• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
malaria checkout
 

malaria checkout

on

  • 3,135 views

 

Statistics

Views

Total Views
3,135
Views on SlideShare
2,722
Embed Views
413

Actions

Likes
1
Downloads
0
Comments
0

4 Embeds 413

http://www.webicina.com 409
http://www.slideshare.net 2
http://translate.googleusercontent.com 1
http://www.google.com.eg 1

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    malaria checkout malaria checkout Presentation Transcript

    • Malaria therapy Issues, Challenges & opportunities
    • Topics for discussion
      • Background of malaria
      • Malaria life cycle
      • Complications of malaria
      • Combination therapy in malaria
      • Artemether – lumefantrine combination
      • Dosage
      • Summary
    • Background of Malaria today Analysis
    • Types of malaria Malaria Vivax Falciparum Plasmodium vivax Plasmodium falciparum Morbidity Mortality Plasmodium
    • Burden of malaria
      • Direct
        • Clinical episodes
        • Cerebral malaria
        • Severe anemia
      • Indirect and comorbid
        • Maternal anemia
        • Low birth weight
        • Impaired child development
        • Poor school performance
        • HIV infection 2/2 transfusion
      • Economic
        • Health system costs
        • Household costs
        • Decreased productivity
        • Reduced economic growth
      ~ 1 deaths ~ 5 severe cases ~ 500 clinical cases ~ 5,000 febrile episodes Numbers in millions
    • Spread of malaria
      • The anopheles mosquito serves as the vector to transmit Malaria to human beings.
      • And in that also, it is the female anopheles mosquito that is responsible for the transmission.
      • This mosquito bites man usually between 5 p.m. and 7 a.m. with maximum intensity at midnight.
      • Anopheles mosquitoes breed in stagnant pools of water.
      • Transmission time of malaria, is 10 days after an infective blood meal during which it must bite a susceptible human host.
    • Lifecycle of Malaria A close understanding
    • Cycle of malaria
    • Cycle of malaria
    • Cycle of malaria
    • Cycle of malaria
    • Cycle of malaria
    • Cycle of malaria
    • Cycle of malaria
    • Cycle of malaria
    • Cycle of malaria
    • Complications of falciparum Malaria An in depth perspective
    • Why is falciparum dangerous ?
      • Increased red cell adhesiveness
      • Decreased peripheral capillary tone
      Pathogenesis Of malaria Circulatory Immunological Metabolic Cytokines Adhesion Cytokines Humoral Vasoactive Enzyme defects
    • Why is falciparum dangerous ?
      • Increased red cell adhesiveness
      • Decreased peripheral capillary tone
    • Why is falciparum malaria fatal ?
      • Resistant to common antimalarials
      • Each cycle releases 20 times more merozoites than vivax
      • Early hemolysis and endotoxins release, cerebral toxicity
      • Bilirubin load affects kidneys, liver
      • Hypovolemia and shock occur
    • 14 Complications of malaria
      • Coma
        • cerebral malaria,
        • convulsions
      • Renal failure
        • black water fever
      • Hyperpyrexia,
      • Acute pulmonary edema
      • Hemolytic Jaundice,
      • Severe bleeding
      • Hypovolemic shock,
      • Hypoglycemia
      • Metabolic acidosis, Coagulopathy,
      • Severe anaemia, hyperparasitemia
    • Case management
      • Cases of malaria should be treated within 24 hours of the onset of symptoms with-
        • correct,
        • affordable, and
        • appropriate treatment
      • Benefits
        • Cure infection
        • Prevent progression
        • Reduce transmission
    • Problems of Malaria therapy today Globally
    • Control strategies Strategies for control of malaria Vector control Preventive treatment Case management Epidemic response
    • Choice of therapy Choice of antimalarials Safety Costs Ease of use
    • Choice of antimalarials
    • Resistance to Chloroquine Countries with at least one study indicating chloroquine total failure rate > 20% No recent data available Countries with at least one study indicating chloroquine total failure rate > 10%
    • Resistance to SP Countries with at least one study indicating sulfadoxine-pyrimethamine total failure rate > 20% No failure reported Sulfadoxine-pyrimethamine total failure rate < 10% No recent data available Countries with at least one study indicating sulfadoxine-pyrimethamine total failure rate > 10%
    • Consequences of resistance
      • Recurrence of symptoms (insidiously later frequently)
      • Anaemia
      • High probability of carrying gametocytes (with resistant genes)
      • High malaria incidence and mortality
    • Slowing resistance emergence
      • Avoid widespread and indiscriminate use of antimalarials
      • Combine antimalarials with different mechanism of action
        • concept of CT [combination therapy]
      • Ensure high cure rates through full adherence to regimens & dosing schedules.
    • Therapy issues in malaria Uncomplicated malaria Severe malaria
      • Cure infection and prevent progression to Severe malaria
      • Prevent additional morbidity from treatment failure
      • Reduce transmission to others
      • Prevent resistance
      • Save life
      • Prevent recrudescence & neurological deficit
    • Recommendations in Malaria therapy Current
    • Current therapy recommendations
      • WHO recommends CT, principally ACT
        • The Basis is to exploit the potential of 2 or more simultaneously administered schizontocidal drugs with independent mode of action:
          • to improve efficacy and
          • to delay the development of resistance
    • What is ACT ?
      • Artemisinin-based combination therapy (ACT) is an antimalarial combination therapy with an artemisinin derivative as one component of the combination given for at least 3 days.
    • Why ACT?
      • Rapidly acting and effective antimalarial treatments
        • Rapid parasite clearance
        • Rapid resolution of symptoms
        • Active on all 4 species of malaria parasites
        • Reduce gametocyte carriage and hence transmission
      • In the rare event of resistance to one of the drugs during the course of the infection, the parasite will be killed by the other drug
    • Why ACT?
      • Artemisinin compound clears most but not all parasites very rapidly
      • Artemisinin when used alone requires a 7 day regimen to prevent recrudescences
      • Partner drug in 3 day regimens is needed to eliminate residual parasites
      • Choice of partner drug depends on resistance patterns, efficacy, cost, tolerability
      0 1 2 week artemisinin level partner level parasitemia
    • What are Artemisinins ? Artemisinin derivatives Qinghaosu (&quot;ching-how-soo&quot;) Methyl Ether Hemisuccinate Ethyl Ether Arteether Artesunate Artemether Dihydroartemesin
    • What are Artemisinins ? Qinghaosu (&quot;ching-how-soo&quot;)
    • Why Artemisinins ?
      • Artemisinin derivatives have short half-life of 2-3 hours, which means that they can produce substantial recrudescence* when used alone for less than 5 days.
      • Hence, a combination of 2 or more antimalarials that contain an artemisinin derivative carries a smaller risk of malaria parasites developing resistance to it, since action can then go on for a longer period of time.
      Recrudescence : a return of malaria after a period of abatement
    • Why Artemisinins ?
      • Such a combination -
        • Facilitates compliance,
        • Enables prompt action fo the artemisinin and sustained slow action fo the partner antimalarial.
        • Prevents patients from taking either drug alone, and thereby prevents the development of resistant Plasmodium strains.
    • Why Artemisinins ?
      • Rapid substantial reduction of the parasite biomass
      • Rapid resolution of clinical symptoms
      • Effective action against multi-drug resistant P. falciparum
      • Reduction of gametocyte carriage
      • No documented parasite resistance yet
      • Few reported adverse effects.
    • WHO recommendations
      • Since 2006, WHO strengthens recommendations
      • ACTS should be:
        • first-line treatment for falciparum malaria everywhere
        • in fixed-dose combinations when possible
        • To start with, coblistering to prevent mono therapy is fine
      • ACTS:
      • Co-formulated artemether-lumefantrine
      • Co-packaged artesunate-amodiaquine
      • Coarsucam
      • Dihydroartemisinin-piperaquine
      WHO recommendations
    • AL in Malaria therapy Artemether - Lumefantrine
    • Artemether-Lumefantrine (AL)
      • Each coartemether tablet contains:
        • artemether(20 mg), a synthetic derivative of artemisinin &
        • lumefantrine (120 mg), a highly lipophilic aryl amino alcohol.
    • Artemether-Lumefantrine (AL)
      • AL contains 20 mg artemether and 120 mg lumefrantrine at a ratio of 1:6.
      • Artemether is fast acting with a short half-life while Lumefantrine acts more slowly and has a longer half-life.
      • AL is a 24 dose, 3 day treatment regimen.4 in the morning, 4 in the evening for 3 days.
    • Artemether-Lumefantrine (AL)
      • AL is very fast acting, within 4 hours of using, the patient feels better, in twelve hours he feels cured of malaria.
      • If a child gets better before finishing all the doses, a misinformed parent will want to save the remaining doses for the next time there a case of malaria.
      • However, failing to finish all the doses of the treatment causes recrudescent malarial infections.
    • The background
      • Lumefantrine has a much longer elimination half-life (several days) than artemether, and is associated with a low recrudescence rate, but has a slower onset of action.
      • However, when used together, the complementary properties of artemether with its fast onset of action and lumefantrine with its long duration of action and high cure rate result in a highly effective combination.
    • Mechanism of action
      • The precise antimalarial action of lumefantrine and artemether is unknown, although both appear to act on the parasite’s organelles, where they are thought to interfere with the conversion of haem to nontoxic compounds.
      • Artemether contains an endoperoxide bridge, which interacts with haem iron to generate reactive metabolites.
      • Lumefantrine is thought to interfere with haem polymerisation, a critical detoxifying pathway for the malaria parasite.
        • Both artemether and lumefantrine have a secondary action, inhibiting nucleic acid and protein synthesis within the parasite.
    • Results of action
      • Artemether rapidly reduces parasite biomass and quickly resolves clinical symptoms, whilst the long-acting activity of lumefantrine is thought to prevent recrudescence.
      • This dual effect also appears to reduce the selective pressure on the parasite to develop resistance.
    • Absorption
      • Under fasted conditions, artemether was rapidly absorbed, reaching peak plasma concentrations about 2 hours after dosing, whilst lumefantrine - a highly lipophilic molecule - was absorbed after a lag time of up to 2 hours.
      • Peak plasma concentrations at 6 to 8 hours
      • Under fasted conditions, the oral bioavailability of both artemether and lumefantrine was variable and low.
      • However, a high-fat meal increased the bioavailability of lumefantrine 16-fold and that of artemether more than 2-fold.
    • Distribution
      • Both artemether and lumefantrine are highly bound to human serum proteins in vitro (95-98% and >99%, respectively) - the higher fraction of artemether (33%) being distributed onto α1 -acid glycoprotein and the main part of lumefantrine (77%) being distributed onto high-density lipoprotein.
    • Metabolism
      • Artemether is rapidly and extensively metabolised by human liver microsomes with a substantial first pass metabolism.
        • The main metabolite is dihydroartemisinin, which is active.
      • Lumefantrine is also metabolised predominantly by the enzyme CYP3A4 in human liver microsomes.
        • Co-administration of compounds with low therapeutic indices and significant metabolism by CYP2D6 (e.g. neuroleptics and tricyclic antidepressants) might cause clinically relevant drug-drug interactions.
    • Elimination & excretion
      • Artemether was rapidly cleared from plasma with an elimination half-life of approximately 2-3 hours.
      • Conversely, lumefantrine is cleared more slowly, showing a terminal half-life of 2-3 days in healthy volunteers, and 4-6 days in patients with falciparum malaria.
      • Lumefantrine was eliminated through the liver and bile.
    • Artemether-Lumefantrine (AL - studies)
      • A variety of studies have evaluated the efficacy of coartemether in terms of speed & degree of parasite elimination, and have shown:
        • Fast parasite elimination
        • Prompt reduction in fever
        • Effective gametocyte clearance
        • Cure rates as good as with current options
        • Effectiveness in multi-drug resistant areas.
    • Artemether-Lumefantrine (AL)
      • A variety of studies have evaluated the efficacy of coartemether in terms of speed & degree of parasite elimination, and have shown:
        • Fast parasite elimination
        • Prompt reduction in fever
        • Effective gametocyte clearance
        • Cure rates as good as with current options
        • Effectiveness in multi-drug resistant areas.
    • Fast parasite elimination
      • Fast elimination of parasites reduces the substantial risk of a falciparum malaria infection progressing to complicated stages of the disease, and even death.
      • Coartemether
        • eliminates parasites faster than the tested competitors and
        • produces near-total parasite reduction within 24 hours.
    • Fast parasite elimination
      • Parasite clearance time: is the time needed to clear asexual parasite forms from the blood (i.e., where parasite numbers fall below the limit of detection in a thick blood smear and remain undetectable for at least 48 hours).
      • Parasite reduction at 24 hours : the percentage reduction of parasites per μL at 24 hours, compared with parasite density before the first treatment dose.
    • Fast parasite elimination
    • Fast parasite elimination
    • Fast parasite elimination
    • Artemether-Lumefantrine (AL)
      • A variety of studies have evaluated the efficacy of coartemether in terms of speed & degree of parasite elimination, and have shown:
        • Fast parasite elimination
        • Prompt reduction in fever
        • Effective gametocyte clearance
        • Cure rates as good as with current options
        • Effectiveness in multi-drug resistant areas.
    • Prompt reduction in fever
      • Fever clearance time (FCT) provides a means of measuring the degree of symptom control achieved by antimalarial treatments.
      • Fever clearance time (FCT) is the time from the first dose to the time when body temperature falls to normal and remains so for at least 48 hours.
      • Studies have shown that artemether alone and coartemether produced a median fever clearance time of 21 and 24 hours respectively (in evaluable patients), but for lumefantrine alone, median fever clearance time was much longer, at 60 hours
    • Prompt reduction in fever
    • Artemether-Lumefantrine (AL)
      • A variety of studies have evaluated the efficacy of coartemether in terms of speed & degree of parasite elimination, and have shown:
        • Fast parasite elimination
        • Prompt reduction in fever
        • Effective gametocyte clearance
        • Cure rates as good as with current options
        • Effectiveness in multi-drug resistant areas.
    • Effective gametocyte clearance
      • Gametocytes are the stages in the malaria parasite’s life cycle that give rise to the sexual reproduction phase in the intestine of Anopheles mosquitoes.
      • Since they link the vector and host infectious cycles, they are of key epidemiological importance.
      • The greater the gametocyte carriage rate from human blood to mosquitoes, the more likely that malaria will be transmitted in a particular geographical area.
      • Therefore, eradication of gametocytes will theoretically lead to extinction of malaria.
      • Drugs that are effective against gametocytes are thus important in the fight against the disease.
    • Effective gametocyte clearance
      • Gametocyte clearance time is defined as the time from the start of treatment in patients who are gametocyte-positive in blood smears at the beginning of a trial, until the first time blood films are negative, and remain so for at least 48 hours.
    • Effective gametocyte clearance
    • Artemether-Lumefantrine (AL)
      • A variety of studies have evaluated the efficacy of coartemether in terms of speed & degree of parasite elimination, and have shown:
        • Fast parasite elimination
        • Prompt reduction in fever
        • Effective gametocyte clearance
        • Cure rates as good as with current options
        • Effectiveness in multi-drug resistant areas.
    • Cure rates
      • The cure rate - the proportion of patients cured - measures the capability of a drug to destroy all malaria parasites acquired during a given infection.
      • Cure rate is usually defined as the 28-day cure rate - i.e., the proportion of patients with clearance of parasites within 7 days, and without subsequent return of the original infection during the 28-day period following the first dose.
    • Cure rates
    • Cure rates
    • Artemether-Lumefantrine (AL)
      • A variety of studies have evaluated the efficacy of coartemether in terms of speed & degree of parasite elimination, and have shown:
        • Fast parasite elimination
        • Prompt reduction in fever
        • Effective gametocyte clearance
        • Cure rates as good as with current options
        • Effectiveness in multi-drug resistant areas.
    • Safety and tolerability
      • A variety of clinical trials conducted to date revealed that coartemether was safe and very well tolerated.
        • The most commonly reported adverse effects following coartemether therapy were gastrointestinal (abdominal pain, anorexia, nausea, vomiting, diarrhoea) and those of the central nervous system (headache, dizziness). Pruritus and rash were reported by less than 2% of patients.
        • Its favourable safety profile means it can be used for all groups of patients.
    • Safety and tolerability
    • Safety and tolerability
    • Safety and tolerability
    • Safety and tolerability
    • Dosage
      • 6 dose regimen
    • Current therapy packs of AL Pack shot
    • Warning
      • Artemisinins should never be used as monotherapy
      • Artesunate combinations always given for 3 days; never single dose of AS.
      • For AL six doses must over 3 days
      • AQ or MQ or SP should never be used alone - lest drug resistance occurs
    • AL essentials
      • To ensure that all the doses of the AL are taken by the patient irrespective of therapy response, clear instructions how to properly treat malaria using 24 doses of AL, must be given to patients.
    • Summary of Lumether
      • Speed of action:
        • Parasite reduction and gametocyte reduction occur significantly faster with coartemether
        • than with competitor drugs (except the free combination of mefloquine + artesunate,
        • which also contains a fast-acting artemisinin derivative).
        • Coartemether may be better suited than competitors to reduce the risk of progression of
        • falciparum malaria to complicated stages and death. Its gametocytocidal efficacy may
        • suggest a role for coartemether in malaria eradication programs.
        • Fever clearance occurs fast with coartemether, thus helping to reduce morbidity.
    • Summary of Lumether
      • Cure rate:
        • The 4-dose regimen of coartemether (16-tablets, 320 mg artemether and 1920 mg lumefantrine given over 48 hours) achieved very good cure rates in areas without multidrug resistant strains, such as India and China.
        • In multi-drug resistant strain areas such as Thailand, very good cure rates (28-day cure rate: 96-98%) were seen with the 6-dose regimen (24 tablets, 480 mg artemether and 2880 mg lumefantrine given over 60 hours), whereas the 4-dose regimen cure rates were suboptimal.
        • The 6-dose regimen is required in AFRICA for 28-day cure rates possibly due to a high parasite burden.
    • Knowing more in Malaria therapy Beyond Artemether - Lumefantrine
    • What to give in pregnancy ?
      • In 1st trimester
        • Quinine + Clindamycin 7 days
      • In 2nd and 3rd trimesters
        • Any ACT combination as per recommendation,or
        • Artesunate + Clindamycin 7 days or
        • Quinine + Clindamycin 7 days
      • Lactating women
        • same ACT
    • Artemisinins parenteral
      • Artesunate 2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended 1 choice
      • Artemether 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day is an acceptable alternative to quinine i.v infusions
      • Rectal artemisinins – STUDIES NOT YET OVER
    • Quinine parenteral
      • A loading dose of quinine of 20 mg salt/kg bw. 10 mg/kg 8th hrly i.v infusion
      • Rate-controlled i.v. infusion is the preferred route of quinine admin.
      • If this cannot be given safely, then i.m. injection is a satisfactory alternative.
      • Rectal admin. is not effective
      • Quinidine can substitute quinine
    • Intermittent Presumptive Therapy (IPT) & Mass Drug Administration (MDA)
      • IPT programs
        • IPTp (pregnancy) - 1 dose in 2nd and in 3rd trimesters
        • IPTi (infants) - follows immunization schedule
        • employ SP+ ACTs - under evaluation
        • benefit of decreased malaria found in most studies
      • MDA has been tried many times with different drugs in different settings
        • generally unsustainable despite successes in short term
    • New drug possibilities
      • Artesunate/Pyronaridine
      • Dihydroartemisinin/Piperaquine
      • Chlorproguanil/Dapsone/Artesunate (CDA)
      • New synthetic trioxolane (OZ) compounds
      • Aminoquinolines effective against chloroquine-resistant parasites (AQ-13, Isoquine)
      • Pyridones less prone to resistance than atovaquone
      • Cysteine protease inhibitors
      • New dihydrofolate reductase inhibitors
    • The time of cheap, poorly effective antimalariafor the poor is over The time is now, for highly effective antimalarials at an affordable price for the poor
    • Amalar-XL From B&B