Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

The time-dependent localization of the metal-to-ligand charge transfer (MLCT) excited states of ruthenium(II) complexes containing 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) ligands was studied by femtosecond transient absorption spectroscopy. Time-resolved anisotropy measurements indicate that the excited state hops randomly among the three ligands of each complex by subpicosecond interligand electron transfer (ILET). Although the bpy- and phen-localized (3)MLCT states have similar energies and steady-state emission spectra, pronounced differences in their excited-state absorption spectra make it possible to observe changes in excited state populations using magic angle transient absorption measurements. Analysis of the magic angle signals shows that the excited electron is equally likely to be found on any of the three ligands approximately 1 ps after excitation, but this statistical distribution subsequently evolves to a Boltzmann distribution with a time constant of approximately 10 ps. The apparent contradiction between ultrafast ILET revealed by time-dependent anisotropy measurements and the slower ILET seen in magic angle measurements on the tens of picoseconds time scale is explained by a model in which the underlying rates depend dynamically on excess vibrational energy. The insight that ILET can occur over multiple time scales reconciles contradictory literature observations and may lead to improved photosensitizer performance.

Perioperative pain is still a major problem, and new pharmacological means should be explored to mitigate such pain. Adenosine is an ubiquitous endogenous substance; when exogenously administered, it provides a number of salutary effects including neuromodulation, antinociception, and cytoprotective actions. The aim of this study was to characterize the perioperative antinociceptive-analgesic effects of intraoperative adenosine infusion and determine the duration of actions in the postoperative period, and compare them to those of remifentanil in patients undergoing major surgical procedures in a double-blind study.Sixty-two patients were randomly assigned to one of the two treatments. After standard induction of anesthesia, the lungs were mechanically ventilated. Anesthesia was maintained with a constant alveolar concentration of inhaled anesthetics (3% desflurane and 65% nitrous oxide in oxygen). A variable-rate of intravenous infusion of adenosine (50-500 microg kg(-1) x min(-1)) or remifentanil (0.05-0.5 microg kg(-1) x min(-1)) was initiated 5 min before the skin incision and was titrated to maintain systolic blood pressure and heart rate within 20% of baseline values during surgery. Postoperative evaluations included the level of sedation, degree of pain severity, opioid analgesic (fentanyl, morphine) consumption, and cardiorespiratory variables for 48 h. Intraoperative inhibition of the cardiovascular responses to surgical stimulation could be equally achieved by adenosine or remifentanil, and both could maintain excellent hemodynamic stability. Postoperatively, however, there were striking differences: (1). initial pain score was reduced by 60% (P<0.001) in the adenosine group compared to the remifentanil group and it remained lower throughout the 48 h recovery period; (2). postoperative morphine requirements during the first 0.25, 2 and 48 h were consistently lower in the adenosine group as compared to the remifentanil group (78, 71 and 42%, P<0.001, respectively); (3). adenosine patients remained significantly less sedated at all evaluations; (4) the end-tidal and arterial carbon dioxide values in the remifentanil group were significantly higher when patients were admitted to the postanesthesia care unit. No adverse effect of adenosine was observed at any time. Intraoperative adenosine infusion provided a salutary recovery from anesthesia associated with a pronounced and sustained postoperative pain relief. Compared to remifentanil, adenosine significantly reduced the opioid requirements and minimized the side effects including protracted sedation, cardiorespiratory instability, nausea, and vomiting in the postoperative recovery period.

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Oral iron supplementation increased the production of Hb in autologous blood donors more than placebo did. Additional intravenous iron did not lead to a further increase in preoperative Hb production.

Background:There remains an unmet medical need for new treatments for patients with sickle cell disease (SCD). Increased oxidant stress plays a major part in the pathophysiology of sickle cell disease. It can lead to disturbance of cell membranes, exposure of adhesion molecules and damage to the contents of the sickle red blood cells (sRBC). Previous work from our laboratory has demonstrated enhancement of nicotinamide adenine dinucleotide (NAD) in sRBC by supplementation with a precursor of NAD, L-glutamine. A multi-center Phase 2 placebo-controlled trial in patients with SCD utilizing oral prescription grade L-glutamine resulted in a trend for a decrease in the incidence of painful crises at 24 weeks and a statistically significant decrease in hospitalization during the same time period in the L-glutamine group without increased adverse events. Based on these results, a large multicenter Phase 3 clinical trial was undertaken to evaluate the efficacy and safety of prescription grade L-glutamine therapy in patients with SCD. Methods: A randomized (2:1), double-blind, placebo-controlled, parallel-group trial was conducted at 31 sites across the United States. Subjects were stratified by hydroxyurea usage. Eligibility criteria included patients ≥ 5 years of age with documented diagnoses of HbSS or HbS/β0-thalassemia with at least two documented episodes of sickle cell crises (SCC) diagnosed in a medical facility during the 12 months prior to screening. Pregnant women and patients with uncontrolled liver disease or renal insufficiency were excluded. Prescription grade L-glutamine at 0.6 g/kg/day (max 30 g), or placebo, was taken in two divided doses. Daily dose was rounded to the closest 10 g. The study drug was given for 48 weeks, then was tapered to zero over 3 weeks and a final evaluation visit was made 2 weeks after last dose. The primary endpoint was number of SCC; secondary endpoints include rates of hospitalization and adverse events; additional analyses include cumulative hospital days, incidence of acute chest syndrome (ACS) and time to first crises. Results:A total of 230 patients were enrolled; ages 5-58; 53.9 % female. 152 were assigned to L-glutamine and 78 to placebo; the groups were well balanced for clinical characteristics. The median incidence of SCC was significantly lower in the treatment group compared to the placebo group (3 events vs. 4 respectively; p=0.008); The median incidence of hospitalization was significantly lower in the treatment group compared to placebo group (2 events vs. 3 events respectively; p=0.005); Median cumulative hospital days were significantly lower by 41% in the treatment group (6.5 days) compared to the placebo group (11 days) (p=0.022); 11.9 % of the L-glutamine group and 26.9% of the placebo group were affected by acute chest syndrome (ACS) (p=0.006). The median time to first crisis was 54 days in placebo group and 87 days in treatment group (p=0.010). Adverse events in the treatment arm were similar to those observed in the placebo arm. Statistically significant improvements for the frequency of painful crises and hospitalization persisted with analysis stratified by hydroxurea use, age, and gender. Conclusion: This Phase 3 study in SCD demonstrated that treatment with prescription grade L-glutamine provided clinical benefit over placebo by reducing the frequency of painful crises and hospitalization. Additional clinical benefit was observed when evaluating ACS, time to first crises and duration of hospital stay. There was no increase in adverse events compared to placebo. Prescription oral L-glutamine is easy to administer and does not require special monitoring. Disclosures Niihara: Emmaus Medical Inc: Employment, Equity Ownership. Tran:Emmaus Medical Inc: Employment, Equity Ownership. Razon:Emmaus Medical Inc: Employment. Macan:Emmaus Medical Inc: Employment. Stark:Emmaus Medical Inc: Employment, Equity Ownership. Wun:Emmaus Medical Inc: Consultancy; Pfizer: Steering Committee Other. Adams-Graves:Emmaus Medical Inc: Consultancy.

Origin of the initial charge separation in optically-excited Ruthenium(II) tris(bidentate) complexes of intrinsic D 3 symmetry has remained a disputed issue for decades. Here we measure the femtosecond two-photon absorption (2PA) cross section spectra of [Ru(2,2′-bipyridine) 3 ] 2 and [Ru(1,10-phenanthroline) 3 ] 2 in a series of solvents with varying polarity and show that for vertical transitions to the lower-energy 1 MLCT excited state, the permanent electric dipole moment change is nearly solvent-independent, Δμ = 5.1-6.3 D and 5.3-5.9 D, respectively. Comparison of experimental results with quantum-chemical calculations of complexes in the gas phase, in a polarizable dielectric continuum and in solutesolvent clusters containing up to 18 explicit solvent molecules indicate that the non-vanishing permanent dipole moment change in the nominally double-degenerate E-symmetry state is caused by the solute-solvent interaction twisting the two constituent dipoles out of their original opposite orientation, with average angles matching the experimental two-photon polarization ratio.

Background: Sickle cell disease (SCD) is characterized by continuous oxidative stress through various mechanisms contributing to the pathophysiology and clinical course of sickle cell crises (SCC) and organ damage. L-glutamine is a precursor for the synthesis of essential metabolic redox cofactors including Nicotinamide Adenine Dinucleotide (NAD). Early studies have demonstrated that altered erythrocyte NAD redox potential was improved by oral L-glutamine therapy, suggesting that higher L-glutamine utilization in SCD exceeded de novo synthesis and its depletion played a role in oxidative stress. A Phase 2 study of Pharmaceutical Grade L-glutamine (L-glutamine) versus placebo showed promising results on clinical endpoints. In a Phase 3 study with 230 SCD patients, randomized 2:1 to L-glutamine or placebo, the median number of SCCs was 25% lower for L-glutamine than placebo (L-glutamine 3.0 vs. placebo 4.0). An analysis of SCC events showed significant differences between groups (p < 0.01). Categories for pre-specified subgroups for Age, Gender and Hydroxyurea (HU) use were defined in the statistical plan. HU use was also a randomization stratification factor since HU is the only FDA-approved drug for SCD treatment. Examination of the HU subgroup for differences in L-glutamine effect across categories (HU vs. no HU) was appropriate since approximately 66% of patients remained on HU throughout the Phase 3 study. To investigate the subgroup treatment effect size, treatment by subgroup interaction and consistency of the primary endpoint across the categories of the subgroups, an examination was performed following the guidelines for reporting subgroup analysis. Methods: The Negative Binomial Regression (NBR) model was utilized to generate an estimate of treatment effect and treatment by subgroup interactions of the three pre-specified subgroups. SCC events are most accurately described as counts and NBR is specifically intended for modeling count variables, usually for over-dispersed counts as seen in SCD studies. Rates of SCC for each treatment arm in a subgroup (Rate L-glutamine per 48 weeks / Rate placebo per 48 weeks) provide rate ratios, and an estimate of effect size, with 95% confidence intervals. A rate ratio <1.0 favored L-glutamine. Tests for treatment by subgroup interactions were conducted simultaneously. A significant interaction could be seen if the treatment is better than placebo for one category and worse than placebo for the other. Predefined categories for subgroups with corresponding sample sizes were as follows: Age: 5 - 18 years (n = 118) and ≥ 18 years (n = 111); Gender: Females (n = 124) and Males (n = 105). HU use before and during study: Yes (n = 153) and No (n = 76). Data for this Phase 3 subgroup report were obtained from an integrated dataset and the NBR model with treatment, subgroup, region and HU use as main effects and a treatment by subgroup interaction term was run with log (time on study) as an offset. Results: Age Subgroup:Both the 5 - 18 years and the > 18 years groups had a lower rate of SCCs per 48 weeks in the L-glutamine arm relative to placebo. The rate ratio was 0.93 [0.67 - 1.29] for the 5 - 18 years group and 0.64 [0.45 - 0.89] in the > 18 years group. There was no treatment by Age Group interaction (p = 0.118). Gender Subgroup: Both the Female and the Male groups had a lower rate of SCCs per 48 weeks in the L-glutamine treatment arm. The rate ratio was 0.81 [0.59 -1.12] for the Female group and 0.73 [0.51 - 1.05] for the Male group, indicating consistent treatment effects across genders. There was no treatment by Gender interaction (p = 0.683). Hydroxyurea Use Subgroup: Both HU groups had a lower rate of SCCs per 48 weeks in the L-glutamine arm. The treatment effects were consistent across groups, with a rate ratio of 0.78 [0.51 - 1.20] for the group without HU use and 0.77 [0.58 - 1.03] for the group with HU use. There was no treatment by HU use interaction (p = 0.961). See Figure 1 for a graphic example. Conclusion: For the Age and Gender subgroups, both categories in each subgroup benefited from L-glutamine but to varying degrees noted by the difference in rate ratios. For the HU use subgroup, both categories (on HU and not on HU) benefited from L-glutamine similarly. Lack of interactions in all subgroups indicated that regardless of category within a subgroup, treatment effect by Pharmaceutical Grade L-glutamine was beneficial. Figure 1 Hydroxyurea Use Subgroup Analysis Figure 1. Hydroxyurea Use Subgroup Analysis Disclosures Niihara: Emmaus Medical, Inc.: Employment, Equity Ownership. Viswanathan:Novartis: Speakers Bureau. Razon:Emmaus Medical, Inc.: Employment. Tran:Emmaus Medical, Inc.: Employment, Equity Ownership. Stark:Emmaus Medical, Inc.: Employment, Equity Ownership.