Current Bioactive Compounds - Volume 4, Issue 4, 2008

Drug development has become increasingly complex, time consuming and expensive. As a result there is an increased focus on making clinically established drugs with enhanced therapeutic performance in terms of efficacy, safety and improved patient compliance. This has led to a paradigm shift not only in drug discovery programs but also in drug formulation technology. In this context, the present issue highlights some of the recent trends with emphasis on new formulation technologies for active pharmaceutical ingredients (API's) along with developments in phytopharmaceutical research. The discovery and development of quality drug leads and clinical candidates, that will eventually become novel marketable drugs, remains a significant challenge to pharmaceutical scientists. For numerous pharmacological reasons, many active compounds or new drug candidates face bioavailability issues due to poor aqueous solubility and are poorly absorbed when dosed orally creating a challenge to prepare formulations that maximize bioavailability and improve API delivery to the intended therapeutic target. The field of API formulations while maximizing exposure in early animal experimentation, so that the pharmacokinetics, pharmacodynamics and toxicological signals can be put into context with the biological response to specific targets, could play a critical role in assessing the biological properties of a molecule during drug discovery. Consequently, many biotech and pharma companies face barriers due to the failure of these otherwise-effective developmental compounds in the pre-clinical/clinical trials and are typically pulled out of the development cycle, further weakening the already dwindling drug pipelines. As a result there is an urgency to develop efficacious formulation methods that will integrate drug-like properties into the early stages of drug discovery advantageous to efficient and effective drug development and which will ideally reflect in critical issues of safety, pharmacokinetics and formulation in addition to in vivo performance. Recent trends indicate that pharmaceutical and biotech companies are looking to enhance the clinical efficacy of experimental as well as known compounds with poor bioavailability by generating homogeneous amorphous solid dispersions of API's in a polymer matrix that significantly improves the bioavailability profile of the active candidate drug by increasing both the dissolution rate and the free-drug concentration over the more typical crystalline forms of therapeutic candidates. In recent years several amorphous API's have been marketed as drug products. Examples include Accolate® (zafirlukast), Ceftin® (cefuroxime axetil), Accupril® (quinapril hydrochloride), and Rezulin® (troglitazone). Lilly's Humulin L® contains both amorphous and crystalline insulin to provide immediate and long-term effects. Design and development of rational amorphous API formulations that will have clinical significance is of paramount importance and will influence future drug discovery and optimization programs. Drug Discovery in current scenario has become unproductive to the point where the economic future of the industry is questionable. Moreover, problems with drug-resistant microorganisms, side effects of modern drugs, emerging diseases where no medicines are available in addition to existing patent expirations, the scientific community is experiencing difficulty in identifying new lead structures, templates and scaffolds in the finite world of chemical diversity. To push into the future, the R&D thrust in the pharmaceutical sector needs to be focused not only on the cost-effective development of new drugs and innovative processes and formulations for known/new drugs but also on the development of plant-based drugs/extracts through investigation of leads from the traditional systems of medicine which could provide the necessary impetus into the drug development process. While plants and marine organisms inherit a unlimited pool information, new molecules and medicines, drug discovery via integration of phytopharmaceutical research with modern medicine potentially offers an attractive strategy for faster, cheaper development and screening of alternative drug discovery platforms that could work more effectively and could therefore help address the growing need of large pharmas/biotech to fuel their diminishing pipelines. The use of powerful new technologies such as automated separation techniques and high-throughput screening can greatly facilitate intentional, focused and safe natural product drug discovery and help to rediscover the drug discovery process. However, though timetested evidences vouch immense therapeutic benefits for phytochemicals (plants, marine organisms, and nutraceuticals) and their formulations, several important issues are required to be resolved with rigorous guidelines of standardization, manufacture, quality control, and scientific research before successful implementation of these principles to present drug discovery methodologies. Additionally, clinical examination directed towards understanding the pharmacokinetics, bioavailability, efficacy, safety and drug interactions of newly developed phytodrugs and their formulations (extracts) are required to be carefully evaluated. Nevertheless, by looking at the historical trends in drug and medical developments, it is possible to understand how current drug development and formulation will benefit from this partnership to create an equitable system of health.

While biotechnological advances, genomics and high throughput screenings or combinatorial and asymmetric syntheses have opened new vistas in drug discovery, the industry is facing a serious innovation deficit. Critics suggest that “we have become high throughput in technology, yet have remained low throughput in thinking”. Post marketing failures of blockbuster drugs have become major concerns of industries, leading to a significant shift in favor of single to multi targeted drugs and affording greater respect to traditional knowledge. Typical reductionist approach of modern science is being revisited over the background of systems biology and holistic approaches of traditional practices. Scientifically validated and technologically standardized botanical products may be explored on a fast track using innovative approaches like reverse pharmacology and systems biology, which are based on traditional medicine knowledge. Traditional medicine constitutes an evolutionary process as communities and individuals continue to discover practices transforming techniques. Many modern drugs have origin in ethnopharmacology and traditional medicine. Traditions are dynamic and not static entities of unchanging knowledge. Discovering reliable ‘living tradition’ remains a major challenge in traditional medicine. In many parts ‘little traditions’ of indigenous systems of medicine are disappearing, yet their role in bioprospecting medicines or poisons remains of pivotal importance. Indian Ayurvedic and traditional Chinese systems are living ‘great traditions’. Ayurvedic knowledge and experiential database can provide new functional leads to reduce time, money and toxicity - the three main hurdles in the drug development. We begin the search based on Ayurvedic medicine research, clinical experiences, observations or available data on actual use in patients as a starting point. We use principles of systems biology where holistic yet rational analysis is done to address multiple therapeutic requirements. Since safety of the materials is already established from traditional use track record, we undertake pharmaceutical development, safety validation and pharmacodynamic studies in parallel to controlled clinical studies. Thus, drug discovery based on Ayurveda follows a ‘Reverse Pharmacology’ path from Clinics to Laboratories. Herein we describe such approaches with selected examples based on previous studies.

A large number of the new pharmaceutical small molecules under development today are found to have poor water solubility. This in turn may lead to low bioavailability, which can have a significant impact on the development of the compound. Compounds with low bioavailability pose a greater challenge in early preclinical work involving animal studies, where obtaining maximum exposure is the primary goal especially in toxicology studies designed to establish the safe dose. From the standpoint of maximizing exposure, the amorphous phase is of great interest as pharmaceutical materials since it is the most metastable state and as such offers the potential of higher solubility and better bioavailability. However, the amorphous approach is not actively pursued in preclinical work owing to the tendency of the amorphous phase to crystallize thereby neutralizing the solubility advantage. This review focuses on (i) methods to generate the amorphous phase, (ii) methods to estimate the degree of crystallinity of the amorphous phase, (iii) methods to predict the stability of the amorphous phase against crystallization, and (iv) choice of polymers carrier and formulation of the amorphous phase for preclinical studies.

Extensive use of certain drugs, changes in lifestyles and food habits, as well as stress factors in modern human lives have led to an exponential increase in the incidence of gastric ulceration. The ideal anti-ulcer drug with less side effects and recurrence, and affordability has so far remains elusive, providing avenues for innovation, especially with phytochemicals. This review furnishes extensive information on the earlier works carried out in this area and rationalizes the mode of action of them, citing limitations of the previous studies. The primary aim was to cover different classes of potent natural compounds that have impressive gastro-protective property against various ulcerogens (except Helicobacter pylori infection), and are available in large quantities from the natural sorces. A few examples of synthetic congeners have also been included to highlight the type of innovation that may be required for developing new drugs.

Microorganisms manufacture prolifically bioactive compounds. For example, fungi produce antibiotics and mycotoxins. However, many are difficult to identify and classify. Methods which rely on nucleic acid (DNA/RNA) are increasingly being used for this purpose where strains are grown in liquid or agar culture and often subjected to polymerase chain reaction (PCR) analyses. It has not been considered that self-produced mutagenic and inhibitory secondary metabolites (SM) affect DNA analysis of the target fungi. The most obvious mycotoxins and fungi to consider in this regard are aflatoxins (AFB) and Aspergillus, as AFB are the most mutagenic natural compounds. Many other fungi and SM are relevant and fungi act as a model for bacteria and plants. In fact, fungi repair damaged nucleic acid (NA) and are capable of removing toxins by employing transporter proteins. Nevertheless, these could be inhibited by bioactive metabolites. Mutagenic effects may involve inhibition of DNA stabilising enzymes. In addition, PCR is subject to false negative results. Samples of fungi with the genes of interest (e.g. a mycotoxin) may be categorized as negative and safe as a consequence. Internal amplification controls (IACs) will ameliorate the situation and need to become mandatory. These are conventionally NA that posses a sequence which will provide a PCR product (a) using the same primers employed for the target gene and (b) that will not coincide on the gel with the product of the target gene. Inhibitors and mutagens in cultures need to be minimized, and SM are an obvious source. This is a crucial issue in developing diagnostic and phylogenetic methods. The conclusions are (a) previous reports are compromised because IACs have not been employed in PCR and (b) mutagens and inhibitors may affect the very stability essential for NA analyses used in diagnostics and phylogenetics.

Due to their biological importance, oligosaccharides and glycoconjugates have recently gained much attention. Investigations of such compounds often require chemically synthesized oligosaccharides. In the oligosaccharide synthesis, glycosylation reaction is frequently the most important step. Recently, one-pot multi-step glycosylations have become popular using the glycosyl donors with different reactivities and a polymer-supported technology that can reduce the laborious purification operations. For such methodologies, stereoselective glycosylation is essential. Compared to the 1,2-trans-glycoside formation, highly cis-selective glycosylation has remained relatively elusive. To enhance cis-selectivity, protection of the 2-position using a benzyl type ether and solvent effects are often employed. Recent reports have described the manipulation of protecting groups to afford novel donors that allow improved cisselective glycosylation. This manuscript reviews such donors that have been reported within the last five years. We hope this manuscript proves to be helpful in furthering the chemical syntheses of oligosaccharides while improving our understanding of the glycosylation reaction including stereoelectronic effects.