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Eleven strains of species in the apiculate yeast genera Hanseniaspora, Nadsonia, and Saccharomycodes were examined for partial base sequence determinations of 18S and 26S rRNAs. In the partial base sequence of 26S rRNA (positions 493-622, 130 bases), percent similarities were 65-79, 76-84, and 70-76 between the genera Hanseniaspora and Nadsonia, the genera Hanseniaspora and Saccharomycodes, and the genera Nadsonia and Saccharomycodes, respectively. These apiculate yeasts showed 72-85 percent similarity with S. cerevisiae. In the partial base sequences of 26S rRNA (positions 1611-1835, 225 bases) and of 18S rRNA (positions 1451-1618, 168 bases), the number of base differences was calculated to be 38-26, 27-9, and 30-23, and 12-8, 11-5, and 13-8 between the above-mentioned genera, respectively. These apiculate yeasts showed 33-9, and 12-4 base differences, respectively, with S. cerevisiae. The three apiculate yeast genera were recognized phylogenetically based on the sequence data obtained. Some discussions were made, especially on dividing the members of the genus Hanseniaspora into two groups at the generic level.The teleomorphic species of apiculate yeasts equipped with coenzyme Q-6 (Q-6 or Q6) are currently classified in the following three genera: Hanseniaspora Zikes, t Significance of the coenzyme Q system in the classification of yeasts and yeast-like organisms .

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BackgroundThe unmet medical needs of individuals with very rare diseases are high. The clinical trial designs and evaluation methods used for ‘regular’ drugs are not applicable in the clinical development of ultra-orphan drugs (<1000 patients) in many cases. In order to improve the clinical development of ultra-orphan drugs, we examined several points regarding the efficient evaluations of drug efficacy and safety that could be conducted even with very small sample sizes, based on the review reports of orphan drugs approved in Japan.ResultsThe clinical data packages of 43 ultra-orphan drugs approved in Japan from January 2001 to December 2014 were investigated. Japanese clinical trial data were not included in the clinical data package for eight ultra-orphan drugs, and non-Japanese clinical trial data were included for six of these eight drug. Japanese supportive data that included retrospective studies, published literature, clinical research and Japanese survey results were clinical data package attachments in 22 of the 43 ultra-orphan drugs. Multinational trials were conducted for three ultra-orphan drugs. More than two randomized controlled trials (RCTs) were conducted for only 11 of the 43 ultra-orphan drugs. The smaller the number of patients, the greater the proportion of forced titration and optional titration trials were conducted. Extension trials were carried out for enzyme preparations and monoclonal antibodies with high ratio. Post-marketing surveillance of all patients was required in 36 of the 43 ultra-orphan drugs.For ultra-orphan drugs, clinical endpoints were used as the primary efficacy endpoint of the pivotal trial only for two drugs. The control groups in RCTs were classified as follows: placebo groups different dosage groups, and active controls groups. Sample sizes have been determined on the basis of feasibility for some ultra-orphan drugs.We provide “Draft Guidance on the Clinical Development of Ultra-Orphan Drugs” based on this research.ConclusionsThe development of ultra-orphan drugs requires various arrangements regarding evidence collection, data sources and the clinical trial design. We expect that this draft guidance is useful for ultra-orphan drugs developments in future.