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The effects of rose hip (Rosa canina) on plasma antioxidative activity and C-reactive protein in patients with rheumatoid arthritis and normal controls: a prospective cohort study.

doi: l0.1016/j.phymed.20l1.02.008

ABSTRACT

Objectives: Rose hip (Rosa canina) has been used as an herbal remedy against a wide range of ailments including inflammatory disorders. The anti-inflammatory and antioxidant properties of rose hips have been evaluated in vitro and active constituents have been isolated. Rose hip contains antioxidant nutrients and an anti-inflammatory galactolipid. Rheumatoid arthritis (RA) is an inflammatory disease where activated cells release reactive oxygen substances. Thus it could be relevant to investigate if rose hip had an anti-inflammatory and/or antioxidant effect in this situation.

Methods: In this open case-control study 20 female patients with RA and 10 female controls were given 10.5 g rose hip powder daily (Litozin[R]) for 28 days. Blood samples were analysed at baseline and follow-up for the capacity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase and the inflammatory marker C-reactive protein (CRP). The participants kept a food diary for the first 3 days and the last 3 days of the intervention period. The RA-patients completed The Stanford Health Assessment Questionnaire at baseline and follow-up.

Results: CRP-concentrations of both patients and healthy controls did not change. Nor was any effect found on the activity of antioxidant enzymes. There was no difference in food intake at baseline, but in the last week the RA-group reduced their energy intake.

Conclusions: 10.5g Litozin[R] in 28 days had neither effect on clinical symptoms or laboratory measurements in patients with RA or healthy controls. This is in contrast to previous intervention studies with rose hip powder that found a reduction in the concentration of CRP. The results of the present study indicate that a daily amount of approximately lOg rose hip powder for one month has no anti-inflammatory and/or antioxidant effect.

[c] 2011 Elsevier GmbH. All rights reserved.

ARTICLE INFO

Keywords: Rose hip Rosacanina Antioxidants Free radicals Antioxidant enzymes C-reactive protein Rheumatoid arthritis

Introduction

Patients with chronic painful inflammatory diseases such as rheumatoid arthritis (RA) often seek alternative therapy. Rose hips and in particular those of dog rose (Rosa canina L, Rosaceae) have traditionally been used for the prevention and therapy of infections, and inflammatory diseases (Kharazmi and Winther 1999; Winther et al. 1999; Rein et al. 2004; Willich et al. 2010). Inflammation is associated with increased generation of reactive oxygen-and nitrogen species (ROS/RNS), which is thought to play an important role in the inflammatory process and to contribute to tissue damage. Antioxidant nutrients such as vitamin

C, vitamin E, carotenoids, polyphenols and antioxidant enzymes play a significant role in the protection against the damaging effects of ROS/RNS. Important antioxidant enzymes are superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and cata-lase (Halliwell and Gutteridge 1999). A rose-hip powder (Litozin[R]) has shown to reduce symptoms associated with rheumatoid inflammation in clinical trials and extracts of this powder has shown strong anti-inflammatory activities (Kharazmi and Winther 1999; Warholm et al. 2003; Rein et al. 2004) as well as high total antioxidant capacity (TAC) in vitro (Daels-Rakotoarison etal. 2002; Wenzig et al. 2008). Evidence from in vitro studies indicates that rose hip powder exert anti-inflammatory properties via reduced chemotaxis of peripheral blood neutrophils and monocytes in healthy subjects, and a reduction in C-reactive protein (CRP) is seen after 4 weeks supplementation in patients with osteoarthritis (OA) (Winther et al. 1999; Kharazmi and Winther 1999). A specific galactolipid (l,2-di-O-[alpha]-linolenoyl-3-O-[beta]-D-galactopyranosyl-sn-glycerol; GOPO) isolated from rose hip powder by bioassay-guided fractionation and has been shown in vitro to reduce chemotaxis of peripheral blood polymorphonuclear leukocytes and monocytes, and therefore could play an important role as a mediator of the pain reducing property of rose hips (Larsen et al. 2003). Rose hips also contain high amounts of vitamin Cf minerals, carotenoids, polyphenols and fatty acids that may contribute to the antioxidant and/or anti-inflammatory activities (Jager et al. 2007; Wenzig et al. 2008). These considerations have been confirmed in other in vitro studies, where extracts of rose hips were shown to have potent anti-inflammatory activities and to inhibit cyclooxygenase (COX)-1 and -2 (Jager et al. 2007; Wenzig et al. 2008). The inhibition of COX was found to be related to particular unsaturated fatty acids but also other constituents such as triterpenoic acids were found to contribute to the COX inhibitive activity (Jager et al. 2007; Wenzig etal.2008).

The net-result of a meta-analysis of rose hip powder from Rosa canina for symptomatic treatment of OA was a small but relevant reduction of pain and a significant reduction of the use of medication (Christensen et al. 2008).

Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs) and biologic agents are used for the treatment of symptoms in RAt but patients seek complementary-alternative therapy for various reasons. Some do not respond successfully, some suffer serious side effects from the traditional medication, and some try to maximize the effect by a combination of traditional medicine and alternative medicine. If alternative therapy exerts positive effects that can be validated, they will be of interest in the traditional treatment of patients with RA.

The objectives of the present study were to investigate if intervention with rose hip powder from Rosa canina (i) affect the inflammatory marker CRP level in RA patients and controls, (ii) affect functional status and pain evaluated by the Health Assessment Questionnaire (HAQ) in RA patients, and (iii) affect the level of antioxidant enzyme activity in RA patients and/or controls.

Materials and methods

Subjects

Twenty consecutive, female patients with RA as defined by the American Rheumatism Association (ARA) were recruited from the outpatient clinic, Department of Rheumatology, the Parker Institute, Frederiksberg Hospital. The inclusion criteria for the RA-group were stable RA disease activity and unchanged pharmacological treatment for at least 3 months. Patients with other systemic, immunologic, or inflammatory diseases such as reactive arthritis, MB Bechterew, fibromyalgia or psoriatic arthritis were not included in the trial. Ten healthy, age-matched female controls were recruited from volunteering hospital staff members. Persons with body mass index > 30 kg/[m.sup.2], plant allergy, odd food habits, and vegetarians were not included.

Intervention

A standardised rose hip powder of Rosa canina (Litozin[R]) made from the seeds and husks of the fruits from a subtype of Rosa canina was used in this study. This common wild-growing hedgerow rose is marked as a food supplement with antioxidant properties and has been on the Scandinavian market for a decade (Warholm et al. 2003; Rein et al. 2004; Willich et al. 2010). The powder used was from a single batch.

The plants used for the preparation of the rose hip powder in Litozin[R] are grown in standardised fields in Denmark (Lange-land) according to good agriculture practice (GAP). The rose hips are harvested when they are mature and brought immediately to freezing facilities. The selection of rose hips for production of the powder is made by laser technique and the temperature never exceeds 40 C (Rein et al. 2004). The standardised rose hip powder used in this study is assumed to be of the same quality, and hence contain the same amounts of GOPO, vitamins, minerals and other constituents (Larsen et al. 2003; Rein et al. 2004) as the rose hip powder used in other clinical trials (Winther et al. 1999; Kharazmi and Winther 1999; Warholm et al. 2003; Rein et al. 2004; Willich et al. 2010) because (i) the same subtype of R. can-ina has been used, (ii) the plants have been grown in the same fields and (iii) the production of the rose hip powder has been performed under the same standardised conditions as described above.

Study design

The study was designed as an open 4-week prospective cohort study, carried out between February and April 2008. Patients and controls received 10.5g rose hip powder daily (2x7 capsules) for 28 days. Each capsule contained 750 mg rose hip powder. The capsules were taken two times a day along with a meal. During the study period, the patients and controls were instructed not to change exercise habits, medication, consumption of medicine, food, drinks and vitamin- and minerals or dietary supplements. All participants filled out a form with these information at baseline and at follow up. The study was approved by the Regional Ethical Committee and in accordance with the Declaration of Helsinki. The volunteers all gave their oral and written informed consent.

Dietary assessments

For the calculation of dietary intake of energy and nutrients, the participants completed a 2 x 3 day food dairy (first and last three days of the intervention period). To estimate the portion size standard household measurements were used. The average estimated intake was calculated using the Dankost 3000 calculation program (Dansk Catering Center, Herlev, Denmark) based on the food-composition database of the Danish Veterinary and Food Administration. The use of any kind of supplementation (e.g., fish oils, vitamins, minerals, etc.) prior to the study was recorded. The intake of GOPO was estimated after analyses of some of the most popular types of fruits, vegetables, cereals, and potato (Larsen and Christensen 2007).

Outcome measures

At study entry and at the end of the intervention period the following items were assessed: HAQ, a 100 mm VAS for pain assessment, a 100 mm VAS for assessment of disease severity (patients global). At the same time, blood samples were drawn for analyzing the plasma concentration of CRP and antioxidant enzymes activity: SOD, GPx, GR and catalase. Compliance was assessed by counting the total number of returned capsules, and the participants were instructed to report any adverse event.

Blood collection and biochemical analysis

Fasted blood (20 ml) was drawn (at baseline and endpoint) into evacuated tubes with EDTA anticoagulant (Vacutainer: Bee-ton Dickenson Lot no 367525). Fasted blood samples were stored on ice for a maximum of 1 h prior to centrifugation (4 [degrees] C, 1500 x g, l0min). Plasma and leukocytes were removed, and erythrocytes were washed twice in NaCl 0.9%, lysated with MilliQ-water, and stored at-80 [degrees] C until analyzing. GPx, catalase, SOD and GR activities were measured in erythrocyte lysates by previously published procedures (Wheeler et al. 1990) on a Cobas Mira Plus+ analyzer (Roche Diagnostic System, Basel, Schweiz).

The enzymatic activities were calculated relative to the amount of hemoglobin. All samples were run in duplicate. Laboratory controls were: SOD: RANDOX RANSOD KONTROL Lot nr 228RD; GPx: RANDOX RANSEL KONTROL Lot nr 291RS; GR: RANDOX GLUTATHIONE REDUCTASE KONTROL Lot nr. 110GR in supplement to the internal standard.

CRP: Blood samples (1.4 ml) were collected in sterile tubes and allowed to stand at room temperature for a minimum of 15min before centrifugation (20 [degrees] C, 2500xgt lOmin). CRP was determined in serum on an ABX Pentra 400 (Horiba ABX, France) with a high sensitive latex-enhanced immunonephelometric assay (CRP CP from ABX Pentra).

Statistics

The primary statistical analyses were based on observed mean differences (i.e. changes in scores, denoted with a [DELTA]). In order to compare groups we used two-sample t tests (or the Mann-Whitney test when appropriate)-testing for potential differences between changes in the RA- and the control group, respectively after 28 days intervention. Testing the statistical hypothesis [H.sub.0]: [DELTA] healthy control = [DELTA] RA. As this was designed and prespecified as an explorative analysis, we applied the paired test statistics as well: one-sample t-test and Wilcoxon's test for matched pairs were used to compare baseline findings with those after 28 days intervention in each group separately.

All data were handled as recommended by STROBE for estimating epidemiologic data (http://www.strobe-statement.org). Data are given as mean [+ or -] standard deviation (SD) unless otherwise stated. Any P-value associated with a two-sided hypothesis equal to or <5% was regarded as statistically significant perse.

Results

The base-line characteristics of RA patients and controls are presented in Table 1. None of the potential prognostic factors in RA such as age and body mass index were significantly different (P>0.47). The same applied for the use of anticonception, vitamins and mineral supplements, dietary supplements and use of alternative medications. There were only few smokers in both groups, and the frequency of exercise was similar in the two groups. All participants succeeded in maintaining their usual medication, intake of vitamin-and dietary supplements or exercise habits during the intervention period. Two RA patients but no controls dropped-out from the study. One RA patient dropped out before the intervention, and one after two weeks because of mild abdominal symptoms. The effects of Rosa canina powder (Litozin[R]) on plasma CRP, erythrocyte antioxidant enzyme activity and HAQare shown in Table 2.
Table 1
Baseline characteristics for 19 patients with rheumatoid arthritis
(RA) and 10 healthy controls.

                          RA(n =          Control (n =     Difference
                      19)Mean [+ or  10)Mean[+ or -]SD     RA and
                          -] SD                           controlP
                                                           values

Subject
characteristics
Age (years)           59.8 [+ or -]  55.6 [+ or -] 14.7       0.465
                               13.7
BMI (kg/k             23.8 [+ or -]   24.2 [+ or -] 2.6
[m.sup.2])                        3
Anticonception (%)                0               1(10)       0.690
Exercise, h/week       5.3 [+ or -]    3.6 [+ or -] 2.3       0.083
                                2.6
Vitamins and                 12(63)               5(50)
minerals, n (%)
Herbal remedies, n           11(58)               3(33)
(%)
Complementary and              0(0)                0(0)
alternative
medicine, n (%)
Vegetarian, n (%)              0(0)                0(0)
Smoker, n (%)                 2(11)               1(10)
Clinical data
HAQdisahility          0.6 [+ or -]
                               0.47
VAS, pain              2.8 [+ or -]
                                1.5
VAS, global            3.3 [+ or -]
                                1.6
Biochemical data
CRP(mg/l)              4.2 [+ or -]    2.1 [+ or -] 2.8       0.179
                                5.4
Catalase, U/g Hb      12.6 [+ or -]     12.2 [+ or -] 2       0.613
                                2.5
GR. U/g Hb            12.1 [+ or -]   11.7 [+ or -] 1.3       0.503
                                1.6
GPx, U/g Hb           35.1 [+ or -]    323 [+ or -] 6.2       0.255
                                5.7
SOD, U/g Hb           1195 [+ or -]    1325[+ or -] 141       0.143
                                322
Characteristics of
diet
Energy intake, kj/d   7342 [+ or -]   7422 [+ or -] 294       0.876
                               1266
Energy intake,         114 [+ or -]     112 [+ or -] 18       0.820
kj/kg                            28
EI/ [BEE.sub.est]      1.2 [+ or -]   1.3 [+ or -] 0.17       0.109
                                0.2
Protein, g/d            68 [+ or -]      70 [+ or -] 15       0.741
                                 14
Protein, g/kg          1.1 [+ or -]    1.1 [+ or -] 0.2       0.972
                                0.3
Vitamin A, RE/d       2244 [+ or -]  2365 [+ or -] 2166       0.912
                               3555
Vitamin C, mg/d        164 [+ or -]    149 [+ or -] 107       0.714
                                103
Vitamin E, a-TE/d      7.1 [+ or -]    7.3 [+ or -] 2.4       0.875
                                2.4
Selenium,             36.4 [+ or -]  37.6 [+ or -] 10.8       0.777
[mu]g/d                        10.6
Fruit (g/d)            256 [+ or -]    250 [+ or -] 144       0.902
                                  8
Vegetable, g/d          210[+ or -]    236 [+ or -] 105       0.572
                                122
Fish, g/d                27[+ or -]      43 [+ or -] 47       0.354
                                 31
Galactolipid (GOPO),  58.7 [+ or -]  44.2 [+ or -] 28.8       0.292
mg/d                           42.5

Abbreviations: SD: standard deviation; d; day; El; energy intake; BEE;
estimated basal energy expenditure; CRP; C-reactive protein; Hgb;
hemoglobin; GR; glutathione reductase; GPx; glutathione peroxidase;
SOD; superoxide dismutase; HAQ; Health Assessment Questionnaire; VAS;
visual analog scale.


Baseline plasma levels of the inflammation marker CRP did not differ significantly between the two groups. Intervention with Litozin[R] had no effect on CRP in RA patients or controls. At follow-up there was no significant change in CRP between the two groups (P= 0.156). Furthermore, no difference was found between the of antioxidant enzyme activity at baseline in the two groups (Table 1). None of the four erythrocyte antioxidant enzyme activities were affected by intervention with Litozin[R] (Table 2). Rosa canina powder also had no significant effect on HAQ, VAS pain or VAS patient global in the RA-group (Table 2).
Table 2
Difference from baseline to follow-up inside the groups and between
the groups, for 19 patients with rheumatoid arthritis (RA) and 10
healthy controls.

Variable            RA(n =    D RA(n =   Control   Control (n
difference A       19)Mean   19)P-value    (n =        =
                     [+ or                 10)Mean   10)P-value
                     -] S                  [+ or
                                           -] SD

Biochemical data
[DELTA] CRP,         1.0 [+       0.636   -1.3 [+       0.838
mg/1                  or -]                 or -]
                        5.6                   2.8
[DELTA] Catalase,   -0.4 [+       0.993    0.2 [+       0.838
U/g Hgb               or -]                 or -]
                        1.9                   1.0
[DELTA]              0.0 [+       0.928    0.1 [+       0.881
CR.U/gHgb             or -]                 or -]
                        0.9                   0.5
[DELTA] GPx, U/g    -0.2 [+       0.918    0.0 [+       1.000
Hgb                   or -]                 or -]
                        3.1                   2.2
[DELTA] SOD, U/g    -0.6 [+       0.918   -10.8[+       0.853
Hgb                   or -]                 or -]
                       92.8                 121.2
Clinical data
[DELTA] HAQ         -0.1 [+       0.424
                      or -]
                       0.17
[DELTA] VAS,         0.1 [+       0.871
pain                  or -]
                        2.2
[DELTA] VAS,         0.7 [+       0.182
patient global        or -]
                       1.58
Characteristics
of diet
[DELTA] Energy       -824[+       0.058    162 [+       0.836
intake, kj/d          or -]                 or -]
                       1171                  1026
[DELTA] Energy      -13.2[+       0.123       4.3       0.696
intake, kj/kg         or -]
                       18.6
[DELTA]EI/BEEcst    -0.1 [+       0.105   0.05 [+       0.648
                      or -]                 or -]
                       0.23                  0.19
[DELTA] Protein,    -6.4 [+       0.129    1.9 [+       0.843
g/d                   or -]                 or -]
                       14.7                  18.2
[DELTA] Protein,    -0.1 [+       0.238    0.0 [+       0.795
g/kg                  or -]                 or -]
                        0.2                   0.3
[DELTA] Vit, A,      -954.7       0.251   -978 [+       0.202
RE/d                  [+ or                 or -]
                    -] 3219                  1974
[DELTA] Vit, C,     -14.2[+       0.626    6.1 [+       0.887
mg/d                  or -]                 or -]
                       78.1                  91.8
[DELTA] Vit, E,      0.2 [+       0.248   -0.1 [+       0.932
a-TE/d              or -] 4               or -] 3
[DELTA] Selenium,    4.8 [+       0.537   -5.8 [+       0.325
[mu]g/d               or -]                 or -]
                       32.7                  13.2
[DELTA] Fruit,     -18.3 [+       0.645   31.8 [+       0.594
g/d                   or -]                 or -]
                        127                   122
[DELTA]             -8.2 [+       0.818    l.8 [+       0.963
Vegetable, g/d        or -]                 or -]
                        103                    87
A Fish, g/d         17.7 [+       0.086  -19.9 [+       0.317
                      or -]                 or -]
                       32.7                  51.4
[DELTA]            -3.76 [+       0.632  -0.22 [+       0.208
galactolipid          or -]                 or -]
GOPO, mg/d             59.6                  26.9

Variable           Difference
difference A         RA and
                     control
                     P-value
Biochemical data
[DELTA] CRP,            0.156
mg/1
[DELTA] Catalase,       0.322
U/g Hgb
[DELTA]                 0.769
CR.U/gHgb
[DELTA] GPx, U/g        0.240
Hgb
[DELTA] SOD, U/g        0.819
Hgb
Clinical data
[DELTA] HAQ
[DELTA] VAS,
pain
[DELTA] VAS,
patient global
Characteristics
of diet
[DELTA] Energy          0.029
intake, kj/d
[DELTA] Energy          0.014
intake, kj/kg
[DELTA]EI/BEEcst        0.039
[DELTA] Protein,        0.231
g/d
[DELTA] Protein,        0.505
g/kg
[DELTA] Vit, A,         0.981
RE/d
[DELTA] Vit, C,         0.561
mg/d
[DELTA] Vit, E,         0.852
a-TE/d
[DELTA] Selenium,       0.227
[mu]g/d
[DELTA] Fruit,          0.314
g/d
[DELTA]                 0.786
Vegetable, g/d
A Fish, g/d             0.056
[DELTA]                 0.831
galactolipid
GOPO, mg/d

Abbreviations: SD: standard deviation; d: day; El: energy intake;
BEE: estimated basal energy expenditure; CRP: C-reactive protein;
Hgb: hemoglobin; GR: glutathione reductase; GPx: glutathione
peroxidase; SOD: superoxide dismutase; HAQ: Health Assessment
Questionnaire; VAS: visual analog scale.


The average habitual dietary intakes in the two groups are shown in Table 1. At baseline, there were no significant differences between the consumption of specific food groups that influence intake of antioxidant nutrients such as fruits, vegetables, cereals, legumes or the anti-inflammatory n-3 PUFA such as fish. The mean daily intake of energy, protein, vitamin A, vitamin C, vitamin E, selenium, and galactolipid (GOPO) was the same in the two groups at baseline and at end of the intervention (Tables 1 and 2). The RA-groups reduced their intake of energy significantly more that the control-group from baseline to follow-up (P=0.029) (Table 2).

Compliance

Compliance was calculated from the amount of returned capsules. Compliance was 98.8 [+ or -] 1 A% for the RA group and 99.3 [+ or -] 1.3% for the control group.

Discussion

Intervention with Litozin[R] had no effect on CRP level in the RA or control group in the present study. This result is contrary to the studies by Kharazmi and Winther (1999) and Winther et al. (1999) where an initial intervention with 45 g Litozin[R] a day significantly reduced CRP levels in OA patients (Winther et al. 1999) and healthy participants (Winther et al. 1999; Kharazmi and Winther 1999). 45 g Litozin[R] is a much higher dose than used in this study, and baseline CRP levels were also higher in the two previous studies than in the present study. This could explain the differences in outcome, and indicate that a dose of approximately 10 g rose hip powder a day is insufficient. Another confounder could be the low CRP level in our RA patients. At baseline there were no significant difference in CRP level between the RA group and the control group, which could indicate that the patients were well treated. A low CRP level at baseline means a reduced possibility for a further decline.

The amount of GOPO in the used Litozin[R] was not analysed, but according to previous investigations, the estimated total amount of this bioactive galactolipid in lOg standardised Rosa canina powder is approximately 2.5 mg (Larsen et al. 2003). The standardised rose hip powder investigated in the study of Larsen et al. (2003) originate from the same subtype of Rosa canina as the standardised rose hip powder of Litozin[R] capsules used in this and other studies (Kharazmi and Winther 1999; Winther et al. 1999; Warholm et al. 2003; Rein et al. 2004; Willich et al. 2010). Because the rose hip powder in Litozin[R] are produced from the fruits of Rosa canina plants grown according to GAP on standardised fields, at the same locality in Denmark, and by standard procedures, it is reasonable to assume that the content of GOPO, vitamins, and other constituents in this standardised rose hip powder is approximately the same despite of the production year. This is also supported by previous investigations of batches of fresh prepared Litozin[R] rose hip powder between 2002 and 2007 for the content of GOPO by analytical HPLC (Larsen and Christensen 2007). According to these investigations a rather constant level of GOPO between 2.4 and 2.8 mg GOPO in lOg Litozin[R] rose hip powder was found (unpublished results). In this study, the average estimated intake of GOPO and related galactolipids from food was 50 mg a day. It seems that lOg Litozin[R] contribute with a small amount of GOPO compared with intake from normal food. GOPO is a combination of galactose, glycerol and a-linolenic acid, and is probably digested in the gastro-intestinal tract before absorption. Animal studies show that pancreas preparations hydrolyzed galactolipids into free fatty acids and water-soluble galactose-containing compounds (Andersson et al. 1996), and that no radiolabeled intact galactolipid appeared in chyle lipids in rats (Ohlsson et al. 1998). It is further suggested that galactosylglycerols will be fermented into galactose and glycerol in colon (Sugawara and Miyazawa 2000). A human in vitro study showed that pancreas juice and duodenal content hydrolyze galac-tolipids and liberate free fatty acids (Andersson et al. 1995). An unpublished in vivo study with 10 volunteers that had undergone ileostomy surgery, was given a triglyceride emulsion containing 2 g galactolipid-phospholipid mixture to a drink. There were almost no intact galactolipid in the intestinal content and it was concluded that humans efficiently hydrolyse galactolipids.

Rosehip contains fatty acids such as palmitic, linoleic, and a-linolenic acids, which are known to affect inflammatory processes. Intervention with 10 g Litozin [R] contributes with 0.4 g fat, and even if all of it was PUFA, it is hard to believe that such a small amount could have any biologic or clinical effect when the daily dietary intake was around 80 g in total fat and 20 g PUFA (data not shown). Jager et al. (2007) have suggested that PUFA are the active components in rose hip acting via the COX system. However, Wenzig et al. (2008) found that rose hip fatty acids only play a minor role in the anti-inflammatory process, and concluded that unidentified constituents or a synergistic effect is causing the observed antiinflammatory effect of rose hip.

Antioxidant enzyme

No effect on antioxidant enzyme activity was detected in erythrocytes from RA patients or controls in this study. To the best of our knowledge, an effect of Rosa canina on antioxidant enzyme activity has never been published, whereas two previous studies have measured the effect of 10 ml extract of Rosa roxburghii on antioxidant activity in healthy humans. The study of van Rensburg et al. (2005) was small-scale, short-term, and intervention had no effect on GR, GPx or SOD. Yong-Xing et al. (1997) showed an effect on SOD and cataiase activity after two months intervention in 120 healthy participants. Other intervention studies of varying length with for example spinach (Castenmiller et al. 1999), parsley (Nielsen et al. 1999) or grape fruit (Young et al. 2000) have observed varied effects on enzyme activity in healthy human subjects.

A high production of ROS/RNS as a result of inflammation might result in different levels in antioxidant enzyme activities in healthy persons and RA patients. This was not the case in this study. Previous studies have shown inconsistent results with regard to the difference in antioxidant enzyme activities in RA patients compared to healthy controls. Some studies have shown higher levels of SOD activity (Cimen et al. 2000; Taysi et al. 2002) some lower SOD activity (Kiziltunc et al. 1998; Vipartene et al. 2006) and some the same level of activity (Kiziltunc et al. 1998). The same pattern applies to GPx where some studies show low activity (Taysi et al. 2002; Kamanli et al. 2004; Vipartene et al. 2006) and some similar levels (Cimen et al. 2000) in RA patients and healthy controls. Seven et al. (2008) and Kamanli et al. (2004) found a correlation between high degree of RA-disease activity and low antioxidant enzyme activity. Contrary to this finding Cimen et al. (2000) found a higher degree of RA-inflammation and SOD activity but an unchanged activity of GPx and cataiase. So far there is no consensus on the assumption that RA patients have an affected and weakened antioxidant enzyme activity. In this study, blood samples were taken 12-14 h after the consumption of rosehip and an antioxidative and/or anti-inflammatory effect may not have been detected if bioactive components have been cleared from the organism within this period. A rat study showed that injected radioactive galactolipid (10 mg) was rapidly cleared from plasma manly by the liver. T1/2 from plasma was 1-5 min and less than 6% of intact galactolipid was left after 4 h in liver and plasma together (Blometal. 1996).

Health Assessment Questionnaire (HAQ)

RA-patients are monitored with different kinds of subjective self-reported instruments, where HAQis widely used for determining functional status and pain. Rosa canina (Litozin [R]) had no effect on HAQ-scores in this study. A study by Willich et al. (2010) investigating the effect of 5 g Rosa canina powder a day in RA-patients, showed effect on HAQ after 3 months but effect was first significant after 6 month intervention on Physician's Global Scale and Health-related Quality of Life instruments. This might indicate a late onset of clinical effect and that 28 days are too short time to gain benefits. Besides, HAQmay not be the right instrument for short-term studies. Petri et al. (2003) compared different kinds of instruments and found that HAQ reflects effects later than other questionnaires.

It is difficult to judge the external validity of the findings in this study. The female patients, with good disease control and interest and energy to participate, were not a representative sample of a RA population and the controls were all educated and working in the health area. It should therefore be considered that while Rosa canina powder proved ineffective in this short-term and small-scale study of well treated RA patients and healthy controls, their effect in a larger study on individuals with higher risk of endogenous oxidative stress (such as cigarette smokers, elderly people, and RA with a higher degree of inflammation) remains to be investigated.

In conclusion, the short-term supplementation with 10.5 g Rosa canina powder a day did not influence the inflammatory marker CRP, the erythrocyte levels of the antioxidant enzymes SOD, GPx, GR, catalase or the self-reported HAQ. in well treated female RA patients or healthy female controls.

Acknowledgements

We are grateful to Hyben-Vital International, Langeland, Denmark for provision the rose hip powder (Litozin [R]) capsules. The Parker Institute is supported by grants from The Oak Foundation. The authors thank Mrs. Pia Madsen for her technical assistance.

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Bente Kfrkeskov (a), Robin Christensen (b), Susanne Bugel (a), Henning Bliddal (b), Bente Danneskiold-Samsoe (b), Lars Porskjaer Christensen (c), Jens Rikardt Andersen (a), (d) *

(a.) Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 30, DK-1958 Frederiksberg C, Denmark

(b.) The Parker Institute, Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg C, Denmark

(c.) Institute of Chemical Engineering, Biotechnology and Environmental Technology, Faculty of Engineering, University of Southern Denmark, Niels Bohrs Alle 1, DK-5230 Odense M, Denmark

(d.) Clinical Nutrition Unit 5711, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

0944-7113/$-see front matter [c] 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2011.02.008

* Corresponding author at: Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 30, DK-1958 Frederiksberg CT Denmark. Tel.: +45 3533 2504; fax: +45 3533 2483; mobile: +45 2334 6654.

E-mail address: jra@life.ku.dk (J.R. Andersen).
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Author:Kirkeskov, Bente; Christensen, Robin; Bugel, Susanne; Bliddal, Henning; Danneskiold-Samsoe, Bente; P
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:4EUDE
Date:Aug 15, 2011
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