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.     

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     

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。     

棒酸(Clavulanic Acid)

异名 Augmetin、MM-14151、BRL-14151 化学名 (Z)-(2R,5R)-3-(2-羟基乙叉)-7-氧代-4-氧杂-1-氮杂二环[3,2,0]庚烷-2-羧酸药效分类广谱抗生素开发单位 (英)Beecham 上市厂商 (英)Beecham 1981年10月首次报道 J Antibio 29:668,1976 药理棒酸系由 Streptomyces clavuligerus发酵液分离得到的天然产品。它是一个β-内酰胺酶抑制剂,可保护抗生素免受β-内酰胺酶的攻击。棒酸仅有微弱的抗菌活性,但有很强的抑制β-内酰胺酶的作用。棒酸对广范围的革兰氏阳性菌和革兰氏阴性菌产生的β-内酰胺酶均有抑制作用。它具有二相性作用:它与酶形成暂时稳定的复     

新型口服降脂药物——Bempedoic Acid

Bempedoic Acid是一种新型口服降血脂药物,于2020年在美国和欧洲获批上市,用于治疗已接受最大耐受剂量他汀类药物,而低密度脂蛋白胆固醇(LDL-C)仍没有达标的杂合子家族性高胆固醇血症(HeFH)或动脉粥样硬化性心血管疾病(ASCVD).Bempedoic Acid是一种三磷酸腺苷-柠檬酸裂解酶(ACL)抑...     

吡哌酸(Pipemidic Acid)的合成

呲哌酸为一合成抗菌剂,对革兰氏阴性杆菌、绿脓杆菌都有较强的抗菌作用,临床上常用于全身性感染及各种泌尿系统感染的疾病,本文列举了目前所采用的尿素路线所存在的严重问题,并详细介绍了甲基异硫脲路线的特点及其工艺过程。本路线的总收率可达44.27%。     

Nonlinear Binding of Valproic Acid (VPA) and E-Δ2-Valproic Acid to Rat Plasma Proteins

The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-²-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-²-VPA than with VPA (10⁴–10⁶ versus 10³ M ^–1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-²-VPA compared with VPA (<<10 versus >20% at total concentrations of less than 100 µg/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin.     

Preparation of Calcium Phosphate Nanocapsule Including Deoxyribonucleic Acid–Polyethyleneimine–Hyaluronic Acid Ternary Complex for Durable Gene Delivery

Our plasmid delivery systems comprising deoxyribonucleic acid (DNA), polyethyleneimine (PEI), and hyaluronic acid (HA) have already achieved the high‐extragene expression in tumor tissues. Repeated transfection with certain cytokine genes effectively induced tumor regression and complete disappearance of the tumor in some cases. Frequent injection is sometimes difficult depending on the tumor site. However, single injection often leads to an unsatisfactory efficacy owing to the short duration of the gene expression. In this study, we prepared calcium phosphate (CaP) nanocapsule including plasmid DNA complexes as a durable gene transfection system, which would be slowly degraded, and release DNA complex in the body. CaP nanocupsule including DNA complexes with a diameter of approximately 200 nm was prepared by immersing HA‐coated DNA–PEI complex in simulated body fluid. It showed gene expression in cultured cells with duration longer than 2 weeks. By this slow‐releasing system, significant tumor‐growth suppression and, finally, complete tumor disappearance were observed after single injection into the tumor. Capsulated DNA complex with Ca thus seems promising as a sustained gene expression device. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:179–184, 2014     

抗粉刺药 壬二酸(Azelaic Acid)

异名 Skinoren 化学名壬二酸 HOOC-(CH_2)_7-COOH 药效分类皮肤科用药(抗粉刺) 开发单位 (德)Schering AG 上市厂商 (德)Schering AG 1989年在法国上市药理本品系天然存在的饱和直链二羧酸,对皮肤粉刺内各种需氧菌和厌氧菌有抑菌和杀菌活性。局部使用20％壬二酸霜可使皮肤微球菌和滤泡内丙酸菌的密度明显减少,并使皮肤表面脂肪的游离脂肪酸含量减少。本品对皮脂的产生和组成以及皮脂腺的形态学无明显影响。在体外,本品20～50mmol/L时对正常人、新生小鼠的角质细胞、小鼠黑素瘤细胞和人皮肤和脉络膜的黑素瘤细胞有时间和浓度相关性的抗增殖作用,在大于40 mmol/L时     

Synthesis and Bioactivity of Xanthene-9-carboxylic Acid Derivatives

合成了二十个９羧基氧杂蒽类衍生物并通过ＣＩＭＳ和ＥＩＭＳ确定了所有化合物的结构。初步的药理实验表明部分化合物具有明显的抗痉挛作用     

ε-Aminocaproic Acid Esters as Transdermal Penetration Enhancing Agents

The synthesis of -aminocaproic acid esters is described. Two representative members from a group of five of the 1-alkyl homologues synthetized as flexible analogues of 1-alkylazacycloheptanone derivatives were evaluated in vitro for their effectiveness on the transport of theophylline through the excised human cadaver skin in comparison with Azone. The 1-octyl- and 1-dodecyl--aminocaproic acid esters (OCEAC and DDEAC) show excellent penetration enhancement. Donor samples contained 2.5% theophylline and 1% enhancers tested in three different vehicles. Fluxes of theophylline were increased with OCEAC about 19 times from olive oil, 45 times from water, and about 38 times from water–propylene glycol (3:2) vehicle toward controls (with DDEAC about 17, 39, and 35 times, respectively) and they were markedly higher than Azone under the given conditions. Acute LD₅₀'s (i.p. in mice) of OCEAC (DDEAC) were 245 mg/kg (352 mg/kg), with a slightly lower toxicity than Azone. OCEAC and DDEAC did not exhibit acute dermal irritation in vivo on rabbits at a 5% concentration in white petrolatum.     

丹参的一个新缩酚酸Salvianolic Acid A

丹参(Salvia miltiorrhiza Bunge)广泛用治冠心病,其醚提取物的几种二酮化合物(丹参酮类)具有抗菌活性。近从水提取物中分得原儿茶醛、D-(+)-β-(3,4-二羟基苯基)-乳酸和两个缩合物。作者又从根中分得一个新的D-(+)-β-(3,4-二羟苯基)-乳酸和2-(3,4-二羟基苯乙烯基)-咖啡酸的缩合物,称为salvianolicacid A(SAA),初步药理试验表明具有抗凝活性。     

Bongkrekic Acid—a Review of a Lesser-Known Mitochondrial Toxin

Introduction

Bongkrekic acid (BA) has a unique mechanism of toxicity among the mitochondrial toxins: it inhibits adenine nucleotide translocase (ANT) rather than the electron transport chain. Bongkrekic acid is produced by the bacterium Burkholderia gladioli pathovar cocovenenans (B. cocovenenans) which has been implicated in outbreaks of food-borne illness involving coconut- and corn-based products in Indonesia and China. Our objective was to summarize what is known about the epidemiology, exposure sources, toxicokinetics, pathophysiology, clinical presentation, and diagnosis and treatment of human BA poisoning.

Methods

We searched MEDLINE (1946 to present), EMBASE (1947 to present), SCOPUS, The Indonesia Publication Index (http://id.portalgaruda.org/), ToxNet, book chapters, Google searches, Pro-MED alerts, and references from previously published journal articles. We identified a total of 109 references which were reviewed. Of those, 29 (26 %) had relevant information and were included. Bongkrekic acid is a heat-stable, highly unsaturated tricarboxylic fatty acid with a molecular weight of 486 kDa. Outbreaks have been reported from Indonesia, China, and more recently in Mozambique. Very little is known about the toxicokinetics of BA. Bongkrekic acid produces its toxic effects by inhibiting mitochondrial (ANT). ANT can also alter cellular apoptosis. Signs and symptoms in humans are similar to the clinical findings from other mitochondrial poisons, but they vary in severity and time course. Management of patients is symptomatic and supportive.

Conclusions

Bongkrekic acid is a mitochondrial ANT toxin and is reported primarily in outbreaks of food-borne poisoning involving coconut and corn. It should be considered in outbreaks of food-borne illness when signs and symptoms manifest involving the liver, brain, and kidneys and when coconut- or corn-based foods are implicated.

     

Novel β-Amino Acid Derivatives as Inhibitors of Cathepsin A

Cathepsin A (CatA) is a serine carboxypeptidase distributed between lysosomes, cell membrane, and extracellular space. Several peptide hormones including bradykinin and angiotensin I have been described as substrates. Therefore, the inhibition of CatA has the potential for beneficial effects in cardiovascular diseases. Pharmacological inhibition of CatA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt-induced hypertension. However, so far no small molecule inhibitors of CatA with oral bioavailability have been described to allow further pharmacological profiling. In our work we identified novel β-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led to the identification of a hitherto unknown pathophysiological role of CatA in cardiac hypertrophy. One of our inhibitors is currently undergoing phase I clinical trials.     

Discovery of a Novel Noniminosugar Acid α Glucosidase Chaperone Series

Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models.     

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.     

A Novel 4′-O-Diglycoside of Decarboxyrosmarinic Acid from Blepharis ciliaris

Abstract

A novel natural phenolic 1 was isolated from the hydroalcoholic extract of the aerial parts of Blepharis ciliaris (L.) B.L. Burtt (Acanthaceae), in addition to apigenin 7-O-glucoside 2 and apigenin-7-O-(3″-acetyl-6″-E-p-coumaroyl glucoside) 3. The structure of 1 was established as 3′,4′-dihydroxy-β-phenyl ethyl caffeate-4′-β-O-D-galactopyranosyl-(1′″→4″)-α-O-L-rhamnopyranoside [= 9′-decarboxy rosmarinic acid-4′-O-(1→4)-galactosyl rhanmoside]. Structures were determined by conventional methods of analysis, as well as by different MS and NMR techniques.     

肌肉骨骼系统用药——CHMP建议批准Ibandronic Acid Teva

美国Vertex Pharmaceuticals公司报告了其丙型肝炎治疗药telaprevir（Ⅰ）的Ⅲ期试验阳性结果。     

野甘草中Scopadulcic Acid的细胞毒活性和抗肿瘤活性

野甘草Scoparia dulcis L。在巴拉圭被用于促进消化和健胃,从中分离到一种新型结构的二萜化合物scopadulcic acid B(SDB)。曾报道SDB有抑制疱疹活性,其化学结构与aphidicolin相关,后者是一种四环二萜类化合物,为真核DNA聚合酶α的专属抑制剂,在低浓度(1μmol/L)可通过抑制细胞中DNA合成而抑制细胞生长,并且有抑制单纯性疱疹病毒活性。本文旨在研究SDB对体外