High altitude hypoxia and oxidative stress: The new hope brought by free radical scavengers.

Various strategies can be employed to prevent and manage altitude illnesses, including habituation, oxygenation, nutritional support, and medication. Nevertheless, the utilization of drugs for the prevention and treatment of hypoxia is accompanied by certain adverse effects. Consequently, the quest for medications that exhibit minimal side effects while demonstrating high efficacy remains a prominent area of research. In this context, it is noteworthy that free radical scavengers exhibit remarkable anti-hypoxia activity. These scavengers effectively eliminate excessive free radicals and mitigate the production of reactive oxygen species (ROS), thereby safeguarding the body against oxidative damage induced by plateau hypoxia. In this review, we aim to elucidate the pathogenesis of plateau diseases that are triggered by hypoxia-induced oxidative stress at high altitudes. Additionally, we present a range of free radical scavengers as potential therapeutic and preventive approaches to mitigate the occurrence of common diseases associated with hypoxia at high altitudes.

Comprehensive Investigation of the Influence of High-Altitude Hypoxia on Clopidogrel Metabolism and Gut Microbiota.

BACKGROUND: The amount of metabolites converted into active metabolites is correspondingly reduced since only more than 50% of clopidogrel is absorbed. OBJECTIVE: Exploring the effect of gut microbiota altered by altitude hypoxia on the pre-absorption metabolism of clopidogrel. METHODS: In vitro and in vivo experiments were conducted to analyze the metabolism of clopidogrel through LCMS/ MS, while 16S rRNA analysis was used to investigate the changes in the gut microbiota of high-altitude animals. RESULTS: We demonstrated that the intestinal flora is involved in the metabolism of clopidogrel through in vivo and in vitro experiments. In addition, the plateau environment caused changes in the number and composition of intestinal microbes. Intriguingly, alterations in the microbial population could lead to an increase in the pre-absorption metabolism of clopidogrel after rapid entry into the plateau, the amount of absorbed blood is thus reduced, which may affect the bioavailability and therapeutic effect of clopidogrel. CONCLUSION: Our results not only as a first clinical reference for dose adjustment of clopidogrel in high-altitude environments but also would be helpful to provide a statement on the broader significance within the field of pharmacokinetics or personalized medicine.

New strategy for rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments.

High-altitude hypoxic environments have critical implications on cardiovascular system function as well as blood pressure regulation. Such environments place patients with hypertension at risk by activating the sympathetic nervous system, which leads to an increase in blood pressure. In addition, the high-altitude hypoxic environment alters the in vivo metabolism and antihypertensive effects of antihypertensive drugs, which changes the activity and expression of drug-metabolizing enzymes and drug transporters. The present study reviewed the pharmacodynamics and pharmacokinetics of antihypertensive drugs and its effects on patients with hypertension in a high-altitude hypoxic environment. It also proposes a new strategy for the rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments. The increase in blood pressure on exposure to a high-altitude hypoxic environment was mainly dependent on increased sympathetic nervous system activity. Blood pressure also increased proportionally to altitude, whilst ambulatory blood pressure increased more than conventional blood pressure, especially at night. High-altitude hypoxia can reduce the activities and expression of drug-metabolizing enzymes, such as CYP1A1, CYP1A2, CYP3A1, and CYP2E1, while increasing those of CYP2D1, CYP2D6, and CYP3A6. Drug transporter changes were related to tissue type, hypoxic degree, and hypoxic exposure time. Furthermore, the effects of high-altitude hypoxia on drug-metabolism enzymes and transporters altered drug pharmacokinetics, causing changes in pharmacodynamic responses. These findings suggest that high-altitude hypoxic environments affect the blood pressure, pharmacokinetics, and pharmacodynamics of antihypertensive drugs. The optimal hypertension treatment plan and safe and effective medication strategy should be formulated considering high-altitude hypoxic environments.

Possible strategies to reduce altitude-related excessive polycythemia.

We sought to determine the effects of three treatments on hemoglobin (Hb) levels in patients with chronic mountain sickness (CMS): 1) descent to lower altitude, 2) nocturnal O2 supply, 3) administration of acetazolamide. Nineteen patients with CMS living at an altitude of 3,940 ± 130 m participated in the study, which consisted of a 3-wk intervention phase and a 4-wk postintervention phase. Six patients spent 3 wk at an altitude of 1,050 m (low altitude group, LAG), six received supplemental oxygen for 12 h overnight (oxygen group, OXG), and seven received 250 mg of acetazolamide daily (acetazolamide group, ACZG). Hemoglobin mass (Hbmass) was determined using an adapted carbon monoxide (CO) rebreathing method before, weekly during, and 4 wk postintervention. Hbmass decreased by 245 ± 116 g (P < 0.01) in the LAG and by 100 ± 38 g in OXG, and 99 ± 64 g in ACZG (P < 0.05, each), respectively. In LAG, hemoglobin concentration ([Hb]) decreased by 2.1 ± 0.8 g/dL and hematocrit by 7.4 ± 2.9% (both P < 0.01), whereas OXG and ACZG only trended toward lower values. Erythropoietin concentration ([EPO]) decreased between 81 ± 12% and 73 ± 21% in LAG at low altitude (P < 0.01) and increased by 161 ± 118% 5 days after return (P < 0.01). In OXG and ACZG, the [EPO] decrease was ∼75% and ∼50%, respectively, during the intervention (P < 0.01). Descent to low altitude (from 3,940 m to 1,050 m) is a fast-acting measure for the treatment of excessive erythrocytosis in patients with CMS, reducing Hbmass by 16% within 3 wk. Nighttime oxygen supplementation and daily acetazolamide administration are also effective, but reduce Hbmass by only 6%.NEW & NOTEWORTHY To our knowledge, this is the first study examining the effect of three different treatments [descending to lower altitude (from 3,900 m to 1,050 m), nocturnal oxygen supply, and administration of acetazolamide] on changes in hemoglobin mass in patients experiencing chronic mountain sickness (CMS). We report that descent to low altitude is a fast-acting measure for the treatment of excessive erythrocytosis in patients with CMS, reducing Hbmass by 16% within 3 wk. Nighttime oxygen supplementation and daily acetazolamide administration are also effective, but reduce Hbmass by only 6%. In all three treatments, the underlying mechanism is a reduction in plasma erythropoietin concentration due to higher oxygen availability.

Prophylaxis and treatment of mountain sickness.

More and more people travel to high altitudes, some develop mountain sickness, a possible life-threatening condition. The most common and benign case of mountain sickness is acute mountain sicknes, this condition is easily treatable by descending or low dose aceatazolamide. Treatment is important to avoid development to the more severe cases of mountain sickness high-altitude cerebral oedema and high-altitude pulmonary oedema. These conditions require early recognition and treatment. This review gives an overview of available treatment of these conditions and how to avoid them in the first place.

The Impact of Acetazolamide and Methazolamide on Exercise Performance in Normoxia and Hypoxia.

Doherty, Connor J., Jou-Chung Chang, Benjamin P. Thompson, Erik R. Swenson, Glen E. Foster, and Paolo B. Dominelli. The impact of acetazolamide and methazolamide on exercise performance in normoxia and hypoxia. High Alt Med Biol. 24:7-18, 2023.-Carbonic anhydrase (CA) inhibitors are commonly prescribed for acute mountain sickness (AMS). In this review, we sought to examine how two CA inhibitors, acetazolamide (AZ) and methazolamide (MZ), affect exercise performance in normoxia and hypoxia. First, we briefly describe the role of CA inhibition in facilitating the increase in ventilation and arterial oxygenation in preventing and treating AMS. Next, we detail how AZ affects exercise performance in normoxia and hypoxia and this is followed by a discussion on MZ. We emphasize that the overarching focus of the review is how the two drugs potentially affect exercise performance, rather than their ability to prevent/treat AMS per se, their interrelationship will be discussed. Overall, we suggest that AZ hinders exercise performance in normoxia, but may be beneficial in hypoxia. Based upon head-to-head studies of AZ and MZ in humans on diaphragmatic and locomotor strength in normoxia, MZ may be a better CA inhibitor when exercise performance is crucial at high altitude.

The Influences and Mechanisms of High-altitude Hypoxia Exposure on Drug Metabolism.

BACKGROUND: The special environment of high-altitude hypoxia not only changes the physiological state of the body but also affects the metabolic process of many drugs, which may affect the safety and efficacy of these drugs. The number of drugs is huge, so it is not wise to blindly repeat the pharmacokinetic studies of all of them on the plateau. Mastering the law of drug metabolism on the plateau is conducive to the comprehensive development of rational drug use on the plateau. Therefore, it is very important to determine the impacts and elucidate the mechanism of drug metabolism in hypobaric hypoxia conditions. METHODS: In this review, we searched published studies on changes in drug metabolism in hypoxia conditions to summarize and analyze the mechanisms by which hypoxia alters drug metabolism. RESULTS: Although the reported effects of high-altitude hypoxia on drug metabolism are sometimes controversial, metabolism kinetics for most of the tested drugs are found to be affected. Mechanism studies showed that the major reasons causing metabolism changes are: regulated drug-metabolizing enzymes expression and activity mediated by HIF-1, nuclear receptors and inflammatory cytokines, and change in direct or indirect effects of intestinal microflora on drug metabolism by itself or the host mediated by microflora-derived drug-metabolizing enzymes, metabolites, and immunoregulation. CONCLUSION: Altered enzyme expression and activity in the liver and altered intestinal microflora are the two major reasons to cause altered drug metabolism in hypoxia conditions.

Deciphering the Efficacy and Mechanism of Astragalus membranaceus on High Altitude Polycythemia by Integrating Network Pharmacology and In Vivo Experiments.

Hypoxic exposure makes plateau migrators susceptible to high altitude polycythemia (HAPC). Astragalus membranaceus (AM) is an edible and medicinal plant with remarkable immunomodulatory activities. The purpose of this study was to discover if AM could be a candidate for the prevention of HAPC and its mechanism. Here, network pharmacology was applied to screen active compounds, key targets, and enriched pathways of AM in the treatment of HAPC. Molecular docking evaluated the affinity between compounds and core targets. Subsequently, the mechanisms of AM were further verified using the hypoxia exposure-induced mice model of HAPC. The network pharmacology analysis and molecular docking results identified 14 core targets of AM on HAPC, which were predominantly mainly enriched in the HIF-1 pathway. In the HAPC animal models, we found that AM inhibited the differentiation of hematopoietic stem cells into the erythroid lineage. It also suppressed the production of erythrocytes and hemoglobin in peripheral blood by reducing the expression of HIF-1α, EPO, VEGFA, and Gata-1 mRNA. Furthermore, AM downregulated the expression of IL-6, TNF-α, and IFN-γ mRNA, thereby alleviating organ inflammation. In conclusion, AM supplementation alleviates hypoxia-induced HAPC in mice, and TNF-α, AKT1, HIF-1α, VEGFA, IL-6, and IL-1B may be the key targets.

Pharmacological inhibition of mitochondrial division attenuates simulated high-altitude exposure-induced cerebral edema in mice: Involvement of inhibition of the NF-κB signaling pathway in glial cells.

High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness, which is still lack of effective therapy. This study investigated for the first time the protective effect of mitochondrial division inhibitor-1 (mdivi-1) against cerebral edema induced by simulated high-altitude exposure in mice. It was found that mdivi-1 effectively inhibited phosphorylation of dynamin-related protein-1 (Drp1), reduced expression of AQP4, decreased secretion of IL-6 and TNF-α, and alleviated cerebral edema in mice. In primary cultured astrocytes or microglia, mdivi-1 significantly decreased the hypoxia-induced Drp1 phosphorylation and mitochondrial fragmentation, inhibited the activation of the NF-κB signaling pathway, reduced the secretion of IL-6 and TNF-α. In addition, mdivi-1 inhibited mitochondrial reactive oxygen species (ROS) generation induced by hypoxia in both astrocytes and microglia. When astrocytes were treated with the conditioned medium of microglia exposed to hypoxia (H-MCM), the protein levels of p-Drp1, p-p65, and AQP4 as well as the mRNA levels of IL-6, TNF-α, and IL-1ß in astrocytes were increased. When the mitochondrial components in H-MCM were removed, the influence of microglia on astrocytes under hypoxia was significantly alleviated. Treated with mdivi-1, the integrity of mitochondria released from microglia induced by hypoxia were significantly improved. In conclusion, pharmacological inhibition of mitochondrial division by mdivi-1 alleviated cerebral edema induced by simulated high-altitude exposure in mice. Inhibition of ROS/NF-κB signaling pathway may contribute to the protective effect of mdivi-1. Under hypoxic conditions, mdivi-1 may attenuate the activation of astrocytes by reducing the release of damaged mitochondria from microglia.

Protective effect of 5,6,7,8-Tetrahydroxyflavone on high altitude cerebral edema in rats.

High altitude cerebral edema (HACE) is a potentially life-threatening disease encountered at high altitudes. However, effective methods for HACE prophylaxis are limited. Convincing evidence confirms that oxidative stress induced by hypobaric hypoxia (HH) is one of the main factors that account for the development of HACE. 5,6,7,8-Tetrahydroxyflavone (THF), a flavone with four consecutive OH groups in ring A, exhibited excellent antioxidant activity in vitro and could attenuate HH induced injury in vivo. The aim of this study was to investigate the protective effect of THF against HACE and its underlying mechanisms. THF administration significantly suppressed HH induced oxidative stress by reducing the formation of hydrogen peroxide and malondialdehyde, by increasing the levels of glutathione and superoxide dismutase in brain tissue. Simultaneously, THF administration inhibited inflammatory responses by decreasing the levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in serum and brain tissue. In addition, THF administration mitigated the energy metabolism disorder induced by HACE as evidenced by decreased levels of lactic acid, lactate dehydrogenase and pyruvate kinase as well as increased ATP levels and ATPase activities. Furthermore, THF administration decreased the expression of matrix metalloproteinase-9, aquaporin 4, hypoxia-inducible factor-1α and vascular endothelial growth factor, which attenuated blood-brain barrier (BBB) disruption and brain edema. Additionally, THF administration improved HACE induced cognitive dysfunction. These results show that THF is a promising agent in the prevention and treatment of HACE.

Effects of acetazolamide on pulmonary artery pressure and prevention of high-altitude pulmonary edema after rapid active ascent to 4,559 m.

Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg (P < 0.001) without a group difference (P = 0.68). Arterial Po2 fell to 36 ± 9 mmHg (P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude (P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%-100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m.NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.

Chemical characteristics of Rhodiola Crenulata and its mechanism in acute mountain sickness using UHPLC-Q-TOF-MS/MS combined with network pharmacology analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhodiola crenulata (Hook.f. & Thomson) H.Ohba has a long history of clinical application for the prevention and treatment of acute mountain sickness (AMS) in traditional Chinese medicine. However, gaps in knowledge still exist in understanding the underlying mechanisms of Rhodiola crenulata against AMS. AIMS: To address this problem, a comprehensive method was established by combining UHPLC-Q-TOF-MS/MS analysis and network pharmacology. MATERIALS AND METHODS: The ingredients of Rhodiola crenulata were comprehensively analyzed using UHPLC-Q-TOF-MS/MS method. On this basis, a network pharmacology method incorporated target prediction, protein-protein interaction network, gene enrichment analysis and components-targets-pathways network was performed. Finally, the possible mechanisms were verified through molecular docking, in vitro and in vivo experiments. RESULTS: A total of 106 constituents of Rhodiola crenulata were charactered via UHPLC-Q-TOF-MS/MS. The 98 potentially active compounds out of 106 were screened and corresponded to 53 anti-AMS targets. Gene enrichment analysis revealed that hypoxia and inflammation related genes may be the central factors for Rhodiola crenulata to modulate AMS. Molecular docking revealed that TNF, VEGFA and HIF-1α had high affinities to Rhodiola crenulata compounds. Subsequently, Rhodiola crenulata extract was indicated to inhibit the protein expression level of TNF in hypoxia induced H9c2 cells. Lastly, Rhodiola crenulata extract was further verified to ameliorate heart injury and decreased the heart levels of TNF, VEGFA and HIF-1α in acute hypoxia-induced rats. CONCLUSIONS: This study used UHPLC-Q-TOF-MS/MS analysis and a network pharmacology to provide an important reference for revealing the potential mechanism of Rhodiola crenulata in the prevention and treatment of AMS.

Treatment of Focal and Segmental Glomerulosclerosis Secondary to High Altitude Polycythemia with Acetazolamide.

Vizcarra-Vizcarra, Cristhian A., Eduardo Chávez-Velázquez, Carmen Asato-Higa, and Abdías Hurtado-Aréstegui. Treatment of focal and segmental glomerulosclerosis secondary to high altitude polycythemia with acetazolamide. High Alt Med Biol. 23:286-290, 2022.-Focal segmental glomerulosclerosis (FSGS) is a morphological pattern, caused by glomerular injury and is the leading cause of nephrotic syndrome in adults. We present the case of a 59-year-old female patient, resident of a high-altitude city (3,824 m), who had polycythemia and nephrotic syndrome. A renal biopsy was performed, and the findings were compatible with FSGS. The patient received phlebotomy 500 ml three times, which reduced, partially, the hemoglobin concentration. However, she had refractory proteinuria, despite the use of enalapril and spironolactone. We observed that proteinuria worsened with the increase in hemoglobin levels. So, she was treated with acetazolamide 250 mg bid for 4 months, which reduced proteinuria and hemoglobin. During the coronavirus disease 2019 (COVID-19) pandemic, the patient did not take acetazolamide and again, she had an increase in hemoglobin and proteinuria levels. We conclude that acetazolamide may be an effective treatment in FSGS due to high altitude polycythemia.

Bilateral choroidal effusions after taking acetazolamide for altitude sickness.

A fit and healthy 44-year-old woman took a single dose of oral acetazolamide (125 mg) in preparation for a hiking trip to Everest base camp. She awoke the next morning with profoundly blurred distance vision. She presented to eye casualty later that morning, approximately 18 hours postingestion: examination demonstrated myopia and bilateral choroidal effusions. Acetazolamide is used to minimise symptoms of altitude sickness. Rarely, its use can be linked with ophthalmic side effects, such as myopia. A handful of case reports also describe choroidal effusions secondary to its use as part of ophthalmic treatment (eg, postoperatively). This is the first reported case in which choroidal effusions have been demonstrated as a side effect of its prophylactic use against altitude sickness.

Salidroside orchestrates metabolic reprogramming by regulating the Hif-1α signalling pathway in acute mountain sickness.

CONTEXT: Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba (Crassulaceae) is used to prevent and treat acute mountain sickness. However, the mechanisms underlying its effects on the central nervous system remain unclear. OBJECTIVE: To investigate the effect of Rhodiola crenulata on cellular metabolism in the central nervous system. MATERIALS AND METHODS: The viability and Hif-1α levels of microglia and neurons at 5% O2 for 1, 3, 5 and 24 h were examined. We performed the binding of salidroside (Sal), rhodiosin, tyrosol and p-hydroxybenzyl alcohol to Hif-1α, Hif-1α, lactate, oxidative phosphorylation and glycolysis assays. Forty male C57BL/6J mice were divided into control and Sal (25, 50 and 100 mg/kg) groups to measure the levels of Hif-1α and lactate. RESULTS: Microglia sensed low oxygen levels earlier than neurons, accompanied by elevated expression of Hif-1α protein. Salidroside, rhodiosin, tyrosol, and p-hydroxybenzyl alcohol decreased BV-2 (IC50=1.93 ± 0.34 mM, 959.74 ± 10.24 µM, 7.47 ± 1.03 and 8.42 ± 1.63 mM) and PC-12 (IC50=6.89 ± 0.57 mM, 159.28 ± 8.89 µM, 8.65 ± 1.20 and 8.64 ± 1.42 mM) viability. They (10 µM) reduced Hif-1α degradation in BV-2 (3.7-, 2.5-, 2.9- and 2.5-fold) and PC-12 cells (2.8-, 2.8-, 2.3- and 2.0-fold) under normoxia. Salidroside increased glycolytic capacity but attenuated oxidative phosphorylation. Salidroside (50 and 100 mg/kg) treatment increased the protein expression of Hif-1α and the release of lactate in the brain tissue of mice. CONCLUSIONS: These results suggest that Sal induces metabolic reprogramming by regulating the Hif-1α signalling pathway to activate compensatory responses, which may be the core mechanism underlying the effect of Rhodiola crenulata on the central nervous system.

[The preventive effect of four drugs on acute mountain sickness: a Bayesian network meta-analysis].

Objective: To compare and predict the preventive effects of acetazolamide and other drugs on acute mountain sickness(AMS). Methods: Following the retrieval strategy of PRISMA statement of systematic review and meta-analysis, we searched the databases of PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, etc. from January 1, 1980 to November 30, 2020, and randomized controlled trials (RCT) consistent with drug prevention of AMS were conducted. Using R and other statistical software, Markov chain-Monte Carlo method was carried out for network meta-analysis under Bayesian framework, and node separation method was performed to check the consistency of closed-loop research. Results: Twenty-three literatures (25 studies) were included to compare the preventive effects of 4 drugs on AMS. Bayesian network meta-analysis showed that the incidence of AMS in acetazolamide group (ACE), dexamethasone group (DEX), ginkgo biloba extract group (GBE) and rhodiola group (RHO) was lower than that in placebo group (PLA). In the comparison of drug groups, the incidence of AMS in ACE, DEX and RHO was lower than that in GBE. There was no statistically significant difference in the incidence of AMS among ACE, DEX and RHO groups. Eight of these studies reported the effects of two drugs on pulse oxygen saturation (SpO2) in people entering the target altitude. Bayesian network meta-analysis showed that SpO2 in RHO was higher than that in ACE and PLA, but there was no statistically significant difference in SpO2 between ACE and PLA. The probability ranking of prevention AMS effect grade showed that the rank 5th probability of AMS in ACE, DEX, GBE, RHO and PLA was 45.72%, 48.80%, 0, 5.48% and 0, respectively. The probability ranking of improving the SpO2 level of the target altitude population showed that the probability of the ACE, RHO and PLA ranking 1st in improving the SpO2 effect at the target altitude was 2.27%, 97.66% and 0.07%, respectively; the results of direct comparison were in good agreement with those of Bayesian prediction model indirectly, and there was no statistical difference. Conclusions: Acetazolamide and dexamethasone can effectively prevent AMS, and should be the first choice for related supplementary research in the future. Rhodiola not only improves the SpO2 of people entering high altitude, but also reduces the incidence of AMS, which needs more attention. Ginkgo biloba extract is not as effective as the above three drugs in preventing AMS and should be used depending on clinical situations.

Compound Danshen Dripping Pill inhibits high altitude-induced hypoxic damage by suppressing oxidative stress and inflammatory responses.

CONTEXT: Previous studies indicate that compound Danshen Dripping Pill (CDDP) improves the adaptation to high-altitude exposure. However, its mechanism of action is not clear. OBJECTIVE: To explore the protective effect of CDDP on hypobaric hypoxia (HH) and its possible mechanism. MATERIALS AND METHODS: A meta-analysis of 1051 human volunteers was performed to evaluate the effectiveness of CDDP at high altitudes. Male Sprague-Dawley rats were randomized into 5 groups (n = 6): control at normal pressure, model, CDDP-170 mg/kg, CDDP-340 mg/kg and acetazolamide groups. HH was simulated at an altitude of 5500 m for 24 h. Animal blood was collected for arterial blood-gas analysis and cytokines detection and their organs were harvested for pathological examination. Expression levels of AQP1, NF-κB and Nrf2 were determined by immunohistochemical staining. RESULTS: The meta-analysis data indicated that the ratio between the combined RR of the total effective rate and the 95% CI was 0.23 (0.06, 0.91), the SMD and 95% CI of SO2 was 0.37 (0.12, 0.62). Pre-treatment of CDDP protected rats from HH-induced pulmonary edoema and heart injury, left-shifted oxygen-dissociation curve and decreased P50 (30.25 ± 3.72 vs. 37.23 ± 4.30). Mechanistically, CDDP alleviated HH-reinforced ROS by improving SOD and GPX1 while inhibiting pro-inflammatory cytokines and NF-κB expression. CDDP also decreased HH-evoked D-dimer, erythrocyte aggregation and blood hemorheology, promoting AQP1 and Nrf2 expression. DISCUSSION AND CONCLUSIONS: Pre-treatment with CDDP could prevent HH-induced tissue damage, oxidative stress and inflammatory response. Suppressed NF-κB and up-regulated Nrf2 might play significant roles in the mechanism of CDDP.