Cholesterol reduction using psyllium husks--do gastrointestinal adverse effects limit compliance? Results of a specific observational study.

Introduction

Despite the known cholesterol reducing effect of psyllium seed husks (PSH) that has been shown in a number of studies (Garvin et al., 1965; Levin et al., 1990; Chan and Schroeder, 1995; Anderson et al., 2000), their use for therapy of mild or moderate hypercholesterolemia in Germany is quite rare. One reason may be that until now there were only a few registered herbal drug products with this indication since PSH is mainly used as a laxative. Although patients often express a preference for herbal products over synthetically manufactured drug products, patients may be somewhat reticent to use the PSH products due to unwanted intestinal effects. It is known that ingesting PSH can cause meteorism from bacterial fermentation in the colon which is associated with gastrointestinal complaints of bloating, flatulence and even painful cramps. Although these unwanted effects are usually considered minor compared with rare but severe adverse reactions associated with commonly prescribed statins used to lower cholesterol, it is possible that the side effects associated with ingesting PSH limit patient compliance. Therefore we designed a study to characterize the incidence and tolerability of PSH treatment in an outpatient population with mild to moderate hypercholesterolemia and a medical indication for laxative treatment.

As an herbal product, PSH (Plantaginis ovatae testa, Ispaghula husks) is differentiated from the unprocessed psyllium (Plantaginis ovatae semen). PSH are processed through fractional grinding of the outer layer of the seed ESCOP (2003). Since the water-binding mucoid substances are located exclusively in the epidermis of the husks (Jamal et al., 1987), PSH have a much higher water-binding capacity swelling up to 40-100 times of their volume compared to unprocessed psyllium. The mucoid polysaccharide fraction of Indian PSH contains highly branched arabinoxylan with a xylose backbone and arabinose- and xylose-containing side chains (Sandhu et al., 1981; Marlett and Fischer, 2003). In contrast to arabinoxylans in cereal grains that are extensively fermented. PSH possesses a structural feature that hinders its fermentation by typical colonic microflora. The increased concentration of gel forming mucoids in PSH compared to unprocessed psyllium correlates with recommended daily dosages of 4-20 g for PSH and 12-40g for unprocessed psyllium. Clinical observations also suggest the bloating effect is higher for PSH.

The mechanism of action for PSH efficacy in lowering cholesterol is thought to involve altered cholesterol metabolism with increased hepatic cholesterol catabolism and increased fecal bile acid excretion (Vahouny et al., 1980; Everson et al., 1992: Romero et al., 2002).

Most studies report a very high compliance with psyllium or with PSH that ranges from 90% to 95% (Levin et al., 1990; Anderson et al., 1991; Chan and Schroeder, 1995). However, other investigators indicate that unpleasant side-effects, including abdominal distention, flatulence, and discomfort may limit adherence to dosing regimens with PSH (Flannery and Raulerson, 2000). Studies may differ in evaluating gastrointestinal adverse drug reactions (ADRs). Flatulence and bloating may be considered as only minor expected complaints or subjects might be reluctant to report unless tactfully queried which may result in possible under-reporting. Additionally study populations selected to investigate the effects of PSH on cholesterol often exclude patients with gastrointestinal disorders. Selected patient populations are likely to impact PSH tolerability outcomes. In a double blinded crossover study, healthy volunteers showed no increase in gas passage with psyllium, but reported a significant increase in bloating sensation (Levitt et al., 1996). Dietary fiber can trigger pain or bloating in some patients among the 10-15% of population with irritable bowel syndrome (Talley, 1999) and large amounts of fiber reaching the colon has been suggested as a potential mechanism of irritable bowel symptoms in patients with overeating disorder (Dapoigny et al., 2003). Interestingly, psyllium was more effective in lowering cholesterol in a population of veterans less than 60 years old compared to older patients undergoing evaluation at a Veterans Administration Medical Center lipid clinic. The study correlated efficacy and compliance for several lipid lowering agents (Schectman et al., 1993).

Flatulence is the gastrointestinal symptom most often associated with PSH that is likely to impact compliance; however, the effect has not been further characterized in terms of dose response for incidence or severity. Reports with healthy volunteers or patients with mild hypercholesterolemia often minimize gastrointestinal effects compared to effects on lipid profiles and emphasize high compliance. We questioned whether high compliance reported in study populations that excluded gastrointestinal disorders would be expected in patients with mild to moderately elevated cholesterol and gastrointestinal disorders requiring laxative therapy. A prospective study in out-patients with mild to moderate hypercholesterolemia and constipation was designed to assess PSH tolerance and compliance. Evaluation instruments included validated questionnaires and patient diaries that were employed to capture in detail all gastrointestinal symptoms over a 3-week treatment period. Additionally, the motivation for PSH continuation and the manner in which PSH was administered relative to meals and amount of liquid were specifically queried.

Methods

Study design and subjects

A prospective single-center, open label, observational study was conducted in adult patients identified from the ambulatory practice for natural healing at the Benjamin Franklin Campus of Charite University Clinics, Berlin, Germany. Inclusion criteria required mild to moderate hypercholesterolemia and documented indication for laxatives as well as stable medical history with no change in diet or medication for at least 4 weeks prior to study enrollment. Patients were excluded with suspected bowel stenosis or if medication regimens included cholestyramine, colestipol or ezetimib because these medications are thought to have an overlapping mode of action with PSH.

Subjects provided written, informed consent and the study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and German drug law.

Test material

The test drug (1) was Indian PSH (husks of Plantago ovata FORSSKAL, synonym: Plantago ispaghula ROXBURGH; plantaginis ovatae testa) in a 100% preparation without fat, sugar, aroma or other additives. PSH has been registered in Germany as an herbal drug for many years as a laxative. The patients were advised to take 1 level measuring spoon (3.5 g) full of the test drug three times daily with foods such as yogurt or in at least 100 ml of liquid without carbonic acid or alcohol. Administration relative to meals and type of liquid or food was determined by the subjects. To avoid the possible binding of other drug substances, the test product was to be taken 1-2 h before or after other medications.

Study conduct

Complete medical histories and physical examinations assured patient eligibility. Patients were instructed about PSH administration, documenting dosage ingestion and recording gastrointestinal symptoms and bowel function in structured patient diaries. Study visits took place at enrollment and at the end of the 3-week test period. A structured telephone interview was conducted at 1 week. At the last study visit, physical examinations and clinical chemistry for plasma lipids was repeated. Patient interviews monitored concomitant medications, adverse reactions and drug tolerability. Remaining study medication was recorded to quantify compliance. At each study visit values for total cholesterol, HDL, LDL and triacylglycerides were determined from blood plasma samples after 12 h of fasting and analyzed immediately with routine lab diagnostics at the central laboratory of Charite University Clinic facilities--Benjamin Franklin Campus, Berlin, Germany.

Part one of the validated Nepean Dyspepsia Index (Talley et al., 1999) was used during clinic visits to evaluate gastrointestinal symptoms. Fifteen questions related to intensity, frequency and impact of upper abdominal symptoms during the previous 2 weeks of treatment. In order to record symptoms for the entire abdomen, 10 additional questions with analogous structure were included that queried function of the lower abdomen. Total scores were calculated as the sum of the single columns of the symptoms.

Patients were given a daily diary that was to be completed each evening during the study. The diary contained 17 questions relating to gastrointestinal complaints including bloating, flatulence, pain, nausea, vomiting, heartburn and frequency and consistency of the defecation. The daily ingestion of PSH was also recorded.

After at least 7 days of study medication, a telephone interview was conducted to evaluate ingestion preference and acceptance of the dosage form. Questions included integration of study medication into the daily routine, intake modalities (before, during or after a meal; with food or mixed with liquid and type of liquid), preference for the dose packaging, positive-negative side effects and whether the patient would be likely to continue PSH ingestion after the study.

Evaluation parameters and statistics

The primary evaluation parameter was the difference of total cholesterol and LDL cholesterol before and after the 3-week intake of PSH. Secondary parameters examined plasma HDL cholesterol and triglycerides, incidence and severity of gastrointestinal symptoms including flatulence, bloating upper and lower abdominal pain and bowel activity. Additionally, dosing form preference and ingestion patterns relative to meals and liquid or food was evaluated as part of patient diaries.

Paired, two-tailed t-tests were used to evaluate the change in plasma lipid parameters at treatment initiation and after 3 weeks of treatment. Descriptive statistics were used to evaluate secondary parameters.

Results

Of the 62 patients enrolled, 54 patients completed the study according to protocol. For enrolled patients 66% were women, mean age was 60 years (range 40-74 years) and mean body mass index was 27.7 kg/[m.sup.2] (range 18.8-40.7 kg/[m.sup.2]). Combined hyperlipoproteinemia was diagnosed for 37 patients, but only 14 showed elevated triglycerides (> 200mg/dl). Four patients discontinued after 6-10 days due to adverse drug reactions, 2 patients had adverse events that were not considered related to study medication, 1 patient did not report a reason for discontinuing and 1 patient violated study protocol by stopping simvastatin therapy and was discontinued.

Of the 54 patients completing the study according to the study protocol, 45 had total cholesterol values over 220 mg/dl. Indication for laxative treatment included 28 patients reporting constipation, 27 patients with hemorrhoids, 3 with anal disease and 4 patients with irritable bowel syndrome. Additionally, 29 patients had medical histories that included other diagnoses relating to the gastrointestinal system, e.g. reflux disease, cholecystectomy, ulcer disease, etc.

No consistent change in body weight was noted during the study, including obese patients with body mass index over 30. This result is consistent with patient diaries and medical histories showing no change in diet during the study.

Primary endpoint

Total plasma cholesterol and LDL-cholesterol levels showed a clear and statistically significant reduction after 3 weeks of administering PSH (Table 1). HDL and fatty acids showed only slight changes during the study that were not significant. Mean reduction was higher in the 45 patients with initial values of total cholesterol over 220, with relative decrease during the study of 6.5% for total cholesterol and 8.2% for LDL-cholesterol.

Secondary parameters

Total gastrointestinal symptom score decreased from a mean value of 27.7 [+ or -] 29.8 at study initiation to 24.1 [+ or -] 32.2 after 3 weeks of PSH dosing. The score for upper abdominal symptoms (calculated using 15 questions in the Nepean Dyspepsia Index for upper abdominal symptoms) decreased from 18.0 [+ or -] 20.0 to 15.2 [+ or -] 20.7. Corresponding mean scores calculated for the lower abdomen (irritable bowel symptoms) had a smaller change from 9.7 [+ or -] 12.5 to 9.0 [+ or -] 12.8. Queries during patient visits showed that fewer patients had high complaint scores after 3 weeks PSH and 14 patients were symptom free with a total score of zero (versus 9 patients at visit 1).

Evaluation of patient diaries showed that only 3 of 54 patients had no symptoms in the first week. The number of symptom free patients increased to 11 during week 3. Consistently the frequency and intensity of gastrointestinal symptoms decreased from week 1 to week 3 (Table 2).

During the first week, 13 patients reported cramps or lower abdominal symptoms that were (n = 10) or were not (n = 9; some patients reported both types) associated with defecation. Eleven patients reported these symptoms during the second week while 10 patients reported the same symptoms during week three. Cramp-like lower abdominal symptoms were persistently reported in 6 patients over the coarse of the study. Only one of these patients suffered from a chronic irritable bowel syndrome. None of the others had any chronic gastrointestinal disorders. With exception of a few cases all those patients with cramp-like lower abdominal pain also reported painful flatulence.

The total number of recorded defecations increased slightly from 571 in the first week to 611 in the second and 606 in the third week, their distribution per day is shown in Table 3.

Days without bowel movements, indicating constipation, decreased only during the second week. Individual patients show some increase of diarrhea-like frequent defecations.

The stool consistency was scored with medians of 2.4, 2.6 and 2.5 during week 1, 2 and 3, respectively (with 2 = soft/formed and 3 = normal). Mucous discharge in fecal stools was reported 6 or fewer patients each week. Blood with the defecation was reported by 4 patients in the first week with a mean frequency of 4.3 times and in the second and third week only 2 patients with mean frequency of 2.5 and 5 times, respectively.

Compliance was verified through diary examinations indicating a mean dosing frequency of 2.6 measuring spoons, equal to 9.1 g PSH/day which corresponded with returned study medication that revealed a mean dosage of 9.3 g PSH/day. At the end of week one, 49 patients confirmed regular intake of the test drug from the telephone interview and 1 patient reported reduced the dosage to once daily (3.5 g/day) due to unacceptable flatulence.

Queries on dosing preferences showed that 51 of 54 patients were able to integrate PSH dosing into their daily life. Thirty-two patients took PSH before their meals, 10 during and 29 after their meals. At the end of the study there was a slight change: 36 patients took PSH before the meal, 12 during and 24 after their meals. The vast majority of patients (51 of 54) ingested PSH mixed in water, 14 also reported other modes of intake including mixed with yogurt (8), granola (3), curd cheese (1), milk (1) and tea (1). Twenty-six patients would prefer a daily dosage sachet.

Queries related to probability for compliance found that 28 patients mentioned positive effects that included a feeling of satiation (5), easier/softer feces (6), increased feces volume (1), formed stool (1), cleaner defecation (saving toilette paper) (2), weight reduction (2), a relieved feeling (2). In contrast, 23 patients reported unfavorable effects like bloating (9), stomach discomfort (1), flatulence (16), regurgitation, resp. heartburn (2), nausea (1), abdominal cramps and abdominal pain (2), awkward intake of drug at noon (4), constipation (2), disturbing moist expansion (1). A total of 31 patients had no complaints regarding the product. At the end of the study, only 16 patients still reported adverse effects.

At study initiation 45 of 54 patients expressed their wish to continue PSH assuming that the expected cholesterol reducing effect was shown. Synthetic drugs to reduce the cholesterol were viewed as acceptable in only 18 patients. Queries on attitude toward the product at the end of the study found 43 patients positive regarding long-term intake of PSH and only 3 patients would accept synthetic drugs as a therapeutic alternative. Positive product properties were recognized by nearly each patient and negative responses correlated with adverse effects.

Safety

Of all the 62 enrolled patients, 34 reported 41 adverse events with most of events (25 patients) occurring during the first week. In 26 incidences, a causal relation was considered as possible or probable with all events involving gastrointestinal symptoms. No cause between study medication and event was determined for 15 adverse events. Four subjects discontinued the study due to adverse events considered possibly or probably related to study medication. Adverse events considered related to study medication included 12 cases of flatulence, 11 cases of stomach pain, 8 incidents of bloating, 4 changes in bowel function, 2 incidents of nausea, one report of heartburn and one report of burping. Most symptoms disappeared after a few days but 4 persisted for the coarse of the study and 10 of 26 adverse events lasted longer than a week. No adverse events required additional treatment.

Of the 16 patients with known gastrointestinal disorders (reflux, irritable colon, irritable stomach, gastritis) only 8 reported gastrointestinal adverse events and only one patient discontinued study medication. This patient's diary indicated symptoms which were consistent with an underlying gastrointestinal disease.

Discussion

Results from this prospective study showed clearly decreased levels of total cholesterol and LDL cholesterol in patients with mild to moderate hypercholesterolemia and confounding gastrointestinal disorders. The effects on cholesterol are consistent with previously reported studies conducted in patients without medical indication for concomitant medication. The study found rapid onset of effects with highly significant decreases in cholesterol within 3 weeks of treatment initiation.

Results of this study are consistent with previous studies showing efficacy of PHS in reducing total cholesterol (discussed in 2003). Doses of 10.2g PHS/day administered for 8-16 weeks decreased total cholesterol (5-15%) and LDL-cholesterol (8-20%) without changing triglycerol and HDL (Bell et al., 1989; Levin et al., 1990) Similarly, a meta-analysis of 8 randomized placebo-controlled studies investigating cholesterol-lowering effects of psyllium enriched cereals adjunctive to diet therapy included a collective of a total of 384 active and 272 placebo patients with mild to moderate hypercholesterolemia showed similar results. After 12 weeks of treatments with 10.2 g PSH/day there was a highly significant reduction of total cholesterol by 4% and of LDL-cholesterol by 7% without a significant influence to HDL (Anderson et al., 2000). In 3-week randomized, double-blind, placebo-controlled clinical study we investigated the effects of PSH in granulate form in 161 patients with hypercholesterolemia during a rehabilitation program. Total cholesterol was reduced significantly in the test treatment group in comparison to the placebo group and LDL-cholesterol and apolipoprotein B were also reduced (Brock et al., 2001). For patients requiring higher cholesterol reduction, a randomized, double-blind, three-arm clinical study in 68 patients investigated the efficacy of PSH in combination with simvastatin over a period of 12 weeks. The authors conclude that combination of 10mg simvastatin and 15 g psyllium supplement show a cholesterol-reducing effect comparable to 20mg simvastatin alone (Moreyra et al., 2005).

In this study of mild to moderate hypercholesterolemia, there was no significant difference between the intention to treat population that included subjects with total cholesterol levels under 220mg/dl and the per protocol population, indicating the robustness of the results. There was no dependence between cholesterol initial levels and effect and similarly, the study showed no dose dependence between recorded daily dose ingested and magnitude of cholesterol change. However, the study was not designed to explore dose response in patients with differing severity of hypercholesterolemia. Significantly, this study identified a 5% decrease in total cholesterol and a 7% decrease in LDL-cholesterol which is nearly identical to previous studies involving placebo controlled blinded designs.

After validating efficacy of PSH on cholesterol in a patient population with gastrointestinal disorders that are consistent with laxative therapy, the study queried parameters likely to impact compliance using the validated Nepean Dyspepsia Index (Talley et al., 1999). Results confirmed that symptoms are transient. Previous studies in otherwise healthy subjects with hypercholesterolemia identified a high compliance with rates higher than 85% (Levin et al., 1990; Anderson et al., 1991; Chan and Schroeder, 1995). The discontinuation rate due to PSH effects was less than 7% in the current study indicating that patients with gastrointestinal dysfunction including irritable bowel syndrome can be expected to have a high compliance with PSH dosing regimens.

These results are consistent with the mild to moderate and transient nature of reported adverse effects shown from diary analysis. An exception was the symptom of heartburn which appeared in more patients at the end of the study than in the beginning (25 versus 18). A cause for this finding remains unexplained. The high incidence of initial symptoms is expected for a group that included 16 of 54 patients with underlying gastrointestinal disorders. Interestingly patients who reported few symptoms at the beginning rarely reported additional symptoms with the exception of flatulence throughout the study.

The recorded ADRs correspond mainly to the gastrointestinal complaints as recorded in the diaries. It is noticeable that of the 16 patients with known gastrointestinal disorders like reflux, irritable bowel syndrome, gastritis only 8 reported gastrointestinal adverse events (in sum 24 patients) and only one patient discontinued from the study. In their diaries these patients showed symptoms, which could also be explained through their gastrointestinal disease. However 10% of all patients showed pronounced and persisting complaints without a known gastrointestinal disease. It is possible that some patients enrolled in the study without diagnosed gastrointestinal disease report newly surfacing gastrointestinal symptoms as adverse events even if they are not very severe.

Our queries regarding acceptance show that nearly all patients were interested in an inexpensive natural product to reduce cholesterol. At the end of the study only 3 of 54 patients expressed a preference for synthetic drug products compared to herbal PSH. PSH was most commonly ingested after mixing with water and was reported as easily integrated into patient's daily routine. The disadvantages of PSH herbal product use center on initial adverse gastrointestinal reactions should be communicated openly and explicitly in order to avoid an early termination of the therapy. Many of our patients wanted to continue taking the medication after the study under the expectation that their cholesterol levels were indeed reduced and consequent risks of heart attack and stroke were decreased.

Conclusion

PSH provides a suitable appropriate herbal medication to reduce slight to moderate hypercholesterolemia, despite the incidence of impressive intestinal symptoms that are associated with the initiation of the therapy. Patients with a sensitive gastrointestinal system and particularly those with constipation can expect positive gastrointestinal effects after some weeks of PSH therapy that are consistent with the agent's laxative effects.

Good compliance and patient acceptability can be expected with PSH compared to synthetic drug alternative treatment regimens that include rare, but severe adverse events. Dose adjustment is easily accomplished with granular PSH. Patients should be informed about the incidence and transient duration of adverse gastrointestinal effects observed with PSH ingestion and dosage may be titrated to minimize adverse symptoms during the first days of therapy.

References

Anderson, J.W., Floore, T.L., Geil, P.B., O'Neal, D.S., Balm, T.K., 1991. Hypocholesterolemic effects of different bulk-forming hydrophilic fibers as adjuncts to dietary therapy in mild to moderate hypercholesterolemia. Arch. Intern. Med. 151 (8), 1597-1602.

Anderson, J.W., Allgood, L.D., Lawrence, A., Altringer, L.A., Jerdack, G.R., Hengegold, D.A., Morel, J.G., 2000. Cholesterol-lowering effects of psyllium intake adjunctive to diet therapy in men and women with hypercholesterolemia: meta-analysis of 8 controlled trials. Am. J. Clin. Nutr. 71 (2), 472-479.

Bell, L.P., K. Hectorne, K., Reynolds, H., Balm, T.K., Hunningshake, D.B., 1989. Cholesterol-lowering effects of psyllium hydrophilic mucilloid. Adjunct therapy to a prudent diet for patients with mild to moderate hypercholesterolemia. JAMA 261 (23), 3419-3423.

Brock, F.E., Uehleke, B., Woehling, H., 2001. Psyllium is an effective and safe drug in the treatment of hypercholesterinemia. Pharm. Pharmacol. Lett. 11 (Part 2), 68-71.

Chan, E.K., Schroeder, D.J., 1995. Psyllium in hypercholesterolemia. Ann. Pharmacother. 29 (6), 625-627.

Dapoigny, M., Stockbrugger, R.W., Azpiroz, F., Collins, S., Coremans, G., Muller-Lissner. S., Oberndorff, A., Pace, F., Smout, A., Vatn, M., Whorwell, P., 2003. Role of alimentation in irritable bowel syndrome. Digestion 67 (4), 225-233.

ESCOP, 2003. ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products. Georg Thieme Verlag, Stuttgart, Germany.

Everson, G.T., Daggy, B.P., McKinley, C., Story, J.A., 1992. Effects of psyllium hydrophilic mucilloid on LDL-cholesterol and bile acid synthesis in hypercholesterolemic men. J. Lipid Res. 33 (8), 1183-1192.

Flannery, J., Raulerson, A., 2000. Hypercholesterolemia: a look at low-cost treatment and treatment adherence. J. Am. Acad. Nurse Pract. 12 (11), 462-466.

Garvin, J.E., Forman, D.T., Eiseman, W.R., Phillips, C.R., 1965. Lowering of human serum cholesterol by an oral hydrophilic colloid. Proc. Soc. Exp. Biol. Med. 120 (3), 744-746.

Jamal, S.A., Ahmad, J., Agarwal, R., Ahmad, M., Osman, S.M., 1987. A novel oxo fatty acid in Plantago ovata seed oil. Phytochemistry 26 (11), 3067-3069.

Levin, E.G., Miller, V.T., Muesisng, R.A., Stoy, D.B., Balm, T.K., LaRosa, J.C., 1990. Comparison of psyllium hydrophilic mucilloid and cellulose as adjuncts to a prudent diet in the treatment of mild to moderate hypercholesterolemia. Arch. Intern. Med. 150 (9), 1822-1827.

Levitt, M.D., Furne, J., Olsson, S., 1996. The relation of passage of gas an abdominal bloating to colonic gas production. Ann. Intern. Med. 124 (4), 422-424.

Marlett, J.A., Fischer, M.H., 2003. The active fraction of psyllium seed husk. Proc. Nutr. Soc. 62 (1), 207-209.

Moreyra, A.E., Wilson, A.C., Koraym, A., 2005. Effect of combining psyllium fiber with simvastatin in lowering cholesterol. Arch. Intern. Med. 165 (10), 1161-1166.

Romero, A.L., West, K.L., Zern, T., Fernandez, F.L., 2002. The seeds from Plantago ovata lower plasma lipids by altering hepatic and bile acid metabolism in guinea pigs. J. Nutr. 132 (6), 1194-1198.

Sandhu, J.S., Hudson, G.J., Kennedy, J.F., 1981. The gel nature and structure of the carbohydrate of ispaghula husk ex Plantago ovata Forsk. Carbohydr. Res. 93, 247-259.

Schectman, G., Hiatt, J., Hartz, A., 1993. Evaluation of the effectiveness of lipid-lowering therapy (bile acid sequestrants, niacin, psyllium and lovastatin) for treating hypercholesterolemia in veterans. Am. J. Cardiol. 71 (10), 759-765.

Talley, N.J., 1999. Irritable bowel syndrome: definition, diagnosis and epidemiology. Baillieres Best Pract. Res. Clin. Gastroenterol. 13 (3), 371-384.

Talley, N.J., Haque, M., Wyeth, J.W., Stace, N.H., Tytgat, G.N., Stanghellini, V., Holtmann, G., Verlinden, M., Jones, M., 1999. Development of a new dyspepsia impact scale: the Nepean Dyspepsia Index. Aliment. Pharmacol. Ther. 13 (2), 225-235.

Vahouny, G.V., Tombes, R., Cassidy, M.M., Kritschevsky, D., Gallo, L.L., 1980. Dietary fibers: V. Binding of bile salts, phospholipids and cholesterol from mixed micelles by bile acid sequestrants and dietary fibers. Lipids 15 (12), 1012-1018.

B. Uehleke*, M. Ortiz, R. Stange

Department for Natural Medicine, Charite--Universitatsmedizin Berlin, Campus Benjamin Franklin, Immanuel Hospital, Konigstr. 63, D-14109 Berlin, Germany

[star] This study has been supported by Kneipp-Werke, Wurzburg.

*Corresponding author. Tel.: [phone]; fax: [phone].

E-mail address: [e-mail] (B. Uehleke).

(1) Now available as Kneipp Cholesterol Control by Kneipp-Werke Wurzburg.

Table 1. Change in primary lipid parameters, total cholesterol and LDL

                    Initial score    End score        Absolute reduction
Parameter (n = 54)  (mg/dl)          (mg/dl)          (mg/dl)

Total cholesterol   252 [+ or -] 39  239 [+ or -] 37  13
LDL                 174 [+ or -] 34  162 [+ or -] 31  12

                    Relative reduction  Significance (paired
Parameter (n = 54)  (%)                 t-test, 1-tailed)

Total cholesterol   5.2                 <0.00002
LDL                 6.9                 <0.00001

Mean [+ or -] SD.

Table 2. Gastrointestinal symptoms according patients diaries

Symptom frequency per
patient per week        1 week           2 weeks          3 weeks

Days with flatulency     4.6 (46)         5.6 (41)        5.2 (37)
  (affected patients)
Frequency of painful     8.1 (18)         5.2 (15)        5.4 (11)
  flatulence (affected
  patients)
Days with the feeling    3.6 (39)         4.3 (25)        4.0 (24)
  of a swollen lower
  abdomen (affected
  patients)
Score of lower           8.2 (25)         5.8 (23)        5.9 (14)
  abdominal complaints
  (affected patients)
Frequency of cramp-      4.4/6.0 (10/9)   4.1/4.3 (7/11)  3.0/3.6 (7/10)
  like lower abdominal
  pain in association
  with defecation/
  without association
  (affected patients)
Pain in the upper        7.6 (15)        10.0 (11)        6.3 (12)
  abdomen (affected
  patients)
Appearance of bloating  11.0 (25)         7.4 (25)        8.1 (22)
  after minimal food
  intake (affected
  patients)
Heartburn (affected      5.5 (19          5.8 (18)        5.2 (25)
  patients)
Nausea (affected         4.0 (13)         4.3 (8)         6.9 (5)
  patients)
Stomach cramps           5.6 (6)          5.0 (4)         4.0 (5)
  (affected patients)
Vomiting (affected       2.0 (1)          2.0 (1)         3.0 (1)
  patients)

Mean score (patients with symptoms from 54).

Table 3. Frequencies of defecations

                                   Week 1    Week 2    Week 3

Days without defecation (affected   36 (16)   17 (9)    32 (17)
  patients)
Days with 1 defecation (affected   170 (45)  154 (41)  147 (38)
  patients)
Days with 2 defecations (affected  118 (41)  122 (41)  137 (37)
  patients)
Days with 3 defecations (affected   47 (21)   56 (24)   47 (17)
  patients)
Days with more that 3 defecations    6 (4)    10 (6)    10 (8)
  (affected patients)

Incidence reported (number of patients from 54 total).