Abstract:
BACKGROUND:Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(-related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored. RESULTS:KH176 was well tolerated up to and including a single dose of 800 mg and multiple doses of 400 mg b.i.d. for 7 Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000 mg and at a multiple dose of 400 mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000 mg and multiple doses of 400 mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000 ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed. CONCLUSION:The study deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d. and has a pharmacokinetic profile supportive for a twice daily dosing. Only at high doses, KH176 causes clinically relevant changes in cardiac electrophysiology, including prolonged QTc interval and changes in T wave morphology. A Phase 2 clinical trial (100 mg b.i.d., orally) has been conducted recently of which the final results are expected Q1 2018. TRIAL REGISTRATION:NCT02544217 . Registered. ISRCTN43372293 . Retrospectively registered.
journal_name
Orphanet J Rare Disjournal_title
Orphanet journal of rare diseasesauthors
Koene S,Spaans E,Van Bortel L,Van Lancker G,Delafontaine B,Badilini F,Beyrath J,Smeitink Jdoi
10.1186/s13023-017-0715-0subject
Has Abstractpub_date
2017-10-16 00:00:00pages
163issue
1issn
1750-1172pii
10.1186/s13023-017-0715-0journal_volume
12pub_type
杂志文章,随机对照试验abstract:BACKGROUND:Primary Ciliary Dyskinesia (PCD) diagnosis relies on a combination of tests which may include (a) nasal Nitric Oxide (nNO), (b) High Speed Video Microscopy (HSVM) and (c) Transmission Electron Microscopy (TEM). There is variability in the availability of these tests and lack of universal agreement whether di...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1116-3
更新日期:2019-06-13 00:00:00
abstract:BACKGROUND:Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated. METHODS:Since 2015, the M...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1189-z
更新日期:2019-12-11 00:00:00
abstract::Warburg micro syndrome (WARBM) is a genetic heterogeneous disease characterized by microcephaly, intellectual disability, brain, ocular, and endocrine anomalies. WARBM1-4 can be caused by biallelic mutations of the RAB3GAP1 (RAB3 GTPase-activating protein 1), RAB3GAP2, RAB18 (RAS-associated protein RAB18), or TBC1D20 ...
journal_title:Orphanet journal of rare diseases
pub_type: 信件
doi:10.1186/s13023-014-0113-9
更新日期:2014-10-21 00:00:00
abstract:BACKGROUND:The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A. RESULTS:In three individuals with developmental delay w...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-019-1020-x
更新日期:2019-02-11 00:00:00
abstract:BACKGROUND:Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive progressive multiorgan disorder due to mutation in the gene encoding the enzyme Arylsulfatase B (ARSB). Dysfunctional ARSB causes lysosomal accumulation of glycosaminoglycans (GAG). Currently, enzyme replacement therapy (ERT) is preferred to hematop...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/1750-1172-8-134
更新日期:2013-09-05 00:00:00
abstract::Brazil is a country of continental dimensions, with many social inequalities. The latter are reflected on its health system, which comprises a large public component called SUS, a small paid health insurance component and a third very small private component, in which patients pay personally for medical services. Seve...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-016-0458-3
更新日期:2016-06-10 00:00:00
abstract:UNLABELLED:DEFINITION AND CLINICAL PICTURE: We propose the minimal definition of Dercum's disease to be generalised overweight or obesity in combination with painful adipose tissue. The associated symptoms in Dercum's disease include fatty deposits, easy bruisability, sleep disturbances, impaired memory, depression, di...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/1750-1172-7-23
更新日期:2012-04-30 00:00:00
abstract:INTRODUCTION:In health services research, there is a special emphasis on the transition from adolescence into adulthood. During this transition period, adolescents change from pediatric to adult medical care. This process must be carefully structured, particularly when special medical care is required. Challenges and d...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-016-0536-6
更新日期:2016-11-16 00:00:00
abstract:BACKGROUND:Skin neurofibromas represent one of the main clinical manifestations of neurofibromatosis 1, and their number varies greatly between individuals. Quantifying their number is an important step in the methodology of many clinical studies, but counting neurofibromas one by one in individuals with thousands of t...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-014-0202-9
更新日期:2014-12-05 00:00:00
abstract:BACKGROUND:Acute hepatic porphyria (AHP) consists of three rare metabolic disorders. We investigated the risk of long-term sick leave, disability pension, and premature death in individuals with AHP compared to the general population. METHODS:In a nationwide cohort study from 1992 to 2017, records of 333 persons (tota...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1273-4
更新日期:2020-02-21 00:00:00
abstract:BACKGROUND:Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-021-01673-z
更新日期:2021-01-22 00:00:00
abstract:BACKGROUND:For many rare diseases, few treatments are supported by strong evidence. Patients, family members, health care providers, and policy-makers thus have to consider whether to accept, recommend, or fund treatments with uncertain clinical effectiveness. They must also consider whether and how to contribute to cl...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01624-0
更新日期:2021-01-12 00:00:00
abstract:BACKGROUND:Myotonic dystrophy type 1 (Steinert's disease or DM1), the most common form of autosomal dominant muscular dystrophy in adults, is a multisystem disorder, affecting skeletal muscle as well as eyes, heart, gastrointestinal tract, endocrine system, and central nervous system, finally responsible of increasing ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-016-0417-z
更新日期:2016-04-04 00:00:00
abstract:BACKGROUND:Congenital Cataract Facial Dysmorphism and demyelinating Neuropathy (CCFDN, OMIM 604468) is an autosomal recessive multi-system disorder which was first described in Bulgarian Gypsies in 1999. It is caused by the homozygous founder mutation c.863 + 389C > T in the CTDP1 gene. The syndrome has been described ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/1750-1172-9-46
更新日期:2014-04-01 00:00:00
abstract:BACKGROUND:The needs and benefits of sharing health data to advance scientific research and improve clinical benefits have been well documented in recent years, specifically in the field of rare diseases where knowledge and expertise are limited and patient populations are geographically dispersed. Understanding what p...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1123-4
更新日期:2019-07-12 00:00:00
abstract:BACKGROUND:Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hep...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-1328-6
更新日期:2020-02-24 00:00:00
abstract::The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic a...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1186-2
更新日期:2019-11-21 00:00:00
abstract:OBJECTIVE:Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions. METHODS:A 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the cl...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01396-7
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abstract:BACKGROUND:Many rare diseases of childhood are life-threatening and chronically debilitating, so living with a rare disease is an on-going challenge for patients and their families. MPS is one of a range of rare inherited metabolic disorders (IMDs) that come under category 3 of life-limiting conditions, where there is ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-016-0521-0
更新日期:2016-10-10 00:00:00
abstract::Huntington's disease (HD) is a progressive neurodegenerative hereditary disease clinically characterised by the presence of involuntary movements, behavioural problems and cognitive decline. The disease-onset is usually between 30 and 50 years of age. HD is a rare disorder affecting approximately 1.3 in 10,000 people ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-016-0405-3
更新日期:2016-03-17 00:00:00
abstract::Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/1750-1172-1-28
更新日期:2006-07-26 00:00:00
abstract:BACKGROUND:Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and de...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1271-6
更新日期:2020-02-26 00:00:00
abstract:OBJECTIVE:High-resolution nerve ultrasound (HRUS) is a painless tool to quickly evaluate peripheral nerve morphology in vivo. This study set out to characterize peripheral nerve involvement in X-linked adrenomyeloneuropathy (AMN) by HRUS. METHODS:Thirteen adults with genetically proven AMN were examined using the Ultr...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-018-0939-7
更新日期:2018-11-03 00:00:00
abstract:BACKGROUND:Infantile spasms represent the catastrophic, age-specific seizure type associated with acute and long-term neurological morbidity. However, due to rarity and heterogenous determination, there is persistent uncertainty of its pathophysiological and epidemiological characteristics. The purpose of the current s...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,meta分析
doi:10.1186/s13023-018-0952-x
更新日期:2018-11-29 00:00:00
abstract::Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD ra...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/1750-1172-5-20
更新日期:2010-07-08 00:00:00
abstract::Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). Although its clinical and radiologic phenotype has been described for more than 50 years, there is still a great deal to be learned about the medical issues that arise secondary to this diagnosis, the manner in...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-018-0972-6
更新日期:2019-01-03 00:00:00
abstract:BACKGROUND:Fibrous dysplasia is a rare bone disorder, commonly associated with pain, deformity and fractures, which may significantly impact on quality of life. In this study we evaluate quality of life in patients with fibrous dysplasia using the Short Form-36 and the Brief Pain Inventory questionnaires. Data were com...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-017-0629-x
更新日期:2017-04-27 00:00:00
abstract:BACKGROUND:Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease leading to dysfunction of multiple organs. SMA can impair the quality of life (QoL) of patients and family. We aimed to evaluate the QoL of children with SMA and their caregivers and to identify the factors associated with QoL in a ...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01638-8
更新日期:2021-01-06 00:00:00
abstract:BACKGROUND:Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. METHODS:In this review, we summar...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
doi:10.1186/s13023-018-0856-9
更新日期:2018-07-11 00:00:00
abstract:BACKGROUND:Prader-Willi-Syndrome (PWS) is characterized by hypothalamic-pituitary dysfunction. Recent research suggests starting growth hormone-treatment (GHT) as soon as possible. The aim of this study is to analyze possible differences in auxological parameters, carbohydrate and lipid metabolism between two groups of...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-020-01527-0
更新日期:2020-10-12 00:00:00