Bioactive Phytocompounds and Future Perspectives
The integration of herbal medicine into modern medical practises, including treat-
ments for infections and cancer, must take into account the interrelated issues of
quality, safety, and efficacy [64]. Quality is the paramount issue because it can af-
fect the efficacy and/or safety of the herbal products being used. Current product
quality ranges from very high to very low due to intrinsic, extrinsic, and regulatory
factors. Intrinsically, species differences, organ specificity, diurnal and seasonal
variations can affect the qualitative and quantitative accumulation of active chemi-
cal constituents in the source medicinal plants. Extrinsically, environmental fac-
tors, field collection methods such as cultivation, harvest, post-harvest transport,
and storage, manufacturing practises, inadvertent contamination and substitution,
and intentional adulteration are contributing factors to the quality of herbal medic-
inal products. Source plant materials that are contaminated with microbes, micro-
bial toxins, environmental pollutants, or heavy metals; or finished products that
are adulterated with foreign toxic plants or synthetic pharmaceutical agents can
lead to adverse events. Substandard source materials or finished products will yield
therapeutically less effective agents. Herbal medicine quality can also be attributed
to regulatory practises. In a number of countries, herbal medicines are unregulat-
ed, which has led to product quality differences.
1.7 Bioactive Phytocompounds and Future Perspectives 21
Product quality improvement may be achieved by implementing control meas-
ures from the point of medicinal plant procurement under Good Agricultural Prac-
tises (GAPs) and the manufacture of the finished botanical products under Good
Manufacturing Practises (GMPs), plus postmarketing quality assurance surveil-
lance. The lack of pharmacological and clinical data on the majority of herbal me-
dicinal products is a major impediment to the integration of herbal medicines into
conventional medical practise. For valid integration, pharmacological and especial-
ly, clinical studies, must be conducted on those plants lacking such data. Adverse
events, including drug–herb interactions, must also be monitored to promote a
safe integration of efficacious herbal medicine into conventional medical practises.
For the developing countries, the approval as drugs of standardized and formu-
lated plant extracts might be the starting point of an innovative and successful lo-
cal pharmaceutical industry, which can compete with the large pharmaceutical
companies, not only for the treatment of minor diseases, but also for the treatment
of severe and life-threatening diseases. It can be stated that the major activities of
natural products research of the past decades have clearly demonstrated that natu-
ral products represent an unparalleled reservoir of molecular diversity to drug dis-
covery and development, and are complementary to combinatorial libraries.
The major disadvantage is the time taken to isolate and to characterize the active
components from the extracts. By improving the diversity and quality of sample
source and screen suitability, by accelerating dereplication and by automating and
standardizing early isolation steps, the effectiveness of natural products research
can be enhanced. The efforts to establish collaboration between universities and lo-
cal pharmaceutical companies to produce new medicines with scientific proof of
safety, quality and efficacy are relevant to progress in this area. This interaction
between the pharmaceutical industry and the universities has in turn stimulated
the appearance of preclinical pharmacological studies and of well-controlled and
randomized clinical trials to prove their worth. Furthermore, emphasis on domes-
tication, production, and biotechnological studies, followed by genetic improve-
ments to medicinal plants, are other fields of science that emerge from such
progress in the use of medicinal plants in the world.
Scientists have dedicated significant efforts to the publishing of both basic and
clinical studies on herbal medicines, and thus certainly will create the scientific ba-
sis for the physician’s prescription of herbal drugs. In spite of this, so far insuffi-
cient data exist to provide an accurate assessment of the quality, efficacy, and safe-
ty of most of the herbal medicines currently available on the market. For all these
reasons, a great effort in training more scientists in the relevant areas is still neces-
sary in order to establish rational and sustainable exploitation of the world’s biodi-
versity.
22 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
References
References 23
1 Newman D.J., Cragg, G.M., Snader, K.M.
J. Nat. Prod. 2003, 6, 1022–1037.
2 Ganesan, A. Drug Discov. Today 2002, 7,
47–55.
3 Mehta, G., Singh, V. Chem. Soc. Rev.
2002, 31, 324–334.
4 Breinbauer R., Vetter, I.R., Waldmann,
H. Angew. Chem. Int. Ed. 2002, 41,
2879–2890.
5 Lee M.L., Schneider, G. J. Comb. Chem.
2001, 3, 284–289.
6 Bajorath, J. J. Comput. Aided Mol. Des.
2002, 16, 431–439.
7 Hall, D.G., Manku, S., Wang, F. J. Comb.
Chem. 2001, 3, 125–150.
8 Hook, D.J., Pack, E.J., Yacobucci, J.J.,
Guss, J. J. Biomol. Screen. 1997, 2,
145–152.
9 Wolfender, J-L., Rodriguez, S.,
Hostettmann, K. J. Chromatogr. 1998,
A794, 299–316.
10 Silva, C.J., Brian, P., Peterson, T. Drugs
Pharmac. Sci. 2001, 114, 357–382.
11 Kuiper, G.G.J.M., Lemmen, J.G.,
Carlsson, B., Corton, J.C., Safe, S.H., van
der Saag, P.T., van der Burg, B.,
Gustafsson, J-A. Endocrinology 1998, 139,
4252–4263.
12 Corley, D.G., and Durley, R.C. J. Nat.
Prod. 1994, 57, 1484–1490.
13 Pannell, L.K., Shigematsu, N. Am. Lab.
1998, 30, 28–30.
14 Eloff, J.N. J. Ethnopharmacol. 1998, 60,
1–8.
15 Miles, D.H., Nguyen, C.L., Miles, D.H.
Curr. Med. Chem. 1998, 5, 421–440.
16 Rojas, A., Hernandez, L.,
Pereda–Miranda, R., Mata, R. J.
Ethnopharmacol. 1992, 35, 275–283.
17 Mazzanti, G., Battinelli, L., Salvatore, G.
Flav. Fragr. J. 1998, 13, 289–294.
18 Lopes, D., Bizzo, H.R., Sobrinho, A.F.S.,
Pereira, M.V.G. Oil Res. 2000, 12,
705–708.
19 Grynberg, N. F., Echevarria, A., Lima,
J.E., Pamplona, S.S., Pinto, A.C., Maciel,
M.A. Planta Med. 1999, 65, 687–689.
20 Rosa, M.S.S., Mendonca Filho, R.R.,
Bizzo, H.R. Rodrigues, I.A., Soares,
R.M.A., Souto-Padron, T., Alviano, C.S.,
Lopes, A.H.C.S. Antimicrob. Agents
Chemother. 2003, 47, 1895–1901.
21 Tassou, C.C., Drosinos, E.H., Nychas,
G.J.E. J. Appl. Bacteriol. 1995, 78, 593–600.
22 Esquenazi, D., Wigg, M.D., Miranda,
M.M.F.S., Rodrigues, H.M., Tostes,
J.B.F., Rozental, S., Da Silva, A.J.R.,
Alviano, C.S. Res. Microbiol. 2002, 153,
647–652.
23 Ibanez, E., Kubatova, A., Senorans, F.J.,
Cavero, S., Reglero, G., Hawthorne, S.B.
J. Agric. Food Chem. 2003, 51, 375–382.
24 Ju, Z., Howard, L. J. Agric. Food Chem.
2003, 51, 5207–5213.
25 Awad, R., Arnason, J.T., Trudeau, V.L.,
Bergeron, C., Budzinski, J.W., Foster,
B.C., Merali, Z. Phytomed. 2003, 10,
640–649.
26 Lewis, W.H., Elvin-Lewis, M.P. Ann. Mo.
Bot. Gard. 1995, 82,16–24.
27 Zhang, Y., Lewis, K. FEMS Microbiol. Lett.
1997, 149, 59–64.
28 Balzarini, J., Schols, D.J., Neyts, E. Van
Damme, W. Peumans., E. De Clercq.
Antimicrob. Agents Chemother. 1991, 35,
410–416.
29 Hui, K.M., Wang, X.H., Xue, H. Planta
Med. 2002, 66, 91–93.
30 Kubo, I., Muroi, H., Himejima, M. J. Nat.
Prod. 1993, 56, 220–226.
31 Moerman, D.E. J. Ethnopharmacol. 1996,
52, 1–22.
32 Heimhuber, B., Galensa, R., Herrmann,
K. J. Chromatogr. 1988, 739, 481–483.
33 Saxena, G., Towers, G.H.N., Farmer, S.,
Hancock, R.E.W. Phytochem. Anal. 1995,
6, 125–129.
34 Wu, A.M., Jiang, Y.J., Hwang, P.Y., Shen,
F.S. Biochim. Biophys. Acta 1995, 1243,
157–160.
35 Schmourlo, G., Mendonca–Filho, R.R.,
Alviano, C.S., Costa, S.S.C. J.
Ethnopharmacol. 2005, 96, 563–568.
36 Farnsworth N.R. Herbal Gram 1993, 29,
36A–367H.
37 World Health Organization, WHO
Guidelines for Methodologies on Research
and Evaluation of Traditional Medicine.
World Health Organization, Geneva,
2001.
38 Bannerman, R., Burton, J., Chen, W.C.
eds. Traditional Medicine and Health Care
Coverage. World Health Organization,
Geneva, 1983.
24 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
39 Awang, D.V.C. Food Drug Law J. 1997, 52,
341–344.
40 World Health Organization, Good Manu-
facturing Practices for pharmaceutical
products: main principles. In WHO
Expert Committee on Specifications for
Pharmaceutical Preparations. Thirty-
seventh report. WHO Technical Report
Series, No. 908. World Health Organiza-
tion, Geneva, 2003, Annex 4.
41 Ahmad, I., Beg, A.Z. J. Ethnopharmacol.
2001, 74, 113–123.
42 Naganawa, R., Iwata, N., Ishikawa, K.,
Fukuda, H., Fujino, T., Suzuki, A. Appl.
Environ. Microbiol. 1996, 62, 4238–4242.
43 Omulokoli, E., Khan, B., Chhabra, C.S.
J. Ethnopharmacol. 1997, 56, 133–137.
44 Ooshima, T., Minami, T., Aono, W.,
Izumitani, A., Sobue, S., Fujiwara, T.,
Kawabata, S., Hamada, S. Caries Res.
1993, 27, 124–129.
45 Bose, P.K. J. Indian Chem. Soc. 1958, 58,
367–375.
46 Stange, R.R., Midland, S.L., Eckert, J.W.,
Sims, J.J. J. Nat. Prod. 1993, 56,
1627–1629.
47 Freiburghaus, F., Kaminsky, R., Nkunya,
M.H.H., Brun, R. J. Ethnopharmacol.
1996, 55, 1–11.
48 Wild, R. (ed.) The Complete Book of
Natural and Medicinal Cures. Rodale
Press, Emmaus, PA, 1994.
49 Perrett, S., Whitfield, P.J., Sanderson, L.,
Bartlett, A. J. Ethnopharmacol. 1995, 47,
49–54.
50 Wan, J., Wilcock, A., Coventry, M.J. J.
Appl. Microbiol. 1998, 84, 152–158.
51 Kubo, A., Lunde, C.S., Kubo., I. J. Agric.
Food Chem. 1995, 43, 1629–1633.
52 Jones, G.A., McAllister, M.A., Muir, A.D.,
Cheng, K.J. Appl. Environ. Microbiol. 1994,
60, 1374–1378.
53 Martinez, M.J., Betancourt, J., Alonso-
Gonzalez, N., Jauregui, A. J.
Ethnopharmacol. 1996, 52, 171–174.
54 Ghoshal, S., Krishna Prasad, B.N.,
Lakshmi, V. J. Ethnopharmacol. 1996, 50,
167–170.
55 Kubo, I., Muroi, H., Kubo, A. J. Nat. Prod.
1994, 57, 9–17.
56 Kadota, S., Basnet, P., Ishii, E., Tamura,
T., Namba, T. Zentbl. Bakteriol. 1997, 286,
63–67.
57 Ofek, I., Goldhar, J., Sharon, N. Adv. Exp.
Med. Biol. 1996, 408, 179–183.
58 Apisariyakul A., Vanittanakom, N.,
Buddhasukh, D. J. Ethnopharmacol. 1995,
49, 163–169.
59 Seedat, Y.K. South Afr. Med. J. 1978, 54,
427–431.
60 Ojogwu L.I., Anah C. East Afr. Med. J.
1983, 60, 478–484.
61 Kadiri S., Ogunlesi A., Osinfade K.,
Akinkugbe O. Afr. J. Med. Med. Sci. 1992,
21, 91–96.
62 Randeree, I.G., Czarnocki, A, Moodley, J.,
Seedat, Y. Ren. Fail. 1995, 17, 147–153.
63 Adelekun, T.A., Ekwere, T.R., Akinsola,
A. West Afr. J. Med. 1999, 18, 60–63.
64 Schwartsmann, G., Ratain, M.J., Cragg,
G.M., Wong, J.E., Saijo, N., Parkinson,
D.R., Fujiwara, Y., Pazdur, R., Newman,
D.J., Dagher, R., DiLeone, L. J. Clin.
Oncol. 2002, 20 (Suppl. 18), 47S–59S.
2
The integration of herbal medicine into modern medical practises, including treat-
ments for infections and cancer, must take into account the interrelated issues of
quality, safety, and efficacy [64]. Quality is the paramount issue because it can af-
fect the efficacy and/or safety of the herbal products being used. Current product
quality ranges from very high to very low due to intrinsic, extrinsic, and regulatory
factors. Intrinsically, species differences, organ specificity, diurnal and seasonal
variations can affect the qualitative and quantitative accumulation of active chemi-
cal constituents in the source medicinal plants. Extrinsically, environmental fac-
tors, field collection methods such as cultivation, harvest, post-harvest transport,
and storage, manufacturing practises, inadvertent contamination and substitution,
and intentional adulteration are contributing factors to the quality of herbal medic-
inal products. Source plant materials that are contaminated with microbes, micro-
bial toxins, environmental pollutants, or heavy metals; or finished products that
are adulterated with foreign toxic plants or synthetic pharmaceutical agents can
lead to adverse events. Substandard source materials or finished products will yield
therapeutically less effective agents. Herbal medicine quality can also be attributed
to regulatory practises. In a number of countries, herbal medicines are unregulat-
ed, which has led to product quality differences.
1.7 Bioactive Phytocompounds and Future Perspectives 21
Product quality improvement may be achieved by implementing control meas-
ures from the point of medicinal plant procurement under Good Agricultural Prac-
tises (GAPs) and the manufacture of the finished botanical products under Good
Manufacturing Practises (GMPs), plus postmarketing quality assurance surveil-
lance. The lack of pharmacological and clinical data on the majority of herbal me-
dicinal products is a major impediment to the integration of herbal medicines into
conventional medical practise. For valid integration, pharmacological and especial-
ly, clinical studies, must be conducted on those plants lacking such data. Adverse
events, including drug–herb interactions, must also be monitored to promote a
safe integration of efficacious herbal medicine into conventional medical practises.
For the developing countries, the approval as drugs of standardized and formu-
lated plant extracts might be the starting point of an innovative and successful lo-
cal pharmaceutical industry, which can compete with the large pharmaceutical
companies, not only for the treatment of minor diseases, but also for the treatment
of severe and life-threatening diseases. It can be stated that the major activities of
natural products research of the past decades have clearly demonstrated that natu-
ral products represent an unparalleled reservoir of molecular diversity to drug dis-
covery and development, and are complementary to combinatorial libraries.
The major disadvantage is the time taken to isolate and to characterize the active
components from the extracts. By improving the diversity and quality of sample
source and screen suitability, by accelerating dereplication and by automating and
standardizing early isolation steps, the effectiveness of natural products research
can be enhanced. The efforts to establish collaboration between universities and lo-
cal pharmaceutical companies to produce new medicines with scientific proof of
safety, quality and efficacy are relevant to progress in this area. This interaction
between the pharmaceutical industry and the universities has in turn stimulated
the appearance of preclinical pharmacological studies and of well-controlled and
randomized clinical trials to prove their worth. Furthermore, emphasis on domes-
tication, production, and biotechnological studies, followed by genetic improve-
ments to medicinal plants, are other fields of science that emerge from such
progress in the use of medicinal plants in the world.
Scientists have dedicated significant efforts to the publishing of both basic and
clinical studies on herbal medicines, and thus certainly will create the scientific ba-
sis for the physician’s prescription of herbal drugs. In spite of this, so far insuffi-
cient data exist to provide an accurate assessment of the quality, efficacy, and safe-
ty of most of the herbal medicines currently available on the market. For all these
reasons, a great effort in training more scientists in the relevant areas is still neces-
sary in order to establish rational and sustainable exploitation of the world’s biodi-
versity.
22 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
References
References 23
1 Newman D.J., Cragg, G.M., Snader, K.M.
J. Nat. Prod. 2003, 6, 1022–1037.
2 Ganesan, A. Drug Discov. Today 2002, 7,
47–55.
3 Mehta, G., Singh, V. Chem. Soc. Rev.
2002, 31, 324–334.
4 Breinbauer R., Vetter, I.R., Waldmann,
H. Angew. Chem. Int. Ed. 2002, 41,
2879–2890.
5 Lee M.L., Schneider, G. J. Comb. Chem.
2001, 3, 284–289.
6 Bajorath, J. J. Comput. Aided Mol. Des.
2002, 16, 431–439.
7 Hall, D.G., Manku, S., Wang, F. J. Comb.
Chem. 2001, 3, 125–150.
8 Hook, D.J., Pack, E.J., Yacobucci, J.J.,
Guss, J. J. Biomol. Screen. 1997, 2,
145–152.
9 Wolfender, J-L., Rodriguez, S.,
Hostettmann, K. J. Chromatogr. 1998,
A794, 299–316.
10 Silva, C.J., Brian, P., Peterson, T. Drugs
Pharmac. Sci. 2001, 114, 357–382.
11 Kuiper, G.G.J.M., Lemmen, J.G.,
Carlsson, B., Corton, J.C., Safe, S.H., van
der Saag, P.T., van der Burg, B.,
Gustafsson, J-A. Endocrinology 1998, 139,
4252–4263.
12 Corley, D.G., and Durley, R.C. J. Nat.
Prod. 1994, 57, 1484–1490.
13 Pannell, L.K., Shigematsu, N. Am. Lab.
1998, 30, 28–30.
14 Eloff, J.N. J. Ethnopharmacol. 1998, 60,
1–8.
15 Miles, D.H., Nguyen, C.L., Miles, D.H.
Curr. Med. Chem. 1998, 5, 421–440.
16 Rojas, A., Hernandez, L.,
Pereda–Miranda, R., Mata, R. J.
Ethnopharmacol. 1992, 35, 275–283.
17 Mazzanti, G., Battinelli, L., Salvatore, G.
Flav. Fragr. J. 1998, 13, 289–294.
18 Lopes, D., Bizzo, H.R., Sobrinho, A.F.S.,
Pereira, M.V.G. Oil Res. 2000, 12,
705–708.
19 Grynberg, N. F., Echevarria, A., Lima,
J.E., Pamplona, S.S., Pinto, A.C., Maciel,
M.A. Planta Med. 1999, 65, 687–689.
20 Rosa, M.S.S., Mendonca Filho, R.R.,
Bizzo, H.R. Rodrigues, I.A., Soares,
R.M.A., Souto-Padron, T., Alviano, C.S.,
Lopes, A.H.C.S. Antimicrob. Agents
Chemother. 2003, 47, 1895–1901.
21 Tassou, C.C., Drosinos, E.H., Nychas,
G.J.E. J. Appl. Bacteriol. 1995, 78, 593–600.
22 Esquenazi, D., Wigg, M.D., Miranda,
M.M.F.S., Rodrigues, H.M., Tostes,
J.B.F., Rozental, S., Da Silva, A.J.R.,
Alviano, C.S. Res. Microbiol. 2002, 153,
647–652.
23 Ibanez, E., Kubatova, A., Senorans, F.J.,
Cavero, S., Reglero, G., Hawthorne, S.B.
J. Agric. Food Chem. 2003, 51, 375–382.
24 Ju, Z., Howard, L. J. Agric. Food Chem.
2003, 51, 5207–5213.
25 Awad, R., Arnason, J.T., Trudeau, V.L.,
Bergeron, C., Budzinski, J.W., Foster,
B.C., Merali, Z. Phytomed. 2003, 10,
640–649.
26 Lewis, W.H., Elvin-Lewis, M.P. Ann. Mo.
Bot. Gard. 1995, 82,16–24.
27 Zhang, Y., Lewis, K. FEMS Microbiol. Lett.
1997, 149, 59–64.
28 Balzarini, J., Schols, D.J., Neyts, E. Van
Damme, W. Peumans., E. De Clercq.
Antimicrob. Agents Chemother. 1991, 35,
410–416.
29 Hui, K.M., Wang, X.H., Xue, H. Planta
Med. 2002, 66, 91–93.
30 Kubo, I., Muroi, H., Himejima, M. J. Nat.
Prod. 1993, 56, 220–226.
31 Moerman, D.E. J. Ethnopharmacol. 1996,
52, 1–22.
32 Heimhuber, B., Galensa, R., Herrmann,
K. J. Chromatogr. 1988, 739, 481–483.
33 Saxena, G., Towers, G.H.N., Farmer, S.,
Hancock, R.E.W. Phytochem. Anal. 1995,
6, 125–129.
34 Wu, A.M., Jiang, Y.J., Hwang, P.Y., Shen,
F.S. Biochim. Biophys. Acta 1995, 1243,
157–160.
35 Schmourlo, G., Mendonca–Filho, R.R.,
Alviano, C.S., Costa, S.S.C. J.
Ethnopharmacol. 2005, 96, 563–568.
36 Farnsworth N.R. Herbal Gram 1993, 29,
36A–367H.
37 World Health Organization, WHO
Guidelines for Methodologies on Research
and Evaluation of Traditional Medicine.
World Health Organization, Geneva,
2001.
38 Bannerman, R., Burton, J., Chen, W.C.
eds. Traditional Medicine and Health Care
Coverage. World Health Organization,
Geneva, 1983.
24 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
39 Awang, D.V.C. Food Drug Law J. 1997, 52,
341–344.
40 World Health Organization, Good Manu-
facturing Practices for pharmaceutical
products: main principles. In WHO
Expert Committee on Specifications for
Pharmaceutical Preparations. Thirty-
seventh report. WHO Technical Report
Series, No. 908. World Health Organiza-
tion, Geneva, 2003, Annex 4.
41 Ahmad, I., Beg, A.Z. J. Ethnopharmacol.
2001, 74, 113–123.
42 Naganawa, R., Iwata, N., Ishikawa, K.,
Fukuda, H., Fujino, T., Suzuki, A. Appl.
Environ. Microbiol. 1996, 62, 4238–4242.
43 Omulokoli, E., Khan, B., Chhabra, C.S.
J. Ethnopharmacol. 1997, 56, 133–137.
44 Ooshima, T., Minami, T., Aono, W.,
Izumitani, A., Sobue, S., Fujiwara, T.,
Kawabata, S., Hamada, S. Caries Res.
1993, 27, 124–129.
45 Bose, P.K. J. Indian Chem. Soc. 1958, 58,
367–375.
46 Stange, R.R., Midland, S.L., Eckert, J.W.,
Sims, J.J. J. Nat. Prod. 1993, 56,
1627–1629.
47 Freiburghaus, F., Kaminsky, R., Nkunya,
M.H.H., Brun, R. J. Ethnopharmacol.
1996, 55, 1–11.
48 Wild, R. (ed.) The Complete Book of
Natural and Medicinal Cures. Rodale
Press, Emmaus, PA, 1994.
49 Perrett, S., Whitfield, P.J., Sanderson, L.,
Bartlett, A. J. Ethnopharmacol. 1995, 47,
49–54.
50 Wan, J., Wilcock, A., Coventry, M.J. J.
Appl. Microbiol. 1998, 84, 152–158.
51 Kubo, A., Lunde, C.S., Kubo., I. J. Agric.
Food Chem. 1995, 43, 1629–1633.
52 Jones, G.A., McAllister, M.A., Muir, A.D.,
Cheng, K.J. Appl. Environ. Microbiol. 1994,
60, 1374–1378.
53 Martinez, M.J., Betancourt, J., Alonso-
Gonzalez, N., Jauregui, A. J.
Ethnopharmacol. 1996, 52, 171–174.
54 Ghoshal, S., Krishna Prasad, B.N.,
Lakshmi, V. J. Ethnopharmacol. 1996, 50,
167–170.
55 Kubo, I., Muroi, H., Kubo, A. J. Nat. Prod.
1994, 57, 9–17.
56 Kadota, S., Basnet, P., Ishii, E., Tamura,
T., Namba, T. Zentbl. Bakteriol. 1997, 286,
63–67.
57 Ofek, I., Goldhar, J., Sharon, N. Adv. Exp.
Med. Biol. 1996, 408, 179–183.
58 Apisariyakul A., Vanittanakom, N.,
Buddhasukh, D. J. Ethnopharmacol. 1995,
49, 163–169.
59 Seedat, Y.K. South Afr. Med. J. 1978, 54,
427–431.
60 Ojogwu L.I., Anah C. East Afr. Med. J.
1983, 60, 478–484.
61 Kadiri S., Ogunlesi A., Osinfade K.,
Akinkugbe O. Afr. J. Med. Med. Sci. 1992,
21, 91–96.
62 Randeree, I.G., Czarnocki, A, Moodley, J.,
Seedat, Y. Ren. Fail. 1995, 17, 147–153.
63 Adelekun, T.A., Ekwere, T.R., Akinsola,
A. West Afr. J. Med. 1999, 18, 60–63.
64 Schwartsmann, G., Ratain, M.J., Cragg,
G.M., Wong, J.E., Saijo, N., Parkinson,
D.R., Fujiwara, Y., Pazdur, R., Newman,
D.J., Dagher, R., DiLeone, L. J. Clin.
Oncol. 2002, 20 (Suppl. 18), 47S–59S.
2
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