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 Antipyretic Effect of Cinnamomum burmannii (Nees & T.Nees) BlumeInfusion in Fever-induced Rat Models

Qatrunnada Zainol1, Eva M. Hidayat 2, Stanza Uga Peryoga31Faculty of Medicine, Universitas Padjadjaran, 2Department of Pharmacology and Therapy, Facultyof Medicine, Universitas Padjadjaran, 3Department of Child Health, Faculty of Medicine, Universitas

Padjadjaran/Dr.Hasan Sadikin General Hospital, Bandung, Indonesia

 Abstract

Background : Fever is a frequent clinical sign encountered in human especially in children. Unfortunately,access to health care and medications (antipyretics) are hampered by shortage of services and affordability,which are accentuated by local resources mainly for those living in remote areas. Therefore, using herbalmedicineas an alternative in treating fever should be developed as substituent reliance on syntheticantipyretic. This study is conducted to observe antipyretic effect of Cinnamomum burmannii (Nees &

T.Nees) Blume infusion using Diphtheria Tetanus Pertussis (DTP) vaccine-induced fever in rats.Methods: Twenty-eight male Wistar rats (150 200 g) were randomly allocated into control and treatmentgroups. Fever was induced with DTP vaccine intramuscularly injected (0.7 mL/200 g body weight) and 4hours later, distilled water (5 mL) was administered orally to the control group while the treatment groupreceived 5 mL of 3%, 6%, and 12% of cinnamon infusion. Rectal temperature was measured before thepretreatment, 4 hours after DTP vaccine-induced fever injection and at a 30-minute interval during 180minutes after the infusion administration. All procedures and protocols were performed in October 2012 atthe Pharmacology Laboratory, Faculty of Medicine, Universitas Padjadjaran, Bandung.

Results: Data analysis using the one way analysis of variance (ANOVA) showed signiicant reduction(p

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Introduction

Fever is an increase of body temperaturedue to changes which occur in the bodythermoregulatory set-point caused bypyrogens. This is a frequent clinical sign

encountered in human, which can be dueto infectious or noninfectious diseases.Developing countries such as Indonesia, withhigh population density and large geographicalarea, may face disparities in the access tohealth care and medication due to limitedresources, especially for those who live inremote areas where the access to the primaryhealth care (PHC) example such aspusatkesehatan masyarakat (Puskesmas), are stilldificult geographically dificult to reach.

Antipyretic side effects such ashypersensitivity, nausea, and vomiting

occasionally occur in higher dosageconsumption.1 Hypersensitivity reactions canbe from mild rashes to a more serious problemsuch as erythema multiforme disorder whichis characterized by multiform skin lesions,Stevens-Johnson syndrome (SJS) and toxic-epidermal necrolysis (TEN) with promisingpoor prognosis.2

Hence, herbal medicine is a kind of healthtreatment which we need to look into as analternative in treating fever since it is relativelyaffordable and accessible so that we do not haveto rely much on synthetic drugs. Cinnamon isone of the examples of herbal medicine that is

believed to have many beneicial health effects.With the genus name Cinnamomum belongingto the family Lauraceae, it comprises of manyspecies and one of the species commonly usedin Indonesia is Cinnamomum burmannii (Nees& T.Nees) Blume.3

In a pharmacological study, a reduction ofbody temperature in mice was observed by theadministration of decoctions of the dried twigsof cinnamon.4 While, an in vitro inding revealsthat cinnamaldehyde, a chemical constituentof cinnamon can suppress production ofendogenous pyrogens example such as tumor

necrosis factor (TNF), interleukin-6 (IL-6), andinterleukin-1 (IL-1)5 thus suggesting the role

of cinnamaldehyde in providing hypothermicand antipyretic action.

Accordingly, we were interested inconducting a research on Cinnamomumburmannii (Nees & T. Nees) Blume, usingthe simplest method of extracting activecompounds; infusion, to provide evidence fora potential role of Cinnamomum burmannii(Nees & T.Nees) Blume in the treatment offever.

Methods

A total of 28 male Wistar rats (150–200g) obtained from Pusat Penelitian AntarUniversitas (PPAU), Institute of Technology,Bandung were used in this research. Therats were housed at the animal facility ofthe Pharmacology Laboratory, Faculty of

Medicine, Universitas Padjadjaran, Bandungwith standard condition of temperature (25 ±2°C). Rats that have been used previously onother studies were excluded. Seven days priorto starting of the experiment, the rats werekept under laboratory conditions and allowedunlimited food and water The rats weresacriiced with formalin injection at the endof experiment. Seven rats were used in eachintervention group. The research protocolsand animal care procedure were approved bythe Health Research Ethics Committee of theFaculty of Medicine, Universitas Padjadjaran,Bandung.

The Cinnamomum burmannii (Nees& T.Nees) Blume originates from Padang,Indonesia was bought from a herbal store inOctober 2012. The sample was identiied asCinnamomum burmannii (Nees & T.Nees)Blume by the Laboratory of Plant Taxonomy,Biology Department, Faculty of Mathematicsand Natural Sciences, Universitas Padjadjaran.The cinnamon barks were measured intosuitable weight of 0.15 g, 0.30 g and 0.60 g.Water is heated in the irst level pot until itis boiled and cinnamon barks mixed with5 mL of water were placed at the second

level pot, heated until 90°C for 15 minuteswith every 5 minutes the preparation is

durasi kerja yang singkat dari Cinnamomum burmannii (Nees & T.Nees) Blume.

Simpulan: Efek antipiretik pada pemberian dosis 6% dan 12% infusa Cinnamomum burmannii (Nees &T.Nees) Blume pada tikus yang diinduksi demam ditemukan pada 30 menit pertama. [AMJ.2014;1(1):81–5]

Kata kunci: Antipiretik, Cinnamomum burmannii (Nees & T.Nees) Blume, demam, pengobatan herbal

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stirred. The preparation was then ilteredusing a lannel cloth and adding hot waterthrough the pulp until the needed volumewas obtained. The iltrate had a brown todark brown colour varying according to thedifferent concentrations. Herbal infusion ofCinnamomum burmannii (Nees & T.Nees)Blume was kept in a container until the timeof treatment.

Twenty-eight male Wistar rats (150 200g) were randomly allocated into 4 groups.The normal body temperature of each rat wasmeasured rectally at predetermined intervalsand recorded. The rectal temperature wasmeasured by gently inserting a digitalthermometer to a length of approximately

2.5cm intra rectal until stable reading wasobtained or for up to 30 60s. For this, ratswere restrained manually at the base of thetail. The accuracy of the thermometer wasaccurate to 0.1°C. After measuring basalrectal temperature, animals were injectedintramuscularly with 0.7 mL/200 g bodyweight of DTP vaccine. Rats were thenreturned to their housing cages.

Four hours after DTP vaccine injection,the rat’s rectal temperature was measuredagain, as described previously. Only rats thatshowed an increase in temperature of at least

0.5°C were used for this study. The cinnamoninfusion with doses of 3%, 6% and 12%were administered 5 mL orally to 3 groups ofanimals. The control group received 5 mL ofdistilled water orally. Rectal temperature wasmeasured at 30 minutes intervals during aperiod of 180 minutes after the infusion anddistilled water administration.

Difference in mean values between groupswere analyzed for each 30 minutes intervalby a one way analysis of variance (ANOVA)followed by Duncan post-hoc test. Statisticalsigniicance was assessed as p

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administration by approximately 0.8°C. Onthe other hand, treatment with 5 mL of 3%cinnamon infusion (group 2) failed to reducethe temperature where it increased the rectaltemperature by 0.4°C, slightly lower by 0.1°Cas compared to the control group at 30 minutesafter oral administration.

The antipyretic effects of 2 doses ofCinnamomum burmannii (Nees & T.Nees)Blume were noted as early as 30 minutesafter oral administration and the effect wasnot maintained for the next 30 minutes until180 minutes after oral administration. Therewere luctuant temperature values with noexact increasing or decreasing trend. Rectaltemperature of the entire group did not reduce

to normal temperature at 180 minutes afteroral administration.

Discussion

Theoretically, antipyretic acts works as aninhibitor on prostaglandin synthesis byinhibiting the enzyme cyclooxygenase (COX).Cyclooxygenase enzyme is also inluencedby the presence of cytokines such as tumornecrosis factor-α (TNF-α), interleukin-6 (IL-6),interleukin-1 (IL-1) and interferon-γ produced

by monocytes and macrophage. Meanwhile,monocytes and macrophage are stimulatedby exogenous pyrogens when the bodyencounters with infection, toxins, or injury. Inthe absence of COX enzyme, arachidonic acidcannot be converted to prostaglandin (PGH2)hence no other prostaglandin as mediators offever can be yield.6

Diptheria Tetanus Pertussis (DTP) vaccineused in this research to induce fever in therats was a combination of vaccine againstinfection of diphtheria, pertussis and tetanus.It is believed to have cause pyrogenic activitydue to pertussis component in the vaccine inwhich the toxins presence in vaccine indirectlyserves as exogenous pyrogens that causefever.7

The antipyretic effect of cinnamon might bedue to cinnamaldehyde content that may haveinhibitory effect on secretion of IL-1 and thenprostaglandin synthesis. This correspond to astudy conducted by a group of researchers fromTaiwan who reveal that cinnamaldehyde cansuppress production of endogenous pyrogens(TNF, IL-6, and IL-1).5  The antipyretic effectof Cinnamomum burmannii (Nees & T.Nees)Blume may be due to these properties which

inluence in the chain breaking and preventionof prostaglandin release that cause fever.

Lower doses of Cinnamomum burmannii(Nees & T. Nees) Blume infusion had lesseficacy in reducing rectal temperature.Increase in temperature at minutes 60 andnot reaching basal temperature could be dueto shorter duration of action of cinnamon indecreasing the high temperature. Whetherreturning to thermal regulatory set point tonormal is due to persistent exist of endogenouspyrogens in the circulation for several hours.8

Cinnamaldehyde, a chemical constituentof cinnamon which has inhibitory effect onsecretion of endogenous pyrogen may notbe suficient enough to fully inhibit releaseof endogenous pyrogens, COX and theprostaglandins. Therefore, a further research

should be conducted on Cinnamomumburmannii (Nees & T. Nees) Blume using othermethods of extracting the active compoundwhich possibly result in higher concentrationof cinnamaldehyde, thus will increases itseffectiveness.

For the control group, the decrease intemperature after 180 minutes can be explainedsince probably rats, as well as humans havetheir own mechanism in regulating bodytemperature. One of the ways is using theirtail as thermoregulatory functions by dilatingtheir tail blood vessel.9

It can be concluded that 5 mL of 6% and12% Cinnamomum burmannii (Nees & T.Nees)Blume infusion per oral had antipyretic effectfor the irst 30 minutes. Additional studies areneeded to determine if the antipyretics effectsof cinnamon were due to inhibitory effect ofcinnamaldehyde on secretion of endogenouspyrogens, and compared with gold standardantipyretics example paracetamol to seewhether there was a signiicant differencein antipyretic effect between cinnamonand paracetamol. The research also shouldbe developed into clinical trial and lastlyexpanded into phytopharmaca.

References

1. Annette OP. OTC pain relievers and feverreducers [cited 2012 April 27]. Availablefrom: http://www.medicinenet.com/analgesics_antipyretics/page4.htm.

2. Lazar AJF, Murphy GF. The skin. In: KumarV, Abbas AK, Aster Jon K: editors. Robbinsand Cotran pathologic basis of disease.8ed.Philadelphia: Saunders Elsevier; 2010.p. 1189–91

3. Katzer G. Indonesian Cinnamon

(Cinnamomum burmannii (Nees & T.Nees)

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Blume[Nees & T. Nees] Blume). [cited2012 April 29]. Available from: http://www.unigraz.at/~katzer/engl/Cinn_bur.html#const.

4. Thampuran RA, Vijayan K. Pharmacologyand Toxicology of Cinnamon and Cassia.Boca Raton: CRC Press; 2003.

5. Chao LK, Hua KF, Hsu HY, Cheng SS, Lin IF,Chen CJ, et al. Cinnamaldehyde inhibitspro-inlammatory cytokines secretionfrom monocytes/macrophages throughsuppression of intracellular signaling.Food Chem Toxicol. 2008;46(1):220–31

6. Kumar, Abbas, Fausto, Aster. Mediators

of inlammation. Robbins and CotranPathologic Basis of Disease. Philadelphia:Saunders Elsevier; 2010.

7. Centers for Disesae Control and Prevention(CDC). Vaccine information statement.[cited n 2012 April 30]. Available from:http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-dtap.pdf.

8. Netea MG, Kullberg BJ , Van der Meer JWM.Circulating cytokines as mediators of fever.Clin Infect Dis. 2000;31 Suppl 5:S178–84.

9. Hanson A. The Rat’s tail. [cited 2012November 15]. Available from: http://www.ratbehavior.org/RatTails.htm.

Qatrunnada Zainol, Eva M. Hidayat, Stanza Uga Peryoga: Antipyretic Effect of Cinnamomum burmannii(Nees & T. Nees) Infusion in Fever-induced Rat Models