Exploring deep sea medicines

Posted AtThe Financial Express

Although the oceans cover 70% of the planet's surface, much of their biomedical potential has gone largely unexplored, particularly in the Indian Ocean. Until now.

Indian scientists have begun collecting various flora and fauna species from the surrounding ocean for developing new life saving medicines and rare biochemicals. Already, eight samples have been identified for new drug development. Under the national project, 'Development of Potential Drugs from Ocean', about 1,700 different species of marine flora and fauna have been collected. About 4,500 extract fractions have been screened from these species by a team of scientists for the desired bioactivity in available disease models, says CM Gupta of the Lucknow-based Central Drug Research Institute.

Various samples are in different stages of trials and analysis. The sample CDR-134, which is derived from the fruit of a mangrove species found in abundance on the coastal regions of the Andaman & Nicobar Islands, showed both antihyperglycemic (antidiabetic) and antidiarrhoeal activities. Though the extracts from the whole fruit exhibited antidiabetic activity, they were found to be toxic during experiments made on monkeys. The observed toxicity was mainly due to severe constipation that it caused at high doses in monkeys.

However, according to Dr Gupta, the fractionation of the fruit successfully separated out the antidiabetic activity (referred to as CDR-134-D-123 in scientific parlance) from the constipation-inducing factor (CDR-134-D-125). Both these fractions have been found completely safe during the rodent and monkey toxicity studies and will be initially developed as herbal drugs. Also a few pure compounds with antidiabetic activity have been isolated specifically from CDR-134-D-123 which are currently being used as leads to design new antidiabetic drugs. Preclinical trials have been completed both for CDR-134-D-123 and CDR-134-D-125.

Another product (CU1-002/004) isolated from a fish exhibited strong lipid lowering activity and has now been found safe during the rodent toxicity studies, says Dr Gupta. Commenting on other samples analysed so far, he says two such samples namely CDR-245 and CDR-258 showed antifungal activity, samples CDR-131 and NIO-492 showed antihyperglycemic activity and the sample CDR-134-D-212 showed antihyperlipidaemic activity. All these activities of the samples identified in Phase III preclinical trials have now been taken up for further studies in Phase IV.

In the Phase IV, most of these samples have been fractionated, subfractionated and some pure compounds with desired activity have been isolated. The structures of some of the purified compounds have already been determined and attempts are now underway to generate several structural prototypes in order to optimise the bioactivity, he says.

According to Dr Gupta the rich marine biota, comprising of over 500,000 species found all along the 7500 km-long coast line offer an enormous untapped potential for India to develop new medicines and rare biochemicals. International agencies realised the untapped potential of ocean's wealth way back in late 1960s, while such efforts was launched in India only in the last decade. Nevertheless, with limited financial resources and marine instrumentation, the scientists have been successful in identifying eight samples for new drug development.

He says that to sustain a high momentum of research, the programme needs more skilled divers who can make collections from deep sea, taxonomists for identification of new species and marine chemists for rapid isolation and charcterisation of pure compounds in sufficient quantities. Finally, it should always be noted that any new drug development needs an investment of about $500 million per product and minimum development period of 8 to 12 years, with a final success rate of less than 0.01%.

Dr Gupta also says that several global organisations based out of India have exploited marine resources of Indian Ocean and have produced anti-cancer and anti-fungal drugs. Amongst the various bioactive substances so derived, at least 13 potential anti-cancer agents and one anti-fungal agent have been successfully isolated. However, most of these are only at the preclinical stage, except two products which have reached Phase-I and II of the clinical development. These two products, Cemadotin and TZT 1027, have been developed from bioactive substance extracted from Indian Ocean seahare, Dolabella auricularia.

Cemadotin is a water-soluble pentapeptide which is an analog of dolastatin 15, a compound isolated from Dolabella auricularia. Cemadotin is presently under Phase-II of clinical trials in Abbott Laboratories, US and in other labs in Europe. Another anti-cancer drug, TZT 1027 developed by Japanese pharmaceutical company, Teikoku Hormone, is under Phase-I of clinical development.

According to Dr Gupta, "Apart from several anti-cancer agents developed by foreign institutions, about 3,500 marine organisms have been collected from the west of Felicite Island on the Indian Ocean and screened by MycoLogics and Harbor Branch Oceanographic Institute, US for anti-fungal activity. They have identified the black sponge, Plakinastrella species with promising anti-fungal activity."

He says that Plakinastrella species, when tested, produced a series of 5-membered ring peroxy acids which inhibited the growth of Candida albicans with minimum inhibitory concentrations of 3 to 6 mg/ml and was also active against Aspergillus fumigatus. Further lead compounds are being investigated and their structures are being elucidated he says.

Among the other anti-cancer drugs developed developed by global organisations from marine resources of Indian Ocean are Cephalostatin 10 and 11 extracted from Cephalodiscus gilchristi by Cancer Research Institute, Arizona State University, US. University of California in Davis in US isolated extracts from Phorbas species to produce an anti-cancer drug, Phorboxazole B. However, there are no reports of further development of the anti-cancer drugs, Cephalostatin 10 and 11 and Phorboxazole B after pre-clinical trials. Nevertheless, the University of Minnesota and the Parker Huges Cancer Center have developed another anti-cancer drug, Phorboxazole A by extracting bioactives from Phorbas sp. This drug is under pre-clinical trials.

Among others, Pharma Mar has developed an anti-cancer drug, PM 605 by extracting bioactives from Indian Ocean tunicate and this drug is presently under pre-clinical trials. Parker Huges Institute have developed a series of anti-cancer drugs, Spongistatin 1, 2, 3, 4 and 6 and Spiket-P by extracting bioactives from a marine sponge in the Indian Ocean. All these drugs are, at present, under pre-clinical trials.

According to Dr Gupta, hundreds of bioactive molecules exhibiting strong activities against a variety of infections like HIV, malaria, Staphylococcal and fungal infections and diseases like cancer including solid tumors and other human disorders like asthama, atherosclerosis, epilepsy, osteoarthritis and inflammation have been isolated and some of these are, at present, in the advanced stage of new drug development. While about a dozen of molecules are in Phase I and II of clinical trials, over 50 molecules are still under pre-clinical trials. A majority of these molecules (over 50%) promise anti-cancer activity.

December 05, 2005