Fever and Chill Pills

There’s a new medication in the works for malaria. Are you excited? Well, you should be, because many of the existing ones are kind of scary. Not only that, but signs of resistance to artemisinin (the most recent addition to the treatment options for the disease) have already been reported in Cambodia. The Thailand-Cambodia border is the region that spawned chloroquine-resistant malaria 50 years ago. Prior to that, Chloroquine had been effectively treating malaria since the 17th century, but nowadays it is useless against all but a few regions’ malaria parasites. Drug resistance is a big concern in treating and preventing malaria.

Before you start freaking out, I should backtrack and explain a few things. To begin with, if you’re reading this from the United States (or some similarly climated and industrialized nation) you’re not in any immediate danger. Most cases of malaria in the U.S. are diagnosed in people returning from trips to parts of the globe where the disease is endemic, often to visit family members. Even foreign travel may not put you in harm’s way. Urban and costal areas are often trouble-free while rural villages just a few hours away may be considered high-risk destinations. This is in part because the anopheles mosquito, which spreads the disease, will only travel a distance of about 1 km over its entire life.

Malaria is caused by a protozoan parasite, which makes the creation of a vaccine more challenging than for a smaller organisms such as bacteria and viruses. There are 4 main species of parasite that cause malaria in humans. This article will focus on Plasmodium falciparum, which accounts for the most lethal form of the disease. P. falciparum has a complex and disgusting life cycle. It splits its time between two hosts - humans and mosquitoes. It needs both of these animals in order to survive and replicate. Mosquitoes spread the mature form of the parasite to humans, but it is in humans that gametocytes (the first stage of reproduction) are generated. These reproductive cells then infect additional mosquitoes* where they grow into gametes, fuse into a zygote and mature into a parasite ready to infect more humans. It’s the circle of life.

P. falciparum ‘s stint within the human body is also divided into 2 portions. Initially, it finds its way into the liver, where it replicates within the hepatic cells. Eventually these rupture and the now copious parasitic cells make their way into the blood and infect the red blood cells. The process in blood cells is similar to that in liver cells – replication which leads to bursting of the cell and release of the parasite into the blood. Some of the released parasitic cells will infect more red blood cells, while others are the gametocytes that can now infect blood-sucking mosquitoes. Only the blood stage of parasitic infection produces symptoms†, and most malaria medications focus on killing this stage of the parasite. Treatment and prevention of malaria are not such different concepts. You should be horrified to know that with 2 of the 3 most commonly used prophylactics‡, even if you dutifully start a course of prescribed antimalarial drugs before ever stepping foot in your disease-ridden travel destination, P. falciparum can still set up camp in your liver and reside there comfortably until it enters your blood. This is the reason your doctor may tell you to continue taking the medication for several weeks after you return. You’re essentially waiting for the liver-stage parasites to hatch before the pills can kill them.

The newest antimalarial hopeful is a class of chemical compounds called spiroindolones. A study on one of these, the whimsically named NITD609, was recently published in Science and found the drug to be effective in killing P. falciparum in rodents. Sadly, this drug too acts only on the blood stage and not the liver stage of the parasite. More reassuring is that its mechanism of action (suppression of protein synthesis) is different enough from that of existing antimalarials that the authors were hopeful it would not be subject to the drug resistance threatening the efficacy of these. The manner in which this novel antimalarial was identified also represents a return to an older method of drug development. In the wake of easier availability of genomic data, much research over the past decade had focused on understanding the molecular structure of the parasite and attempting to identify specific targets for possible medicines. The older approach focused on whole parasites and worked by sequentially blasting said parasites with everything from the chemical library until something worked. While it doesn’t tell us the exact genetic target being hit, this approach has the advantage of being considerably faster.

Despite the potentially encouraging news, NITD609 and friends still need further safety testing before they will be ready for human clinical trials. In the meantime, those of you traveling to Thailand or Haiti or wherever will have to make do with the currently available options. In addition to Malarone, whose pros and cons are discussed in the notes, the other 2 drugs recommended for travelers wishing to avoid falciparum malaria are Mefloquine hydrochloride (aka Lariam) and Doxycycline hyclate (aka Vibramycin) each with its own charming side effect profile. Doxycycline comes with the unglamorous but reasonably manageable woes of sun sensitivity (bring a hat) and possible yeast infections. Mefloquine is a bit more intriguing. Its most widely-publicized side effects are nightmares (common) and psychosis (rare).§ Because these side effects are so potentially disagreeable to travelers, the drug is started a few weeks prior to leaving home to ensure that it can be “tolerated”. A case report in Psychosomatics tells of a 25 year-old woman who experienced paranoid delusions and both auditory and visual hallucinations while taking the drug during a trip to Nigeria. She came to believe that her husband was the Devil and suffered auditory hallucinations that included hearing “conversations between Heaven and Hell”. Keep in mind that psychosis is not the standard result of Mefloquine ingestion, but one can see how this might pose more hindrance than sunburn and stomach aches.

By now you’re probably wondering which, if any, antimalarial drugs you should take for your upcoming trek through the jungle. Thankfully for me, I am not your doctor and needn’t worry myself over this. The Center for Disease Control has a handy guide to risk assessment by country on their website. Whatever you decide, I’d recommend bringing along a lot of bug spray. Bon Voyage.

* The mosquitoes do not appear to suffer any ill effects from their infection with the malaria parasite and are often referred to as a “vector” for the disease. But I try not to marginalize insects, so I’m granting them “host” status here. It seems more dignified.

† Clinical malaria consist of fever, chills, sweating, nausea and vomiting in its “uncomplicated” form, and in its severe form can also feature anemia, respiratory distress, kidney failure, various neurological abnormalities, etc, etc, and also death. It’s no fun. Furthermore these symptoms repeat in attacks as the parasite runs through its cycle of bursting and then re-infecting blood cells.

‡ Atovaquone-proguanil (aka Malarone) is effective against the liver stage of the P. falciparum parasite. It’s expensive but pretty low on side effects as far as malaria pills go. (Nausea, vomiting, stomach pain, headache, or diarrhea, may occur….Ask your doctor about it…)

§ Mefloquine got a lot a bad press back in 2002 when it was considered as a possible cause for a rash of suicides and spousal homicides that occurred over the course of a single summer at the Fort Bragg military base.

Who told you this?

Center for Disease Control website: www.cdc.gov

World Health Organization website: www.who.int

Rottman, M. et al. 2010. “Spiroindolones, a Potent Compound Class for the Treatment of Malaria.” Science 329: 1175-1180.

Wells, T.N.C. 2010. “Is the Tide Turning for New Malaria Medicines?” Science 329: 1153-1154.

Freedman, D.O. 2008. “Malaria Prevention in Short-Term Travelers.” New England Journal of Medicine 359: 603-612.

White, N.J. 2008. “Qinghaosu (Artemisinin): The Price of Success.” Science 320: 330-334.

Kukoyi, O. and Carney, C.P. 2003. “Curses, Madness, and Mefloquine.” Psychosomatics 44: 339-341.