Hydrolytic Degradation and Drug Release of Ricinoleic Acid–Lactic Acid Copolyesters

A systematic study on the degradation and drug release from l-lactic acid and ricinoleic-acid-based copolyesters is reported. These copolyesters were synthesized by ring opening polymerization (ROP), melt condensation (COND) and transesterification (TRANS) of high molecular weight poly(lactic acid) (PLA) with ricinoleic acid (PLA-RA), and repolymerization by condensation to yield random and block copolymers of weight average molecular weights (Mw) between 3000 and 13,000. All polymers showed an almost zero-order weight loss, with a 20–40% loss after 60 days of incubation. Lactic acid release to the degradation solution is proportional to weight loss of the polymer samples. The main decrease in molecular weight was observed during the first 20 days, followed by a slow degradation phase, which kept the number average molecular weight (Mn) at 4000–2000 for another 40 days. Water-soluble 5FU was released from ricinoleic-acid-based polymers faster than slightly water-soluble triamcinolone. Drug release into phosphate-buffered saline (pH 7.4, 0.1 M) at 37°C from P(LA-RA) 60:40 prepared by condensation of the acids was faster than from pasty P(PLA-RA) 60:40 synthesized by transesterification for both drugs.     

Intestinal Transport of Sulfanilic Acid in Rats Immunized with Protein–Sulfanilic Acid Conjugate

Intestinal transport of sulfanilic acid was examined by means of an in vitro everted sac technique in rats immunized with a bovine -globulin–sulfanilic acid conjugate. At a low concentration of sulfanilic acid, the intestinal transport of sulfanilic acid was decreased in rats immunized with bovine -globulin–sulfanilic acid conjugate. This phenomenon was dose dependent and antigen specific, since there was no difference in the transport of sulfanilic acid at a high concentration and of an unrelated hapten. These results suggested that parenteral immunization impaired not only the intestinal transport of macromolecular antigens, as previously shown, but also the transport of the low molecular weight hapten, sulfanilic acid.     

Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

Purpose To evaluate a novel targeted anticancer prodrug consisting of several copies of sialic acid (SA, targeting moiety), doxorubicin (DOX), citric acid (multifunctional spacer) and poly(ethylene glycol) (PEG, carrier). Methods α, ω bis carboxyl PEG was covalently conjugated with multiple copies of SA and DOX through a citric acid spacer and characterized by proton nuclear magnetic resonance (¹HNMR), matrix-assisted laser desorption/ionization-time of flight (MALDI/TOF), and high-performance liquid chromatography (HPLC). The molecular models of conjugates were established using ChemDraw software. Stability, spontaneous and esterase-stimulated drug release was analyzed by HPLC. Cellular internalization (fluorescence microscopy) and cytotoxicity [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay] of free DOX and prodrugs were evaluated. Results ¹HNMR, MALDI/TOF, and HPLC showed the formation of the PEG prodrug conjugates. More than 40% of the drug was released from its conjugate in the presence of esterase enzyme, whereas the conjugate was stable at pH 7.4 in the absence of enzyme. Molecular modeling studies showed stable conformations of conjugates. The targeted prodrug conjugates with two copies of SA and DOX showed enhanced cytotoxicity when compared with non-targeted prodrugs and free DOX. Conclusions Targeting of the conjugate to cancer cells by SA with increased copies of targeting moiety and anticancer drug enhanced prodrug uptake by cancer cells and cytotoxicity of the prodrug.     

Acid–base properties of penicillins and cephalosporins (a review)

Published data on the acid–base properties of penicillin and cephalosporin antibiotics are summarized and systematized. It is suggested to classify penicillins and cephalosporins with respect to the acid–base type. The influence of the structure of antibiotics and the conditions and method used for determining the ionization constants of proton-donor groups in antibiotics are considered.     

Effects of Aspirin and Mefenamic Acid on Soman Poisoning–Induced Neuropathology in Mice

The efficacy of aspirin and mefenamic acid to counteract soman-induced brain damage was investigated in mice. Neuronal damage was evaluated in the hippocampus and amygdala by performing ω3 receptor density measurements and hemalun–phloxin staining. The effect of both drugs on the proliferation of neural progenitors after soman exposure was also assessed. Mefenamic acid aggravated the soman-induced hippocampal neuropathology. On the other hand, aspirin recorded a weak neuroprotective effect in the amygdala. However, this drug also diminished the proliferation of neural precursor cells. The possible neurochemical mechanisms underlying such differences in the efficacy of the two drugs are also reviewed.     

Structure–Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors

d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety exhibited nearly complete glucuronidation within 30 min. The one exception was 6-[2-(3,5-difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one 10, which exhibited some degree of resistance to glucuronidation by liver microsomes from mice, rats, and humans.     

Structure–activity Relationship Studies of Microbiologically Active Thiosemicarbazides Derived from Hydroxybenzoic Acid Hydrazides

Forty-five derivatives of thiosemicarbazide were synthesized, and their antibacterial activity against Gram-positive and Gram-negative bacteria was evaluated. Some of the described compounds exhibited interesting activity against reference strains of Gram-positive bacteria, whereas only two derivatives had the ability to inhibit the growth of Gram-negative species (Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 13883, Proteus mirabilis ATCC 12453). The most potent antimicrobial activity was observed in the cases of salicylic acid hydrazide derivatives. The differences in activity inspired us to conduct conformational analysis using molecular mechanics level. The obtained results suggest that the molecule geometry, especially at the N4–terminus of thiosemicarbazide skeleton, determines the antibacterial activity. Unfortunately, in opposition to what we expected, only one of the tested compounds inhibited the activity of the topoIV enzyme, and none of them was active against DNA gyrase.     

Assessment of the Developmental Toxicity of Ascorbic Acid,Sodium Selenate,Coumarin, Serotonin,and 13–CIS Retlnolc Acid Using Fetax

ABSTRACT

The developmental toxicity of five cornounds was evaluated with the Frog Embryo Teratogenesis Assay: Xenopus (FETAX) and the results were compared to mammalian literature. Small cell Xenopus laevis blastulae were exposed to ascorbic acid, sodium selenate, coumarin, serotonin and 13–cis retinoic acid for 96 hr. Three separate static-renewal assays were conducted for each compound. Teratogenic potential of the test materials was determined based on Teratogenic Index values [TI = LCSO/ECSO (malformation)], types and severity of induced malformations and embryo growth. Ascorbic acid had little or no teratogenic potential. Sodium selenate and coumarin tested as having moderately positive teratogenic potential. Serotonin scored as having moderately strong teratogenic potential and 13–cis retinoic acid scored as having strong teratogenic potential. Results were consistent with mammalian data and support the use of FETAX for the screening of developmental toxicants.     

Investigation of Cortical Glutamate–Glutamine and γ-Aminobutyric Acid in Obsessive–Compulsive Disorder by Proton Magnetic Resonance Spectroscopy

Glutamatergic abnormalities in corticostriatal brain circuits are thought to underlie obsessive–compulsive disorder (OCD). Whether these abnormalities exist in adults with OCD is not clear. We used proton magnetic resonance spectroscopy (¹H MRS) to test our hypothesis that unmedicated adults with OCD have reduced glutamate plus glutamine (Glx) levels in the medial prefrontal cortex (MPFC) compared with healthy controls. Levels of γ-aminobutyric acid (GABA) were also explored. Twenty-four unmedicated adults with OCD and 22 matched healthy control subjects underwent ¹H MRS scans at 3.0 T. Resonances of both Glx and GABA were obtained using the standard J-editing technique and assessed as ratios relative to voxel tissue water (W) in the MPFC (the region of interest) and the dorsolateral prefrontal cortex (DLPFC) to explore the regional specificity of any finding. In the MPFC, Glx/W did not differ by diagnostic group (p=0.98) or sex (p=0.57). However, GABA/W was decreased in OCD (2.16±0.46 × 10⁻³) compared with healthy controls (2.43±0.45 × 10⁻³, p=0.045); moreover, age of OCD onset was inversely correlated with MPFC GABA/W (r=−0.50, p=0.015). MPFC GABA/W was higher in females than in males. In the DLPFC, there were no main effects of diagnosis or gender on Glx/W or GABA/W. These data indicate that unmedicated adults with OCD do not have Glx abnormalities in a MPFC voxel that includes the pregenual anterior cingulate cortex. However, they may have decreased MPFC GABA levels. How GABA abnormalities might contribute to corticostriatal dysfunction in OCD deserves further study.     

Acid–base equilibria and solubility of loratadine and desloratadine in water and micellar media

Acid–base equilibria in homogeneous and heterogeneous systems of two antihistaminics, loratadine and desloratadine were studied spectrophotometrically in Britton–Robinson’s buffer at 25 °C. Acidity constant of loratadine was found to be pK_a 5.25 and those of desloratadine pK_a1 4.41 and pK_a2 9.97. The values of intrinsic solubilities of loratadine and desloratadine were 8.65 × 10⁻⁶ M and 3.82 × 10⁻⁴ M, respectively. Based on the pK_a values and intrinsic solubilities, solubility curves of these two drugs as a function of pH were calculated. The effects of anionic, cationic and non-ionic surfactants applied in the concentration exceeding critical micelle concentration (cmc) on acid–base properties of loratadine and desloratadine, as well as on intrinsic solubility of loratadine were also examined. The results revealed a shift of pK_a values in micellar media comparing to the values obtained in water. These shifts (ΔpK_a) ranged from −2.24 to +1.24.     

16α-Hydroxy-(–)-kauranoic Acid: A Selectively Cytotoxic Diterpene from Annona bullata

Using brine shrimp lethality to direct fractionation, extracts of the bark of Annona bullata Rich. (Annonaceae) have yielded 16-hydroxy-(–)-kauranoic acid as a bioactive plant constituent. This previously known diterpene showed significant (ED₅₀ 8.25 × 10^–2 µg/ml) and selective cytotoxicity against A-549 (lung) cells in our panel of human tumor cells.     

Preparation,Characterization, and Evaluation of Dipfluzine–Benzoic Acid Co-crystals with Improved Physicochemical Properties

Purpose

To prepare and characterize the co-crystal of dipfluzine and benzoic acid. To investigate the feasibility of the co-crystal for improving solubility and a faster dissolution rate in vitro and evaluate the bioavailability and tissue distribution of co-crystal in vivo.

Methods

A novel dipfluzine–benzoic acid co-crystal prepared using the solvent-assisted co-grinding and the solvent ultrasonic methods were identified and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), as well as Raman, solid-state nuclear magnetic resonance (ssNMR), and terahertz (THz) spectroscopy. Pharmacokinetics and tissue distribution were tested in vivo using murine models. Statistics analysis for dissolution data of co-crystal in vitro and animal experiment data in vivo were evaluated using t-test.

Results

Results of PXRD and DSC identified the dipfluzine–benzoic acid co-crystals were formed with a molar ratio of 1:2. The IR, Raman, and ssNMR spectra verified the formation of O-H?·?·?·?O and O-H?·?·?·?F hydrogen bonds. The complex constant, K, was evaluated to be 10⁹ orders of magnitude with Δ _r G?<?0. The co-crystal solubility, the rate of drug dissolution and the relative bioavailability were approximately 500 times, five times and double that of dipfluzine, respectively. Increased solubility of co-crystal did not reduce distribution in the brain; the mean concentrations in the brain increased, but the differences had no statistic significance (p?>?0.05).

Conclusions

The co-crystal of dipfluzine–benzoic acid improved the physicochemical properties of dipfluzine, such as solubility and dissolution rate. Furthermore, the increased relative bioavailability of co-crystal indicated the potential use in further clinical study     

Investigation of the Drug–Drug Interaction Between α-Lipoic Acid and Valproate via Mitochondrial β-oxidation

Purpose  To investigate the potential drug–drug interaction (DDI) between lipoic acid (LA) and valproate (VA) via the mitochondrial β-oxidation pathway in rats. Methods   In vitro mitochondrial assays were performed to compare the biotransformation of VA to valproyl-CoA (VA-CoA), in the absence and presence of LA. In vitro microsomal and protein binding assays were performed to elucidate their potential DDI at the microsomal metabolism and distribution levels. A pharmacokinetic study was conducted in Lister Hooded rats to ascertain the in vivo DDI between LA and VA. Results  LA was shown to decrease significantly (p < 0.05) the in vitro formation of VA-CoA in a concentration-dependent manner. Our in vitro assay results confirmed that there was minimal interaction between LA and VA in microsomal metabolism and protein binding. Based on the pharmacokinetic data, the absolute bioavailability of VA was determined to be 1.3 in the presence of LA. Conclusions  Our study demonstrated for the first time that there is a potential DDI between LA and VA at the mitochondrial β-oxidation level. While further clinical study is essential, our preliminary finding suggested that medical practitioners need to be prudent when managing epileptic patients who are co-administered with both VA and LA.     

Nanocomplexes Based on Amphiphilic Hyaluronic Acid Derivative and Polyethylene Glycol–Lipid for Ginsenoside Rg3 Delivery

Hybrid nanocomplex formulations, based on amphiphilic hyaluronic acid–ceramide (HACE) and lipids, were fabricated for the delivery of 20(S)-ginsenoside Rg 3 [(S)-Rg3]. Nanocomplexes with less than 200 nm mean diameter, narrow size distribution, spherical shape, and negative zeta potential were prepared. The maintenance of the structural stability of the hybrid nanocomplexes in the blood stream was demonstrated by measuring their particle size in serum. Nanocomplexes based on HACE, phosphatidylcholine (PC), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG) showed a sustained drug release profile compared with other formulations. Blank nanocomplexes exhibited negligible cytotoxicity within the tested concentration range in A549 human lung adenocarcinoma cells. The cellular uptake efficiency of hybrid nanocomplexes was improved compared with the HACE-based nanoparticles probably because of interactions between lipids and the cellular membrane. The results of a pharmacokinetic study in rats revealed decreased in vivo clearance of (S)-Rg3, especially in the HACE/PC/DSPE-PEG-based hybrid nanocomplex (F3) group. The hybrid nanostructure and the outer PEG chain likely contributed to improve in vivo performance of the F3 group. Thus, these developed hybrid nanocomplexes could serve as good candidates for tumor-targeted delivery of anticancer agents.     

Fusidic Acid治疗葡萄球菌性角膜炎

本文报告采用眼局部点滴夫西地酸(Fusidicacid)治疗葡萄球菌性角膜炎取得满意效果。 20例葡萄球菌性角膜炎患者,其中3例伴有其它细菌感染。方法:1%夫西地酸混悬液,每2小时滴眼1次,每日6次。治疗后85%患者临床症状改善,55%患者视敏度改善,6例角膜溃疡愈合,视敏度未改善,3例无效,感染症状加重,再次作角膜刮痧培养,未见细菌生长。20例中的17例角膜炎全愈,4例角膜溃疡者,经并用其它抗生素亦无效。角膜溃疡完全重新上皮形成的时间为:5天内3例,6～10天9例,11～15天     

CD44 Receptor–Specific and Redox-Sensitive Nanophotosensitizers of Hyaluronic Acid–Chlorin e6 Tetramer Having Diselenide Linkages for Photodynamic Treatment of Cancer Cells

For reactive oxygen species (ROS)–sensitive and CD44 receptor–mediated delivery of photosensitizers, chlorin e6 (ce6) tetramer was synthesized using tetra acid (TA) via selenocystamine linkages and then conjugated with hyaluronic acid (HA) (abbreviated as HAseseCe6TA). HAseseCe6TA nanophotosensitizers were fabricated by dialysis procedure. HAseseCe6TA nanophotosensitizers showed spherical morphology with small particle sizes less than 100 nm and monomodal pattern. When H₂O₂ was added, size distribution was changed to multimodal pattern and morphological observation showed disintegration of nanophotosensitizers, indicating that HAseseCe6TA nanophotosensitizers have ROS sensitivity. Furthermore, H₂O₂ addition resulted in acceleration of Ce6 release from HAseseCe6TA nanophotosensitizers. In vitro cell culture study, HAseseCe6TA nanophotosensitizers increase Ce6 uptake ratio, ROS production efficiency, and photodynamic therapy efficacy in both B16F10 cells and CT26 cells. Especially, CD44-receptor blocking of cancer cells by pretreatment of HA showed that fluorescence intensity in B16F10 cells was significantly decreased while fluorescence intensity in CT26 cells was not significantly changed, indicating that HAseseCe6TA nanophotosensitizers can be delivered by CD44 receptor–mediated pathway. In vivo animal tumor xenograft study, HAseseCe6TA nanophotosensitizers was selectively delivered to B16F10 tumor rather than CT26 tumor. These results indicated that HAseseCe6TA nanophotosensitizers have ROS sensitivity and have CD44 receptor–recognition properties.     

抗骨质疏松新药——Minodronic Acid

Minodronie Acid（Recalbon）是双膦酸盐类药物，由山之内制药株式会社和小野公司开发，2009年在日本获批准用于治疗骨质疏松。