Multi-component botanical drugs for degenerative diseases

Ashok Kumar, Priti Kumar

Center for Research in Integrative Medicine, SK Biotherapeutics Pvt.Ltd., Aligarh, India

Abstract

Key words: plant; botanical drug; multi-component botanical drug; botanical therapeutic; inflammatory disease; degenerative disease;chronic disease; adverse drug reaction; holistic health; clinical trial

INTRODUCTION

Millions of people around the world are suffering from various types of degenerative diseases.Degenerative diseases cause deterioration of tissues or organs resulting in accelerated aging.1Most of these disease conditions are of longer duration and slow progression and classified as chronic diseases.It is estimated that one out of every two adults suffers with at least one chronic degenerative illness.Most of these diseases are incurable but manageable with presently available therapies.Chronic degenerative disorders such as heart disease, cancer,asthma, arthritis, diabetes, and kidney failure cause 70% of mortality.1Unavailability of curative therapies for these disorders is a matter of great concern prompting World Health Organization to appeal for an urgent action to halt and turn back the growing threat of chronic diseases.

Single molecule drugs have played a major role in managing the symptoms of chronic diseases.2However, issues of unavailability of curative therapeutics, suboptimal response,treatment resistance and adverse drug reactions remain problematic and pose a serious concern.The incidence of serious and fatal adverse drug reactions is found to be high in US hospitals and considered as killer number 4– just after heart disease, cancer and stroke.3Sometimes actions are taken by manufacturers to remove a problematic drug product from the market voluntarily or upon instructions from Food and Drug Administration (FDA).In last 50 years, a large number of USFDA-approved pharmaceutical drugs had to be pulled from the market after discovering that their risks outweigh their benefits and those serious side effects were not known at the time of approval of a particular drug.This health scenario around the globe can be completely changed by using multicomponent botanical drugs (Figure 1).

Figure 1: Schematic diagram.

In our phase I (CTRI/2017/10/010237) and phase II(CTRI/2017/10/010214) single arm clinical trials, multicomponent botanical therapeutic, SKB108 composed of constituents isolated from plants Crinum asiaticum and Crocus sativus was orally administered.4For phase II trial, patients suffering from various chronic inflammatory diseases such as asthma, arthritis, rhinitis, migraine, sinusitis, urticaria, chronic conjunctivitis, food allergy, hypertension,etc.were enrolled.All these patients were suffering from one or more chronic inflammatory disease(s) at least from last one year and taking disease specific standard medical treatment.At baseline all patients were advised to continue to take whatever standard medical treatment they had been taking but gradually reduce the intake of standard medical treatment after remarkable reduction in intensity of disease symptoms.Disease specific self-report questionnaires were developed and provided to every patient.Patients were advised to report the outcomes of oral administration of SKB108 capsules on their health status every month and answer exactly what they think or feel and write the one best answer for every question.In this study, health status of a patient before oral administration of SKB108 was active comparator and compared with experimentali.e.health status of same patient after oral administration of SKB108 capsules.

Oral administration of SKB108 capsules showed almost no toxicity, only 1% of volunteers had nausea for 15–30 minutes if capsules were taken empty stomach but no such problem was encountered if taken after meal.SKB108 has provided complete freedom from chronic inflammatory diseases in patients although total duration of administration varied from few months to a few years depending upon patient’s age,type, severity and duration of disease.During administration of SKB108 capsules, all patients had completely stopped standard medical treatment.Five years after stopping administration of SKB108 capsules, only small number of patients reported recurrence of disease symptoms.These patients were administered again with SKB108 capsules for few to several months to regain a disease free body.SKB108 is complex mixture of several molecules and they have acted together to target several pathways simultaneously and provided complete cure from chronic inflammatory diseases.Laboratory studies have shown that SKB108 is capable of down-regulating tumor necrosis factor α and interleukin 17 and thus exerts strong immune-regulatory effect (unpublished results).

A search strategy was developed with an information specialist undertaken by one reviewer (AK), supported by a second, independent reviewer (PK).The following databases were searched: Google Scholar and PubMed.The keywords were “inflammation; chronic diseases; degenerative diseases;chronic inflammatory diseases; mortality caused by chronic diseases; chronic diseases and aging; problematic drug products; drug or treatment resistance; single molecule drugs;multi component drugs; multi component botanical drugs;herbal drugs or medicines; botanical drugs or medicines”.We restricted searches to studies in English relating to humans,published before May 2018.

BENEFITS OF MULTI-COMPONENT BOTANICAL DRUGS

There are several examples in the literature of multi-component botanical therapeutic formulations showing beneficial effectsin vivoandin vitroin entirely unique and distinct manner.Some examples are as follows:

A.Effect of Gingko biloba extract on skin blood flow in healthy volunteers was studied.It was demonstrated that some subjects had an increased blood flow, some had decreased blood flow and some had no change in blood flow.Apparently,it appeared that this plant has no reproducible activity and is not suited as a drug.While a more detailed analysis revealed that subjects who had normal blood flow before experiment had no change in blood flow.Subjects who had higher blood flow before experiment had decreased blood flow and those who had lower blood flow before experiment had increased blood flow.These findings substantiate that Gingko biloba extract has multi-directional modulating action on blood flow in healthy subjects.5

B.A combination of cinchona bark alkaloids quinine,quinidine, and cinchonine and cinchonidine was found to have activity similar to that of quinine against quinine susceptible P.falciparum strains but was 2 to 10 times more effective against resistant strains.Combinations of cinchona bark alkaloids can be used successfully in areas where P.falciparum is developing resistance against quinine as this combination is much more effective than any of the alkaloids used singly.6

C.In experiments against malaria parasites, whole plant Artemisia annua shows higher activity than comparable dose of pure artemisinin.Components from plant A.annua such as artemetin, casticin, chrysosplenetin, chrysosplenol-D, cirsilineol, eupatorin, isovitexin, kaempferol, luteolin, myricetin,quercetin, and rutin showed antimalarial activity against chloroquine sensitive and chloroquine resistant strains of P.falciparum in absence of artemisinin suggesting that they are acting on different targets.This higher activity is attributable to the synergism of antimalarial activity of A.annua constituents.Whole plant Artemisia annua from which artemisinin is derived can be used successfully to overcome parasite resistance.7

D.Inflammation, infection, and hyperplasia cause many skin problems such as facial redness, acne, and common warts.In a clinical study for assessment of efficacy, botanical moisturizer was applied only on half side of face.After one month,statistically significant improvement was observed on the face side treated with botanical moisturizer in scaling, flaking,tactile smoothness, textural smoothness, firmness, radiance,luminosity and overall appearance.8Sandalwood album oil, an essential oil from Santalum album tree is a traditional botanical medicine used for dermatological problems shows biological activitiesviamultiple routes of action and possesses antiinflammatory, anti-microbial and anti-proliferative activity.

E.5'-Methoxyhydnocarpin (5'-MHC), synthesized by berberine producing Berberis medicinal plants, has no antimicrobial activity alone but strongly potentiates the action of berberine.Multidrug resistance pumps protect microbial cells from berberine antimicrobials.In presence of 5'-MHC level, accumulation of berberine in the cells was increased and bacterial resistance mechanism was disabled.9

F.Annona muricata also known as soursop, graviola or guanabana widely distributed in tropical and subtropical regions is investigated for anti-cancer activity in extracts from fruit,bark, seeds, roots and leaves.Phytochemical studies have identified dozens of acetogenins from the extracts of different parts of graviola.10Similarly, Hemidesmus indicus, a promising anticancer botanical drug stimulates immunogenic tumor cell cytotoxicity in human colorectal cancer cell line characterized by surface expression of calreticulin, increased HSP70 expression and release of ATP and HMGB1.

G.Some plant molecules act as pro-drugs, their beneficial health effects are a consequence of conversion to active molecules in the human digestive system.Willow (Salix) bark produces antipyretic action without causing gastric injury contains the prodrug salicin, which gets converted to saligenin by intestinal bacteria and to salicylic acid after absorption.11Sennosides are converted into laxative anthrones by bacteria in the gut.Conjugated phytoestrogens are hydrolyzed in the gut to show their estrogen-like effects.Phenolic glucoside arbutin is ineffective against urinary tract infections until it is hydrolyzed and oxidized to hydroquinone in the human body.

H.Some botanical components exert their effects by mimicking endogenous metabolites, such as ligands, hormonesetc.For example, anagyrine from Anagyris foetida, cytosine from Laburnum anagyroides, lupanine from Cytisus scoparius and sparteine from Chelidonium majus affect neuroreceptors by forming a quaternary nitrogen configuration which has structural resemblance to a structural motif present in most neurotransmitters.

I.Some plant molecules potentiate the activity of other constituents for example quercetin, catechins, reserveritol and curcumin have ability to potentiate the activity of various other phytochemicals.

Use of plants as medicines is not a new science.This knowledge predates written human history and 80% of people on different continents have used thousands of indigenous plants for treatment of various ailments.More than hundred modern single molecule pharmaceutical drugs such as analgesic agents(opium, salicin, borneol, codeine, morphine, rotundine, tetrahydropalmatine), anti-parasitic agents (quinine, artemisinin,emetine, arecoline), anti- tumor agents (vinblastine, vincristine,topotecan, taxol, teniposide, podophyllotoxin, lapachol, irinotecan, etoposide, demecolcine, colchicine, colchiceine amide,camptothecin, betulinic acid), and cardiotonic (acetyldigoxin,adonicide, convallatoxin, deslanoside, digitalin, digitoxin,digoxin, gitalin, lanatosides A, B, C, ouabain, scillarin A).have been developed from plants.12

Similar to synthetic single molecule drugs, plant derived single molecule drugs are also not 100% effective and safe.Lessons to overcome this hurdle can be learned from plants.To maintain their health, plants produce thousands of extremely diverse secondary metabolites.Several thousands of these plant constituents are identified for which no role has yet been identified in primary functions such as photosynthesis,reproduction, and growth.Thus nature clearly teaches that the efficacy and safety of single molecule drugs might be enhanced by converting in to multi component formulations.Physicians also prescribe more than one single molecule drugs ultimately equalizing to multi components.In multi-component mixture,molecules interact with each other, act antagonistically, synergistically and target multiple physiological and biochemical pathways simultaneously and impart efficacy and safety beyond the reach of single molecule drugs.13

DISCUSSION

For complete relief from various diseases including chronic degenerative diseases plants can be utilized as pharmaceutical bio-factories to produce relatively inexpensive multi-component botanical therapeutic formulations as they appear to possess inbuilt intelligence of nature.As it is known that most of the chronic diseases have Inflammation at the root, availability of a strong and safe anti-inflammatory multi-component botanical formulation like SKB108 described above is capable of curatively treating most of such disorders.Empirical evidences of safety and efficacy can be obtained from ancient traditional knowledge utilizing plants such as Traditional Chinese Medicine (TCM), Indian Systems of Medicine like Ayurvedaetc.14

These traditional botanical drugs are mixture of several components thus fulfill criteria of multi components to target multiple pathways involved in most diseases including degenerative diseases.Development of multi component botanical therapeutics by reverse engineering/reverse pharmacology of traditional botanical drugs of proven safety and clinical efficacy can significantly reduce the cost as well as duration of drug development as compared to synthetic drug development process.15

Multi-component botanical therapeutics can be marketed as prescription drugs.In 2004, US FDA issued Guidance for Industry for “Botanical Drug Products”.According to these guidelines, botanical drugs are products to be used for preventing, curing, mitigating, treating or diagnosing a disease condition.Botanical drug products are defined as formulations containing plant materials, algae, macroscopic fungi, and combinations thereof.Such products do not contain materials from genetically modified plants, animals, fermentation and highly purified substances and are heterogeneous with unidentified active constituents but consistent therapeutic effects of each marketed batch.

Large numbers of applications are pending with US FDA for approval of ‘prescription botanical drugs’ but till date only Veregen (for genital warts) and Mytesi (for diarrhea in patients suffering with HIV/AIDS) have been approved.Nabiximols(Sativex), an extract from Cannabis has also been approved in UK as a mouth spray for patients suffering with Multiple Sclerosis.It is the need of time that the drug approval process for botanical drugs is taken on priority by the regulatory agencies world over.

Author contributions

Both AK and PK contributed to this work equally.

Conflicts of interest

The authors have no conflicts of interest to declare.

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