Resistance to Choroquine

The parasitic resistance to medications is a great interest topic due to the high morbidity and mortality associated. In this document a concept of parasitical resistance to Choroquine (CHL) is revised and some ideas of its mechanism, a possible focus is also presented to the solution of the problem by searching new anti-malarial agents through etnopharmacological methods.

Parasitic resistance is the capacity of survive to greater chemotherapeutic dose than normal. Emergence of strains of P. falciparum that are resistant to CHL has been observed since shortly after its introduction to therapeutics as antimalarial agent. During the past thirty years resistance to CHL has become widespread in all endemic areas where it is prevalent. Resistance appears to emanate from spontaneous chromosomal point mutations. Resistant mutants are able to survive in the presence of antimalarial agents. It is well recognized that erythrocytes harboring resistant strains of malaria are able to concentrate less CHL than sensitive strains. Indirect experimental evidence to resistance came from the finding that the CHL resistant phenotype is characterized by an increase in drug efflux rate compared to sensitive parasites. Resistant parasites pump CHL out 40-50 times faster than sensitive parasites.  When the cells become resistant to a wide variety of antimalarials and present cross-resistance, it is called multidrug resistance (MDR).Then the resistance or lower concentration to the drug may me caused partly by a decrease in the influx of the drug or an increase in the efflux. In resistant P. falciparum verapamil and other calcium channel blockers slows the efflux of CHL, but they do not have that effect in sensitive strains.

         Contrary to these findings there is reported that resistance to CHL could be multigenic and that there is a determinant of resistance that does not involve multidrug resistance.

Fig 1 Giemsa-stained thick blood films showing early trophozoites of P. falciparum (Courtesy JK Baird)

In malarial endemic places CHL and related quinoline derivatives are essentially useless. In addition, CHL resistant strains of P. vivax are now being reported in both Southeast Asia and South America. Where malaria has become resistant to CHL and other chemotherapeutic agent alternative drugs such as mephloquine, halofantrine, artemisin derivatives, and the combination of pyrimethamine and sulfadoxine (Fansidar) are used.  There is genetic diversity among wild strains of P. falciparum that infect humans in a given area. Thus there are differences in their sensitivity to CHL and other antimalarial agents.

There were an estimated 247 million malaria cases among 3.3 billion people at risk in 2006, causing nearly one million deaths, mostly children under five years of age. One hundred six countries were endemic for malaria in 2009, 45 within the WHO African region.

This worsening situation can be explained by resistance of P. falciparum to the current antimalarial drugs, lack of new therapeutic targets, unaffordability and poor quality of antimalarial drugs and their bad storage under tropical conditions. 

Then an urgent need for the development of new anti-malarial agents faces the scientific community. Traditional medical knowledge based on the use of natural products from plants is a promising basis for discovering new drugs. It is estimated that 80% of many developing countries population still use plant-based traditional medicines. These natural products and their derivatives represent almost half of the drugs approved since 1994 and more than 30% of the current anti-malarial market.

In this context, an ethnopharmacological survey of medical plants was carried out in Senegal and data were collected on some plants traditionally used for the treatment of malaria and fevers.

The plant extract and fractions revealed anti-plasmodial activity (IC50<5 microgr/mL) with no toxicity. Anti-plasmodial activity and toxicity of I. senegalensis are reported for the first time and showed promising results in malaria field research.

Journal Reference

Serigne O Sarr , Sylvie Perrotey , Ibrahima Fall , Said Ennahar , Minjie Zhao , Yerim M Diop , Ermanno Candolfi  and Eric Marchioni, 2011, Icacina senegalensis (Icacinaceae), traditionally used for the treatment of malaria, inhibits in vitro Plasmodium falciparum growth without host cell toxicity, Malaria Journal 2011, 10:85doi:10.1186/1475-2875-10-85

http://www.malariajournal.com/content/10/1/85

Risk of cancer and Table sugar

In this review is summarized some findings related to the consumption of sugars and cancer risk, and considers whether current intakes of sugar could be harmful to health. The table sugar and sweeteners are historically associate products with the beginnings of the human cultures.  The use of honey is documented in a recipe against cough that appears in a cuneiform script and goes back to V B.C. The composition of honey is fructose 41% and glucose 36% and was often used as sweetening.  The use of table sugar seems to have its origin in the India since ancient times.  Besides having psychological implications in behavior of who consume it, only at the present time has been related with health concerns.

         Many countries set quantitative targets for added sugars, justifying this by expressing alarm about the likely impact of sugar on weight control, dental health, diet quality, metabolic syndrome or cancer. Diet adequacy appeared to be achieved across sugar intakes of 6-20% energy. Studies on metabolic syndrome reported no adverse effects of sugar in the long-term, even at intakes of 40-50% energy.

                                                              Fig 1 Cuneiform recipe

Sugar-sweetened carbonated beverages, called soft drinks, and juices, which have a high glycemic load relative to other foods and beverages, have been hypothesized as pancreatic risk factors (PCR).  Mueller and others investigated whether higher consumption of soft drinks and juice increases the PCR in Chinese men and women. Regular consumption of soft drinks may play an independent role in the development of pancreatic cancer (1). Results in another study among men, greater intakes of total and specific sweets were associated with PCR. Sweets were not consistently related with increased PCR. In contrast low-calorie soft drinks were associated with increased risk among men only (4).

Prostate cancer PC is the most common male malignancy in the Western world. PC risk is related to age, race, and family history. Environmental factors, including dietary factors, have also related to PC, but this issue remains undefined. 

Some epidemiologic studies have reported a positive association between breast cancer risk (BCR) and high intake of sweets, which may be due to an insulin-related mechanism.

Also high-sucrose consumption is related with increased risk of human colon cancer (HCCR).

No association was found with intake of total proteins, total fat, monounsaturated fats, polyunsaturated fats, monosaccharides, and total carbohydrates. The findings provide evidence that a diet low in trans fat could reduce PC risk. Intake of sucrose and disaccharides was also related to risk of PC, mainly from cereals, cookies, chocolate, and milk (2). The evidence for colorectal cancer suggested an association with sugar, but this appeared have been confounded by energy intake and glycemic load (3).

                             Fig 2 Types of cancer risk for consumption of sugar

The existence of an association between consumption of a food grouping that included dessert foods, sweet beverages, and added sugar with BCR was confirmed. The association with desserts was stronger among pre-menopausal women than post-menopausal, although the interaction with menopause was not statistically significant. This study indicates that frequent consumption of sweets, particularly desserts, may be associated with an increased BCR.

Another Wang preclinical research indicated that high-sucrose diet (vs. cornstarch) promote intestinal epithelial cell proliferation and tumorigenesis as well as increase serum glucose and hepatic IGF-I mRNA levels in APC(Min) (5).

The results provide limited reinforce for the hypothesis that sweets or sugars increase cancer risk (PCR, PC, BCR, HCCR) because some are positives and others do not support that added sugar or sugar sweetened foods and beverages are associated with overall cancer risk (6). Further research is needed on the possible associations of carbohydrates with cancer risk (7).

Reference

1.  Mueller NT, Odegaard A, Anderson K, Yuan JM, Gross M, Koh WP, Pereira MA. (2010) Soft drink and juice consumption and risk of pancreatic cancer: the Singapore Chinese Health Study. Cancer Epidemiol Biomarkers Prev.  Feb;19(2):447-55.

2.   Hu J, La Vecchia C, Gibbons L, Negri E, Mery L. (2010) Nutrients and risk of prostate cancer. Nutr Cancer. 62(6):710-8.

3.    Ruxton CH, Gardner EJ, McNulty HM. (2010) Is sugar consumption detrimental to health? A review of the evidence 1995-2006. Crit Rev Food Sci Nutr. Jan;50(1):1-19.

4.         Chan JM, Wang F, Holly EA. 2009) Sweets, sweetened beverages, and risk of pancreatic cancer in a large population-based case-control study. Cancer Causes Control. Aug;20(6):835-46. Epub 2009 Mar 11.

 5.   Wang B, Bobe G, LaPres JJ, Bourquin LD.(2009) Dietary carbohydrate source alters gene expression profile of intestinal epithelium in mice. Nutr Cancer. 2009;61(1):146-55.

6.    Bao Y, Stolzenberg-Solomon R, Jiao L, Silverman DT, Subar AF, Park Y, Leitzmann MF, Hollenbeck A, Schatzkin A, Michaud DS.(2008) Added sugar and sugar-sweetened foods and beverages and the risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study. Am J Clin Nutr. 2008 Aug;88(2):431-40.

7. Key TJ, Spencer EA. (2007) Carbohydrates and cancer: an overview of the epidemiological evidence. Eur J Clin Nutr. 2007 Dec;61 Suppl 1:S112-21.