Is carbonic anhydrase inhibition useful as a complementary therapy of Covid-19 infection?

The ongoing Covid-19 is a contagious disease, and it is characterised by different symptoms such as fever, cough, and shortness of breath. Rising concerns about Covid-19 have severely affected the healthcare system in all countries as the Covid-19 outbreak has developed at a rapid rate all around the globe. Intriguing, a clinically used drug, acetazolamide (a specific inhibitor of carbonic anhydrase, CA, EC 4.2.1.1), is used to treat high-altitude pulmonary oedema (HAPE), showing a high degree of clinical similarities with the pulmonary disease caused by Covid-19. In this context, this preliminary study aims to provide insights into some factors affecting the Covid-19 patients, such as hypoxaemia, hypoxia as well as the blood CA activity. We hypothesise that patients with Covid-19 problems could show a dysregulated acid-base status influenced by CA activity. These preliminary results suggest that the use of CA inhibitors as a pharmacological treatment for Covid-19 may be beneficial.

Redox-regulation of haemostasis in hypoxic exercising humans: a randomised double-blind placebo-controlled antioxidant study.

KEY POINTS: In vitro evidence has identified that coagulation is activated by increased oxidative stress, though the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial in healthy participants to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise given their synergistic capacity to promote free radical formation. Systemic free radical formation was shown to increase during hypoxia and was further compounded by exercise, responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation at rest in normoxia, and this was normalised only in the face of prevailing oxidation. Collectively, these findings suggest that human free radical formation is an adaptive phenomenon that serves to maintain vascular haemostasis. ABSTRACT: In vitro evidence suggests that blood coagulation is activated by increased oxidative stress although the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise. Healthy males were randomly assigned double-blind to either an antioxidant (n = 20) or placebo group (n = 16). The antioxidant group ingested two capsules/day that each contained 500 mg of l-ascorbic acid and 450 international units (IU) of dl-α-tocopherol acetate for 8 weeks. The placebo group ingested capsules of identical external appearance, taste and smell (cellulose). Both groups were subsequently exposed to acute hypoxia and maximal physical exercise with venous blood sampled pre-supplementation (normoxia), post-supplementation at rest (normoxia and hypoxia) and following maximal exercise (hypoxia). Systemic free radical formation (electron paramagnetic resonance spectroscopic detection of the ascorbate radical (A•- )) increased during hypoxia (15,152 ± 1193 AU vs. 14,076 ± 810 AU at rest, P < 0.05) and was further compounded by exercise (16,569 ± 1616 AU vs. rest, P < 0.05), responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation as measured by thrombin-antithrombin complex, at rest in normoxia (28.7 ± 6.4 vs. 4.3 ± 0.2 µg mL-1 pre-intervention, P < 0.05) and was restored but only in the face of prevailing oxidation. Collectively, these findings are the first to suggest that human free radical formation likely reflects an adaptive response that serves to maintain vascular haemostasis.

Using a new plateau hyperbaric chamber to alleviate high altitude hypoxia: Rabbit and human studies.

OBJECTIVES: To validate the effects of the new plateau hyperbaric chamber on alleviating high altitude hypoxia on Mount Kun Lun. METHODS: A prospective, controlled study of rabbits and adult volunteers was conducted at altitudes of 355, 2880 and 4532m. We obtained arterial blood samples from rabbits and volunteers before and after hyperbaric treatment. The respiratory rate, heart rate, and blood pressure (BP) of adult volunteers were monitored during hyperbaric treatment. RESULTS: The mean PaO2 levels of experimental group rabbits and volunteers increased significantly after 60min of hyperbaric treatment at 350, 2880 and 4532m. The mean PaCO2 and pH levels of rabbits were not significant different before and after hyperbaric treatment at each altitude. The mean PaCO2 and pH levels were not significant different at 355m in the human study. However, at 2880 and 4532m, pH fell with increasing PaCO2 levels in humans before and after hyperbaric treatment. CONCLUSIONS: The new multiplace plateau hyperbaric chamber may be used to alleviate plateau hypoxia by increasing patient PaO2. However, its value in treating AMS must be confirmed in field conditions.

Protective effects of traditional Tibetan medicine Zuo-Mu-A Decoction () on the blood parameters and myocardium of high altitude polycythemia model rats.

OBJECTIVE: To explore the protective effects of Tibetan medicine Zuo-Mu-A Decoction (, ZMAD) on the blood parameters and myocardium of high altitude polycythemia (HAPC) model rats. METHODS: Forty male Wistar rats were randomly divided into 4 groups by a random number table, including the normal, model, Rhodiola rosea L. (RRL) and ZMAD groups (10 in each group). Every group was raised in Lhasa to create a HAPC model except the normal group. After modeling, rats in the RRL and the ZMAD groups were administered intragastrically with RRL (20 mL/kg) and ZMAD (7.5 mL/kg) once a day for 2 months, respectively; for the normal and the model groups, 5 mL of distilled water was administered intragastrically instead of decoction. Then routine blood and hematologic rheology parameters were taken, levels of erythropoietin and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were tested, and ultrastructural change in the left ventricular myocardium was observed using transmission electron microscopy. RESULTS: Compared with the model group, ZMAD significantly reduced the red blood cell count, hemoglobin levels, whole blood viscosity at low/middle shear rates, plasma viscosity, erythrocyte electrophoretic time, erythropoietin and 8-OHdG levels, and also increased the erythrocyte deformation index (P<0.05). There was no difference in all results between the RRL and the ZMAD groups. The cardiac muscle fibers were well-protected, mitochondrial matrix swelled mildly and ultrastructure changes were less prominent in the ZMAD group compared with the model group. CONCLUSION: ZMAD has significant protective effects on the blood parameters against HAPC, and also has the beneficial effect in protecting against myocardial injury.

Effects of Tibetan turnip (Brassica rapa L.) on promoting hypoxia-tolerance in healthy humans.

ETHNOPHARMACOLOGICAL RELEVANCE: Tibetan turnip (Brassica rapa L.), widely distributed in Tibet region, is an edible and medical plant with effects of "tonic and anti-hypoxia" "heat-clearing and detoxification" and "alleviating fatigue" according to traditional Tibetan medical books. AIM OF THE STUDY: This research systematically studied the effects of Tibetan turnip on promoting hypoxia-tolerance in humans and the mechanisms. MATERIALS AND METHODS: A 7-d, self-control and single-blind human feeding trial was conducted among 27 healthy subjects with 8 males and 10 females in feeding group fed with 7.5g turnip powder 2 times daily while 4 males and 5 females in control group fed with 7.5g radish powder twice a day. Subjects were required to undergo a hypoxia tolerance test (7.1% O2) and a cardiopulmonary function evaluation (Bruce treadmill protocol) before (1st day) and after (9th day) the trial. Simultaneously, the anti-oxidative activities (SOD, CAT, GSH-Px, MDA), routine and biochemical analyses of blood samples were evaluated. RESULTS: The females' SpO2 increased significantly by 6.4% at the end of the hypoxia tolerance test after taking turnips (p<0.05), and the hypoxia symptoms in most of the subjects were alleviated as well. The anaerobic threshold, peak O2 pulse and peak VO2/kg were significantly improved after 7-d turnip consumption during the Bruce treadmill test (p<0.05). As for the blood analysis, anti-oxidative activities were boosted effectively after the 7-d treatments. Moreover, mean corpuscular hemoglobin concentration (MCHC) in the males of feeding group increased significantly (p<0.05). However, little changes of all variables were observed in the control group. CONCLUSIONS: Consumption of Tibetan turnips for 7 days likely contributed to the hypoxia tolerance in healthy humans, which could be due to its abilities of improving oxygen uptake and delivery, enhancing body antioxidant capacity and increasing MCHC. However, further studies with larger samples and double-blind design are warranted, and future studies covering more diverse populations (unhealthy, athletic) would be also considered. Moreover, researches on identifying Tibetan turnip's active compounds are desired as well.

Carbohydrate Supplementation Influences Serum Cytokines after Exercise under Hypoxic Conditions.

INTRODUCTION: Exercise performed at the hypoxia equivalent of an altitude of 4200 m is associated with elevated inflammatory mediators and changes in the Th1/Th2 response. By contrast, supplementation with carbohydrates has an anti-inflammatory effect when exercise is performed under normoxic conditions. The objective of this study was to evaluate the effect of carbohydrate supplementation on cytokines and cellular damage markers after exercise under hypoxic conditions at a simulated altitude of 4200 m. METHODS: Seven adult male volunteers who exercised for 60 min at an intensity of 50% VO2Peak were randomly evaluated under three distinct conditions; normoxia, hypoxia and hypoxia + carbohydrate supplementation. Blood samples were collected at rest, at the end of exercise and after 60 min of recovery. To evaluate hypoxia + carbohydrate supplementation, volunteers received a solution of 6% carbohydrate (maltodextrin) or a placebo (strawberry-flavored Crystal Light®; Kraft Foods, Northfield, IL, USA) every 20 min during exercise and recovery. Statistical analyses comprised analysis of variance, with a one-way ANOVA followed by the Tukey post hoc test with a significance level of p < 0.05. RESULTS: Under normoxic and hypoxic conditions, there was a significant increase in the concentration of IL-6 after exercise and after recovery compared to at rest (p < 0.05), while in the hypoxia + carbohydrate group, there was a significant increase in the concentration of IL-6 and TNF-α after exercise compared to at rest (p < 0.05). Furthermore, under this condition, TNF-α, IL-2 and the balance of IL-2/IL-4 were increased after recovery compared to at rest (p < 0.05). CONCLUSION: We conclude that carbohydrate supplementation modified the IL-6 and TNF-α serum concentrations and shifted the IL-2/IL-4 balance towards Th1 in response without glycemic, glutaminemia and cell damage effects.

Effect of Intravenous Iron Supplementation on Acute Mountain Sickness: A Preliminary Randomized Controlled Study.

BACKGROUND: The aim of this study was to assess the role of intravenous iron supplementation in the prevention of AMS. MATERIAL AND METHODS: This was a randomized, double-blinded, placebo-controlled study. Forty-one (n=41) healthy Chinese low-altitude inhabitants living in Beijing, China (altitude of about 50 meters) were randomly assigned into intravenous iron supplementation (ISS group; n=21) and placebo (CON group; n=20) groups. Participants in the ISS group received iron sucrose supplement (200 mg) before flying to Lhasa, China (altitude of 4300 meters). Acute mountain sickness (AMS) severity was assessed with the Lake Louise scoring (LLS) system within 5 days after landing on the plateau (at high altitude). Routine check-ups, clinical biochemistry, and blood tests were performed before departure and 24 h after arrival. RESULTS: A total of 38 participants completed the study (ISS group: n=19; CON group: n=19). The rate of subjects with AMS (LLS>3) was lower in the ISS group compared with the CON group, but no significant differences were obtained (P>0.05). There were no differences in patients' baseline characteristics. The physiological indices were similar in both groups except for serum iron concentrations (19.44±10.02 vs. 85.10±26.78 µmol/L) and transferrin saturation rates (28.20±12.14 vs. 68.34±33.12%), which were significantly higher in the ISS group (P<0.05). Finally, heart rate was identified as a contributing factor of LLS. CONCLUSIONS: These preliminary findings suggest that intravenous iron supplementation has no significant protective effect on AMS in healthy Chinese low-altitude inhabitants.

Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial.

Acute mountain sickness (AMS) is a common and disabling condition that occurs in healthy individuals ascending to high altitude. Based on the ability of iron to influence cellular oxygen sensing pathways, we hypothesized that iron supplementation would protect against AMS. To examine this hypothesis, 24 healthy sea-level residents were randomized to receive either intravenous iron(III)-hydroxide sucrose (200 mg) or saline placebo, before ascending rapidly to Cerro de Pasco, Peru (4340 m). The Lake Louise scoring system was used to assess incidence and severity of AMS at sea level and on the first full day at altitude. No significant difference in absolute AMS score was detected between the two groups either at baseline or at high altitude. However, the mean increase in AMS score was 65% smaller in the iron group than in the saline group (p<0.05), and the change in AMS score correlated negatively with the change in ferritin (R=-0.43; p<0.05). Hematocrit and arterial oxygen saturation were unaffected by iron. In conclusion, this preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of AMS in healthy volunteers.

Hematological indices, mountain sickness and MRI brain abnormalities in professional and amateur mountain climbers after altitude exposure.

The purpose of this work was to correlate the presence of brain abnormalities on magnetic resonance imaging (MRI) with changes in hematological variables and the presence of mountain sickness in 21 mountain climbers involved in two different expeditions to high mountains, Everest and Aconcagua, without supplementary oxygen and recommended acclimatization for this kind of activities. The climbers underwent medical examination, hematological studies, electrocardiogram and MRI of the cerebrum. Wilcoxon signed-rank test was used to evaluate the changes in hematocrit, hemoglobin, red blood cells, iron and ferritin. Mountain sickness was correlated with the age of the climbers and the altitude ascended, final hemoglobin and final mean corpuscular hemoglobin concentration. There were no differences related to conditions of professional or amateur climbers and the changes of those hematological variables, as seen with the nominal regression. We found more brain damage on MRI in amateur than professional climbers. Amateur climbers are more susceptible to suffer acute mountain sickness and permanent cerebral damage than professional climbers after high altitude exposure.

Impaired glucose regulation in a Sherpa indigenous population living in the Everest region of Nepal and in Kathmandu Valley.

The aim of this study was to determine the prevalence of impaired glucose regulation status in Sherpa adults living in the Everest area and in Kathmandu valley. A cross-sectional survey was conducted in Chaurikharka village (Everest area) and Kathmandu city on 119 and 121 randomly selected individuals, aged 30-70 years. They were assessed on conventional risk factors for diabetes, and an oral glucose tolerance test was performed. Based on the 2003 American Diabetes Association criteria, the prevalence in the Kathmandu city and Everest region of any impaired glucose regulation (IGR), isolated impaired fasting plasma glucose (isolated IFG), isolated impaired glucose tolerance (isolated IGT), and combined isolated IFG and isolated IGT were 55.4% vs. 23.5%, 42.1% vs. 14.3%, 1.7% vs. 0.8%, 11.6 vs. 8.4%, respectively. Using the subjects with normal glucose tolerance as the referent group and after adjusting for age, sex, physical activity, calories, and waist circumference, the odds ratios for isolated IFG and combined isolated IFG and isolated IGT of living in the highland region were 0.19 (0.08-0.44) and 0.33 (0.09-1.18), respectively. Isolated IFG was more common among the lowland Sherpas. Unlike combined isolated IFG and isolated IGT, this isolated IFG difference could not be explained by the difference of conventional diabetes mellitus risk factors.

Oxidative stress in humans during and after 4 hours of hypoxia at a simulated altitude of 5500 m.

BACKGROUND: High-altitude hypoxia may induce oxidative stress in humans. However, the effect of acute, severe, and non-acclimatized short-term hypobaric hypoxia exposure in humans has not been described. Additionally, little is known regarding the confounding role of reoxygenation in the extent of oxidative stress and damage markers in hypoxia. Our goals were to analyze the effect of of hypobaric hypoxia and reoxygenation on plasma oxidative stress and oxidative damage. METHODS: There were six male volunteers exposed to a simulated altitude of 5500 m (52.52 kPa) in the INEFC-UB hypobaric chamber over 4 h and returned to sea level (SL) in 30 min. Data were collected at baseline SL at 1 h and 4 h of hypoxia at 5500 m and immediately after return to sea level (RSL). RESULTS: Elevated scores of acute mountain sickness (13) and significant changes in arterial oxygen saturation (97.5 +/- 0.5; 53.3 +/- 1.9; 97.1 +/- 0.3%, p < 0.05 at SL, 4 h, and RSL, respectively) were observed. Significant reductions (p < 0.05) on total glutathione (TGSH) content were measured from SL and 1 h vs. 4 h and RSL. The percentage of oxidized glutathione (%GSSG) as an indicator of redox oxidative changes increased significantly (SL vs. 1 h; 1 h vs. 4 h, and RSL). Lipid peroxidation (TBARS), protein oxidation (SH protein groups), and total antioxidant status (TAS) followed the redox changes suggested by the glutathione system throughout the protocol. CONCLUSIONS: Hypobaric hypoxia increased the burden of plasma oxidative stress and damage markers all through the hypoxia period. However, no additional changes were observed with reoxygenation at the end of the reoxygenation period.

Effect of time exposure to high altitude on zinc and copper concentrations in human plasma.

BACKGROUND: Research has focused mainly on the relationship of zinc and copper contents and physical stresses like running, cycling, etc. It has also been reported that other forms of stresses change the concentration of these trace elements in humans. However,there are no reports on the effects of high altitude induced hypoxic stress on the plasma levels of these metals. Since hypoxia is one of the important stresses, we considered it appropriate to observe the changes in the levels of zinc and copper concentrations and in certain related zinc and copper enzymes and hormones in the plasma of human volunteers on acute induction to high altitude. From these findings, we intended to ascertain whether supplementation of these trace elements would be required for optimal health under such conditions. HYPOTHESIS: On acute induction to hypoxia, contents of these trace elements may change as the requirements of stressed organs and tissue may increase. Hence, further supplementation may be beneficial under hypoxic stress for better adaptability. METHOD: Volunteers were divided into two groups: with and without zinc and copper salt supplementation. Blood samples were collected at sea level and on induction to acute hypoxia on days 3 and 10. Trace mineral contents and their related enzyme (alkaline phosphatase) and hormone (ceruloplasmin) levels were determined in plasma samples. RESULTS: Plasma zinc contents were significantly reduced upon induction to high altitude in the non-supplemented group, but not in the zinc-supplemented group. Alkaline phosphatase activity increased significantly upon induction to the high altitude stress. The enzyme activity remained elevated up to day 10 of the stress. Plasma copper contents and ceruloplasmin activity did not change upon induction to high altitude. CONCLUSION: Under hypoxic stress, circulating levels of zinc and alkaline phosphatase in plasma changed appreciably as plasma zinc was transported into the organs and tissues. However, circulating levels of copper and ceruloplasmin in plasma did not change, indicating no extra supplementation of copper is required under hypoxic stress.

Nifedipine does not prevent acute mountain sickness.

Nifedipine has been shown effective for prevention and treatment of high altitude pulmonary edema (HAPE). Because acute mountain sickness (AMS) and HAPE may share common pathophysiologic mechanisms, we evaluate the prophylactic effect of nifedipine on the development of AMS in 27 mountaineers not susceptible to HAPE. They were randomly assigned to receive in a double-blind manner either nifedipine or placebo during rapid ascent to 4559 m and a subsequent three-day sojourn at this altitude. Nine of 14 subjects on nifedipine and eight of 13 subjects on placebo felt ill at high altitude. Pulmonary artery pressures (PAP) estimated by Doppler echocardiography were significantly lower with nifedipine, but arterial PO2, oxygen saturation, and alveolar-arterial oxygen pressure gradient were not significantly different between groups at high altitude. This study demonstrates that lowering PAP has no beneficial effect on gas exchange and symptoms of AMS in subjects not susceptible to HAPE. Therefore, nifedipine cannot be recommended for prevention of AMS, and its use in high altitude medicine should be limited to prevention and treatment of HAPE.

Pressurization and acute mountain sickness.

Numerous cases of acute mountain sickness (AMS) during trekking were reported to have been successfully treated with portable pressure chambers. The effect of early pressurization during acute altitude exposure in the Alps had not been previously studied. In order to test the hypothesis that an early pressurization of unacclimatized subjects for 3 h could prevent or delay the appearance of symptoms of AMS, 51 previously healthy subjects climbed from 1,030 to 4,360 m within 12 h. Upon arrival at 4,360 m, AMS scores (Lake Louise Consensus Questionnaire '91), oxygen saturation (SaO2), and heart rate (HR) were determined at rest. The subjects were then randomly divided in two groups; one group was pressurized to 200 mBar for 3 h while the other rested. AMS score, HR, and SaO2 were similar in both groups before treatment. AMS score had decreased (from 2.44 +/- 0.41 (S.E.) to 0.89 +/- 0.26, p < 0.05) and SaO2 had increased (from 75.22 +/- 1.32% to 79.07 +/- 1.27%, p < 0.05) in the treatment group 15 min after leaving the pressure chamber whereas the control group had unchanged AMS score (2.50 +/- 0.40 vs. 2.40 +/- 0.40, N.S.) and SaO2 (77.83 +/- 1.41 vs. 76.67 +/- 1.24, N.S.). The next morning, however, AMS score, HR, and SaO2 were similar for both groups. It is concluded that during acute ascent in the Alps, an early 3-h pressurization of unacclimatized subjects does slightly delay the onset of AMS but does not prevent the illness nor does it attenuate its severity upon appearance.