Myth and reality of Morinda citrifolia L. (Noni) (English)

Summary

Background: Morinda citrifolia L. is a traditional medicinal plant, to which ascribe several properties, but there are few published studies that scientifically validate its use.
Objective: To review and update the scientific information that can attest to the medical use of the species, particularly fruit. Methods: We used the keywords Morinda citrifolia, Morinda Morinda bracteata litoralis or to conduct a review in the available databases (PubMed, Cochrane, ESBCO, SciELO, LILACS, CUMED, MEDNAT, RECUE). From the results, were searched for original articles and analyzed the information to associate each ethnomedical use with scientific research that could validate their pharmacological and toxicological safety.
Results: We found a total of 47 references in the databases consulted. Only 5 endorsed, mainly in preclinical models in vitro, the pharmacological activities of the fruit juice for ethnomedical uses related to cancer and immunostimulation, as well as pain and inflammation. Job security was sustained for only 1 acute oral toxicity work carried out with ethanolic extract of fruit and 1 article reported on a patient with chronic renal failure and health problems observed with the ingestion of the juice. The leaves and roots of the plant are less researched than the fruit.
Conclusions: The available scientific information, not to validate the use and safety of traditional use of Morinda citrifolia, because it is limited to studies
Preclinical pharmacological and toxicological research, supporting the safety, are insufficient.

Keywords: Morinda citrifolia, herbal medicine, herbal remedies, complementary medicine, ethnomedicine, toxicity.

There is a growing popular interest in and use the fruit of Morinda citrifolia L. (Syn, Morinda bracteata Roxb. Morinda litoralis and White), family Rubiaceae, has been promoted by various popular publications, including the press, reporting, or rather misinform, to the public on alleged scientifically proven properties that have that species, and some even claim that the figure reached more than 120 health problems which can be treated, even cured, with the plant and its extracts.

Noni, one of its popular names, is one of the most important traditional medicinal plants in Polynesia, where the information is focused primarily on the topical application of the leaves, roots, bark and green fruit. However, it is reported that this pattern has changed towards the use of use of the fruit juice, ripe or in a state of putrefaction, in Hawaii during recent years. Some research publications attributed to Ralph M. Heinicke, based on traditional Polynesian uses, have been a promoter of the use of noni in various indications, including cancer treatment emerging from research results. 

The traditional use of noni by Polynesians related effects attributed antibacterial, antiviral, antifungal, antitumor, anthelmintic, analgesic, antiinflammatory, antihypertensive and immunostimulant, is said to be used for more than 2 000 years. 2

Many health professionals are consulted by their patients and friends about the truth or not such effects and these are devoid of adequate scientific information that will enable a rational response, leading often to give answers that start " I think ... " or "I do not think ..." or simply say "no."

The problem can not be seen in a simple manner, it is not the phrase to be or not to be the illustrious English writer Shakespeare, nor is it a matter of "believing or not believing" as if it were addressed as a philosophical problem of dogmatic in which it decides to accept a myth or refute a priori.

Medicine is a science and decisions have to be supported by research. Every day, advances in medicine method based on events or results, such as items to make the best decision when choosing a behavior, therapeutic or diagnostic, before a health problem.

Available literature on the subject in question, are scattered and many are for specialties that are not available to physicians in clinical practice.

Irrational use of both drugs as medicinal plants or other procedures, it is the opinion of the authors universalized health problem. The World Health Organization recently published a document that addresses this situation for traditional and complementary medicine. 3

Another related, but not least, is given in experience "good" anecdotal personal, medical, or people who have self-medicated with the administration of fruit juice or other parts of M. citrifolia. Those who know, at least elementally the importance of clinical trials, they know that case reports and a series of cases has no scientific value to establish the efficacy and much less the effectiveness of treatment because the expectation of a inadvertently induce favorable response bias in the results that lead to false positives. Perhaps the most misused terms in medicine and pseudo-scientific works are those 2 mentioned above, is often said that one approach is effective or cash without having the results of a clinical trial, with impeccable methodological design to evaluate these goals and then appear show as lacking scientific conclusions. Inferences of this nature, show a lack of knowledge and inexperience of the author of such conclusions. Unfortunately, many colleagues engaged in clinical practice worldwide not know or understand, at least in an elementary way, the methodology for developing a new drug or treatment that includes clinical trials. This deficiency leads to assimilation as "scientifically proven fact" a lot of information they receive by not having developed skills in critical analysis of scientific literature.

The aforementioned reasons, led the authors to perform a search of published scientific papers, in order to review, update and comment on information that would endorse the medical use of the species.

Development

Keywords were used Morinda citrifolia, Morinda and Morinda bracteata litoralis as well as the names of authors in pseudo-scientific texts are attributed circulating important role in the investigation or use of the species (Ralph M. Heinicke, Walter Lübeck Hendrik Hannes and Charles Garnier) to search the available databases, which were:

• International:
  PubMed: http://www.ncbi.nlm.nih.gov
  COCHRANE: http://cochrane.bireme.br

• Regional:
  EBSCO: http://web23.epnet.com
  SCIELO: http://scielo.sld.cu
  LILACS: http://bases.bireme.br

• Cuban:
  CUMED: http://bmn.sld.cu
  MEDNAT: http://bvs.sld.cu
  RECUE: http://bvs.sld.cu

Research in the foundations was held on June 25, 2004.

From the references found, original articles were searched and analyzed the information to associate each ethnomedical use with the scientific work that could validate their pharmacological and toxicological safety.

Searches on Morinda citrifolia and their synonyms, made ​​in the bibliographic databases were positive only PubMed and EBSCO; in the other found no reference. PubMed found 44 references from 1955 through to 2004 and only 3 EBSCO were obtained that corresponded to the period 1998-2004.

Of scientific papers published by RM Heinicke 7 items found in PubMed in the years 1953-1972, but none were related to the medicinal species that was the subject of this review.

The search for the perpetrators and Hendrik Hannes Walter Lübeck PubMed gave no results of the first and the second only 3 articles in the period 1967-1968, but none of them was on the M. citrifolia.

Charles Garnier, another researcher said, is the author of scientific articles, but none is on the species of interest.

It commented that the lack of these authors and their publications on M. citrifolia can not be denied the reality of such items, but if you can say that has not been published in international journals indexed in several databases. However, it is surprising that researchers from developed countries have not published their results in scientific journals of wide circulation.

The information found in the databases were divided according to the plant parts used and pharmacological actions to facilitate analysis.

1. Fruit

1.1 Action anticancer

Fruit juice at concentrations of 5% v / v or higher, significantly inhibited compared with the controls of equivalent volumes of saline 0.9%, the initiation of new vascular sprouts in human placental vein explants. These concentrations of the juice also reduced the rate of growth and proliferation of capillary sprouts of new development. The concentration of 10% of juice in the culture medium, induced vascular degeneration and apoptosis in wells with established capillary cells within a few days after being applied.

The authors also found that the juice, at a concentration of 10% in the culture medium inhibited the capillary initiation in explants of human mammary tumor explants and, sprouting capillaries, the vessels rapidly degenerated.

The models mentioned above, matrix of three-dimensional fibrin clot and placental vein explants of human breast tumor are developing models to assess vascular angiogenesis. 4

A study of Tahitian noni juice, marketed as dietary supplements, administered to 10% in the drinking water for 1 week, prevented the formation of an adduct of 7-12 dimethylbenz [a] anthracene (DMBA)-DNA. The DMBA-DNA concentrations were reduced in the heart (30%), lungs (41%), liver (42%) and kidneys (80%) in Sprague-Dawley females. However, the effect was much greater in C57BL-6 males, which reduced the DMBA-DNA in the heart (60%), liver (70%) and kidneys (90%). The juice had an antioxidant effect in vitro which was comparable to that produced by vitamin C, grape seed powder, and pycnogenol in daily doses equivalent to those recommended in the United States. These results prompted the authors to suggest that could help prevent cancer. 5

A polysaccharide-enriched fraction of the juice had potential prophylactic and therapeutic effects against Sarcoma 180 model sensitive to immunomodulators. The antitumor activity of the extract produced a cure for 25 to 45% in allogeneic mice and the effect was completely abolished by simultaneous administration of specific inhibitors of macrophages (2-chloro adenosine), T cells (cyclosporine) or natural killer cells (GM1 antibody antiasialo). The fraction produced beneficial synergistic effects when combined with anticancer drugs such as cisplatin, adriamycin, mitomycin C, bleomycin, etoposide, 5-fluorouracil, vincristine or camtotecina. It was not favorable when associated with paclitaxel, cytosine arabinoside, or immunosuppressive anticancer drugs such as cyclophosphamide, methotrexate and 6-thioguanine. He was also co-administration with favorable Th1 cytokine and interferon gamma, but the activity was abolished when combined with Th2 cytokine, interleukin-4 or interleukin-10, suggesting that the fraction induces, in vivo, a Th1 dominant immune status. The association of imexón fraction, a synthetic immunomodulator, was also beneficial, but was unfavorable combination with MVE-2 copolymer, a high molecular weight immunomodulator, interleukin-2 or interleukin-126.

A polysaccharide-rich fraction of the fruit juice with antitumor activity in peritoneal carcinomatosis model of Lewis lung (LLC), significantly increased the survival of tumor-bearing mice isogenic LLC. He had no significant cytotoxic effect in cell culture LLC, LLC1, but could activate peritoneal exudate cells (PEC) to transmit toxicity when co-culture with tumor cells. This suggests that the fraction suppressed tumor growth by stimulating the host immune system. The combined treatment with the immunosuppressive agent 2-chloroadenosine (C1-Ade) or cyclosporin A (Cys-A) decreased the effect of the fraction of the juice, supporting an immunomodulatory mechanism. In addition, several mediators released fraction of murine effector cells, such as tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-10, IL-12 p70, interferon-gamma (IFN-gamma ) and nitric oxide (NO), but had no activity on IL-2 and suppressed the release of IL-4. The increased survival time and healing occurred by combining sub-optimal doses of chemotherapeutic agents such as adriamycin, cisplatin, 5-fluorouracil and vincristine, suggesting the clinical application of the polysaccharide fraction of the juice as a supplement in the treatment of cancer. 6.7

1.2 Chemicals and their actions

Fruit juice has 2 glycosides, 6-O-(beta-D-glucopyranosyl)-1-O-octanoyl-beta-D-glucopyranose asperulosídico acid. These compounds suppressed cell transformation induced by 12-O-tetradecanoilphorbol-13-acetate (TPA) or epidermal growth factor (EGF) and AP-1 activity associated in JB6 mouse epithelial cells. The c-Jun phosphorylation induced by TPA or EGF, but not extracellular signal-regulated kinases or p38 kinases, was blocked by the compounds of noni described above, this indicates that N-terminal kinases c-Jun were critical in mediation of AP-1 activity induced by TPA or EGF and subsequent cell transformation in JB6 cells. 8

Other compounds have been found in fruit juice. 3 glycosides have been identified: 6-O-(beta-D-glucopyranosyl)-1-O-octanoyl-beta-D-glucopyranose, 6-O-(beta-D-glucopyranosyl)-1-O-hexanoyl-beta- D-glucopyranose and 3-methylbutan-3-enyl 6-O-beta-D-glucopyranosyl-beta-D-glucopyranoside. 9 In addition, the soluble fraction of the fruit were identified n-butanol glycosides, rutin and asperulosídico acid; and a trisaccharide fatty acid ester identified as 2,6-di-O-(beta-D-glucopyranosyl)-1-O-octanoyl-beta-D-glucopyranose. 10

1.3 Actions inflammatory

The ethanol extract of the powdered fruit inhibited in vitro, cyclooxygenase-1 (COX-1) and had a half inhibitory concentration (IC 50) equal to 163 mg / mL, while controls with aspirin or indomethacin inhibited COX-1 with IC 50 equal to 241 and 1.2 mg / mL, respectively. 11 However, administration of mature fruit juice (50% weight by weight in water), administered in doses of 20 g of fresh plant material / kg, orally had no analgesic effect in the writhing model induced by intraperitoneal acetic acid 0.75% (0.1 ml/10 g) in mice OF-1 (F. Morón and others. Central Laboratory of Pharmacology, unpublished results ).

1.4 Toxicity and Precautions

There is a report that the juice caused hyperkalemia in a patient with chronic renal failure who had a low potassium diet. The potassium concentration in various juice samples was 56.3 mEq / L, similar to that found in orange juice and tomato. 12

A 50% hydroalcoholic extract of dried fruit, administered at doses of 10 g of dry plant material / kg orally or subcutaneously, did not cause general toxicity in mice. 13

2. Sheet

2.1 Chemicals and their actions

The leaves contain an iridoid dimer consisting of 2 units linked by a rare iridoid ether group significantly inhibited activator protein-1 (AP-1) induced by ultraviolet B (UVB) in cell culture. 14

In the leaf iridoid glycoside identified a flavonol glycosides and 5. The epimeric mixture irinoide exists as in solution. All these compounds were active free radical scavenging, antioxidant effect in vitro, in concentrations of 30 mM. 15

The irinoide, citrifolinosida inhibited activator protein-1 (AP-1) induced by UVB in cell culture. 16

Other studies report that the leaf contains the glycoside irinoide, citrifolinosida A, and asperula irinoides asperulosídico acid. 17 In addition, the leaves have a benzofuran (5-benzofuran carboxylic acid-6-formyl methyl ester) and a bis-nor-isoprenoid (4 - (3 '(R)-hydroxybutyl) -3,5,5, trimethyl-cyclohex-2-en-1-one). 18

2.2 Activity anthelmintic

The alcoholic extract of fresh leaves showed in vitro anthelmintic activity against human Ascaris lumbricoides. 19

2.3 Activities antimutagenic

Chloroform extracts, hexane and methanol dried leaf, cold applied dose, respectively, <2 mg / plate,> 1mg/placa and <1 mg / plate, were antimutagenic activity against indirect mutagens in vitro model of Salmonella typhimurium TA100. However, had no effect against direct mutagens at doses up to 10 mg / plate. 20

3. Root

3.1 Chemicals and their actions

Damnacanthal, an anthraquinone isolated from the root, potently inhibited the tyrosine kinases such as Lck, Src, Lyn and EGF receptor. In addition, the authors concluded that increased UV radiation-induced phosphorylation of extracellular regulated kinases and protein kinases activated by stress, pretreated with damnacanthal could be related to the stimulatory effect of damnacanthal on apoptosis induced by UV radiation. 21

3.2 Activities central analgesic

The lyophilized aqueous extract of root bark, administered at doses of 800 mg / kg, intraperitoneally had significant analgesic activity and models of hot plate and writhing in mice. The effect of the extract was antagonized by naloxone, indicating a central effect morphine type, and showed no toxicity in mice. In addition, the extract at doses of 1.6 g / kg, intraperitoneally, all parameters decreased behavioral models of 2 compartments, selection of light / dark and staircase, together with the induced sleep time. These results suggest that the extract had a sedative effect. 22

General Considerations

In this review, we found relatively few references, a total of 47, consulted on the bases.

Only 5 endorsed, mainly in preclinical models in vitro, the pharmacological activity of juice for ethnomedical uses, which could be grouped as related to cancer and immunostimulation, 4-8 as well as pain and inflammation. 11 The latter was made ​​in the model cyclooxygenase 1 (COX-1) in vitro. This enzyme, although it is inhibited by nonspecific nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin, is called constitutive cyclooxygenase considered mainly related adverse effects, unlike COX-2 which is related to the pharmacological actions of therapeutic interest.

The lack of analgesic effect of the juice that was found does not contradict that may be able to inhibit COX-1, as reported previously by other authors, 11 but suggests that noni juice has no effect on COX-2 and thus lacks of peripheral-type analgesic and NSAIDs. Not expected to have activity in vivo models for studying central effect, morphine-like, because the drugs in this group are active in experimental models for both peripheral and central pain.

Items on activities of the fruit juice or cancer-related are characterized by only 2, an in vitro 4 and another in vivo 5, assessed the juice, 2 studied in vivo polysaccharide fractions 6.7 and another one isolated chemical from the fruit. 8

Experience, on the validation of medicinal plant extracts in the Central Laboratory of Pharmacology, Faculty of Medical Sciences "Doctor. Salvador Allende in Havana, Cuba, since 1988, has led to the conclusion that in vitro studies are, quite often lead to false positive or negative. This is because the extracts, which most resemble the preparation of traditional use, are often very complex aqueous mixtures with ionic content, osmolarity, pH and other characteristics, able to produce responses in experimental models, to make falsely suggests the existence of active ingredients, when in reality we are seeing an effect caused by other factors of the composition of the extract can not be controlled.

Another very important aspect to consider is the response to pure active principles extracted from the plant under study, the demonstration of a biological effect of a compound or active moiety, does not ensure that the crude extract to produce the same activity the multiple interactions of its many components.

The safety of use in humans, is supported only by a work on acute toxicity of a hydroalcoholic extract of the fruit, 13 whereas 1 article explains in patients with renal failure the possibility of adverse effects for its rich content of K +. Many of the uses proposed for the juice required doses for prolonged periods, which needs to be evaluated, at least in subchronic toxicity models and study the genotoxicity. Adverse effects may escape the lore and go unnoticed when prolonged use makes it harder for causal association with the remedy you use. Anecdotally, people who consume or consumed authors have commented that lost weight, this can be seen by some as another beneficial effect, but worth asking: is it not a toxic effect? In fact, loss or weight gain is one of the possible signs of toxicity when making a subchronic preclinical animal study.

14-20 leaves and roots of the plant 21-22 are less researched than the juice.

For the above, it can be concluded that the available scientific information to validate the uses and safe use of Morinda citrifolia because it is limited to preclinical pharmacological and least lacks toxicological research supporting the safety. This is particularly relevant in health treatments for complex problems such as cancer.

Popular usage and interesting scientific information, although limited, led to recommend that more detailed studies preclinical pharmacological and toxicological investigations are conducted in standardized extracts, which will allow for a clinical trial in patients in the near future in order to actually establish the efficacy and effectiveness eventually.

Summary

Antecedents: Morinda citrifolia L. is a traditional medicinal plant, Which Has Been Attributed diverse properties, howeve, Have Been A Few published papers validating scientifically ITS use.
Objective: To review and update the scientific information support supporting the medical use of This species, particularly of STI fruit.
Methods: The key words Morinda citrifolia, Morinda Morinda bracteata litoralis or Were Used to make a review in the available databases (Pubmed, Cochrane, ESBCO, SciELO, LILACS, CUMED, MEDNAT, RECUE). Starting From These results, the original articles and information searched WAS Were Analyzed to relate to the use Each etnomedical That Could validate scientific papers Their pharmacological action and the Toxicological safety.
Results: 47 references found in the consulted Were databases. Only 5 supported, in preclinical models in vitro Mostly, The Pharmacological Activities of the fruit juice for use etnomedical and immunostimulation Connect with cancer, pain and Inflammation. The safety of ITS use Was Only one paper supported by acute oral toxicity on Carried Out With ethanolic extract from fruit and one patient That article reporting to show The potentiality of adverse-effects in renal Those with failure. The leaves and roots of the plant are less Than Investigate the fruit.
Conclusions: The available scientific information does not allow to validate the use and safety of the traditional utilization of Morinda citrifolia, since it is limited to preclinical pharmacological studies and the Toxicological Investigations are Insufficient Supporting STI safety.

Key words: Morinda citrifolia, fitotherapy, medicinal plants, complementary medicine, ethnomedicine, toxicity.

References

1. McClatchey W. From Polynesian healers to health food stores: changing perspectives of Morinda citrifolia (Rubiaceae). Integr Cancer There. 2002, 1 (2) :110-20.
2. Wang MY, West BJ, Jensen CJ, Nowicki D, Su C, Palu AK, et al. Morinda citrifolia (Noni): a literature review and Recent Advances in Noni research. Acta Pharmacol Sin. 2002, 23 (12) :1127-41.
3. World Health Organization. WHO Guidelines on Developing Consumer Information on proper use of traditional, complementary and alternative medicine. Geneva: World Health Organization, 2004.
4. Hornick CA, Myers A, Sadowska-Krowicka H, ​​Anthony CT, Woltering EA. Inhibition of angiogenic initiation and disruption of newly ESTABLISHED human vascular networks by juice from Morinda citrifolia (noni). Angiogenesis. 2003, 6 (2) :143-9.
5. Wang MY, Su C. Cancer preventive effect of Morinda citrifolia (noni). Ann NY Acad Sci 2001, 952:161-8.
6. Furusawa E, Hirazumi A, Story S, Jensen J. Antitumour Potential of a polysaccharide-rich Substance from the fruit juice of Morinda citrifolia (noni) on sarcoma 180 ascites in mice Tumour. Phytother Res 2003; 17 (10) :1158-64.
7. Hirazumi A, Furusawa E. An immunomodulatory polysaccharide-rich Substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity. Phytother Res 1999; 13 (5) :380-7.
8. Liu G, Bode A, Ma WY, Sang S, Ho CT, Dong Z. Two novel glycosides from the fruits of Morinda citrifolia (noni) inhibit AP-1 transactivation and cell transformation in mouse epidermal JB6 the cell line. Cancer Res 2001, 61 (15) :5749-56.
9. Wang M, Kikuzaki H, Jin Y, Nakatani N, Zhu N, Csiszar K, et al. Novel glycosides from noni (Morinda citrifolia). J Nat Prod 2000, 63 (8) :1182-3.
10. Wang M, Kikuzaki H, Csiszar K, Boyd CD, Maunakea A, Fong SF, et al. Novel trisaccharide fatty acid ester from the fruits of Identified Morinda citrifolia (noni). J Agric Food Chem 1999, 47 (12) :4880-2.
11. Li RW, Myers SP, Leach DN, Lin GD, Leach G. A cross-cultural study: anti-inflammatory activity of Australian and Chinese plants. J Ethnopharmacol. 2003, 85 (1) :25-32.
12. Mueller BA, Scott MK, Sowinski KM, KA Prag. Noni juice (Morinda citrifolia): hidden Potential for hyperkalemia? Am J Kidney Dis. 2000, 35 (2) :310-2.
13. Mokkhasmit M, Swatdimongkol K, Satrawaha P. Study on toxicity of Thai medicinal plants. Bull Dept Med Sci 1971, 12 (2 / 4) :36-65.
14. Sang S, Liu G, He K, Zhu N, Dong Z, Zheng Q, et al. New unusual iridoids from the leaves of noni (Morinda citrifolia L.) show inhibitory effect on ultraviolet B-induced transcriptional activator protein-1 (AP-1) activity. Bioorg Med Chem 2003, 11 (12) :2499-502.
15. Sang S, Cheng X, Zhu N, Stark RE, Badmaev V, Ghai G, et al. Flavonol glycosides and novel iridoid glycoside from the leaves of Morinda citrifolia. J Agric Food Chem 2001, 49 (9) :4478-81.
16. Sang S, He K, Liu G, Zhu N, Cheng X, Wang M, et al. A new unusual iridoid with inhibition of activator protein-1 (AP-1) from the leaves of Morinda citrifolia L. Org Lett. 2001, 3 (9) :1307-9.
17. Sang S, Cheng X, Zhu N, Wang M, Jhoo JW, Stark RE, et al. Iridoid glycosides from the leaves of Morinda citrifolia. J Nat Prod 2001, 64 (6) :799-800.
18. Siddiqui BS, Ismail FA, Gulzar T, Begum S. Isolation and structure determination of a benzofuran and a bis-nor-isoprenoid from Aspergillus niger grown on the water soluble fraction of Morinda citrifolia Linn. leaves. Nat Prod Res 2003; 17 (5) :355-60.
19. RK Raj. Screening of indigenous plants for anthelmintic action Against human Ascaris lumbricoides: Part - II. Indian J Physiol Pharmacol. 1975, 19 (1) :47-9.
20. Kusamran WR, Tepsuwan A, Kupradinun P. Antimutagenic and anticarcinogenic potentials of Some Thai vegetables. Mutat Res 1998; 402 (1 / 2) :247-58.
21. Hiwasa T, Aras Y, Chen Z, Kita K, Umezawa K, Ito H, et al. Stimulation of ultraviolet-induced apoptosis of human fibroblast cells by UVR-1 tyrosine kinase inhibitors. FEBS Lett. 1999, 444 (2-3) :173-6.
22. Younos C, Rolland A, Fleurentin J, Lanhers MC, Misslin R, Mortier F. Analgesic and behavioral effects of Morinda citrifolia. Plant Med 1990; 56 (5) :430-4.

Received: November 1, 2004. Approved: November 2, 2004.
CRD. Francis J. Moron Rodriguez. Faculty of Medicine "Dr. Salvador Allende." Central Laboratory of Pharmacology. Carvajal and / Freshwater A, Cerro. Havana, Cuba. CP 12000
Tel (53-7) 406571 ext 1048 to 73 or 1034. e-mail: moron@infomed.sld.cu