Biomedical Engineering Reference
In-Depth Information
CH
3
N
+
O
OH
H
3
C
H
3
C
P
(CH
2
)
15
CH
3
O
O
21.4
FIGURE 21.4
Coni guration of miltefosin (
21.4
).
against cells performing phagocytosis such as the macrophages. Since the macrophages host the
parasites some selectivity in activity is obtained. The main mechanism of action of amphotericin
B is based on the amphiphilic nature of the molecule consisting of a lipophilic heptaene region
and a hydrophilic polyol region. The polyene region complexes with steroids in the parasite's mem-
brane. The hydrophilic polyol region form an ion channel permeable to small ions (Figure 21.3).
Some selectivity is obtained because the drug has higher afi nity for the double bonds of ergosterol
dominating in the cell membrane of the parasites than for cholesterol in the membrane of mam-
malian cell.
Serendipitously it was discovered that the cancer drug miltefosine (
21.4
) (Figure 21.4) is an orally
active drug against visceral leishmaniasis. Growth inhibition of leishmania parasites induced by
miltefosine is correlated with a change in the phosphatidylcholine to the phosphatidylethanolamine
ratio in the parasite's membrane. The selectivity might reside on different ways of formation of
phosphatidylcholine in vertebrates and in leishmania parasites.
21.4 MALARIA
Malaria is a leading cause of morbidity and mortality in the tropical world; some 300-500 million
of the world population are infected with malaria parasites, presenting 120 million clinical cases
each year. It is estimated that between 1.5 and 2.7 million persons die from malaria each year and
that 1 million of those are African children younger than 5 years. Among the more than 100 species
of
Plasmodium
parasites, only four can infect humans:
P. falciparum
(causing malignant tertian
malaria),
P. malariae
(quartan malaria),
P. ovale
(ovale tertian malaria), and
P. vivax
(benign tertian
malaria).
P. falciparum
is responsible for the majority of deaths.
The life cycle of the malaria parasite encompassing several stages is depicted in Figure 21.5.
A bite from an infected female mosquito belonging to the genus
Anopheles
introduces malarial
parasites in the sporozoite stage into human with the salvia, which contains agents that prevent
clotting of the blood. The sporozoites grow and multiply in the liver for about 5-15 days depend-
ing on the species. During this period, the patient has no symptoms. After having multiplied in
the liver, the parasites enter the bloodstream as merozoites and invade the red blood cells (the
erythrocytes). In the erythrocytes, the parasites proliferate and emerge as merozoites in a syn-
chronous manner in about 48 h (tertian malaria) or 72 h (quartan malaria). This results in the
clinical symptoms of the disease, namely, chills with rising temperatures, followed by fever and
intense sweating. In addition, there might be severe headache, fatigue, dizziness, nausea, lack of
appetite, and vomiting. Since the sporozoites catabolize the hemoglobin of the erythrocytes, a
heavy infection will also induce anemia. After eruption, some merozoites reinvade erythrocytes
and complete a new erythrocytic cycle. In the erythrocytes, some parasites change into game-
tocytes. After entering a mosquito stomach, blood meal gametocytes undergo another cycle in
the mosquitoes. Merozoites will be digested in the stomach. The falciparum parasites cause the
erythrocytes to adhere to the walls of capillary vessels resulting in reduced blood l ow to organs.
Reduced blood l ow to brain contributes to cerebral malaria, which can be fatal. Because of the
symptoms, some persons chronically infected with malaria, such as, the majority of Africans
perform poorly. Studies suggest that national income in some African countries was suppressed
by much as 18% because of malaria.
