Transdermal carbon monoxide delivery.

Overuse injuries or acute trauma in joints often lead to painful tendinopathy, and pharmacological treatment effects are limited. The site of the disease is hard to reach with drugs, both systemically and through the skin. Therapeutic gases may close this gap, as they permeate easier through tissues than conventional small molecules. We present a patch device releasing the anti-inflammatory gas carbon monoxide (CO) through the skin to the subcutaneous tendons and tissues. CO is chemically generated upon device activation and its design maximizes CO exposure to the underlying skin and protects the patient from all side and degradation products. The patch delivered CO successfully through the intact skin, granting lasting, subcutaneous CO exposure for up to 16 h. Furthermore, the released CO induced the proliferation of fibroblasts and the polarization of monocytes into anti-inflammatory M2 macrophages. In conclusion, the CO-releasing device might open an entirely new treatment option against tendinopathies in case of a positive outcome of future in vivo studies.

Oral Use of Therapeutic Carbon Monoxide for Anyone, Anywhere, and Anytime.

Carbon monoxide (CO) is a therapeutic gas with therapeutic potential in intestinal bowel disease. Therapeutic efficacy in the gastrointestinal tract (GIT) must be paired with safe and convenient use. Therefore, we designed an oral CO releasing system (OCORS) pairing tunable CO release into the GIT while preventing the release of any other molecule from within the device, causing safety concerns. The dimensions of the device, which is manufactured from 3D printed components, are within compendial limits. This is achieved by controlling CO decarbonylation from a molybdenum complex with a FeCl3 solution. OCORS' surrounding silicon membranes control release rates, as does the loading with carbonylated molybdenum complex and FeCl3 solution. Herein we describe the development of the system, the characterization of the CO releasing molecule (CORM), and the CO release kinetics of the overall system. Neither the CORM nor isocyanoacetate as a potential reaction byproduct were cytotoxic. Finally, we demonstrated by design validation in an in vivo porcine model that, except for the release of the therapeutic CO, OCORS isolates all components during transit through the stomach. We could show that OCORS generated and released CO locally into the stomach of the animals without systemic exposure, measured as the carboxyhemoglobin content in the blood of the pigs. In conclusion, OCORS derisks oral development by limiting patient exposure to (desirable) CO while preventing contact with any further (undesirable) chemical, by-, or degradation products. CO generating devices come in reach, which now can be used by anyone, anywhere, and anytime.

Cerebral air emboli differentially alter outcome after cardiopulmonary bypass in rats compared with normal circulation.

BACKGROUND: Cerebral air emboli (CAE) are thought to contribute to adverse cerebral outcomes following cardiac surgery with cardiopulmonary bypass (CPB). This study was designed to investigate the effect of escalating volumes of CAE on survival and neurologic and histologic outcomes. In addition, the effect of xenon administration during CAE on these outcomes was determined. METHODS: With institutional review board approval, four groups were studied (n = 15). In two CPB-CAE groups, rats were subjected to 90 min CPB with 10 repetitively administered CAE. Rats in two sham-CAE groups were also exposed to CAE but not to CPB. Rats were randomly assigned to sequential dose cohorts receiving CAE ranging from 0.2 to 10 microl in a dose-escalating fashion. Groups were further subdivided into xenon (56%) and nitrogen groups. Rats with severe neurologic damage were killed; others were neurologically tested until postoperative day 7, when infarct volumes were determined. Survival and neurologic and histologic outcomes were tested with logistic regression analyses (P < 0.05). RESULTS: This study demonstrates a dose-dependent relation between CAE volumes and survival, neurologic outcome, and histologic outcome. For all outcomes, CPB adversely affected the dose-effect curves compared with sham-CAE groups (P < 0.05). Xenon demonstrated no impact on either outcome. CONCLUSIONS: This study describes the successful incorporation of CAE in a rodent CPB model and allows identifying suitable CAE volumes for subsequent studies. CAE exhibit a differential effect on outcome in rats undergoing CPB versus those not exposed to CPB. Perioperative administration of xenon remained without any effect on outcome.

Xenon impairs neurocognitive and histologic outcome after cardiopulmonary bypass combined with cerebral air embolism in rats.

BACKGROUND: The neuroprotective properties of xenon may improve cerebral outcome after cardiac surgery using cardiopulmonary bypass (CPB). However, its disposition to expand gaseous bubbles that during CPB present as cerebral air emboli (CAE) could abolish any beneficial effect or even worsen cerebral outcome. Therefore, the authors studied the impact of xenon on neurologic, cognitive, and histologic outcome after CPB combined with CAE in rats. METHODS: With institutional review board approval, 40 rats were assigned to four groups (n = 10). In two CPB-CAE groups, rats were subjected to 90 min of normothermic CPB with 10 repetitively administered CAEs (0.3 microl/bolus). Rats in two sham groups were not exposed to CPB and CAE. Groups were further subdivided into xenon (56%; 20 min before, during, and 30 min after CPB) and nitrogen groups. Neurologic and cognitive function was tested until postoperative day 14, when cerebral infarct volumes were determined. RESULTS: Animals of the CPB-CAE groups showed transient deficits in gross neurologic function. Further, rats of the CPB-CAE-xenon group demonstrated impaired fine motor and cognitive performance persisting until postoperative day 14. Consistently, infarct volumes were larger in the CPB-CAE-xenon group compared with the CPB-CAE-nitrogen group (P = 0.03). CONCLUSIONS: This is the first demonstration in which the neurologic effects of CAE have been examined in a rat model of CPB. Xenon exposure aggravated the neurologic dysfunction that is produced by CAE during CPB; potential neuroprotective effects of xenon may have been masked by the effects of xenon on CAE.

Xenon prevents cellular damage in differentiated PC-12 cells exposed to hypoxia.

BACKGROUND: The neuroprotective effect of xenon has been demonstrated for glutamatergic neurons. In the present study it is investigated if dopaminergic neurons, i.e. nerve-growth-factor differentiated PC-12 cells, are protected as well against hypoxia-induced cell damage in the presence of xenon. RESULTS: Pheochromocytoma cells differentiated by addition of nerve growth factor were placed in a N2-saturated atmosphere, a treatment that induced release of dopamine, reaching a maximum after 30 min. By determining extracellular lactate dehydrogenase concentration as marker for concomitant cellular damage, a substantial increase of enzymatic activity was found for N2-treated cells. Replacement of N2 by xenon in such a hypoxic atmosphere resulted in complete protection against cellular damage and prevention of hypoxia-induced dopamine release. Intracellular buffering of Ca2+ using the Ca-chelator 1, 2-bis(2-Aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester (BAPTA) reduced the neuroprotective effect of xenon indicating the essential participation of intracellular Ca2+-ions in the process of xenon-induced neuroprotection. CONCLUSIONS: The results presented demonstrate the outstanding property of xenon to protect neuron-like cells in a hypoxic situation.

Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon.

Hypoxia-induced neuronal damage and glutamate release were investigated in a N(2)- or in xenon-atmosphere for embryonic rat cortical neurons; cellular damage and glutamate over-release were observed in N(2)-treated cells whereas xenon protected the cells from the hypoxic insult. The protective effect of xenon was strongly reduced by pre-incubating neurons with the calcium-chelator BAPTA-AM indicating a role for calcium in this process. The results demonstrate (a) the neuroprotective properties of xenon, suggest (b) a relationship between the prevention of neurotransmitter release in a hypoxic situation and neuroprotection and present (c) evidence that such neuroprotection may be based on yet other xenon-dependent mechanisms.