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Journal of Postgraduate Medicine July 2012 Vol 58 Issue 3 199

Introduction

I n India, since ancient times Coleus forskohlii hasbeen used in Hindu and Ayurvedic traditional

medicine.[1,2] Forskolin was named after the Finnish botanist,Forskal.[3,4] Coleus forskohlii is a perennial member of the mintor Lamiaceae (also known as Labiatae) family that was firstdiscovered in the elower elevations of India. It was recordedin the ancient Sanskrit texts that Coleus forskohlii has beenused as a medical herb to treat hypertension, congestive heartfailure, eczema, colic, respiratory disorders, painful urination,insomnia, convulsions, asthma, angina, psoriasis and forprevention of cancer metastases.[3-5] The literature searchmethod used was databases (PubMed, IPA, Google, MAPA)and websites and the following keywords were used while

searching the literature “Coleus forskohlii”, “Forskolin” and“Forskolin + Glaucoma”.

Description of Forskolin

Forskolin is an active constituent of Coleus forskohlii. Unlike theother coleus species C. forskohlii is used for health purposes.[6] Forskolin is a labdane diterpene which was derived as an activealkaloid from the roots of C. forskohlii. The synonyms used forforskolin are Colforsin and Coleonol. Detailed analysis revealsapproximately 20 constituents in various parts of the plant,but forskolin and other coleonols are present only in the rootportion.[7] Forskolin is the primary constituent of clinical interestin Coleus forskohlii. It was discovered by Western scientists in1974. Initially it was referred to as coleonol.[8] The name waschanged to forskolin as other coleonols and diterpenoids havebeen identified later. All pharmacological activities relatedto Coleus forskohlii are due to the active constituent named

forskolin.[9]

Specifications of Forskolin

Forskolin is derived from the roots of Coleus forskohlii[10] belonging to family Lamiaceae or Labiatae.[5,10] Its Sanskrit nameis Pashanbedi, Makandi[11] and it is commonly known as Coleus,Karpuravali and Sughandabalu, (Hindi: Pathatchur; Kannada:Makandiberu; Gujarati: Maimul, Marathi: Garmai)[8,10,11] andits parts used are roots only.[7] Coleus Forskohlii grows wild onsun-exposed arid and semi-arid hill slopes of the Himalayas in

Department ofPharmaceutics,R. C. Patel Instituteof PharmaceuticalEducation and Research,Near Karwand Naka,1Department of Botany,H. R. Patel Junior Collegeof Science, Shirpur,Maharashtra, India

Address for correspondence:

Dr. Vijay D Wagh,E-mail: [email protected]

Received : 13-12-2011

Review completed : 26-01-2012

Accepted : 27-03-2012

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Quk ree ce: webte:

www.jpgmonline.com

doi:

10.4103/0022-3859.101396

pubme id:

***

D rug Review

Forskolin: Upcoming antiglaucoma molecule

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ABSTRACTForskolin is the first pharmaceutical drug and product derived from a plant to be approved in India by the DCGI in

2006. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6b, 9a-trihydroxy-labd-14-en-11-one) is a diterpenoid isolated

from plant Coleus forskohlii (Lamiaceae). It is a lipid-soluble compound that can penetrate cell membranes

and stimulates the enzyme adenylate cyclase which, in turn, stimulates ciliary epithelium to activate cyclic

adenosine monophosphate, which decreases intraocular pressure (IOP) by reducing aqueous humor inflow.

The topical application of forskolin is capable of reducing IOP in rabbits, monkeys, and humans. In its drug

interactions, forskolin may act synergistically with epinephrine, ephedrine and pseudoephedrine. Whereas

the effects of anti-clotting medications like warfarin, clopidogre, aspirin, anoxaparin, etc., may be enhanced

by forskolin. Forskolin is contraindicated in the medications for people with ulcers as forskolin may increase

acid level. Forskolin has a very good shelf-life of five years. Recently, its Ophthalmic inserts and in situ gelsfor sustained and delayed-release drug delivery systems were tested in New Zealand Albino Rabbits for its

antiglaucoma efficacy. This drug review explains Forskolin as a drug, its antiglaucoma potential and recent

findings of forskolin as an antiglaucoma agent. The literature search method used for this review was different

databases and search engines like PubMed, International Pharmaceutical Abstracts, Google, Medicinal and

Aromatic Plants (MAPA).

KEY WORDS: Antiglaucoma drug, coleus forskohlii , forskolin, glaucoma, nanoparticles, ophthalmic insert

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200 Journal of Postgraduate Medicine July 2012 Vol 58 Issue 3

Wagh, et al.: Forskolin and glaucoma

Figure 1: Structure of Forskolin

Uttar Pradesh, from Shimla eastward to Sikkim and Bhutan,the Deccan Plateau, Eastern Ghats, Eastern Plateau and rainshadow regions of the Western Ghats in India.[10]

Structure[8,10]

Forskolin is the labdane diterpene produced by root portion ofthe Coleus forskohlii. Its chemical name is 7beta-Acetoxy-8,13-epoxy-1a, 6b, 9a-trihydroxy-labd-14-en-11-one. Its molecularweight[10] is 410.5 g/mole (anhydrous) and molecular formula[10] is C

22H

34O

7. Forskolin appears[10] as an off-white crystalline solid;

having l-max[10] at 210 nm, 305 nm and its melting point[10] is228°C-230°C; while as it is soluble in DMSO, Ethanol, Methanoland Dichloromethane. It may be dissolved in 2% ethanol inwater, by dissolving it first in ethanol and then subsequentlydiluting this solution with water [Figure 1].[10]

Mechanism of actionForskolin’s primary mode of action is to increase cyclic adenosinemonophosphate (cAMP) and cAMP-mediated functions,via activation of the enzyme adenylate cyclase.[12] Forskolinactivation of adenylate cyclase accrues primarily though a direct

action of the diterpene on the catalytic subunit of adenylatecyclase, however, Forskolin requires the presence of guaninenucleotide-binding protein, the G8 protein, for maximalstimulation of the enzyme. High-affinity binding sites forforskolin have been described in rat brain membranes and humanplatelet membranes, and these sites have structural requirementfor forskolin analogues that are similar to those for activationof adenylate cyclase. It was suggested that these binding sitesfor forskolin are an activated complex of adenylate cyclase.[13]

Forskolin stimulates adenylate cyclase activity withoutinteracting with cell surface receptors. Forskolin has theability to stimulate adenylate cyclase activity and increase

cyclic adenosine monophosphate (cAMP) which regulatesand activates critical enzymes required for the cellular energyrequired to move fluid out of the eye.[13] Forskolin lowers theintraocular pressure (IOP) of rabbits, monkeys, and humans. Inrabbits, net aqueous humor inflow decreases, outflow facilityremains unchanged and ciliary blood flow increases. Forskolinhas a different molecular mechanism from any previously usedantiglaucoma drug. Its effect on IOP should be additive withother drugs because its tachiphylaxis might not occur becauseforskolin’s action is not believed to involve the cell surface

receptors. In vitro forskolin activates adenylate cyclase of crudeparticulate homogenates prepared from cultured human ciliaryepithelia or from dissected ciliary epithelial processes of rabbitor human eyes.[13]

Forskolin has been shown to increase cAMP formation in alleukaryotic cells except sperm, without hormonal activation ofadenylate cyclase.[14] Forskolin’s potentiation of cAMP in turninhibits basophil and mast cell degranulation and histaminerelease,[15] lowers blood pressure[16] and IOP,[17] inhibits plateletaggregation,[18,19] promotes vasodilation,[16,20] bronchodilation,[21] and thyroid hormone secretion,[22,23] and stimulates lipolysisin fat cells.[24] Forskolin also has a positive inotropic action oncardiac tissue via increased cAMP levels.[25] The cAMP level isimportant for retinal ganglion cells neurotrophic responsivenessto neurotrophins which is important for neuron survival. cAMPmay inhibit some forms of neurotrophin-mediated neuronalsurvival and suggests that a number of PI3-kinase-regulatedprocesses in neurons may be inhibited by cAMP.[26]

In addition to its cAMP-stimulating activity, forskolin inhibits

the binding of platelet-activating factor (PAF), independentlyof cAMP formation. This may be a result of forskolin’s directeffect on PAF or via interference with PAF binding to receptorsites.[19] Forskolin also appears to have an effect on severalmembrane transport proteins, and inhibits glucose transport inerythrocytes, adipocytes, platelets, and other cells.[27]

Drug interactions, safety, contraindications and storage of forskolinForskolin may enhance the effects of beta-agonists suchas albuterol. Forskolin may also act synergistically withepinephrine, ephedrine and pseudoephedrine. Decrease inneeded dosage of beta-agonist may occur due to use of forskolin.

The effect of anti-clotting medication like warfarin, clopidogre,aspirin, anoxaparin, etc., may be enhanced by the forskolin asit inhibits platelet aggregation and clotting. Coleus forskohlii

have an excellent safety profile and generally are without toxicityor side-effects at the recommended dosage. As warnings andcontraindications of forskolin; avoid its use in the people withulcers as forskolin may increase acid level.[14,28] When stored asindicated, forskolin has a shelf-life of five years.

Forskolin and its antiglaucoma potential glaucoma[8,29]

Glaucoma is a condition in which the pressure in the eye istoo high (>22 mm/Hg), due to an imbalance between theaqueous humor formation and draining out of the eye. Increasein IOP results in irreversible damage to the nerve and impaired

vision culminating in blindness, if left untreated. There are noclinically proven alternative therapies for glaucoma, but thereare several beneficial treatments and coleus is one of them.Forskolin reduces IOP by reducing aqueous humor inflow withno change in outflow facility which indicates the potential offorskolin as a therapeutic agent in the treatment of glaucoma.Reduction in IOP by forskolin was studied with animals likemonkeys, rabbits and in healthy human volunteers also.

Recent findings of forskolin as an antiglaucoma agentGlaucoma is a progressively degenerative disease of the optic

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Journal of Postgraduate Medicine July 2012 Vol 58 Issue 3 201


nerve and is the second leading cause of blindness in theworld affecting 67 million people globally. Sami Labs is thefirst pharmaceutical company which derived a product from aplant to be approved in India, it is also the first such eye careproduct worldwide. The drug Forskolin Ophthalmic Solutionhas been accorded approval by the Drug Controller General ofIndia in August 2006; developed by the Bangalore-based SamiLabs, a subsidiary of Sabinsa, this eye drops’ formulation willbe available in the market under the brand name “Ocufors2%”.[30] Hoechst had identified the efficacy of forskolin in thetreatment of glaucoma but they could not make an effectiveformulation and subsequently dropped the studies midwaythrough. According to the company’s official press release,“Ocufors” is 30 per cent more effective than the most populardrug for glaucoma in the market with no side-effects.

Wagh et al., formulated forskolin ophthalmic drug deliverysystems to test its efficacy in New Zealand albino rabbits forits antiglaucoma efficacy.[31] Ophthalmic Inserts[32] of forskolinextract (OIE) and pure forskolin 98% (OIF) were prepared asmatrix-controlled delivery with the aim of achieving once a

day administration. Ophthalmic Insert Drug Delivery System(OIDDS) for forskolin showed a significant reduction in IOPup to 24 h and an increased corneal residence time up to 12 hwith sustained therapeutic action which is a desirable featurefor an antiglaucoma agent.[31,33-37] Gupta et al., preparedforskolin nanocrystals and stabilized by poloxamer 407. Theirinvestigations proven that the pH and thermoreversiblepolymeric in situ gel forming nanosuspensions with ability ofcontrolled drug release exhibits a greater potential for glaucomatherapy.[38]

Forskolin and rutin are the main ingredients of a foodsupplement, when given in a open-label pilot study to

16 patients with Primary Open Angle Glaucoma undertreatment with different topical drugs and with stable IOPwere given additional treatment with the food supplement for40 days, and their IOP values measured at enrolment, at theend of treatment and 40 days after treatment interruption. Thisassociation treatment resulted in a further decrease of IOP byroughly 20% of the initial value. The effect was reversible uponsuspension of the treatment.[39]

Thus, forskolin is a wonder drug with a proven antiglaucomadrug candidature. Though the forskolin eye drops have crossedall clinical trial phases there is a necessity to undergo humanvolunteer studies for newly developed ophthalmic dosage formand drug delivery systems. It is the need of the hour to exploreForskolin drug for its applications and therapeutic efficacyin other diseases also. There might be a perfect solution toincrease the solubility of forskolin either by different solubilityenhancement techniques in the formulation industry or bynanoparticles, nanocrystals, nanosuspension, nanoemulsionand nanocomposites in nanotechnology.

Acknowledgment

The author Vijay D Wagh, is thankful to Indian Council of MedicalResearch for its assistance as Senior Research Fellowship to him, for

this research work. The authors are also thank Sami Labs Pvt. Ltd,Bangalore, Karnataka, India for the gift sample of Forskolin (98% pure).

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h t te t tle:Wagh VD, Patil PN, Surana SJ, Wagh KV. Forskolin:

Upcoming antiglaucoma molecule. J Postgrad Med 2012;58:199-202

sue f sut: Nil, Conict of Interest: None declared.

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