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DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Memorandum 1188 __ ‘03 MAR13 1~48 Date: March 7,2003 From: Consumer Safety Officer, Division of Standards and Labeling Regulations, Office of Nutritional Products, Labeling and Dietary Supplements, HFS-821 Subject: 75Day Premarket Notification of New Dietary Ingredients To: Dockets Management Branch, HFA-305 Subject of the Notification: Asmakure Firm: Port Orchard Nutriceuticals Date Received by FDA: December 9,2002 90-Day Date: March 9,2003 In accordance with the requirements of section 413(a) of the Federal Food, Drug, and Cosmetic Act, the attached 75day premarket notification and related correspondence for the aforementioned substance should be placed on public display in docket number 958-03 16. Thank you for your assistance. CSO/Lead Reviewer Attachments DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Food and DNg Administration College Park, MD 1189 '03 MAR13 P1:48 JamesKao, B. Pharm,MBA Junwei Sun, M.S., MBA Port Orchard Nutraceuticals 1800 Sidney Avenue l-203 Port Orchard, Washington 98366 Dear Mr. Kao and Mr. Sun: This is to inform you that the notification you submittedpursuantto 21 U.S.C. 35Ob(a)(2)was received and filed by the Food and Drug Administration (FDA) on Dewmber 9,2002. Your notification concernsthe substances,Abies Webbiana2.1 l%, Adhatoda Vasica 10.30%, Zingiber officinale 6.27%, Piper Longum 8.25%, Piper nigrum 4.07% Cnmamomum Zeylanicum 1.OO%,AmmomumSubulatum1.OO%,and Ntsadal 1.OO%under the name Asmakure,and HemidesmusJndicus(Anantamul) 100 mg, Ricinus communis(Shetverenda) 100 mg, Moringa Pterygosperma(Sajina) 100 mg, Tinospora Cordifolia (Gulancha)125 mg, and BoerhaaviaDiffusa (Rakta Punamaba)75 mg underthe namePanekurem that you assert are new dietary ingredients. The law at 21 U.S.C. 35Ob(a)(2)requiresthat a manufactureror distributor of a dietaty supplementthat containsa new dietaryingredient submit certain information to FDA at least 75 daysbefore the dietary ingredientis introduced or deliveredfor introduction into interstate commerce. This information must include the basison which the manufactureror distributor has concludedthat a dietary supplementcontaining suchnew dietary ingredientwill reasonablybe expectedto be safe. FDA reviews this information to determinewhether it provides an adequatebasisfor such a conclusion. Under section 3SOb(a)(2),there must be a history of use or other evidenceof safety establishingthat the dietary ingredient,when used under the conditionsrecommendedor suggestedin the labelingof the dietary supplement,will reasonablybe expectedto be safe. Jf this requirementis not met, the new dietary ingredientis deemedto be adulteratedunder 21 U.S.C. 342(f)(l)(B), becausethere is inadequate informationto provide reasonableassurancethat the new dietary ingredient does not presenta significantor unreasonablerisk of ihnessand injury. Federalregulationsfound at 21 CFR 190.6 specify the requirementsfor a premarket notification on a new dietary ingredient. The notification you sentus concerningthe dietary supplementswith tradenamesPanekurem and Asmakuredoes not comply with the requirementsof 21 CFR 190.6 and is incomplete. For exampleit fails to: Page 2 - Messrs.Kao and Sun l l provide copiesof the referencesto publishedinformation offered in support of the notification which shallbe reprints or photostaticcopiesof such references,also,if any part of the materialsubmittedis in a foreign language,it shall be accompaniedby an accurateand completeEnglish translation; sufficiently describePanekuremand Asmakure(e.g., identify the Latin bmomial namesof the botanicals(herbalingredients)includingthe genus,species,and the (author) and any other known relevantpropertiesof the botanicalingredient(s)and all relevantpropertiesof the mineralingredientNisdal, including its chemicalformula. Accordingly, there is inadequateinformation in your notification for FDA to determine whether there is an adequatebasisto concludethat the use of a dietary supplementthat containsthe ingredientsidentifiedin your notification will reasonablybe expectedto be safe. Therefore,your product may be adulteratedunder 21 U.S.C. 342(f)(l)(B) as a dietary supplementthat containsnew dietary ingredient(s)for which there is inadequateinformation to provide reasonableassurancethat it does not presenta significantor unreasonablerisk of illnessor injury. Introduction of such products into interstatecommerceis prohibited under 21 U.S.C. 331(a)and(v). ~fyou wish, you may sendus the requiredinformation and addressthe issuesidentified above to correct the deficienciesin your current notification in the form of an amendmentin triplicate (i.e., an original and two copies). However, in order to serveas an amendmentto the current notification, the information you submit must be deliveredto this office by no later than February22,2003, which is 75 days after the current not&&ion’s Sling date. We note that if the requiredinformation is not receivedwithin the 75&y timeframe,your notification will be filed in the FDA’s Docket ManagementBranch 90 daysTom the effective filing date. Another option is to sendus at any time a new notification, in triplicate, that is completeand fidly complieswith 21 CFR 190.6. The datethat we receivethe additionali&ormation for either an amendedor new notification is consideredthe new tiling date. Pleaseindicatein the cover letter ifit is an amendedor new notification. Your not&ation will be kept contidentialfor 90 days from the date of the e@ctive filing date. After the 9Oday period, your notification will be placedon public displayat FDA’s Docket ManagementBranch in docket number 958-0316. Prior to the 9Oday period, you may wish to ident@ in writing specificallywhat information you believeis proprietary in your current notification for FDA’s consideration Page 3 - Messrs. Kao and Sun For you information, the following FDA Internet sitesand their correspondinglinks may be usefill: http:kvww.cfsan.fda.gov/-dms/supplmnt.html http://wwv.cfkan.fda.aovHrd/fB7923e.html (21 CFR 190.6) pleasemdact me at (301) 436-2371,if you haveany questionsconcerningthis matter. SusanJ. Walker, M.D. Acting Division Director Division of Dietary SupplementPrograms and Compliance Office of Nutritional Products,Labeling and Dietary Supplements Centerfor Food Safkty and Applied Nutrition Divisionof Standards andLabelingRegulations Of&iceof NutritionalProducts,L&&g, andDietaq Supplements (HPS-820) Centerfor FoodSafbtyaddAppliedNutrition FoodandDrugAdministration 51OOPaintBranchParkway CollegePark,MD, 20740-3835 Telephone Numk (301)4362371 Dear Director: In accordanceto the requirementsof Section 413(a)(2) (21 U.S.C. 350b) of the Federal Food, Drug and Cosmetic Act, XxXx if filing for pre-marketing notice of new diq ingredients in two Ayurvedic products (Asmakure and Pauekure): The new dietary ingredients are: Asmakure: Abies Webbiana is a high altitude herb fmd in the Himalayaswith a very high anti-a&ma& 1) property. Adhatoda Vasica is a @uclitionallyproven herb to combatbronchial disorders.The principals of 2) this plant are ahloids vasicine (mw 188, C 11H12N20),vasicinoneand vasicinol which are usedas brochodialators. Zingiber offiinale is a herb containingessentialoils like &giber&e and alpha-terpinone.These 3) essentialoils havepotent auti-M propertieswhich reducethe acutenessof bronchial infection. Piper longum is another kind of traditional herb whoseactive &redient, monocyclic 4) sesquiterpencshascounterirritant and analgesicprop&es for reducingmuscularpain and Mamma&n. Previousresearchhas found this to be effective in bronchial spasmand inflammation. Piper nigrum is a medicinal herb which enhancesantibacterial function and increasesbio9 availability of other herbsnsed in the formulation. Cinnamomum Zeylanicum is the herb having depressant action on centralnervoussystem(CNS) 6) and thus, reducesstressinducedasthma. Ammomum subulabm is the herb which provides a soothingeffect on bronchop*hara@al 7) region and hasa bronchosedativeaction. Nisadal is a kind of white crystalline mineral substancewhich has mucolitic (i.e liquefying effect 8) on dry cough) and expectorant(i.e expelsliquefied cough)properties. Pyekure: Hemidesmus Indicus L%nantamul) :¢ reseanhs have proved exclusively that the active 1) principles of this plant consist of an enzyme, an essentialoil and a saponin. Rutin has been isolated from leaves. Detectionof hexatriacontane,lupeol, its octa-cosanoate,mp. 8 lo, a - amyrin, p - amyrin, its acetate and sitosterol in roots by chromamgraphy. Ridnus Communis tSt&verenda) : castor oil consists of the glycerides of ricinoh5c, 2) isoricinoleic, stearicand dihydroxy - stearic acids, Detection of palmitic (1.2), stearic(0.7), arachidic(0.3), hexadecenoic(02), oleic (3.2), linoleic (3.4), hnolenic (OJ), ricinoleic (89.4%) and dihydro&aric acids as Me-estersin castoroil was doneby GLC. The plant yields about 1% ricinine. Lupeol and 30 - norlupan3~-ol-2o-Onehavebeenisolated~thecoatofcastorbean. Seedcoatcomainedl.SO-1.62%lipids and higher amountsof phosphatidesand non sapomtiablematter than seedkernel. Morhwa Ptervnosrwma tSaiiua1 : A reddish brown oil called ptergospermin with strong 3) antibiotic activity has beenchemically isoW hm this plant. Aldotriouronic acid from acid hydrolysis of gumhasbeencbatacterisedasO-(P-D-glucopyranosyhnoniccacid)(1~6)-B-D-galactopyranosyl (1 3 6) - D - gala&ue. Presenceof aspartic acid, ghxtamic acid, glycine, threonine, alanine, w&e, leucine, isoleucine,histidine, lysine, arginine, phenylalarine, tryptophan, cysteine and methionine have ‘( . . been detectedin leaves. Alanine, arginine, glycine, tie, &nine, valine, gh@mic and aspartic acids have been detectedin flowers and iiuits; lysine in flowers, sucroseand gl~se in flowers and sucrosein hits. 4-hydroxy-mellein,vanillin, octacosanoicacid, p - sitosteroland p - sitostenonehave been isolated km stems. Tinoswra Cordifolii tGulancha~ : Chemical analysis revealedthat the plant contained an 4) &&id, glycosidesand sterol. An unidentifiedcompound,mp. 114“,an amorphouscompound,mp. 90”, a physiologically active unidentified compound,mp. 119, a sterol, mp. 134“and a fatty acid, mp. 84’, have been isolated f?om the plant. Al ditqenoid of columbin type - tinospoti (0.02%), mp. 184’ and thmporide mp. 236”and cordifolide, mp. 176’havealso beenisolatedfrom the plant. Tinosporidineand f3 - sifosterol have beenisolatedfkom stems;and cordSol, heptauxano1and octacosanolm leaves. A new fkranoid diterpene- tiuosporidehasbeenisolatedfrom stems. Boerhaavia Diffusa (Rakta Punarnabal : Chemicalanalysisrevealsthe presenceof an alkaloid 5) and an oily mass. Sulphates,chloridesand tracesof nitmtes and chloratesare obtainedl?om the ash. Ash (11.8), Ca (1.2) and K 2.3%), presenceof alkaloids, ke and combinedamino acids have been determined in aerial pmts of the plant. Boerhaavicacid, low tannins, phlobaphenes,reduchq sugars(glucose), and 0.01% of a crystalline basenamed punamavine were also isolad Hexa-triacontane,B - sitosterol and msolic acid have been isolated fkom roots, a polysaccharidewas isolated which on hydrolysii yielded glucose, xylose, glucuronic acid, galactose,L - avabinoseand L - rhamnose;a glycoprotein with a molemlar weight of 16,000- 20,000daltonswas isolatedfrom roots. All the relevant in vivo and clinical information is enclosed. These new dietary ingredients will not be marketed in the US for 75 days after your expected receipt of this Notice Port orchard Nutraceuticals / 1800 Sidney Ave l-203 Port Orchard, WA 98366 HERBiCURE PRNATE LIMITED Metro Garden Cii, Pailan, 24 PGS(S) PANEKURETM (A herbal research medicine) Each Capsule Contents : Hemidesmus indicus Recinus communis Moringa pterygospenna Tinospom cordifolia Boerhaavia diffusa Exepient (filler) Indication 100 mg; 100 mg; 100 mg; 125 mg; 75 mg; QS : Oesteoarthritis, synositis. pain, inflammation, ankylosis, cervical spondylosis, arthralgia, myalgia, V Panekure inhibits prostaglandians synthesis by COX2 inhibition. 2) Panekure does not induced gastric or intestinal ulceration. Moreover, it promotes secretion of cytoprotective mucus in the intestine and prevents mucosal damage. 3) 4) Panekum has no damagingeffect on kidneys. 5) Panekure is non-toxic and a very safe herbal medicine treatment by Panekure may be safely continued for any length of time. Dose : 1 - 2 capsule thrice a day or as directed by the physician. Properties 1) 2) 3) 4) 5) 2) 3) 4) 5) : Hemidesmus indicus possesses a very good anti-inflammatory properties (Ref.1). Ricinus communist has pain cure activity (Ref. 2). Moringa pterygosperum is useful in fever and pain (Ref. 3). Tinospora cordifolia is used as anti-inflammatory agents (Ref. 4). Boerhaavia diffusa is useful in controlling pain and inflammation (Ref. 5). References 1) of Ingredients : Indigenous Drugs of India 2”d ed. 1982, Academic Publisers, p.188. Ibid, p.236. Ibid, p.364. Ibid, p.426 Ibid, p-494 HERBICURE PRIVATE LIMITED Factory: Metro Garden Ci, Pailan, 24 PGS(S) TOXICOLOGICAL DATA OF PANEKURE IN S - D RATS IN P. 0. ROUTE FOR 6 WEEKS Route P. 0. (Per OS1 For 6 Weeks Parameters SI. No. I A. 1 Haematological I Test : Normal (Saline Control) Tmated (Panekure) , I I I 8.9 (7.2 - 9.8) 14.8 (12.0 - 17.5) 1240 (1100 - 1380) 8.6 (7.3 - 9.5) 14.7 (12.1 - 17.4) 1200 (1050 - 1240) Cholesterol (mg/lOO ml blood) 127.5 f 2.0 120.5 f 1.9 (2) Bilirubin Total (mg/lOO ml blood) 0.48 f 0.1 0.49 f 0.2 (3) SGOT Unit/ml Serum 89.4 f 3.0 90.2 f 4.0 (4) SGPT Unit/ml Serum 33.2 f 1.9 35.5 f 1.8 C. Kidney Function Test : (1) (2) Creatinine Clearance mUmin Urea Clearance ml/min/m2 10.1 (6.3 - 15.2) 14.4 (3 - 28) 11.2 (7.5 - 16.0) 15.5 (4 - 291 (1) (2) (3) Erythrocyte Value of Rat (million I dl) Hemoglobin (gm I 100 ml) Plateles : Thousands/d1 of blood --- B. Liver Function Test : (1) ’ . 8 HERBICURE PRNATE LIMITED Factory: Metro Garden City, Pailan, 24 PGS(S) Effect of plant extract of PANEKURE, Phenylbutatone & lndomethacin on the hydwryproline content of carrageenin induced granuloma tissue in rats. Plant Extract foorrgA<gMay S.C.(PcO.01) lndom@Mn Piwnybmm 5wwdY S.C.(PeO.01) IWmslKsMaY 8.C.(PcO.01) . I 8 H E R B K U R E P R IV A T EU M ITE D Factory: M e tro G a r d e n City, P a i l a n , 2 4 P G S (S) E ffect o f p l a n t extract o f P A N E K U R Eo t? peroxide (glucose sxidase) i n d u c e d inflam m a tio n . 70 60 50 G 40 c .E 53 Lo 20 10 0 . . I , I 8 HERBICURE PRIVATE LIM ITED Factory: Metro Garden City, Pailan, 24 PGS(S) Effect Mpirin of plant extract of PANEKURE and (ref. standard) on right hind paw of adjuvant induced arthritis rats. 2 1.8 1.8 1.4 Q, 1.2 5 91 3 m r* 0.8 0.6 Piant Extract 80 m3$NoM&P. < . Aopirinloo mM$Vojw,‘-~. c . I l , .:,’ ‘ . 8 H E R B I C U R EP R IV A T EU M ITE D Factory: M e tro G a r d e n City, P a i l a n , 2 4 P G S (S) A B R J E FO N A S M A K U R E H e r b i c u r e ’s a n ti-asthmatic h e r b a l medicine, called A s m a k u r e , h a s b e e n d e v e l o p e d b y th e D e p a r tm e n to fP h a r m a c e u ticalTechnology,J a d a v p u rUniversity a fter a p r o l o n g e da n d rigorous R & D s p a n n i n gm o r e th a n 7 years. D u r i n g th e researchwork, very large b a s e o f pre-clinical studies a n d p o s t-clinical observations w e r e carried o u t to reveal n o n - toxic e ffect o f th e m e d i c i n ewith h i g h th e r a p e u ticv a l u e in asthmaticdisorder. A collaborative e ffort b e t w e e n H e r b i c u r e a n d J a d a v p u rUniversity h a s b r o u g h t a n a m a z i n g ayurvedicmedicine,called A s m a k u r e ,u n d e r In d i a n S c h o o lo f M e d i c i n e (EM), w h i c h a i m s a t p e r m a n e nrelief t o f th e p a tie n tsfrom th e a g o n y o f asthma. C o m p o s i tio n s : A s far a s th e fo r m u l a tio n o f th e m e d i c i n e is c o n c e r n e dA, s m a k u r eis very different from th o s e o f o th e r prevalent ayurvedic medicines. W h ile th e similarity generally fo u n d b e t w e e n A s m a k u r e a n d th e o thers is only A d h a to d a Vasica, o th e r ingredients in A s m a k u r e a r e c o m p l e telydifferent. A s m a k u r eis c o m p o s e do f e i g h t establishedh e r b s w h i c h all h a v e u n i q u e e m u l tid i m e n s i o n a l th e r a p e u ticvaluesa s follows : 1 . A b i e s W e b b i u n ais a h i g h altitude h e r b fo u n d in th e m o s t difficult terrains o f H i m a l a y a s with a very h i g h a n ti-asthmatic property. H e r b i c u r e h a s p e r m a n e n ta r r a n g e m e n tfor u n i n terruptedsupply o f this m o s t p o te n th e r b fio m Himalayas. 2 . A d h a to d u V u & a is traditionally p r o v e n h e r b to c o m b a t bronchial disorders. T h e principals o f p l a n t a r e alkaloids vasicine ( m w 1 8 8 , Crr H r 2 Nzo), vasicinone a n d vasicinol w h i c h a r e u s e d a s brochodialators. 3 . Zingiber o ~ c i n a fe is a h e r b c o n ta i n i n g e s s e n tial oils like zingiberine a n d a l p h a te r p i n o n e T. h e s ee s s e n tialoils h a v e p o te n ta n ti-bacterialpropertiesw h i c h r e d u c e th e a c u te n e s so f bronchialinfection. 4 . P @ e rl o n g u m is a n o th e rkind o f traditional h e r b w h o s e active ingredient, monocyclic sesquiterpenes h a s c o u n ter irritant a n d a n a l g e s i cpropertiesfor r e d u c i n gm u s c u l a r p a i n a n d inflammation. Thus, fo u n d in researchm o s t e ffective in bronchial s p a s m a n d inflammation. 0’ 5 . P iper n i g r u m is a m e d i c i n a lh e r b w h i c h e n h a n c e sa n ti-bacterialfu n c tio n a n d increases bio-availabilityo f o th e r h e r b su s e d in th e fo r m u l a tio n . 1 ’ . 8 6. Cinnamomum Zeyfunicum is the herb having depressant action on central nervous system (CNS) and thus, reduces stress induced asthma. 7. A m m o m u m subulatum is the herb which provides soothing effect on broncho pharangial region and has a broncho sedative action. 8. Nisadal is a kind of white crystalline m ineral substance which has mucolitic (i.e lequifying effect on dry cough) and expectorant (i.e. expels lequified cough) properties. Formulations Research has revealed that most of the medicinal plants have a tendency to hydrolise in presence of water which reduces the therapeutic efficacy. While some ayurvedic medicine is formulated in syrup form (water base), Asmakure is formulated in dry-dry powder form keeping moisture content less than 4% to avoid any possible hydrolysis and thus, to increase its shelf life. Jn liquid base, synthetic preservative is generally used to avoid m icrobial growth and all these synthetic preservatives are prone to toxicity leading to asthmatic attack. But in Asmakure, there is no use of any preservative or synthetic additive and has been kept in natural form . Further, any pH shift can precipitate out some active ingredients from the syrup base, which is ruled out in Asmakure for its dry-dry powder form . Mode of Action of Asmakure vis-&vis other urevalent anti-asthmatic ayurvedic medicines Asthma is a chronic inflammatory disorder of airway. Mast Cells are releasing various inflammatory mediators like prosta-glandins, leukotrienes, cytokine and histam ines. All are broncho-constrictors and released due to disintegration of mast cell. While the prevalent herbal medicines aim at only single mediator called leukotrienes, Asmakure covers ail mediators which act as broncho-constrictors and it mainly performs as mast cell stabilizer and thus, prevents the release of inflammatory mediators which lead to various kinds of asthmatic attack. Asmakure, thus, has approached the root of the asthmatic disorder and aims at permanent protection. Apart from the above, Asmakure has a strong anti-bacterial mucolytic and expectorant action and thus, offering a complete package of relief to asthmatic patients and even those suffering from common cold and cough, and bronchitis. Steu down auuroach Asmakure has been designed in such a way so as to ensure assured result with sustained use of the prescribed dosage which brings down even the steroid taking patients to the level of normal breathing and tranquility. Regular use of Asmakure along with pure honey at least for a period of six months also provides immunity to the asthmatic patients. Clinical Trial The clinical trial of Asmakure was carried out by the State Ayurvedic Medical College & Hospital. The drug was administered orally among 32 patients (age between 12-55 years of either sex, male 20 and female 12) for consecutive 28 days. The report concludes “clinical results revealed that most of the patients who were su#ering jkom bronchial asthma, and chronic dry cough, got reIief from asthma complications due to Ayurvedic drug, Talishadiherbi (Asmakure). The patients ’compliance of the drug was satisfactory and it can be strongly recommended that the drug can be very use&l in asthmatic management. ” Patent of Asmakure Keeping in view the inventions made towards the process management of the various extracts of active ingredients of the herbs used in the formulation of Asmakure and the exclusivity of Abbies Webbiana, in particular, Herbicure has applied for domestic as well as international patent of the product. ************************************** HERBICURE PRIVATE LIMITED Factmy: Metro Garden Cii, Pailan, 24 PGS(S) ASMAKURE Annexure -I PRODUCT DATA SHEET Presentation Dry-Dry Powder in 100gm bottle. Uses- Effective against allergic Bronchitis and Asthma. Also brings relief in common cold and persistent cough. Doses- l-2 tsf twice daily. Administration- Administration through P.O. along with honey. Contra-indication : Nil Use in pregnancy and lactation: Not yet established. Sideeffects:‘No known side effect. Precaution: Sudden withdrawal of any existing medication (anti asthmatic) is advised against. Warning: Not found. Absorption: Good. Fate: Metabolism, partly through first by pass. Distribution: Apparent volume distribution (vd) is moderate. Metabolism: Mainly by liver cells. Excretion: Elimination: Entrance excretion through high pH (alkaline) urine. Related with urinal pH. Package Quantity: 60 bottles (each of 100 gm) in a single carton. HERBICURE PRIVATE LIMITED Factoty: Metro Garden City, Paibn, 24 PGS(S) ASMAKURE Annexure - II TECHNICAL DATA a) Acute test (single dose). Test in which single doses of the drug are used on each animal on one occasion only for determination of LDSOor Median Lethal Dose (MLD), i.e. the dose which will kill 50% of the animals of a particular species. Lbvalue is determined in a 24 hour test using two species (mice or rats) and one non rodent (usually rabbits). Acute toxicity studies of ASMAKURE in animals studies revealed: 0 Even a very high dose in animal by p.o. route did not produce any mortality in rats and or rabbits. So, there is no question of LDSOvalue determination. Behavioral patterns (like motor activity, CNs stimula dep.) were also unaffected due to Asmakure. Subacute test (daily dose): Tests in which animals (usually rats) are given dose daily starting at around expected therapeutic level and increasing stepwise every two to three days until toxic signs are observed. Hematological and biochemical monitoring are carried out. After 24 weeks pathological and histological examination are dose after killings the animals. Subacute toxicitv studies of ASMAKURE in rats for 4 weeks revealed: 1) Dose in oral route (P.O.) was well tolerated by the animals for continuous 4 weeks treatment. 2) There were no haematological abnormalities in animal due to ASMAKURE treatment. Hb, WBC, RBC were unchanged and there was no depression of bone marrow due to the herbal medicines. 3) Liver function tests were also unaltered due to Asmakure SGOT SGPT. Bilirubin level of treated rats were within limit after subacute treatment with Asmakure. Histological findings confirmed about unaltered liver cells architecture. 4 Mutagenicity studies revealed that the herbal drug ASMAKURE any mutagenic effect. cl If the drug is to be used in women of child- bearing age, its effect on fertility as well as its teratogenic potential must be investigated. Asmakute was tested on pregnant rats extensively for conformation of its safety in women of child-bearing age. However, we have not performed the clinical test on human subject to find say the drugs safety in pregnancy. d) Other find toxicological .studies, like kidney function tests also confirm the drug’s safety. is totally free from HERBICURE PRIVATE LIMITED Factory: Metro Garden City, Pailan, 24 FGS(S) ASMAKURE Annexure - III PHARMACOLOGICAL 1) DATA Human Phamracokinetic and metabolism. a) The drug is acidic in nature. So its ionization in gastric pH is less (low pk value). The drugs absorption of gastric region is very high. b) Oral absorption is very good and bio availability is also good. cl Apparent volume distribution0/d) is moderate. d) Half life(t l/4) : 10-12 hrs. e) Biotransformation: Through hepatic enzyme. 9 Heptic/renal failure: Dose should be adjusted in hepatic or renal failure patients. 9) Au: Elimination of drug in alkaline urine (high pH) is high. 2) Studies mainly done on mast cell stabilization and bronchodilatation activity in animal to establish the drug’s anti-asthmatic value. 3) Secondary pharmacological action like mucolytic and expectoration action of the drug has confirmed its action as mucolytic expectorant. 4) Drug Interaction Studies: There was no such drug interactions found with modem antiasthmatic drugs. HERBICURE PRNATE LIMITED Factory: Metro Garden City, Pailan, 24 PGS(S) ASMAKURE ANNEXURE- IV TECHNOLOGICALDATA - ‘A’ COMPOSITIONFORMULAOF ASMAKURE SY w.,, I INGREDIANTS ___-__--- -_-- - I % COMPOSITION 1 ABIES WEBBIANA(TALISHPATRA) 2.11 2 ADHA TODA VASICA (VASAK) 10.30 3 CINNAMOMUMZEYLANICUM(DARUCHINI) 1.00 4 AMMOMUMSUBUlATUM (BARA ELAICHI) 1.00 5 PIPER NIGRUM(GOLMORICH) 4.07 6 PIPER LONGUM(PIPUL) 8.25 7 ZINGIBEROFFICINABLE(ADA) 6.27 8 NISADAL 1.00 9 SUGAR 68.00 6 HERBICURE PRIVATE LIMITED Factory: Metro Garden Cii, Pailan, 24 PGS(S) ASMAKURE ANNEXURE- IV TECHNOLOGICALDATA - ‘B’ MANUFACTURINGINSTRUCTIONSFOR ASMAKURE PRODUCTION RAW MATERIALS WEIGHINGOF ’ EXTRACT& HERBAL POWDER GRINDINGOF MISHRI& HERBS -+ WEIGHING d&&-~~~ SHRINKING --• T QUALlTYCHECK HERBICURE PRIVATE LIMITED Factory : Metro Garden Cii, Pailan, 24 PGS(S) ASMAKURE ANNEXURE- N TECHNOLOGICALDATA - ‘C’ CONTROLDATA FORTHE ACTNE CONSTITUENTS OF ASMAKURE ACTlVE CONSTITUENTS Sl# REMARKS ALKALOIDS 01 VASICINE PIPERINE PIPERLONGUMINE PIPERLONGUMININE iv) VOLATILEOILS i) PRESENTWITHINLIMIT ii) iii) 02 0 ii) EUGENOL CINEOLEZINGIBEROLE PRESENTWITHINLIMIT 03 ESSENTIALOILS PRESENTWITHINLIMlT 04 TERPENES PRESENTWITHINLIMIT HERBICURE PRIVATE LIMITED Factory : Metro Garden City, Pailan, 24 PGS(S) ASMAKURE ANNEXURE-IV TECHNOLOGICALDATA - ‘D’ CONTROLDATA FORFINISHEDPRODUCT/ASMAKURE) TOTALWEIGHTOF THE SAMPLE 01 NLT 100GM. 02 MESH iKE 99% THROUGH20 # 03 SOLUBlLllY ( IN WATER) NLT69% pH OF ASMAKURESOLUTION 10% (W/v) SOLUTIONIN WATER 20% (W/V) SOLUTIONIN WATER 30% (IV/V-)SOLUTIONIN WATER 1% (W/V) SOLUTIONIN WATER 4.0 TO 4.0 4.0 TO 4.8 4.0 TO 4.8 4.0 TO 6.0 05 MICROBIALCOUNT 10000CFUIGM. 06 TEXI-URE COARSEPOWDER 07 COLOUR LIGHT BROWN 08 TASTE SWEETISH,PUNGENT,HEATING 09 ODOUR SWEET PUNGENT 10 L.O.D.(%W/W AT 105oC) NMT5% 11 BULK DENSlTY NLT 0.75GMIC.C. 12 REFERENCE AYURVEDlCPHARMACOPEIAAiD INDIAN PHARMACOPEIA 04 i) ii) iii) iv) HERBKURE PRIVATE LIMITED Factory : Metro Garden City, Pailan, 24 PGSfS) ASMAKURE ANNEXURE- IV TECHNOLOGICALDATA - ‘E’ STABILITYDATA AND PROPOSEDSHELF-LIFEOF FINISHEDPRODUCT(ASMAKURE) THE STABILITYSTUDIESOF THE DRUG WAS CARRIEDOUTAT THE THREETEMPERATURESNAMELY 37oC,40% & 50% AND IT WAS FOUNDTO BE STABLE. THE SHELFLIFEOF THE DRUGHAS BEEN PROPOSEDTO BE THREEYEARSFROMTHE DATEOF MANUFACTURING AS MENTIONEDIN THE LABEL. HERBICURE PRIVATE LIMITED Factory : Metro Garden City, Pailan, 24 PGS(S) ASMAKURE Annexure -V CLINICAL DATA ** (Reference a) No.JBR/PS-1 g/2001 Dt: 19/02/2001) Phase I Clinical Trial ReDort : The drug (Asmakure) was administered orally to a number of patients(Age between 12-55 years of either sex, male 20, female 12) who were suffering from asthma, in the done range of l-2 teaspoonful twice daily (B.D.) with honey for 28 days consecutively day. Clinical trial revealed that, most of the patients who were suffering from bronchial asthma, and chronic dry cough (non productive cough) got relief from asthma complication due to this Ayurvedic drug. In most of the cases, it has been found that the drug has a definite expectorant action. The patients compliance of the drug was satisfactory and it can be strongly recommended that Asmakure can be very useful in asthma management. W Phase II Clinical trial : Not done. cl No side effect /adverse reactions was found in human subject who received the drug for 28 days consecutively. d) Report on clinical and pharmacological studies are in process for publication. Name 8 Address of the lnvestinator : Dr. Gopal Chandra Sengupta Principal - Superintendent J. B. Roy State Ayurvedic Medical College & Hospital Kolkata, West Bengal l * As per recent guidelines of WHO, the Ayurvedic medicines require less stringent Clinical Trials to go throughsince these medicines are based on time-tested traditional practice spread over a long periodof time. I ’ . . 0 . 0 . HERBICURE PRIVATE LIM ITED Factory: Metro Garden City, Pailan, 24 PGS(S) Table-l Effectof AsnmakweondShrentsymptosmsands’tgarofAsthma Present before 5. Ronchi 6. Difficultyof expectoration After treatment 8110 40150 am 6150 3150 0150 au0 30150 0150 0150 O/50 0150 Table41 Svrirometm Studv Retort of Asmakwe Treatment Asmakure Treated Group . , * . 0 HERBICURE PRIVATE LIMITED Factory: Metro Garden City, Pailan, 24 PGS(S) Table-Ill EffectoiAsnma kure on Respirators Rate of Asthma Patients Treatment with Asmakure 4'hweek 2"Week Treatment with placebo V Week 8thweek 25.0 f 1.9 21.07**1.2 18.72**0.01 18.52*iO.O2 17.97*f 0.05 P values < 0.05 c 0.001 < 0.05 c 0.001 Table-IV, Treatment with placebo 1”Week Treatment with Asmakure 4thweek 2dWeek 1230~10.50 1570 *9.3 1680~~11.5 Pvalues < 0.001 < 0.001 8thweek 1930i13.2 2100 *7.3 < 0.001 < 0.001 HERBICURE PRNATE LIMITED Factory: Metro Garden Cii, Pailan, 24 PGS(S) PrickTest (SkhTestingwithdiEkemtAUe!rgens tothePatietrtr~edAsmakure] Treatmentwith Asmakure Cat (furs) +I- +I- Rabbit(furs) -. * +t + Ship wool (fabric) +k -4-t + @N +t + Milk + + + Grass (pollen) +I- +I- + Cheese ++ ++ - a c 0 :’ . . . - . . HERBKURE PRlVATE LIMITED Factory: Metro GardenCity, Pailan,24 PGS(S) Table-W BiochemicaJ Chanws to the Patients who received Asmakure for 8 Weeks Contluuoud~ Parameters Treatmentwith placebo (No. of Patients 10) Treatmentwith Asmakure (No. of Patients 30) Haemogbbin 12 AZ4 gm/dl.* 13 * 2 gm/dl.* Red cell count 4.3 f 0.1x 10s/ ur 4.5 f 0.2x 1061ur MCHC 30 + 9 % ” 33 f 8%* Eosinophil 13 f 0.1% 6 * 0.010/6"" ESR 22 f 1 m m lhr. 20 f 2 mnVhr. Glucosetolerance 175 f 5 mg/lOOm l 175 f 7 mg/lOOm l+’ 0.1 A 0.2 mg/dl. 0.1 f 3 mg/dl.* 6.0 i 1 gm/dl. 6.1 f 9 gm/dl.* 14 f 4 units/ml. 12 f 3 units/ml.* 20 f 4 units/ml 19 * 8 units/ml. 80 f 8 umolA 78 f 4 umolA 40 f 7 umol/l 38 f 4 umol/l* Hematolo&al Liver Function Test Bilinrbin(Total) Protein(Total) SGOT SGPT Kidney Function Test Creafnine Creatine