A real-world evidence study evaluating Geffer effervescent granules for the symptomatic relief of digestive symptoms.

Objectives: Geffer effervescent granules (active ingredients: metoclopramide, dimethicone, and sodium bicarbonate) is an established over-the-counter medication available in Italy for the symptomatic treatment of hyperacidity (pain and/or heartburn) when accompanied by slowing of gastric transit, nausea, aerophagia, and bloating, all symptoms that can occur in functional dyspepsia and can negatively impact individuals' quality of life. The aim of this observational study was to explore the perceived benefits of, and consumer experience with, Geffer effervescent granules used for the symptomatic treatment of digestive disorders suggestive of functional dyspepsia under real-life conditions in Italy. Methods: Adults (aged 35-65 years) experiencing symptoms suggestive of functional dyspepsia/indigestion at least once a month and who had used Geffer effervescent granules within the previous 6 months completed an online questionnaire eliciting information on symptom relief (speed of onset and duration) and quality of life. Results: Geffer effervescent granules provided rapid onset of symptom relief, with 21% of respondents perceiving an effect within 10 min and 88% reporting an improvement in overall symptoms within 30 min. A similarly rapid onset of complete resolution of gastric pain/cramps, acidity, bloating, nausea, and bothersome fullness symptoms was reported by 65%-83% of respondents; 50%-59% of respondents were free from such symptoms for more than 3 h or until the next meal. Most participants (92%) reported that their quality of life improved when taking Geffer effervescent granules to treat hyperacidity symptoms. Overall, 95% of the respondents were satisfied with the effectiveness of Geffer effervescent granules on overall symptom relief. Conclusions: In Italian consumers with digestive disorders likely due to functional dyspepsia, Geffer effervescent granules was associated with rapid, complete, and durable relief of symptoms of gastric pain/cramps, acidity, bloating, nausea, and bothersome fullness; an improvement in quality of life; and a high level of consumer satisfaction.

Dissolution rates of over-the-counter painkillers: a comparison among formulations.

BACKGROUND: We wanted to compare the dissolution profile of several over-the-counter analgesics to understand whether the different formulation techniques employed to enhance absorption were associated with variations in the dissolution rate, a parameter known to affect drug absorption. METHODS: We considered 5 formulations currently marketed in Italy: aspirin tablets (Aspirina Dolore e Infiammazione®), ibuprofen tablets and liquid capsules (Moment®), ibuprofen lysine tablets (Nurofenimmedia®) and dexketoprofen trometamol tablets (Enantyum®). Dissolution tests were performed according to the current USP/NF monograph dissolution procedure. Drug dissolution was evaluated at 1, 3, 6, 15, and 30 minutes since the start of the test. Dissolution was evaluated at three different pH: 1.2, 4.5 and 6.8. Every test was repeated 12 times. RESULTS: The aspirin formulation was by far the most rapid dissolving formulation, among those tested, with more than 80% of the tablet dissolved at 6 minutes for every pH considered. At pH 1.2 and 4.5, only the dexketoprofen formulation was able to reach the dissolution level of aspirin at 30 minutes, but had lower levels of dissolution at the previous time points. Instead, at pH 6.8, most of the formulations approached aspirin dissolution level, but only after 15 minutes. Ibuprofen capsules had the slowest kinetics, with a lag phase the first 6 minutes. CONCLUSIONS: Different formulation strategies can lead to great differences in the dissolution rates even among drugs of the same class, suggesting that enhancements in the formulation of painkillers can lead to improvements in drug absorption, and thus in the onset of analgesia.

Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension.

AIMS: Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. METHODS AND RESULTS: PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca(2+) was increased and Ca(2+) release was facilitated. K(+) currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca(2+) content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. CONCLUSION: PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.

Effect of a mixture of calcium, vitamin D, inulin and soy isoflavones on bone metabolism in post-menopausal women: a retrospective analysis.

OBJECTIVES: Aging might affect the effectiveness of the sole supplementation of calcium and vitamin D in post-menopausal women, due to the development of vitamin D resistance in the gut, which limits calcium absorption. Thus, we wanted to test the efficacy of a mixture of calcium (500 mg), 25-hydroxyvitamin D [25(OH)D; 300 IU], inulin (3 g) and soy isoflavones (40 mg), to improve calcium absorption in this type of population. STUDY DESIGN: It is a retrospective study on otherwise healthy post-menopausal women. MAIN OUTCOME MEASURES: The following parameters were evaluated at baseline and after 3 months of supplementation: daily calciuria as an indirect marker of calcium absorption, serum 25(OH)D, parathormone, insulin-like growth factor 1 (IGF1) as a marker of bone anabolism, collagen telopeptide and osteocalcin as markers of bone resorption and bone turnover, respectively. RESULTS: Twenty-eight women (median age 67 years) were included in the analysis. The supplementation markedly increased daily calciuria (+60 %; p = 0.00009), while reducing parathormone levels (-18 %; p = 0.02) and leaving 25(OH)D unaltered. An increase in IGF1 (+16 %; p = 0.01) and a reduction in collagen telopeptide (-17 %; p = 0.04) were observed, too, as well as a modest trend towards osteocalcin reduction, although not significant. CONCLUSIONS: These results suggest that the considered mixture improved intestinal calcium absorption and bone metabolism in post-menopausal women. Since the amount of supplemented calcium was relatively low and 25(OH)D levels were unchanged, the observed effects are likely due to the combined contributions of inulin and soy isoflavones.

The management of erectile dysfunction: innovations and future perspectives.

Phosphodiesterase 5 (PDE5) inhibitors are recommended as first line therapy for the treatment of erectile dysfunction (ED). To date, three PDE5 inhibitors are on the market: sildenafil, vardenafil and tadalafil. These compounds are available as oral tablets; they are rapidly absorbed in the gastrointestinal tract and are excreted mainly in the fces and to a lexer extent in the urine. Recently, an orodisnersible formulation of feces and, to a lesser extent, in the urine. Recently, an orodispersible formulation of vardenafil (vardenafil ODT) has been developed, which is able to dissolve in the mouth within seconds, releasing a minty flavor, without the need of being swallowed with water. The clinical studies so far performed showed that vardenafil ODT has a bioavailability superior to the traditional film-coated tablet. Among the other PDE5 inhibitors under development we report mirodenafil, lodenafil carbonate, avalafil and SLx-2101 It is likely that in the future molecules that act on pathways other than the one of NO/cGMP will be available. Such as Rho-kinase inhibitors, which inhibit the mechanism that leads to smooth muscle contraction thus allowing erection and hydrogen sulphide (H2S), an endogenous molecule synthesized from cysteine that can be both a vasodilator and a vasoconstrictor according to its concentration.

Role and mechanism of subcellular Ca2+ distribution in the action of two inotropic agents with different toxicity.

Pro-arrhythmic risk strongly limits the therapeutic value of current inotropic interventions. Istaroxime (previously PST2744) is a novel inotropic agent, significantly less pro-arrhythmic than digoxin that, in addition to block Na(+)/K(+) pump, stimulates sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2). Here we compare istaroxime and digoxin effects to further address the role of SR modulation in reducing the toxicity associated with Na(+)/K(+) pump blockade. In murine ventricular myocytes both compounds increased cell twitch (inotropy) in a concentration-dependent fashion. At high concentrations digoxin, but not istaroxime, induced unstimulated contractions, a sign of pro-arrhythmic toxicity. To evaluate the mechanism of this difference, we compared the two drugs at concentrations exerting equal inotropy but different toxicity. At these concentrations: (1) the two drugs equally inhibited the Na(+)/K(+) pump; (2) digoxin induced larger increases in resting Ca(2+) and in diastolic Ca(2+) during pacing; (3) neither drug affected the relationship between RyR-mediated SR Ca(2+) leak and Ca(2+) content; (4) istaroxime, but not digoxin, enhanced SR Ca(2+) reuptake rate. In conclusion, digoxin toxicity was associated to larger accumulation of cytosolic Ca(2+), which did not result from RyR facilitation, but which might ultimately induce it to promote unstimulated Ca(2+) release. The lower toxicity of Na(+)/K(+) pump blockade by istaroxime may thus reflect improved Ca(2+) confinement within the SR, likely to result from concomitant SERCA2 stimulation.

Celecoxib blocks cardiac Kv1.5, Kv4.3 and Kv7.1 (KCNQ1) channels: effects on cardiac action potentials.

Celecoxib is a COX-2 inhibitor that has been related to an increased cardiovascular risk and that exerts several actions on different targets. The aim of this study was to analyze the effects of this drug on human cardiac voltage-gated potassium channels (Kv) involved on cardiac repolarization Kv1.5 (I(Kur)), Kv4.3+KChIP2 (I(to1)) and Kv7.1+KCNE1 (I(Ks)) and to compare with another COX-2 inhibitor, rofecoxib. Currents were recorded in transfected mammalian cells by whole-cell patch-clamp. Celecoxib blocked all the Kv channels analyzed and rofecoxib was always less potent, except on Kv4.3+KChIP2 channels. Kv1.5 block increased in the voltage range of channel activation, decreasing at potentials positive to 0 mV. The drug modified the activation curve of the channels that became biphasic. Block was frequency-dependent, increasing at fastest frequencies. Celecoxib effects were not altered by TEA(out) in R487Y mutant Kv1.5 channels but the kinetics of block were slower and the degree of block was smaller with TEA(in), indicating that celecoxib acts from the cytosolic side. We confirmed the blocking properties of celecoxib on native Kv currents from rat vascular cells, where Kv1.5 are the main contributors (IC(50)≈ 7 µM). Finally, we demonstrate that celecoxib prolongs the action potential duration in mouse cardiac myocytes and shortens it in guinea pig cardiac myocytes, suggesting that Kv block induced by celecoxib may be of clinical relevance.

Modulation of sarcoplasmic reticulum function by PST2744 [istaroxime; (E,Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione hydrochloride)] in a pressure-overload heart failure model.

PST2744 [Istaroxime; (E,Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione hydrochloride)] is a novel inotropic agent that enhances sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) 2 activity. We investigated the istaroxime effect on Ca(2+) handling abnormalities in myocardial hypertrophy/failure (HF). Guinea pig myocytes were studied 12 weeks after aortic banding (AoB) and compared with those of sham-operated animals (sham). The gain of calcium-induced Ca(2+) release (CICR), sarcoplasmic reticulum (SR) Ca(2+) content, Na(+)/Ca(2+) exchanger (NCX) function, and the rate of SR reloading after caffeine-induced depletion (SR Ca(2+) uptake, measured during NCX blockade) were evaluated by measurement of cytosolic Ca(2+) and membrane currents. HF characterization: AoB caused hypertrophy and failure in 100 and 25% of animals, respectively. Although CICR gain during constant pacing was preserved, SR Ca(2+) content and SR Ca(2+) uptake were strongly depressed. Resting Ca(2+) and the slope of the Na(+)/Ca(2+) exchanger current (I(NCX))/Ca(2+) relationship were unchanged by AoB. Istaroxime effects: CICR gain, SR Ca(2+) content, and SR Ca(2+) uptake rate were increased by istaroxime in sham myocytes and, to a significantly larger extent, in AoB myocytes; this led to almost complete recovery of SR Ca(2+) uptake in AoB myocytes. Istaroxime increased resting Ca(2+) and the slope of the I(NCX)/Ca(2+) relationship similarly in sham and AoB myocytes. Istaroxime failed to increase SERCA activity in skeletal muscle microsomes devoid of phospholamban. Thus, clear-cut abnormalities in Ca(2+) handling occurred in this model of hypertrophy, with mild decompensation. Istaroxime enhanced SR function more in HF myocytes than in normal ones; almost complete drug-induced recovery suggests a purely functional nature of SR dysfunction in this HF model.