the active principle of the potato juice for a proprietary preparation may be desirable and produce a product that might compete with synthetic medication. Although two-thirds of the patients rated taste as excellent (n ¼ 12) or good (n ¼ 20) and the taste of the juice had no statistical impact on its effectiveness, improvement in taste of the juice may increase its acceptability to patients (see webpage). A number of clinical trials indicate that herbal medicinal products do play a role in the treatment of non-ulcer dyspepsia, e.g. combination preparations containing peppermint and caraway (Thompson and Ernst, 2002). A meta-analysis on a proprietary product composed of fresh plant extract of Iberis amara and of eight other herbal extracts demonstrated a highly significant overall therapeutic effect in functional dyspepsia (Gundermann et al., 2003; Madisch et al., 2004). Artichoke leaf extract may be another alternative as shown by Holtmann et al. (2003). The fact that seven of the 15 patients on reflux medications discontinued the synthetics on their own may indicate that there is still a need for effective dyspepsia phytomedicines. Dyspepsia has shown to impair health-related quality of life compared with the general healthy population (Chang 2004). Since the different dyspepsia outcome measures (GIS, QOLRAD and self-rated efficacy) reflect different dimensions of the complaints, all three measures and in particular a quality of life measure, should be included when evaluating the effectiveness of phytomedicines for upper gastrointestinal complaints.
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