Estructura del salario y costes de la mano de obra directa en el sector de la

Generally, the same screening methods are used for both synthesised compounds and natural products. The main difference is in the approach that is followed. As discussed earlier, some natural product screens begin by screening large database of natural products to identify leads whilst others involve choosing compounds based on ethnopharmacological anecdotal evidences and might begin with human studies (reverse pharmacology). Which ever approach is followed, there are some drawbacks to the current methods used currently in natural product research. In malaria research for example, there is a high successful hit rate,

with several compounds showing low IC50 values (Cerventes et al., 2012). The main

drawback is there is no standard for antimalarial screening of natural product remedies and

there is no bench mark IC50 value that malariologist could refer to when investigating new

compounds.

Several researchers have attempted to address these issues. Wells et al., 2011 suggests that

natural product research should be replaced by a patient data led approach which should involve standardised clinical observational system of ethnopharmacological compound used in patients. This approach is in support of previous suggestions by Chen Guofu in 1952. He suggested that the starting point for investigation of natural products should be by checking the activity in humans. This view faced various objections at the time, especially by clinicians and the international community whose major concerns were using unpurified

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products in humans. Over the years, several factors have led to an acceptance of Guofu’s suggestion. The biggest milestone is the acceptance by authorities such as the European medicines agency (EMA), the United States Food and Drug Agency (US-FDA) and WHO. The main reason for the acceptance of the view was that since patients and communities take these medicinal herbal products, it is a public health concern/responsibility to validate their efficacy. Below is a flow chat of Wells suggestions.

Fig 1.26: Natural product screening: Showing the developmental stages for screening a natural product suggested by Wells, 2011 using a reverse pharmacology approach. The natural product is chosen based on the ethnopharmacological usage and clinical observation begins.

With regard to natural product research, researchers tend to focus on purification and isolation of the active compound in an extract. Natural products usually exist as complex mixtures of various phytochemical compounds. These compounds sometimes act in synergy

and the combination gives the total overall effect seen in an extract (Ulrich-Merzenich et

al., 2010). Hence by purifying the extract, it is likely that some important compounds are

lost along the way. In the case of malaria, the parasite has developed resistance to all new antimalarials that have been developed including artemisinins. Although a number of antimalarials are natural product derived compounds, all have actually gone though the same process of isolating the active compound. The parasite is probably able to develop this resistance due to the simplistic nature of the compounds it is exposed. This theory can be substantiated by looking back at the history of quinine use. Quinine was used in its natural form for centuries with no issue of resistance. Chloroquine was successfully isolated in the

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1950’s and it only took 10 years for resistance to develop. As mentioned earlier, fansidar, a combination drug of pyrimethamine and sulfadoxine, also developed resistance less than 6 years after its introduction. Another example is mefloquine and the list goes on. Most of these antimalarials are natural product derived. Hence these examples substantiate the

argument that the Plasmodium is too complicated for simple isolated compounds and might

have the ability to evolve quickly and develop resistance. This point can also be emphasised using the artemisinins as a case study. Like quinine, artemisinins have a very long history of use. There has never been a record of resistance. After successful development of artemisinins for malaria, (in a semi-synthetic form) they have remained the last hope over decades. Recent reports have however shown that resistance has developed in these drugs. Fig 1.27 shows is a timeline representation of the development of resistance after isolation of both quinine and artemisinin.

1650 Quinalones 1950 2012 Artemisinins 2011 Malaria parasite resistance to quinine and artemisinin

1970

Fig 1.27: A Schematic representation of resistance drug development timeline for malaria: Showing the timeline for the development of resistance of antimalarials after active compound isolation of some antimalarial natural products. The traditional usage of the drug is represented by the green horizontal line whilst point of drug isolation is represented by the vertical green line. Resistance development is represented by the red horizontal line. Malaria parasite resistance developed within 10 years after chloroquine was isolated from the quinolones. The development of resistance took longer with the artemisinins probably owing to their use as semisynthetic drugs and as part of combination therapy regimes.

1960 Antifolates

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Antifolate drug resistance developed in less than 5 years after it was isolated as a pure compound.

So far, there has been no successful competitor to the artemisinins. In holding on to this last hope, the WHO has mandated its use as a combination therapy (earlier discussed). The artemisinins started to be used in a ‘semisynthetic’ form around the 1970s. These drugs are till the cornerstone on antimalarial therapy, thirty years on. In 2006 the first clinical case of resistance was reported in the Thai-Cambodian border (WHO report, 2015). It is thought that resistance might have began as early as 2001 when the drug was used as a monotherapy. The question is why have the artemisinins been successfully used for much longer the quinine? The answer could well lie in the fact that it has been used in a semisynthetic form. Artemisinin has a very complex structure which has kept several chemist on their toes. It has not been successfully synthesised to a commercially viable form and for this reason, it has been used in a semisynthetic form. This could be one of the possible reasons for the delayed resistance seen with these class of drugs. Fig 1.28 shows some structures or artemisinin related compounds.

Fig 1.28: Artemisinin related compounds: Showing the complex structures of artemisinin related products. (Source: http://www.scielo.br/scielo)

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Fig 1.29: Semi-synthetic production of artemisinin: Showing the production of a semi- synthetic form of artemisinin though cellular engineering, allowing for a faster production of the medicine. (Source: http://www.jscimedcentral.com/Cell/cell-1-1002.php).