Solubility enhancementofcefixime trihydrate by solid dispersions using hydrotropic solubilization technique and their characterization

Abstract The aqueous solubility of cefixime trihydrate (a water insoluble drug) using different hydrotropic agents was determined and solid dispersions of cefixime trihydrate were prepared by hydrotropic solubilization technique. The drugs content were determined. The aqueous solubility of v was increased many fold in presence of sodium acetate trihydrate as hydrotropic agent. This hydrotropic agent was used to prepare solid dispersion of cefixime trihydrate. Cefixime trihydrate and sodium acetate trihydrate were accurately weighed and taken in a 200 mL beaker. Distilled water 10-15 mL was taken to dissolve hydrotropic agent using heat (48-50 °C). The drug was then added to it and magnetically stirred till whole mass get viscous. The solid dispersions of cefixime trihydrate were characterized by XRD, DSC and IR studies. DSC thermogram, XRD and Infra-Red spectra were studied. Solid dispersions, thus prepared, showed faster release of the drug as compared to pure drug and physical mixture.

The effects of 0.9% saline versus Plasma-Lyte 148 on renal function as assessed by creatinine concentration in patients undergoing major surgery: A single-centre double-blinded cluster crossover trial.

OBJECTIVES: Saline and Plasma-Lyte have different physiochemical contents; consequently, they may differently affect patients' renal function. We compared the effects of fluid therapy with 0.9% saline and with Plasma-Lyte 148 on renal function as assessed by creatinine concentration among patients undergoing major surgery. METHODS: We conducted a prospective, double-blinded cluster crossover trial comparing the effects of the two fluids on major surgery patients. The primary aim was to establish the pilot feasibility, safety and preliminary efficacy evidence base for a large interventional trial to establish whether saline or Plasma-Lyte is the preferred crystalloid fluid for managing major surgery patients. The primary efficacy outcome was the proportion of patients with changes in renal function as assessed by creatinine concentration during their index hospital admission. We used changes in creatinine to define acute kidney injury (AKI) according to the RIFLE criteria. RESULTS: The study was feasible with 100% patient and clinician acceptance. There were no deviations from the trial protocol. After screening, we allocated 602 patients to saline and 458 to Plasma-Lyte. The median (IQR) volume of intraoperative fluid received was 2000 mL (1000:2000) in both groups. Forty-nine saline patients (8.1%) and 49 Plasma-Lyte patients (10.7%) developed a postoperative AKI (adjusted incidence rate ratio [aIRR]: 1.34; 95% CI: 0.93-1.95; p = 0.120). No differences were observed in the development of postoperative complications (aIRR: 0.98; 95% CI: 0.89-1.08) or the severity of the worst complication (aIRR: 1.00; 95% CI: 0.78-1.30). The median (IQR) length of hospital stay was six days (3:11) for the saline group and five days (3:10) for the Plasma-Lyte group (aIRR: 0.85; 95% CI: 0.73-0.98). There were no serious adverse events relating to the trial fluids, nor were there fluid crossover or contamination events. CONCLUSIONS: The study design was feasible to support a future follow-up larger clinical trial. Patients treated with saline did not demonstrate an increased incidence of postoperative AKI (defined as changes in creatinine) compared to those treated with Plasma-Lyte. Our findings imply that clinicians can reasonably use either solution intraoperatively for adult patients undergoing major surgery. TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; ACTRN12613001042730; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364988.

Effect of 0.9% NaCl compared to plasma-lyte on biomarkers of kidney injury, sodium excretion and tubular transport proteins in patients undergoing primary uncemented hip replacement - a randomized trial.

BACKGROUND: Isotonic saline (IS) is widely used to secure perioperative cardiovascular stability. However, the high amount of chloride in IS can induce hyperchloremic acidosis. Therefore, IS is suspected to increase the risk of acute kidney injury (AKI). Biomarkers may have potential as indicators. METHODS: In a double-blinded, placebo-controlled study, 38 patients undergoing primary uncemented hip replacement were randomized to IS or PlasmaLyte (PL). Infusion was given during surgery as 15 ml/kg the first hour and 5 ml/kg the following two hours. Urinary samples were collected upon admission and the day after surgery. As surgery was initiated, urine was collected over the course of 4 h. Hereafter, another urine collection proceeded until the morning. Urine was analyzed for markers of AKI neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Arterious and venous blood samples for measurements of pH and plasma electrolytes including chloride (p-Cl) were collected as surgery was initiated, at the end of surgery and the following morning. RESULTS: IS induced an increase in p-Cl (111 ± 2 mmol/L after IS and 108 ± 3 after PL, p = 0.004) and a decrease in pH (7.39 ± 0.02 after IS and 7.43 ± 0.03 after PL, p = 0.001). Urinary NGAL excretion increased in both groups (ΔNGAL: 5.5 [4.1; 11.7] µg/mmol creatinine p = 0.004 after IS vs. 5.5 [2.1;9.4] µg/mmol creatinine after PL, p < 0.001). No difference was found between the groups (p = 0.839). Similarly, urinary KIM-1 excretion increased in both groups (ΔKIM-1: IS 115.8 [74.1; 156.2] ng/mmol creatinine, p < 0.001 vs. PL 152.4 [120.1; 307.9] ng/mmol creatinine, p < 0.001). No difference between the groups (p = 0.064). FENa increased (1.08 ± 0.52% after IS and 1.66 ± 1.15% after PL, p = 0.032). ENaC excretion was different within groups (p = 0.019). CONCLUSION: A significantly higher plasma chloride and a lower pH was present in the group receiving isotonic saline. However, u-NGAL and u-KIM-1 increased significantly in both groups after surgery despite absence of changes in creatinine. These results indicate that surgery induced subclinical kidney injury. Also, the IS group had a delayed sodium excretion as compared to the PL group which may indicate that IS affects renal sodium excretion differently from PL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:  NCT02528448 , 19/08/2015.

Alcohol metabolite acetic acid activates BK channels in a pH-dependent manner and decreases calcium oscillations and exocytosis of secretory granules in rat pituitary GH3 cells.

Acetaldehyde and acetic acid/acetate, the active metabolites of alcohol (ethanol, EtOH), generate actions of their own ranging from behavioral, physiological, to pathological/cancerogenic effects. EtOH and acetaldehyde have been studied to some depth, whereas the effects of acetic acid have been less well explored. In this study, we investigated the effect of acetic acid on big conductance calcium-activated potassium (BK) channels present in GH3 rat pituitary tumor cells in more detail. In whole cell voltage clamp recordings, extracellular application of acetic acid increased total outward currents in a dose-dependent manner. This effect was prevented after the application of the specific BK channel blocker paxilline. Acetic acid action was pH-dependent-in whole cell current and single BK channel recordings, open probability (Po) was significantly increased by extracellular pH reduction and decreased by neutral or base pH. Acetic acid hyperpolarized the membrane potential, whereas acidic physiological solution had a depolarizing effect. Moreover, acetic acid reduced calcium (Ca2+) oscillations and exocytosis of growth hormone contained secretory granules from GH3 cells. These effects were partially prevented by BK inhibitors-tetraethylammonium or paxillin. In conclusion, our experiments indicate that acetic acid activates BK channels in GH3 cells which eventually contribute to acetic acid-induced membrane hyperpolarization, cessation of Ca2+ oscillations, and decrease of growth hormone release.

Maintenance enteral electrolyte solutions for neonatal calves: sodium acetate and osmolarity effects / Soluções eletrolíticas enterais de manutenção para bezerros neonatos: efeitos do acetato de sódio e da osmolaridade

The use of hypotonic electrolytic solutions in enteral fluid therapy is still understudied in calves. The objective of the present study was to evaluate the effects of maintenance enteral electrolytic solutions with different concentrations of sodium acetate and different osmolarities in calves. For this, 18 Holstein calves, six male and 12 female, 20 days old and weighing around 52kg, were used. The animals were randomly divided into three groups and each group received one of the treatments. The three electrolytic solutions contained the same components in different concentrations, resulting in a hyposmotic, an isosmotic and a hyperosmotic solution. Each animal was maintained in enteral fluid therapy for 12 hours with infusion rate of 15mL kg-1 h-1. Abdominal circumference, body weight, feces consistency, glucose and plasma lactate, pH, pCO2, HCO- 3 and BE were measured at the following times: T0h, T6h, T12h and T24h. The hyposmotic solution did not generate the onset of diarrhea, while the isosmotic and the hyperosmotic did. Regardless of the dose used, acetate did not cause metabolic alkalosis in the evaluated animals. The results suggest that the use of hyposmotic solution in diarrheic calves, dehydrated and without metabolic acidosis, may be clinically important.(AU)

O uso de soluções eletrolíticas hipotônicas na hidratação enteral ainda é pouco estudado em bezerros. O objetivo do presente estudo foi avaliar os efeitos de soluções eletrolíticas enterais de manutenção com diferentes concentrações de acetato de sódio e diferentes osmolaridades em bezerros. Para isso, foram utilizados 18 bezerros, seis machos e 12 fêmeas, holandeses, com 20 dias de nascidos e pesando por volta dos 52kg. Os animais foram divididos aleatoriamente em três grupos e cada grupo recebeu um dos tratamentos. As três soluções eletrolíticas continham os mesmos componentes, mas em diferentes concentrações, resultando em uma solução hiposmótica, uma isosmótica e uma hiperosmótica. Cada animal foi mantido em hidratação enteral durante 12 horas com taxa de infusão de 15mL kg-1h-1. Foram aferidos perímetro abdominal, peso corporal, consistência das fezes, glicose e lactato plasmático, pH, pCO2, HCO- 3 e excesso de base nos seguintes tempos: T0h, T6h, T12h e T24h. A solução hiposmótica não gerou aparecimento de diarreia, enquanto a isosmótica e a hiperosmótica geraram. Independentemente da dose utilizada, o acetato não causou alcalose metabólica nos animais avaliados. Os resultados sugerem que o uso da solução hiposmótica em bezerros diarreicos, desidratados e sem acidose metabólica, pode ser clinicamente importante.(AU)

[Effect of sodium acetate Ringer injection on perioperative fluid therapy in children with cyanotic congenital heart disease].

OBJECTIVE: To evaluate the efficacy of volume therapy with sodium acetate Ringer solution during the perioperative period in children with cyanotic congenital heart disease (CHD). METHODS: The children who underwent elective surgery for cyanotic CHD admitted to Shanghai Children's Medical Center Affiliated to the Medical School of Shanghai Jiaotong University from September to December 2018 were divided into three groups according to random number table with the informed consent of their legal representatives. All of the children received volume therapy with infusion of sodium acetate Ringer solution intravenously upon anesthesia induction. The volume of infusion was calculated according to the "4-2-1" formula (group A, the rehydration volume was 4 mL×kg-1×h-1 for the first 10 kg body weight, 2 mL×kg-1×h-1 for the second 10 kg, and 1 mL×kg-1×h-1 for the third 10 kg and above), and the volume was increased by 50% or 100% in groups B and C, respectively. The intravenous infusion lasted for 30 minutes in all the three groups. Arterial blood gas analysis was performed before and 30 minutes after infusion to observe the acid-base status and electrolyte level. Pulse oxygen saturation (SpO2), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) before and 10, 20, 30 minutes after infusion, central venous pressure (CVP) at 30 minutes after infusion were recorded, as well as adverse events occurred after infusion. RESULTS: Twenty-six children with cyanotic CHD, 17 male and 9 female, aged from 1 to 36 months, body weight 3.6 to 16.0 kg, and America Society of Anesthesiologists (ASA) level of III or IV, were enrolled in the study. The pH value in group B at 30 minutes after infusion was significantly higher than that before infusion (7.35±0.05 vs. 7.32±0.06, P < 0.05), while no significant changes were found before and after infusion in the other two groups. The hematocrits (Hct) after infusion in three groups were significantly lower than those before infusion (0.433±0.141 vs. 0.473±0.146 in group A, 0.324±0.054 vs. 0.372±0.063 in group B, 0.363±0.097 vs. 0.418±0.111 in group C, all P < 0.01), indicating that all the children in the three groups achieved effective hemodilution. However, there was no significant difference in blood gas analysis before and after infusion among the three groups. The level of blood lactic acid (Lac) in all CHD children was decreased from (1.33±0.63) mmol/L to (0.98±0.36) mmol/L after infusion of sodium acetate Ringer solution, the serum Ca2+ concentration was decreased from (1.22±0.06) mmol/L to (1.19±0.06) mmol/L, and the serum Cl- concentration was increased from (108.74±2.70) mmol/L to (109.77±2.54) mmol/L with the statistically significant differences (all P < 0.01). However, no significant difference was found in Lac or electrolyte levels before and after infusion among the three groups. There was no significant difference in vital signs before and after infusion among the three groups, but the period of infusion had an effect on SpO2 (F = 5.998, P < 0.01), HR (F = 34.279, P < 0.01) and SBP (F = 4.345, P < 0.05). HR in groups A and C were significantly lower than those before infusion, and SBP in group A was decreased gradually with the prolongation of infusion time. The CVP value at 30 minutes after infusion in group B was higher than that in group A. No adverse reactions such as rash or anaphylactic shock occurred after infusion of sodium acetate Ringer solution in all children. CONCLUSIONS: The perioperative volume therapy with sodium acetate Ringer solution in children with cyanotic CHD can effectively prevent the increase in Lac level and does not aggravate metabolic acidosis. The volume of infusion was well tolerated by all the children without disturbing the hemodynamic parameters.

Oral Methods of Urinary Alkalinization for High-dose Methotrexate Administration: Alternatives to Intravenous Sodium Bicarbonate During a Critical Drug Shortage.

A nationwide shortage of intravenous (IV) sodium bicarbonate required institutions to explore alternative options for urinary alkalinization for high-dose methotrexate (HDMTX). Children's Hospital Colorado implemented a protocol utilizing oral alkalinizing agents as alternatives to intravenous sodium bicarbonate during the shortage. The purpose of this study was to determine the safety and efficacy of oral alkalinization strategies for HDMTX administration. This retrospective study was conducted at a pediatric institution and evaluated cycles of HDMTX administered with at least one dose of oral sodium bicarbonate tablets or sodium citrate-citric acid oral solution. The time to achieve urine pH of ≥7 was 3.48 hours from the start of alkalinization. A median dose of 66.4 mEq/m/day of oral sodium bicarbonate was administered to maintain a urine pH of ≥7 until methotrexate was cleared. Gastrointestinal side effects occurred with 43% of HDMTX cycles and patients switched to IV sodium acetate in 25.5% of HDMTX cycles, primarily due to inadequate alkalinization or intolerance. During a shortage of IV sodium bicarbonate, oral alkalinization is an effective strategy for most patients to allow for administration of HDMTX.

Effect of 0.9% Saline or Plasma-Lyte 148 as Crystalloid Fluid Therapy in the Intensive Care Unit on Blood Product Use and Postoperative Bleeding After Cardiac Surgery.

OBJECTIVE: To evaluate the effect of Plasma-Lyte 148 (PL-148) compared with 0.9% saline (saline) on blood product use and postoperative bleeding in patients admitted to the intensive care unit (ICU) following cardiac surgery. DESIGN: A post hoc subgroup analysis conducted within a multicenter, double-blind, cluster-randomized, double-crossover study (study 1) and a prospective, single-center nested-cohort study (study 2). SETTING: Tertiary-care hospitals. PARTICIPANTS: Adults admitted to the ICU after cardiac surgery requiring crystalloid fluid therapy as part of the 0.9% saline vs. PL-148 for ICU fluid therapy (SPLIT) trial. INTERVENTIONS: Blinded saline or PL-148 for 4 alternating 7-week blocks. MEASUREMENTS AND MAIN RESULTS: 954 patients were included in study 1; 475 patients received PL-148, and 479 received saline. 128 of 475 patients (26.9%) in the PL-148 group received blood or a blood product compared with 94 of 479 patients (19.6%) in the saline group (OR [95% confidence interval], 1.51 [1.11-2.05]; p = 0.008). In study 2, 131 patients were allocated to PL-148 and 120 patients were allocated to saline. There were no differences between groups in chest drain output from the time of arrival in the ICU until 12 hours postoperatively (geometric mean, 566 mL for the PL-148 group v 547 mL in the saline group; p = 0.60). CONCLUSIONS: The findings did not support the hypothesis that using PL-148 for fluid therapy in ICU following cardiac surgery reduces transfusion requirements compared to saline. The significantly increased proportion of patients receiving blood or blood product with allocation to PL-148 compared to saline was unexpected and requires verification through further research.

Sodium acetate inhibits Staphylococcus aureus internalization into bovine mammary epithelial cells by inhibiting NF-κB activation.

Bovine mastitis is one of the most costly and prevalent disease affecting dairy cows worldwide. It was reported that Staphylococcus aureus could internalize into bovine mammary epithelial cells (bMEC) and induce mastitis. Some short chain fatty acids (SCFA) have shown to suppress S. aureus invasion into bMEC and regulate antimicrobial peptides expression. But it has not been evaluated that sodium acetate has the similar effect. The aim of this study was to investigate the effect of sodium acetate on the invasion of bovine mammary epithelial cells (bMEC) by S. aureus. Gentamicin protection assay showed that the invasion of S. aureus into bMEC was inhibited by sodium acetate in a dose-dependent manner. Sodium acetate (0.25-5 mM) did not affect S. aureus growth and bMEC viability. The TAP gene level was decreased, while the BNBD5 mRNA level was enhanced in sodium acetate treated bMEC. In sodium acetate treated and S. aureus challenged bMEC, the TAP gene expression was increased and BNBD5 gene expression was not modified at low concentrations, but decreased at high concentrations. The Nitric oxide (NO) production of bMEC after S. aureus stimulation was decreased by sodium acetate treatment. Furthermore, sodium acetate treatment suppressed S. aureus-induced NF-κB activation in bMEC in a dose manner. In conclusion, our results suggested that sodium acetate exerts an inhibitory property on S. aureus internalization and modulates antimicrobial peptides gene expression.

A randomized-controlled trial of high- or low-volume intravenous Plasma-Lyte(®) to prevent hypotension during sedation for colonoscopy.

PURPOSE: The purpose of this study was to compare the incidence of hypotension during sedation in adults presenting for elective colonoscopy and randomized to intravenous Plasma-Lyte 148(®) at either 2 mL·kg(-1) (low volume) or 20 mL·kg(-1) (high volume). METHODS: Patients aged ≥ 18 yr presenting for elective colonoscopy, with or without gastroscopy, after oral bowel preparation were randomized to receive the intervention immediately before the start of the procedure. Hypotension was defined as a ≥ 25% decrease in systolic blood pressure (SBP) from baseline during the procedure. Secondary outcomes included SBP < 90 mmHg, lowest SBP during sedation, duration of hypotension, use of vasopressors, postoperative outcomes, and cost. RESULTS: Seventy-five patients were randomly allocated to either the low-volume or high-volume group, respectively (total n = 150). The incidence of hypotension was similar in the two groups (59% vs 56%, respectively; odds ratio, 0.90; 95% confidence interval, 0.47 to 1.71; P = 0.74). The incidence of SBP < 90 mmHg, the lowest SBP during sedation, the duration of hypotension, the use of vasopressors, and postoperative outcomes were also similar in the two groups. CONCLUSIONS: This study does not support the routine use of 20 mL·kg(-1) of intravenous Plasma-Lyte 148 to prevent hypotension and other complications during sedation for elective colonoscopy in adult patients. Clinical Trials Registry (ANZCTR 12615001288516).

Sodium reduction during cardiopulmonary bypass: Plasma-Lyte 148 versus trial fluid as pump primes.

OBJECTIVES: We compared effects on plasma sodium concentrations plus calculated plasma tonicity of two "balanced" crystalloid solutions used as 2 L pump primes during cardiopulmonary bypass (CPB): Plasma-Lyte 148 (sodium concentration, 140 mmol/L; potassium concentration, 5 mmol/L) versus a bicarbonate-balanced fluid (sodium concentration, 140 mmol/L; potassium concentration, 0 mmol/L). DESIGN, SETTING AND PARTICIPANTS: We analysed pooled data from two prospective interventional studies performed in university-affiliated hospitals, from 50 patients undergoing elective cardiac surgery. INTERVENTIONS: Participants were allocated equally to Plasma-Lyte 148 or bicarbonate-balanced fluid, with plasma electrolytes measured by direct ion selective electrodes immediately before bypass (pre-CPB), within 3 minutes of commencement (T2), and before bypass cessation (end-CPB). RESULTS: Plasma sodium fell at T2 in 46 patients (92%) (P<0.0005). With Plasma-Lyte 148, the mean sodium decreased by 3.0 mmol/L (SD, 1.7 mmol/L), and with bicarbonate-balanced fluid it decreased by 2.2 mmol/L (SD, 1.1 mmol/L) (P=0.002). The mean tonicity fell by >5 mOsm/kg for both groups (P<0.0005). At end-CPB, the mean sodium for both groups remained reduced by >2 mmol/L (P<0.0005). In the group receiving Plasma-Lyte 148, 52% of patients were hyponatraemic (sodium<135 mmol/L) at T2 and end-CPB. CONCLUSIONS: Sodium reductions were common with both priming solutions, but more severe with Plasma-Lyte 148. Crystalloid priming solutions require sodium concentrations>140mmol/L to ensure normonatraemia throughout CPB.

Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha.

In animals, colonic infusion of SCFA does not affect glucagon-like peptide-1 (GLP-1) release whereas intravenous infusion does and SCFA may directly stimulate peptide YY (PYY) release. It is unknown whether SCFA and their route of administration affect human blood concentrations of GLP-1 and PYY. Our aim was to conduct a pilot study to determine the effects of intravenous and rectal acetate on blood concentrations of GLP-1, PYY, ghrelin, adiponectin and TNF-alpha in hyperinsulinaemic human subjects. Six hyperinsulinaemic female subjects were given 20 mmol sodium acetate intravenously, 60 mmol acetate rectally, or normal saline rectally or intravenously on four separate occasions in randomised order, with blood samples collected at 0, 10, 15, 30, 45 and 60 min. Change in plasma PYY was significantly higher after acetate and rectal infusions (9.69 and 13.78 pg/ml) compared with saline and intravenous (0.60 and - 3.1 pg/ml; P < 0.01), respectively. Change in plasma GLP-1 was increased by rectal and acetate infusions (0.25 and 0.23 mmol/l) v. intravenous and saline ( - 0.26 and - 0.19 mmol/l; P < 0.01). Acetate decreased TNF-alpha v. saline ( - 0.8 and 0.15 pg/ml; P < 0.05). Rectal infusions increased TNF-alpha and ghrelin (0.2 and 98.27 pg/ml) v. intravenous ( - 0.9 and - 40 pg/ml; P < 0.01). There was no effect of treatment on plasma adiponectin. These preliminary results suggest that acetate raises plasma PYY and GLP-1, and suppresses TNF-alpha. Also, distending the rectum increases PYY, GLP-1, TNF-alpha and ghrelin in hyperinsulinaemic females. Increasing colonic fermentation products, particularly acetate, could yield a new mechanism for modifying weight gain.