Impact of dosing regimen of custirsen,an antisense oligonucleotide,on safety,tolerability and cardiac repolarization in healthy subjects

Aims

Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.

Methods

Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.

Results

AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.

Conclusion

Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.     

Ethnic Background,Socioeconomic Status,and Problem Severity as Dropout Risk Factors in Psychotherapy with Youth

Background

Dropout from child and adolescent psychotherapy is a common phenomenon which can have negative consequences for the individual later in life. It is therefore important to gain insight on dropout risk factors.

Objective

Several potential risk factors [ethnic minority status, a lower socioeconomic status (SES), and higher problem severity] were analyzed in present study. Innovations are that these risk factors were examined for children and adolescents separately, and a distinction was made in termination status between referred patients, dropouts and completers.

Methods

For ethnic majority and minority outpatient children (age 5–11, n = 399) and adolescents (age 12–20, n = 352) problem severity, ethnic background, SES, and treatment termination status (completer, dropout, referral) were specified. Multinomial logistic regression models were used as main method of analysis.

Results

For children, a Moroccan/Turkish ethnicity and higher externalizing scores were risk factors for being referred. For adolescents, a Surinamese/Antillean ethnicity, being female, being older, and lower parental SES occupation levels were risk factors for dropout.

Conclusions

Different dropout risk profiles emerged for children versus adolescents, and for dropouts versus referrals. Also, it depended on the specific ethnic background whether ethnic minority status was a predictor for dropout, and the relationship between SES and termination status differed by whether parental SES occupation or parental SES education were used as SES indicator. Professionals should thus be aware of these potential risk factors for dropout or referral when treating children and adolescents.

     

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond

The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C–H⋯O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.

The impact of weak intramolecular C–H⋯O interactions on the conformational stability of bis-arylsulfones is discussed, suggesting different role of sulfonyl group in the ligand – 5HT₆ receptor interaction.     

Do patients’ information requirements for choice in health care vary with their socio‐demographic characteristics?

Objectives

This study examines whether the information used to inform hospital choice, and the sources of that information, varies with patients’ socio‐demographic characteristics. It also examines whether information used by patients to inform choice is associated with attending their local hospital.

Methods

A survey of 1033 patients who were offered a choice of hospital provider for elective treatment in England. Logistic regression was used to examine associations between patient characteristics and information used to inform choice of a hospital provider and sources of information used.

Results

Factors most important to patients in choosing a hospital were quality of care, cleanliness, standard of facilities and reputation. While quality of care and related factors are important to the majority of patients, those with lower levels of education were more likely to report that location and appointment times were important. Those who thought quality important were more likely to attend their local hospital provider. The main sources of information used to inform choice of hospital were own experience, family and friends and the general practitioner (GP). Patients who sought advice from their GP or booking advisors were less likely to attend their local hospitals.

Conclusions

Differences among patients as to what factors are important when choosing a hospital provider and what information and support they access suggest there needs to be a variety of information sources and support available to promote choice. Greater shared decision making through active involvement and support by GPs or booking advisors may be required if they are to make choices in line with their preferences.     

Socioeconomic inequalities in children’s diet: the role of the home food environment

Background

It is well documented in the literature that low socioeconomic status (SES) is associated with lower consumption of healthy foods and that these differences in consumption patterns are influenced by neighborhood food environments. Less understood is the role that SES differences in physical and social aspects of the home food environment play in consumption patterns.

Methods

Using data on 4^th grade children from the 2009–2011 Texas School Physical Activity and Nutrition (SPAN) study, we used mixed-effects regression models to test the magnitude of differences in the SPAN Health Eating Index (SHEI) by parental education as an indicator of SES, and the extent to which adjusting for measures of the home food environment, and measures of the neighborhood environment accounted for these SES differences.

Results

Small but significant differences in children’s SHEI by SES strata exist (-1.33 between highest and lowest SES categories, p<0.01). However, incorporating home food environment and neighborhood environment measures in this model eliminates these differences (-0.7, p=0.145). Home food environment explains a greater portion of the difference. Both social (mealtime structure) and physical aspects (food availability) of the home food environment are strongly associated with consumption of healthy and unhealthy foods.

Conclusions

Our findings suggest that modifiable parent behaviors at home can improve children’s eating habits and that the neighborhood may impact diet in ways other than through access to healthy food.