Arsenic trioxide： safety issues and their management

Arsenic trioxide (As2O3) has been used medicinally for thousands of years. Its therapeutic use in leukaemia was described a century ago. Recent rekindling in the interest of As2O3 is due to its high efficacy in acute promyelocytic leukaemia (APL). As2O3 has also been tested clinically in other blood and solid cancers. Most studies have used intravenous As2O3, although an oral As2O3 is equally efficacious. Side effects of As2O3 are usually minor, including skin reactions, gastrointestinal upset, and hepatitis. These respond to symptomatic treatment or temporary drug cessation, and do not compromise subsequent treatment with As2O3. During induction therapy in APL, a leucocytosis may occasionally occur, which can be associated with fluid accumulation and pulmonary infiltration. The condition is similar to the APL differentiation syndrome during treatment with all-trans retinoic acid, and responds to cytoreductive treatment and corticosteroids. Intravenous As2O3 treatment leads to QT prolongation. In the presence of underlying cardiopulmonary diseases or electrolyte disturbances, particularly hypokalaemia and hypomagnesaemia, serious arrhythmias may develop, with torsades du pointes reported in 1% of cases. This may be related to a dose-dependent arsenic-mediated inhibition of potassium ion channels that compromises cardiac repolarization. Because of slow intestinal absorption, oral-As2O3 gives a lower plasma arsenic concentration, which is associated with lesser QT prolongation and hence a more favorable cardiac safety profile. As2O3 does not appear to enter the central nervous system. However, if the blood brain barrier is breached, elemental arsenic may enter the cerebrospinal fluid. As2O3 is predominantly excreted in the kidneys, and dose adjustment is required when renal function is impaired.     

Isatin–azole hybrids and their anticancer activities

Isatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug development. Isatin and azole derivatives possess promising in vitro and in vivo anticancer activity, and many of them, such as semaxanib, sunitinib, and carboxyamidotriazole, could be used to treat various cancers. Thus, it is conceivable that hybridization of the isatin moiety with azole may provide a valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop isatin–azole hybrids as novel anticancer agents, and some of the isatin–azole hybrids exhibited considerable activity. This review emphasizes isatin–azole hybrids with potential anticancer activity, covering articles published between 2010 and 2019. The structure–activity relationships as well as the mechanisms of action are also discussed to provide insights for the rational design of more effective candidates.     

Design and Synthesis of Aza-β-Carboline Analogs and their Antibacterial Evaluation

Pharmaceutical Chemistry Journal - Bacterial drug resistance has become a growing problem worldwide due to the excessive use of antibiotics in recent decades. Two small focused libraries of...     

Excipient–Process Interactions and their Impact on Tablet Compaction and Film Coating

The objective of this study was to establish the effects of the level of minor formulation components (sodium lauryl sulfate: SLS, and magnesium stearate: MgSt) and manufacturing process on final blend compaction properties and the performance of the tablets during film coating. A 2 × 2 × 3 factorial study was conducted at two levels of SLS (0% and 1%, w/w) and MgSt (0.5% and 1.75%, w/w), along with three different manufacturing processes (direct compression, high‐shear wet granulation, and dry granulation). The tablets were compressed to the same solid fraction (0.9) and the resulting tablet hardness values were found to vary over a range of 13–42 SCU, highlighting large compactability differences among these batches. Increase in the level of SLS or MgSt in the formulation had a significant negative effect on compactability and the performance of film‐coated tablets. The detrimental effects on compaction and coating performance were magnified for the dry granulation process, likely due to the overall increased shear experienced by excipients (SLS, MgSt, microcrystalline cellulose) during the roller compaction and milling steps. The findings of this study highlight the importance of the manufacturing process when considering the use‐level of formulation components such as SLS and MgSt in the formulation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3666–3674, 2014     

Ultrasound-assisted synthesis of novel α-aminophosphonates and their biological activity

The synthesis of a series of novel α-aminosubstituted phosphonates was accomplished by the reaction of various substituted aldehydes with an amine amlodipine (3-ethyl 5-methyl (±)2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridene-3,5-dicarboxylate) followed by diethylphosphite/dibutylphosphite in ethanol using SnCl(2).2H(2)O as a Lewis acid catalyst, under conventional and ultrasonic irradiation. Their structures were established by analytical and spectral data. The title compounds showed good antibacterial, antifungal and antiviral activity depending on the nature of the bioactive groups at the α-carbon.     

Novel potent and selective σ ligands: evaluation of their agonist and antagonist properties

Novel enantiomers and diastereoisomers structurally related to σ ligand (+)-MR200 were synthesized to improve σ(1)/σ(2) subtype selectivity. The selective σ(1) ligand (-)-8 showed an antagonist profile determined by phenytoin differential modulation of binding affinity in vitro, confirmed in vivo by an increase of κ opioid analgesia. The σ(2) ligand (-)-9 displayed agonist properties in an in vitro isolated organ bath assay and antiproliferative effects on LNCaP and PC3 prostate cancer cell lines.     

A facile synthesis of emodin derivatives,emodin carbaldehyde,citreorosein, and their 10-deoxygenated derivatives and their inhibitory activities on μ-calpain

A new procedure for the preparation of emodin carbaldehyde and citreorosein was described, in which, ω,ω′-dibromomethylemodin triacetate was prepared as a key intermediate by NBSmediated bromination of 1,3,8-triacetylemodin. Reduction of emodin and citreorosein with SnCl₂ in a 1:1 mixture of HOAc and HCl afforded the corresponding anthrones in 90% and 92% yield, respectively, while the corresponding 10-desoxyemodin carbaldehyde was prepared by MnO₂ oxidation of 10-desoxycitreorosein. 10-Desoxycitreorosein and emodin carbaldehyde showed feasible μ-calpain inhibitory activities with IC₅₀ values of 20.15 and 25.77 M, respectively.     

PTP1B and α-glucosidase inhibitors from Selaginella rolandi-principis and their glucose uptake stimulation

Journal of Natural Medicines - As part of an ongoing search for new protein tyrosine phosphatase 1B inhibitors and glucose uptake stimulators from nature, a new coumarin, selaginolide A (1) and...     

Phytochemicals from Dodonaea viscosa and their antioxidant and anticholinesterase activities with structure–activity relationships

Context Dodonaea viscosa (L.) Jacq (Sapindaceae) has been used in traditional medicine as antimalarial, antidiabetic and antibacterial agent, but further investigations are needed.

Objective This study determines the antioxidant and anticholinesterase activities of six compounds (1–6) and two crystals (1A and 3A) isolated from D. viscosa, and discusses their structure–activity relationships.

Materials and methods Antioxidant activity was evaluated using six complementary tests, i.e., β-carotene-linoleic acid; DPPH^?, ABTS^?+, superoxide scavenging, CUPRAC and metal chelating assays. Anticholinesterase activity was performed using the Elman method.

Results Clerodane diterpenoids (1 and 2) and phenolics (3–6) – together with three crystals (1A, 3A and 7A) – were isolated from the aerial parts of D. viscosa. Compound 3A exhibited good antioxidant activity in DPPH (IC₅₀: 27.44?±?1.06?μM), superoxide (28.18?±?1.35% inhibition at 100?μM) and CUPRAC (A_0.5: 35.89?±?0.09?μM) assays. Compound 5 (IC₅₀: 11.02?±?0.02?μM) indicated best activity in ABTS assay, and 6 (IC₅₀: 14.30?±?0.18?μM) in β-carotene-linoleic acid assay. Compounds 1 and 3 were also obtained in the crystal (1A and 3A) form. Both crystals showed antioxidant activity. Furthermore, crystal 3A was more active than 3 in all activity tests. Phenol 6 possessed moderate anticholinesterase activity against acetylcholinesterase and butyrylcholinesterase enzymes (IC₅₀ values: 158.14?±?1.65 and 111.60?±?1.28?μM, respectively).

Discussion and conclusion This is the first report on antioxidant and anticholinesterase activities of compounds 1, 2, 5, 6, 1A and 3A, and characterisation of 7A using XRD. Furthermore, the structure–activity relationships are also discussed in detail for the first time.     

Preparation of aromatic β-Selenolactams and their bioactivities as agricultural chemicals

The purpose of this study was to investigate the possibility of aromatic beta-selenolactams being used in agricultural chemicals. A series of beta-selenolactams with aromatic substituents at the 1-, 2- and 3-positions were synthesized and their bioactivities were evaluated. Acarianicidal and insecticidal activity against common destructive insects, antibacterial activity against seven common plant pathogens, and plant growth activity of typical food crops were investigated. We found that introduction of 4-chloro and 4-methyl groups on 2- or 3-phenyl groups of the beta-selenolactam ring brought about acarianicidal activity against adults and eggs of Plutella xylostella. However, except for moderate to weak effect on fatality of Culex pipiens molestus Forskal, insecticidal activity against two other kinds of insects, antibacterial activity against plant pathogens, and activity on plant growth regulation were not detected among the beta-selenolactam derivatives.     

Antidiabetic potential and enzyme kinetics of benzothiazole derivatives and their non-bonded interactions with α-glucosidase and α-amylase

Benzothiazole derivatives were synthesized and their antidiabetic potential evaluated using α-glucosidase, α-amylase, non-enzymatic glycosylation of hemoglobin and advanced glycation end product inhibition assays. Compound 3l showed low IC₅₀ values of 0.31, 0.98, 0.59 and 0.19 mM in α-amylase, α-glucosidase, non-enzymatic glycosylation of hemoglobin and AGE inhibition assays, respectively, and outperformed the standard acarbose. Enzyme kinetic studies revealed that it has a K _i of 0.39 and 1.5 mM for α-amylase and α-glucosidase, respectively. The non-bonded interactions of 3l with α-amylase (3OLD) and α-glucosidase (2ZE0) showed that it binds in the active site pocket and is surrounded by residues Asp197, Glu233, Asp300 in 3OLD and Asp199, Glu256, Asp326 in 2ZE0.     

Compounds from Platycladus orientalis and their inhibitory effects on nitric oxide and TNF-α production

Four new compounds: an abietane (1), two isopimarane (2 and 3) diterpenes, and a dihydrobenzofuran neolignan (5), together with a sesquiterpene glycoside (6) firstly isolated from a natural source, and a known phenol glycoside (4) were isolated from leaves of Platycladus orientalis. The structures and relative configurations of these compounds were assigned on the basis of MS, IR, 1D and 2D NMR data. The absolute configuration of compound 1 was determined via density functional theory calculations of its electronic circular dichroism. In addition, the results of bioassays indicated that compounds 4 and 6 showed a potent inhibitory effect on NO production with IC?? values of 24.4 and 11.9 μM, respectively. Meanwhile, compounds 1, 2, and 3 moderately inhibited TNF- α release.     

Hydroxypropyl-β-cyclodextrin copolymers and their nanoparticles as doxorubicin delivery system

A novel biodegradable amphiphilic copolymer composed of hydroxypropyl-β-cyclodextrin, polylactide, and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, was successfully synthesized. The chemical structures of copolymers were determined by FT-IR, (1)H nuclear magnetic resonance (NMR) spectroscopy, (13)C NMR, (31)P NMR, thermogravimetric analysis ,and differential scanning calorimetry. Doxorubicin (DOX)-loaded copolymer nanoparticles (NPs) were prepared by double emulsion and nanoprecipitation methods. The factors of copolymer composition and fabrication methods, which influence size and encapsulation efficiency (EE) were investigated. Their EE to DOX could reach 90.6% at an available condition. In vitro release behavior of NPs showed a continuous release after a burst release. The antitumor activity of the DOX-loaded NPs against cancer HepG2 and A549 cells was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. The DOX-loaded copolymer NPs showed comparable anticancer efficacy with the free drug.     

Pharmacists and their customers: a personal or anonymous service?

Aims — To explore the existence and nature of the pharmacist‐customer relationship. Methods — A qualitative approach was adopted. Semi‐structured interviews were conducted with 20 customers recruited from two pharmacies differing in type and location: Pharmacy A, a multiple chain pharmacy in a more affluent area, and pharmacy B, a small chain pharmacy. Key findings — Customers' views differed according to the pharmacy from which they were recruited. Pharmacy B customers had a personal relationship with the pharmacist and used the pharmacy as a health care resource, while pharmacy A customers did not have a personal relationship with the pharmacist and used the pharmacy simply for medicine supply. Several pharmacy A customers had their own different local pharmacist whom they used for more personal advice and counselling. Both groups described disadvantages of multiple chain pharmacies. Consumerist behaviour was identified among customers whereby they preferred to control the provision of advice, assess it and act upon it. However, lack of information was mentioned by several interviewees, which suggested that different types of customers have different needs from the pharmacy. The pharmacist has therefore to recognise these different needs and to meet them accordingly to provide services, whether anonymous or personal, within their “extended role.” While most customers viewed pharmacists as drug experts and considered managing minor ailments to be part of their job, they were less supportive of a more extended role in the therapeutic monitoring of drug therapy. This presents a serious barrier to pharmacists wishing to extend their role into a more patient‐oriented and clinical domain. Conclusion — This study reinforces the importance of considering customers' views when policies and strategies concerning the development of the “extended role” are considered. Recognising customers' views helps the profession to adapt and respond to changing consumer behaviour. Issues identified through this in‐depth exploration of public perceptions of pharmacists have implications for the extension of pharmacists' roles into areas favoured and appreciated by customers.     

9β-hydroxyparthenolide esters from Inula montbretiana and their antiprotozoal activity

In continuation of ongoing studies on the potential of natural products as antiprotozoal leads or drugs, it was found that the CH?Cl? extract obtained from the flowering aerial parts of Inula montbretiana DC. (Asteraceae, tribe Inuleae) displays antiprotozoal activity, especially against Trypanosoma brucei rhodesiense (IC??: 3.38?μg/mL). Isolation of the possible active constituents led to the identification of six sesquiterpene lactones, all esters of 9 β-hydroxyparthenolide. Two isolates, namely, 9 β-(3',4'-epoxy-3'-methylpentanoyloxy)-parthenolide and 9 β-(3'-oxo-2'-methylbutanoyloxy)-parthenolide, represented diastereomeric mixtures differing only in the configuration within the acyl moieties. According to in vitro test results, the mixture of esters with diastereomeric 3,4-epoxy-3-methylpentanoic acid was the most active constituent against Trypanosoma brucei rhodesiense (IC??: 0.26?μg/mL) and was less cytotoxic against rat skeletal myoblasts (L6 cell line) with a selectivity index of about 9. The mixture of diastereomeric 2-methyl-3-oxobutyric acid esters was the most potent against Plasmodium falciparum (IC??: 1.48?μg/mL) and displayed a selectivity index of about 35.     

Different response types of neurotrophins and their receptors to immune stress

Immune stress has been proved involved in the process of neurodegenation such as Alzherimer's disease or multiple sclerosis.The neurotrophins play an important role in neuronal survival of many nerve system diseases and the relationship between immune stress and neurotrophins have been proved in several disease models but the fine mechanism still open.In the present experiment we reported that there were different response     

Native and β-cyclodextrin-enclosed curcumin: entrapment within liposomes and their in vitro cytotoxicity in lung and colon cancer

With a view to improving the solubility and delivery characteristics of poorly water-soluble drugs, we prepared β-cyclodextrin-curcumin (βCD-C) inclusion complexes (hydrophilic curcumin) and entrapped both native curcumin (hydrophobic) and the complexes separately into liposomes; these were then assessed for in vitro cytotoxicity in lung and colon cancer cell lines. Optimization of curcumin entrapment within βCD was achieved, with the resultant βCD-C complexes prepared by methanol reflux. Inclusion complexes were confirmed using UV spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction. The water solubility of βCD-C complexes improved markedly (c.f. native curcumin) and successful entrapment of complexes into liposomes, prepared using a thin-film hydration approach, was also achieved. All the liposomal formulations were characterized for curcumin and βCD-C complex entrapment efficiency, particle size, polydispersity and stability at 2–8°C. Curcumin, βCD-C complex and their optimized liposomal formulations were evaluated for anticancer activity in lung (A-459) and colon (SW-620) cancer cell lines. All curcumin-containing formulations tested were effective in inhibiting cell proliferation, as determined via an MTT assay. The median effective dose (EC₅₀) for all curcumin formulations was found to be in the low µM range for both lung and colon cancer cell lines tested. Our results confirm that βCD inclusion complexes of poorly water soluble drugs, such as curcumin can be entrapped within biocompatible vesicles such as liposomes, and this does not preclude their anticancer activity.