Delhi Belly +

Last week, I had the most unusual of Delhi Bellies.

As far as I can remember, this is the first time I spent more than 24 hours with symptoms that went way beyond the usual stomach upset. Even after I thought my body had expelled the last traces of a mutton biryani, I continued to double up with a stabbing pain on my sides, moving restlessly from the bed to the floor, to violent bouts of vomiting, as though the body was trying to yank out a knife that had got stuck deep inside my empty intestines.

Finally when we go around to seeing a doctor, this seemed to be so mundane, so ordinary a case that I was out in a few minutes with this Rx in hand:

•  Esoga RD (Abott) - Enteric coated Rabeprazole Sodium & Domperidone SR Capsules (BB 1-0-0 before breakfast) - ₹103 for strip of 10
• Taxim-O 200 (Alkem House) - Cefixime tablets IP (1-0-1 after meals) - ₹130/strip
• Drotin (Martin & Harris) - Drotaverine Hydrochloride (SOS) -
• Floristore (Zyventus) - Probiotic culture concentrate not less than 2.5B CFU capsules (1-0-1 about 30 minutes after meals)

The relief was almost immediate. That little knife in my intestines seemed to melt away, the vomiting ceased and I was up and about with a few hours.

How did this little miracle come about? What did the pills actually do inside my body?

Domperidone, seems to have acted on the dopamine receptors and stopped me from vomiting while the Rabeprazole Sodium - a proton pump inhibitor (PPI) - reduce the levels of acid in my stomach so that the real hero, an antibiotic named cephalosporin (Taxim / Cefixime) busted the bacteria (most likely Helicobacter pylori) which was the root-cause of the stomach infection.

On the sidelines, Drotaverine Hydrocholoride (Drotin) acting as an anti-spasmodic, helping with the vomit-control mechanisms. It is interesting to know that the same drug is used to 'enhance cervical dilation during childbirth'!

Th last set of capsules (Floristore) contained probiotic cultures to restore the ecosystem of friendly bacteria in my stomach that would have got destroyed by the antibiotics.

Medical science seems to have got the entire game figured out. The experience leaves me wondering how people coped with food poisoning before the advent of antibiotics...and with rising levels of antimicrobial resistance (AMR), who will we cope with bacteria that have learnt how to deal with broad-spectrum antibiotics like cephalosporins?

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REFERENCES & LINKS

http://www.rxlist.com/aciphex-side-effects-drug-center.htm

https://www.nlm.nih.gov/medlineplus/druginfo/meds/a690007.html

Drug Discovery in Noida

Recently, a small company I admire - Curadev Pharma PL - signed a $555 million deal with Roche, one of the oldest and largest bio-pharma companies in the world.

Amazingly, the news seems to have gone completely unnoticed by India's 'mainstream media'.

To be sure, there are a number of good reasons why this development was "newsworthy", especially when everybody seems to harping on the "Make in India" mantra:

Curadev is based out of Noida, a New Delhi suburb, miles away from the nearest biotechnology park or national lab. It has created and sustained world-class R&D facilities in a neighborhood prone to extended, unscheduled power outages;  It has built a team of dedicated professionals in an industry where loyalties are fickle at best and, now, it has entered into a partnership with a pharma major at a time when industry counterparts have settled themselves into making "copycat" drugs & formulations.

So what exactly has Curadev achieved?

An Investigational New Drug (IND) developed by Curadev holds the promise of medical treatment for a wide range of cancers. IND is an FDA technical term for a drug that is 'the subject of an approved marketing application' before it is transported or distributed. In this case the IND is for new drug molecule that could inhibit IDO1 (indoleamine-2, 3-dioxygenase-1) and TDO (tryptophan-2, 3-dioxygenase) -- two enzymes that mediate cancer-induced immune suppression.

Cancer cells grow and proliferate because they are able to fool our immune systems. Many different types of cancer cells produce enzymes like IDO1 and TDO which break down our neurotransmitters before they can alert our immune systems. The new molecule discovered by Curadev would inhibit IDO1 and TDO produced by cancerous cells, allowing our immune system to do its job of marking and destroying unwanted, dangerous cells.

Most Indian companies that reach the IND stage do not have the financial stamina to run the drug discovery marathon. They usually end up selling their discoveries to Big Pharma. Curadev has bucked this trend and entered into a strategic partnership for the next stage.

Lets hope this will lead Curadev to a real blockbuster that is 'Made in India'!

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REFERENCES / LINKS

• Curadev website - www.curadev.in 
• CNBC (20Apr15) - Curadev Announces Research Collaboration and Licensing Agreement to Develop Cancer Immunotherapeutic -http://www.cnbc.com/id/102600552
• http://www.prnewswire.com/news-releases/curadev-announces-research-collaboration-and-licensing-agreement-to-develop-cancer-immunotherapeutic-500630711.html
• FDA - types of applications - http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/default.htm
• Tryptophan - http://en.wikipedia.org/wiki/Tryptophan
• Indolamines- http://en.wikipedia.org/wiki/Indolamines

Plantibodies

Drugs based on antibodies have been in use for a long time now. So far, almost all these antibody-based drugs have been derived from animal sources -- usually mammalian cells from hamsters -- and then grown in large stainless steel vats. US-FDA has approved around 30 such drugs, including blockbuster cancer therapies such as Avastin and Rituxan (Roche).

The ongoing Ebola epidemic has brought into focus antibodies derived from plants (aka Plantibodies!). In the absence of any credible therapies, Mapp Pharmaceuticals (San Diego, USA) has been permitted to produce experimental 'Plantibodies' to treat two infected medical workers. Despite lower costs of plant-based production (~1/10th!) not many companies are into this area. The only such FDA approved drug is Elelyso, an enzyme produced from genetically engineered carrots, manufactured by Israel's Protalix Biotherapies, and marketed by Pfizer.

Which are the ~30 animal-derived drugs currently in the market? Why is it that major pharma companies are shying away from plant-based production lines that is supposed to be cheaper?

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REFERENCES /LINKS

* Plantibodies (Reuters, 18Aug14) --  http://www.reuters.com/article/2014/08/17/us-health-ebola-plants-analysis-idUSKBN0GH0DU20140817

* Ebola puts focus on drugs made in Tobacco plants -- http://www.jamaicaobserver.com/latestnews/Ebola-puts-focus-on-drugs-made-in-tobacco-plants

CDRI & Drug Discovery in India

India is currently a world leader in the manufacture of generic drugs. These are generally off-patent medicines marketed under their original chemical name, without advertising.

Since these drugs are usually produced and sold in bulk, profit margins are wafer thin. The real meat in the pharmaceutical business lies in the branded block-buster drugs that have taken years to develop.

How many new drugs have been developed or discovered in India, since 1947?

According to the Central Drug Research Institute (CDRI, Lucknow), the answer is 16. Nearly 70% of these have been developed in CDRI itself.  They are --

• Centchroman - world's first non-steroidal oral contraceptive  - marketed by Hindustan Latex Ltd under the trade name, Saheli and as Centron by Torrent Pharma.
• Arteether: antimalarial, from the plant Artemisia annua. Marketed by Themis Chemicals Ltd. under the trade name E-Mal. 
• Standardised Herbal Remedy (can this be called a drug?):  memory enhancer derived from the plant Bacopa monniera. Marketed as Memory Sure
• Consap (spermicidal cream) derived from soapnut
• Bulaquin, an antirelapse antimalarial, comparable to primaquine. Marketed by Nicholas Piramal as a combination therapy along with chloroquine under the trade name Aablaquin. 
• Gugulipid, a hypolipidaemic, is a standardised fraction of the plant Commiphora mukul. Cipla is marketing it under the trade name Guglip.
• Chandoniun Iodide - ??
• Cent bufinodole - ??
• Centpropazine (antidepressant) - ??
• Centbucridine, a local anaesthetic mktd by Themis Chemicals Ltd. as Centoblok. 
• Centimizon -??

The CDRI list seems to be in descending order to oblivion. The further you're down the list, the URLs too go wonky, linking you to completely unrelated pages.

In any case, the only one that remembered seeing at a medical store, was Saheli, and Memory Sure.

If this is what we get after spending public money for 64 years at CDRI?

Which are the other five drugs discovered in India? Do they - hopefully - fare better than CDRI's star-performers?

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LINKS
* "New drugs" from CDRI -- http://www.cdriindia.org/newdrugs.htm
* Centchroman / Saheli -- http://www.cdriindia.org/centchroman.htm
* (ToI, 18 Feb 2012) -- http://timesofindia.indiatimes.com/city/lucknow/CDRI-underlines-its-2011-progress-on-61st-annual-day/articleshow/11932436.cms

The How of 'Schedule Y'

Last week the Supreme Court of India pulled the brakes on a thriving drug trial industry in India.

Valued at over $300 million a year this industry was engaged in a rather unusual business. Big pharmaceutical MNCs spending billions of dollars in the discovery of New Chemical Entities (NCEs) would conduct their first human-level trials in countries like India. If the new drugs turned out to be blockbusters, the chances of their being available to patients in India was next to zero.

Out of 475 global clinical trails conducted from 2005 to 2012 using Indian patients, only 17 patented drugs were freely available for the  participants. This is doubly significant because it was in 2005 that Indian pharma laws were amended to allow 'concurrent' testing of NCEs. With this removal of a phase-lag in the testing regime, drugs of  unproven safety and efficacy could be tested on patients in this country.

So it came as not surprise that on 3 Jan., 2013, the Supreme Court directed the Central Drug Standards Control Organisation (CDSCO) to put in place a three-tier scrutiny of all clinical trails. Drugs & Cosmetics Rules already had a separate section - Schedule Y - setting the procedures for such trails but they were never really implemented.

Even after the SC directive, for the next 10 months neither CDSCO nor the health ministry did  to improve the safety of Indians participating in these trails. Taking note of this tardy response, on 21 October 2013, the court has ordered the government to stop all 'concurrent' clinical trails.

Even though this affects only 331 or 1122 trails (30%); and even though our gains from these trails were limited (no patent rights, no affordable drugs) it is interesting to see the MNC pharma lobby portraying this as a zero-sum game where 'India's loss is Bangladesh's gain'!

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LINKS & REFERENCES

* Mascarenhas, Anuradha (2013): DRUG TRAILS - LAX REGULATIONS COST THE COUNTRY DEAR, Indian Express, 25Oct13

* Jesani, Amar (2013): TRIED, TESTED AND FAILED, Indian Express 28Oct13

* Schedule Y -- http://cdsco.nic.in/html/D&C_Rules_Schedule_Y.pdf