The details of incompatibility between aripiprazole (ARIP) oral solution and green tea were examined. When the ARIP oral solution was mixed with a commercial PET bottled green tea beverage, the ...residual rate of ARIP in the mixed solution decreased to 15.7–17.6%. Mixing with ARIP reduced the content of gallate-type green tea polyphenols (GTPs) in the mixed solution but not the content of non-gallate-type GTPs. Furthermore, using pH 3.0 lactic acid buffer, 2.23 mM ARIP solution and 2.23 mM GTP solution were prepared, and the same volumes of ARIP solution and GTP solution were mixed. When the gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution decreased. On the other hand, when the non-gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution did not decrease. From the above results, it was found that the main reason for the incompatibility between ARIP oral solution and green tea was the formation of an insoluble substance composed of ARIP and gallate-type GTPs in green tea. Furthermore, experimental results using the continuous variation method revealed that ARIP and (−)-epigallocatechin gallate, which is the most representative gallate-type GTP, interact at a molar ratio of 3 : 2.
We report the preparation of new C3- and CS-symmetrical molecules constructed on a triazine (TAZ) template. Anti-herpes simplex virus type 1 (anti-HSV-1) and cytotoxic activities against Vero cells ...of synthesized TAZ derivatives were evaluated. The results suggested that the presence of an electron-donating group(s) on the benzene ring in benzylamine groups on the TAZ template is an important structural factor for expressing a high level of anti-HSV-1 activity and low cytotoxicity for these C3 types of TAZ derivatives. Among the tested TAZ derivatives, compounds 4f and 7h showed the highest anti HSV-1 activities (EC50=0.98 and 1.23 µM, respectively) and low cytotoxic activities to Vero cells (50% cytotoxic concentration (CC50)=292.2 and >200 µM, respectively).
The inclusion of catechins with cyclodextrin (CD) is performed for the purpose of improving the water solubility and reducing the bitterness of catechins. In this study, the effect of catechins’ ...conformation on the formation of an inclusion complex between catechins and β-CD was examined by density functional theory (DFT) calculation at the B3PW91/cc-pVDZ level. It is known that the main components of catechins in tea leaves are (−)-epigallocatechin (EGC), which is a non-gallate-type catechin, and (−)-epigallocatechin gallate (EGCg), which is a gallate-type catechin. Catechins have a plurality of sites that can be included by β-CD (EGC: AC ring and B ring, EGCg: AC ring, B ring, and B′ ring). First, initial models for the calculation in which each ring of catechins gradually approaches into the cavity of β-CD were built. These initial models were optimized in water and then the optimized structure of the inclusion complex in water was determined. From the results of calculation, the degree of penetration of each ring into the β-CD cavity, the complex formation energy, and the number of intermolecular hydrogen bonds were examined. The results of calculation showed that the AC ring of catechins is most deeply included in the β-CD cavity and the B′ ring of catechins forms an energetically stable complex with β-CD. It was found that the inclusion complex of catechins and β-CD is stabilized energetically by intermolecular hydrogen bonds.
In connection with our studies on hydantoin derivatives, a conventional regioselective chemical transformation of 5-methylene hydantoins 4a–c to 5-aminomethyl-substituted hydantoins 5–10 or to ...5-amino-5-methyl-disubstituted hydantoins 11–14 is described. Synthesis of bivalent twin-drug type hydantoin derivatives 19–24 and the binding property of a bivalent symmetrical hydantoin derivative 24b to sulfated glycosaminoglycans are also described.
In terms of molecular symmetry and bioactivity, new C3- and CS-symmetrical derivatives based on the tris(2-aminoethyl)amine scaffold were designed and synthesized. The synthesized compounds were ...evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1) by a plaque reduction assay and for cytotoxic activity with Vero cells. Most of the compounds showed no significant anti-HSV-1 activity, but some of the symmetrical derivatives showed high levels of cytotoxic activitiy.
Carbohydrate recognition of some bioactive symmetrical tripodal receptor type tris(2-aminoethyl)amine (TAEA) derivatives was investigated. In calorimetric experiments, the highest binding constant (
...K
a) of compound
C
(C
35
H
49
N
5
O
4
S) with methyl α-
d
-mannopyranoside was
K
a = 858 M
−1
with 1:1 stoichiometry. Formation of hydrogen bonds in binding between symmetrical tripodal receptor type compound
C
and sugars was suggested by the large negative values of ∆
H
° (=−34 to −511 kJ mol
−1
). In a comparison of each set of α- and β-anomers of some monosaccharides (methyl α/β-
d
-galactopyranoside, methyl α/β-
d
-glucopyranoside, and methyl α/β-
l
-fucopyranoside), compound
C
showed that the binding constant of β-anomer was larger than that of the corresponding α-anomer, indicating higher β-anomer selectivity. The calculated energy-minimized structure of the complex of compound
C
with guest methyl α-
d
-mannopyranoside is also presented. The experimental results obtained from this work indicated that symmetrical tripodal receptor type TAEA derivative
C
has a lectin-like carbohydrate recognition property.
Here, we studied the incompatibility between an oral solution of propericiazine (PCZ), an antipsychotic drug, and various commercially available bottled tea-based drinks. When 0.5 mL of the PCZ oral ...solution (10 mg/mL) was mixed with 16.5 mL of a tea-based drink (such as green tea, oolong tea, and black tea), the residual PCZ content declined to approximately 50% in some mixed solutions. After mixing with other tea-based drinks, the residual PCZ content declined to approximately 30%, while in others, it changed very little. The residual PCZ content declined immediately after mixing with tea-based drinks, but the rate remained almost unchanged for the next 24 h. Furthermore, the pH of the mixture increased to 4.5-5.1 after the oral solution of PCZ (original pH 3.8) was diluted with various tea-based drinks. Afterwards, the pH did not change for 24 h. The mixture became cloudy immediately after diluting PCZ oral solution with tea-based drinks, and the insoluble substance gradually precipitated. In order to elucidate factors responsible for the decline in the content of PCZ, a (−)-epigallocatechin gallate solution, which is a main ingredient of green tea polyphenol, was mixed with the PCZ oral solution. After mixing, the residual PCZ content declined to approximately 60-75%. On the other hand, the content of PCZ did not decline when a (−)-epigallocatechin solution was mixed with the PCZ oral solution. The results from this study demonstrated that PCZ content was reduced after dilution in tea-based drinks because of the interaction between PCZ and polyphenol with a galloyl group in tea-based drinks.
To establish the role of patient characteristics in estimating doses of digoxin for infants and young children using routine therapeutic drug monitoring data, the steady‐state blood‐level data (n = ...245) after repetitive oral administration in 117 hospitalized infants and young children were analyzed using nonlinear mixed effects modeling (NONMEM), a computer program designed for analyzing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a 1‐compartment pharmacokinetic model. Estimates generated by NONMEM indicated that the clearance of digoxin (CL/F; L/h) was influenced by the following demographic variables: total body weight (TBW), presence of congestive heart failure (CHF), and infant‐young children clearance factor (trough serum concentration of digoxin; Conc). These influences could be modeled by the equation CL/F (L/h) = 0.302 · TBW (kg)1.17 · 0.905CHF · Conc (trough serum digoxin concentration >1.7 ng/mL)−0.540; F = 0.754, where CHF is 1 for presence of congestive heart failure, 0 otherwise; F is bioavailability, 1 for elixirs, 0.754 for powders; and Conc−0540 is 1 for digoxin concentration <1.7 ng/mL. Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of his or her clinical need for the drug.
The aim of this study was to develop an efficient fully automated synthesis method to achieve a high radiochemical yield of
18FFAZA with a small amount of precursor. A small cartridge containing 25
...mg of the QMA resin was prepared and evaluated to obtain
18FF
− in a small quantity of base (K
2CO
3), which might allow the use of a small amount of precursor. The labeling and hydrolyzing conditions for
18FFAZA synthesis were also investigated manually. No-carrier-added
18FF
− was trapped on the small QMA cartridge and eluted with a mixture of Krytofix 222 (2.26
mg, 6.0
μmol) and K
2CO
3 (0.69
mg, 5.0
μmol) in 70% MeCN (0.4
mL). The automated synthesis of
18FFAZA was optimally performed with a modified NIRS original synthesis system for clinical use, by labeling 2.5
mg (5.2
μmol) of the precursor in DMSO (0.4
mL) at 120
°C for 10
min, and then by hydrolyzing the
18F-labeled intermediate with 0.1
M NaOH (0.5
mL) at room temperature for 3
min. Using the above condition, the
18FFAZA injection was obtained with a high radiochemical yield of 52.4±5.3% (decay-corrected,
n=8) within 50.5±1.5
min.
Background: Optimal use of digoxin in the elderly population requires information about the drug's pharmacokinetics and the influence of various factors on the drug's disposition. However, because of ...sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in elderly patients. Objective: This study was conducted to determine the apparent total clearance of digoxin from serum after oral administration (CL/F) and to establish the role of patient characteristics in estimating doses of digoxin for elderly patients (age ≥65 years), using routine therapeutic drug monitoring data. Methods: Analyses of the pharmacokinetics of digoxin were conducted using the nonlinear mixed-effects modelling (NONMEM®) software, a computer program designed to analyse pharmacokinetics in study populations by allowing pooling of data. Steady-state data (140 observations) obtained by routine therapeutic drug monitoring following repeated oral administration of digoxin in 94 hospitalized elderly patients (age ≥65 years) were analysed to establish the role of patient characteristics in estimating doses of digoxin for elderly patients. Results: Estimates generated by NONMEM® indicated that digoxin CL/F was influenced by the demographic variables of total bodyweight (TBW), serum creatinine (SCr), age (AGE), presence of congestive heart failure (CHF), concomitant administration of the calcium channel antagonists (calcium channel blockers CCBs: verapamil, diltiazem or nifedipine), sex (SEX) and elderly clearance factor (trough serum concentration of digoxin; C trough Figure omitted. θ). The full version of the final NONMEM® model was Figure omitted. where CCB is 1 for concomitant administration of a CCB and is 0 otherwise; CHF is 1 for patients with CHF and is 0 otherwise; SEX is 0 for male and is 1 for female; and the elderly clearance factor Ctrough-0.180 is 1 for digoxin Ctrough <1.7 ng/mL. Conclusions: We developed a new model for elderly patient dosing of digoxin with good predictive performance. Clinical application of the findings of the present study to patient care may permit selection of an appropriate initial digoxin maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. However, the digoxin dosage regimen should be based on an appraisal of the individual patient's clinical need for the drug. PUBLICATION ABSTRACT
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