Plants as Sources for Novel Medicines

Plants as Sources for Novel Medicines

Plants as Sources for Novel Medicines

Ameyatma Mahajan

Plants as Sources for Novel Medicines

Ameyatma Mahajan

ISBN - 9789361525933

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Preface

Plants have been of great use for humans since down the ages and have been the savior for the entire population of living beings. Be it man, animals, birds, the entire clan of living things, depend on plants for various uses.

Thus in the following chapters, the plant usage in drug discovery from ancient to modern ages has been mentioned. Plants are used in different methods in various forms, and thus, plants have a very important role.

The plants such as herbs especially have a unique value for ages. The traditional methods of preparing medicines are imposed on plants. Thus plants have been used in other traditional medicine globally.

The plants nowadays are used to cure many diseases that have been listed under the no cure section. Hence the plants are listed and now used to cure many diseases using modern techniques and unique measures.

The advantages of using plants that have active compounds that have an amazing effect on the disease have been listed and being studied. Research studies have been conducted to study in detail.

The plants, however beneficial to humans, have to be treated well. Still, somehow few exploitations are being carried out and have a severe impact in the future. Thus the plants which are enlisted as endangered have many benefits in drug discovery.

As globally, the plants have unique features. The discoveries and preparations of various drugs using such plants have been discussed in the chapters. Thus the discovery, preparation, and analysis have been discussed in brief.

The book helps to have sound knowledge of how plants are being used in drug discovery and how to analyze them in detail on the plants' usage in a right beneficial way. Thus using the plants to get maximum benefits from them.

Table of CONTENT

Chapter 1. Drug discovery 1

1.1 Use of plants in drug discovery 5

1.2 Plants used 12

1.3 Preparation methods 16

1.4 Summary 26

1.5 Exercise 28

Chapter 2. Different Fields Of Botany 32

2.1 Usage of Ethnobotany and pharmacognosy 37

2.2 Medicinal plants usage 43

2.3 Drug development 48

2.4 Summary 52

2.5 Exercise 54

Chapter 3. Phytomedicine 57

3.1 Drugs from plant source 64

3.2 Herbal plants formulae 68

3.3 Alkaloid compounds 74

3.4 Summary 82

3.5 Exercise 84

Chapter 4. Drugs Components From Plants 88

4.1 Introduction 88

4.2 Market Demands of Medicinal Plants 92

4.3 Plant-Derived Anti-Diabetic Agents 96

4.4 Plant-Derived Drugs from Chinese Herbal Remedies and Other

Systems of Traditional Medicine 102

4.5 Chinese Traditional Medicine 102

4.6 Source of medicines 103

4.7 Drug delivery system 107

4.8 Synthetic drug molecules 112

4.9 Summary 118

4.10 Exercise 121

Chapter 5. Plants Usage In Drugs Preparation Globally 124

5.1 Various plants used by different countries

5.2 Anti-cancer drugs 131

5.3 Plant to pill 138

5.4 Strategy developed for drug discovery 141

5.5 Summary 146

5.6 Exercise 151

Chapter 6. Role Of Plants In Drug Discovery 155

6.1 Usage of natural products in drugs 160

6.2 Success of natural products 165

6.3 Bioactive molecules from herbal plants 169

6.4 Summary 174

6.5 Exercise 176

Chapter 7. Research On Plants 179

7.1 Introduction 179

7.2 Investigations on plants 187

7.3 Overview of drug discovery and development 194

7.4 Extraction, purification, and analysis 200

7.5 Opportunities for new drug discoveries because of the

unmatched availability of chemical

7.6 Summary 206

7.7 Exercise 213

Drug Therapy 216

8.1 Chromotherapy 219

8.2 Drug delivery system 223

8.3 Pharmacokinetics 226

8.4 Extracts of medicinal plants 232

8.5 Summary 236

8.6 Exercise 242

Glossary 245

Index249

Introduction

Increasing the use of some active agents leads to a greater incidence of adverse events, often due to prescription drug interactions. Clinical awareness of the potential for these types of interactions has led to several studies that have recently been published, prompting regulatory authorities to issue guidance on the use of some products.

While this could be viewed negatively for herbal products, it does, however, serve to show that many herbs can produce significant pharmacological effects and supports the developing view that their use requires improved regulation and control.

During the 1990s, some futurists and, more recently, pharmaceutical scientists, including Dr. George Poste, have predicted that one of the significant advances in the next couple of decades will be therapy’s individualization. This proposal has been linked mainly to the advances in genomics. For many hundreds if not thousands of years, however, some ethnic cultures have been individualizing patients’ treatments.

Two important examples utilizing plant-derived medicines come from China – Traditional Chinese Medicine, and India – Ayuverdic Medicine. Thousands of herbs have been associated with beneficial effects, often given in multiple combinations designed by practitioners for each patient’s total wellbeing.

More recently, academic researchers have investigated pharmacological activity for many more widely used herbs, utilizing Western cultures’ methods. For example, many herbal products available in China for the treatment of benign prostatic hypertrophy are now being screened for their activity in mice with testosterone-induced hyperplasia, a classic test for alpha-reductase inhibition

An extract of the plant Serenoa repens is more effective and associated with fewer side effects than finasteride

This has contributed to a growing interest in using and developing herbs as potential new medicines in the Western world. A significant example of this is developing a Chinese herbal mixture for the treatment of eczema by Phytopharm Plc, based on the observation that a patient receiving treatment from a TCM practitioner in London showed unexpected signs of significant improvement.

R&D programs to develop a new drug by de novo synthesis can typically take up to 20 years: establish a new research program; define the target; synthesize and screen the activity of potential leads; select the optimal few and further define their pharmacological and safety profile. Optimistically, one or two candidates make it into development.

If clinical efficacy and safety are demonstrated to achieve product license approval, a period of product exclusivity will follow. The return on investment will be related to the effectiveness of a company’s patent strategy and product life cycle management.

Advances in technology have been designed to reduce the time to identify candidate new drugs, for example, high throughput screening, combinatorial chemistry, and most recently, genomics and proteomics. The evidence to date of these increasing the chances of success is limited, but that is not to say that these significant investments will not come to fruition shortly.

In addition to others like cell culture and cloning, these technologies can also be applied to plant-derived substances. When embarking on a program to identify therapeutically active plant components or mixtures, one can often have a head start in the race due to prior knowledge about potential activity associated with a particular species or genus.

By reducing uncertainty, the time, cost, and complexity of de novo synthesis, one can substantially reduce the time to reach the market and increase the chances of success.

It is relevant here to add that evidence of clinical exposure. Thus safety can often be documented for traditional herbal medicines. Such products can be evaluated in small, well-designed and controlled, clinical studies to test ‘proof of concept,’ negating the need for significant investment in pre-clinical safety before having confidence that one has a potential product.

Regulatory issues for licensing of plant-derived medicines and how are they evolving?

This is not to say that the development of plant-derived medicines is without complication. The key issues for development programs, where it is difficult or for other reasons, are not desirable to synthesize the active plant component, related to identification, standardization, and consistency of the material.

Fears of adulteration or even contamination of plant material by potentially toxic materials are not unfounded and serve to substantiate regulators’ long-standing attitude towards combination products and a frank ‘adverse reaction’ to complex mixtures like herbal extracts. As a result, many companies have shied away from this potentially fruitful area of R&D.

It is reassuring for those interested in developing plant-derived medicines that the anticancer taxol has been therapeutically and commercially successful. The recent European approval of galanthamine for Alzheimer’s disease in Sweden further supports the premise that plants are a new medicine source.

Major initiatives have been underway in Europe and the US to address the regulation of herbal medicines. This is mainly in recognition of a lack of continuity of, or complete absence of regulation, for herbal products used as medicines, nutraceuticals, functional foods, and consumers’ desire to access such products. The final rule relating to the DSHEA regulations has recently been published.

This relates to statements that can be made about the effects of dietary supplements on bodily structure or function and are of major significance to manufacturers of herbal products targeted at the general consumer. Europe is not as advanced in this specific area of regulation. Still, the European Agency for the Evaluation of Medicinal Products has made significant progress towards achieving a European-wide assessment of herbal medicinal products, including evaluating monographs for well-recognized herbs.

While regulatory approval of some of the more widely known medicinal herbs is potentially being made easier, new chemical entities remain as stringent as ever. New plant-derived chemicals, extracts, and their derivatives fall within the latter category.

Some phytopharmaceutical companies focus their efforts on single molecules or plant extracts to simplify the regulatory process by avoiding complex mixtures and combinations. Others are looking to the future success of their new technologies to facilitate approval.

India has a very long, safe, and continuous usage of many herbal drugs in the officially recognized alternate health system.

Herbal therapy is an ancient science of the Indian system of medicine. The traditional formulation contains plant material as its core ingredient. Herbal medicines are the oldest form of health care known to mankind. As we know, medicine’s future is rooted in the past, before chemists undertook to synthesize synthetic silver bullets for all that ailments and before pharmaceutical companies hitched our collective health to what has become for them a multibillion-dollar wagon.

In the past, almost all the medicines were from the plants, the plant being man’s only chemist for ages. Herbs are staging a comeback; herbal ‘renaissance’ is happening worldwide. More and more people are taking note of herbal therapies to treat various kinds of ailments in place of mainstream medicine. There are three main reasons for herbal medicines’ popularity:

There is a growing concern over the reliance and safety of drugs and surgery.

Modern medicine is failing to treat many of the most common health conditions effectively.

Many natural measures are being shown to produce better results than drugs or surgery without the side effects.

Knowledge and use of plants as herbal medicines have occurred in various populations throughout human evolution World Health Organization [WHO] has defined herbal medicines as finished, labeled medicinal products that contain active ingredients, aerial or underground parts of the plant or other plant material or combinations, WHO estimates that 80% of the world populations presently use herbal medicine for primary health care. However, during the second half of the twentieth century, herbal medicines were gradually replaced by allopathic medicines, especially in the Western world.

Allopathic treatments are currently more widely used than traditional medicines, especially in developed countries. However, most developing countries continue to use these natural medicines, most likely because obtaining a synthetic drug is expensive

Herbal medicine’s therapeutic and phytochemical importance has been built to improve human health, but its broader application is restricted due to the low bioavailability; the problems come with poor lipid-soluble compounds due to limited membrane permeability. Many herbal products demonstrated low therapeutic action due to their solubility problems, resulting in low bioavailability despite their extraordinary potential.

But there is a large population that depends on traditional medicinal practices to fulfill their basic health needs. The nature of the molecule plays an essential role in enhancing the rate and extent of molecules’ absorption when administered through any path. Generally, to overcome these limitations of absorption, developing a novel herbal drug delivery system with a better absorption profile is of premier importance.

In the past few decades, considerable attention has been focused on developing novel drug delivery systems [NDDS] for herbal drugs. The novel carriers should ideally fulfill two prerequisites.

Chapter 1. Drug discovery

As technology advances, the pharmaceutical industry is increasingly focusing on the human genome as a source of the many unanswered questions relating to how the disease is prevented, diagnosed, and treated. It is easy to forget one of the other life forms contributing much to our current understanding of medicine and many effective therapies.

Plants are an abundant natural source of potential new medicines. As a pharmaceutical company seeks to achieve an optimally balanced R&D portfolio, this potential should be kept in mind as a target for new or additional funding. In assessing the potential risks and benefits associated with such investment, some insight into the following should contribute to decision making:

●historical evidence

●current research trends

●future opportunities

●development issues

●regulatory hurdles

●facilitative technologies

●market potential and competition

Before the advances in synthetic chemistry and the discovery of anti-microbials in the late 19th early 20th centuries, plants provided the major source of medicines. Evidence of their use as long as 50,000 years ago comes from the Middle Eastern gravesite of a Neanderthal man containing plant specimens, seven of which are still in use medicinally today by the local population

The hugely diverse plant kingdom, consisting of some 250,000-300,000 species, continues to evolve and adapt to a diversity of environmental conditions and protect from pathogens and predators. Whether by fate or design, the human species appears, in contrast, to have stabilized its genetic code.

Many characterized human endogenous receptors, important in physiological function, are activated by plant-derived chemicals, for example, the opioid and the more recently discovered cannabinoid receptors.

It is unreasonable to hypothesize that many more structure-activity relationships of physiological and pharmacological significance involving plant molecules have yet to be characterized.

Over 20% of pharmaceutical companies’ ethical turnover today is generated from plant-derived medicinal products. Some of these are original natural products. Others are the synthetic equivalent or synthetic derivatives designed to improve efficacy or decrease associated side effects.

Another area of interest in the West is herbal medicine, which has proved extremely popular in some continental European countries with many products licensed as medicines and is growing in significance in the UK and the US as herbal remedies, nutraceuticals or functional foods. Herbal medicine application goes back centuries in Traditional Chinese, Ayurvedic, Unani, and other cultures in the developing world.

Thousands of plants are used as a basis for these traditional medicine practices. While many in the West are skeptical of any therapeutic value, more beneficial effects are being demonstrated.

A number of new companies have begun to focus on plant-derived medicines with a number of products, some new others derived from traditional medicine, already being investigated in clinical trials.

The accumulated evidence derived from centuries of use in traditional medicine or how species of plants have evolved and adapted to their environment can substantially reduce the time to identify development candidates.

Thousands of plant-derived products have been prescribed for patients by practitioners of traditional medicine for centuries, providing supporting, although often only anecdotal, evidence of potential efficacy and lack of frank toxicity. These data are becoming more accessible in today’s world of advanced communication, information technology, and improvements in global standards of education and welfare.

Scientists and clinicians in the Far East and Asia, many trained in the West, are applying Western clinical research and practice to traditional products and publishing their results in reputable, peer-reviewed journals.

Further significant pre-clinical and clinical research is published in original language journals. Still, it is becoming more easily available from databases like Medline. Some of the newer companies involved in phytopharmaceuticals have specialist internal staff and/or have established links with companies, experts, and academic institutions in the countries used to source materials. All these avenues can facilitate narrowing the search for potentially effective medicinal plants.

The demands and expectations of the increasingly knowledgeable, health-conscious, and environmentally aware consumers and patients of the Western world are increasing pressure on regulators, clinicians, and politicians. A recent example of where this has impacted is the pressure to recognize the medicinal qualities of the plant Cannabis sativa.

While the psychotropic properties of cannabis are well recognized, and the therapeutic effect of its major component, 9-tetrahydrocannabinol, in alleviating nausea and vomiting caused by chemotherapy has been proven, evidence of efficacy in other diseases like multiple sclerosis, while compelling, is mainly anecdotal. However, a vast database of research on cannabis, its components, and synthetic derivatives now exists.

Relatively recently, endogenous cannabinoid receptors were identified in men and animals, opening up a new field of research into cannabinoid receptor agonists and antagonists. Compounds synthesized by companies in the past, shelved or abandoned because of the associated stigma, may well be resurrected or utilized to refine the search for more specific targeted candidates.

While the stigma of abuse is not associated with traditional ethnic medicines, an element of quackery is sometimes applied to it by the so-called educated West. It should not be forgotten. However, that much of our current understanding of medicine is based on the discovery of the medical application of plant-derived substances like opium, curare, atropine, and ephedrine

To overcome the major regulatory concern related to the quality of plant-derived material, a few companies specializing in phytopharmaceuticals, including PharmaPrint, CV Technologies, and Oxford Natural Products, are independently developing patenting new technologies.

Some of these technologies address the agricultural process and practice leading to raw materials of consistent source, quality, and yield, essentially to facilitate Good Agricultural Practice.

It is worth noting in this context that their infrastructure and economic growth in part influence the ability to develop countries and emerging nations to pay for expensive new medicines Sourcing of plant materials from their natural habitat, grown under controlled conditions, can contribute to local economies and the provision of better quality lower-priced medicines. This can also contribute to the conservation of rare species and the obligations laid down by The Convention on Biological Diversity.

Other of these new technologies are combining advanced chemical and biological assays that will enable the raw material to be identified and standardized to meet the stringent regulatory requirements for quality. It is of relevance to note that PharmaPrint Inc has recently been granted a US patent for the application of its PharmaPrint process technology for saw palmetto, a product that they are investigating under an IND for benign prostatic hypertrophy.

If ultimately successful in their application, these new technologies will facilitate regulatory approval of a new generation of safe and effective products containing unique, ‘fingerprinted’ plant extracts and afford a greater degree of product exclusivity and protection of both intellectual property and investment.

Many herbal product companies are taking advantage of the new DSHEA regulations in the US for nutraceuticals and exploiting ways of suggesting that their products’ quality is better than their competitors.

With a major interest in consumer products, some of the multinational pharmaceutical companies establish links with herbal product companies and capitalize on the growing consumer interest in herbal remedies and their environmentally friendly or ‘green’ association. This is a significant and growing market but is still dwarfed by prescription pharmaceuticals.

Some of the multinationals have natural product R&D programs that have been in existence for a considerable number of years where the focus is broader than plants or has moved away from plants as a source of new medicines in recent years.

Where large screening programs are in place, there is the opportunity to adapt and take advantage of the increasing database of plants’ information. Many companies today, however, are streamlining their internal R&D organizations and seeking licensing opportunities from outside.

Therefore, it would seem prudent to maintain a watching brief on the proliferating number of small companies specializing in plant-derived medicines. These companies have the relevant internal expertise to identify significant leads. They recognize and understand the issues associated with developing plant-derived medicines.

Access to their new technologies should enable the development of safe and effective plant-derived medicines of high and consistent quality in the shorter term.

Shortly, we may well start to see the emergence of a new class of prescription medicine containing complex mixtures of plant extracts designed or inherently containing the active synergistic components to cure disease, treat associated symptoms and prevent a recurrence.

Plants produce diverse compounds (secondary metabolites) during their lifetime, resulting from the metabolic activities occurring within them. During the last decade, most of the ethnopharmacology resources were available in comprehensive medical manuals. One of them is the Ayurvedic Pharmacopoeia of India

These manuals do not provide suitable methodologies for in silico screening applications. Researchers have developed several databases that store all the information that will accelerate novel herbal drugs. Undoubtedly, database technologies opened the door for new and multiple avenues to facilitate access to higher levels of data complexity

There are various libraries constructed by computational chemists for natural products that aim to provide excellent resources for screening and the selection of natural products

Fortunately, different databases have been developed with the aim of in silico screening of ethnopharmacology records

The diverse range of phytochemicals is being exploited by chemoinformatics which ultimately accelerates the pipeline of drug development. In silico High-throughput Screening (HTS), based on molecular docking, is frequently used to minimize in vitro and in vivo screening drugs. Thus, HTS is a powerful tool for screening the maximum number of natural compounds in a very short time to identify potential drugs.

The drug discovery market worldwide is on the rise. By 2025 the market is expected to be valued at 71 billion US dollars. As of 2016, the market was valued at just 35.2 billion US dollars. The largest segment of the drug discovery market has been small molecule drug discovery. By 2025 the small molecule drug discovery market will be valued at some 48 billion U.Sdollars.

Top R&D pharmaceutical companies

Pharmaceutical research and development (R&D) is an essential part of new drug discovery and manufacturing. The top pharmaceutical companies based on their research and development spending are Roche, Johnson & Johnson, and Novartis. It is estimated that by 2024 the top worldwide pharmaceutical companies based on research and development spending will be Johnson & Johnson, Roche, and Merck & Co.

Research and development trends

Research and development in the pharmaceutical industry is an expensive endeavor. Companies are responsible for new drug approvals, clinical trials and are subject to specific rules and regulations. In general, the average cost to develop new drugs has been increasing, despite new technologies. While costs to develop drugs are increasing, returns on research and development investments are decreasing over time. That is one reason why pharmaceutical companies are increasingly outsourcing R&D to academic or private research contractors.

1.1 Use of plants in drug discovery

New drug discovery faces serious challenges due to a reduction in the number of new drug approvals coupled with exorbitant rising costs. The advent of combinatorial chemistry provided new hope of higher success rates of new chemical entities (NCEs); however, even this scientific development has failed to improve the new drug discovery’s success rate.

A novel approach of integrated drug discovery, where Ayurvedic wisdom can synergize with drug discovery from plant sources. Initial steps in new drug discovery involve identifying NCEs, either sourced through chemical synthesis or isolated from natural products through biological activity-guided fractionation.

The sources of many of the new drugs and active ingredients of medicines are derived from natural products. The starting point for plant-based new drug discovery should be an identification of the right candidate plants by applying Ayurvedic wisdom, traditional documented use, tribal non-documented use, an exhaustive literature search.

Frequency analysis of the ingredients of the ancient documented formulations and analysis of their Ayurvedic attributes may provide an in-depth idea of the predominance of particular Ayurvedic characteristics based on which appropriate candidate plants may be selected bioactivity-based fractionation.

The integration of Ayurvedic wisdom with drug discovery also brings a paradigm shift in the extraction process from sequential to parallel extraction. Bioassay-guided fractionation of the identified plant may lead to standardized extract or isolated bioactive druggable compound as the new drug. This integrated approach would save cost and time, coupled with an enhanced success rate in drug discovery.

Fig. 1.1 Drug discovery

The development of a new drug is a complex, time-consuming, and expensive process. The time taken from discovering a new drug to its reaching the clinic is approximately 12 years. Essentially, the new drug discovery involves the identification of new chemical entities (NCEs), having the required characteristic of druggability and medicinal chemistry.

These NCEs can be sourced either through chemical synthesis or through isolation from natural products. Initial success stories in new drug discovery came from medicinal chemistry inventions, which led to the need for the development of a higher number of chemical libraries through combinatorial chemistry.

This approach, however, was proven to be less effective in terms of overall success rate. The second source of NCEs for potential use as drug molecules has been natural products. Before the advent of high throughput screening and the post-genomic era, more than 80% of drug substances were purely natural products or were inspired by the molecules derived from natural sources

An analysis of the sources of new drugs from 1981 to 2007 reveals that almost half of the drugs approved since 1994 were based on natural products. During the years 2005–2007, 13 natural product-related drugs were approved.

There are various examples of the development of new drugs from plant sources. Morphine was isolated from opium produced from cut seed pods of the poppy plant (Papaver somniferum) approximately 200 years ago.

Pharmaceutical research expanded after the second world war to include a massive screening of microorganisms for new antibiotics, inspired by the discovery of penicillin. Few drugs developed from natural sources have undoubtedly revolutionized medicine, like antibiotics (e.g., penicillin, tetracycline, erythromycin), antiparasitics (e.g., avermectin), antimalarials (e.g., quinine, artemisinin), lipid control agents (e.g., lovastatin and analogs), immunosuppressants for organ transplants (e.g., cyclosporine, rapamycin), and anticancer drugs (e.g., paclitaxel, irinotecan).

Clinical trials are ongoing on more than 100 natural product-derived drugs. At least 100 molecules/compounds are in the pre-clinical development stage. Most of these molecules in the developmental pipeline are derived from leads from plants and microbial sources.

Cancer and infections are the two predominant therapeutic areas for which the drug discovery program is based on natural products. Still, many other therapeutic areas also get covered, such as neuro-pharmacological, cardiovascular, gastrointestinal, inflammation, metabolic, etc.

Among the different projects in various therapeutic areas, around 108 projects are based on plants. A further division of these projects indicates that 46 are in the