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REVERSE PHARMACOLOGY
Phytocannabinoids, Banned and
Restricted Herbals

Amritpal Singh Saroya

Herbal Consultant
Punjab
India

p,
p,
A SCIENCE PUBLISHERS BOOK
A SCIENCE PUBLISHERS BOOK
Cover illustrations provided by the author of the book, Amritpal Singh Saroya.

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Library of Congress Cataloging-in-Publication Data

Names: Amritpal Singh, 1971- author.

Title: Reverse pharmacology : phytocannabinoids, banned and restricted
herbals / Amritpal Singh Saroya.
Description: Boca Raton, FL : CRC Press, 2017. | “A Science Publishers book.”
| Includes bibliographical references and index.
Identifiers: LCCN 2017021748| ISBN 9781138037076 (hardback : alk. paper) |
ISBN 9781315178059 (e-book)
Subjects: | MESH: Plant Preparations--pharmacology |
Nanoparticles--therapeutic use | Drug Discovery--methods |
Pharmacognosy--methods | Cannabinoids--pharmacology
Classification: LCC RS164 | NLM QV 766 | DDC 615.3/21--dc23
LC record available at https://lccn.loc.gov/2017021748

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 Preface

The book titled REVERSE PHARMACOLOGY Phytocannabinoids, Banned

and Restricted Herbals has been prepared on the persistent demand of the
herbal drug industry. Part A deals with REVERSE PHARMACOLOGY &
NANOPHYTOMEDICINE. The linkage of Reverse Pharmacology with
Phytomedicine and Ayurvedic medicine has been discussed. Nanocurcumin,
nanoandrographolide, nanohypericum, nanohypericin and nanohyperforin,
nanotaxol, nanosilymarin and nanoparticles of other bioactive compounds and
herbal extracts have been discussed to examine pharmacological aspects and
possible application in therapeutics.
PART B: PHYTOCANNABINOIDS deals with botany, chemistry, pharmacology
and toxicology of Cannabis indica, C. sativa and C. ruderalis. A chapter on Herbal
Cannabinomimetics is the salient feature of this section. Separate chapters have
been devoted to Cannabis oil and Leonotis leonurus (Wild Cannabis) explaining
the chemistry and pharmacological investigations. A–Z of the restricted and banned
herbal drugs is integral part of the part b. This section is of particular importance for
regulatory affairs of restricted and banned herbs of commerce.
I sincerely hope the book shall be welcomed by the herbal fraternity and serve as
a handy collection in ever expanding market of herbal drugs. Suggestions and critics
for improving the quality of the book are welcome.
 Contents

Preface v

PART A: REVERSE PHARMACOLOGY & NANOPHYTOMEDICINE

1. Introduction 3
2. Reverse Pharmacology and Phytomedicine 7
3. Reverse Pharmacology and Ayurvedic Medicine 10
4. Introduction to Nanophytomedicine 19
5. Nanocurcumin 27
6. Nanoandrographolide 34
7. Nanohypericum, Nanohypericin and Nanohyperforin 36
8. Nanotaxol 39
9. Nanosilymarin 43
10. Nanoparticles of Other Bioactive Compounds 47
11. Nanoparticles of Herbal Extracts 55

PART B: PHYTOCANNABINOIDS
12. Cannabis indica—Historical Aspects 63
13. Botany of Cannabis 68
14. Chemistry of Cannabis indica 70
15. General and Clinical Pharmacology of Cannabis sp. 76
16. Herbal Cannabinomimetics 83
17. Cannabis Oil 91
18. Wild Cannabis—Leonotis leonurus (L.) R.Br. 97
19. Restricted and Banned Herbals 102
Index 207
 PART A
REVERSE PHARMACOLOGY &
NANOPHYTOMEDICINE
 CHAPTER 1

Introduction

1.1 What is Reverse Pharmacology?

Reverse and forward pharmacology are two paths generally adopted for the purpose
of the drug-discovery (Takenaka 2001). The difference between reverse and forward
pharmacology is depicted in the following diagram (Fig. 1).
Reverse pharmacology (RP) has also been addressed as target-based drug
discovery (Lee et al. 2012). As per standard definition available, reverse pharmacology
is defined as the science integrating documented clinical/experiential hits, into leads by
transdisciplinary exploratory studies and further developing these into drug candidates
by experimental and clinical research. The reverse pharmacognosy is aimed at finding
novel biological targets for discovering natural compounds (Ernst 2009). This may
involve virtual or real screening and identification of the natural resources that may
be source of the active molecules (Do et al. 2005).

Identification

Fig. 1. Forward and reverse pharmacology approaches in drug-discovery.

4 Reverse Pharmacology: Phytocannabinoids, Banned and Restricted Herbals

1.2 Reverse Pharmacognosy

Forward pharmacology is also called classical pharmacology. Pharmacognosy, the
science dealing with study of physical, chemical and biological properties, cultivation
and storage of herbal drugs is essentially viewed as classical pharmacology. The
sciences of pharmacognosy and classical pharmacology are generally compared with
reverse pharmacology (see definition).
In pharmacognosy, the folk medicines undergo clinical testing for possible efficacy.
Once the efficacy is established, studies are done so as to study the biological target
of the drug. This approach or path defines the classical pharmacognosy.
In terms of a routine protocol, preliminary phytochemical screening is done
and the characterisation and isolation of the active ingredient (active constituent
or bioactive) is done. When we talk about the routine protocol of reverse
pharmacognosy, knowledge of a key enzyme being affected by a bioactive is vital.
This approach or path can identify medicinal plants as source of novel bioactives
(Do and Bernard 2004).

Pharmacognosy Reverse pharmacognosy

Plants Molecules

SELNERGY
Extracts

Biological
Biological Assays
Assays

Bio-guided Compound
fractionation Source

Bioactive Bioactive
Molecule(s) Plant(s)

Fig. 2. Pharmacognosy and reverse pharmacognosy approaches in drug-discovery.

Reverse pharmacognosy is a potential tool for addressing certain issues in current

drug discovery process. A few to mention are scarcity of hits for clinical purpose
and toxicology data by exploitation of existing pharmacognosy data (Do et al. 2005;
Blondeau et al. 2016). Integration of pharmacognosy and reverse pharmacognosy for
the purpose of research can be a handy and fast-flowing tool for drug discovery from
natural resources (Ernst 2009).
 Introduction 5

1.3 Viniferin
Epsilon-viniferin or ε-viniferin (Fig. 3), is employed as an active ingredient in
cosmetic products. This compound is basically a phenolic compound and occurs in
Vitis coignetiae Pulliat ex Planch. (crimson glory vine), Vitis vinifera Linn. (grapevine)
and Dryobalanops aromatica Gaertn (camphor tree).
Despite wide usage in cosmetology, biological properties of viniferin are poorly
understood. SelnergyTM is a novel tool employed for the purpose of drug discovery.
It consists of a docking software which predicts interaction of ligands with proteins.
Selnergy has been used for identification of binding targets for viniferin.
As far as cosmetic application is concerned, cyclic nucleotide phosphodiesterase
4 (PDE4) was the most promising candidate. The others PDE1, 2, 3, 5 and 6 subtypes
were not retained, which clearly indicates for a selectivity for PDE4. Investigatory
tests with 6 subtypes of phosphodiesterase demonstrated a significant selectivity for
phosphodiesterase 4 subtype. Evaluation of ε-viniferin on the secretion of markers of
inflammation confirmed the selectivity (Do et al. 2005).
OH

OH

OH

O OH

OH

Fig. 3. Chemical structure of viniferin.

1.4 Meranzin
Meranzin (Fig. 4) is a coumarin compound isolated from Limnocitrus littoralis
(Miq.) Swingle (Limnocitrus). This plant is endemic to Central Java. Like ε-viniferin,
SelnergyTM was used for identification of putative binding targets of the coumarin.
Cyclooxygenase 1 (COX1), Cyclooxygenase 2 (COX2) and peroxisome proliferator-
activated receptor (PPAR gamma) were the targets selected. The results obtained from
the software were comparable with the experimental findings. This proved that an
extract of the herbal drug containing meranzin modulated COX1, COX2 and PPAR
gamma (Do et al. 2007).
6 Reverse Pharmacology: Phytocannabinoids, Banned and Restricted Herbals

O O O

O
O

Fig. 4. Chemical structure of meranzin.

Further Reading
Blondeau S, Do QT, Scior T, Bernard P, Morin-Allory L. Reverse pharmacognosy: another way to harness
the generosity of nature. Curr Pharm Des. 2010; 16: 1682–96.
Do QT, Bernard P. Pharmacognosy and reverse pharmacognosy: a new concept for accelerating natural
drug discovery. Drugs. 2004; 7: 1017–27.
Do QT, Renimel I, Andre P, Lugnier C, Muller CD, Bernard P. Reverse pharmacognosy: application of
selnergy, a new tool for lead discovery. The example of epsilon-viniferin. Curr Drug Discov Technol.
2005; 2: 161–7.
Do QT, Lamy C, Renimel I, Sauvan N, André P, Himbert F, Morin-Allory L, Bernard P. Reverse
pharmacognosy: identifying biological properties for plants by means of their molecule constituents:
application to meranzin. Planta Med. 2007; 73: 1235–40.
Ernst E. Reverse pharmacognosy: Editorial. J Diet Suppl. 2009; 6(3): 201–202.
Lee JA, Uhlik MT, Moxham CM, Tomandl D, Sall DJ. Modern phenotypic drug discovery is a viable,
neoclassic pharma strategy. J Med Chem. 2012; 55: 4527–38.
Takenaka T. Classical vs reverse pharmacology in drug discovery. BJU Int. 2001; 88: 49–50.
Vaidya BD. Reverse pharmacology—A paradigm shift for drug discovery and development. Curr Res
Drug Discov. 2014; 1: 39–44.
 CHAPTER 2

Reverse Pharmacology and

Phytomedicine

2.1 The Decoction of Argemone mexicana for the Treatment of

Uncomplicated Falciparum Malaria
An exceptional, dose-escalating clinical trial conducted in Mali investigated the
efficacy of a decoction of Argemone mexicana L. (Papaveraceae) in the treatment of
uncomplicated malaria caused by Plasmodium falciparum. A dose-escalating clinical
trial refers to a progressive increase in the amount of any drug. The purpose is either
to improve the tolerability or to maximize the effect.
The eighty patients enrolled for the clinical trial. Majority of the patients (75%)
were in the age group of less than five years. Rest of the patients (25%) were less than
one year. The patients were assigned to consume the dose of decoction of A. mexicana
in three regimens as follows:
Dose patterns of a decoction of A. mexicana in a dose-escalating clinical trial.
S. No. Group N Duration Dose
1. A 23 3 days OD
2. B 40 7 days BD
3. C 17 7 days QD (4 days) followed by BD (3 days)

The eighty patients diagnosed with P. falciparum malaria has parasitaemia > 2000/
microl. As far as clinical response was concerned, it was 35%, 73% and 65% in three
groups, respectively. On the 14th day, whole dimensions of the adult:child ratio were
found to be lower in case of children aged < one year. It was higher in case of patients
aged > 5 years. A complete clearance of P. falciparum was not achieved. However,
67% of the patients achieved parasitaemia < 2000/microl (Willcox et al. 2007).

2.2 A. mexicana Decoction versus Artesunate-amodiaquine for

the Management of Malaria in Mali
A study evaluated the efficacy of a decoction of Argemone mexicana in 301 patients
diagnosed with malaria in age group of five years. The patients were randomised to
receive the herbal decoction or standard antimalarials (artesunate-amodiaquine). The
8 Reverse Pharmacology: Phytocannabinoids, Banned and Restricted Herbals

Cl N

N
N

O
Fig. 5. Chemical structure of amodiaquine.

patients tolerated both the drugs. After a treatment of twenty-eight days, alternative
treatment was not required in 89% of the patients receiving the herbal decoction. In
contrast, 95% of the patients receiving artesunate-amodiaquine responded well (Graz
et al. 2010).

2.3 Reverse Pharmacology Approach Applied to the Decoction

of A. mexicana
Three alkaloids, allocryptopine, berberine and protopine were isolated from
A. mexicana through bioguided fractionation. Allocryptopine (Fig. 6), protopine (Fig.
7) and berberine (Fig. 8) demonstrated antimalarial activity in vitro. Allocryptopine
and protopine showed selective response towards the parasite, Plasmodium falciparum.
The study emphasised the need of pharmacokinetic studies in order to determine
whether the three alkaloids in question can be utilised as marker compounds for
the purpose of quality control and standardisation of the decoction of A. mexicana
(Simoes-Pires et al. 2014).

O
N
O

O
O

Fig. 6. Chemical structure of allocryptopine.