The Novel Combination of Theophylline and Bambuterol as a Potential Treatment of Hypoxemia in Humans

Hypoxemia can be life-threatening both, acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the β2 adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% O2). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20mg) on adverse events (AEs), plasma K+, pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low K+ (The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n-butoxyethylpyridylporphyrin-based redox modifier

Combinations of radiotherapy (RT) and chemotherapy have shown efficacy toward brain tumors. However, therapy-induced oxidative stress can damage normal brain tissue, resulting in both progressive neurocognitive loss and diminished quality of life. We have recently shown that MnTnBuOE-2-PyP5+ (Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium -2-yl)porphyrin) rescued RT-induced white matter damage in cranially-irradiated mice. Radiotherapy is not used in isolation for treatment of brain tumors; temozolomide is the standard-of-care for adult glioblastoma, whereas cisplatin is often used for treatment of pediatric brain tumors. Therefore, we evaluated the brain radiation mitigation ability of MnTnBuOE-2-PyP5+ after either temozolomide or cisplatin was used singly or in combination with 10 Gy RT. MnTnBuOE-2-PyP5+ accumulated in brains at low nanomolar levels. Histological and neurobehavioral testing showed a drastic decrease (1) of axon density in the corpus callosum and (2) rotorod and running wheel performance in the RT only treatment group, respectively. MnTnBuOE-2-PyP5+ completely rescued this phenotype in irradiated animals. In the temozolomide groups, temozolomide/ RT treatment resulted in further decreased rotorod responses over RT alone. Again, MnTnBuOE-2-PyP5+ treatment rescued the negative effects of both temozolomide ± RT on rotorod performance. While the cisplatin-treated groups did not give similar results as the temozolomide groups, inclusion of MnTnBuOE-2-PyP5+ did not negatively affect rotorod performance. Additionally, MnTnBuOE-2-PyP5+ sensitized glioblastomas to either RT ± temozolomide in flank tumor models. Mice treated with both MnTnBuOE-2-PyP5+ and radio-/chemo-therapy herein demonstrated brain radiation mitigation. MnTnBuOE-2-PyP5+ may well serve as a normal tissue radio-/chemo-mitigator adjuvant therapy to standard brain cancer treatment regimens. Environ. Mol. Mutagen. 57:372–381, 2016. © 2016 Wiley Periodicals, Inc

Enhanced Drug Delivery to the Skin Using Liposomes

Background:. Enhancing drug delivery to the skin has importance in many therapeutic strategies. In particular, the outcome in vascularized composite allotransplantation mainly depends on systemic immunosuppression to prevent and treat episodes of transplant rejection. However, the side effects of systemic immunosuppression may introduce substantial risk to the patient and are weighed against the expected benefits. Successful enhancement of delivery of immunosuppressive agents to the most immunogenic tissues would allow for a reduction in systemic doses, thereby minimizing side effects. Nanoparticle-assisted transport by low temperature–sensitive liposomes (LTSLs) has shown some benefit in anticancer therapy. Our goal was to test whether delivery of a marker agent to the skin could be selectively enhanced. Methods:. In an in vivo model, LTSLs containing doxorubicin (dox) as a marker were administered intravenously to rats that were exposed locally to mild hyperthermia. Skin samples of the hyperthermia treated hind limb were compared with skin of the contralateral normothermia hind limb. Tissue content of dox was quantified both via high-performance liquid chromatography and via histology in skin and liver. Results:. The concentration of dox in hyperthermia-treated skin was significantly elevated over both normothermic skin and liver. (P < 0.02). Conclusions:. We show here that delivery of therapeutics to the skin can be targeted and enhanced using LTSLs. Targeting drug delivery with this method may reduce the systemic toxicity seen in a systemic free-drug administration. Development of more hydrophilic immunosuppressants in the future would increase the applicability of this system in the treatment of rejection reactions in vascularized composite allotransplantation. The treatment of other skin condition might be another potential application

Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude - Figure 1

<p>A: The combination of ephedrine (20 mg/kg) and ambrisentan (0.1 mg/kg), but not the single compounds, significantly increase the time run to fatigue of rats under simulated high altitude (Log rank test p = 0.0024 after correction for multiple comparison). Lower concentrations of ephedrine (2 mg/kg) were not ergogenic, neither alone nor if combined with ambrisentan (not shown). N = 28–31 per treatment group. B: Methylphenidate (10 mg/kg) combined with ambrisentan, but not the single compounds, enhanced time run to fatigue under simulated high altitude (Log Rank test p = 0.044 after correction for multiple comparison). Lower dose methylphenidate (4 mg/kg) did not have ergogenic effects, alone or in combination with ambrisentan (not shown). N = 14–15 per treatment group. N = 10–11 per treatment group. All drugs were injected IP.</p

Averaged tissue pO₂ values in mmHg (means ± SD), acquired with Oxylite probes.

<p><i>Time point 1: averaged over last 5 min before onset of 1^st cycle of hypoxia; time point 2: averaged over last 5 min before return to normoxia; time point 3: averaged over last 5 min before injection; time point 4: averaged over last 5 min before onset of 2^nd cycle of hypoxia; time point 3: averaged over 30–40 minutes post injection, i.e. during post-treatment hypoxia; Ambr = Ambrisentan, Eph = Ephedrine.</i></p

Hemodynamic effects of high-dose ephedrine in anesthetized rats.

<p>“Pre-injection” were averaged data −5 to 0 minutes pre injection, “post injection” was averaged −5 to 0 minutes before onset of hypoxia, and “hypoxia” was averaged 30–40 minutes post injection. A: Changes in heart rates, normalized to the time of injection. The addition of ephedrine at 20 mg/kg IP significantly increased heart rates, alone and combined with ambrisentan. Heart rates remained significantly elevated under hypoxia in ephedrine treated groups (one-way ANOVA/Bonferroni, p<0.01, N = 7–13). B: Changes in blood perfusion velocity in hind leg muscle after treatment, measured directly on the muscle, using a laser Doppler probe. Both ephedrine and the combination significantly enhanced muscle blood flow under hypoxia (N = 6–9). The onset of hypoxia triggered a distinct increase in muscle flow in all groups containing ephedrine, and to a lesser degree in control treated animals (example laser Doppler tracings from rat leg muscle; EA = ephedrine and ambrisentan; C = combination; first arrow: injection, second: hypoxia). C: Repeated injection of combined ephedrine (20 mg/kg) and ambrisentan (0.1 mg/kg) significantly enhances heart rates, and concomitantly, pulmonary blood flow, measured by pulmonary window blood flow measurements, and pulse oximetry (paired T-test, corrected for multiple comparison, p<0.05, N = 5). D: injection of ephedrine, alone or in combination with ambrisentan, caused a significant increase of breathing rates (one-sided ANOVA with Bonferroni correction, p<0.001, N = 5–13/group). Hypoxia further increased breathing rates in all groups (repeated measures ANOVA/Bonferroni, p<0.001). E: Changes in blood oxygenation after treatment: HbO₂ decreased significantly in all treatment groups after onset of inspired hypoxia (repeated measure ANOVA/Bonferroni, p<0.001), but there was no difference in this parameter between treatment groups (one-way ANOVA/Bonferroni, N = 5–9).</p

Validation of a Novel Assay to Distinguish Bacterial and Viral Infections

Reliably distinguishing bacterial from viral infections is often challenging, leading to antibiotic misuse. A novel assay that integrates measurements of blood-borne host-proteins (tumor necrosis factor-related apoptosis-inducing ligand, interferon γ-induced protein-10, and C-reactive protein [CRP]) was developed to assist in differentiation between bacterial and viral disease