Cost-effectiveness analysis in the treatment of heavy menstrual bleeding in Spain.

OBJECTIVE: To compare the effectiveness and costs associated with first-line medical treatments for chronic heavy menstrual bleeding (HMB) in Spain. STUDY DESIGN: A cost-effectiveness analysis was conducted comparing the levonorgestrel-releasing intrauterine system (LNG-IUS) with the estradiol valerate/dienogest multiphase oral contraceptive (E2V/DNG), combined oral contraceptives (COC) and progestins (PROG). Study patients were fertile women diagnosed with HMB who initially wished to remain fertile. A Markov model based on reported clinical data and the opinion of a panel of experts was used. The time horizon of the analysis was 5 years. The analysis was conducted from the perspective of the Spanish National Health System (NHS), discounting both costs (€ 2013) and future effects at an annual rate of 3%. One-way sensitivity analyses and probabilistic sensitivity analysis were performed to test the robustness of the results. RESULTS: In the analysis at 5 years, the LNG-IUS was associated with a gain of 0.67, 2.22, and 3.53 symptoms free months (SFM) compared with E2V/DNG, COC and PROG, respectively. LNG-IUS contributed more quality-adjusted life months (QALM) than the other treatment alternatives (+1.74 vs. E2V/DNG, +3.33 vs. COC +3.53 vs. PROG). First-line LNG-IUS treatment resulted in savings of € 583, € 988, and € 1891 vs. E2V/DNG, COC and PROG, respectively. These cost benefits, coupled with the greater clinical benefits in terms of SFM and QALM, show that LNG-IUS is the dominant option (less costly and more effective). CONCLUSION: LNG-IUS is the medical treatment of choice and cost-saving option for the control of HMB in Spain.

Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles.

The Sanfilippo syndrome type C [mucopolysaccharidosis IIIC (MPS IIIC)] is caused by mutations in the HGSNAT gene, encoding an enzyme involved in heparan sulphate degradation. We report the first molecular study on several Spanish Sanfilippo syndrome type C patients. Seven Spanish patients, one Argentinean and three Moroccan patients were analysed. All mutant alleles were identified and comprised nine distinct mutant alleles, seven of which were novel, including four missense mutations (p.A54V, p.L113P, p.G424V and p.L445P) and three splicing mutations due to two point mutations (c.633+1G>A and c.1378-1G>A) and an intronic deletion (c.821-31_821-13del). Furthermore, we found a new single nucleotide polymorphism (SNP) (c.564-98T>C). The two most frequent changes were the previously described c.372-2A>G and c.234+1G>A mutations. All five splicing mutations were experimentally confirmed by studies at the RNA level, and a minigene experiment was carried out in one case for which no fibroblasts were available. Expression assays allowed us to show the pathogenic effect of the four novel missense mutations and to confirm that the already known c.710C>A (p.P237Q) is a non-pathogenic SNP. Haplotype analyses suggested that the two mutations (c.234+1G>A and c.372-2A>G) that were present in more than one patient have a common origin, including one (c.234+1G>A) that was found in Spanish and Moroccan patients.

Retention of ionizable compounds on HPLC. 8. Influence of mobile-phase pH change on the chromatographic retention of acids and bases during gradient elution.

The relationships between retention and mobile-phase pH in gradient elution are studied for acids and bases. The apparent pH shift caused by the increasing amount of acetonitrile and methanol has been determined starting from a wide range of pH values. It is shown that good relationships between the retention of ionizable compounds and the pH of the aqueous buffer can be established if the same type of buffer (ammonium acetate in this work) is used for all pH points. Equations are proposed to fit the gradient retention data to the pH of the aqueous buffer. The proposed equation gives an account of the relative variation of the pKa of the compound in the reference to the variation of the pH of the buffer as both parameters change during gradient elution.

Retention of ionizable compounds on HPLC. 6. pH measurements with the glass electrode in methanol-water mixtures.

The relationship, delta values, between the two rigorous pH scales, S(S)pH (pH measured in a methanol-water mixture and referred to the same mixture as standard state) and S(W)pH (pH measured in a methanol-water mixture but referred to water as standard state), in several methanol-water mixtures was determined (delta = S(W)pH-S(S)pH). Delta values were measured using a combined glass electrode and a wide set of buffer solutions. The results are consistent with those obtained with the hydrogen electrode. This confirms the aptness of the glass electrode to achieve rigorous pH measurements in methanol-water mixtures. An equation that relates delta and composition of methanol-water mixtures, and allows delta computation at any composition by interpolation, is proposed. Therefore, S(S)pH can be achieved from the experimental S(W)pH value and delta at any mobile phase composition. S(S)pH (or S(W)pH) values are related to the chromatographic retention of ionizable compounds through their thermodynamic acid-base constants in the methanol-water mixture used as mobile phase. These relationships were tested for the retention variation of several acids and bases with the pH of the mobile phase. Therefore, the optimization of the mobile phase acidity for any analyte can be easily reached avoiding the disturbances observed when W(W)pH is used.

Retention of ionizable compounds on HPLC. 4. Mobile-phase pH measurement in methanol/water

The different procedures used in HPLC to measure the pH of a mobile phase are evaluated in terms of the rigorous IUPAC definition of pH. The three procedures evaluated are as follows: measurement of the pH of the aqueous HPLC buffer before mixing it with the organic modifier, measurement of the pH of the HPLC buffer after mixing it with the organic modifier using a pH electrode system calibrated with aqueous buffers, and measurement of the pH of the HPLC buffer after mixing it with the organic modifier but calibrating the electrode system with reference buffers prepared in the same mixed solvent used as mobile phase. Following IUPAC definitions and recommendations, the three pH values can be related with the pH scales: w(w)pH, s(w)pH, and s(s)pH, respectively. The relationships between these three pH scales are also presented. The retention of several compounds with acid/base behavior in a C-18 and a polymeric column with buffered methanol/water as mobile phase is related to the mobile phase pH value measured in the three pH scales. It is demonstrated that the s(w)pH and s(s)pH scales give better relationships than the w(w)pH scale (pH measured in the aqueous buffer before mixing it with the organic modifier), commonly used on HPLC. The s(w)pH scale is specially recommended because of its simplicity of measurement: the pH is measured after mixing the aqueous buffer with the organic modifier, but the pH calibration is performed with the common aqueous reference buffers.

Retention of Ionizable Compounds on HPLC. 2. Effect of pH, Ionic Strength, and Mobile Phase Composition on the Retention of Weak Acids.

A new model that relates the retention of a weak acid in HPLC columns with the pH and ionic strength of the mobile phase is derived and tested for different benzoic acids in methanol-water mobile phases. The proposed model uses the pH value in the mobile phase instead of the pH value in water, takes into account the effect of the activity coefficients, and considers different holdup times for the neutral and ionic species. The dependence of the holdup time of the ionic species on the mobile phase properties (pH, solvent composition, and ionic strength) is evaluated. It is demonstrated that the holdup time of the neutral species does not depend on the mobile phase properties, but the holdup time of the ionic species depends on the particular buffer used. The proposed equations can be combined with previously derived equations that relate the retention with the solvent composition of the mobile phase to establish a general model that relates the retention of the solute with the significant mobile phase properties: composition, pH, and ionic strength.