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JPNDDS
Journal of Pharmaceutics and NDDS
Editorial
Open Access
Ameliorating the Anti-Malarial Efficacy of Frontline Therapy
in Conjugation with Neuroprotective Agents
Vanka Ravisankar*1 and Gowthamrajan Kuppusamy2
Department of Pharmaceutics, JSS College of Pharmacy, Ootacamund, Jagadguru Sri Shivarathreeswara University, Mysuru, India
1,2
*Corresponding Author:
Vanka Ravisankar
JSS College of Pharmacy, Ootacamund, Jagadguru Sri Shivarathreeswara University, Mysuru, India
Email: [email protected]
Received on: February 20, 2017 | Accepted on: February 20, 2017 | Published on: March 13, 2017
Citation: Vanka Ravisankar et al. Ameliorating the Anti-Malarial Efficacy of Frontline Therapy in Conjugation with Neuroprotective Agents. J Pharma and NDDS 2017;
1(1): 19-20. doi: 10.00000/jpndds.2017.104
Copyright: © 2016 Vanka Ravi et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY)
(http://creativecommons.org/licenses/by/4.0/) which permits commercial use, including reproduction, adaptation, and distribution of the article provided the
original author and source are credited.
Published by Scientific Synergy Publishers
Editorial
Malaria is still the world’s dangerous parasitic disease and life threatening disease that is responsible for high morbidity and
mortality especially in tropical and sub tropical regions of the world. This mainly affects the children in African region and adults
in South East Asia. In humans malaria is caused by five various blood borne Apicomplexan parasite species of genus Plasmodium:
Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi [1,2,3]. Among the Plasmodium species P. falciparum and P.
vivax are most lethal. The parasite has a complex (two phase) life cycle that is divided into a vertebrate indefinite host (humans/
animals) and an insect vector definite host (mosquito). It undergoes sexual stages in mosquito and traverse through liver stage
in human before entering into the clinically active blood stage.
Cerebral Malaria (CM), is a fatal neurological complication
of P. falciparum and P. vivax is characterized frequently by
coma, febrile illness with convulsions, other neurological
impairments [4,5]. World Health Organization (WHO) defines
CM as unarousable coma in a patient in whom the presence of P.
falciparum asexual parasitemia has been demonstrated, after
other causes of encephalopathy have been excluded. Some
surviving patients have an increased risk of neurological and
cognitive deficits, behavioural difficulties, sensory disorders
and epilepsy (collectively known as post malaria neurological
sequelae.), making CM a leading cause of childhood
neurodisability in the malaria transmission area [6]. The risk of
CM is significantly higher in high-endemic areas than in lowendemic areas [7]. Several processes have been implicated in
CM pathogenesis, micro-vascular obstruction by P. falciparum,
P. vivax Infected Red Blood Cells (IRBCs), production of
excessive
pro-inflammatory
cytokine,
micro-vascular
thrombosis, loss of endothelial barrier dysfunction and
endothelial deregulations.
There were 214 million new cases of malaria and an
estimated 4,38,000 malaria deaths worldwide have been
reported in 2015. The African Region accounted for most global
cases of malaria (90%) followed by the South-East Asia Region
J Pharma and NDDS 2017
(7%) and the Eastern Mediterranean Region (3%). Children
under five years of age are more susceptible to malaria illness,
infection and death. Malaria killed an estimated 3,06,000
globally, including 2,92,000 children in African Region in 2015
[8]. CM kills more than 1 million children each year in Africa.
Anti- malarial agents are administered parent rally to
patients with severe malaria, because gastrointestinal
absorption may be erratic. Oral treatment is not possible in CM.
In a life-threatening situation such as severe malaria, all efforts
should be directed to ensuring that effective levels of these
drugs are attained in patients. The frontline drugs are quinine
(i.v. or i.m.), quinidine (i.v.) and first generation of artemisinin
derivatives, artemether (i.m.) and artesunate (i.v. or i.m.) [9,10].
However, artemisinin derivatives have an edge over quinine
due to their better safety profile and fewer side effects [11].
Despite, front line therapy with quinine or artemisinin
derivatives and intensive care is quite effective against the P.
falciparum and P. vivax related uncomplicated malaria, however
the mortality from cerebral malaria and other forms of the
severe malaria is still very high i.e. 10-25% [12,13], and the
survivors who recovered from the disease are still suffering
from long term neurological impairments (CM) especially in
children of below 5 years old. The front line therapy with anti-
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malarial agents may effectively reduce the parasite burden but
it may fail to regulate the neurological impairments and
cognitive deficits associated with parasite sequestration even
after elimination [4, 14].
Any additional drug therapy administered in combination
with the front line therapy that modifies altered physiological
processes during malaria is referred as adjunctive therapy.
These therapies may act directly on specific biological pathways
altered by malaria or more generally on end-stage factors
produced in malaria by a number of different specific processes.
Thus several targets were selected among factors believed to be
key in the path physiological processes of severe malaria (e.g.
elevated levels of TNFα or low levels of NO) or agent that
control end-stage factors associated with poor clinical outcomes
(e.g. hypovolemia or metabolic acidosis) [15]. Adjunctive
therapy may help to save the patient but not an alternative for
anti-malarial treatment [16]. Considering the fact that the multi
factorial nature of the neuropathology even the most effective
anti-malarial drugs cannot ensure complete survival [11,17,18]
and due to the poor understanding of its pathogenic processes,
candidate adjunctive therapies to decrease in CM have been
unsuccessful so far [15-20].
Gross neurological impairment occurs in 10% of children
surviving CM and long term alterations in behaviour and
cognition may be more common [4]. Hypoxia-reoxygenation is
Drug/Therapeutics
Mode
Experimental model used
Levetiracetam
Single
2-6 years children (HCM)
Erythropoietin
Combination with
6 months-14 years children
quinine
a potent cause of neurological damage in the developing brain,
and these insults may affect neuronal function and integrity.
Free radicals, cytokines and excitatory amino acids may
contribute to neural damage. Neuroprotective agents or no
tropic agents are compounds that improve mental functions
such as cognition, memory, intelligence, motivation attention,
and concentration. They act by variety of mechanisms. A
compound having anti-oxidant, anti-inflammatory, and antiapoptotic properties or effective reversal of blood brain barrier
leakage or its downstream effects may be an example of this
class. The following neuroprotective compounds are explored
in the treatment of Human Cerebral Malaria (HCM) and
Experimental Cerebral Malaria (ECM) as adjunctive therapy.
Conclusion
CM is associated with high fatality rates and long term
neurological impairments despite optimal anti-malarial therapy
and intensive care. There is an urgency need of adjunctive
therapeutic interventions that improve the outcome of CM in
terms of reducing the mortality and improving neurocognitive
outcome in survivors. The neuroprotective agents might be
useful in this context of CM by reducing the mortality, shorten
the duration of coma and diminishing the severity of
neurological impairments and cognitive deficits.
Outcome/Conclusion
References
Treatment of seizures, epilepsy and improves CM outcome in African children
These data provide the first evidence of the short-term safety of erythropoietin
at higher doses combined with quinine; however efficacy studies not yet
reported
[21]
Rosiglitazone PPAR
gamma agonist
AtovaquoneProguanilCombined
14-56 years patients (Severe
malaria)
Decreases the levels of pro-inflammatory factors (IL-6 and MCP-1); elevates
BDNF levels (day2) and lowers Ang-2/Ang-1 ratio (day3)
[22] Heme-Oxigenase1(HO-1) and carbon
monoxide (CO)
Adjunctive
C57BL/6 mice BALB/c mice
Decreases parasitemia, prevents BBB disruption, brain microvasculature
congestion, neuro-inflammation and CD8+ T-cell brain sequestration during
ECM
[23]
Pressurized oxygen
(HBO) therapy
Adjunctive
C57BL/6 mice
Prevents ECM signs; reduces expression of TNF, IFN-γ and IL-10 mRNA
levels and percentage of γδ and αβ CD4+ and CD8+ T cell sequestration,
prevents BBB dysfunctiuon
[24]
Thiol pantethine
Adjunctive
CBA/J female mice
Down regulated platelet reactivity, decreases the circulating microparticles and
protects BBB integrity
[25]
[22,26]
Rosiglitazone PPAR
gamma agonist
Adjunctive
C57BL/6 mice
As an agonist of Peroxisome proliferator-activated receptor-γ (PPARγ),
modulates host inflammatory responses and improves the clinical outcome in
ECM; prevents the development of brain atrophy and neurocognitive
impairment
Erythropoietin
Single
C57BL/6 mice
Reverses the development of ECM and degree of neural hypoxia; reduces
clinical signs of CM and cerebral pathology features
[27, 28]
Leads endothelial protection and reduction in BBB permeability; neuroprotective nature, decreases mortality
[29,30,31]
Neuregulin-1
(NRG-1)
Single; compared Adult male Sprague-Dawley
with artemether
rats
Citicoline
Adjunctive
Female CBA mice
Citicoline reduces the production of microparticles in vitro; confers protection
against ECM
[32]
Fasudil
Single
ICR mice C57BL/6 mice
No significant effect on parasitemia, survival of the treated mice were
significantly increased and cerebral malaria development was either delayed or
prevented
[33,34]
Curcumin
Single
C57BL/6 mice ICR mice
No significant effect on parasitemia, survival of the treated mice were
significantly increased and cerebral malaria development was either delayed or
prevented
[34]
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