Rationale: We previously discovered the human 10T3 C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene. Objective: We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation. Methods and Results: We now report the generation and detailed analysis of the corresponding Mlp W4R/؉ and Mlp W4R/W4R knock-in animals, which develop an age-and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry. Conclusions: Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that W4R-MLP might contribute significantly to human cardiovascular disease. (Circ Res. 2010;106:695-704.)Key Words: genetics Ⅲ mechanosensation Ⅲ mechanotransduction Ⅲ cardiomyopathy Ⅲ heart failure Ⅲ circulation C ardiomyopathies are primary disorders of cardiac muscle and represent major causes of morbidity and mortality at all ages. 1 With a prevalence of 200 per 100 000 individuals, hypertrophic cardiomyopathy (HCM) is the most common cardiovascular disease inherited as an autosomal dominant trait and accounts for Ϸ36% of all sudden deaths in the United States in competitive athletes. Onset of disease is variable and can be late in adolescence. 1 In the majority of cases, the disease is caused by mutations in sarcomeric and/or structural components. 2 However, the underlying molecular mechanisms remain unclear.We cloned and sequenced previously the human MLP gene (CLP, CRP3, or CSRP3), which is encoded by Ϸ20 000 bp and organized into 6 exons, giving rise to a 194-aa LIM only protein. 3 Homozygous loss of Mlp in a genetically engineered mouse model results in cardiac hypertrophy followed by dilated cardiomyopathy (DCM), 4 the first model for this condition in a genetically manipulatable organism. In addition, we discovered and characterized the 10T3 C (Trp4Arg) missense mutation in exon 2 of the MLP gene, the first human MLP mutation (and together with a telethonin mutation, the first Z-disk mutation in general) linked to cardiomyopathy, and proposed a role for this gene in cardiac mechanosensation. 3 Because of the well-known limitations of human studies, owing in part to differences in environmental and epigenetic factors, it is often impossible to perform an in depth functional analysis of mutations in the human setting. Therefore, we generated Mlp W4R/ϩ and Mlp W4R/W4R knock-in (KI) animals and compared the phenotype with Mlp ϩ...
IntroductionTapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009.MethodsThis is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials.ResultsThe first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses.ConclusionMore than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population.FundingGrünenthal GmbH.Electronic supplementary materialThe online version of this article (10.1007/s12325-017-0654-0) contains supplementary material, which is available to authorized users.
Background: This trial is part of the global pediatric clinical development program investigating the administration of the strong analgesic tapentadol in children and adolescents. Patients and methods: The single site, open-label phase 2 trial evaluated the pharmacokinetic profile of tapentadol and its major metabolite, tapentadol-O-glucuronide, as well as safety and tolerability and efficacy of a single dose of tapentadol oral solution (1 mg/kg) in patients (2 to <18 years) undergoing dental, ear, nose, or throat surgery. Blood sampling and pain intensity measurements were conducted using age-appropriate schedules and rating scales, respectively. Adverse events were monitored throughout the trial. Results: Sixty-six patients were treated. They were stratified by age: Group 1 (12 to <18 years), n=21; Group 2 (6 to <12 years), n=28; and Groups 3 (3 to <6 years) and 4 (2 to <3 years), n=17. Serum tapentadol concentrations observed in these pediatric patients were within the range observed in adults after administration of a single tapentadol immediate-release dose (50–100 mg), whereas those of the metabolite tapentadol-O-glucuronide were within the same range or lower than in adults who received comparable single doses of tapentadol. Pain intensity improved over time across all age groups. The most common treatment-emergent adverse events were nausea (24.2%), vomiting (16.7%), dizziness (9.1%), and headache (6.1%). Conclusion: A single dose of tapentadol oral solution (1 mg/kg) administered to pediatric patients (2 to <18 years) resulted in serum tapentadol concentrations within the targeted range shown to be safe and efficacious in adults. Tapentadol demonstrated good tolerability and safety; within the limitations of the trial design, improvements in postsurgical pain intensity were observed across the age groups. Tapentadol may provide a new treatment option in the management of moderate to severe pediatric pain.
Objective: To investigate efficacy and tolerability of tapentadol immediate release (IR) in the treatment of moderate to severe acute pain in three surgical pain models. Design: Three randomized, double-blind, placebo- and active-controlled, multicenter, phase 3 trials were performed in total hip replacement surgery, abdominal hysterectomy, and bunionectomy with trial medications administered every 4-6 hours as needed for up to 72 hours. Tapentadol IR was included in all trials, oxycodone IR in the total hip replacement trial, and morphine IR in the abdominal hysterectomy and bunionectomy trials; active controls ensured assay sensitivity.Main outcome measures: The primary efficacy endpoint was the sum of pain intensity differences over the first 24 hours of treatment (SPID24) in the abdominal hysterectomy trial and SPID48 in the other two trials. Tolerability was assessed by adverse events reporting.Results: A total of 330, 832, and 285 patients with total hip replacement, abdominal hysterectomy, and bunionectomy, respectively, were assessed for efficacy. All three trials demonstrated statistically significant improvements of tapentadol IR on the primary endpoint versus placebo and similar improvements compared to morphine IR or oxycodone IR. These findings were consistent with results of total pain relief assessments and patients’ global impressions of change in their overall health status after 72 hours (abdominal hysterectomy, bunionectomy). The tolerability profile of tapentadol IR was as expected for a centrally acting analgesic in the post-surgery setting.Conclusions: Tapentadol IR has strong analgesic efficacy and is well tolerated in multiple post-surgery conditions of moderate to severe pain.
Background Pharmacokinetics (PK), efficacy, and safety of the opioid analgesic tapentadol in the treatment of moderate-to-severe acute pain have so far not been investigated in pediatric patients <2 years of age. Patients and Methods Two multicenter, open-label trials assessed the pharmacokinetic profile, safety, tolerability, and efficacy of single doses of tapentadol oral solution (OS; NCT02221674; n=19) or intravenous infusion (IV, EudraCT 2014-002259-24; n=38) in children from birth to <2 years of age. Of these, 8 preterm neonates were included in the IV trial. A third randomized, double-blind, placebo-controlled trial (NCT02081391) investigated the efficacy and safety of multiple tapentadol OS doses in patients from birth to <2 years (placebo n=4, tapentadol n=11) using an immediate rescue trial design. Patients in all three trials underwent surgery that, in the investigator’s opinion, reliably produced moderate-to-severe pain requiring opioid treatment. Results Administration of single tapentadol doses resulted in tapentadol serum concentrations within the targeted range known to be safe and efficacious in adults and compared well to the range observed for children aged 2 to <18 years. Pain intensity already improved 15 min after administration. In the multiple dose trial, amounts of supplemental opioid analgesic medication within the first 24 h after start of trial medication were low (placebo 0.02 mg/kg, tapentadol 0.05 mg/kg). All patients stopped treatment with the trial medication because opioid analgesics were no longer required. Treatment-emergent adverse events occurred in 42.1% (tapentadol OS single dose), 28.9% (tapentadol IV), and 75% of placebo and 54.5% of tapentadol patients (tapentadol OS multiple doses), none of them serious. Conclusion Tapentadol showed a favorable PK and safety profile in children <2 years of age. Multiple tapentadol OS dosing is efficacious and generally well tolerated in children ≥2 years and might also be a useful treatment option for children <2 years in need of strong analgesics.
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