Effects of rosiglitazone and sumatriptan on human isolated small and large coronary arteries Kathryn Bagot, Mozam Ali, Lee Dawson, Sandy Williams, Bob SheldrickAsterand UK Ltd, 2 Orchard Road, Royston, Hertfordshire, SG8 5HD, UK. Introduction Species differences in receptor type, expression level or coupling can lead to marked differences in responses between laboratory animals a
malaria update 2012Malaria update 2012
Gunnar Holmgren, Infectious diseases clinic, Ryhov Hospital, Jönköping, Sweden May 2012
About 3.3 billion people are at risk of malaria globally, 350 million have the parasite
in their body and 250 million will be ill with malaria in 2011 with almost 1 million
dying as a result. Some new research suggests that 1.24 million died of malaria in
2010 with 85% of the deaths in Sub-Saharan Africa. This is the most important
parasitic disease in the world.
The majority of countries in tropical Sub-Saharan Africa (SSA) have a reduction of
their potential income by between 1-1.3% per year due malaria and that over a 15
year period this loss of income amounts to almost 20% of their potential earnings.
Put in another way probably 20% of their poverty is due to malaria. In the worst
affected countries malaria accounts for 40% of public health expenditure, 30-50% of
in-patient admissions and up to 60% of out-patient clinic visits. In 1997 it was
estimated at the Global Malaria Conference in Hydrabad that annual deaths from
malaria were between 2.5 million and 3.5 million.
Malaria is spread by the bite of the female Anopheles mosquito (45 species are
important vectors with A. gambiae being the most effective) in which the parasite
goes through a complicated life-cycle ending up in the salivary glands. A bite from a
mosquito infected with such parasites is accompanied by the injection of saliva to
stop the blood from clotting. With the saliva are injected parasites at the sporozoite
stage where they can spread within 20 - 45 minutes through the blood stream of man
and reach the hepatocytes of the liver. They bore into these hepatocytes and start
asexual reproduction into schizonts and finally discharge merozoites into the blood
stream. In Plasmodium falciparum (the main malaria parasite in Tropical Africa) the
liver stage lasts 5.5 days. In P. malariae it lasts 15 days.
The merozoites bore into red cells and form a vacuole with the invaginated red cell
membrane. About 36 hours (54 hrs. in P. malariae) after invasion repeated nuclear
division forms a schizont or better termed a meront and finally the growing parasite
fills the red cell and is packed with merozoites. It then bursts and 6-36 merozoites are
released to invade new red blood cells. The infection expands logarithmically at
around 10-fold per cycle. The release of several substances at this bursting stage
brings about the symptoms of malaria which include fever, headache, pain in
muscles, nausea and vomiting. Finally, if untreated, so many red blood cells are
damaged that the person becomes anaemic due to lack of intact blood cells. The
spleen which is the dumping ground of broken down red cells may become enlarged
and tender. The person may even become jaundiced as the break down products of
haemoglobin finally overwhelm the liver's capacity to deal with them and the
inflammatory effect of malaria on the liver cells function. After a series of asexual
cycles in P. falciparum a sub-population of the parasite develops into sexual forms
(gametocytes) with the process taking about 7-10 days. This is the stage that is then
taken up by the female anopheles. The parasite then goes through the complex
process within the mosquito which brings us back to our starting point as
sporozoites in the salivary glands.
The effect of malaria on nutrition
Many episodes of malaria coming close together will decrease the intake of nutrients
since the child that is acutely ill with the disease has nausea and vomiting, and may
have a poor appetite even after the acute illness is over. The malaria medicines may
also affect the appetite. The high fever increases catabolism and thus increases the
need for nutrients.
The effect of nutrition on malaria
Paradoxically severe malnutrition has a relative protective effect against the severe
complications of malaria. Children with kwashiorkor virtually never develop
cerebral malaria until they have recovered from their malnutrition; they may then
suddenly become sick with severe malaria. Maybe the parasite becomes as
malnourished as the human host in severe malnutrition. Replication is slower with
less severe complications of malaria. Conversely, most children with cerebral malaria
are in the well-nourished group.
It may be that iron deficiency anaemia also provides a limited protection against
severe malaria, and iron supplements may aggravate the disease.
There are 4 main types of parasites: Plasmodium falciparum, P. malariae, P. ovale,
and P. vivax. (P. knowlesi is found on Borneo and parts of peninsular Malaysia)
Plasmodium falciparum is virtually the only life-threatening type and is also the
dominant type in most parts of tropical Africa. In Zambia this type accounts for 95%
of all malaria. In many parts of Asia the malaria threat is smaller than in Africa and
P. vivax is dominant in many countries (India, Pakistan, Sri Lanka etc.)
Only P. vivax and P. ovale can have a long-term liver stage where the parasite can
hide for several years and flare-up again. This stage needs special treatment with
primaquine to clear the parasite.
There are four situations of malaria threat that are so different from each other that it
is as if four different diseases are being described:
1. High transmission with an extremely effective vector (Anopheles gambiae) of P.
falciparum. Here malaria will almost certainly be the main cause of morbidity and
mortality in children under 5 and the main cause of illness amongst adults.
Chloroquine treatment is virtually always useless. Impregnated mosquito nets and
more effective treatment are the only hope in the community.
2. Low transmission of P. falciparum. Here the disease may occasionally come as
epidemics (e.g. during El Nino-associated climate changes) that are a threat to the life
and health of both adults and children with massive outbreaks of severe anaemia
and cerebral malaria during the outbreaks but little impact otherwise. In an outbreak,
there may even be discussion about short-term prophylaxis for children and
pregnant women, as well as impregnated mosquito nets and early effective
3. Moderate transmission of P. vivax and ovale. Here both prophylaxis and
treatment with chloroquine are usually effective but follow-up treatment of the liver
stage with primaquine is still needed. Environmental changes such as draining
marshlands and separating human from animal dwellings often make a big impact.
4. Low transmission of P. vivax, ovale and malariae. Here malaria is an exotic
disease without much impact at the community level.
There are 4 main symptoms: headache, muscular pain, fever + rigors (shaking of the
body due to the shivering attack), nausea + vomiting. These are usually in the
absence of symptoms of respiratory infection such as sore throat, runny nose and
coughing. There could be an almost identical presentation with influenza but here
there are virtually always respiratory symptoms. Almost always after two days there
will be some period completely without fever and the other symptoms.
There are 4 main signs on examining a person with malaria: raised temperature,
anaemia, enlarged spleen, jaundice. However all four may be absent although the
absence of fever throughout is rare. Intermittent fever is the usual picture with a
normal temperature at times. The latter three signs are less usual in the first attack of
Blood films with both thin and thick films are still the main-stay of diagnosis but
these need to be accurately made, stained and assessed by an experienced technician
to be useful.
There are 4 new methods that are all expensive and mainly useful in looking for
falciparum malaria: ParaSight-F, PCR, QBC malaria test, and HRP-2 (Malaquick)
There are 4 main severe life-threatening complications all with P. falciparum and are
due to inflammatory processes resulting from the release of cytokines when the red
blood cells burst. Also the parasite causes red blood cells to become more sticky and
to form aggregations including rosettes which slow down or stop circulation in the
microcirculation to essential organs. This starts in the venules.:
1. cerebral malaria,
2. severe anaemia,
3. renal failure and blackwater fever (passing very dark urine because of a massive
break-down of red blood cells with the release of free haemoglobin into the blood at
a level that the kidneys cannot control and hence a leak of haemoglobin with its very
dark colour in the urine),
4. pulmonary oedema (water in the lungs which become stiff and dangerously
There are 4 important clinical assessments to follow the course of severe malaria:
daily (or twice daily) parasite counts, fluid input/output assessment, daily weighing
for assessing fluid balance, measurement of conscious level using e.g. Glasgow or
Blantyre coma score.
There are 4 rapidly-acting groups of drugs for treating acute malaria:
1. chloroquine or amodiaquine for P. vivax, malariae and ovale
2. artemether combination therapy (ACT) for malaria due to P. falciparum
3. quinine or quinidine for severe malaria due to P. falciparum,
4. mefloquine for malaria due to P. falciparum (Lariam®).
Halofantrine has been very useful for P. falciparum treatment but now potentially
life-threatening cardiac side-effects have been described which limit its value. A
closely related drug, lumefantrine, without the cardiac side effects is now the
commonest linked drug to artmesinine in ACT
In an area with chloroquine resistant P. falciparum malaria, which means virtually
all of Africa, (resistance to chloroquine with the other 3 types of malaria is still
unusual) the strongly recommended treatment is “dual therapy.” Here are 4
*1. Artemether + lumefantrine (Coartem®). Because of the Roll-Back-Malaria
programme this is now widely available and is the best. In Europe it is marketed as
2. Atovaquone + proguanil (Malarone®) is a rapidly acting anti-malarial which is
good for early P. falciparum but very expensive.
3. Amodiaquine (Camoquin®) + Fansidar®. Cheap and well tested in Uganda but is
likely to show resistance developing.
4. A new low-cost dual therapy was about to be launched but had to be dropped
because of potential problems in those with G6PD deficiency: chloproguanil +
dapsone (LapDap®) which was to have been combined with artmether.
If single treatment with amodiaquine is used a follow-up treatment will almost
certainly be needed with doxycycline.
For severe malaria choose artemether i.m. or artesunate i.v. or quinine i.v. as these
are the three that have been shown to give the quickest response. A short course with
one of these until there is good improvement should be followed by oral Coartem®
or doxycycline to clear the last parasites (in the early stages oral Coartem® may be
possible). Some countries have suppositories with Artenam available where i.v.
treatment is not possible.
There are 4 follow-up slow-acting treatments when there are resistance problems:
doxycycline, clindamycin (can be used in pregnancy), Fansidar® or cotrimoxazole.
There are 4 levels of resistance to chloroquine: no resistance; R1: good clinical effect
and the blood slide becomes negative but the symptoms come back without new
infection within 28 days; R2: same as R1 but blood slide never becomes negative;
R3: no improvement either clinically or on parasite counts.
There are 4 main ways of avoiding malaria in Africa:
1. Avoid mosquito bites: e.g. use of mosquito nets impregnated with permethrin or
deltamethrin over beds (97% effective in semi-immunes). Combine this with local
insect repellants e.g. DEET. Put self-closing doors on all outside doors and mosquito
nets on all windows.
2. Prophylaxis with an effective drug e.g. in East and Central Africa with mefloquine,
or malarone or doxycycline(all 90% effective). Less effective: proguanil + chloroquine
3. Spray all houses within 1 km radius of an institution with insecticide regularly;
such programmes of Residual indoor spraying (IRS) are mainly relevant in high
density living areas.
4. Drain all puddles, marsh areas, remove tyres, cans and all rain-water accumulating
Dosages in P. falciparum malaria treatment in Africa
First choice when available
Artemether-lumefantrine (Coartem®) For adults: 4 tablets as a single initial dose, 4
tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for
the following two days (total course of 24 tablets). For children: 5-15 kg: one tablet as
an initial dose, one tablet again after 8 hours and then one tablet twice daily
(morning and evening) for the following two days (total course of 6 tablets); 15-25 kg:
two tablets as an initial dose, two tablets again after 8 hours and then two tablets
twice daily (morning and evening) for the following two days (total course of 12
tablets); 25-35 kg: three tablets as an initial dose, three tablets again after 8 hours and
then three tablets twice daily (morning and evening) for the following two days
(total course of 18 tablets). Above 35 kg as for adults.
Second choice when available
Atovaquone 1000 mg daily plus proguanil 400mg (Malorone®) daily by mouth after
fatty meal for 3 days.
In children 11-20 kg the dosage of atovaquone/proguanil is 250mg/100mg; 21-30
kg 500mg/200mg; 31-40 kg 750mg/300mg and above 40kg adult dose.
Third choice when the above are not available: Amodiaquine 600mg daily by
mouth for 2 days then 300 mg on 3rd day (total of 25mg/kg over three days)
combined with Fansidar ® 3 tablets single dose.
This is usually adequate treatment but if single treatment with amodiaquine is used
and fever or symptoms come back after this add doxycycline 200 mg daily by mouth
for 7-10 days
Dosages in P. vivax, P. ovale and P. malariae
First choice when chloroquine resistance is rare or at a low level of resistance. Start
Full chloroquine course 10mg base/kg PO stat; then 5mg/kg at 12, 24 and 36 hrs in
semi-immunes. Follow up in P. vivax and P. ovale with primaquine 0.25 - 0.5 mg/kg
once daily with food for 14 days (in adults usual dose is 15-30 mg daily).
Dosages in Severe malaria
First choice when available
Artemether (artemisinine derivative) 160 mg (children 1.6 mg/kg) i.m. twice a day
for 3-7 days (an i.v. preparation of artenam is available in Sweden but rare in Africa)
or if the person is not vomiting an alternative is oral Artemether + lumefantrine as
above or artesunate 4 mg/kg daily for 3 days then doxycycline 200 mg orally daily
for 7 days. Artenam by suppository is an excellent alternative but not yet widely
Second choice (more likely to be available)
Quinine dihydrochloride 20 mg salt/kg of body weight (loading dose) by infusion in
5% dextrose saline (5-10 ml/kg related to hydration level) over 4 hours or by i.m.
injection. Eight to twelve hours later give a maintenance dose of quinine 10 mg
salt/kg in dextrose saline over 4 hours. Repeat this dose every 8-12 hours until oral
therapy is possible. If available then go over to Artemether + lumefantrine as above.
Otherwise Oral therapy: quinine 10mg salt/kg orally thrice daily for 3 days then
doxycycline 200 mg daily PO for 7 days,
Alternative: mefloquine 15mg base/kg orally as first dose followed by one further
dose of 10mg/kg 8 hrs later but more side-effects than above.
There is undoubtedly an important improvement in malaria research, prevention
including indoor residual spraying and impregnated bed-nets, better diagnosis
including both microscopy and the rapid tests as well as Dual treatment with
Coartem all resulting from the Roll-Back-Malaria interventions and the financing
from the Global Fund and many others. Much discussion has taken place about
whether eradication is possible and there is still no consensus about the right
strategy in the most affected countries. Some feel that in this setting more lives will
be saved if the focus is on containment rather than on eradication. It seems likely that
until a highly effective and affordable vaccine is widely available, the idea of
eradication of malaria in these areas is still a dream.
In the field there are some precautions where Roll-Back-Malaria programmes have
not yet been introduced and only microscopy is available for diagnosis.
Make sure that the diagnosis is certain. In some laboratories in Africa many blood
slides are falsely reported* as positive (especially if it is known by the laboratory
assistant that the slide came from an expatriate). In some laboratories even if the slide
is found negative, this is inevitably reported as “scanty malaria parasites seen” just
so that the lab assistant is covered in case he missed a rare parasite. This can lead to
many unnecessary treatments with all their side-effects
* In one study in Tanzania blood slides were first assessed in the local hospital
laboratory and then the same slide was taken to a malaria reference laboratory in
Sweden and assessed by a very experienced expert. The results were very interesting.
When the slide was reported as:
+ for malaria parasites there were 50% false positives.
++ for malaria parasites there were 10% false positives
+++ for malaria parasites there were 3% false positives
Only when the report stated ++++ for malaria parasites were all the slides truly
Overall there were 3% false negatives.
Of course such mistakes are understandable when the microscope is old, the stain
reagents are old, the light source is poor and the laboratory assistant is poorly
motivated (his salary may not have been paid for 6 months) or inadequately trained.
Tropical Medicine and International HealthCan a comprehensive voucher programme prompt changes indoctors’ knowledge, attitudes and practices related to sexualand reproductive health care for adolescents? A case study fromLatin AmericaLiesbeth E. Meuwissen1,2, Anna C. Gorter2, Arnold D. M. Kester3 and J. A. Knottnerus1,41 Department of General Practice, University of Maastricht, The Netherland