BIRM - Medical Information Magazine

MEDICAL INFORMATION MAGAZINE

November, 2019

MED I C A L INF O R M AT I O N M AG A Z INE

Introduction Immunomodulator product of natural origin extracted from the Dulcamara plant from the Ecuadorian Amazon, a powerful regulator of homeostatic balance and strengthening agent of the immune system.

Scope BIRM, an acronym of Biological Immune Response Modulator is a product with proven scientific efficacy, which can be administered from pediatric ages to older adults, with high levels of efficacy and with a spectrum of zero toxicity.

Purpose The purpose of the following scientific review is the dissemination of information in a timely manner and the promotion of the credibility and sustainability of the product. This will allow accessibility to the benefits of the product, as the only drug that acts in the immune system as a potent immunomodulator capable of acting at the cellular level, producing apoptosis of cancer cells reaching the remission of acute, chronic and serious diseases, as well as the prevention and control of autoimmune and infectious diseases.

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Biographical Review Dr. Edwin Cevallos Arellano

ACADEMIC TRAINING Undergraduate Studies 1. Physician and Surgeon, Ecuadorian Central University (Universidad Central del Ecuador), August 1969.

2. Health Lieutenant of the Ecuadorian Army 1967-1969.

Graduate Studies: 1. Postgraduate degree in Oncology and Radiotherapy, Oncology Hospital of the National Medical Center, Mexican Social Security Institute (IMSS), 1973-1976.

2. Postgraduate degree in Oncology and Radiotherapy, Autonomous University of Mexico (Universidad Autónoma de México) 1973-1976.

PROFESIONAL EXPERIENCE National: 1.

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Health Lieutenant of the Ecuadorian Army since December 1969.

Professor, Clinical Instructor of the Faculty of Medicine of the Central University of Ecuador, April 19, 1972.

Chief of Internal Medicine Residents of the Carlos Andrade Marín Hospital, of the Ecuadorian Social Security Institute of Ecuador, 1973.

Oncologist Radiotherapist of Hospital Carlos Andrade Marín, 1980.

Radio-Health Physician of the Ecuadorian Atomic Energy Commission of Ecuador, 1990.

Professor of the Faculty of Medicine of the Central University of Ecuador, 1993.

Director of the Tumor Institute of Quito, Ecuador, 1976-2003.

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Editor of the Discovery Salud magazine, Madrid-Spain.

Treating Physician specializing in Clinical Oncology and Radiation Therapy conferred by the Zacatecas Hospital Center, February 28, 1976.

NATIONAL AND INTERNATIONAL SCIENTIFIC COMPANIES 1.

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Founding member of the Ecuadorian Society of Hepatology, 1974.

Founding member of the Latin American Hepatology Society, 1974.

Member of the Latin American Society of Pediatric Oncology, 1980.

Member of the American Chemotherapy Society, 1982.

Member of the International AIDS Society since 1994.

Member of The Radiological Society of North America, since 1996.

Member of the American Society of Radiology, 1997.

Member of the New York Academy of Science since January, 1998.

Member of the American Association for the Advancement of AAAS since May, 2000.

MED I C A L INF O R M AT I O N M AG A Z INE

ACADEMIC ACKNOWLEDGEMENTS National: 1.

Participation as an active member, November 26, 1966; National Association of Medical Students, third medical student workdays of Ecuador.

2. Diploma from the Faculty of Medical Sciences of the Central University of Ecuador of the Department of Graduates, March 17, 1972.

3. Certificate from the president of the Medical Education and Teaching Commission of the Carlos Andrade Marín Hospital in appointment as a Clinical Instructor Professor and member of the commission, October 2, 1972.

4. Participation diploma conferred by the Ecuadorian Society of Gastroenterology, International Course of Gastroenterology, Quito, November 8-11, 1972.

5. Participation in Breast Pathology Course, diploma conferred by the Central University of Ecuador, IESS, SOLCA and the Ecuadorian Society of Gynecology, December 2, 1972.

6. Certificate of the Department of the Ecuadorian Institute of Social Security in appointment as Chief Physician of Residents of Internal Medicine, January 19, 1973.

7. First International BIRM Congress at the Radisson Inti Hotel in Quito, sponsored by the Ministry of Government, Ministry of Public Health, CONACYD, Catholic University of Quito and Catholic University of Guayaquil, 1977.

8. Founding partner, Metropolitan Hospital of Quito. 1985 9. Speaker with the topic: “Cancer, Genes and BIRM” at the first International Colposcopy Congress, Marriot Hotel, April 23, 2003.

10. Medal conferred by the National Congress of Ecuador for the work as “Ecuadorian Scientist and Researcher”, March 2004.

11. “The Pan American Medical Association” (PAMA) grants the highest award to Scientific Merit for having contributed exceptionally to the progress of Ecuadorian Medicine. University of Guayaquil. January 7, 2005.

12. The Pan American Medical Association (PAMA) awards the highest award to “Scientific Merit” for having contributed exceptionally to the progress of Ecuadorian Medicine. Guayaquil, Ecuador.

October 25, 2019.

13. Presentation of BIRM® at the VIII International Congress of Naval Health 2019, II Conference of Medical Specialties with the Theme: “Crossing the frontiers of medicine - News in infection management”. Holy Spirit University (Universidad Espíritu Santo). Guayaquil, Ecuador. November 6-7, 2019.

14. Presentation of BIRM® at PANAMERICAN MEDICAL ASOCIATION - PAMA, a nonprofit medical and scientific organization, will hold the Congress of Surgical and Ultrasound Medicine, number 62 that will be named after Dr. Teófilo Lama, a prestigious physician from Guayaquil and founder of the Kennedy Clinic in Guayaquil, Ecuador. November 15, 2019.

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Diploma of the Mexican Society of Oncological Studies for attendance at the Eighth National Workdays of Cancerology, participation in the course of Chemotherapy and Cancer, Mexico, 1975.

Diploma of the Association of Resident and Ex-Resident Doctors of the AC Oncology Hospital, which accredits him as an active partner, Mexico, 1976.

Diploma awarded by the World Cultural Council in recognition of his extensive scientific trajectory for research on Incurable Cerebral Cysticercosis treated with cobalt therapy, Stockholm - Sweden, November 21, 1985.

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Diploma as Emeritus Doctor awarded by the Republic of Cuba, 1991.

Interview with the discoverer of the AIDS virus and current Nobel Prize in Medicine Dr. Luc Montagnier, France, 1996.

Appointment as a researcher at the Autonomous University of Madrid of Immunomodulators and Antitumor Agents of Natural Origin, 2000.

Delegate to the “First World Congress of Traditional Naturist Doctors in Bolivia”, La Paz, 2002.

Patent granted to BIRM by the United States of America as “Anti-Prostate Cancer” USA - since July, 2007.

Presentation of BIRM at the seventh World Congress of Urological Diseases, New Orleans, November, 2009.

Presentation of BIRM at the Natural Medicine Congress in Havana, Cuba, May, 2010.

Medal awarded by the illustrious Municipality of Rumiñahui Canton called “General Rumiñahui” for having collaborated with the progress and development of Medical Science with the creation of BIRM, May 2010.

Presentation of BIRM at the XX Cuban Congress of Urology, Havana, October, 2013.

Sponsor of the University of Miami Symposium entitled “Cancer Prevention and Treatment” organized by the University of Miami, FL-USA, January 24, 2014.

From left to right: PH.D. Balakrishna Lokeshwar, PH.D.Vinata Lokeshwar, Dr. Mark Soloway, Dr. Edwin Cevallos A., Decano Dr. Pascal Goldschmidt, Director de Sylvester Cancer Center Dr. Stephen Nimer. en University of Miami Miller School of Medicine.

14. International Medical Scientific Congress and Business Development in Health (SIISDET) in the “Maximum Classroom and Auditorium” Cloister of San Agustín - University of Cartagena, Conferred the acknowledgement: “PRIZE TO THE LEADER IN RESEARCH AND HEALTH SCIENCES FOR THE BENEFIT OF MANKIND 2018 ”. Cartagena, Colombia from November 21 to 24, 2018.

PRIZE TO THE LEADER IN RESEARCH AND HEALTH SCIENCES FOR THE BENEFIT OF MANKIND 2018

Maximum distinction granted to the distinguished professionals of the different health sciences for recognized achievements, professional performance, merit, dedication, ethics, perseverance, effort and dedication.

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AWARD FOR THE BEST INVESTIGATION WORK 2018: “MODULADOR BIOLÓGICO DE LA RESPUESTA INMUNE BIRM, PREVENCIÓN Y TRATAMIENTO EN CÁNCER”

For the scientific relevance demonstrated in academic presentation and bibliographic support, referring to the opportunity and convenience of the research topic in the national and international context.

CERTIFICATE OF INTERNATIONAL HEALTH COACH

For his participation in the III International Medical Scientific Congress and Business Development in Health SIISDET - We integrate World Health.

15. HARVARD MEDICAL SCHOOL, Office of Online Learning, External Education “HMX Fundaments – Inmunology” 14 de June, 2019.

16. Acknowledgement and honorary title “Honoris Causa Doctor in Medical Sciences” granted by SIISDET to Dr. Edwin Cevallos A., MD from Ecuador. Held in University of Miami Miller School of Medicine.

Miami, FL - USA. October 26, 2019.

17. Presentation of BIRM® in the 2nd Emirates Congress on Integrative and Complementary Medicine 2019.

Dubai, UAE. November 22, 2019.

18. The “Dr. Vicente Rocafuerte” Recognition of Scientific and Research Merit granted by the National Assembly of Ecuador. November 27,2019.

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RESEARCH WORK: 1.

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New Scheme of Chemotherapy in Advanced Uterine Cervical Cancer, presented at the Medical Conference held at the Acapulco Convention Center. Mexico, 1974.

Research conducted at the Southern Research Institute in Birmingham - Alabama, USA as an Antiviral evaluation of BIRM (plant extract) against the Human Immunodeficiency Virus (HIV), July 1990.

Vancouver - Canada World AIDS Congress, with studies carried out it is ratified and it is concluded that BIRM proves to be the most potent stimulator and modulator of the immune system, 1996.

Study of the efficacy of BIRM as an analgesic agent and a neuropathic pain reducer. Maharaja Sayijirao University of Baroda-India, 2015.

Research conducted by the University of Miami on the application of BIRM in prostate cancer, in which it concludes that its application achieves the programmed death (apoptosis) of malignant cells, Miami 2016.

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UNITED STATES PATENT, 2007.

The United States Patent and Trademark Office after rigorous analysis and verification; granted BIRM the patent No. US 7,250,180 B2 in which the originality of the product is recognized authorizing its medicinal use in the prevention and cure of various diseases. This certificate guarantees BIRM’s quality and protects it from any counterfeiting attempts.

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ANTITUMOR AND CHEMOPREVENTIVE ACTIVITY OF THE ECUADORIAN PLANT EXTRACT BIRM, 2007.

Lokeshwar, Bal L. University of Miami School of Medicine, Coral Gables, FL, United States

Patients with malignant diseases commonly consume poorly characterized medicine or dietary supplements.

Extensive use of untested formulations, provide both opportunities and danger. BIRM, an Ecuadorian oral solution, is a dietary supplement developed from the Andean variety of Solanum dulcamara L, which is widely consumed in the Americas for a variety of diseases, including prostate and breast cancers, without any noted toxicity. Initial laboratory studies of BIRM on prostate cancer models showed strong cytotoxic antitumor activity, including induction of apoptosis, cell-cycle arrest, reduction in androgen receptor levels and down-regulation of pro-survival genes. Oral dosing of BIRM in a rat Dunning MAT LyLu model and in human prostate cancer xenografts showed chemopreventive and antimetastatic activities of BIRM. It decreased tumor incidence (75%), tumor growth (50%) and metastasis (63%). These observations provide the basis for further investigation into the use of BIRM as a chemopreventive dietary supplement. The main hypothesis, to be tested in this project, is that BIRM is a non-toxic, chemopreventive, natural product with the potential to retard tumor growth, progression and recurrence. The main objective of this application is to establish the chemopreventive and antimetastatic activity of BIRM in transgenic models of prostate cancer with the goal of establishing its safety and efficacy for use in controlled clinical trials.

In Aim 1, the minimum effective dose, optimum effective dose and maximum tolerated dose of BIRM will be established in the TRAMP (transgenic adenocarcinoma of the mouse prostate) model. In addition, the chemopreventive and antitumor activities of BIRM will be investigated using two distinct transgenic models that develop prostate tumor by either an androgen-independent (GvT-15 model) mechanism or by the conditional knock-out of a tumor suppressor gene (PTEN) in the prostate (PTEN loxp/loxpPBCre-4).

In Aim 2, the molecular mechanism of BIRM induced apoptosis, cell cycle arrest and androgen receptor degradation will be investigated by delineating the alterations in the molecular signatures of respective signaling pathways.

In Aim 3, the efficacy of BIRM either alone, or in combination with standard chemotherapy, will be evaluated for preventing the emergence of hormone-refractory prostate cancer in two human prostate cancer orthotopic xenograft models, LNCaP and LAPC-4, which demonstrate distinct molecular forms of androgen receptor.

Relevance: This study will establish safety and toxicity profiles of BIRM and determine whether BIRM, a complex natural product, has 1. a proven chemopreventive efficacy against prostate cancer and 2. if the efficacy of proven cancer therapies are enhanced or significantly compromised by BIRM. This study should also provide a rationale for further development (if any), of this chemopreventive agent, i.e., clinical trials for orostate cancer and other malignant cancers.

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Funding Agency Agency Institute Type Project # Application # Study Section Program Officer Project Start Project End Budget Start Budget End Support Year Fiscal Year Total Cost Indirect Cost

National Institute of Health (NIH) National Center for Complementary & Alternative Medicine (NCCAM) Research Project (R01) 1R01AT003544-01A1 7197505 Chemo/Dietary Prevention Study Section (CDP) Sorkin, Barbara C 2007-08-01 2011-07-31 2007-08-01 2008-07-31 1 2007 $302,940

Institution Name Department Type DUNS # City State Country Zip Code

University of Miami School of Medicine Urology Schools of Medicine 052780918 Coral Gables FL United States 33146

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Related projects NIH 2010 R01 AT Antitumor and chemopreventive activity of the Ecuadorian plant extract BIRM Lokeshwar, Bal L. / University of Miami School of Medicine

$293,913

NIH 2009 R01 AT Antitumor and chemopreventive activity of the Ecuadorian plant extract BIRM Lokeshwar, Bal L. / University of Miami School of Medicine

$296,881

NIH 2008 R01 AT Antitumor and chemopreventive activity of the Ecuadorian plant extract BIRM Lokeshwar, Bal L. / University of Miami School of Medicine

$296,881

NIH 2007 R01 AT Antitumor and chemopreventive activity of the Ecuadorian plant extract BIRM Lokeshwar, Bal L. / University of Miami School of Medicine

$302,940

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Publications Shamaladevi, Nagarajarao; Araki, Shinako; Lyn, Dominic A et al. (2016) The andean anticancer herbal product BIRM causes destabilization of androgen receptor and induces caspase-8 mediated-apoptosis in prostate cancer.

Oncotarget 7:84201-84213

Salazar, Nicole; Castellan, Miguel; Shirodkar, Samir S et al. (2013) Chemokines and chemokine receptors as promoters of prostate cancer growth and progression.

Crit Rev Eukaryot Gene Expr 23:77-91

Shamaladevi, Nagarajarao; Lyn, Dominic A; Shaaban, Khaled A et al. (2013) Ericifolin: a novel antitumor compound from allspice that silences androgen receptor in prostate cancer.

Carcinogenesis 34:1822-32

Zhang, Lei; Lokeshwar, Bal L (2012) Medicinal properties of the Jamaican pepper plant Pimenta dioica and Allspice.

Curr Drug Targets 13:1900-6

Singh, Rajendra Kumar; Lokeshwar, Bal L (2011) The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth.

Cancer Res 71:3268-77

Lokeshwar, Bal L (2011) Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers.

Pharmacol Res 63:146-50

Shamaladevi, Nagarajarao; Lyn, Dominic A; Escudero, Diogo O et al. (2009) CXC receptor-1 silencing inhibits androgen-independent prostate cancer.

Cancer Res 69:8265-74

Singh, Rajendra K; Lokeshwar, Bal L (2009) Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs.

Mol Cancer 8:57

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SCIENTIFIC PUBLICATIONS 1. Synthesis newsletter of the General Coordination of Scientific Research of the Central University of Ecuador. January, 1994. No. 22 Page 3, 4,5 Scientific News: Science and Nature against AIDS. BIRM® vs. AZT - DDC, final report July, 1991.

2. Vision Magazine with the subject: BIRM®: Amazon Vegetable slows the effects of AIDS. Mexico. March 25, 1992 3. BIRM® Carbohydrate of Low Molecular Weight ECA 10-142 controls AIDS, 1994.

4. Binational Experience in the treatment of IDS with a low molecular weight natural carbohydrate (ECA-10-142), as stimulate of the immunology system, 1994.

5. BIRM®, Therapeutic Strategy, World AIDS Congress Vancouver, 1996.

6. Induction of caspase mediated apoptosis and inhibition of prostate tumor Growth and Metastasis by a Plant extract - BIRM®, 2003.

7. Discovery Salud Magazine No. 53, article “BIRM®, an effective product against Cancer”.

Madrid Spain. September, 2003.

8. Book “Cancer, what is it, what causes it and how to treat it” pg. 290-297 article “The treatment of cancer with BIRM®” published in Madrid - Spain. December, 2005.

9. Miami Herald newspaper, article “Mysterious Cure for Prostate Cancer” by Fred Tasker.

October 16, 2007.

10. Cancer Prevention and Treatment, Miami 2014.

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Content Scientific Studies 1. Southern Research Institute, Results Of Evaluation, 1990.

2. Tenth International Conference On Aids Yokohama, Japan; 1994.

3. An Orally Active Amazonian Plant Extract (BIRM) Inhibits Prostate Cancer Growth And Metastasis, 2003.

4. Amazonian Plant Extract BIRM Reverses Chronic Neuropathic Pain In Rat Sciatic Nerve Chronic Constriction Injury Model, 2015.

5. The Andean Anticancer Herbal Product BIRM Causes Destabilization Of Androgen Receptor And Induces Caspase-8 Mediated-Apoptosis In Prostate Cancer, 2016.

6. Antioxidant Activity Study of the “BIRM” Immunomodulator Product, 2018.

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SOUTHERN RESEARCH INSTITUTE, RESULTS OF EVALUATION, 1990.

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TENTH INTERNATIONAL CONFERENCE ON AIDS, YOKOHAMA, JAPAN; 1994.

PB0294 BINATIONAL EXPERIENCE IN THE TREATMENT OF AIDS WITH A LOW MOLECULAR WEIGHT NATURAL CARBOHIDRATE (ECA-10-142), AS STIMULATE OF THE INMUNOLOGY SISTEM. Objectives:

To evaluate the stimulant properties of the immunological system of the (ECA-10-142) a low weight natural origen carbohydrate, in 70 IV CDC stage AIDS patients. Methods: 70 patients with AIDS confirmed diagnosis were selected, 30 Colombians and 40 Ecuadorian, for oral treatment with (ECA10-142). In a period of 9 months. In the evaluations were considered clinical symptoms and signs, total percentage of linfocites, CD4 and CD8 cells percentage and its relationships. In In vitro studies was demonstrated also that this carbohydrate stimulates the immunological system in the AIDS patients.

Results:

The obtain results in the 9 months demonstrated a clinical improvement as to signs and symptoms in 64 (91.4%) patients, immunological recuperations of the CD4 levels in 66 (94.3%) patients, clinical and immunological improvement were presented in 64 (91.4%) patients, 4 (5.7%) patients died due to their advanced state of the sickness. They only received treatment during one month and had their CD4 levels under 100.

Discussion and Conclusion:

The (ECA 10-142) has demonstrated to be useful vitro and invivo stimulated of the immunological system as inhibits the formation of sincitiales masses in a 59% and is effective as the clinical and immunological improvement of AIDS patients. Kinetics studies are required and observations in a longer time in order to conclude its imunostimulating activity in AIDS patients.

PB0294 BIRM CARBOHIDRATE OF LOW MOLECULAR WEIGHT ECA 10-142 CONTROLS AIDS. Objectives:

Results:

Discussion and Conclusion:

The BIRM® ECA 10-142 in vitro, reports non-cytotoxic even at the highest concentration tested, and moderated and its HIV activity with % reduction in syncytia-formation of 59%; (Southern Research Institute, Birmingham Alabama, U.S.A.; July 1991) In vivo double-blind reported an elevation in the number of CD4 cells. The Chemical analysis report in Nuclear Magnetic Resonance stablished the empirical formula C3H502, or a multiple thereof. Methods: Twenty patients in state IV of CDC, were chosen, and survived from January 1989 to April 1993. In every patient the CD4 cells were elevated notoriously. For example: 149 CD4 cells to 480 CD4 cells, in 3 months of treatment with BIRM®.

The results were evaluated based on the number of CD4, CD8 and quotient CD4/CD8; clinical evolution of the patient in his signs and symptoms. Patients with CD4 so low like 1%, survived for 15 months, and in the second group the patients are still alive after 22 months of treatment.

The BIRM® ECA 10-142 has demonstrated been effective in all the states of HIV/AIDS, BIRM® has been evaluated “in-vitro*”and “in-vivo”; and its composition has demonstrated to be an carbohydrate of low molecular weight, which per moms at the level of cellular adhesion and reduces in 59% the syncytia formation. The elevation in the number of CD4 cells indefinitely in all the patients treated, shows that we are in front of a modulator and stimulator substance of the Immune System, a substance of enormous application in this kind of patients.

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AN ORALLY ACTIVE AMAZONIAN PLANT EXTRACT (BIRM) INHIBITS PROSTATE CANCER GROWTH AND METASTASIS, 2003.

Authors:

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Devendra S. Dandekar Æ Vinata B. Lokeshwar Edwin Cevallos-Arellano, Mark S. Soloway Balakrishna L. Lokeshwar

Abstract Purpose:

Poor efficacy of conventional chemotherapeutic drugs against metastatic hormone-refractory prostate cancer (CaP) drives patients to try ‘‘alternative medicine’’. The antitumor activity of one such agent, ‘‘BIRM’’ (biological immune response modulator; ‘‘Simple Ecuadorian Oral Solution: an extract of an Amazonian plant’’), was characterized in vitro and in vivo using established CaP cell lines and a tumor model.

Methods:

The cytotoxicity of BIRM in four human and one rat CaP cell line was evaluated using cell proliferationinhibition and clonogenic survival assays. BIRM induced apoptosis, alterations in cell cycle phase progression and inhibition of the extracellular matrix-degrading enzyme hyaluronidase were also investigated in these cells. The in vivo efficacy of BIRM was evaluated in rats with subcutaneous tumor implants of Dunning EGFP-MAT LyLu cells. The active species in BIRM were characterized by gel filtration chromatography. Results: BIRM inhibited cell proliferation and clonogenic growth of the CaP cells (IC50 about 8.0 ll/ ml). It increased cell accumulation in the G0/G1 phase by 33.8% and decreased the proportion of cells in S phase by 54.6%. Apoptotic cell death in BIRM-treated cells was associated with activation of cell death-associated caspases. BIRM inhibited the activity of hyaluronidase, a hyaluronic acid-degrading enzyme, at 1 ll/ml. Treatment of MAT LyLu tumor-bearing rats with BIRM by oral gavage resulted in a significant decrease in tumor incidence (50%), tumor growth rate (18.6±1.3 days for 1 cc tumor growth in control rats and 25.7±2.6 days in BIRM-treated rats), and only one out of six BIRM treated rats versus four out of six in the control group developed lung metastasis. Three active ingredients in BIRM with a relative molecular mass (Mr) of ‡3500 were identified by ultracentrifugation and gel filtration chromatography and were found to be resistant to proteinase and heat (100C).

Conclusion:

The plant extract BIRM contains antitumor compounds of Mr ‡3500 with potent antiproliferative activity in vitro and in vivo against prostate cancer cells.

Keywords:

Natural herbal anticancer products, Prostate cancer, Invasion and metastasis Chemoprevention, Apoptosis.

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AMAZONIAN PLANT EXTRACT BIRM REVERSES CHRONIC NEUROPATHIC PAIN IN RAT SCIATIC NERVE CHRONIC CONSTRICTION INJURY MODEL, 2015.

Authors:

Ravalji, M., Buch, P., Uggini, G. K., Awasthi, A., Cevallos – Arellano, E.; Balakrishnan, S. University of India, 2015.

Abstract:

Neuropathic pain condition remains poorly managed by currently available therapeutics. There is therefore a dire need for development of efficacious therapeutics with minimal side effects. BIRM (Biological Immune Response Modulator), an extract of Amazonian plant Solanum Dulcamara, consumed as a dietary supplement by natives in Ecuador, is considered as a natural remedy for a number of ailments (AIDS and Cancer, among others). The aim of the current study was to test the efficacy of BIRM in vivo neuropathic pain model to elucidate its anti-neuroinflammatory potential. Rats subjected to chronic constriction injury (CCI) were divided into CCI-control, CCI-Gabapentin and CCI-BIRM groups along with a normal control group. BIRM was administered orally (4 ml/kg, daily) to animals of CCI-BIRM group from day 14 post-surgery till day 28. Repeated oral administration of BIRM inhibited CCI-induced mechanical allodynia and thermal hyperalgesia. It also inhibited CCI-induced activation of microglial cells and upregulation of COX-2 and TNF-α in the dorsal horn of the lumbar spinal cord. These data indicate that the marketed formulation BIRM, has anti-neuroinflammatory and anti-nociceptive properties in neuropathic rats and can serve as an adjuvant to standard therapy or as a stand-alone therapeutic agent for the treatment of neuropathic pain disorders.

Discussion:

The present study demonstrates that microglia cells are the useful tool for evaluating the effects of antineuroinflammatory effects of novel compounds. Repeated oral administration of BIRM, an aqueous extract of dried roots of a plant of the species Dulcamara, has significantly inhibited thermal hyperalgesia and mechanical allodynia in animal model of CCI-induced neuropathic pain. The immunohistochemical results have shown the CCI induced microglia activation, which is evident from their morphologies in CCI-VC group. The western blot results showed increased expression of Iba-1 protein in lumbar spinal cord in CCI induced neuropathic pain which supports the immunohistochemical data. Increased expression of Iba-1 protein under neuropathic condition indicates activation of microglia cells in the spinal cord. Repeated administration of BIRM orally, improved pathological conditions in animal model of neuropathic pain in the spinal cord by reducing the expression of Iba-1 protein and the proportion of activated microglia cells along with significant inhibition of neuropathic pain symptom, thermal hyperalgesia and mechanical allodynia. Microglial cells are the resident immune cells of the central nervous system (CNS). They act as the main form of active immune defense in the CNS and upon getting activated following any insult to the nervous tissue, they become the main source of inflammatory mediators (e.g.: IL-1β, IL-6, TNF-α, PGE2, NO, BDNF etc.) in the nervous system.

Conclusion:

In summary, our study with BIRM shows inhibition of microglia activation in the CNS and downregulates pro-inflammatory cytokines and COX-2. As demonstrated in this study, BIRM attenuates the development of hyperalgesia and allodynia in the rat model of neuropathic pain. Overall, this study not only demonstrates the effectiveness of BIRM in improving pathological conditions of nerve injury induced neuropathic pain but also showed the important role played by microglia in regulating the induction of a chronic pain state induced by peripheral nerve ligation. Based on the results obtained using BIRM as a therapeutic agent in neuropathic pain model at preclinical stage, BIRM has potential to improve pain condition or reduce the disease progression as a standalone therapeutic or adjuvant to standard therapy.

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THE ANDEAN ANTICANCER HERBAL PRODUCTBIRM CAUSES DESTABILIZATION OF ANDROGEN RECEPTOR AND INDUCES CASPASE-8 MEDIATED-APOPTOSIS IN PROSTATE CANCER, 2016.

Authors:

Nagarajarao Shamaladevi1,*, Shinako Araki1, 6,*, Dominic A. Lyn1, Rajnikanth Ayyathurai2, Jie Gao3, Vinata B. Lokeshwar4, Hugo Navarrete5, Bal L. Lokeshwar3 University of Miami, 2016.

Abstract:

BIRM is an anticancer herbal formulation from Ecuador. Previous study established its antitumor and antimetastatic activity against prostate cancer models. The activity of BIRM against human prostate cancer (PCa) cells was investigated to uncover its mechanism of antitumor activity. In androgen receptor (AR)expressing PCa cells BIRM was 2.5-fold (250%) more cytotoxic in presence of androgen (DHT) compared to cells grown in the absence of DHT. In AR-positive cells (LAPC-4 and LNCaP) BIRM caused a dose and time-dependent down-regulation of AR and increased apoptosis. Exposing cells to BIRM did not affect the synthesis of AR and AR promoter activity but increased degradation of AR via proteasome-pathway. BIRM caused destabilization of HSP90-AR association in LAPC-4 cells. It induced apoptosis in PCa cells by activation of caspase-8 via death receptor and FADD-mediated pathways. A synthetic inhibitor of Caspase-8 cleavage (IETD-CHO) aborted BIRM–induced apoptosis. The effect of BIRM on AKT-mediated survival pathway in both AR+ and AR- negative (PC-3 and DU145) showed decreased levels of p-AKTser 473 in all PCa cell lines. BIRM dosed by oral gavage in mice bearing PC-3ML tumors showed selective efficacy on tumor growth; before tumors are established but limited efficacy when treated on existing tumors. Moreover, BIRM inhibited the LNCaP tumor generated by orthotropic implantation into dorsal prostate of nude mice.

Partial purification of BIRM by liquid-liquid extraction and further fractionation by HPLC showed 4-fold increased specific activity on PCa cells. These results demonstrate a mechanistic basis of anti-tumor activity of the herbal extract BIRM.

Materials and Methods:

Discussion:

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BIRM was a gift from EcuaBIRM Inc. (Quito, Ecuador). BIRM was prepared by extracting the powdered roots of a medicinal plant widely referred to as “Dulcamara” or “Life Root” in Ecuador. The botanical identification of Dulcamara was performed at the Catholic University of Quito. The reference specimen from the identified plant, Kalanchoe gastonis-bonnieri [formerly known as Bryophyllum gastonisbonnieri (RayamHamet & H Perrier)] is deposited and maintained at the QCA Herbarium, Pontific a Catholic University of Quito, Ecuador. BIRM was prepared by organoleptic method of the Government of Ecuador certified contractor, Renase CIA LTDA following authentication of the starting material by QCA Herbarium. The roots were dried at 65°C in an indoor oven and the liquid extraction of BIRM was processed as per the EcuaBIRM established proprietary standards; each batch was certified by the Department of Sanitation, Government of Ecuador. Before use, BIRM was clarified by centrifugation at 10, 000 g for 10 min, supernatant that contained active principle and solubilized fiber were separated from insoluble fiber and used for all in vitro experiments. BIRM used in oral gavage to test its anti-tumor activity in vivo was not separated from insoluble fibers before. Further standardization of the product used in the present study is described under Results (in section: molecular characterization of BIRM).

These studies were conducted to demonstrate mechanistic basis of anti-tumor activity of BIRM specific to PCa. Our previous reports [18] presented the evidence of anti-neoplastic activity of BIRM on PCa cells. The activities of BIRM included inhibition of cell proliferation (arrested at G0/G1 in PC-3ML and LNCaP), inhibition of clonogenic growth of both androgen dependent (LNCaP) and castration–resistant PCa cells (DU145 and PC-3) and induction of apoptosis. More importantly, BIRM reduced incidence,

MED I C A L INF O R M AT I O N M AG A Z INE

delayed tumor growth and caused a significant decrease of metastasis of Dunning EGFP-MAT Lylu tumors [18]. However, the molecular target of BIRM and its mechanism of therapeutic action on prostate cancer was not investigated at that time. Our present study showed the mechanistic action of BIRM inhibition of cell growth in both androgen dependent and independent PCa cells. LAPC-4 cells were more sensitive to BIRM mediated cell growth inhibition in the presence of DHT-mediated growth when compared to that in androgen deprived LAPC-4 cells (Figure 1A). BIRM caused an inhibition of PSA production in LAPC4 cells with DHT (Figure 1B), suggesting that BIRM suppressed AR signaling even at the basal signaling level. A repressed AR signaling in androgen dependent.

STUDY OF ANTIOXIDANT ACTIVITY 0F THE “BIRM� INMUNOMODULATOR PRODUCT, SOUTHBOROUGH, MA; 2018.

Background.

Ecuador is one of the eight originating centers of native plants, since the influence of geographic and ecological factors grants it a wide diversity of flora. It is estimated that Ecuador is one of the countries with the widest genetic diversity per surface unit, with 20,000 to 25,000 species of vascular plants being reported. Many of the Ecuadorian species are cataloged as plant genetic resources within agriculture and food. They have local and global importance, and have an incalculable potential value.

Phenolic compounds in particular are considered as one of the most important classes of natural antioxidants. One or more aromatic rings with one or more hydroxyl groups make up its molecules.

Chemically, polyphenols can be divided into several classes, such as phenolic acids, flavonoids, anthocyanins, isoflavones, stilbenes, lignans and tannins (Machu et.al., 2015).

Polyphenols are directly related to the antioxidant activity of a particular food, plant or product, since they inhibit the oxidative degradation of organic materials, including a large number of aerobic biological organisms and commercial products (Rappoport, 2004).

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Informative help about BIRM® What is this medicine recommended for?

BIRM® is a product that balances the immune system of people who consume it, preparing the body to fight disease.

Does BIRM® have no side effects?

It is true. BIRM® is harmless. It lacks toxicity so it has no side effects.

What is the difference between BIRM® and concentrated BIRM®?

The difference is in the concentration. The preventive version is meant, as indicated by its name, to prevent and maintain a balanced immune system, allowing us to have the necessary defenses to deal with internal and external aggressions. BIRM® is a coadjutant to other treatments because it lacks toxicity. The concentrate version is for already compromised immune systems.

How must BIRM® be taken?

2ml de BIRM® natural supplement, twice a day with meals.

Can you take BIRM® while having other treatments?

BIRM® has no contraindications with other medications. Our goal is for you to feel calm and secure about our product, so we recommend that if your immune system is compromised, contact consultas@birm.com.ec.

Who can take BIRM®?

If you are a healthy person and want to maintain your health, strengthen your defenses, increase your energy and generally feel a sense of well being, the preventive version is what you need.

If you are a person who has an immune system that is struggling to defend itself, gets sick easily, is always taking medication or is already compromised, the concentrate version is what you need.

It can be consumed from newborns to older adults.

For how long must BIRM® be taken?

The minimum suggested time is 3 months, at which time your body generates an important immune reserve with the help of BIRM®. However, you can always take it indefinitely, making it part of a daily health routine.

Can a diabetic person consume it?

Yes, since BIRM® does not contain sugar of any kind.

How can I mask the taste?

You can put it in juices, smoothies, yogurt or water.

What is the benefit if a patient has cancer?

It is an adjuvant for the treatment of cancer. It can be taken as support for treatment with many benefits, improving the response and quality of life of the patient.

Can it be taken even when the infection is being treated? Or when it is already cured?

You can take it preventively or as a coadjutant in treatment.

Does taking too much damage the liver?

Is not true. The product has shown 0 toxicity in studies and in no side effects in more than 30 years of application.

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What active substance does BIRM® have?

It is an extract of natural plants that boosts and balances your immune system.

What interactions does BIRM® have with other medicines?

None, because it is a product without toxicity.

Can BIRM® be taken during chemotherapy?

Yes, because it helps reduce the toxicity of chemotherapy.

What is the dosage for children and adults of BIRM® and BIRM® Concentrate?

DOSAGE BIRM® For prevention: Respiratory illness: Chronic diseases such as asthma, rhinitis, allergies: Major diseases with toxic treatments:

Children: 1ml every 12 hours.

Adults: 2ml to 2.5ml every 12 hours.

Children: 2.5ml every 12 hours.

Adults: 2.5ml every 8 hours.

Children: 2.5ml every 8 hours.

Adults: 2.5ml every 8 hours.

Children: 5ml every 8 hours.

Adults: 5ml every 8 hours.

CONCENTRATED BIRM® DOSAGE Cronic diseases of more than a year’s duration: Chronic diseases of more than 4 years: Cancer in children from 1 month old to 12 years old:

2.5ml with breakfast and 2.5ml with dinner.

2.5ml with breakfast, 2.5ml with lunch and 2.5ml with dinner.

2.5ml with breakfast and 2.5ml with dinner.

Adults with cancer of any kind:

2.5ml with breakfast, 2.5ml with lunch and 2.5ml with dinner.

Patients with autoimmune and degenerative diseases:

2.5ml with breakfast, 2.5ml with lunch and 2.5ml with dinner.

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Products in the BIRM® family

BIRM ® 120ML BIRM ® 120ML Sales presentation in Ecuador

CONCENTR ATED Sales presentation in Ecuador

BIRM ® 240ML Sales presentation in Ecuador

BIRM ® 120ML International sales presentation

www.birmproducts.com

BIRM ® 120ML BIRM ® 120ML CONCENTR ATED International sales presentation www.birmproducts.com

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Sales presentation in Colombia

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Cosmetic products in the BIRM® family

NACE CREAM 30G

VIVA SHAMPOO 200ML

VIVA CONDITIONER 200ML

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During more than 30 years, BIRM has been the most tested and studied immunomodulator. Laboratories and Universities around the world, have examined its healing properties with incredible results:

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