Keywords: unconventional therapies, pharmacological interactions, life quality
Roberto Adamoli (Exodus Foundation Poiesis Center)
XII National Conference ANLAIDS, october 1998

HAART (Highly Active Antiretroviral Treatment) introduction into clinical practice changed therapeutic perspectives, life expectations collective and individual awareness of people living with HIV and AIDS (PlwHA). The first issue is whether and how PlwHA still use unconventional therapies (UT). 26 researches (9.882 patients) conducted prior to 1997 show a 16-25% (M 47%) range of use; a review published in 1997 (Ernst E. 1997) shows similar results (27/100%). In 1997-98 10 researches (9 in 1998) which involved 6.574 persons with a UT use range of 36-88% (M 60%) (Adamoli et al., 1998) have been published or presented at conferences. 7 researches were conducted in Italy, 5 before and 2 after HAART introduction. Italian researches involved 2.966 persons with 16-52% (M 38%) range of use and were conducted at the 1st Clinic of Infectious Diseases in Genova, at the Ward of Infectious Diseases of the Spallanzani Hospital in Rome, at the S. Orsola Hospital in Bologna, at the Niguarda Hospital in Milan and at the premises of some AIDS associations. The last two researches presented in Geneva (one of them funded by ISS) involved 1.312 and 468 PlwHA and showed a frequency of use of 36% and 39%. In these researches UT use resulted complementary with respect to conventional treatments. Thus, UT use was confirmed and a trend of growth seems show with good agreement rates by PlwHA: in a recent research, 81% of patients said to be very satisfied with these treatments (Fairfield K.M. et al., 1998). All over the world, different attention has been given to UT. Among countries currently mostly committed in this sector there are, the U.S., where the American Medical Association has placed UT also among its priorities and has dedicated the 11 Nov. 1998 issue of JAMA to these therapies, publishing different clinical studies. In the U.S., since '90, upon order of the Congress, an Office of Alternative Medicine was created inside the National Institutes of Health (OAM-NIH). OAM-NIH funded and still funds several research centers on specific UTs or single pathologies (CAM, Complementary and Alternative Medicine, for NIH). The OAM-NIH reference Centre for UTs in AIDS is the AIDS Research Centre at the Bastyr University in Seattle. In this University (and several other centers) also clinical researches - as on Chinese medical plants against sinusitis in persons with AIDS and high dilutions vs. placebo, are under conduction. Very important seems to be also a longitudinal observational study on a cohort of 1.689 PlwHA using UT, which are monitored and will be followed for years to record and evaluate the trend of phenomenon and to find out useful elements to plan more detailed actions in this sector (Standish LJ et al., 1997). From a preliminary evaluation of this cohort emerged that 52% of people use acupuncture, 49% massage-therapy, 35% nutritional supplements, 30% Chinese medical plants. Among plants mostly used we find garlic (54%), Echinacea (35%), Ginseng (33%). But Bastyr University performed also another research on 117 UT providers (12.285 patients followed), 80% of them were practitioners. According to these practitioners, UTs prescribed showed to be effective in disease management (96%), life's quality (98%), CD4+ increase or maintenance (66%), to slow evolution to AIDS (69%) and to increase time of survival (73%) (Calabrese C et al., 1998). These statements have, of course, no meaning in terms of validation, but they represent an evidence and a reality to consider and to clarify.

Indeed, the serious and dramatic matter of UT is that, although they are widely used, they are not studied enough and their use is, in almost all cases, entrusted to anecdotal or to a few controversial clinical studies. Below, a partial overview about 3 main UT is proposed: Phytotherapy, Chinese Traditional Medicine (CTM) and Homeopathy. Nutrition is not treated, being in common of Conventional Therapies (CT) and UT.

Anti-HIV in vitro activity (at different viral replication levels) of many medical plants was widely shown (Vlietinck AJ et al., 1998). In literature, antiretroviral activity in vitro, among others, of the following 28 medical plants (MP) and/or active principles (AP) - in brackets - was documented: Achyrocline s. and Baccaris g. (dycaffeoylquinic acid derivatives), Allium s. (ajoene), Aloe v., Ancistrocladus k. (michellamine B), Buxus s., Calophyllum I. (A and B calanolides), Castanospermum a. (castanospermine and derivatives), Curcuma I. (curcumine), Phytolacca sp. (Pokeweed Antiviral Protein - APP), Fusarium (equisetine), Garcinia m., Geissospermum v. (flavopereirine), Geum japonicum t., Glycyrrhiza g. (glicirrhizine), Grifola f., Holomantus n. (prostratine), Hypericum p. (Hypericine), Momordica c. (MAP 30), Phyllantus sp. (phyllamicine B e retrojusdicine, niruri), Pinus s. (polisaccharides, fraction VI and VII), Prunella v. (Prunelline), Rosmarinus o., (carnosic acid, carnosol), Spiruline p. (calcium-spirulate), Tabebuia i. (betalapacione), Trikosanthes k. (trichosantine), plants with caffeyc acid and derived (Hypossus o. etc.), Viscum a.

Activity of those MP and AP is performed by one or more mechanisms of action, sometimes co-present and combined: inhibition of main viral enzymes as reverse transcriptase (9 MP and/or AP), protease (3) and integrase (5); proteic synthesis (2), LTR (3), adsorption (4) and inhibition of syncitia formation (9). Although an in vitro anti- HIV activity was documented, for some MP and/or AP, mechanism of action is unknown yet (Buxus, Grifola, Prunella, Spirulina, Viscum). Also the activity of following 11 MP was documented: Aloe v. (acemannan), Buxus s., Echinacea p., Eleuterococcus s., Geissospermum v., red Corean Ginseng, Glycyrrhiza g. (glycyrrhizine), Lentinus e. (lentinane), Spirulina p., Uncaria t. (idosindolici alkaloids), Viscum a. These plants' activity has shown to be realized by an increase of IL-2 (3), NK (3), INF-g (1), Macrophages (7); T (6) and B (4) Lymphocytes production. For 2 MP, TNF-a inhibition was documented and for one stimulation. Further, in literature there are (publications or communications at the International Conference on AIDS) data of 42 phase I (8), I/II (23), II (2) clinical studies (11 observational, 31 on protocol, 8 of which controlled) and 9 not better defined. 28 of those studies used medical plants which showed in vitro antiretroviral activity, according to mechanisms cited above. Further 14 trials examined the activity of plants with in vitro (and sometimes in vivo) proven immunomodulatory action of active principles as indicated above (Bianchi et al., 1997). In vitro data in most cases were obtained with rigor and confirmed by different authors, while clinical data are still controversial or insufficient to give a scientific validation. Recent data confirmed the interest for medical plants. At the World Conference in Geneva some results of clinical studies on plants were presented. Related to a study on Echinacea a., at the moment of the Conference were available data of 12 patients out of 61, which completed the experimental path (crossover, double-blind, controlled or with placebo). From these preliminary data an increase of the NK killing ability on HIV-transfected cells in 11 out of 12 patients (from 3.7+/-3.5 LU to 23.1+/-11.7 LU in the treatment group versus a 4.1+/-3.2 stability of placebo group) emerged. On these results authors state that the use of Echinacea in immuno-reconstruction should be further examined (Berman S et al., 1998). It is important to note that Echinacea is one of the few contraindicated plants in HIV by English and German pharmacopoeia (Commission E Monograph) right because of its immunomodulatory properties on T lymphocytes which could favor HIV infection. Theoretically, for this very reason, Echinacea could be considered in order to evaluate its usefulness and to boost immunity (under antiretrovirals) and/or flush out virus from latent reservoirs. Another study (phase II, double blind, controlled versus placebo) showed effectiveness (statistically meaningful) of Croton I. on weight reduction and stools frequency in AIDS related diarrhea (Holodniy M. et al., 1998). Moreover, a possible role of Th2 in Candida pathogenesis was reported and the modulatory role of Glycyrrhiza glabra on Th2. Still in Geneva the results of a research on MAIDS cavies (characterized by a Th2 prevalence) were presented. It was shown how cavies, after being infected by Candida, showed a mycotic infection 100 times higher than normal cavies. In these same guinea pigs treated with Glycyrrhiza, sensitivity to Candida turned back similar to that of normal guinea pigs (Utsonomiya et al., 1998). This pre-clinical data on Candida and this modulating action on Th2 could be further examined. Finally, still this year, a study was published on "AIDS", from which the effectiveness of Melaleuca alternfolia on fluconazole-resistant Candida emerged (Jandourek A 1998). We also have to remind that this year first data about phase I/II on the use of A Calanolide (synthesis), a non nucleoside reverse transcriptase inhibitor extracted from Calophyllum I., one of the few plants selected from the huge work of screening of the National Cancer Institute were presented. Other pathologies on which medical plants could be studied are depression and viral Hepatitis. Depression affects over than 30% of PlwHA (4-18% major) and many drugs used for its treatment show side effects similar to HAART, thus, increasing lack of adherence and/or a life's quality worsening. Several medical plants have been evaluated by controlled clinical studies (not in persons with HIV) and recently, the use of Kava-kava against anxiety and Hypericum perforatum against light and medium depression recorded many confirmations, showing to be better than some conventional drugs (Schulz V et al. 1997). In the US OAM-NIH funded, with 7000 million of liras, a multicentric study on Hypericum and depression. Concerning hepatitis there are clinical studies on Phyllantus sp., Glycyrrhiza and Milk Thistle and it would be useful to realize more in depth studies, particularly about Glycyrrhiza (van Rossum TG et al., 1998) against hepatitis and on Milk Thistle as hepatoprotector (Flora K et al., 1998).

With respect to traditional Chinese medicine (TCM), many publications and studies were realized during years, with different results. In particular, different formulations are used (HY1-39, Enhance, Herbal Tea 1, Resist, Composition A, Sho-saiko-to, EOSOL, ZY-II, xq9302 etc.) which include from 12 to 35 different medical plants as Glycyrrhiza g., Curcuma I., Tricosanthes k., Scutellaria r., Prunella v., Arctium I., Violay., Zizyphi f., Andrographis p. and many other. Some of these trials produced positive results, others none (as a recent Swiss-American study on 35 medical plants presented in Geneva) and all, however, gave only indicative data which should be further examined. At present, clinical studies about AIDS-related sinusitis, about diarrhea related to cryptosporidiosis and others are going to be carried out. Another very important TCM area is acupuncture. Several studies examined the use of acupuncture on peripheral neuropathy pain with contradictory results, a study recently published on JAMA showed the ineffectiveness of acupuncture on this pathology, while a recent Italian research conducted at the 2nd ward of Infectious diseases at the Sacco Hospital (Milan) (on grant of ISS) and by the Milan Clinic of the Brescia University seem to give positive results. The Sacco Hospital acupuncture team, formulated the hypothesis that controversial data could emerge from the different nature of treated neuropathies (axonal or demyelinating). To notice that in the US and particularly in San Francisco, an important experience of TCM integration into conventional clinical practice is about to be realized (Cohen et al., 1998).

In the field of Homeopathy also some clinical studies have been realized, some of them recently published or presented (Rossi E. 1999)

Several other UTs are used in HIV infection (Ayurvedic and Tibetan Medicine , DNCB - dinitrochlorobenzene - body techniques, mental training etc.) which are not treated in this report. After these observations on UT it is important to remind that in this area also there are, not very serious and/or uninformed therapists. HIV infection and AIDS are complex realities where superposition and interaction of virological, immunological, metabolic disorders and a series of other possible pathologies are present. For this reason the practitioner responsible of intervention in such a situation must have a knowledge not only about AIDS, but also a sufficient preparation in the immunological and pharmacological field. It is therefore important for PlwHA to test this circumstances and expressly ask the practitioner for documentation which supports suggested treatments and to give them to their own infectious diseases specialist for evaluation. Moreover, he/she should know whether the practitioner is available to contact the infectious diseases specialist (Pascale R et al., 1997).

In conclusion, there are several good reasons to deal with UT. We noticed they are widely used with satisfaction by PlwHA. To promote research means also to help persons to understand what is useless, if not harmful (with respect to efficient therapies), and what is useful. Still, HAART is becoming more complex and the introduction of PI generated a new series of problems as to pharmacological interactions. From a quick search on Medline resulted 69 works about interactions among medicinal plants and p-450 cytochrome, most of them about grapefruit which effects are known and researched. There are also studies about other plants as, for example, Glycyrrhiza, used by PlwHA. An Italian study carried out by the Pharmacological Department of the Bologna University highlighted a p-450 induction on mice, and this circumstances, brought the researcher to sustain that the extended high dosage Glycyrrhiza consumption may cause an acceleration of the co-administered drugs metabolism, with important implications as to their availability (Paolini M. et al., 1998). This study uses Glycyrrhiza concentrations 20 times higher than those used by PlwHA; but further analysis is required to evaluate possible interactions among medical plants and conventional drugs. At this point, the case of Glycyrrhiza results emblematic, since that plant shows a composite profile of in vitro activity with: inhibition of HIV adsorption and syncytia creation, with the availability of some pilot studies on PlwHA (Bianchi et al., 1997); potential activity against hepatitis C, as emerged from some pilot studies (van Rossum TG et al., 1998); activity on Candida in animal models (Utsonomiya T 1998); induction of the p-450 cytochrome, as we just saw. May be, now, it would be better to put things in order. Following our line of reasoning on why to deal with UT, we find the problem of bias in experimentation, since the wide use of UT could produce bias during experimentation (Abrams D 1997). Further, UT experimentation could lead to the discovery of new active compounds, as already happened in the past; it could further lead to the discovery of useful resources to improve life's quality. In all recent conferences, the importance to identify new drugs active at different phases of viral replication, was underlined, and it has to be reminded that different plants showed an activity in vitro - for example - against integrase, an important viral enzyme. A further potentiality of UT is that of immuno-reconstruction, since different plants and other unconventional remedies showed active in this direction. We also shall not forget that it would be important to establish a collaboration protocol among conventional and unconventional practitioners as regards individuals showing relevant intolerance and therapeutic failures. Finally, but not last, there is the huge health and ethic problem of developing countries. Currently, less than 10% of PlwHA use HAART. We ask ourselves whether in next future these drugs will be available for these persons. At present a HAART treatment requires drug availability, practitioners able to prescribe, monitor, and if requested, to change it; there is a need of a virological and immunological monitoring and more and more, of an evaluation of resistances (genotypic and phenotypic) and of single pharmacokinetics and pharmacodynamics (in order to avoid drop-outs due to side effects which are in reality due to overdoses caused by individual metabolic peculiarities and drop-outs caused by therapeutic failure, in reality due to sub-dosages still related to the individual metabolizing of the drug), besides basic nutritional regimens for an appropriate drug assimilation. The whole, in a situation where a sub-dosage of 20% for three days may be predictive of therapeutic failure. Who believes that in the mean time those countries will be able to use these therapies, support them financially, have physicians and settings adequate to their administration and management? In this context, one of the International Community's priorities (politic and scientific), should be the research for alternatives and, among those, also possible optimization of UTs available in these countries. Between very effective but not available and less effective but accessible therapies, choice is almost obligatory (at least in the meantime). Us, we could do much in this direction, realizing international cooperation projects (through the Ministry of Foreign Affairs and/or European Union) with the purpose to rationally evaluate UT accessible in these countries and to support regulation of appropriate technologies able to pharmacologically transform them.

In conclusion, it is important to promote and to put into practice a greater collaboration among conventional and unconventional practitioners; to promote the establishment of a UT Center (not AIDS only) at the Superior Institute of Health with the goal to properly inform citizens and, considering that only when Institution will have its own background, an authentic comparison and planning of a serious research plan will be possible; to promote an authoritative and rigorous information among PlwHA, without fear of promoting, since PlwHA already use these therapies, most times in social isolation and without the chance of an authoritative comparison and support. Finally, it would be of great usefulness if an important AIDS organization as ANLAIDS would promote a UT working team (with conventional and unconventional practitioners and PlwHA) with the purpose to produce a rational review on this topic. This organization's rootedness in the scientific and medical community would enable to realize a work with adequate scientific credibility.

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