The famous five

Innovation is the key to survival. There are quite a few R&D innovations on the anvil which offer a lot of promise. Katya Naidu takes a look five such progressive areas.

Pharma companies have been coming up with various ways of combating diseases. However, ever since lifestyles changed and pathogens evolved, challenges on the R&D front have become manifold. Yet, there is no question that science cannot answer. Here are some innovative processes, which are all set to revolutionarise pharmaceutical research.

N for nanotechnology

As drug discovery has reached micro levels (ie at the cellular level), a requirement has come forth for drugs which can travel into the cells. This task is made possible by advances made in the area of nanotechnology. By the virtue of their size, nanoparticles possess properties that give them special abilities. They have more atoms at the surface than in the bulk. Hence, surface properties dominate the bulk properties allowing nanoparticles to reach where no other particles can. And when they do, they carry with them significant value. "All sorts of drugs, including those that have a very low toxic threshold, can be advantageously delivered by using nanoparticles. They can be delivered specifically to parts where conventionally it has been difficult to reach, like the posterior chamber of the eye," says Prof Jayesh Bellare, Department of Chemical Engineering at School of Biosciences and Bioengineering, IIT Bombay.

There are certain untamed diseases where nanoparticles can seep to help, like say cancer. Nanotechnology has the potential to play three main roles in cancer—detection, drug delivery and in rehabilitation after the surgery. “Nanotechnology has great utility in cancer research. It will be very helpful in developing anti-cancer drugs, so that you can target it specifically to cancer and deliver it to cancer tissues. Both targeting and delivery can be done using nanotechnology," reveals Dr Rama Mukherjee, Director, Dabur Research Foundation.

To serve these purposes nanoparticles are effectively engineered to nanometric size. "For example, in the treatment of cancer, nanoparticles may be of platelet shape so as to absorb radiation very effectively. Or they may be made hollow and filled with a life-saving drug. Or they may be made magnetic such that the magnetic particles lose their magnetism at a given temperature so that they can be used to heat up cancerous tissues without affecting nearby healthy tissues," explains Bellare. However, there are challenges that are to be addressed too. One such obstacle is the bio-availability of nanoparticles.

Nevertheless, a number of research efforts are directed towards this technology. Dabur Pharma is working on developing a nanoparticulate delivery system for the generic molecule, Paclitaxel. Paclitaxel is indicated for late stage cancer. IIT Bombay too has taken up a number of projects in the nanobiotechnology area like novel surfactant particles for respiratory disease and controlled drug delivery systems and nanoparticles. They are also researching on nanoparticles in Ayurveda; micro-devices for cardiac use (minimally invasive surgery) and cellular and molecular engineering for nanobiotechnology based drug discovery.

The process of RNA interference

RNA story

An ingenious way of cracking a disease is to mark the causative target. And in most of the diseases, the target happens to be the genes. Zeroing in on a gene, which is responsible for a diseased condition, and controlling its expression can soon revolutionarise the way drugs act in the future. RNA interference (RNAi) is one such futuristic area, which is on the verge of success.

RNAi implies interference by RNA in gene expression thereby preventing it. The phenomenon is caused by the production of small interfering RNAs called siRNAs. These siRNAs are one of the intermediates in RNAi pathway. Generally, in the ordinary mechanism, DNA in the nucleus of a cell possesses the code for the production of a protein. This code is copied on to the RNA by a process called translation. This RNA or messenger RNA (mRNA) enters the cytoplasm and conveys the message of the type of protein that is to be produced and that is how gene expression occurs. In RNA interference, small interfering RNAs (siRNAs) come into the picture. They attach themselves to mRNA and render them dysfunctional, thereby halting the expression of a gene.

This phenomenon can mean a million bucks in the treatment of a disease. Wherever there is a disease, there has to be a protein and wherever there is a protein, theoretically there is an RNA. A disease is caused because a protein is either wrongly produced or produced in greater amounts or lower amounts or produced in the right amounts but in a wrong way. If siRNAs that can target a specific gene are produced, a number of diseases can be controlled. But as of now, there is only one siRNA-based molecule indicated for macular degeneration. The molecule by Alnylam Pharmaceuticals uses RNAi to silence expression of Vascular Endothelial Growth Factor (VEGF), which is a key mediator in ocular diseases.

One size fits none

It is a universally accepted truth that drugs do not have the same effect on every individual. The reason behind this is the variation in genetic makeup of an individual, which plays a role in the metabolisation of a drug. Genetics decide the rate and extent of drug absorption, distribution, metabolism and excretion. Since a drug reaction in an individual is specific and unique, a doctor faces a plethora of issues while prescribing a drug given the danger of adverse drug reactions.

"Genomics gave us valuable tools to decipher the variations in the gene-enzyme make-up of an individual" - Prof Harish Padh Director BV Patel PERD Centre

The answer to the predicament lies in pharmacogenomics, which holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's genetic make-up. "Genomics gave us valuable tools to decipher the variations in the gene-enzyme make-up of an individual. This combination has resulted in the concept of pharmacogenomics which is an extension of the concept of pharmacogenetics," says Prof Harish Padh, Director of B V Patel Pharmaceutical Education and Research Development (PERD) Centre.

According to pharmacogenomics, genotyping methods are used to classify individuals into four classes to produce drugs depending on which personalised medicine is prepared. The four classes are poor metabolisers (PMs), intermediate metabolisers (IMs), extensive metabolisers (EMs) and ultra rapid metabolisers (UMs). The PM subjects develop higher serum drug concentrations in comparison with EMs, resulting in increased risk of suffering from concentration-dependent side-effects when subjected to standard recommended doses. On the other hand, UM subjects do not reach therapeutic serum concentration upon treatment with standard doses. They may fail to respond to treatment. PERD Centre is in the process of genotyping individuals for various cytochromes responsible for metabolism of commonly used drugs like beta-adrenoceptor blockers, anti-depressants, neuroleptics and anti-epileptics.

Though the concept of personalised medicine sounds feasible ideally, it brings with it, certain heavy payloads. Classifying the patient population will narrow down the profits as it reduces the target market. It will also dilute the chances of blockbuster drugs which pharma companies thrive on. However, this possibility has not deterred many companies like Eli Lilly and Novartis from embracing this concept of the future.

Cocktail drugs

"If proper research is not done, the combination will cause antagonist action " - Dr Abha Doshi Principal MET Institute of Pharmacy

As pharmaceutical research progressed, the number of complications with respect to diseases has increased too, the gravest of all being drug resistance. Combination therapy has emerged as a boon to many such medications. Infectious diseases like malaria and tuberculosis have observed variations in terms of popular treatment methodologies, thanks to the constantly mutating organisms. These parasites with short lifecycles have mutated to become resistant to a number of popular drugs like quinone; rendering them ineffective. No medical system can afford to discover drugs as frequently as a parasite mutates.

When given a combination of drugs, it is assumed that the parasite finds it hard to mutate. "The biggest advantage of combination therapy is the prevention of emergence of resistance to individual drugs and thereby, losing the use of that drug. In the treatment of infectious diseases, the main reason for combination therapy is to prevent the emergence of drug resistance against the individual drugs," says Dr P R Narayanan, Director, Tuberculosis Research Centre (TRC). The constituent drugs of a combination drug have individual modes of action and yet, have the same consequence, which is killing the parasite. Combination drugs are also being advocated for wider use in the treatment of non-communicable diseases.

Combinations increase the efficacy of treatments and reduce the dosages given thereby controlling the side-effect profile of a disease. Experts also claim that constituting a drug with a smaller half-life in a combination, can also reduce the treatment time. In spite of the availability and popularity of combination drugs, there are a number of challenges ahead for researchers. First of all, the compatibility of the drugs to be combined should be assessed. "If proper research is not done, then the combination will cause antagonist action," warns Dr Abha Doshi, Principal of MET Institute of Pharmacy. In addition, the percentage of the constituent drugs is yet another factor that needs extensive research. In combination therapy, the doctor determines the type and the dosage of drug that is given to a patient depending on diagnosis. Similar parameters are to be considered while designing combination drugs.

Stem cells

It is nothing short of a miracle that a cell, a combination of ova and a sperm, duplicates into a human body in nine months. That is the power of stem cells. Simply put, stem cells are the most basic cells in the human body. They are those unspecialised cells that can regenerate into a specific specialised cell. Stem cell therapy involves replacing diseased or degenerated cells with healthy, functioning ones. "These new techniques are being applied to a wide range of human diseases, including many types of cancer, neurological diseases such as Parkinson's and spinal cord, multiple sclerosis, diabetes, myocardial infarction," explains Dr Satish Totey, Director, Manipal Acunova.

The power of regeneration endows stem cells the ability to mutate. Among others, treatment of myocardial infarction (heart attack) finds good application in this phenomenon. After a person gets a heart attack, the cardiomyocites can die within 20 minutes due to the occlusion of the artery. Once dead, the heart starts remodelling itself to maintain the normal cardiac output and to meet the demands of the body. Stem cells, if injected at the appropriate time, help in regenerating the damaged muscles and healing the scarred tissue, thereby, bringing the cardiac functions to almost normal without causing remodelling.

When injected into the heart, stem cells know exactly where they have to home in, based on the chemo attraction. "The dead muscle gives out certain chemocytes, which attract stem cells to go there and convert into that lineage," states V K Shah, Interventional Cardiologist and Principal Investigator at the Mumbai-based Hurkisondas Hospital. "Before we ventured on to humans, we have seen this being proved through various experiments on small and big animals," he adds. Unfortunately, there is no way to control multiplying stem cells into different non-desirable tissues. "However, there is not a single report which shows that stem cells, after injection into particular organ, have developed into undesirable tissue or cells. That shows that stem cells injection are quite safe," reveals Totey. With a clear safety profile to its credit, all it needs is a thorough research before it gets to human trials.

(With inputs from Nandini Patwardhan)
editorial@expresspharmaonline.com