By Naftali MUNGAI

Last year, the government of Kenya adopted Artemisinin-Combination Therapy (ACT) as the first-line treatment for malaria. This recommendation followed failure by most malaria drugs to treat the disease following widespread development of resistance by the malaria parasites, especially Plasmodium falciparum, the parasite that causes the most severe form of malaria. Artemisinin is derived from the herb Artemisia annua, and its leaves have been used in China for more than 2000 years to treat febrile illnesses including malaria, in the form of herbal tea.
Studies in China in the 1970s led to the isolation and characterization of artemisinin as the principal anti-malarial compound. The treatment was so effective that the Chinese undertook further research into the herb for treating malaria.
In the last few decades, artemisinin and its synthetic derivatives artemether and artesunate have been established as safe and effective anti-malarial drugs, even against resistant strains of P. falciparum.
Significant adverse effects or signs of toxicity have not been reported with therapeutic doses. However, there has been a major problem of relatively high rates of recrudescence observed in all clinical trials based on purified artemisinin or its synthetic derivatives. Recrudescence is the recurrence of malaria after treatment and is thought to be triggered by parasites that lie dormant in the liver and become virulent later.
Malaria continues to be the biggest killer in Africa and because of the heavy toll it takes and the demand for more effective drugs for its management, giant pharmaceutical corporations have invested millions of Euros in R&D, which led to the identification development of ACT. This includes coartem, the malaria drug that has been approved by the World Health Organisation as a first-line anti-malarial.
But even as the WHO has adopted coartem, developed by Novartis, as the drug of choice for malaria in Africa, the drug continues to be out of reach of most victims due to its high price. A curative dose of this drug costs about Shs 500 ($7) and this in a country where more than 60 per cent of the population lives below the poverty line, defined as living on less than a dollar a day. This in stark comparison to chloroquine, for long the mainstay of malaria treatment in Africa, which cost about Shs 10 (US Cts 8) per dose.
In an effort to redress this sorry state of affairs and ensure that the poor can access these life-saving drugs, the International Centre of Insect Physiology and Ecology has partnered with the Kenya Medical Research Institute and Natural Uwamba System for Health (NUSAG), a Tanzanian organisation, in a search for a cheap artemisinin-based cure for malaria that is affordable by the poor in Africa.
“The study, which has taken 18 months, was undertaken to provide ‘proof-of-concept’ relating to the special efficacy of the natural phytochemical blend of whole A. annua in malaria therapy and to the feasibility of a quality control production process with reproducible phytochemical content in whole leaf drugs produced from selected hybrids of A. annua grown in East Africa. “We set out to demonstrate that ethno-medicine can be lifted to a higher level by injecting scientific control and analysis into what mankind has practised for centuries. This shift in paradigm in the search for an affordable malaria cure has proved successful,” says Professor Ahmed Hassanali, a Principal Scientist at the ICIPE and head of the Chemical Ecology Department. He is also a principal investigator of this project.
The first step in the ‘proof of concept’ was to select clones that had a high artemisinin content. These were found in Arusha, Tanzania, with an artemisinin content of 0.6-0.8 per cent, which is even higher than some of Chinese origin. They were available by the NUSAG. This was followed by standardization of the leaf drying conditions so that the ensuing product would have a more or less standard amount of artemisinin.
Prof Hassanali observes that apart from artemisinin, there are another 13 closely related compounds that have been isolated from the herb, some with probable synergistic effects on artemisinin against malaria parasites when whole leaf extracts or tablets are used to treat malaria. “This joint project set out to establish whether such constituents, through their apparent synergism to artemisinin, could avoid or minimize recrudescence associated with monotherapy based exclusively on artemisinin or its derivatives,” Prof. Hassanali told Biosafety News.
Thus, the joint project aimed at showing that whole leaf A. annua tablets produced under good manufacturing conditions from high yielding plants is a safe, efficacious and tolerable treatment for uncomplicated P. falciparum malaria.
The justification for the study was predicated on the observation that if safe, efficacious and tolerable medication could be produced from locally grown medicinal plants, such preparations may offer an additional tool for malaria control, especially in socio-economic circumstances that preclude the availability or accessibility of the more expensive synthetic anti-malarial drugs. It is also hoped, says Prof Hassanali, that the cultivation of this plant will spread into other suitable areas of eastern African countries and serve as a cash crop for economic empowerment of farming communities.
This is particularly significant when one considers that this year alone, over 60 million doses of ACT courses will be required for malaria treatment. This is unlikely to be met due to inadequate availability of artemisinin.
After harvesting the leaves of the Arusha plants at eight months, these were dried under shade for three weeks and transported to Switzerland where they were crushed to a fine powder, mixed thoroughly to ensure uniformity in the artemisinin content, and then pressed into 500mg tablets.
Random groups of the so compounded batch of tablets were then analysed by a process known as High Performance Liquid Chromatography (HPLC) to see whether they had uniformity in the artemisinin content. This was found to be the case and they were even subjected to further tests in mice at KEMRI, where, again, it was shown that they gave a relatively uniform performance.
After this, the tablets were ready to enter the next phase of clinical trials, which is being tested in humans. This study was conducted in the St. Judes clinic, situated along the scenic shores of Lake Victoria at the ICIPE Mbita field research station, recently named Thomas Odhiambo Mbita Campus, in honour of the founder director of ICIPE, the late Professor Thomas Risley Odhiambo. Other tests were conducted at the MOH clinic.
Mbita District is among the poorest in the country with the majority of families earning less than Shs 2000 (US$ 27) per month. Malaria is the leading cause of illness, accounting for 42-48 per cent of all illnesses clinically diagnosed and endemicity varies from moderate to intense.
The community was sensitized on the availability of free malaria treatment through schools, churches and the provincial administration and all patients who enlisted were counseled on the principle of the study, the consequences, and on acceptance, were screened for malaria.
The study recruited 48 patients with uncomplicated malaria who were divided into four groups or cohorts of 12 each. The study was designed to provide the maximum potential therapeutic efficacy of the test drug while also defining the maximum tolerated dosage in the recruited patients. It was therefore an open-label, dose-rising, non-randomised single centre study for the efficacy, safety and tolerance of increasing doses of A. annua tablets in informed consenting individuals with uncomplicated malaria.
The medicine was supplied as 500mg tablets prepared from dried crushed finely powdered whole leaf of the herb, each containing approximately 3.74 mg of artemisinin.
It was carried out as an out-patient study in which morning doses of the drug were given under supervision. Each patient was observed for 10 minutes to ensure no vomiting of the drug occurred, and to look out for the acute reactions that may have occurred. The patient was then told exactly what time to swallow the tablets at home and this information counterchecked on the patient’s next visit.
The drug was administered orally in progressively increasing doses on four cohorts (C1, C2, C3, C4) as follows (level of artemisinin shown in brackets).
C1: 2 tablets (7.4mg) twice a day for day 1; 1 (3.7mg) tablet twice daily for the next 5 days.
C2: 3 tablets (11.1mg) twice a day for day 1; 2 tablets (7.4mg) twice daily for the next 5 days.
C3: 4 tablets (14.8mg) twice a day for day 1; 3 tablets (11.1mg) twice daily for the next 5 days.
C4: 5 tablets (18.5mg) twice a day for day 1; 4 tablets (14.8mg) twice daily for the next 5 days.
The use of other drugs known to have potential anti-malarial effects such co-trimoxazole, erythromycin, azithromycin and doxycycline was banned in order to ensure that any anti-malarial effect was due to artemisinin and related chemicals.
The clinical results were recorded from 10th June 2004 to 9th February 2005.
In Cohort 1, out of 12 patients, seven patients were females and five were males. The average age of the first cohort was 21.42 years. The ages ranged between 16 and 29 years.
Eleven (91.66 per cent) of the 12 patients reported relief of clinical symptoms and signs by the third day of treatment. Of these 12 patients, 83.33 per cent (10) had no malaria parasites by day six.
Eleven patients (91.6 per cent) had no parasitaemia or clinical complaints by day seven.
On day 14, 10 of the patients (83.33 per cent) had negative blood smears. And on day 28, nine (75 per cent) of the patients had negative blood smears on Giemsa staining for malaria parasites.
There was a case of recrudescence on day 14. This was a 29 year-old lady whose parasitaemia had cleared on day seven but she was symptomatic and parasitaemic on day 14.
There was also had a further case of recrudescence or probable re-infection as occasioned by the reappearance of parasitaemia on day 28 in patients who had no parasitaemia or clinical features of malaria by the seventh day.
Of the first 12 patients, six reported absolutely no adverse events related to the medication throughout the 6 days they were on treatment and on the follow-up days. “It should be noted that this was the case despite study clinicians specifically asking them whether they experienced any symptoms after taking the study medication at every visit to theclinic,” says the principal investigator.
The remaining six patients mentioned the following adverse events. The numberof times the symptom was mentioned is shown in brackets: nausea (twice), vomiting(once), abdominal pain (once), dizziness (twice), backache (once), tiredness (once), andbody itchiness (once). The only adverse event that bothered the patient who complainedof it was the general body itchiness that made the 18-year-old female to swallow antihistamine tablets but still disturbed her sleep. This is in line with the conclusion of
many studies that the adverse events profile of this medicine has generally been reassuring.
In conclusion, says Hassanali, it was shown that the A. annua tablets, given at the specified dose for six days, are effective in clinical and parasitological regression of uncomplicated malaria, with minimal adverse events noted.