The burden of “Neglected Diseases”: resistance to drugs or ...cdm.unimo.it/home/dipfarm/costi.mariapaola/Bisoffi.pdf · The burden of “Neglected Diseases”: resistance to drugs

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The burden of “Neglected Diseases”:

resistance to drugs or resistance to

care about the health of the poor?

Zeno Bisoffi, Centro per le Malattie Tropicali, Ospedale

Sacro Cuore, Negrar (Verona)

Medicinal Chemistry in Parasitology

Modena, 23 January 2004

Global Burden of Infectious Diseases

• Infectious Diseases = 32% of Total Global Deaths

• Infectious Diseases = 68% of deaths in Africa

WHO,WHR, 2001

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Neglected diseases

“Neglect” = to give not enough

care or attention to something

that is of your responsibility

Health Burden of Malaria

•400-900 million febrile

infections/year

•0.7-2.7 million deaths/year,

>75% African children

•<20% come to attention of

the health system

WHO

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Plasmodium life cycle

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Uncomplicated Uncomplicated

malariamalariaClinical featuresClinical features

•• FeverFever

•• Malaise and Malaise and headacheheadache

•• Chills Chills and and sweatingsweating

•• MyalgiaMyalgia

Uncomplicated Uncomplicated malaria malaria is not immediately is not immediately life life threatening threatening

but must be treated but must be treated promptlypromptly((failure tofailure to diagnosediagnose and and treat uncomplicated treat uncomplicated malaria can malaria can rapidlyrapidly leadlead to to severe severe

malaria)malaria)

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TheThe central pathological featurescentral pathological features of severe of severe

malaria are: malaria are:

•• SequestrationSequestration ofofparasitised parasitised erythrocyteserythrocytes in thein themicrovasculaturemicrovasculature of of thethe brain brain and and other other internal organsinternal organs

•• Local effectLocal effect ofofproinflammatory proinflammatory citokines produced citokines produced in in excess excess (TNF, IL2…(TNF, IL2…

Severe malariaSevere malaria

•• impaired consciousness impaired consciousness / / unrousable unrousable comacoma

•• respiratory distressrespiratory distress ((acidosisacidosis) )

•• acute acute renal failurerenal failure

•• pulmonary oedemapulmonary oedema ((radiologicalradiological))

•• abnormal bleedingabnormal bleeding

•• severe severe normocyticnormocytic anemia (Hg < 5 g/dl) anemia (Hg < 5 g/dl)

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•• childrenchildren 11--3 3 years years in in hyperendemic areashyperendemic areas

•• adultsadults and and elderly childrenelderly children in in ipoendemic areasipoendemic areas

•• travellers from travellers from non non endemic areasendemic areas

•• pregnant womenpregnant women

Severe falciparum malariaSevere falciparum malaria

Who is mostly Who is mostly at at riskrisk

Triggering factorsTriggering factors:: Delayed diagnosisDelayed diagnosis

Delayed Delayed treatmenttreatment

History and frustration of

malaria control

• 1955: Global Malaria Eradication Campaign (W.H.O.): insecticide spraying

• 1955: first report of dieldrin resistance in Nigeria

• Mass chemotherapy (chloroquine, pyrimethamine, medicated salts)

• Rapid spread of resistance

(>> pyrimethamine)

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Permethrin impregnated bed nets

PLUS

timely access to effective

treatment

ACTUAL STRATEGIES OF MALARIA CONTROL

History of malaria chemotherapy162 BC - Artemisinin

1712 – Torti describes the specific action of the cinchona bark on intermittent fevers (probably known for centuries by incas)

1920s - Primaquine

1930s - Pyrimethamine

1940s – Chloroquine, Proguanil

Late 1940s - Amodiaquine

1950s – Sulfadoxine, Atovaquone

1966 - Doxicycline

1970s – WRAIR identifies WR142490 as a suitable antimalarial

1980s – WRAIR identifies halofantrine as an antimalarial agent

2000s – Artemisinin, once again

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Resistance to antimalarial drugs

1940

Chloroquine

16 years

Fansidar

6 years

Mefloquine

4 years

Atovaquone

6 months

1950 1960 1970 1980 1990

Barry R. Bloom, 2001

Resistance to antimalarial drugs:

CLQ, SP

• R to chloroquine:mutation of pfCRT gene

• Starting frequency very low

• Replaced quinine before significant R to

quinine was observed

• R to SP: mutation of DHFR and/or DHPS

• Starting freq much higher, faster spread of R

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Resistance to antimalarial drugs:

quinine

• Very difficult to select for R in vitro

• Several genes required

• Starting freq exceedingly low

quinine

• Quinine still very effective vs. virtually all

African isolates

• First choice in imported malaria

• Problems of compliance (7 days)

• 3 d. course plus SP equally effective

• Only weapon for severe malaria until

recently

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Artemisinin derivatives

• Similarly to quinine, very difficult to select

for R in vitro (multiple genes required?)

• Association should keep the starting freq of

R even lower

Actual strategy: combination

therapies

• Rationale: starting freq of R strains

• Drug A freq 0.005%, Drug B 0.0001% then:

• A+B 0.005x 0.0001=0.0000005%

• Constraint: COST!!!

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Research needs

• Fixed-dose, short term combinations

(increase compliance)

• Safe in pregnancy

• Drugs with multiple effects on the parasite

metabolism (more mutations required for R)

“Truly neglected diseases”

• African trypanosomiasis (“sleeping sickness”)

• American trypanosomiasis (“Chagas”)

• Visceral leishmaniasis (“Kala azar”)

• Only injectable drugs, long treatment

• Serious side effects

• Lack of any effective treatment (Chagas)

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Visceral leishmaniasis (“Kala azar”)

estimated 60 thousand deaths per year

Visceral leishmaniasis (“Kala azar”)

• Zoonosis (difficult control): dogs reservoir

of L. infantum in Italy

• In India man only significant reservoir

(good news) but: failures of antimonials

known for > 20 years

• R now widespread

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Visceral leishmaniasis (“Kala azar”)

• Pentavalent antimonials: long, parenteral

treatment, high toxicity, R

• Alternatives: amphotericin B (toxic), lipid

associated amphotericin B (out of reach)

• Miltefosine (tolerated, orally administerd)

in phase IV trial: but long half life and

teratogenic potential

Visceral leishmaniasis (“Kala azar”):

future drugs

• Aminosidine (an aminoglycoside):

promising and extensively studied,

production stopped by manufacturer…

• Sitamaquine oral compound but slow

development, still in phase I-II

• Other??

• Shift to combination treatment to delay R?

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American trypanosomiasis

• First cause of cardiovascualr deaths in

endemic areas os Latin America

• Virtually untreatable disease (both

nifurtimox and benzimnidazole only

effective in acute phase, but acute phase

almost never diagnosed!)

African trypanosomiasis: epidemiology

Source:

W.H.O.1997

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African trypanosomiasis: epidemiology

Source: W.H.O.

at least 50 thousand deaths per year

African trypanosomiasis: clinical features

• late stages T. gambiense

– severe wasting

– somnolence

– CNS signs

• both forms are always fatal without treatment

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African trypanosomiasis: treatment of neurological phase

• if evidence of CNS involvement: melarsoprol (Mel B)

• Introduced in 1949!!

• drug-related mortality up to 5%!!

• uncertainty about diagnosis may lead to death from unnecessary treatment!!

• relapses may occur

African trypanosomiasis: treatment of neurological phase

• Eflornithine (1979: from oncologic research)

• First used for A.T. in 1981

• Much better tolerated

• Only drugs for MelB failures

• Withdrawn from the producing firm for economic reasons in late 90ies!!!

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“Eflornithine story…”

• Now re-introduced for AT

• Oral formulation being tested

• And that's wonderful news!

• How shall we treat A.T. in the future??

Anti-helmintic drugs

• Virtually all come from veterinary research!!

• R not widespread (most data from vet

medicine…)

• Good example of lack of access/availability

(schistosomiasis alone: 15,000 deaths/year,

despite praziquantel effective at single dose!)

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Concluding remarks

• Real risk to be left without any effective

treatment for many parasitic diseases

• R&D of “orphan drugs” cannot be left

entirely to the “God” Market

• Public responsibility of rich countries, if we

still think that health is a Human Right