Cysteamine bitartrate delayed-release capsules control leukocyte cystine levels and promote statural growth and kidney health in an open-label study of treatment-naïve patients <6 years of age with nephropathic cystinosis.

Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease that is characterized by accumulation of cysteine and formation of crystals within cells of different organs and tissues causing systemic manifestations in childhood that include poor linear growth, ocular involvement, hypothyroidism, and progressive kidney disease. This study was a long-term, prospective open-label evaluation of twice-daily delayed release (DR) cysteamine capsules in cystinosis patients <6 years of age who were naïve to any form of cysteamine treatment. Fifteen treatment-naïve patients <6 years old (mean age 2.

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study.

Purpose: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare.

Design: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial.

Participants: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC.

Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials.

Background: Thyroid eye disease manifests inflammation and treatment-resistant proptosis and diplopia. Teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody, was approved in the USA on Jan 21, 2020, on the basis of two randomised trials. In this analysis we evaluated the short-term and long-term aggregate response to teprotumumab from the two trials, focusing on proptosis and diplopia.

Pharmacokinetics and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor-Blocking Antibody, in Thyroid Eye Disease.

Background And Objective: Thyroid eye disease (TED) is characterized by inflammation/expansion of orbital tissues, proptosis, and diplopia. Teprotumumab is the first US Food and Drug Administration-approved therapy for TED, administered as an initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks for an additional seven infusions. The objective of this article is to discuss the pharmacokinetics and exposure-response profile for teprotumumab in patients with TED.

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

Background: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.

Methods: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24.

Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.

Background: Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria.

CLCNKB-T481S and essential hypertension in a Ghanaian population.

Objective: Prior to the discovery of chloride channel Kb with a variant threonine change to serine at position 481 (CLCNKB-T481S) there were no variants or clinical disorders associated with gain-of-function defects in thick ascending limb of the kidney channels or transporters. CLCNKB-T481S is a novel gain-of-function variant that has been associated with essential hypertension. This finding has not been replicated until our current study.

A likelihood ratio test of population Hardy-Weinberg equilibrium for case-control studies.

Testing Hardy-Weinberg equilibrium (HWE) in the control group is commonly used to detect genotyping errors in genetic association studies. We propose a likelihood ratio test for testing HWE in the study population using both case and control samples. This test incorporates underlying association models.

Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema.

Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema.

Functional BSND variants in essential hypertension.

Background: Defects in the handling of renal salt reabsorption may contribute to interindividual differences in blood-pressure regulation and susceptibility to hypertension. Sodium chloride reabsorption in the thick ascending limb (TAL) is dependent in part on the chloride channel, ClC-Kb (encoded by CLCNKB), and its accessory subunit, barttin (encoded by BSND).

Methods: We investigated genetic variations in BSND in a screening population, and genotyped a homogenous cohort of normotensive and hypertensive Ghanaian subjects, in addition to four ethnically defined control populations.

Haplotype diversity in four genes (CLCNKA, CLCNKB, BSND, NEDD4L) involved in renal salt reabsorption.

Objective: Differences exist among various populations with regards to hypertension prevalence, severity, progression and response to therapy. Such differences may be due to genetic or environmental factors. We characterized the genetic variation and haplotype diversity of four hypertension candidate genes (CLCNKA, CLCNKB, BSND, NEDD4L) in four different ethnic groups (Caucasian Americans, African-Americans, Han Chinese, and Mexican-Americans).

Molecular physiology of renal ClC chloride channels/transporters.

Purpose Of Review: Recent findings relevant to the renal ClC chloride channels/transporters are reviewed with a focus on structure-function relationships, regulation of trafficking, role in blood pressure control, and pharmacology.

Recent Findings: The ClC proteins include plasma membrane Cl channels and vesicular Cl/H exchangers. Recent experiments have revealed further details regarding the structure and mechanism of the permeation path.

Congenital long QT syndrome aggravated by salt-wasting nephropathy.

Long QT syndrome (LQTS) is characterized by episodes of fainting or by sudden death as a result of torsades de pointes (TdP). In both the congenital and acquired forms of the syndrome, symptoms often become manifest upon exposure to additional clinical stressors of repolarization, such as drugs or hypokalemia. We report here the case of a patient with congenital LQTS in a 6-year-old boy who manifested symptoms only in the presence of electrolyte abnormalities associated with the inherited salt-wasting renal disorder Gitelman syndrome.