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Ali M. The use of High-resolution microscopy for in vitro evaluation of safety of injectable herbal extracts
J Integrative Medicine 1998;2:70-72

The use of High-resolution microscopy for in vitro evaluation of safety of injectable herbal extracts

Majid Ali, M.D.

Objective
    To describe an in vitro method for evaluating the safety of whole herb extracts for parenteral use by examination of blood cells and plasma after exposing them to various concentrations of extracts with high- resolution phase-contrast microscopy.

Methods
    The ingredients of six herbs extensively used at the Institute for a variety of chronic disorders were extracted in phosphate-buffered saline at physiological pH followed by ultracentrifugation and ultrafiltration. The immediate and delayed effects of various concentrations of such extracts on the peripheral blood plasma and corpuscles were evaluated directly with high-resolution (15,000x) phase-contrast microscopy. The potential for immediate and delayed adverse local and systemic effects of injections of optimized concentrations of herbal extracts was investigated by administering intramuscular injections to five volunteers after appropriate consent was obtained.

Results
    Strong concentrations (1:10 to 1:100) of all extracts caused a variety of erythrocyte membrane deformities, including loss of normal plasticity, wrinkling, spiking, and agglutination. Some cells were lysed. The plasma changes accompanying cellular changes included formation of zones of congealing, microclots, and microplaques. With the use of different dilutions of herbal extracts, it was possible to select dilutions of herbal extracts that caused limited and spontaneously resolving patterns of damage to blood cells or plasma. Intramuscular injections of ultrafiltered herbal extracts in those dilutions to four volunteers, after obtaining appropriate consents, did not cause any immediate or delayed adverse local and systemic effects.

Conclusions
    The preliminary observations reported in this study warrant additional study of the value of high- resolution microscopy for evaluating effects of herbal extracts on peripheral blood cells and plasma. Such microscopy not only allows easy and early detection of herbal extracts that may cause hemolysis (by their hemagglutinins or other components), it also permits selection of the optimal dilutions of extracts that may be safe for parenteral use.

Preparation of Whole Herb Extracts
    The injectable extracts of six herbs were prepared by extraction of active ingredients with phosphate-buffered saline followed by ultracentrifugation and utrafilteration as described elsewhere.1 The following herbs were included in this preliminary study: Hydrastis canadensis (goldenseal root), Foeniculum vulgare (fennel seeds), Hypericum perforatum (St. John's wort), Glycerrhiza (licorice root), Rubus villosus (blackberry root), and Herba impatiens pallida.

High-Resolution Phase-Contrast and Darkfield Microscopy.
    The details of morphologic of study of freshly prepared, unstained peripheral blood smears with high- resolution (15,000x) phase-contrast microscopy are described on page 7 of this issue of the Journal.2 For evaluating the immediate and delayed effects of various concentrations of the herbal extracts on the plasma components and blood corpuscles, a drop of 1:10, 1:100, 1:500, 1:1,000, 1:5,000, 1:10,000, and 1:100,000 dilutions of each herbal extract was added to the freshly prepared smears, followed by gentle mixing of the extract with blood elements. The smears were then covered with a coverslip and examined with phase- contrast microscopy. All extracts tested in 1:10 dilutions caused diffuse erythrocyte agglutination and other forms of membrane damage. With increasing dilutions, such changes were observed with decreasing frequency. Still, some evidence of erythrocyte membrane damage was seen with all herbal extracts in dilutions less than 1:1,000 when smears were examined immediately. However, in most cases, such changes resolved spontaneously within 30 to 60 minutes, indicating reversibility of such membrane changes involving most cells with weaker dilutions. A small number of erythrocyte in most smears did not recover, and a few underwent lysis. Such changes are similar to those observed with intravenous infusions of hydrogen peroxide and ozone as described on page 11 of this issue of the Journal. (See discussion on pages 42 and 43 for the paradox of oxidants serving as antioxidant therapies and for potential benefits of clearance from the blood of such presumably senescent or "unhealthy" cells).

Dilution Studies for Assessing Effects of Herbal Extracts on Erythrocyte Morphology

    Table 1 shows results of dilution studies performed to investigate reversibility of erythrocyte membrane changes induced by exposure to herbal extracts. All extracts used were in 1:20 w/v strengths. Peripheral smears were examined immediately and 30 minutes after the addition of one drop of the herbal extract dilutions shown.

DISCUSSION

    A large number of pharmacologic agents are derived from plant sources. The traditional approach to preparation of such pharmaceutical agents employs fractionation of natural, plant-derived substances into their individual bioactive components followed by chemical characterization of one or more fractions for use as single drugs. While this approach has yielded a rich formulary of potent drugs for managing acute disorders, the long-term effects of such drugs carry significant potential for adverse effects. The use of whole herb extracts, by contrast, are generally not as potent as plant-derived drugs. This has been validated by the author by his empirical observations with combinations of herbs formulated to restore altered bowel, blood, liver, and other body organ ecosystems.2- 5 It seems likely that such safety follows use of a large number of herbs in smaller amounts. Beyond that, there is the important issue of plant substances carrying their own "counteracting" components that neutralize some of the toxicity of individual and highly concentrated fractions such as those used in plant-derived drugs. Thus, highly purified plant fractions (drugs), while effective in acute illnesses, may not be optimal for use for slow and sustained reparative work for damaged body organ ecosystems.
   
    Herbs have been used for medicinal uses by the oral route for hundreds of years.6-9 Injectable extracts of individual compounds derived from plant sources, such as colchicine, have been used for their medicinal values for decades in many countries. The Chinese have clinically used extracts of whole herbs with increasing frequency during the last few decades. It is known that certain herbs, when administered intramuscularly, produce results that contrast with those empirically observed with oral use.10 One possible explanation for that phenomenon may be that active ingredients of such herbs undergo conformational changes when they are subjected to the normal digestive/absorptive processes after oral administration.
    The potential clinical benefits of parenteral use of mixtures of whole herb extracts need to be explored for several reasons. First, extensive empirical experience indicates that injectable forms of many therapeutic agents are far more effective than the preparations for oral use. The author's own clinical observations with a host of injectable nutrients and some herbs, such as colchicine, has convinced him of the validity of the above statement. Empirical experience with mixture of injectable herbal extracts, though limited, suggests the possibility that the clinical outcome with the use of injectable extracts may be improved. Second, there is the potential of injectable herbal mixtures providing greater benefits just as oral herbal mixtures give superior results than the use of single herbs. Third, there are many anecdotal reports of control of malignant neoplasms and other serious autoimmune disorders with injectable herbal mixtures for which there are no effective drug therapies. However, details of such therapies are rarely published, and the safety of their use cannot be assumed.

Phytoagglutinins (Lectins) and Potential for Hemolytic Reactions

    The clinical safety of herbs, in general, has been established by empirical use by herbologists and integrative physicians. A central issue in parenteral use of herbal formulations, however, is the potential danger of serious hemolytic and nonhemolytic reactions when they are given parenterally. Specifically, there is the issue of phytoagglutinins, natural plant-derived substances with ability to bind a large variety of cell membrane ligands, causing serious hemolytic and nonhemolytic reactions.11-13 An example of a highly toxic phytoagglutinin is that derived from beans of the castor plant. Even commonly ingested wheat germ agglutinins are know to cause agglutinin reactions in certain individuals.11 The microscopic method described in this report can evidently provide an early warning of the potential hemolytic reactions caused by parenterally herbal extracts. Thus, an in vitro microscopic method focusing on the effects of injectable herbal extracts can provide valuable information on some immediate and delayed "net" adverse effects on blood cellular and plasma components, and so can be of considerable value.

CONCLUSIONS

    An in vitro microscopic methods for direct assessment of the immediate and delayed effects of addition of whole herb extracts on erythrocytes and plasma components is described. The preliminary observation reported here warrant additional studies of the value of this approach for initial assessment of the safety whole herb extracts for parenteral use.

References

1.    Ali M. Ramanarayanan M. A method for preparing whole herb extracts for parenteral administration. J Integrative Medicine 1998 (in press)
2.    Ali M. Oxidative regression to primordial cellular ecology (ORPEC): Evidence for the hypothesis and its clinical significance. J Integrative Medicine 1988;2:4-55.
3.    Ali M. Empiricism in medicine: The Cortical Monkey and Healing. pp The Institute of Preventive Medicine, Bloomfield, New Jersey 1989.
4.    Ali M. The Cortical Monkey and Healing. pp 73-75. 1990. Institute of Preventive Medicine, Bloomfield, New Jersey.
5.    Ali M. Healing, Miracles and the Bite ofthe      Gray Dog. Life Span, Denville, New Jersey 1997.
6.    Theophrastus (370-285 BC). "Enquiry into Plants". in 2 vols., translated by A. Hort, W. Heinmann, London.,  1916.
7.    "Herbs, Spices, and Medicinal Plants: Recent Advances in Botany, Horticulture, and Pharmacology. Lyle E. Cracker and James E. Sinom, eds. Oryx Press. Phoenix, Arizona. Vol 1, 1986.
8.    Folk Medicine: The Art and the Science. Richard P. Steiner, Ed. American Chemical Society, Washington, D.C., 1986, ISBN-0-8412-0939-1.
9.    Duke, James A. "CRC Handbook for Medicinal Herbs". CRC Press. Boca Raton. Florida 1985.
10.    Duke, James A. "The Green Pharmacy".  Rodale Press,   Emmaus, PA. 1997. ISBN 0-87596-316-1.
11.    Freed DLJ. Dietary lectins and disease. In: Food Allergy and Intolerance. Eds: Brostoff J, Challacombe SJ. 1987 Bailliere Tindall, East Sussex, England.
12.    Ganguly P, Fossett NG. Evidence for multiple mechanisms of interaction between wheat gern agglutinin and human platelets. Biochim Biophys Acta 1980;627:256-261.
13.    Hilgert I, Horejsi VA, Angelisova P, Kristofova H. Lentil lectin effectively induces allotransplantation tolerance in mice. Nature 1980;284:273-5.

Index of Article Authors
Majid Ali, MD
Omar Ali, MD
Mary Ann Carroll, RN
Alfred Fayemi, MD
C.Grieder-Brandenburger, RN
Judy Juco, MD
Tsuneo Kobayashi MD
Jean A. Monro, MB, BS
(This index is incomplete and will be completed shortly)

Past and
Current Editors
Omar Ali, M.D.
Robert Atkins, M.D.
Robert Bradford, D.Sc
Paul Cheney, M.D., Ph.D.
Steven Davies, M.D.
Alfred O. Fayemi, M.D.
Claus Hanke, M.D.
Doug Hutto, N.D.
Judy Juco, M.D.
Paris Kidd, Ph.D.
Oscar Kruesi, M.D.
Derrick Lonsdale, M.D.
D. Vijen Poleszynski, B.S.
Christine Radulescu, Ph.D.
Ray Russamono, M.D.
Susan Test, Ph.D.
Lowell Weiner, D.D.S.
John C. Williams, M.D.

The Journal of Integrative Medicine shall not be held responsible for statements of the contributing authors. The views and opinions expressed are those of the submitting authors and do not necessarily reflect those of The Journal of Integrative Medicine, The American Academy of Integrative Medicine,
The American Academy of Preventive Medicine, any advertisers or staff members of The Journal of Integrative Medicine
 

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The Journal of Integrative Medicine shall not be held responsible for statements of the contributing authors. The views and opinions expressed are those of the submitting authors and do not necessarily reflect those of The Journal of Integrative Medicine, The American Academy of Integrative Medicine, The American Academy of Preventive Medicine, any advertisers or staff members of The Journal of Integrative Medicine