Effects of propranolol on fear of dental extraction: Study protocol for a randomized controlled trial

Background: Undergoing an extraction has been shown to pose a significantly increased risk for the development of chronic apprehension for dental surgical procedures, disproportionate forms of dental anxiety (that is, dental phobia), and symptoms of post-traumatic stress. Evidence suggests that intrusive emotional memories of these events both induce and maintain these forms of anxiety. Addressing these problems effectively requires an intervention that durably reduces both the intrusiveness of key fear-related memories and state anxiety during surgery. Moreover, evidence suggests that propranolol is capable of inhibiting "memory reconsolidation" (that is, it blocks the process of storing a recently retrieved fear memory). Hence, the purpose of this trial is to determine the anxiolytic and fear memory reconsolidation inhibiting effects of the ß-adrenoreceptor antagonist propranolol on patients with high levels of fear in anticipation of a dental extraction. Methods/Design: This trial is designed as a multicenter, randomized, placebo-controlled, two-group, parallel, double-blind trial of 34 participants. Consecutive patients who have been referred by their dentist to the departments of oral and maxillofacial surgery of a University hospital or a secondary referral hospital in the Netherlands for at least two tooth and/or molar removals and with self-reported high to extreme fear in anticipation of a dental extraction will be recruited. The intervention is the administration of two 40 mg propranolol capsules 1 hour prior to a dental extraction, followed by one 40 mg capsule directly postoperatively. Placebo capsules will be used as a comparator. The primary outcome will be dental trait anxiety score reduction from baseline to 4-weeks follow-up. The secondary outcomes will be self-reported anxiety during surgery, physiological parameters (heart rate and blood pressure) during recall of the crucial fear-related memory, self-reported vividness, and emotional charge of the crucial fear-related memory. Discussion: This randomized trial is the first to test the efficacy of 120 mg of perioperative propranolol versus placebo in reducing short-term ("state") anxiety during dental extraction, fear memory reconsolidation, and lasting dental ("trait") anxiety in a clinical population. If the results show a reduction in anxiety, this would offer support for routinely prescribing propranolol in patients who are fearful of undergoing dental extractions. Trial registration: ClinicalTrials.gov identifier: NCT02268357 , registered on 7 October 2014. The Netherlands National Trial Register identifier: NTR5364 , registered on 16 August 2015

Pharmacogenomics and the Management of Mood Disorders-A Review

Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients' (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians' experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for CYP2D6 and CYP2C19, when there is an indication (side effects or inefficacy)

Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?

In recent decades, very few new psychiatric drugs have entered the market. Thus, improvement in the use of antidepressant and antipsychotic therapy has to focus mainly on enhanced and more personalized treatment with the currently available drugs. One important aspect of such individualization is emphasizing interindividual differences in genes relevant to treatment, an area that can be termed neuropsychopharmacogenomics. Here, we review previous efforts to identify such critical genetic variants and summarize the results obtained to date. We conclude that most clinically relevant genetic variation is connected to phase I drug metabolism, in particular to genetic polymorphism of CYP2C19 and CYP2D6. To further improve individualized pharmacotherapy, there is a need to take both common and rare relevant mutations into consideration; we discuss the present and future possibilities of using whole genome sequencing to identify patient-specific genetic variation relevant to treatment in psychiatry. Translation of pharmacogenomic knowledge into clinical practice can be considered for specific drugs, but this requires education of clinicians, instructive guidelines, as well as full attention to polypharmacy and other clinically relevant factors. Recent large patient studies (n > 1,000) have replicated previous findings and produced robust evidence warranting the clinical utility of relevant genetic biomarkers. To further judge the clinical and financial benefits of preemptive genotyping in psychiatry, large prospective randomized trials are needed to quantify the value of genetic-based patient stratification in neuropsychopharmacotherapy and to demonstrate the cost-effectiveness of such interventions

Experimental study on long-term exposure to a biocompatible, hypertonic, pyruvate-buffered dialysis solution

BACKGROUND: Chronic exposure to glucose and glucose degradation products (GDPs) in dialysis solutions is involved in the pathogenesis of peritoneal neoangiogenesis and fibrosis, potentially leading to encapsulating peritoneal sclerosis (EPS). High lactate concentrations may contribute to glucose toxicity by creating a state of pseudohypoxia, which stimulates the formation of various growth factors. OBJECTIVE: To study the effects of long-term peritoneal exposure to a filter-sterilized pyruvate-buffered solution with a combination of 3 osmotic agents (amino acids, glycerol, glucose: PYRAGG) on peritoneal function and morphology. METHODS: Rats were exposed daily for a period of 20 weeks to PYRAGG, or to a conventional heat-sterilized solution (LH), or to a filter-sterilized solution (LF), after which a peritoneal function test was done and peritoneal tissue was obtained. RESULTS: Peritoneal solute and fluid transport characteristics at 20 weeks were similar in all groups. Fibrosis was most pronounced in the LH group compared to the others, suggesting an effect of GDPs. A marked reduction in the number of omental vessels was noted in the PYRAGG group (59% reduction compared to LH). A modest reduction (28%) was found in the LF animals. This points to a marked effect of reduced exposure to glucose. CONCLUSIONS: PYRAGG was more biocompatible than a filter-sterilized glucose/lactate solution because it did not induce marked peritoneal abnormalities after long-term exposure. This did not lead to altered peritoneal transport characteristics. It is likely that further development of PYRAGG-like solutions will decrease the incidence of EP

Clinical advantages of new peritoneal dialysis solutions

A review is given of the various mechanisms by which conventional glucose/lactate-based peritoneal dialysis solutions can induce damage to the peritoneal membrane. The potential advantages of newly developed dialysis solutions and the results of recent studies on their use in patients are discusse