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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 96, Num. 8, 2001, pp. 1185-1186
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Untitled Document
Mem Inst Oswaldo Cruz, Rio de
Janeiro, Vol. 96(8) 2001, pp. 1185-1186
BOOK REVIEW
Antimalarial Chemotherapy.
Mechanisms of Action, Resistance, and New Directions in Drug Discovery, Edited
by Philip J. Rosenthal, MD
Antoniana Ursine Krettli, PhD, MD
Centro de Pesquisas René Rachou-Fiocruz,
30190-002 Belo Horizonte, MG, Brasil, Fax: +55-31-3295.3115, E-mail: akrettli@cpqrr.fiocruz.br
Code Number: oc01227
Antimalarial Chemotherapy. Mechanisms
of Action, Resistance, and New Directions in Drug Discovery
Publisher: Edited by Philip J. Rosenthal, MD
Humana Press, Totowa, New Jersey, USA
396
pages, Price US$ 135.00
Malaria, one of the most ancient human diseases
affects 400 million people yearly and causes over 2.5 million deaths, mostly
children, in sub-Saharan Africa, where the disease is hyperendemic. Africa accounts
for more than 90% of the total cases, followed by India and Brazil, in disease
prevalence. In Brazil, malaria remains endemic in the Amazon, with 630,000 cases
per year, mostly in adults with a mortality rate of 225 last year, mainly due
to late diagnosis, to inadequate treatment or multi-drug resistant parasites.
Being an acute disease , with typical symptoms (headache, recurrent fever, among
others), individuals affected by malaria in endemic areas often self-medicate
with available antimalarial drugs or with medicinal plants.
The book on malaria chemotherapy meets high standards,
is enjoyable reading, and presents data on all antimalarial drugs, how they
work and mechanisms of drug resistance. It is an excellent guide for searching
for new molecules or working with the available ones. It has 20 chapters written
by specialists in the field, ideal for specialists, mainly chemists, but certainly
helpful to those catching up on the subject (parasitologists, pharmacologists)
and to graduate students working on drug discovery. There are not many groups
working on drug development, in Brazil, but the fact that several phytochemists
have become interested in antimalarial drug discovery and isolating molecules
from plants makes these scientists a target for the book.
The book is divided in three parts. Part I -
Introduction (5 chapters): the needs for new approaches to antimalarial chemotherapy;
the history of antimalarial drugs; the transport and routes in the Plasmodium
infected red blood cells; the food vacuole of the parasites; clinical and public
health implications of antimalarial drug resistance. Part II - Established antimalarial
drugs and compounds under clinical development (7 chapters): chloroquine and
other quinolines; 8-aminoquinolines; mechanisms of drug resistance; folate antagonists;
artemisinin and derivatives; atavaquone-proguanil combination; antimalarial
drug portfolio and research pipeline (ranging from promising lead compounds
to those still undergoing research). Part III - New compounds, new approaches
and new targets (8 chapters): novel quinolines; trioxanes and endoperoxides;
antibiotics, the plasmodial plastid organelle; antimetabolites; iron chelators;
protease inhibitors; inhibitors of phospholopid metabolism; and antimalarial
drugs based on parasite-induced transport.
The analysis on malaria situation worldwide (Chapter
1) shows that after 50 years of efforts, the control transmission is far from
ideal; the disease is still endemic in 56% of the exposed population. The main
problem for malaria control, at present, is the antimalarial drug resistance,
specially of P. falciparum, the most deadly malaria parasite, and also
of P. vivax, the most common in Brazil. Problems with monotherapy, how
drug combinations work, which drugs reverse chloroquine resistance (a hope for
chloroquine treatment) are in focus in the book. The approaches described to
the discoveries of antimalarial drugs are based on development of analogs from
existing agents (chloroquine, amodiaquine, mefloquine, Chapter 6); or on primaquine,
an 8-aminoquinoline which prevents late relapses by malaria parasites like P.
vivax. Its possible substitute, tafenoquine is not commercially available
(Chapter 7).
The antimalarial drug discovery so far has been
totally based on empiric approaches, and control of the disease still depends
on those discoveries from the first half of the twentieth century (Chapter 2)
i.e., (i) quinine, the first antimalarial drug discovered in the Western, in
the barks of Cinchona sp. (a South American tree), used as the basis
of most other antimalarial drugs of the quinoline group; and, (ii) artemisinine,
a compound isolated and characterized more recently by Chinese scientists from
the medicinal plant Artemisia annua, (based on its usage in China for
millenium). Curiously, both quinine and artemisine derivatives are largely used
to treat drug resistant parasites at present. The first report regarding decreased
sensitivity of malaria parasites to drugs was on quinine in 1910, in Brazil,
but such resistance is not comparable to that of chloroquine, although quinine
started being used 250 years ago and chloroquine during the Second World War.
Differences in the metabolism of both drugs, among many factors, such as why
drug resistance is acquired at different speeds and how to reverse it, have
not been elucidated.
The studies on mechanisms of parasite resistance
to quinoline drugs, as well as on drugs reversal of chloroquine resistance (Chapter
8), point to the mutations of pfmdr-1 and pfcrt, incriminated
as advantageous to the parasite, less important when malaria acquired immunity
exists (like in African hyperendemic countries). Immune adults may clear parasitemia
in cases of drug resistance, thus, the presence of pfcrt mutations per
se cannot predict drug resistance. How to optimize therapy of drug resistant
parasites with the existing agents like artemisinin-derivative combinations,
or with the generated mixtures like atavaquone-proguanil (malarone as one of
the most promising drugs) and the search for drugs from natural products and
their derivatives like quinine, artemisinin are described (Chapter 12) as well
as testing compounds like folate antagonists (Chapter 9) antibiotics (Chapter
15) and atavaquone (Chapter 17), active against other diseases.
During decades, chloroquine, a 4-aminoquino-line,
was largely used for treatment and prophylaxis of acute malaria with an amazing
impact on malaria control. The problems of chloroquine drug-resistant parasites
appeared in the early sixties, described in South East Asia and South America,
and appeared much later in the African continent. Drug resistant parasites have
now spread to most malaria affected countries, including Brazil. Here, the campaign
of malaria eradication, based on chloroquine, launched by the World Health Organization
and the Ministry of Health in the fifties, reduced transmission in most populated
areas, in the Northeast, Southeast and South, but not in the North which is
still endemic. As a consequence of drug resistance, the present situation is
alarming and new drugs are urgently needed. There is no ideal drug to replace
chloroquine or primaquine, there are no vaccines available and no way to block
the mosquito transmission at present.
The analyses of clinical and public health implications
of antimalarial drug resistance, diagnosis and measurements of drug resistance,
and treatment failure (Chapter 5) raise an interesting point about whether money
should be used to develop new drugs or to improve access to existing drugs.
The argument considers the meager resources allocated for malaria, its prevalence
in the developing world, the lack of financial incentives and the consequent
lack of interest by the pharmaceutical industry, a crude reality. Since resistance
is the prime determinant of a drug's life span, protecting its effective use
must be the number one priority in control programs.
Although not all chapters have summaries, they
all have an impressive number of references, for example Chapter 6, on chloroquine
and other quinoline antimalarial drugs, with 278 references! The book's references
are valuable and encompass most of the work published in malaria chemotherapy,
including the recent approaches to novel drugs but hardly cited any work from
Brazil, where randomized clinical trials have been performed (one example Duarte
et al. 1996 Am J Trop Med Hyg 54: 197-202) including on mefloquine, tatracycline,
artemisine derivatives as well as on experimental work on antimalarial activity
of medicinal plants and their molecules (reviewed by Krettli et al. 2001 Mem
Inst Oswaldo Cruz 96: 1033-1042).
Antoniana Ursine Krettli,
PhD, MD
Full Professor and Head of the Malaria Laboratory
Centro de Pesquisas René Rachou-Fiocruz
30190-002 Belo Horizonte, MG, Brasil
Fax: +55-31-3295.3115
E-mail: akrettli@cpqrr.fiocruz.br
Copyright 2001 Instituto Oswaldo
Cruz - Fiocruz.
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