29 Aug 2016

Centchroman (Non-steroidal oral contraceptive)

The ever increasing population burden has devoured all the benefits that India gained due to rapid Industrial and agricultural development after the independence. The population growth has been the prime concern of the planners. It is no surprising that the concern for having smaller families has been equally, if not more, widespread among the scientific community as well as the decision makers of the nation. Even though the educated and otherwise population of the nation has been convinced of the need of having smaller children, there were hardly safer and acceptable method to restrict population growth. Safer antifertility drugs were the main motto of all research on antifertility projects.

CDRI, being one of the leading research labs of the country had obviously put enough attention and intellectual resources to develop safer and acceptable antifertility drugs. One of the main focus was to have an alternative to steroidal pills available in the market which were not free from side effects.

The need for a safer alternative to Progestogen – Estrogen combination pills has been felt ever since the sixties. Clearer understanding of the role of estrogen-progesterone balance in the development of fertilized ovum and the priming of the uterus for implantation served as the basis for developing an agent that would prevent pregnancy by interfering with implantation but without disturbing the hypothalamus-pituitary-ovarian axis. Researchers the world over have been designing and synthesising non-steroidal estrogen antagonists that would act by disturbing the delicate balance between estrogen and progesterone at the uterine level without interfering with their synthesis or blood levels. This task was sucessfully completed by CDRI when the first non-steroidal once a week pil, centchroman was devloped by CDRI taht reached the general public by the end of the 1980’s.

Centchroman is a novel non-steroidal agent unrelated to any conventionally used contraceptive. This is the only anti-implantation agent approved for clinical use in the world. It offers a unique combination of weak estrogenic and potent antiestrogenic properties. Due to this subtle mix of estrogenic and antiestorgenic action it inhibits the fertilized ovum from nidation and thus prevents pregnancy, but at the same time it does not appear to disturb the other estrogen effects.

Use of Centchroman as a contraceptive has been extensively evaluated in more than 2000 women of the reproductive age groups who wanted to space their children. Intensive monitoring by clinical examination, haematology and biochemical tests as well as laparascopy and ultrasonographic examinations of ovaries and uterus have shown the drug to be quite safe. Centchroman does not cause nausea, vomiting, dizziness and break through bleeding and has no adverse effect on lipid profile and platelet function as is seen with steroidal contraceptives. Babies born to use failure cases have shown normal milestones. The contraceptive effect is readily reversible and subsequent pregnancy and its outcome is normal. It scores over steroidal contraceptive pills because it does not disturb the endocrine system and the normal ovulatory cycle is maintained.


Discovered and developed by Zydus, Saroglitazar is a first-in-class molecule to be approved by the Drug Controller General of India to treat diabetic dyslipidemia or hypertriglyceridemia in type-2 diabetes not controlled by statins alone. Researched & developed over a span of 12 years, LipaglynTM is the first New Chemical Entity (NCE) from India to successfully complete the journey from the lab to the market.


Surgeons all over the country had been experiencing the need of a more effective and safer low dose local anesthetics. The currently available local anesthetic agents were not very quick in action and the duration of anesthetic effect was also not very long.

CDRI drug research programme has addressed to this need of the country and has come up Centbucridine. This compound is not only safer and more effective than the currently available local anesthetic, lignocaine but also has features that give it better acceptability. This drug is a totally new chemical moiety and has no relation whatsoever with lignocaine.

Centbucridine is superior to lignocaine in many aspects. Centbucridine has been found to possess several desirable properties. As compared to lignocaine, it is 4 to 5 times more potent, its onset of action is much quicker, and the duration of action is longer. Due to its vasoconstrictor activity, it does not require simultaneous administration of adrenaline. It does not effect the cardiovascular parameters due to its moderate antihistaminic activity and is not likely to show skin sensitivity. Moreover, it can be used in patients showing hypersensitivity to lignocaine.

It had earlier been licensed to Themis Chemicals Ltd., Mumbai which marketed it under the brand name Centoblok.


 Arteether is a semi synthetic derivative of artemisinine, the active constituent of the plant, Artemisia annua. CDRI conducted extensive preclinical, toxicological and other regulatory studies in which the drug was not only found to be very safe but also proved to be a fast acting, blood schizontocidal agent which attacks at the erythrocytic stage of malaria in blood. Extensive clinical trials were conducted at 7 centres in malaria prone areas of India. Over 500 patients showed excellent response and the recrudescent rate was very low. Arteether has been developed by CDRI and is being prescribed to the patients as second line of treatment for chloroquine-resistant P. falciparim malaria including cerebral malaria.

Though choloroquine has been and still remain one of the most extensively used first line drug for malaria, resistance against this drug is quite frequent. Search for a drug which could be more effective than chloroquine and which could minimize the chance of resistance development has been going on the world over. CDRI has always been quite in the forefront in searching for natural or synthetic drug that could be used as a weapon to fight malaria since it is causing so much of devastation in tropical countries, especially India. Many plants used by traditional systems of medicine have been tried and many of the leads are being pursued.

CDRI got a major success when it developed Arteether from the plant Artemisia annua while working in collaboration with, Central Institute of Medicinal and Aromatic plants (CIMAP), the other CSIR laboratory based at Lucknow.

The Drugs Controller General (India) has allowed the drug exclusively for use in hospitals and nursing homes.

Being a new drug, it is indicated for use only in severe P. falciparum malaria including cerebral malaria as a second line treatment for chloroquine resistant cases. It is not recommended to be used as a first line treatment for malaria to avoid its overuse which may lead to the emergence of resistance against this drug once again.

CDRI has licensed the drug to Themis Chemicals Ltd., Mumbai which is marketing it under the trade name E-Mal as an injectable formulation.

Post marketing surveillance data on 400 patients received from clinicians from 6 states has validated the efficacy and safety of Arteether in uncomplicated/complicated cases of P.falciparum malaria. No drug related side effects have been observed so far.

EBULAQUIN (Aablaquine)

 The Central Drug Research Institute has developed an antimalarial Drug – given in house number “Compound 80/53” and allotted International Nonproprietary Name (INN) as Bulaquin – which is a primaquine derivative.

Primaquine is the only drug available for use as anti-relapse, antimalarial for prophylactic in P.vivax malaria. However, this drug causes many side effects and the most commonly cited effect is methaemoglobinaemia in patients with G6PD deficiency. Higher doses of primaquine cause methaemoglobinaemia in most subjects and leukopenia in some. However, there is a small fraction of black population with G6PD deficiency who develop anaemia due to intravascular haemolysis at daily dose levels of 15 mg (base) and above.

It is being increasingly felt that the eroding efficacy of commonly used antimalarials has contributed substantially to the resurgence of malaria during last three decades. Although new antimalarials have appeared in the market during this time, none has yet supplemented chloroquine. There are no drugs in the market or in advanced stages of development that appear to be as well tolerated as chloroquine.

Combinations of existing antimalarials especially those now available in rural clinics and market hold great potential for effective, self-administered therapies for uncomplicated malaria, particularly where relapses are frequently encountered. Applying combined therapies to the problem should demand a high standard of proof of safety and efficacy in randomised double blind, placebo controlled trials.

Bulaquin is without any side effects that have been observed with primaquine. A comparative data analysis on initial (0 day pre-drug) and final (+7 day post-drug) values of haemoglobin, methaemoglobin, prothrombin time, partial thromboplastin time and fibrinogen in healthy human subjects treated with primaquine (15 mg OD x7 days) and Bulaquin (25 mg OD x7 days) have been carried out. The study has shown that one week primaquine treatment leads to rise in methaemoglobin levels from 3.97% to 16.32%, which is highly significant in comparison to the 2.29% and 3.02% levels of methaemoglobin before and after 7 days treatment with Bulaquin respectively. Thus, it is evident that primaquine treatment produces rise in methaemoglobin contrary to Bulaquine does not produce rise in methaemoglobin levels. This result manifests a clear superiority of Bulaquin over Primaquine.

Bulaquin has been licenced to Nicholas Piramal India Ltd., Mumbai for marketing. Nicholas Piramal has introduced Bulaquin alongwith chloroquine into the market as a combination pack under the trade name Aablaquine. The objective of the combined therapy is to control P.vivax malaria more effectively by providing initial cure and thereafter preventing relapses by use of this combination pack. It is hoped that the introduction of this combination pack of Bulaquin should contribute substantially to the ongoing National Malaria action programme advocated by Government of India.

GUGULIPID (Hypolipidaemic)


 CDRI has developed gugulipid, a cholesterol lowering drug taking the lead from ancient Indian system of medicine, Ayurveda. The Drug has been developed from the plant, Commiphora mukul.

Ayurvedic Practitioners have been utilizing the gum of the tree of Commiphora mukul commonly known as “Gugglu”. Ayurvedic literature also mentions the gugglu as a drug for the treatment of goutt, arthritis, rheumatism and lipid disorders.

The establishment of promising hypolipidaemic activity in a non-toxic fraction of guggulu led to the identification of the active constituents, gugulsterones. However, as the fraction was equally active as the individual active entities, this fraction designated Gugulipid has been developed as a drug. Gugulipid passed through all the three phases of clinical trials successfully and was found to possess hypolipidaemic activity comparable to the present drug of choice, Clofibrate.

Clinical trials conducted on a large number of patients have clearly indicated the supremacy of gugulipid over other drugs due to absence of any significant side effect. The cholesterol lowering effect is also quite remarkable

The use of Gugulipid led to the average reduction in serum cholesterol and triglycerides by 24% and 22% respectively and there were 80% responders in a group of 330 hyperlipidemic patients. As clofibrate is on the verge of being phased out on account of toxic manifestations, there is a scope for introduction of Gugulipid at international level. The future of this material as a drug will, however, depend on the availability of the plant material.

Drug controller General of India, after the three phases of clinical trials approved the drug for marketing in 1986.

Guggulipid is being manuactured and marketed by Cipla Ltd, Mumbai under the brand name Guglip.

MEMORY ENHANCER (Standardised Brahmi)

Since the time of Vedas, Brahmi, a perennial creeping plant (Bacopa monnieri) has been in use as a nerve tonic for rejuvenating mental health and for enhancing memory. This plant, found extensively in wet, marshy and damp areas, has been mentioned by ancient sages, medical men in almost all social, medical and religious treatises. Ayurveda, the ancient science of life has more than one reference of the plant for the enhancement of memory and mental agility of mankind. The famous Charaka Samhita written in the 1st century refers this plant for curing mental retardation leading to psychosis. Pharmacological properties of this plant have been clearly mentioned as having properties of cognitive enhancement and anxiolytic effect. The other treatise Sushruta Samhita makes this more explicit and describes Brahmi to be effective in memory loss.

Initially, CDRI’s interests in Brahmi were prompted by its effect on learning and memory described in ancient Ayurvedic treatises. The early systematic studies carried out at the institute were very encouraging and therefore, it was taken up for detailed investigation of active plant component and pharmacological and other studies. Subsequently, it was decided to develop the plant as a herbal remedy. As a result, a quality herbal preparation has been developed from B. monnieri which has been standardised in terms of its bacosides contents.

During efficacy and safety studies in rodent and non-rodent models, the Brahmi extract was found safe and efficacious. Preclinical neuropharmacological studies demonstrate that both the standardised extract and bacosides improve short-term and intermediate memories, thus , improving the long-term memory. The bacosides also significantly enhance protein synthesis in those regions of the brain which are implicated in the memory formation, a possible explanation for its memory improving effect.

Double blind cross over clinical studies have been carried out in children, elderly persons and normal healthy volunteers. Studies carried out in normal healthy volunteers, elderly subjects with age associated memory impairment and children with attention deficit hyperactivity disorder (ADHD) have shown that the drug is safe, well tolerated, efficacious and devoid of any side effects. Study on children with ADHD has shown that the preparation , after 12 weeks of its use, significantly improves sentence repetition, logical memory and paired associate learning.

This standardised preparation has been licensed to M/s Lumen Marketing Company, Chennai, for commercialisation. They have launched the preparation in the market under the brand name Memory Sure .

Isaptent – (Cervical Dilator)

Isaptent was developed by CDRI for its use as a cervical dilator for carrying out Medical Termination of Pregnancy (MTP) or abortion as well as for performing minor gynecological surgeries.

Before Isaptent was made available, Laminaria tents were being imported which were not only expensive but were also not readily available. CDRI made use of the husk of the plant, Plantago ovata (Isapgol) which is an agricultural product. Isapgol has this unique property of getting swelled in contact with water. The swelling is up to seven times of the original volume when the seed husk gets absorbed in water. This swelling property has been utilized for dilating the cervix for performing abortion or operation. The added natural advantage is the lubrication that the husk provides.

Isapgol seed husk is granulated and compressed into stick of appropriate size, which are encapsulated in cloth tubes either lined inside with a resized paper or coated with a thin film of micro-crystalline cellulose. These tubes are then compressed, packed in glass or polythene containers and sterilized under gamma radiation.

Isaptent is being extensively used by primary healthcare centers, family planning establishments, hospitals and individual gynecologists for performing MTP. The Isaptent, due to its indigenous characteristics and abundantly available raw materials comes quite cheap and can be made easily available.

The Isptent is commercially made available by M/s Unichem Ltd, Mumbai under the brand name Dilex ‘C’.

ENTPROPAZINE (Antidepressant)

Interest in the development of antidepressants had its beginning in early sixties after the introduction of imipramine. This was followed by introduction of several antidepressants belonging to the major groups of “tricyclic antidepressant” and “monoamine oxidase inhibitors”. However, following their increasing use in psychiatry and general practice, several limitations were observed such as they were not effective in 20-30% patients; the onset of effect takes 2-3 weeks; excess consumption risk by patients having suicidal tendency; and adverse effects of anticholinergic and cardiovascular nature.

Limitations of existing antidepressant drugs have led to persistent global efforts to develop newer drugs. Centpropazine is a new antidepressant compound with a different pharmacological profile. The early clinical studies showed it to be safe and well tolerated in normal human volunteers. Multicentric clinical efficacy studies were carried out in nearly 250 patients suffering from depression. These studies reveal Centpropazine to have comparable response rate with remarkably safer tolerability profile.

  CONSAP (local contraceptive cream, spermicide)

C D R I’s Contraceptive development programme has acieved anther great success in this area of national and international importance. It’s contraceptive Cream, CONSAP has now been approved bu the Drugs Controller General of India for its marketing and use. CONSAP is a sterile contraceptive cream developed from the saponins obtained from soap nuts (Reetha) collected from the plant, Sapindus mukorosii. The cream is recommended for all women of reproductive age group who want to space their children. It is safe and free from systemic side effects on continuous prolonged use.The preparation has been developed by using saponins from the soapnut or reetha (Sapindus mukorossi). The cream went through all regulatory testing and Phase I, II and III clinical trials and proved to be an effective contraceptive product. DCG(I) cleared the cream for use.

The CONSAP Cream has been licensed to the Hindustan Latex Limited who are going to market the product in very near future


                                         Picroliv is a hepatoprotective agent of plant origin. It is an iridoid glycoside mixture containing 60% picroside I and kutoside in the ratio of 1:1.5 obtained from the plant, Picrorhiza kurrooa ( root and rhizome ). Picroliv ( 6 and 12.5 mg/ kg ) has shown efficacy comparable to silymarin ( 10 and 20 mg/ kg ) in rodent models of galactosamine, paracetamol, thioacetamide and CC14 induced hepatic damage. Picroliv has shown cholerectic effect in rat and anti-cholestatic effect in rat, guinea pigs and cats treated with paracetamol and ethinyl estradiol. It has also antiviral and immunostimulant activities. Picroliv is devoid of any significant CNS and CVS , autonomic and other systemic activity.

Picroliv appears to be safe in rats and monkeys and has excellent therapeutic index. Phase I and II clinical trials have been conducted and the drug has shown no side effect and is well tolerated.

Diagnostic Vaccine          

PCR-based diagnostic probe for leishmaniasis

                A probe for early detection of visceral leishmaniasis has been developed by using a pair of oligonucleotide primers constructed from predominant sequence class of kinetoplast DNA minicircle of Leishmania donovani. Indian patent has been filed for the technology.

Direct agglutination test (DAT) for leishmaniasis

                A sensitive, specific (98%) and inexpensive assay for diagnosis of visceral leishmaniasis has been developed and validated in sera of over 3,000 human subjects from endemic and non-endemic areas and can be performed on very small quantities of blood. This is the first global introduction of a simple and reliable test developed for the early diagnosis of kala-azar. The application potential of DAT test has been increased with the preparation of freeze-dried antigen.

LDH-based diagnosis of malaria

                This comprises an immunodot enzyme staining test, employing anti-LDH polyclonal antibodies for the diagnosis of malaria. The test is highly specific and sensitive.

PCR based diagnostic probe for tuberculosis

                A novel DNA fragment of M. tuberculosis useful in early diagnosis of tuberculosis coupled with PCR technology has been developed. Indian patent has been filed.


                A potential marker of coronary heart disease and atherosclerosis Clinical significance of serum lipoprotein Lp(a), a cholesterol rich protein, in determining degree of risk of coronary heart disease (CHD) has been established. Serum Lp(a) concentration of 10mg/dl or more has been demonstrated as a potential risk marker in the Indian population. The assay will be a potential risk marker in the Indian population. The assay will be useful in the diagnosis of human subjects at a higher risk of CHD.

Cholera Vaccine

                The role of plasmid in the regulation of toxin biosynthesis, virulence factors, novel adhesive and colonisation factors of Vibrio cholerae have been demonstrated. A new subunit vaccine based on these colonisation antigens is being developed.

An anti-leprosy vaccine developed using Mycobacterium habana antigen could not be taken to phase II and III trials because other two anti-leprosy vaccines developed in the country were showing equally promising protection. The same strain of M. habana is being evaluated as anti-TB vaccine, as an alternative to BCG.

Posted By Dr Jayesh Rajgopal.