Herbal Remedies Connected to Malaria like Fever in Iranian Ancient Medicinal Books- Brief Review Article.

Malaria is a major international public health problem. Drug-resistant parasites have made treatment and control of malaria more difficult. Therefore, safe, affordable and effective new drugs are urgently needed. Traditional medicine is an important source for new drugs. Determining the ancient medicinal books was the first step of this study for finding malaria or disease that has symptoms like malaria. Then the plants that used to treat "Ghebbe Khalesseh fever" were listed. Finally, recent antimalarial researches were explored. About 31 plants were identified. Information from these resources is valuable for the selection of plants for antiplasmodial screening programs.

Introduction

Malaria is a major international public health problem. In 2010, there were about 219 million cases of malaria and an estimated 660000 deaths mostly among young children below 5 years of age living in Africa (1).

Malaria is an acute febrile illness. It is caused by Plasmodium parasites. The parasites are transmitted to humans via the bites of infected Anopheles mosquitoes, called “malaria vectors”. There are four types of human malaria: Plasmodium falciparum, P. vivax, P. malariae and P. ovale. Plasmodium falciparum and P. vivax are the most common. Plasmodium falciparum is the most deadly. The first symptoms – fever, headache, chills and vomiting – may be mild and difficult to recognize as malaria (2).

There are three different forms of malaria:

Malaria tertiana caused by P. vivax and P. ovale with recurring fevers every 48h.

Malaria quartana caused by P. malariae and fevers occur every 72h.

The most dangerous form is malaria tropica “tropical fever” caused by P. falciparum and also cause high fevers every 48h or else irregulatory (3).

Drug – resistant parasites and insecticide – resistant mosquito vectors have made treatment and control of malaria more difficult. Therefore safe, affordable, and effective new drugs are urgently needed (4). Throughout history man has searched for remedies to fight against disease and used plants for the treatment of ailments such as malaria. In Africa and probably in many parts of the world, populations use traditional medicines more than modern medicine. This is because traditional medicines are easily accessible to the majority of the populations (5).

The search for natural product derived antimalarials has been ongoing over the past four decades and resulted in notable discoveries, quinine and artemisinin (6,7).

Over 1200 plant species from 160 families are used to treat malaria and fever. On average, a fifth of patients used traditional herbal remedies for malaria in endemic countries. The Research Initiative on Traditional Antimalarial Methods (RITAM) was founded in 1999 with the aim of furthering research on traditional medicines for malaria (8). Nowadays, even the WHO suggests basic procedures for the validation of drugs of plant origin in developing countries (9). Geographical location and climatic condition variety as well as abundance of medicinal herbs species have provided Iran with very high potential for the manufacturing of medicinal herb products.

Malaria had been widely prevalent for a long time in Iran. Avicenna, the Iranian philosopher and physician, (980-1037 A.D.) about 1000 years ago described the clinical features of an intermittent febrile attack with 4-12 hours period of cold, hot and sweating stages which is actually the characters of paroxysm of malaria (10). The term malaria (mal’aria) was probably first used by the Italian physician Francisco Torti (1658–1741) in 1740, and literally means “bad air” referring to the swamp vapours, which supposedly caused the disease (11). The term of malaria was thus not used in these books. Among the symptoms of malaria, fever attacks are the most common symptom. According to this symptom, in the ancient medicinal books found a kind of fever that named “Ghebbe Khalesseh fever”. Symptoms of this fever were very near to malaria. It had four distinct phases like malaria: I. Initial phase with muscle aches and headaches that named “Malileh”. II. Cold phase with uncontrollable tremors and severe chills. III. Hot phase with very high fever for several hours. IV. Final phase that the body starts to sweat to lower body temperature. Its treatment in traditional medicine included these ways: the first step was bringing down the temperature with cold and moisture foods and medicinal plants. The second step was softening the abdomen with laxatives plants and finally removing the putridity from the body (12).

Traditional medicine dates back more than 3000 years in Iran. This research aimed to identify the important herbal remedies for treatment of the most related disease to malaria used in traditional medicine of Iran.

Materials and Methods

Ancient medicinal books

This research is based on the ancient books of medicine and pharmacy produced from 800s – 1700s A.D. These books were amongst the most important Iranian physicians’ authors. The books used in this work are listed in Table 1.

Table 1

Ancient medicinal books used for the research

Name of book	Author	Description	Century of publication (A.D.)
Al-Mansouri	Muhammad ibn Zakariya Razi (Rhazes)	Medical book	9
Hedayat al-Motaallemin fi-Tebb	Ahmad Akhawayni Bukhari	Medical book	10
Qanun fi al-Tebb (Canon in Medicine)	Ibn Sina (Avicenna)	Medical and pharmacy book	11
Zakhireyi Kharazmshahi	Ismaeil Jurjani	Medical book	12
Khulasat al-Tajarub	Bahaaddin Nurbakhsh	Medical book	15
Tebbe Akbari	Hakim Mohammad Akbar Arzani	Medical book	17
Makhzan al-Adwiyyah	Seyyid Mohammad Hossein	Pharmacy book	18

Herbal remedies

As the term of malaria did not exist in the ancient medicinal books, so we searched the term of “fever”. The textbooks were in Persian and Arabic, so we investigated keywords such as “Tab” in Persian and “Hommaa” in Arabic books. In these books, fever falls into three categories based on ethiology and period of fever: “Yomiyyeh fever (ephemeral fever)” “Degh fever (hectic fever)” “Ofouni fever (infectious fever)”. If the external heat effects on Arwah (vital forces of life), yomiyyeh fever (one day fever) occurs and if the external heat effects on Adha (Fully-Grown Organs), degh fever (every day fever) occurs. Infectious fever occurs when Akhlat (structural components) receive external heat. This kind of fever is periodical like malaria. Physician of traditional medicine said “Nobeh fever” to this fever. The infection of phlegm, yellow bile, blood and black bile can cause fever. “Ghebbe Khaleseh” is a kind of yellow bile (safra) fever that takes 12h and then 36h without any fever. It means the fever recurring every 48h (Like tertian fever). The other symptoms of this fever include initial tremor, body tempreture (40 °C), headache and sweating are similar to malaria (12-17). So the term “Ghebbe Khalesseh fever” was nearer to malaria.

In the next step, we searched the plants used to treat “Ghebbe Khalesseh fever” (12-18). The Persian, Arabic or other names of plants are matched with scientific names compared with reference books (19-21).

Additionally recent antiplasmodial results of the plants in the world were reviewed.

Results and discussion

In total, 31 species of plants in 21 families were identified used for treating “Ghebbe Khaleseh” (Like tertian fever) in ancient medicinal books (Table 2). Plants are listed alphabetically by traditional name. The last column describes which books reported on them.

Table 2

Plants, found in the seven books to treat malaria, are sorted by family, genus and species. Species names given in bold indicate those plants discussed in the text

Traditional name	Scientific name	Common name	The book listing the plant (Reference No.)
Adas	Fabaceae Lens culinaris = Lens esulenta	Adas	Q.(12)
Ajaas or Ejaas	Rosaceae Prunus domestica or Prunus divaricata or Prunus spinosa	Aalou	H.(14), Q.(12), Z.(15), A.(17), T.(16), MA.(18)
Baghlat-al-homghaa	Portulacaceae Portulaca oleracea	Khorfe	Z.(15), A.(17), MA.(18)
Banafsaj	Violaceae Viola odorata	Banafshe	Q.(12), Z.(15), T.(16), MA.(18)
Bazr-eghatouna or Esparze or Espaghul	Plantaginaceae Plantago psyllium or Plantago ovata	Esfarze	Q.(12), Z.(15), T.(16)
Bettikh-e hindi	Cucurbitaceae Cucumis vulgaris	Kharbozeh hindi	M.(13), Q.(12), Z.(15), MA.(18)
Ehlilaj-e Kaboli	Combretaceae Terminalia chebula	Halile	M.(13), H.(14), Q.(12), MA.(18)
Esfaanaakh	Amaranthaceae Spinacia oleracea	Esfenaaj or Spenaaj	Z.(15),A.(17)
Hendebaa	Asteraceae Cichorium intybus	Kaasni	H.(14), A.(17), MA.(18)
Khasse	Asteraceae Lactuca sativa	Kahou	A.(17), Q.(12)
Khatmi or Khetmi	Malvaceae Althaea officinalis	Khatmi	Q.(12), Z.(15)
Kheyaar shanbar or Folus	Fabaceae Cassia fistula	Kheyaar chanbar	M.(13), H.(14), Q.(12), Z.(15), A.(17), MA.(18)
Kozborah or Kazborah	Apiaceae Coriandrum sativum	Geshniz or Keshniz	A.(17)
Lablaab-e kabir or Qassus	Araliaceae Hedera helix	Lablaab	Q.(12)
Maash	Fabaceae Vigna radiate = Phaseolus radiates	Maash	Z.(15), A.(17), MA.(18)
Onnab	Rhamnaceae Ziziphus jujube = Ziziphus vulgaris	Onnab or Annab	H.(14), Q.(12)
Oroz or Aroz	Poaceae Oryza sativa	Berenj	A.(17), MA.(18)
Qará or Yaqtin	Cucurbitaceae Cucurbita pepo	Kadou	M.(13), Q.(12), Z.(15), A.(17), MA.(18)
Qasad	Cucurbitaceae Cucumis sativus	Kheyaar-e sabz or Kheyaar-e baalang	M.(13), Q.(12), Z.(15), A.(17), T.(16), MA.(18)
Romman or Anaareyn	Punicaceae Punica granatum	Anaar-e meykhosh	Q.(12), Z.(15), A.(17), T.(16), MA.(18)
Saghmouneya or Mahhmoude	Convolvulaceae Convolvulus scammonia	Saghmouneya	M.(13), H.(14), Q.(12), MA.(18)
Sanaa makki	Fabaceae Cassia angustifolia	Sanaa or Senaa	Q.(12)
Selq	Chenopodiaceae Beta vulgaris	Choghondar	Q.(12), T.(16)
Sepestaan or Sebestaan	Boraginaceae Cordia myxa	Sepestaan	Q.(12), Z.(15), MA.(18)
Shaah-e tare or Shaah-e taraj	Fumariaceae Fumaria parviflora	Shaahtare	Q.(12)
Shir khesht or Shir khoshk	Rosaceae Cotoneaster nummularia	Shir khesht	Q.(12), Z.(15), A.(17), T.(16), MA.(18)
Sous	Fabaceae Glycyrrhiza glabra	Shirin bayaan	Q.(12), MA.(18)
Tabaashir	Poaceae Bambusa arundinaceae	Tabaashir	A.(17)
Tamarr-e hindi or Khormay-e hindi	Fabaceae Tamarindus indica	Tamarr-e hindi	H.(14), Q.(12), Z.(15), A.(17), T.(16), MA.(18)
Taranjabin or Khar shotor	Papilionaceae Alhagi persarum = Alhagi camelorum	Taranjebin	M.(13), H.(14), Q.(12), Z.(15), MA.(18)
Zereshk – e abi	Berberidaceae Berberis integerrima or Berberis densiflora	Zereshk	T.(16)

Al-Mansouri (M), Hedayat al-Motaallemin fi-Tebb (H), Qanun fi al-Tebb (Q), Zakhireh kharazmshahi (Z), Tebbe Akbari (A), Khulasat al-Tajarub (T) and Makhzan al-Adwiyyah (MA)

A further research was done to find recent scientific results relevant to possible antiplasmodial activities of the plants. Plants with reported activity are highlighted in bold in the table. Most remedies in the traditional books were prepared by boiling or soaking in water. Rhazes said “soak Halile (Terminalia chebula) in hot water for 24 hours, then filter the preparation and add Taranjebin (Alhagi persarum). Then give it in the morning when the patient has no fever”. In a recent study, Pinmai et al. (2010) evaluated the in vitro and in vivo antiplasmodial activity of Terminalia chebula in Plasmodium falciparum K1 multidrug-resistant strain. It showed in vitro antimalarial activity with IC50 15.41±0.61(μg/ml).

A standard 4-day suppressive test on P.berghei infected mice was used to evaluate the in vivo antiplasmodial activity of the extract at 250 mg/kg/day. The result showed good suppression activity (68.89%) (22).

In “Tebbe Akbari” the author recommended to boil Kaasni (Cichorium intybus) in water and give to the patient before the onset of fever. Bischoff et al. (2004) studied the effects of Kaasni (Cichorium intybus) because of its use as antimalarial in Afghanistan that need to be prepared in a special process in the dark. They used the HB3 clone of the Honduras-1 Plasmodium falciparum and quantified parasite numbers by GIEMSA stained smears after 48h. At 10 μg/ml and 50 μg/ml the sesquiterpene lactones inhibited the growth of the parasites completely (23).

Avicenna described about soaking fruits of Tamarr-e hindi (Tamarindus indica) in water and then boiling it. The preparation is then filtered. The extract could be consumed with sugar. The patient should drink it every night. Asase et al. (2005) studies in Ghana showed that instead of leaf decoction, bark decoction can effectively be used to treat malaria (24). Koudouvo et al. (2011) investigated the antimalarial effect of a few plants in Togo folk medicine. Aqueous extract of fruit of T. indica has antimalarial activity with IC50 4.786 μg/ml (25).

In “Tebbe Akbari” author said: “Sweet and sour Anaar (Punica granatum) juice with a little sugar is good for relief of fever”. Dell’Agli et al. (2009) evaluated antiplasmodial activity of Punica granatum L. fruit rind. The P. granatum methanolic extract inhibited parasite growth in vitro with a IC50 of 4.5 and 2.8 μg/ml, for D10 and W2 strain, respectively. The activity was found to be associated to the fraction enriched with tannins (IC50 2.9 and 1.5 μg/ml) in which punicalagins, punicalins, ellagic acid and its glycoside could be identified. Both the P. granatum methanolic extract and the fraction enriched with tannins did not show any in vivo efficacy in the murine model (26).

Shirin bayaan (Glycyrrhiza glabra) in the form of extract was given for treatment of fever. Esmaeili et al. (2009) studied antimalarial effects of methanolic extract of Glycyrrhiza glabra (27). The chalcone licochalcone A can be isolated from all Glycyrrhiza species in different amounts and has been shown to exhibit good antimalarial activity. In in vivo tests against P. yoelii in mice, oral doses of 1000 mg/kg resulted in the complete eradication of the malaria parasite and no toxicity was noted (28). Licochalcone A inhibited in vitro growth of both chloroquine-susceptible (3D7) and chloroquine-resistant (Ddz) strains of Plasmodium falciparum to same extent in [3H] hypoxanthine uptake assay (29).

Ruiz et al. (2011) evaluated the antimalarial potential of traditional remedies used in Peru. The survey took place on six villages and led to the collection of 59 plants. Thirty five hydro-alcoholic extractions were performed on the 21 most cited plants. The extracts were then tested for antiplasmodial activity in vitro on Plasmodium falciparum chloroquine resistant strain (FCR-3). Coriandrum sativum L. showed antiplasmodial activity with IC50>10 (μg/ml) (30).

The family Fabaceae was represented by six species and the family Cucurbitaceae was represented by three species. The other families had one or two species each. Two plants of Fabaceae, Glycyrrhiza glabra and Tamarindus indica have showed antiplasmodial effect.

Conclusion

A quick glance at the PubMed database (http://www.ncbi.nlm.nih.gov/) with the keywords: “malaria drug”, 13,147; “malaria and immunity”, 5,300; while searching “malaria and plants”, 769; and “malaria and traditional medicine” only gives 216 references (citations dating back to the mid-1950s) (9). According to table (2), only 20% of plants have recent scientific results against Plasmodium. Very little antimalarial research has been done with traditional medicine (especially traditional medicine of Iran), and the vast majority of plants described here for their effects on fever have never been studied for antiplasmodial activity. Research on active principles present in these plants should be studied to produce lead compound for treatment of malaria.