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Antiviral activity of Rwandan medicinal plants against human immunodeficiency virus type-1 (HIV-1).

Summary

Selected plants used in Rwandan traditional medicine for the treatment of infections and/or rheumatoid diseases were investigated for antiviral activity in vitro against human immunodeficiency virus human immunodeficiency virus
n.
HIV.


Human immunodeficiency virus (HIV)
A transmissible retrovirus that causes AIDS in humans.
 type-1 (HIV-1). Of the 38 tested 80% ethanolic extracts, belonging to plants of 21 different families only the extracts from the leaves of Aspilia pluriseta (Asteraceae) and Rumex bequaertii (Polygonaceae) had interesting selectivity indices (SI = ratio of the 50% cytotoxic concentration to the 50% effective antiviral concentration) higher than 1.

Further fractionation fractionation /frac·tion·a·tion/ (frak?shun-a´shun)
1. in radiology, division of the total dose of radiation into small doses administered at intervals.

2.
 of the initially antivirally inactive ethanolic extract of Tithonia diversifolia, however, led to an aqueous fraction with a high anti-HI V-1 activity (SI > 461), indicating that the cytotoxicity of some plant components may mask the antiviral properties of the active plant substances in total plant extracts.

Key words: African medicinal plants, antiviral, HIV-1, MTT MTT 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide
MTT Machine Tool Technology
MTT Microwave Theory and Techniques
MTT Mobile Task Team
MTT Multi-Table Tournament (poker) 
, Rwanda

* Introduction

Acquired immunodeficiency syndrome acquired immunodeficiency syndrome, see AIDS.  (AIDS) is a pandemic immunosuppressive Immunosuppressive
Any agent that suppresses the immune response of an individual.

Mentioned in: Antirheumatic Drugs, Graft-vs.-Host Disease, Immunosuppressant Drugs


immunosuppressive

1. pertaining to or inducing immunosuppression.

2.
 disease that results in life-threatening opportunistic infections and malignancies. AIDS is caused by the human immunodeficiency virus (HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. ), a lentivirus lentivirus /len·ti·vi·rus/ (len´ti-vi?rus) any virus of the subfamily Lentivirinae.
Lentivirus /Len·ti·vi·rus/ (len´ti-vi?rus 
 within the family Retroviridae. From the two known types of HIV HIV-1 is the most pathogenic. Due to the high number of HIV-infected people and the rapid emergence of drug-resistant strains, the demand for new antiviral therapeutics against HIV-1 is great. However, the standard antiviral therapies are too expensive for most of the Africans. In order to manage the AIDS epidemic in Africa, alternative treatments are clearly needed. One of the possible approaches is the screening of plants based on their ethnomedicinal data (Locher et al., 1996; Vlietinck et al., 1998). In this study, Rwandan plants were selected on base of their ethnomedicinal use against infections and rheumatic rheu·mat·ic
adj.
Relating to or characterized by rheumatism.

n.
One who is affected by rheumatism.



rheumatic

pertaining to or affected with rheumatism.
 diseases (Baerts and Lehmann, 1989; Rwangabo, 1993; Van Puyvelde et al., 1977). Ethanolic extracts of the se lected plants were tested for their activity against HIV-1.

* Materials and Methods

Plant material

All plants were collected by J. Mvukiyumwami in the district of Butare in Rwanda at a mean altitude of 1700 m. Voucher specimens were deposited in the herbarium herbarium, collection of dried and mounted plant specimens used in systematic botany. To preserve their form and color, plants collected in the field are spread flat in sheets of newsprint and dried, usually in a plant press, between blotters or absorbent paper.  of the Institut de la Recherche Scientifique et Technique (IRST IRST Istituto per la Ricerca Scientifica e Tecnologica (Centre for Scientific and Technological Research, Istituto Trentino di Cultura, Trento, Italia)
IRST infrared search and track (US DoD) 
) at Butare, Rwanda.

The air-dried plant material was ground and extracted with 80% ethanol by maceration mac·er·a·tion
n.
1. Softening by soaking in a liquid.

2. Softening of the tissues after death by autolysis, especially of a stillborn fetus.
. The macerate macerate /mac·er·ate/ (mas´er-at) to soften by wetting or soaking.

mac·er·ate
v.
1. To make soft by soaking or steeping in a liquid.

2.
 was filtered and the marc was percolated with 80% ethanol until exhaustion. The filtrate filtrate /fil·trate/ (fil´trat) a liquid or gas that has passed through a filter.

fil·trate
v.
To put or go through a filter.

n.
 and percolate percolate /per·co·late/ (per´kah-lat)
1. to strain; to submit to percolation.

2. to trickle slowly through a substance.

3. a liquid that has been submitted to percolation.
 were combined and concentrated under reduced pressure at 40 [degrees]C. The residue was taken up in 60% methanol and defatted with petroleum ether (non-polar fraction). The residual polar fraction was lyophilized and tested for anti-HIV-1 activity. In the case of Tithonia diversifolia, the residual fraction was further extracted with ethylacetate and the resulting ethylacetate and water fractions were tested for anti-HIV-1 activity.

HIV inhibition assays

The antiviral screening was determined by evaluating cell death caused by plant extract cytotoxicity and viral cytopathic effect as previously described (Pauwels et al., 1988).

Cell cultures

The MT-4 cells were grown in RPMI RPMI Rapid Prototyping & Manufacturing Institute
RPMI Roswell Park Memorial Institute
RPMI Royal Park Memorial Institute (culture medium) 
 1640 DM ("Dutch modification") medium, supplemented with 10% (v/v) heat-inactivated fetal calf serum (FCS FCS - Frame Check Sequence ) and 20[micro]g/ml gentamicin gentamicin /gen·ta·mi·cin/ (jen?tah-mi´sin) an aminoglycoside antibiotic complex isolated from bacteria of the genus Micromonospora, . The cells were maintained at 37 [degrees]C in a humidified atmosphere containing 5% [CO.sub.2]. Every 3-4 days, cells were spun down and seeded in new culture flasks at a density of 2 x [10.sup.5] cells/ml.

Virus

HIV (strain HTLV-[III.sub.B]/LAI) was obtained from the culture supernatant of HIV-infected HUT-78 cell line. The virus titer of the supernatant was determined in MT-4 cells. The virus stock was stored at -70[degrees]C until used.

Anti-HIV assay

Flat bottom, 96-well microtiter plates were filled with 100 [micro]l of complete medium using a Titertek multidrop dispenser (Flow Laboratories). Subsequently, stock solutions (10 x final test concentration) of plant extracts were added in 25 [micro]l volumes to two series of triplicate wells to allow simultaneous evaluation of their effects on HIV- and mock-infected cells. Serial five-fold dilutions of plant extracts were made directly in the microtiter plates using a Biornek 1000 robot (Beckman, Fullerton, California, USA). Thus each plant extract had final concentrations of 200, 40, 8, 1.6 and 0.32 [micro]g/ml in each experiment.

Fifty [mu]l of HIV-1 stock at 100 [TCID TCID

tissue culture infective dose; that amount of a pathogenic agent that will produce pathological change when inoculated on tissue cultures.
.sub.50] (Tissue Culture Infectious Dose) or medium was added to either the HIV- or mock-infected part of the microtiter plate. Exponentially growing MT-4 cells were centrifuged for 5 minutes at 140 g and the supernatant was discarded. The MT-4 cells were resuspended at 6 x [10.sup.5] cells/ml in a flask which was connected with an autoclavable dispensing cassette of a Titertek multidrop dispenser. Under slight magnetic stirring 50 [mu]l volumes were then transferred to the microtiter tray wells. The outer row wells were filled with 200 [mu]l of medium. The cells were incubated at 37 [degrees]C in a humidified atmosphere containing 5% [CO.sub.2]. Five days after infection the viability of mock- and HIV-infected cells was examined spectrophotometrically by the MTT-method.

MTT assay

The MTT assay is based on the reduction of the yellow colored 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma, St. Louis, Missouri, USA) by mitochondrial mitochondrial

pertaining to mitochondria.


mitochondrial RNAs
a unique set of tRNAs, mRNAs, rRNAs, transcribed from mitochondrial DNA by a mitochondrial-specific RNA polymerase, that account for about 4% of the total cell RNA that
 dehydrogenases of metabolically active cells to a blue formazan which can be measured spectrophotometrically.

To each well, 20 [mu]l of a 7.5 mg/ml MTT solution in phosphate-buffered saline was added using the Titertek multidrop. After incubation for one hour at 37 [degrees]C, a fixed volume of 150 [mu]l medium was removed from each well using an M96 washer (ICN ICN International Council of Nurses.  flow). Solubilization of the formazan crystals was achieved by addition of 100 [mu]l 10% (v/v) Triton X-100 in acidified acidified /acid·i·fied/ (ah-sid´i-fid) having been made acid.  isopropanol isopropanol, isopropyl alcohol, or 2-propanol (ī'səprō`pənōl, ī'səprō`pĭl), (CH3)2CHOH, a colorless liquid that is miscible with water.  (2 ml concentrated HCl per 500 ml solvent). Complete dissolution of the formazan crystals was obtained by shaking the plates for 10 minutes on a plate shaker (ICN flow). Finally, the optical density of each well was measured using an automatic plate reader (Multiscan MCC (The Microelectronics and Computer Technology Corporation, Austin, TX) The first high-tech research and development consortium in the U.S., created in 1982 by leading companies within the electronics industry. , ICN Flow) with a test wavelength of 540 nm and a reference wavelength of 690 nm. Blanking was carried out with wells containing all reagents except MT-4 cells, virus, and plant extract.

The 50% cytotoxic concentration ([CC.sub.50]) was defined as the concentration of the test compound that reduces the absorbance absorbance /ab·sor·bance/ (-sor´bans)
1. in analytical chemistry, a measure of the light that a solution does not transmit compared to a pure solution. Symbol .

2.
 ([OD.sub.540]) of the mock-infected control sample by 50%. The percent protection achieved by the test compound in HIV-infected cells was calculated by the following formula:

[([OD.sub.t]).sub.HIV] - [([OD.sub.c]).sub.HIV] / [([OD.sub.c]).sub.mock] - [([OD.sub.c]).sub.HIV] x 100 (expressed in %)

where [([OD.sub.t]).sub.HIV] is the optical density measured with a given concentration of the test compound in HIV-infected cells; [([OD.sub.c]).sub.HIV] is the optical density measured for the control untreated HIV-infected cells; and [([OD.sub.c]).sub.mock] is the optical density measured for control untreated mock-infected cells. The concentration achieving 50% protection according to the formula above was defined as the 50% effective concentration ([EC.sub.50]). The selectivity index was defined as [CC.sub.50]/[EC.sub.50].

Results and Discussion

A total of 38 different plant species from 21 families were investigated on their antiviral activity against HIV-1 (Table 1). The anti-HIV-1 activity was measured using a tetrazolium-based colorimetric col·or·im·e·ter  
n.
1. Any of various instruments used to determine or specify colors, as by comparison with spectroscopic or visual standards.

2.
 assay in infected MT-4 cells. The results of the screening are shown in Table 2. Antiviral activity was found for the ethanolic extracts from the leaves of Aspilia pluriseta and Rumex bequaertii with selectivity index (SI) values higher than 12 and 11, respectively. The ethanolic extract of Aspilia pluriseta showed a complete cell protection against HIV-induced cytopathic effect compared to cell controls, while the ethanolic extract of Rumex bequaertii exhibited 89% protection. A previous study reported the isolation of the photosensitiser thiarubrine-A, a dithiacyclohexadiene polyacetylene, from the leaves of Aspilia pluriseta (Rodriguez et al., 1985). It was shown that thiarubrine-A had a phototoxic phototoxic /pho·to·tox·ic/ (fo´to-tok?sik) having a toxic effect triggered by exposure to light.

pho·to·tox·ic
adj.
Rendering the skin susceptible to damage by light.
 activity against cytomegalovirus cytomegalovirus (sī'təmĕg'əlōvī`rəs), member of the herpesvirus family that can cause serious complications in persons with weakened immune systems.  and Sindbis virus, both of which are enveloped viruses (Hudson et al., 1986).

The ethanolic extract of Tithonia diversifolia showed a high cytotoxicity (Table 2). The ethanolic residue was suspended in 60% methanol and further extracted with petroleum ether and ethylacetate, consecutively. The residual aqueous fraction showed a pronounced anti-HIV-1 activity with a SI higher than 461 (Table 3).

The genus Tithonia (Asteraceae) comprising 11 species and 13 taxa, ranges from the south-western United States to Panama, although one species, Tithonia diversifolia (Hemsl.) A. Gray, has been escaped to Africa, Australia, Asia, and North America where it is locally abundant. Several studies reported the isolation of sesquiterpene sesquiterpene (sesˑ·kw·terˑ·pēn),
n
 lactones from T. diversifolia (Kuo and Chen, 1998; Pereira et al., 1997). In one study, three sesquiterpene lactones, i.e. diversifolin, diversifolin methyl ether, and tirotundin, were isolated from the leaves of T. diversifolia Rungeler et al., 1998). They inhibited the DNA DNA: see nucleic acid.
DNA
 or deoxyribonucleic acid

One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes.
 binding activity of the transcription factor NF-[kappa]B, resulting in a decreased production of inflammatory mediators, such as cytokines and chemokines. In another study, a new artemisinic acid analogue compound was isolated from mature stems of T. diversifolia (Bordoloi et al., 1996). Artemisinic acid, is the biogenetic bi·o·gen·e·sis   also bi·og·e·ny
n.
1. The principle that living organisms develop only from other living organisms and not from nonliving matter.

2. Generation of living organisms from other living organisms.

3.
 precursor of artemisinin Artemisinin (IPA: [artɛˈmɪsɪnən]) is a drug used to treat multi-drug resistant strains of falciparum malaria. , a potent antimalarial drug isolated from Artemisia annua. In ad dition, several semi-synthetic derivatives of artemisinin, such as 12-n-butyldeoxoartemisinin, showed an anti-HIV activity (Jung et al., 2000). It must be emphasized that the anti-HIV-1 activity of T. diversifolia was found in the polar layer, indicating that the active ingredients are hydrophilic hydrophilic /hy·dro·phil·ic/ (-fil´ik) readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water.

hy·dro·phil·ic
adj.
 compounds. Various sulfated polysaccharides have been found to be the anti-HIV active substances of many antivirally active plant extracts (Vlietinck et al., 1998). These compounds are targeted at the interaction between the viral envelope glycoprotein glycoprotein (glī'kōprō`tēn), organic compound composed of both a protein and a carbohydrate joined together in covalent chemical linkage.  gp120 and the [CD.sub.4], receptor, and as a consequence, they inhibit not only virus adsorption to the cells but also virus-induced syncytium syncytium /syn·cy·ti·um/ (sin-sish´e-um) a multinucleate mass of protoplasm produced by the merging of cells.

syn·cy·ti·um
n. pl.
 (giant cell) formation. In addition, sulfated polysaccharides may also directly interfere with the binding of HIV particles to the heparin sulfate sulfate, chemical compound containing the sulfate (SO4) radical. Sulfates are salts or esters of sulfuric acid, H2SO4, formed by replacing one or both of the hydrogens with a metal (e.g., sodium) or a radical (e.g., ammonium or ethyl).  proteoglycan proteoglycan /pro·teo·gly·can/ (pro?te-o-gli´kan) any of a group of polysaccharide-protein conjugates present in connective tissue and cartilage, consisting of a polypeptide backbone to which many glycosaminoglycan chains are covalently  of the cell surface (Vlietinck et al., 1998). Alternatively, polyphenolic compounds such as hydrolysable tannins show anti-HIV activity, which is partly mediated by inhi bition of HIV adsorption to the cells. Experiments are underway to determine if polysaccharides or polyphenolic compounds are responsible for the observed antiviral activity of the aqueous extract of T. diversifolia.

Plant extracts are complex mixtures of many compounds. This study clearly shows that the cytotoxicity and the antiviral activity of a total extract are not necessary due to the same compound(s), and that the cytotoxicity of some plant compounds may mask the antiviral properties of other plant substances. Our results suggest that the separation of apolar apolar /apo·lar/ (a-po´ler) having neither poles nor processes; without polarity.

apolar

having neither poles nor processes; without polarity.
 from polar components can increase the chance to find highly active antiviral compounds with low cytotoxicity. The two other active plants are currently investigated and the results of these studies will be published in due course.
Table 1

List of Rwandan medicinal plants studied (Baerts and Lehmann, 1989;
Rwangabo, 1993).

Family and species                  Vernacular name

ACANTHACEAE

Monechma subsessile                 Umubazi
(Oliv.) C.B. Clarke

AMARANTHACEAE

Cyathula uncinulata                 Igifashi
(Schrad.) Schinz

APIACEAE

Caucalis incognita                  Akaturambisiti
(Norman) Heywood et Jury

ASTERACEAE

Aspilia pluriseta Schweinf.         Icyumwa cy'agasozi
Berkkeya spekeana Oliv.             Ikigwarara
Bidens pilosa L.                    Inyabarasanya
Guizotia scabra (Vis.) Chiov.       Igishikashike
Guthenbergia cordifolia             Umweza
Benth. Ex Oliv
Microglossa pyrifolia               Umuhe
(Lam.) Kuntze
Senecio maranguensis O. Hoffm.      Imbatura
Spilanthes mauritiana               Gashegenyura
(Rich. et Pers.) DC.
Tagetes minuta L.                   Nyiramunukanabi
Tithonia diversifolia               Lkicamahirwe
(Hemsl.) A. Gray
Vernonia amygdalina Del.            Umubilizi
Vernonia miombicola Wild.           Idoma

CAESALPINIACEAE

Cassia didymobotrya Fresen.         Umubagabaga

CHENOPODIACEAE

Chenopodium ugandae                 Umugombe
(Aellen) Aellen

CRASSULACEAE

Kalanchoe crenata                   Igitenetene
(Andr.) Haw.

EUPHORBIACEAE

Clutia abyssinica Jaub. et Spach.   Umutarishonga
Macaranga kilimandscharica Pax      Umusekera

FABACEAE

Eriosema montanum Baker f.          Umugfunyantoke
Indigofera arrecta                  Umusororo
Hochst. ex A. Rich

HYPERICACEAE

Hypericum revolutum Vaml.           Ikinyamucucu

LAMIACEAE

Coleus kilimandschari Gurke         Igicunshu
Leonotis nepetaefolia R.Br.         Igicumucumu

MALVACEAE

Hibiscus fuscus Garcke              Umutozo

MELASTOMATACEAE

Dissotis throthae Gilg              Icyeba

MIMOSACEAE

Entada abyssinica                   Umusange
Steud ex A. Rich.

PEDALIACEAE

Sesamum angolense Welw.             Delele, Sope

PHYTOLACCACEAE

Phytolacca dodecandra               Umuhoko
l'Herit.

POLYGONACEAE

Rumex bequaertii De Wild            Nyiramuko

RANUNCULACEAE

Clematis hirsuta Per. et Guill.     Umunkamba
var. hirsuta

RUBIACEAE

Pavetta ternifolia (Oliv.) Hiern.   Umumenamabuye
Pentas longiflora Oliver            Isagara
Virectaria major (Schumann) verdc.  Umukilyi

TILIACEAE

Triumfetta rhomboidea Jacq.         Umushyigura

VERBENACEAE

Clerodendrum myricoides (Hochst.)   Umukuzanyana
R.Br. ex Vatke
Lantana trifolia L.                 Umuhengeri

Family and species                  Traditional Uses

ACANTHACEAE

Monechma subsessile                 Acne, cough, dehydration
(Oliv.) C.B. Clarke

AMARANTHACEAE

Cyathula uncinulata                 Dehydration, diarrhoea, wounds
(Schrad.) Schinz

APIACEAE

Caucalis incognita
(Norman) Heywood et Jury

ASTERACEAE

Aspilia pluriseta Schweinf.         Kwashiorkor, worms, wounds
Berkkeya spekeana Oliv.             Anthrax, cough
Bidens pilosa L.                    Furuncle, hepatitis, otitis, wounds
Guizotia scabra (Vis.) Chiov.       Agalactia, gonorrhoea, hepatitis
Guthenbergia cordifolia             East coast fever
Benth. Ex Oliv
Microglossa pyrifolia               Cough, elephantiasis, wounds
(Lam.) Kuntze
Senecio maranguensis O. Hoffm.      Cough, otitis, wounds
Spilanthes mauritiana               Malaria, pneumonia, tonsillitis
(Rich. et Pers.) DC.
Tagetes minuta L.                   Impotence, toothache
Tithonia diversifolia               Ascariasis, diarrhoea
(Hemsl.) A. Gray
Vernonia amygdalina Del.            Ascariasis, hepatitis, malaria
Vernonia miombicola Wild.           Gonorrhoea, malaria, worms

CAESALPINIACEAE

Cassia didymobotrya Fresen.         Ascariasis, neuropsychopathy

CHENOPODIACEAE

Chenopodium ugandae                 Eczema, hepatitis, snake bite
(Aellen) Aellen

CRASSULACEAE

Kalanchoe crenata                   Otitis, skin diseases
(Andr.) Haw.

EUPHORBIACEAE

Clutia abyssinica Jaub. et Spach.   Abortifacient, gonorrhoea
Macaranga kilimandscharica Pax      Afterpains

FABACEAE

Eriosema montanum Baker f.          Conjunctivitis, cough, snake bite
Indigofera arrecta                  Emetic, furuncle, scabies
Hochst. ex A. Rich

HYPERICACEAE

Hypericum revolutum Vaml.           Cough, respiratory diseases

LAMIACEAE

Coleus kilimandschari Gurke         Cough, worms
Leonotis nepetaefolia R.Br.         Hepatitis, pneumonia, wounds

MALVACEAE

Hibiscus fuscus Garcke              Diarrhoea, pneumonia, sprain

MELASTOMATACEAE

Dissotis throthae Gilg              Diarrhoea, wounds

MIMOSACEAE

Entada abyssinica                   Ascariasis, fever
Steud ex A. Rich.

PEDALIACEAE

Sesamum angolense Welw.             Skin diseases

PHYTOLACCACEAE

Phytolacca dodecandra               Emetic, otitis, pneumonia
l'Herit.

POLYGONACEAE

Rumex bequaertii De Wild            Furuncle, kwashiorkor, worms

RANUNCULACEAE

Clematis hirsuta Per. et Guill.     Abortifacient, urinary
var. hirsuta                        diseases

RUBIACEAE

Pavetta ternifolia (Oliv.) Hiern.   Skin diseases, worms
Pentas longiflora Oliver            Fever, worms
Virectaria major (Schumann) verdc.  Eye diseases, wounds

TILIACEAE

Triumfetta rhomboidea Jacq.         Abortifacient, snake bite

VERBENACEAE

Clerodendrum myricoides (Hochst.)   Constipation, hepatitis,
R.Br. ex Vatke                      syphilis
Lantana trifolia L.                 Gonorrhoea, heart failure
Table 2

Anti-HIV-1 activity of Rwandan plant extracts.

Family and species          Plant part (a)  [EC.sub.50] ([mu]g/ml) (b)

ACANTHACEAE

Monechma subsessile         LF              > 103.77

AMARANTHACEAE

Cyathula uncinulata         LF              > 134.52
Cyathula uncinulata         RT              > 168.92

APIACEAE

Caucalis incognita          LF                > 10.1

ASTERACEAE

Aspilia pluriseta           LF                 16.13
Berkheya spekeana           LF              > 200.00
Bidens pilosa               LF              > 153.79
Guizotia scabra             LF              > 141.37
Guthenbergia cordifolia     LF               > 29.18
Microglossa pyrifolia       LF              > 140.10
Microglossa pyrifolia       ST              > 125.41
Senecio maranguensis        LF               > 28.01
Spilanthes mauritiana       LF              > 140.72
Tagetes minuta              LF              > 143.38
Tithonia diversifolia       LF                > 1.60
Vernonia amygdalina         LF               > 19.66
Vernonia miombicola         LF               > 14.62

CAESALPINIACEAE

Cassia didymobotrya         LF              > 133.54

CHENOPODIACEAE

Chenopodium ugandae         LF               > 91.92

CRASSULACEAE

Kalanchoe crenata           LF               > 13.86
Kalanchoe crenata           ST                > 11.1

EUPHORBIACEAE

Clutia abyssinica           LF              > 128.01
Macaranga kilimandscharica  LF                > 5.23
Macaranga kilimandscharica  ST                 > 8.2

FABACEAE

Eriosema montanum           LF              > 166.03
Indigofera arrecta          LF               > 280.1
Indigofera arrecta          ST                > 20.0

HYPERICACEAE

Hypericum revolutum         LF              > 131.13
Hypericum revolutum         RT                > 11.9

LAMIACEAE

Coleus kilimandschari       LF              > 158.45
Leonotis nepetaefolia       LF              > 140.33

MALVACEAE

Hibiscus fuscus             LF              > 144.74
Hibiscus fuscus             RT                > 1.19

MELASTOMATACEAE

Dissotis throthae           LF              > 174.36

MIMOSACEAE

Entada abyssinica           LF               > 56.68
Entada abyssinica           ST               > 89.65

PEDALIACEAE

Sesamum angolense           LF               > 50.52

PHYTOLACCACEAE

Phytolacca dodecandra       LF               > 62.82

POLYGONACEAE

Rumex bequaertii            LF                17.695

RANUNCULACEAE

Clematis hirsuta            LF               > 23.98

RUBIACEAE

Pavetta ternifolia          LF              > 133.43
Pavetta ternifolia          RT              > 346.71
Pentas longiflora           LF               > 20.79
Pentas 1ongiflora           RT              > 125.40
Virectaria major            LF              > 186.23

TILIACEAE

Triumfetta rhomboidea       LF                > 0.03

VERBENACEAE

Clerodendrum myricoides     LF              > 114.19
Lantana trifolia                              > 4.01

Family and species          [CC.sub.50]([mu]g/ml) (c)  SI (d)

ACANTHACEAE

Monechma subsessile           103.77                     < 1

AMARANTHACEAE

Cyathula uncinulata           134.52                     < 1
Cyathula uncinulata           168.92                     < 1

APIACEAE

Caucalis incognita              10.1                     < 1

ASTERACEAE

Aspilia pluriseta           > 200.00                    > 12
Berkheya spekeana           > 200.00                   > < 1
Bidens pilosa                 153.79                     < 1
Guizotia scabra               141.37                     < 1
Guthenbergia cordifolia        29.18                     < 1
Microglossa pyrifolia         140.10                     < 1
Microglossa pyrifolia         125.41                     < 1
Senecio maranguensis           28.01                     < 1
Spilanthes mauritiana         140.72                     < 1
Tagetes minuta                143.38                     < 1
Tithonia diversifolia         < 1.60                     < 1
Vernonia amygdalina            19.66                     < 1
Vernonia miombicola            14.62                     < 1

CAESALPINIACEAE

Cassia didymobotrya           133.54                     < 1

CHENOPODIACEAE

Chenopodium ugandae            91.92                     < 1

CRASSULACEAE

Kalanchoe crenata              13.86                     < 1
Kalanchoe crenata               11.1                     < 1

EUPHORBIACEAE

Clutia abyssinica             128.01                     < 1
Macaranga kilimandscharica      5.23                     < 1
Macaranga kilimandscharica       8.2                     < 1

FABACEAE

Eriosema montanum             166.03                     < 1
Indigofera arrecta             280.1                     < 1
Indigofera arrecta            > 20.0                   > < 1

HYPERICACEAE

Hypericum revolutum           131.13                     < 1
Hypericum revolutum             11.9                     < 1

LAMIACEAE

Coleus kilimandschari         158.45                     < 1
Leonotis nepetaefolia         140.33                     < 1

MALVACEAE

Hibiscus fuscus               144.74                     < 1
Hibiscus fuscus                 1.19                     < 1

MELASTOMATACEAE

Dissotis throthae             174.36                     < 1

MIMOSACEAE

Entada abyssinica              56.68                     < 1
Entada abyssinica              89.65                     < 1

PEDALIACEAE

Sesamum angolense              50.52                     < 1

PHYTOLACCACEAE

Phytolacca dodecandra          62.82                     < 1

POLYGONACEAE

Rumex bequaertii            > 200.00                    > 11

RANUNCULACEAE

Clematis hirsuta               23.98                     < 1

RUBIACEAE

Pavetta ternifolia            133.43                     < 1
Pavetta ternifolia            346.71                     < 1
Pentas longiflora              20.79                     < 1
Pentas 1ongiflora             125.40                     < 1
Virectaria major              186.23                     < 1

TILIACEAE

Triumfetta rhomboidea           0.03                     < 1

VERBENACEAE

Clerodendrum myricoides       114.19                     < 1
Lantana trifolia                4.01                     < 1

Family and species          % protection (e)

ACANTHACEAE

Monechma subsessile           2

AMARANTHACEAE

Cyathula uncinulata           2
Cyathula uncinulata           4

APIACEAE

Caucalis incognita            6

ASTERACEAE

Aspilia pluriseta           103
Berkheya spekeana            12
Bidens pilosa                 2
Guizotia scabra               9
Guthenbergia cordifolia       5
Microglossa pyrifolia         1
Microglossa pyrifolia        -5
Senecio maranguensis         11
Spilanthes mauritiana         8
Tagetes minuta                0
Tithonia diversifolia       -26
Vernonia amygdalina          -7
Vernonia miombicola           0

CAESALPINIACEAE

Cassia didymobotrya          -2

CHENOPODIACEAE

Chenopodium ugandae           1

CRASSULACEAE

Kalanchoe crenata             9
Kalanchoe crenata            -5

EUPHORBIACEAE

Clutia abyssinica             0
Macaranga kilimandscharica    7
Macaranga kilimandscharica    7

FABACEAE

Eriosema montanum            -4
Indigofera arrecta           11
Indigofera arrecta           26

HYPERICACEAE

Hypericum revolutum          -4
Hypericum revolutum          21

LAMIACEAE

Coleus kilimandschari         5
Leonotis nepetaefolia        -5

MALVACEAE

Hibiscus fuscus               2
Hibiscus fuscus              21

MELASTOMATACEAE

Dissotis throthae           -10

MIMOSACEAE

Entada abyssinica             1
Entada abyssinica            22

PEDALIACEAE

Sesamum angolense            0

PHYTOLACCACEAE

Phytolacca dodecandra        3

POLYGONACEAE

Rumex bequaertii            89

RANUNCULACEAE

Clematis hirsuta            -1

RUBIACEAE

Pavetta ternifolia           5
Pavetta ternifolia           1
Pentas longiflora            5
Pentas 1ongiflora            2
Virectaria major            -5

TILIACEAE

Triumfetta rhomboidea       26

VERBENACEAE

Clerodendrum myricoides     -2
Lantana trifolia             1

(a) LF - leaves

RT - roots

ST - stem

(b) [EC.sub.50] = 50% Effective inhibitory concentration

(c) [CC.sub.50] = 50% Cytotoxic concentration

(d) SI = Selectivity Index ([CC.sub.50]/[EC.sub.50])

(e) Precent protection of viral cytopathic effect compared to control
wells
Table 3

Anti-HIV-1 activity of subfractions of Tithonia diversifolia.

Tithonia         [EC.sub.50]     [CC.sub.50]     SI (c)  % pro-
diversifolia     ([mu]g/ml) (a)  ([mu]g/ml) (b)          tection (d)

Petroleum ether  > 18.3            18.3            < 1   -20
Ethylacetate      > 0.2           < 0.2            < 1    -2
Water               0.04         > 20.0          > 461   104

(a) [EC.sub.50] = 50% Effectiv inhibitory concentration

(b) [CC.sub.50] = 50% Cytotoxi concentration

(c) SI = Selectivity Index ([CC.sub.50]/[EC.sub.50])

(d) Percent protection of vira cytopathic effect compared to control
wells


Acknowledgements

This work was supported by grant no. 92/94-09 of the Flemish Government. T. De Bruyne and S. Apers are postdoctoral researchers of the Fund for Scientific Research -- Flanders (Belgium).

* References

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Jung, M., Lee, S., Kim, H., Kim, H.: Recent studies on natural products as anti-HIV agents. Curr. Org. Chem. 7: 649-661, 2000.

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Pauwels, R., Balzarini, J., Baba, M., Snoeck, R., Schols, D., Herdewijn, P., Desmyter, J., De Clercq, E.: Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods. 20: 309-321, 1988.

Pereira, P.S., Dias, D.A., Vichnewski, W., Nasi, A.M.T.T., Herz, W.: Sesquiterpene lactones from Brazilian Tithonia diversifolia. Phytochemistry 45: 1445-1448, 1997.

Rodriguez, E., Aregullin, M., Nishida, T., Uchara, S., Wrangham, R., Abramowski, Z., Finlayson, A., Towers G.H.N. Thiarubrine A, a bioactive constituent of Aspilia (Asteracene) consumed by wild chimpanzees. Experientia 41: 419-420, 1985.

Rungeler, P., Lyss, G., Castro, V., Mora MORA, In civil law. This term, in mora, is used to denote that a party to a contract, who is obliged to do anything, has neglected to perform it, and is in default. Story on Bailm. Sec. 123, 259; Jones on Bailm. 70; Poth. Pret a Usage, c. 2, Sec. 2, art. 2, n. , G., Pahl, H.L., Merfort, I.; Study of three sesquiterpene lactones from Tithonia diversifolia on their anti-inflammatory activity using the transcription factor NF-[kappa]B and enzymes of the arachidonic acid pathway as targets. Planta Med. 64: 588-593, 1998.

Rwangabo, P.C.: La medecine traditionnelle au Rwanda. Paris: Editions Karthala et ACCT ACCT Cardiology A clinical trial–Amlodipine Cardiovascular Community Trial–that evaluated the effect of sex and age on response to the antihypertensive, amlodipine. See Amlodipine, Antihypertensive, Hypertension. , 1993.

Van Puyvelde, L., Mukarugambwa, S., Rwangabo, P.C., Ngaboyisonga, M., Runyinya, B.: Plantes medicinales et toxiques du Ruanda (II). Afrique medicale 16: 531-534, 1977.

Vlietinck, A.J., De Bruyne, T., Apers, S., Pieters, L.A.: Plant-derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection. Planta Med. 64: 97-109, 1998.

P. Cos (1), N. Hermans (1), T. De Bruyne (1), S. Apers (1), J. B. Sindambiwe (1), M. Witvrouw (2), E. De Clercq (2), D. Vanden Berghe (1), L. Pieters (1), A. J. Vlietinck (1)

(1.) Faculty of Pharmaceutical Sciences, University of Antwerp University of Antwerp (Dutch: Universiteit Antwerpen) is a university located in Antwerp, Belgium. History
It was founded in 2003 after the merger of the three universities that were previously known as RUCA (State University Centre Antwerp), UFSIA (University Faculties
, Antwerp, Belgium

(2.) Department of Microbiology and Immunology, Rega Institute for Medical Research The Rega Institute for Medical Research is a Belgian scientific establishment that is part of the Catholic University of Leuven (Leuven) in central Belgium. The Rega Iinstitute is an interfacultary biomedical research institute of the Catholic University of Leuven and consists of , Katholieke Universiteit Leuven The KATHOLIEKE UNIVERSITEIT LEUVEN (Catholic University of Leuven in English) or in short K.U.Leuven, is the largest, oldest, and most prominent university in Belgium. , Leuyen, Belgium

* Address

A.J. Vlietinck, Faculty of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B - 2610 Antwerp, Belgium Tel: ++32-3-820 27 33; Fax: ++32-3-820 27 09; e-mail: vlietink@uia.ua.ac.be
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Author:Cos, P.; Hermans, N.; De Bruyne, T.; Apers, S.; Sindambiwe, J.B.; Witvrouw, M.; De Clercq, E.; Bergh
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Date:Jan 1, 2002
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