Artemesinin and derivatives
Artemesinin is a Chinese herb (inghaosu)
that has been used in the treatment of fevers for over 1,000 years,
thus predating the use of Quinine in the western world. It is derived from the
plant
Artemisia annua, with the first documentation as a successful
therapeutic agent in the treatment of malaria is in 340 AD by
e Hong in
his book Zhou Hou Bei Ji Fang (A Handbook of Prescriptions for
Emergencies).
The active compound was isolated first in 1971 and named Artemsinin. It is a
sesquiterpene lactone with a chemically rare peroxide bridge linkage. It is
this that is thought to be responsible for the majority of its anti-malarial
action. At present it is strictly controlled under WHO guidelines as it has
proven to be effective against all forms of multi-drug resistant P.
falciparum, thus every care is taken to ensure compliance and adherence
together with other behaviours associated with the development of resistance. It
is also only given in combination with other anti-malarials.
- Artemesinin has a very rapid action and the vast majority of acute
patients treated show significant improvement within 1-3 days of receiving
treatment. It has demonstrated the fastest clearance of all anti-malarials
currently used and acts primarily on the trophozite phase, thus preventing
progression of the disease. It is converted to active metabolite
dihydroartemesinin that then inhibits the
sarcoplasmic/ndoplasmic
reticulum
Calcium ATPase encoded by P. falciparum. On the first day of
treatment 20 mg/kg should be given, this dose is then reduced to 10mg/kg per
day for the 6 following days. Few side effects are associated with
artemesinin use. However, headaches, nausea, vomiting, abnormal bleeding,
dark urine, itching and some drug fever have been reported by a small number
of patients. Some cardiac changes were reported during a clinical trial,
notably non specific ST changes and a first degree
atrioventricular block (these disappeared when the patients recovered
from the malarial fever).
-
Artemether is a
methyl ether derivative of Dihydroartemesinin. It is similar to
Artemesinin in mode of action but demonstrates a reduced ability as a
hypnozoiticidal compound, instead acting more significantly to decrease
gametocyte carriage. Similar restrictions are in place, as with Artemesinin,
to prevent the development of resistance, therefore it is only used in
combination therapy for severe acute cases of drug-resistant P.
falciparum. It should be administered in a 7 day course with 4mg/kg
given per day for 3 days, followed by 1.6 mg/kg for 3 days. Side effects of
the drug are few but include potential neurotoxicity developing if high
doses are given.
-
Artesunate is a
hemisuccinate derivative of the active metabolite Dihydroartemisin.
Currently it is the most frequently used of all the Artemesinin-type drugs.
Its only effect is mediated through a reduction in the gametocyte
transmission. It is used in combination therapy and is effective in cases of
uncomplicated P. falciparum. The dosage recommended by the WHO is a 5
or 7 day course (depending on the predicted adherence level) of 4mg/kg for 3
days (usually given in combination with Mefloquine) followed by 2mg/kg for
the remaining 2 or 4 days. In large studies carried out on over 10,000
patients in Thailand no adverse effects have been shown.
-
Dihydroartemisinin is the active metabolite to which Artemisinin is
reduced. It is the most effective Artemesinin compound and the least stable.
It has a strong blood schizonticidal action and reduces gametocyte
transmission. It is used for therapeutic treatment of cases of resistant and
uncomplicated P. falciparum. 4mg/kg doses are recommended on the
first day of therapy followed by 2mg/kg for 6 days. As with Artesunate, no
side effects to treatment have thus far been recorded.
-
Arteether is an
ethyl ether derivative of Dihydroartemisinin. It is used in combination
therapy for cases of uncomplicated resistant P. falciparum. The recommended
dosage is 150mg/kg per day for 3 days given by IM injections. With the
exception of a small number of cases demonstrating neurotoxicity following
parenteral administration no side effects have been recorded.
Other agents
Doxycycline
Doxycycline is a
Tetracycline compound derived from
Oxytetracycline. The tetracyclines were one of the earliest groups of
antibiotics to be developed and are still used widely in many types of
infection. It is a
bacteriostatic agent that acts to inhibit the process of
protein synthesis by binding to the
0S
ibosomal
subunit thus preventing the 50s and 30s units from bonding. Doxycycline is used
primarily for chemoprophylaxis in areas where quinine resistance exists. It can
be used in resistant cases of uncomplicated P. falciparum but has a very
slow action in acute maleria, therefore it should never be used in monotherapy.
When treating acute cases and given in combination with Quinine; 100mg/kg of
Doxycycline should be given per day for 7 days. In prophylactic therapy, 100mg
(adult dose) of Doxycycline should be given every day during exposure to
malaria.
The most commonly experienced side effects are permanent
enamel hypoplasia, transient depression of bone growth, gastrointestinal
disturbances and some increased levels of
photosensitivity. Due to its effect of bone and tooth growth it is not used
in children under 8, pregnant or lactating women and those with a known hepatic
dysfunction.
Tetracycline is only used in combination for the treatment of acute cases of
P.Falciparum infections. This is due to its slow onset. Unlike Doxycycline it is
not used in chemoprophylaxis. For Tetracycline, 250mg is the recommended adult
dosage (it should not be used in children) for 5 or 7 days depending on the
level of adherence and compliance expected. Oesophageal ulceration,
gastrointestinal upset and interferences with the process of
ossification and depression of bone growth are known to occur. The majority
of side effects associated with Doxycycline are also experienced.
Clindamycin
Clindamycin is a derivative of
incomycin,
with a slow action against blood schizonticides. It is only used in combination
with Quinine in the treatment of acute cases of resistant P. falciparum
infections and not as a prophylactic. Being more expensive and toxic than the
other antibiotic alternatives, it is used only in cases where the Tetracyclines
are contraindicated (for example in children).
Clindamycin should be given in conjunction with Quinine as a 300mg dose (in
adults) four times a day for 5 days. The only side effects recorded in patients
taking Clindamycin are nausea, vomiting and abdominal pains and cramps. However
these can be alleviated by consuming large quantities of water and food when
taking the drug.
Pseudomembranous colitis (caused by
Clostridium difficile} has also developed in some patients; this
condition may be fatal in a small number of cases.
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