A Cross-National Comparison of Biosimilars Pricing in Argentina, Australia, Brazil, and Italy.

BACKGROUND: Biosimilar medicines are defined as biological products highly similar to an already licensed biological product (RP). The market entry of biosimilars is expected to reduce the costs of biological treatments. OBJECTIVE: This study aims to evaluate the range of differences between the prices of biosimilars and the corresponding RP for biologicals approved in four countries. METHOD: This is a cross-national comparison of pricing of biosimilars in Argentina, Australia, Brazil, and Italy. The study examined online price databases provided by the national authorities of the investigated countries. Biosimilar price difference was calculated by subtracting the unit price of the biosimilar by the unit price of the RP, and then dividing it by the unit price of the RP. The results were presented as percentage. RESULTS: Brazil had the highest median price reduction (- 36.3%) in biosimilars price, followed by Italy (- 20.0%) and Argentina (- 18.6%). All the biosimilars in Italy were priced below the RP presenting a minimum reduction of 6.3%, while in Australia, most of the prices of biosimilars were equal to the RP. In Argentina, one infliximab-biosimilar displayed price above the RP (40.7%) while the lower priced brand had a reduction of 14.4%. Brazil had four biosimilars with prices above the respective RP, including isophane insulin (1), insulin glargine (1) and somatropin (2). CONCLUSION: The study revealed a marked dispersion in the price's differences between biosimilars and RP across the studied countries. Governments should evaluate whether their policies have been successful in improving affordability of biological therapies.

Piperlongumine Induces Apoptosis in Colorectal Cancer HCT 116 Cells Independent of Bax, p21 and p53 Status.

BACKGROUND/AIM: Colorectal cancer is a common type of cancer with reported resistance to treatment, in most cases due to loss of function of apoptotic and cell-cycle proteins. Piperlongumine (PPLGM) is a natural alkaloid isolated from Piper species, with promising anti-cancer properties. This study investigated whether PPLGM is able to induce cell death in colorectal carcinoma HCT 116 cells expressing wild-type or deficient in Bax, p21 or p53. MATERIALS AND METHODS: PPLGM was extracted from roots of Piper tuberculatum. Cell viability was determined by reduction of 3-(4,5-dimethilthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assay. Cell death was evaluated by acridine orange/ethidium bromide staining and flow cytometry. Plasmid cleavage activity and circular dichroism DNA interaction were also analyzed. RESULTS: PPLGM induced selective cell death in all cell lines (IC50 range from 10.7 to 13.9 µM) with an increase in the number of late apoptotic cells and different profiles in cell-cycle distribution. Plasmid DNA analysis showed that PPLGM does not interact directly with DNA. CONCLUSION: This paper suggests that PPLGM may be a promising candidate in colorectal cancer therapy.

Cytotoxic activity of halogenated sesquiterpenes from Laurencia dendroidea.

Red algae of the genus Laurencia J. V. Lamouroux are found in tropical and subtropical regions throughout the world and are an extremely rich source of active secondary metabolites with diverse structural features. In the present study, 6 sesquiterpenes (obtusol, (-)-elatol, dendoidiol, debrome-elatol, triquinane, and obtusane) isolated from Laurencia dendroidea were investigated for their cytotoxicity, using 4 cancer cell lines (U937, Jurkat, B16F10, and Colo-205). Among all sesquiterpenes tested, obtusol and (-)-elatol showed a promising activity in the treatment of Colo-205 strain, with IC50 of 1.2 ± 1.4 and 2.5 ± 1.3 µg/ml, respectively. In addition, fluorescence microscopy results indicated that, at 100 µg/ml, obtusol induced apoptosis at 79% and (-)-elatol at 95%. Activation of Caspases 2, 4, 6, and 8 showed to be involved in (-)-elatol activity and only Caspase 6 in obtusol activity. These data demonstrated the effective apoptosis-inducing activity of the sesquiterpene (-)-elatol and obtusol in the treatment of Colo-205 strain. Therefore, more studies should be done so that the sesquiterpenes (-)-elatol and obtusol might become promising chemotherapy.

Nitric Oxide Production Inhibition and Anti-Mycobacterial Activity of Extracts and Halogenated Sesquiterpenes from the Brazilian Red Alga Laurencia Dendroidea J. Agardh.

BACKGROUND: Red algae of the genus Laurencia J. V. Lamouroux are a rich source of secondary metabolites with important pharmacological activities such as anti-tumoral, anti-inflammatory, anti-fungal, anti-viral, anti-leishmanial, anti-helminthic, anti-malarial, anti-trypanosomal, anti-microbial as well as anti-bacterial against Mycobacterium tuberculosis. OBJECTIVE: In the present study, we evaluated the inhibition of nitric oxide (NO) and tumor necrosis factor-α production and the anti-mycobacterial activity of crude extracts from the red Alga Laurencia dendroidea (from the South-Eastern coast of Brazil). Halogenated sesquiterpenes elatol (1), obtusol (2) and cartilagineol (3), previously isolated from this Alga by our group, were also studied. MATERIALS AND METHODS: The lipopolysaccharide-activated macrophage cells (RAW 264.7) were used as inflammation model. Cytotoxic effect was determined using a commercial lactate dehydrogenase (LDH) kit and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The growing Mycobacterium inhibition was verified against Mycobacterium bovis Bacillus Calmette-Guérin and M. tuberculosis H37 Rv strains. RESULTS: The crude extract from Alga collected at Angra dos Reis, RJ, Brazil, was the most active inhibitor of both mycobacterial growth (half maximal inhibitory concentration [IC50] 8.7 ± 1.4 µg/mL) and NO production by activated macrophages (IC50 5.3 ± 1.3 µg/mL). The assays with isolated compounds revealed the anti-mycobacterial activity of obtusol (2), whereas (-)-elatol (1) inhibited the release of inflammatory mediators, especially NO. To our knowledge, this is the first report describing an anti-mycobacterial effect of L. dendroidea extract and demonstrating the association of this activity with obtusol (2). CONCLUSION: The described effects of active compounds from L. dendroidea are promising for the control of inflammation in infectious diseases and specifically, against mycobacterial infections associated with exacerbated inflammation. SUMMARY: Inflammation is strongly involved in the pathogenesis of most infectious diseases, including TB. The treatment of TB is based on the use of anti mycobacterial drugs, however the most severe forms of TB, require additional anti inflammatory therapy to prevent excessive inflammation. A combination of these properties in one compound could provide additional therapeutic benefits. In this work, we studied L. dendroidea extracts and purified compounds and demonstrated that the LDA extract and (-)-elatol (1) were potent in inhibiting NO production by macrophages through the specific inhibition of iNOS expression. The LDA and LDM extracts and obtusol (2) were active against virulent strain of M. tuberculosis. This is the first report demonstrating that the anti-inflammatory activities of L. dendroidea were associated with the presence of (-)-elatol (1), whereas anti-mycobacterial activities of L. dendroidea extracts were associated with obtusol (2).

Sesquiterpenes from the Brazilian red alga Laurencia dendroidea J. Agardh.

Two new chamigrane sesquiterpenes 1-2 and three known compounds 3-5 were isolated from a lipophilic extract of the red alga Laurencia dendroidea collected from the Southeastern Brazilian coast. Dendroidone (1) and dendroidiol (2) were isolated from samples collected at Biscaia Inlet, Angra dos Reis, Rio de Janeiro and at Manguinhos Beach, Serra, Espírito Santo, respectively. Debromoelatol (3), obtusane (4) and (1S*,2S*,3S*,5S*,8S*,9S*)-2,3,5,9-tetramethyltricyclo[6.3.0.0¹·5]undecan-2-ol (5) were obtained from specimens collected at Vermelha Beach, Parati, Rio de Janeiro. The structures of new compounds were elucidated by extensive NMR (¹H-, ¹³C-, COSY, HSQC, HMBC and NOESY) and high resolution mass spectrometry analysis. Additionally, the absolute configuration of compound 2 was assigned by X-ray analysis. Full spectroscopic data is described for the first time for compound 3. Anti-inflammatory and antimycobacterial activities of compounds 2-5 were evaluated. Compounds 3-5 inhibited the release of inflammatory mediator NO while TNF-α levels were only affected by 3. All compounds tested displayed moderate antimycobacterial action.

Antileishmanial sesquiterpenes from the Brazilian red alga Laurencia dendroidea.

Investigation of the bioactive crude extracts from two populations of the red alga Laurencia dendroidea from the southeastern Brazilian coast led to the identification of five sesquiterpenes: (+)-obtusane (1), a triquinane derivative (2), (-)-elatol (3), obtusol (4), and cartilagineol (5). An antileishmanial bioassay against Leishmania amazonensis was conducted for crude lipophilic extracts and for sesquiterpenes 2, 3, and 4. Compounds 3 and 4 displayed in vitro and in vivo leishmanicidal activity and very low cytotoxicity.