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Hypericum Perforatum

This page report syntethically principal information about HYPERICUM PERFORAUM and HIV. The complete research text is available only in Italian language and is published in the volume: Bianchi, Adamoli, " Piante Medicinali e AIDS", Ed. Tecniche Nuove, 1997. For a better result we suggest to print this document in landscape mode.

IN VITRO DATA

Antiviral action may happen at two levels: virus assembly and anchorage (Lavier et a., 1989). According to several authors Hypericum would operates on HIV principal capsid causing radical change in movements (De Gar et al., 1992). Other authors think Hypericum action may be at bound level between gp120 and CD4 receptor of lymphocites, where Hypericum would inhibits Sincizia generation and fusion.
Importance seem to have light in Hypericum action mechanism (Stevenson et al., 1993; Hidson et al., 1993). Light action exposes Hypericum preparates to photosensibilization and phototoxicity risks.

IN VIVO DATA

Duration (weeks) Type of Study Principal Markers and
Study stage (F)
Starting CD4
(mm³)
and/or Stage
Starting Viral Load(CV) (copies/ml) Results Treated Controls Total treated cases

Reference Dosage

ATN n° 91 1989 Different (os) N. Q Symptoms Several stages Benefice 112

Payne Posology DNR. N. 24 SC CD4-CD8-Ag p24. (F=I/II) ARC None 60

Cooper 1990
James 1990
~1 mg/die (os) N.
Allowed AZT
16 SO Safety, CD4, Ag p24 Several stages 10 with Ip. Slight impr. In CD4 26

Furner 1991 0,5 mg, 2mg, 4 mg e 8 mg/die 12 SO Safety, CD4. (F= I) Several stages Safety see study,
CD4 none
40

McAuliffe 1993 0.75 mg/kg X 3/set o
1 mg/kg X 2/set (ev) S.
SC Safety, CD4. (F=I) < 300 Safety see study,
CD4 none
25

Steinbeck-Klose 1993 2 ml ev 2 times week + 1.8 mg/die (os) N. 160 SC CD4, CD4/CD8. (F=I/II) Classific. CDC: 3=II, 8=III, 4= IVB, 3=IV-C1 Improvement 18

Vansover 1996 1.2 ml/set ev + 3.6 mg/die (os) N. 192 SC CV, Ag p24. (F=I/II) 5 log10 Improvement 18

Pitisuttithum 1996 0.05 mg/kg (os) o
0.16 mg/kg (os) S.
4 SC Safety. (F=I) 217-423, 1° dose
24-406, 2° dose.
Safety see study, 4

Clinical Data - Legenda
DNR = Data Not Available X = Media
M = Improves A = Years Me = Median
S = Synthesis N = Natural SN = Permanently
CC = Clinical Casuistics Negative
Q = Questionnaire S = Stabiliser
SCC = Controlled Cl. Study SA = Open Study

Considerations:

Natural substance for which one of the largest documentation on its in vitro antiviral and anti-HIV activity is available.
Its antiviral activity depends upon photoactivation consequently of which activated HY produces monovalent oxygens and in a smaller amount, free radicals.
It seems that its action on HIV virus may be on two levels: that of assembly and particularly at the gp120 protein/CD4 receptor level. It is likely that photoactivation and monovalent oxygen production alter PKC and TK functionalities, compromising those CD4 receptor phosphorylation processes being essential for the virus to enter cell.
With respect to the problem of photoactivation of this molecule, up to now there are no exact data on a clinically effective dosage, which is important particularly in light of possible toxic effects. Recent studies seem to have found a safe dosage on 0,05 mg/Kg, but further research is requested to confirm this data. Moreover, it would be important to obtain different data for products while a synthetic HY base and natural extracts of Hypericum containing titrated HY.
Currently, an interesting possible future application of HY is studied for the sterilisation of blood products.

Riferimenti bibliografici

Agostini P, Donella-Deana A, Cuveele J, Vandenbogaerde A, Sarno S, Merlevede W, de Witte P (1996)
A Comparative Analysis of the Photosensitized Inhibition of Growth-factor-regulated Protein Kinases by Hypericin-derivatives.
Biochem Biophys Res Commun, vol. 220: 613-7

Aids Daily Summary (1994)
VIMRx Pharmaceutics Inc. Announces Johns Hopkins University to Begin Clinical Study with Hypericin.
AIDS Daily Summ, 30/6/1994.

Aids Daily Summary (1995)
VIMRx Pharmaceutics Inc. Announces Results of NIH-Sponsored.
AIDS Daily Summ, 10/1/ 1995

Aids Treatment News (1989)
Hypericin survey report.
AIDS Treat News, vol 91,17/11/1989

Bihari B (1992)
Hypericin for the Treatment of HIV Disease: an Update
Bull Exper Tr AIDS, 5/1992: 33-34

Blandt S e al (1994)
Inhibition of MAO by Fractions and Constituents of Hypericun Extract
J Geriatr Psych Neurol, Vol 7(1): 57-9

Carpenter S, Fehr MJ, Kraus GA, Petrich JW (1994)
Chemiluminescent Activation of the Antiviral Activity of Hypericin: a Molecular Flashlight.
Proc Nat Acad Sci USA, vol 91: 12273-12277

Cohen DI, Tani Y, Tian H, Boone E, Samelson L, Lane HC (1992)
Participation of Tyrosine Phosphorylation in the Cytopathic Effect of Human Immunodeficiency Virus-1.
Science, vol: 256: 542-545

Cooper WC, James J (1990)
An Observational Study of the Safety and Efficacy of Hypericin in HIV+ Subjects.
VI Int. Conf. AIDS, San Francisco, vol 6(2):369 (abstract 2063)

De Witte P, Agostinis P, Van Lint J, Merlevede W, Vandenheede JR (1993)
Inhibition of Epidermal Growth-factor Receptor Tyrosine-Kinase Activity by Hypericin.
Biochem Pharmac, vol 46: 1929-1936

Degar S, Prince AM, Pascual D, Lavie G, Levin B, Mazur Y, Lavie D, Ehrlich LS, Carter C, Meruelo D (1992)
Inactivation of the Human Immunodeficiency Virus by Hypericin: Evidence for Photochemical Alteration of p24 and Block in Uncoating.
AIDS Res Hum Retrov, vol 8: 1929-1936

Degar S, Lavie G, Meruelo D (1993)
Photodynamic Inactivation of Radiation Leukemia Virus Produced From Hypericum Treated Cells
Virology, vol 197: 796-800

Ernst (1995)
St John’s Wort, an Anti-depressant? A Systematic Criteria-based Review. (1995)
Phytomed, vol 2(1): 67-71

Fields AP, Bednarik DP, Hess A, May WS (1988)
Human Immunodeficiency Virus Induces Phosphorylation of its Cell Surface Receptor.
Nature, vol 333: 278-280

Furner V., Bek M., Gold J. (1991)
A Phase I/II Unblinded Dose Ranging Study of Hypericin in HIV Positive Subjects.
VII Int. Conf. AIDS Florence, vol 7(2):199 (Abst WB 2071)

Gulick R, Lui H, Anderson R, Kollians N, Hussey S, Crumpacket C, (1992)
Human Hypericism: a Photosensitivity Reaction to Hypericin (St. John’s Wort).
VIII Int Conf AIDS Amsterdam, vol 8(2):B90 (abst PoB 3018)

HIV & AIDS treatments directory (1995)
Hypericin
NAM Publ, London

Hudson JB, Lopez-Bazzocchi I, Towers GHN (1991)
Antiviral Activities of Hypericum
Antiv Res, vol 15: 101-112

Hudson JB, Harrish L, Towers GH (1993)
The Importance of Light in the Anti-HIV Effect of Hypericin.
Antiv Res, vol 20(2): 173-8

James JS (1990)
Hypericin Results: Community Research Alliance Study.
AIDSTreat News, vol 96: 2/2/1990

James JS (1992)
Hypericin.
AIDS Treat News,vol 146: 6/3/1992

Kraus GA, Pratt D, Tossberg J, Carpenter S (1990)
Antiretroviral Activity of Synthetic Hypericin and Related Analogs.
Biochem Biophys Res Commun, vol 172: 149-153

Lavie G, Valentine F, Levin B, Mazur Y, Gallo G, Lavie D, Weiner D, Meruelo D (1989)
Studies of the Mechanism of Action of the Antiretroviral Agents Hypericin and Pseudohypericin.
Proc Nat Acad Sci, vol 86: 5963-5967

Lavie, Mazur, Lavie, Meruelo (1995a)
The Chemical and Biological Properties of Hypericin-a Compound with a Broad Spectrum of Biological Activities.
Med Res Rev, vol 15: 111-119

Lavie G, Mazur Y, Lavie D, Prince AM, Pascual D, Liebes L, Levin B, Meruelo D (1995b)
Hypericin as an Inactivator of Infectious Viruses in Blood Components.
Transfusion, vol 35: 392-400

Lenard J, Rabson A, Vanderoef R (1993)
Photodynamic Inactivation of Infectivity of Human Immunodeficiency Virus and Enveloped Viruses Using Hypericin and Rose Bengal: Inhibition of Fusion and Syncytia Formation.
Proc Nat Acad Sci USA, vol 90: 158-162

Lui H, Gulick R, Kollias N, Wimberley J, Crumpacker C, Andersen R (1992)
Evaluation of Photosensitivity in Human Hypericism
Photochem Photobiol, vol 55 Suppl 1, 155

MacAuliffe e al (1993)
A Phase I Dose Escalation Study of Sinthetic Hypericin in HIV Infected Patients (ACTG 150).
I Nat Conf Hum Retrov, Washington, Abst 570

Meruelo D, Degar S, Amari N, Mazur Y, Lavie D, Levin B, Lavie G (1992)
Mode of Action of Hypericin as an Antiretroviral Agent and other Relevant Findings.
In Chu CK and Cutler HG Natural Products as Antiviral Agents ,Plenum Press, New York

Meruelo D, Lavie G, Lavie D (1988)
Therapeutic Agents with Dramatic Antiretroviral Activity and Little Toxicity at Effective Doses: Aromatic Polycyclic Diones Hypericin and Pseudohypericin.
Proc Natl Acad Sci USA, vol 85(14):5230-4

Moraleda G, Wu TT, Jilbert AR, Aldrich CE, Condreay LD, Larsen SH, Tang JC, Colacino JM, Mason WS (1993)
Inhibition of Duck Hepatitis B Virus Replication by Hypericin.
Antiv Res, vol 20: 235-247

Nishiuchi T, Utsumi T, Kanno T, Takehara Y, Kobuki H., Yasihioka T, Horton AA, Yasuda T; Utsumi K (1995)
Inhibition of Neutrophil Superoxide Generation by Hypericin, an Antiretroviral Agent.
Arch Bioch Bioph, vol 2: 335-42

Notes from the Underground (1996)
Info Sheet - Hypericin (St. John’s Wort), Marzo 1996

Okpanyi von SN, Weishcer ML (1987)
Experimental Studies on the Psycotropic Activity of a Hypericum Extract.
Azneim-Forsch, vol 37: 10-11

Pitisuttithum P, Migasena S, Suntharasamei P, Sutthan R, Perathamanond P, Wasi C, Shikan U, Peeters P, Tobia (1996)
Hypericin: Safety and Antiretroviral Activity in Thai HIV Positive Volunteers
XI Int Conf AIDS, Vancouver, vol 1: 285(Abst Tu B2121)

Schinazi RF, Chu CK, Babu JR, Oswald BJ, Saalmann V, Cannon DL (1990)
Anthraquinones as a New Class of Antiviral Agents against Human Immunodeficiency Virus.
Antivir Re, vol 13: 265-272.

Someya H.(1985)
Effect of a Costituent of Hypericum-erectum on Infection and Multiplication of Epstein-Barr Virus.
J Tokyo Med Coll, vol 3:110-13

Sparemberg B, Demish L, Hölzl J (1993)
PZ Wiss, vol 138(2): 50-54

Steinbeck-Klose A Wernet P (1993)
Succesful Long Term Treatment over 40 Months of HIV Patients with Intravenous Hypericin.
IX Int Conf AIDS, Berlin, vol 9(1): 470 (abstract B26-2012)

Stevenson NR, Lenard J (1993):
Antiretroviral Activities of Hypericin and Rose Bengal: Photodynamic Effect on Friend Leukemia Virus Infection of Mice.
Antiv Res,vol 21: 119-127.

Suzuki O, Katsumata Y, Oya M, Bladt S, Wagner H (1984)
Inhibition of Monoamine Oxidase by Hypericin.
Pl Med,vol 50: 272

Takahashi I, Nakanishi S, Kobayashi E, Nakano H, Suzuki K, Tamaoki T (1989):
Hypericin and Pseudohypericin Specifically Inhibit Protein Kinase C: Possible Relation to their Antiretroviral Activity.
Biochem. and Biophys. Research Comm., 165, 1207-1212

Tang J, Colacino JM, Larsen SH, Spitze W (1990)
Virucidal Activity of Hypericum against Enveloped and Non-enveloped DNA and RNA Virus.
Antivir Res,vol 13: 313-325.

Thiede HM, Walper A (1994)
Inhibition of MAO and COMT by Hypericin Extracts and Hypericin.
J Geriatr Psych Neurol, vol 7(Suppl) :854-6

Thomas C, McGill RS, Miller GC, Pardini RS (1992):
Photoactivation of Hypericin Generates Singlet Oxigen in Mitochondria and Inhibits Succinoxidase.
Photochem. Photobiol,vol 55: 47-53.

Utsumi T, Okuma M, Utsumi T, Kanno T, Yasuda T, Kobuchi H, Horton A A, Utsumi K (1995)
Light-Dependent Inhibition of Protein Kinase C and Superoxide Generation of Neutrophils by Hypericin, an Antiretroviral Agent.
Arch Bioch Bioph, vol 316(1): 493-497

Vansover A, Steinbeck Klose A, Rudich C, Mazur Y, Lavie D, Mandel M, Lavie G (1996)
HIV-1 Virus Load in the Serum of AIDS Patients Undergoing Long Term Therapy with Hypericin.
XI Int Conf Aids, Vancouver, vol 1: 120 (Abst Mo B 1377)

VIMRx (1996)
Pharmaceutical Manufacturer Update
In http://www.hivpositive.com/f-NewsLine/f-
Manufactures News/mVIMRxReport.html

			Duration (weeks)	Type of Study	Principal Markers and Study stage (F)	Starting CD4 (mm³) and/or Stage	Starting Viral Load(CV) (copies/ml)	Results	Treated	Controls	Total treated cases
Reference		Dosage	Duration (weeks)	Type of Study	Principal Markers and Study stage (F)	Starting CD4 (mm³) and/or Stage	Starting Viral Load(CV) (copies/ml)	Results			Total treated cases
ATN n° 91 1989	Different (os) N.			Q	Symptoms	Several stages		Benefice	112
Payne	Posology DNR. N.		24	SC	CD4-CD8-Ag p24. (F=I/II)	ARC		None	60
Cooper 1990 James 1990	~1 mg/die (os) N. Allowed AZT		16	SO	Safety, CD4, Ag p24	Several stages		10 with Ip. Slight impr. In CD4	26
Furner 1991	0,5 mg, 2mg, 4 mg e 8 mg/die		12	SO	Safety, CD4. (F= I)	Several stages		Safety see study, CD4 none	40
McAuliffe 1993	0.75 mg/kg X 3/set o 1 mg/kg X 2/set (ev) S.			SC	Safety, CD4. (F=I)	< 300		Safety see study, CD4 none	25
Steinbeck-Klose 1993	2 ml ev 2 times week + 1.8 mg/die (os) N.		160	SC	CD4, CD4/CD8. (F=I/II)	Classific. CDC: 3=II, 8=III, 4= IVB, 3=IV-C1		Improvement	18
Vansover 1996	1.2 ml/set ev + 3.6 mg/die (os) N.		192	SC	CV, Ag p24. (F=I/II)		5 log10	Improvement	18
Pitisuttithum 1996	0.05 mg/kg (os) o 0.16 mg/kg (os) S.		4	SC	Safety. (F=I)	217-423, 1° dose 24-406, 2° dose.		Safety see study,	4