Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.

Stability of premixed syringes of diamorphine and hyperbaric bupivacaine.

BACKGROUND: It is common clinical practice to add diamorphine to heavy bupivacaine when performing spinal anaesthesia for either obstetric or general surgical procedures. If pre-filled syringes were available potential problems arising due to the wrong mixture being administered could be reduced, whilst also providing greater assurances of sterility and accuracy of dosage. It is therefore necessary to establish whether diamorphine 100 microg/mL is stable in solution with 0.5% hyperbaric bupivacaine, to allow production of pre-filled syringes for use in spinal anaesthesia. METHOD: Diamorphine hydrochloride was dissolved in water for injection, and added to hyperbaric bupivacaine then stored in 5-mL plastic syringes. Eleven syringes were stored at 40 degrees C/75% relative humidity, 25 degrees C/60% relative humidity and 7 degrees C for 90 days. Samples were taken at five time points for measurement of diamorphine and bupivacaine concentrations using high performance liquid chromatography. RESULTS: Diamorphine concentrations fell over the study period. No significant changes were observed the bupivacaine content of the samples. There was 10% degradation of diamorphine after 4 days at 40 degrees C, after 7 days at 25 degrees C, and after 26 days at 7 degrees C. CONCLUSION: Diamorphine is stable in hyperbaric bupivacaine at 7 degrees C for long enough to allow preparation of pre-filled syringes in advance (by hospital pharmacy aseptic units) for use in spinal anaesthesia.

Anti-(herpes simplex virus) activity of 4'-thio-2'-deoxyuridines: a biochemical investigation for viral and cellular target enzymes.

The antiviral activity of several nucleoside analogues is often limited by their rapid degradation by pyrimidine nucleoside phosphorylases. In an attempt to avoid this degradation, several modified nucleosides have been synthesized. A series of 4'-thio-2'-deoxyuridines exhibits an anti-[herpes simplex virus (HSV)] activity significantly higher (20-600 times) than that shown by the corresponding 4'-oxy counterpart. We investigated the mode of action of these compounds and we found that: (i) several 4'-thio-2'-deoxyuridines are phosphorylated to the mono- and di-phosphates by HSV-1 thymidine kinase (TK) more efficiently than their corresponding 4'-oxy counterpart; (ii) both are inhibitors of cellular thymidylate synthase; (iii) 4'-thio-2'-deoxyuridines are resistant to phosphorolysis by human thymidine phosphorylase; (iv) both 4'-oxy- and 4'-thio-2'-deoxyuridines are phosphorylated to deoxyribonucleotide triphosphate in HSV-1-infected cells and are incorporated into viral DNA; (v) 4'-thio-2'-deoxyuridines are better inhibitors than their 4'-oxy counterparts of [(3)H]thymidine incorporation in HSV-1-infected cells; (vi) 4'-thio-2'-deoxyuridines are not recognized by HSV-1 and human uracil-DNA glycosylases. Our data suggest that 4'-thio-2'-deoxyuridines, resistant to pyrimidine phosphorylase, can be preferentially or selectively phosphorylated by viral TK in HSV-infected cells, where they are further converted into triphosphate by cellular nucleotide kinases. Once incorporated into viral DNA, they are better inhibitors of viral DNA synthesis than their corresponding 4'-oxy counterpart, either because they are not recognized, and thus not removed, by viral uracil-DNA glycosylase, or because they preferentially interfere with viral DNA polymerase.

Efficient syntheses of (E)-5-(2-bromovinyl)-2'-deoxy-4'-thiouridine; a nucleoside analogue with potent biological activity.

(E)-5-(2-Bromovinyl)-2'-deoxy-4'-thiouridine (S-BVDU) is a potent antiherpesvirus agent and its use in gene therapy as an anticancer agent has recently been described. We here outline 2 efficient methods for the synthesis of S-BVDU. The decision as to which method is to be used depends upon the starting materials available but starting from BVU, an overall yield of beta-nucleoside of 35% can be expected. From 5-ethyl-2'-deoxy-4'-thiouridine, radical bromination using bromine will give a quantitative conversion to S-BVDU if unreacted starting material is recycled (50%) or using N-bromosuccinimide, a one step yield in excess of 80% can be obtained.

Correlation between hydrolysis of the -lactam bond of the cephalosporin nucleus and expulsion of the 3-substituent.

The hydrolysis of two cephalosporins by three different beta-lactamases has been studied. Each enzyme caused a decrease in ultraviolet absorption, a loss of biological activity, and the release of the leaving group from the 3-position. The changes occurred at the same rate and to the same extent with each enzyme, and it is inferred that the loss of the leaving group is a consequence of, and not a prerequisite for, hydrolysis of the beta-lactam ring.

Mass of pluto.

Analysis of the observations of Neptune indicates a reciprocal mass of Pluto of 1,812,000 (0.18 Earth masses). If the density is the same as that of Earth, the diameter would be 7200 kilometers. If 6400 kilometers is accepted (from other sources) as the upper limit of the diameter, then Pluto must be at least 1.4 times as dense as Earth.