Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability.

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.

[The Effect of Exercise Therapy on Adolescent Mental Health: A Systematic Review with Practical Example]. / Wirkung von Sportinterventionen auf die psychische Gesundheit von Jugendlichen: Ein systematisches Review mit Praxisbeispiel Boulderpsychotherapie.

The Effect of Exercise Therapy on Adolescent Mental Health: A Systematic Review with Practical Example Abstract: The mental health of children and adolescents in Germany is currently highly burdened. Because of the psychotherapeutic care situation, easily accessible, less stigmatizing, and efficient offers are urgently needed. Exercise therapy would be one possibility. However, the effectiveness of such offers must first be proven. We conducted a systematic review concerning the effectiveness of exercise therapy on the mental health of children and adolescents which included studies since 2020 (subsequent to Hale et al., 2021). We analyzed a total of 17 intervention studies based on the PRISMA statement. The results show that exercise therapy interventions significantly affect certain populations: Attention and cognitive skills significantly improved in children and adolescents with ADHD; for depression, we found positive effects for affection. Some studies revealed significant effects across populations on the quality of life and sleep. In children and adolescents with autism or learning disabilities, we found positive effects on social behavior. Thus, according to the literature, exercise therapy is a recommendable therapy option for children and adolescents with mental health problems. As an illustration, we present a boulder intervention as a combined exercise intervention and psychotherapy along with its feasibility as a possible practical example.

Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults.

Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.

Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK.

Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0-inf , whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0-inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax , AUC0-24 , or AUC0-inf . In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.

Postnatal sonographic spectrum of prenatally detected abdominal and pelvic cysts.

OBJECTIVE: The purpose of this article is to illustrate the sonographic findings of a spectrum of neonatal abdominal and pelvic cystic lesions. CONCLUSION: Neonatal abdominal and pelvic cystic lesions can arise from many organs, and they have a broad differential diagnosis. Distinctive sonographic findings may be present and can help establish the correct cause and guide proper management.

Underutilized ultrasound applications in the neonatal intensive care unit.

Bedside duplex/color Doppler sonography is used for a wide gamut of abnormalities encountered in the neonatal intensive care unit. This article emphasizes the use of bedside sonography for evaluation of infants with necrotizing enterocolitis, infants requiring line placement, and those in whom a diaphragmatic abnormality is suspected. Although the assessment of those infants requires excellent operator skills, learning to do so is a definite benefit to these babies who would otherwise be exposed to ionizing radiation.

Does the rate of rewarming from profound hypothermic arrest influence the outcome in a swine model of lethal hemorrhage?

BACKGROUND: Rapid induction of profound hypothermic arrest (suspended animation) can provide valuable time for the repair of complex injuries and improve survival. The optimal rate for re-warming from a state of profound hypothermia is unknown. This experiment was designed to test the impact of different warming rates on outcome in a swine model of lethal hemorrhage from complex vascular injuries. METHODS: Uncontrolled lethal hemorrhage was induced in 40 swine (80-120 lbs) by creating an iliac artery and vein injury, followed 30 minutes later (simulating transport time) by laceration of the descending thoracic aorta. Through a thoracotomy approach, a catheter was placed in the aorta and hyperkalemic organ preservation solution was infused on cardiopulmonary bypass to rapidly (2 degrees C/min) induce profound (10 degrees C) hypothermia. Vascular injuries were repaired during 60 minutes of hypothermic arrest. The 4 groups (n = 10/group) included normothermic controls (NC) where core temperature was maintained between 36 to 37 degrees C, and re-warming from profound hypothermia at rates of: 0.25 degrees C/min (slow), 0.5 degrees C/min (medium), or 1 degrees C/min (fast). Hyperkalemia was reversed during the hypothermic arrest period, and blood was infused for resuscitation during re-warming. After discontinuation of cardiopulmonary bypass, the animals were recovered and monitored for 6 weeks for neurologic deficits, cognitive function (learning new skills), and organ dysfunction. Detailed examination of brains was performed at 6 weeks. RESULTS: All the normothermic animals died, whereas survival rates for slow, medium and fast re-warming from hypothermic arrest were 50, 90, and 30%, respectively (p < 0.05 slow and medium warming versus normothermic control, p < 0.05 medium versus fast re-warming). All the surviving animals were neurologically intact, displayed normal learning capacity, and had no long-term organ dysfunction. CONCLUSIONS: Rapid induction of hypothermic arrest maintains viability of brain during repair of lethal vascular injuries. Long-term survival is influenced by the rate of reversal of hypothermia.