Safety and efficacy of transitioning from selexipag to oral treprostinil in pulmonary arterial hypertension: Findings from the ADAPT registry.

PURPOSE: Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil. METHODS: ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions. RESULTS: Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging. CONCLUSION: Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Visualizing the solvent-inaccessible core of a group II intron ribozyme.

Group II introns are well recognized for their remarkable catalytic capabilities, but little is known about their three-dimensional structures. In order to obtain a global view of an active enzyme, hydroxyl radical cleavage was used to define the solvent accessibility along the backbone of a ribozyme derived from group II intron ai5gamma. These studies show that a highly homogeneous ribozyme population folds into a catalytically compact structure with an extensively internalized catalytic core. In parallel, a model of the intron core was built based on known tertiary contacts. Although constructed independently of the footprinting data, the model implicates the same elements for involvement in the catalytic core of the intron.

Sustainability of prevention.

This paper outlines the guidelines for sustaining prevention and makes suggestions for getting from the field's current status to greater levels of permanence for prevention. The paper begins by reviewing the status of prevention, then focuses on major considerations for achieving sustainability, including two processes of institutionalization, comprehensive programming and professionalism.

Pharmacological modulation of fluid secretion in the pigmented rabbit conjunctiva.

We determined net fluid secretion rate across the pigmented rabbit conjunctiva in the presence and absence of pharmacological agents known to affect active Cl- secretion and Na+ absorption. Fluid flow across a freshly excised pigmented rabbit conjunctiva mounted between two Lucite half chambers was measured by a pair of capacitance probes in an enclosed cabinet maintained at 37 degrees C and a relative humidity of 70%. Fluid transport was also measured in the presence of compounds known to affect active Cl- secretion (cAMP, UTP, and ouabain), Na+ absorption (D-glucose), or under the Cl--free condition on both sides of the tissue. Net fluid secretion rate across the pigmented rabbit conjunctiva in the serosal-to-mucosal direction at baseline was 4.3+/-0.2 microl/hr/cm2 (mean +/- s.e.m.). Net fluid secretion rate was increased approximately two-fold by mucosally applied 1 mM 8-Br cAMP (8.4+/-0.4 microl/hr/cm2) and 10 microM UTP (9.8+/-0.6 microl/hr/cm2), but was abolished by either serosally applied 0.5 mM ouabain (0.3+/-0.1 microl/hr/cm2) or under the Cl--free conditions (0.06+/-0.04 microl/hr/cm2). Mucosal addition of 20 mM D-glucose decreased net fluid secretion rate to 1.0+/-0.5 microl/hr/cm2. In conclusion, the pigmented rabbit conjunctiva appears to secrete fluid secondary to active Cl- secretion. This net fluid secretion is subject to modulation by changes in active Cl- secretion rate and in mucosal fluid composition such as glucose concentration.

Assembly of exogenous fibronectin into type II cell extracellular matrix.

Type II pulmonary epithelial cells (T2P) in primary culture assemble a biologically active extracellular matrix (ECM) from endogenously synthesized components, including fibronectin. Fibronectin is a well-recognized attachment protein that mediates cell adhesion, migration, and cytodifferentiation. In some cell types, exogenous fibronectin also is incorporated into ECM. The latter pathway of ECM assembly was thus investigated in T2P. Cells were cultured for 3-days in Dulbecco's modified Eagle's medium (DMEM) with or without 10% fetal calf serum (FCS), a source of exogenous fibronectin. Cell and matrix fractions were harvested on culture days 1, 2, and 3 to determine synthesis of cell and matrix proteins and matrix fibronectin content. During 3 days in DMEM containing 10% FCS, T2P flattened and spread to confluence more rapidly than cells in DMEM; they also produced ECM with higher fibronectin content than did cells in DMEM alone. On culture days 2 and 3, 10% FCS doubled (on average) synthesis of ECM fibronectin; in contrast, ECM fibronectin content increased nearly 10-fold. These observations suggest that cultured type II cells incorporate exogenous fibronectin into newly assembled ECM to a greater extent than the newly synthesized glycoprotein. Components of both endogenous and exogenous origin may therefore contribute to T2P assembly of a biologically active ECM.

Experimental evaluation of "The Images Within": an alcohol education and prevention program.

A program titled "The Images Within" was implemented and evaluated in three sites on the east coast of the United States. This school curriculum uses art work developed by children of alcoholics to stimulate classroom discussions of the problems of parental alcohol abuse. The evaluation with 278 experimental and 310 control students indicated increased knowledge about the effects of alcohol and improved skills in coping with alcohol problems and help seeking behavior. Process data indicated that related programs were initiated, students were stimulated by the program and teachers were positive in their perceptions of the program. Schools implementing this program need to have developed referral networks to handle the individual concerns that are expressed as a result of participation in "The Images Within."

In vitro modeling of spinal anesthesia. A digital video image processing technique and its application to catheter characterization.

BACKGROUND: Maldistribution of intrathecal local anesthetic has recently been implicated as a contributor to neurotoxic injury. In vitro modeling can be used to understand the distribution of anesthetic agents within the subarachnoid space. We describe an in vitro modeling technique that uses digital video image processing and its application to catheter injection of local anesthetic. METHODS: A clear plastic model of the subarachnoid space, including a simulated spinal cord and cauda equina, was filled with lactated Ringer's solution. Phthalocyanine blue dye of known concentration was injected into the model through small-bore (28-G) and large-bore (18-G) catheters. Injections were performed at a variety of controlled rates and sacral catheter positions, and the propagation of dye throughout the model was recorded on videotape, digitized by computer, and converted to a two-dimensional image of dye concentration. A subset of data was compared with results obtained from spectrophotometric analysis. RESULTS: There was a strong correlation (r = 0.98) between data obtained with analysis by digital video image processing and those obtained spectrophotometrically. Catheter size, catheter angle, and injection rate significantly influenced the distribution and peak concentration of simulated anesthetic. No major differences in distribution or peak concentration were observed with the two types of 28-G catheters. CONCLUSIONS: The digital video image processing technique can be used to quantify anesthetic distribution rapidly within a model of the subarachnoid space without disturbing the distribution. The current results demonstrate a strong dependence of anesthetic distribution on catheter angle, catheter size, and injection rate. Comparisons between 28-G catheters suggest that the difference in reported incidence of cauda equina syndrome associated with different 28-G catheters cannot be explained on the basis of differences in anesthetic distribution.

Soman intoxication in hypothyroid rats: alterations in brain neuronal RNA, acetylcholinesterase and survival.

Studies were conducted to investigate relationships among soman (pinacolyl methylphosphonofluoridate) induced seizure activity, central metabolic impairments and lethality in normal vs thyroid-deficient rats. Quantitative cytophotometric measurements of individual cerebrocortical (layer V) and striatal neuron RNA contents were made following dosages of 0.5, 0.9 and 1.5 LD(50) soman (LD(50) = 135 ?g/kg, sc). Hypothyroidism was associated with a marked diminution of overt convulsive activity and reduced susceptibility to lethal actions of soman as indicated by enhanced 24- and 48-h survival rates at 0.9, 1.2 and 1.5 LD(50). Hypothyroidism per se produced RNA depletion in both cortical and striatal neurons. Soman treatment diminished cortical RNA to essentially the same extent in thyroid-deficient rats as in euthyroids, whereas there was no further reduction of striatal neuron RNA. It was found that amelioration of convulsive activity and lethal- ity in hypothyroid rats was accompanied by reduced cerebral acetylcholinesterase (AChE, EC 3.1.1.7) inactivation, and that plasma cholinesterase (EC 3.1.1.8) and aliesterase (EC 3.1.1.1) levels were significantly higher in hypothyroid than in euthyroid saline-control rats. The overall data indicate that soman- induced central metabolic impairments can occur independent of paroxysmal neural activity and lethal actions of the agent. Resistance to soman observed with thyroid deficiency may be due in large part to increased binding to plasma enzymes and diminished delivery of soman to AChE in vital cholinergic sites.

Scanning cytophotometric analysis of myocardial nucleic acid and chromatin changes in soman toxicated rabbits.

Myocardial nucleic acid responses were analysed in New Zealand White rabbits 20 min-1 h and 6-8 h following single subcutaneous injections of soman (20, 30, or 40 micrograms kg-1). Scanning-integrating microdensitometry was used to quantify Azure B-RNA and Feulgen-DNA (F-DNA) levels, and changes in the susceptibility of chromatin to Feulgen acid hydrolysis (F-DNA reactivity) of individual ventricular myocardial cells. With a dosage of 20 micrograms kg-1 soman, no RNA alterations were evidenced at 1 h whereas at 6-8 h myocardial cells exhibited higher RNA levels and an increase in F-DNA reactivity of chromatin. With dosages of 30 and 40 micrograms kg-1 soman there was an augmentation in RNA levels and in the acid hydrolysability of nuclear chromatin at both 20 min-1 h and 6-8 h. It is postulated that the observed cellular transformations represent a compensatory augmentation in myocardial metabolic functioning presumably in response to an increased functional demand on the ventricular myocardium. The absence of cytopathic or cytochemical evidence of impairment in nucleic acid metabolism is inconsistent with the premise that soman exerts direct cytotoxic effects on rabbit myocardium.

A review of the reliability and validity of the Drug Abuse Warning Network.

The Drug Abuse Warning Network (DAWN) is a government-funded drug abuse data gathering system used extensively at the federal, state, and local levels in policy formulation and program evaluation, and as an indicator of changing trends in substance abuse. This paper (1) briefly describes the DAWN data, (2) examines reviews of the DAWN system, (3) assesses the strengths and limitations of the DAWN data, and (4) illustrates some possible further uses of these data for research and policy purposes.