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.

The therapeutic importance of acid-base balance.

Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on the pharmacokinetic properties of drugs. Our review considers all major organ systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.

Citrate Supplementation Restores the Impaired Mineralisation Resulting from the Acidic Microenvironment: An In Vitro Study.

Chronic metabolic acidosis leads to bone-remodelling disorders based on excessive mineral matrix resorption and inhibition of bone formation, but also affects the homeostasis of citrate, which is an essential player in maintaining the acid-base balance and in driving the mineralisation process. This study aimed to investigate the impact of acidosis on the osteogenic properties of bone-forming cells and the effects of citrate supplementation in restoring the osteogenic features impaired by the acidic milieu. For this purpose, human mesenchymal stromal cells were cultured in an osteogenic medium and the extracellular matrix mineralisation was analysed at the micro- and nano-level, both in neutral and acidic conditions and after treatment with calcium citrate and potassium citrate. The acidic milieu significantly decreased the citrate release and hindered the organisation of the extracellular matrix, but the citrate supplementation increased collagen production and, particularly calcium citrate, promoted the mineralisation process. Moreover, the positive effect of citrate supplementation was observed also in the physiological microenvironment. This in vitro study proves that the mineral matrix organisation is influenced by citrate availability in the microenvironment surrounding bone-forming cells, thus providing a biological basis for using citrate-based supplements in the management of bone-remodelling disorders related to chronic low-grade acidosis.

Enteric-coated sodium bicarbonate supplementation improves high-intensity cycling performance in trained cyclists.

PURPOSE: Enteric-coated sodium bicarbonate (NaHCO3) can attenuate gastrointestinal (GI) symptoms following acute bicarbonate loading, although the subsequent effects on exercise performance have not been investigated. The purpose of this study was to examine the effects of enteric-coated NaHCO3 supplementation on high-intensity exercise performance and GI symptoms. METHODS: Eleven trained male cyclists completed three 4 km time trials after consuming; a placebo or 0.3 g∙kg-1 body mass NaHCO3 in enteric-coated or gelatin capsules. Exercise trials were timed with individual peak blood bicarbonate ion concentration ([HCO3-]). Blood acid-base balance was measured pre-ingestion, pre-exercise, and post-exercise, whereas GI symptoms were recorded pre-ingestion and immediately pre-exercise. RESULTS: Pre-exercise blood [HCO3-] and potential hydrogen (pH) were greater for both NaHCO3 conditions (P < 0.0005) when compared to placebo. Performance time was faster with enteric-coated (- 8.5 ± 9.6 s, P = 0.044) and gelatin (- 9.6 ± 7.2 s, P = 0.004) NaHCO3 compared to placebo, with no significant difference between conditions (mean difference = 1.1 ± 5.3 s, P = 1.000). Physiological responses were similar between conditions, although blood lactate ion concentration was higher with gelatin NaHCO3 (2.4 ± 1.7 mmol∙L-1, P = 0.003) compared with placebo. Furthermore, fewer participants experienced GI symptoms with enteric-coated (n = 3) compared to gelatin (n = 7) NaHCO3. DISCUSSION: Acute enteric-coated NaHCO3 consumption mitigates GI symptoms at the onset of exercise and improves subsequent 4 km cycling TT performance. Athletes who experience GI side-effects after acute bicarbonate loading may, therefore, benefit from enteric-coated NaHCO3 supplementation prior to exercise performance.

Dietary supplementation with garcinol during late gestation and lactation facilitates acid-base balance and improves the performance of sows and newborn piglets1.

The present study was conducted to evaluate the effects of dietary garcinol supplementation during late gestation (from the 90th day of pregnancy; day 90) and lactation on the acid-base balance of the umbilical cord blood and performance of sows and piglets. Sixty sows (Duroc × Yorkshire × Landrace; second- or third-parity; n = 20) were randomly divided into 3 gestation (day 90 of pregnancy) or lactation treatments, control diet (CON; basal diet), basal diet with 200 mg garcinol, and basal diet with 600 mg garcinol per kg of feed. The body weight (BW); backfat thickness and litter size of the sows; and birth weight, weaning weight, and mortality of piglets were recorded. Sows' blood and piglets' umbilical cord blood were collected for the measurements of hematological parameters and antioxidative and immune indexes, and acid-base balance parameters, respectively. The colostrum and milk and fecal samples of the sows were also collected for analysis of milk composition and apparent total tract nutrient digestibility. Garcinol had no effect on the BW and backfat thickness of the sows but significantly increased the birth weight and weaning weight of piglets (P < 0.05) and decreased the mortality (P < 0.05). Moreover, the white blood cell counts and neutrophil count, mean cell hemoglobin, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity in the plasma of the sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group, whereas the malondialdehyde (MDA) content was decreased (P < 0.05). The garcinol treatment significantly increased the pH, HCO3- and base excess values (P < 0.05), whereas it decreased the pCO2 and lactate content (P < 0.05) in the umbilical blood. Dry matter (DM), ash, and ether extract in the colostrum were similar between groups (P > 0.05), whereas the garcinol significantly increased the crude protein (CP) in the milk. In addition, the content of immunoglobulin A (IgA) and immunoglobulin G (IgG) in the plasma of piglets and in colostrum and milk of sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group. The apparent total tract nutrient digestibility was similar between treatments. Collectively, this study indicates that sows fed with garcinol in late gestation and lactation showed improved maternal health and antioxidative status, milk protein content, acid-base balance in the umbilical cord blood, and growth performance in piglets, showing promise in natural plant extract nutrition for sows.

Control of metabolic predisposition to cardiovascular complications of chronic kidney disease by effervescent calcium magnesium citrate: a feasibility study.

AIMS: Cardiovascular (CV) complications are common in chronic kidney disease (CKD). Numerous metabolic disturbances including hyperphosphatemia, high circulating calciprotein particles (CPP), hyperparathyroidism, metabolic acidosis, and magnesium deficiency are associated with, and likely pathogenic for CV complications in CKD. The goal of this feasibility study was to determine whether effervescent calcium magnesium citrate (EffCaMgCit) ameliorates the aforementioned pathogenic intermediates. METHODS: Nine patients with Stage 3 and nine patients with Stage 5D CKD underwent a randomized crossover study, where they took EffCaMgCit three times daily for 7 days in one phase, and a conventional phosphorus binder calcium acetate (CaAc) three times daily for 7 days in the other phase. Two-hour postprandial blood samples were obtained on the day before and on the 7th day of treatment. RESULTS: In Stage 5D CKD, EffCaMgCit significantly increased T50 (half time for conversion of primary to secondary CPP) from baseline by 63% (P = 0.013), coincident with statistically non-significant declines in serum phosphorus by 25% and in saturation of octacalcium phosphate by 35%; CaAc did not change T50. In Stage 3 CKD, neither EffCaMgCit nor CaAc altered T50. With EffCaMgCit, a significant increase in plasma citrate was accompanied by statistically non-significant increase in serum Mg and phosphate. CaAc was without effect in any of these parameters in Stage 3 CKD. In both Stages 3 and 5D, both drugs significantly reduced serum parathyroid hormone. Only EffCaMgCit significantly increased serum bicarbonate by 3 mM (P = 0.015) in Stage 5D. CONCLUSIONS: In Stage 5D, EffCaMgCit inhibited formation of CPP, suppressed PTH, and conferred magnesium and alkali loads. These effects were unique, since they were not observed with CaAc. In Stage 3 CKD, neither of the regimens have any effect. These metabolic changes suggest that EffCaMgCit might be useful in protecting against cardiovascular complications of CKD by ameliorating pathobiologic intermediates.

Alkaline water improves exercise-induced metabolic acidosis and enhances anaerobic exercise performance in combat sport athletes.

Hydration is one of the most significant issues for combat sports as athletes often use water restriction for quick weight loss before competition. It appears that alkaline water can be an effective alternative to sodium bicarbonate in preventing the effects of exercise-induced metabolic acidosis. Therefore, the main aim of the present study was to investigate, in a double blind, placebo controlled randomized study, the impact of mineral-based highly alkaline water on acid-base balance, hydration status, and anaerobic capacity. Sixteen well trained combat sport athletes (n = 16), were randomly divided into two groups; the experimental group (EG; n = 8), which ingested highly alkaline water for three weeks, and the control group (CG; n = 8), which received regular table water. Anaerobic performance was evaluated by two double 30 s Wingate tests for lower and upper limbs, respectively, with a passive rest interval of 3 minutes between the bouts of exercise. Fingertip capillary blood samples for the assessment of lactate concentration were drawn at rest and during the 3rd min of recovery. In addition, acid-base equilibrium and electrolyte status were evaluated. Urine samples were evaluated for specific gravity and pH. The results indicate that drinking alkalized water enhances hydration, improves acid-base balance and anaerobic exercise performance.

Borage oil restores acidic skin pH by up-regulating the activity or expression of filaggrin and enzymes involved in epidermal lactate, free fatty acid, and acidic free amino acid metabolism in essential fatty acid-deficient Guinea pigs.

Borage oil (BO) reverses a disrupted epidermal lipid barrier and hyperproliferation in essential fatty acid deficiency (EFAD). However, little is known about its effect on skin pH, which is maintained by epidermal lactate, free fatty acids (FFAs), and free amino acids (FAAs) which is generated by lactate dehydrogenase (LDH), secreted phospholipase A2 (sPLA2), or filaggrin degradation with peptidylarginine deiminase-3 (PADI3). We hypothesized that BO restores skin pH by regulating epidermal lactate, FFA metabolism, or FAA metabolism in EFAD. To test this hypothesis, EFAD was induced in guinea pigs by a hydrogenated coconut oil (HCO) diet for 8 weeks, followed by 2 weeks of a BO diet (group HCO + BO). As controls, groups HCO and BO were fed HCO or BO diets for 10 weeks. In group HCO + BO, skin pH, which was less acidic in group HCO, was restored; and epidermal lactate and total FFAs, including palmitate, stearate, linoleate, arachidate, behenate, and lignocerate, were higher than in group HCO. LDH and sPLA2 (mainly the PLA2G2F isoform) activities and protein expressions were similar between groups HCO + BO and BO. Epidermal acidic FAAs, as well as filaggrin and PADI3 protein and mRNA expressions were higher in group HCO + BO than in group HCO. Oleate, total FAAs including other FAAs, and LDH and sPLA2 mRNA expressions were not altered between groups HCO and HCO + BO. Basic FAAs were not altered among groups. Dietary BO restored acidic skin pH and increased epidermal levels of lactate, most FFAs, and acidic FAAs by up-regulating LDH, sPLA2, filaggrin, and PADI3 activities as well as protein or mRNA expressions in EFAD.

Potassium Citrate Supplementation Decreases the Biochemical Markers of Bone Loss in a Group of Osteopenic Women: The Results of a Randomized, Double-Blind, Placebo-Controlled Pilot Study.

The relationship involving acid-base imbalance, mineral metabolism and bone health status has previously been reported but the efficacy of the alkalizing supplementation in targeting acid overload and preventing bone loss has not yet been fully elucidated. In this randomized, double-blind, placebo-controlled study, the hypothesis that potassium citrate (K citrate) modifies bone turnover in women with postmenopausal osteopenia was tested. Three hundred and ten women were screened; 40 women met the inclusion criteria and were randomly assigned to the treatment or the placebo group. They were treated with K citrate (30 mEq day-1) or a placebo in addition to calcium carbonate (500 mg day-1) and vitamin D (400 IU day-1). At baseline and time points of 3 and 6 months, serum indicators of renal function, electrolytes, calciotropic hormones, serum bone turnover markers (BTMs), tartrate-resistant acid phosphatase 5b (TRACP5b), carboxy-terminal telopeptide of type I collagen (CTX), bone alkaline phosphatase (BAP), procollagen type 1 N terminal propeptide (PINP)), and urine pH, electrolytes, and citrate were measured. The follow-up was completed by 17/20 patients in the "K citrate" group and 18/20 patients in the "placebo" group. At baseline, 90% of the patients exhibited low potassium excretion in 24 h urine samples, and 85% of cases had at least one urine parameter associated with low-grade acidosis (low pH, low citrate excretion). After treatment, CTX and BAP decreased significantly in both groups, but subjects with evidence of low-grade acidosis gained significant benefits from the treatment compared to the placebo. In patients with low 24h-citrate excretion at baseline, a 30% mean decrease in BAP and CTX was observed at 6 months. A significant reduction was also evident when low citrate (BAP: -25%; CTX: -35%) and a low pH (BAP: -25%; CTX: -30%) were found in fasting-morning urine. In conclusion, our results suggested that K citrate supplementation improved the beneficial effects of calcium and vitamin D in osteopenic women with a documented potassium and citrate deficit, and a metabolic profile consistent with low-grade acidosis.

Benefits and safety of dietary protein for bone health-an expert consensus paper endorsed by the European Society for Clinical and Economical Aspects of Osteopororosis, Osteoarthritis, and Musculoskeletal Diseases and by the International Osteoporosis Foundation.

A summary of systematic reviews and meta-analyses addressing the benefits and risks of dietary protein intakes for bone health in adults suggests that dietary protein levels even above the current RDA may be beneficial in reducing bone loss and hip fracture risk, provided calcium intakes are adequate. Several systematic reviews and meta-analyses have addressed the benefits and risks of dietary protein intakes for bone health in adults. This narrative review of the literature summarizes and synthesizes recent systematic reviews and meta-analyses and highlights key messages. Adequate supplies of dietary protein are required for optimal bone growth and maintenance of healthy bone. Variation in protein intakes within the "normal" range accounts for 2-4% of BMD variance in adults. In older people with osteoporosis, higher protein intake (≥ 0.8-g/kg body weight/day, i.e., above the current RDA) is associated with higher BMD, a slower rate of bone loss, and reduced risk of hip fracture, provided that dietary calcium intakes are adequate. Intervention with dietary protein supplements attenuate age-related BMD decrease and reduce bone turnover marker levels, together with an increase in IGF-I and a decrease in PTH. There is no evidence that diet-derived acid load is deleterious for bone health. Thus, insufficient dietary protein intakes may be a more severe problem than protein excess in the elderly. Long-term, well-controlled randomized trials are required to further assess the influence of dietary protein intakes on fracture risk.

Association of Urinary Citrate With Acid-Base Status, Bone Resorption, and Calcium Excretion in Older Men and Women.

Context: Elevated urine net acid excretion (NAE), indicative of subclinical metabolic acidosis, has been associated with higher bone turnover. Urine citrate, which is a common clinical measure, changes in response to acid-base status but its association with bone turnover is uncertain. Objective: We evaluated the association between change in urine citrate and change in bone turnover and calcium excretion. Design, Intervention, and Participants: A total of 233 healthy men and women ≥60 years old were randomly assigned to 1.0 mmol/kg/d potassium bicarbonate (KHCO3), 1.5 mmol/kg/d KHCO3, or placebo for 84 days. Outcome Measures: Urine citrate, NAE, N-telopeptide of collagen type-I (NTX), calcium excretion, and serum amino-terminal propeptide of type 1 procollagen (P1NP) were measured before and after intervention. Results: Urine citrate increased dose dependently after KHCO3 supplementation (P trend < 0.001). The urine citrate change was significantly inversely associated with P1NP change (P = 0.021) but not with change in NTX (P = 0.051) or calcium excretion (P = 0.652). The NAE change was positively associated with change in NTX and calcium excretion (P ≤ 0.003) but not with change in P1NP (P = 0.051). When the urine citrate change and NAE change were included in the same model, the urine citrate change was not associated with change in NTX, calcium excretion, or serum P1NP (P ≥ 0.086), whereas change in NAE remained associated with change in NTX and calcium excretion (P ≤ 0.003). Conclusion: Urine citrate may not be a suitable alternative to NAE when assessing acid-base status in relation to bone turnover in older adults.

Superior Efficacy of Lipid Emulsion Infusion Over Serum Alkalinization in Reversing Amitriptyline-Induced Cardiotoxicity in Guinea Pig.

BACKGROUND: Tricyclic antidepressants (TCAs) are a major cause of fatal drug poisoning due to their cardiotoxicity. Alkalinization by sodium bicarbonate (NaHCO3) administration, the first-line therapy for TCA-induced cardiotoxicity, can occasionally yield insufficient efficacy in severe cases. Because most TCAs are highly lipophilic, lipid emulsion may be more effective than alkalinization. However, it remains to be determined whether lipid emulsion is more beneficial than alkalinization in reversing amitriptyline-induced cardiotoxicity. METHODS: Hemodynamic variables were recorded from in vivo guinea pig models and Langendorff-perfused hearts. Whole-cell patch-clamp experiments were conducted on enzymatically isolated ventricular cardiomyocytes to record fast sodium currents (INa). Lipid solutions were prepared using 20% Intralipid. The pH of the alkaline solution was set at 7.55. We assessed the effect of lipid emulsion on reversing amitriptyline-induced cardiotoxicity, in vivo and in vitro, compared to alkalinization. The data were evaluated by Student t test, 1-way repeated-measures analysis of variance, or analysis of covariance (covariate = amitriptyline concentration); we considered data statistically significant when P < .05. RESULTS: In the in vivo model, intervention with lipids significantly reversed the amitriptyline-induced depression of mean arterial pressure and prolongation of QRS duration on electrocardiogram more than alkalinization (mean arterial pressure, mean difference [95% confidence interval]: 19.0 mm Hg [8.5-29.4]; QRS duration, mean difference [95% confidence interval] -12.0 milliseconds [-16.1 to -7.8]). In the Langendorff experiments, perfusion with 1% and 2% lipid solutions demonstrated significant recovery in left ventricular developed pressure (LVdevP), maximum change rate of increase of LVdevP (dP/dtmax) and rate-pressure product compared with alkaline solution (LVdevP [mm Hg], alkaline 57 ± 35, 1% lipid 94 ± 12, 2% lipid 110 ± 14; dP/dtmax [mm Hg/s], alkaline 748 ± 441, 1% lipid 1502 ± 334, 2% lipid 1753 ± 389; rate-pressure product [mm Hg·beats·minute], alkaline 11,214 ± 8272, 1% lipid 19,025 ± 8427, 2% lipid 25,261 ± 4803 with analysis of covariance). Furthermore, lipid solutions (0.5%-4%) resulted in greater recovery of hemodynamic parameters at 3 µM amitriptyline. Amitriptyline inhibited INa in a dose-dependent manner: the half-maximal inhibitory concentration (IC50) was 0.39 µM. The IC50 increased to 0.75 µM in the alkaline solution, 3.2 µM in 1% lipid solution, and 6.1 µM in 2% lipid solution. Furthermore, the lipid solution attenuated the use-dependent block of sodium channels by amitriptyline more than alkaline solution. On 30 consecutive pulses at 1 Hz, the current decreased to 50.1 ± 2.1, 60.3 ± 1.9, and 90.4% ± 1.8% in standard, alkaline, and 1% lipid solution, respectively. Even 0.5% lipid solution showed greater effects than the alkaline solution in all experiments. CONCLUSIONS: Lipid emulsion significantly suppressed amitriptyline-induced INa, inhibition, which was likely related to the marked improvement in hemodynamic status observed in vivo and in isolated perfused hearts. These results suggest the superiority of lipid emulsion as the first-line therapy for TCA-induced cardiotoxicity compared to alkalinization therapy.

The role of oral sodium bicarbonate supplementation in maintaining acid-base balance and its influence on the cardiovascular system in chronic hemodialysis patients - results of a prospective study.

Background: Major acid-base variations during dialysis and the imbalances in serum calcium levels intensified by them play a role in cardiovascular damage of hemodialysis patients. Early vascular walls modifications can be objectified by determining the pulse wave velocity (PWV) - a marker of vascular stiffness that is associated with increased risk of cardiovascular events. Material and methods: This was a prospective study conducted on 63 chronic hemodialysis patients with diuresis above 500 mL/ 24 hours and predialysis blood pressure below 160 mmHg (treatment controlled) randomized in two groups for 12 months - the study group receiving interdialitic oral sodium bicarbonate doses and control group, without oral sodium bicarbonate supplementation, but receiving higher bicarbonate prescriptions in dialysis. All the patients were monthly evaluated by biochemical tests (serum calcium, phosphate, iPTH, bicarbonate), the assessment of prescribed doses of phosphate binders being undergone. Two PWV determinations and chest X-ray exams for coronary calcifications were done - at the beginning and end of the study for every patient. Results: In the study group (n = 29), the mean age was 56.48 ± 12.78 years and the average duration of dialysis was 55.51 ± 34.53 months, the mean dialysis bicarbonate was 29.81 ± 1.41 mEq/ L and 27 of them (subgroup 0) had alkaline reserve (AR) 20-22 mEq/ L. The control group (n = 34) had a mean age of 57.35 ± 15.32 years and the mean dialysis duration 59.67 ± 34.79 months, with an average level of dialysis bicarbonate of 33 ± 2.2 mEq/ L necessary to maintain AR within guidelines. Depending on the mean AR obtained, this group was divided into three subgroups (subgroup 1, subgroup 2, and subgroup 3). There were statistically significant differences regarding the necessary of dialysis bicarbonate (p < 0.001), average serum calcium levels (p < 0.001) and serum phosphorus (p < 0.001), as well as PWV mean values and the number of vascular calcifications (p = 0.036) between the study and the control group. The average dose of phosphate binders was significantly higher in the study group (p = 0.01). At the end of the study, the serum iPTH average levels were decreased in the study group (p < 0.001) and significantly increased in the control group (p < 0.001). Conclusions: Avoiding large variations in serum bicarbonate levels is an important step in hemodialysis patients' management because wide acidosis-alkalosis variation can increase cardiovascular risks in terms of altering the vessel walls elasticity and favoring their calcifications. Abbreviations: GFR = glomerular filtration rate,PWV = pulse wave velocity, iPTH = intact parathyroid hormone,AR = alkaline reserve, BP = blood pressure,mEq = milliequivalents,L = liter.

Acute Citrulline-Malate Supplementation and High-Intensity Cycling Performance.

Cunniffe, B, Papageorgiou, M, O'Brien, B, Davies, NA, Grimble, GK, and Cardinale, M. Acute citrulline-malate supplementation and high-intensity cycling performance. J Strength Cond Res 30(9): 2638-2647, 2016-Dietary L-citrulline-malate (CM) consumption has been suggested to improve skeletal muscle metabolism and contractile efficiency, which would be expected to predispose exercising individuals to greater fatigue resistance. The purpose of this study was to examine the effects of CM supplementation on acid-base balance and high-intensity exercise performance. In a double-blind, placebo-controlled, crossover study, 10 well-trained males consumed either 12 g of CM (in 400 ml) or lemon sugar-free cordial (placebo [PL]) 60 minutes before completion of 2 exercise trials. Each trial consisted of subjects performing 10 (×15 seconds) maximal cycle sprints (with 30-second rest intervals) followed by 5 minutes recovery before completing a cycle time-to-exhaustion test (TTE) at 100% of individual peak power (PP). Significant increases in plasma concentrations of citrulline (8.8-fold), ornithine (3.9-fold), and glutamine (1.3-fold) were observed 60 minutes after supplementation in the CM trial only (p ≤ 0.05) and none of the subjects experienced gastrointestinal side-effects during testing. Significantly higher exercise heart rates were observed in CM condition (vs. PL) although no between trial differences in performance related variables (TTE: [120 ± 61 seconds CM vs. 113 ± 50 seconds PL]), PP or mean power, ([power fatigue index: 36 ± 16% CM vs. 28 ± 18% PL]), subjective rating of perceived exertion or measures of acid-base balance (pH, lactate, bicarbonate, base-excess) were observed (p > 0.05). This study demonstrated that acute supplementation of 12 g CM does not provide acute ergogenic benefits using the protocol implemented in this study in well-trained males.

Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials.

Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

Effects of goal-directed fluid therapy with different lactated Ringer's: hydroxyethyl starch ratios in hemorrhagic shock dogs.

The effects of goal-directed fluid therapy, with lactated Ringer's (LR) and 6% hydroxyethyl starch (HES) solution, on hemorrhagic shock dogs are unknown. We aimed to determine the optimal LR: HES ratio for the resuscitation of hemorrhagic shock dogs. Hemorrhagic shock was induced in 40 ventilated dogs by drawing an estimated 60% blood volume. The animals were randomly divided into five groups (N = 8) according to the LR: HES ratio of the resuscitation fluid (3:1, 2:1, 1:1, 1:2, and 1:3), and were then resuscitated for 24 h to reach the stroke volume variation (SVV) and hemoglobin (Hb) goals by fluid infusion and autologous blood perfusion. The extravascular lung water index (EVLWI), pH, partial pressure of oxygen (PaO2), base excess (BE), sodium, chloride, Hb and creatinine clearance (Clearcrea) were checked after 24 h (R24). The EVLWI of the 3:1 group at R24 were higher than that of the 1:3 group and the baseline value (P < 0.05), whereas the PaO2 was lower (P < 0.05). In contrast to the 3:1 group at R24 and baseline, plasma chloride and sodium in the 1:3 and 1:2 groups increased; however, pH, BE, and Clearcrea decreased (P < 0.05). No significant differences were found in the 1:1 and 2:1 groups at R24 compared with baseline (P > 0.05). Resuscitation with LR and HES at 2:1 and 1:1 ratios are superior in maintaining the acid-base, electrolyte, and lung water balances as well as renal function in hemorrhagic shock dogs than at ratios of 3:l, 1:2, and1:3.

Effects of intravenous solutions on acid-base equilibrium: from crystalloids to colloids and blood components.

Intravenous fluid administration is a medical intervention performed worldwide on a daily basis. Nevertheless, only a few physicians are aware of the characteristics of intravenous fluids and their possible effects on plasma acid-base equilibrium. According to Stewart's theory, pH is independently regulated by three variables: partial pressure of carbon dioxide, strong ion difference (SID), and total amount of weak acids (ATOT). When fluids are infused, plasma SID and ATOT tend toward the SID and ATOT of the administered fluid. Depending on their composition, fluids can therefore lower, increase, or leave pH unchanged. As a general rule, crystalloids having a SID greater than plasma bicarbonate concentration (HCO3-) cause an increase in plasma pH (alkalosis), those having a SID lower than HCO3- cause a decrease in plasma pH (acidosis), while crystalloids with a SID equal to HCO3- leave pH unchanged, regardless of the extent of the dilution. Colloids and blood components are composed of a crystalloid solution as solvent, and the abovementioned rules partially hold true also for these fluids. The scenario is however complicated by the possible presence of weak anions (albumin, phosphates and gelatins) and their effect on plasma pH. The present manuscript summarises the characteristics of crystalloids, colloids, buffer solutions and blood components and reviews their effect on acid-base equilibrium. Understanding the composition of intravenous fluids, along with the application of simple physicochemical rules best described by Stewart's approach, are pivotal steps to fully elucidate and predict alterations of plasma acid-base equilibrium induced by fluid therapy.

Whey versus soy protein diets and renal status in rats.

Different dietary protein sources can promote different renal statuses. We examined the effects of whey protein (WP) and soy protein (SP) intake on plasma, urinary, and morphological renal parameters in rats. One hundred and twenty Wistar rats were randomly distributed into 2 experimental groups fed with either WP or SP diets over 12 weeks. These diets were based on commercial WP or SP isolates. The urinary calcium content was higher in the WP diet compared to the SP diet group (P<.001) whereas the urinary citrate level was lower (P<.001). The urinary pH was more acidic in the WP diet group compared to the SP diet group (P<.001); however, no differences were observed between the groups for any of the renal morphological parameters analyzed (all, P>.05) or other plasma renal markers such as albumin or urea concentrations. The increase of acid and urinary calcium and the lower urinary citrate level observed in the WP diet group could increase the incidence of nephrolithiasis compared to the SP diet group. Despite the WP showed poorer acid-base profile, no significant morphological renal changes were observed. These results suggest that the use of SP instead of WP appears to promote a more alkaline plasma and urinary profile, with their consequent renal advantages.

Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate.

Alkali therapy of metabolic acidosis in patients with chronic kidney disease (CKD) with plasma total CO2 (TCO2) below 22 mmol/l per KDOQI guidelines appears to preserve estimated glomerular filtration rate (eGFR). Since angiotensin II mediates GFR decline in partial nephrectomy models of CKD and even mild metabolic acidosis increases kidney angiotensin II in animals, alkali treatment of CKD-related metabolic acidosis in patients with plasma TCO2 over 22 mmol/l might preserve GFR through reduced kidney angiotensin II. To test this, we randomized 108 patients with stage 3 CKD and plasma TCO2 22-24 mmol/l to Usual Care or interventions designed to reduce dietary acid by 50% using sodium bicarbonate or base-producing fruits and vegetables. All were treated to achieve a systolic blood pressure below 130 mm Hg with regimens including angiotensin converting enzyme inhibition and followed for 3 years. Plasma TCO2 decreased in Usual Care but increased with bicarbonate or fruits and vegetables. By contrast, urine excretion of angiotensinogen, an index of kidney angiotensin II, increased in Usual Care but decreased with bicarbonate or fruits and vegetables. Creatinine-calculated and cystatin C-calculated eGFR decreased in all groups, but loss was less at 3 years with bicarbonate or fruits and vegetables than Usual Care. Thus, dietary alkali treatment of metabolic acidosis in CKD that is less severe than that for which KDOQI recommends therapy reduces kidney angiotensin II activity and preserves eGFR.

Effect of lactate supplementation and sodium bicarbonate on 40-km cycling time trial performance.

The use of nutritional supplements to improve sporting performance and increase training adaptations is commonplace among athletes and is an expanding market in terms of product choice and availability. The purpose of this study was to examine the effects of 2 ergogenic aids with extracellular blood buffering potential, namely sodium bicarbonate (NaHCO3) and a lactate supplement, during a 40-km cycling time trial. Seven recreationally active men (age, 22.3 ± 3.3 years; height, 182.5 ± 6.5 cm; body mass, 79.2 ± 6.3 kg) completed five 40-km cycling time trials, including a familiarization trial in a randomized, blind, double placebo-controlled design. Subjects ingested (a) 300 mg·kg-1 body mass NaHCO3 (BICARB), (b) 45 mg·kg-1 body mass sodium chloride (PL-BICARB) as the placebo for the NaHCO3 trial, (c) 1115 mg lactate (LACTATE), or (d) plain flour as the placebo for the lactate trial (PL-LACTATE) 60 minutes before exercise. There was no significant difference in performance between the 4 conditions (p > 0.05). Although NaHCO3 ingestion induced significant changes in all the acid-base variables (all p < 0.05), no significant change was seen following lactate ingestion (p > 0.05). Subjects in the LACTATE condition did have a significantly higher heart rate (p < 0.05) without experiencing any greater perceived exertion (p > 0.05) than the other 3 conditions. Neither NaHCO3 nor lactate supplementation seem to improve 40-km cycling time trial performance. However, the potential benefits following LACTATE regarding perceived exertion require further research.