The potency of plant antimalarial

Malaria has remained a major cause of morbidity and mortality in all parts of the world. It is associated with high economic burden on the nation, high prevalence of mortality in children, pregnant women and non-immune individuals, thus malaria is a global public health problem. This protozoan infection is mainly characterized by fever, pains, loss of appetite and anaemia, researchers had discovered potent antimalarial drugs mainly from plant sources in order to overcome resistance of antimalarials, vectors, inability to develop malarial vaccines and also toxic effects of conventional antimalarial drugs. Antimalarials obtained from plants have significant roles in drug discovery and development for the treatment of fever, pains, inflammation as well as Plasmodium falciparum infection, therefore this review focuses on the analgesics, antipyretics and anti-inflammatory activities as well as antiplasmodial activities of plants.


Introduction
Malaria is a protozoan infection which causes the highest burden in Africa because the deadliest species (Plasmodium falciparum) is most common in Africa.It is one of the public health disease associated with high mortality rate (of about 600,000 deaths yearly) as well as morbidity [1].This deliberating disease affects mostly children under the age of five years as well as pregnant women, one death every 30 seconds is recorded because malaria causes about 400-900 million cases of fever and approximately 1-3 million deaths every year [2].
A heavy malaria burden in some countries is marked by economic impact which includes costs of health care, working days lost due to sickness, days lost in education, reduced productivity due to cerebral malaria brain damage, and loss of investment and tourism.The infection is responsible for 40% of public health expenditure, 30-50% of inpatient admissions and up to 50% of outpatient visits [3].
The reemergence of P.falciparum parasite to all conventional drugs is a major problem because the high prevalence of multi-resistant strain of this parasite continues to reduce the potency of antimalarial drugs [4,5].This problem is also compounded by non-availability of malaria vaccine, therefore drugs from natural sources (plants) play important functions in the prevention and treatment of fever, pain, inflammation and P.falciparum infections.
Plants from different botanical sources have been used by various Traditional Medicinal Practitioners (TMP) for the prevention and treatment of pains, fever, inflammation and P. falciparum infection (Malaria) [6,7].Numerous claims on the potency and use of various plant species for prophylaxis and cure of malaria have been cited by the TMP, some of these claims have been validated scientifically [8].
Medicinal Antimalarial drugs may be collected from wild or cultivated plants, many factors including time of the year, time of the day, stage of maturity and age, these may vary during the course of plant growth and may affect quality of the active substances [9].Secondary plant materials can be used as fresh or dried plant materials, the drying of the crude drugs may be by natural, artificial method or Lyophilization (Freeze-drying).Several research indicated that the assessment of antimalarial activities of many plants were conducted in lyophilized forms [9].
Different parts of plant such as leaf, bark, stem, root, fruit etc. are used for prevention and treatment of malaria.Decoction (boiled teas) may be used to prepare some of these plant antimalarial drugs in order to replicate the methods used by the TMP, other methods of preparations are infusions (hot teas), tinctures (alcohol and water extracts), paste, powder and macerations (cold-soaking) [5,9].
The bark of Cinchona tree was the first plant antimalarial drug used by the natives of Peru for the prevention and treatment of malaria, quinine was synthesized from this and served as a lead structure for the synthesis of several antimalarial drugs such as quinidine, cinchonine, and cinchonidine followed by chloroquine, mefloquine, pyrimethamine, proguanil, atovaquone (sold together with proguanil as "Malarone"), or primaquine.Quinine (alone or in combination with doxocycline, tetracycline or clindamycin) is still used today to treat acute cases of severe P. falciparum infections [10].
Artemisinin was the second Plant antimalarial drug isolated and synthesized from Artemisia annua in China in the seventies.As a result of recrudescence associated with Artemisinin, Artemisinin-combined therapies (ACT) were formally adopted as first-line treatment of uncomplicated malaria in Nigeria from 2005 onwards and atovaquone (Malarone®) [11], which is a synthetic compound (2-alkyl-3-hydroxynaphthoquinone) analogue of lapachol from the Tabebuia species (Bignoniaceae).There is need to reduce unnecessary treatment and delay the emergency of resistance to ACT while ensuring the effective treatment of malaria by ACT [12].About 1,200 plant species are used traditionally all over the world for the prevention and treatment of pains, fever, inflammatory conditions and P.falciparum infections, thus Plant kingdom has proven an effective source of antimalarial drugs in the past.
Plant antimalarials are accessible and inexpensive, therefore have fitted the immediate personal need and commonly used in medicine from time immemorial [8].
The most commonly used antimalarial drugs are produced traditionally from natural plants, with the achievements of synthetic chemistry specifically Structure Activity Relationship (SAR) and the advancement of rational antimalarial drug design, plant antimalarials play important roles in the provision of traditional antimalarial drugs and these serve as stepping points for the development of synthetic antimalarial drugs [3,5].This review highlights plants from various natural sources used traditionally for the prophylaxis and treatment of pains, fever, inflammation and P.falciparum infections.
Analgesics are the most commonly used drugs for alleviating pains and curing fever as well as inflammatory conditions.Pain is an unpleasant emotional condition which affects quality of life and general function of the body [13,14] this condition is managed by analgesics.Analgesics also known as pain relievers are categorized into non-narcotic (nonopioid) which include acetaminophen, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and narcotic analgesics [13,14].
Acetaminophen (paracetamol) is used for mild pain, fever, as an alternative for aspirin and lacks anti-inflammatory activity.Therapeutically, acetaminophen is used for pain relief in the symptomatic treatment of various musculoskeletal and joint disorders.Acetaminophen is devoid of gastrointestinal side effects like the NSAIDs.At a chronic use, paracetamol saturates the hepatic pathway normally involved in its metabolism, hence it is being metabolized by an alternative pathway to N-acetyl-p-benzoquinone imine(NABQI), a toxic metabolite, which is deactivated by glutathione.Excess NABQI causes necrosis of the liver and renal tubules since glutathione may be easily depleted [14,15].Aspirin (acetyl salicylic acid) has analgesic, anti-inflammatory and antipyretic properties which many analgesics do not have.Aspirin is used for pains related to headache, myalgia, rheumatoid arthritis and rheumatic fever, neuralgia, dysmenorrhea and arthralgia.The adverse effects are gastrointestinal effects, blood dysfunction, auditory and vestibular disturbances and skin reactions [14,15].Non-steroidal anti-inflammatory drugs (NSAIDs) possess analgesic, anti-inflammatory and antipyretic activities.They are ibuprofen, piroxicam, diclofenac, and naproxen and have been used successfully to relieve biliary pain, acute pain of renal colic, postoperative pain, mild pain of sickle cell crisis, and ectopic bone formation pain and dysmenorrhea.They are mostly associated with gastrointestinal side effects [14,15].Narcotic analgesics (opioid analgesics).They are classified into strong opioids and they are full agonists such as morphine, diamorphine, hydromorine, methadone, pethidine, oxycodone, levorpharmol, fentanyl and alfetanil.Partial agonists such as etazocine, butorphanol, halbuphine and dezocine.They are mostly effective in severe pain and chronic or terminal pain.Morphine or related drugs are associated with drug dependence and withdrawal syndrome [14,15].
Codeine is a mild opioid analgesic, analogues include dextropropoxyphene and dihydrocodeine.They are usually combined with non-opioid analgesics for the treatment of moderate to severe pain.The adverse effects include constipation, respiratory depression and allergic reactions [14,15] with the set back of creating efficient vaccines, in addition to severe adverse effects of the conventional antimalarial drugs, this article showcases the analgesics, antipyretic, anti-inflammatory activities and antiplasmodial activities of indigenous plants.Numerous variety of plants possessing antimalarial activities is illustrated in Table 1.

Antimalarial activities of natural plants 2.1. Agelathus dodoneifolius
The analgesic, antipyretic and anti-inflammatory activities of methanolic extract of African mistletoe had been validated.The extract indicated a significant (p < 0.01) and dose-dependent inhibition of the acetic acid-induced abdominal constriction in mice, increased threshold for pain perception dose-dependently in the hot plate test in mice and decreased acute and delayed phases of formalin-induced pain dose dependently (p < 0.01) [16].
The extract also exhibited a significant (p < 0.01) dose-dependent anti-inflammatory effect in carrageenan-induced oedema in rats.Significantly reduced dose -dependent rectal temperature in rats was also showed by the extract.The anti-inflammatory effect of A. dodoneifolius and its potential use for the treatment of neutrophil-dependent inflammatory diseases, dose-dependent inhibitory activities on the oxidant activities of neutrophils were observed by all the tested extracts [16].
The water extract of A.dodoneifolius showed a dose-dependent inhibition of parasitaemia in the in vivo antiplasmodial tests likewise, the in vitro screening demonstrated a strong and concentration-dependent activity (21.54 μg/ml < IC50< 50 μg/ml) of the extract against the clinical isolates of Plasmodium falciparum.The methanol whole plant extract of African mistletoe and its methanolic fraction exhibited significant (p< 0.01) and dose -dependent chemo -suppressive effect and these correlated with in the survival times of the infected mice [1,16].

Allium sativum
The in vivo evaluation of analgesic activities of A.sativum displayed reduced number of acetic acid writhing (abdominal constriction ) (37-48.1% )in mice at different doses while the in vitro evaluation demonstrated potent inhibitory activity against P. falciparum with IC 50 of 0.5 ± 0.42μg/ml [5,17].

Anacardium occidentale
Anacardium occidentalis extract significantly reduced acetic acid induced writhing in mice and the number and time of paw licking induced by formalin (P < 0.05) in a dose related manner.It also displayed the neurogenic and inflammatory phases of formalin (P < 0.05).Analgesia was exihibited in the inhibition of nociception induced by tail immersion in 55 o C hot water.The extract increased the latencies of tail withdrawal to a similar degree as pentazocine.The extract caused significant reduction of carrageenan induced paw oedema in rats (P < 0.05) in a dose dependent manner.These results show that the leaf extracts of Anacardium occidentalis possess highly potent analgesic and anti-inflammatory activities [18].
Evaluation of ethanolic extract of A.occidentalis indicated moderate in vivo inhibition of parasitaemia against P.berghei berghei and the extract also displayed potent in vitro antiplasmodial activities (IC50 0.577 ug/ml) against P.falciparum [19].

Artemisia annua
Various species of Artemisia have been reported to display potent analgesic, antipyretic and anti-inflammatory in accordance with numerous studies [20].Research had shown that A. annua exhibited weak to strong in vitro inhibition (3.27-4-95 Ug/ml) of P.Falciparum parasitaemia and in vivo inhibition of 52.8-95.3%against P.berghei berghei [5].

Azadirachta indica
The potency of Analgesic, antipyretic and anti-inflammatory activities of the extract of Azadirachta indica indicated significant analgesic activities, at the doses of 250mg and 500mg/kg per body weight.It also exhibited significant antiinflammatory and antipyretic activities at doses of 125mg, 250mg and 500mg/kg per body weight in dose related manner [8].
The antiplasmodial activities of A. indica have been associated with the vast bioactive components of the plant in relation to their potent antioxidant activities reported by several researchers [5].

Carica papaya
Research had indicated that the extract C.papaya leaves at different doses of 100, 300, and 600 mg/kg BW exihibited similar analgesic potency with paracetamol as control group (P<0.05)[21].The antiplasmodial evaluation of C.papaya indicated 100% inhibition against in vivo P.berghei berghei and IC 50 of 15.2-16.8(μg/ml) in vitro reduction against P.falciparum [5].

Cymbopogon citratus
A dose-dependent analgesia of C.citratus for the hyperalgesia induced by subplantar injections of either carrageenin or prostaglandin E2 was investigated.The potency of this plant was further confirmed by the isolation of Myrcene which exhibited higher analgesic activities [22].The in vivo antiplasmodial activities and in vitro antiplasmodial activities of C.citratus were reported to be 87.2% and 9.1-12.1ug/mlaccording to a research [5].

Euphorbia hirta
Research showed that the extract of E.hirta potently inhibited acetic acid induced writhing in mice, yeast induced hyperpyrexia in rats and dextran-induced rat paw edema [23].E.hirta was investigated to cause 59.1% in vivo inhibition of P.berghei berghei and in vitro inhibition of IC 50 of 4.33-10.7(μg/ml)against P.falciparum [5].

Moringa oleifera
Ethanolic extract of M.oleifera exhibited potent analgesic activities in both hotplate and tail immersion model at the dose of 25mg/kg/body weight.The extract also displayed potent anti-inflammatory activities in both indomethacine induced oedema and carrageenan induced oedema at the dose of 750mg/kg/body weight [27].M.oleifera ethanolic extract also indicated potent inhibition of P.berghei berghei in vivo (100%) and in vitro inhibition of P.falciparum at the IC 50 of 15.1 μg/ml [5].

Musa sapientum
The water extract of M.sapientum exhibited potent anti-inflammatory activities in Nitric Oxide inhibition model according to research.The decoction of leaves of species (M.paradidisaca) similar to M.sapientum displayed potent antiplasmodial activities against chloroquine-resistant strain of P.falciparum in vitro [28].

Nauclea latifolia
The aqueous extract of the root bark of N. latifolia showed potent analgesic, antipyretic and anti-inflammatory activities in both acetic acid-induced abdominal constriction and hot-plate tests in mice and formalin-induced pain test in rats, as models of nociception.The extract also displayed potent anti-inflammatory activities in egg-albumin induced inflammation and pyrexia induced by yeast in rats at the dose of 50-200mg/kg/body weight [29].The extracts of N. latifolia also exhibited remarkable inhibition of parasitaemia against P.berghei berghei in vivo at 63.8% and potent in vitro inhibition of P.falciparum of IC50 of 0.60 ug/ml [5].

Ocimum gratissimum
Evaluation of O.gratissimum essential oil in classic pain models (hot plate test and formalin test) indicated potent analgesic activities and potent anti-inflammatory activities in murine pain models at a dose of 40 mg/kg/body weight [30].In vivo antiplasmodial activities of O.gratissimum extract against P.berghei berghei were reported to be 88% inhibition and in vitro antiplasmodial activities against P.falciparum were investigated to 1.84 ug/ml IC50 [5].

Parkia biglobosa
The extract from the bark of P. biglobosa exhibited dose-dependent analgesic, antipyretic and anti-inflammatory activities in acetic acid induced nociception test in mice and yeast induced pyrexia test in rats.The extract also displayed potent anti-inflammatory activities in croton oil ear inflammation in test animals and carrageenin-induced rat paw oedema at the dose of 25-100mg/kg/body weight [31].The antiplasmodial activities of the stem bark extract of P.biglobosa were evaluated against malaria model Plasmodium berghei berghei and clinical isolates of Plasmodium falciparum.The extract exhibited potent dose -dependent reduction of parasitaemia in vivo (55.6%-100%) and in vitro (IC50 of 12.9-56.2ug/ml) clinically [1,5,8,23].

Psidium guajava
Psidium guajava ethanolic extract was evaluated for analgesic and antipyretic activities in rats using yeast induced hyperpyrexia, hot plate latency assay and formalin induced paw licking test in rats.The research confirmed the potency of analgesic and antipyretic activities of P.guajava [32].
The ethanolic extract of P.guajava was investigated for antiplasmodial activities against in vivo P.bergehei berghei and in vitro against P.falciparum.The extract exhibited potent inhibition of parasitaemia (<80%) and remarkable inhibition of parasitaemia (IC50 of 6.00ug/ml) [5].

Sida acuta
The extract of s. acuta was evaluated for analgesic activities in hot plate and tail immersion models at the three dose levels in mice.The extract indicated potent analgesic activities at a dose of 500mg/kg/body weight.The antipyretic activities of the extract were also reported to be potent according to research.Evaluation of anti-inflammatory activities of the extract in tail immersion and mouse ear oedema model showed potent dose -dependent reduction of oedema [33].
S. acuta extract was investigated for antiplasmodial activities against P.falciparum in vitro.The extract indicated potent inhibition of P.falciparum chloroquine resistant strain with IC50 of 0.92-3.90ug/ml [5].

Vernonia ambigua
A species (Vernonia hymenolepis) similar to V.ambigua was investigated for analgesic activities using both formalin test and sensorimotor Activity Testing in mice.Potent dose-dependent analgesic activities were reported [34].The whole plant extract of V.ambigua was evaluated for both in vivo and in vitro antiplasmodial activities.The extract exhibited moderate inhibition against P.berghei berghei in suppressive, curative and prophylactic antiplasmodial test (56.9%,56.7% and 63.0% respectively).The extract also displayed remarkable inhibition of P.falciparum in vitro with IC50 of 31.6 ug/ml [ 34 ].

Vernonia amydalina
Evaluation of the analgesic, antipyretic and anti-inflammatory activities of ethanolic extract of V.Amydalina was conducted in tail withdrawal, formalin-induced nociception test and yeast induced pyrexia test in mice and rats.The findings indicated potent dose-dependent analgesic, antipyretic and anti-inflammatory activities at the dose of 25-200mg/kg/body weight [35].
In vivo antiplasmodial activities and in vitro antiplasmodial activities of V.Amydalina showed potent inhibition (97.8%) of parasitaemia in P.berghei berghei antiplasmodial model and moderate IC50 of 4.10 ug/ml against P.falciparum in vitro [5].

Zingiber officinale
Investigation of the analgesic activities of Z. officinale potent anti-nociceptive activities according to research.Potent anti-inflammatory activities were also exhibited in cyclooxygenase-1, cyclooxygenase-2 inhibition model and 5lipoxygenase inhibition model [36].
Z. officinale extract exhibited moderate inhibition of parasitaemia against P.bergehei berghei model in vivo and also demonstrated moderate inhibitory antiplasmodial activities against P.falciparum in vitro with IC50 of 15.9 ug/ml [5].

Phytochemicals
Traditional products act at different stages in malaria treatment, thus they are useful in combination therapy.Evaluation of plant extracts has resulted in production of various secondary metabolites (Phytochemicals) with potent antimalarial activities [5].Phytochemicals isolated from these plants are indicated in Table 2.

Mechanisms of pharmacological activities of plant antimalarials
Several studies have attributed the potency of anticonceptive, antipyretic, and anti-inflammatory activities of plant products to be related to the inhibition of pathways of some enzymes namely lipo-oxygynase , cyclooxygenase and nitric oxide synthase (NOS) .Some of these plants also exert their pharmacological effects through the inhibition of tumor necrosis factor (TNF)-α-induced neutrophil adherence as well as production of vasoconstrictor nitric oxide production (NO) [ 30].The suppression of both peripherally non-opioid mediated and centrally opioid mediated nociceptive and inflammatory activities also play roles in these activities [27].The cyclic monophosphate guanosin/triphosphate adenosine (NO/cGMP/ATP)-sensitive-K(+) channel pathway and/or facilitation of the GABAergic transmission were also implicated in these actions [29].The inhibition of some other pathways including ( opioidergic, ATP sensitive K+ channels, nitric oxide, muscarinic, adrenergic and voltage-gated calcium channel ) were not left out [ 35,36].
The antiplasmodial activities of these natural plants may be explained by their phytochemical composition due to the presence of bioactive components which are also regarded as the antioxidants.These antioxidants are also represented in the remaining antimalarial activities including analgesics, suppression of hyperpyrexia and reduction of inflammatory activities in accordance with numerous research [5,8,23,31].

Conclusion
The plant kingdom comprises phytochemicals which are secondary metabolites found in plants, the pharmacological activities including the analgesics, antipyretics, anti-inflammatory activities as well as antiplasmadial activities also known as antimalarial activities have been related to various documentation of potent phytocomponents which are antioxidants.The antimalarial activities of several active compounds isolated from natural plants are remarkable which suffer limited investigation, there is need to establish the efficacy and safety of plant antimalarials due to their potency, with the hope that they will serve as alternatives to the currently used analgesics and less effective ACT which may be monotherapy or in combination therapy.

Table 1
Natural plants used for the treatment of malaria

Table 2
Phytochemicals isolated from plant antimalarials