New Drug Research And its Development: An Arduous Path

Throughout history, various methods have contributed to the advancement of public health and quality of life. Of these methods, Drug therapy (pharmacotherapy) has certainly been the major factor in extending our life expectancy. The history of drug research and development is a most important event in the story of man’s triumph over diseases. The arrests of epidemics of life-threatening and widespread infectious diseases, the control of intractable diseases and physiological disorders and genetic illnesses have come under the influence of powerful and relatively safe drug products. It is painful for us to imagine that a century back more than 15 million people in Asia were wiped out by the plague; that the same period every seventh German over age of 16 died of tuberculosis; 20 million people died worldwide from an influenza epidemic in 1918-19; and just six decades ago every second patient with pneumonia succumbed to this disease. Today in advanced countries a person can, on the average, live twice as long as his great-grandparents, whose life expectancy at the end of

Today in advanced countries a person can, on the average, live twice as long as his great-grandparents, whose life expectancy at the end of the nineteenth century was barely 40 years! This is expected to touch 100 years by 2020. In India, a person born in 1920 could expect to live only 32 years. Today we can expect to live over 69 years and the life expectancy is estimated to cross 78 years by 2021 with improved sanitation and public health along with drug therapy. Public today best recognizes the great achievements of drug research who owe drugs and medicines their good health and frequently even their lives.

New drug development: Since the thalidomide disaster in the 1960’s and following Kefauver-Harris amendments to the FDC Act in 1962, the development of a new drug had to meet increasingly stringent requirements. Federal food and drug administration’s (FDA) approval is required for a new drug to be marketed in the USA and many other countries. Marketing approval in India and most countries depends on the status of the drug in other countries particularly in the USA, Great Britain, and Germany. United States FDA in this regard is considered to be the most thorough in the world. After the discovery of a new chemical entity (NCE) and only when the requisite series of pre-clinical studies (in animals) demonstrate adequate safety, the drug’s sponsor can file an Investigational New Drug application (IND) to the FDA. The total time of drug development from the period of discovery to final approval averages approximately 12 years (depicted in Fig. 1).

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At pre-clinical testing stage animal pharmacology and toxicology data are obtained to determine some degree of safety and efficacy of the drug. The clinical testing takes place after submission of the IND application to the FDA. The post-marketing surveillance of drug usage is conducted to detect infrequent but significant adverse effects. The progressive sequence of clinical testing is given in Table 1.

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When all the clinical trials are completed, an NDA is submitted to the FDA for review and approval. The resulting prolongation of development times through different steps leads to higher expenditure before a new drug goes to market. Today invention of a new drug and its development costs as high as US$ 1.1 billion at 2011 prices. This cost, however, does not include the cost of numerous failures.

The normal development time for a drug varies between eight and fourteen years (average 12 years). The rule of thumb in search for a new drug: only one out of approximately 10,000 compounds synthesized in the laboratory manages all the obstacles and become a drug. The road to a new drug is long. Even when a chemical entity close to being a marketable drug has cleared all the phases of test and development, there is another cumber- some procedure- the application to the registration authority. The application with thousands of pages of documentation carrying evidence of quality, safety, and efficacy is submitted to legal authority. All these efforts required to solve the equation: – optimal efficacy plus minimal side effects equals a safe drug.

Meanwhile, the question confronting today is one side society’s justified desire to reduce health problems with the use of the drug and the other side its escalating cost resulting from the development of a new drug. FDA approval certifies a drug as safe and efficacious for its labeled indication(s). It doesn’t address the key issue, whether the additional cost associated with possibly only marginal benefits can be justified.

A man has existed for million of years but has been assured of quality drug products and good drug therapy from about 1940’s. Notwithstanding the public, in general, pay more attention to the degree of potential risks and higher cost of a new drug than to its benefit. Drug research is still indispensable. Of roughly 30,000 diseases that we know today, only about 10,000 can be treated pharmacologically, many of them inadequately. In addition the possibility that a drug that is safe today may have to ban tomorrow as a result of new findings. The need of drug research and its development is greater today in face of many incurable diseases and of course the impending worldwide life-threatening catastrophe.

 

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Transdermal Patch: An innovative approach for controlled drug delivery

Medicines that are administered by oral and parenteral routes still dominate the technology by which drugs are delivered to the patients for treating diseases and ailments. However one form of delivery system where drugs are delivered smoothly through the pores of skin into systemic circulation, known as transdermal drug delivery (TDD) has provided an attractive alternative to oral delivery of drugs and is poised to provide an alternative to hypodermic injection too. These delivery systems are Band Aid-like strips and are broadly known as transdermal patches or simply a TD patch.

The patients have only to attach a patch to a suitable and convenient part of the body (upper arm, chest, behind ear, trunk etc.) and do nothing except reapply it every predetermined time. Besides, you don’t need a doctor or a nurse to put the patches on you. The first transdermal patch, a three-day patch that delivers scopolamine to treat nausea and vomiting associated with motion sickness—was approved for use in the United States way back in the year 1979. This TD patch provided a novel form of drug delivery and was a therapeutic breakthrough. Today, there are more than 20 drug molecules as transdermal products containing drug(s) for chronic pain management, contraception, hormone replacement, and tobacco cessation. Some of the molecules are scopolamine, nitroglycerin, estradiol, clonidine, nicotine, testosterone, lidocaine, fentanyl, norethidrone acetate and oxybutymin The transdermal patch marked the beginning of the advanced era of non-invasive systemic drug delivery.

The transdermal patch or the device which is the cornerstone of this innovative technology comprises five discrete layers. The outermost layer is a backing layer of polyester film, followed by a drug reservoir which is a suspension or solution of a drug in a suitable vehicle. The third layer consists of micro-porous membrane of varying pore size that controls the release of the drug from the system to the skin surface. The fourth is a thin, adhesive membrane, which is used to fix the patch to the skin. And the fifth and lowermost is the protective peel strip.

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A Generic Transdermal Device

As soon as the patch is attached to the skin, drug diffuses out of the system through the skin into blood circulation by percutaneous absorption. The amount of the drug to be released can be adjusted by controlling the membrane or polymer matrix complex.  The size of the patch is consistent with the type of the drug and the dose required. For example, a dose of 0.5 mg scopolamine for three days requires a patch of 2.5 sq. cm. in area.

The transdermal patch offers a number of advantages scores over oral medications that include the avoidance of first pass metabolism & GIT degradation, allows for the administration of drugs with narrow therapeutic window, can reduce frequency of dose for relatively short acting drugs, eliminates the need for hypodermic injections, and simple application. The drug needs only once in 2/3 days or even a week from a patch instead of several times a day.

The major limitation of transdermal patch is the low skin permeability of most of the drugs. Only relatively low dose drug are suitable for (first-generation) transdermal delivery.  Nonetheless many drugs have been developed with skin penetration enhancer (categorize as second generation) and third generation tragedy targets layer of stratum corneum to enhance penetration of drug. These advances in third generation transdermal delivery, particularly with microneedles, are enabling a wider range of drugs to be delivered through the skin.

Considering the recent advancements and all those discussed, time is not far away when patients need not take drugs orally or through injections, simply to attach a TD patch to a convenient part of body instead.

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The Allure of Famed Hoysala Architechture at Belur and Halebidu

My earliest memory of Belur and Halebidu in Hassan District of Karnataka, a State of India  was in February 1986 when I visited it as a group of newly joined faculties and was completely taken aback in by these architectural splendours which were built centuries ago.

Known for its famed impeccable masterpiece of temples on intricate stone carvings and sculpture, Belur and Halebidu provides an insight into ancient Hindu culture and Karnataka’s rich history.

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Chennakeshava Temple, Belur

On 14th August, 2016 I made a leisure trip to the ancient capital  twin temple towns of the Hoysala Dynasties with my family (daughter and wife) to soak in the beauty of amazing artistry  created on stone amid the backdrop of quaint landscapes.  Being only around 220 KM from Bangalore, we reached the destinations by an Ola cab. The drive to all the way to Hassan is smooth and mesmerizing with paddy fields and distant rocky hills on both sides of the  road.

The Chennakeshava Temple of Belur, dedicated to Lord Vishnu was built between 11th and 12th centuries by the Hoysala Dynasties. It is the temple that is the highlight of this town, which is a mix of tradition and modernity.

The guide has answers to all queries of visitors. The temple was built to commemorate Hoysala’s victory over the Cholas. The guide explains, the four steps of carving that forms the base; Elephants in the lowest frieze denotes the stability & strength,  above these are the Lions that symbolize courage, next are Horses showing speed and finally Flowers representing the king as considerate towards his people.But whats most astonishing is that no two elephants, lions, horses or flowers are similar in carving!

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Four steps of carvings along the walls of Chennakeshava Temple, Belur

The surface of the temple exterior is intricately filled with carvings, stories from the Ramayan, Mahabharata, Puranas, Upanishads and other mythological stories executed in the most authentic way, and also the beauty of womanhood and tradition followed in the past.

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Beautiful ornate horizontal pieces of stone art depicting God and Goddess

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Lord Vishnu as Narasimha

Around 16 KM from Belur is Halebidu, the Old City. It was one of the capitals of Hoysala Dynasties in the 12th century. Magnificent Hoysaleswara temple, dedicated to Lord Shiva is the major attraction here. Similar to Belur temple, it is adorned with the exquisite portrayals of the mythological tales.

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Hoysaleswara Temple, Halebidu

Hoysalas were great patrons of art and architecture. They built  more than 1500 temples to establish their supremacy in the region. Chennakeshava at Belur and Hoysaleswara at Halebidu are the most spectacularly ornate temples in the area.

Belur and Halebidu, I believe, cannot be explored in one 2 hour visit. Like many others who thinks that the ancient capital towns of Belur and Halebidu is all about those stone carvings, a visit to this places is an eye-opener. A short visit can barely seen anything beyond the tourist angle, nonetheless one takes a lot back from here.

Amid these stone carvings, one did not need to know the story or the history in details, but for me just being there was a great feeling. It was simply overwhelming.

 

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A visit to Tranquebar: A forgotten rich Danish colonial heritage

Located on the Coromandel coast, Tranquebar is a small fishing panchayat town with some 7,000 inhabitants in Nagapattinam district in Indian State of Tamilnadu,  120 KM south  of Puducherry and 50 KM south of Chidambaram. Tanquebar was a Danish colony in India from 1620 to 1845. Spelled Tanquebar in Danish, it’s name in local Tamil Tarangambari, meaning “place of dancing and/or singing waves”.

I visited the place on number of occasions with friends and family members, particularly when we visit nearby important tourist and religious places such as Poompuhar,  Thirunallar, and Karaikal. Recently I got an opportunity to have the splash of the wild sea waves in the lovely tranquebar beach.

Sea Beach at Tranquebar

Sea Beach at Tranquebar

Tranquebar was a town which, in the years 1620- 1845, served as Danish trading colony for spices and textiles trade. The landmark in Tranquebar is the Dansborg or Danish Fort, a seat of power, located on the beach established by the Danes in 1620. They (Danes) had been in the town for 225 years before finally relinquishing the territory to the strengthening English Empire.

Dansborg, the first built in 1620 AD

Dansborg, the first built in 1620 AD

The Dansborg ( has two levels)  which under renovation and currently houses a archaeological museum.

Dansborg Fort, a closer view

Dansborg Fort, a closer view

A lovely place in this tiny town to stay for couple days is the Neermrana property, the Bungalow on the beach.

Bungalow on the Beach, to undergo soulful refuge

Bungalow on the Beach and scenic landscape

The allure of Tranquebar is a fascinating albeit seamless cultural concoction – a  magical mixture  of languages, cultures and religions. Two centuries of Danish heritage has left important cultural and architectural imprints which can be seen even today once anyone enters the town through an arched gate – the colonial past  comes alive with missionary schools,  churches, old cemeteries as you come to the beach.

"Bungalow on the Beach"  in the left and the Masilamani Temple (built in 1306) in the extreme right

“Bungalow on the Beach” in the left and the Masilamani Temple (built in 1306) in the extreme right

Tranquebar is not only a lost colonial heritage yet it is place of soulful refuge and a mystic silence except splash of the wild waves with the magnetic effect of openness of the sea.

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The H-Index: A Current Tool for Evaluating a Researcher

Scientometrics, the quantitative measurement and analysis of science, has been used to investigate the impact of research publications and other research outputs. In recent years, a scientometric indicator called h-index has gained popularity and recognition in the assessment of research output.

Aspiring scientist and researcher need  to constantly be reminded to research a lot, publish a lot more and keep on writing scientific papers. One of the ways to be motivated to work harder and to get better is to know  performance. H-index is one way to measure a researcher’s performance. H-index is increasingly used to provide information on the scholarly output in connection with a researcher’s  career advancement or award of financial assistance.

What is the h-index? H-index stands for Hirsch index. First introduced by Jorge E. Hirsh in 2005, it is a relatively simple way to calculate and measure the impact of a scientist.  The h-index is a measure of an individual’s scientific research output. According to Hirsch, “A scientist has index h if h of his/her Np papers have at least h citations each, and the other (Np − h) papers have no more than h citations each”. The h-index is  a small number with a big impact.

How is h-index calculated? The h-index is computed through a plot based on the distribution of citations received to the publications of a researcher. An individual has an index of h, if h papers have at least h citations each. This index translates the impact (the number of citations) and the scope (the number of papers) of a scientist’s work into a straight number. For example, if your h-index is 11, it means that you have 11 papers that have been cited at least 11 times. You may have more papers, suppose 24 papers, only 11 of these papers are cited at least 11 times by other researchers, indicating that other 13 papers have 10 or fewer citations. The h-index will reach 12, only if 12 papers receive a minimum of 12 citations.

The following is the calculation method:

To determine the h-index of the above researcher, organize articles in descending order, based on the number of times they have been cited. Thus, he has twenty-four papers that have been cited 37, 35, 30, 28, 27,21,17, 17, 17, 16, 15,10 and 4 times, o times (paper 14 to 24)  the individual’s h-index would be 11. The first paper 37, gives us a 1 – there is one paper that has been cited at least once, the second paper gives a 35, there are two papers that have been cited at least twice, the third paper, 30 and all the way up to 11 with the eleventh highest paper –the remaining  thirteen papers have no effect in this case as they have been cited less than eleven times

Paper Citation
1 37
2 35
3 30
4 28
5 27
6 21
7 17
8 17
9 17
10 16
11 15
12 10
13 4
14 to 24 0

Key h-index tools

One should cite the database source from which the h-index was derived. It depends on which database you use: Web of Science (Thomson Reuters), Scopus (Elsevier) or Google Scholar. Web of Science  and Scopus collect and organize citation counts and can calculate an individual’s h-index. Likewise, Google Scholar collects citations and calculates and author’s via Google Scholar Citation. However, each source may determine a different value of the h-index for each individual.

Each database considers only those citations in the journals listed in each of the databases. The Web of Science, as mentioned earlier, is not an open access database. Scopus allows viewing your only h-index (without Scopus account). The Google Scholar searches all web-based information both peer and non-peer reviewed literature, which results in considerably higher h-indices. In general, it is found that Google Scholar gives a higher h-index for the same researcher when compared to other two databases. Google Scholar is the only one of the three that is freely accessible to the general population. One can easily create Homepage of Google Scholar citation by signing in Gmail account that automatically calculates and updates h-index and its metrics.

Citations to papers mean that someone used your work or thought it was relevant to mention in the context of their own work. Academician especially young researchers are always favourable towards metrics that make them look good. By keeping track of  h-index one can have an idea of how well you have done in your research domain. Despite a few limitations, there is now enough evidence to show that the use of the h-index has become popular and acceptable.

 

 

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My Thoughts of Feeling Good

WHAT GOOD FEELING MEANS TO ME .…..

  • Eating Bengali cuisine: right from alur dom, mochar ghonto, alu potoler dalna .. to the aroma of panch phoron in the fish curry
  • Receiving the bank’s SMS at last working day of a month, informing me of credit of month’s salary
  • Drinking a cup of Darjeeling tea with a half teaspoon of sugar, with no milk, at the beginning of every morning
  • Receiving appreciation from my wife
  • Googling my name and finding a lot of results
  • Receiving Google Scholar’s Gmail alert, notifying the citations of my articles
  • Receiving praises for my articles, especially from someone unknown
  • Crossing the busy road in the city holding my daughter’s hand
  • Connecting friends of distant past on social network
  • Gifting to my close relatives
  • Visiting an old place after years
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Hallowed Town of Cosmic Dancer, Chidambaram

The first image that comes to mind at the mere mention of the Chidambaram is the majestic (Nataraja) temple town and the religious specialty attached to it. The sense of consciousness one feels in the town, and the architectural excellence depicted, is divine and symbolic. It is here that Lord Shiva as Nataraja, the Dancing Shiva is believed to have performed the cosmic dance. The Nataraja is one of the most celebrated images of any Hindu deity, renowned widely across all of India and all over the world.

Sivaganga Tank and north gopuram in the Nataraja Temple

Sivaganga Tank and north gopuram in the Nataraja Temple

Situated about 240 KM south of the capital city of Chennai on about 10 KM inland of the Coromandel Coast, is reputed to be sacred place and one of the holiest of all Shiva temples in South India. In the centre of the town stands the grandiose Nataraja Temple spreads over 40 acres, with its four gopurams (tower gates) towering over the town and is visible from a long distance.

Magnificent four gopurams is visible from a long distance

Magnificent four gopurams is visible from a long distance

Chidambaram is synonymous with exquisite Nataraja Temple. Its origin dates back to the Chola reign from AD 907 to 1310; and the Nataraja Temple was built during the latter part of Chola administration. Coastal plain along the Coromandel Coast south of Pondicherry is a highly fertile delta of Cauvery River and is famous for its intensely green rice field that has been farmed since ancient times. This fertile Cauvery delta formed the heartland of the Chola Empire, which reached its pinnacle of glory in the period between 10th and 14th centuries during which they stamped their influence on religious art, cultural richness and the sheer scale on profession of architectural creation.

Green paddy fields in Cauvery delta area

Green paddy fields in Cauvery delta area

A visit to the Nataraja Temple affords a fascinating glimpse into ancient Tamil religious practice and belief and the huge temple complex with its majestic gopurams speak testimony to the splendid specimens of the Chola architecture. A visitor approaches at the temple main entrance through the east gopuram, off East Car street, is bound to overwhelmed by the exquisitely sculptures of 108 different dance postures of the classical dance form, Bharatnatyam inside the gopuram corresponding to the descriptions in the Sanskrit treatise,  NATYA SHASTRA.  The west gopuram also has similar carved figures.

Main entrance through east gopuram, off East Car Street

Main entrance through east gopuram, off East Car Street

Classical dance postures carved inside eastern gopuram

Classical dance postures carved on inside eastern gopuram

The Nataraja and Parvati are enshrined in the sanctum (known as chit sabha), and the roof of sanctum is covered with golden plates. Five silver plated steps lead to the chit sabha representing five syllables of the Shiva mantra “na-ma-si-va-ya”. It is unique in the sense that it is the only temple where Shiva is worshiped as an idol rather than the customary Lingam. To the right of Nataraja in the sanctum there is an empty space, covered with a silk curtain and is lifted during the time of worship, is believed to symbolize the void (or space) is known as Rahasayam (mystery). It is considered as a formless manifestation of Shiva –representing the deity is an empty space.  The temple is also unique in that it has both Shiva and Vishnu sanctums near each other.

citsabha Nataraj

Chitsabha, the sanctum with golden roof (Image source: web)

Chidambaram’s Nataraja Temple draws thousands of pilgrims, worshipers and visitors from all around the world. The annual 5-day Natyanjali festival in February/March attracts dancers to celebrate and pay their tribute to Lord Nataraja. The place is a living testimony of ancient astrological and geological knowledge. It is the center point of world’s magnetic equator and is said to be the centre of Universe.

Dance performance at Natyanjali festival

Dance performance at Natyanjali festival

Chidambaram is also home to Annamalai University established in 1929 and located on the eastern outskirts of the town.

Administrative Building - Annamalai University

Administrative Building – Annamalai University

Another source of attraction for the visitors is the Pichavaram forest, located 15 KM east of town which is an area of backwaters fringed by mangroves with rare species of flora and fauna – a paradise for nature-lovers.

Pichavaram forest with backwater and mangroves, 15 KM east of Chidambaram

Pichavaram forest with backwater and mangroves, 15 KM east of Chidambaram

Chidamabaram is an extremely friendly and safe town. It has all the facilities for modern lifestyles. There seems to be something for everyone in the town. A visit to this place would definitely leave everyone with memories that will not fade away over time.

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