Individual heat map assessments demonstrate vestronidase alfa treatment response in a highly heterogeneous mucopolysaccharidosis VII study population.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, progressively debilitating, life-threatening lysosomal disease caused by deficiency of the enzyme, β-glucuronidase. Vestronidase alfa is an approved enzyme replacement therapy for MPS VII. UX003-CL301 was a phase 3, randomized, placebo-controlled, blind-start study examining the efficacy and safety of vestronidase alfa 4 mg/kg intravenously administered every 2 weeks to 12 patients with MPS VII.

Correction to: Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials.

Introduction section, para 3, lines 2-4 which previously read.

Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials.

Introduction: Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a progressive, debilitating, ultra-rare lysosomal storage disorder caused by the deficiency of β-glucuronidase (GUS), an enzyme required for breakdown of glycosaminoglycans (GAGs). Vestronidase alfa, a recombinant human GUS, is an enzyme replacement therapy approved in the US and EU for the treatment of MPS VII.

Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of vestronidase alfa were evaluated in 23 adult and pediatric subjects with MPS VII enrolled in phase I-III clinical trials to optimize the clinical dosing regimen of vestronidase alfa.

Effect of γ-hydroxybutyrate (GHB) on driving as measured by a driving simulator.

Rationale: Gamma-hydroxybutyrate acid (GHB), a GABA receptor agonist approved for treatment of narcolepsy, impairs driving ability, but little is known about doses and plasma concentrations associated with impairment and time course of recovery.

Objective: To assess effects of oral GHB (Xyrem®) upon driving as measured by a driving simulator, and to determine plasma concentrations associated with impairment and the time course of recovery.

Methods: Randomized, double-blind, two-arm crossover study, during which 16 participants received GHB 50 mg/kg orally or placebo.

A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease.

Background: Drug development for ultra-rare diseases is challenging because small sample sizes and heterogeneous study populations hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate valid treatment effects.

Methods: To overcome these challenges, a novel Blind Start design was utilized in a study of vestronidase alfa in mucopolysaccharidosis VII (Sly syndrome), an ultra-rare lysosomal disease, that demonstrates the strengths of this approach in a challenging drug-development setting. Twelve subjects were randomized to 1 of 4 blinded groups, each crossing over to active treatment in a blinded fashion at different timepoints with efficacy analysis comparing the last assessment before cross over to after 24 weeks of treatment.

Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.

Purpose: Morquio A syndrome (mucopolysaccharidosis IVA [MPS IVA]) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetylgalactosamine-6-sulfatase, which is required to degrade the glycosaminoglycan keratan sulfate. Morquio A is associated with extensive morbidity and early mortality. Elosulfase alfa is an enzyme replacement therapy that provides a treatment option for patients with Morquio A.

Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial.

Objective: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA).

Methods: Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.

Design and methods of a postmarketing pharmacoepidemiology study assessing long-term safety of Prolia® (denosumab) for the treatment of postmenopausal osteoporosis.

Purpose: To describe the rationale and methods for a prospective, open-cohort study assessing the long-term safety of Prolia(®) for treatment of postmenopausal osteoporosis (PMO) in postmarketing settings.

Methods: Data will be derived from United States Medicare, United Healthcare, and Nordic (Denmark, Sweden, Norway) national registries. Observation will begin on the date of first Prolia(®) regulatory approval (May 26, 2010) and continue for 10 years.

Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals.

Recent advances in our understanding of disease biology, biomarkers, new therapeutic targets, and innovative modalities have each fueled a dramatic expansion in the development of novel human therapeutics. Many are biotechnology-derived biologics possessing high selectivity and affinity for their intended target; as such they often pose challenges in the development path to approval. One challenge is the selection of the first-in-human (FIH) dose.

Adverse drug events associated with yohimbine-containing products: a retrospective review of the California Poison Control System reported cases.

Background: Herbal supplements are classified as foods rather than drugs and are not required to undergo premarketing review by the Food and Drug Administration. Yohimbine is an alpha(2)-antagonist available in both prescription and herbal supplement products.

Objective: To determine the prevalence and severity of yohimbine-related adverse drug events (ADEs) reported to the California Poison Control System (CPCS).

Prevalence of smoking assessed biochemically in an urban public hospital: a rationale for routine cotinine screening.

Cotinine, a metabolite of nicotine, has been used to study tobacco smoke exposure in population studies, but the authors are unaware of its use to screen hospitalized patients. The authors measured serum cotinine levels in 948 patients admitted to an urban public hospital in San Francisco, California, between September 2005 and July 2006. On the basis of cotinine levels, they classified patients as active smokers (cotinine > or = 14 ng/mL), recent smokers or significantly exposed to secondhand smoke (SHS) (0.

Dietary supplement adverse events: report of a one-year poison center surveillance project.

Background: The safety and efficacy of dietary supplements is of growing concern to regulators, health-care providers and consumers. Few scientific data exist on clinical effects and potential toxicities of marketed products. Harmful supplements may not be identified for months or years with existing adverse event monitoring mechanisms.

Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations.

Objectives: Polymorphism in the genes for cytochrome (CYP)2C9 and the vitamin K epoxide reductase complex subunit 1 (VKORC1) affect the pharmacokinetics and pharmacodynamics of warfarin. We developed and validated a warfarin-dosing algorithm for a multi-ethnic population that predicts the best dose for stable anticoagulation, and compared its performance against other regression equations.

Methods: We determined the allele and haplotype frequencies of genes for CYP2C9 and VKORC1 on 167 Caucasian, African-American, Asian and Hispanic patients on warfarin.

Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.

What Is Already Known About This Subject: Performance-enhancing dietary supplements have not been clinically tested for safety or efficacy. In clinical trials performed under resting conditions, performance-enhancing supplements raise blood pressure and affect glucose homeostasis. The effect of exercise on the pharmacokinetics and pharmacodynamics of stimulant herbals is unknown.

Incomplete recovery of prescription opioids in urine using enzymatic hydrolysis of glucuronide metabolites.

Confirmation of opioids in urine samples of clinical patients requires liberation of opioids from their glucuronide conjugates. Both acid hydrolysis and enzyme hydrolysis using beta-glucuronidase from various sources have been reported, with the latter approach prevailing in most clinical toxicology laboratories. The goal of this study was to compare the efficiency of acid versus different enzyme hydrolysis methods in recovering morphine and common semisynthetic opioids from glucuronide standards and 78 patient urine samples that were screened positive for opioids as a class.

Gamma-hydroxybutyrate and ethanol effects and interactions in humans.

Background: Gamma-hydroxybutyrate (GHB) is a common drug of abuse that can produce serious toxicity, particularly when used with other sedatives. We examined the individual and combined effects of GHB and ethanol in human volunteers.

Methods: Sixteen healthy adults (7 men) were given 50 mg/kg GHB (Xyrem), 0.

GHB urine concentrations after single-dose administration in humans.

Gamma-hydroxybutyric acid (GHB) is used as an illicit drug and is implicated in drug-facilitated sexual assault, but it also has some therapeutic uses. Detection of GHB in urine is important for forensic testing and could be of clinical benefit in overdose management. Urine GHB concentration-time profiles have not been well-characterized or correlated with doses used therapeutically.

Comparison of an automated and point-of-care immunoassay to GC-MS for urine oxycodone testing in the clinical laboratory.

OxyContin, a controlled-release formulation of oxycodone, is increasingly abused. Monitoring patient compliance by urine drug testing may deter illegal diversion of OxyContin. Two urine immunoassays were evaluated with a 100 ng/mL cutoff for oxycodone.

Hemodynamic effects of ephedra-free weight-loss supplements in humans.

Purpose: Ephedra-free weight loss dietary supplements containing bitter orange (Citrus aurantium), a botanical source of the adrenergic amines synephrine and octopamine, have quickly emerged on consumer markets to replace banned ephedra products. These supplements may have some of the health risks associated with ephedra, but studies in humans are lacking. Our aim was to characterize the pharmacokinetics and cardiovascular effects of C.

Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.

Objective: Serious adverse health events have been reported with the use of dietary supplements containing ephedra and guarana. We sought to determine whether repeated dosing and multi-ingredient formulations contribute to the adverse effects of these supplements.

Methods: In this study, 16 healthy adults (8 women) took 2 doses each of ephedra-guarana alone, Xenadrine RFA, a multicomponent dietary supplement containing 25 mg ephedra alkaloids and 200 mg caffeine, or placebo 5 hours apart in a randomized, double-blind, 3-arm crossover study.

Colchicine-related death presenting as an unknown case of multiple organ failure.

A 45-year-old man presented to the emergency department (ED) with acute renal and hepatic failure as well as hypotension and metabolic acidosis. Despite aggressive intensive care, he had continued hypotension, leukocytosis, fever, renal and hepatic failure, and lactic acidosis. On hospital day 3, pancytopenia was noted.

Seizures reported in association with use of dietary supplements.

Background: Seizures in persons using dietary supplements (DS) have been reported through the Food and Drug Administration's (FDA) MedWatch system, but not formally reviewed.

Methods: Sixty-five cases of DS-associated seizures reported to MedWatch from 1993 to 1999 were obtained through the Freedom of Information Act and independently evaluated by three reviewers for probability of causation based on temporal relationship, biological plausibility, and underlying risk factors. Our aims in this review were 1) to assess the probability of causation in each case; 2) to characterize the patterns of use and types of supplements involved in cases of seizures; and 3) to identify trends that may explain potential risks factors for dietary supplement-related seizures.