Systematic review on the evaluation criteria of orphan medicines in Central and Eastern European countries.

BACKGROUND: In case of orphan drugs applicability of the standard health technology assessment (HTA) process is limited due to scarcity of good clinical and health economic evidence. Financing these premium priced drugs is more controversial in the Central and Eastern European (CEE) region where the public funding resources are more restricted, and health economic justification should be an even more important aspect of policy decisions than in higher income European countries. OBJECTIVES: To explore and summarize the recent scientific evidence on value drivers related to the health technology assessment of ODs with a special focus on the perspective of third party payers in CEE countries. The review aims to list all potentially relevant value drivers in the reimbursement process of orphan drugs. METHODS: A systematic literature review was performed; PubMed and Scopus databases were systematically searched for relevant publications until April 2015. Extracted data were summarized along key HTA elements. RESULTS: From the 2664 identified publications, 87 contained relevant information on the evaluation criteria of orphan drugs, but only 5 had direct information from the CEE region. The presentation of good clinical evidence seems to play a key role especially since this should be the basis of cost-effectiveness analyses, which have more importance in resource-constrained economies. Due to external price referencing of pharmaceuticals, the relative budget impact of orphan drugs is expected to be higher in CEE than in Western European (WE) countries unless accessibility of patients remains more limited in poorer European regions. Equity principles based on disease prevalence and non-availability of alternative treatment options may increase the price premium, however, societies must have some control on prices and a rationale based on multiple criteria in reimbursement decisions. CONCLUSIONS: The evaluation of orphan medicines should include multiple criteria to appropriately measure the clinical added value of orphan drugs. The search found only a small number of studies coming from CEE, therefore European policies on orphan drugs may be based largely on experiences in WE countries. More research should be done in the future in CEE because financing high-priced orphan drugs involves a greater burden for these countries

Examination of the Rumen Bacteria and Methanogenic Archaea of Wild Impalas (Aepyceros melampus melampus) from Pongola, South Africa

Although the rumen microbiome of domesticated ruminants has been evaluated, few studies have explored the rumen microbiome of wild ruminants, and no studies have identified the rumen microbiome in the impala (Aepyceros melampus melampus). In the present study, next-generation sequencing and real-time polymerase chain reaction were used to investigate the diversity and density of the bacteria and methanogenic archaea residing in the rumen of five adult male impalas, culled during the winter dry season in Pongola, South Africa. A total of 15,323 bacterial 16S rRNA gene sequences (from five impala), representing 3,892 different phylotypes, were assigned to 1,902 operational taxonomic units (OTUs). A total of 20,124 methanogen 16S rRNA gene sequence reads (from four impala), of which 5,028 were unique, were assigned to 344 OTUs. From the total sequence reads, Bacteroidetes, Proteobacteria, and Firmicutes were the most abundant bacterial phyla. While the majority of the bacterial genera found were unclassified, Prevotella and Cupriavidus were the most abundant classified genera. For methanogens, the genera Methanobrevibacter and Methanosphaera represented 94.3 % and 4.0 % of the classified sequences, respectively. Most notable was the identification of Methanobrevibacter thaueri-like 16S rRNA gene sequence reads in all four impala samples, representing greater than 30 % of each individual’s total sequences. Both data sets are accessible through NCBI’s Sequence Read Archive (SRA), under study accession number SRP [048619]. The densities of bacteria (1.26×1010–3.82×1010 cells/ml whole rumen contents) and methanogens (4.48×108–7.2×109 cells/ml of whole rumen contents) from five individual impala were similar to those typically observed in domesticated ruminants.http://link.springer.com/journal/2482016-04-30hb201

Carbohydrate Transport by Group Translocation: The Bacterial Phosphoenolpyruvate: Sugar Phosphotransferase System.

The Bacterial Phosphoenolpyruvate (PEP) : Sugar Phosphotransferase System (PTS) mediates the uptake and phosphorylation of carbohydrates, and controls the carbon- and nitrogen metabolism in response to the availability of sugars. PTS occur in eubacteria and in a few archaebacteria but not in animals and plants. All PTS comprise two cytoplasmic phosphotransferase proteins (EI and HPr) and a species-dependent, variable number of sugar-specific enzyme II complexes (IIA, IIB, IIC, IID). EI and HPr transfer phosphorylgroups from PEP to the IIA units. Cytoplasmic IIA and IIB units sequentially transfer phosphates to the sugar, which is transported by the IIC and IICIID integral membrane protein complexes. Phosphorylation by IIB and translocation by IIC(IID) are tightly coupled. The IIC(IID) sugar transporters of the PTS are in the focus of this review. There are four structurally different PTS transporter superfamilies (glucose, glucitol, ascorbate, mannose) . Crystal structures are available for transporters of two superfamilies: bcIICmal (MalT, 5IWS, 6BVG) and bcIICchb (ChbC, 3QNQ) of B. subtilis from the glucose family, and IICasc (UlaA, 4RP9, 5ZOV) of E. coli from the ascorbate superfamily . They are homodimers and each protomer has an independent transport pathway which functions by an elevator-type alternating-access mechanism. bcIICmal and bcIICchb have the same fold, IICasc has a completely different fold. Biochemical and biophysical data accumulated in the past with the transporters for mannitol (IICBAmtl) and glucose (IICBglc) are reviewed and discussed in the context of the bcIICmal crystal structures. The transporters of the mannose superfamily are dimers of protomers consisting of a IIC and a IID protein chain. The crystal structure is not known and the topology difficult to predict. Biochemical data indicate that the IICIID complex employs a different transport mechanism . Species specific IICIID serve as a gateway for the penetration of bacteriophage lambda DNA across, and insertion of class IIa bacteriocins into the inner membrane. PTS transporters are inserted into the membrane by SecYEG translocon and have specific lipid requirements. Immunoelectron- and fluorescence microscopy indicate a non-random distribution and supramolecular complexes of PTS proteins