Assessment of the stability of citrate-buffered flucloxacillin for injection when stored in two commercially available ambulatory elastomeric devices: INfusor LV (Baxter) and Accufuser (Woo Young Medical): a study compliant with the NHS Yellow Cover Document (YCD) requirements.

Objectives: To investigate the effect of pH and buffers on the degradation rate of flucloxacillin and to determine if flucloxacillin can be stabilised using a buffered diluent for up to 14 days when stored at 2°C-8°C including a 24-hour infusion period at 32°C in two elastomeric devices (Accufuser and INfusor LV) filled to 240 mL. Testing as per the NHS Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. Methods: A validated stability indicating high-performance liquid chromatography method was used for assessing the stability of flucloxacillin diluted in 0.3% w/v citrate-buffered saline pH 7.0 when stored at 2°C-8°C in two ambulatory devices (Accufuser and INfusor LV). Flucloxacillin at 10 and 50 mg/mL diluted in 0.3% w/v citrate-buffered saline pH 7.0 to a final volume of 240 mL and stored at 2°C-8°C, including 24 hours at 32°C, was tested from two batches in replicate (n=3) at five time points for up to 14 days according to the requirements of the YCD. Results: Greater than 95% of the zero-time concentration of flucloxacillin at 10 and 50 mg/mL remained when stored at 2°C-8°C after 14 days including 24 hours at 32°C in both Accufuser and INfusor LV devices. Conclusions: Flucloxacillin sodium stability was improved, and complied with UK national standards, by using a diluent of 0.3% w/v citrate-buffered saline pH 7 in both Accufuser and INfusor LV ambulatory devices when filled to 240 mL. The data support assigning a shelf-life of up to 14 days (13 days stored at 2°C-8°C and 24 hours at 32°C). Flucloxacillin may now be used appropriately as a continuous 24-hour infusion in outpatient parenteral antimicrobial therapy services, providing further opportunity to avoid or shorten patient hospital stays, as well as support ideal antimicrobial stewardship principles.

Accuracy of Oral 67Gallium Citrate Scintigraphy in assessment of inflammatory activity of Crohn's disease.

AIM: The main goal in Crohn´s disease (CD) is a sustained suppression of inflammatory activity associated with mucosa healing in endoscopic evaluation. During clinical routine, there are small numbers of good markers to monitor inflammatory activity under treatment. We postulated that Oral 67Gallium Citrate Scintigraphy is able to mark inflammatory disease in mucosa and deep inflammation in CD, when used in oral form. OBJECTIVE: Measure the accuracy of Oral 67Gallium Citrate Scintigraphy in intestinal inflammatory activity of Crohn´s disease. PATIENTS AND METHODS: In a prospective consecutive cross-sectional study from January 2018 to June 2019, the ileocolonic region of 32 patients with CD were studied by dividing into four regions of interest (ROI) from the ileum to the rectum. A total of 128 intestinal segments were analyzed in cluster data. Accuracy values of Oral 67Gallium Scintigraphy and colonoscopy tests were evaluated with the histological reference test. Values of the respective receiver operating characteristic (ROC) curves were obtained  and compared. The reliability between the tests was evaluated by Kappa statistical with the segment-level analyses using variance adjustments. All statistical analyses were performed with a test significance level of 0.05. RESULTS: The study population included 32 patients with CD (10 men, 22 women; average age 39 years). Disease time was five years on average. Anti-TNFs treatment was found in 71%. The most found phenotype of the Montreal classification was L3. Differences in ROC curves for colonoscopy (0.94) and Oral 67Ga Scintigraphy (0.96) did not show significant value (p = 0.32). The sensitivity of scintigraphy to detect intestinal inflammatory activity in CD was 64%, specificity of 96% and accuracy of 84%. A high agreement was found between oral scintigraphy and histological measurements with kappa = 0.64. CONCLUSIONS: Oral 67Ga Scintigraphy had similar accuracy and agreement compared to colonoscopy in the identification of inflammatory activity in Crohn´s Disease. This new approach may be useful and less invasive for long term follow-ups.

Rat Palatability Study for Taste Assessment of Caffeine Citrate Formulation Prepared via Hot-Melt Extrusion Technology.

Developing a pediatric oral formulation with an age-appropriate dosage form and taste masking of naturally bitter active pharmaceutical ingredients (APIs) are key challenges for formulation scientists. Several techniques are used for taste masking of bitter APIs to improve formulation palatability; however, not all the techniques are applicable to pediatric dosage forms because of the limitations on the kind and concentration of the excipients that can be used. Hot-melt extrusion (HME) technology is used successfully for taste masking of bitter APIs and overcomes some of the limitations of the existing taste-masking techniques. Likewise, analytical taste assessment is an important quality control parameter evaluated by several in vivo and in vitro methods, such as the human taste panel, electrophysiological methods, electronic sensor, and animal preference tests to aid in selecting a taste-masked formulation. However, the most appropriate in vivo method to assess the taste-masking efficacy of pediatric formulations remains unknown because it is not known to what extent the human taste panel/electronic tongue can predict the palatability in the pediatric patients. The purpose of this study was to develop taste-masked caffeine citrate extrudates via HME and to demonstrate the wide applicability of a single bottle-test rat model to record and compare the volume consumed of the taste-masked solutions to that of the pure API. Thus, this rat model can be considered as a low-cost alternative taste-assessment method to the most commonly used expensive human taste panel/electronic tongue method for pediatric formulations.

Trisodium citrate: an alternative to unfractionated heparin for hemodialysis catheter dwells.

The use of tunneled hemodialysis catheters, or permcaths, either for temporary dialysis access before arteriovenous fistula or arteriovenous graft maturation or for long-term dialysis access, is associated with increased risk of catheter clotting and infection. Catheter locking solutions are routinely used to maintain patency in these catheters between dialysis sessions. Unfractionated heparin has traditionally been used for this purpose; however, trisodium citrate (also known as sodium citrate or citrate) has recently been shown to be an efficacious alternative to heparin as a locking solution. Citrate exerts both its anticoagulant and antimicrobial properties by chelating calcium to disrupt the normal coagulation pathway and by interfering with the formation of biofilm and the bacterial cell wall. Citrate is at least equivalent to heparin as an anticoagulant and antimicrobial agent for catheter locking, and in some clinical studies citrate was shown to be superior. Two different concentrations of sodium citrate were previously available; however, concerns of safety led to the removal of citrate 46.7% from the United States and Canadian markets in 2000, leaving only citrate 4% available for use as a catheter locking solution. The systemic hypocalcemic effects that were reported with citrate 46.7% have not been observed with citrate 4% in clinical trials, and the risk of systemic anticoagulation and bleeding was shown to be lower than that with unfractionated heparin. In addition, most comparative cost data indicate that citrate is a more cost-effective alternative than heparin; however, costs can vary by institution. Despite inconclusive evidence of clinical superiority, citrate 4% appears to provide a safe and at least equivocal alternative to heparin as a catheter locking agent.

Therapeutic drug monitoring for caffeine in preterm neonates: an unnecessary exercise?

OBJECTIVE: Our goal was to determine the value of measuring plasma caffeine levels in preterm neonates treated with caffeine for apnea. We evaluated plasma concentrations of caffeine attained in preterm neonates at standard doses, at varying postconceptual ages, with renal or hepatic dysfunction and when there was clinical lack of efficacy. We hypothesized that measurement of plasma caffeine concentrations during apnea therapy is not clinically helpful. PATIENTS/METHODS: An observational study was conducted at Hutzel Women's Hospital between January 2000 and September 2005. Preterm neonates who were being treated with caffeine and who had a plasma caffeine level measured on at least 1 occasion were included. RESULTS: A total of 231 caffeine blood levels were obtained from 101 preterm neonates with a median gestation of 28 weeks (range: 23-32 weeks) and birth weight of 1030 g (range: 540-2150 g). The caffeine citrate dose used ranged form 2.5 to 10.9 mg/kg (median: 5 mg/kg), and the levels ranged from 3.0 to 23.8 mg/L. Levels were between 5.1 and 20 mg/L in 94.8%, <5 mg/L in 2.1%, and >20 mg/L in 3.1%. Levels in the 5.1 to 20 mg/L range were attained on 91.3% of occasions when there was concomitant renal dysfunction (n = 23) and in all cases of hepatic dysfunction (n = 13). The median (25th, 75th quartiles) levels drawn for lack of efficacy (14.1 [10.2, 8.3] mg/L; n = 94) were comparable to those obtained for routine monitoring (13.7 [11, 9] mg/L; n = 107). CONCLUSIONS: A majority of preterm neonates attain plasma caffeine levels between 5 and 20 mg/L, independent of gestation. This observation held even for the small number of subjects with elevated blood urea nitrogen, serum creatinine, or liver enzyme levels. Therapeutic drug monitoring is not necessary when caffeine is used for the treatment of apnea of prematurity in neonates.

The effect of the beta-emitting yttrium-90 citrate on the dose-response of dicentric chromosomes in human lymphocytes: a basis for biological dosimetry after radiosynoviorthesis.

The production of dicentric chromosomes in human lymphocytes by beta-particles of yttrium-90 (Y-90) was studied in vitro to provide a basis of biological dosimetry after radiosynoviorthesis (RSO) of persistent synovitis by intra-articular administration of yttrium-90 citrate colloid. Since the injected colloid may leak into the lymphatic drainage exposing other parts of the body to radiation, the measurement of biological damage induced by beta-particles of Y-90 is important for the assessment of radiation risk to the patients. A linear dose-response relationship (alpha = 0.0229 +/- 0.0028 dicentric chromosomes per cell per gray) was found over the dose range of 0.2176-2.176 Gy. The absorbed doses were calculated for exposure of blood samples to Y-90 activities from 40 to 400 kBq using both Monte Carlo simulation and an analytical model. The maximum low-dose RBE, the RBE(M) which is equivalent to the ratio of the alpha coefficients of the dose-response curves, is well in line with published results obtained earlier for irradiation of blood of the same donor with heavily filtered 220 kV X-rays (3.35 mm copper), but half of the RBE(M) relative to weakly filtered 220 kV X-rays. Therefore, it can be concluded that for estimating an absorbed dose during RSO by the technique of biological dosimetry, in vitro and in vivo data for the same radiation quality are necessary.

Final report on the safety assessment of acetyl triethyl citrate, acetyl tributyl citrate, acetyl trihexyl citrate, and acetyl trioctyl citrate.

Acetyl Triethyl Citrate, Acetyl Tributyl Citrate, Acetyl Trihexyl Citrate, and Acetyl Trioctyl Citrate all function as plasticizers in cosmetics. Additionally, the Trihexyl and Trioctyl forms are described as skin-conditioning agents-emollients, although there are currently no reported uses of Acetyl Trihexyl Citrate or Acetyl Trioctyl Citrate. Acetyl Triethyl Citrate and Acetyl Tributyl Citrate are used in nail products at concentrations up to 7%. Recognizing that there are no reported uses of Acetyl Trihexyl or Trioctyl Citrate, if they were to be used in the future, their concentration of use is expected to be no higher than that reported for Acetyl Triethyl and Tributyl Citrate. These ingredients were sufficiently similar in structure that safety test data on one were considered applicable to all. Approximately 99% of orally administered Acetyl Tributyl Citrate is excreted-intermediate metabolites include acetyl citrate, monobutyl citrate, acetyl monobutyl citrate, dibutyl citrate, and acetyl dibutyl citrate. In acute, short-term, subchronic, and chronic feeding studies, these ingredients were relatively nontoxic. Differences from controls were either not statistically significant or not related to any organ toxicity. Ocular exposures produced moderate reactions that cleared by 48 hours after instillation. Dermal application was not toxic in rabbits. In a guinea pig maximization test, Acetyl Triethyl Citrate was a sensitizer whereas Acetyl Tributyl Citrate was not. Limited clinical testing of Acetyl Triethyl Citrate and Acetyl Tributyl Citrate was negative for both skin irritation and sensitization. These clinical data were considered more relevant than the guinea pig maximization data, suggesting to the Cosmetic Ingredient Review Expert Panel that none of these ingredients would be a sensitizer. Physiologic effects noted with intravenous delivery of Acetyl Triethyl Citrate or Acetyl Tributyl Citrate include dose-related decreases in blood pressure and intestinal muscular spasms. These ingredients were not genotoxic in bacterial or mammalian test systems. No significant differences in tumor induction (lymphomas) were noted in rats fed Acetyl Tributyl Citrate for 2 year. Acetyl Tributyl Citrate was not a developmental or reproductive toxicant in studies in mice and rats. Based on all the available data, these ingredients were considered safe as used in cosmetics.

The effects of 2-week ingestion of (--)-hydroxycitrate and (--)-hydroxycitrate combined with medium-chain triglycerides on satiety, fat oxidation, energy expenditure and body weight.

OBJECTIVE: Assessment of the effect of 2-week supplementation with (--)-hydroxycitrate (HCA) and HCA combined with medium-chain triglycerides (MCT) on satiety, fat oxidation, energy expenditure (EE) and body weight (BW) loss. DESIGN: Three intervention periods of 2 weeks separated by washout periods of 4 weeks. Double-blind, placebo-controlled, randomised and cross-over design. SUBJECTS: Eleven overweight male subjects (mean+/-s.d.; age, 47+/-16 y; body mass index, 27.4 +/- 8.2 kg/m(2)). INTERVENTION: Subjects consumed three self-selected meals and four iso-energetic (420 kJ) snacks daily with either no supplementation (PLA), 500 mg HCA (HCA) or 500 mg HCA and 3 g MCT (HCA+MCT). Each intervention ended with a 36 h stay in the respiration chamber. RESULTS: There was a significant BW loss during the 2 weeks of intervention (PLA, -1.0 +/- 0.4 kg, P<0.05; HCA, -1.5 +/- 0.5 kg, P<0.01; HCA+MCT, -1.3 +/- 0.2 kg, P<0.001), but this reduction was not different between treatments. 24 h EE (PLA, 11.8 +/- 0.2 MJ; HCA, 11.7 +/- 0.1 MJ; HCA+MCT, 11.5 +/- 0.1 MJ), 24 h RQ (0.85 +/- 0.00 in all treatments) and the area under the curve of the appetite-related parameters were not different between treatments. CONCLUSION: Two-week supplementation with HCA and HCA combined with MCT did not result in increased satiety, fat oxidation, 24 h EE or BW loss compared to PLA, in subjects losing BW.

Assessment of anticollagenase treatments after insertion of a keratoprosthetic material in the rabbit cornea.

PURPOSE: This study was performed to evaluate the enzyme production in response to implantation of the hydrogel material used in the experimental Chirila keratoprosthesis (KPro) and to assess the effects of five topical drugs on enzyme production and activity. KPros may be extruded from the cornea as a result of tissue melting, a process that involves excessive enzyme activity. To reduce the possibility of implant loss for the hydrogel Chirila KPro, a number of antiinflammatory drugs that have been used to treat other corneal melting conditions were investigated for their effect on initial collagenase activity after the implantation of KPro material into the rabbit cornea. METHODS: Poly(2-hydroxyethyl methacrylate) sponge pieces were implanted into rabbit corneas. Prednisolone, tetracycline, medroxyprogesterone, acetylcysteine, and sodium citrate were assessed for effects on gelatinolytic activity and stromal collagenase [matrix metalloprotease-1 (MMP-1)] production in vivo and in vitro by using zymography and Western blotting techniques. RESULTS: Whereas all five anticollagenase drugs were effective in reducing gelatinolytic activity in vitro, many were ineffective in vivo. However, medroxyprogesterone caused a reduction of gelatinolytic activity in vivo. The amount of MMP-1, as measured by immunoblotting, also was reduced by medroxyprogesterone treatment when compared with untreated controls. An increase in the apparent molecular weight of MMP-1 in operated corneas appears to be the result of the association of MMP-1 with collagen fragments resulting from the surgical trauma. CONCLUSION: This study indicates that topical medroxyprogesterone may be a useful adjunctive therapy after prosthokeratoplasty.

In vitro buffering capacities of proprietary non-particulate antacids available in New Zealand.

Four commercially available non-particulate antacid preparations were titrated against 1M hydrochloric acid to assess buffering capacity as compared to 30 ml 0.3M sodium citrate solution. All antacids were used in the manufacturers "unit dose". All antacids tested demonstrated some in vitro buffering capacity, and "Eno" (Reckitt and Colman) had a buffering capacity similar to that of sodium citrate. The retail cost per unit dose was established for each proprietary antacid and for sodium citrate. It was concluded that while proprietary antacids are cheaper per dose than sodium citrate, preparations differ in their acid-neutralising capacity.

The barium enema scout film: cost effectiveness and clinical efficacy.

The authors prospectively evaluated 1,001 consecutive double-contrast barium enema examinations to determine the efficacy of the preliminary film. The scout films were evaluated for the presence of unsatisfactory amounts of residual feces and clinically significant extracolonic abnormalities. The contrast studies were independently evaluated in a double-blind manner for satisfactory colonic preparation as well as extracolonic abnormalities. The routine use of the scout film resulted in an increase in health care charges and departmental costs. In addition, there was no significant increase in the detection of extracolonic abnormalities. Our data suggest that routine use of scout films prior to contrast studies is unnecessary, although selective use in some clinical situations may be justified.