Other Therapeutic Areas

Ruboxistaurin (LY333531) 41 (Eli Lilly) is being evaluated in a Phase III trial for the treatment of diabetic macular oedema.224 Lilly had submitted an NDA in February 2006 to the FDA for the treatment of diabetic retinopathy and received an Approvable Letter in September 2006 that requested another Phase III trial for additional efficacy data. The EMEA also required further clinical data and, as a consequence, Lilly withdrew its European MAA. Ruboxistaurin 41225 228 competitively inhibits adenosine triphosphate (ATP) binding to PKC/i and is a synthetic analogue of staurosporine 42. 

Voclosporin (ISA-247, R1524) 88 (Isotechnika) is being evaluated in a Phase III trial for the treatment of psoriasis,250 as well as a Phase III trial by Lux Biosciences as for the treatment of uveitis (coded as LX211, Luveniq ).251,252 In addition, voclosporin 88 has completed a Phase lib trial for the prevention of kidney graft rejection. Voclosporin 88253,254 is a slightly more potent but less toxic semi-synthetic derivative of the fungal-derived immunosuppressant cyclosporin A 89, which has the same mechanism of calcineurin inhibition. Cyclosporin A 89 was first isolated from Tolypocladium inflatum by workers at Sandoz and its structure was published in 1976.255,256 

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In other therapeutic areas, such an approach in Phase III may not be feasible. This is particularly true for conditions where the endpoint in Phase III is a surrogate for the endpoint of interest to physicians and payers. Examples would include hypertension, h)rpercholesterolemia or HIV infection. 

The high attrition rate of new chemical entities (NCEs) in preclinical and clinical phases can be attributed to many factors. According to Kola and Landis [50], NCEs fail mainly to insufficient efficacy, bioavailability, safety, toxicological and economic reasons. All these factors are somehow interrelated - a less soluble drug might be less bioactive and thus less efficient. Additionally, the attrition rate can depend on the therapeutic area the drug comes from. For example, compounds tend to fail more for CNS and oncology indications than in other therapeutic areas [50]. 

Compared to other therapeutic areas, the predinical and clinical development of a biotechnology drug for use in oncology requires consideration of several additional unique issues [12] ... 

Actinonin has also shown activity against a broad panel of tumor cell lines and various cancer mice models, but the mechanism of action is not well understood. Actinonin has also been investigated in other therapeutic areas where metalloproteases play a role. For example, the presence of PDF in Plasmodium falciparum led to its investigation as an antimalarial agent. Likewise, its capacity to inhibit... 

Though it is well known that most current devices are difficnlt to nse optimally and are frequently misnsed, useful therapeutic effects are still obtained, and therefore there has been relatively little pressure to produce devices appropriate to the twenty-first centnry. This may change dne to developments in other therapeutic areas. 

Outside the CNS (central nervous system), pyrrole Mannich bases have found utility in other therapeutic areas as well. The Mannich reaction between iminoibitol and 9-deazahypoxanthine took place at the C3 position to provide an A-pyrrolylmethyl substituted iminoribitol as an inhibitor of a purine-specific nucleoside hydrolase. In terms of regiochemistry, this particular Mannich reaction of 9-deazahypoxanthine behaved similarly to indole rather than to pyrrole. The resulting Mannich bases are potential treatment for parasitic infections. 

Natural products have been created by various organisms as secondary metabolites and the organisms with these cytotoxic chemical weapons can siuvive in the biochemical warfare over billion years. The organisms we observe today are the survival of the fittest, and natural products isolated from these organisms can have such a diverse biological activity, especially excellent cytotoxicity that is the reason why most of anticancer agents and antibiotics have originated from natural products. However, natural products were not as effective as in other therapeutic areas such as type 2 diabetes, depression, osteoporosis ... 

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