Biomedical Engineering Reference
In-Depth Information
to explain its effects on
-cells undergo apoptosis, caspase-3
activity is high. However,
SRR-15
reduced the caspase-3 activity in a dose-dependent
manner in apoptotic
-cell biology. When
-cell apoptosis has been shown to
decrease mitochondrial membrane potential, and
SRR-15
restored mitochondrial
membrane potential, suggesting that
-cells. Cytokine-induced
-cells are protected from cytokine-induced
apoptosis. The most important physiological function of
-cells is to secrete insulin
on stimulation with glucose. However, when
-cells were treated with cytokines,
glucose-stimulated insulin secretion (GSIS) was abolished after two days. It is remark-
able that when 5
Mof
SRR-15
was used, GSIS returned to normal levels even in the
presence of cytokines. These data provide convincing evidence that
SRR-15
protects
-cells from apoptotic cell death induced by cytokines.
17.3 CASE STUDY 2: IDENTIFICATION OF ANTIMALARIALS
Malaria is a devastating worldwide parasitic disease that affects approximately 225
million people annually, killing 781,000 mostly young children in sub-Saharan Africa
[27]. The disease is caused by five different species of malaria parasite,
Plasmodium
falciparum
being the most virulent and deadly [28]. In terms of chemotherapy, a major
challenge with this disease is resistance [29]. Drugs effective against the parasite lose
their potency over time, with resistance to some drugs being documented almost as
soon as it has been introduced [30]. This has led us to our current situation, where
the parasite has gained resistance to almost every antimalarial developed. The only
exceptions are artemisinin and its derivatives, but even here the signs are worrying,
as populations in certain areas have experienced reduced clinical response to this
drug, although detectable resistance has not been found [31]. Given the lack of an
effective vaccine, it is imperative that chemotherapy remains a frontline solution to
this problem.
While the search for antimalarials is centuries old, no new class of drug has been
introduced into clinical practice since 1996 (Figure 17.7) [28]. The high risk of
parasite resistance to current therapies highlights the need for additions to our current
arsenal. An additional challenge in antimalarial development is safety, as the most
vulnerable malaria patient populations are young children and pregnant women with
limited access to medical supervision [32]. For the same reason, there is a need for
antimalarials to be orally bioavailable for ease of administration, and for the cost
of the drug to be low. A chemist approaching the antimalarial drug discovery effort
is faced with these harsh realities plus the fact that these parasites have overcome
almost every chemotype presented to them. The question then becomes: What is a
starting point for a drug discovery program? Many of the drugs in development are
based on existing pharmacophores (e.g., aminoquinolines and peroxides), chemically
modified to improve upon their predecessors. It has been estimated that the number of
distinct small-molecule scaffolds with genuine in vivo activity against
P. falciparum
is fewer than 30, with most of these not suitable for the clinic [33]. Although these
compounds may represent an important strategy in the treatment of malaria, it has
become increasingly difficult to manipulate these molecules to overcome resistance.
It would be preferable to discover chemotypes with novel mechanisms of actions [34],
