Synthesis and Study of the Analgesic and Antiinflammatory Activity of α-Acetoxyphenylacetic Acid Amides

Pharmaceutical Chemistry Journal -     

Two New Oleanolic Acid Saponins from the Root Bark of Aralia taibaiensis

从新种太白木（ＡｒａｌｉａｔａｉｂａｉｅｎｓｉｓＺＺＷａｎｇｅｔＨＣＺｈｅｎｇ）根皮中分离得到两个新的齐墩果酸皂甙和一个已知化合物，齐墩果酸２８ＯβＤ吡喃葡萄糖甙（１）。经理化性质和光谱数据分析，鉴定两个新化合物结构为：３ＯβＤ吡喃葡萄糖醛酸丁酯齐墩果酸２８ＯβＤ吡喃葡萄糖甙（２）和３ＯβＤ吡喃葡萄糖醛酸癸酯齐墩果酸２８ＯβＤ吡喃葡萄糖甙（３），分别命名为太白木皂甙Ⅳ和太白木皂甙Ⅴ。     

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.     

Effect of Microenvironmental pH Modulation on the Dissolution Rate and Oral Absorption of the Salt of a Weak Acid – Case Study of GDC-0810

Purpose

The purpose of this work is to investigate the effect of microenvironmental pH modulation on the in vitro dissolution rate and oral absorption of GDC-0810, an oral anti-cancer drug, in human.

Methods

The pH-solubility profile of GDC-0810 free acid and pH_max of its N-Methyl-D-glucamine (NMG) salt were determined. Precipitation studies were conducted for GDC-0810 NMG salt at different pH values. GDC-0810 200-mg dose NMG salt tablet formulations containing different levels of sodium bicarbonate as the pH modifier were tested for dissolution under the dual pH-dilution scheme. Three tablet formulations were evaluated in human as a part of a relative bioavailability study. A 200-mg dose of GDC-0810 was administered QD with low fat food.

Results

Intrinsic solubility of GDC-0810 free acid was found to be extremely low. The pH_max of the NMG salt suggested a strong tendency for form conversion to the free acid under GI conditions. In vitro dissolution profiles showed that the dissolution rate and extent of GDC-0810 increased with increasing the level of sodium bicarbonate in the formulation. The human PK data showed a similar trend for the geometric mean of C_max and AUC_0-t for formulations containing 5%, 10%, and 15% sodium bicarbonate, but the difference is not statistically significant.

Conclusion

Incorporation of a basic pH modifier, sodium bicarbonate, in GDC-0810 NMG salt tablet formulations enhanced in vitro dissolution rate of GDC-0810 via microenvironmental pH modulation. The human PK data showed no statistically significant difference in drug exposure from tablets containing 5%, 10%, and 15% sodium bicarbonate.

     

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.     

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

The transport of monocarboxylates, such as lactate and pyruvate, is mediated by the SLC16A family of proton-linked membrane transport proteins known as monocarboxylate transporters (MCTs). Fourteen MCT-related genes have been identified in mammals and of these seven MCTs have been functionally characterized. Despite their sequence homology, only MCT1-4 have been demonstrated to be proton-dependent transporters of monocarboxylic acids. MCT6, MCT8 and MCT10 have been demonstrated to transport diuretics, thyroid hormones and aromatic amino acids, respectively. MCT1-4 vary in their regulation, tissue distribution and substrate/inhibitor specificity with MCT1 being the most extensively characterized isoform. Emerging evidence suggests that in addition to endogenous substrates, MCTs are involved in the transport of pharmaceutical agents, including gamma-hydroxybuytrate (GHB), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), salicylic acid, and bumetanide. MCTs are expressed in a wide range of tissues including the liver, intestine, kidney and brain, and as such they have the potential to impact a number of processes contributing to the disposition of xenobiotic substrates. GHB has been extensively studied as a pharmaceutical substrate of MCTs; the renal clearance of GHB is dose-dependent with saturation of MCT-mediated reabsorption at high doses. Concomitant administration of GHB and L: -lactate to rats results in an approximately two-fold increase in GHB renal clearance suggesting that inhibition of MCT1-mediated reabsorption of GHB may be an effective strategy for increasing renal and total GHB elimination in overdose situations. Further studies are required to more clearly define the role of MCTs on drug disposition and the potential for MCT-mediated detoxification strategies in GHB overdose.     

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.     

Fatty Acid Binding Proteins: Potential Chaperones of Cytosolic Drug Transport in the Enterocyte?

Purpose  

Several poorly water-soluble drugs have previously been shown to bind to intestinal (I-FABP) and liver fatty acid binding protein (L-FABP) in vitro. The purpose of this study was to examine the potential role of drug binding to FABPs on intestinal permeability and gut wall metabolism in vivo.     

β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

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Stereospecific Inversion of l-α-Methylfluorene-2-acetic Acid to its d-Enantiomer in the Dog

1. After administration of dl-α-methylfluorene-2-acetic acid to dogs, the optical rotation of the drug in blood increased with time. Of the total drug in blood, the d-enantiomer increased from 61 to 80% between 3 and 24 h after administration; by 384 h it was 100%.

2. Both l- and d-enantiomers had plasma half-lives and excretion characteristics similar to those of the dl-racemic mixture, indicating that the increase in the proportion of the d-enantiomer was not due to more rapid excretion of the l-enantiomer.

3. Studies of optical rotation and circular dichroism demonstrated that the l-enantiomer was converted to the d-enantiomer in the blood of the dog, but the d-enantiomer remained unchanged. After administration of the l-enantiomer, the d-enantiomer increased from 26 to 71% of the total drug in blood between 0.3 and 2 days after administration; 14 days after dosing, almost all of the drug was present as the d-enantiomer.

4. Isomerization of l-α-methylfluorene-2-acetic acid to its d-enantiomer also occurs in rat. monkev and man.     

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.     

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.     

Neuronal Sparing and Behavioral Effects of the Antiapoptotic Drug, (−)Deprenyl,Following Kainic Acid Administration

(−)Deprenyl is an irreversible inhibitor of monoamine oxidase B (MAO-B) frequently used as an adjunct therapy in the treatment of Parkinson’s Disease. Recent evidence, however, has found that deprenyl’s metabolites are associated with an antiapoptotic action within certain neuronal populations. Interestingly, deprenyl’s antiapoptotic actions appear not to depend upon the inhibition of MAO-B. Due to a paucity of information surrounding (−)deprenyl’s ability to spare neurons in vivo, a series of studies was conducted to further investigate this phenomenon within an apoptotic neuronal death model: kainic acid induced excitotoxicity. Results indicated that (−)deprenyl increased hippocampal neuronal survival compared to saline-matched controls following kainic acid insult. Furthermore, it was discovered that (−)deprenyl treatment could be stopped 14 days following CNS insult by kainate, with evidence of neuronal sparing still present by day 28. In open-field locomotor activity testing of kainate-treated animals, those given subsequent (−)deprenyl treatment showed habituation curves similar to control subjects, while saline-treated animals did not. Given deprenyl’s antiapoptotic actions, it is proposed that (−)deprenyl may be beneficial in the treatment of a variety of neurodegenerative diseases where evidence of apoptosis exists, such as Parkinson’s and Alzheimer’s Disease, by slowing the disease process itself.     

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     

Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition

We have analyzed the response of primary cultures derived from tumor specimens of non small cell lung cancer (NSCLC) patients to choline kinase α (ChoKα) inhibitors. ChoKα inhibitors have been demonstrated to increase ceramides levels specifically in tumor cells, and this increase has been suggested as the mechanism that explain its proapoptotic effect in cancer cells. Here, we have investigated the molecular mechanism associated to the intrinsic resistance, and found that other enzyme involved in lipid metabolism, acid ceramidase (ASAH1), is specifically upregulated in resistant tumors. NSCLC cells with acquired resistance to ChoKα inhibitors also display increased levels of ASAH1. Accordingly, ASAH1 inhibition synergistically sensitizes lung cancer cells to the antiproliferative effect of ChoKα inhibitors. Thus, the determination of the levels of ASAH1 predicts sensitivity to targeted therapy based on ChoKα specific inhibition and represents a model for combinatorial treatments of ChoKα inhibitors and ASAH1 inhibitors. Considering that ChoKα inhibitors have been recently approved to enter Phase I clinical trials by the Food and Drug Administration (FDA), these findings are anticipating critical information to improve the clinical outcome of this family of novel anticancer drugs under development.     

α-Lipoic Acid and Superoxide Dismutase in the Management of Chronic Neck Pain: A Prospective Randomized Study

Background and Objective

Since oxidative stress plays a pathogenetic role in chronic neck pain (CNP), we investigated whether a combination of α-lipoic acid (ALA) and superoxide dismutase (SOD) might improve pain control and the efficacy of physiotherapy (“multimodal therapy”) in patients with CNP.

Setting

This study was conducted in the Rehabilitation Unit of the Department of Surgical and Oncological Sciences at the University Policlinic in Palermo, Italy.

Design and Patients

This was a prospective, randomized, open study in outpatients.

Intervention

Patients randomly received either physiotherapy alone (group 2; n = 45) or a combination of ALA 600 mg and SOD 140 IU daily in addition to physiotherapy (group 1; n = 51), for 60 days. Pain was assessed by a visual analogue scale (VAS) and a modified Neck Pain Questionnaire (mNPQ). Treatment compliance and safety were also evaluated.

Results

Both groups experienced a significant reduction in the VAS and mNPQ scores after 1 month; however, while no further improvement was observed in group 2 at 60 days, group 1 showed a further VAS reduction (p < 0.001). In addition, in the mNPQ at 60 days, more patients in group 1 than in group 2 reported that their neck pain was improved (p < 0.01), and they showed greater compliance with prescribed physiotherapy (p = 0.048). No drug reaction was observed.

Conclusion

Use of ALA/SOD in combination with physiotherapy may be a useful approach to CNP, being antioxidants that act on nerve inflammation and disease progression.

Clinical Rehabilitation Impact

These preliminary observations suggest that some interesting goals (better pain control and physical wellbeing) can be achieved by multimodal therapy in CNP patients.     

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.

     

Utility of Mannitol and Citric Acid for Enhancing the Solubilizing and Taste Masking Properties of β-Cyclodextrin: Development of Fast-Dissolving Tablets Containing Extremely Bitter Drug

Introduction

Development of Fast dissolved tablets (FDTs) in which taste is masked, and drug dissolution is improved, is a major challenge especially in case of extremely bitter drug with poor water solubility such as aceclofenac.

Purpose

The purpose of this study was to enhance the taste masking and solubilizing properties of β-cyclodextrin using citric acid and mannitol through preparation of acid soluble taste masked granules of aceclofenac (ASTMGA).

Methods

General factorial design was applied to optimize FDTs containing ASTMGA so to have short disintegration time (<30 sec.), acceptable taste and enhanced drug dissolution in gastric fluid. Three formulation variables; the type of sugar / cellulose based diluents, X₁ (Galen IQ® and Prosolv®), superdisintegrant type, X₂ (Crospovidone®, Glycolys® and Ac-Di-Sol®) and superdisintegrant concentration, X₃ (10 % and 20 %) were included in the design. The systems were assessed for hardness, friability, in vitro disintegration, wetting time, in vitro dissolution and in vivo oral study.

Results

The combination of Prosolv® and Crospovidone® in the formulation of FDT gave optimum disintegration time. The stability of the optimized FDT in different package materials was retained after storage at 40 ?C/75 % RH for six months. Contrary to FDT containing conventional aceclofenac β-cyclodextrin inclusion complex, FDT containing ASTMGA showed highest dissolution rate in both simulated salivary and gastric fluids and excellent ability to mask the bitterness of drug.

Conclusions

Our results propose that the combination of citric acid, mannitol and β-cyclodextrin could be promising to improve taste masking and solubilizing properties of β-cyclodextrin.     

Evaluation of the in Vivo Disintegration of Solid Dosage Forms of a Bile Acid Sequestrant in Dogs Using γ-Scintigraphy and Correlation to in Vitro Disintegration

Purpose. To evaluate the in vivo disintegration behavior of tablets and capsules of a bile acid sequestrant, DMP 504, in beagle dogs and to assess the significance of the in vitro disintegration of the dosage forms on subsequent in vivo behavior in order to draw possible in vitro-in vivo correlations. Methods. Tablet and capsule formulations of a bile acid sequestrant, DMP 504, were formulated with samarium oxide and neutron activated to produce radioactive ¹⁵³Sm to noninvasively evaluate their in vivo behavior in beagle dogs by -scintigraphy. A four-way crossover design was completed (n = 4) in which (a) tablets from two different batches were administered under the fasted condition and manufactured using different lots of drug substance where one batch exhibited relatively faster in vitro disintegration time (30 min) than the other tablet batch, which resulted in slower disintegration (45 min), (b) a capsule formulation was administered to fasted beagles, and (c) the tablet having slower in vitro disintegration was also administered in the fed state, and its in vivo disintegration was compared to that observed in the fasted state. Results. Tablets manufactured using a lot of DMP 504 having relatively fast in vitro disintegration (30 min) resulted in relatively rapid in vivo disintegration time (15 min) in the fasted condition. This in vivo disintegration time was comparable to the in vivo disintegration of the capsules (17 min) even though the in vitro capsule disintegration time was considerably faster (2 min). Tablets prepared using a drug substance that provided a longer in vitro disintegration time (45 min) resulted in a slower in vivo disintegration (63 min). There was no difference observed in the in vivo disintegration behavior in fasted and fed dogs for the tablets that provided slower in vitro disintegration. Conclusion. In vivo disintegration of tablets of the bile acid sequestrant DMP 504 correlated with in vitro disintegration times. -Scintigraphy continues to be a good tool to use during early stages of product development to investigate in vivo performance of dosage forms. The results of this study provided evidence that the physical chemical specifications of the drug substance may not always be indicative of in vitro or in vivo performance of tablet dosage form, even when formulation and process are not changed.     

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.