Evaluation for Blood Concentration and Efficacy/Safety of Continuous Administration of Thiamylal in Children.

BACKGROUND: Thiamylal exerts excellent sedative effects. However, it is not routinely used because of its serious adverse effects. This study aimed to clarify the target blood concentration range and infusion rate of thiamylal in children by measuring its blood concentration and evaluating its relationship with efficacy and adverse effects. METHODS: This study was approved by the Ethics Committee of Japanese Red Cross Kumamoto Hospital. The authors included 10 children aged between 1 and 7 years who had received continuous intravenous (IV) infusion of thiamylal for the management of refractory status epilepticus, excluding those who met the exclusion criteria. After a 2 mg/kg bolus injection of thiamylal, continuous IV infusion was initiated at a rate of 2-3 mg/kg/h. Thiamylal concentration in the blood was measured using high-performance liquid chromatography. The State Behavioral Scale and the frequency of bolus injections were used to evaluate efficacy. Blood pressure and heart rate were measured to evaluate adverse effects. Statistical analyses of the time to awakening and the factors affecting it were also conducted. RESULTS: The State Behavioral Scale score during thiamylal administration was -2 or lower in all cases, suggesting that the depth of sedation was sufficient. The frequency of bolus injections decreased in a blood concentration-dependent manner, suggesting that the frequency tended to decrease, especially at thiamylal blood concentrations of 20 mcg/mL or higher. An increase of the infusion rate to 3 mg/kg/h was recommended, because the blood concentration may not reach 20 mcg/mL at an infusion rate of 2 mg/kg/h. There was also a case in which a rapid increase in blood concentration accompanied by a decrease in blood pressure and heart rate was observed when the infusion rate was increased to 4 mg/kg/h. Furthermore, the time to awakening after the end of administration correlated with the highest blood concentration during administration; therefore, delayed awakening was noted when using a high dose of thiamylal. CONCLUSIONS: The target blood concentration of thiamylal in children should be 20-30 mcg/mL, and the infusion rate should be based on 3 mg/kg/h.

The Use of Enteric Capsules for Releasing a Fragrance over an Extended Period of Time.

A system for releasing a fragrance, citral (CR) over an extended period of time using three types of enteric capsules is reported. The L- and M-type capsules released CR into media with a pH above 6, while the H-type capsule released CR at a pH above 7. The pH of the releasing medium was controlled by sodium borate (SB), i.e., by adding SB-methylcellulose (MC) prepared in different weight ratios (SB-MC 1 : 2, 1 : 1 and 2 : 1) to tablets and by compressing them at different pressures. The tablet containing a large amount of SB and that was pressed at higher pressures permitted the pH of the releasing medium to be changed from 5 to 9, at 4-5 h after the addition of SB to the tablets, while negligible changes were observed for tablets containing low amounts of SB and which were compressed at lower pressures. Reflecting these pH changes, CR was released after different periods of time when SB-MC tablets and capsules containing CR were simultaneously added to the releasing medium. When enteric capsules containing CR and the pH adjusting tablets were simultaneously added to a benzyl acetate (BA) solution, BA was released at a constant rate, while CR was released for different periods of time depending on the type of capsule used. The results suggest that fragrances could be released over different time frames by using enteric capsules and pH adjusting agents, for example, the release of fragrances with sedative effects at night time and with stimulating effects in the morning.

Surface-Deacetylated Chitin Nano-Fiber/Hyaluronic Acid Composites as Potential Antioxidative Compounds for Use in Extended-Release Matrix Tablets.

In this study, we examined a possible use of a surface-deacetylated chitin nano-fiber (SDCH-NF) and hyaluronic acid (HA) interpolymer complex (IPC) tablet as a potential antioxidative compound in extended-release matrix tablets. The antioxidant properties of untreated chitin (UCH), SDCH-NF, and HA were examined using N-centered radicals derived from 1,1'-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). SDCH-NF and HA had acceptable scavenging abilities and were relatively efficient radical scavengers, but UCH was much less effective. The results suggest that SDCH-NF and HA could serve as scavengers of compounds related to the development of oxidative stress. An SDCH-NF/HA IPC tablet was prepared and evaluated as an extended-release tablet matrix using famotidine (FMT) as a model drug. The release of FMT from the IPC tablet (DCF-NF:HA=1:1) was slower than that from a SDCH-NF only tablet. Turbidity measurements and X-ray diffraction (XRD) data also indicated that the optimum complexation ratio for IPC between SDCH-NF/HA is 1/1, resulting in a good relationship between turbidity or XRD of the complex and the release ratio of FMT. These results suggest that an SDCH-NF/HA tablet has the potential for use in an extended-release IPC tablet with a high antioxidant activity.

Preparation of amorphous indomethacin from aqueous 2,6-di-O-methyl-beta-cyclodextrin solution.

Indomethacin precipitated exclusively in an amorphous form from aqueous 2,6-di-O-methyl-beta-cyclodextrin solutions, whereas it precipitated in Form V polymorph from the solutions of the drug alone, parent cyclodextrins and 2-hydroxypropyl-cyclodextrins. The polymorphic transition of the amorphous form to Form V crystals in aqueous solution was markedly inhibited by the addition of 2,6-di-O-methyl-beta-cyclodextrin, keeping the amorphous state for at least 5 days at 4 degrees C, whereas it quickly transformed to Form V crystals in the absence of 2,6-di-O-methyl-beta-cyclodextrin. 2,6-Di-O-methyl-beta-cyclodextrin suppressed the solution-mediated polymorphic transition of amorphous form of indomethacin to Form V crystals in aqueous solution. The current results suggested that 2,6-di-O-methyl-beta-cyclodextrin is useful for isolation of amorphous indomethacin that occurs at an early stage of crystallization according to "Ostwald's Rule of Stages".

Pharmacokinetics studies of 4'-cyano-2'-deoxyguanosine, a potent inhibitor of the hepatitis B virus, in rats.

OBJECTIVES: 4'-cyano-2'-deoxyguanosine (CdG), a novel nucleoside analogue, has a high degree of antiviral activity against the chronic hepatitis B virus (HBV). The objective of this study was to develop an analytical method for quantitatively determining CdG levels in biological samples by liquid chromatography-mass spectrometry (LC/MS) and to investigate the pharmacokinetic properties of CdG in rats after intravenous and oral administration. METHODS: An analytical method using a UPLC system interfaced with a TOF-MS system was developed and validated. The pharmacokinetic properties after the intravenous and oral administration of CdG to rats were evaluated. In vivo pharmacokinetic interactions between CdG and entecavir were also investigated. KEY FINDINGS: A rapid, simple and selective method for the quantification of CdG in biological samples was established using LC/MS with solid-phase extraction. In vivo pharmacokinetic studies of CdG in rats demonstrated that CdG is highly bioavailable, is rapidly absorbed from the intestinal tract, is then distributed to the liver rather than kidney and is ultimately excreted via the urine in an unchanged form. The co-administration of CdG and entecavir led to pharmacokinetic interactions with each other. CONCLUSIONS: The data generated in this study provide support for the clinical development of CdG for use in the treatment of HBV.

Pharmacokinetic properties of a novel inosine analog, 4'-cyano-2'-deoxyinosine, after oral administration in rats.

4'-cyano-2'-deoxyinosine (SK14-061a), a novel nucleoside analog based on inosine, has antiviral activity against the human immunodeficiency virus type 1 that has the ability to acquire resistance against many types of reverse transcriptase inhibitors based on nucleosides. The aim of this study was to investigate the pharmacokinetics studies after its oral administration to rats. For this purpose, we first developed and validated an analytical method for quantitatively determining SK14-061a levels in biological samples by a UPLC system interfaced with a TOF-MS system. A rapid, simple and selective method for the quantification of SK14-061a in biological samples was established using liquid chromatography mass spectrometry (LC-MS) with solid phase extraction. The pharmacokinetic properties of SK14-061a in rats after oral administration were then evaluated using this LC-MS method. SK14-061a was found to be relatively highly bioavailable, is rapidly absorbed from the intestinal tract, and is then mainly distributed to the liver and then ultimately excreted via the urine in an unchanged form. Furthermore, the simultaneous administration of SK14-061a with the nucleoside analog, entecavir, led to a significant alteration in the pharmacokinetics of SK14-061a. These results suggest that the SK14-061a has favorable pharmacokinetic properties with a high bioavailability with the potential for use in oral pharmaceutical formulations, but drug-drug interactions should also be considered.

Surface-deacetylated chitin nanofibers reinforced with a sulfobutyl ether ß-cyclodextrin gel loaded with prednisolone as potential therapy for inflammatory bowel disease.

Surface-deacetylated chitin nanofibers (SDACNFs) reinforced with a sulfobutyl ether ß-cyclodextrin (SBE-ß-CD) (NFs-CDs) gel were developed to obtain a controlled release carrier of prednisolone (PD) for the treatment of colitis. PD was released slowly from the gel at both pH 1.2 and 6.8. The in vitro slow release of PD from the NFs-CDs gel was reflected in the in vivo absorption of the drug after oral administration to rats. These results suggest that a simple gel composed of a mixture of SDACNFs and SBE-ß-CD has the potential for use in the controlled release of PD. We also evaluated the therapeutic effects of the NFs-CDs gel containing PD on dextran sulfate sodium (DSS)-induced colitis model mice. The administration of the NFs-CDs gel at intervals of 3days from the beginning of the DSS treatment resulted in a significant improvement, not only in colitis symptoms but also histopathological changes in colon tissue. In addition, the therapeutic effects of the NFs-CDs gel on colitis can be attributed to decreased levels of neutrophil infiltration and the development of oxidative stress. These efficacy profiles of the NFs-CDs gel containing PD suggest that it has the potential for use in the treatment of, not only colitis, but also a variety of other disorders associated with inflammation and oxidative injuries.

Tyrosine411 and Arginine410 of Human Serum Albumin Play an Important Role in the Binding of Sodium 4-Phenylbutyrate to Site II.

Sodium 4-phenylbutyrate (PB) has many pharmacological activities; therefore extending its clinical use to the treatment of a wider variety of diseases would be desirable. However, our knowledge of the binding of PB to plasma proteins is not extensive. To address this issue in more detail, we characterized the protein binding of PB. Binding experiments showed that PB mainly binds to human serum albumin (HSA) in plasma. PB was also found to bind to a single site on HSA, which was identified as site II by fluorescent probe displacement experiment. Furthermore, an appropriate alkyl chain length and a carboxylic group in the PB structure were required for PB binding to HSA, suggesting that hydrophobic (and van der Waals) and electrostatic interactions are involved as binding modes. The contributions of hydrogen bonding and/or van der Waals interactions were also indicated by thermodynamic analyses. Tyrosine411 and arginine410 were identified as being involved in the binding of PB to site II, based on binding experiments using chemically modified- and mutant-HSA preparations. In conclusion, the available evidence indicates that PB binds to site II of HSA with assistance by multiple forces and that tyrosine411 and arginine410 both play important roles in this phenomenon.

Cyclodextrins improve oral absorption of a novel factor Xa inhibitor by interfering with interaction between the drug and bile acids in rats.

OBJECTIVES: Poor oral absorption of a factor Xa inhibitor, DX-9065, is partly due to the interaction with bile acids in the gastrointestinal tract. The aim of this study is to improve the oral bioavailability of DX-9065 by cyclodextrins (CyDs) capable of interfering with such interaction. METHODS: The abilities of the CyDs to interfere with the interaction between DX-9065 and sodium chenodeoxycholate were evaluated using equilibrium dialysis. The interaction between DX-9065 and the CyDs was studied spectroscopically. Effects of the CyDs on the oral absorption of DX-9065 were examined in rats. KEY FINDINGS: Hydroxypropyl-ß-CyD and γ-CyD were effective in interfering with the interaction between DX-9065 and sodium chenodeoxycholate as a representative bile acid. Spectroscopic studies revealed that DX-9065 was included into the CyD cavity to form inclusion complexes in an acidic medium. With dissociation of the carboxyl group of DX-9065 in a neutral medium, the stability of the complexes was decreased to such an extent that DX-9065 in the cavity is replaced with co-existing bile acids. The average area under the plasma concentration-time curve value after oral administration of DX-9065 with hydroxypropyl-ß-CyD was 2.5 times higher than that of DX-9065 alone with a statistical difference in rats. CONCLUSIONS: We suggest that the CyDs are useful in designing oral formulations of DX-9065 with an improved bioavailability.

Reduction of bitterness of antihistaminic drugs by complexation with ß-cyclodextrins.

Reduction of bitterness of antihistaminic drugs by cyclodextrin (CyD) complexation was examined. The stability constant (Kc) of the 1:1 CyD inclusion complexes with antihistaminic drugs increased in the order of 2-hydroxypropyl-ß-CyD (HP-ß-CyD) ≈ ß-CyD > γ-CyD > α-CyD for diphenhydramine and epinastine, and HP-ß-CyD ≈ ß-CyD > α-CyD > γ-CyD for hydroxyzine, cetirizine, and dl-chlorpheniramine. The inclusion complexes inhibited the adsorption of antihistaminic drugs to lipid membrane using liposomes, as the magnitude of Kc increased. From human gustatory sensation tests, ß-CyD and HP-ß-CyD potently suppressed the bitterness of antihistaminic drugs in a dose-dependent manner. Further, an artificial taste sensor analysis revealed that ß-CyD and HP-ß-CyD inhibited the bitterness of antihistaminic drugs in solution. The results suggest that CyDs suppress the bitterness of antihistaminic drugs in solutions through the formation of inclusion complexes. These results may provide useful information for masking or elimination of bitterness of drugs using CyDs.

Some pharmaceutical and inclusion properties of 2-hydroxybutyl-ß-cyclodextrin derivative.

2-Hydroxybutyl-ß-cyclodextrins (HB-ß-CyDs) with different degrees of substitution (D.S.) were prepared and their physicochemical and biological properties and solubilizing abilities were studied and compared with those of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CyD). The surface activity of HB-ß-CyD was higher than that of HP-ß-CyD (D.S. 5.6) and increased with its concentration and D.S. The moisture sorption of HB-ß-CyD (D.S. 5.5) was less than that of HP-ß-CyD (D.S. 5.6), because of the introduction of hydrophobic hydroxybutyl groups in a molecule. The hemolytic activity (rabbit erythrocytes) decreased in the order of 2,6-di-O-methyl-ß-cyclodextrin (DM-ß-CyD)>methyl-ß-cyclodextrin (M-ß-CyD)>HB-ß-CyD (D.S. 5.5)>ß-CyD>HP-ß-CyD (D.S. 5.6). The hemolytic activity of HB-ß-CyD increased with D.S. and HB-ß-CyD induced echinocyte (or crenation), as well as DM-ß-CyD does. It was suggested from the solubility study of membrane components that HB-ß-CyD interacted predominantly with cholesterol in erythrocytes, resulting in the hemolysis. The inclusion ability of HB-ß-CyD was higher than that of HP-ß-CyD (D.S. 5.6), especially for poorly water-soluble drugs with long linear structures such as biphenylylacetic acid and flurbiprofen (FP). For example, HB-ß-CyD formed the inclusion complex with FP in a molar ratio of 1:1, by including the biphenyl moiety in the host cavity. The dissolution rate of FP/HB-ß-CyD (D.S. 5.5) complex was faster than that of HP-ß-CyD (D.S. 5.6) complex. The results suggested that HB-ß-CyDs have considerable pharmaceutical potential and can work as a fast-dissolving carrier for poorly water-soluble drugs.

Improvement of some physicochemical properties of arundic acid, (R)-(-)-2-propyloctanonic acid, by complexation with hydrophilic cyclodextrins.

Arundic acid, (R)-(-)-2-propyloctanonic acid, is a novel neurological agent for intractable neurodegenerative diseases. However, arundic acid, an oily drug, has low aqueous solubility and severe bitter/irritating tastes. Consequently, these physicochemical properties of arundic acid need to be improved to develop its pharmaceutical preparations. In the present study, we evaluated whether parent cyclodextrins (CyDs) and 2-hydroxypropylated CyDs (HP-CyDs) can interact with arundic acid, and have powderization, solubilization and taste-masking properties. Of various CyDs, HP-ß-CyD had the most potent solubilizing effect for arundic acid. UV and (1)H NMR spectroscopic studies demonstrated that arundic acid formed inclusion complexes with CyDs at a molar ratio of 1:1 in solution. The complexation with CyDs changed an oily form of arundic acid to a solid form. The gustatory sensation studies indicate that of various CyDs, HP-ß-CyD and γ-CyD showed the most significant taste-masking effects in solution and powders, respectively. HP-ß-CyD significantly reduced the response of the electric potential caused by the adsorption of arundic acid to the taste sensor. These results suggest that hydrophilic CyDs have potential as multifunctional excipients for preparing solutions and powders containing arundic acid.

Crystallization and polymorphic transitions of chlorpropamide in aqueous 2-hydroxybutyl-beta-cyclodextrin solution.

Effects of cyclodextrins on crystallization of chlorpropamide and the polymorphic transition mechanism of the drug in aqueous solution were investigated. In the presence of 2-hydroxybutyl-beta-cyclodextrin, chlorpropamide was exclusively crystallized to metastable Form II and III polymorphs, whereas it was crystallized to stable Form A in the absence of the beta-cyclodextrin at 4 degrees C. The crystallization to metastable Form II or III polymorph was dependent upon 2-hydroxybutyl-beta-cyclodextrin concentrations employed, i.e. crystallization to Form III at a lower concentration (0.5 mM), whereas to Form II in a higher concentration (5 mM). At an intermediate concentration (2 mM), the least stable Form II crystal was initially precipitated, but it was transformed to Form III crystal. At higher temperature, Form III crystal was converted to stable Form A crystal. In aqueous solution, chlorpropamide crystallized to stable Form A crystal consecutively through metastable Forms II and III, according to "Ostwald's Rule of Stages". 2-Hydroxybutyl-beta-cyclodextrin inhibits the transition of Form II to Form III at higher concentrations and that of Form III to Form A at lower concentrations. The results suggest that 2-hydroxybutyl-beta-cyclodextrin is useful for selective preparation of metastable chlorpropamide polymorphs occurring during crystallization according to the Ostwald's rule.

Enhancement of the aqueous solubility and masking the bitter taste of famotidine using drug/SBE-beta-CyD/povidone K30 complexation approach.

The objective of the present study was to evaluate the potential of ternary system (comprised of famotidine, beta-cyclodextrin (beta-CyD) or its derivatives and a hydrophilic polymer) as an approach for enhancing the aqueous solubility and masking the bitter taste of famotidine. The aqueous solubility of famotidine increased in the presence of beta-CyDs, particularly sulfobutyl ether beta-CyD (SBE-beta-CyD), and it was further enhanced by the combination of SBE-beta-CyD and polyvinyl pyrrolidone (Povidone) K30. The solid binary (drug-beta-CyDs) and ternary (drug-beta-CyDs-Povidone K30) systems were prepared by the kneading and freeze-drying methods. The dissolution rates of these solid systems were much faster than that of the drug alone. A taste perception study was carried out, initially using a taste sensory machine and subsequently on human volunteers to evaluate the taste masking ability of the ternary complexation. Our results indicated that the combination of SBE-beta-CyD and Povidone K30 is effective not only in the enhancement of the solubility and dissolution rate of famotidine, but also in masking of the bitter taste of the drug. This technique may be of value for the pharmaceutical industries, especially in preparation of rapidly disintegrating tablets dealing with bitter drugs to improve patient compliance and thus effective pharmacotherapy.