Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia

Epinephrine Infusion in Diagnosis of CPVT. Introduction: A test involving intravenous infusion of epinephrine has been proposed as a method alternative to exercise stress test in diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed at estimating the predictive value of intravenous epinephrine administration in CPVT patients with frequent exercise‐induced ventricular ectopy. Methods and Results: We recruited 81 subjects, including 25 CPVT‐linked ryanodine receptor 2 (RYR2) mutation carriers, 11 genetically undefined CPVT patients, and 45 unaffected family members. All subjects underwent a maximal exercise stress test and an intravenous epinephrine infusion test. Exercise stress test was positive in 25 (31%) patients including 14 of 25 (56%) established RYR2‐mutation carriers and all 11 (100%) genetically undefined CPVT patients. Epinephrine infusion induced arrhythmias in 3 (12%) RYR2‐mutation carriers, 4 (36%) genetically undefined CPVT patients, and 1 (2%) unaffected family member. A total of 18 exercise stress test positive patients did not respond to intravenous epinephrine administration, whereas only 1 epinephrine test responder had a normal exercise stress test. Thus, if exercise stress test is used as a standard, the sensitivity of the epinephrine infusion test is 28% and specificity is 98%. Conclusions: Intravenous epinephrine infusion has low sensitivity and may not be considered as an alternative method for a maximal exercise stress test in diagnosis of CPVT. (J Cardiovasc Electrophysiol, Vol. 23, pp. 194‐199, February 2012)     

Characterizing patient compliance over six months in remote digital trials of Parkinson’s and Huntington disease

Background

A growing number of clinical trials use various sensors and smartphone applications to collect data outside of the clinic or hospital, raising the question to what extent patients comply with the unique requirements of remote study protocols. Compliance is particularly important in conditions where patients are motorically and cognitively impaired. Here, we sought to understand patient compliance in digital trials of two such pathologies, Parkinson’s disease (PD) and Huntington disease (HD).

Methods

Patient compliance was assessed in two remote, six-month clinical trials of PD (n =?51, Clinician Input Study funded by the Michael J. Fox Foundation for Parkinson’s Research) and HD (n =?17, sponsored by Teva Pharmaceuticals). We monitored four compliance metrics specific to remote studies: smartphone app-based medication reporting, app-based symptoms reporting, the duration of smartwatch data streaming except while charging, and the performance of structured motor tasks at home.

Results

While compliance over time differed between the PD and HD studies, both studies maintained high compliance levels for their entire six month duration. None (??1%) to a 30% reduction in compliance rate was registered for HD patients, and a reduction of 34 to 53% was registered for the PD study. Both studies exhibited marked changes in compliance rates during the initial days of enrollment. Interestingly, daily smartwatch data streaming patterns were similar, peaking around noon, dropping sharply in the late evening hours around 8?pm, and having a mean of 8.6 daily streaming hours for the PD study and 10.5?h for the HD study. Individual patients tended to have either high or low compliance across all compliance metrics as measured by pairwise correlation. Encouragingly, predefined schedules and app-based reminders fulfilled their intended effect on the timing of medication intake reporting and performance of structured motor tasks at home.

Conclusions

Our findings suggest that maintaining compliance over long durations is feasible, promote the use of predefined app-based reminders, and highlight the importance of patient selection as highly compliant patients typically have a higher adherence rate across the different aspects of the protocol. Overall, these data can serve as a reference point for the design of upcoming remote digital studies.

Trial registration

Trials described in this study include a sub-study of the Open PRIDE-HD Huntington’s disease study (TV7820-CNS-20016), which was registered on July 7th, 2015, sponsored by Teva Pharmaceuticals Ltd., and registered on Clinicaltrials.gov as NCT02494778 and EudraCT as 2015–000904-24.

     

Structure-activity relationship of quinoline derivatives as potent and selective alpha(2C)-adrenoceptor antagonists

Starting from two acridine compounds identified in a high-throughput screening campaign (1 and 2, Table 1), a series of 4-aminoquinolines was synthesized and tested for their properties on the human alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)). A number of compounds with good antagonist potencies against the alpha(2C)-adrenoceptor and excellent subtype selectivities over the other two subtypes were discovered. For example, (R)-{4-[4-(3,4-dimethylpiperazin-1-yl)phenylamino]quinolin-3-yl}methanol 6j had an antagonist potency of 8.5 nM against, and a subtype selectivity of more than 200-fold for, the alpha(2C)-adrenoceptor. Investigation of the structure-activity relationship identified a number of structural features, the most critical of which was an absolute need for a substituent in the 3-position of the quinoline ring. The 3-position on the piperazine ring was also found to play an appreciable role, as substitutions in that position exerted a significant and stereospecific beneficial effect on the alpha(2C)-adrenoceptor affinity and potency. Replacing the piperazine ring proved difficult, with 1,4-diazepanes representing the only viable alternative.     

Clinician's ability to identify caries risk subjects

Abstract – The clinician's ability to identify caries risk children without saliva tests was studied in five health care centers. 77 examiners predicted, after the annual check-up and treatment, whether, during the following 12 months, the child would develop new dentinal caries lesions to be filled. 7917 children aged 5–16 yr were included. Only information routinely available at clinical examinations was used. In general, the overall sensitivity was 44% and specificity 90%. Some clinicians were able to identify the caries risk children with high sensitivity and specificity figures.     

Xylitol chewing gum in caries prevention: a field study in children

As the prevalence of dental caries decreases in industrialized nations like the United States, it simultaneously increases in developing nations and Third World countries. The decrease in the West is attributed to increased use of fluorides, but the increase in developing countries has been explained by an increase in the consumption of sugar. As this information continues to propel researchers to find sucrose substitutes, xylitol has been singled out as a proposed sucrose replacement. The question tackled by this study was: Can the daily use of chewing gum containing xylitol increase the efficacy of the existing caries-preventive measures now regularly used for 11- to 15-year-old children in most industrialized western countries?     

The optimum time to initiate habitual xylitol gum-chewing for obtaining long-term caries prevention

Habitual xylitol gum-chewing may have a long-term preventive effect by reducing the caries risk for several years after the habitual chewing has ended. The goal of this report was (1) to determine if sorbitol and sorbitol/xylitol mixtures provide a long-term benefit, and (2) to determine which teeth benefit most from two-year habitual gum-chewing - those erupting before, during, or after habitual gum-chewing. Children, on average 6 years old, chewed gums sweetened with xylitol, sorbitol, or xylitol/sorbitol mixtures. There was a "no-gum" control group. Five years after the two-year program of habitual gum-chewing ended, 288 children were re-examined. Compared with the no-gum group, sorbitol gums had no significant long-term effect (relative risk [RR], 0.65; 95% confidence interval [c.i.], 0.39 to 1.07; p < 0.18). Xylitol gum and, to a lesser extent, xylitol/sorbitol gum had a long-term preventive effect. During the 5 years after habitual gum-chewing ended, xylitol gums reduced the caries risk 59% (RR, 0.41; 95% c.i., 0.23 to 0.75; p < 0.0034). Xylitol-sorbitol gums reduced the caries risk 44% (RR, 0.56; 95% c.i., 0.36 to 0.89; p < 0.02). The long-term caries risk reduction associated with xylitol strongly depended on when teeth erupted (p < 0.02). Teeth that erupted after 1 year of gum-chewing or after the two-year habitual gum use ended had long-term caries risk reductions of 93% (p < 0.0054) and 88% (p < 0.0004), respectively. Teeth that erupted before the gum-chewing started had no significant long-term prevention (p < 0.30). We concluded that for long-term caries-preventive effects to be maximized, habitual xylitol gum-chewing should be started at least one year before permanent teeth erupt.     

Xylitol candies in caries prevention: results of a field study in Estonian children

All field studies have unequivocally reported significant reductions in dental caries occurrence associated with the use of chewing gum containing xylitol. No other xylitol products besides chewing gum have so far been tested in field trials. A 5-year follow-up study with 2- or 3-year xylitol consumption periods began in Estonia in 1994 with 740 10-year-old children in 12 schools at baseline examinations. For the study, 3 clusters each including 3-5 schools were formed on the basis of baseline caries experience. The products were used under the supervision of the teachers 3 times per day during school days but not during weekends or during the 3-month summer holiday. The daily dose of xylitol was 5 g in all groups. The children were examined every year in September by two experienced clinicians. Dental caries was recorded according to WHO criteria. After 3 years, all xylitol groups showed a highly significant 35%-60% reduction in caries incident, compared with the corresponding control groups. The differences between candies, between candies and chewing gum, and between 2- and 3-year users in the xylitol groups were non-systematic, indicating no trends between the groups. The results suggest that not only xylitol chewing gum but also xylitol candies are effective in caries prevention, and that a school-based delivery system seems to offer a practical way to distribute and control the use of the xylitol products.     

Assessment of drug-lipid complex formation by a high-throughput Langmuir-balance and correlation to phospholipidosis

Phospholipidosis, the accumulation of phospholipids in cells, is a relatively frequent side effect of cationic amphiphilic drugs. In response to the industry need, several methods have been recently published for the prediction of the phospholipidosis-inducing potential of drug candidates. We describe here a high-throughput physicochemical approach, which is based on the measurement of drug-phospholipid complex formation observed by their effect on the critical micelle concentration (CMC) of a short-chain acidic phospholipid. The relative change due to the drug, CMC(DL)/CMC(L) provides a direct measure of the energy of the drug-phospholipid association, irrespective of the nature of the interaction. Comparison of results for 53 drugs to human data, animal testing, cell culture assays, and other screening methods reveals very good correlation to their phospholipidosis-inducing potential. The method is well suited for screening already in early phases of drug discovery.