Efficacy and safety of a new low-volume PEG with citrate and simethicone bowel preparation for pediatric elective colonoscopy: Phase 3 RCT.

Background and study aims Currently available polyethylene glycol (PEG)-based preparations continue to represent a challenge in children. The aim of this study was to compare the efficacy and safety of a new low-volume PEG preparation with a conventional PEG-electrolyte solution (PEG-ES) in children and adolescents. Patients and methods This was a multicenter, randomized, observer-blind, parallel-group, phase 3 clinical trial, where patients were randomized between PMF104 (Clensia) and a conventional PEG-ES (Klean-Prep), and stratified by age stratum (2 to <6; 6 to < 12;12 to <18 years). The primary endpoint was to test the non-inferiority of PMF104 versus PEG-ES, in terms of colon cleansing. Safety, tolerability, acceptability, palatability, and compliance were also assessed. Efficacy endpoints were analyzed in the per protocol set (PPS) and full analysis set (FAS) and safety and tolerability endpoints in the safety set (SAF). Results Of the 356 patients enrolled, 258 were included in the PPS, 346 in the FAS, and 351 in the SAF. Non-inferiority of PMF104 was confirmed for children aged > 6 years and for all age groups in PPS and FAS, respectively. Optimal compliance was reported more frequently in the PMF104 than in the PEG-ES group, in both PPS (86.1% vs. 68.4%) and FAS (82.9% vs. 65.3%). Both preparations were equally safe and tolerable. Palatability and acceptability were considered better in the PMF104 group than in the PEG-ES group (27.1% vs. 15.3% and 15.3% vs. 3.5%, respectively). Conclusions In children aged 6 to 17 years, the new low-volume product PMF104 is non-inferior to the reference PEG-ES in terms of bowel cleansing, safety, and tolerability, with slightly better results in compliance, palatability, and acceptability.

A randomized, double-blind, placebo-controlled, phase 2b study of the efficacy and safety of velusetrag in subjects with diabetic or idiopathic gastroparesis.

BACKGROUND: This study assessed the efficacy and safety of velusetrag-a 5-HT4 agonist with pan-gastrointestinal prokinetic activity-for gastroparesis symptom management and gastric emptying (GE). METHODS: In this multicenter, double-blind, randomized, placebo-controlled study, subjects with diabetic or idiopathic gastroparesis received velusetrag 5, 15, or 30 mg or placebo for 12 weeks. The primary efficacy outcome was a 7-day mean Gastroparesis Cardinal Symptom Index 24-h composite score (GCSI-24H) change from baseline at week 4; GE was evaluated using scintigraphy (GES) and breath tests, and safety from adverse events (AEs). KEY RESULTS: 232 subjects (183 females; 113 idiopathic gastroparesis) received treatment from February 2015 through June 2017. Least-squares mean improvement from baseline GCSI-24H (primary endpoint) at week 4 was -1.5 following velusetrag 5 mg vs -1.1 following placebo (treatment difference, -0.4; 95% confidence interval, -0.75 to -0.03; nominal p = 0.0327; Hochberg-adjusted p = 0.0980 [not significant]). Symptom improvement from baseline was achieved only with velusetrag 5 mg, which resulted in greater improvement from baseline vs placebo in all gastroparesis core symptoms, especially in subjects with idiopathic gastroparesis. Improvement from baseline GE by GES was greater in subjects receiving velusetrag (all doses) vs placebo; >70% of subjects receiving velusetrag 30 mg had GE normalization at 4 h. Treatment-emergent AEs were generally mild. CONCLUSIONS AND INFERENCES: Velusetrag treatment was generally well-tolerated and associated with improved GE vs placebo in subjects with diabetic or idiopathic gastroparesis; however, only the lowest dose, velusetrag 5 mg, was associated with short-term improvement in gastroparesis symptoms. CLINICALTRIALS: GOV: NCT02267525.

A multicenter, double-blind, randomized, placebo-controlled study of rifaximin for the treatment of bacterial vaginosis.

OBJECTIVE: To compare efficacy and tolerability between different regimens of rifaximin vaginal tablets and a placebo for treatment of bacterial vaginosis. METHODS: In a prospective study carried out at 13 sites in 3 European countries between August 2009 and October 2010, White, non-pregnant, premenopausal women with bacterial vaginosis were randomly assigned to receive rifaximin at 100mg for 5 days (100mg/5 days), 25mg/5 days, or 100mg/2 days, or placebo. Women were assessed at 7-10 and 28-35 days. Diagnosis and cure were based on Amsel criteria and Nugent score. Fisher exact test was used to compare cure rates. RESULTS: Among 114 women recruited, 103 were evaluable for drug efficacy. Therapeutic cure rate at first follow-up was higher in the rifaximin 25mg/5 days (48%, P=0.04), 100mg/2 days (36.0%), and 100mg/5 days (25.9%) groups than in the placebo group (19.0%). At second follow-up, therapeutic cure rate was 28.0%, 14.8%, and 4.0% in the respective groups versus 7.7% in the placebo group. No difference in adverse events was observed. CONCLUSION: Rifaximin at 25mg/5 days showed better therapeutic cure rates and maintenance of therapeutic cure after 1 month versus placebo. All treatment regimens were well tolerated. EudraCT number: 2009-011826-32.

Efficacy of rifaximin vaginal tablets in treatment of bacterial vaginosis: a molecular characterization of the vaginal microbiota.

Bacterial vaginosis (BV) is a common vaginal disorder characterized by an alteration of the vaginal bacterial morphotypes, associated with sexually transmitted infections and adverse pregnancy outcomes. The purpose of the present study was to evaluate the impact of different doses of rifaximin vaginal tablets (100 mg/day for 5 days, 25 mg/day for 5 days, and 100 mg/day for 2 days) on the vaginal microbiota of 102 European patients with BV enrolled in a multicenter, double-blind, randomized, placebo-controlled study. An integrated molecular approach based on quantitative PCR (qPCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) was used to investigate the effects of vaginal tablets containing the antibiotic. An increase in members of the genus Lactobacillus and a decrease in the BV-related bacterial groups after the antibiotic treatment were demonstrated by qPCR. PCR-DGGE profiles confirmed the capability of rifaximin to modulate the composition of the vaginal microbial communities and to reduce their complexity. This molecular analysis supported the clinical observation that rifaximin at 25 mg/day for 5 days represents an effective treatment to be used in future pivotal studies for the treatment of BV.

A randomised, two-period, cross-over, open-label study to evaluate the pharmacokinetic profiles of single doses of two different flurbiprofen 8.75-mg lozenges in healthy volunteers.

AIMS: To compare the bioavailability of a new oromucosal formulation of flurbiprofen 8.75-mg lozenges, developed by Alfa Wassermann S.p.A. (test drug) to that of marketed flurbiprofen 8.75-mg lozenges (Benactiv Gola®, reference drug). METHODS: This was an open, randomised, two-period, crossover, pharmacokinetic (PK) study in which flurbiprofen plasma levels were compared in 12 healthy volunteers after the administration of single doses (8.75 mg × 2) of two different oromucosal lozenges to be sucked and slowly dissolved in the mouth. A wash-out period of at least 7 days separated the two study periods. Blood samples were collected prior to dosing and at predefined intervals for 24 h after dose. Flurbiprofen plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. PK parameters maximum plasma concentration (C(max)), time to maximum plasma concentration (T(max)), area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-t)), area under the plasma concentration-time curve from time zero to infinity (AUC(0-)∞) and half-life were calculated and compared by analysis of variance using treatment, period and sequence as sources of variation. Bioequivalence between the two formulations was based on 90% confidence intervals of the ratio of the geometric means of C(max) and AUC falling within the 0.80-1.25 range as defined in bioequivalence guidelines by regulators. Tolerability of the two formulations was assessed by adverse event monitoring, routine laboratory tests, physical examination, electrocardiographic tracing and vital sign measurements. RESULTS: All enrolled subjects completed the study. Bioequivalence without significant treatment effect was demonstrated between the test drug/reference drug ratios of mean C(max) and AUCs. Moreover, mean T(max) was superimposable. No safety parameter presented a clinically relevant variation after administration of either formulation that were therefore well tolerated. CONCLUSION: The new formulation of flurbiprofen 8.75-mg compressed lozenges developed by Alfa Wassermann S.p.A. is bioequivalent to the reference product flurbiprofen 8.75-mg lozenges (Benactiv Gola) in healthy volunteers.

Nanoparticles as drug delivery agents specific for CNS: in vivo biodistribution.

The pharmacological treatment of neurological disorders is often complicated by the inability of drugs to pass the blood-brain barrier. Recently we discovered that polymeric nanoparticles (NPs) made of poly(D,L-lactide-co-glycolide), surface-decorated with the peptide Gly-L-Phe-D-Thr-Gly-L-Phe-L-Leu-L-Ser(O-beta-D-glucose)-CONH2 are able to deliver, after intravenous administration, the model drug loperamide into the central nervous system (CNS). This new drug delivery agent is able to ensure a strong and long-lasting pharmacological effect, far greater than that previously observed with other nanoparticulate carriers. Here we confirmed the effectiveness of this carrier for brain targeting, comparing the effect obtained by the administration of loperamide-loaded NPs with the effect of an intracerebroventricular administration of the drug; moreover, the biodistribution of these NPs showed a localization into the CNS in a quantity about two orders of magnitude greater than that found with the other known NP drug carriers. Thus, a new kind of NPs that target the CNS with very high specificity was discovered. FROM THE CLINICAL EDITOR: This paper discusses a nanoparticle-based technique of targeted drug delivery through the blood-brain barrier. The biodistribution of these novel nanoparticles showed two orders of magnitude greater efficiency compared to other known NP drug carriers.

How children and parents evaluate the Headache Centre's intervention.

BACKGROUND: While adult headache patients' satisfaction with treatments has been widely investigated, less attention has been paid to children and adolescent headache patients' opinions and their parents' views. OBJECTIVE: The aim of our follow-up survey was to analyze the outcomes of the Headache Centre's intervention and the evolution of headache according to patients until the age of 16 and their parents. METHODS: We studied all outpatients suffering from episodic primary headache according to International Classification of Headache Disorders 2nd edition criteria, seen for the first time in 2005-2006 at the Headache Centre of the University Hospital of Modena (Italy), and at least one of their parents. The duration of the follow-up ranged from 1 to 3 years. For the purpose of the study, a specific questionnaire was created and administered by a telephone interview. RESULTS: We enrolled 84 patients (38 females, 45%; 46 males, 55%; mean age +/- SD: 12.9 +/- 2.9 years) with primary headache: migraine without aura 66%, episodic tension-type headache 23%, migraine with aura 11%. At the follow-up, 70% of the patients reported that headache had improved; frequency had decreased significantly more than severity (P = .000, Fisher's exact test), both in those who had followed a prophylactic treatment and in those who had not. A high percentage of the children and parents could precisely indicate trigger factors for headache: especially excessive worrying and studying. The patients reporting an improvement attributed it to pharmacological prophylactic treatment, but also to other factors: first of all, better school results and more happiness than before. Seventy-seven percent of the parents thought that the Headache Centre's intervention had helped them to better understand and manage their children's headache. CONCLUSIONS: Children's and adolescents' headache has in most cases a favorable prognosis; the Headache Centre's intervention is considered effective by most parents. We must increase and focus therapeutic efforts addressed to the few patients with worsening headaches in spite of treatment, since these children's/adolescents' headache also is at risk to progress in the adult age.

Brain effects of melanocortins.

The melanocortins (alpha, beta and gamma-melanocyte-stimulating hormones: MSHs; adrenocorticotrophic hormone: ACTH), a family of pro-opiomelanocortin (POMC)-derived peptides having in common the tetrapeptide sequence His-Phe-Arg-Trp, have progressively revealed an incredibly wide range of extra-hormonal effects, so to become one of the most promising source of innovative drugs for many, important and widespread pathological conditions. The discovery of their effects on some brain functions, independently made by William Ferrari and David De Wied about half a century ago, led to the formulation of the term "neuropeptide" at a time when no demonstration of the actual production of peptide molecules by neurons, in the brain, was still available, and there were no receptors characterized for these molecules. In the course of the subsequent decades it came out that melanocortins, besides inducing one of the most complex and bizarre behavioural syndromes (excessive grooming, crises of stretchings and yawnings, repeated episodes of spontaneous penile erection and ejaculation, increased sexual receptivity), play a key role in functions of fundamental physiological importance as well as impressive therapeutic effects in different pathological conditions. If serendipity had been an important determinant in the discovery of the above-mentioned first-noticed extra-hormonal effects of melanocortins, many of the subsequent discoveries in the pharmacology of these peptides (feeding inhibition, shock reversal, role in opiate tolerance/withdrawal, etc.) have been the result of a planned research, aimed at testing the "pro-nociceptive/anti-nociceptive homeostatic system" hypothesis. The discovery of melanocortin receptors, and the ensuing synthesis of selective ligands with agonist or antagonist activity, is generating completely innovative drugs for the treatment of a potentially very long list of important and widespread pathological conditions: sexual impotence, frigidity, overweight/obesity, anorexia, cachexia, haemorrhagic shock, other forms of shock, myocardial infarction, ischemia/reperfusion-induced brain damage, neuropathic pain, rheumathoid arthritis, inflammatory bowel disease, nerve injury, toxic neuropathies, diabetic neuropathy, etc. This review recalls the history of these researches and outlines the pharmacology of the extra-hormonal effects of melanocortins which are produced by an action at the brain level (or mainly at the brain level). In our opinion the picture is still incomplete, in spite of being already so incredibly vast and complex. So, for example, several of their effects and preliminary animal data suggest that melanocortins might be of concrete effectiveness in one of the areas of most increasing concern, i.e., that of neurodegenerative diseases.

Sucrose intake: increase in non-stressed rats and reduction in chronically stressed rats are both prevented by the gamma-hydroxybutyrate (GHB) analogue, GET73.

It has been previously shown that the gamma-hydroxybutyrate analogue N-(4-trifluoromethylbenzyl)-4-methoxybutanamide (GET73) inhibits consumption and reinforcing effect of palatable food, in rats, at doses that have no detrimental effect on open-field behaviour. Here we show that GET73 is also able to prevent both the development of preference for a sucrose solution in non-stressed rats, and the reduction of preference for a sucrose solution induced by the daily exposure to continuously varied mildly stressful situations. Adult male Wistar Kyoto rats (180-190 g) were subjected to chronic unpredictable mild stress. Other rats of the same sex and strain were used to study the development of preference for a sucrose solution. Daily exposure to continuously varied mildly stressful situations produced a reduction of sucrose solution intake that started the 3rd week, and such reduction became highly significant during the 5th week. Treatment with GET73 (10 mg kg(-1), 50 mg kg(-1) or 100 mg kg(-1) once daily per os) produced a more evident reduction of sucrose solution intake during the 2nd and 3rd week, but during the 4th and 5th weeks the intake dose-dependently increased to values that, for the dose of 100 mg kg(-1), were not significantly different from those of non-stressed, vehicle-treated rats. In the same range of doses GET73 dose-dependently prevented the development of preference for a sucrose solution in non-stressed rats. The present data indicate that rats treated with GET73 do not develop the "depression-like" condition produced by the daily exposure, for several weeks, to continuously and unpredictably varied stressful situations in a valid (face, predictive, and construct validity) "depression" model. Moreover, GET73 prevents the development of preference for a sucrose solution in non-stressed rats. Concurrently, present and previous data suggest that GET73 "stabilize" the behaviour of rats, either preventing the development of a "depression-like" condition in a continuously stressful environment, or the rewarding effect of alcohol, sucrose, and palatable food.

Preference for palatable food is reduced by the gamma-hydroxybutyrate analogue GET73, in rats.

Palatability and variety of foods are major reasons for "hedonic" eating, and hence for overeating and obesity. Palatable food and drugs of abuse share a common reward mechanism, and compounds that block the reinforcing effect of drugs of abuse preferentially suppress the intake of palatable foods. This research was aimed at studying the influence of the gamma-hydroxybutyrate analogue N-(4-trifluoromethylbenzyl)-4-methoxybutanamide (GET73) - that inhibits alcohol consumption - on consumption and reinforcing effect of palatable food. Adult male rats were used. For place preference conditioning, sweetened corn flakes were used as the reinforcer, and GET73 (50, 100 and 200mgkg(-1)) or vehicle were orally (p.o.) administered either 30min before each training session and the test session, or only before the test session. To study the influence on consumption, GET73 was given p.o. at the same doses once daily for 12 days to rats given free access to both palatable and varied food (cafeteria diet) or to standard chow. Both acquisition and expression of palatable food-induced conditioned place preference were inhibited by GET73, either administered throughout the conditioning period or only before the test session. GET73 reduced also the consumption of cafeteria food, while that of standard chow was increased. At these doses, GET73 had no detrimental effect on open-field behaviour. GET73 seems to specifically attenuate the gratification produced by varied and palatable food, without affecting the consumption of not particularly palatable chow. Since, overweight and obesity are mostly due to the overeating of palatable and varied foods, drugs like GET73 could represent a somewhat ideal and rational approach to obesity treatment.

Paracetamol: new vistas of an old drug.

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.