Effect of mechanochemical inclusion of triamterene into sulfobutylether-ß-cyclodextrin and its improved dissolution behavior.

The formation of inclusion complexes between triamterene (TT) and cyclodextrins (CDs) to increase the water apparent solubility of TT was investigated. UV data showed that the binding constant of the TT/sulfobutylether-ß-cyclodextrin (SBE-ß-CD) inclusion complex was 510 L/mol. The phenyl ring of TT was inserted into the secondary hydroxy face of SBE-ß-CD, as demonstrated by 1H-1H rotating frame nuclear Overhauser effect spectroscopy NMR. Physicochemical properties of solid TT/SBE-ß-CD complexes prepared by physical mixing, kneading, freeze-drying, and mechanochemical methods were studied by X-ray diffraction and 13C cross-polarization and magic angle spinning NMR. With the mechanochemical method, the diffraction peak corresponding to TT disappeared, indicating the formation of an inclusion complex. The results of the dissolution test revealed that the solid complex obtained by the mechanochemical method improved the dissolution of TT. The water apparent solubility of TT can be improved by simple mechanical mixing without organic solvents, and improved bioavailability after oral administration is expected.

Amikacin Pharmacokinetics in Terminal Stage of Hematological Malignancy.

BACKGROUND: The influence of cancer cachexia on the pharmacokinetics of and kidney injury caused by amikacin remains unclear. This study investigated whether the pharmacokinetics of amikacin and the risk of kidney injury are altered with the progression of cancer cachexia. METHODS: A retrospective analysis was conducted using therapeutic drug monitoring data obtained from 52 cancer patients who received amikacin intravenously for infection(s). The patients were classified into 2 groups based on the status of cachexia using a consensus definition: noncachexia group (n = 31) and cachexia group (n = 21). Differences in amikacin pharmacokinetics and occurrence of kidney injury were compared between the 2 groups. Amikacin pharmacokinetics was calculated based on a 1-compartment model using peak and trough concentrations measured clinically for therapeutic drug monitoring. In addition, intrapatient analysis was conducted based on patients who received amikacin treatments more than once during the study period to examine the alteration in amikacin pharmacokinetics with the progression of cancer cachexia. RESULTS: Systemic clearance of amikacin [median (range)] was significantly (P < 0.05) lower in the cachexia group [37.3 (11.2-87.3) (mL/min)] than in the noncachexia group [52.0 (19.1-133.4) (mL/min)]. In contrast, volume of distribution was significantly (P < 0.05) increased in the cachexia group [0.47 (0.20-1.45) L/kg] compared with the noncachexia group [0.32 (0.21-1.00) L/kg]. There was no difference in the occurrence of kidney injuries between the 2 groups. In an intrapatient analysis of the longitudinal alteration of amikacin pharmacokinetics, an approximately 50% reduction in clearance and 30% increase in volume of distribution were observed as cancer cachexia progressed. CONCLUSIONS: The present study suggests that progression of cancer cachexia may reduce amikacin clearance and increase the volume of distribution, but cancer cachexia does not increase amikacin-induced kidney injury.

Induration at Injection or Infusion Site May Reduce Bioavailability of Parenteral Phenobarbital Administration.

BACKGROUND: Phenobarbital is well tolerated and effective for controlling agitation or preventing convulsion at the end of life. No information is available concerning parenteral bioavailability of phenobarbital when induration develops at the injection or infusion site. We investigated whether induration at injection or infusion site is related to phenobarbital bioavailability via parenteral routes of continuous subcutaneous infusion and intermittent subcutaneous or intramuscular injection. METHODS: A retrospective analysis was conducted on the medical data obtained from 18 patients who received chronic subcutaneous or intramuscular injections of phenobarbital for the prevention of convulsions and underwent plasma concentration monitoring of the drug. Patients whose concomitant medications were altered during the observation periods were excluded from the analysis. Comparisons were performed for concentration/dose (C/D) ratios obtained from patients with induration at injection or infusion sites (induration group, n = 6) and those without induration (noninduration group, n = 12). P < 0.05 was considered statistically significant. RESULTS: The induration group showed significantly reduced C/D ratio compared with the noninduration group [median (range): 0.131 (0.114-0.334) versus 0.219 (0.180-0.322) d/L, P < 0.05). Assuming that systemic clearance was constant in our patients, changes in the C/D ratio would have contributed to 40% (median) reduction in bioavailability of the drug from the injection or infusion site. CONCLUSIONS: Our data suggest that absolute bioavailability of phenobarbital may be reduced when induration develops at the injection or infusion site in patients treated parenterally by continuous subcutaneous infusion or intramuscular injection.

Eculizumab Dosing Intervals Longer than 17 Days May Be Associated with Greater Risk of Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Eculizumab given bi-weekly is widely recommended for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). We undertook a retrospective analysis on the medical records of 763 dosings of 14 PNH patients to investigate whether a threshold would exist in dosing intervals associated with breakthrough hemolysis. We identified 12 events of breakthrough hemolysis in 4 patients. Multivariate logistic regression and receiver operating characteristics (ROC) analysis revealed a significant association between increased risk of breakthrough hemolysis and prolonged dosing intervals of 17 days or more and concomitant inflammation: odds ratios (OR) and 95% confidence intervals (CIs) were 1.6 (1.3-2.0, p<0.01) and 5.5 (1.3-22.8, p=0.02), respectively. ROC analysis showed that the best cut-off dosing interval discriminating breakthrough hemolysis was 16.5 days. We consider that eculizumab dosing intervals longer than 17 days may be associated with an increased risk for developing breakthrough hemolysis in patients with PNH.

Complex formation with layered double hydroxides for the remediation of hygroscopicity.

Layered double hydroxides (LDHs) have been used commercially as antacids, to stabilize drugs, to allow the controlled release of incorporated drugs, and to act as drug carriers to reduce drug accumulation within the body. Several types of LDH were investigated: nitrate type (LDH-NO3); chloride type (LDH-Cl); and carbonate type (LDH-CO3). Each type was added to an aqueous or methanol (MeOH) solution containing a drug (pravastatin or nateglinide). With pravastatin sodium, the interlayer distance expanded after reaction with LDH-NO3 and LDH-Cl in aqueous solution. In contrast, the interlayer distance of LDH-CO3 increased in methanol with nateglinide. Each drug was intercalated into the interlayer space of LDH by ion exchange. The hygroscopicity of the drug substances, complexes, and physical mixtures were determined at 70% relative humidity. Increases in weight (%) of the complexes were less than those of the physical mixtures, which demonstrates that hygroscopicity was reduced upon complexation with LDH due to the layer of LDH over the drugs.

Is higher lymphocyte count a potential strategy for preventing chronic kidney disease in patients receiving long-term dasatinib treatment?

BACKGROUND: Dasatinib, which is used to treat treating chronic myeloid leukemia, induces increases in blood lymphocytes during the treatment. In addition, neutrophil-lymphocyte count ratio (NLR) is associated with the related to development of chronic kidney disease (CKD). However, it has not been reported whether development of CKD during long-term dasatinib treatment is related to lymphocyte count or NLR. This study aimed to reveal the relationship between CKD and lymphocyte count or NLR during long-term dasatinib treatment. METHODS: A retrospective study was conducted in patients treated with dasatinib for 6 months or longer. Risk factors for CKD development were explored using multivariate analysis. Changes in maximal lymphocyte count and NLR over time were examined separately. RESULTS: A total of 33 patients in CKD group (n = 8) and No CKD group (n = 25) who received dasatinib were enrolled. In univariate analysis, significant differences between the groups were observed in maximal lymphocyte count, lymphocytosis, age, and estimated glomerular filtration rate at baseline. As the factor independently associated with the development of CKD, maximal lymphocyte count (odds ratio 0.999, 95% confidence interval: 0.999-1.000, p = 0.033) was identified. In this analysis, age had borderline significance (odds ratio 1.073, 95% CI: 0.999-1.153, p = 0.054)]. After 6 months of dasatinib therapy, lymphocyte count was significantly lower in CKD group [median (range), 2184 (878‒3444)/µL] than in the No CKD group [3501 (966‒7888)/µL] (p = 0.020). However, no significant difference in lymphocyte count was observed between the groups at the last follow-up. During the study period, the median NLR in the No CKD group fluctuated between 1.11 and 1.42, and median NLR in CKD group was increased from 1.13 to 2.24 between after 6 months of dasatinib therapy and the last follow-up. CONCLUSIONS: The development of CKD during dasatinib therapy was associated with lower maximal lymphocyte counts. In contrast, the higher levels of lymphocytes induced during dasatinib treatment may prevent CKD progression.

Abrupt increased serum creatinine in a hyperferritinemia patient treated with deferoxamine after cord blood transplantation: a case report with literature review.

BACKGROUND: Erythrocyte transfusion is an indispensable component of supportive care after hematopoietic stem cell transplantation (HSCT). However, HSCT recipients are susceptible to the development of acute kidney injury (AKI) with multifactorial causes. We report a case of a rapid elevation in serum creatinine associated with deferoxamine after cord blood transplantation (CBT). CASE PRESENTATION: A 36-year-old Japanese male diagnosed with relapsed Philadelphia-positive acute lymphoblastic leukemia received CBT. At day 88 post-CBT, multidrug-resistant Pseudomonas aeruginosa (MDRP) was isolated from urine culture. Subsequently, colistin 200 mg/day was administered parenterally for treatment of epididymitis from day 91 to 117 post-CBT. Despite concomitant administration of potential nephrotoxic agents such as piperacillin-tazobactam, acyclovir, and liposomal amphotericin B, no development of AKI was observed during this period. At day 127 post-CBT, MDRP was detected in blood and urine cultures, and colistin 200 mg/day was re-started parenterally. Due to extremely higher ferritin level, deferoxamine was administered intravenously at day 133 post-CBT. While serum creatinine was 1.03 mg/dL before starting deferoxamine, the level increased to 1.36 mg/dL one day after commencing deferoxamine (day 134 post-CBT), and further increased to 2.11 mg/dL at day 141. Even though colistin was discontinued at day 141 post-CBT, serum creatinine continued to increase. Deferoxamine was withdrawn at day 145 post-CBT, when serum creatinine peaked at 2.70 mg/dL. In addition, no cylinduria is observed during the period of development of AKI. In adverse drug reaction (ADR) assessment using Naranjo probability score, the scores of 3 in deferoxamine and 2 in colistin, respectively, indicated "possible" ADR. However, while colistin-associated AKI manifested early onset, recovery time within 2 weeks after discontinuation and development of cylinduria, this case was discordant with the properties. Furthermore, in the literature review, development of AKI within 1 day, including sudden increase in serum creatinine or abrupt reduction in urine volume, was reported in 3 identified cases. CONCLUSIONS: We considered the rapid creatinine elevation to be the result of deferoxamine rather than ADR caused by colistin. Therefore, careful monitoring of kidney function is required in recipients of HSCT treated with deferoxamine.

Phosphorylation of 5'-deoxy-5-fluorouridine with inorganic phosphorylating agents.

The phosphorylation of 5'-deoxy-5-fluorouridine (doxifluridine, 5'-DFUR) has been achieved using inorganic cyclo-triphosphate (P(3m), Na(3)P(3)O(9)) and monoimido-cyclo-triphosphate (MCTP, Na(3)P(3)O(8)NH) in aqueous solution. In the reaction of 5'-DFUR with P(3m), 2'-monophospho-5'-DFUR and 3'-monophospho-5'-DFUR were synthesized with a total yield of more than 95%. In the reaction of 5'-DFUR with MCTP, 2'-diphosphoramidophosphono-5'-DFUR and 3'-diphosphoramidophosphono-5'-DFUR were synthesized with a total yield of more than 40%. The phosphorylated products with P(3m) and MCTP were stable in neutral and alkaline solutions.

Preparation and characterization of lipid emulsions containing styrene maleic acid copolymer for the development of pH-responsive drug carriers.

Lipid emulsions are potential carriers for poorly water-soluble drugs. Previously, we revealed that lipid nanoparticles complexed with styrene maleic acid copolymer (SMA) disintegrate under acidic pH. In the present study, SMA-containing lipid emulsions (SMA emulsions) were prepared and their physicochemical and biological properties were examined to test whether SMA emulsions could be used as a trigger to facilitate drug release in response to pH reduction. By sonicating lipid and SMA mixtures, homogeneously sized SMA emulsion particles were prepared as verified via dynamic light scattering and transmission electron microscopy. Upon the reduction of solution pH, disintegration of SMA emulsions was observed, which may be utilized for drug release at mildly acidic pH. In addition, the sensitivity to pH changes could be controlled by altering the lipid composition. Serum proteins bound to SMA emulsions were analyzed to predict the metabolic fate upon intravenous injection. Predictably, apolipoproteins were abundantly bound, suggesting that SMA emulsions should avoid being recognized as foreign substances. Furthermore, subcellular distribution studies using a human breast cancer cell line (MDA-MB-231) demonstrated that SMA emulsions localize to lysosomes, which have a lower pH. These results suggest that SMA emulsions could be promising pH-responsive drug carriers.

Urinary lipocalin-type prostaglandin D synthase: a potential marker for early gentamicin-induced renal damage?

Urinary excretion of lipocalin-type prostaglandin D synthase (L-PGDS) has been suggested to be a useful biomarker of early diabetic nephropathy. We studied whether L-PGDS is also a marker of gentamicin (GM)-induced renal damage in the "creatinine-blind" range. A prospective study was conducted in 6 patients who were given long-term intravenous administration of GM (18-42 days in combination with a beta-lactam/carbapenem antibiotic or vancomycin) for the treatment of infective endocarditis. Urinary excretions of L-PGDS, beta2-microglobulin, and N-acetyl-beta-D-glucosaminidase were measured in the early (within 10 days from commencement) and late (thereafter) phases of GM therapy. Systemic clearance of GM (CLGM) and creatinine clearance (CLcr) was also measured concomitantly. CLGM was reduced significantly (P < 0.05) by 10% from the early to late treatment phase, whereas urinary L-PGDS excretion showed a significant (P < 0.05) increase (from 7.3 +/- 4.6 to 8.7 +/- 5.0 mg/g creatinine, mean +/- SD) concomitantly. In contrast, no significant changes were observed for urinary beta2-microglobulin and N-acetyl-beta-D-glucosaminidase concentrations. In conclusion, urinary L-PGDS may be a promising biomarker for the early phase of GM-induced renal impairment.

Reduced Clearance of Phenobarbital in Advanced Cancer Patients near the End of Life.

BACKGROUND AND OBJECTIVES: Little is known about the pharmacokinetics of phenobarbital in terminally ill cancer patients. We investigated whether phenobarbital clearance alters depending on the length of survival. METHODS: We retrospectively reviewed the clinical, laboratory, and therapeutic drug monitoring (TDM) records of patients who received parenteral or oral phenobarbital for 21 consecutive days or longer between 2000 and 2016. Patients were divided into non-cancer and cancer groups. Cancer patients were further stratified according to the survival interval after TDM: those who survived > 3 months were classified as long-surviving and the remainders short-surviving cancer patients. Phenobarbital clearance (CLPB) was calculated at steady state. Multiple comparisons of median CLPB were conducted among the three groups. RESULTS: Data were collected from 44 non-cancer patients and 34 cancer patients comprising 24 long-surviving and 10 short-surviving cancer patients. Among 10 short-surviving cancer patients, 4 had hepatic metastasis. Median CLPB (range) in short-surviving cancer patients [0.076 (0.057‒0.114) L/kg/day] was significantly (p < 0.05) lower than that in non-cancer patients [0.105 (0.060‒0.226) L/kg/day] and in long-surviving cancer patients [0.100 (0.082‒0.149) L/kg/day]. CONCLUSION: Terminally ill patients with advanced cancer may have reduced CLPB, thereby TDM is recommended for these patients particularly near the end of life.

Vancomycin Pharmacokinetics in Patients with Advanced Cancer Near End of Life.

BACKGROUND AND OBJECTIVE: The effect of cancer cachexia on the pharmacokinetics of vancomycin remains unclear. We investigated whether the pharmacokinetics of vancomycin and the risk of kidney injury are altered with the development of cancer cachexia. METHODS: A retrospective analysis was conducted using therapeutic drug monitoring data obtained from 86 cancer patients who received vancomycin intravenously for infection. The patients were classified into four groups according to the stage of cachexia defined by international consensus-non-cachexia (n = 26), pre-cachexia (n = 10), cachexia (n = 21) and refractory cachexia (n = 29). Vancomycin pharmacokinetics were analyzed by a traditional one-compartment model and Bayesian method using plasma concentrations measured in these patients. Renal function and pharmacokinetic parameters were compared between the non-cachexia patients (n = 26) and total cancer cachexia patients (n = 60). RESULT: No significant difference in estimated glomerular filtration rate was observed between the non-cachexia and the total cancer cachexia patients. In contrast, systemic clearance of vancomycin was significantly lower in the total cancer cachexia patients compared with the non-cachexia patients when analyzed by the traditional one-compartment model [median (range)-49.7 (9.8‒98.7) vs 70.2 (12.5‒211.8) mL/min, p < 0.01] and by the Bayesian method [45.6 (12.5-84.7) vs 63.3 (12.2-102.5) mL/min, p < 0.05]. None of the non-cachexia patients developed kidney injury, whereas 15% (9 of 60 patients) of the total cancer cachexia patients developed kidney injuries (p = 0.052). CONCLUSIONS: The present study revealed that cancer patients with cachexia may have reduced vancomycin clearance compared with those without cachexia. Cancer cachexia may be a risk factor of vancomycin-associated kidney injury, independent of renal function.

Isolation of an Acremonium sp. capable of liquefying cross-linked poly(gamma-glutamic acid) hydrogels and the fungal enzyme involved in the disruption of gamma-ray irradiation-mediated cross-linking.

A microorganism capable of liquefying cross-linked poly(gamma-glutamic acid) (C-L PGA) was isolated and identified to be an Acremonium sp. The fungus produced an enzyme that can disrupt the cross-linkages of C-L PGA generated by gamma-ray irradiation. The enzyme can also liquefy C-L PGA prepared by chemical cross-linkage, suggesting the involvement of ester bonds in the gamma-ray irradiation-mediated cross-linking of PGA.

Regioselective phosphorylation of branched cyclodextrins with cyclo-mono-mu-imidotriphosphate.

The phosphorylation of the branched cyclodextrins, mono-6-O-(alpha-D-glucopyranosyl)cyclomaltohexaose, mono-6-O-(alpha-D-maltosyl)cyclomaltohexaose, mono-6-O-(alpha-D-glucopyranosyl)cyclomaltoheptaose, and mono-6-O-(alpha-D-maltosyl)cyclomaltoheptaose, in aqueous solution by sodium cyclo-mono-mu-imidotriphosphate (cMITP) was examined. In these reactions, only the 2-OH group of a single alpha-D-glucopyranosyl residue of the cyclodextrin ring was phosphorylated, in a maximum yield of 67%. A possible mechanism for the phosphorylation is discussed.

Flocculating activity of cross-linked poly-gamma-glutamic acid against bentonite and Escherichia coli suspension pretreated with FeCl3 and its interaction with Fe3+.

Cross-linked poly-gamma-glutamic acid (C-L gamma-PGA) at 5 microg/ml flocculated bentonite suspension pretreated with polyaluminum chloride (PAC) at 2 microg/ml Al3+-PAC to a transparency of approximately 30% after 30 min and more than 90% after 4 h, while Al3+ concentration in the upper phase of the suspension decreased with incubation time. When pretreated with FeCl3 at 16 microg/ml Fe3+-FeCl3, similar results were obtained. In the case of Escherichia coli suspension, the combination of C-L gamma-PGA and FeCl3 demonstrated a more marked flocculating activity with a satisfactory transparency occurring after 30 min of treatment, accompanied by a decrease in residual Fe3+ concentration. In the above two suspensions pretreated with FeCl3, small visible floats appeared in the early stage of incubation. These floats were found to be due to the direct interaction between FeCl3 and C-L gamma-PGA, indicating the formation of a water-insoluble complex. After allowing the suspension to stand for a long time, elemental analysis and inductively coupled plasma spectroscopy of the precipitates produced suggested that not only the complex was formed due to the interaction between Fe3+ in FeCl3 and COO- in the C-L gamma-PGA molecule, but also Fe2O3 and Fe(OH)3 might be entrapped in this complex. This could be applied to scavenge metal ions including Fe3+ from polluted water.

Proposals for wastewater treatment by applying flocculating activity of cross-linked poly-gamma-glutamic acid.

Cross-linked poly-gamma-glutamic acid (C-L gamma-PGA) markedly purified polluted water collected from rivers and ponds by flocculation and precipitation. This effect of C-L gamma-PGA occasionally required pretreatment with polyaluminum chloride (PAC). Components of polluted water in rivers or ponds are generally thought to be clay minerals, microorganisms and chemical compounds. In this study, the flocculating activities of C-L gamma-PGA against suspensions of bentonite, diatomaceous earth, Escherichia coli and Mycrocystis aeruginosa, and against solutions of crystal violet and bisphenol A were investigated. The mode of action of C-L gamma-PGA is thought to be based on electrostatic interaction between flocculants, C-L gamma-PGA and PAC, and the surface of polluted water components, which may lead to neutralization of the zeta-potential of those components.

Inclusion complexes of trihexyphenidyl with natural and modified cyclodextrins.

The solubility of trihexyphenidyl (Thp) was improved by its combination with ß-cyclodextrin (ß-CD) and modified ß-CDs. The solubility of Thp was found to be increased in the presence of ß-CD, hydroxypropyl-ß-cyclodextrin (HP-ß-CD), methyl-ß-cyclodextrin (Me-ß-CD) and sulfobutylether-ß-cyclodextrin (SBE-ß-CD). In particular, the solubility of Thp in conjunction with SBE-ß-CD was increased by a factor of 11. The formation constant (K c ) for the Thp/SBE-ß-CD inclusion complex was determined to be 2300 L/mol based on fluorometry data. The structure of the Thp/SBE-ß-CD complex in aqueous solution was examined by (1)H-(1)H rotating frame nuclear Overhauser effect spectroscopy (ROESY) NMR, and the phenyl moiety of the Thp was found to coordinate with the secondary hydroxyl face of the SBE-ß-CD. A solid Thp/SBE-ß-CD inclusion complex was prepared by freeze-drying.

Preparation of 1-hydroxyethylidene-1,1-diphosphonic acid-intercalated layered double hydroxide and its physicochemical properties.

The intercalation of 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), which is a drug for osteoporosis, in layered double hydroxide (LDH) was examined with the goal of developing a novel drug delivery system (DDS) of HEDP. To prevent side reactions, the intercalation reaction was carried out at 0 degrees C, and at pH 4-6. The uptake of HEDP was determined as 3.5 mmol x g(-1) of LDH, and the interlayer distance increased from 7.8 to 13 A. The HEDP-release profiles into K(2)CO(3) aqueous solution and into various buffer solutions were also examined.