Cost-Effectiveness of Combination Therapy for Patients With Systemic Sclerosis-Related Pulmonary Arterial Hypertension.

Background To evaluate the cost-effectiveness of combination pulmonary arterial hypertension specific therapy in systemic sclerosis-related PAH. Methods and Results Health outcomes and costs were captured through data linkage. Health utility was derived from Medical Outcomes Study Short Form-36 scores. A probabilistic discrete-time model was developed to simulate lifetime changes in costs and health utility. Mortality was predicted using a Gompertz parametric survival model. For both treatment arms, the simulations were started using the same cohort of 10 000 patients. Probabilistic sensitivity analysis was performed using the Monte Carlo simulation with 1000 sets of sampled parameter values. Of 143 patients with systemic sclerosis-related pulmonary arterial hypertension, 89 were on monotherapy and 54 on combination therapy. Mean simulated costs per patient per year in monotherapy and combination therapy groups were AU$23 411 (US$16 080) and AU$29 129 (US$19 982), respectively. Mean life years and quality-adjusted life years from pulmonary arterial hypertension diagnosis to death of patients receiving monotherapy were 7.1 and 3.0, respectively, and of those receiving combination therapy were 9.2 and 3.9, respectively. Incremental costs per life year and quality-adjusted life year gained of combination therapy compared with monotherapy were AU$47 989 (US$32 920) and AU$113 823 (US$78 082), respectively. At a willingness-to-pay threshold of AU$102 000 (US$69 972) per life year gained, and of AU$177 222 (US$121 574) per quality-adjusted life year gained, the probability of combination therapy being cost-effective was 0.95. Conclusions The incremental cost per quality-adjusted life year gained of combination therapy compared with monotherapy was substantial in the base case analysis. Given the fatal prognosis of systemic sclerosis-related pulmonary arterial hypertension and the incremental cost per life year of AU$47 989 (US$32 920), combination therapy could be considered cost-effective in systemic sclerosis-related pulmonary arterial hypertension.

A genetic algorithm-based framework for wavelength selection on sample categorization.

In forensic and pharmaceutical scenarios, the application of chemometrics and optimization techniques has unveiled common and peculiar features of seized medicine and drug samples, helping investigative forces to track illegal operations. This paper proposes a novel framework aimed at identifying relevant subsets of attenuated total reflectance Fourier transform infrared (ATR-FTIR) wavelengths for classifying samples into two classes, for example authentic or forged categories in case of medicines, or salt or base form in cocaine analysis. In the first step of the framework, the ATR-FTIR spectra were partitioned into equidistant intervals and the k-nearest neighbour (KNN) classification technique was applied to each interval to insert samples into proper classes. In the next step, selected intervals were refined through the genetic algorithm (GA) by identifying a limited number of wavelengths from the intervals previously selected aimed at maximizing classification accuracy. When applied to Cialis®, Viagra®, and cocaine ATR-FTIR datasets, the proposed method substantially decreased the number of wavelengths needed to categorize, and increased the classification accuracy. From a practical perspective, the proposed method provides investigative forces with valuable information towards monitoring illegal production of drugs and medicines. In addition, focusing on a reduced subset of wavelengths allows the development of portable devices capable of testing the authenticity of samples during police checking events, avoiding the need for later laboratorial analyses and reducing equipment expenses. Theoretically, the proposed GA-based approach yields more refined solutions than the current methods relying on interval approaches, which tend to insert irrelevant wavelengths in the retained intervals. Copyright © 2016 John Wiley & Sons, Ltd.

Development and validation of alternative methods by non-aqueous acid-base titration and derivative ultraviolet spectrophotometry for quantification of sildenafil in raw material and tablets

Sildenafil citrate (SILC) is a potent phosphodiesterase-5 inhibitor used for erectile dysfunction and pulmonary hypertension. This study shows two simple, fast and alternative analytical methods for SILC determination by non-aqueous titration and by derivative ultraviolet spectrophotometry (DUS) in active pharmaceutical ingredient and/or dosage forms. The quantitation method of SILC active pharmaceutical ingredient by non-aqueous acid-base titration was developed using methanol as solvent and 0.1 mol/L of perchloric acid in acetic acid as titrant. The endpoint was potentiometrically detected. The non-aqueous titration method shows satisfactory repeatability and intermediate precision (RSD 0.70-1.09%). The neutralization reaction occurred in the stoichiometric ratio 1:1 in methanol. The determination of SILC active pharmaceutical ingredient or dosage forms by DUS was developed in the linear range from 10 to 40 µg/mL, in 0.01 mol/L HCl, using the first order zero-peak method at λ 256 nm. The DUS method shows selectivity toward tablets excipients, appropriate linearity (R2 0.9996), trueness (recovery range 98.86-99.30%), repeatability and intermediate precision in three concentration levels (RSD 1.17-1.28%; 1.29-1.71%, respectively). Therefore, the methods developed are excellent alternatives to sophisticated instrumental methods and can be easily applied in any pharmaceutical laboratory routine due to simple and fast executions.

Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide.

Inhaled nitric oxide (iNO) is approved for use in persistent pulmonary hypertension of the newborn (PPHN) but does not lead to sustained improvement in oxygenation in one-third of patients with PPHN. Inhaled NO is less effective in the management of PPHN secondary to congenital diaphragmatic hernia (CDH), extreme prematurity, and bronchopulmonary dysplasia (BPD). Intravenous pulmonary vasodilators such as prostacyclin, alprostadil, sildenafil, and milrinone have been successfully used in PPHN resistant to iNO. Oral pulmonary vasodilators such as endothelin receptor antagonist bosentan and phosphodiesterase-5 inhibitors such as sildenafil and tadalafil are used both during acute and chronic phases of PPHN. In the absence of infection, glucocorticoids may also be effective in PPHN. Many of these pharmacologic agents are not approved for use in PPHN and our knowledge is based on case reports and small trials. Large multicenter randomized controlled trials with long-term follow-up are required to evaluate alternate pharmacologic strategies in PPHN.

HDL particle subpopulations: Focus on biological function.

Low levels of high-density lipoprotein-cholesterol (HDL-C) constitute an independent biomarker of cardiovascular morbi-mortality. However, recent advances have drastically modified the classical and limited view of HDL as a carrier of 'good cholesterol', and have revealed unexpected levels of complexity in the circulating HDL particle pool. HDL particles are indeed highly heterogeneous in structure, intravascular metabolism and biological activity. This review describes recent progress in our understanding of HDL subpopulations and their biological activities, and focuses on relationships between the structural, compositional and functional heterogeneity of HDL particles.

Comparative study of Puerariae lobatae and Puerariae thomsonii by HPLC-diode array detection-flow injection-chemiluminescence coupled with HPLC-electrospray ionization-MS.

An on-line HPLC-diode array detection-flow injection chemiluminescence (HPLC-DAD-FICL) method was applied to estimate the difference of Puerariae lobatae and Puerariae thomsonii. Their chemical and active profiles could be obtained by HPLC-DAD-FICL in one run. Seventeen compounds in two species were tentatively identified by HPLC-electrospray ionization-MS (HPLC-ESI-MS) method. The main antioxidants were rapidly screened by active fingerprints coupled with MS data. Similarity and Hierarchical clustering analysis (HCA) were used to distinguish different samples. The results suggested that the chemical fingerprints of 16 batches of samples were similar by similarity evaluation, while HCA could discriminate the two species. The active fingerprints of Puerariae lobatae and Puerariae thomsonii were significantly different. More antioxidants were found in Puerariae lobatae than in Puerariae thomsonii. Main antioxidants, including 3'-hydroxypuerarin, genistein 8-C-glycoside-xyloside, puerarin, 6″-O-xylosylpuerarin, mirificin and daidzein in two species, may be reasonable markers for the discrimination of the two species. The integrated fingerprint based on the chemical and active characteristics may provide an objective quality evaluation for Puerariae lobatae and Puerariae thomsonii.

Cross-sectional characterization of all classes of antihypertensives in terms of central blood pressure in Japanese hypertensive patients.

BACKGROUND: Central blood pressure (CBP) has been reported to be superior to brachial blood pressure (BP) as a cardiovascular risk predictor in hypertensive patients; however, the effects of antihypertensives on CBP have not been fully examined. This cross-sectional hypothesis-generating study aimed to tentatively characterize all classes of antihypertensives in relation to CBP. METHODS: Calibrated tonometric radial artery pressure waveforms were recorded using an automated device in 1,727 treated hypertensive patients and 848 nonhypertensive (non-HT) participants. Radial artery late systolic BP (SBP) has been reported to reflect central SBP. The difference between late and peak SBPs (DeltaSBP2) was assessed with linear regression model-based adjustments. Separate regression models for DeltaSBP2 were constructed for both participant groups as well as specified sub-populations. RESULTS: DeltaSBP2 was 3.3 mm Hg lower in patients treated with any single-vasodilating (VD) antihypertensive agent without significant interclass difference than with non-VD agents, and was 2.0 mm Hg lower than estimated in nonhypertensive subjects. Combinations of two vasodilators were 6.6 and 2.9 mm Hg lower in DeltaSBP2 than nonvasodilator combinations and nonhypertensive subjects, respectively (P < 0.001 for all comparisons). Nonvasodilators and their combination showed high DeltaSBP2, 1.1 and 3.7 mm Hg higher than in nonhypertensive subjects (P < 0.001 for both). Additional adjustment of the pulse rate reduced high DeltaSBP2 with beta-blockers (betaBLs). CONCLUSIONS: This cross-sectional observation suggests that vasodilatory antihypertensives lower CBP independently of peripheral BP levels without evident class-specific differences, whereas nonvasodilators may raise CBP.

Vasodilator effects of red wines in subcutaneous small resistance artery of patients with essential hypertension.

BACKGROUND: It has been suggested that in animal models, red wine may have a protective effect on the vascular endothelium. However, it is not known whether this effect is also present in human small vessels and whether it is specific for certain wines. The objective of this study is to compare the vasodilator effects in subcutaneous small resistance arteries of wines with different flavonoid content as well as of ethanol vs. wines in normotensive (NT) subjects and in patients with essential hypertension (EH). METHODS: Twenty-six EH and 27 NT were included in the study. Subcutaneous small resistance arteries were dissected and mounted on a micromyograph. Then we evaluated vasodilator responses as concentration-response curves (20, 30, and 50 microl) to the following items: (i) a red wine produced in small oak barrels ("en barrique": EB) (Barolo Oberto 1994), (ii) a red wine produced in large wood barrels (LB) (Barolo Scarzello 1989), (iii) a red wine produced in steel tanks (Albarello Rosso del Salento 1997), and (iv) a white wine produced in steel tanks in the presence or absence of an inhibitor of the nitric oxide (NO) synthase (L-NMMA 100 micromol/l). RESULTS: A dose-dependent vasodilator effect of red wines (particularly EB and LB) was detected in both NT and HT. The observed response was not reduced after preincubation with L-NMMA. CONCLUSIONS: Our results suggest red wines are more potent vasodilator than ethanol alone, possibly depending on the content of polyphenols or tannic acid. HT show similar responses compared with NT, indicating that red wine is not harmful in this population.

Design, synthesis, and biological evaluation of prenylated chalcones as vasorelaxant agents.

Five prenylated chalcones and one allylated chalcone were prepared according to the analysis based on support vector machine (SVM) classification model. Most of the synthesized chalcones showed potent vasorelaxant activities through evaluation in aortic rings with the endothelium pre-contracted by phenylephrine (PE), indicating that the experimental activities were in good agreement with the theoretical ones. Structure-activity relationship of these compounds showed that the substituent pattern and number of hydroxyl groups were crucial for their vasorelaxant activities and that the replacement of prenyl group with allyl group retained the potent activity.

[Third generation beta-blockers: current state of research on vasodilating beta-blockers]. / Betablocker der 3. Generation: Stand der Forschung zu den Betablockern mit vasodilatierenden Zusatzeigenschaften.

Nebivolol (Nomexor) is a third generation, vasodilating beta-blocker with a high beta(1)-adrenoceptor selectivity. Nebivolol acts as an agonist at the beta(3) adrenoceptor as well as the estrogen receptor thereby releasing nitric oxide in blood vessels via eNOS. Pleiotropic effects of nebivolol furthermore include a positive influence on cholesterol and triglycerides and a decrease in thrombocyte activity. Nebivolol is recommended in the guidelines of the European cardiac society (ESC) for patients with metabolic syndrome. Nebivolol's main properties in combination with its broad range of beneficial pleiotropic effects allow it to be clearly distinguished from other second and third generation beta-blockers.

Methyl (11aS)-1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo-[3',4':1,2]pyridin[3,4-b]indol-2-substituted acetates: synthesis and three-dimensional quantitative structure-activity relationship investigation as a class of novel vasodilators.

To find selective inhibitor of phosphodiesterase type 5 (PDE5), the essential structure elements of clinically used drugs sildenafil, vardenafil, and tadalafil were combined and a tetracyclic parent was constructed to which in 2-positions substituted acetic acid methylesters were introduced to form 17 novel vasodilators, methyl (11aS)-1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3',4':1,2]- pyridin[3,4-b]indol-2-substituted acetates. By molecular field analysis (MFA), an equation of three-dimensional quantitative structure-activity relationship (3D QSAR) was established, which not only revealed the dependence of the in vitro vasorelaxation activities on the structures but also pointed out the way to design new lead compounds properly. Docking these novel vasodilators into the hydrophobic pocket of phosphodiesterase type 5 (PDE5) revealed that their adaptabilities to this pocket did significantly affect on their vasorelaxation activity. Actually, the docking adaptabilities of these novel vasodilators to PDE5 were consistent with the conformational requirements of them to MFA and with the crystal conformation of two representatives.

Prostacyclin therapies for the treatment of pulmonary arterial hypertension.

Prostacyclin and its analogues (prostanoids) are potent vasodilators and possess antithrombotic, antiproliferative and anti-inflammatory properties. Pulmonary hypertension (PH) is associated with vasoconstriction, thrombosis and proliferation, and the lack of endogenous prostacyclin may considerably contribute to this condition. This supports a strong rationale for prostanoid use as therapy for this disease. The first experiences of prostanoid therapy in PH patients were published in 1980. Epoprostenol, a synthetic analogue of prostacyclin, and the chemically stable analogues iloprost, beraprost and treprostinil were tested in randomised controlled trials. The biological actions are mainly mediated by activation of specific receptors of the target cells; however, new data suggest effects on additional intracellular pathways. In the USA and some European countries, intravenous infusion of epoprostenol and treprostinil, as well as subcutaneous infusion of treprostinil and inhalation of iloprost, have been approved for therapy of pulmonary arterial hypertension. Iloprost infusion and beraprost tablets have been approved in few other countries. Ongoing clinical studies investigate oral treprostinil, inhaled treprostinil and the combination of inhaled iloprost and sildenafil in pulmonary arterial hypertension. Combination of other targeted therapies with prostanoids appears to be effective and safe. After 25 yrs of continued knowledge, prostanoids remain a mainstay in the treatment of pulmonary arterial hypertension.

Searching for new NO-donor aspirin-like molecules: a new class of nitrooxy-acyl derivatives of salicylic acid.

A new class of products in which the phenol group of salicylic acid is linked to alkanoyl moieties bearing nitrooxy functions has been synthesized and studied for their polyvalent actions. The products were stable in acid and neutral media, while they were hydrolyzed in human serum. Their half-lives were dependent upon the structure of alkanoyl moieties. The products showed anti-inflammatory activities similar to aspirin when tested in the carrageenan-induced paw edema assay in the rat. Interestingly, unlike aspirin, they showed reduced or no gastrotoxicity in a lesion model in rats at equimolar doses. A number of them were able to inhibit platelet aggregation induced by collagen in human platelet-rich plasma. All of the products were capable of relaxing rat aortic strips precontracted with phenylephrine in a concentration-dependent manner. Selected members of this new class of nonsteroidal anti-inflammatory drugs might represent possible safer alternatives to aspirin in different clinical settings.

Pulmonary vasodilators.

Pulmonary vasodilators are an important treatment for pulmonary arterial hypertension. They reduce pulmonary artery pressure; improve hemodynamic function; alter ventilation/perfusion matching in the lungs; and improve functional quality of life, exercise tolerance, and survival in patients with severe pulmonary arterial hypertension. This paper reviews the currently available pulmonary vasodilators and those under development, many of which can be administered via inhalation. I will also give an overview of the clinical pharmacology of, the indications for, and the evidence supporting pulmonary vasodilators, their delivery via inhalation, and potential toxic and adverse effects.

Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution.

BACKGROUND: Veno-active drugs (VAD) have effects on edema and symptoms related to chronic venous disease (CVD), especially so-called venous pain. VAD's effectiveness, although well established, is regularly debated. OBJECTIVE: Our purpose was to select all randomized controlled trials (RCTs) and meta-analyses devoted to VAD and symptoms in CVD, to submit them to a group of international experts in CVD and to vote with secrete ballot to determine the level of efficacy of each drug, according to EBM (Evidence-Based Medicine) rules and critical analysis. METHODS: Publications in any language devoted to VAD and venous symptoms were searched for in different databanks and submitted to the experts prior to the meeting. RESULTS: 83 papers were analyzed, including 72 RCTs or meta-analyses. Experts determined the level of EBM of each drug, according to the literature and personal experience, using 3 levels of recommendation, A, B and C (from large RCTs to non-randomized trials). CONCLUSIONS: VAD are effective and may be applied in CVD when symptomatic, from C0s to C6s. However, etiological treatment of venous reflux and venous hypertension has always priority. In some cases VAD may replace compression and/or complement its effects. If respecting these prerequisites, VAD are safe and effective.

The therapeutic dilemma: how to use tadalafil.

Tadalafil, a type 5 phosphodiesterase inhibitor, is a new and effective therapy for erectile dysfunction. It has unique pharmacokinetic properties in its drug class, which also includes sildenafil and vardenafil. It is also well tolerated with few side-effects, and can be used in difficult patients such as neuropaths or diabetics.