1091_ftp.pdf

6
Effect of Oral Administration of Hypericum perforatum Extract (St. John’s Wort) on Skin Erythema and Pigmentation Induced by UVB, UVA, Visible Light and Solar Simulated Radiation Christoph M. Schempp, 1 * Barbara Winghofer, 1 Knut Mu ¨ller, 1 Ju ¨rgen Schulte-Mo ¨nting, 2 Marcus Mannel, 3 Erwin Scho ¨pf 1 and Jan C. Simon 1 1 Department of Dermatology, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany 2 Department of Medical Biometry and Statistics, University of Freiburg, Stefan-Meier-Str. 26, 79104 Freiburg, Germany 3 Lichtwer Pharma AG, Wallenroderstr. 8-10, 13435 Berlin, Germany Hypericin from St John’s wort (Hypericum perforatum L.) is a photosensitizing agent that may cause a severe photodermatitis when higher amounts of St John’s wort are ingested by animals. Although Hypericum extracts are widely used in the treatment of depressive disorders, only a little information on the photosensitizing capacity of St John’s wort in humans is available. In the present prospective rando- mized study we investigated the effect of the Hypericum extract LI 160 on skin sensitivity to ultraviolet B (UVB), ultraviolet A (UVA), visible light (VIS) and solar simulated radiation (SIM). Seventy two volun- teers of skin types II and III were included and were divided into six groups, each consisting of 12 volun- teers. In the single-dose study the volunteers (n = 48) received 6 or 12 coated tablets (5400 or 10 800 mg hypericin). In the steady-state study the volunteers (n = 24) received an initial dose of 6 tablets (5400 mg hypericin), and subsequently 3 1 tablets (2700 mg hypericin) per day for 7 days. Phototesting was per- formed on the volar forearms prior to medication and 6 h after the last administration of Hypericum extract. The erythema-index and melanin-index were evaluated photometrically using a mexameter. After both single-dose and steady-state administration, no significant influence on the erythema-index or melanin-index could be detected, with the exception of a marginal influence on UVB induced pigmenta- tion (p = 0.0471) in the single-dose study. The results do not provide evidence for a phototoxic potential of the Hypericum extract LI 160 in humans when administered orally in typical clinical doses up to 1800 mg daily. This is in accordance with previous pharmacokinetic studies that found hypericin serum and skin levels after oral ingestion of Hypericum extract always to be lower than the assumed phototoxic hypericin threshold level of 1000 ng/mL. Copyright # 2003 John Wiley & Sons, Ltd. Keywords: erythema-index; hypericin; hypericum; melanin-index; skin reflectance. INTRODUCTION Hypericum perforatum L. (St John’s wort) which belongs to the Hypericaceae plant family is a herbal remedy with more than a 2000 year history of use in folk medicine. Traditionally, preparations from Hypericum have been recommended as a diuretic, for febrile illnesses, for the topical treatment of wounds, burns and neuralgias, and also for a wide spectrum of what we would call today ‘mental diseases’ and many other conditions (Roth, 1990). During the past 10 years, an increasing number of investigations using methodological standards of scien- tific medicine revealed substantial evidence that the oral administration of hydroalcohol extracts from St John’s wort are effective and safe in the treatment of depressive disorders (Kasper, 2001; Greeson et al., 2001). Recently, the constituent hypericin has gained interest as an agent with antiviral activity (Meruelo et al., 1988; Lavie et al., 1989) and as a potential new photosensitizer for photodynamic therapy (Chung et al., 1994; Koren et al., 1996; Fox et al., 1998; Schempp et al., 1999b). The photodynamic action of hypericin is associated with the generation of highly reactive singlet oxygen molecules (Duran and Song et al., 1986; Thomas et al., 1992). In vitro, hypericin induces photohaemolysis in red blood cells (Yu et al., 1996), increases lipid peroxidation and decreases cellular glutathione levels (Hadjur et al., 1996). Due to the content of hypericin, St John’s wort displays several photodynamic actions that may cause photo- dermatitis, so-called ‘hypericism’, that was first de- scribed in grazing animals (Pace, 1942; Giese, 1980; Araya and Ford, 1981). To date, only limited data on the photosensitizing properties of St John’s wort in humans are available. PHYTOTHERAPY RESEARCH Phytother. Res. 17, 141–146 (2003) Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ptr.1091 Copyright # 2003 John Wiley & Sons, Ltd. * Correspondence to: C. M. Schempp, Department of Dermatology, Haupstr. 7, 79104 Freiburg, Germany. E-mail: [email protected] Contract/grant sponsor: Lichtwer Pharma AG, Germany; Contract/grant number: LI 160-SF1; Contract/grant number: LI 160-SF2. Received 12 September 2001 Accepted 13 November 2001

Upload: eduardo-mafra

Post on 06-Feb-2016

2 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: 1091_ftp.pdf

Effect of Oral Administration of Hypericumperforatum Extract (St. John’s Wort) on SkinErythema and Pigmentation Induced by UVB,UVA, Visible Light and Solar SimulatedRadiation

Christoph M. Schempp,1* Barbara Winghofer,1 Knut Muller,1 Jurgen Schulte-Monting,2

Marcus Mannel,3 Erwin Schopf1 and Jan C. Simon1

1Department of Dermatology, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany2Department of Medical Biometry and Statistics, University of Freiburg, Stefan-Meier-Str. 26, 79104 Freiburg, Germany3Lichtwer Pharma AG, Wallenroderstr. 8-10, 13435 Berlin, Germany

Hypericin from St John’s wort (Hypericum perforatum L.) is a photosensitizing agent that may cause asevere photodermatitis when higher amounts of St John’s wort are ingested by animals. AlthoughHypericum extracts are widely used in the treatment of depressive disorders, only a little information onthe photosensitizing capacity of St John’s wort in humans is available. In the present prospective rando-mized study we investigated the effect of the Hypericum extract LI 160 on skin sensitivity to ultraviolet B(UVB), ultraviolet A (UVA), visible light (VIS) and solar simulated radiation (SIM). Seventy two volun-teers of skin types II and III were included and were divided into six groups, each consisting of 12 volun-teers. In the single-dose study the volunteers (n = 48) received 6 or 12 coated tablets (5400 or 10800�ghypericin). In the steady-state study the volunteers (n = 24) received an initial dose of 6 tablets (5400�ghypericin), and subsequently 3 � 1 tablets (2700�g hypericin) per day for 7 days. Phototesting was per-formed on the volar forearms prior to medication and 6 h after the last administration of Hypericumextract. The erythema-index and melanin-index were evaluated photometrically using a mexameter.After both single-dose and steady-state administration, no significant influence on the erythema-index ormelanin-index could be detected, with the exception of a marginal influence on UVB induced pigmenta-tion (p = 0.0471) in the single-dose study. The results do not provide evidence for a phototoxic potentialof the Hypericum extract LI 160 in humans when administered orally in typical clinical doses up to1800mg daily. This is in accordance with previous pharmacokinetic studies that found hypericin serumand skin levels after oral ingestion of Hypericum extract always to be lower than the assumed phototoxichypericin threshold level of 1000ng/mL. Copyright � 2003 John Wiley & Sons, Ltd.

Keywords: erythema-index; hypericin; hypericum; melanin-index; skin reflectance.

INTRODUCTION

Hypericum perforatum L. (St John’s wort) which belongsto the Hypericaceae plant family is a herbal remedy withmore than a 2000 year history of use in folk medicine.Traditionally, preparations from Hypericum have beenrecommended as a diuretic, for febrile illnesses, for thetopical treatment of wounds, burns and neuralgias, andalso for a wide spectrum of what we would call today‘mental diseases’ and many other conditions (Roth,1990). During the past 10 years, an increasing number ofinvestigations using methodological standards of scien-tific medicine revealed substantial evidence that the oraladministration of hydroalcohol extracts from St John’s

wort are effective and safe in the treatment of depressivedisorders (Kasper, 2001; Greeson et al., 2001). Recently,the constituent hypericin has gained interest as an agentwith antiviral activity (Meruelo et al., 1988; Lavie et al.,1989) and as a potential new photosensitizer forphotodynamic therapy (Chung et al., 1994; Koren etal., 1996; Fox et al., 1998; Schempp et al., 1999b). Thephotodynamic action of hypericin is associated with thegeneration of highly reactive singlet oxygen molecules(Duran and Song et al., 1986; Thomas et al., 1992). Invitro, hypericin induces photohaemolysis in red bloodcells (Yu et al., 1996), increases lipid peroxidation anddecreases cellular glutathione levels (Hadjur et al., 1996).Due to the content of hypericin, St John’s wort displaysseveral photodynamic actions that may cause photo-dermatitis, so-called ‘hypericism’, that was first de-scribed in grazing animals (Pace, 1942; Giese, 1980;Araya and Ford, 1981). To date, only limited data on thephotosensitizing properties of St John’s wort in humansare available.

PHYTOTHERAPY RESEARCHPhytother. Res. 17, 141–146 (2003)Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ptr.1091

Copyright � 2003 John Wiley & Sons, Ltd.

* Correspondence to: C. M. Schempp, Department of Dermatology, Haupstr.7, 79104 Freiburg, Germany.E-mail: [email protected]/grant sponsor: Lichtwer Pharma AG, Germany; Contract/grantnumber: LI 160-SF1; Contract/grant number: LI 160-SF2.

Received 12 September 2001Accepted 13 November 2001

Page 2: 1091_ftp.pdf

Significant phototoxic skin reactions were observedafter repeated administration of high doses of hypericinin HIV-infected patients (intravenously; Gulick et al.,1999) and in patients suffering from hepatitis C virusinfection (orally; Jacobson et al., 2001), respectively.One case-report describes a reproducible increase ofphotosensitivity to UVB after oral administration of a StJohn’s wort extract preparation (Golsch et al., 1997). In arecent study, photosensitivity towards UVB and UVAradiation was investigated in healthy volunteers after anoral single-dose and steady-state administration ofHypericum extract (Brockmoller et al., 1997). In thisstudy, UV light sensitivity was not (single-dose) or onlymarginally (steady-dose) increased by Hypericum extract(Brockmoller et al., 1997). However, the authors onlyinvestigated light within the UV range, but not high-dosevisible light or solar simulated radiation that includes theabsorption maximum of hypericin at 588 nm (Duran andSong, 1986). Therefore, we tested UVB, UVA, visiblelight (VIS) and solar simulated radiation (SIM) after asingle-dose, and VIS and SIM after steady-dose admin-istration of the Hypericum extract LI 160. Using a visualerythema score, no increased photosensitivity could bedetected in any of the groups (Schempp et al., 2001).Here, we report the effect of the Hypericum extract LI160 on skin erythema and pigmentation. The erythema-index and melanin-index was measured by skin reflec-tance, a sensitive photometric technique that allows thedetection of small changes in skin redness and pigmenta-tion (Diffey et al., 1984; Schempp et al., 1999a; Edwards,

1995). Irradiation was performed prior to and 6 h aftermedication, since recent pharmacokinetic studies haveshown that hypericin plasma levels peak 6 h after oraladministration (Staffeldt et al., 1994; Kerb et al., 1996;Brockmoller et al., 1997; Schempp et al., 1999c).

MATERIAL AND METHODS

Subjects. The protocol of the randomized prospectivestudy was approved by the local ethics committee andwritten informed consent was obtained from all subjectswho participated in the study. Seventy two healthyvolunteers (both sexes; age range 18–59 years; skin typesII and III) with no history of skin disease or photo-sensitivity were included. The skin type was determinedaccording to the classification of sun reactive skin typesby Fitzpatrick (1988).

Study protocol. The study consisted of two parts. (i) Inpart I (single-dose study), the subjects (n = 48) wererandomly allocated to light sources and dosage ofmedication. Subjects were tested unmedicated in fourparallel groups on their volar forearms with UVB(n = 12), UVA (n = 12), SIM (n = 12) or VIS (n = 12) asdescribed below. Subsequently, the volunteers fastedovernight and received 6 tablets (n = 8) or 12 tablets(n = 4) of the Hypericum extract LI 160 (LichtwerPharma AG, Berlin, Germany) the next morning (8:00

������ �� �������� ����� � �� ���� ������� ���� �� ��� ������ ���� ������ ���� ������ ��� !" #$�� %&� ��'%�� �(�� &�����##)$ �%'*��

142 C. M. SCHEMPP ET AL.

Copyright � 2003 John Wiley & Sons, Ltd. Phytother. Res. 17, 141–146 (2003)

Page 3: 1091_ftp.pdf

a.m.), corresponding to 5400�g or 10800�g totalhypericin (calculated as the sum of hypericin andpseudohypericin from HPLC analysis). After 6 h, whenhypericin plasma levels were peaking (Staffeldt et al.,1994; Kerb et al., 1996; Brockmoller et al., 1997;Schempp et al., 1999c), phototesting was repeated on theother forearm. On both forearms (treated and untreated)several subsequent readings of erythema and pigmenta-tion were performed as detailed below. (ii) In part II(steady-state study) two groups were tested unmedicatedon their volar forearms with solar SIM (n = 12), or VIS(n = 12). Then, all subjects (n = 24) received an initialdose of 6 coated tablets of Hypericum extract (corre-sponding to 5400�g total hypericin), followed by 7 daysof steady-state administration of 3 � 1 coated tablet perday (corresponding to 2700�g total hypericin per day).Six hours after the last dosage phototesting was repeatedon the other forearm and subsequent readings oferythema and pigmentation were performed.

Radiation sources. The emission spectra of the lightsources are illustrated in Fig. 1. UVB radiation between270 and 400 nm (Fig. 1a) was delivered from 10fluorescent Philips TL20W/12 lamps (Philips GmbH,Hamburg, Germany), housed in a UV 800 unit (Wald-mann GmbH, VS-Schwenningen, Germany). UVB irra-diance was measured with a calibrated radiometer (UV-Meter, Waldmann) and was 2.5 mW/cm2 at a tube totarget distance of 40 cm (Schempp et al., 1999a). UVAradiation between 340 and 450 nm (Fig. 1b) wasdelivered from a Uvasun 5000 device (Mutzhas, Munich,Germany). Irradiation was 128 mW/cm2 at a tube totarget distance of 30 cm as determined with a UVA-meter(Waldmann). The solar simulator (Model 81192, Oriel,Stratford, CT) was equipped with a 1000 W Xenon arclamp. Its emission spectrum was between 290 and2500 nm with a maximal output between 300 and800 nm (Fig. 1c) (Schempp et al., 1999b). The tube totarget distance was 20 cm and the fluence rate was 276mW/cm2 as measured with a calibrated spectroradi-ometer (SR 9910, Macam, Livingston, UK). Visible lightwas delivered from the PDT 1200 SOA (Waldmann)described previously (Schempp et al., 1999b). The PDT1200 SOA emission spectrum was between 520 and750 nm (Fig. 1d). The fluence rate was 120 mW/cm2 at alamp to target distance of 30 cm as monitored by anintegrated calibrated radiometer.

Phototesting procedures. Phototesting was performedon circular test areas (2 cm in diameter) in a lineararrangement on the volar aspects of the forearms asdescribed (Schempp et al., 1999a). Before irradiation,skin erythema and pigmentation was determined byphotometric measurement in all test areas as describedbelow. Irradiation was performed before and after oraladministration of Hypericum extract. The light doseswere 20, 40, 90, 130, 170 and 210 mJ/cm2 (UVB); 15, 20,30, 50, 70 and 90 J/cm2 (UVA); 24, 48, 96 and 144 J/cm2

(SIM); and 30, 60, 120 and 180 J/cm2 (VIS). Photometricmeasurement was performed immediately after irradia-tion (0 h, only UVA and VIS), after 6 h (only UVB), after24 h and after 48 h. Additionally, visual assessment ofcharacteristic erythema threshold levels was performed6 h after medication. The results have been reportedelsewhere (Schempp et al., 2001).

Photometric measurement. Photometric measurementwas performed with a mexameter MX 16 (Courage &Khazaka Electronic GmbH, Koln, Germany) as described(Schempp et al., 1999a). The test principle is based ondiffuse remittance spectrometry, using LED light sourcesand a silicone diode detector. In brief, erythema(haemoglobin) is measured by remittance of 568 and660 nm and the erythema index (EI) is calculated by theinstrument according to the formula: EI = 500/ log5� (log infrared-remittance/ red-remittance � log 5).

Data and statistics. The raw data were processedelectronically and were checked for correct data transferand plausibility. Data were analysed with SASTM 6.12using the procedures UNIVARIATE, GLM and GPLOT.Raw data from the photometric measurements weresubjected as relative values (RV, see Materials andMethods) to repeated measures analysis of variance(ANOVA) (BMDP Statistical Software, LA). Values ofp �0.05 were considered significant. As an example forthe distribution of photometric values, SIM inducederythema and pigmentation before and after single-dose(Fig. 2) and steady-state (Fig. 3) administration areillustrated.

������ � '�+���� � ������,(��� �(���������� � �������� �-�� �� �.�� ��/���� ��� ��( ���������� �����(��( �/ %'*� 0��(���� ��� ����( $1 � � �� ����(�������� ���2�� �������( �.��� � ������� ����( �.��� ������

HYPERICUM PERFORATUM EXTRACT ON SKIN ERYTHEMA 143

Copyright � 2003 John Wiley & Sons, Ltd. Phytother. Res. 17, 141–146 (2003)

Page 4: 1091_ftp.pdf

RESULTS

Influence of single-dose administration of Hypericumextract on skin erythema and pigmentation inducedby UVB, UVA, VIS and SIM

Phototesting was done prior to and 6 h after ingestion ofthe single-dose medication (6 or 12 tablets LI 160), andsubsequent readings were done up to 48 h after irradiationas detailed in Materials and Methods. Analysis of thephotometric values with ANOVA revealed a marginaleffect of Hypericum extract on UVB induced pigmenta-tion (p = 0.0471), and a trend to an increase of VISinduced erythema (p = 0.0568) (Table 1A). These effectswere not dependent on the dose (6 or 12 tablets). Nosignificant effect on the other variables and light sourceswas detectable (Table 1A). Figure 2 illustrates thedistribution of erythema and pigmentation 24 h afterirradiation with the solar simulator. Although a trendtowards an increase of erythema and pigmentation aftersingle-dose administration was observed, the differencebetween treated and untreated skin was not significant.

Influence of steady-state administration ofHypericum extract on skin erythema andpigmentation induced by VIS and SIM

Since no marked effects of the single-dose administrationon photosensitivity were observed and serum levels ofhypericin were expected to be lower after steady-stateadministration of Hypericum extract (Schempp et al.,1999c), we only tested VIS and SIM in the steady-dosegroup. The spectra of VIS and SIM include the absorptionmaximum of hypericin at 588 nm. The volunteersreceived an initial dose of 6 coated tablets LI 160 andsubsequently 3 � 1 coated tablets for 7 days. Phototestingwas performed prior to medication and 6 h after ingestionof the last dose of medication. Readings were done up to48 h after irradiation as detailed in Materials andMethods. Analysis of the photometric values withANOVA showed no significant effect of Hypericumextract on erythema-index and melanin-index (Table 1B).The distribution of erythema and pigmentation 24 h afterirradiation with the solar simulator is illustrated in Fig. 3.There was no difference between treated and untreatedskin.

DISCUSSION

The present study could not detect photosensitizingeffects of oral single-dose or steady-state administrationof typical clinically used doses of the Hypericum extractLI 160 for the treatment of depressive disorders. Themedication, dosage and study design was identical torecent studies that investigated pharmacokinetics of theHypericum extract LI 160 (Staffeldt et al., 1994; Kerb etal., 1996; Brockmoller et al., 1997; Schempp et al.,1999c). All these studies found comparable serum levelsof hypericin that were always below 100ng/ mL (Table2). In a previous study, we also investigated hypericinconcentrations in skin blister fluid (Schempp et al.,1999c). We found hypericin skin levels to be about 10times lower than serum levels (Schempp et al., 1999c).This is in accordance with the findings of Chung et al.who investigated hypericin uptake of various organs inrabbits and nude mice (Chung et al., 1994). In anotherstudy, we demonstrated that a phototoxic skin reactioncould be elicitated in vivo after an intracutaneousinjection of 1000ng/mL hypericin, but not after 100ng/

������ � '�+���� � ���(/,��� �(���������� � �������� �-�� �.�� ��/���� ��� ��( ���������� ��� ��(��(�/ %'*� 0��(���� ��� ����( $1 � � �� ����(����� ��� ���2��� ������( �.��� � ������� ����( �.��� 3 �����

Table 1. Influence of oral single-dose (A) and steady-state(B) administration of the Hypericum extract LI 160 on skinerythema and pigmentation. In each group 12 volunteerswere included

4��� ����� ��/���� ���5� ��������� ���6�

�� %�����,(������ �� 7 #$�8� ����#9 ���1:#��� �� 7 #$��� ���)�1 ���:�9�'% �� 7 #$��� ����9� ��))��%'* �� 7 #$���� ��9#�; �����1�� %��(/,����'% �� 7 #$���� ��1;:1 ��;�:;%'* �� 7 #$���� ��)�1� ����$$

� 0�����( �������� ����/��� � ������� ��<&��� 2����� ����( 2�� ������� ������ ��( � ������ ��� ��(���(�

144 C. M. SCHEMPP ET AL.

Copyright � 2003 John Wiley & Sons, Ltd. Phytother. Res. 17, 141–146 (2003)

Page 5: 1091_ftp.pdf

mL (Schempp et al., 1999b). In vitro studies with HaCaTkeratinocytes found complete growth inhibition with50�g/mL of a Hypericum extract, containing 1500ng/mLhypericin (Bernd et al., 1999) and with 1000ng/mL ofpurified hypericin (Schempp et al., 1999b). Takentogether, the results from the existing studies withHypericum extracts and hypericin suggest that thephototoxic hypericin threshold level is between 100ng/mL and 1000ng/mL. Hypericin serum and skin levelsafter oral uptake of Hypericum extracts are always below100ng/mL. Accordingly, in the present study we couldnot find photosensitizing properties of oral single-doseand steady-state administration of the Hypericum extractLI 160.

Although we have not performed a sample sizecalculation, we think that our study provides valid databecause the effect on erythema and pigmentation of theirradiation itself was highly significant (not shown in thepaper). This indicates that the ANOVA had the power todetect significant differences in the study.

From the findings presented here one can assume thatthe repeated administration of typical hydroalcohol

Hypericum extract preparations with a hypericin contentof about 0.3 % in daily doses up to 1800mg bears nosignificant risks for the vast majority of patients in termsof photosensitization. This assumption can be verified bythe data from the German federal pharmacovigilancesystem, reporting a frequency of only one case of ‘skinreactions’ per 300000 6-week treatments with LI 160(Schulz, 2001). Nevertheless, we suggest caution with theapplication of Hypericum extracts since abnormalresorption of hypericin may occur in single individuals.Furthermore, in fair skinned individuals and afterextended solar irradiation, increased susceptibility tothe photosensitizing properties of hypericin may occur.

Acknowledgements

This study was supported by grants LI 160-SF1 and LI 160-SF2 fromLichtwer Pharma AG (Berlin, Germany). We thank Dr Grobel(Marxzell, Germany) for help with the spectroradiometric measure-ments.

REFERENCES

���/� &%� =��( �>?� #)�#� �� ����������� � �� /�� � ����������@���� ����( �/ �� �������� � % >���A�2�� �������� ���� ���� �/ ������ � � � ���� ��B#;�3#1#�

����( �� %���� %� 0�����@,���� � �� ���� #)))� ����-�� �� � ������� �-��� �� ������ � �����.������/�� ������( 2�� ���� � ��������� �� � ���� �� � �� � ��B $#�3$$#�

���.��C ���� >� 0��� "� ����� %� D��� 0� ?���� E!� 0��� '�#)):� ?/������ ��( ����(��/������B �������.�������( � �� �� ������������/ �� ������� ������ ����������� B �939;�

F���� %� %�-�� 0�� ���� *� �� ���� #))1� ?/������ ���.��� ������ ��( ��(� ��� ���������( 2�� ������G������ ��� ��������B ��(/ � � ��2 ������@�� ������� ���������/� ������ �� �� � �B #1:#3#1:9�

!� �/ �4� &����� 0>� =��� *� #)�1� � ������� �������� ��G���� /��� ��/���� ��(��( �/ ��������� ��(������ ��� ����� � ���B 99;39:$�

!���� <� %��� %� #)�9� ?/������ ��( �� ����(/��������� �� � ��� �� � �� � �B 9::39���

�(2��(� F� #))�� "�� *�-����� *H #9"*� '� �� ������������ � ��� ����� ���� � �� !���������� �� �����(����� ������ � E������ D � *����� ?' ��(��� F0F ����B��� 0���� =4� #$:3#$)�

=�@����. "�� #)��� "�� ����(�/ ��( �������/ � ���,������ �.�� /��� ' ������ �'� "��� ����� � ��B �9)3�:#�

=�- =�� <�� I� "���� �� 0��. �?� #))�� ��������(�/������ �� �� ���,����� ������ ���� �� ��(��� � ����

��� � ������ (��� � ������� ���� ����(� ��(�������� " �/����/��B ���������� �� �� ������� ������� �/��������� ������ ��( ��+������/ (��,��(���� � !�#��� ����� � ���B ;$:3;;$�

J���� �F� #)��� ?/�������� �� � ��� �� � �� � $�# �B$$)3$���

J���� %� ��.� �� 0�.��.� >� ���.�2 D� 0��� >� #)):�0��������� ������� � ������������/ �/ %� >���A�E�� �-��� �����%� ��B $1)3$�$�

J������ >*� %�� ��( �� *��� !�� $��#� %� >���A� 2���������� ���� ����B � �����2 � �� ����� ������,�������� �-��������� ��( ������ ��������� ����� ������� � �� ��B 1�$31#1�

J���. 0*� *���� � �� ?��(��,E���� > �� ���� #)))� ���� '��(��� � �/������� �� ���� ������( �� %� >���A�2��� �� �� ������������ ���� �� ?'�,�� ��( �(����"�� !����� �� � B �#�3�#1�

?�(K�� F� 0����( *>� ��� *&� >��(�� � =����� �� #))9� ���(/���� � �� � �/������ �� ����( ����-�(������( ����-�(�� ���� �� �������� ����� �� � ����� � �� � ��B ;:�3;�#�

>������ >*� =������ 4� 4����� 4 �� ���� $��#� ������.�,����� �� �/� ��( �������� � �� � �/������� �(�������� � %� >���A� 2�� ����� �� ������ 2������� ������� F ����� �� ����� "������ � "�������� ���� ��B �#:3�$1�

D����� % $��#� ������� ���� ���L� �����2 � ��������(���� ������ ���������� � �%����� #�B �#3���

D��� 0� ���.��C ���� >� %� ��( �� ��� *� 0��� '� #))9�%�����,(��� ��( ���(/,��� �������.����� � �/����,

Table 2. Comparison of mean hypericin serum levels after oral single-dose and steady-state administration of the Hypericumextract LI 160 as reported in published studies

%� ��( �� ��� #))1 ���-

���M�4�D��� �� ��� #))9 ���-

���M�4����.��C ���� �� ��� #)):

���- ���M�4�%����� �� ��� #)))

�9� ���M�4�

%�����,(��� 11�� �� 7 1� 19�; �� 7 #;� 9#�� �� 7 #;� 1;�� �� 7 #$�%��(/,��� #1�; �� 7 $� #:�; �� 7 #;� 11�� �� 7 ��� #$�� �� 7 #$�

"�� ��� � �/������ ��( ����(��/������ ���� �/������� �� ��(���(� %�����,(���B �(���������� � 9 ���( ����� 4' #9��%��(/,���B �(���������� � ;� # ���( ����� 4' #9� ��� (�/ �� : (�/�� �-�� �� �� ��(/ � ���.��C ���� �� ��� #)):B ;� $���( ����� 4' #9� ��� (�/ �� #� (�/�� ���- 7���� � ��-���� ����� ������� ������/ �����( 9 � � �� (������ �9� 7 ���� � ����� ������ 9 � � �� (������

HYPERICUM PERFORATUM EXTRACT ON SKIN ERYTHEMA 145

Copyright � 2003 John Wiley & Sons, Ltd. Phytother. Res. 17, 141–146 (2003)

Page 6: 1091_ftp.pdf

�� ��( ����(��/������� "������ � "����� ��� ����� B $��:3$�);�

D���� ?� %���. J*� >��(�� 0? �� ��� #))9� ?/������ �����������/� � �� � ��� �� � �� � ��� �B ##;3##)�

4���� J� �������� =� 4���� � �� ���� #)�)� %�(��� � ����������� � ���� � �� ������������ ����� �/����,�� ��( ����(��/������� �� � &��� "�� ��� '�" ��B�)9;3�)9:�

*������ !� 4���� J� 4���� !� #)��� "�������� ����� 2��(����� ������������ ����/ ��( ���� �-��/ �� ���� (����B ������ ���//�� (����� �/��������( ����(��/������� �� � &��� "�� ��� '�" ��B �$;�3�$;1�

�� <� #)1$� "�� ������/ � �/�������� � ������������/���(��( �/ %� >���A� 2��� " � ����� � ��B 9��39�9�

0�� 4� #))�� �������(���������� ����(B 4��(�����M4��� J�����/�

%����� F*� *�C ���� D� %����,*�C ���� >� %��C � �� %����>F� #)))�� %�� 2��� ������ ����� � ��,� ����(��������(� � � (������ � �� *�! ��( �� �������(��/���� ��(�- 2���� � ���� �.�� ������������� � ��� �� � �� � ��B ;1#3;11�

%����� F*� *�C ���� D� E����� �� �� %����,*�C ���� >�%���� >F� $��#� %�����,(��� ��( ���(/,��� �(�����,����� � ������� ���� ��� �-�� �%� >���A� 2���(��� �� ��+���� �.�� ��������/ � ���� ���� ����������� ��( ����� �������( ��(������ "��� ����� � ��B�#$3�#;�

%����� F*� %����,?������� �� ?���� �� %��C � �� %����>F� #)))�� !� #��� ��( �� #�# ������� � �/������ 2���� �������� ���� ����� !" #$�� %&� ��$�3:�� �����( 2�� ����� �������( ��(����� �$)�3$��� ���� �� � � ���� � �� � �� � �� � � ��B #;3#:�

%����� F*� E����� �� �� %��C � �� %���� �� #)))�?/������ ��( ����(��/������ ������ �� ����� �������( �.�� ������ +��( � �� �/���� ��������� � ������� ���� ��� �-�� �%� >���A� E���� ���������� � �B $))3;�1�

%���@ �� $��#� '��(��� ��( ������ �������� � ����������� ��( ��(� � �� � ?/������ ���������������� � ����� �B #�$3#9��

%� ��( �� D��� 0� ���.��C ���� >� ��� *� 0��� '� #))1� ������.����� � �/������ ��( ����(��/������ � ������ ���.� � �� ������� ���� ��� �-�� 4' #9� �������/ ���������� � )������ ���������� &�� � � �%�����#�B 1:3�;�

"����� F� 0��(��� %� *�J��� %� *����� JF� ��(��� 0%� #))$� ���������� � �/������ �������� ������ �-/��� ��������(��� ��( ������� ����/��-�(���� �� � ����� � �� � ��B 1:3�;�

N� ?� E�� ��( %"� D���(� 0� I��� E� &�2����� !� #))9�?/������,��(��( �����-��/ �� �����( O����������( �2��� ��/���/��� �� � ��� �� � �� � ��B #9�3#:;�

146 C. M. SCHEMPP ET AL.

Copyright � 2003 John Wiley & Sons, Ltd. Phytother. Res. 17, 141–146 (2003)