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The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUC last and C max at Day 91) was greater in males than females, suggesting sex differences. AUC last and C max at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed T max and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Diltiazem hydrochloride is a calcium channel-blocker with a plasma elimination half-life of 4.4 ± 1.3 h and has a narrow absorption window. So, this work aimed to prepare a gastro-retentive floating matrix tablet., Methods: The direct compression method was used to manufacture tablets. 3 2 factorial design was applied for optimization, taking Hydroxypropyl Methylcellulose K100M (HPMC K 100M) and the amount of sodium bicarbonate as independent factors and cumulative percentage release at 1 h, at 6 h, and at 12 h and floating lag time as dependent variables., Results: The high amount of HPMC K100M and sodium bicarbonate shows good results. The optimized preparation was evaluated for differential scanning calorimetry, in-vivo gastric retention in male albino rabbits, kinetic modeling, and stability study. An in vivo study revealed gastric retention of tablets up to 6 h in healthy male Albino rabbits. The stability study indicated no significant change in the buoyancy and release profiles of the drug., Conclusion: From this study, it can be concluded that the gastro-retentive diltiazem hydrochloride floating matrix tablet was successfully prepared and retained inside the rabbit stomach for up to 6 h and was stable under accelerated stability study., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Proton pump inhibitors (PPIs) differ in onset of action and bioavailability. This trial was conducted to investigate the pharmacokinetics and pharmacodynamics of an immediate-release capsule formulation containing lansoprazole 30 mg and sodium bicarbonate 1100 mg (T preparation) in healthy Chinese subjects. This was an open, single-center, randomized, single and multiple oral doses, and two-period crossover study in 30 healthy subjects. After single- and multiple-dose oral administration, blood samples were obtained and lansoprazole concentration in serum was measured for pharmacokinetic analysis. Meanwhile, the intragastric pH was monitored continuously to evaluate the pharmacodynamics of the investigational drugs. The T max of the T preparation was 0.5 hours, while the T max of the R preparation was 1.5 hours after multiple doses, which indicated that the absorption speed of the T preparation was significantly faster than that of the R preparation. The same characteristics also existed after single-dose administration. The area under the curve (AUC) ss of the T preparation was bio-equivalent to that of the R preparation under steady state. The time percentage of intragastric pH > 4.0 for the T preparation was higher than that of the R preparation after 1 hour for both single- and multiple-dose. It suggested compared with R preparation, the time percentage of intragastric pH > 4.0 met the criteria for superiority after 1 hour administration for the T preparation. In addition, no serious adverse events occurred in this study. Across this study, the T preparation was better than the R preparation at improving drug absorption and increasing intragastric pH, and had a favorable safety profile., (© 2023, The American College of Clinical Pharmacology.)

Purpose: To describe the reliability of blood bicarbonate pharmacokinetics in response to sodium bicarbonate (SB) supplementation across multiple occasions and assess, using putative thresholds, whether individual variation indicated a need for individualized ingestion timings., Methods: Thirteen men (age 27 ± 5 yr; body mass [BM], 77.4 ± 10.5 kg; height, 1.75 ± 0.06 m) ingested 0.3 g·kg BM SB in gelatine capsules on three occasions. One hour after a standardized meal, venous blood was obtained before and every 10 min after ingestion for 3 h, then every 20 min for a further hour. Time to peak (Tmax), absolute peak (Cmax), absolute peak change ([INCREMENT]Cmax), and area under the curve were analyzed using mixed models, intraclass correlation coefficient, coefficient of variation and typical error. Individual variation in pharmacokinetic responses was assessed using Bayesian simulation with multilevel models with random intercepts., Results: No significant differences between sessions were shown for blood bicarbonate regarding Cmax, [INCREMENT]Cmax or area under the curve (P > 0.05), although Tmax occurred earlier in SB2 (127 ± 36 min) than in SB1 (169 ± 54 min, P = 0.0088) and SB3 (159 ± 42 min, P = 0.05). Intraclass correlation coefficient, coefficient of variation, and typical error showed moderate to poor reliability. Bayesian modeling estimated that >80% of individuals from the population experience elevated blood bicarbonate levels above +5 mmol·L between 75 and 240 min after ingestion, and between 90 and 225 min above +6 mmol·L., Conclusions: Assessing SB supplementation using discrete values showed only moderate reliability at the group level, and poor reliability at the individual level, whereas Tmax was not reproducible. However, when analyzed as modeled curves, a 0.3-g·kg BM dose was shown to create a long-lasting window of ergogenic potential, challenging the notion that SB ingestion individualized to time-to-peak is a necessary strategy, at least when SB is ingested in capsules.

Background: We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation., Methods: We examined baseline total body water (TBW), Na+ space, HCO3- space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO3 infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na+ space that exceeds TBW uncovers nonosmotic sodium storage., Results: Na+ space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na+ space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = -0.01x + 1.4, p= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked., Conclusions: This study demonstrates that hypobicarbonatemic animals have a Na+ space that exceeds TBW after an acute infusion of hypertonic NaHCO3 indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na+ space, these animals have a larger HCO3- space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO3- loading whenever initial [HCO3-]e is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium., (© 2020 S. Karger AG, Basel.)

Background: Oral sodium bicarbonate (NaHCO 3 ) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown., Methods: This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO 3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m 2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO 3 ; 0.8 meq/kg of lean body wt per day; n =90) or lower-dose (LD-NaHCO 3 ; 0.5 meq/kg of lean body wt per day; n =52) NaHCO 3 or matching placebo ( n =52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose., Results: Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m 2 , serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO 3 , 96% in LD-NaHCO 3 , and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO 3 , 98% in LD-NaHCO 3 , and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO 3 compared with LD-NaHCO 3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group., Conclusions: Both NaHCO 3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO 3 may be a reasonable choice for future trials., (Copyright © 2020 by the American Society of Nephrology.)

Enteric-formulated capsules can mitigate gastrointestinal (GI) side effects following sodium bicarbonate (NaHCO3) ingestion; however, it remains unclear how encapsulation alters postingestion symptoms and acid-base balance. The current study aimed to identify the optimal ingestion form to mitigate GI distress following NaHCO3 ingestion. Trained males (n = 14) ingested 300 mg/kg body mass of NaHCO3 in gelatin (GEL), delayed-release (DEL), and enteric-coated (ENT) capsules or a placebo in a randomized cross-over design. Blood bicarbonate anion concentration, potential hydrogen, and GI symptoms were measured pre- and postingestion for 3 hr. Fewer GI symptoms were reported with ENT NaHCO3 than with GEL (p = .012), but not with DEL (p = .106) in the postingestion phase. Symptom severity decreased with DEL (4.6 ± 2.8 arbitrary units) compared with GEL (7.0 ± 2.6 arbitrary units; p = .001) and was lower with ENT (2.8 ± 1.9 arbitrary units) compared with both GEL (p < .0005) and DEL (p = .044) NaHCO3. Blood bicarbonate anion concentration increased in all NaHCO3 conditions compared with the placebo (p < .0005), although this was lower with ENT than with GEL (p = .001) and DEL (p < .0005) NaHCO3. Changes in blood potential hydrogen were reduced with ENT compared with GEL (p = .047) and DEL (p = .047) NaHCO3, with no other differences between the conditions. Ingestion of ENT NaHCO3 attenuates GI disturbances for up to 3 hr postingestion. Therefore, ENT ingestion forms may be favorable for those who report GI disturbances with NaHCO3 supplementation or for those who have previously been deterred from its use altogether.

Background: Esomeprazole is the most effective treatment for acid-related disorders and is widely used with enteric coating due to rapid degradation in the acidic environment. However, the enteric-coated formulation delays absorption and onset of action. To overcome this limitation, an immediate-release formulation containing esomeprazole 20 mg and sodium bicarbonate 800 mg (IR-ESO) was developed., Purpose: To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics of IR-ESO compared to those of esomeprazole 20 mg (ESO)., Methods: A randomized, open-label, multiple-dose, two-treatment, two-sequence crossover study was conducted in 40 healthy male subjects. Subjects received either IR-ESO or ESO for 7 days. After single and multiple dosing, blood samples were collected for PK analysis, and intragastric pH was assessed by 24-hr pH monitoring., Results: Plasma esomeprazole exposure of IR-ESO was similar to that of ESO after single and multiple dosing. Time to peak concentration of IR-ESO (0.50-0.75 hr) was shorter than that of ESO (1.25-1.50 hr). Percentage changes in 24-hr integrated gastric acidity from baseline for IR-ESO were similar to those for ESO. In addition, mean time to maintain gastric pH >4 for 24 hr was similar for both drugs (IR-ESO 55.5-69.9% vs ESO 56.8-70.2%). Evaluation of time to first reach pH 4 after dosing indicated that IR-ESO showed a faster onset than ESO. All subjects found the drug tolerable, and there were no significant differences in adverse events between two drugs., Conclusion: This study showed that IR-ESO produced a rapid, safe and sustained gastric acid suppression (ClinicalTrials.gov: NCT03211143)., Competing Interests: Shin Jung Park is a full-time employee of Chong Kun Dang Pharmaceutical Corp. The authors report no other conflicts of interest in this work., (© 2019 Kim et al.)

Acidic pH in the tumor microenvironment is associated with cancer metabolism and creates a physiological barrier that prevents from drugs to penetrate cells. Specifically, ionizable weak-base drugs, such as doxorubicin, freely permeate membranes in their uncharged form, however, in the acidic tumor microenvironment these drugs become charged and their cellular permeability is retarded. In this study, 100-nm liposomes loaded with sodium bicarbonate were used as adjuvants to elevate the tumor pH. Combined treatment of triple-negative breast cancer cells (4T1) with doxorubicin and sodium-bicarbonate enhanced drug uptake and increased its anti-cancer activity. In vivo, mice bearing orthotropic 4T1 breast cancer tumors were administered either liposomal or free bicarbonate intravenously. 3.7 ± 0.3% of the injected liposomal dose was detected in the tumor after twenty-four hours, compared to 0.17% ± 0.04% in the group injected free non-liposomal bicarbonate, a 21-fold increase. Analyzing nanoparticle biodistribution within the tumor tissue revealed that 93% of the PEGylated liposomes accumulated in the extracellular matrix, while 7% were detected intracellularly. Mice administered bicarbonate-loaded liposomes reached an intra-tumor pH value of 7.38 ± 0.04. Treating tumors with liposomal bicarbonate combined with a sub-therapeutic dose of doxorubicin achieved an improved therapeutic outcome, compared to mice treated with doxorubicin or bicarbonate alone. Interestingly, analysis of the tumor microenvironment demonstrated an increase in immune cell' population (T-cell, B-cell and macrophages) in tumors treated with liposomal bicarbonate. This study demonstrates that targeting metabolic adjuvants with nanoparticles to the tumor microenvironment can enhance anticancer drug activity and improve treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Sodium bicarbonate (SB) is an ergogenic supplement shown to improve high-intensity exercise via increased blood bicarbonate buffering. Substantial amounts of the ingested bicarbonate are neutralized in the stomach. Bariatric surgery results in a small gastric pouch which dramatically reduces exposure time of any ingested food in the stomach. The aim of this study was to examine the pharmacokinetics of orally ingested SB in a postgastric bypass individual to determine the magnitude of changes in blood bicarbonate and associated side effects. We hypothesized that SB supplementation in a gastric bypass model would result in greater blood bicarbonate increases and fewer side effects than in healthy individuals due to minimal bicarbonate losses in the stomach. One postbariatric male ingested 0.3 g/kg·body mass of SB on three occasions (SB1, SB2, and SB3) and 0.3 g/kg·body mass of placebo on a further occasion. Blood bicarbonate was determined before and every 10 min following supplement ingestion for 3 hr and then every 20 min for a further 1 hr. Side effects were reported using an adapted questionnaire at identical time points. Maximal increases in blood bicarbonate with SB were +20.0, +15.2, and +12.6 mM, resulting in maximal bicarbonate concentrations of 42.8, 39.3, and 36.2 mM. Area under the curve was SB1: 8,328 mM/min; SB2: 7,747 mM/min; SB3: 7,627 mM/min, and 6,436 mM/min for placebo. Side effects with SB were scarce. Maximal bicarbonate increases were well above those shown previously, with minimal side effects, indicative of minimal neutralization of bicarbonate in the stomach. The large increases in circulating bicarbonate and minimal side effects experienced by our postgastric surgery bypass patient are indicative that minimizing neutralization of bicarbonate in the stomach, as would occur with enteric coated capsules, may optimize SB supplementation and thus warrants investigation.

Background: Emergency department (ED) treatment of hyperkalemia often involves shifting potassium into the intracellular space. There is uncertainty whether transcellular shifting causes insufficient potassium removal during hemodialysis, resulting in a subsequent need for further medical therapy or multiple sessions of hemodialysis., Objective: We sought to determine whether transcellular potassium shifting in ED patients with hyperkalemia who undergo hemodialysis is associated with recurrent hyperkalemia with or without repeat hemodialysis within 24 h., Methods: This was a retrospective observational study of ED patients with a potassium value > 5.3 mmol/L and ≥1 hemodialysis run. Transcellular shifting medications were defined as albuterol, insulin, and sodium bicarbonate. Primary outcomes were recurrent hyperkalemia with and without repeat hemodialysis within 24 h of the initial dialysis run. Generalized estimating equation models were created for the outcomes using administration of a shifting medication as the primary predictor., Results: Four hundred seventy-nine encounters were identified. In 238 (50%) encounters, a shifting medication was administered. There were 85 outcomes of recurrent hyperkalemia and 36 outcomes of recurrent hyperkalemia with repeat hemodialysis. After adjustment, administration of shifting medications was not associated with recurrent hyperkalemia (adjusted odds ratio 1.26, 95% confidence interval 0.71-2.23) or recurrent hyperkalemia with repeat dialysis (adjusted odds ratio 1.90, 95% confidence interval 0.80-4.48)., Conclusions: Administration of transcellular shifting medications for hyperkalemia in the ED was not associated with either recurrent hyperkalemia after hemodialysis or the need for a second dialysis session within 24 h. Our findings address the uncertainty regarding transcellular potassium shifting before emergent dialysis and support safe ED administration of medications that shift potassium to the intracellular space., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this prospective, randomized, double-blind study was to evaluate the effect of a buccal infiltration of sodium bicarbonate on the anesthetic success of the inferior alveolar nerve block (IANB) for mandibular first molars in patients with symptomatic irreversible pulpitis., Methods: One hundred patients diagnosed with symptomatic irreversible pulpitis of a mandibular first molar were selected. The patients randomly received a buccal infiltration injection of either 0.7 mL 8.4% sodium bicarbonate with 0.3 mL 2% lidocaine containing 1:80,000 epinephrine or 0.7 mL sterile distilled water with 0.3 mL 2% lidocaine containing 1:80,000 epinephrine in a double-blind manner. After 15 minutes, all the patients received conventional IANB injection using 3.6 mL 2% lidocaine with 1:80,000 epinephrine. Access cavity preparation was initiated 15 minutes after the IANB injection. Lip numbness was a requisite for all the patients. Success was determined as no or mild pain on the basis of Heft-Parker visual analog scale recordings upon access cavity preparation or initial instrumentation. Data were analyzed using the t, chi-square and Mann-Whitney U tests., Results: The success rate after the buccal infiltration of sodium bicarbonate was 78%, whereas without the buccal infiltration of sodium bicarbonate it was 44% (P < .001)., Conclusions: A buccal infiltration of 0.7 mL 8.4% sodium bicarbonate increased the success rate of IANBs in mandibular first molars with symptomatic irreversible pulpitis., (Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Carbopol (CP) is a biocompatible bioadhesive polymer used as a matrix for gastroretentive (GR) tablets, however, its rapid hydration shortens its bioadhesion and floating when incorporated in effervescent formulae. The interpolymer complexation of CP with polyvinylpyrrolidone (PVP) significantly reduced the excessive hydration of CP, prolonging floating and maintaining the mucoadhesiveness. In early attempts, a lengthy process was followed to prepare such an interpolymer complex. In this study, an in situ interpolymer complexation between CP and two grades of PVP (K25 and K90) in 0.1 N HCl was investigated and characterized by Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Hence, directly compressed GR tablets of different combinations of PVP and CP with sodium bicarbonate (SB) as an effervescent agent were examined for prolonged gastroretention and sustained release of ranitidine hydrochloride (RHCl) as a model drug. Tablets were evaluated for in vitro buoyancy, bioadhesiveness, swelling, and drug release in 0.1 N HCl. All GR tablets containing PVP-CP combinations achieved more prolonged floating (>24 h) than CP tablets (5.2 h). Their bioadhesiveness, swelling, and drug release were dependent on the PVP molecular weight and its ratio to CP. Drug release profiles of all formulae followed non-Fickian diffusion. Formula containing the PVP K90-CP combination at a respective ratio of 1 : 3 (P90C13) was a promising system, exhibiting good floating and bioadhesive properties as well as sustained drug release. Abdominal X-ray imaging of P90C13 formula, loaded with barium sulfate, in six healthy volunteers showed a mean gastric retention period of 6.8±0.3 h.

Although much research has investigated the types of exercise that are enhanced with sodium bicarbonate (NaHCO3) ingestion, to date, there has been limited research on the dosage and timing of ingestion that optimizes the associated ergogenic effects. This study investigated the effects of various NaHCO3 loading protocols on the time-dependent blood-buffering profile. Eight male volunteers (age, 22.4 +/- 5.7 yr; height, 179.8 +/- 9.6 cm, body mass, 76.3 +/- 14.1 kg) completed Part A, measures of alkalosis throughout 120 minutes after ingestion of various single NaHCO3 dosages (0.3 gxkg-1, 0.2 gxkg-1, 0.1 gxkg-1, and placebo); and Part B, similar profiles after alternative NaHCO3 loading protocols (single morning dosage [SMD], single evening dosage [SED], and dosages ingested on 3 consecutive evenings [CED]). Results from Part A are as follows. Blood buffering in the 0.1 gxkg-1 condition was significantly lower than the 0.2 g.kg-1 and 0.3 gxkg-1 conditions (p < 0.002), but there was no significant differences between the 0.2 gxkg -1and 0.3 g.kg-1 conditions (p = 0.34). Although the blood buffering was relatively constant in the 0.1 and 0.2 conditions, it was significantly higher at 60 minutes than at 100 minutes and 120 minutes in the 0.3 gxkg-1 condition (p < 0.05). Results from Part B are as follows. Blood buffering for SMD was significantly higher than for SED and CED (p < 0.05). Blood buffering in the SMD condition was significantly lower at 17:00 hours than at 11:00 hours (p = 0.007). The single 0.2 and 0.3 gxkg-1 NaHCO3 dosages appeared to be the most effective for increasing blood-buffering capacity. The 0.2 gxkg-1 dosage is best ingested 40 to 50 minutes before exercise and the 0.3 gxkg-1 dosage 60 minutes before exercise.

Methods for the simultaneous polarization of multiple 13C-enriched metabolites were developed to probe several enzymatic pathways and other physiologic properties in vivo, using a single intravenous bolus. A new method for polarization of 13C sodium bicarbonate suitable for use in patients was developed, and the co-polarization of 13C sodium bicarbonate and [1-(13)C] pyruvate in the same sample was achieved, resulting in high solution-state polarizations (15.7% and 17.6%, respectively) and long spin-lattice relaxation times (T1) (46.7 s and 47.7 s respectively at 3 T). Consistent with chemical shift anisotropy dominating the T1 relaxation of carbonyls, T1 values for 13C bicarbonate and [1-(13)C] pyruvate were even longer at 3 T (49.7s and 67.3s, respectively). Co-polarized 13C bicarbonate and [1-(13)C] pyruvate were injected into normal mice and a murine prostate tumor model at 3T. Rapid equilibration of injected hyperpolarized 13C sodium bicarbonate with 13C CO2 allowed calculation of pH on a voxel by voxel basis, and simultaneous assessment of pyruvate metabolism with cellular uptake and conversion of [1-(13)C] pyruvate to its metabolic products. Initial studies in a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model demonstrated higher levels of hyperpolarized lactate and lower pH within tumor, relative to surrounding benign tissues and to the abdominal viscera of normal controls. There was no significant difference observed in the tumor lactate/pyruvate ratio obtained after the injection of co-polarized 13C bicarbonate and [1-(13)C] pyruvate or polarized [1-(13)C] pyruvate alone. The technique was extended to polarize four 13C labelled substrates potentially providing information on pH, metabolism, necrosis and perfusion, namely [1-(13)C]pyruvic acid, 13C sodium bicarbonate, [1,4-(13)C]fumaric acid, and 13C urea with high levels of solution polarization (17.5%, 10.3%, 15.6% and 11.6%, respectively) and spin-lattice relaxation values similar to those recorded for the individual metabolites. These studies demonstrated the feasibility of simultaneously measuring in vivo pH and tumor metabolism using nontoxic, endogenous species, and the potential to extend the multi-polarization approach to include up to four hyperpolarized probes providing multiple metabolic and physiologic measures in a single MR acquisition., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective: To determine and compare the effects of 4 oral replacement therapy (ORT) solutions on acid-base balance, abomasal emptying rate, and plasma volume expansion in calves with naturally acquired diarrhea and moderate dehydration., Design: Prospective study., Animals: 20 calves., Procedures: 20 calves up to 45 days of age were randomly allocated (n = 5/group) to receive 2 L of 1 of 4 treatments via oroesophageal intubation: sodium bicarbonate (150 mmol/L or 300 mmol/L) or sodium acetate (150 mmol/L or 300 mmol/L). The 4 test solutions contained acetaminophen (50 mg/kg [22.7 mg/lb]) and 50 g of glucose monohydrate. Jugular venous blood samples were obtained periodically before and after administration of the ORT solution. Abomasal emptying rate was determined by use of the time to maximal plasma acetaminophen concentration., Results: Plasma bicarbonate concentration increased more rapidly in calves administered bicarbonate-containing ORT solutions, whereas the rate of systemic alkalinization, as assessed via blood pH, did not differ consistently among treatments. The 300 mmol/L ORT solutions were emptied at a significantly slower rate from the abomasum than 150 mmol/L ORT solutions, with no difference in emptying rate between acetate and bicarbonate-containing ORT solutions of similar molality. The 300 mmol/L sodium acetate ORT solution significantly increased plasma volume., Conclusions and Clinical Relevance: Clinically important differences in the resuscitative response to 300 mmol/L or 150 mmol/L ORT solutions of sodium acetate or sodium bicarbonate were not identified.

Background: To determine nutrient requirements by the carbon oxidation techniques, it is necessary to know the fraction of carbon dioxide produced during the oxidative process but not excreted. This fraction has not been described in critically ill children. By measuring the dilution of (13)C infused by metabolically produced carbon dioxide, the rates of carbon dioxide appearance can be estimated. Energy expenditure can be determined by bicarbonate dilution kinetics if the energy equivalents of carbon dioxide (food quotient) from the diet ingested are known., Objective: We conducted a 6-h, primed, continuous tracer infusion of NaH(13)CO(3) in critically ill children fed parenterally or enterally or receiving only glucose and electrolytes, to determine bicarbonate fractional recovery, bicarbonate rates of appearance, and energy expenditure., Design: Thirty-one critically ill children aged 1 mo-20 y who were admitted to a pediatric intensive care unit at a tertiary-care center were studied. Patients were stratified by age, BMI, and severity score (PRISM III)., Results: Fractional bicarbonate recovery was 0.69, 0.70, and 0.63, respectively, for the parenterally fed, enterally fed, and glucose-electrolytes groups, and it correlated with the severity of disease in the parenteral (P < 0.01) and glucose-electrolytes (P < 0.05) groups. Rates of appearance varied between 0.17 and 0.19 micromol . kg(-1) . h(-1) With these data and estimates of the energy equivalents of carbon dioxide (a surrogate for respiratory quotient), energy expenditure was determined., Conclusions: The 2001 World Health Organization and Schofield predictive equations overestimated and underestimated, respectively, energy requirements compared with those obtained by bicarbonate dilution kinetics. Bicarbonate kinetics allows accurate determination of energy needs in critically ill children.

Objective: the aim of this relative bioavailability study was to determine the rate and extent of absorption of Alikal Dolor (effervescent powder containing paracetamol 500 mg/sodium bicarbonate 2318 mg)--test formulation (T) in relation to Parageniol (paracetamol 500 mg coated tablets)--reference formulation (R)., Methods: 18 healthy volunteers (10 male and 8 female aged between 21 and 46 years) received, after 2 h of standardized breakfast, a single oral dose with 220 ml of water, in an open, randomized, crossover study, with a 7-day wash-out period. Paracetamol concentrations were established at 0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 90 min and at 2, 4, 6, 8 and 10 h postdose by HPLC with an ultraviolet detector., Results: the regression coefficient determined for paracetamol calibration curves was 0.9983 +/- 0.0034 and the working range was from 0.2 to 50 microg/ml. The quantification limit was 0.2 microg/ml. The rate of absorption was significantly greater (p < 0.03) for T (T(max) = 20.4 min) compared with R (T(max) = 38.4 min). Extent of absorption over the first 30 min postdose AUC((0-30 min)) was 4.21-fold greater (p < 0.03) for T compared with R, without differences between C(max.) The 90% CI on the geometric mean for C(max), AUC((0-10 h)) and AUC((0-)) ratios (T/R) were within the limits of 0.80-1.25, indicating both formulations were bioequivalent with respect to these parameters., Conclusion: paracetamol was absorbed at least twice as fast from T-containing sodium bicarbonate compared with R. This pharmacokinetic feature could prove crucial from the therapeutic point of view as it would allow a lower latency in the action time of paracetamol in producing its analgesic and antithermal effect.

The amount needed to change the concentration of a solute requires the knowledge of its volume of distribution in the solution. Electrolytes that do not participate in active metabolic reactions have a fixed volume of distribution that corresponds to the volume of water in which they solubilize. Bicarbonate infusion is used to correct hyperchloremic metabolic acidosis. Its volume of distribution (bicarbonate space) changes with its participation in the blood buffer systems. In other words, it is not a fixed physical volume, like that of other solutes. In this paper, we shall review experimental studies that supported evidence for this knowledge and analyze the basic hypothesis to explain the phenomena. Since we have not found clinical studies in children, we shall report our experience in a group of patients with metabolic acidosis treated with bicarbonate infusion in whom apparent bicarbonate space was measured and compared with data in adults from the literature. Guidelines for amount of bicarbonate needed to increase its concentration according to baseline bicarbonate concentration will be suggested.

We describe a 40-month-old male infant with renal failure, treated with peritoneal dialysis, who developed massive calcification of soft tissues including the heart and lungs with subsequent cardiopulmonary insufficiency. A diagnosis of Jeune syndrome was made. After starting peritoneal dialysis, the patient exhibited an intractable metabolic acidosis of unknown etiology necessitating treatment with intravenous or oral sodium bicarbonate. Myocardial calcification was first detected by 2-dimensional echocardiography performed 3 months after starting dialysis. The patient was not suitable for renal transplantation because of his cardiac dysfunction and died of cardiac and respiratory failure at the age of 6 years. Although the patient exhibited a variety of risk factors for ectopic calcification including hyperphosphatemia, hyperparathyroidism, high calcium-phosphate product and treatment with vitamin D, the early and massive soft tissue calcification may have been accelerated by correction of the metabolic acidosis. Therefore, the use of sodium bicarbonate may be involved in the etiology of the myocardial calcification.

Objective: An autoregulatory mechanism involving a reciprocal relationship between gluconeogenesis and glycogenolysis regulates endogenous glucose production (EGP) in healthy individuals. In type 2 diabetes, fasting hyperglycemia may be due to increased EGP., Material and Methods: To examine gluconeogenesis and autoregulation of EGP in type 2 diabetes, 9 type 2 diabetics and 8 healthy controls were studied during a 3-h infusion of 30 micromol/kg/min Na-lactate. The diabetics were also studied during a control infusion of Na-bicarbonate. To standardize levels of glucoregulatory hormones, plasma insulin, growth hormone, and glucagon were clamped at identical levels during the three experiments. Glucagon levels were elevated from basal levels to approximately 330 ng/l when the lactate or bicarbonate infusions were started, in order to mimic the hyperglucagonemia often seen in diabetes. Lactate gluconeogenesis and total EGP were measured by infusions of [6-(3)H] glucose and [U-14C] lactate., Results: In the bicarbonate experiments, hyperglugagonemia increased lactate gluconeogenesis in the diabetic patients from 4.3+/-1.8 to 6.1+/-2.4 micromol/kg/min (p=0.04). EGP did not change significantly (basal EGP: 15.3+/-3.9, EGP at the end of the study: 14.2+/-3.9 micromol/kg/min, p=0.14). During both lactate experiments, plasma lactate increased more than 4-fold. The increase in lactate gluconeogenesis was significantly higher in diabetics than in controls (values obtained at the end of experiments minus basal values: 10.8+/-3.6 versus 6.4+/-3.6 micromol/kg/min, p=0.03). Compared with normal subjects, the diabetic patients had higher EGP values both at basal conditions (p=0.001) and during lactate infusion (p=0.005). Despite augmented gluconeogenesis, EGP did not change during lactate and glucagon infusion in any of the groups (diabetics, basal EGP: 15.4+/-2.7 versus EGP at the end of experiments: 15.6+/-3.6 micromol/kg/min, p>0.30. Controls, basal EGP: 11.8+/-0.8 versus EGP at the end of experiments: 11.6+/-1.9 micromol/kg/min, p>0.30)., Conclusions: Although type 2 diabetics have increased EGP and increased lactate gluconeogenesis, the hepatic autoregulation of EGP during increased substrate-induced gluconeogenesis seems to be intact.

The cardiotoxicity of tricyclic antidepressants is a well-described phenomenon requiring serious consideration in patients who have taken an overdose. In patients who are at high risk for suicide attempts, selective serotonin reuptake inhibitors (SSRIs) were thought to constitute a safe alternative. However, evidence is accumulating that they, too, possess proarrhythmic properties, which must be reconciled in the setting of an overdose. An 82-year-old woman intentionally ingested citalopram 1.6 g. Several hours after presentation, she developed sinus arrest and junctional bradycardia that resolved after infusion of intravenous sodium bicarbonate solution. Thereafter, she demonstrated no further electrocardiographic abnormalities and was safely transferred to the psychiatry service without the need for a temporary transvenous pacemaker. The dramatic effect of the sodium bicarbonate on the arrhythmia represents a probable event according to the Naranjo probability scale. Intravenous sodium bicarbonate may serve as an effective antidote to SSRI-induced bradyarrhythmias.

Novel, controlled-release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO-based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC-based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner-Nelson technique, and a level A "in vitro-in vivo correlation" was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.

Objective: To compare the effects of sodium bicarbonate and lactate for continuous veno-venous hemodiafiltration (CVVHDF) in critically ill patients., Design and Settings: Prospective crossed-over controlled trial in the surgical and medical ICUs of a university hospital., Patients: Eight patients with multiple organ dysfunction syndrome (MODS) requiring CVVHDF., Intervention: Each patient received the two buffers in a randomized sequence over two consecutive days., Measurements and Results: The following variables were determined: acid-base parameters, lactate production and utilization ((13)C lactate infusion), glucose turnover (6,6(2)H(2)-glucose), gas exchange (indirect calorimetry). No side effect was observed during lactate administration. Baseline arterial acid-base variables were equal with the two buffers. Arterial lactate (2.9 versus 1.5 mmol/l), glycemia (+18%) and glucose turnover (+23%) were higher in the lactate period. Bicarbonate and glucose losses in CVVHDF were substantial, but not lactate elimination. Infusing (13)C lactate increased plasma lactate levels equally with the two buffers. Lactate clearance (7.8+/-0.8 vs 7.5+/-0.8 ml/kg per min in the bicarbonate and lactate periods) and endogenous production rates (14.0+/-2.6 vs 13.6+/-2.6 mmol/kg per min) were similar. (13)C lactate was used as a metabolic substrate, as shown by (13)CO(2) excretion. Glycemia and metabolic rate increased significantly and similarly during the two periods during lactate infusion., Conclusion: Lactate was rapidly cleared from the blood of critically ill patients without acute liver failure requiring CVVHDF, being transformed into glucose or oxidized. Lactate did not exert undesirable effects, except moderate hyperglycemia, and achieved comparable effects on acid-base balance to bicarbonate.

Primary cultures of rat inner medullary collecting duct (IMCD) cells Na(+) dependently import HCO(3)(-) across the basolateral membrane through an undefined transport protein. We used RT-PCR, immunoblotting, and immunohistochemistry to identify candidate proteins for this basolateral Na(+)-HCO(3)(-) cotransport. The mRNA encoding the electroneutral Na(+)-HCO(3)(-) cotransporter NBCn1 was detected as the only Na(+)-HCO(3)(-) cotransporter in the rat inner medulla (IM) among the five characterized Na(+)-dependent HCO(3)(-) transporters. The mRNA of a yet uncharacterized transporter-like protein, BTR1, was also present in the IM, but its expression in microdissected tubules seemed restricted to the thin limbs of Henle's loop. Immunoblotting confirmed the presence of NBCn1 as an approximately 180-kDa protein of the rat IM. Anti-NBCn1 immunolabeling was confined to the basolateral plasma membrane domain of IMCD cells in the papillary two-thirds of the IM. Consistent with the presence of NBCn1, IMCD cells possessed stilbene-insensitive, Na(+)- and HCO(3)(-)-dependent pH recovery after acidification, as assessed by fluorescence microscopy using a pH-sensitive intracellular dye. In furosemide-induced alkalotic rats, NBCn1 protein abundance was decreased in both the IM and inner stripe of outer medulla (ISOM) as determined by immunoblotting and immunohistochemistry. In contrast, NBCn1 abundance in the IM and ISOM was unchanged in NaHCO(3)-loaded animals, and the NBCn1 abundance increased only in the ISOM after NH(4)Cl loading. In conclusion, NBCn1 is a basolateral Na(+)-HCO(3)(-) cotransporter of IMCD cells and is differentially regulated in IMCD and medullary thick ascending limb.

Santarus Inc. is developing an immediate-release formulation of omeprazole in combination with an antacid (sodium bicarbonate) as a powder for suspension, known as Acitreltrade mark [SAN 05] and also as Rapinex powder for oral suspension. This omeprazole powder suspension will be used to treat gastrointestinal haemorrhage, gastro-oesophageal reflux disease, heartburn and peptic ulcers. Acitreltrade mark is based on technology licensed from the University of Missouri. Santarus have also licensed technology from Tulane and North Carolina Universities relating to potential treatments for gastrointestinal (GI) diseases. Santarus has licensed exclusive, worldwide rights to patent applications covering specific combination formulations of proton pump inhibitors (PPIs) and antacids for treating various upper GI diseases and disorders. Santarus plans to license the development, distribution and marketing rights of omeprazole powder for oral suspension 20 mg outside the US, to one or more well established pharmaceutical companies. The US FDA has requested that Santarus pursue a name other than Rapinex for the product. Santarus is currently discussing potential alternative names for the product with the FDA. Santarus announced positive results in August 2003 from a phase III trial comparing oral Acitrel (Rapinex 40 mg) with intravenous cimetidine in preventing upper GI bleeding in 359 critically ill adult patients. Santarus has also completed an open-label clinical trial in 243 patients, including 97 patients with gastric ulcers, evaluating the safety of this omeprazole 40 mg powder suspension for an 8-week period. In connection with the NDA for omeprazole powder suspension 40 mg, Santarus provided notice to the NDA holder for Prilosec delayed-release capsules and related patent owners that omeprazole powder suspension 40 mg does not infringe currently listed patents for Prilosec or that those patents are invalid.

A systemic biokinetic model is presented for radiocarbon taken into the body as carbon dioxide or bicarbonate. Parameter values describing retention and excretion of carbon during the first few weeks after administration are based on studies of the fate of radiocarbon in human subjects after injection of labelled bicarbonate or inhalation of carbon dioxide. Data on laboratory animals administered labelled bicarbonate, carbonate or carbon dioxide provide information on the tissue distribution and long-term retention of carbon. Model predictions of the time-dependent distribution and retention of carbon differ considerably from those of models recommended by the International Commission on Radiological Protection.

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions.

We examined the effects of pre-exercise sodium bicarbonate (NaHCO3) ingestion on the slow component of oxygen uptake (VO2) kinetics in seven professional road cyclists during intense exercise. One hour after ingesting either a placebo or NaHCO3 (0.3 g x kg body mass(-1)), each cyclist (age, 25 +/- 2 years; VO2max, 74.7 +/- 5.9 ml x kg(-1) x min(-1); mean +/- s) performed two bouts of 6 min duration at an intensity of 90% VO2max interspersed by 8 min of active recovery. Gas exchange and blood data (pH, blood lactate concentration and [HCO3-]) were collected during the tests. In both bouts, the slow component of VO2 was defined as the difference between end-exercise VO2 and the VO2 at the end of the third minute. No significant difference was found in the slow component of VO2 between conditions in the first (NaHCO3, 210 +/- 69 ml; placebo, 239 +/- 105 ml) or second trial (NaHCO3, 123 +/- 88 ml; placebo, 197 +/- 101 ml). In conclusion, pre-exercise NaHCO3 ingestion did not significantly attenuate the VO2 slow component of professional road cyclists during high-intensity exercise.

The indicator amino acid oxidation technique has been widely used as a rapid and sensitive method to determine amino acid requirement. In this technique, the indicator 14C-amino acid is continuously infused and breath 14CO2 is collected to determine oxidation rate, which is used to predict requirement. However, a portion of the 14CO2 produced from amino acid oxidation is retained in the body and must be determined to correct oxidation rates based on breath 14CO2 collection. To develop the indicator amino acid oxidation technique for use in poultry, it is important to accurately measure expired and retained CO2; these measurements were accomplished using intravenous infusion of NaH14CO3. Oxidation chambers were constructed and calibrated to ensure complete collection of breath 14CO2. Hydrochloric acid was infused over 1 h into a beaker containing NaH14CO3 in four closed oxidation chambers, and the 14CO2 released was collected over 2 h. Of the initial radioactivity dose, 99.3 +/- 1.9% was recovered in collected 14CO2. We concluded that the oxidation chamber apparatus is adequate for complete recovery of expired 14CO2. In Experiment 2, we determined bicarbonate retention in five broiler breeder roosters from a primed, constant infusion of NaH14CO3 into the jugular vein for 4 h. At steady state, 86.0 +/- 1.4% of NaH14CO3 infusion was recovered in breath. Because 14% of infused 14C is retained within the body, the present results demonstrate the need to determine bicarbonate retention in chickens during oxidation studies and use it as a correction factor in subsequent experiments.

Background: High-carbohydrate (HC) diets are recommended for lowering the risk of coronary heart disease because they decrease plasma LDL-cholesterol concentrations. However, an unfavorable effect of HC diets is an increase in plasma triacylglycerol concentrations. The underlying mechanisms of this effect are still unclear., Objective: We examined the effect of diet composition on VLDL-triacylglycerol metabolism using in vivo isotopically labeled VLDL-triacylglycerol tracers., Design: Six healthy subjects were studied on 2 occasions: after 2 wk of an HC diet (75% carbohydrates, 10% fat, and 15% protein) and after 2 wk of an isoenergetic high-fat (HF) diet (30% carbohydrates, 55% fat, and 15% protein)., Results: The plasma VLDL-triacylglycerol concentration was higher after the HC diet than after the HF diet (690 +/- 186 compared with 287 +/- 104 micromol/L; P < 0.05) because of higher rates of VLDL-triacylglycerol production (0.76 +/- 0.12 compared with 0.45 +/- 0.15 micromol x kg(-1) x min(-1); P < 0.05) rather than diminished VLDL-triacylglycerol clearance (1.5 +/- 0.5 compared with 1.7 +/- 0.5 mL x kg(-1) x min(-1) after the HC diet than after the HF diet, respectively). The increase in VLDL-triacylglycerol production was probably mediated by a decrease in hepatic fatty acid oxidation after the HC diet (0.13 +/- 0.02 compared with 0.69 +/- 0.24 micromol x kg(-1) x min(-1); P < 0.05), which presumably increased hepatic fatty acid availability for triacylglycerol synthesis., Conclusions: The increase in fasting plasma triacylglycerol concentrations in response to short-term HC diets is due to accelerated VLDL-triacylglycerol secretion. Increased hepatic fatty acid availability, resulting from reduced hepatic fatty acid oxidation, is most likely responsible for the observed increase in VLDL-triacylglycerol secretion.

Purpose: To determine the clearance of hydrogen peroxide from the oral cavity of infants (3-4 yrs of age), juveniles (7-12 yrs of age), adults (35-66 yrs of age), and adults with impaired salivary flow (34-71 yrs of age)., Materials and Methods: In all subjects, the amount of H2O2 present in the oral cavity was assessed following a 1-min brushing period with an experimental dentifrice formulated with 3% hydrogen peroxide for up to 9 mins postbrushing. In addition, the oral clearance of 3% hydrogen peroxide delivered in an experimental dentifrice formulated with 5% baking soda was determined in a control population of adults and adult subjects with impaired salivary flow., Results: Most of the hydrogen peroxide decomposed during brushing, with less than 30% of the prebrushing dose of hydrogen peroxide remaining in the oral cavity after 1 min of brushing. No differences between infants, juveniles, and adults were seen in levels of hydrogen peroxide recovered from the oral cavity after tooth brushing. When a mixture of hydrogen peroxide and baking soda was used for brushing, less than 5% of the hydrogen peroxide was recovered from the oral cavity after 1 min of brushing. In conclusion, clearance of hydrogen peroxide from the oral cavity was very rapid in children, adults, and adults with impaired salivary flow. Decomposition of hydrogen peroxide was enhanced approximately six-fold in adults by the presence of baking soda in the dentifrice. No substantial amount of hydrogen peroxide survived beyond the brushing period, and very little material would be present to interact with soft tissues in the oral cavity after expectorating any remaining dentifrice containing hydrogen peroxide.

Background & Aims: Cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels play an important role in HCO(3)(-) secretion by pancreatic duct cells (PDCs). Our aims were to characterize the CFTR conductance of guinea pig PDCs and to establish whether CFTR is regulated by HCO(3)(-)., Methods: PDCs were isolated from small intralobular and interlobular ducts, and their Cl(- )conductance was studied using the whole-cell patch clamp technique., Results: Activation of a typical CFTR conductance by adenosine 3',5'-cyclic monophosphate (cAMP) was observed in 114 of 204 cells (56%). A larger (10-fold), time- and voltage-dependent Cl(-) conductance was activated in 39 of 204 cells (19%). Secretin had a similar effect. Coexpression of both conductances in the same cell was observed, and both conductances had similar anion selectivity and pharmacology. Extracellular HCO(3)(-) caused a dose-dependent inhibition of both currents (K(i), approximately 7 mmol/L), which was independent of intracellular and extracellular pH, and the PCO(2) and CO(3)(2-) content of the bathing solutions., Conclusions: Two kinetically distinct Cl(-) conductances are activated by cAMP in guinea pig PDCs. Because these conductances are coexpressed and exhibit similar characteristics (anion selectivity, pharmacology, and HCO(3)(-) inhibition), we conclude that CFTR underlies them both. The inhibition of CFTR by HCO(3)(-) has implications for the current model of pancreatic ductal HCO(3)(-) secretion.

Effects of Na+, Cl-, OH- and HCO3-, and an inorganic anion exchange inhibitor (HCO3-/Cl-), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, on Cd uptake from the apical membrane of LLC-PK1 cells were investigated to elucidate the mechanism of Cd uptake by these cells. Furthermore, the initial uptake of Cd incubated at different temperatures was analyzed by using the Arrhenius plot to test if Cd is taken up by the cells via the carrier-mediated process. The cells were incubated with 1 microM CdCl2 for 30 min. at 37 degrees in phosphate buffer containing NaCl at pH 5.5 or 7.4. Cd accumulation by the cells at pH 7.4 was about 5 times higher than at pH 5.5. Replacement of NaCl in the phosphate buffer with KCl or mannitol decreased the Cd accumulation at pH 7.4 about 80%, but had no effect at pH 5.5. The addition of 2 mM NaHCO3 to the pH 7.4 buffer containing NaCl significantly increased the Cd accumulation, and pretreatment of the cells with the inorganic anion exchange inhibitor abolished this effect of NaHCO3 on Cd accumulation. The cells were incubated for 10 min. at different temperatures with 1 microM CdCl2 in the phosphate buffer containing NaCl at pH 7.4 in the presence or absence of 2 mM NaHCO3 or at pH 5.5 in the absence of NaHCO3. In all cases, the Arrhenius plots of Cd accumulation were nonlinear. The breakpoint was observed at about 30 degrees in the Cd accumulation at pH 7.4 in the presence of NaHCO3, suggesting the involvement of a carrier-mediated process. This breakpoint was not as clear in the Cd accumulation at pH 7.4 in the absence of NaHCO3 and not observed at all at pH 5.5. These findings suggested that Cd is partially taken up from the apical membrane of LLC-PK1 cells via the inorganic anion exchanger and the uptake of Cd is more efficient at alkaline pH and in the presence of Na+, Cl- and HCO3-.

This study was aimed to evaluate the efficacy of combination therapy of bicarbonate and salbutamol for hyperkalemia in 9 hemodialysis patients. Simultaneous administration of 8.4% sodium bicarbonate (i.v., 2 mEq/kg) for 1/2 hour and salbutamol (15 mg) in nebulized form for 10 min was compared with treatment modality of either bicarbonate or salbutamol alone. Infusion of sodium bicarbonate induced a significant rise in plasma bicarbonate from 17.3 +/- 3.2 to 22.1 +/- 2.4 mEq/L (p < 0.01), but was ineffective in lowering plasma potassium (-0.13 +/- 0.06 mEq/L). As expected, salbutamol significantly lowered plasma potassium (-0.57 +/0 0.03 mEq/L, p < 0.02 vs. basal value) in all except 2 patients. The combined regimen of bicarbonate and salbutamol to a total 9 patients including 2 patients without hypokalemic effect to salbutamol alone revealed a substantially greater fall in plasma potassium (-0.96 +/- 0.08 mEq/L, p = 0.000 vs. either drug alone) accompanied with significant increase in plasma bicarbonate and blood pH. Treatment with salbutamol or the combined regimen produced slight increases in heart rate but not in blood pressure. It is concluded that the combined regimen of bicarbonate and beta(2)-adrenergic agonist (salbutamol) could be recommended as an efficient alternative for severe hyperkalemia in uremic patients, and is suggested that the enhanced transcellular hypokalemic effects of salbutamol in this combined regimen with bicarbonate would be related to the activation of Na-K pump with acute correction of underlying metabolic acidosis.

1. The effect of euglycaemic hyperinsulinaemia on the recovery of 13C in expired CO2 has been assessed in six normal subjects. Each was studied on three occasions: once with a 6 h primed constant infusion of NaH13CO3 combined with a euglycaemic hyperinsulinaemic clamp for the last 3 h (study 1), once with a 6 h primed constant infusion of NaH13CO3 alone (study 2) and once with a 6 h infusion of normal saline combined with a hyperinsulinaemic clamp for the last 3 h (study 3). Measurements of 13C enrichment of expired CO2 were made in the third and sixth hour of each infusion. 2. There was no significant increase in enrichment during study 3 (3 h 0.00047 +/- 0.00016 versus 6 h 0.00069 +/- 0.00028 atom per cent excess) with potato-starch-derived D-glucose used to maintain euglycaemia. 13C recovery increased in the sixth hour of both study 1 and 2 (study 1: 3 h 74.4 +/- 2.0 versus 6 h 85.5 +/- 2.6%, P < 0.01; study 2: 3 h 72.1 +/- 2.4 versus 6 h 81.7 +/- 1.4%, P < 0.01). There was no significant difference in recovery between studies 1 and 2. 3. These results suggest that increased recovery during a sequential euglycaemic clamp is predominantly time-dependent. Studies which use this technique to examine the effect of insulin on substrate oxidation should take this into account.

Objectives: To examine: a) the rate and extent of delivery of radioactive tracers to the central circulation from the tibial, medial malleolar, distal femoral, and humeral intraosseous sites, as well as from a peripheral intravenous site; and b) the end-tidal CO2 response to injected sodium bicarbonate at these sites., Design: Prospective, descriptive study., Setting: Animal laboratory at a university medical center., Subjects: Twenty anesthetized and mechanically ventilated piglets were cannulated with 18-gauge bone marrow needles at intraosseous sites and 22-gauge Teflon catheters in peripheral veins. A 22-gauge angiocath was placed in the right carotid artery of each subject. Drug kinetics were studied in the normovolemic and hypovolemic (acute bleeding of 25 mL/kg) states., Interventions: Sodium bicarbonate (1 mEq/kg) was injected into each of the three intraosseous and one intravenous sites with simultaneous monitoring of end-tidal CO2. A 10-min period for stabilization was allowed between injections. Aliquots of 99mtechnetium were injected at randomly selected sites and blood samples were obtained at 1.5-sec intervals via carotid artery for radioactive counts. Experiments were repeated after withdrawal of 25 mL/kg of blood., Measurements and Main Results: Assessment by end-tidal CO2 monitoring after 1-mEq/kg injections of bicarbonate demonstrated a mean initial end-tidal CO2 increase at 12.8 secs and a mean maximal end-tidal CO2 increase of 8 torr (1.06 kPa), with no significant site differences noted. Radioactive tracer injections were detected in the carotid artery after 15.4 secs in normovolemic animals and after 21.4 secs in hypovolemic animals, with no significant site differences detected. The proportion of injected tracer at 2, 5, 10, 20, 30, and 40 mins identified no significant differences between various intraosseous and intravenous sites., Conclusions: Our study demonstrated similar rapid transit and proportion of bicarbonate and radioactive tracers, reaching the central circulation from multiple intraosseous sites and a peripheral intravenous site. This finding suggests that adjustments in drug dosage may not be required, using various intraosseous locations as an alternative to peripheral intravenous drug therapy.

It is now becoming common practice to co-administer H2-receptor antagonists and anti-reflux agents in the treatment of reflux oesophagitis. The mechanism by which anti-reflux agents achieve flotation requires a small amount of gastric acid to be present in the stomach. This study investigated whether an anti-reflux agent would remain effective after the decrease in acid secretion produced by a typical clinical dosage regimen of cimetidine (400 mg q.d.s., 7 days). Gastric distribution and residence of a meal and an anti-reflux agent were assessed in 12 normal subjects using gamma scintigraphy. The area under the gastric and fundal emptying curves demonstrated that Liquid Gaviscon (sodium alginate compound) had a significantly greater gastric residence than the meal, both during the control period and after cimetidine pretreatment, and that the majority of the Gaviscon was located in the fundus. The distribution of Gaviscon into the fundus was not affected by cimetidine pretreatment. Cimetidine pre-treatment slightly, but not significantly, increased the time for half the meal and the Gaviscon to empty from the stomach. The results suggest that the mechanism of action of Liquid Gaviscon is not compromised by concurrent H2-antagonist therapy.