Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers

Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (i.v./s.c.) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8-96.1%) and 106% (99.4-113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.     

Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia

The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total mycophenolic acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose samples) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC(0-6)) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = -0.54, P < 0.0001). Receiver operating characteristic (ROC) curve analysis was performed on the albumin versus percentage free MPA data. The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA (defined as > or = 3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin < or = 31 g/L), clinicians should consider monitoring the free MPA concentration.     

The HORIZON Recurrent Fracture Trial: design of a clinical trial in the prevention of subsequent fractures after low trauma hip fracture repair

OBJECTIVE: To present the novel design of a trial testing the safety and efficacy of a yearly bisphosponate, zoledronic acid, in preventing new clinical fractures in patients with recent low trauma hip fracture repair. Research design and methods: Randomized, placebo-controlled, triple-blind study. One hundred and fifteen clinical centers worldwide are recruiting approximately 1714 subjects aged 50 years and over (no upper age limit, median age of enrolled subjects to date 79 years) who have undergone surgical repair of a low trauma hip fracture in the preceding 90 days. Patients will be assigned at random to an intervention group (5 mg zoledronic acid intravenously yearly) or a control group (placebo infusion yearly). Both groups receive a loading dose of Vitamin D2 or D3 IM or orally, followed by 800-1200 IU Vitamin D and 1000-1500 mg elemental calcium orally on a daily basis. Concomitant therapy with calcitonin, hormone replacement therapy, selective estrogen receptor modulators, tibolone, and external hip protectors are allowed. MAIN OUTCOME MEASURES: The primary endpoint is subsequent skeletal fractures as adjudicated by a clinical endpoints committee blinded to intervention status. Secondary outcomes include delayed hip fracture healing, changes in bone mineral density, and health resource utilization. Subjects will be recruited over a 3-4 year period and will be followed until 211 primary endpoints are accrued and adjudicated. CONCLUSIONS: This randomized clinical trial is novel among osteoporosis therapies as it (1). targets hip fracture patients, a previously understudied group, and (2). uses only clinically evident fractures as the primary outcome. Ethical and practical considerations in studying this frail population are discussed.     

Analysis of moonshine for contaminants

OBJECTIVES: In the past, some moonshine products contained potentially toxic contaminants. Although moonshine production continues in the United States, no studies have analyzed the content of moonshine since the early 1960s. We hypothesize that moonshine continues to contain potentially toxic concentrations of contaminants. METHODS: Forty-eight samples of illicitly distilled moonshine were obtained from law enforcement agencies. An independent laboratory, blinded to both the moonshine source and a control sample of ethanol, conducted the analysis. Lead content was determined using atomic absorption spectrophotometry with a graphite tube atomizer. Alcohol content, including ethanol, acetone, isopropanol, methanol, and ethylene glycol, was determined using gas liquid chromatography with flame ionization detection. RESULTS: Ethanol content ranged from 10.5% to 66.0% with a mean value of 41.2%. Lead was found in measurable quantities in 43 of 48 samples with values ranging from 5 to 599 parts per billion (ppb) with a mean value of 80.7 ppb. A total of 29 of 48 (60%) of samples contained lead concentrations above or equal to the EPA water guideline of 15 ppb. Methanol was found in only one sample at a concentration of 0.11%. No samples contained detectable concentrations of acetone, isopropanol, or ethylene glycol. CONCLUSIONS: Many moonshine samples contain detectable concentrations of lead. Extrapolations based on the described moonshine lead content suggest that chronic consumers of moonshine may develop elevated lead concentrations. Physicians should consider lead toxicity in the differential diagnosis when evaluating patients consuming moonshine.     

Measuring factors underlying intendedness of women's first and later pregnancies

CONTEXT: Unintended pregnancy is associated with poor health outcomes for mothers and infants, and is indicative of gaps in family planning services. Conventional measures of pregnancy intendedness do not reflect the multiple factors affecting a woman's pregnancy-related intentions and attitudes. METHODS: Data collected between March 2002 and February 2003 from 701 women in a public family planning clinic and 671 women in a public prenatal clinic in New Orleans were analyzed to examine factors underlying intendedness (including attitudes toward pregnancy and motivations to achieve or avoid pregnancy). RESULTS: In factor analyses, variables measuring pregnancy intendedness were represented by a single latent factor, pregnancy desirability. For first pregnancy, variables that best captured desirability were those measuring happiness, effort in achieving the pregnancy, extent of looking forward to telling friends, whether the pregnancy was intended (i.e., came at the right time or later), and whether the woman wanted to have a baby with her partner. For last or current pregnancies that were second or higher order ones, they were happiness, pregnancy wantedness, effort in achieving the pregnancy, whether the pregnancy was planned and whether the woman wanted to have a baby with her partner. Among women younger than 18 at first pregnancy, happiness and whether a woman wanted a baby with her partner were the only items that captured pregnancy desirability. CONCLUSIONS: Future surveys on pregnancy intendedness could reduce the number of questions used to capture pregnancy desirability. This should help standardize surveillance systems and permit better assessment of trends in pregnancy desirability over time.     

Editorial: Wishful thinking

As a supplement to our lead editorial, the editors of the new journal, Epidemiologic Perspectives & Innovations, provide a partial list of specific analyses and topic areas they would like to see submitted to the journal.     

The harmful consequences of elevating the doctor-patient relationship to be a primary goal of the general practice consultation

Introduction In the UK, it has been estimated that an ‘average’GP will undertake 8000 face to face clinical interactions annually.¹The consultation has come to be identified as the cornerstoneof general practice,² and to be seen more than an occasion forthe medical work of diagnosis and treatment.³ Beginning withthe work of Balint,⁴ it has also come to be seen as a ‘meeting’of individuals in which (often undifferentiated) symptoms areexpected to be understood and accommodated in relation to theirsocial and psychological contexts. Much effort in educationand research has been invested in giving the consultation thisdeeper meaning and wider range of potential practice.⁵ Thus,whilst the doctor–patient relationship is a given in today'sprimary care, achieving a satisfactory doctor–patientrelationship has also been elevated to be an outcome or goalof every consultation. In many ways, exploring that