ERBB RECEPTORS AND CANCER: THE COMPLEXITY OF TARGETED INHIBITORS Nancy E. Hynes* and Heidi A. Lane‡ Abstract ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor and ERBB2 are altered in many epithelial tumours, and clinical studies indicate that they have important roles in tumour aetiology
Most often, when a man first has problems with lowered potency or with sexual dysfunction cialis australia shipping to pharmacies, paying purveyors, training personnel, or having a huge advertising budget.
Malaria case managementMALARIA CASE MANAGEMENT
DESK GUIDE FOR C
HEALTH CARE P ROVIDERS
DIRECTORATE OF MALARIA CONTROL
MINISTRY OF HEALTH
MALARIA CASE MANAGEMENT
DESK GUIDE FOR C
HEALTH CARE P ROVIDERS
Developed with the Technical Assistance of
The Technical Assistance Management Agency
DIRECTORATE OF MALARIA CONTROL
MINISTRY OF HEALTH
The Malaria Control Programme in Pakistan dates back to the 1960s when it was directed as the Malaria Eradication Programme. Within a decade it became evident that eradication was too ambitious a goal and the more realistically achievable goal of Malaria control was adopted. The programme was implementing the strategies for control until Pakistan joined the international partnership for Roll Back Malaria (RBM) established by the World Health Organization (WHO) in collaboration with the World Bank, (UNICEF)(UNDP) in 1999 and adopted the RBM strategies for the control of malaria in the country. Early and appropriate Treatment is a key RBM strategy. Up till 2003 the national programme continued with the treatment policy and protocols of the malaria control era. In the year 2003 the national programme with technical assistance from WHO drafted the first national treatment policy and protocol. A treatment desk guide and training and monitoring manuals based on the policy, were developed and are currently being used in the country. The national treatment policy was revised in the year 2006 to conform to the WHO most recent guidelines on the radical treatment of falciparum and vivax malaria. The aim is not only to control malaria but to rationalise the use of Antimalarials. Under the new policy mono-therapy and treatment based on clinical diagnosis are being discouraged. Rapid Diagnostic Tests are being introduced in areas where microscopy facilities are not available and artesunate plus sulphadoxine pyrimethamine combination therapy is being promoted for the treatment of uncomplicated falciparum malaria, while chloroquine and primaquine therapy is still reserved for vivax malaria. This desk guide has been prepared with the aim of providing clinicians and health care
providers, both in public and private sector, with guidelines on the management of
malaria cases according to the national case management policy. Sufficient details are
given to enable the care provider to understand the rationale for the management being
recommended and to motivate them to sincerely join the national effort to control malaria
in the country.
Directorate of Malaria Control
The author most gratefully acknowledges the Directorate of Malaria Control, Islamabad,
for providing her the opportunity for preparing this guide and the Technical Assistance
Management Agency (TAMA), Islamabad for funding the activity.
The activity couldn't have been completed without the help, support and valuable
contribution of the following:
1. Dr. Faisal Mansoor, Director National Malaria Control Programme 2. Dr. Mukhtar, Senior scientific Officer, directorate of Malaria control (DOMC), 3. Dr Qutbudin Kakar, WHO Technical Officer, DOMC, Islamabad 4. The Provincial Malaria Control coordinators and focal persons (list attached) 5. The participants of the consultative workshop held on September 18, 2007(list
The information contained in this document has been taken from the following
1. Final draft of National Malaria Control Strategy 2007
2. National malaria control programme draft PCI 2007
3. Malaria Case Management ; Desk Guide
4. National Treatment Guidelines for Malaria 2005
5. Malaria Case Management Training Manual
6. WHO Guidelines for the Treatment of Malaria 2006
7. Roll Back Malaria Strategy notes
8. Roll Back Malaria- World Malaria Report 2005
9. WHO EMRO website
Objectives and target audience of the Guidelines
The objective of this desk guide is to create awareness among clinicians and care providers: 1. Of the high burden of malaria in the country; 2. The national treatment policy 3. Correct malaria case management 4. Their immense responsibility in the control of malaria in the country Information is presented on 1. The current situation of malaria in Pakistan 2. Pakistan's national malaria treatment policy 3. Management of malaria: 3.1. Case definitions • Uncomplicated malaria (UM) • Malaria treatment failure (MTF) • Complicate /Severe malaria (SM) 3.2. History and physical examination 3.3. Diagnosis-clinical, Rapid Diagnostic Tests(RDTs), micrscopy 4. Antimalarials and their appropriate combinations, dosage and duration of 5. Malaria in vulnerable groups: • Pregnant women 6. Patient Counseling and education 7. Follow-up of patients 8. Malaria case-management during epidemics and national emergencies Dr. Tasleem Akhtar, FRCP (Paediatrics) Contents
Malaria in Pakistan – A Situation analysis-----------------------7
Distribution and prevalence Control strategies National Malaria Case Management Policy Policy Rationale Section-3:
Case Definitions General Plan for Malaria diagnosis and Treatment Case History and Physical Examination Section-4:
Clinical Diagnosis Parasitological diagnosis Section-5:
Treat ment of Uncomplicated Malaria Treatment of Complicated or Severe Malaria Management of treatment failures (recrudescence) Incorrect approaches to treatment Section-6
Treatment in specific populations -------------------------------23
Pregnant women Children Section- 7:
Patient Counseling and Education-------------------------------26
Malaria case management In epidemics and--------------------
Section-10: PHARMACOLOGY OF ANTIMALARIAL DRUGS-------------30
What is Malaria
Malaria is caused by infection of red blood cells with protozoan parasites of the genus Plasmodium. The parasites are inoculated into the human host by a feeding female anopheline mosquito. The four Plasmodium species that infect humans are P. falciparum, P. vivax, P. ovale and P. malariae. In Pakistan P.faciparum and P. vivax are the prevalent infecting parasites. There are many species of the vector Anopheles. In Pakistan the two major vector species are Anopheles culcifacies and Anopheles stephensi. Anopheles typically breed in natural water bodies with clean, slow moving, warm water, with sufficient aquatic vegetation. However, ecological requirements of particular species may deviate from these typical conditions; An. stephensi can easily breed in closed artificial containers and An claviger prefer relatively cold water. The nature of the clinical disease depends very much on the pattern and intensity of malaria transmission in the area of residence, which determines the degree of protective immunity acquired and, in turn, the clinical disease profile. Where malaria transmission is "stable" – meaning where populations are continuously exposed to a high frequency of malarial inoculations partial immunity to the clinical disease and to its severe manifestations is acquired early in childhood. In such situations, which prevail in much of sub-Saharan Africa and parts of Oceania, the acute clinical disease is almost always confined to young children who suffer high parasite densities and acute clinical disease.
If untreated, this can progress very rapidly to severe malaria. In stable and high-
transmission areas, adolescents and adults are partially immune and rarely suffer clinical
disease, although they continue to harbor low blood-parasite densities. Immunity is
reduced in pregnancy, and can be lost when individuals move out of the transmission
In areas of unstable malaria, the situation prevailing in Pakistan and much of Asia, Latin
America and the remaining parts of the world where malaria is endemic, the rates of
inoculation fluctuate greatly over seasons and years. This retards the acquisition of
immunity and results in people of all ages, adults and children alike, suffering acute
clinical malaria, with a high risk of progression to severe malaria if untreated. Epidemics
may occur in areas of unstable malaria when inoculation rates increase rapidly.
Epidemics manifest as a very high incidence of malaria in all age groups and can
overwhelm health services. Severe malaria is common if effective treatment is not made
Malaria in Pakistan – A Situation analysis
Pakistan is among 107 countries with endemic malaria. Currently Pakistan is listed
among moderately endemic countries for malaria. The Pakistan Health Management
Information System (HMIS)'s 2006 report shows malaria as the second most frequently
reported disease from public health sector facilities. Although at the aggregate level the
prevalence of malaria in Pakistan is moderate, there is variation in prevealence from
province to province and area to area. In the Province of Baluchistan, the Federally
Administered Tribal Area (FATA), 5 districts of Sindh and 14 district of the North West
Frontier Province (NWFP), both the overall parasite prevalence and the relative
proportion of falciparum malaria are high.
The slide positivity rate for Pakistan is 7% where as it is 16.5% for Balochistan, 17.5%
for FATA, 8.9% for NWFP, 6.5% and for Punjab it is 1.5%(all decimals rounded of)
Distribution and prevalence
Source: Directorate of Malaria Control, Islamabad
Directorate of Malaria Control, Islamabad The province of Balochistan which is home to about 5% of the population of the country, contributes over 30% of the reported cases while the Punjab province with over 52% of the country population reports less than 10%. World Malaria Report 2005
Pakistan's successful Malaria Control Programme of the 1960s and early 1970s was stopped in its tracks by the emergence of resistance to DDT and later chloroquine. As elsewhere the goal was downgraded to control of malaria and treatment and vector control strategies were modified to deal with the challenge of the fast spreading resistance to Antimalarials and insecticides. The well performing system for malaria eradication however went into decline and in some provinces, its was merged with communicable diseases control sections of the general health directorates. The launching of the Roll Back Malaria (RBM) initiative by WHO in partnership with the World Bank(UNICEF), and (UNDP) in 1998 and the incorporation of the RBM goal in the Millennium Development Goals (MDGs) in 2000, revitalized the world wide effort for the control of malaria. Pakistan joined the RBM Partnership in 1999 and since then is endeavoring to strengthen the malaria control system in the country to achieve the RBM and MDGs goal of halving the number of malaria reported cases by the year 2015. Pakistan is committed to achieving the RBM and MDGs goal
of halving the number of reported cases of malaria by the
year 2010. All stakeholders are urged to join the national
effort to honour this national commitment
Pakistan's National Strategy for the Control of Malaria,2007, has been developed within the RBM strategic framework and has the following strategic priorities • Early Diagnosis and Appropriate Treatment, • Multiple Prevention, • Epidemic Preparedness and Behavioral Change Communication and • Two conditional priorities upon which these strategic priorities depend: o Program Management o Operational Research Early diagnosis and prompt appropriate treatment is a key
strategy for the control of Malaria. Clinicians and care
providers have therefore a key role and responsibility in the
control of malaria in the country.
Health care providers in areas with endemic malaria have a
special responsibility of reducing the incidence of severe
malaria and the malaria specific mortality rate as low as
National Malaria Case Management Policy
The National Malaria Case Management Policy while guided by the WHO guidelines,
fully takes into account local epidemiological, biological, and cultural considerations.
Malaria in Pakistanis is epidemiologically unstable. Peak transmission occurs in the post
monsoons months of August to November and as mentioned previously the major vector
species are Anopheles culcifacies and Anopheles stephensi and the prevalent causative
parasites are Plasmodium vivax and Plasmodium falciparum. Over 40% cases of
falciparum are resistant to chloroquine.
Pakistan revised and updated its national malaria treatment policy in 2006 to bring it into
conformity with the latest World Health Organisation (WHO)'s recommendations. The
WHO guidelines recommend antimalarials for which there is adequate evidence of
efficacy and safety, and which are unlikely to be affected by resistance in the near
future. The essential new ingredients of the latest policy are:
• Treatment based on clinical diagnosis alone should be reduced by making available
Rapid Diagnostic Tests(RDTs) in health facilities where microscopy is not available; • The use of monotherapy should be discouraged and discontinued and o Artemisinin-based combination therapies (ACTs) should be introduced for uncomplicated falciparum malaria. o Chloroquine and Primaquine therapy be used for vivax malaria Monotherapy must be avoided in the treatment of malaria.
All clinicians and care providers are urged to use
combination therapy as recommended in these guidelines.
2.3.1. Policy Rationale:
The new policy not only aims to counter the widespread high antimalarial resistance in
the country but also aims for radical cure of the disease to interrupt transmission in the
population. The high prevalence of drug resistance is believed to be due to the
indiscriminate and inappropriate use of antimalarials medication on the basis of clinical
diagnosis of malaria. While WHO estimates an annual malaria burden of 1.6 million
cases for Pakistan, in 2006, the Lady Health Workers alone prescribed over 4.4 million
doses and the prescription of these drugs by the private sector amounted to a
staggering 70 million doses. The colossal waste of resources is obvious.
Implementation of the new policy ia aimed to achieve the following major objectives:
1) Fast and effective relief for the patient;
2) Total elimination of parasite from the patient's body which will result in interruption of
transmission of the parasite; 3) Containment of the spread of resistance and ; 4) Reduction of financial burden on the health care system. All health care providers are urged to understand the
rationale and objectives of the national malaria treatment
policy and fully comply with its implementation
Clinical Case Management
The responsibility of appropriate case management starts when the patient enters a
clinic or health facility or when a health care provider is called to see a patient at home.
For the purpose of management malaria cases are categorized as follows: 3.1.1. Uncomplicated malaria (UM)
The case definition for UM is as follows: • High index of suspicion due to possible exposure to malaria transmission • Fever or history of fever within last 72 hours (continuous, intermittent or irregular) • Absence of signs of other diseases 3.1.2. Complicated /Severe malaria (SM)
The case definition for SM is as follows: • Presence of asexual form of malarial parasite in blood slide examination (BSE) and not other cause of their symptoms in the presence of one or more of the following: 1. Prostration 2. Impaired consciousness 3. Respiratory distress (acidotic breathing) 4. Multiple convulsions 5. Circulatory collapse 6. Pulmonary oedema (radiological) 7. Abnormal bleeding 8. Jaundice 9. Haemoglobinuria 10. Severe anaemia 11. Hypoglycemia 12. Acidosis 13. Renal impairment 14. Hyperlactataemia 15. Hyperparasitaemia 3.1.3. Malaria treatment failure malaria (MTF)
Treatment failures may result from drug resistance, poor adherence or unusual pharmacokinetic properties in that individual. It is important to determine from the patient's history whether he or she vomited previous treatment or did not complete a full course. The case definition for MTF is as follows: • Recurrence of asexual parasitaemia detected by blood slide examination after taking a full antimalarial treatment received during the previous 4 weeks 3.2. Clinical Assessment
The general plan for malaria diagnosis and treatment given below, gives the step by
step approach to the management of each of the above given types of malaria case.
3.2.1. Case History and Physical Examination
a. Introduction and recording of patients particulars
To develop rapport and a friendly environment greet and introduce yourself and then
start recording the following patient's particulars:
Full Name, Name of father or husband in case of married women, Age (in children 5
years or less date of birth should be recorded), full Address, telephone number/ mobile
telephone number (if available)
Travel history in the past 4 weeks
In case of married women ask about pregnancy status and month of gestation.
b. Record the complaints of the patient. First let the patient describe his/her
complaints unprompted. This helps in identifying the complaint which bothers the patient most.
There are no specific symptoms of malaria: most patients
First record the patient's complaints unprompted. complain of headache, lassitude, fatigue, abdominal discomfort
and muscle and joint aches, followed by fever, chills,
perspiration, anorexia, vomiting and worsening malaise
Ask about the following:
• Details of treatment, if any, taken by the patient in the past 2 months.
• If you are in non-endemic part of the country, ask the patient about travel history to a
malaria endemic area of the country in the past 4 weeks.
c. On Physical examination check:
• The patients general condition, consciousness level and state of hydration
• The patient's temperature. Fever is present if axillary temperature is above 37.5˚ C
or more than 101˚ F. • Clinical anemia by noting the colour of skin, conjunctiva and nails. The colour of nails is especially helpful in the diagnosis of anemia, and the presence of palmar pallor is a good sign of anaemia in children under five. • Examine the abdomen for enlargement of the spleen. An enlarged, tender spleen, with recent history of fever and anemia, is a clinical predictive indicator of malaria. A complete physical examination is important in order not to miss conditions
with similar presenting complaints and other causes of febrile conditions which
may be present
A patient presenting with fever, parasitological confirmation of malaria
and any of the following danger sign(s) should be managed as a case of
• convulsions or fits within the last two days or at present • not able to drink or breast-feed vomiting everything • altered mental state (lethargy, drowsiness, unconsciousness or confusion) • prostration or extreme weakness (unable to stand or sit without support) • severe respiratory distress or dif icult breathing • severe anaemia (severe pallor of palms and mucous membranes) • severe dehydration (sunken eyes, coated tongue, lethargy, inability to drink)
Treatment should not be delayed if parasitological confirmation of malaria
is not immediately available.
Pakistan's national case management policy discourages treatment
on the basis of clinical diagnosis. Care providers are urged to use
parasitological confirmation to guide the treatment of malaria
following the diagnostic approach described below
Guidelines for selection of method of diagnosis
• Use light microcopy where it is available; • If microscopy is not available use a falciparum detecting RDT; • If the test result is negative but strong clinical evidence of malarial infection is present, make a clinical/presumptive diagnosis of vivax malaria and treat as such • Base treatment on clinical diagnosis only if both microscopy and RDTs are not Clinical Diagnosis
Use the following WHO recommendations for making a clinical diagnosis.
• In general clinical diagnosis of uncomplicated malaria should be based on history of
possible exposure to malaria and a history of fever in the previous 3 days with no other obvious causes of fever. • Various unspecific signs and symptoms may be also present, such as nauseas, vomiting, headache, body aches, sweating, rigors, history of intermittent fever. Presence of anemia in children warrants the suspicion of malaria. Parasitological diagnosis
The introduction of Artemisinin based combination therapy (ACTs) has increased the urgency of improving the specificity of malaria diagnosis. The relatively high cost of these medicines makes unnecessary treatment of patients without parasitaemia unsustainable. In addition to cost savings, parasitological diagnosis has the following advantages: • Improved patient care in parasite-positive patients owing to greater certainty that the patient has malaria; • Identification of parasite-negative patients in whom another diagnosis must be • Prevention of unnecessary exposure to Antimalarials, thereby reducing side-effects, drug interactions and selection pressure;
• Improved health information;
• Confirmation of treatment failures.
In Pakistan the following two methods of parasitological diagnosis are recommended by
the national malaria control programme:
1. Light microscopy
2. rapid diagnostic Tests (RDTS)
4.2.1. Light microscopy
In Pakistan in the public sector, light microscopy facilities are available in hospitals and
at Rural Health Centers (RHCs). In addition to providing a diagnosis with a high degree
of sensitivity and specificity when performed well, microscopy allows quantification of
malaria parasites and identification of the infecting species. It is inexpensive and is
considered to be the "gold standard" against which the sensitivity and specificity of other
methods must be assessed. A skilled microscopist is able to detect asexual parasites at
densities of fewer than 10 per μl of blood but under typical field conditions the limit of sensitivity is approximately 100 parasites per μl.
Light microscopy has important advantages:
• Low direct costs if the infrastructure to maintain the service is available,
• High sensitivity if the quality of microscopy is high,
• Differentiation between plasmodia species,
• Determination of parasite densities,
• Can be used to diagnose many other conditions.
4.2.2. Rapid diagnostic tests
Rapid diagnostic tests (RDTs) are immuno-chromatographic tests that detect parasite-
specific antigens in a finger-prick blood sample. Current tests are based on the detection
of histidine-rich protein 2 (HRP2), which is specific for P. falciparum, pan-specific or
species-specific parasite lactate dehydrogenase (pLDH), or other pan-specific antigens
such as aldolase. HRP2 based tests therefore detect only Plasmodium falciparum
species , pLDH and aldolase based tests detect one or more of the other three species
of human malaria parasites (P. vivax, P. malariae and P. ovale) (10–12). RDTs are
available commercially in different formats, as dipsticks, cassettes or cards. Cassettes and cards are easier to use in difficult conditions outside health facilities. RDTs are simple to perform and interpret, and do not require electricity or special equipment. WHO recommends that such tests should have a sensitivity of > 95% in detecting plasmodia at densities of more than 100 parasites per μl of blood. Programme and project managers should make their own choice among the many products available, using the criteria recommended by WHO (www.wpro.who.int/rdt) as there is as yet no international mechanism for pre-qualification of RDTs. RDTs have many potential advantages, including: • The ability to provide rapid results, • Fewer requirements for training and skilled personnel (a general health worker can be trained in one day), • Reinforcement of patient confidence in the diagnosis and in the health service in There are also potential disadvantages, including: • The inability in the case of some RDTs, to distinguish new infections from a recently and effectively treated infection; this is due to the persistence of certain target antigens (e.g. HRP2) in the blood for 1–3 weeks after effective treatment.
• Unpredictable sensitivity in the field (13–20), mainly because test performance is
greatly affected by adverse environmental conditions such as high temperature and humidity. • As for microscopical examination, there is a risk of misinterpreting a positive result as indicating malaria in semi-immune patients with concomitant illness.
Under the national malaria case management policy falciparum detecting RDTs are
being provided to facilities where microscopy is not available.
Treatment of Uncomplicated Malaria in adults (excluding pregnant women):
5.1.1. The objective of treating uncomplicated malaria is to cure the infection. This is
important as it will help prevent progression to severe disease and prevent additional
morbidity associated with treatment failure. Cure of the infection means eradication from
the body of the infection that caused the illness.
The public health goal of treatment is to reduce transmission of the infection to others,
i.e. to reduce the infectious reservoir.
A secondary but equally important objective of treatment is to prevent the emergence
and spread of resistance to antimalarials.
Antimalarial combination therapy is the simultaneous use of two or more blood
schizontocidal drugs with independent modes of action and thus unrelated
biochemical targets in the parasite. Two or more simultaneously administered
schizontocidal drugs with independent modes of action improve therapeutic
efficacy and also to delay the development of resistance to the individual
components of the combination.
ACT should only be given in confirmed falciparum cases
The table below gives the dosage and duration of treatment of uncomplicated
malaria in adults excluding pregnant women at all levels of the health care system
5.1.2. Drugs, dosages and duration of treatment: Table-1 gives the recommended
drug combinations, dosages and duration of treatment for radical treatment of malaria
Radical Treatment of Malaria
Chloroquine + Primaquine
(150 mg base tablets) (15mg base tablets)
• Slide positive or
• Clinically diagnosed
One tablet a day for
pyrimethamine + Artesunate
(500mg +25mg tablets) (50 mg tablets)
The Artemisinin derivatives and partner medicines of ACTs should not be
given as monotherapies and should not be available as monotherapies.
Antimalarials should be taken with water
Ideally the first dose should be given in front of the care provider (DOT)
Treatment of Severe Malaria
5.2.1. Treatment objectives
The main objective is to prevent the patient from dying, secondary objectives
are prevention of recrudescence, transmission or emergence of resistance and
prevention of disabilities.
The mortality of untreated severe malaria is thought to approach 100%. With
improvement of the management of severe malaria the case fatality rate of severe
malaria can be reduced below 10% overall.
The risk of death from severe malaria is greatest in the first 24 h. It is therefore very
important that health care providers at the first level of contact of the patient initiate
appropriate antimalarial treatment.
Pakistan's national treatment policy recommends the following management at different
levels of the health care system:
5.2.2. Management at peripheral level facilities and private clinics
• In unconscious patients secure the airway
Treatment at community level and first level health care facilities:
Take a slide
Give first dose of Inj. Artemether im (3.2 mg/kg) as a single loading dose or
Artesunate suppositories (10 mg/kg)
• Refer to hospital along with slide and evidence of injection
5.2.3. Treatment in Hospitals
a. Emergency care: Severe malaria is a medical emergency. The following must be
done immediately the patient arrives in hospital: • The airway should be secured in unconscious patients • Breathing and circulation should be assessed. • The patient should be weighed or body weight estimated so that drugs, including antimalarials and fluids can be given on a body weight basis. • An intravenous cannula should be inserted and immediate measurements of blood glucose (stick test), haematocrit/haemoglobin, parasitaemia and, in adults, renal function should be taken. • A detailed clinical examination should then be conducted, with particular note of the level of consciousness and record of the coma score. The Glasgow coma scale is suitable for adults, and the simple Blantyre modification or children's Glasgow coma scale are easily performed in children. • Unconscious patients should have a lumbar puncture for cerebrospinal fluid analysis to exclude bacterial meningitis. • The degree of acidosis is an important determinant of outcome; the plasma bicarbonate or venous lactate level should therefore be measured if possible. • If facilities are available, arterial or capillary blood pH and gases should be measured in patients who are unconscious, hyperventilating or in shock. • Blood should be taken for cross-match, and (if possible) full blood count, platelet count, clotting studies, blood culture and full biochemistry should be conducted. • The assessment of fluid balance is critical in severe malaria. Respiratory distress, in particular with acidotic breathing in severely anaemic children, often indicates hypovolaemia and requires prompt rehydration and, where indicated, blood transfusion). b. Specific antimalarial treatment:
It is essential that antimalarial treatment in full doses is given as soon as possible in
Two classes of drugs are currently available for the parenteral treatment of severe
• the cinchona alkaloids (quinine and quinidine) and
• the artemisinin derivatives (artesunate, artemether and artemotil).
Quinidine commonly causes hypotension and concentration-dependent prolongation of
ventricular repolarization (QT prolongation). Quinidine is thus considered more toxic than
quinine and should only be used if none of the other effective parenteral drugs are
available. Electrocardiographic monitoring and frequent assessment of vital signs are
required if quinidine is used.
Chloroquine (parenteral) is no longer recommended for the treatment of severe
malaria because of widespread resistance. Intramuscular sulfadoxine–
pyrimethamine is also not recommended
Recommended treatment is Artesunate which is soluble in water and can be
given either by intravenous or intramuscular injection, 2.4 mg//kg bw given on
admission (time = o), then at 12 h and 24 h, than once daily
Artesunate is dispensed as a powder of artesunic acid. This is dissolved in sodium
bicarbonate (5%) to form sodium artesunate. The solution is then diluted in
approximately 5 ml of 5% dextrose and given by intravenous injection or by
intramuscular injection to the anterior thigh. The solution should be prepared freshly for
each administration and should not be stored.
Quinine must never be given by bolus intravenous injection, as lethal
hypotension may result. It is always given as an constant infusion
Quinine dihydrochloride should be given by rate-controlled infusion in saline or dextrose
solutions at a rate not exceeding 5 mg salt/kg bw per hour. If this is not possible then it
should be given by intramuscular injection to the anterior thigh, not the buttock (to avoid
sciatic nerve injury). The first dose of 20 mg salt/kg bw should be split, 10 mg salt/kg bw
to each thigh. Undiluted quinine dihydrochloride at a concentration of 300 mg/ml is acidic
(pH 2) and painful when given by intramuscular injection, so it is best either formulated
or diluted to concentrations of 60–100 mg/ml for intramuscular injection. Gluconate salts
are less acidic and better tolerated than the dihydrochloride salt when given by the
The dosage of artemisinin and artemisinin derivatives does not need
adjustment in vital organ dysfunction. Quinine (and quinidine) levels may
accumulate in severe vital organ dysfunction.
The maintenance dose of 10 mg salt/kg bw should be repeated every 8 hours. If there is
no clinical improvement or the patient remains in acute renal failure the dose should be
reduced by one-third after 48 h. Dosage adjustments are not necessary if patients are
receiving either haemodialysis or haemofiltration. Dosage adjustment by one-third is
necessary in patients with hepatic dysfunction.
Following initial parenteral treatment, once the patient can tolerate oral therapy, it is
essential to continue and complete treatment with an effective oral antimalarial. Current
practice is to continue the same medicine orally as given parenterally, i.e. quinine to
complete a full 7 days of treatment. In non-pregnant adults, doxycycline is added to
quinine and should also be given for 7 days (clyndamycin, where available, should be
given instead of doxycycline to pregnant women and children, as doxycycline cannot be
given to these groups).
Adjunct therapy with corticosteroids is not recommended. No significant
difference in mortality between dexamethasone and placebo has been found
on systematic review, but gastrointestinal bleeding and seizures were more
common with dexamethasone
Management of treatment failures (recrudescence)
Malaria treatment failures may result from drug resistance, poor adherence or unusual
pharmacokinetic properties in that individual. It is important to determine from the
patient's history whether he or she vomited the medicine or did not complete a full
course of treatment.
Recurrence of falciparum malaria after treatment can be the result of a re-infection, or
a recrudescence (i.e. treatment failure). In an individual patient it may not be possible to
distinguish recrudescence from re-infection, although if fever and parasitaemia fail to
resolve or recur within 4 weeks of treatment then this is considered a failure of treatment
Wherever possible treatment failure must be confirmed parasitologically by
blood slide examination.
HRP2-based tests may remain positive for weeks after the initial infection even
without recrudescence and are not helpful in detecting treatment failure
Treatment failure is present if a patient with confirmed malaria has taken the antimalarial
treatment in correct dosage according to the national treatment guidelines but fails to
clear asexual parasitaemia within 4 weeks of the start of treatment.
Treatment failure within 14 days of receiving an ACT is very rare. The few ACT
treatment failures generally occur after 2 weeks of initial treatment, during the 3rd and 4th
week after treatment. In many cases failures are missed because patients presenting
with malaria are not asked whether they have received full antimalarial treatment within
the preceding 1–2 months.
5.3.2. Guidelines for management of malaria treatment failures
• Malaria treatment failures confirmed parasitologically should be treated with a
second-line antimalarial. • Parasitological confirmation is desirable but not a absolute precondition. On the basis of the evidence from current practice and the consensus opinion of the WHO Guidelines Development Group, the following second-line treatments are recommended, in order of preference: • alternative ACT known to be effective • quinine + tetracycline or doxycycline or clindamycin.
The alternative ACT ( Artemether + Lumifentrine) has the advantages of simplicity, and
where available, co-formulation to improve adherence. The 7-day quinine regimes are
not well tolerated and adherence is likely to be poor due to the complexity of the drug
regimen (three daily doses for 7 days).
Quinine dosage and duration of treatment
Drug & Number of tablets
Quinine* (300mg tablets)
* quinine dosage = 10mg/kg 8 hourly for 7 days
Incorrect approaches to treatment
In endemic regions, some semi-immune malaria patients could be cured using partial
treatment with effective medicines (i.e. use of regimens that would be unsatisfactory in
patients with no immunity). This had led in the past to different recommendations for
patients considered to be semi-immune and those considered to be non-immune. This
is no longer recommended.
Another potentially dangerous practice is to give only the first dose of the treatment
course for patients with suspected but unconfirmed malaria, with the intention of giving
full treatment once the diagnosis is eventually confirmed. This is no longer
If malaria is suspected and the decision to treat is made, then a full effective
treatment is required whether or not the diagnosis is confirmed by a test.
Partial treatments should not be given even when patients are considered to be
semi-immune or the diagnosis is uncertain. A full course of effective treatment
should always be given once the decision has been taken to give antimalarial
Treatment in specific populations and situations
Pregnant women with symptomatic acute malaria are a high-risk group, and must
receive effective antimalarials. Maternal mortality is approximately 50% higher than in
non-pregnant women. Fetal death and premature labour are common. Malaria in
pregnancy is associated with an increased risk of severe malaria often complicated by
pulmonary oedema and hypoglycaemia.
There is insufficient information on the safety and efficacy of most antimalarials in
pregnancy, particularly for exposure in the first trimester, and so treatment
recommendations are different to those for non-pregnant women. Organogenesis occurs
mainly in the first trimester and this is therefore the time of greatest concern for potential
teratogenicity, although nervous system development continues throughout pregnancy.
The antimalarials considered safe in the first trimester of pregnancy are
quinine, chloroquine, proguanil and sulfadoxine–pyrimethamine. Of these,
quinine remains the most effective and can be used in all trimesters of
Women often do not declare their pregnancies in the first trimester and so,
early pregnancies may often be exposed inadvertently to the available first-
line antimalarials. Inadvertent exposure to antimalarials is not an indication
for termination of the pregnancy
Current assessment of benefits compared with potential risks suggests that artemisinin
derivatives should be used to treat uncomplicated falciparum malaria in the second and
third trimesters of pregnancy, but should not be used in the first trimester until more
safety information becomes available.
Primaquine and tetracyclines should not be used in pregnancy.
Despite these many uncertainties, effective treatment must not be delayed in pregnant
women. Given the disadvantages of quinine, i.e. the long course of treatment, and the
increased risk of hypoglycaemia in the second and third trimesters, ACTs are considered
suitable alternatives for these trimesters. In practice, if first-line treatment with an
artemisinin combination is all that is immediately available to treat in the first trimester of
pregnancy pregnant women who have symptomatic malaria, then this should be given.
Pharmacovigilance programmes to document the outcome of pregnancies where there
has been exposure to ACTs, and if possible documentation of the development of the
infant, are encouraged so that future recommendations can stand on a firmer footing.
Treatment of malaria in Children
The acutely ill child requires careful clinical monitoring as they may deteriorate rapidly.
Referral to a health centre or hospital is indicated for young children who cannot take
6.2.1. Uncomplicated malaria
The same combination therapies as given above for adults are used to treat malaria in
children. Tables below give the age specific dosages for children
Chloroquine dosage and duration of treatment for children with P.
Chloroquine (150 Chloroquine (150 Chloroquine (150 mg base tablets) mg base tablets) mg base tablets) 12 – 35 months Table-4:
Primaquine dosage and duration of treatment for children with P.
Weight in Kg (Age) No. of tablets to be taken together Do not give primaquine
15 – 24 Kg (5 – 7 yrs) ¼ once day for 14 days 25 – 35 Kg (8 – 10 yrs) 2/4 once a day for 14 days 36 – 50 Kg (11 – 13 yrs) ¾ once a day for 14 days
Artesunate+ Sulfadoxine pyrimethamine dosage and duration of
treatment in children with P. falciparum malaria
(500 + 25 mg tablets) Children should be given tablets crushed & mixed with sugar solution
rather than anti malarial syrups
6.2.2. Severe Malaria
Immediate referral to hospital after
• Clearing airways in unconscious patients
• Giving one of the following pre-referral treatment options a. Artesunate or Artemisinin 10 mg/kg bw by rectal administration b. Inj. Artemether 3.2 mg/kg bw c. Quinine i.m. 10 mg salt /kg bw • Administering anticonvulsant in patients with convulsions
6.2.2. Supportive Treatment
• Fever: In young children, high fevers are associated with vomiting, including of
medication, and seizures. Treatment is with antipyretics Paracetamol (acetaminophen) 15 mg/kg bw every 4 hrs. alternatively Ibuprofen (5 mg/kg bw) may also be used. Acetylsalicylic acid (aspirin) should not be used in children because of the risks
of Reye's syndrome.
If necessary, tepid sponging may be done. Care should be taken to ensure that the
water is not too cool as, paradoxically, this may raise the core temperature by inducing
There has been some concern that antipyretics might attenuate the host defence against
malaria, as their use is associated with delayed parasite clearance. However, this
appears to result from delaying cytoadherence, which is likely to be beneficial. There is
no reason to withhold antipyretics in malaria.
• Vomiting is common in acute malaria and may be severe. Antiemetics are widely
used. There have been no studies of their efficacy in malaria, and no comparisons between different antiemetic compounds, although there is no evidence that they are harmful.
• Generalized seizures are more common in children with falciparum malaria than in
those with the other malarias. This suggests an overlap between the cerebral pathology resulting from malaria and febrile convulsions. Sometimes these seizures are the prodrome of cerebral malaria. If the seizure is ongoing, the airway should be maintained and anticonvulsants given (parenteral or rectal benzodiazepines or intramuscular paraldehyde). ection- 7:
Patient Counseling and Education
This is a very important part of case management.
Advice/Counseling re treatment prescribed:
Tell the patient/ caregiver • The diagnosis which has been made. • Inform them that malaria is curable provided full treatment as advised is taken. • Show them each type of tablets prescribed and make sure that they have understood the dosage and duration of treatment. This can be done by asking the patient to repeat the instruction. • Advise them to drink plenty of water and other liquids. This is very important for • Advise them to take their normal food. No food is contra-indicated in malaria or its • Explain to them the danger of self medication and incomplete treatment. • Tell them to report back (or report to a nearest health facility/provider) if symptoms persist, worsen or new symptoms appear. • Make sure that they understand when they have to return to the clinic for another Counseling for prevention of malaria
Explain to the patient/caregivers the various measures which can prevent future
episodes of malaria. Tell them to:
• To use bed nets. Inform them about the availability and cost of bed nets in their area.
• Inform them about vector-control measures being undertaken in their area. Motivate
them to cooperate with and assist in the vector control activities of their areas.
• Use of screens on the doors and windows, to reduce the risk of mosquito bites.
Follow up of patient is very important under the current strategy for the control of
The objectives of follow up are:
8.1. To monitor clinical improvement;
8.2. To ensure parasitological clearance;
8.3. To monitor compliance with treatment
8.4.To monitor recrudescence due to malaria drug resistance;
8.5. To monitor suspected adverse drug effects
Since the aim of treatment is radical cure, it is very important to follow up
Patients are given follow up appointments for days 3, 7, 14, 21, and 28 of the start of patients which are still sick to ensure that radical cure has been achieved.
Patients should be advised to return if the illness persists, deteriorates or recurs and if new symptoms appears, and must be motivated to return for another examination.
Patient's/care givers should be informed with precision on where and when to return
providing also indication for emergency care in case of need.
Malaria case management in epidemics and complex
In epidemic and complex emergency situations, facilities for parasitological diagnosis
may be unavailable or inadequate to cope with the case-load. In such circumstances, it
is impractical to demonstrate parasitemia before malaria treatment of febrile patients.
However, there is a role for parasitological diagnosis even in these situations: RDTs
should be deployed if microscopy is not available.
In all suspected cases of severe malaria, if a delay is expected in obtaining
parasitological confirmation of diagnosis, patients should be treated immediately for
severe malaria on clinical grounds.
Management of severe falciparum malaria in epidemic situations will often take place in
temporary clinics or in situations in which staff shortages and high workloads make intensive care
monitoring difficult. Drug treatment should therefore be as simple and safe as possible, with
simple dosing schedules and a minimum need for monitoring.
Artesunate has been shown to reduce mortality of severe malaria, but with the current artesunate
formulation, drawing the drug into a syringe takes two dissolution-dilution steps. In some
circumstances this may not be possible.
Parenteral quinine requires either intravenous infusions or a three times a day intramuscular
regimen, plus monitoring of blood glucose.
Intramuscular artemether is the treatment of choice for severe malaria in
situations of epidemics and complex emergencies, also for pregnant women
Section 10: Malaria Chemoprophylaxis
Malaria chemoprophylaxis is not recommended for residents in the malaria endemic
areas of Pakistan. It should also not be prescribed as a remedy after treatment to prevent
re-infections in an endemic area. This section on chemoprophylaxis will enable clinicians
and care providers to give correct advice on chemoprophylaxis to compatriots and
visitors from abroad.
Malaria chemoprophylaxis is not advised for residents of malaria endemic
countries like Pakistan. It should also not be prescribed as a remedy to prevent
re-infections in an endemic area.
For travelers the risk of contracting malaria depends on the region visited, the length of
stay, time of visit, type of activity, protection against mosquito bites, compliance with
chemoprophylaxis etc. Malaria can be severe in the non-immune therefore all visitors
from non-malarious areas to a malarious area should be protected by both prevention of
mosquito bites and antimalarial chemoprophylaxis. Pregnant women, infants and young
children and people who have undergone splenectomy should avoid travel to a malarious
area as these people are at higher risk of severe malaria. If travel is unavoidable, these
people should observe all preventive measures, and should know where to seek early
diagnosis and treatment in case of suspected clinical attack of malaria.
Anti malarial medicines offer protection against clinical attacks of malaria. Correctly
taken, appropriate chemoprophylaxis provides 75%–95% protection against acquiring
malaria. There is considerable experience on good safety data on most
chemoprophylactic regimens recommended for Pakistan.
Malaria can be severe in the non-immune therefore all visitors from non-
malarious areas to a malarious area should be protected.
Anti malarial drugs offer protection against clinical attacks of malaria.
Correctly taken, appropriate chemoprophylaxis provides 75%–95% protection
against acquiring malaria.
The following types of chemoprophylaxis is advised:
12.1. Primary Prophylaxis: Use of antimalarial drugs at recommended dosage, started
1-21 days before departure to a malarious area and continued for the duration of stay and
for 1-4 weeks after return. The time required to take chemoprophylaxis either before or
after entering the malaria endemic area varies among the different antimalarial medicines.
This is of two types:
• Causal prophylaxis: This prevents the establishment of infection in the liver by
inhibiting the pre-erythrocytic schizogony. Primaquine and proguanil are effective as causal prophylactic drugs. Potential adverse effects on long term use and non-availability of primaquine make it a difficult drug for this purpose. Daily doses of proguanil are therefore recommended for causal prophylaxis, in association with chloroquine in areas where resistance to this drug is not present. • Suppressive prophylaxis: Use of blood schizonticides suppresses the blood
forms of the malaria parasite and thus protects against clinical illness. However, P. vivax and P. ovale may cause relapses from the hypnozoites in liver cells and these cannot be prevented with the use of chemoprophylaxis with blood schizontocides. If P. vivax and P. ovale relapse occurs after taking malaria chemoprophylaxis, then the patient should receive a full radical treatment with chloroquine, followed by primaquine for two weeks
For long term travelers there are the following alternate options:
• Chemoprophylaxis only during periods of high malaria transmission: An option
is to take chemoprophylaxis only during periods of high malaria transmission, with the use of stand-by emergency treatment if malaria is contracted. Adopting this option requires careful mosquito avoidance, knowledge of local malaria epidemiology, and prompt access to medical care in the event of a febrile illness. It should be remembered that interruption of chemoprophylaxis at the end of the malaria season is associated with an increased risk of malaria, once the suppressive effect on malaria infection is discontinued.
• Stand-by emergency treatment (SBET) is the self-administration of malaria
treatment carried by the traveler, and is recommended by the World Health Organization in remote situations where medical attention is not available within 24 hours of the onset of symptoms. It can be recommended either for people taking malaria chemoprophylaxis or for those who visit areas with very low malaria risk and decide not to take chemoprophylaxis. However, the use of SBET requires a knowledgeable and responsible user, always take measure to protect from mosquito bites, always carry of course of antimalarial medicines for SBET, seel immediate medical care in case of fever and take SBET if prompt medical help is not immediately available. Travellers using SBET are exposed to the following risks: i) they might incorrectly treat as malaria potentially serious non-malarious febrile illnesses, ii) fail to seek appropriate medical care promptly, and iii) make mistakes with dosing during self-administration. SBET is currently recommended as a sole strategy for dealing with malaria risk for travellers from Switzerland and Germany visiting areas of low malaria transmission. This approach is not recommended by UK, US or Canadian authorities. 12.3. Chemoprophylaxis Regimen: Chemoprophylaxis should preferably, be started
some time before traveling to a malarious area. The interval varies between 1 day
(atovaquone-proguanil, chloroquine-proguanil or doxycycline) up to three weeks
(mefloquine). In addition to assuring adequate blood levels of the drug, this regimen allows for evaluation of any potential side effects (especially with mefloquine). Chemoprophylaxis should continue during all the period of stay in the malarious area and for further period of 1-4 weeks after departure from the area. The chemophylaxis should be continued for one week with atovaquone-proguanil, but for 4 weeks with all other chemoprophylaxis regimens. The following factors should be considered while choosing an appropriate
1. The travel itinerary should be reviewed in detail and compared with the information on areas of risk within a given country to determine whether the traveler will actually be at risk of acquiring malaria. 2. The risk of acquiring chloroquine resistant P. falciparum malaria (CRPF) is high in all endemic areas of Pakistan. 3. Any previous allergic or other reaction to the antimalarial drug of choice and the accessibility of medical care during travel must also be determined.
Chemoprophylactic drugs recommended for travelers to Pakistan
Atovaquone/proguanil or doxycycline or mefloquine The dosage regimens of medicines used for malaria chemoprophylaxis are given in the table below. Table- 5: Drugs used for chemoprophylaxis with dosage
Drugs and dosage for chemoprophylaxis
Pros and Cons
11-20kg: ¼ adult Daily dosing; Atovaquone 1 tab.
Nausea, vomiting, (250 mg) once 21-30kg: ½ adult departure and abdominal pain, diarrhea,
increased liver enzyme Proguanil
31-40kg: ¾ adult levels; rarely seizures, rash, >40kg: 1 adult Abdominal discomfort, vaginal candidiasis, Doxycycline 100mg <25kg or <8 yr: departure and photosensitivity, worsening
of renal function tests in daily not recommended continue for 4 renal diseases, allergic exposure; not reactions, blood dyscrasias, 36-50kg or 11-13 in pregnancy esophageal ulceration >50kg or >14 yr: Weekly dosing; Dizziness, headache, sleep disorders, nightmares, nausea, vomiting, diarrhea, seizures, abnormal <5kg or <3 mo: continue for 4 coordination, confusion, Mefloquine 250 not recommended
forgetfulness, emotional problems including anxiety, 250mg base, base aggression, agitation, 274mg salt) once depression, mood changes, patients with panic attacks, psychotic or neuropsychiatric >35 kg: 1 tab/wk disorders, prior reactions, restlessness, occasional reports of halofantrine or severe intolerance,suicidal ideation and suicide Source; www.malariasite.com/malaria/Prophylaxis.htm
PHARMACOLOGY OF ANTIMALARIAL DRUGS
Only antimalarials recommended under the national treatment policy are included in this
Halofantrine has been banned in Pakistan. Health care providers are advised to
avoid using halofantrine in any formulation
Chloroquine is a 4-aminoquinoline currently being used extensively as a first line
treatment for malaria in Pakistan. Over 40% P. falciparum resistance to chloroquine is
being reported from P. falciparum prevalent areas of Pakistan like Baluchistan and
Chloroquine interferes with parasite haem detoxification. Resistance is related to genetic
changes in transporters (PfCRT, PfMDR), which reduce the concentrations of
chloroquine at its site of action, the parasite food vacuole.
As with other 4-aminoquinolines, chloroquine does not produce radical cure of P.vivax
Tablets containing 100 mg or 150 mg of chloroquine base as hydrochloride, phosphate
Chloroquine has a low safety margin and is very dangerous in overdosage. At normally
recommended doses the drug is generally well tolerated. The principle limiting adverse
effects in practice are the unpleasant taste, which may upset children, and pruritus,
which may be severe in dark-skinned patients. Other less common side effects include
headache, various skin eruptions and gastrointestinal disturbances, such as nausea,
vomiting and diarrhoea. More rarely central nervous system toxicity including,
convulsions and mental changes may occur.
Acute overdosage is extremely dangerous and death can occur within a few hours. The
patient may progress from feeling dizzy and drowsy with headache and gastrointestinal
upset, to developing sudden visual disturbance, convulsions, hypokalaemia, hypotension
and cardiac arrhythmias. There is no specific treatment, although diazepam and
epinephrine (adrenaline) administered together are beneficial.
Acute over dosage with Chloroquine is extremely dangerous and death can
occur within a few hours. Chloroquine Injections are not recommended for use
in treatment of any form of malaria
11.1.3. Drug interactions
Major interactions are very unusual. There is a theoretical increased risk of arrhythmias
when chloroquine is given with halofantrine or other drugs that prolong the
electrocardiograph QT interval; a possible increased risk of convulsions with mefloquine;
reduced absorption with antacids; reduced metabolism and clearance with cimetidine; an
increased risk of acute dystonic reactions with metronidazole; reduced bioavailability of
ampicillin and praziquantel; reduced therapeutic effect of thyroxine; a possible
antagonistic effect on the antiepileptic effects of carbamazepine and sodium valproate;
and increased plasma concentrations of cyclosporine
Sulfadoxineis a slowly eliminated sulfonamide. It is very slightly soluble in water.
Sulfonamides are structural analogues and competitive antagonists of p-aminobenzoic
acid. They are competitive inhibitors of dihydropteroate synthase, the bacterial enzyme
responsible for the incorporation of p-aminobenzoic acid in the synthesis of folic acid.
Sulfadoxine is used in a fixed-dose combination of 20 parts sulfadoxine with1 part
pyrimethamine and may be administered orally or by the intramuscular route:
• Tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine.
• Ampoules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine in 2.5 ml of
injectable solution for intramuscular use.
Sulfadoxine shares the adverse effect profile of other sulfonamides, although allergic
reactions can be severe because of its slow elimination. Nausea, vomiting, anorexia and
diarrhoea may occur. Crystalluria causing lumbar pain, haematuria and oliguria is rare
compared with more rapidly eliminated sulphonamides. Hypersensitivity reactions may
effect different organ system.
Cutaneous manifestations can be severe and include pruritus, photosensitivity reactions,
exfoliative dermatitis, erythema nodosum, toxic epidermal necrolysis and Stevens-
Johnson syndrome. Treatment with sulfadoxine should be stopped in any patient
developing a rash because of the risk of severe allergic reactions.
Hypersensitivity to sulfadoxine may also cause interstitial nephritis, lumbar pain,
haematuria and oliguria. This is due to crystal formation in the urine (crystalluria) and
may be avoided by keeping the patient well hydrated to maintain a high urine output.
Alkalinization of the urine will also make the crystals more soluble. Other adverse
effects, which may be manifestations of a generalized hypersensitivity reaction include
fever, hepatitis, myocarditis, pulmonary eosinophilia, fibrosing alveolitis, peripheral
neuropathy and systemic vasculitis, including polyarteritis nodosa. Anaphylaxis has been
reported only rarely. Other adverse reactions that have been reported include
Blood disorders that have been reported include agranulocytosis, aplastic anaemia,
thrombocytopenia, leucopenia and hypoprothrombinaemia. Acute haemolytic anaemia is
a rare complication, which may be antibody mediated or associated with glucose-6-
phosphate dehydrogenase (G6PD) deficiency.
Jaundice in neonates, aseptic meningitis, drowsiness, fatigue, headache, ataxia,
dizziness, drowsiness, convulsions, neuropathies, psychosis and pseudomembranous
Pyrimethamine is a diaminopyrimidine used in combination with a sulfonamide, usually
sulfadoxine or dapsone. It is a slow-acting blood schizontocide and is also possibly
active against pre-erythrocytic forms of the malaria parasite and inhibits sporozoite
development in the mosquito vector. It is effective against all four human malarials,
although resistance has emerged rapidly. Pyrimethamine is no longer used alone as an
antimalarial, only in synergistic combination with slowly eliminated sulfonamides for
treatment (sulfadoxine, sulfalene) or with dapsone for prophylaxis.
Pyrimethamine is currently used mainly in a fixed-dose combination with slowly
eliminated sulfonamides, either of 20 parts sulfadoxine with 1 part pyrimethamine for
which there are oral and parenteral formulations:
• Tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine.
• Ampoules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine
in 2.5 ml of injectable solution for intramuscular use.
Pyimethamine is generally very well tolerated. Administration for prolonged periods may
cause depression of haematopoiesis due to interference with folic acid metabolism. Skin
rashes and hypersensitivity reactions also occur. Larger doses may cause
gastrointestinal symptoms such as atrophic glossitis, abdominal pain and vomiting,
haematological effects including megaloblastic anaemia, leukopenia, thrombocytopenia
and pancytopenia, and central nervous system effects such as headache and dizziness.
Acute overdosage of pyrimethamine can cause gastrointestinal effects and stimulation of
the central nervous system with vomiting, excitability and convulsions. Tachycardia,
respiratory depression, circulatory collapse and death may follow. Treatment of
overdosage is supportive.
11.3.3. Drug interactions
Administration of pyrimethamine with other folate antagonists such as cotrimoxazole,
trimethoprim, methotrexate or with phenytoin may exacerbate bone marrow depression.
Given with some benzodiazepines, there is a risk of hepatotoxicity.
Artemisinin also known as qinghaosu, is a sesquiterpene lactone extracted from the
leaves of Artemisia annua (sweet wormwood). It has been used in China for the
treatment of fever for over a thousand years. It is a potent and rapidly acting blood
schizontocide and is active against all Plasmodium species. It has an unusually broad
activity against asexual parasites, killing all stages from young rings to schizonts. In P.
falciparum malaria, artemisinin also kills the gametocytes – including the stage 4
gametocytes, which are otherwise sensitive only to primaquine.
Artemisinin has now largely given way to the more potent dihydroartemisinin and its
derivatives, artemether, artemotil and artesunate. The three latter derivatives are
converted back in vivo to dihydroartemisinin. These drugs should be given as
combination therapy to protect them from resistance.
A wide variety of formulations for oral, parenteral and rectal use are available.
• Tablets and capsules containing 250 mg of artemisinin.
• Suppositories containing 100 mg, 200 mg, 300 mg, 400 mg or 500 mg of artemisinin.
Artemisinin and its derivatives are safe and remarkably well tolerated. There have been
reports of mild gastrointestinal disturbances, dizziness, tinnitus, reticulocytopenia,
neutropenia, elevated liver enzyme values, and electrocardiographic abnormalities,
including bradycardia and prolongation of the QT interval, although most studies have
not found any electrocardiographic abnormalities.
The only potentially serious adverse effect reported with this class of drugs is type 1
hypersensitivity reactions in approximately 1 in 3000 patients.
Artemisinin has not been evaluated in the first trimester of pregnancy so should be
avoided in first trimester patients with uncomplicated malaria until more information is
11.4.3. Drug interactions
Artemether is the methyl ether of dihydroartemisinin. It is more lipid soluble than
artemisinin or artesunate. It can be given as an oil-based intramuscular injection or
orally. It is also coformulated with lumefantrine (previously referred to as benflumetol) for
• Capsules containing 40 mg of artemether.
• Tablets containing 50 mg of artemether.
• Ampoules of injectable solution for intramuscular injection containing 80 mg of
artemether in 1 ml for adults or 40 mg of artemether in 1 ml for paediatric use.
Toxicity is similar to that of artemisinin.
11.5.3. Drug interactions
Artesunate is the sodium salt of the hemisuccinate ester of artemisinin. It is soluble in
water but has poor stability in aqueous solutions at neutral or acid pH. In the injectable
form, artesunic acid is drawn up in sodium bicarbonate to form sodium artesunate
immediately before injection. Artesunate can be given orally, rectally or by the
intramuscular or intravenous routes. There are no coformulations currently available.
• Tablets containing 50 mg or 200 mg of sodium artesunate.
• Ampoules: intramuscular or intravenous injection containing 60 mg of anhydrous
artesunic acid with a separate ampoule of 5% sodium bicarbonate solution.
• Rectal capsules containing 100 mg or 400 mg of sodium artesunate.
As for artemisinin.
11.6.3. Drug interactions
Dihydroartemisinin is the main active metabolite of the artemisinin derivatives, but can
also be given orally and rectally as a drug in its own right. It is relatively insoluble in
water, and requires formulation with suitable excipients to ensure adequate absorption. It
achieves cure rates similar to those of oral rtesunate. A fixed-dose formulation with
piperaquine is currently undergoing evaluation as a promising new artemisinin-based
combination therapy (ACT).
• Tablets containing 20 mg, 60 mg or 80 mg of dihydroartemisinin.
• Suppositories containing 80 mg of dihydroartemisinin.
As for artemisinin.
11.7.3. Drug interactions
Artemotil previously known as arteether, is the ethyl ether of artemisinin, and is closely
related to the more widely used artemether. It is oil-based so water insoluble. It is given
by intramuscular injection only.
• Ampoules containing 150 mg of artemotil in 2 ml of injectable solution.
As for artemisinin.
11.8.3. Drug interactions
Primaquine is an 8-aminoquinoline and is effective against intrahepatic forms of all types
of malaria parasite. It is used to provide radical cure of P. vivax and P. ovale malaria, in
combination with a blood schizontocide for the erythrocytic parasites. Primaquine is also
gametocytocidal against P. falciparum and has significant blood stage activity against P.
vivax (and some against asexual stages of P. falciparum). The mechanism of action is
• Tablets containing 5.0 mg, 7.5 mg or 15.0 mg of primaquine base as diphosphate.
The most important adverse effects are haemolytic anaemia in patients with G6PD
deficiency, other defects of the erythrocytic pentose phosphate pathway of glucose
metabolism, or some other types of haemoglobinopathy. In patients with the African
variant of G6PD deficiency, the standard course of primaquine generally produces a
benign self-limiting anaemia. In the Mediterranean and Asian variants (which are found
in north-western part of Pakistan), haemolysis may be much more severe. Therapeutic
doses may also cause abdominal pain if administered on an empty stomach. Larger
doses can cause nausea and vomiting. Methaemoglobinaemia may occur. Other
uncommon effects include mild anaemia and leukocytosis. Overdosage may result in
leukopenia, agranulocytosis, gastrointestinal symptoms, haemolytic anaemia and
methaemoglobinaemia with cyanosis.
11.9.3. Drug interactions
Drugs liable to increase the risk of haemolysis or bone marrow suppression
should be avoided.
Quinine is an alkaloid derived from the bark of the Cinchona tree. Four antimalarial
alkaloids can be derived from the bark: quinine (the main alkaloid),quinidine, cinchonine
and cinchonidine. Quinine is the L-stereoisomer of quinidine.
Quinine acts principally on the mature trophozoite stage of parasite development and
does not prevent sequestration or further development of circulating ring stages of P.
falciparum. Like other structurally similar antimalarials, quinine also kills the sexual
stages of P. vivax, P. malariae and P. ovale, but not mature gametocytes of P.
falciparum. It does not kill the pre-erythrocytic stages of malaria parasites. The
mechanisms of its antimalarial actions are thought to involve inhibition of parasite haem
detoxification in the food vacuole, but are not well
• Tablets of quinine hydrochloride, quinine dihydrochloride, quinine sulfate and quinine
bisulfate containing 82%, 82%, 82.6% and 59.2% quinine base, respectively.
• Injectable solutions of quinine hydrochloride, quinine dihydrochloride and quinine
sulfate containing 82%, 82% and 82.6% quinine base, respectively.
Administration of quinine or its salts regularly causes a complex of symptoms known as
cinchonism, which is characterized in its mild form by tinnitus, impaired high tone
hearing, headache, nausea, dizziness and dysphoria, and sometimes disturbed vision.
More severe manifestations include vomiting, abdominal pain, diarrhoea and severe
Hypersensitivity reactions to quinine range from urticaria, bronchospasm, flushing of the
skin and fever, through antibody-mediated thrombocytopenia and haemolytic anaemia,
to lifethreatening haemolytic-uraemic syndrome. Massive haemolysis with renal failure
("black water fever") has been linked epidemiologically and historically to quinine, but its
etiology remains uncertain.
The most important adverse effect in the treatment of severe malaria is
hyperinsulinaemic hypoglycaemia . This is particularly common in pregnancy
(50% of quinine-treated women with severe malaria in late pregnancy).
Intramuscular injections of quinine dihydrochloride are acidic (pH 2) and cause pain,
focal necrosis and in some cases abscess formation, and in endemic areas are a
common cause of sciatic nerve palsy.
Hypotension and cardiac arrest may result from rapid intravenous injection.
Intravenous quinine should be given only by infusion, never by injection.
Quinine has been used as an abortifacient, but there is no evidence that it causes
abortion, premature labour or fetal abnormalities in therapeutic use.
Overdosage of quinine may cause oculotoxicity, including blindness from direct retinal
toxicity, and cardiotoxicity, and can be fatal.
Cardiotoxic effects are less frequent than those of quinidine and include conduction
disturbances, arrhythmias, angina, hypotension leading to cardiac arrest and circulatory
failure. Treatment is largely supportive, with attention being given to maintenance of
blood pressure, glucose and renal function, and to treating arrhythmias.
Antiarrhythmics, such as flecainide and amiodarone, should be avoided. There might be an increased risk of ventricular arrhythmias with antihistamines such as terfenadine, and with antipsychotic drugs such as pimozide and thioridazine. Halofantrine, which causes marked QT prolongation, should be avoided but combination with other antimalarials, such as lumefantrine and mefloquine is safe. Quinine increases the plasma concentration of digoxin. Cimetidine inhibits quinine metabolism, causing increased quinine levels and Rifampicin increases metabolic clearance leading to low plasma concentrations and an increased therapeutic failure rate.
Treatment for Osteosarcoma Lung Metastasis in Dogs Metastasis is more common in dogs with appendicular osteosarcoma, hemangiosarcoma, and chondrosarcoma. Metastasis is rare in dogs with axialtumors, except for osteosarcoma of the ribs, scapula or pelvis.1 The diagnosis of osteosarcoma with metastatic disease is historically associated with apoor prognosis for long term survival. One study showed that dogs with a Stage III osteosarcoma (distant metastasis) showed a median survival timeof 76 days, with a range of 0-1583 days with various treatment options including surgery, palliative radiation therapy, and chemotherapy (Boston etal, JAVMA 2006).In other words, without any treatment, the prognosis for this stage of osteosarcoma is about two months. With treatment, about six months.