Paul N Newton; Facundo M Fernández; Aline Plançon; Dallas C Mildenhall; Michael D Green; Li Ziyong; Eva Maria Christophel; Souly Phanouvong; Stephen Howells; Eric McIntosh; Paul Laurin; Nancy Blum; Christina Y Hampton; Kevin Faure; Leonard Nyadong; C. W. Ray Soong; Budiono Santoso; Wang Zhiguang; John Newton; Kevin Palmer

“ Fake artesunate is devastating for malaria control: it causes avoidable death, reduces confidence in the drug, and takes away profit from legitimate manufacturers. Of major concern also is the potential for subtherapeutic counterfeit artesunate to fuel the parasite's resistance to the artemisinin group of drugs. ”

“ Concerned health workers and scientists, the regional World Health Organization (WHO) office and the International Criminal Police Organization (INTERPOL) got together to discuss what could be done in May 2005 when it became clear the counterfeit artesunate situation was worsening in the Greater Mekong Sub-Region of South East Asia (comprising Cambodia, Lao People's Democratic Republic, Myanmar, Thailand, Vietnam, and Yunnan Province in the People's Republic of China) . ”

“ Fakes with stickers were only found in Vietnam, Cambodia, and northern and southern Laos whilst those with holograms were only found in Myanmar (Burma) , the Thai/Myanmar border, and both northern and southern Laos. Samples collected in Cambodia and Vietnam bore fake stickers and none with fake holograms was found in Vietnam. The fake holograms all have mis-registration of the outer ring and although mis-registrations differ between all types, they have been made in the same way, suggesting the use of similar technology and machines (D. Pizzanelli personal communication) . ”

“ There are very few laboratories (only one in Asia/Pacific) with the appropriate reference collections and ability to analyse pollen assemblages in tablets and the work is very labour intensive and specialised and therefore expensive. Similarly, there are very few (less than ten) public laboratories or research groups with the adequate tools and human resources to perform detailed forensic chemistry of fakes and the equipment required is expensive. ”

“ In SE and East Asia there are at least 16 manufacturers of artemisinin and its derivatives [6] and millions of tablets are produced each year both for consumption in Asia and export to Africa. Artesunate is a crucial component of artemisinin derivative-based combination therapy, but is often used inappropriately as monotherapy outside of national malaria programmes.
Since 1998 an epidemic of multiple types of counterfeit artesunate tablets, both primitive and highly sophisticated copies, have affected patients with malaria in mainland SE Asia (Figures 1, 2, and S1) . ”

“ It is possible that this pollen was derived from the source plant for artemisinin, Artemisia annua, but the pollen does not allow speciation. Isoetes species spores (found in type 11) are endangered aquatic plants found in east and SE Asia [34] . The presence of spores and pollen in the tablets are more a reflection of source than flowering times as these palynomorphs have the ability to survive after dispersal for over a year and can be picked up during the processing of the tablets at any time of year. ”

“ Genuine samples were supplied by a manufacturer to provide a comparator. The authors examined the physical appearance of the packages and subjected the tablets to a wide range of chemical and biological tests that allowed an analysis of the components contained in the tablets.
When comparing the collected packages and tablets against the genuine samples, the researchers found considerable diversity of fake artesunate in SE Asia. Sixteen different fake hologram types (the stickers contained on packages meant to identify them as genuine) were found. ”

“ IMPACT holds international conferences and maintains a rapid alert system for counterfeit drugs.# The drug industry's anticounterfeit organization, Pharmaceutical Security Institute, works to develop improved systems to identify the extent of the counterfeiting problem and to assist in coordinating international inquiries. ”

“ However, the samples analysed did point to the apparent source of the fakes and it is unlikely that a larger sample size would have changed the outcome.
Further evidence was also obtained of the potential harm of these criminal products, both to individual patients and public health. A wide diversity of potentially dangerous wrong active ingredients has been described from fake artesunate tablets. The presence of unexpected pharmaceuticals, such as chloramphenicol and metamizole, may lead to inexplicable clinical syndromes such as bone marrow failure. ”

“ Until 2005 the golden foil and Myanmar Registration Number, characteristic of Guilin Pharmaceutical artesunate exported to Myanmar (Burma) , had not been used in the fakes—but samples with both these features appeared in 2006 (type 14) .
Hologram inspection demonstrated that the central image of the genuine hologram was made in ‘2D–3D' style from flat graphic line artwork [8] . Fake stickers such as type 2 were made from diffractive ‘rainbow' foil deeply etched to form an image. ”

“ All the counterfeits analysed from Vietnam contain calcite. The C and O stable isotope ratios of the calcite are consistent with a geologically high temperature intrusive or volcanic origin and not with a marine or terrestrial limestone or tap water precipitation origin (except one, type 12) . The presence of a small amount of aragonite could indicate marine limestone origin but heavy industrial crushing will convert non-marine calcite to aragonite, which is also found in open fissures in volcanic rocks. ”

“ Of 51 artesunate counterfeits that underwent mass spectrometry, a wide variety of unexpected ‘wrong' pharmaceuticals were found, including paracetamol (n = 24) , sulphadoxine (n = 18) , pyrimethamine (n = 11) , dimethylfumarate (n = 17) , erythromycin (n = 8) , erucamide (n = 5) , safrole (n = 6) , artemisinin (n = 10) metamizole (n = 10) , 2-mercaptobenzothiazole (n = 5) , chloramphenicol (n = 4) , metronidazole (n = 2) and chloroquine (n = 2) . In addition, four samples contained subtherapeutic amounts of artesunate within fake packaging; (Tables S1 and S2) [7] , [19] . ”

“ The task force membership includes international organizations, nongovernmental organizations, enforcement agencies, pharmaceutical manufacturers' associations, and drug and regulatory authorities. IMPACT's Web site notes that trade in counterfeit medicines is widespread and affects both developed and developing countries but is more prevalent in countries that have weak drug regulatory systems, poor supply of basic medicines, unregulated markets, high drug prices and/or significant price differentials. ”

“ Large pharmaceutical companies are active in investigating and facilitating prosecutions, but these actions are rarely reported publicly and smaller companies in the tropics do not have the resources to act. ”

“ There has been a trend of increased sophistication of the fake holograms but not of the fake stickers. Some confidential security features present on the genuine were not copied on the counterfeits perhaps because of the cost and difficulty of doing so or because the counterfeiters were ignorant of their presence. ”

“ These results should be interpreted with caution as the spore and pollen content could be indicative of either the place of manufacture, the source of the individual ingredients, or both, and be influenced by their wide wind dispersal and seasonality. Invertebrate remains and other organic materials embedded in the tablets were also identified.
Intelligence
Associations between location and chemical, biological, and packaging features were examined and geographical distributions mapped. Statistical analysis was performed using Stata v8. ”

“ This family is common throughout SE Asia but, except for the north east coastal plains of China, dies out in southern China north of the borders with Myanmar (Burma) , Vietnam, and Laos [27] . Three of the 11 samples containing calcite have little or no spore/pollen contamination suggesting that the contamination does not come from the calcite or its source. In terms of the different types of fake hologram/sticker, type 2 appears different from the others with no smooth trilete fern spores; type 1 contained little material but appears similar to type 3 ”

“ A subset of 27 fakes from this collection and five genuine packets, along with four fake (collected in Cambodia) and two genuine samples from the United States Pharmacopeia (USP) Drug Quality and Information Program, representing a sample of the oral artesunate labelled as made by Guilin Pharmaceutical available in 2005, also underwent detailed forensic chemical and botanical examination as part of the Jupiter operation. ”

“ Van Damme, W & Smithuis, FM, “Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials”, Trop Med Int Hlth 9: 1241–1246 1 2 3 4 Fernández, FM; Cody, RB; Green, MD; Hampton, CY & McGready, R, “Characterization of solid counterfeit drug samples by desorption electrospray ionization and direct-analysis-in-real-time coupled to time-of-flight mass spectrometry”, ChemMedChem 1: 702–705, pmid:16902921 ↑ de Veij, M ”

“ Qing, HR & Yang, C, “Multistage hydrothermal dolomites in the Middle Devonian (Givetian) carbonates from the Guilin area, South China”, Sedimentology 51: 1029–1051 ↑ Overall evaluations of carcinogenicity to humans, International Agency for Research on Cancer, . Retrieved on August 11, 2007 ↑ Mildenhall, DC, “Forensic palynology in New Zealand”, Rev Palaeobot Palynol 64: 227–234 ↑ Bryant, VM ”