Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies.

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge.

Is It Time to Use Modeling of Cellular Transporter Homeostasis to Inform Drug-Drug Interaction Studies: Theoretical Considerations.

Mathematical modeling has been an important tool in pharmaceutical research for 50 + years and there is increased emphasis over the last decade on using modeling to improve the efficiency and effectiveness of drug development. In an earlier commentary, we applied a multiscale model linking 6 scales (whole body, tumor, vasculature, cell, spatial location, time), together with literature data on nanoparticle and tumor properties, to demonstrate the effects of nanoparticle particles on systemic disposition. The current commentary used a 4-scale model (cell membrane, intracellular organelles, spatial location, time) together with literature data on the intracellular processing of membrane receptors and transporters to demonstrate disruption of transporter homeostasis can lead to drug-drug interaction (DDI) between victim drug (VD) and perpetrator drug (PD), including changes in the area-under-concentration-time-curve of VD in cells that are considered significant by the US Food and Drug Administration (FDA).

Target Site Delivery and Residence of Nanomedicines: Application of Quantitative Systems Pharmacology.

Quantitative systems pharmacology (QSP), an emerging field that entails using modeling and computation to interpret, interrogate, and integrate drug effects spanning from the molecule to the whole organism to forecast treatment outcomes, is expected to enhance the efficiency of drug development. Since late 2017, the U.S.

Systemic Bioequivalence Is Unlikely to Equal Target Site Bioequivalence for Nanotechnology Oncologic Products.

Approval of generic drugs by the US Food and Drug Administration (FDA) requires the product to be pharmaceutically equivalent to the reference listed drug (RLD) and demonstrate bioequivalence (BE) in effectiveness when administered to patients under the conditions in the RLD product labeling. Effectiveness is determined by drug exposure at the target sites. However, since such measurement is usually unavailable, systemic exposure is assumed to equal target site exposure and systemic BE to equal target site BE.

A physiologically-based model to predict individual pharmacokinetics and pharmacodynamics of remifentanil.

Remifentanil based anesthesia is nowadays spread worldwide. This drug is characterized by a rapid onset of the analgesic effects, but also by a rapid onset of the side effects. For this reason, the knowledge of the remifentanil concentration in the human body is a key topic in anesthesiology.

A physiologically based model for tramadol pharmacokinetics in horses.

This work proposes an application of a minimal complexity physiologically based pharmacokinetic model to predict tramadol concentration vs time profiles in horses. Tramadol is an opioid analgesic also used for veterinary treatments. Researchers and medical doctors can profit from the application of mathematical models as supporting tools to optimize the pharmacological treatment of animal species.

Engineering approaches in siRNA delivery.

siRNAs are very potent drug molecules, able to silence genes involved in pathologies development. siRNAs have virtually an unlimited therapeutic potential, particularly for the treatment of inflammatory diseases. However, their use in clinical practice is limited because of their unfavorable properties to interact and not to degrade in physiological environments.

Chemical Engineering in the "BIO" World.

Modern Chemical Engineering was born around the end of the 19th century in Great Britain, Germany, and the USA, the most industrialized countries at that time. Milton C. Whitaker, in 1914, affirmed that the difference between Chemistry and Chemical Engineering lies in the capability of chemical engineers to transfer laboratory findings to the industrial level.

Innovations and Improvements in Pharmacokinetic Models Based on Physiology.

Background: Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies.

Method: This article summarizes the features we recently introduced in PBPK modeling within a threeyear research project funded by Italian Research Ministry.

Clinical trial on the efficacy of a new symbiotic formulation, Flortec, in patients with acute diarrhea: a multicenter, randomized study in primary care.

Objectives: Few randomized studies have been carried out on adult patients affected by acute diarrhea especially in primary care, which is the natural context for this kind of disorder. Lactobacillus paracasei B 21060 is a novel strain of lactobacillus, which has been shown to be effective in relieving symptoms associated with diarrhea of irritable bowel syndrome subtype and in shortening diarrhea duration. In this study, we compared the therapeutic efficacy, safety, and tolerability of a new symbiotic formulation, Flortec, containing L.

The effect of a new symbiotic formulation on plasma levels and peripheral blood mononuclear cell expression of some pro-inflammatory cytokines in patients with ulcerative colitis: a pilot study.

Background: During intestinal inflammation white blood cells are recruited from the blood, and they represent the major contributors to tissue perpetuation of inflammation via their production of chemokines and proinflammatory cytokines.

Objectives: Investigate the effect of a symbiotic formulation containing Lactobacillus Paracasei B 20160 versus placebo, on serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)alpha, IL-8, IL-1beta and IL-10 and on mRNA lymphomonocyte expression of TNFalpha, IL-8 and IL-1beta in patients with ulcerative colitis.

Materials And Methods: Eighteen patients entered the study with histologically proven not complicated ulcerative colitis, treated with mesalazine.

Clinical trial on the efficacy of a new symbiotic formulation, Flortec, in patients with irritable bowel syndrome: a multicenter, randomized study.

Objectives: Efficacy of symbiotics in patients with irritable bowel syndrome (IBS) remains unknown.

Methods: Patients were randomized to a prebiotic (n=135), or a symbiotic formulation containing Lactobacillus paracasei B21060 (Flortec, n=132). Primary efficacy was the responder rate for pain and global relief of symptoms in the overall population and in patients with predominant diarrhea (n=47).

Psychological status and depression in patients with liver cirrhosis.

Background: Previous studies reported an impairment of both the physical and mental dimensions of quality of life in patients with cirrhosis. Very few data are available on the psychological impact of the disease and its relation to liver function.

Aim: To measure the psychological status of patients with cirrhosis in relation to the severity of the liver impairment.

Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial.

Background & Aims: The role of oral supplementation with branched-chain amino acids (BCAA) in advanced cirrhosis is far from settled. A nutritional approach might prevent progressive liver failure and improve nutritional parameters and quality of life.

Methods: A multicenter, randomized study comparing 1-year nutritional supplementation with BCAA against lactoalbumin or maltodextrins was performed in 174 patients with advanced cirrhosis.

Reduced quality of life of patients with hepatocellular carcinoma.

Background: It has been shown that health-related quality of life is reduced in patients with cirrhosis and with chronic hepatitis in relation to antiviral therapy. No data are available on patients with hepatocellular carcinoma.

Aim: To assess health-related quality of life in cirrhotic patients with hepatocellular carcinoma.

Factors associated with poor health-related quality of life of patients with cirrhosis.

Background & Aims: Increasing interest is being given to health-related quality of life in chronic diseases. In cirrhosis, both physical functioning and mental well-being may be altered, but no study has investigated factors associated with a poor perceived health status.

Methods: We measured quality of life by Short Form-36 and Nottingham Health Profile questionnaires in 544 patients with cirrhosis.

[Late reactions to a radiologic contrast media (Iopamidol-Bracco). Prospective study].

Purpose: This prospective, non-randomized study was aimed at evaluating the incidence of Delayed Adverse Drug Reactions (DADRs) to iodinated contrast agents and to evaluate possible risk factors to the development of these reactions. DADRs are those reactions occurring one to 48 hours after contrast medium administration. Their symptoms and frequency are not well defined, but the majority of DADRs are mild in intensity and resolve spontaneously without sequelae.

The Italian experience of a Pap test and speculoscopy based screening programme.

Objectives: The main objective of the study was to evaluate if speculoscopy, a magnified chemiluminescent examination, combined with a Pap smear, could improve the detection of early cervical lesions compared with the Pap smear alone.

Setting: Pap tests and speculoscopies were performed in two family planning centres located in the surrounding areas of Modena. Colposcopic investigations and biopsies of the uterine cervix were performed in a second level centre (Gynaecological Prevention Centre of Modena Policlinico).

Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial.

Background: 5-Fluorouracil (FU) in association with folinic acid (FA) is the most frequently used chemotherapeutic agent in colorectal cancer but it often causes diarrhoea. Animal and human studies suggest that glutamine stimulates intestinal mucosal growth.

Aim: To determine if oral glutamine prevents changes in intestinal absorption (IA) and permeability (IP) induced by FU/FA.

Reduced quality of life in patients with chronic hepatitis C: effects of interferon treatment.

Background: Quality of life is an area of increasing interest in hepatology. Studies, so far, have assessed quality of life in patients with chronic virus C-related hepatitis in relation to antiviral therapy by means of generic questionnaires.

Aim: To measure quality of life in chronic hepatitis patients without cirrhosis by means of the Nottingham Health Profile questionnaire, a measure of "distress" in comparison with the Medical Outcome Survey SF-36, an index of well-being.

Speculoscopy for Triage of Patients with an Abnormal Pap Smear: Data from the GISPE Study.

Objective: This study evaluates the performance of Papanicolaou smear combined with speculoscopy in improving the predictive value of minor grade cervical cytological abnormalities.

Materials And Methods: A total of 3,300 asymptomatic women who had routine cervical smears were studied in 32 Italian centers. All these women underwent Pap smear and speculoscopy.

Improvement of Pap smear sensitivity using a visual adjunctive procedure: a co-operative Italian study on speculoscopy (GISPE).

The present study evaluates whether speculoscopy, a magnified chemiluminescence examination, combined with Pap smear can improve the detection of cervical lesions, as compared with Pap smear alone. The investigation was a prospective practice-based research carried out as a multicentre cohort study throughout the Italian territory. The participants were 3,300 asymptomatic women age > or = 18 years undergoing routine pelvic and cytological screening.

Immunostimulating effect of oral glutamine.

Glutamine represents the principal metabolic substrate for all rapidly proliferating cells. Since part of the glutamine efficacy could be related to immunoregulating properties, we assessed the effects of orally administered glutamine on serum interleukin-2 (IL-2) levels and intestinal T-cell populations in 48 athymic (nude) mice. Twenty-four mice received a standard diet enriched by glutamine (added to drinking water at a 4% concentration), while the other 24 served as the control group and received the same diet without glutamine.

Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy.

In 40 patients with cirrhosis on a dietary protein regimen of 1 g/kg b.w., we determined the effect on chronic hepatic encephalopathy of long-term administration of Enterococcus faecium (SF68) versus lactulose.