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Artequick: programmed for failure

December 13, 2014 - 19:28 -- Irene Teis

The competitive product Artequick which the Chinese launched against Coartem and Coarsucam is now confronted by resistance like any other monotherapy. A letter to the editor by DL Saunders et al., in NEJM July 2014 describes the dihydroartemisinin-piperaquine failure in Cambodia. The drug was adopted as first line treatment in this country in 2010. Three years later the efficacy has decreased from 92% to 64%. At 72 hours 56% of patients still had persistent parasitemia. Another research team (R Leang et al., Antimicrobial Agents and Chemotherapy, May 2015, doi:10.1128/AAC) assessed the clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria in western and eastern Cambodia over 42 days. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) compared to eastern Cambodia (2.5%). Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients was also noticed in Central Vietnam (Thriemer et al., Antimicrobial Agents and Chemotherapy, 2014, 58, 7049-55).

A disaster for Cambodia and Vietnam now, but a genocide looming for African countries, after the failure of other ACTs.

WHO believes that increasing treatment failures are "most probably due to piperaquine resistance," according to Pascal Ringwald, coordinator of WHO's Drug Resistance and Containment program. Researchers at the University of Uppsala indicated (Science Translational Medicine, 30 Oct 2014) that even moderate resistance to piperaquine can be expected to drastically compromise the usefulness of piperaquine in preventive therapy.

Comments

Submitted by Bangaly Danfakha (not verified) on

Unsubstantiated, false, disgraceful claims. Irene Steins should do a serious research before spilling on the internet unscientific claims about a drug she knows nothing about. Artequick is NOT a combination of dihydroartemisinin+piperaquine. And it was NOT and is NOT a first line treatment in Combodia. Furthermore, in Cambodia-Thailand border, where in history malaria drug resistance has emerged first, almost all antimalarial drugs have lower efficacy to the parasites. It is misleading to single out just one drug.

Artequick is a combination of Artemisinin 62.5mg and Piperaquine 375mg. Dihydroartemisinin is just different. It is a derivative form. Artequick is undoubtedly one of the safest and most efficient ACTs currently available on the African market. Its efficacy is as high as 98%. The side effects are few, less than 3%. Also, one of its characteristics is its short regimen: 24hrs malaria treatment, with only 4 tablets.

Artequick is officially registered and sold in 24 countries around the world such as China, Thailand, Nigeria, Kenya, Tanzania, Benin, Togo, Ghana, DRC, Gabon, Liberia etc.

A recent study in Nigeria, published on clinicaltherapeutics.com on August 2015 shows the efficacy, safety and tolerability of Artequick.
http://www.clinicaltherapeutics.com/article/S0149-2918%2815%2900342-2/fu...

Submitted by Bangaly Danfakha (not verified) on

Efficacy, safety and tolerability study of artemisinin-piperaquine combination (ArtequickR) versus artemeter-lumefantrine (Co-ArtemR) for the treatment of uncomplicated plasmodium falciparum T Malaria in Ijebu ode local government health services in Nigeria

Background
Artemisinin-based combination therapy (ACT) has become the standard of care for the treatment of uncomplicated Plasmodium falciparum malaria in the world. Data guiding optimal choices of ACTs are limited. Artemisinin-based combination therapy of artemether-lumefantrine (CoartemR) is currently used for the first line treatment of uncomplicated Plasmodium falciparum malaria. However, limited efficacy and tolerability data are available on alternative forms of ACT. This study was conducted to compare the efficacy and tolerability of two fixed- dose formulation of ACT, artemisinin-piperaquine (ArtequickR) and (Coartem), for the treatment of P. falciparum in Nigeria.

Methods/Materials
A randomized, open-label trial was conducted comparing the efficacy of a one-day regimen of Artequick (2.8 mg/kg artemisinin plus 17.1 mg/kg of piperaquine per day for 24 hours) and Coartem (24 tablets, total dosage of 3360 mg, eight tablets over three days) for the treatment of adults with uncomplicated falciparum malaria. The primary end point was a day 42, PCR-corrected, parasitological cure rate; secondary end points were parasites and fever clearance time. Of 64 patients enrolled, 31 were administered with Artequick and 33 with Coartem.
Result
Of the patients who completed the test, 28 were on Artequick and 29 were on Coartem. Recrudescence parasitemia was PCR confirmed for all patient in each treatment group, with cure rates at day 42 of 97% (96% CL: 90–100) for both forms of ACT.

Conclusion
The median parasite clearance time was significantly slower in the Coartem group compared with the Artequick group (48 h vs 36 h, P < 0.05), and fever clearance times were shorter in the Artequick group (12 h vs 24 h, P < 0.05). The two forms of ACT were well tolerated with no serious adverse events.

Source: http://www.clinicaltherapeutics.com/article/S0149-2918%2815%2900342-2/fulltext

Submitted by Pierre Lutgen on

We are all fighting the same battle againt malaria. Our approaches may be different, sometimes with conflicting interests, but that does not allow anyone of us to insult others.

To treat Irene Steins approach as unsubstantiated, false, disgraceful because she raises some questions about resistance, based on published peer reviewed papers, is below the level of documents or blogs so far published on www.malariaworld.org.

Science is asking questions and raising concerns. Science is not claiming to be in possession of the ultimate truth.

The exchange of comments published over the last days on this issue is intriguing. So I wanted to dig a little bit deeper into all these claims.

Bangaly Danfaktha is right stating that there is some confusion between Artequick and Artekin. The Chinese manufacturer Artepharm for example advertises for a combination of dihydroartemisinin and piperaquine under the brandname Artequick and uses it massively in the Comoros (www.pharmafinder.co.ke). Others reserve this denomination for the combination artemisinin/piperaquine. But does it really matter as artemisinin is largelly metabolized into dihydroartemisinin.

It is unfortunate that the full text of the paper Bangaly refers to is not available on internet. It is difficult and/or impossible to find the manufacturer (Florson Pharmaceutical Ltd) of the Artequick used in these trials on internet. It would be important to know the efficacy of this ACT before PCR correction. Because as Ahmed Hassanali asks on a document dated 13 February 2013 on www.malariaworld.org « Is PCR genotyping of Plasmodium falciparum a reliable tool to monitor drug resistance ? ».

A document published by CBS NEWS on November 11, 2014 under the title

« CHINA TESTS MALARIA DRUG ON AN ENTIRE AFRICAN NATION

is intriguing.

(Excerpts)

In the Comoros, more than 700,000 people were given three doses of Artequick -- a new combination of anti-malaria drugs which has not been approved for use in humans by any international health body. "The vision is to contribute to the elimination of malaria in the world," Pan Longhua, General Manager of Artequick's maker, Artepharm Co. Ltd (China)., tells CBS News. But the new combination of drugs used to formulate Artequick remains untested and unapproved by the global healthcare community, and there are concerns about testing it on so many people all at once.

"This is a new medicine, and it has not been studied a lot and it is not widely available, says Andrea Bosman of the World Health Organization's Global Malaria Program. "This is new. This is very new." But Artepharm, the drug's maker, is already citing the experiment in the Comoros as proof of the drug's effectiveness. The company is marketing the drug throughout Africa, advertising Artequick as a malaria treatment with a longer shelf-life, fewer side effects, a shorter regimen and lower cost than other options on the market. All of which makes it a "very promising" drug to treat the disease, according to company boss Pan Longhua

Bosman, of the WHO's Global Malaria Program, is critical of how the Chinese experiment's managers are handling reported side effects from Artequick.

Dr. Yao Kassankogno, the WHO representative in the Comoros, fears China's mass drug administration will rob the population of its built-up immunity to malaria, creating conditions for an epidemic if the disease is ever re-introduced to the islands.

Critics also say administering a malaria drug to such a large population could build up resistance to artemesinin, one of the key ingredients in Artequick and one of the most widely-depended upon treatments for malaria in the world today (end of the excerpts ) »

Submitted by Bangaly Danfakha (not verified) on

A document published by Theeconomist on January 25, 2014 under the title

“Cure all?”

“WHAT if it were possible to get rid of malaria? Not just bring it under control, but wipe it from the face of the Earth, saving 660,000 lives a year, stopping hitherto endless suffering, and abolishing a barrier to economic development reckoned by the World Bank to cost Africa $12 billion a year in lost production and opportunity? It is an alluring prize, and one that Li Guoqiao, of Guangzhou University of Chinese Medicine, thinks within reach.

Dr Li is one of the researchers who turned a Chinese herbal treatment for the disease into artemisinin, one of the most effective antimalarial drugs yet invented. Now he is supervising experiments in the Comoros, using a combination drug therapy based on artemisinin, to see if malaria can be eradicated from that island country. If it works, he hopes to move on to somewhere on the African mainland, and attempt to repeat the process there.

The current approach to dealing with malaria is to control the mosquitoes (one of which is pictured above) that spread it—either by killing them with chemical insecticides or by draining the bodies of stagnant water that their larvae live in. That has worked in many places. In Europe, for example, malaria once existed as far north as Murmansk, in Russia. Now it is rare-to-non-existent. But it was never the plague in Europe that it is in Africa, and on that continent mosquito-control programmes may need a helping hand.

Dr Li’s approach is to attack not the mosquito, but the disease-causing parasite itself. This parasite’s life cycle alternates between its insect host (the mosquito) and its vertebrate one (human beings). Crucially, as far as is known, humans are its only vertebrate host. Deny it them and it will, perforce, wither away—an approach that worked for the smallpox virus, which had a similarly picky appetite. In the case of smallpox, a vaccine was used to make humans hostile territory for the pathogen. Since there is no vaccine against malaria, Dr Li is instead using drugs.

A combined assault

The drugs in question are artemisinin and a second antimalarial called piperaquine—a combination made and sold under the brand name “Artequick” by Artepharm, a firm based in Guangdong which Dr Li helped found. Adding piperaquine to the mix reduces the risk of a strain of parasite resistant to artemisinin evolving, because the chance that an individual parasite will be immune to both forms of attack is negligible. (A similar approach is employed in the combination therapies used to treat HIV infection.)

To deny the parasites their human hosts long enough to exterminate them in a given area, the researchers administer three doses of Artequick, spaced a month apart. To add extra power, the first dose is accompanied by a third drug, primaquine. Dr Li and his colleagues call this approach Fast Elimination of Malaria through Source Eradication, or FEMSE.

And it works—almost. The Comoros has three islands: Moheli, Anjouan and Grande Comore. Before the experiment started, more than 90% of the inhabitants of some villages on these islands had malaria. Song Jianping, Dr Li’s lieutenant in the Comoros, blitzed Moheli with Artequick in 2007. The number of cases there fell by 95%, though reinfection from other islands caused a small subsequent rebound. In 2012 he did the same thing on Anjouan. There, the number of cases fell by 97%. In October 2013 the campaign moved to Grande Comore, the most populous island. When the process is complete there, nearly all of the 700,000 Comorans will have taken part in FEMSE.

Ninety-five percent, or even 97%, is not eradication. But it is an enormous improvement and creates a position from which eradication can be contemplated. To do that, though, means keeping an effective surveillance programme permanently in being so that those who become infected can be treated quickly, to stop them spreading the parasite.

That is especially important, in the view of Yao Kassankogno, the World Health Organisation’s representative in the Comoros, because eradicating malaria will stop people building up immunity to the disease as children. Almost everyone in a place like the Comoros gets infected as a child, and the immune systems of those who survive thus learn to combat the disease, meaning that for many people subsequent bouts are not much worse than catching a cold. If malaria did return after a longish period of absence, Dr Kassankogno fears it could wreak havoc.

Whether FEMSE, or something similar, could be made to work on the African mainland—or anywhere else that is not an isolated island—will also depend on this sort of long-term monitoring, for in that case leakage from the outside would mean even 100% local eradication would not be enough to eliminate the parasites. In the case of the Comoros, not everyone is convinced sufficient surveillance is happening. Dr Kassankogno says the government’s current surveillance for the disease is weak. Dr Song, however, says that his team has trained more than 200 Comorans to monitor rates of malaria, with a view to detecting and preventing its return.

Safe and sound?

A more immediate concern is the safety of the drugs. Artemisinin and piperaquine are pretty safe, but primaquine ruptures red blood cells in people with a deficiency of an enzyme called G6PD. That can kill. And a lot of Africans—in particular, 15% of Comorans—are G6PD-deficient.

Andrea Bosman, the head of the diagnosis, treatment and vaccines unit of the global malaria programme at the World Health Organisation, is critical of the experiment’s approach to looking for side-effects. He says neither the scientists running it nor the Comoran government have been monitoring side-effects from the drugs in a systematic way. That, in Dr Bosman’s view, not only risks harming participating Comorans, it is also a missed opportunity to learn lessons from the project that would be of help to other countries in the fight against malaria.
Dr Song does not, however, believe side-effects will be a problem, because the dose he uses is so low. He also says he has seen no evidence of side-effects, though one hospital in Grande Comore said that the number of patients it treated doubled in the week after the drug-administration programme began, with people reporting nausea, fever, stomach and back pain, headaches and chills. These are symptoms of red-blood-cell rupture, but some are also common side-effects of artemisinin, so would be expected anyway.

Four deaths that occurred shortly after people took the drugs have been reported. There is no evidence that these were any more than coincidence, but family members seem reluctant to talk about them with journalists. Fouad Mhadji, the country’s health minister, shows no similar reluctance. He says the four in question died of natural causes: “One of them had the problem of cancer. One had the problem of hepatitis B. The flu was not only in the Comoros. It was also in the region of the Indian Ocean.”

There is also the question of informed consent to the drugs. Smallpox vaccination permanently protected the person being vaccinated. There was thus an individual as well as a collective benefit to offset any possible side-effects. Prophylactic drug treatment protects only for as long as the drugs stay in the body—which is a few weeks (and explains the need for three rounds of treatment). Dr Song’s results suggest the benefit is real. But it is a collective benefit. That changes the moral calculus. On the one hand, there is the risk of healthy people being harmed by side-effects. On the other, there is the risk of their free-riding, by taking the collective benefits while not taking the drugs themselves.

To avoid such free-riding, a lot of official encouragement to participate has happened—encouragement some people regard as tipping over into pressure and propaganda. In a public meeting in Niumadzaha, a village in the south of Grande Comore, for example, the chief doctor of the local health centre shouted through a megaphone: “This drug is safe and effective. You are not being used as guinea pigs. The WHO would not allow this administration to happen if you were being used as guinea pigs.”

Certainly, there is a lot riding on the project. Dr Mhadji says FEMSE will save the Comoros $11m a year in direct and indirect costs (for comparison, its annual health-care budget is $7.6m), as well as preserving many lives that would otherwise have been lost and saving survivors from the brain damage malaria can cause. The eradication of malaria will also, he hopes, make the Comoros more attractive as a destination for tourists.

Others hope to profit, too. Artepharm has high expectations of Artequick and is using the drug’s success in the Comoros in its marketing campaigns in South America, South-East Asia and Africa. Moreover, the arm of the Chinese government that administers that country’s foreign aid, and is thus helping pay for the project, is the Ministry of Commerce—for Chinese largesse is more explicitly tied to the promotion of the country’s business than is aid from most Western countries.

Not that the West is a disinterested party, for Western firms, too, manufacture artemisinin-based malaria therapies. On that point Dr Mhadji has strong views. He dismisses criticism of the experiment as fuelled by competition between Western and Chinese pharmaceutical companies.

As Nick White, a malaria researcher at Oxford University’s School of Tropical Medicine who has been working for years on eradicating malaria, says, “This research is radical. It is controversial. It is led by a very famous Chinese physician and investigator. There are lots of very serious questions here and a lot of unknowns.” Or, as Oscar Wilde more succinctly put it, “The truth is rarely pure and never simple.”

http://www.economist.com/news/science-and-technology/21594956-novel-approach-using-drugs-instead-insecticides-may-make-it-easier

Submitted by Marc Vanacker (not verified) on

U d’Alessandro had already reported in 2009 (Curr Opin Infect Dis 22, 588-92) that patients treated with dihydroartemisinin-piperaquine might have a higher rate of gametocytemia after a few weeks .

This is the case for sulfadoxine-pyrimethamine (C Puta et al., Trop Med Int Health, 1997, 2, 227-229; A Sowunmi1; AA Adedeji et al., Mem. Inst. Oswaldo Cruz vol.101 no.8 . 2006).

Similar findings have been published for artemisinin-piperaquine and dyhydroartemisinin-piperaquine. In a trial in 4 clinics and 7 villages along the China-Myanmar border it was found that after treatment patients had detectable gametocytes and a large portion of these were persistent from the first 53 days of the treatment (Y Wang et al., Am J Trop Med Health 2015, 93, 577-83). The same persistency had previously been seen in Indonesia (I Sutanto et al, Clin Infect Dis, 2013, 56, 685-695). In Uganda it was found that gametocyte detection was significantly higher in patients treated with dihydroartemisinin-piperaquine than for artemether-lumefantrine. The test involved 312 children receiving more than 4000 treatments. A review paper from 2013 comparing the gametocyte clearance time of dihydroartemisinine-piperaquine versus mefloquine-artesunate in Myanmar, Cambodia and Thailand, with artemether-lumefantrine in Uganda, with artesunate-amodiaquine and with amodiaquine-sulfadoxpyrimethamine in Rwanda showed that in all cases the gametocyte clearance time was longest for dihydroarteminin-piperaquine (J Zwang et al., PloS ONE, 2009 4-7, e6358).

The recent reply by Bangaly Danfakha does not answer the questions raised by P Lutgen. It creates more concern than clarification. Providing the Fulltext of the paper quoted by Bangaly would by far have been preferable than an article from The Economist, whatever the merit of this magazine might be.

Piperaquine is of the same family as chloroquine and amodiaquine. Both have led to massive resistance. Wikipedia states that piperaquine is an antimalarial drug first syntesised in the 1960 and used extesively in China and by the Vietcong in the battlefield (pill No.3 piperaquine phosphate). Usage declined in the 1980s as piperaquine resistant strains of P. falciparum arose. This resistance took massive proportions (De-quan Liu, Infectuous Diseases and Poverty, 2014, 3 :8, 8 pages). In the Hainan province in vitro tests on 216 cases showed an increase in resistance rate from 15.8% in 1985 to 72.9% in 1997 and in in vivo tests on 126 patients the resistance rate increased from 17.2% in 1984 to 50.0% in 1997).

If piperaquine leads to higher transmission and is prone to cause resistance of ACTs, the inhabitants from the Comoros are really used as guinea pigs.

Submitted by Marc Vanacker (not verified) on

"Using artemisinin the way Li wants to use it could increase the prospect of resistance," said TU YOUYOU, director of the Artemisinin Research Center at the China Academy of Chinese Medical Sciences in Beijing, and the scientist credited with first extracting the drug from the sweet wormwood bush years ago. "We went through all the trouble to invent this medicine so we should protect it. We should not abuse it."
This ist he reaction of Youyou Tu in an article published in the International Herald Tribune in June 27, entitled“ Chinese Artequick goes to Africa to wipe out malaria“.

Li and his team from the Tropical Medicine Institute at the Guangzhou University of Traditional Chinese Medicine propose to take the medical world's last line of defense against malaria, the drug artemisinin, and dispense it in combination with another drug as a mass treatment to the 40,000 people living on Moheli Island, a small island off the east coast of Africa where the disease in endemic.
„We need to do more than control this disease," Li said in an interview. "My goal is to eliminate it because if you simply try and control it, as soon as you relax your efforts, it will get away again."

In the eyes of some scientists and public health experts it is a risky plan. They fear that mass treatments with artemisinin, particularly without associated measures to control the mosquitoes that carry the disease, could hasten the onset of resistance to the world's most effective antimalarial drug.

Submitted by Anton Alexander (not verified) on

I am saddened by the outburst of Bangaly Danfakha's comment on 21st October last when writing that Irene Teis's article was "Unsubstantiated, false, disgraceful claims. ...."

Such outbursts quietly do incalculable harm and damage, and discourage other MalariaWorld readers from ever introducing their findings for fear of being rubbished. It was good to read Pierre Lutgen's comment.

Submitted by Lucas Redding (not verified) on

I agree.

However, I'm not surprised at Bangalay's response.

The title "Artequick: programmed for failure" is very inflammatory and provocative. It does not naturally invite scientific debate.

I think a more objective and less inflammatory title would have encouraged an objective and less inflammatory response.

I can personally vouch for Artequick.

My brother can thank Artequick for being alive today. All other medicines failed to cure his malaria.

My nephew (My brothers son) can also say the same.

I am sure there are hundreds of thousands more people thanking Artequick for saving their lives.

So it is better not to belittle it, and hold it in the respect it deserves, regardless of possible impending issues that definitely require objective and scientific discussion.

So lets chill out, shake hands, and look at these things objectively, specifically with respect to those thanking Artequick.

;¬)

Submitted by Marc Vanacker (not verified) on

Results from a large study (Bo Huang et al., Parasites and Vectors 2015, 8:634) in Grande Comore where mass drug administration of Artequick is now applied since several years showed that the number of mutations in Plasmodium falciparum has significantly increased. This is worrying.
Similar mutations or resistance to ACT drugs has been reported in at least 8 African countries over recent years.

Submitted by Marc Vanacker (not verified) on

A year ago a blog posted by Irene Teis where she asked if Artequick was programmed for failure had raised a violent debate. Bangaly Danfakha stated that this was a false, disgraceful claim. Anton Alexander was saddened by this outburst. Pierre Lutgen quoted a document published by CBS NEWS on November 11, 2014 under the title « CHINA TESTS MALARIA DRUG ON AN ENTIRE AFRICAN NATION » in the Comoros and fin’s this approach intriguing, if not unethical.

It appears now that Irene’s concern was valid.

This week a paper by S.Chaorattanakawee in Malaria Journal (Oct 21, 15, 519) informs us that ex vivo piperaquine resistance developed rapidly in Plasmodium falciparum isolates in northern Cambodia. This raises a lot of concern as DHA-PPQ is being introduced as first-line treatment in neighbouring countries.
This urgently requires alternative therapy. The temporary re-introduction of artesunate-mefloquine is the current response. A very bad choice as mefloquine is known for severe psychologic effects and is banned in several countries.

Why not use Artemisia annua infusions or powdered leaves ? The large scale, randomized, double blind clinical trials in RDC have shown a 98% efficacy, no side effects,absence of gametocytes, no recrudescence on day 28.

Submitted by Pierre Lutgen on

A recent study of WHO and UNICEF examined the behaviour of DHA in plasma and erythrocyte lysate at different temperatures and pH ranges. A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3h and almost completely abolished after 24 h. In vivo disorders such as fever, haemolysis or acidosis associated with malaria severity may contribute to instability and clinical efficacy.

 

S Parapini, P Olliaro, V Navaratnam, N Basilico. Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions: implications for clinical treatment. Antimicrob Agents and Chemotherapy, 2015, 59, 7.4046-4056

Submitted by Irene Teis on

Medecins sans Frontières run a large scale IPT trial in a refugee camp in Uganda with dihydroartemisinin-piperaquine (DP). The trial involved 13 537 children. Distributions of DP took place in March 2015, May 2015 and July 2015. Final impact was evaluated in September 2015. Average parasitemia raised from 6.6 in May to 18.7% in September. The authors qualify this as a positive impact of DP on malaria incidence!
(Mc Coldiron, E Lasry, R Grais, Malaria Journal 2017 16:218)
On may wonder why MSF persists in this mass drug administration. In a paper covering results from 2014 they had already concluded that “The low effectiveness of dihydroartemisinin–piperaquine (DHA–PPQ) for symptomatic cases indicates that PPQ is no longer able to complement the reduced potency of DHA to treat falciparum malaria and highlights the need for an alternative first-line treatment”. (G Falq, R van den Bergh, Malaria Journal 2016, 15(1) 446).
And this is not the first failure of Artekin in IPT. In a trial in Zambia no difference was found in the two treatment arms (Eisele TP, Bennett A, Silumbe K, Short-term Impact of Mass Drug Administration With Dihydroartemisinin Plus Piperaquine on Malaria in Southern Province Zambia: A Cluster-Randomized Controlled Trial. J Infect Dis. 2016 Dec 15;214(12):1831-1839).
There is serious concern over the widespread deployment of IPT and that this will enhance the spread of drug resistance

And it confirms that African children are guinea pigs for mass drug administration

Submitted by delvin (not verified) on

Irene i fully disagree with your article. atrequick is a combination of artemisinin and not dihyroartemisinin. duo cortexin has that combination of dihydro. so maybe you referring to that. am a medical representative of artequick and i have also been a patient of the same. artequick is 98% compliant with less than 3% side effects.