Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial.

OBJECTIVE: To test and compare the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections with the current standard prophylaxis of daily low dose antibiotics. DESIGN: Multicentre, open label, randomised, non-inferiority trial. SETTING: Eight centres in the UK, recruiting from June 2016 to June 2018. PARTICIPANTS: Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment. INTERVENTIONS: Random assignment (1:1, using permuted blocks of variable length via a web based system) to receive antibiotic prophylaxis or methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed. MAIN OUTCOME MEASURE: Absolute difference in incidence of symptomatic, antibiotic treated, urinary tract infections during treatment. A patient and public involvement group predefined the non-inferiority margin as one episode of urinary tract infection per person year. Analyses performed in a modified intention-to-treat population comprised all participants observed for at least six months. RESULTS: Participants were randomly assigned to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The modified intention-to-treat analysis comprised 205 (85%) participants (antibiotics, n=102 (85%); methenamine hippurate, n=103 (86%)). Incidence of antibiotic treated urinary tract infections during the 12 month treatment period was 0.89 episodes per person year (95% confidence interval 0.65 to 1.12) in the antibiotics group and 1.38 (1.05 to 1.72) in the methenamine hippurate group, with an absolute difference of 0.49 (90% confidence interval 0.15 to 0.84) confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) in the antibiotic group and 35/127 (28%) in the methenamine group and most reactions were mild. CONCLUSION: Non-antibiotic prophylactic treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections, informed by patient preferences and antibiotic stewardship initiatives, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial. TRIAL REGISTRATION: ISRCTN70219762.

Residues of salicylic acid and its metabolites in hen plasma, tissues and eggs as a result of animal treatment and consumption of naturally occurring salicylates.

Salicylates are among the most known anti-inflammatory drugs, used both in human and veterinary medicine. They also occur naturally in plants. Residues of salicylic acid in tissues and eggs may occur after drug administration or exposure of animals to feed material with high salicylate content. An animal study was performed on laying hens. The birds received sodium salicylate or acetylsalicylic acid (10 mg/kg b.w.) for 7 days or were given corn containing 1.18 mg/kg of salicylic acid. Samples of liver, muscle and plasma were collected at 0, 4, 8, 24 and 72 h after treatment; eggs were collected daily for 14 days. Salicylic acid and its metabolites: gentisic acid, salicyluric acid and gentisuric acid were determined using liquid chromatography coupled with tandem mass spectrometry. In both liver and muscle, the residues after administration of sodium salicylate were initially higher than for acetylsalicylic acid but they depleted at the same time. The deposition and depletion profile of salicylic acid in eggs was similar for groups receiving both drugs; the plateau level reached 248 ± 61.5 µg/kg and 275 ± 82.1 µg/kg. The concentration of salicylic acid in tissues and eggs of animals receiving salicylic acid was low. Gentisic acid was found in individual samples of liver, muscle and eggs from all treated groups. The exposure of hens to the salicylates at feed additive levels and to naturally occurring salicylates results in low residue concentrations and fast depletion of salicylic acid. The eggs do not pose any risk to consumers sensitive to salicylates.

Safety and efficacy of methenamine hippurate for the prevention of recurrent urinary tract infections in adult renal transplant recipients: A single center, retrospective study.

BACKGROUND: Recurrent urinary tract infections (UTI) are an important cause of morbidity and mortality in renal transplant recipients (RTR). METHODS: In this retrospective study we gathered clinical data from patients prescribed methenamine hippurate to prevent recurrent UTI pre- and post-intervention. Thirty-eight RTR ≥18 years old at Northwestern Memorial Hospital from 2006-2017 were included in the final analysis. RESULTS: The median and range for follow-up days were 365 (299-365) pre- vs 314 (105-365) post-methenamine. Total UTI frequency (9.16 vs 5.01/1000 patient follow-up days), days of antibiotic therapy to treat UTI (215 vs 132/1000 patient follow-up days), and hospitalization due to UTI (2.64 vs 1.07/1000 patient follow-up days) decreased while patients took methenamine. Escherichia coli and Klebsiella pneumoniae were the most commonly identified cause of UTI both pre- and post-intervention. Drug resistant bacteria (ESBL-producing or VRE) affected 3 patients pre- and recurred in 1 of those patients plus 3 new patients post-methenamine. Methenamine had few adverse side effects for patients. One patient had nausea and 1 was intolerant. CONCLUSION: We found that methenamine is well tolerated and is useful in reducing UTI, antibiotic prescriptions, and hospitalization in RTR with recurrent UTI. Larger prospective studies are needed to confirm these findings.

Association between hippuric acid and left ventricular hypertrophy in maintenance hemodialysis patients.

BACKGROUND: Left ventricular hypertrophy (LVH) is one of the most common cardiac abnormalities in patients with end-stage renal disease. Hippuric acid (HA), a harmful uremic toxin, is known to be elevated in patients with uremia, and serum HA levels are associated with neurological symptoms, metabolic acidosis, and accelerated renal damage associated with chronic kidney disease. However, the pathophysiological role of HA in patients with uremia remains unclear. We investigated the association between serum HA levels and echocardiographic measurements in patients undergoing hemodialysis (HD) treatment. METHODS: Eighty consecutive patients treated at a single HD center (44 males, 36 females; mean age 66 y, mean HD duration 6 y) were included in this study. Comprehensive echocardiography was performed after HD. Blood samples were obtained before HD. RESULTS: Pearson's correlation analysis revealed that serum HA levels were positively correlated with diastolic blood pressure, serum creatinine, left ventricular mass index, end diastolic interventricular septal thickness, left ventricular end-diastolic diameter, left ventricular end systolic diameter, end systolic left ventricular posterior wall thickness, and left atrium diameter, and negatively correlated with age. Furthermore, the HD patients with LVH had higher median serum HA levels than those without LVH (34.2 vs. 18.1 µg/ml, p = 0.003). Multiple logistic regression analysis revealed that HA was independently associated with LVH even after adjusting for known biomarkers. Moreover, the receiver operator characteristics curve of HA showed that a HA level of >26.9 µg/ml was associated with LVH. CONCLUSIONS: HA was significantly associated with LVH. HA could be a novel biomarker of left ventricular overload, which is closely associated with an increased risk of death in HD patients.

Benzyl [(11)C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice.

Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several (11)C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding (11)C-labeled organic acids in target tissues. Among the compounds screened, benzyl [(11)C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3(-/-) and Mrp4(-/-) mice, respectively, compared with that of control mice after the intravenous administration of benzyl [(11)C]hippurate. Benzyl [(11)C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively.

Pharmacokinetic study of multiple active constituents after oral gavage of Guizhi decoction in rats using a LC-MS/MS method.

Guizhi decoction (GZD) is a classic traditional Chinese medicine formula, clinically used for the treatment of influenza, common cold, and other pyretic conditions. A sensitive, specific, and validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to investigate the pharmacokinetic properties of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid in rat. After single dose oral administration of 7.9 g extract/kg body weight GZD in rats, plasma concentrations of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid were measured by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data. The values of AUC0-t, half-life (t 1/2), and C max were 7.2 ± 2.3 µg h/mL, 1.2 ± 0.3 h, and 9.2 ± 5.2 µg/mL for cinnamic acid, 53 ± 31 µg h/mL, 2.8 ± 2.0 h, and 17 ± 3 µg/mL for hippuric acid, 1.1 ± 0.5 µg h/mL, 1.9 ± 1.1 h, and 0.6 ± 0.3 µg/mL for paeoniflorin, and 11 ± 6 µg h/mL, 6.6 ± 2.5 h, and 0.9 ± 0.6 µg/mL for glycyrrhetic acid, respectively. The results would offer useful information for effective components of GZD in vivo.

Sensibilidad antimicrobiana de cepas hipurato-negativas de Campylobacter spp. y de Helicobacter pullorum aisladas de enfermos con diarrea / Antimicrobial sensitivity of hippurate-negative Campylobacter and Helicobacter pullorum strains isolated from patients with diarrhea

El género Campylobacter, tanto C. jejuni como algunas especies hipurato-negativas y géneros relacionados, son la principal causa de gastroenteritis en nuestro entorno a lo largo de todo el año. El objetivo del presente estudio es determinar la sensibilidad de cepas hipurato negativas de Campylobacter spp. y de Helicobacter pullorum aislados de heces diarreicas humanas. Se estudiaron 39 cepas de Campylobacter coli, dos de C. lari y cinco de Helicobacter pullorum identificadas por espectrometría de masas MALDI-TOF. La sensibilidad a amoxicilina- clavulánico, eritromicina, azitromicina, gentamicina, ciprofloxacino, levofloxacino, tetraciclina, tigeciclina y cloranfenicol se determinó por E-test. La mayoría de las cepas de Campylobacter hipurato-negativos y H. pullorum estudiadas presentaron una elevada resistencia a las dos fluoroquinolonas probadas y a la tetraciclina. Por otro lado, todas las cepas fueron sensibles a amoxicilina-clavulánico, a tigeciclina y a cloranfenicol, mientras que la mayoría lo fueron a los macrólidos y a la gentamicina(AU)

C. jejuni as well as some hippurate-negative Campylobacter species and related diarrheagenic organisms, are the leading cause of gastroenteritis in our environment all throughout the year. The aim of the present study was to determine the sensitivity of hippurate-negative Campylobacter and Helicobacter pullorum strains isolated from the stools of patients with diarrhea. We tested 39 Campylobacter coli, two C. lari and five Helicobacter pullorum strains identified by mass spectrometry analysis. The sensitivity to amoxicillin-clavulanic acid, erytrhomycin, azithromycin, gentamicin, ciprofloxacin, levofloxacin, tetracycline, tigecycline and chloramphenicol was tested by E-test. Most hippurate-negative Campylobacter and H. pullorum isolates studied showed high resistance to tetracycline and to the two fluorquinolones tested. On the other side, all strains were sensitive to amoxicillin-clavulanic acid, tigecycline and chloramphenicol, while most of them were sensitive to both macrolides tested and to gentamicin(AU)

Synergistic potentiating effect of D(+)-mannose, orotic, and hippuric acid sodium salt on selective toxicity of a mixture of 13 substances of the circulatory system in culture for various tumor cell lines.

Despite global immune system abnormalities in the autoimmune deficiency syndrome, the incidence of only a few tumor types increases, and the degree of immunosuppression does not seem to be critical in the development of these tumors, indicating that the immune system does not prevent tumor development. Consequently, because tumors do not develop in most individuals, other defense systems may exist. We demonstrated previously that 13 substances in the circulatory system acting synergistically induced apoptosis in vitro and in vivo in different tumor cell lines, but not in normal cells and animals. We investigated another 17 compounds and five ions in the circulatory system to determine their participation in the defense provided by the 13 substances. Three of the 17 substances but no ions had a potentiating effect on the mixture of substances used previously. The new 16-component mixture suppressed in vitro growth of six human and murine tumor cell lines, including multidrug-resistant tumor cells, without cytotoxic effects in two normal cell lines. The selectivity also was demonstrated by investigating the mixture's effect over time on tumor and normal cell growth.

Hepatic uptake of hippurate: a multiple-indicator dilution, perfused rat liver study.

The hepatic transport of hippuric acid (HA), a glycine-conjugated metabolite of benzoic acid that exhibits only modest plasma albumin binding (binding association constant of 2.1 x 10(3) M-1), was studied in the single-pass perfused rat liver (12 ml/min), using the multiple indicator dilution (MID) technique. The venous recovery of [3H]HA on portal venous injection of a MID dose containing a mixture of a set of noneliminated reference indicators and [3H]HA revealed a survival fraction of unity, corroborating the lack of disappearance of bulk HA from plasma. When the outflow recovery was fitted to the barrier-limited model of Goresky et al. (C.A. Goresky, G. G. Bach, and B. E. Nadeau. J. Clin. Invest. 52: 991-1009, 1973), the derived influx (P(in)S) and efflux (P(out)S) permeability-surface area products were found to be dependent on the concentration of HA (1-930 microM); P(in)S and P(out)S were approximately 3.5 times the plasma flow rate at low HA concentration, but decreased with increasing HA concentration. All values, however, greatly exceeded the expected contribution from passive diffusion, because the equilibrium distribution ratio of chloroform to buffer for HA was extremely low (0.0001 at pH 7.4). The tissue equilibrium partition coefficient (P(in)/P(out), or ratio of influx to efflux rate constants, k1/k-1) was less than unity and decreased with concentration. The optimized apparent Michaelis-Menten constant and maximal velocity were 182 +/- 60 microM and 12 +/- 4 nmol.s-1.g-1, respectively, for influx and 390 +/- 190 microM and 29 +/- 13 nmol.s-1.g-1, respectively, for efflux. In the presence of L-lactate (20 mM), however, P(in)S for the uptake of HA (174 +/- 3 microM) was reduced. Benzoic acid (10-873 microM) was also effective in reducing hepatic uptake of HA (5.3 +/- 0.9 microM). These interactions suggest that MCT2, the monocarboxylate transporter that mediates the hepatic uptake of lactate and other monocarboxylic acids, may be involved in HA transport.

An assessment of finger doses received by staff while preparing and injecting radiopharmaceuticals.

Good working practice and legal obligation impose a duty on nuclear medicine departments to check syringe activities before administration to a patient. If syringe guards are used to reduce staff exposure while drawing up injections, the guard has to be removed to measure the activity in a conventional reentrant ionization chamber type calibrator. Alternatively, the activity may be checked in a purpose-built syringe calibrator which allows the assay of the activity in the syringe without the need to remove the syringe guard. Finger doses received during the dose preparation and injection are a cause for concern. This study investigated the finger and whole-body doses received when using each of these calibrators, and compared the results with those obtained by an operator who did not measure the dose at all. The results demonstrated that although the finger doses are small, measurement of the syringe activities in a conventional ionization chamber increases the dose by a factor of 2 above that which would occur if no activity measurements were made, whereas the use of the specialized syringe calibrator gave finger doses only marginally above those obtained with no activity measurement.

Evaluation of liver function by co-administration methodology using 13C-labelled benzoic acid and hippuric acid coupled with nuclear magnetic resonance spectroscopy.

The amount of hippuric acid synthesized and excreted in the urine after benzoic acid loading (hippuric acid test) is a useful index of liver function. However, the hippuric acid test gives erroneous results in the event of failure of renal excretory function. A new stable isotope co-administration methodology using nuclear magnetic resonance (NMR) spectroscopy has been developed to overcome this defect. [7-(13)C]Benzoic acid and [glycine carbonyl-13C]hippuric acid ([gly-13C]hippuric acid), each 0.4-0.6 mmol kg(-1) were simultaneously administered intravenously as probes to normal or liver-injured rats and the urine was analysed by 100 MHz 13C NMR spectroscopy. Consequently, urinary excretion of [7-(13)C]hippuric acid formed from [7-(13)C]benzoic acid and [gly-13C]hippuric acid was successfully traced with very simple and convenient procedures. The urinary excretion of [7-(13)C]hippuric acid indicated the combined functions of hippuric acid synthesis and renal excretion, whereas that of [gly-13C]hippuric acid was indicative of renal excretion of hippuric acid only. The heights of resonances for C7 of [7-(13)C]hippuric acid and the glycine carbonyl carbon of [gly-13C]hippuric acid were used to calculate the concentrations of labelled hippuric acids. [7-(13)C]Hippuric acid was excreted more slowly than [gly-13C]hippuric acid by both normal and liver-injured rats. The liver-injured rats excreted the labelled hippuric acids more slowly than the normal rats. The kinetic parameters were computed for the individual rats on the basis of Michaelis-Menten elimination for benzoic acid and first-order elimination for hippuric acid. The maximum rates of metabolism (Vmax) (4.8-5.8 micromol min(-1) kg(-1)) and the renal elimination rate constants of hippuric acid (Kre) (0.010-0.021 min(-1)) in the liver-injured rats were lower than those (Vmax 6.7-11.8 micromol min(-1) kg(-1); Kre 0.026-0.045 min(-1)) in the normal rats. These results have demonstrated that liver function can be evaluated from the Vmax value even though the renal function of hippuric acid excretion (Kre) is impaired. Thus the co-administration methodology is feasible and can remove the defect of the previous hippuric acid test. These results could form the basis for a more convenient and reliable hippuric acid test in man.

Improvement of aqueous solubility and rectal absorption of 6-mercaptopurine by addition of sodium benzoate.

The solubility of 6-mercaptopurine (6-MP) in water increased as the concentration of sodium benzoate or sodium hippurate in the solution increased. The solubility of 6-MP in 20% (w/v) sodium benzoate or sodium hippurate solution was about 6-fold larger than that of 6-MP alone. The stability constant of the soluble complex of 6-MP with sodium benzoate was estimated to be 2-8 M-1 from (1) phase-solubility study and (2) analysis of chemical shifts observed in 1H-NMR. Partition of 6-MP from the saturated solution to n-octanol was also greatly increased by the addition of sodium benzoate or sodium hippurate, the degree being less in the latter. Administration of 6-MP with 20% (w/v) sodium benzoate to rat rectum resulted in enhanced absorption and the area under the plasma concentration-time curve was comparable to that obtained by intravenous administration (bioavailability = 100%), while the bioavailability after intrarectal administration of 6-MP with 20% (w/v) sodium hippurate was only 9%. The reason for the difference was discussed.

[Protein fractions in workers exposed to organic solvents]. / Zachowanie sie frakcji bialkowych u ludzi eksponowanych na rozpuszczalniki organiczne.

Industrial workers exposed to organic solvents were subject to examinations consisting in the assessment of the composition of serum proteins. The analysis revealed frequent shifts in protein fraction pattern. It was noted that the increased concentrations of organic solvents metabolites in urine have been usually accompanied by the increased gamma-globulins levels with a simultaneous decrease in albumin fraction and plasmatic index.

Effect of fasting on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms.

The effect of fasting on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms was investigated. The blood concentration of salicyluric acid and salicylic acid following oral, intracecal and rectal administration of salicyluric acid was determined. In fasted rabbits (24 and 48 h), the blood concentration of salicylic acid after oral administration was changed compared to the control. However, a significant effect of fasting was not observed in the blood concentration of salicylic acid after rectal administration. Following intracecal administration, the blood concentration of salicylic acid was increased in fasted rabbits compared to the control. From these results, it seems that the slow rate of stomach emptying due to coprophagy during fasting is the principal reason for the change of blood concentration of salicylic acid following oral administration of salicyluric acid.

Sustained blood concentration of salicylic acid following rectal administration of salicyluric acid in dogs.

The blood concentrations of salicyluric acid and salicylic acid following rectal, intravenous and oral administrations of salicyluric acid (5, 10 and 60 mg/kg, respectively: salicylic acid equivalent) were determined in dogs. After rectal administration, a small amount of salicyluric acid was absorbed in intact form. The rest was hydrolyzed to salicylic acid, which was subsequently absorbed. The blood concentration of salicylic acid was maintained at 0.4-0.7 microgram/ml from 2 to 12 h. Following intravenous administration of salicyluric acid, salicyluric acid was detected in the blood but was rapidly eliminated. A trace amount of salicylic acid was detected, suggesting that systemic de-conjugation of glycine was involved. After oral administration of salicyluric acid, salicyluric acid was well absorbed. Salicylic acid was detected at low concentration for 12 h. Species difference in the metabolic fate of salicyluric acid in dogs, rabbits, rats and humans reported previously is discussed.

Hydrolysis of salicyluric acid in intestinal microorganisms and prolonged blood concentration of salicylic acid following rectal administration of salicyluric acid in rats.

The blood concentrations of salicyluric acid and salicylic acid following oral, intravenous, intracecal and rectal administration of salicyluric acid were determined in rats. After oral administration of salicyluric acid, salicyluric acid was rapidly absorbed. Salicylic acid was detected at low concentration. Following intravenous administration of salicyluric acid, salicyluric acid was detected in the blood and was rapidly eliminated. A trace amount of salicylic acid was detected, suggesting that systemic deconjugation of glycine was involved. Furthermore, in vitro incubation of salicyluric acid with contents of the gut showed that the major source of the hydrolysis was the hind gut. Immediate and very extensive salicylic acid formation in the cecum was found following intracecal administration of salicyluric acid. The blood concentration of salicylic acid was maintained at 2.6-4.0 micrograms/ml from 4 to 12 h following rectal administration of salicyluric acid (10 mg/kg: salicylic acid equivalent). Species difference in the metabolic fate of salicyluric acid in rats and rabbits reported previously is discussed.

Further studies on the hydrolysis of salicyluric acid in intestinal microorganisms and prolonged blood concentration of salicylic acid following rectal administration of salicyluric acid in rabbits.

The blood concentrations of salicyluric acid and salicylic acid following intracecal and rectal administration of salicyluric acid were determined in rabbits. Immediate and very extensive salicylic acid formation in the cecum was found following intracecal administration. After rectal administration, a small amount of salicyluric acid was absorbed in intact form. The rest was rapidly hydrolyzed to salicylic acid, which was subsequently absorbed. The blood concentration of salicylic acid was maintained at 1.3-1.8 micrograms/ml from 2 to 12 h. Three doses of salicyluric acid were administered rectally. The peak level of salicyluric acid increased with dose. However, salicylic acid concentration in the blood following administration of salicyluric acid at 10.0 mg/kg (salicylic acid equivalent) was not double that observed following administration of salicyluric acid at 5.0 mg/kg (salicylic acid equivalent). It appears that a larger amount of salicyluric acid in the rectal lumen may have saturated the glycine deconjugation system.

Hydrolysis of salicyluric acid in rabbit intestinal microorganisms.

The fate of salicyluric acid (SU) after oral administration was examined in rabbits. Salicylic acid (SA) and unchanged SU were detected in the blood after oral administration of SU. However, SU only was found after intravenous administration of SU, suggesting that presystemic deconjugation of glycine was involved. After treatment of rabbits with kanamycin sulfate, complete inhibition of the formation of SA after oral administration of SU was demonstrated, indicating that the intestinal microflora was responsible for the biotransformation. Furthermore, in vitro incubation of SU with contents of gut showed that the major source of the hydrolysis was the hind gut. Based on the findings described above, the time course data for blood concentration of SU and SA after oral administration of SU have been subjected to curve-fitting by a nonlinear least squares program. The SU and SA values obtained with the simplified model containing only first-order kinetic process which is proposed by the present authors were found to agree with those obtained from experiments.