Paracetamol Effect on Oxidative Stress and Renal Function in Severe Malaria
Information source: University of Oxford
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Malaria
Intervention: Paracetamol (Drug); No Paracetamol (Drug)
Phase: N/A
Status: Recruiting
Sponsored by: University of Oxford Official(s) and/or principal investigator(s): Katherine Plewes, MD, Principal Investigator, Affiliation: University of Oxford
Overall contact: Katherine Plewes, MD, Phone: +6683-821-4103, Email: katherine@tropmedres.ac
Summary
Blackwater fever, characterized by intravascular haemolysis and hemoglobinuria, is an
important cause of renal impairment and mortality in severe malaria caused by Plasmodium
falciparum. The largest malaria clinical trials report blackwater incidences of 5-7% in
Asian adults and 4% in African children with severe malaria treated with artesunate or
quinine. The prevalence of blackwater fever in Chittagong, Bangladesh is 15% with associated
rates of renal failure and mortality of 42. 9% and 14. 2% respectively.
The fundamental characteristic of blackwater fever is the presence of intravascular
hemolysis of both infected and uninfected erythrocytes and release of free haemoglobin. The
cytotoxic free haemoglobin present can cause severe oxidative damage as a result of haem
redox cycling yielding ferric and ferryl heme, which generate radical species that induce
lipid peroxidation and subsequent production of F2-isoprostanes (F2-IsoPs). Evidence
suggests that F2-IsoPs generated by the hemoprotein-catalyzed oxidation of lipids are
responsible for the oxidative damage and vasoconstriction associated with renal injury in
haemolytic disorders and rhabdomyolysis.
A novel mechanism of paracetamol was recently demonstrated, showing that paracetamol is a
potent inhibitor of hemoprotein-catalyzed lipid peroxidation by reducing ferryl heme to its
less toxic ferric state and quenching globin radicals. In a recent proof of concept trial,
paracetamol at therapeutic levels was shown to significantly decrease oxidant kidney injury,
improve renal function and reduce renal damage by inhibiting the hemoprotein-catalyzed lipid
peroxidation in a rat model of rhabdomyolysis-induced renal injury. Since adults with severe
malaria demonstrate increased concentrations of cell-free haemoglobin, and urinary F2-IsoPs,
the investigators hypothesize that this novel inhibitory mechanism of paracetamol may
provide renal protection in this population by reducing the hemoprotein-induced lipid
peroxidation. As there is currently no consensus that exists concerning adequate medical
treatment for blackwater fever, the potential application of this safe and extensively used
drug would be of great benefit.
Clinical Details
Official title: Paracetamol Effect on Oxidative Stress and Renal Function in Severe Falciparum Malaria With Intravascular Haemolysis: A Randomised Controlled Clinical Trial
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Effect of paracetamol concentrations
Secondary outcome: Compare treatment arm with control arm with respect to duration of Acute Kidney Injury (AKI) and development of AKI.Oxidative stress assessed by measuring F2-isoprostanes (F2-IsoPs) Assessment of Blackwater fever Mortality trends Intravascular Haemolysis Fever clearance time Parasite clearance time Parasite sequestration Assessment of Acute Kidney Injury Creatinine clearance Safety assessment assess the antimalarial drug sensitivity of patients treated with paracetamol
Detailed description:
Mortality in severe malaria remains ~15% despite the best available parasiticidal
antimalarial therapy, intravenous artesunate. Adjunctive therapies in combination with
anti-parasitic drugs have the potential to improve outcomes. However, currently there are no
proven adjunctive therapies for the treatment of severe malaria, which can improve
case-fatality when used in combination with anti-parasitic drugs. This research proposal
focuses on exploring if paracetamol prevents renal dysfunction caused by free haemoglobin
induced oxidative damage in severe malaria.
Blackwater fever epidemiology As early as the 1800s, blackwater fever complicating severe
malaria caused by Plasmodium falciparum was recognized as an important cause of morbidity
and mortality, with a 25-30% mean mortality rate. The etiology and pathogenesis is poorly
understood but it is characterized by massive intravascular haemolysis and passage of black
or red urine, which can lead to renal impairment and death. This manifestation was linked to
quinine therapy as its occurrence nearly disappeared during the chloroquine era from 1950 to
1980. Since 1990, the resurgence in the number of cases noted in both malaria-free and
malarious areas in non-immune and immune individuals has generated renewed interest into
this manifestation of severe malaria. The largest malaria clinical trials report blackwater
fever incidences of 7% and 4% in Asian adult patients with severe malaria treated with
artesunate and quinine, respectively and 4% in African children treated with either drug.
The prevalence of blackwater fever in Chittagong, Bangladesh was recently determined in a
pilot study to be 15% with associated renal failure and mortality rates of 42. 9% and 14. 2%
respectively.
Blackwater fever pathogenesis Although the exact mechanism linking falciparum malaria and
blackwater fever is uncertain, numerous explanations have been suggested. It has been
proposed to occur in 4 specific circumstances: (1) in case patients with G6PD deficiency
with or without malaria who take oxidant drugs (primaquine) (2) in case patients with G6PD
deficiency and malaria untreated and treated with quinine (3) when patients (normal G6PD)
with severe malaria are treated with quinine (4) when people exposed to malaria
self-medicate with quinine or related amino-alcohol drugs. However, new circumstances of
blackwater fever have emerged, occurring in patients with normal G6PD levels with severe
malaria who have received artesunate rather than quinine.
Role of oxidative stress and free haem The fundamental characteristic of blackwater fever is
the presence of massive haemolysis of both infected and uninfected erythrocytes and release
of free haemoglobin. The free haem is highly cytotoxic, and an important scavenger of nitric
oxide, promoting endothelial damage and is proposed to be involved in the pathogenesis of
renal injury and cerebral malaria. When the degree of intravascular haemolysis exceeds the
capacity of plasma haptoglobin to bind the haemoglobin released from red blood cells, free
haemoglobin is then filtered by the glomeruli and enters the renal tubules. In a series of
renal biopsies, fine and coarse haemoglobin granules are present in the proximal tubules,
while haemoglobin casts and granular casts predominate in the distal and collecting tubules
in patients with blackwater fever and intravascular haemolysis. This classic theory of
renal damage by tubular precipitation is challenged by recent findings of reversing
oxidative properties of free haem can prevent renal damage. The free haemoglobin present is
pathogenic as the ferrous haem can be oxidized to the ferric state (FeIII) subsequently
conferring peroxidase activity to the haemoglobin. Consequently, the haemoglobin can reduce
hydroperoxides, such as hydrogen peroxide (H2O2) and lipid hydroperoxides, which generate
the ferryl state (FeIV=O) of haemoglobin and a globin protein radical.
Haem Fe(III) protein + H2O2 - -> haem [Fe(IV)=O] protein• + H+ + H2O The ferryl haem and
protein radical can then generate lipid radicals by oxidation of free and
phospholipid-esterified unsaturated fatty acids. The arachidonic side chains of membrane
phospholipids are particularly vulnerable to this free radical-mediated damage in the
complex cascade of lipid oxidation leading to the generation of F2-isoprostanes (F2-IsoPs).
Evidence suggests that F2-isoPs generated by the haemoprotein-catalyzed oxidation of lipids
are responsible for the oxidative damage and vasoconstriction associated with renal injury
in the setting of hemolytic disorders and rhabdomyolysis.
Paracetamol and oxidative stress A novel mechanism of paracetamol was recently demonstrated,
showing that paracetamol acts as a potent inhibitor of haemoprotein-catalyzed lipid
peroxidation by reducing ferryl haem to its less toxic ferric state and quenching globin
radicals. This effect is enhanced 14-fold in an acidic milieu. In a recent proof of concept
trial, paracetamol at therapeutic levels was shown to significantly decrease oxidant injury
in the kidney, improve renal function and reduce renal damage by inhibiting the
haemoprotein-catalyzed lipid peroxidation, mediated by redox cycling of the haem moiety of
myoglobin, in a rat model of rhabdomyolysis-induced renal injury.
Rationale Since adults with severe malaria and blackwater fever associated with haemolysis
demonstrate increased concentrations of cell-free haemoglobin, severe acidosis and urinary
F2-IsoPs, the investigators hypothesize that this novel inhibitory mechanism of paracetamol
may provide renal protection in this population by reducing the haemoprotein-induced lipid
peroxidation. As there is currently no consensus that exists concerning adequate medical
treatment for blackwater fever, the potential application of this safe and extensively used
drug would be of great benefit.
Proposed activities The main activity proposed is a randomised open label controlled study
of paracetamol in patients with severe falciparum malaria to assess its modulating effect on
renal function and oxidative stress.
Eligibility
Minimum age: 12 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Patient age >12 years
2. Presence of severe or moderately severe P. falciparum malaria, with and without
blackwater fever, confirmed by positive blood smear with asexual forms of P.
falciparum
3. Temperature >38 degrees Celsius on admission or fever during the preceding 24hours
4. Written informed consent from patient or attending relative able to and willing to
give informed consent. Consent form and information sheets will be translated into
Bangla and copies provided to the patient.
Exclusion Criteria:
1. Patient or relatives unable or unwilling to give informed consent
2. History of chronic liver disease
3. History of alcohol use (>3drinks per day)
4. Contraindication or allergy to paracetamol or artesunate therapy
5. Contraindication to nasogastric tube insertion i. e. facial fracture, bleeding
diathesis
6. Pregnancy
Locations and Contacts
Katherine Plewes, MD, Phone: +6683-821-4103, Email: katherine@tropmedres.ac
Chittagong Medical College Hospital, Chittagong, Bangladesh; Recruiting Katherine Plewes, MD, Phone: +6683-821-4103, Email: katherine@tropmedres.ac Katherine Plewes, MD, Sub-Investigator
Additional Information
Starting date: July 2012
Last updated: June 10, 2014
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