In Defense of the Anti-Dengue Cocktail

10 December 2014

By G. U. Stuart, MD

I became aware of the ActRx TriAct controversy only after the the study was pulled or suspended by the powers that be. It wasn’t clear why, and it still isn’t. There was no outright allegation that the researchers tweaked data or fabricated results—that would certainly have justified killing the study. Instead, the DOH and a complicit media have been spewing out allegations, discrediting, questioning the validity of the study and the verity of its conclusions. Non-compliance and deficiency issues? Were there application issues? Conditions that were not met? Design flaws? Ethical issues? Monitoring failures? Statistical or methodological problems? Why was it pulled only after the Phase III results were released? Is it all “politics,” as some suggest?  In the absence of clear evidence of a bad study, I chose to give the ActRx TriAct cocktail the benefit of the doubt.

This is not a defense of Ona. I don’t know Ona from Adam. This is a defense of the public’s right to know, of the right of patients to access a drug that could potentially prevent deaths from a disease that claims thousands of fatalities a year.

There continues to be a dearth of supportive or explanatory documents relating to the ActRx TriAct phase III clinical trial study. My search always dead-ends at the ActRx website. Even if the complete study were available, I would not have the acumen to comb through the scientific minutiae. What is urgently needed is an independent review board to look at the study—to document its faults and justify the suspension, or to disprove the criticisms and dismiss the doubts.

The criticisms have been mostly negative—that the studies did not go through the usual preclinical trials or were dubiously sped through some clinical trial phases; that it is monotherapy treatment because it uses two artemisinin derivatives; that berberine, a plant derivative, should not be used as a third component; that berberine, for lack of scientific studies, was not approved by the FDA; that experts say the combination of the three drugs poses sides effects and that their use in clinical trials poses a “clear and present danger” to public health; that there is no legal basis for the study; and, horrors, that no other studies on ActRx TriaAct have been done or are being conducted elsewhere in the world.

THE CLINICAL TRIALS

The main components of ActRx TriAct are artemether and artesunate, drugs long ago studied and approved for use in malaria. Both have gone through the necessary preclinical studies. When repurposing or repositioning drugs—finding new uses for old drugs—the studies are usually allowed to skip some of the phases, certainly, preclinical trials that are done in animals to test for toxicity and pharmacokinetics. Possibly, too, it was fast-tracked and sped through Phase 0 and Phase 1 studies, getting to clinical trials faster.

Drug Repurposing or Repositioning: Drug repositioning is the process whereby a drug that is patented for treating a particular disease is discovered to be useful in treating a second disease, and developed further for that purpose. Simply said, it is a process of finding new use for an existing drug. As mentioned above, this is the case with artemether and artesunate—old drugs already approved for malaria, already tested in humans with known information on pharmacology, formulation and potential toxicity—now being tested as potential dengue treatment, allowing the new therapy to be ready for clinical trials early, hoping for a speedy review and integration into health care. Hopefully, this answers PCHRD’s concern of “deficiency”—that the study lacks scientific justification for use of artemether and artesunate for dengue therapy.

Cocktail Components

Artesunate: Oral artesunate was probably chosen for ease of administration, with a longer half-life (20-45 minutes) and higher bioavailability of DHA, dihydroartemisnin, its active metabolite (>80%), half life of 0.5 to 1.5 hours—values not achieved by intramuscular and intravenous administration, and without the ease of oral administration.

Artemether: Artemether has been available in the tablet, capsule, and injectable formulations. A study on sublingual spray formulation showed twice the bioavailability—1.7 to 2.2 times more absorption as a sublingual spray compared to oral tablet formulation. The sublingual route also bypasses the first-pass liver metabolism.

Berberine: Berberine is an alkaloid extracted from various plants. (See below). It has been studied extensively. Its mechanisms of action are as varied as the many conditions it is used as supplement for.

Patent Pending

There is a patent pending on the ActRx TriAct cocktail, a two-day regimen, composed of artemether sublingual spray, artesunate and berberine tablets. Possibly, the combination use of artemether with artesunate, where the drugs might act in complementary or synergistic manner, together with the addition of berberine, is a way to get exclusivity—via an MoU (method of use) patent protection—for old drugs in a new formulation with a unique sublingual delivery system for artemether.

MONOTHERAPY

There is much criticism that using derivatives from the same plant constitutes monotherapy. True, both artemether and artesunate are derivatives of artemisinin, a peroxide lactone isolated from the antimalarial plant, Artemesia annua (sweet wormwood). The plant has been used in many traditional systems of medicine, for at least 2000 years in China. Artemether is a methyl ester derivative, while artesunate is a semisynthetic analogue derivative. Although both are artemisinin derivatives—artemether, sublingually; artesunate, orally—they may differ in their potencies with the peroxide mechanisms, half life and elimination time. Perhaps, the combination was based on peaks, half-life and elimination time, that give a synergistic effect, or delay or prevent resistance? This is a personal conjecture. I would like to know the ActRx Triact researchers’ rationale for the use of the combination.

BERBERINE and PLANTS

• The inclusion of berberine, a plant material, has also raised the hackles of some. But the landscape of medical therapies is rich with plant-derived pharmaceuticals. Like artemisinin, which is derived from the antimalarial plant Artemesia annua, berberine,  the third component of the Actrx Triact cocktail, is an isoquinoline alkaloid of protoberberine, which is found in many plants and has been used in many traditional medical systems for hundreds of years.

• In search of an herbal medicinal source for dengue cure, a 2011 study investigated the in-vitro anti-dengue activity of ten Thai medicinal plants; four plants viz. Rhizophora aciculate, Flagellaria india, Cladogynos orientalis, and Houttuynia cordite, showed significant effect on the dengue virus in-vitro and suggested potential sources for the development of an anti-DENV drug. Herbal Antivirals: Natural Remedies for Emerging & Resistant Viral Infections by Stephen Harrod Buhner lists 29 plants that have shown anti-dengue activity; four, maybe more, of them yield berberine.  Other reviews list berberine-bearing plants used in botanical medical practice: Goldenseal (Hydrastis canadensis), Oregon grape (Berberis aquifolium) Barberry (Berberia vulgarism) and Chinese Goldthread (Coptis chinensis), and two berberine-containing plants popular in Chinese medicine, Phellodendron chinense and Phellodendron amurese.

LACK OF SCIENTIFIC STUDIES ON BERBERINE?

“For lack of scientific studies on berberine, the Food and Drug Administration did not give it certification for sale in the Philippines.” Huh? Berberine has been much studied—over a third of the 2,800 studies on berberine listed on PubMed, were published in the last 5 years. The studies suggest a wide range of clinical applications—from cholesterol lowering, anti-inflammatory, antimicrobial, anti-diabetic effects to benefits for cardiovascular and neurodegenerative afflictions.

• Berbrine is an over-the-counter supplement, considered by some studies as a supplement with some effects comparable to pharmaceuticals. Its standard dose is 900-2000 mg a day in 3 or 4 divided doses. A recent study reported a concern for long-term use and a tendency to accumulate in the CNS with potential neurotoxicity. What dosages are used and what risks are entailed in a two-dose ActRx TriAct cocktail protocol should be answered by the ActRx TriAct researchers.

SIDE EFFECTS? CLEAR AND PRESENT DANGER TO PUBLIC HEALTH?

What side effects are the “experts” attributing to the ActRx TriAct treatment? Artemether and artesunate are two drugs extensively studied and used in the treatment of malaria. Berberine is a supplement in use for hundreds of years in many traditional systems, with a known good safety profile, especially for short-term use. “Clear and present danger ” to public health? Huh?

NO LEGAL BASIS FOR THE STUDY

The DOH says the controversial ActRx TriAct has not been registered with the FDA, and that the study which started in 2012 should not have happened in the first place. Is this true? By whose authority and edict was it allowed to continue? Why did they wait so long before terminating it? Were people threatened by the reported beneficial study results? What political power plays are at work? Does the non-registration mistake totally nullify the study?

THE RIGHT TO PIONEER RESEARCH

Criticism was also made that no other studies on ActRx TriAct have been done or is being done elsewhere in the world. Does the criticism imply that our scientists cannot or should not pursue original investigative studies? That is an insult, an affront, to the Philippine scientific research community.

The criticisms have remained unanswered. I am surprised and dismayed by the silence from Ona’s side, from the doctors who were involved with the actual clinical study, and from others somewhere out there in the medical community who must have a dissenting opinion to what seems to be one-sided multiple rants against Ona’s work.

Also, let us hear from those on the Garin side, who according to a post by Jarius Bondoc, “were pacified by Garin’s move—regulators, researchers, ethicists, and field doctors who, documents show, resist the remedy.” It would be most enlightening to hear from this august array of professionals what aspects of the study or remedy they resisted and why.

The Promise of a Vaccine Tomorrow, The Need for a Treatment Today

Dengue vaccine trials are being done. The experimental Dengue vaccine developed by Sanofi showed to be about 60% effective in the second large clinical trial, a slight improvement from the 56.5 percent reduction in the first trial. The scientific adviser to the Dengue Vaccine Initiative admits it’s not anywhere close to the 90s they hoped for. The vaccine was found to be more effective in people previously exposed to dengue. There are four serotypes, with lifelong immunity gained only for the specific infecting serotype—making the vaccine useful in endemic areas where people are often exposed more than once. Also, while providing 60-90% efficacy against dengue virus 1, 3, and 4, efficacy was lacking (42%) against DENV serotype 2 which accounts for almost 60% of all virologically confirmed dengue episodes. Also, in the first trial, the vaccine was found less effective in younger children, the population most vulnerable to the disease.  The early availability of the vaccine will also be limited. No matter these early limitations, a vaccine that may reduce the number of cases by half and hospitalizations by 80 percent represents a big advance.  Sanofi plans to apply for approvals in the first quarter of 2015, with sales in the 4th quarter in priority countries of Mexico, Brazil and Columbia, and possibly Singapore and Malaysia.

While the vaccine shows promise, there will still be a significant number of those vaccinated who will still contract dengue. Also, there will be many who will refuse vaccination, and many who will not be reached by vaccination programs. The WHO estimates that 2.5 billion people are at risk annually for dengue infections. Between 50 million and 100 million contract the disease each year; newer estimates suggest a number closer to 400 million. Thousands of deaths are still predictable.

Drug therapy is needed. For now there is none. The Actrx Triact cocktail presents as a potential anti-dengue drug therapy for that group of patients diagnosed with severe dengue where the risk of fatalities are high. And while the WHO has warned of the dangers of drug resistance in areas where both malaria and dengue are coendemic, there are 23 designated malaria-free provinces in the Philippines. They present testing grounds to evaluate the efficacy of the anti-dengue therapy: Cebu City, designated malaria free, topped the list with 3,081 cases of dengue with 12 deaths; Iloilo, also designated malaria-free, reported a 71% surge in dengue cases. Aklan, also malaria-free, has seen an increase of 75%, up 1,340 cases compared to 763 last year. The data collected from these malaria-free testing grounds can potentially lay the groundwork for more widespread testing and use of the cocktail.

The conflicts surrounding ActRx TriAct should be urgently resolved. Politics should be pushed aside. Let us hear from the experts, the field doctors, and ethicists, without masks of anonymity. I have heard that people in the know are afraid to talk. I have been forewarned, the issue is dead. That the powers that be have already decided.

I hope not. Yet that is what I sense from reading the press releases—a demolition stonewalling blackballing campaign. A rain of criticisms, charges and insinuations—everthing from A to Y. But there’s the Z question: Does the drug work?

It is too important a drug to die a political death. Either debunk it or release it back into testing and use. And until or unless the treatment benefit is utterly and completely debunked, dengue patients who are not involved in the clinical trials but are seriously ill should be allowed the ActRx TriAct cocktail treatment by access through compassionate use.

Posted in health, politics

33 Responses to In Defense of the Anti-Dengue Cocktail

  1. December 11, 2014 at 3:04 pm
    Bert

    In the meantime, the snake oil salesmen will be laughing their way to the bank, :).

    • December 11, 2014 at 5:06 pm

      hey, this is no joking matter!

      • December 11, 2014 at 6:29 pm
        Bert

        Sorry, Angela, if this comes across as a joke, it’s not, merely a smile. You see, if a person or an entity is selling something without any proven value but just claim of effectiveness without explaining why or how it is effective, then it’s suspect to various interpretation mostly negative. Same with the supplier/distributor of this supposed effective medicine for dengue. That’s just me anyway. You may delete my comment if you find it offensive to you and I won’t mind. Nothing to it.

        • December 12, 2014 at 10:47 am
          Mark

          From the trials, it seems they have a 100% efficacy rate in San Lazaro Hospital. Are you really calling that snake oil?

          • December 12, 2014 at 11:26 am
            Bert

            That’s new, Mark, I mean the 100% efficacy rate in San Lazaro Hospital. Where did you get that information? I hope that’s true.

        • May 26, 2015 at 11:05 pm
          Random Sam

          BS. All the ingredients, including berberine have been EXTENSIVELY studied and used!! They are used world wide right now. You are a fake and CERTAJNLY not a knowledgeable person.

    • May 26, 2015 at 11:03 pm
      Random Sam

      You mean the pharmaceutical companies and their lobbyist such as Garin herself?! The main issue here is blocking of inn ative and simple temedies by large cartels that CONTROL the Phillipines. Period. So many ignorant people in the PI believe the straight up lies from bought and paid for officials. Sickening.

  2. December 13, 2014 at 12:00 am

    “(Dr. Jovencio) Ordonia says that in testing done among 288 human test subjects in San Lazaro Hospital, the 288 patients all recovered from dengue.

    “As Ordonia tells it, the manufacturers of ActRx TriAct, based in the United States, were thinking of starting human trials in Latin America when a friend of theirs, former senator Heherson Alvarez, heard about it. It was Alvarez who convinced the manufacturers to move the human trials to the Philippines, says Ordonia, arguing that dengue and malaria are major diseases in the country. (Dengue is counted among the top 10 causes of death in the Philippines, with more than 62,000 cases recorded from January to August in 2010.)

    “It’s not quite clear how Preferred and Proven Therapies Inc., the local company overseeing the trials of ActRx TriAct and headed by Alvarez’s son, managed to win DOH support for its trials, conducted earlier in Palawan (for malaria) before the studies were transferred to San Lazaro and, reportedly, other public hospitals. Secretary Ona has yet to formally issue an explanation after the story was carried by the media.”
    Read more: http://opinion.inquirer.net/80814/just-do-it-at-doh#ixzz3LhS9URPq

    • December 13, 2014 at 9:31 am
      Bert

      Ah, okay, clear enough. Does it says that those 288 patients recovered from dengue because of the effect of ActRx…? It does not, does it? Because in various hospitals, like for example hospitals in my province in Bicol, dengue patients also recovered from dengue without being administered ACTRx…

      Still, I’m hoping the efficacy of this medicine is as true as the claim of the distributor, but I think it’s their duty and obligation to explain why and how it is effective by following the proper procedure as demanded by medical science protocol.

      • December 13, 2014 at 6:02 pm
        baycas

        Alvarez claimed that there were 100 malaria patients and 144 dengue patients administered with the ActRx TriAct.

        http://www.gmanetwork.com/news/story/392361/news/nation/distributor-of-anti-dengue-actrx-triact-disputes-doh-criticisms

        Kung tama ang total 288 dengue patients who survived as reported…then 144 must have been given standard supportive treatment ALONE and the other 144 were given standard supportive treatment with ActRx Triact.

        Dr. Miranda must justify the advantage of adding the combination drug to the standard supportive treatment VERSUS the standard supportive treatment alone for the self-limiting disease by releasing the manuscript of her clinical trial done at San Lazaro.

        Let it also be published in a reputable peer-reviewed medical journal.

        • December 18, 2014 at 9:51 pm
          Bert

          baycas,

          According to reports, of the 288 dengue patients in San Lazaro, 144 were given ActRx while the other 144 were not. The claim was that all 144 dengue patients given ActRx survived. The claim did not mention that the other 144 dengue patients who were not given the medicine also survived.

          • December 19, 2014 at 3:37 pm
            baycas

            I remember I linked this in a previous blog post…

            In a December 1 letter obtained by Rappler, PCHRD Executive Director Jaime Montoya told Acting Secretary Janette Garin that their technical review “confirmed the potential of the compound as a new treatment modality for dengue.”

            There were also no significant adverse effects observed among the 288 patients included in the study,” the letter read, referring to the clinical trial of ActRx TriAct in San Lazaro Hospital.

            – Jee Y. Geronimo, Dec. 4, 2014

            http://www.rappler.com/nation/76903-anti-dengue-drug-trial-ethical-enrique-ona

            Well, the PMA President and the representatives of the Philippine College of Physicians (PCP) and Philippine Society for Microbiology and Infectious Diseases (PSMID) had already spoken after they reviewed the clinical trial (still unavailable online at present) done by Dr. Edna Miranda. Please see links below.

            The PCP and PSMID also made an official statement entitled “Position Statement on the Urgent Need for Good Research on New Dengue Treatments” and was published as a paid ad in two leading newspapers last December 15, 2014. Again, please see links below for the gist of the official statement.

          • December 19, 2014 at 10:30 pm
            Bert

            baycas, below is part of an article I read I copy-pasted here for farther clarification:

            “Flawed analysis

            Leachon, for his part, said that based on the Filipino physicians’ own review, there was no extensive pre-clinical testing done before the clinical trial of the drug on humans was conducted.

            He also pointed out that the analysis of the clinical trial saying that ActRx TriAct is a “promising” treatment for dengue was “flawed.”

            “In this study, every subject of the clinical trial survived including those who did not receive the treatment,” he said.

            There were a total of 290 dengue patients involved in the clinical trial in San Lazaro Hospital, of these half were administered with ActRx TriAct, while the other half were given the hospital’s standard care for dengue.

            “The only basis for expanding the use of this drug combination to several [Department of Health] hospitals was a study on 290 dengue patients in one medical center,” Dr. Mario Panaligan, member of the PCP Board of Regents and Vice President of PSMID, said.

            “They claimed there were no deaths due to dengue among 145 patients who received this treatment in the clinical trial. However, they are not saying in public that those who did not get this treatment also survived, which does not provided extra benefit in preventing deaths,” he added.

            This was echoed by Dr. Francisco Tranquilino, PCP Ethics Committee regent, who said it usually takes 10 to 15 years before a particular drug can be proven effective to cure a virus as the preclinical testing and the actual clinical testing are very elaborate processes.”

  3. December 13, 2014 at 5:34 pm
    baycas

    Alvarez released some information…

    http://www.gmanetwork.com/news/story/392361/news/nation/distributor-of-anti-dengue-actrx-triact-disputes-doh-criticisms

    Still, there were no manuscripts of the clinical trials for Dr. Butch to critically appraise.

    • December 13, 2014 at 5:40 pm
      baycas

      Earlier, Lee Suy announced…

      “The combination of berberine, artemether, and artesunate may have long-term effects that have not yet been studied adequately. These long-term effects may possibly ruin the lives of Filipino malaria and dengue patients,” Lee Suy said.

      By not complying with the International Conference on Harmonization Guidelines for Good Clinical Practice, the 2012 malaria study “lacked strong scientific merit and study participants were not afforded their due protection,” he added.

      The 2013 dengue clinical study was noted by the Philippine Council for Health Research and Development (PCHRD) to have the following deficiencies: missing baseline characteristics of study participants, lack of scientific justification for the use of artemether and artesunatef for dengue treatment, and the absence of pre-clinical studies on each of the three drugs (berberine, artemether, and artesunate) as to which drug has anti-dengue properties

      Lee Suy said the 2013 dengue study “did not comply with the basic steps of a sound scientific research using people as subjects.” He said the ActRx TRIACT has not been registered with the Food and Drug Administration whether “as a drug or as a food or a supplement.”

      “It has no legal basis to be present in the Philippines, especially for clinical trials,” he added.

      “Upon further review, it has been found that no other studies on ActRx TRIACT have been or are being conducted in other parts of the world. This is highly irregular and dangerous because in not following and complying with the basic protocol of scientific experiments using human subjects, the researchers are endangering the lives of the Filipino people who were given ActRx TRIACT without any accountability and transparency,” Lee Suy said.

      http://www.gmanetwork.com/news/story/390520/news/nation/doh-ona-approved-anti-dengue-treatment-placed-lives-in-danger

      Alvarez, Dr. Miranda (for dengue) and the other clinical trialist (for malaria) should make public their “informed consent” forms.

  4. December 14, 2014 at 8:31 am
    baycas

    Angela (and Dr. Butch too),

    Itong nagsulat dito may nalalaman sa research…

    A prospective study, especially when bias is eliminated by “blinding” the researchers or clinical investigators and providing a control group, is a reliable way to demonstrate the effectiveness and safety of a drug or product.

    http://business.inquirer.net/183492/doh-dengue-trial-protocol-approved-by-pchrd

    Pero ang Dengue clinical trial ni Dr. Miranda sa San Lazaro (144 patients, Phase I malamang ito) at ang research protocol para sa anim (6) na ospital (2,000 patients, maaaring Phase II ito) na nabasa ko sa DOH website noong available pa ito ay parehas OPEN-LABELLED.

    • December 16, 2014 at 4:56 am
      baycas

      But there are some basic flaws that anyone with general knowledge of research methods and statistics would notice. In my opinion, they are fatal flaws. The study is not a double-blind study and its randomization of the participants is questionable.

      http://www.rappler.com/thought-leaders/78054-medical-horror-story

      The parent knows his/her child will be given the drugs.

      The investigator also knows he/she will administer the drugs.

      Bias not eliminated.

      • December 16, 2014 at 5:10 am
        baycas

        With “questionable randomization” there will also be a bias in the selection process.

        Selecting only those patients who will likely to survive the disease may have happened.

  5. December 17, 2014 at 3:51 pm
    baycas

    The PCP and the Philippine Society for Microbiology and Infectious Diseases (PSMID) during the forum rejected the 2013 clinical trial of ActRx TriAct for dengue treatment saying that “the trial was poorly designed and the data analysis was seriously flawed.”

    http://www.gmanetwork.com/news/story/392880/news/nation/pma-backs-nixing-expanded-clinical-trial-of-disputed-anti-dengue-drug

    The PMA President is a clinical epidemiologist.

    • December 17, 2014 at 3:56 pm
      baycas

      In another news item…

      At a health forum yesterday, Dr. Francisco Tranquilino, a clinical epidemiologist, said the long route to approval of a new drug usually took 10 to 15 years and adhered to strict guidelines.

      “It would start from an idea, of a possibility of a new drug, all the way to its registration with the FDA [and], in between, going through different exploratory development processes and phases of clinical trials before going into full development study,” Tranquilino, also the PCP ethics committee regent, explained.

      Read more: http://newsinfo.inquirer.net/657614/doctors-urge-solons-to-probe-dengue-drug-trials-on-humans

    • December 17, 2014 at 3:59 pm
      baycas

      “The only basis for expanding the use of this drug combination to several DOH hospitals was a study on 290 dengue patients in one medical center. They claimed there were no deaths due to dengue among 145 patients who received this treatment in the clinical trial,” said Dr Mario Panaligan, PSMID vice president and a member of the PCP Board of Regents.

      “However, they are not saying in public that those who did not get this treatment also survived, which does not provide extra benefit in preventing deaths,” Panaligan added.

      http://www.rappler.com/nation/78163-pcp-psmid-statement-anti-dengue-drug-trial

  6. December 25, 2014 at 5:09 pm
    Dok Margel

    Bottom line: Granting that the study has numerous flaws, it does not mean however that the ActRx TriAct cocktail is ineffective or unsafe to use. Let us redo the study but this time do it in the right way. Anybody from DOH, PCHRD or any government agency? No more politics please.

    • December 25, 2014 at 11:24 pm

      dok margel, welcome to my blog! at last, a doctor in the thread… may your tribe increase :)

    • December 29, 2014 at 12:03 pm
      Bert

      Totally agree with you, Dok Margel. The manufacturer and supplier of this ActRx… should redo the study of their product by doing it the right way and scientifically prove it that their product is actually effective against dengue. There is no need for politics there.

  7. December 26, 2014 at 10:02 am

    naku, baycas at gabbyd, deleted your last comments, parang di naman niyo binasa talaga si dr. stuart. mas marurunong pa kayo sa mga doctor. siguro doon na lang kayo sa comment threads ng mga supporter ni garin.

    • December 26, 2014 at 10:58 am
      GabbyD

      in case it wasnt clear, i am supportive of scientific testing, and my only point is that the fear of drug resistance alone is insufficient to block said testing.

      i think this is in line with dr. stuart’s ideas. feel free to correct me if im wrong.

      • December 29, 2014 at 4:00 am

        gabbyd, nadamay ka lang. my apologies.

  8. January 8, 2015 at 12:42 pm
    Dennis

    Greetings!

    I am one of the co-investigators of study..

    In behalf of the medical research team, we would like to express our gratitude in your support to our cause!

    The reason why we, as medical practitioners and researchers, have not gone out to the press and release our statements is because first of all, we do not want to involve ourselves in politics. Secondly, we have not received any formal complaint against us or the study. All issues being thrown at us are all allegations and speculations.

    Last November 30, the DOH has released a statement with regards to the suspension of the DOH Department Order 2014-0161 regarding the implementation of the Clinical Trial on Dengue. We got hold of the said statement and we have answered everything point by point. I will be sharing to you a copy of our response to the DOH statement.

    1. Berberine was used in the studies even without specific and definitive scientific bases for the researchers’ claims that in can cure malaria or dengue

    SCIENTIFIC BASIS BEHIND DENGUE

    In a study done by Jia, F., et al, entitled Identification of palmatine as an inhibitor of West Nile virus published 2010 in Arch Virol, it was found out that palmatine, which is a member of the protoberberine class isoquinoline alkaloid, was able to suppress West Nile Virus without detectable cytotoxicity. The study has shown that the compound is able to “block the activity of NS3 protease which flaviviruses like the West Nile Virus and Dengue Virus encode.”
    West Nile Virus is member of the virus family Flaviviridae wherein the dengue virus is also a member. It can also be noted that the article suggests that the compound “might be a potential candidate for treatment of flavivirus infections (including dengue).”
    It is the objective of the researchers to test the hypothesis that berberine has an anti-viral effect on dengue virus.
    Artemisinin Derivatives, such as artemether and artesunate, also have established effects as an anti-viral drug. In an article that was published by Efferth, et. al., in the Clinical Infectious Diseases in the US last 2008, entitled, The Antiviral Activities of Artemisinin and Artesunate, it expounded on some of the different anti-viral properties of artemether and artesunate. Some of the viruses listed in the article include CMV, Herpes, HBV, HCV, even HIV-1. “The value of this compound is not limited to the treatment of malaria, and a wealth of studies have demonstrating the activity of artemisinin and its derivatives against…various viral diseases.”
    With this premise, the researchers would like to study if artemisinin and its derivatives also have anti-viral properties against dengue.

    SCIENTIFIC BASIS BEHIND MALARIA

    In a research conducted by Sheng, et. al., which was internationally published in 1997 by the East African Medical Journal entitled “Treatment of chloroquine-resistant malaria using pyrimethamine in combination with berberine, tetracycline or cotrimoxazole,” results showed that berberine has a greater clearing effect than the other treatment arms.
    Since there is proof that berberine has anti-malarial properties, the researchers now aim to test whether berberine plus artemether, artesunate, and primaquine may be efficacious for the treatment of malaria

    2. The use of artemether and artesunate is considered as “artemisinin monotherapy”, which increases the prevalence of resistance to anti-malarial drug.

    The ActRx Malaria study does not use an artemisinin monotherapy, rather, it utilizes a combination of artemether, artesunate, primaquine, and berberine. The purpose of the study to be able to develop a new combination of drugs that would be an available alternative treatment that the filipino malaria patients would be able to use. The use of the artemether plus artesunate, primaquine, and berberine might be the combination we are looking for to prevent the development of resistance from the “artemisinin monotherapy.”

    3. The combination of berberine, arthemether, and artesunate may have long-term effects that have not yet been studied adequately.

    Review of literatures do not show any data that proves that the individual drugs have long-term deleterious effects.
    The research team have data to show that berberine is safe for use for all ages. In a study done be Gupte, et. al. last 1971, entitled The of Berberine in Treatment of Giardiasis, a total of 137 subjects with ages ranging from 5months to 14years of age received berberine as a treatment of giardiasis, which is an intestinal parasite causing severe diarrhea.
    In another study done by Zhang et. al., in 2006, Assessment of taste development in 62 newborn infants they administered berberine to assess the taste reaction of neonates 90 minutes after birth. This proves that berberine is safe for consumption even for neonates.

    4. By not complying with the International Conference on Harmonization Guidelines for Good Clinical Practice, the 2012 malaria study lacks strong scientific merit and study participants were not afforded their due protection.

    ALL of the studies being questioned have undergone ethical and technical review by the independent review boards of the participating institutions wherein the studies were conducted, as this is the requirement by the International Conference on Harmonization Guidelines for Good Clinical Practice.
    ALL of the subjects were also afforded their due protection since all subjects were covered by a deed of legal undertaking wherein any form of complications that would be directly related to the test drugs would be the responsibility of the sponsor of the study.
    ALL of the subjects, based on the International Conference on Harmonization Guidelines for Good Clinical Practice, have been given and have signed the informed consent and assent forms. The informed consent means that all subjects were informed of the study protocol and have willingly consented to become part of the study. Patients who did not sign the informed consent were not included in the study.

    5. The 2013 dengue clinical study was noted by the Philippine Council for Health Research and Development (PCHRD) to have the following deficiencies:

    Missing baseline characteristics of study participants;
    The baseline characteristics were included in the research report handed to the members of the review board.
    Lack of scientific justification for the use of artemether and artesunate for dengue treatment;
    Answers from number 1
    Absence of pre-clinical studies on each of the three drugs (berberine, artemether, and artesunate) as to which drug has anti-dengue properties

    Each of the three drugs have already scientific bases that show possible effects in the treatment of dengue from other clinical studies. Answers can be found in number 1.

    This item also seems contradictory to the updated memorandum that the PCHRD has released last December 1

    6. In addition to all these, to date, ActRx TRIACT has not been registered with the FDA whether as a drug or as a food or a supplement. Thus, it has no legal basis to be present in the Philippines, especially for clinical trials.

    ActRx TriAct is NOT registered as a drug or as a food or a supplement basically because it is still undergoing clinical trials to have a basis for the registration to the FDA. The Philippine FDA has approved the use of the drug for clinical research purposes only.

    7. This is highly irregular and dangerous because in not following and complying with the basic protocol of scientific experiments using human subjects, the researchers are endangering the lives of the Filipino people who were given ActRx TRIACT without any accountability and transparency.

    Upon review of literatures, there were NO evidence that showed that the use of these drugs are irregular and dangerous. Further review show that there are strong evidences that Artemisinin derivatives and berberine are very safe for the consumption of the general population. Examples of these are sited in number 1.

    8. If something happens to those who had taken the ActRx TRIACT months or years from now, how and where do they seek legal remedy?

    All subjects enrolled in the study are covered by the Deed of Legal Undertaking and Informed Consent and Assent between the subjects, the researchers, and the sponsors.

    Also, let it be known that the investigators are members of Good-Standing of the Philippine College of Physicians(PCP) and of the Philippine Society for Microbiology and Infectious Diseases(PSMID). We would like to express our concern on how the societies have released a statement in the newspapers without consulting the concerned people. The joint statement by the PCP and PSMID was released in newspaper advertisements “so that the public may know”, yet up to present, we have not released any letter of communication from our societies. If they were really concerned of how we have conducted our clinical trials, they should have talked to us and not the media.

    There was even another statement from Dr. Leachon urging the Senate to probe the people behind the study. If Dr Leachon really believes we have done something illegal, why doesn’t he himself file a case against us? Why urge the senate to probe if they know that something was wrong? And on what grounds are being charged? The Medical Research Team behind the study is ready and willing to go through any investigation and answer all accusations against us.

    Again, in behalf of the research team, we would like to express our sincerest gratitude in your support of continuing medical education. Rest assured we would will continue to strive to provide our patients a better regimen for the treatment of dengue.

    • May 26, 2015 at 11:13 pm
      Random Sam

      Exactly. Novartis has their former lobbyist, Garin. What many fail to truly grasp is that Novartis and other pahrma companies bribe officials regularly and have even taken control of WHO. It is a VERIFIABLE fact.
      So, in light of the FACT that all components in these products are KnOWN to work, but are NOT synthesized drugs that can be controlled, the they must be blocked for better profits of the cartels.
      Duh,

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