Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
1.
Environ Monit Assess ; 195(10): 1225, 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37725220

RESUMO

The seasonal and interannual variation in the partial pressure of carbon dioxide in water [pCO2(water)] and air-water CO2 exchange in the Mahanadi estuary situated on the east coast of India was studied between March 2013 and March 2021. The principal aim of the study was to analyze the spatiotemporal variability and future trend of pCO2 and air-water CO2 fluxes along with the related carbonate chemistry parameters like water temperature, pH, salinity, nutrients, and total alkalinity, over 9 years. The seasonal CO2 flux over nine years was also calculated using five worldwide accepted equations. The seasonal map of pCO2(water) followed a general trend of being high in monsoon (2628 ± 3484 µatm) associated with high river inflow and low during pre-monsoon (445.6 ± 270.0 µatm). High pCO2 in water compared to the atmosphere (average 407.6-409.4 µatm) was observed in the estuary throughout the sampling period. The CO2 efflux computed using different gas transfer velocity formulas was also consistent with pCO2 water acquiring the peak during monsoon in the Mahanadi estuary (6033 ± 9478 µmol m-2 h-1) and trough during pre-monsoon (21.66± 187.2 µmol m-2 h-1). The estuary acted as a net source of CO2 throughout the study period, with significant seasonality in the flux magnitudes. However, CO2 sequestration via photosynthesis by phytoplankton resulted in lower emission rates toward the atmosphere in summer. This study uses the autoregressive integrated moving average (ARIMA) model to forecast pCO2(water) for the future. Using measured and predicted values, our work demonstrated that pCO2(water) has an upward trend in the Mahanadi estuary. Our results demonstrate that long-term observations from estuaries should be prioritized to upscale the global carbon budget.


Assuntos
Dióxido de Carbono , Estuários , Estações do Ano , Monitoramento Ambiental , Modelos Estatísticos
2.
Dig Dis ; 37(2): 93-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30205397

RESUMO

BACKGROUND: Pulmonary dysfunction often accompanies esophageal squamous cell carcinoma (SCC). AIMS: This study examined the use of carbon dioxide (CO2) insufflation and its safety during esophageal endoscopic submucosal dissection (ESD) while under conscious sedation. METHODS: ESD using CO2 insufflation (1.4 L/min) was performed in 102 consecutive esophageal SCC patients. Patients with a forced expiratory volume of 1.0 s/forced vital capacity (FEV1.0%) < 70% or a vital capacity < 80% were defined as having pulmonary dysfunction. Transcutaneous partial pressure of CO2 (PtcCO2) was recorded before, during, and after ESD. RESULTS: A history of smoking was found in 90 patients (88%), while 43 patients (42%) had pulmonary dysfunction. No significant differences were found between the pulmonary dysfunction and normal groups for the baseline PtcCO2 before ESD, peak PtcCO2 during ESD, and median PtcCO2 after ESD. There was a significant correlation between the PtcCO2 elevation from baseline and the ESD procedure time (r = 0.32, p < 0.01), with the correlation for the pulmonary dysfunction group much stronger (r = 0.39, p < 0.05) than that for the normal group (r = 0.30, p < 0.01). Neither of the groups exhibited any differences for either the complication incidence or the hospital stay. CONCLUSIONS: Although the use of CO2 insufflation during esophageal ESD under conscious sedation is safe with regard to the risk of complications, longer procedure times can potentially induce CO2 retention in patients with obstructive lung disease. Thus, it is necessary to both shorten the procedure times and perform CO2 monitoring.


Assuntos
Dióxido de Carbono/efeitos adversos , Ressecção Endoscópica de Mucosa , Carcinoma de Células Escamosas do Esôfago/cirurgia , Insuflação/efeitos adversos , Idoso , Ressecção Endoscópica de Mucosa/efeitos adversos , Feminino , Humanos , Incidência , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fatores de Tempo , Resultado do Tratamento
3.
Sci Total Environ ; 935: 173410, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-38782272

RESUMO

River CO2 emissions, which contribute 53 % of the basin's overall carbon emissions, are essential parts of the global and regional carbon cycles. Previous CO2 flux calculates are mostly based on single samples collected during ice-free periods; however, little is known about the effects of freeze-thaw cycles on the river CO2 flux (FCO2) of inland rivers in alpine regions. Based on one year-round monthly continuous field sampling, we quantified the FCO2 and determined their driving factors in typical rivers during different freeze-thaw periods in the Qinghai Lake Basin (QLB) using the thin boundary layer model (TBL) and the path analysis method. The findings indicated that (1) the average FCO2 in the typical rivers was 184.98 ± 329.12 mmol/m2/d, acting as a carbon source during different freeze-thaw periods, and showed a decreasing trend with completely thawed periods (CTP, 303.15 ± 376.56 mmol/m2/d) > unstable freezing periods (UFP, 189.44 ± 344.08 mmol/m2/d) > unstable thawing periods (UTP, 62.35 ± 266.71 mmol/m2/d); (2) pH, surface water temperature (Tw) and total alkalinity (TA) were the dominant controlling factors during different freeze-thaw periods. Interestingly, they significantly affected FCO2 more before completely frozen than after frozen, with Tw and TA changing from having promoting effects to having limiting effects; (3) in addition, dissolved carbon components indirectly affected FCO2, primarily through the indirect effects of pH and Tw in the UTP; wind speed (U) directly promoted FCO2 in the CTP; and Ca2+ and dissolved inorganic carbon (DIC) were susceptible to indirect effects, which promoted/limited the release of FCO2 in the UFP, respectively. Our results reveal the changes of FCO2 and the factors influencing it in inland rivers within alpine regions during different freeze-thaw periods, thereby offering valuable support for carbon emission-related studies in alpine regions.

4.
Environ Sci Pollut Res Int ; 30(51): 111021-111038, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37798521

RESUMO

Small estuaries often remain neglected while characterizing air-water CO2 flux dynamics. This study reports the seasonal, spatial, and multi-annual variability of carbon biogeochemistry, emphasizing air-water CO2 flux from a small tropical mangrove-dominated estuary (Dhamra Estuary) of the Bay of Bengal, based on the 9-year-long sampling survey (2013 to 2021). The sampling covered twelve pre-fixed locations of this estuary. A suite of biogeochemical parameters was kept within the purview of this study to deliniate the interrelationship between CO2 fluxes and potential factors that can regulate/govern pCO2(aq) dynamics. Air water CO2 exchange rates were calculated using five globally accepted empirical gas transfer velocity equations and varied in a range of - 832.5 to 7904 µmol m-2 h-1. The estuary was a sink for CO2 in monsoon season, having the highest average flux rates of - 380.9 ± 125.5 µmol m-2 h-1, whereas a source in pre-monsoon (38.29 ± 913.1 µmol m-2 h-1) and post-monsoon (91.81 ± 1009.8 µmol m-2 h-1). The significant factors governing pCO2 were pH, salinity, total alkalinity and dissolved inorganic carbon (DIC). This long-term seasonal study emphasizes the need to include small regional estuaries for more accurate estimates of global CO2 flux to upscale the global carbon budget and its controlling mechanism.


Assuntos
Estuários , Água , Dióxido de Carbono/análise , Baías , Monitoramento Ambiental , Índia , Carbono/análise
5.
Environ Sci Pollut Res Int ; 30(7): 19410-19426, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36239897

RESUMO

The exchange of carbon dioxide (CO2) flux between rivers and the atmosphere is an important part of the global carbon cycle. Reservoir development and environmental changes gradually transform rivers into river-reservoir systems. However, the current estimates of CO2 exchange flux at the water-air interface in river-reservoir systems, especially in ecologically fragile regions, are still largely uncertain. In this study, the CO2 partial pressure (ρCO2) and exchange flux (FCO2) from river-reservoir systems in the upper reaches of the Yellow River (YeUR) were investigated using the CO2SYS system and a boundary layer approach. The spatiotemporal dynamics and driving factors of the partial pressure of ρCO2 and FCO2 were revealed. Our results demonstrated that, driven by the freeze-thaw cycle of the permafrost active layer and the development of cascade reservoirs, the average ρCO2 in the two water periods was higher in the cascade reservoir section (CR) than in the source region section (SR) and higher in the flood period than in the dry period. Driven by water temperature stratification and light conditions, the ρCO2 of each reservoir in the CR exhibited seasonal variations along with water depth. The environmental factors TN, TP, T, DO, and DOC were the main influencing factors of ρCO2 distribution and could be used as predictors of ρCO2 in the dry period (R2 = 0.40 P < 0.01). In the dry period, the FCO2 in the SR was - 112.91 ± 165.94 mmol/(m2·d), which was a sink of CO2, and the FCO2 in the CR was 131.02 ± 156.77 mmol/(m2·d), which was a source of CO2. In the flood period, the FCO2 in the SR was 686.54 ± 624.33 mmol/(m2·d), and the FCO2 in the CR was 466.10 ± 366.67 mmol/(m2·d). Both the SR and the CR were sinks of CO2. Our results contribute to the understanding of CO2 exchange in river-reservoir systems and carbon cycle processes.


Assuntos
Dióxido de Carbono , Rios , Dióxido de Carbono/análise , Pressão Parcial , Água , China , Monitoramento Ambiental
6.
Mar Pollut Bull ; 193: 115185, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37364337

RESUMO

Inorganic carbon parameters were observed in Marian Cove, King George Island, Western Antarctic Peninsula, to assess the impact of the Antarctic coastal regions on air-sea CO2 exchange. The variations in total alkalinity (TA) and dissolved inorganic carbon (DIC) were caused by ice melting, formation, and biological activities. The net annual air-sea CO2 flux (5.6 ± 11.8 mmol m-2 d-1) indicated that Marian Cove was a CO2 source in the atmosphere, suggesting the opposite role of the Antarctic coastal regions to the Southern Ocean in CO2 flux estimates. Finally, this study identified the controlling factors of the annual variation of TA and DIC for the first time through direct field observations in King George Island. This study indicated that Antarctic coastal regions can act as a CO2 source to the atmosphere. Thus, further investigations and continuous monitoring are required in the coastal areas to improve our understanding of global carbon cycles.


Assuntos
Dióxido de Carbono , Ecossistema , Estações do Ano , Regiões Antárticas , Carbono
7.
Life (Basel) ; 13(4)2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-37109391

RESUMO

The present study reviewed the carbon-biogeochemistry-related observations concerning CO2 and CH4 dynamics in the estuaries adjoining the Indian Sundarbans mangrove ecosystem. The review focused on the partial pressure of CO2 and CH4 [pCO2(water) and pCH4(water)] and air-water CO2 and CH4 fluxes and their physical, biogeochemical, and hydrological drivers. The riverine-freshwater-rich Hooghly estuary has always exhibited higher CO2 emissions than the marine-water-dominated Sundarbans estuaries. The mangrove sediment porewater and recirculated groundwater were rich in pCO2(water) and pCH4(water), enhancing their load in the adjacent estuaries. Freshwater-seawater admixing, photosynthetically active radiation, primary productivity, and porewater/groundwater input were the principal factors that regulated pCO2(water) and pCH4(water) and their fluxes. Higher chlorophyll-a concentrations, indicating higher primary production, led to the furnishing of more organic substrates that underwent anaerobic degradation to produce CH4 in the water column. The northern Bay of Bengal seawater had a high carbonate buffering capacity that reduced the pCO2(water) and water-to-air CO2 fluxes in the Sundarbans estuaries. Several authors traced the degradation of organic matter to DIC, mainly following the denitrification pathway (and pathways between aerobic respiration and carbonate dissolution). Overall, this review collated the significant findings on the carbon biogeochemistry of Sundarbans estuaries and discussed the areas that require attention in the future.

8.
Water Res ; 213: 118158, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35149362

RESUMO

The global increase in the construction of reservoirs has drawn attention given its documented hydrological and biogeochemical impacts on downstream rivers; however, the impact of reservoirs on downstream pCO2 (partial pressure of carbon dioxide) is still poorly understood. To evaluate these impacts, the interactions between reservoirs and their corresponding upstream and downstream rivers were analyzed for three reservoirs in the Seine Basin based on monthly measurement during two hydrological years. The seasonal variations of water quality in the reservoirs were mainly driven by the entering water and the biogeochemical processes occurring in the reservoirs. Our results unravel the crucial role of reservoir in downstream water quality, which significantly increased DOC (dissolved organic carbon) and BDOC (biodegradable DOC) concentrations, while lowered DSi (dissolved silica) concentrations during emptying period (p < 0.01). Furthermore, the impacts of reservoirs on the annual fluxes of DOC, BDOC, and DSi were quantified and suggested that the three reservoirs respectively increased 20% and 23% of annual fluxes of DOC and BDOC, while decreased 33% of annual DSi fluxes in their downstream rivers. Additionally, the reservoirs significantly decreased downstream riverine pCO2 (p < 0.01), and enhanced the gas transfer coefficient of CO2 in downstream rivers by 1.3 times during the emptying period, which highlights the necessity to consider the potential impact of reservoirs on riverine CO2 emissions. Overall, our results highlight the importance of combining biogeochemical and hydrological characteristics to understand the impacts of reservoirs on downstream rivers, and emphasize the need of similar studies under the current context of increasing reservoir constructions.

9.
Ying Yong Sheng Tai Xue Bao ; 31(6): 1783-1790, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34494728

RESUMO

The flux and form of dissolved inorganic carbon (DIC), an important part of carbon budget, play a key role in the biogeochemistry of aquatic ecosystem. By analyzing physicochemical parameters and water DIC and δ13CDIC characteristics in Wanfenghu Reservoir, we examined the behavior and source of DIC. In the epilimnion, water pH in the entire reservoir was conservative, being weakly alkaline. Nitrate (NO3--N) had the maximum coefficient of variation and a high spatio-temporal variation. Due to the dilution effect, the lowest values of electrical conductivity (EC), partial pressure of carbon dioxide (pCO2) and DIC appeared during the summer high flow phase. On the water column in summer, redox potential (Eh) and NO3--N did not change with water depth, while other indicators changed significantly, with greatest variation in the thermocline. Water temperature (T), pH and Eh all decreased with increasing water depth in both seasons, while pCO2 showed an opposite trend. Water EC, total alkalinity (TA), and DIC decreased with increa-sing water depth in summer, but with a smaller gradient of change in winter. The DIC in water was negatively correlated with water pH and Eh, while positively correlated with EC and pCO2 in both seasons. 2) The concentration of DIC was 2.66-4.9 mmol·L-1 in summer and 3.38-4.52 mmol·L-1 in winter. During the period of thermal stratification, the variation gradients of DIC and δ13CDIC in the thermocline were most significant. DIC was positively correlated with δ13CDIC of epilimnion in summer. DIC was negatively correlated with δ13CDIC in epilimnion in winter and on water column in both summer and winter. However, the variation of DIC and δ13CDIC with water depth was not obvious in winter. 3) In summer, δ13CDIC was -7.71‰- -1.38‰, indicating that the dissolution of carbonate minerals was dominant. In winter, δ13CDIC was -16.93‰- -9.44‰, signifi-cantly lower than that in summer but with a wider range, indicating biological input of CO2 and mineralization of organic matter were the main sources. The δ13CDIC varied significantly in different seasons and water depths because of differences in carbon sources and changes in the relative contribution proportion of carbon sources.


Assuntos
Ecossistema , Monitoramento Ambiental , Isótopos de Carbono/análise , China , Estações do Ano
10.
Environ Sci Pollut Res Int ; 26(25): 25733-25748, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31267392

RESUMO

Accurate quantification of the emission of CO2 from streams and rivers is one of the primary challenges in determining the global carbon budget because our knowledge of the spatial and seasonal heterogeneity on these CO2 emissions is limited. In karst areas, the groundwater-stream continuum is likely ubiquitous because the carbon-rich groundwater discharges into some of the streams through springs or subterranean streams, which results in more complex spatial and seasonal variations in the CO2 emissions. To address this issue, the spatial and seasonal characteristics of partial pressure of CO2 (pCO2), the δ13CDIC, and the CO2 emission flux of the Guancun surface stream (GSS) karst groundwater-stream continuum in southern China were investigated from the stream head (groundwater outlet) to the downstream mouth during the 2014-2017 period. Our results reveal that the pCO2 and CO2 emissions exhibit high spatial and seasonal heterogeneities over ~ 1300 m in the GSS. Spatially, the pCO2 and CO2 emissions decrease sharply from the stream head (mean 8818.4 µatm for pCO2 and mean 423.4 mg m-2 h-1 for CO2 emission) to the site farthest downstream (mean 2752.7 µatm for pCO2 and 257.0 mg m-2 h-1 for CO2 emission). Except for the dates when extreme rainfall occurred, the pCO2 and CO2 emission values were higher in the rainy season than in the dry season. This suggests that in a groundwater-stream continuum, CO2 emission occurs very soon after the water is transferred from the karst groundwater to the surface water. We estimate that the total amount of CO2 released to the atmosphere from the GSS is 21.75 t CO2/year, which is only 1.71-5.62% of the dissolved inorganic carbon loss flux in the GSS during the study period. It is important to note that the measured CO2 emission and pCO2 levels decrease farther downstream, so carbon loss is underestimated when it is calculated using downstream sampling points. Therefore, accurate assessments of the CO2 emission flux need to take into consideration the high spatio-temporal heterogeneity in order to reduce the bias of the entire CO2 emission flux.


Assuntos
Dióxido de Carbono/análise , Carbono/análise , Atmosfera , Dióxido de Carbono/química , China , Água Subterrânea , Nascentes Naturais , Chuva , Rios , Estações do Ano , Água
11.
J Nucl Med ; 59(1): 100-106, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28619736

RESUMO

Elevation of the end-tidal partial pressure of CO2 (PETco2) increases cerebral and myocardial blood flow (MBF), suggesting that it may be a suitable alternative to pharmacologic stress or exercise for myocardial perfusion imaging. The purpose of this study was to document the pharmacodynamics of CO2 for MBF using prospective end-tidal targeting to precisely control arterial Pco2 and PET to measure the outcome variable, MBF. Methods: Ten healthy men underwent serial 82Rb PET/CT imaging. Imaging was performed at rest and during 6-min hypercapnic plateaus (baseline; PETco2 at 50, 55, and 60 mm Hg; repeat of PETco2 at 60 mm Hg; and repeat of baseline). MBF was measured using 82Rb injected 3 min after the beginning of hypercapnia and a 1-tissue-compartment model with flow-dependent extraction correction. Results were compared with those obtained during an adenosine stress test (140 µg/kg/min). Results: Baseline PETco2 was 38.9 ± 0.8 (mean ± SD) mm Hg (range, 35-43 mm Hg). All PETco2 targets were sustained, with SDs of less than 1.5 mm Hg. Heart rate, systolic blood pressure, rate × pressure product, and respiratory frequency increased with progressive hypercapnia. MBF increased significantly at each level of hypercapnia to 1.92-fold over baseline (0.86 ± 0.24 vs. 0.45 ± 0.08 mL/min/g; P = 0.002) at a PETco2 of 60 mm Hg. MBF after the administration of adenosine was significantly greater than that with the maximal hypercapnic stimulus (2.00 vs. 0.86 mL/min/g; P < 0.0001). Conclusion: To our knowledge, this study is the first to assess the response of MBF to different levels of hypercapnia in healthy humans with PET. MBF increased with increasing levels of hypercapnia; MBF at a PETco2 of 60 mm Hg was double that at baseline.


Assuntos
Circulação Coronária , Voluntários Saudáveis , Hipercapnia/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adenosina/farmacologia , Adulto , Dióxido de Carbono/farmacologia , Circulação Coronária/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hemodinâmica/efeitos dos fármacos , Humanos , Hipercapnia/diagnóstico por imagem , Masculino , Tomografia por Emissão de Pósitrons
12.
Biol Bull ; 231(2): 142-151, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27820906

RESUMO

Ocean acidification is expected to cause energetic constraints upon marine calcifying organisms such as molluscs and echinoderms, because of the increased costs of building or maintaining shell material in lower pH. We examined metabolic rate, shell morphometry, and calcification in the sea hare Aplysia punctata under short-term exposure (19 days) to an extreme ocean acidification scenario (pH 7.3, ∼2800 µatm pCO2), along with a group held in control conditions (pH 8.1, ∼344 µatm pCO2). This gastropod and its congeners are broadly distributed and locally abundant grazers, and have an internal shell that protects the internal organs. Specimens were examined for metabolic rate via closed-chamber respirometry, followed by removal and examination of the shell under confocal microscopy. Staining using calcein determined the amount of new calcification that occurred over 6 days at the end of the acclimation period. The width of new, pre-calcified shell on the distal shell margin was also quantified as a proxy for overall shell growth. Aplysia punctata showed a 30% reduction in metabolic rate under low pH, but calcification was not affected. This species is apparently able to maintain calcification rate even under extreme low pH, and even when under the energetic constraints of lower metabolism. This finding adds to the evidence that calcification is a largely autonomous process of crystallization that occurs as long as suitable haeomocoel conditions are preserved. There was, however, evidence that the accretion of new, noncalcified shell material may have been reduced, which would lead to overall reduced shell growth under longer-term exposures to low pH independent of calcification. Our findings highlight that the chief impact of ocean acidification upon the ability of marine invertebrates to maintain their shell under low pH may be energetic constraints that hinder growth of supporting structure, rather than maintenance of calcification.


Assuntos
Exoesqueleto/química , Exoesqueleto/metabolismo , Aplysia/fisiologia , Calcificação Fisiológica/fisiologia , Água do Mar/química , Animais , Aplysia/química , Aplysia/metabolismo , Concentração de Íons de Hidrogênio , Oceanos e Mares
13.
AoB Plants ; 72015 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-26433706

RESUMO

Plant growth at high elevations necessitates physiological and morphological plasticity to enable photosynthesis (A) under conditions of reduced temperature, increased radiation and the lower partial pressure of atmospheric gases, in particular carbon dioxide (pCO2). Previous studies have observed a wide range of responses to elevation in plant species depending on their adaptation to temperature, elevational range and growth habit. Here, we investigated the effect of an increase in elevation from 2500 to 3500 m above sea level (a.s.l.) on three montane species with contrasting growth habits and leaf economic strategies. While all of the species showed identical increases in foliar δ(13)C, dark respiration and nitrogen concentration with elevation, contrasting leaf gas exchange and photosynthetic responses were observed between species with different leaf economic strategies. The deciduous shrub Salix atopantha and annual herb Rumex dentatus exhibited increased stomatal (Gs) and mesophyll (Gm) conductance and enhanced photosynthetic capacity at the higher elevation. However, evergreen Quercus spinosa displayed reduced conductance to CO2 that coincided with lower levels of photosynthetic carbon fixation at 3500 m a.s.l. The lower Gs and Gm values of evergreen species at higher elevations currently constrains their rates of A. Future rises in the atmospheric concentration of CO2 ([CO2]) will likely predominantly affect evergreen species with lower specific leaf areas (SLAs) and levels of Gm rather than deciduous species with higher SLA and Gm values. We argue that climate change may affect plant species that compose high-elevation ecosystems differently depending on phenotypic plasticity and adaptive traits affecting leaf economics, as rising [CO2] is likely to benefit evergreen species with thick sclerophyllous leaves.

14.
J Pharmacol Toxicol Methods ; 69(1): 49-60, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24211663

RESUMO

INTRODUCTION: Safety Pharmacology studies were conducted in mouse, rat, and non-human primate to determine in vivo effects of antisense oligonucleotides (ASOs) on the central nervous system, respiratory system, and cardiovascular system. Effects on the hERG potassium channel current was evaluated in vitro. METHODS: ASOs contained terminal 2'-O-methoxyethyl nucleotides, central deoxy nucleotides, and a phosphorothioate backbone. Neurobehavior was evaluated by Functional Observatory Battery in rodents. Respiratory function was directly measured in rodents by plethysmograph; respiratory rate and blood gases were measured in monkey. Basic cardiovascular endpoints were measured in rat; cardiovascular evaluation in monkey involved implanted telemetry units. In single and repeat dose studies ASOs were administered by subcutaneous injection at up to 300 mg/kg, 250 mg/kg, and 40 mg/kg in mouse, rat, or monkey, respectively. Assays were performed in HEK293 or CHO-K1 cells, stably transfected with hERG cDNA, at ASO concentrations of up to 300 µM. RESULTS: No apparent effects were noted for respiratory or CNS function. Continuous monitoring of the cardiovascular system in monkey demonstrated no ASO-related changes in blood pressures, heart rate, or ECG and associated parameters (i.e., QRS duration). Specific assessment of the hERG potassium channel indicated no potential for actions on ventricular repolarization or modest effects only at excessive concentrations. DISCUSSION: The absence of direct actions on neurobehavior and respiratory function associated with the administration of ASOs in safety pharmacology core battery studies is consistent with published toxicology studies. The combination of in vitro hERG studies and in vivo studies in rat and monkey are consistent with no direct actions by ASOs on cardiac cell function or electrical conduction at relevant concentrations and dose levels. Taken as a whole, dedicated studies focused on the safety pharmacology of specific organ systems do not appear to add significant data for interpretation of potential adverse effects. The need for dedicated studies for future ASOs in the same class is questionable, as a more encompassing data set can be collected in repeat dose and longer-term toxicology studies.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/farmacologia , Sistema Respiratório/efeitos dos fármacos , Animais , Pressão Sanguínea , Células CHO , Sistema Cardiovascular/metabolismo , Células Cultivadas , Sistema Nervoso Central/metabolismo , Cricetulus , Feminino , Células HEK293 , Haplorrinos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oligonucleotídeos Antissenso/genética , Primatas , Ratos , Ratos Sprague-Dawley , Sistema Respiratório/metabolismo , Telemetria/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA