Dope on drugs

Combination is the answer

 
Published: Thursday 15 June 2006

Dope on drugs

As good as a placebo: Incomple (Credit: Surya Sen / CSE)Latest reports suggest that resistance has to be countered by using combination therapy involving the Chinese cutting edge drug -- artemisinin. This strategy has problems -- apart, of course, from bureaucratic inertia -- related mostly to finance and availability.

The demand for artemisinin has been continuously on the rise, both in India and worldwide. The drug is derived from a plant found mainly in China -- Artemisia annua (see box: Disease stymied). Artemisinin is considered as of now to be the only effective drug against Pf, which has developed a resistance to it only in stray cases, invariably when it has been used in monotherapy. Experts warn, therefore, that unless it is used in combination this might well happen.

Most manufacturers of artemisinin derivatives in India import a semi-synthetic version of the drug, called artesunate, from China and Vietnam. Industry observers say that if, or when, the health bureaucracy moves to a universal combination regime, pharmaceutical companies may be forced to grow A annua. One company, Ipca Laboratories Limited, Mumbai, has already started doing this.

The government has also taken fitful stabs at promoting the cultivation of A annua. Various institutes have taken up projects for the development of artemisinin-based drugs. In India, the Central Drug Research Institute, Lucknow, in collaboration with the Central Institute of Medicinal and Aromatic Plants (cimap) has developed arteether, a semi-synthetic derivative of artemisinin, the active component of the plant A annua. Themis Medicare, Ltd, Mumbai, has been given a contract to manufacture the drug, christened emal. The National Institute of Pharmaceutical Research, Mohali, Punjab, is also working on a project to cultivate A annua and isolate artemisinin.

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Recently, cimap has developed a new high artemisinin-yielding variety, ' cim -Arogya'. Besides, an improved process for isolating artemisinin from the herb has cut costs of producing artemisinin from Rs 40,000 per kg to about Rs 15,000 per kg. Six companies have contracted farmers to cultivate the plant, which they will buy back to produce artemisinin-related compounds. Under the new arrangement, farmers will stand to make a profit of about Rs 40,000 per hectare for a single season of five months, the Centre claims.

Whose initiative
While there are such sporadic initiatives, the government has made no real attempt to shift to a more rational drug regime, despite promptings from who.

who has been suggesting for a long time that all countries where Pf has shown more than 10 per cent resistance to chloroquine, amodiaquine or sp, should use combination therapies, preferably containing artemisinin derivatives. These are known as artemisinin combination therapies (acts).

act has to be administered for two to three days compared to seven days of artemisinin as monotherapy. And since the pathogen is removed quickly, the chances of it developing resistance are further reduced.

On the northwestern border of Thailand, there was a 47 per cent reduction in the incidence of Pf infections in the 12 months after acts containing artesunate and mefloquine were introduced, without vector control programmes. Over the next 10 years, there was a six-fold reduction in malaria transmission. Similarly in Vietnam, use of acts has led to a substantial drop in malaria incidence. And in KwaZulu Natal, South Africa, a reduction in malaria cases, and fatalities, of more than 90 per cent has been sustained over the past three years after vector control programmes were introduced along with acts.

Supply side

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All available evidence suggests a shift to act is necessary to ensure there are effective drugs that can be used in the combination. To ensure that artemisinin derivatives are not used as monotherapy, who reached an agreement, in May, 2006, with 13 pharmaceutical companies to stop producing single-drug artemisinin medicines. A total of 23 companies make the drug. The remaining 10 have said that they are willing to collaborate with who.

While who is promoting the use of artemisinin derivatives -- artesunate, artemether and dihydroartemisinin -- it is likely that if more is used, there could be a raw material shortfall. In 2004, global production capacity was estimated to be around 25-50 million courses. That was way behind demand, which in 2005 was estimated at around 131-219 million. To meet this demand, who has been promoting cultivation of the herb. Besides, promotion of artemisinin is likely to suffer from crippling cost constraints. Globally act costs us $2.40 (a little over Rs 90) per course, which is the price at which Novartis is selling the drug right now, compared to just us $0.10 (roughly Rs 4.50) for chloroquine. msf estimates that for all Asia Pacific countries, act would cost about us $10.7 million a year. Given that malaria occurs in the poorer countries, a shift to act would require massive funding from donor agencies. The Global Fund to fight aids, Tuberculosis and Malaria (gfatm) is the largest financer of act s. So far, it has given enough to fund six million courses a year, which, obviously, is peanuts. Donors like dfid and Aus aid have not yet reached a firm conclusion on funding strategy and are still pushing the old treatment.

Since 2001, 56 countries have followed who 's recommendation in favour of act as the first-line treatment for malaria, which has created a surge in demand -- from two million courses in 2003 to at least 25 million in 2004. Countries are expected to place orders for at least 130 million courses in 2006. Technically supply can be ratcheted up to meet the demand, but the cost constraints have to be overcome through injection of funds by donors. This will give industry the signal that production should be increased.

Already, for instance, gfatm disbursements have sparked positive responses within the pharmaceutical industry. Novartis has announced that it will produce 210 million courses of acts soon. At an average price of us $1.5 (Rs 68.25) per treatment, when sold in bulk, this works out to purchases worth us $315 million (Rs 1,433.25 crore) over two years. This means that Novartis will be producing in excess of gfatm- financed demand. Novartis can meet the shortfall by selling to the private sector or other funding agencies. Sanofi will produce up to 15 million artesunate/amodiaquine courses in 2006. Ipca is producing 2 million courses per month, while Cipla is also into production of a generic version of the only combination approved by who. gfatm, established in 2002, is the largest funder of acts. In the first four rounds of funding, a total of us $230 million (Rs 1,046.5 crore) has been approved over the first two years, mostly for African countries. In a report, the Institute of Medicine in the us has recommended that combination therapies be sold to both governments and private wholesalers at the same price as chloroquine. Globally, this would cost donors and development agencies us $150-200 million (between Rs 682.5-910 crore) a year.

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Efforts have also been made to step up production of artemisinin. A annua has been cultivated in several countries since 2004-2005. While the largest producers are still China and Vietnam, East African countries (Kenya, Uganda and Tanzania) are also scaling up production and are expected to account for about 20 per cent of world production by the end of 2006. Cultivation of the plant requires a minimum of six to eight months from planting to harvesting, and extraction, processing and manufacturing of the final products require at least two to five months.

There is more hope though. Research into anti-malarial drugs is uncovering substitutes for artemisinin. One of the most advanced products being developed by Medicines for Malaria Venture (mmv), an ngo, is oz 277/ rbx 11160. Ranbaxy is the commercial partner for this drug. The product has entered phase- ii of clinical development and is likely to be in the market by 2009.

This drug too will have to be used in combination therapy because of concerns related to Pf acquiring resistance. "The future of malaria treatment is going to be very different in the next 10 years. mmv is funding 21 projects that are expected to provide a new drug every five years," says P Venugopal, mmv' s international operations director.

With 105 proposals on the list, research input is guaranteed. Researchers in the us are also experimenting with artemisinin culture in yeast cultures (see 'Malaria in a ferment', Down To Earth, May 15, 2006). The hunt for artemisinin is on, but without appropriate cost-effective technology not much can be expected.

Despite these initiatives, India has to import A annua and drugs derived from it. As a result, artemisinin-based drugs cost more in India than in the global market -- recently India bought combination drugs from Indian manufacturers (who are hampered by cost problems) for Rs 110 per course.

But all this will make sense only when the government gets out of denial mode and starts looking seriously at combination therapy.12jav.net12jav.net

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