alpinia 2010.pdf

Volum e 4, Issue 1, Sept em ber – Oct ober 2010; Art icle 006 ISSN 0976 – 044X STUDY OF THE EFFICACY AND CLINICAL SAFETY OF ALPINIA SPECIOSA (JC W ENDL.) K. SCHUM CRUDE EXTRACT ON ARTERIAL HYPERTENSION 1 2* Vargas JHA , Carvalho JCT 1 Division of Phyt ot herapy of It apem irim , M unicipal Healt h Cent er of Cachoeiro de It apem irim , Cachoeiro de It apemirim , Espírit o Sant o, Brazil. 2 * Laborat ório de Pesquisa em Fárm acos, Universidade Federal do Am apá, UNIFAP, Rod. JK, km 2, 68902-380, M acapá-AP, Brazil. ABSTRACT The crude hydroalcoholic ext ract of Alpinia speciosa (JC Wendl.) K. Schum was administ ered for six weeks to t went y-t wo pat ient s, t hirt een of which had mild hypertension (st age 1 hypert ension) and nine of which had moderate hypertension (st age 2 hypert ension). Patient s were submit ted t o the following laborat ory t est s prior t o and aft er t reatment : complet e blood count , glucose, serum urea and creat inine, t ot al cholest erol, t riglycerides, uric acid, t ransaminases, bilirubins, alkaline phosphat ase, serum sodium and pot assium, urinalysis and EKG. Thirteen pat ients were t reated wit h only one capsule of 250 mg/ day cont aining t he crude hydroalcoholic ext ract of A. speciosa. Eight patient s were t reat ed wit h t wo capsules, and only one was t reat ed wit h the maximum dose under st udy, which was six capsules of crude hydroalcoholic A. speciosa ext ract . The biochemical and hematological t est s performed showed no st atistically significant differences bet ween pret reat ment and post-t reat ment , and t he dosing regimen used was effective in significantly reducing blood pressure in st ages 1 and 2. Furt hermore, t here was no report or ident ificat ion of t oxic side-effects, t hereby demonst rat ing good t olerance. Keywords: Alpinia speciosa ; crude hydroalcoholic ext ract ; clinical efficacy INTRODUCTION The phyt ot herapeutic agent st udied w as t he crude hydroalcoholic extract of Alpinia speciosa (JC Wendl.) K. Schum , a plant species popularly know n as ‘m acassá’, ‘pacová’ or ‘colônia’, and used in t raditional m edicine as a 1 diuretic and hypot ensive agent. This species is an arom atic herb of Asian origin, but it is widespread in Brazil, w here it is cult ivat ed as an ornam ent al and m edicinal plant. It is a rhizom at ous perennial grass t hat form s large grow t h clum ps. It has long broad lanceolated leaves, and it s flowers show a pink and w hit e-yellow 1 t inge. Preclinical pharm acological st udies have proven it s ant ihypert ensive and mild tranquilizing act ivit ies. How ever, t he t herapeut ic efficacy of derivat ives of this plant species needs t o be st udied in order t o provide support for it s safe use in phyt ot herapy. Alpinia speciosa cont ains essent ial oils and ot her com ponent s, but t he act ive principle responsible for t he ant ihypert ensive act ion is not know n. Am ong it s fixed const it uent s, flavonoids and kavalact ones have been found. It w as det erm ined t hat t he essential oil pot ent iat es barbit urate sleeping t im e and ant agonizes convulsions induced by pentylenet et razol in m ice, indicat ive of a cent ralized effect. The essent ial oil has also 2 show n peripheral analgesic act ivit y . In m ice, t he aqueous ext ract of t he leaves produced depression of t he cent ral nervous syst em , neurom uscular blocking and bot h 3 spasm olyt ic and hypot ensive effect s, t he hydroalcoholic 4 ext ract also produced hypotension and t he et hanolic 5 ext ract show ed antiedem at ogenic act ivit y . It is possible t hat at least part of t he hypot ensive and spasm olyt ic 6 act ivit ies are due t o t he presence of 4-t erpineol . It has been demonst rat ed t hat t he vasodilat ory effect of t he hydroalcoholic extract of Alpinia speciosa is endotheliumdependent and probably due t o t he release of nit ric oxide 7 (NO) . The M acassá collect ed in t he Nort heast seem s t o be m ore pot ent as a vasodilat or com pared t o t he plant grow n in t he Sout heast. The observed hypot ensive action is due, at least in part , t o t he presence of flavonoids and 8 kavapyrones in t he plant leaves . The chemical const it uent s of plant s of t he genus Alpinia are m ainly sesquit erpenes and flavonoids that are found in alm ost all species. In t he quant it ative and qualit at ive analysis, t he leaves of A. zerumbet present ed an essent ial oil yield of around 0.3%, cont aining terpene alcohols (41.4%), t erpinene (19.8%) and p -cym ene (14.6%) as t he m ain const it uent s. Am ong the fixed const it uent s, kavalact ones and flavonoids w ere found in different concentrat ions in t he aqueous ext ract of M acassá leaves 8 collect ed in various part s of Brazil. This st udy aimed t o clinically evaluate t he efficacy and t olerance of t he crude hydroalcoholic ext ract of Alpinia speciosa in hypert ensive pat ient s t hrough a clinical t rial prot ocol. M ATERIALS AND M ETHODS Test product The t est product was present ed in t he form of a 250 mg capsule cont aining t he crude hydroalcoholic extract of Alpinia speciosa , w hich w as kindly provided by t he International Journal of Pharmaceutical Sciences Review and Research Available online at ww w .globalresearchonline.net Page 27 Volum e 4, Issue 1, Sept em ber – Oct ober 2010; Art icle 006 ISSN 0976 – 044X Laborat ory Selachii Lt da. in Fort aleza, Ceará, Brazil, and w as dispensed t o t he volunt eers included in t he st udy by t he Phyt otheraphic Division of t he Departm ent of Pharm aceut ical Care of t he It apem irim M unicipal Healt h Secret ariat (Divisão de Fit ot erapia do Depart am ent o de Assist ência Farm acêutica da Secret aria M unicipal de Saúde de Cachoeiro de It apem irim), Espirit o Sant o, Brazil. eight w eeks preceding t he st udy; had a hist ory of alcohol abuse (m ore t han 30 m l of et hanol, 720 m l of beer, 300 m l of w ine or 60 ml of w hisky per day for m en or half t hat am ount for wom en) or drugs; present ed any ot her condition t hat t he invest igat or judged relevant t o nonpart icipation in the st udy. Collection of the crude hydroalcoholic extract The crude hydroalcoholic ext ract w as obt ained from t he leaves of Alpinia speciosa collect ed in Fort aleza-CE, w hich w ere dried at room tem perat ure and m acerated w it h a 70% hydroalcoholic solut ion for 15 days. The ext ract obt ained w as concentrat ed under reduced pressure t o provide t he crude extract. This ext ract was st andardized based on t he concent ration of flavonoids, w hich w as 2.5%. Selection of volunteers Pat ient select ion w as perform ed t hrough m edical consult at ion, including t horough hist ory and physical exam inat ions in t he out pat ient clinic of t he M unicipal Healt h Cent er, as w ell as laborat ory test s and m edical procedures det ailed below. Once evaluated, t he subject s w ere submit t ed t o a free interview t o evaluat e t he em otional condit ion of t he participant s in t he invest igat ion. Subject s w ere inform ed about t he t rial and signed a free inform ed consent form approved by t he Et hics in Research Comm it t ee of t he Alfenas Universit y, M inas Gerais, Brazil, t o part icipat e in t he st udy. Tw ent yt w o pat ient s, sixt een of w hom w ere w om en and six w ere m en w it h a m ean age of 48 ± 2.3 years, were select ed and followed over an est im at ed period of six w eeks, ret urning every t w o w eeks for m edical evaluation. Aft er t he st udy, t he w hole routine w as conducted again (m edical consult at ions, m edical procedures and laborat ory test s). Criteria for inclusion in the study The following criteria w ere applied for pat ient inclusion in t he st udy: diagnosis of st age 1 hypert ension (mild) or 2 (m oderat e) according t o t he VI Joint (NIH, 1997); a syst olic pressure bet w een 140-180 m m Hg; diast olic pressure bet w een 90 t o 110 m m Hg; no use of ant ihypert ensive in t he last 30 days; older t han 35 years and body m ass index under 27; pat ient freely signed t he consent form aft er all t he essent ial element s of t he prot ocol had been m ade clear prior. In t he pre-st udy m edical evaluation, of t he t w ent y-t w o select ed pat ient s, t hirt een w ere classified as m ildly hypertensive and nine as m oderat ely hypert ensive. Exclusion criteria The following crit eria w ere used t o exclude patient s from part icipation in the st udy: hist ory of secondary hypert ension; renal insufficiency; cardiopat hy (CHF, left vent ricular hypert rophy, arrhyt hm ia requiring m edical t reatm ent , infarction); patient part icipated in any experiment al st udy in t he t hree mont hs prior t o t he st udy; pat ient w as hospit alized for any reason w it hin t he Clinical and laboratory tests Pat ient s underw ent t he following laborat ory t est s: com plet e blood count , glucose, serum urea and creatinine, t ot al cholest erol, t riglycerides, uric acid, t ransaminases, bilirubins, alkaline phosphat ase, serum sodium and pot assium , urinalysis and EKG. The result s of m edical exam inations and laborat ory t est s w ere recorded in spreadsheet s for each pat ient. Treatment regimen A capsule cont aining 250 m g of crude hydroalcoholic ext ract of Alpinia speciosa Schum w as adm inist ered orally in t he m orning. When necessary, in t he case of no response by t he pat ient , t he dose w as increased by one capsule (w hen blood pressure levels w ere m aint ained) t o 6 capsules (if t he blood pressure increased) in t he aft ernoon and/ or at bedt im e. The t ot al t reat ment period w as 6 w eeks of t here w as no discontinuat ion of t reatm ent. Of t he t w enty-t w o patient s treat ed, t hirt een pat ient s t ook only one capsule, eight t ook t w o capsules and only one took t he m axim um dose, six capsules of crude hydroalcoholic ext ract of A. speciosa . Data collected The dat a collected from t he clinical prot ocol consist ed of t he m edical assessm ent , blood pressure measurem ent s, adverse event s report ed every t w o w eeks on ret urn of t he pat ient and t he result s of laborat ory t est s and electrocardiogram s perform ed before and aft er t he st udy period. Target blood pressure The t arget blood pressure in t his st udy w as a syst olic blood pressure <140 m m Hg and a diast olic blood pressure < 90 mm Hg. As a secondary t arget , w e aimed t o obt ain a significant reduct ion in syst olic and/ or diast olic blood pressure. Aft er a six-week period, at t he conclusion of t he st udy, t he patient s were again evaluated (Post -St udy) according t o t he routine at the initial assessm ent. Discontinuation of Study M edication Pat ient s could wit hdraw from t he st udy for m edical reasons, in t he case of persist ent high blood pressure even aft er a m edicat ion dose increase, upon t he occurrence of adverse event s, or for breach of prot ocol. In t he case of persist ent high blood pressure, ot her ant ihypert ensive m edications were prescribed aft er careful medical evaluat ion. Clinical Evaluation The researcher provided adequat e inform ation regarding any findings t hat suggest ed significant risks, International Journal of Pharmaceutical Sciences Review and Research Available online at ww w .globalresearchonline.net Page 28 Volum e 4, Issue 1, Sept em ber – Oct ober 2010; Art icle 006 cont raindicat ions, side effect s or precaut ions relevant t o t he safety of t he m edicat ion under st udy. Adverse Events Included in t he " adverse event s" w as one of t he follow ing t hat possibly developed or increased in severit y during t he st udy: a) any suspect ed signs or sympt om s related or not to t he st udy condit ions; b) any clinically significant laborat ory abnorm alit y; c) any abnorm alit y evaluation. detect ed during m edical Signs and symptoms Signs and sym pt om s w ere classified as mild, m oderat e or severe by invest igat ors according t o t he follow ing definit ions: a) m ild: not causing limit at ion of norm al act ivit ies; b) m oderat e: causing some limit at ion act ivit ies; c) severe: causing act ivit ies. inabilit y to of norm al perform norm al Serious adverse events A serious adverse event w as defined as any event t hat suggest ed a significant risk, cont raindicat ion, side effect or precaution. A serious adverse event included any event t hat w as fat al or life t hreat ening, w as disabling, required hospit alizat ion or was an overdose. Statistical analysis For st at ist ical analysis, variance analysis (ANOVA, onew ay) w as applied follow ed by t he Tukey-Kram er t est for m ultiple com parisons of blood pressure values before, during and aft er t reatm ent . Result s w it h p<0.05 w ere considered st atist ically significant. ISSN 0976 – 044X RESULTS AND DISCUSSION The first piece of dat a t o note from t his st udy w as t he fact t hat t he t w ent y-tw o hypert ensive pat ient s w ho received one t o six capsules cont aining 250 mg of crude hydroalcoholic ext ract of Alpinia speciosa did not report unpleasant side effect s from t his t reat ment regim en, indicat ing t hat t he t olerability w as good. There w as one pat ient w it hdraw al, but it w as unrelated t o t he t reatm ent. Hypert ension, in general, is an asym pt om at ic disease in it s early st ages. The best w ay t o detect it early is by rout inely measuring blood pressure. In som e cases of hypert ension, t he init ial sym pt om is headache, especially occipit al and in t he m orning. In t his st udy, sevent een patient s present ed wit h headache as a sym pt om . The crude hydroalcoholic ext ract of A. speciosa w as effect ive in reducing headache w it hin t he first follow-up (second w eek) in all patient s w ho experienced low ered blood pressure. These pat ient s also show ed im provem ent in insom nia and agit at ion, slept bet t er and felt m ore relaxed, indicat ive of central effect s, 2 in accord wit h t he preclinical st udy in mice by M aia et al. The result s show ed t hat t he crude hydroalcoholic ext ract of Alpinia speciosa w as effective at reducing blood pressure in st ages 1 and 2 of t he hypert ension classificat ion (Figure 1, Tables 1 and 2). The result s obt ained dem onst rated t he efficiency aft er six w eeks of t reatm ent in reducing syst olic blood pressure in t w ent y of t he t w ent y-tw o pat ient s. Only one pat ient show ed no change (pat ient 02) and anot her w ithdrew from t he experiment (patient 22), com plaining of undefined m alaise t hat w as not correlat ed w it h laborat ory t est s or electrocardiography (Table 1). International Journal of Pharmaceutical Sciences Review and Research Available online at ww w .globalresearchonline.net Page 29 Volum e 4, Issue 1, Sept em ber – Oct ober 2010; Art icle 006 ISSN 0976 – 044X Table 1: Syst olic blood pressure of pat ient s undergoing t reat m ent for 6 w eeks w ith t he crude hydroalcoholic extract of Alpinia speciosa. Table 2: Diast olic blood pressure of pat ient s undergoing t reatm ent for 6 weeks wit h t he crude hydroalcoholic extract of Alpinia speciosa. W eek Patient Pre Study 01 10 9 9 9 02 9 9 9 9 03 9 8 9 9 04 9 10 9 8 05 10 8 9 8 06 9 8 9 8 07 9 9 8 8 08 9 9 9 8 09 9 8 9 8 10 9 10 9 8 11 9 9 9 7 2 nd 4 th Post Study 12 9 9 9 7 13 10 10 10 8 14 10 10 9 6 15 10 10 10 9 8 16 9 9 8 17 11 10 10 9 18 9 9 9 8 19 9 8 9 8 20 11 11 11 9 21 9 11 10 7 22 9 11 9 10 M ean 9,409 9,286 9,190 8,100 SD 0,666 1,007 0,680 0,912 Variance 0 1 0 1 International Journal of Pharmaceutical Sciences Review and Research Available online at ww w .globalresearchonline.net Page 30 Volum e 4, Issue 1, Sept em ber – Oct ober 2010; Art icle 006 ISSN 0976 – 044X Table 4: Clinical and laborat ory result s of pat ient s undergoing t reat ment for 6 w eeks w it h t he crude hydroalcoholic ext ract of Alpinia speciosa . 22 Patients M ean Tests RBC Haemogram W BC . Leukocyt es Pre 6.850 Standard Deviation Post 6.673 Pre 1.763 Post 3.295 . Basophils - - - . Eosinophils 2 2 2 3 . M yelocyt es - - - - . M et amyelocyt es - - - . M ast cells 4 2 1 3 . Neut rophils 55 54 6 6 . Lymphocyt es 37 38 6 7 . M onocyt es 2 4 1 1 . Hemat ology 4 4 0 0 13,3 - - . HGB 13,1 1,4 1,4 . HCT 38 40 4 4 . HGM 30 30 2 3 . VGM 90 91 6 6 . CAGH 33 33 1 1 108 108 56 57 21 23 7 5 0,8 0,8 0 0 200 194 48 45 212 Hemat oscopy . Glucose . Ur ea . Creat inine Blood biochemist ry . Cholest erol . Triglycerides 144 61 . Uric Acid 5 5 1 1 . TGO 31 23 8 13 . TGP 26 22 10 16 . Bilirubin 1,0 1,0 0,2 0,3 . BD 0 0 0 0 . BI 1 1 0 0 . FA 147 153 39 39 . Sodium 139 137 2 3 4,1 3,8 0,3 0,4 General Charact erist ics . Pot assium . Densit y 191 1.024 1.022 3 5 . PH 5,3 5,9 0,5 0,5 . Volum e 47 39 15 11 68 68 8 10 . Color . React ion Abnormal element s Urine contents . Deposit . Prot eins . Ket one bodies . Bile salt s . Reducing salt s . Bilirubin . Hemoglobin Sedimentoscopy . Pyocyt es . Eryt hrocyt es . Desquamat ed cells . Cryst als . Cylinders . Prot ozoans . Yeast . Bact erial flora . CR . SAP . SAQRS EKG . SAT . PR int erval . QRS durat ion . QT . HR . Conclusion SPS Abnor malit y International Journal of Pharmaceutical Sciences Review and Research Available online at ww w .globalresearchonline.net Page 31 Volum e 4, Issue 1, Sept em ber – Oct ober 2010; Art icle 006 ISSN 0976 – 044X The efficiency of t he crude hydroalcoholic ext ract of Alpinia speciosa in reducing diast olic blood pressure w as also dem onst rated in ninet een of t he t went y-t w o patient s aft er six weeks of st udy (Figure 1, Tables 1 and 2). Tw o pat ient s did not show a reduct ion in diast olic blood pressure (pat ient 02 and 03), and anot her experienced increased blood pressure (pat ient 22) aft er having w it hdraw n from t he st udy (Table 2). t hat in relat ion t o the action of t he crude hydroalcoholic ext ract of Alpinia speciosa, t hese effect s present ed wit h decreased int ensit y. However, on out patient evaluat ion, t he result s show ed an initial drop in heart rat e (Table 3), w hich w as sust ained until the end of t he st udy, at w hich point a slight increase in HR w as observed, possibly a reflex m echanism t o m aint ain homeost asis. Polyuria w as also observed by m ost patient s in t he st udy, w it h report s of a transit ory increase in urine volum e and frequency. This effect can also be at t ribut ed t o t he diuretic action of direct vasodilat ors t hrough t he increase of renal plasm a flow and consequent increase in diuresis of t he glom erular filtrat e. Table 3: Heart rat e of patient s undergoing treatm ent for 6 w eeks wit h t he crude hydroalcoholic ext ract of Alpinia speciosa . W eek Patient Pre Study 01 80 80 80 86 02 90 90 80 90 03 80 80 80 80 04 84 84 80 80 05 80 80 84 84 06 84 84 80 80 07 80 80 92 80 08 89 89 80 89 09 86 86 80 86 10 89 84 89 89 11 80 80 80 80 12 84 84 84 84 13 86 86 86 86 14 82 82 82 80 15 82 82 82 82 16 89 89 89 89 17 80 80 80 80 18 80 80 80 80 19 86 86 86 86 20 84 84 84 84 21 76 76 76 86 84 84 2 nd 4 th 22 84 M ean 83,409 SD 3,775 3,651 3,954 Variance 14 13 15 83,143 82,667 Post Study 84 84,150 3,573 13 9 In preclinical st udies, Soares de M oura et al. showed t hat t he ant ihypert ensive effect of t he crude hydroalcoholic ext ract of Alpinia speciosa m ay be due t o a direct action 7 on vascular sm oot h m uscle, and Em iliano et al. dem onst rat ed t hat t he vasodilat ory effect of t he hydroalcoholic ext ract of t his plant is endotheliumdependent and is probably due t o the release of nitric oxide (NO). Should the same effect s occur at t he clinical level, w e propose t hat t he antihypert ensive act ion of t he crude hydroalcoholic extract of Alpinia speciosa occurs t hrough vasodilat at ion. Based on t his hypot hesis, one can correlat e t he ant ihypertensive action of Alpinia t o t hat of synt het ic antihypert ensive drugs of t he class of direct vasodilat ors w hose mechanism of action is correlated. Ot her effect s relat ed t o t he m echanism of action of direct vasodilat ors, such as reflex t achycardia and polyuria, could also be observed in t his st udy. The difference w as Aft er com plet ing t he treatm ent period w it h t he crude hydroalcoholic extract of Alpinia speciosa , t he hem at ological and biochem ical t est s performed show ed no st at ist ically significant differences (Table 4), dem onst rat ing no t oxicit y at t he hem at ological and biochemical levels during the st udy period. However, in anim als t reat ed wit h t he t ea and hydroalcoholic extract , 4 an increase in transaminases and HDL w as observed. It is not ew ort hy t hat one pat ient showed significant im provem ent s in t he result s of several laborat ory paramet ers after com pletion of t he st udy, wit h an em phasis on leukocyt es and t riglycerides. The post t reatm ent urinalysis did not show result s t hat could be considered abnorm al, and t he result s w ere sim ilar t o t hose perform ed before t reatm ent . Addit ionally, t he electrocardiogram s perform ed before and aft er t he st udy revealed no significant changes. Changes in pre-st udy EKG remained practically unchanged aft er com plet ion of t he st udy. A 46 year-old pat ient w ho w as treat ed w it h a dose equivalent t o 1.5 g per day of crude hydroalcoholic ext ract of Alpinia speciosa show ed t he best result s in post -st udy laborat ory t est s. This patient drew clinical at t ent ion not only due t o t he laborat ory t est result s result ing from a drop in blood pressure at t he end of t he st udy but also due to t he excellent clinical response. The pat ient show ed im provement of sym pt om s of hypert ension (headache) and m enopause (hot flushes) and show ed visible improvem ent of varicose veins, insom nia and anxiet y. These result s suggest t hat the use of t he crude hydroalcoholic ext ract of Alpinia speciosa in cases of hypert ension can be a useful t herapeutic alternative. This species showed no side effect s, indicative of it s safet y, and m ost im port ant ly, is inexpensive w hen com pared t o current treatm ent s. M oreover, t he species is abundant t hroughout Brazil and w ould t herefore not require an im port investm ent. Acknowledgments Laborat ory Selachii Lt da. from t he cit y of Fort aleza, Ceará, Brazil. 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