Endothelin antagonists in hypertension and kidney disease

The endothelin (ET) system seems to play a pivotal role in hypertension and in proteinuric kidney disease, including the micro- and macro-vascular complications of diabetes. Endothelin-1 (ET-1) is a multifunctional peptide that primarily acts as a potent vasoconstrictor with direct effects on systemic vasculature and the kidney. ET-1 and ET receptors are expressed in the vascular smooth muscle cells, endothelial cells, fibroblasts and macrophages in systemic vasculature and arterioles of the kidney, and are associated with collagen accumulation, inflammation, extracellular matrix remodeling, and renal fibrosis. Experimental evidence and recent clinical studies suggest that endothelin receptor blockade, in particular selective ET_AR blockade, holds promise in the treatment of hypertension, proteinuria, and diabetes. Concomitant blockade of the ET_B receptor is not usually beneficial and may lead to vasoconstriction and salt and water retention. The side-effect profile of ET receptor antagonists and relatively poor antagonist selectivity for ET_A receptor are limitations that need to be addressed. This review will discuss what is currently known about the endothelin system, the role of ET-1 in the pathogenesis of hypertension and kidney disease, and summarize literature on the therapeutic potential of endothelin system antagonism.     

Children With Chronic Pain: Response Trajectories After Intensive Pain Rehabilitation Treatment

Intensive pain rehabilitation programs for children with chronic pain are effective for many patients. However, characteristics associated with treatment response have not been well documented. In this article we report trajectories of pain and functional impairment in patients with chronic pain up to 1 year after intensive pain rehabilitation and examine baseline factors associated with treatment response. Patients (n?=?253) with chronic pain and functional disability were assessed at 5 time points (admission, discharge, 1-month, 4-month, and 12-month follow-ups). Individual trajectories were empirically grouped using SAS PROC TRAJ. For functional disability, 2 groups emerged: treatment responders (88%) and nonresponders (12%). Using a binomial logistic regression model to predict disability trajectory group, no baseline variables were significant predictors for the disability trajectory group. For pain, 3 groups emerged: early treatment responders (35%), late treatment responders (38%), and nonresponders (27%). Using multinomial regression analyses to predict pain trajectory group, older age, higher pain scores, fewer social difficulties, higher anxiety levels, and lower readiness to change were characteristics that distinguished nonresponders from responders; no significant predictors distinguished the late responders from the early responders. These results provide key information on the baseline factors that influence intensive pain rehabilitation outcomes, including risk factors that predict treatment nonresponse. Our findings have implications for developing more targeted treatment interventions.

Gene and antisense delivery in alcoholism research

This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. Drs. Yedy Israel and Fulton Crews were organizers and co-chairpersons. The presentations were (1) Introduction to the symposium, by Yedy Israel; (2) Gene delivery to the brain, by Fulton T. Crews; (3) Gene therapy in alcoholic liver injury, by Ronald Thurman; and (4) Antisense oligonucleotides and antisense-gene delivery, by Yedy Israel.     

The pharmacokinetics of epidural ropivacaine in infants and young children

The pharmacokinetic variables of ropivacaine were characterized after epidural bolus injection in pediatric patients. The subjects, 7 infants (aged 3-11 mo) and 11 young children (aged 12-48 mo), received 1.7 mg/kg of ropivacaine via a lumbar epidural catheter. Total plasma concentrations of ropivacaine measured over 24 h were assayed by high-pressure liquid chromatography, and pharmacokinetic modeling was performed by Nonlinear Mixed Effects Modeling analysis. The median peak venous plasma concentrations (C(max)) in infants and young children were 610 microg/L (interquartile range [IQR], 550-725 microg/L) and 640 microg/L (IQR, 540-750 microg/L), respectively. The median times to maximum plasma ropivacaine concentration (T(max)) were 60 min (IQR, 60-120 min) in infants and 60 min (IQR, 30-90 min) in young children. There were no statistical differences between median values of C(max) and T(max) between infants and young children. The calculated clearance (CL) in infants was 4.26 mL x min(-1) x kg(-1) (9% coefficient of variation), and in young children it was 6.15 mL x min(-1) x kg(-1) (11% coefficient of variation). The CL for infants was significantly less than the CL for young children (P < 0.01). The volume of distribution was estimated to be 2370 mL/kg (9% coefficient of variation) for both young children and infants. No systemic toxicity was observed in either group. IMPLICATIONS: This study revealed that the pharmacokinetic variables of lumbar epidural bolus ropivacaine in pediatric patients aged 3 to 48 mo are similar to those of adults, except that drug clearance was less in infants compared with older children.     

The Response of Patients with Duchenne's Muscular Dystrophy to Neuromuscular Blockade with Vecuronium

Background: The authors hypothesized that patients with Duchenne's muscular dystrophy (DMD) are more sensitive to nondepolarizing muscle relaxants.

Methods: Eight children with DMD and eight healthy children having orthopedic procedures were studied. Anesthesia consisted of thiopental, 60% nitrous oxide in 40% oxygen, and intravenous fentanyl and midazolam. Using electromyography, the ulnar nerve was stimulated and the electromyographic train-of-four ratio (TOFr) of the first dorsal interosseous muscle was recorded every 60 s. After baseline TOFr recording, all patients received 50 micro gram/kg vecuronium and the TOFr at 3 min was compared. Vecuronium (10 micro gram/kg) was then administered every minute until TOFr was or= to 0.01. Then 10 micro gram/kg of vecuronium were administered to maintain TOFr Results: The initial dose of vecuronium resulted in greater TOFr depression in patients with DMD than in controls (0.14 vs. 0.86). Less vecuronium was needed to produce TOFr or= to 0.1 after the initial dose was longer in the patients with DMD than in the controls (28 vs. 20 min; P = 0.03), and the maintenance dose of vecuronium was less in patients with DMD (0.6 vs. 1.3 micro gram [center dot] kg sup -1 [center dot] min sup -1; P < 0.01). The time for TOFr recovery from 0.1 to 0.25 was 36 min in the patients with DMD and 6 min in the controls (P <0.01). After neostigmine, the TOFr was 1.0 in the controls and 0.91 (P = 0.03) in the patients with DMD.