Tadalafil improves oxygenation in a model of newborn pulmonary hypertension.

OBJECTIVES: Sildenafil, a phosphodiesterase-5 inhibitor, significantly improves oxygenation when used in animal models and patients with pulmonary hypertension. Tadalafil is a new and clinically available phosphodiesterase-5 inhibitor that, aside from causing pulmonary vasodilation, has been shown to increase cardiac output in pulmonary hypertensive adults. Its hemodynamic effects on the newborn, however, have not been tested. The objective was to evaluate the effect of tadalafil on central hemodynamics and arterial oxygenation in a piglet model of acute pulmonary hypertension. DESIGN: Laboratory experiment. SETTING: University laboratory. SUBJECTS: Seven anesthetized and mechanically ventilated newborn piglets. INTERVENTIONS: Pulmonary hypertension was induced and maintained in seven anesthetized and mechanically ventilated newborn piglets following acute exposure to 11% oxygen. The experimental animals received orla tadalafil (1 mg/kg), whereas the control animals were given an equal volume of normal saline. Systemic and pulmonary hemodynamic variables were measured, and the cardiac output and ejection fraction were obtained from two-dimensional echocardiogram and Doppler measurements in all animals. Serial arterial blood gases were also obtained, and the alveolar-arterial oxygen gradient was calculated. MEASUREMENTS AND MAIN RESULTS: In contrast with the control animals, in which no significant changes were noted, in the experimental animals pulmonary arterial pressure decreased on average by 54% and cardiac output increased by 88% following tadalafil administration (p < .05). Tadalafil increased the PaO2 by 48% +/- 21% (p < .01), likely as a result of a 74% +/- 13% reduction in the alveolar-arterial oxygen gradient (p < .01). CONCLUSIONS: In a newborn animal model of acute pulmonary hypertension, oral tadalafil administration reduces pulmonary vascular resistance and increases arterial oxygenation by increasing cardiac output and reducing the lung shunt fraction. This previously untested compound deserves additional investigation in laboratory models of persistent pulmonary hypertension of the newborn.     

Drug Target Interference in Immunogenicity Assays: Recommendations and Mitigation Strategies

Sensitive and specific methodology is required for the detection and characterization of anti-drug antibodies (ADAs). High-quality ADA data enables the evaluation of potential impact of ADAs on the drug pharmacokinetic profile, patient safety, and efficacious response to the drug. Immunogenicity assessments are typically initiated at early stages in preclinical studies and continue throughout the drug development program. One of the potential bioanalytical challenges encountered with ADA testing is the need to identify and mitigate the interference mediated by the presence of soluble drug target. A drug target, when present at sufficiently high circulating concentrations, can potentially interfere with the performance of ADA and neutralizing antibody (NAb) assays, leading to either false-positive or, in some cases, false-negative ADA and NAb assay results. This publication describes various mechanisms of assay interference by soluble drug target, as well as strategies to recognize and mitigate such target interference. Pertinent examples are presented to illustrate the impact of target interference on ADA and NAb assays as well as several mitigation strategies, including the use of anti-target antibodies, soluble versions of the receptors, target-binding proteins, lectins, and solid-phase removal of targets. Furthermore, recommendations for detection and mitigation of such interference in different formats of ADA and NAb assays are provided.     

Fibrin glue: an alternative technique for nerve coaptation--Part II. Nerve regeneration and histomorphometric assessment

The results of nerve repair with fibrin glue and microsuture were evaluated in rat nerve transection models. Ninety Wistar-Furth rat median nerves were exposed, transected, and repaired in an end-to-end fashion with one of four substances/techniques: 1) human fibrin sealant (Quixil); 2) autologous graft and human fibrin sealant (Quixil); 3) bovine fibrin sealant (Tissucol); and 4) nylon microsuture, epineurial technique. Histologic analyses were performed at 3-, 6-, and 9-month postoperative intervals, and factors evaluated included: presence of inflammatory cells (i.e., macrophages and T cells); number of Schwann cells at the repair site; number of blood vessels; fibrosis; axonal regeneration; and fiber alignment. An additional group underwent histologic analysis at 3 weeks following repair with Quixil. Surgical time of repair was also measured. Nerve repairs performed with fibrin sealants produced less inflammatory response and fibrosis, and better axonal regeneration and fiber alignment than nerve repairs performed with microsuture. In addition, the fibrin sealant techniques were quicker and easier to use. The authors conclude that fibrin sealant represents a good alternative technique to microsuture for peripheral-nerve repair.     

De novo gastrointestinal tumours after renal transplantation: role of CMV and EBV viruses

The development of new and more effective immunosuppressive agents has provided long-term survival for transplant recipients, thereby increasing the risk of de novo malignancy in chronic immunocompromised hosts. While de novo post-transplant lymphoproliferative diseases and skin cancer has been shown to have an increased incidence in long-term surviving solid organ transplant recipients, the association with gastrointestinal (GI) cancer is controversial. Over 12 yr, 20 patients (5%) out of 395 renal transplant recipients developed 23 de novo tumours; 11 skin cancer and 12 non-skin cancer. Four patients (1%) developed de novo tumours of the GI tract (three colon, and one gastric cancer). Immediately after tumour's diagnosis, immunosuppressive therapy was reduced; all patients were shifted from cyclosporine to Rapamicine within 30 d. The tumour was surgically resected with curative intent in three cases, while one patient had only palliative surgery because of metastatic disease. The post-operative courses was uneventful. All patients maintained normal graft function. However, three out of four patients (75%) died of progression of the neoplasm, within a median time from the diagnosis of 12 months. Further, we investigated a possible correlations between de novo GI cancer and HCV, HBV status, infections, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation, episodes of rejection, and blood transfusions. All cases with GI de novo cancers reported in this paper developed CMV and EBV reactivation within three months after transplantation. Thereafter we suggest a closer follow-up for de novo GI cancer in renal transplants with early CMV and EBV reactivation in order to avoid delayed diagnosis.     

Open-label olanzapine treatment in bipolar I disorder: clinical and work functional outcomes

OBJECTIVES: The objective of this study was to describe clinical and work functional outcomes associated with 6-month open-label olanzapine treatment for bipolar I disorder. METHODS: The study consisted of 249 patients entering a 6-month open label phase after 12 weeks of acute double-blind haloperidol or olanzapine treatment. Baseline for analysis was defined as the beginning of open-label treatment. The clinical outcomes were symptomatic remission defined by a Y-MRS total score < or = 12 and a HAM-D total score < or = 8 at the end of 6 months of treatment. The work functional outcomes included work functional scores, the proportion of patients who reported to 'work' as employee, volunteers, students, or house workers and the proportion of patients who specifically reported to 'work for pay'. RESULTS: A total of 240 patients reported work functional outcomes post open-label baseline. Among them, 15.4% patients moved into a 'work group' from a 'no-work group' at baseline, while 7.1% did the opposite (p = 0.0065) and 13.3% reported an improvement to 'work for pay' status from a 'not working for pay' status at baseline, while there was 4.2% of worsening in employment status (p = 0.0007). Overall, improvement in the work functional score was found at all post-baseline time points, beginning at month two (p = 0.003).Limitations: Results of this study need to be confirmed by double-blind randomized controlled studies. There was a lack of detailed information on work functioning from the questionnaire. CONCLUSIONS: Open-label olanzapine treatment for 6 months was associated with improvements in work functional outcomes in patients with bipolar disorder.     

Long-term effect of laser treatment for dry age-related macular degeneration on choroidal hemodynamics

PURPOSE: To determine whether laser treatment applied according to the complications of age-related macular degeneration prevention trial (CAPT) has an effect on the choroidal circulation. DESIGN: Randomized controlled trial. METHODS: This study included 30 CAPT patients with bilateral drusen. Laser Doppler flowmetry was used to measure relative choroidal blood flow (Ch(flow)) in the fovea. Measurements were obtained through dilated pupils in both eyes of each patient before photocoagulation was applied in one eye. Measurements were repeated at three months (30 patients) and 28 months (23 patients). RESULTS: Average Ch(flow) at baseline, three months, and 28 months was 7.2 +/- 2.1 (+/-1 SD), 7.3 +/- 2.5, and 6.8 +/- 2.7 arbitrary units (AU) in the control eyes and 6.6 +/- 1.6, 7.0 +/- 2.3, and 7.8 +/- 3.0 AU in the treated eyes. In comparison to control eyes, there was no significant change in Ch(flow) in the treated eyes at three months after treatment. At 28 months, however, there was a 5.6% drop in Ch(flow) in control eyes and an 18.2% increase in Ch(flow) in treated eyes from baseline. The average difference of 23.8% between the percentage changes in Ch(flow) observed in the control and treated eyes was statistically significant (paired two-tailed Student t test; P = .05). CONCLUSIONS: Our results suggest an increase in choroidal blood flow 28 months after laser treatment according to the CAPT protocol. This increase may play a role in the mechanism leading to the disappearance of drusen after photocoagulation. Whether removal of drusen after photocoagulation is beneficial to the patients is not known at this time.