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Background: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases. Objective: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies. Methods: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews. Results: The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues. Conclusions: The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.
Making rare disease research attractive to companies The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to speed the diagnosis and treatment of rare diseases through research. The IRDiRC Chrysalis Task Force, comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders, identified key factors that make rare disease research and development attractive to companies. The Task Force distributed a survey to companies with varied investment portfolios and interests in rare disease research, followed by in-depth interviews based on the survey results. The survey and interview respondents identified both attractive factors and barriers to rare disease research and development. The concept of Return On Investment was used to frame discussion of factors that companies weighed differently, depending on a number of issues that were a function of both the company itself and outside factors. The identified challenges can be addressed by funders, academic researchers, patients and their families, companies, regulators, and payers, which hopefully will lead to significant advances in the research and development of treatments for rare diseases.
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ETHNO-PHARMACOLOGICAL RELEVANCE: Hyptis suaveolens (L) Poit and Boerhavia diffusa Linn are medicinal herbal plants commonly found in the tropics and sub-tropics. They are used to treat various conditions among them boils, dyslipidaemia, eczema, malaria, jaundice and gonorrhoea. Thus, the herbal medicinal extracts are now found as part of some commercial herbal formulations. There has not been adequate characterization of these medicinal herbs on their effects on drug metabolising enzymes. AIM OF THE STUDY: To investigate the effects of extracts of Hyptis suaveolens (HS) and Boerhavia diffusa (BD) on activity of drug metabolising enzymes, CYP1A2, CYP2D6 and CYP3A4, as well predict their potential for herb-drug interaction. A secondary aim was to identify constituent compounds such as polyphenolics, in the crude extract preparations of Hyptis suaveolens and Boerhavia diffusa and measure them for activity. MATERIALS AND METHODS: CYP450 inhibition assays using recombinant CYP450 (rCYP) and fluorescence screening employing individual isozymes (CYP1A2, CYP2D6 and CYP3A4) were used to determine reversible- and time-dependent inhibition (TDI) profiles of extracts of Hyptis suaveolens and Boerhavia diffusa. Inhibition kinetic parameters, Ki and Kinact were also estimated. UPLC-MS employing a Synapt G2 (ESI negative) coupled to a PDA detector was used to identify polyphenolic compounds in crude extracts of Hyptis suaveolens and Boerhavia diffusa. RESULTS: The inhibitory potency of Hyptis suaveolens and Boerhavia diffusa extracts varied among the different enzymes, with CYP1A2 (3.68 ± 0.10µg/mL) being the least inhibited by HS compared to CYP2D6 (1.39 ± 0.01µg/mL) and CYP3A4 (2.36 ± 0.57µg/mL). BD was most potent on CYP3A4 (7.36 ± 0.94µg/mL) compared to both CYP2D6 (17.79 ± 1.02µg/mL) and CYP1A2 (9.48 ± 0.78µg/mL). Extracts of Hyptis suaveolens and Boerhavia diffusa exhibited TDIs on all CYPs. The most prominent phenolic candidates identified in both medicinal herbs using UPLC-MS analysis included caffeic acid, rutin, quercetin, citric acid, ferulic acid and gluconic acid. These phenolic compounds are thought to potentially give HS and BD their therapeutic effects and inhibitory characteristics affecting CYP450 activities. In vivo predictions showed the potential for HS and BD extracts to cause significant interactions if co-administered with other medications. CONCLUSIONS: The study reveals that crude aqueous extracts of HS and BD potentially inhibit drug metabolising isozymes CYP1A2, CYP2D6 and CYP3A4 in a reversible and time-dependent manner. Thus care should be taken when these extracts are co-administered with drugs that are substrates of CYP1A2, CYP2D6 and CYP3A4.