In order to understand the current need for new drug development to combat the malaria parasite, the disease itself and previous treatment must be thoroughly understood. Unlike many other infectious agents of the current day, malaria has been recognized and treated for many centuries. Although the transmission of malaria was not understood and the disease was still unnamed, the infamous fever of malaria has been long familiar to many. Malaria was first mentioned in ancient Chinese writings in 2700 BC (Cox 606). In Greece, Hippocrates described malaria symptomology as early as 400 BC and later Shakespeare spoke of the debilitating Spanish fever that caused "one to shake" in Julius Caesar.
The word malaria comes from the Italian, mala meaning "bad" and aria for "air". The term was first coined by John MacCulloch in the 1827 publication of his essay, Malaria: An Essay on the Production and Propagation of this Poison (Honigsbaum 192), who, like many of his peers, recognized that this illness seemed to inflict those who spent a lot of time in swamps where the air was polluted.
Malaria the Parasite
The disease itself and mode of transmission were finally documented during the 19th Century, concurrent with the birth of Microbiology (Cox 606). The malaria parasite is a single-celled eukaryotic parasite (Weisman et al. 2006). It is believed, similar to the Human Immunodeficiency Virus that human malaria evolved to humans from primates (Cox 606), probably in South-east Asia. From there, it spread to Africa and finally Europe (Markell 79).
The life cycle of malaria in the human is complex, with stages in the human liver and blood stream as well as the body of the female Andopheles mosquito.
Malaria Prevention:
There are many different efforts that can be employed to prevent malaria, one of which is the use of anti-malarial drugs for prophylaxis. Many of the drugs used to treat malaria are also used as prophylaxis for the disease. The central difference between how these drugs are used as prophylaxis and treatment lies in the doses and intervals. The 2006 Sanford Guide to Antimicrobial Therapy currently recommends Chloroquine as the number one malaria prophylactic drug in regions where drug resistance to Chloroquine is not a problem. In areas where there is drug resistance to Chloroquine, the Atoroquone/Proguanil combination trademarked Malarone® is recommended. Second tier is Mefloquine hydrochloride or Larium® and thirdly, the drug Doxycyline.
Malaria Treatment:
It is important to note that doses and intervals of drugs vary significantly when used for prophylaxis versus treatment. For example, Malarone® is taken one tablet daily as prophylaxis throughout stay in malaria endemic region, but when used to treat uncomplicated malaria, 4 tablets are taken for three consecutive days (CDC 2006).
Issues of treatment versus prophylaxis are also complicated by the fact that Malarone®, for example, is only effective as a treatment if this drug is not being used as a chemoprophylaxis by the infected individual (CDC 2006) and with regards to drug resistance, combination therapy is highly recommended.
Quinine: Prior to World War I, before synthetic anti-malarial drugs were developed, Quinine was the primary treatment for malaria (O'Dowd 234). Quinine is derived from the bark of the Cinchona tree from South America and has been used for centuries by native populations who recognized the Cinchona's bark as an effective fever treatment. Carolus Lineaus gave the name Cinchona to the quinine tree in 1742, after hearing the romantic tale of how it healed Dona Francisca Henriques de Ribera, the fourth Condesa de Chinchon (Honigsbaum 21).
Many cultures have specific rituals and traditional treatments to deal with malaria and its symptoms; however, when many synthetic anti-malarials became available in the 1920s, the realm of malaria treatment was revolutionized.
Alebrin (Mepacrine®): Alebrin was developed in the 1930s and is known for its use both as prophylactic and treatment during World War II for soldiers in South and East Asia. However, the side effects of this drug were such that it was removed from the market soon after (Lambert, Malaria: Past and Present).
Chloroquine: During World War II, Chloroquine was developed, which remained the principle treatment until widespread drug-resistant strains of P. falciparum malaria began emerging in the 1950s (Markell 97). Chloroquine is relatively inexpensive as well as being successful both as prophylaxis and treatment. Over the second half of the past century more drugs were developed, many of them very similar to or even derivatives of quinine and chloroquine.
Mefloquine (Larium®): This drug, famous for its hallucinogenic side effects, was developed in 1971 and is structurally very similar to quinine. Larium® is used both as a malaria prophylactic, when it conveniently needs to be taken only once a week, and also as a treatment. It is also important to note that because Larium® is so similar to quinine, the two cannot be used concurrently.
Halofantrine (Halfan®): Developed in the 1980s, Halofantrine is another anti-malarial associated with psychological side effects. Unfortunately the half-life of this pharmaceutical is only a few days, so its use as a prophylactic is not feasible and resistance to Halofantrine is becoming somewhat widespread (Lambert Malaria: Past and Present).
Doxycycline: Doxycycline is another anti-malarial that is recommended both for prophylaxis and treatment. It is an antibiotic and is used to treat many other pathogens including anthrax.
Atovaquone/Proguanil HCl (Malarone®): Malarone® was put on the market in the 1990s and remains popular. Clinical trials demonstrate that Malarone® is 95% effective against P. falciparum malaria that otherwise proved resistant. This particular drug is actually a combination of Atovaquone and Proguanil (Lambert Malaria: Past and Present). Unfortunately, Malarone® is a very expensive drug in America costing on average $7 per pill. Another consideration about the use of Malarone® as a prophylactic is the risk of developing drug resistance at a faster rate.
Artemisinin and ACTs: Today, the most effective drugs for the treatment of malaria come from a little herb nicknamed ‘Sweet Annie.’ Artemisinin is actually a Chinese herb used in traditional medicine, which comes from sweet wormwood (Purcell, 2004) and is active in a group of substances, the two most common of which are called Artesunate and Artemether. These are the key drugs in Artemisinin Combination Therapy (ACT), which is the most common malaria therapy employed worldwide today (WHO 2006). It was reported in 2004 that Chloroquine treatment rates fail 64% of the time; sulfadoxine-pyrimethamine fails 45% of the time, while ACTs fail less than 10% of the time (Attaran). Another issue that has recently emerged with Artemesinin treatment is the problem of counterfeit drugs.
Counterfeit Anti-malarial Drugs:
A 2006 Warning Sheet reads, "At least fourteen different types of fake Artesunate are being sold in mainland South East Asia". Features of counterfeits mentioned in this report include poorly printed bar codes on packets and containers and fake emblems.
Companies produce these counterfeits and then profit off the sales of fake medications that contain little or none of the advertised treatment. With a disease such as malaria, this means that innocent people do not get the treatment that they need and many have died already because of this.
Drug Resistance and the Need for New Anti-malarial Drugs:
Drug resistance is a growing problem with anti-malarial Drugs. The malaria parasite, particularly P. falciparum, continues to develop resistance to increasingly more anti-malarial compounds. Now, as "chloroquine-resistant strains of P. falciparum are now common in most malaria endemic regions" 
(Weisman et al. 2006), there is a demand for alternatives. Drug resistance is in part due to improper diagnosis and adherence or overuse of anti-malarial drugs, such as for prophylaxis. In some areas of the world, the strains of malaria are resistant to nearly every anti-malarial drug available (Olliero & Blolando). This issue is complicated further by the fact that the majority of malaria cases occur in regions such as Sub-Saharan Africa and are outside the range of easy clinical care. Consequently, drugs are sold over the counter or the black market and contribute to increased resistance. Because of this, "the need to discover and develop new anti-malarial therapeutics is overwhelming" (Weisman et al. 2006). The human factors, aspects such as easy compliance, low-cost, availability, and perceived acceptability, are increasingly important to consider in drug development.
Combination therapies:
Within the malaria community, mono-therapy is currently considered inappropriate malaria treatment (Hein 1993). This is because as discussed previously, as new drugs are employed to deal with this disease, malaria becomes resistant to more drugs. The strategy of combining drug treatments has become widely accepted in order to “improve efficacy, delay development and selection of drug-resistant parasites and thus prolong the therapeutic life of existing anti-malarial drugs” (WHO Consultation on Anti-malarial Combination Therapy 2001).
One of the most common types of combination is ACT, which uses Artemisinin and another anti-malarial. Some combinations recommended by the WHO include the Artemether/lumefantrine combination, Artesunate (for 3 days) plus sulfadoxine/pyrimethamine (SP) in areas where SP efficacy is high and Amodiaquine plus SP, in areas where efficacy of both drugs remains high—mainly limited to countries in West Africa. Cheaper alternatives include combinations of chloroquine, mefloquine, or pyronaridine-artesunate (WHO Consultation on Anti-malarial Combination Therapy 2001).
Current Drug Development Strategies:
Scientists are currently attempting to find new successful and cost-effective treatments options. However, as far as new anti-malarial drug development, it is important to keep in mind that the actual success rate of new drugs is low. This is demonstrated by the fact that only one new anti-malarial chemotherapeutic has been approved for clinical use by the FDA in the last decade, which is Malarone® made by GlaxoSmithKline.
Artemesinin Analogs: trioxane-based compounds
Dr. Gary Posner of the Johns Hopkins Malaria Research Institute is currently developing analogs of Artemisinin. He hopes that these will be more effective treatments for drug resistance malaria while exhibiting fewer side effects due to lower toxicity. These drugs work by activating ferris iron (II) in the malaria-infected human red blood cells.This activates the peroxides in the drug, which causes a "cascade of interactions that leads to cytotoxic intermediates of which one or more will kill the malarial parasite" (Posner, 5/22/07). Dr. Posner’s newly designed drugs are designed to be "chemically robust" because they have two trioxane based "warheads", one of which will likely activate the cytotoxic cascade. These compounds are also very stable, increasing their potential shelf lives and effects. Posner's research group has thus far been able to successfully test some of their drug analogs in mice and the drugs will have to undergo a number of other tests in larger animals and eventually humans before they make it onto the market. This "bench to bedside" process could take anywhere from 5-10 years, according to Dr. Posner. Despite the many hurdles these Artemisinin analogs will have to overcome before they are available for use, Dr. Posner is hopeful saying, "during drug development, we get either red flags and green flags. So far only gotten green flags, but we are still at the beginning of the race" (Posner, 5/22/07).
Artemesinin Analogs: trioxolane-based compounds
At the University of Nebraska, Dr. Vennerstrom is a bit further along in the process. Vennerstron researches in a partnership with Monash University of Australia, The Swiss Tropical Institute and F. Hoffman-LaRouche, Switzerland.Current findings on trioxolane-based compounds (as opposed to the trioxane based compounds that Dr. Ponser is working on) have afforded Dr. Vennerstrom and his team extensive publicity.The new compounds are promising because they last for a long time inside the body and since growing natural Artemisinin takes a very long time, the hope is that synthetic drugs will be available at a much greater quantity than the natural drugs (Amitabh, 2004).These synthetic peroxide drugs will address problems with current natural Artemisinin, which include a lack of chemical purity, high cost, decreased success if patients do not finish treatment and only a short time in the body (Vennerstrom, 2004).According to Vennerstom, "These compounds are not only more rapid and effective; they also avoid all the problems inherent to the extraction of active ingredients from natural plant sources" (qtd. Vennerstrom, 2002).
“Novel Scaffolds” of Pre-existing Anti-malarial Drugs
Jennifer Weisman of the University of California, San Francisco comments, "the current state of anti-malarial chemotherapeutics is particularly bleak for those living in malaria endemic regions of the world because of the low economic incentive for drug development and the rise of resistance strains" (Weisman et al. 2006).
Her work includes the exploration for new malaria treatment alternatives through the examination of many diverse compounds to identify "novel scaffolds" (Weisman et al. 2006). As Weisman and others at the DaRisi Lab research drugs that are currently on the market, their efforts are expedited by the fact thatextensive data is available about these substances. Through several studies of this sort, Weisman et al. have been able to identify many compounds among previously known drugs that inhibit growth of Plasmodium falciparum in the human erythrocyte. Specifically these drugs included 19 therapeutics. Interestingly enough, several of these compounds were found be successful against Trypanosoma brucei, another devastating parasite, which may enhance their clinical value.