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ARTICLE IN PRESS
Phytomedicine 15 (2008) 1032–1037
www.elsevier.de/phymed
Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers
Mohammad-Hadi Modaghegha, Masoud Shahabiana, Habib-Allah Esmaeilib,
Omid Rajbaic, Hossein Hosseinzadehd,
a
Mashhad Vascular Surgery Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences,
Mashhad (MUMS), Islamic Republic of Iran
b
Department of Public Health & Epidemiology, MUMS, Mashhad, Islamic Republic of Iran
c
Department of Medicinal Chemistry, School of Pharmacy, MUMS, Mashhad, Islamic Republic of Iran
d
Pharmaceutical Research Center, School of Pharmacy, 1365-91775, MUMS, Islamic Republic of Iran
Abstract
Saffron (Crocus sativus) stigma tablets were evaluated for short-term safety and tolerability in healthy adult
volunteers. The study was a double-blind, placebo-controlled design consisting of a 1 week treatment of saffron tablets.
Volunteers were divided into 3 groups of 10 each (5 males and 5 females). Group I received placebo; groups 2 and 3
received 200 and 400 mg saffron tablets, respectively, for 7 days. General measures of health were recorded during the
study such as hematological, biochemical and electrocardiographic parameters done in pre- and post-treatment
periods. Clinical examination showed no gross changes in all volunteers after intervention. Saffron with higher dose
(400 mg) decreased standing systolic blood pressure and mean arterial pressures significantly. Saffron decreased
slightly some hematological parameters such as red blood cells, hemoglobin, hematocrit and platelets. Saffron
increased sodium, blood urea nitrogen and creatinine.
This study showed that saffron tablets may change some hematological and biochemical parameters. However, these
alterations were in normal ranges and they were not important clinically.
r 2008 Elsevier GmbH. All rights reserved.
Keywords: Saffron (Crocus sativus); Clinical trial; Safety assessment; Human volunteers
Introduction and dye materials (e.g. crocetin and its glycosidic,
crocin) (Rio’s et al., 1996). Saffron and its constituents
Crocus sativus L. stigma commonly known as saffron are widely evaluated for their pharmacological activities
is a perennial stemless herb of the Iridaceae family that such as treatment of memory impairment, antidepres-
is widely cultivated in Iran. Commercial saffron sant, anticonvulsant and especially for their antitumor
comprises the dried red stigma with a small portion of effect (Abdullaev and Espinosa-Aguirre, 2004).
the yellowish style attached. Compounds considered In animal study, LD50 values of saffron stigma and
pharmacologically active and important are volatile petal extracts were 1.6 and 6 g/kg (intraperitoneally
agents (e.g. safranal), bitter principles (e.g. picrocrocin) injection), respectively, in mice. In sub-acute study, the
aqueous extract of stigma decreased hematocrit, hemo-
Corresponding author. Tel.: +98 511 8823252; globin and erythrocytes but it did not induce any
fax: +98 511 8823251. significant pathological effects on different organs such
E-mail address: hosseinzadehh@mums.ac.ir (H. Hosseinzadeh). as heart, liver, lung, spleen and kidneys (Karimi et al.,
0944-7113/$ - see front matter r 2008 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2008.06.003ARTICLE IN PRESS
M.-H. Modaghegh et al. / Phytomedicine 15 (2008) 1032–1037 1033
2004). Information on toxicology and safety of saffron Table 2. Weight (kg) of healthy adult volunteers treated with
is not consistent. In some reports doses between 1.2 and saffron tablets
2 g showed nausea and followed vomiting, diarrhea and
Placebo Saffron Saffron
bleeding (Schmidt et al., 2007). As there is inadequate
200 mg 400 mg
background information on toxicological evaluation of
saffron to give an assurance of safety in developing this Male (weight, 75.4072.07 68.4077.19 72.4077.33
spice for foods or pharmaceutical uses, in this study the kg)
stigma of saffron was evaluated for short-term safety Female (weight, 57.20711.36 53.4077.92 61.0074.84
and tolerability in healthy adult volunteers. kg)
Material and methods Test substance
Study design Plant material
Crocus sativus L. stigma was taken from Novin
The study was a double-blind, placebo-controlled Saffron Co. Mashhad, IR. Iran. It was formulated as
study consisting of 1 week treatment. Thirty normal, tablets which each tablet contained 200 or 400 mg dried
apparently healthy adults (age range 20–50 years) were saffron stigma.
selected for the study. Before treatment, pulse rate and
blood pressure readings were also taken, and a non-
Quantification saffron stigma
fasting pre-screen blood sample was taken for clinical
To quantificate crocin and safranal in an aqueous
examination and laboratory (hematology and blood
saffron extraction, a modified method was used (Sujata
biochemistry) investigations as well as urine analysis and
et al., 1992; Hadizadeh et al., 2007). The extract of
electrocardiogram (ECG). The study outcome measures
authentic stigmata of an aqueous saffron extraction was
were also evaluated on the day 8. All participants
passed through a 0.2 mm Millipore filter (Millipore,
provided written informed consent prior to the start of
Bedford, MA, USA) and eluted with 100% methanol.
the study.
These quantification was carried out by Shimadzu
HPLC LC-10ADvp system integrated with a Shimadzu
SCL-10Avp system controller and a SPD-10Avp UV-
Volunteers visible spectrophotometric on a reversed-phase Shim-
pak C18, VP-ODS analytical column (25 cm 4.6 mm
Volunteers were divided into 3 groups of 10 each (5 I.D with a 12.071.0 nm pore size and 4.670.3 mm
males and 5 females). Group I received placebo; groups particle size), using an isocratic mobile phase of
2 and 3 received 200 and 400 mg saffron tablets, acetonitrile:water (76:24%)) at a flow rate of 1.2 ml/
respectively, for 7 days (Tables 1 and 2). min. A Rheodyne Shimadzu Model 7725i injector was
used to inject 25 ml of the sample from a 25 ml Hamilton
straight-edge needle syringe onto the column. All data
were recorded and analyzed on a chromatography
TM
Study centre workstation Shimadzu Class-VP 6.10 software (Hadi-
zadeh et al., 2007). As reported before (Hosseinzadeh
This study was done at Vascular Surgery Research et al., 2008), using the calibration curve, the quantifica-
Center, Imam Reza Hospital in association with tion of crocin and safranal in a sample of C. sativus
Department of Pharmacology and Toxicology of extract achieved about 19.7 and 0.25 mg/g, respectively.
Mashhad University of Medical Science.
Inclusion criteria
Healthy adult volunteers and willing to give voluntary
Table 1. Age of the healthy volunteers (years) treated with written informed consent were selected to participate in
saffron tablets this study. The volunteers were proven to be healthy
Placebo Saffron Saffron through clinical examination by the physician along
200 mg 400 mg with hematological and biochemical investigations as
well as ECG.
Female (age, 27.4074.44 25.2073.34 26.0073.39
year)
Male (age, 30.0078.00 29.8079.12 31.4077.26 Exclusion criteria
year) Volunteers were excluded from study if any of the
following criteria applied at the time of study:ARTICLE IN PRESS
1034 M.-H. Modaghegh et al. / Phytomedicine 15 (2008) 1032–1037
1 – history of allergy to saffron, 2 – history of blood (400 mg) decreased standing systolic blood pressure
disease, for example: iron deficiently, anemia, hemophi- and mean arterial pressures significantly (Table 3).
lia, 3 – history of cardiovascular disease including ECG recordings discovered no irregularities in all
vascular or conductive cardiac disease, hypertension, treated volunteers and were within normal limits.
orthostatic hypotension, 4 – history of renal disorder or Saffron at a dose of 200 mg decreased RBC, Hb, HCT
electrolytes disorder, 5 – history of endocrine disease for (po0.05) and at a dose of 400 mg decreased RBC
example: hypo or hyper-thyroidism, diabetic mellitus, (po0.05) but Hb and HCt were decreased near
hyperlipidemia, hypercholestrolemia, 6 – history of significant (Hb: p ¼ 0.06, HCt: p ¼ 0.09) (Table 4).
gynecologic or any menstrual disturbance, 7 – pregnant Only saffron at a dose of 200 mg decreased platelets,
or lactating women, 8 – addicted to smoking or any INR and bleeding time (Table 5).
substance, 9 – volunteers who have taken any drugs. Saffron at a dose of 200 mg increased creatinine
(po0.05) and at a dose of 400 mg increased Na, BUN
Statistical analysis and creatinine (po0.05) (Table 6).
Saffron with both doses did not change triglyceride,
Data are expressed as mean7SD. Statistical analysis cholesterol, HDL and LDL parameters after 7-day
was done using Student’s paired t-test with SPSS administration in healthy volunteers (Table 7).
software. P-Values less than 0.05 were considered to No major adverse events were reported during the
be statistically significant. trial. Saffron at a dose of 400 mg in 4 volunteers (% 40)
increased their mood. One female volunteer in each
groups of 200 and 400 mg received saffron showed
Results abnormal uterine bleeding.
Through clinical examination showed no gross
changes in clinical sign and symptoms in all volunteers Discussion
after intervention.
No significant differences were noted in the mean The result of present study showed that saffron
values of body weight, sitting systolic and diastolic change slightly some clinical and laboratory parameters
blood pressure as well as standing diastolic blood in the healthy adult volunteers at high oral dosage of
pressure. Sitting and standing pulse rate in three groups 200 and 400 mg of saffron tablets.
before and after the intervention was not changed In this study, saffron tablet with higher dose (400 mg)
(Table 3). In this study, saffron with higher dose decreased to some extent standing systolic blood
Table 3. Effect of Crocus sativus stigma tablets on cardiovascular system study done in healthy adult volunteers
Variables Intervention Placebo Saffron 200 mg Saffron 400 mg
Sitting systolic BP (mmHg) Before 113.5713.75 11179.66 11479.36
After 11476.14 109711.41 11574.11
Sitting diastolic BP (mmHg) Before 6775.68 63.5711.06 64.576.85
After 6475.67 66.577.83 66.675.05
Standing systolic BP (mmHg) Before 121.50v10.01 12578.16 126.579.73
After 12377.88 12078.16 115.578.31 *
Standing diastolic BP (mmHg) Before 75.578.31 75.577.97 7576.66
After 72.073.49 76.076.99 73.076.74
Mean sitting arterial pressure (mmHg) Before 82.4977.98 79.32710.25 80.9977.33
After 80.6675.39 80.8378.47 81.5674.00
Mean standing arterial pressure (mmHg) Before 90.8376.90 91.9977.10 92.1677.41
After 88.9974.66 90.6676.04 87.1677.03 *
Sitting pulse rate (rate/min) Before 70.5710.51 70.376.86 72.3076.29
After 71.6713.43 68.2713.43 73.377.05
Standing pulse rate (rate/min) Before 76.7710.04 78.677.41 76.674.9
After 73.777.84 77.4710.24 76.677.94
Values presented as the mean7SEM; n ¼ 10 in each group. *po0.05, as compared to before intervention (paired t-test).ARTICLE IN PRESS
M.-H. Modaghegh et al. / Phytomedicine 15 (2008) 1032–1037 1035
Table 4. Effect of Crocus sativus stigma tablets on blood counts study done in healthy adult volunteers
Blood cells Intervention Placebo group 200 mg group 400 mg group
RBC (million/ml) Before 5.2770.66 4.9570.36 4.8770.50
After 5.2170.78 4.8270.40* 4.7470.45*
Hemoglobin (g/dl) Before 14.5471.95 14.4071.52 14.2071.30
After 14.1971.49 14.0171.27* 13.7971.27*
Hematocrit (%) Before 43.3570.83 44.1273.78 43.7473.93
After 43.6070.97 42.8173.56* 42.6173.77
Mean corpuscular volume (MCV), fl Before 85.8177.55 88.8874.19 89.5373.10
After 85.6577.15 87.9374.01 89.5574.46
Mean corpuscular hemoglobin (MCH), pg Before 27.5173.04 28.8472.14 29.0171.09
After 28.3373.49 33.32714.62 29.1371.62
Mean corpuscular hemoglobin concentration (MCHC) g/dl Before 32.2371.65 32.4971.14 32.3970.68
After 32.5671.52 32.3570.88 32.9871.09
WBC ( 1000/cu mm) Before 6.1671.08 6.1971.65 6.3271.04
After 6.4771.46 6.1671.60 5.8171.02
Polymorphonuclear cells (PMN) % Before 53.3977.53 55.5679.85 51.3977.70
After 58.6075.32 57.9578.93 52.1779.73
Lymphocyte % Before 34.6077.56 36.7678.95 38.6276.47
After 33.9776.42 36.36710.88 41.1577.01
Values presented as the mean7SEM; n ¼ 10 in each group. *po0.05, as compared to before intervention (paired t-test).
Table 5. Effect of Crocus sativus stigma tablets on coagulation factors and platelets study done in healthy adult volunteers
Coagulation factors Intervention Placebo group 200 mg group 400 mg Group
Platelets ( 1000/cu mm) Before 251746.58 232.5738.31 226.3769.81
After 221758.90 217.7738.08* 220.9757.28
Prothrombin time (PT) (sec) Before 13.4270.69 13.9170.93 13.2670.56
After 13.0270.65 13.4870.83 12.9270.59
Partial thrombin time (PTT) (sec) Before 28.8973.44 27.7773.40 28.0573.94
After 31.2973.25 28.8073.65 30.0974.43
International normalized ratio (INR) Before 1.0770.08 1.1270.06 1.0570.05
After 1.0870.10 1.0870.09* 1.0370.06
Bleeding time (sec) Before 93717.02 108732.25 96723.66
After 102720.97 75732.40* 85717.79
Clothing time (min) Before 5.4770.69 4.7470.67 5.1170.71
After 5.8870.74 4.6270.99 5.3870.89
Values presented as the mean7SEM; n ¼ 10 in each group. *po0.05, as compared to before intervention (paired t-test).
pressure and mean arterial pressures. The aqueous and a dose of 200 mg decreased platelets, INR and bleeding
ethanol extracts of C. sativus petals reduced the blood time. However, crocin, as a constituent of saffron,
pressure in a dose-dependent manner in rats (Fatehi prolonged blood coagulation time in mice, inhibited
et al., 2003). Recently, antihypertensive effect of saffron platelet aggregation in rabbits, prevented thrombus
stigma and its constituents safranal and crocin was also formation in rats and relieved respiratory distress due
seen in rats (unpublished data). A higher antihyperten- to pulmonary thrombosis in mice (Ma et al., 1999). A
sive effect may be seen in hypertensive patients. platelet aggregation inhibitor was isolated from stigma
Saffron reduced some hematological parameters but of C. sativus. The active substance was identified as
these changes were not dose dependent. Saffron tablet at adenosine (Okano et al., 1992). Thus, this effect needsARTICLE IN PRESS
1036 M.-H. Modaghegh et al. / Phytomedicine 15 (2008) 1032–1037
Table 6. Effect of Crocus sativus stigma tablets on biochemistry function of kidney study done in healthy adult volunteers
Variables Intervention Placebo Group 200 mg Group 400 mg Group
Na+ (mEq/dl) Before 140.3072.21 139.6071.83 138.5072.27
After 138.8073.58 138.1074.67 140.5072.79*
K+ (mEq/dl) Before 3.8970.25 4.0570.29 4.0470.27
After 4.0770.60 4.2270.37 4.1670.23
BUN (mg/dl) Before 13.4072.21 11.2073.19 12.3074.78
After 14.8074.77 14.2270.37 16.0076.99*
Creatinine (mg/dl) Before 0.7670.15 0.7370.17 0.7270.20
After 0.8170.21 0.9170.22* 0.8970.26*
Values presented as the mean7SEM; n ¼ 10 in each group. *po0.05, as compared to before intervention (paired t-test).
Table 7. Effect of Crocus sativus stigma tablets on lipid profiles study done in healthy adult volunteers
Lipid profiles Intervention Placebo group 200 mg group 400 mg group
Triglyceride (mg/dl) Before 125.60794.05 125.907105.07 137.30781.49
After 133.90776.77 111.40769.87 125.70794.88
Cholesterol (mg/dl) Before 177.90735.39 167.50734.89 192.80757.23
After 187.30740.22 158.50731.60 196.90741.24
HDL (mg/dl) Before 48.874.15 54.50715.83 49.2077.82
After 50.477.15 47.6078.36 47.40711.93
LDL (mg/dl) Before 103.00733.19 96.60723.09 119.40748.44
After 108.50729.40 91.50729.01 124.30729.15
Values presented as the mean7SEM; n ¼ 10 in each group. *po0.05, as compared to before intervention (paired t-test).
further study in a larger sample size and longer time extent the content of cholesterol, triglyceride and density
period. lipoprotein in blood and also increased the content of
Saffron increased some kidney function parameters such high density lipoprotein (Xu et al., 2005). Although in
as creatinine and BUN. However, this effect is not our study saffron tablets did not change lipid profile but
important clinically and these factors are in normal range. it seems in a longer period study (at least 2 months)
Saffron with both doses did not change triglyceride, saffron may reduce serum lipids in especially hyperlipi-
cholesterol, HDL and LDL parameters after 7-day demic patients.
administration in healthy volunteers. In rabbits, after 8 No major adverse events were reported during the
weeks of feeding on high lipid diet and supplementation trial. Saffron at a dose of 400 mg in 4 volunteers (% 40)
with crocetin, a constituent of saffron stigma, markedly increased their mood. Our previous studies showed
reduced the progression of atherosclerotic lesions and that saffron and its constituents have antidepressant
plasma levels of oxidized low-density lipoprotein (Ox- activity in mice (Karimi et al., 2001; Hosseinzadeh
LDL), whereas plasma lipids level remained unchanged. et al., 2004). Recently, the antidepressant activity of
These findings suggest that suppression of LDL oxida- saffron stigma and petal has been evaluated in clinical
tion by crocetin contributes, at least partly, to the trials (Akhondzadeh et al., 2005; Akhondzadeh et al.,
attenuation of atherosclerosis (Zheng et al., 2006). 2007).
However, in another study in quail and at the 9th week, One female volunteer in each groups of 200 and
the atherosclerosis model was established by feeding 400 mg administration of saffron showed abnormal
hyperlipidamic diet. Crocetin reduced the levels of uterine bleeding. Saffron induced uterine stimulant
serum total cholesterol, triglyceride, low density lipo- and estrogenic effects in guinea pigs and mice, respec-
protein cholesterol and inhibit the formation of aortic tively (Chang et al., 1964). Saffron induces menstruation
plaque (He et al., 2007). (an emmenagogue) and in traditional medicine, the
In experimental hyperlipemia rats with 2 months aqueous extract of saffron has been used for amenor-
feeding heavy cholesterol, crocin decreased to a great rhea and dysmenorrhea.ARTICLE IN PRESS
M.-H. Modaghegh et al. / Phytomedicine 15 (2008) 1032–1037 1037
In respect to dose of saffron, in the previous studies Fatehi, M., Rashidabady, T., Fatehi-Hassanabad, Z., 2003.
different amounts of this plant were administered. In a Effects of Crocus sativus petals’ extract on rat blood
double-blind, placebo-controlled, single-centre and ran- pressure and on responses induced by electrical field
domized trial, depressed patients received a capsule of stimulation in the rat isolated vas deferens and guinea-pig
saffron 30 mg/day (an ethanol extract, about 60 mg ileum. J. Ethnopharmacol. 84, 199–203.
Hadizadeh, F., Mahdavi, M., Emami, S.A., Seifi, M., Nassirli,
dried powder) for a 6-week study (Akhondzadeh et al.,
N., Khashayarmanesh, H., Hassanzadeh, M., Asili, J.,
2005). In a recent study, women were randomly assigned
Shariatimoghadam, A., Noorbakhsh, R., 2007. Evaluation
to receive the same dose for the treatment of pre- of ISO method in saffron qualification in: proceedings of
menstrual syndrome during two menstrual cycles (about the second international symposium on saffron biology and
2 months) (Agha-Hosseini et al., 2008). In antioxidant technology. Acta Hort. 739, 405–410.
study in human subjects, 50 mg of saffron dissolved in He, S.Y., Qian, Z.Y., Wen, N., Tang, F.T., Xu, G.L., Zhou,
100 ml of milk was administered twice a day for 6 weeks C.H., 2007. Influence of crocetin on experimental athero-
(Verma and Bordia, 1998). For estimation of maximum sclerosis in hyperlipidamic-diet quails. Eur. J. Pharmacol.
tolerated dose, we studied higher doses of saffron 200 554, 191–195.
and 400 mg (about 4–6 times of the previous doses) for 1 Hosseinzadeh, H., Karimi, G., Niapoor, M., 2004. Antide-
week. Our results are encouraging, although the short pressant effect of Crocus sativus L. stigma extracts and their
constituents, crocin and safranal, in mice. Acta Hort. 650,
study time (1 week) and small sample size (20 subjects)
435–445.
limit assurance in the results.
Hosseinzadeh, H., Ziaee, T., Sadeghi, A., 2008. The effect of
This study showed that saffron tablets may change saffron, Crocus sativus stigma, extract and its constituents,
some hematological and biochemical parameters. How- safranal and crocin on sexual behaviors in normal male
ever, these alterations were in normal ranges and they rats. Phytomedicine 15, 491–495.
were not important clinically. Karimi, G., Hosseinzadeh, H., Khaleghpanah, P., 2001. Study
of antidepressant effect of aqueous and ethanolic extract of
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Mashhad University of Medical Sciences for financial
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