Characterization of the Reaction between Sialic Acid (N-Acetylneuraminic Acid) and Hydrogen Peroxide

In a previous report, we had demonstrated the antioxidant activity of the sialic acid N-acetylneuraminic acid (Neu5Ac, NANA). This activity can counteract the cytotoxicity of hydrogen peroxide (H2O2), and the antitoxicity is a result of a direct chemical reaction, whereby NANA reduces H2O2 in the culture media. The influence of the potential of hydrogen (pH) and temperature in this reaction was investigated. The reaction velocity is remarkably less at low pH and/or low temperature, but it increases with these parameters. Furthermore, the reaction product generated in the slow reaction under acidic conditions (pH 3.1) was analyzed. We detected 4-(acetylamino)-2,4-dideoxy-D-glycero-D-galacto-octonic acid (ADOA) as the decarboxylation product of NANA; this is the same product we previously obtained in a faster reaction at neutral pH (pH 7.5). Furthermore, ADOA was generated not only from the reaction with the NANA monomer but also from that with alpha(2-->8) homodimer of NANA (DP2). Thus, it can be considered that the reaction between NANA and H2O2 can occur under various pH conditions and for NANA residues in a glycochain.     

Evaluation of Protection by Caffeic Acid,Chlorogenic Acid,Quercetin and Tannic Acid against the In Vitro Neurotoxicity and In Vivo Lethality of Crotalus durissus terrificus (South American Rattlesnake) Venom

Systemic envenomation by Crotalus durissus terrificus (South American rattlesnake) can cause coagulopathy, rabdomyolysis, acute kidney injury, and peripheral neuromuscular blockade, the latter resulting in flaccid paralysis. Previous studies have shown that plant products such as tannic acid and theaflavin can protect against the neuromuscular blockade caused by C. d. terrificus venom in vitro. In this work, we used mouse-isolated phrenic nerve-diaphragm preparations to examine the ability of caffeic acid, chlorogenic acid, and quercetin to protect against C. d. terrificus venom-induced neuromuscular blockade in vitro. In addition, the ability of tannic acid to protect against the systemic effects of severe envenomation was assessed in rats. Preincubation of venom with caffeic acid (0.5 mg/mL), chlorogenic acid (1 mg/mL), or quercetin (0.5 mg/mL) failed to protect against venom (10 μg/mL)-induced neuromuscular blockade. In rats, venom (6 mg kg⁻¹, i.p.) caused death in ~8 h, which was prevented by preincubation of venom with tannic acid or the administration of antivenom 2 h post-venom, whereas tannic acid given 2 h post-venom prolonged survival (~18.5 h) but did not prevent death. Tannic acid (in preincubation protocols or given 2 h post-venom) had a variable effect on blood creatinine and urea and blood/urine protein levels and prevented venom-induced leukocytosis. Tannic acid attenuated the histological lesions associated with renal damage in a manner similar to antivenom. The protective effect of tannic acid appeared to be mediated by interaction with venom proteins, as assessed by SDS-PAGE. These findings suggest that tannic acid could be a potentially useful ancillary treatment for envenomation by C. d. terrificus.     

Metabolism of 2-Benzylthio-5-Trifluoromethyl Benzoic Acid (BTBA) by the Rat,Dog and Man

Abstract

1. Benzylthio-5-trifluoromethylbenzoic acid (BTBA) is well absorbed by rat, dog and man. The time course of disappearance from plasma in all three species suggests enterohepatic circulation.

2. The principal excretion product in rat urine has been identified as 2-mercapto-5-trifluoromethylbenzoic acid arising via S-dealkylation.

3. 2-Mercapto-5-trifluoromethylbenzoic acid is also converted to the disulphide metabolite, [2,2′-dithiobis(5-trifluoromethyl)benzoic acid], which is secreted together with BTBA and their glucuronide conjugates in rat bile. Rapid hydrolysis in the intestine results in faecal elimination of largely free BTBA and disulphide metabolite (2,2′-dithiobis[5-trifluoromethyl]benzoic acid).

4. In man, approximately 50% of the dose is recovered from urine as amino-acid and glucuronide conjugates of the drug and its debenzyl metabolite (2-mercapto-5-trifluoromethylbenzoic acid).

5. The drug is not readily metabolized by the dog and is secreted with bile and eliminated unchanged with faeces.     

Pharmacological Aspects of the Use of Lipoic Acid (Review)

Pharmaceutical Chemistry Journal - Lipoic (thioctic) acid (LA) [R-5-(1,2-dithiolan-3-yl)pentanoic acid] is a natural compound that enters the human body with food. LA is used to treat many diseases...     

替诺福韦艾拉酚胺半D-(-)-酒石酸盐的制备及其稳定性研究

目的 制备替诺福韦艾拉酚胺半D-( )-酒石酸盐,并开展稳定性研究。方法 以替诺福韦（PMPA）为原料,经亚磷酸三苯酯缩合、二氯亚砜氯代、L-丙氨酸异丙酯缩合制得替诺福韦艾拉酚胺,再与D-( )-酒石酸成盐。结果 制得的替诺福韦艾拉酚胺半D-( )-酒石酸盐,经1H-NMR、13P-NMR、MS确证结构,并与半富马酸盐进行稳定性比较。结论 替诺福韦艾拉酚胺半D-( )-酒石酸盐比半富马酸盐具有更好的稳定性,值得进一步开发。     

2-(2-芳基)乙基苯甲酸的合成

以邻氰基氯苄为原料,与苯甲醛或2-噻吩甲醛经Wittig-Horner反应、水解及氢化反应制得2-(2-苯乙基)苯甲酸或2-(2-噻吩基)乙基苯甲酸,总收率分别约64%和60%。     

(4-甲氧基-3-硝基苄磺酰基)乙酸的制备

取代的苄磺酰基乙酸类化合物可用于合成多种抗肿瘤药~([1,2]).其中(4-甲氧基-3-硝基苄磺酰基)乙酸(1)可用于合成Polo-like激酶1抑制剂类抗肿瘤药novonex(ON-01910),文献~([1,2])用4-甲氧基-3-硝基溴(氯)苄和巯基乙酸缩合得(4-甲氧基-3-硝基苄硫基)乙酸(2),再用过氧羧酸(如过氧乙酸)在回流条件下氧化,反应结束后蒸去溶剂得1,但由于存在过氧酸容易发生爆炸.     

Isolation and Structure Elucidation of Seco-neokadsuranic Acid A and 3,4-Seco-(24Z)-lanosta-4(30),8,24-triene-3,26-dioic Acid1

Seco-neokadsuranic acid A, the second natural triterpenoid with the unusual 14(13-->12) ABEO-lanostane skeleton was isolated from KADSURA HETEROCLITA together with 3,4-seco-(24 Z)-lanosta-4(30),8,24,triene-3,26-dioic acid. The present paper deals with the isolation and structure elucidation of these two new compounds and the preparation of two new 7-oxo-lanostane triterpenoid derivatives.     

Isolation and structure elucidation of 12beta-acetoxycoccinic Acid, 12beta-hydroxycoccinic Acid, 12alpha-acetoxycoccinic Acid, and 12alpha-hydroxycoccinic acid1

Four new triterpenoid acids, possessing a lanost-9(11)-en-3-one skeleton, were isolated from KADSURA HETEROCLITA. Based on chemical and spectral analyses, they were assigned as 12beta-acetoxycoccinic acid, 12beta-hydroxycoccinic acid, 12alpha-acetoxycoccinic acid, and 12alpha-hydroxycoccinic acid.     

In Vitro Skin Absorption and Metabolism of Benzoic Acid,p-Aminobenzoic Acid,and Benzocaine in the Hairless Guinea Pig

The percutaneous absorption and metabolism of three structurally related compounds, benzoic acid, p-aminobenzoic acid (PABA), and ethyl aminobenzoate (benzocaine), were determined in vitro through hairless guinea pig skin. Benzocaine was also studied in human skin. Absorption of benzocaine was rapid and similar through both viable and nonviable skin. The absorption of the two acidic compounds, benzoic acid and PABA, was greater through nonviable skin. A small portion (6.9%) of absorbed benzoic acid was conjugated with glycine to form hippuric acid. Although N-acetyl-benzocaine had not been observed as a metabolite of benzocaine when studied by other routes of administration, both PABA and benzocaine were extensively N-acetylated during percutaneous absorption. Thus, the metabolism of these compounds should be considered in an accurate assessment of absorption after topical application.David Nathan: Results submitted as partial fulfillment of requirements for the M.S. in Pharmaceutical Science degree (Cosmetic Science)     

4-(2-溴乙酰基)-3-氟苯硼酸的制备

4-溴-2-氟苯基氰经格氏反应得到4-溴-2-氟苯乙酮,先保护羰基,再经格氏反应和二羟硼基取代、溴代制得4-(2-溴乙酰基)-3-氟苯硼酸,总收率54%.     

Hydroxycinnamic Acid Derivatives, Caffeoylmalic and New Caffeoylaldonic Acid Esters, from Chelidonium majus*,1

HPLC analysis of a hydrolyzed extract obtained from the aerial parts of CHELIDONIUM MAJUS yielded 0.4% caffeic, 0.06% P-coumaric, and 0.02% ferulic acids; gentisic and P-hydroxybenzoic acids were below 0.01%. The caffeic acid derivatives occur as esters of which four were isolated using gel permeation chromatography, centrifugal partition chromatography and HPLC; they were assigned on the basis of their spectroscopic data ( (1)H-, (13)C-NMR, UV, MS) as the new (-)-2-( E)-caffeoyl- D-glyceric acid, (-)-4-( E)-caffeoyl- L-threonic acid, (-)-2-( E)-caffeoyl- L-threonic acid lactone, and the known (+)-( E)-caffeoyl- L-malic acid.     

Species Differences in the Biotransformation of 4-(2-Methyl-3-(4-chlorobenzoyl)phenyl)butanoic Acid (RU16029)

1. 4-(2-Methyl-3-(4-chlorobenzoyl)phenyl)butanoic acid (RU 16029) is a potent anti-inflammatory and analgesic agent. In humans, its ketone group is rapidly reduced to an alcohol, whereas in rats, mice and dogs, its butanoic sidechain is rapidly oxidized to the corresponding acetic acid.

2. The extent of this oxidation was studied in eleven species. Cats, dogs, rabbits, hens and rodents readily oxidized the side-chain; humans, baboons and pigs showed only weak oxidizing capacity.

3. Species differences were also recorded in the secondary biotransformations. The acetic metabolite is excreted as an acylglucuronide in humans and rats, but as an amide-like conjugate in mice.

4. Comparison with biotransformations undergone by structurally related compounds confirms that the metabolism of a new compound in different species is unpredictable.     

Preparation and characterization of poly(D,L-lactic-co-glycolic Acid) microspheres containing flurbiprofen sodium

This study aimed to prepare biodegradable microspheres containing flurbiprofen sodium, a nonsteroidal anti-inflammatory drug (NSAID), as the drug delivery system to the periodontal pocket. Microspheres were prepared from biodegradable copolymers of poly (D,L-lactic-co-glycolic acid) (PLGA) using solvent evaporation method. The effects of the different copolymers and amounts of polyvinyl alcohol (PVA) as a dispersing agent on characteristics of the microspheres were evaluated. Although there was no correlation between microsphere size and amount of PVA, an optimum PVA concentration was essential to achieve narrower size distributions of microspheres. As the concentration of PVA increased, the drug loading of the microspheres increased. The effect of PVA on drug loading was found to be statistically significant for those microspheres prepared from PLGA 50:50 (p < 0.05). Regarding copolymer composition, PLGA 85:15 provided higher drug loading into the microspheres than PLGA 50:50 (p < 0.05). The recoveries of microspheres (60-80%) were affected neither by different PVA concentrations nor by copolymer compositions (p > 0.05). According to the first-order release rate constants of the microspheres, the microspheres of PLGA 50:50 released the drug at the highest rate consistently, with the highest hydrophilicity of this copolymer.     

Acid secretagogue action of structurally gamma-aminobutyric acid (GABA)-related compounds in rats

The properties of GABA related compounds on gastric function were studied in standardized perfused rat stomach preparations. Intravenous GABA (400 mg/kg) produced a rapid increase in acid secretion. Acid secretagogue actions of 3-aminobutyric acid and 2-aminobutyric acid were less potent than that of GABA. Intravenous injection of 5-amino-n-valeric acid (400 mg/kg) stimulated gastric acid secretion, but 6-amino-n-caproic acid was inactive. Isoguvacine (40 mg/kg, s.c.) stimulated acid output, whereas guvacine, an isomer of isoguvacine, did not. Systemically administered 3-hydroxy-GABA and beta-(p-chlorophenyl)-GABA (PCPGABA) showed significant secretagogue actions. Acid responses to GABA-related compounds were significantly reduced by surgical truncal vagotomy and completely antagonized by atropine. The acid responses to PCPGABA and isoguvacine were partially augmented by yohimbine and propranolol. These results suggest that the secretagogue action of GABA is mimicked by structurally GABA-related compounds, which is mediated through cholinergic receptors, with slight implication of alpha-2 and beta-adrenoceptor mechanisms.     

Comparison between the Absorption of Nicotinic Acid and Pentaerythritol Tetranicotinate (Perycit®) from Ordinary and Enterocoated Tablets

Nicotinic acid was shown to be rapidly absorbed from the gastrointestinal tract but also rapidly eliminated from the blood stream. Administration of nicotinic acid was therefore associated with large fluctuations of nicotinic acid concentration in the plasma. Two alternative ways of maintaining a moderate but more constant increase of the nicotinic acid concentration in the blood were studied. One way was to give nicotinic acid as a “sustained release” preparation. Nicotinic acid in enterocoated tablets with dissolution times of 2 hrs (in simulated intestinal juice), induced only an irregular and transitory increase of the plasma nicotinic acid concentration after 5 hrs and in some subjects only a reduction in plasma FFA. Enterocoated tablets with a dissolution time of 4 hrs were ineffective. Nicotinic acid is a weak acid and as such is poorly absorbed from the more distal parts of the digestive tract. Therefore the biological prerequisites for this alternative method were not so good. The second alternative method studied was to give a nicotinic acid ester which would continuously release nicotinic acid in the body. The nicotinic acid ester used (pentaerythritol tetranicotinate, perycit®, Bofors) given in an oral dose of 1 g, was found to give a moderate but consistent and prolonged increase in the free nicotinic acid concentration and a consistent decrease in the FFA-level of plasma with a moderate flush. Nicotinic acid in ordinary tablets and in an equivalent dose induced a considerably more pronounced flush and a somewhat larger reduction in plasma FFA which however was of shorter duration. The decrease was accompanied by a secondary and prolonged elevation of the plasma FFA concentration. This secondary increase was not observed in the experiments with pentaerythritol tetranicotinate. The possible importance of these differences from a pharmacotherapeutical point of view is discussed.     

Enzymatic Synthesis of (S-(−)-3-(3,4-Dihydroxyphenyl)lactic Acid

The first enzymatic synthesis of (S)-(?)-3-(3,4-dihydroxyphenyl)lactic acid, a DOPA metabolite and naturally occurring compound with a broad spectrum of pharmacological activities, is described. L-Hydroxyisocaproate dehydrogenase was used as enzyme.     

当归及其成分阿魏酸对小鼠免疫功能的影响

本文研究了当归及阿魏酸对小鼠免疫功能的影响,结果表明:当归(给药剂量分别为15g/kg和30g/kg)与阿魏酸(给药剂量分别为12.5mg/kg和25mg/kg)可明显地增加小鼠脾脏和胸腺重量,促进小鼠腹腔巨噬细胞吞噬功能、小鼠碳粒廓清速率、由SRBC致敏的小鼠血清溶血素的形成、小鼠抗体生成细胞的形成等.当归(剂量为3.25mg/ml)与阿魏酸(0.12mg/ml)可促进ConA诱导的小鼠脾淋巴细胞的增殖,其刺激指数分别为1.47和1.98.说明当归和阿魏酸对非特异性免疫、体液免疫和细胞免疫功能均有较强的促进作用.     

复方氨基酸注射液（20AA）包装材料改进及其稳定性的研究

目的：研究复方氨基酸注射液（20AA）在非PVC五层共挤膜软袋包装基础上,另加外阻隔袋内置抗氧剂并抽真空封口包装条件下的稳定性。方法：根据《药物稳定性研究指导原则》和复方氨基酸注射液（20AA）的质量标准,对样品进行光照试验、加速试验和长期试验。结果与结论：复方氨基酸注射液（20AA）在非PVC五层共挤膜软袋包装基础上,另加外阻隔袋内置抗氧剂并抽真空封口包装条件下,与非PVC五层共挤膜软袋包装比较,其性状、透光率、含量明显改善,但pH值有所下降。     

Evidence for Overlapping Substrate Specificity Between Large Neutral Amino Acid (LNAA) and Dipeptide (hPEPTl) Transporters for PD 158473, an NMDA Antagonist

Purpose. The objective of this research was to investigate the substrate specificity of large neutral amino acid carrier (LNAA) and di/tripeptide (hPEPTl) transporters with respect to PD 158473, an NMDA antagonist. Methods. Cellular uptake studies were carried out using two types of Chinese Hamster Ovary (CHO). CHO-K1 cells represent the wild type with inherent large neutral amino acid (LNAA) activity. CHO-PEPT1 cells were generated by stable transfection of hPEPTl gene into CHO cells. Therefore, these cells possess both LNAA activity and di/tripeptide transporter activities as a result of the transfection. Cellular uptake of PD 158473 was quantified using a HPLC method previously developed in our laboratory. Results. The utility of the CHO-PEPT1 cell model was demonstrated by determining the uptake kinetics of Gly-Sar, a prototypical dipeptide transporter substrate. Uptake kinetics of PD 158473 displayed two carrier-mediated transport components in CHO-PEPT1 cells, while in CHO-K1 cells the relationship was consistent with classic one component Michaelis-Menten kinetics. These results confirmed the affinity of PD 158473 for both LNAA and di/tripeptide transporters. Further, results from inhibition experiments using these two cell types indicate that the high affinity-low capacity system was the LNAA carrier and the low affinity-high capacity carrier was the di/tripeptide transporter. Conclusions. This study demonstrates overlapping substrate specificity between LNAA carrier and di/tripeptide transporter (hPEPTl) for PD 158473, an amino acid analog. Establishing Structure Transport Relationship (STR) for this overlap will aid in a design strategy for increasing oral absorption or targeting specific drugs to selected tissues.