Limited data are available concerning the mechanisms 5. Benjamin RS. Rationale for the use of mitoxantrone in the older patient: cardiac toxicity. Semin Oncol 1995;22(Suppl.1):11-3. ORIGINAL ARTICLE of tissue wasting and weight loss in cancer patients. 6. Bezwoda WR, Bernasconi C, Hutshinton RM, Windfield DA, De Bock R, Malnutrition associated with malignancy has been docu- Mandelli F. Mitoxantrone for refractory and relapsed acute leukemia. Cancer 1990;96:418-22. mented in many hospitalised cancer patients. This charac- 7. Carter WH Jr, Wampler GL, Stablein DM, Campbell ED. Drug activity and the- LONG TERM EFFECT OF FIBRE SUPPLEMENT AND REDUCED ENERGY teristic state of malnutrition and progressive tissue wasting rapeutic synergism in cancer treatment. Cancer Res 1982;42:2963-71. is referred to as cancer cachexia and is believed to result 8. De Jager R, Capeleare P, Earl H et al. Phase II clinical trial of mitoxantrone on INTAKE ON BODY WEIGHT AND solid tumours and lymphomas. Trial NCI/EORTC. Symposium on New Drugs on from a combination of decreased intake, altered Cancer Therapy. Brussels, Belgium: Institut Jules Bordet, 1998:Abst 39. IN OVERWEIGHT SUBJECTS energy expenditure and abnormal substrate utilisation. 9. Delogu G, De Simone C, Famularo G, Fegiz A, Paoletti F, Jirilio E. Anaesthetics modulate tumour necrosis factor (: effect of L-carnitine supplementation in sur- 1 2 1 3 However, recent literature suggests that this response is also gical patients. Preliminary results. Mediat Inflam 1993;2:33-6. Grethe Sto/a Birketvedt , Jan Aaseth , Jon R. Florholmen and Kjeld Ryttig a result of complex metabolic alterations and not only a re- 10. Endicott JA, Ling V. The biochemistry of p-glycoprotein mediated multidrug re- sistance. Annu Rev Biochem 1989;58:137-71. sult of starvation (16,26). Thus the presence of cancer ap- / 1 2 11. Fattorossi A, Bisseli R, Casciaro A, Tzantzoglou S, De Simone C. Regulation of University Hospital of Tromso, Norway; Laboratory of Gastroenterology ; Kongsvinger Hospital, Norway ; Karolinska 3 pears to cause metabolic alterations in the host (22,26). normal human polymorphonuclear leukocytes by carnitine. Mediat Inflam Hospital, Sweden: Unit All these data suggest the probable beneficial role of 1993;2:37-41. 12. Fritz IB. Carnitine and its role on fatty acid metabolism. Adv Lipid Res nutritive (i.e. supportive) care in cancer treatment. When 1963;1:285-324. using ALC in combination with MX, we observed a sub- 13. Gasparetto A, Corbucci GG, De Blasi RA. Influence of acetyl-L-carnitine infusi- Summary: A weight-reducing potential has been ascribed to high dietary fibre intake. To investigate the practical reliability on on haemodynamic parameters and survival of circulatory - shock patients. Int 2 stantial increase in length of survival of treated animals J Clin Pharm Res XI 1991;2:83-92. of this hypothesis, fifty-three moderately overweight females (BMI > 27.5 kg/m ) on reduced energy intake (1200kcal/day) compared to MX alone. Intravenous application seems to 14. Hansson J. Mechanisms of tumour cell resistance to cancer chemotherapeutic were treated for 24 weeks with a fibre supplement on a randomly, double-blind, placebo-controlled basis. The fibre was ad- be the best way of MX application. However intraperitone- drugs. Eur J Surg 1991;(Suppl 561):35-44. ministered as an initial dose of 6 g and a maintenance dose of 4 g. Body weight and blood pressure were recorded weekly 15. Kenneth RH. Clinical applications of anticancer drugs targeted to topoisomera- al application was demonstrated as effective in this experi- se II. Biochim Biophys Acta (BBA)/Gene Struct Expres 1998;1400:173-84. during the first 3 months and thereafter every second week. Blood samples were drawn at start and at end of the study. ment. The contact with tumour cells in situ is probably 16. Kern KA, Norton JA. Cancer cachexia. J Parent Ent Nutr 1988;12:286-92. Initial body weights were 75.6 ± 1.6 kg in the fibre group versus 75.5 ± 1.6 kg in the placebo group. After treatment, mean 17. Koloničný A. Synthesis of Mitoxantrone (Ph.D.Thesis). Pardubice, Czech necessary for the expression of the cytocidal effect of the Republic: Technical University of Chemical Technology, 1990. weight loss in the fibre group was 8.0 kg versus 5.8 kg in the placebo group (p < 0.05). Systolic and diastolic blood pres- drug. 18. Minofti G. Adriamycin-dependent release of iron from microsomal membranes. sures were significantly reduced in both groups without differences between the groups. Serum concentrations of chole- Our hypothesis was not only to modulate the adverse ef- Arch Biochem Biophys 1989;268:398-403. 19. Myers CE, McGuire WP. Liss RH. et al. Adriamycin: the role of lipid peroxidati- sterol, and uric acid were significantly reduced in the group with reduced energy intake, whereas no additional fect of MX therapy but also to make a change in energetic on in cardiac toxicity and tumour response. Science 1977;197:165-9. effect was observed when fibre was supplemented. Serum concentrations of potassium and sodium did not change signi- balance in favour of the host. The clinical use of ALC as an 20. Nielson D, Skovsgaard T. P-glycoprotein as multidrug transporters; a critical re- ficantly. The results suggest that a dietary fibre supplement in combination with a hypocaloric diet is of value as an ad- view of current multidrug resistant cell lines. Biochim Biophys Acta adjuvans to MX and other antineoplastic agents may be 1992;1139:169-83. junct in the management of overweight. a useful contribution in improving the metabolic state. 21. Pacciuci PA, Ohmuma T, Ambinder E. Effects of mitoxantrone on patients with refractory acute leukemia. Blood 1981;(Suppl 58):145. 22. Richards EW, Long CL, Nielson KM et al. Glucose metabolism in advanced lung Acknowledgements cancer patients. Nutrition 1992;8:245-51. Key words: Dietary fibre; Obesity; Weight reduction; Blood pressure 23. Ruggiero V, D’Vrso M, Albertoni C, Campo S, Foresta P, Martelli EA. LPS - in- duced serum TNF production and lethality in mice: effect of L-carnitine and Anna Kargerová and Jitka Šedivá from the Research some acyl-derivatives. Mediat Inflam 1993;2:43-50. Institute for Pharmacy and Biochemistry Prague are ack- 24. Silliprandi ND, Lias F, Menabo R, Ciman M, Sartyoreli L. Transport functions of carnitine in muscles. J Clin Chem Clin Biochem 1990;28:303-6. nowledged for technical assistance in experiments involving 25. Tewey KM, Rowe TC, Yang L et al. Adriamycin-induced DNA damage mediated Introduction Material and methods mice. by mammalian DNA topoisomerase II. Science 1984;226:446-68. 26. Zadák Z, Shenkin A, Bláha V, Sobotka L, Cerman J, Solichová D. Metabolic res- This work was supported by the Charles University ponse to glucose and insulin in weight-stable and weight loosing patients. Clin Increased dietary intake of fibres has been recommen- Subjects grant no. 73/93 and the Research Institute of Organic synt- Biochem Metab 1996;25:125-30. ded to obtain stable energy intake and avoid metabolic di- Sixty healthy, mildly overweight females who voluntee- hesis of Pardubice (VÚOS a.s.). sorders such as obesity, type 2 diabetes, hyperlipidemia and red to participate in the study were recruited by announce- Submitted June 2000. cardiovascular disease (1,2,5,7,8,10). The effect of a dietary ment in the local newspaper. The inclusion criteria were References Accepted June 2000. fibre supplement to a hypocaloric diet in the treatment of age 18-67 year and body mass index (BMI) > 27.5kg/m2. overweight is still controversial (6,14). When critically re- Patients with serious cardial, renal and hepatic diseases 1. Aureli T, Michelli R, Ricciolini M et al. Effect of acetyl-Lcarnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR PharmDr. Mohamed Niang, viewed, only a few controlled studies have shown a modest were excluded. Patients with a history of gastrointestinal di- spectroscopy. Brain Res 1989;526:108. Charles University in Prague, weight loss induced by soluble fibre supplement (11,12,13). sease, type 1 diabetes, , and patients treated with 2. Bachur NR, Yu F. Johnson R. et al. Helicase inhibition by anthracycline antican- Faculty of Medicine in Hradec Králové, In addition, there are numerous studies with only limited antacids, diuretics, H -blockers, bulk laxatives, anorectics, cer agents. Mol Pharmacol 1992;41:993-8. 2 3. Beck WT, Danks MK, Wolverton JS et al. Resistance of mammalian tumour cells Department of Medical Biochemistry, value due to lack of comparison groups, inadequate sample and oral contraceptives were also excluded. to inhibitors of DNA topoisomerase II. Adv Pharmacol 1994;29B:145-69. Šimkova 870, 500 01 Hradec Králové, sizes and short duration of the observations (4). 4. Bellei MD m, Battelli DM, Guarriero U et al. Changes in mitochondrial activity caused by ammonium salts and the protective effect of carnitine. Biochim Czech Republic. Fibre supplement in long term studies involves problems Study design Biophys Res Commun 1989;158:181. e-mail: [email protected] with compliance as well as with the adherence to a low-ener- All subjects were randomised into two groups according gy diet regimen throughout the observation period. More- to BMI, the fibre group and the placebo group. Fibre tablets over, it is unknown whether metabolic adjustments to high (Farma Food, Copenhagen, Denmark) and placebo tablets fibre intake may take place during long-term addition leading (identical in taste and appearance as fibre) were prescribed to a reduction in the fibre efficacy. Therefore, the aim of the three times daily, 6 tablets to be taken 15 min before meals present study was to investigate the effect of the fibre supp- with 250 ml of water and 4 tablets to be taken at 3 p.m. lement Dumovital (grain and citrus fibre) (Farmafood, for 8 weeks (high dosage). The dosage was then reduced to Copenhagen, Denmark) on body weight and blood lipids in 5 tablets prescribed three times daily for the rest of the tre- healthy overweight subjects in a controlled, randomised de- atment period (maintenance dosage). The tablets contained sign for 24 weeks. a mixture of fibres from grain and citrus and consisted of

128 ACTA MEDICA (Hradec Králové) 2000;43(3):129-132 129 15 % soluble fibre and 85 % insoluble fibre. Patients were were measured using the routine methods of the Central the fibre group from week 4 and onwards as compared to energy excretion (11) or a combination of these reasons. told to follow a 1200 kcal diet (Libra Slimming Club diet), Laboratory Department of Sentralsykehuset of Akershus, the placebo group p <0.05) (Fig 1). One mechanism could be that fibre compounds bind to perform their regular exercise program, and not change Norway. The systolic and diastolic blood pressures were signifi- cholic acids and thereby reduces the fat absorption (9). their smoking habits during the study. In addition to the cantly reduced in both groups (p<0.01) without differences However, this effect has been ascribed to the soluble type of food fibre (estimated about 15g/day), each subject consu- Ethics between the groups (Table 2). fibre (14). The fibre supplement used in this study consis- med 6 g of fibres during the high dosage period of 8 weeks The study was conducted according to Helsinki decla- ted mostly of insoluble fibre. However, as far as we know and 4 g of fibres during the maintenance dosage period, res- rations and with the approval of the Ethical Committee of Biochemical parameters there are no reports comparing the weight reducing effect pectively. In addition, each subject received one multi- the Health Region I in Norway. All subjects gave their in- Laboratory values before and after treatment are given of the two type of fibres. Moreover, in this long term study vitamin tablet daily. For vitamins and minerals, the content formed consent. in Table 3. Haemoglobin and serum uric acid decreased in the weight reducing effect of fibre was not attenuated, sug- in this tablet was equal to 100 % Recommended Daily both groups during treatment (p < 0.01) but no significant gesting that no rebound mechanisms of actions have occur- Allowance. In order to keep the subjects motivated, they Statistical analysis differences were observed between the groups (p > 0.5). red. were informed in group sessions, regarding health consequ- Statistical analysis was performed in those patients who Serum concentrations of and triglycerides were Concomitant to the weight loss, reductions of serum ences of overweight three times during the treatment period. fulfilled the study according to the protocol. Differences in significantly reduced in both groups during treatment. No concentrations of cholesterol and triglycerides were obser- At start, a physical examination was performed, inclu- consecutive weight changes between the fibre and the pla- additional effects in blood lipids were observed in the fibre ved. We were, however, not able to confirm previous re- ding blood pressure measurement, height, weight and BMI cebo group were evaluated by using Wilcoxon rank sum test. group. Treatment did not change the serum concentrations ports that a dietary fibre supplement can enhance (kg/m2). These procedures were repeated every week du- Significance of differences between the groups was assessed of potassium and sodium. a reduction of these blood lipids beyond that of a hypoca- ring the first 12 weeks and every fourth week during the rest by the paired Student’s t tests, defining a p-value < 0.05 as loric diet per se (5). When reviewing the literature, most of the treatment period. statistically significant. Tab. 3: Biochemical parameters (mean ± SEM) before and studies report that soluble fibre improves the lipid profile in Duration of the study was 24 weeks with clinical visits after treatment with fibre supplement in healthy overweight blood except for triglycerides (3,5,16), whereas in one re- scheduled at the same time each week. Subjects were weig- Results subjects. * indicates significant difference from value befo- port in hamsters insoluble fibre was linked to a reduction of hed each week and side effects were recorded. Compliance re start. the serum concentration of cholesterol (15). Therefore, the with the drug treatment was checked by the returned tab- Of the 60 intended-to-treat patients (30 in each group) lack of reduction of serum cholesterol observed in this stu- Fibre Placebo lets; 80% compliance was considered acceptable. randomised to fibre and placebo treatment, 53 subjects dy, is most likely ascribed to a low soluble fibre content in start end start end Adherence to the 1200 kcal diet was evaluated regular- (28/25) in the fibre group and placebo group, respectively the supplement. Hb ly during the treatment period using a standardised questi- entered the study. Seven of the subjects were not included 13.5 ± 0.1 12.6 ± 0.2* 13.9 ± 0.1 13.1 ± 0.2* In conclusion, the present investigation shows that this (g l-1) onnaire. An adherence of 20% was considered acceptable. due to sudden events between the randomisation and the dietary fibre supplement is of value as an adjunct in the ma- start. The remaining 53 subjects completed the study accor- b-glucose -1 5.3 ± 0.1 5.1 ± 0.1* 5.6 ± 0.1 5.2 ± 0.1* nagement of overweight. Laboratory tests ding to the protocol. The treatment was well tolerated. No (mmol l ) s-cholesterol Blood samples were drawn after an overnight fast at start side effects were reported in neither group. 5.7 ± 0.2 5.2 ± 0.2* 6,0 ± 0.3 5.5 ± 0.2* References and after 24 weeks. The blood samples were withdrawn into (mmol l-1) s-triglycerides vacutainer tubes containing EDTA (1mg/ml, final concen- Characteristics of subjects 1.34 ± 0.2 0.92 ± 0.1* 1.47 ± 0.2 0.92 ± 0.1* 1. Alfieri MA, Pomerleau J, Grace DM, Anderson L. Fiber intake of normal weight, tration), and centrifuged at 1000 g for 10 min at 4°C. Hemo- At start of the study there were no significant differen- (mmol l-1) moderately obese and severely obese subjects. Obes Res 1995;3:541-7. s-uric acid 2. Bennett WG, Cerda JJ. Benefits of . Myth or medicine? Postgrad globin and glucose in blood and serum concentrations of ces between age, gender, body weight, BMI and duration of Med 1996; 99:153-6,166-8,171-2. -1 270 ± 11 217 ± 10* 259 ± 14 206 ± 12* cholesterol, triglycerides, uric acid, sodium and potassium overweight (Table 1). There was a significant weight loss in (mmol l ) 3. Brown L; Rosner B; Willett WW, Sacks FM. Cholesterol-lowering effects of die- s-potassium tary fiber: a meta-analysis [see comments]. Am J Clin Nutr 1999;69:30-42. -1 4.3 ± 0.0 4.3 ± 0.0 4.3 ± 0.0 4.2 ± 0.0 4. Evans E, Miller DS. Bulking agents in the treatment of obesity. Nutr Metabol (mmol l ) 1975;18: 199-203. Tab. 1: Characteristics of healthy overweight subjects trea- Fig. 1: The long term effect of fibre supplement (n=28) and s-sodium 5. Glore SR, Van-Treeck D, Knehans AW, Guild M. Soluble fiber and serum lipids: 144 ± 0.3 143 ± 0.4 144 ± 0.5 144 ± 0.5 ted with fibre supplement. placebo (n=25) on body weight in healthy overweight sub- (mmol l-1) a literature review. J Am Diet Assoc 1994;94:425-36. jects. * indicates significant difference from placebo. For 6. Kraemer WJ, Volek JS, Clark KL et al. Physiological adaptations to a weight-loss Variable Fibre Placebo p-value dietary regimen and exercise programs in women. J Appl Physiol 1997;83:270-9. (n=28) (n=25) further details, see text. 7. Liu S, Stampfer MJ, Hu FB et al. Whole-grain consumption and risk of coronary Discussion heart disease: results from the Nurses’ Health Study. Am J Clin Nutr 1999;70: Age (years) 37.0 ± 1.7 43.2 ± 2.1 n.s. 78 412-9. Body weight (kg) 75.6 1.6 75.5 1.6 n.s. 8. Ludwig DS, Pereira MA, Kroenke CH et al. Dietary fiber, weight gain, and car- ± ± 77 In the present study we have studied the long term ef- 2 diovascular disease risk factors in young adults. JAMA 1999;282:1539-46. BMI (kg/m )27.5± 0.7 27.5 ± 0.6 n.s. fibre fect of fibre supplement in mildly overweight subjects for 9. Marlett JA, Hosig KB, Vollendorf NW, Shinnick FL, Haack VS, Story JA. 76 placebo 24 weeks. Using a treatment regimen with a combination of Mechanism of serum cholesterol reduction by oat bran. Hepatology 75 a hypocaloric diet, and a dietary fibre supplement in addi- 1994;20,1450-7. Tab. 2: Blood pressures (mm Hg) (mean ± SEM) before 10. Nelson LH, Tucker LA. Diet composition related to body fat in a multivariate stu- and after treatment with fibre supplement in healthy over- 74 tion to regular information meetings, we succeeded in ob- dy of 203 men. J Am Diet Assoc 1996;96:771-7. weight subjects. * indicates significant difference from va- taining a high patient compliance and a sustained weight 11. Rigaud D, Ryttig KR, Leeds AR, Bard D, Apfelbaum M. Effects of a moderate di- 73 * etary fibre supplement on rating, energy input and faecal energy output in lue before start. reduction. The weight loss was more pronounced in the fib- 72 young, healthy volunteers: A randomised, double-blind, cross-over trial. Int * re group than in the placebo group. This agrees with other J Obesity 1987;11(suppl 1):73-8. Fibre Placebo (kg) body weight 71 fibre studies although of short duration (1,8). 12. Ro/ssner S, von Zweigbergk D, O/hlin A, Ryttig K. Weight reduction with dietary start end start end * * fibre supplements: Results of two double-blind randomized studies. Acta Med 70 The explanation for the more rapidly achieved weight Scand 1987;222: 83-8. Systolic 13. Ryttig KR, Larsen S, Hćgh L. Treatment of slightly to moderately overweight per- 69 * loss in the fibre group is still not clear, but may be due to blood 127.1 ± 2.7 120.5 ± 2.6*134.0 ± 3.1126.8 ± 2.1* the physical properties of the fibre. Fibres with differing sons: A double-blind placebo-controlled investigation with diet and fibre tablets 68 (DumoVital). Tidsskr Nor Lćgeforen 1984;104:989-91. pressure * physical characteristics can alter gastrointestinal motility 14. Saltzman E, Roberts SB. Soluble fiber and energy regulation. Current knowledge Diastolic 67 and transit times in different ways. Therefore several pos- and future directions. Adv Exp Med Biol 1997;427:89-97. blood 81.1 ± 2.3 70.5 ± 1.6* 82.9 ± 2.2 74.6 ± 1.5* 15. Wilson TA, Romano C, Liang J, Nicolosi RJ. The hypocholesterolemic and anti- 0 8 16 24 sible modes of action have been proposed, such as lower atherogenic effects of Cholazol H, a chemically functionalized insoluble fiber pressure time in weeks energy intake (12), enhanced satiety (13), increased faecal with sequestrant properties in hamsters. Metabolism 1998;47: 959-64.

130 131 15 % soluble fibre and 85 % insoluble fibre. Patients were were measured using the routine methods of the Central the fibre group from week 4 and onwards as compared to energy excretion (11) or a combination of these reasons. told to follow a 1200 kcal diet (Libra Slimming Club diet), Laboratory Department of Sentralsykehuset of Akershus, the placebo group p <0.05) (Fig 1). One mechanism could be that fibre compounds bind to perform their regular exercise program, and not change Norway. The systolic and diastolic blood pressures were signifi- cholic acids and thereby reduces the fat absorption (9). their smoking habits during the study. In addition to the cantly reduced in both groups (p<0.01) without differences However, this effect has been ascribed to the soluble type of food fibre (estimated about 15g/day), each subject consu- Ethics between the groups (Table 2). fibre (14). The fibre supplement used in this study consis- med 6 g of fibres during the high dosage period of 8 weeks The study was conducted according to Helsinki decla- ted mostly of insoluble fibre. However, as far as we know and 4 g of fibres during the maintenance dosage period, res- rations and with the approval of the Ethical Committee of Biochemical parameters there are no reports comparing the weight reducing effect pectively. In addition, each subject received one multi- the Health Region I in Norway. All subjects gave their in- Laboratory values before and after treatment are given of the two type of fibres. Moreover, in this long term study vitamin tablet daily. For vitamins and minerals, the content formed consent. in Table 3. Haemoglobin and serum uric acid decreased in the weight reducing effect of fibre was not attenuated, sug- in this tablet was equal to 100 % Recommended Daily both groups during treatment (p < 0.01) but no significant gesting that no rebound mechanisms of actions have occur- Allowance. In order to keep the subjects motivated, they Statistical analysis differences were observed between the groups (p > 0.5). red. were informed in group sessions, regarding health consequ- Statistical analysis was performed in those patients who Serum concentrations of cholesterol and triglycerides were Concomitant to the weight loss, reductions of serum ences of overweight three times during the treatment period. fulfilled the study according to the protocol. Differences in significantly reduced in both groups during treatment. No concentrations of cholesterol and triglycerides were obser- At start, a physical examination was performed, inclu- consecutive weight changes between the fibre and the pla- additional effects in blood lipids were observed in the fibre ved. We were, however, not able to confirm previous re- ding blood pressure measurement, height, weight and BMI cebo group were evaluated by using Wilcoxon rank sum test. group. Treatment did not change the serum concentrations ports that a dietary fibre supplement can enhance (kg/m2). These procedures were repeated every week du- Significance of differences between the groups was assessed of potassium and sodium. a reduction of these blood lipids beyond that of a hypoca- ring the first 12 weeks and every fourth week during the rest by the paired Student’s t tests, defining a p-value < 0.05 as loric diet per se (5). When reviewing the literature, most of the treatment period. statistically significant. Tab. 3: Biochemical parameters (mean ± SEM) before and studies report that soluble fibre improves the lipid profile in Duration of the study was 24 weeks with clinical visits after treatment with fibre supplement in healthy overweight blood except for triglycerides (3,5,16), whereas in one re- scheduled at the same time each week. Subjects were weig- Results subjects. * indicates significant difference from value befo- port in hamsters insoluble fibre was linked to a reduction of hed each week and side effects were recorded. Compliance re start. the serum concentration of cholesterol (15). Therefore, the with the drug treatment was checked by the returned tab- Of the 60 intended-to-treat patients (30 in each group) lack of reduction of serum cholesterol observed in this stu- Fibre Placebo lets; 80% compliance was considered acceptable. randomised to fibre and placebo treatment, 53 subjects dy, is most likely ascribed to a low soluble fibre content in start end start end Adherence to the 1200 kcal diet was evaluated regular- (28/25) in the fibre group and placebo group, respectively the supplement. Hb ly during the treatment period using a standardised questi- entered the study. Seven of the subjects were not included 13.5 ± 0.1 12.6 ± 0.2* 13.9 ± 0.1 13.1 ± 0.2* In conclusion, the present investigation shows that this (g l-1) onnaire. An adherence of 20% was considered acceptable. due to sudden events between the randomisation and the dietary fibre supplement is of value as an adjunct in the ma- start. The remaining 53 subjects completed the study accor- b-glucose -1 5.3 ± 0.1 5.1 ± 0.1* 5.6 ± 0.1 5.2 ± 0.1* nagement of overweight. Laboratory tests ding to the protocol. The treatment was well tolerated. No (mmol l ) s-cholesterol Blood samples were drawn after an overnight fast at start side effects were reported in neither group. 5.7 ± 0.2 5.2 ± 0.2* 6,0 ± 0.3 5.5 ± 0.2* References and after 24 weeks. The blood samples were withdrawn into (mmol l-1) s-triglycerides vacutainer tubes containing EDTA (1mg/ml, final concen- Characteristics of subjects 1.34 ± 0.2 0.92 ± 0.1* 1.47 ± 0.2 0.92 ± 0.1* 1. Alfieri MA, Pomerleau J, Grace DM, Anderson L. Fiber intake of normal weight, tration), and centrifuged at 1000 g for 10 min at 4°C. Hemo- At start of the study there were no significant differen- (mmol l-1) moderately obese and severely obese subjects. Obes Res 1995;3:541-7. s-uric acid 2. Bennett WG, Cerda JJ. Benefits of dietary fiber. Myth or medicine? Postgrad globin and glucose in blood and serum concentrations of ces between age, gender, body weight, BMI and duration of Med 1996; 99:153-6,166-8,171-2. -1 270 ± 11 217 ± 10* 259 ± 14 206 ± 12* cholesterol, triglycerides, uric acid, sodium and potassium overweight (Table 1). There was a significant weight loss in (mmol l ) 3. Brown L; Rosner B; Willett WW, Sacks FM. Cholesterol-lowering effects of die- s-potassium tary fiber: a meta-analysis [see comments]. Am J Clin Nutr 1999;69:30-42. -1 4.3 ± 0.0 4.3 ± 0.0 4.3 ± 0.0 4.2 ± 0.0 4. Evans E, Miller DS. Bulking agents in the treatment of obesity. Nutr Metabol (mmol l ) 1975;18: 199-203. Tab. 1: Characteristics of healthy overweight subjects trea- Fig. 1: The long term effect of fibre supplement (n=28) and s-sodium 5. Glore SR, Van-Treeck D, Knehans AW, Guild M. Soluble fiber and serum lipids: 144 ± 0.3 143 ± 0.4 144 ± 0.5 144 ± 0.5 ted with fibre supplement. placebo (n=25) on body weight in healthy overweight sub- (mmol l-1) a literature review. J Am Diet Assoc 1994;94:425-36. jects. * indicates significant difference from placebo. For 6. Kraemer WJ, Volek JS, Clark KL et al. Physiological adaptations to a weight-loss Variable Fibre Placebo p-value dietary regimen and exercise programs in women. J Appl Physiol 1997;83:270-9. (n=28) (n=25) further details, see text. 7. Liu S, Stampfer MJ, Hu FB et al. Whole-grain consumption and risk of coronary Discussion heart disease: results from the Nurses’ Health Study. Am J Clin Nutr 1999;70: Age (years) 37.0 ± 1.7 43.2 ± 2.1 n.s. 78 412-9. Body weight (kg) 75.6 1.6 75.5 1.6 n.s. 8. Ludwig DS, Pereira MA, Kroenke CH et al. Dietary fiber, weight gain, and car- ± ± 77 In the present study we have studied the long term ef- 2 diovascular disease risk factors in young adults. JAMA 1999;282:1539-46. BMI (kg/m )27.5± 0.7 27.5 ± 0.6 n.s. fibre fect of fibre supplement in mildly overweight subjects for 9. Marlett JA, Hosig KB, Vollendorf NW, Shinnick FL, Haack VS, Story JA. 76 placebo 24 weeks. Using a treatment regimen with a combination of Mechanism of serum cholesterol reduction by oat bran. Hepatology 75 a hypocaloric diet, and a dietary fibre supplement in addi- 1994;20,1450-7. Tab. 2: Blood pressures (mm Hg) (mean ± SEM) before 10. Nelson LH, Tucker LA. Diet composition related to body fat in a multivariate stu- and after treatment with fibre supplement in healthy over- 74 tion to regular information meetings, we succeeded in ob- dy of 203 men. J Am Diet Assoc 1996;96:771-7. weight subjects. * indicates significant difference from va- taining a high patient compliance and a sustained weight 11. Rigaud D, Ryttig KR, Leeds AR, Bard D, Apfelbaum M. Effects of a moderate di- 73 * etary fibre supplement on hunger rating, energy input and faecal energy output in lue before start. reduction. The weight loss was more pronounced in the fib- 72 young, healthy volunteers: A randomised, double-blind, cross-over trial. Int * re group than in the placebo group. This agrees with other J Obesity 1987;11(suppl 1):73-8. Fibre Placebo (kg) body weight 71 fibre studies although of short duration (1,8). 12. Ro/ssner S, von Zweigbergk D, O/hlin A, Ryttig K. Weight reduction with dietary start end start end * * fibre supplements: Results of two double-blind randomized studies. Acta Med 70 The explanation for the more rapidly achieved weight Scand 1987;222: 83-8. Systolic 13. Ryttig KR, Larsen S, Hćgh L. Treatment of slightly to moderately overweight per- 69 * loss in the fibre group is still not clear, but may be due to blood 127.1 ± 2.7 120.5 ± 2.6*134.0 ± 3.1126.8 ± 2.1* the physical properties of the fibre. Fibres with differing sons: A double-blind placebo-controlled investigation with diet and fibre tablets 68 (DumoVital). Tidsskr Nor Lćgeforen 1984;104:989-91. pressure * physical characteristics can alter gastrointestinal motility 14. Saltzman E, Roberts SB. Soluble fiber and energy regulation. Current knowledge Diastolic 67 and transit times in different ways. Therefore several pos- and future directions. Adv Exp Med Biol 1997;427:89-97. blood 81.1 ± 2.3 70.5 ± 1.6* 82.9 ± 2.2 74.6 ± 1.5* 15. Wilson TA, Romano C, Liang J, Nicolosi RJ. The hypocholesterolemic and anti- 0 8 16 24 sible modes of action have been proposed, such as lower atherogenic effects of Cholazol H, a chemically functionalized insoluble fiber pressure time in weeks energy intake (12), enhanced satiety (13), increased faecal with bile acid sequestrant properties in hamsters. Metabolism 1998;47: 959-64.

130 131 16. Wolever TM, Hegele RA, Connelly PW, Ransom TP, Story JA, Furumoto EJ, Jenkins DJ. Long-term effect of soluble-fiber foods on postprandial fat metabolism in ORIGINAL ARTICLE dyslipidemic subjects with apo E3 and apo E4 genotypes. Am J Clin Nutr 1997;66: 584-90. COSTS AND OUTCOMES OF USE OF AMITRIPTYLINE, CITALOPRAM Submitted April 2000. Accepted June 2000. AND FLUOXETINE IN MAJOR DEPRESSION: EXPLORATORY STUDY

1 1 1 2 Grethe Sto/a Birketvedt, MD. Ph.D., Ladislav Hosák , Ivan Tůma , Herbert Hanuš , Libor Straka Laboratory of Gastroenterology, 1 Institute of Clinical Medicine, Charles University in Prague, Faculty of Medicine in Hradec Králové: Department of Psychiatry , Department of Medical 2 University of Tromso/, Biophysics Norway. e-mail: [email protected] Summary: Background: The increasing cost of pharmaceuticals in the Czech Republic has led to the restriction on prescriptions of expensive new antidepressants. The aim of the study was to compare the costs and outcomes of using amit- riptyline, citalopram and fluoxetine in the treatment of major depression. Methods: Ninety patients (69 women) with a mean age of 44.5 years (S.D.=14.3) suffering from major depression were treated with amitriptyline (N=31), citalopram (N=29) and fluoxetine (N=30). Direct medical costs and effectiveness (indicated by the number of hospitalization-free days) were assessed in a prospective, open, intent-to-treat study. Results: Neither cost nor effectiveness were significantly different among the treatment groups. Conclusion: Amitriptyline treatment is not less expensive nor more effective than citalopram or fluoxetine therapies. There is no advantage in restricting patients from treatment with SSRIs, which have fe- wer adverse effects and a decreased risk of a lethal overdosage in comparison with tricyclic antidepressants.

Key words: Depression; Amitriptyline; Citalopram; Fluoxetine; Costs; Outcomes

Introduction Amitriptyline, citalopram and fluoxetine are the most fre- quently used antidepressants in the CR (15). Health care expenditures in the Czech Republic (CR) The aim of the study was to compare the direct costs totaled $ 4 billion in 1998 as compared to $ 3.1 billion in and effectiveness in reducing hospitalization of antidepres- 1995 (21). If health care expenditures had only increased sive treatment with amitriptyline in comparison with treat- by the general rate of inflation, they would only have equa- ment with the SSRIs, citalopram and fluoxetine in the led $ 3.6 billion in 1998 (2). One reason for this increased Czech Republic. The costs were assessed from a perspecti- rate of expenditures is the significant increase in the cost of ve of the General Health Insurance Company of the Czech medications. Medication costs in the CR in 1996 were five Republic. This institution is a dominant health care policy times higher than in 1990 (5). Health insurance companies maker in the CR which does not track indirect costs of di- have set financial limits and increased administrative regu- seases. Owing to this fact, the indirect costs of depression lations upon drug prescriptions in order to prevent further were not assessed by the authors. increases in medication costs. If medication costs are too This study represents a pharmacoeconomic extension high, the prescribing physician’s reimbursement is reduced. of an original clinical antidepressant trial in hospitalized This strategy has not been entirely successful and has come patients. at the cost of preventing patients from obtaining modern drugs that are known to cause fewer side effects. Material and Methods Restrictions in the Czech Republic are designed to inc- rease the use of older tricyclic antidepressants (TCAs) in- Subjects stead of selective serotonin re-uptake inhibitors (SSRIs) in All patients diagnosed with depressive episodes treated the treatment of major depression. The international litera- with amitriptyline, citalopram or fluoxetine, who had just ture suggests that use of tricyclic antidepressants does not been discharged from the inpatient unit of the Department lead to savings in direct treatment costs in major depressi- of Psychiatry, University Hospital in Hradec Králové from on in comparison with the SSRIs (4,9,13,17,18,25). No pro- September 1st, 1994 to August 31st, 1997 were included in spective pharmacoeconomic study related to this issue has the study. Patients provided informed consent. Ninety pati- been performed in a former communist country. This is an ents were followed. There were more women (N=69) than interesting setting to study this issue, given the rapid trans- men (N=21). Diagnoses according to the International formation of the health care system in these countries. Classification of Diseases-10th Version (20) were as follows:

132 ACTA MEDICA (Hradec Králové) 2000;43(4):133-136 133