Natural Products in Clinical Trials

Natural products have been the greatest source of novel medicines currently used in the treatment of several human diseases. In past decades, a notable quantity of natural molecules has been obtained from several marine sources. The huge biodiversity existing in the marine environment, from among which marine invertebrates stand out as a major contributors to the discovery of new molecules, has encouraged investigators from all over the world to identify new marine natural compounds with therapeutic potential. With the discovery of cytarabine and vidarabine in 1974 promising natural products isolated from marine invertebrates became part of the pharmacopeia used in human therapeutic. In 2004, ziconotide was approved for moderate to severe pain treatment and in 2007, trabectedin received European approval to treat patients with soft tissue sarcoma, and finally in 2009 it was approved for treatment of ovarian carcinoma. The largely unexplored marine world harbors a great biodiversity and provides a unique and rich source of natural products with interesting pharmaceutical activities and potential therapeutic applications. In this context, this chapter focuses on the marine invertebrates and reviews marine natural products that are currently being assessed in clinical trials and provides a glimpse of these compounds potential to expand the pharmacopeia in the treatment of diverse human diseases.

Natural products derived drugs are usually associated with secondary metabolites, produced by different natural sources including plants, microorganisms, insects, animals, marine sources, etc, which can be used as a drug for the treatment of various diseases including, cancer, infectious disease, cardiovascular diseases, carbohydrate and cholesterol mediated diseases, inflammatory, neurological and immunological diseases. In this chapter, we describe the natural products derived drugs that are under clinical trials (Phase studies) for the treatment of inflammatory and immunological diseases. These diseases are named as immune-mediated inflammatory disorders (autoimmune disorders), which are associated with many other disorders. Voclosporin is under Phase IIb trials for the prevention and treatment of kidney graft rejection. KRP-203 is a fingolimod analogue undergoing Phase study for transplantation, autoimmune diseases and inflammatory bowel diseases. PG490-88 (14-succinyl triptolide sodium salt) is a semisynthetic analogue of triptolide, isolated from Tripterygium wilfordii, which exhibits anti-autoimmune and anti-inflammatory properties. Didemnin B (first compound obtained from the sea that directly entered into human clinical trials against cancer) feasibly modulates the activity of FK-506 binding proteins as part of its immunomodulatory process and thus leads to cell death via apoptosis. Didemnin B has been withdrawn subsequently due to its toxic and immunosuppressive effects. Some natural compounds such as manoalide and luffariellolide (with anti-inflammatory effects) are in clinical studies. Inflazyme Pharmaceuticals Ltd, Canada and Avantis Pharma Inc, Germany has reported some derivatives of the IPL576 series for asthma and other diseases. The derivative (IPL550,260) possessed anti-inflammatory activity and is currently in clinical studies. This chapter provides knowledge to the readers on the recent development on the clinical trials drugs derived from natural products for these diseases.

Use of natural products as therapeutics, has been in practice even before the advent of modern medicine. Traditional medicinal systems like Ayurveda, Siddha and Unani which prescribe medicines based on natural products have been in practice for centuries, authenticating the medicinal efficacy of these drugs. However, with the advent of modern medicine, the focus shifted from medicines based on formulations to mostly single component drugs. Also, norms were established to standardize methodologies for clinical trials that will establish safety and efficacy of the drugs before human use. These stringent norms meant that most of the traditional medicines could not be used in the current medicinal system of treatment as drugs. Nevertheless, researchers have repeatedly mined these traditional natural sources and other similar materials for compounds with potential therapeutic value. Such research has yielded compounds like acetylsalicylic acid (aspirin), morphine, quinine and even Nobel prize winning natural products like artemisinin (anti-malarial agent) and avermectin (antibiotic). In fact, more than half of the drugs approved by FDA have either direct or indirect inspiration from natural products. Apart from these, several interesting natural products are also under various stages of clinical trials varying from inflammation, infection to dietary supplements. The present chapter reviews some of these attractive natural products namely curcumin, camptothecin, astaxanthin, and biochanin that are currently under various stages of clinical trials for their application as therapeutics in various diseases. The chapter also deals with challenges such as lead optimization, formulations and delivery systems that should be addressed by researchers to move the natural product from the realm of nutraceuticals to the area of clinical medicine.

Plants have been an integral part of the ancient culture of India, China and Egypt as a medicine, and their importance even dates back to the Neanderthal period. Historically, a majority of new drug is generated from compounds derived from natural products and secondary metabolites. Natural products show the large structural diversity and various modern techniques for structure elucidation, separation, combinatorial synthesis and screening have led to the revitalization of plant products as the sources of new drugs. Currently, there is a substantial decline in new drug approvals and in the impending loss of patent protection for important medicines. Considering this, the present review mainly focused on all types of the main groups of compounds classified as Natural products, semi-synthetic NPs and NP-derived compounds that have been registered, undergoing registration or in clinical development for antibacterial and antifungal activity. The review mainly enlights the need for new antibacterial and antifungal drugs along with a contribution of natural products in the discovery of new antibacterial and antifungal drugs. The review briefly discuss all the molecules obtained from natural sources which are in preclinical and clinical development.

From the prehistoric time man has always struggle to fight and control diseases and motivated to nature for inspiration and guidance. During thousands of years of early human existence, number of natural materials by instinct or intuition has been used as folk medicines for human ailments. This brought to the forefront a large number of herbs used in Indian indigenous system for their approved efficiency and administration in modern medicines. Acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) is an immuno-suppressive disease that results in life-threatening opportunistic infections and malignancies. Now, there is an urgent need for novel anti-HIV/AIDS drugs for global concern. In addition to obvious economical and commercial obstacles, HIV/AIDS patients are faced with varied difficulties associated with the currently approved anti-HIV drugs. The therapeutic usefulness of the various reverse transcriptase and protease inhibitors available in the market have been limited due to its adverse effect, emerging drug resistance and low activity. This encourages many scientists to look for new antiretrovirals with better efficacy, safety and affordability. Several natural products isolated from plants have been shown to possess promising activities that could assist in the prevention and/or amelioration of the disease. Biodiversity of the plant kingdom has always been a source of new drug candidates for various diseases. The appearance of drug resistant virus urged the scientists to explore new anti-HIV agents and targets. In this regard, natural products embody a treasure-trove of anti-HIV drugs waiting to be explored by all the modern techniques. Numerous natural product based anti-HIV drugs such as Robustaflavone, Chamaeflavone A, Longipedunins A, Binankadsurin A, Schisanlactone A, Anibamine, Altertoxine, Betulinic acid, Baicalin, Hinokiflavone, etc., have been reported in the literature which possess promising anti-HIV activity. This chapter embodies the recent progress that has been accomplished in the discovery of promising anti-HIV agents from natural sources.