Gaia Pellegatta

Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations

ABSTRACT Introduction: About 30–40% of GERD patients report an inadequate response to proton pump inhibitors (PPIs) due to their suboptimal pharmacological profiles. Recently, a new synthesized P-CABs, vonoprazan, showed higher suppression of gastric acid secretion as compared to lansoprazole. Areas covered: This review provides an update on the pharmacokinetic properties of vonoprazan and their correlates with pharmacodynamics; preliminary data on the therapeutic efficacy of vonoprazan as compared to lansoprazole in GERD patients Expert opinion: At variance from all available PPIs, vonoprazan acts directly on H+,K+-ATPase irrespectively of its activity, providing a fast onset of action without requiring acid activation and specific administration timing. Clinical and pharmacological investigations have confirmed a more rapid, potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability, as compared with PPIs. Preliminary data in patients with erosive esophagitis (EE) have shown the non-inferiority of vonoprazan to lansoprazole in terms of symptom relief and healing rate. Since these pharmacokinetic advantages, it is expected that it will have a significant favorable impact on GERD management. However, the clinical use of vonoprazan raises also some issues about its efficacy and safety in the long-term that deserve verification and careful investigation.

Application of the Intermediate-Stage Subclassification to Patients With Untreated Hepatocellular Carcinoma.

OBJECTIVES:The Barcelona Clinic Liver Cancer (BCLC) intermediate stage (BCLC B) includes a heterogeneous population of patients with hepatocellular carcinoma (HCC). Recently, in order to facilitate treatment decisions, a panel of experts proposed to subclassify BCLC B patients. In this study, we aimed to assess the prognostic capability of the BCLC B stage reclassification in a large cohort of patients with untreated HCC managed by the Italian Liver Cancer Group.METHODS:We assessed the prognosis of 269 untreated HCC patients observed in the period 1987–2012 who were reclassified according to the proposed subclassification of the BCLC B stage from stage B1 to stage B4. We evaluated and compared the survival of the various substages.RESULTS:Median survival progressively decreased from stage B1 (n=65, 24.2%: 25 months) through stages B2 (n=105, 39.0%: 16 months) and B3 (n=22, 8.2%: 9 months), to stage B4 (n=77, 28.6%: 5 months; P<0.0001). Moreover, we observed a significantly different survival between contiguous stages (B1 vs. B2, P=0.0002; B2 vs. B3, P<0.0001; B3 vs. B4, P=0.0219). In multivariate analysis, the BCLC B subclassification (P<0.0001), MELD score (P=0.0013), and platelet count (P=0.0252) were independent predictors of survival.CONCLUSIONS:The subclassification of the intermediate-stage HCC predicts the prognosis of patients with untreated HCC. The prognostic figures identified in this study may be used as a benchmark to assess the efficacy of therapeutic intervention in the various BCLC B substages, whereas it remains to be established whether incorporation of the MELD score might improve the prognosis of treated patients.

Adalimumab trough serum levels and anti-adalimumab antibodies in the long-term clinical outcome of patients with Crohn’s disease.

Abstract Objective: Few data are available on the relevance of adalimumab (ADA) trough serum levels and anti-ADA antibodies (AAA) during long-term follow-up of patients with Crohn’s Disease (CD), and their association with disease outcome. In this study, our aim was to assess ADA trough serum levels and the presence of AAA according to disease activity and clinical response during long-term follow-up in a series of patients with CD treated with ADA monotherapy. Material and methods: We prospectively evaluated 23 consecutive, infliximab-naïve CD patients who achieved clinical remission/response after induction and were in maintenance treatment with ADA, and who were followed-up for at least 72 weeks. Blood samples were drawn at standardized time points to assess ADA through levels, AAA. Results: At week 48, we found significantly (p = 0.027) different ADA trough serum levels in patients in remission (10.1 mcg/mL), mild (7.4 mcg/mL), and moderate/severe disease (4.5 mcg/mL). Median ADA trough levels were significantly lower in patients with AAA (3.7 mcg/mL versus 9.3 mcg/mL, p = 0.006). At the end of follow-up (median 102 weeks, range 73–112 weeks), ADA trough serum concentrations were significantly higher (11.9 mcg/mL) as compared to patients with mild and moderate/severe disease (5.5 mcg/mL, p = 0.0002). Furthermore, median ADA trough concentrations showed a trend towards lower levels in AAA positive patients (5.2 mcg/mL versus 7.2 mcg/mL, p = 0.371). Conclusions: Our results emphasize the relevance of therapeutic drug monitoring in CD patients on biologic treatment. ADA trough serum levels and the presence of AAA are important features in the management of patients on ADA treatment.

Years of life that could be saved from prevention of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved.

A review of pharmacotherapy for treating gastroesophageal reflux disease (GERD)

ABSTRACT Introduction: Medical therapy of gastroesophageal reflux disease (GERD) is based on the use of proton pump inhibitors (PPIs) as first choice treatment. Despite their effectiveness, about 20–30% of patients report an inadequate response and alternative drugs are required. Areas covered: This review provides an overview of current pharmacotherapy for treating GERD by showing the results of PPIs, reflux inhibitors, antidepressants and mucosa protective medications. Expert opinion: Medical therapy of GERD does not definitely cure the disease, because even PPIs are not able to change the key factors responsible for it. However, they remain the mainstay of medical treatment, allowing us to alleviate symptoms, heal esophagitis and prevent complications in the majority of cases. Nevertheless, many patients do not respond, because acid does not play any pathogenetic role. Prokinetics and reflux inhibitors have the potential to control motor abnormalities, but the results of clinical trials are inconsistent. Antidepressant drugs are effective in specific subgroups of NERD patients with visceral hypersensitivity, but larger, controlled clinical studies are necessary. Protective drugs or medical devices have been recently adopted to reinforce mucosal resistance and preliminary trials have confirmed their efficacy either combined with or as add-on medication to PPIs in refractory patients.

Epidemiology and natural history of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is highly prevalent in Western countries, particularly when considering its most classic symptom that is heartburn. This symptom is very frequent in the community and ranges from 10% to more than 30%, according to the various population-based studies. This disease is much more represented in Europe and USA than in Asiatic countries. It has been shown that GERD prevalence increases in parallel with the remarkable growth of obesity, as this condition is able to favor all the pathogenetic mechanisms leading to it. Current information regarding the phenotypic presentation of GERD shows that there are two main phenotypic manifestations, that are erosive reflux disease (ERD) and non-erosive reflux disease (NERD) and the latter includes the majority of patients (up to 70%). The major complication of GERD is the development of Barrett esophagus, a pre-malignant lesion potentially leading to esophageal adenocarcinoma. Data from medical literature on the natural history of this disease are scant and mainly retrospective, so the interpretation of them is very difficult. However, they seem to suggest that both NERD and mild esophagitis tend to remain as such overtime and the progression from NERD to ERD, from mild to severe ERD and from ERD to Barretts esophagus may occur only in a small number of cases, ranging from 0% to 30%, 10-22% and 1-13%, respectively. Future studies should help us in elucidating better the real transition from one category to another and to do this, we have to exclude from the world of GERD all the functional conditions that nowadays can be easily recognized by means of impedance-pH monitoring.

Positive PET in a Patient With Esophageal Leiomyoma

A 50-year-old man undergoing treatment with 6-thioguanine for ulcerative colitis was admitted to the gastroenterology unit with suspected sinusoidal obstruction syndrome (SOS). Clinical diagnosis, made according to Seattle modified criteria and Baltimore criteria, was supported by magnetic resonance imaging (MRI) showing a diffuse patchy pattern in the portal phase (left, panel a), the “clover-like sign,” in which liver parenchyma surrounding the main hepatic veins shows normal enhancement compared with the rest of the patchy enhanced area of liver (left, panel b), paraumbilical vein patency (left, panel c), and gallbladder wall thickening (left, panel d). Six months after 6-thioguanine was stopped, MRI showed complete resolution of the SOS; in particular, the patchy pattern disappeared (right, panel a), the hepatic veins were enhanced (right, panel b), the paraumbilical vein disappeared (right, panel c), and the gallbladder wall was normal (right, panel d).

Correction to: Application of the Intermediate-Stage Subclassification to Patients With Untreated Hepatocellular Carcinoma (The American Journal of Gastroenterology, (2016), 111, 1, (70-77), 10.1038/ajg.2015.389)

In the Italian Liver Cancer (ITA.LI.CA) Group, contributor name Alberta Capelli is misspelled and should be corrected to Alberta Cappelli.

Proton pump inhibitors: use and misuse in the clinical setting

ABSTRACT Introduction: The introduction of proton pump inhibitors (PPIs) into clinical practice has greatly improved our therapeutic approach to acid-related diseases for their efficacy and safety. Areas Covered: The following evidence-based indications for PPI use are acknowledged by many scientific societies: treatment of the various forms and complications of gastroesophageal reflux disease, eradication of H. pylori infection in combination with two or more antibiotics, short- and long-term therapy of H. pylori-negative peptic ulcers, healing, and prevention of NSAID/COXIB-associated gastric ulcers, co-therapy with endoscopic procedures to control upper digestive bleeding and medical treatment of Zollinger Ellison syndrome. Expert Commentary: Despite the above well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries and the endless expansion of the PPI market has created important problems for many regulatory authorities for two relevant features: the progressive increase of the costs of therapy and the greater potential harms for the patients. The major reasons for the misuse of PPIs are the prevention of gastro-duodenal ulcers in patients without risk factors and the stress ulcer prophylaxis in non-intensive care units, steroid therapy alone, anti-platelet or anti-coagulant treatment in patients without risk of gastric injury and the overtreatment of functional dyspepsia.

Erratum: Positive PET in a Patient With Esophageal Leiomyoma.

This corrects the article DOI: 10.1038/ajg.2016.205