Safety of long-term treatment with Pegvisomant: analysis of Spanish patients included in global ACROSTUDY.

PURPOSE: To evaluate the long-term safety of Pegvisomant (PEG) in the Spanish cohort of ACROSTUDY. METHODS: As of July 2013, 199 Spanish patients were included in ACROSTUDY, a global non interventional safety PEG surveillance study. Patients were observed for safety, biochemical outcome and magnetic resonance imaging evaluations. RESULTS: PEG was administered during an average period of 6.7 ± 2.1 years and a mean daily dose of 15.5 ± 7.5 mg. 48.2% of patients received PEG monotherapy. 90.9% of patients had received other medical treatment before PEG start. 195 adverse events (AEs) were reported in 88 patients (44.2%), and serious AEs were described in 31 patients (15.6%). There were no cases of liver tests >10 ULN, or permanent liver damage. Tumor size changes were locally reported in 61 cases (33.5%), with increases observed in 11 patients (6%). In acromegalic patients with diabetes mellitus a decrease in fasting serum glucose value was reported, reaching statistical significance after 1 and 4 years of treatment (-24.6 and -25.9 mg/dl, p = 0.04). After 60 months, normal or lower limit of normal (LLN) IGF-I levels were found in 67.9% of patients. 85.5% of patients showed an IGF-I normal or

Coupling liquid membrane and flow-injection technique as an analytical strategy for copper analysis in saline water.

A tandem system based on the coupling of a bulk liquid membrane and a flow injection analysis for the separation, preconcentration and spectrophotometric determination of copper in saline water is presented. The ligand pyridine-2-acetaldehyde benzoylhydrazone has been used as a carrier in the liquid membrane as well as a spectrophotometric reagent for UV-VIS detection. Simultaneous and sequential experimental designs were used to optimise the chosen variables of each technique, respectively. The metal was separated and preconcentrated from the sample with an efficiency of 100.5 ±â€¯0.9% and a metal preconcentration factor of 16.1. The on-line FIA determination was accomplished after metal complexation by the reagent at pH 3. A linear response was obtained in a range from 6.9 to 984.5 µg L-1 Cu(II), providing a detection limit of 1.8 µg L-1. Saline matrix and other metal ions were not cause of interferences with relative errors below 4.6% for 50 µg L-1 of Cu(II) determination. The proposed tandem system was successfully tested using a TMDA-62 certified reference material providing a relative error of + 1.9%; it was also applied to the Cu(II) determination in coastal seawater samples with low relative errors ranging from - 3.8% to 0.0% (using DPASV as reference method).

Study of the kinetics of the transport of Cu(II), Cd(II) and Ni(II) ions through a liquid membrane.

The coupled transport of Cu(II), Cd(II) and Ni(II) ions through a bulk liquid membrane (BLM) containing pyridine-2-acetaldehyde benzoylhydrazone (2-APBH) as carrier dissolved in toluene has been studied. Once the optimal conditions of extraction of each metal were established, a comparative study of the transport kinetics for these metals was performed by means of a kinetic model involving two consecutive irreversible first-order reactions. The kinetic parameters (apparent rate constants of the metal extraction and re-extraction reactions (k(1), k(2)), the maximum reduced concentration of the metal in the liquid membrane (R(o)max), the time of the maximum value of R(o)(t(max)) and the maximum entry and exit fluxes of the metal through the liquid membrane (J(f)max and J(s)max) of the extraction and stripping reactions were evaluated and results showed good agreement between experimental data and theoretical predictions. Complete transport through the membrane took place according to the following order: Cd(II)>Cu(II)>Ni(II), with similar kinetic parameters obtained for Cu(II) and Cd(III). The transport behaviour of Ni(II) was different to that of Cu(II) and Cd(III), probably due to the different stoichiometry of the nickel complex compared to those of the other metal ions and the different chemical conditions required for its formation. The influence of the sample salinity on the transport kinetics was studied. k(1) values decreased slightly when the feed solution salinity was increased for Cu(II) and Ni(II), but not for Cd(II). Values of k(2) were practically unaffected. The proposed BLM was applied to the preconcentration and separation of metal ions (prior to their determination) in water samples with different saline matrices (CRM, river water and seawater), and good agreement with the certified values was obtained.

[Antihypertensive and/or lipid-lowering treatments pattern of compliance in hypertense and/or dyslipemic patients in Primary Care]. / Patrón de cumplimiento terapéutico de antihipertensivos y/o hipolipemiantes en pacientes hipertensos y/o dislipémicos en Atención Primaria.

BACKGROUND AND OBJECTIVE: Lack of compliance is a major factor responsible for the differences between clinical trial results and real effectiveness in daily medical practice, contributing to an insufficient control of the cardiovascular risk factors (CVRF). Knowledge of the factors contributing to lack of compliance is limited, and in Spain data are scarce. The objectives of this study are: a) to indirectly determine the level of compliance among patients with hypertension and/or dyslipidemia; and b) to determine factors associated with compliance. MATERIAL AND METHOD: 9,001 hypertensive and/or dyslipidemic patients from four primary care centres in Catalonia were enrolled in Disease Management programmes during the previous four years. Compliance was estimated by the relationship between the amount of dispensed and prescribed pills: a) the levels of compliance of dyslipidemic patients without hypertension (DL-non HT), hypertensive patients with dyslipidemia (HT+DL) and hypertensives without dyslipidemia (HT-non DL) were compared; and b) an stepwise, multivariate, descriptive; multiple regression model was designed in order to explain compliance. RESULTS: 1. Compliance was 79% in DL-non HT, significantly lower than in HT+DL (81.2%, p=0.000) and in HT-non DL (82.4%, p=0.000). There were also statistically significant differences between these last two groups (p=0.001). 2. Explanatory variables of a better compliance in the multivariate analysis were: a) patient related factors: labour inactivity (p = 0.000); b) management related factors: specific doctor (p = 0.000) and intensity of follow-up (p = 0.04); and c) drug related factors: the drug group (p < 0.0001); the drug price (the higher price determines higher compliance, p = 0.006) and the number of active principles used (the higher number determines lower compliance, p = 0.019). CONCLUSIONS: 1. Dyslipidemic patients show a worse compliance than hypertensive patients, and dyslipidemia worsened global compliance in hypertensive patients. 2. Patient characteristics, doctor attitude, follow-up intensity, drug group and simplicity of treatment are related to compliance in daily medical practice.

Synthesis and characterization of 1,2-cyclohexanedione bis-benzoyl-hydrazone and its application to the determination of ti in minerals and rocks.

The synthesis, spectroscopic characteristics and analytical applications of 1,2-cyclo-hexanedione bis-benzoylhydrazone are reported. The reaction of this new compound with titanium(IV) has been studied spectrophotomelrically. An orange 1:2 metal/ligand complex (lambda(max)= 477 nm, = 1.05 x 10(4) l.mole(-1).cm(-1)) is formed at pH 1.75-3.0 in 3:2 v v ethanol-water medium. The method is simple and selective and has been satisfactorily applied to the determination of titanium in bauxite, Portland cement, amphibolites and granites.

Fluorimetric determination traces of aluminium in soil extracts.

Salicylaldehyde picolinoylhydrazone (SAPH) form a fluorescent complex with aluminium (lambda(ex) = 384 nm, lambda(em) = 468 nm) in acidic medium (stoichiometry 1:3, Al:SAPH). Two procedures based on the direct or standard additions methods has been proposed for the determination of concentrations down to 1-2 mug/dm(3) of Al(III). The effects of 72 ions in the method has been evaluated and different masking agent reactions have been tested. The method has been used satisfactorily for the determination of aluminium at a level of mug/dm(3) in acetate extracts of several agricultural soils. The method has been compared favourably with ICP spectroscopy emission.

Acrylic polymer-grafted polypropylene sutures for covalent immobilization or reversible adsorption of vancomycin.

Glycidyl methacrylate (GMA) and acrylic acid (AAc) were separately grafted onto polypropylene (PP) monofilament sutures by means of pre-irradiation using a (60)Co γ-source, with the purpose of loading vancomycin via (i) covalent immobilization through the glycidyl groups of GMA and (ii) ionic interaction with AAc moieties. The effect of absorbed radiation dose, monomer concentration, temperature and reaction time on the grafting degree was evaluated in detail. GMA grafting ranged from 25% to 800% while the grafting yield of AAc onto PP could be tuned between 9% and 454%, at doses from 5 to 50 kGy and a dose rate 13.7 kGy/h. Grafting of GMA or AAc decreased the decomposition temperature and made the sutures swellable to a certain extent. GMA grafting led to a continuous, smooth and thick coating, which was suitable for immobilization of up to 1.9 µg vancomycin per gram. The immobilized vancomycin enabled a reduction in the Staphylococcus aureus CFU adhered to the suture surface. On the other hand, dried AAc-functionalized sutures exhibited a rough and cracked surface which was responsible for a minor increase in the coefficient of friction. PP-g-AAc sutures exhibited pH-dependent swelling and remarkably high capability to host vancomycin (up to 109.9 mg/g), particularly those with an intermediate degree of grafting. Some AAc-functionalized sutures were shown able to inhibit bacterial growth after successive challenges with fresh lawns. Therefore, tuning the yield of grafting of GMA or AAc may enable the preparation of drug-suture combination products that retain or release, respectively, antimicrobial agents.

Cost-effectiveness of anidulafungin in confirmed candidaemia and other invasive Candida infections in Spain.

BACKGROUND: Candidaemia and invasive Candida infections can cause patient death and are expensive. Anidulafungin, a newly-licensed candin, has proven effective in treating candidaemia. Our study evaluates the cost-effectiveness of anidulafungin compared with fluconazole, the current standard of care, for treating invasive candidiasis and candidaemia in Spain. METHODS: A decision tree model from the hospital perspective was constructed to examine the cost-effectiveness of anidulafungin compared with fluconazole in treating confirmed candidaemia. Treatment success, patient treatment patterns, and patient survival were based on the results from a randomised, double-blind multicentre trial (Reboli et al., 2007 [41]). Only in-hospital (2011 €) direct costs per-patient obtained from a Spanish national database were considered. Renal toxicity probabilities and costs were extracted from the published literature. The incremental cost per successfully treated patient was calculated. One-way sensitivity analyses were performed to test model robustness. RESULTS: The percentage of successfully treated patients was higher with anidulafungin than with fluconazole (74% versus 57%). Treatment with anidulafungin resulted in higher antifungal drug costs (5991€ versus 3149€) but lower overall costs (40047€ versus 41350€) due to reductions in other medical costs. Univariate sensitivity analyses showed that anidulafungin was the most cost-effective. CONCLUSIONS: Anidulafungin demonstrated improved clinical efficacy versus fluconazole in treating confirmed candidaemia. Despite increased drug costs, treating confirmed candidaemia with anidulafungin is a cost-effective strategy.

[Cost analysis of 3 candins in the treatment of invasive candidiasis in adult non-neutropaenic patients in Spain]. / Análisis de costes de tres candinas en el tratamiento de la candidiasis invasora en pacientes adultos no neutropénicos en España.

OBJECTIVE: To estimate the cost of 3 candins (anidulafungin, caspofungin and micafungin) in the treatment of adult non-neutropaenic patients with invasive candidiasis (IC) in a Spanish hospital pharmacy setting. METHODS: The overall cost impact was evaluated by varying the percentage dosage required of each candin in different possible scenarios. The prices (in euros) for each presentation were obtained from the Drug Catalogue (in August 2010). Only drug purchase costs were considered. The results are expressed as total cost for each of the 3 candins. RESULTS: The cost per episode (14 days) of anidulafungin was constant at €5400 per patient. The cost of caspofungin varied from €4281 to €7991, depending on patient weight and liver dysfunction. The cost of micafungin varied from €6000 (100mg/day) to €9000 (when increasing the dose due to inadequate response). Based on a hypothetic cohort of 100 patients with IC, the total cost of anidulafungin treatment would be €540,000, for caspofungin it would be €631,459, and for micafungin it would be €632,998, depending on any dose adjustment required. CONCLUSION: Patients treated with anidulafungin did not require dose adjustment, unlike those treated with caspofungin or micafungin. The use of anidulafungin is a cost-saving treatment for adult non-neutropaenic patients with IC, which would result in better control of the Spanish pharmacy budget.

Solid phase extraction of copper traces using poly(styrene-divinylbenzene) membrane disks modified with pyridoxal salicyloylhydrazone in water samples.

A simple technique for the isolation, concentration and matrix simplification of Cu(II) ion in natural waters is proposed. This method has been developed using poly(styrene-divinylbenzene) membrane disks modified with the synthesized ligand pyridoxal salicyloylhydrazone (PSH). The retained ions on the disks were eluted with 10 mL 1 mol L(-1) HNO(3) and measured by flame atomic absorption spectrometry at 324.8 nm. The influence of pH, amount of ligand, type and amount of eluent for the stripping of copper ion from the membrane over extraction efficiency were evaluated. Extraction efficiencies >99% were obtained by elution of the disks with minimal amount of solvent with a preconcentration factor up to 100. The precision of the method for 10 replicate measurements of aqueous solutions containing 40 µg L(-1) Cu(II) was 1.5% at significance level of 95%. The breakthrough volume for 5 µg of Cu(II) was found to be 1000 mL and the detection limit of the method was 4 ng L(-1) of metal ion. The present method was successfully applied to the extraction and determination of copper in lake and sea waters.

Assessment of the metal pollution, potential toxicity and speciation of sediment from Algeciras Bay (South of Spain) using chemometric tools.

A study to determine total and mobile heavy metals concentrations in sediments from Algeciras Bay was performed and pollution hotspots were identified. The effects on aquatic organisms were established using sediment quality guidelines (SQGs). Ni and Cr exceeded the effect range medium and low levels, respectively, around industrial area. Potential toxicity of metals was determined by diethylenetriaminepenta-acetic acid (DTPA) extractions and low alert levels of Co, Cu, Zn, Cd, Ni and Pb were exceeded at most sampling sites. Three pollution indicators were used showing significant values for As, Ni, Cr, Pb and Cd. Sediment speciation using the sequential extraction BCR procedure was carried out, being Cd, Zn, Pb and As the most available metals. Principal component, cluster and ANOVA analyses were performed in order to assess the sources of metals and the influence of seasonality and anthropogenic activities on the sediment quality. Two principal component analysis (PCA) factors were obtained identifying the sampling sites affected by anthropogenic activities; Ni-Cr and Zn-Cu-V clusters were also obtained associated with stainless steel and petrochemical industrial activities. ANOVA showed the outstanding sites because of total metal concentration and significant differences among sampling sites by the acid extractable and reducible fractions for all metals except for Ba and V.

An efficient approach to designing and optimizing the analysis of Ni(II) by AdCSV in seawater.

A highly sensitive voltammetric method was developed for the determination of nickel in seawater at nanomolar concentrations. The measurement is based on the differential pulse cathodic adsorptive stripping of Ni(II) complexed with pyridoxal salicyloylhydrazone at a hanging mercury drop electrode. Optimal conditions were found following a two-step study strategy based on a Plackett Burman design and subsequently a modified simplex method. They were: deposition potential -0.8 V; deposition time 120 s; differential pulse scan mode; pulse amplitude -0.07 V; pulse time 0.04 s; voltage step 0.017 V; time interval for voltage step 0.05 s; supporting electrolyte ammonium chloride/ammonia (0.08 M, pH=8.9) and concentration of PSH 5.32 × 10(-6)M. The response of the system was found to be linear in a range of Ni concentrations from 0 to 306.7 × 10(-9)M. The detection limit was found to be 0.04 × 10(-9)M of Ni(II). The precision of the method was 1.4% for 3.4×10(-8)M of Ni(II) and 1.48% for the blank at a significance level of 95% (n=9). The method was free from interferences of inorganic salts and trace metals at usual concentrations in seawater. The application to seawater was demonstrated by analysis of CRM 505 and LGC 6016 certified reference estuarine water and real seawater samples from Tangier Bay (Morocco).

Sensitive adsorptive stripping voltammetric method for determination of lead in water using multivariate analysis for optimization.

A sensitive adsorptive cathodic stripping voltammetric (AdCSV) method is presented for direct determination of Pb(II) at nanomolar levels in water based on metal complexation with 2-acetylpyridine salicyloylhydrazone (2-APSH) and subsequent adsorptive deposition onto hanging mercury drop electrode (HMDE). The instrumental and chemical factors were optimized using exploratory (Plackett-Burman) and sequential (Simplex) designs. Under optimal conditions (pH 5.6, -0.552 V for deposition voltage, 0.0083 V for voltage step and 0.87 s for time interval for voltage step) a limit of detection of 0.17 nM was obtained and the relative standard deviation of five measurements of 17.3 nM was 1.20%. The voltammetric responses increased linearly with metal ion concentrations ranging from 2.4 to 145 nM. The method was free from interferences of inorganic salts and trace metals usually present in seawater. The proposed method was successfully validated using certified reference estuarine water (LGC 6016) with relative error of -2.15% and applied to real seawater samples (relative errors of -4.40% and +1.84%).

A permeation liquid membrane system for determination of nickel in seawater.

The use of a permeation liquid membrane system for the preconcentration and separation of nickel in natural and sea waters and subsequent determination by atomic absorption spectroscopy is presented. 2-Hydroxybenzaldehyde N-ethylthiosemi-carbazone (2-HBET) in toluene is used as the active component of the liquid membrane. A study strategy based on a simplex design has been followed. Several chemical and physical parameters were optimized. Maximum permeation coefficient was obtained at a feed solution pH of 9.4, 0.3mol l(-1) of HNO(3) in the stripping solution and 1.66mmol l(-1) of 2-HBTE in toluene as carrier. The precision of the method was 4.7% at 95% significance level and a detection limit of 0.012microg l(-1) of nickel was achieved. The preconcentration procedure showed a linear response within the studied concentration range from 3 to 500microg l(-1) of Ni in the feed solution. The method was validated with different spiked synthetic seawater and certified reference water samples: TMDA-62 and LGC 6016, without matrix interferences and showing good concordance with the certified values, being the relative errors -5.9% and -2.2%, respectively. Under optimal conditions, the average preconcentration yield for real seawater samples was 98+/-5%, with a nickel preconcentration factor of 20.83 and metal concentrations ranging between 2.8 and 5.4microg l(-1).

Applicability of a liquid membrane in enrichment and determination of nickel traces from natural waters.

In this work, a bulk liquid membrane method has been applied for Ni enrichment and separation from natural waters. The carrier-mediated transport was accomplished by pyridine-2-acetaldehyde benzoylhydrazone dissolved in toluene as a complexing agent. The preconcentration was achieved through pH control of source and receiving solutions via a counterflow of protons. The main variables were optimized by using a modified simplex technique. High transport efficiencies (101.2 +/- 1.8-99.7 +/- 4.2%) were provided by the carrier for nickel ions in a receiving phase of 0.31 mol L(-1) nitric acid after 9-13 h depending on sample salinity. The precision of the method was 2.05% (without a saline matrix) and 4.04% (with 40 g L(-1) NaCl) at the 95% confidence level and the detection limit of the blank was 0.015 mug L(-1) Ni for detection by atomic absorption spectroscopy. The applicability of the method was tested on certified reference and real water samples with successful results, even for saline samples. The relative errors were -0.60% for certified reference materials and ranged from -0.39 to 2.90% and from 0.3 to 11.05% for real samples, obtained by comparison of inductively coupled plasma mass spectrometry and adsorptive cathodic stripping voltammetry measurements, respectively.

Reverse flow-injection manifold for spectrofluorimetric determination of aluminum in drinking water.

A simple reverse flow-injection (rFIA) manifold for the direct determination of aluminum in drinking water is proposed. This rapid and sensitive method is based on the formation of an Al(3+) complex with salicylaldehyde picolinoylhydrazone (SAPH), which shows a maximum blue-green fluorescence (lambda(ex)=384 nm, lambda(em)= 468 nm) at pH 5.4. Operative conditions both for batch and rFIA procedures were investigated including reagent concentration, buffer solutions, injection loop, reacting coil and wavelengths used for the fluorimetric detection. The tolerance limits of foreign ions have been also evaluated, before and after the addition of masking agents. The reverse flow-injection procedure allows determination of Al(3+) at ppb level (LOD: 1.9 mug l(-1)) within a working range of 5-30 mug l(-1). The proposed method was successfully employed for the determination of Al(3+) in several commercial drinking, soft drinking (as certified reference material), and tap water samples.