Simultaneous Application of Photothermal Therapy and an Anti‐inflammatory Prodrug using Pyrene–Aspirin‐Loaded Gold Nanorod Graphitic Nanocapsules

Photothermal therapy (PTT) has been extensively developed as an effective approach against cancer. However, PTT can trigger inflammatory responses, in turn simulating tumor regeneration and hindering subsequent therapy. A therapeutic strategy was developed to deliver enhanced PTT and simultaneously inhibit PTT‐induced inflammatory response. 1‐Pyrene methanol was utilize to synthesize the anti‐inflammatory prodrug pyrene–aspirin (P‐aspirin) with a cleavable ester bond and also facilitate loading the prodrug on gold nanorod (AuNR)‐encapsulated graphitic nanocapsule (AuNR@G), a photothermal agent, through π–π interactions. Such AuNR@G‐P‐aspirin complexes were used for near‐infrared laser‐triggered photothermal ablation of solid tumor and simultaneous inhibition of PTT‐induced inflammation through the release of aspirin in tumor milieu. This strategy showed excellent effects in vitro and in vivo.     

The Prodrug Platin‐A: Simultaneous Release of Cisplatin and Aspirin

Cancer‐associated inflammation induces tumor progression to the metastatic stage, thus indicating that a chemo‐anti‐inflammatory strategy is of interest for the management of aggressive cancers. The platinum(IV) prodrug Platin‐A was designed to release cisplatin and aspirin to ameliorate the nephrotoxicity and ototoxicity caused by cisplatin. Platin‐A exhibited anticancer and anti‐inflammatory properties which are better than a combination of cisplatin and aspirin. These findings highlight the advantages of combining anti‐inflammatory treatment with chemotherapy when both the drugs are delivered in the form of a single prodrug.     

Simultaneous determination of carisoprodol and aspirin in human plasma using liquid chromatography–tandem mass spectrometry in polarity switch mode: application to a human pharmacokinetic study

A simple, sensitive and rapid LC‐MS/MS‐ESI method has been developed and validated for simultaneous quantification of the carisoprodol and aspirin in human plasma. Carisoprodol was detected in positive ion mode, whereas aspirin was detected in negative ion mode. Carbamazepine and furosemide were used as internal standards (IS) for quantification of carisoprodol and aspirin, respectively. The extraction procedure involves a liquid–liquid extraction method with ter‐butyl methyl ether. Chromatographic separation was achieved on a Zorbax XDB‐Phenyl (4.6 × 75 mm, 3.5 µm) column using an isocratic mobile phase (5 mm ammonium acetate:methanol, 20:80, v/v) at a flow rate of 0.8 mL/min with a total run time of 2.2 min. A detailed method validation was performed as per the FDA guidelines. The standard curves found to be linear in the range of 25.5–4900 and 15.3–3000 ng/mL for carisoprodol and aspirin, respectively. The results met the acceptance criteria. Carisoprodol and aspirin were found to be stable in various stability studies. The validated method was successfully applied to a pharmacokinetic study following co‐administration of carisoprodol (250 mg) and aspirin (75 mg) tablets by oral route to human volunteers. Copyright © 2012 John Wiley & Sons, Ltd.     

Real‐Time Interrogation of Aspirin Reactivity,Biochemistry, and Biodistribution by Hyperpolarized Magnetic Resonance Spectroscopy

Hyperpolarized magnetic resonance spectroscopy enables quantitative, non‐radioactive, real‐time measurement of imaging probe biodistribution and metabolism in vivo. Here, we investigate and report on the development and characterization of hyperpolarized acetylsalicylic acid (aspirin) and its use as a nuclear magnetic resonance (NMR) probe. Aspirin derivatives were synthesized with single‐ and double‐¹³C labels and hyperpolarized by dynamic nuclear polarization with 4.7 % and 3 % polarization, respectively. The longitudinal relaxation constants (T₁) for the labeled acetyl and carboxyl carbonyls were approximately 30 seconds, supporting in vivo imaging and spectroscopy applications. In vitro hydrolysis, transacetylation, and albumin binding of hyperpolarized aspirin were readily monitored in real time by ¹³C‐NMR spectroscopy. Hyperpolarized, double‐labeled aspirin was well tolerated in mice and could be observed by both ¹³C‐MR imaging and ¹³C‐NMR spectroscopy in vivo.     

Real‐Time Interrogation of Aspirin Reactivity,Biochemistry, and Biodistribution by Hyperpolarized Magnetic Resonance Spectroscopy

Hyperpolarized magnetic resonance spectroscopy enables quantitative, non‐radioactive, real‐time measurement of imaging probe biodistribution and metabolism in vivo. Here, we investigate and report on the development and characterization of hyperpolarized acetylsalicylic acid (aspirin) and its use as a nuclear magnetic resonance (NMR) probe. Aspirin derivatives were synthesized with single‐ and double‐¹³C labels and hyperpolarized by dynamic nuclear polarization with 4.7 % and 3 % polarization, respectively. The longitudinal relaxation constants (T₁) for the labeled acetyl and carboxyl carbonyls were approximately 30 seconds, supporting in vivo imaging and spectroscopy applications. In vitro hydrolysis, transacetylation, and albumin binding of hyperpolarized aspirin were readily monitored in real time by ¹³C‐NMR spectroscopy. Hyperpolarized, double‐labeled aspirin was well tolerated in mice and could be observed by both ¹³C‐MR imaging and ¹³C‐NMR spectroscopy in vivo.     

The Biological Activity of Zeise’s Salt and its Derivatives

With the aim to design new biologically active bioinorganic drugs of aspirin, whose mode of action is based on the inhibition of the cyclooxygenase(COX) enzymes, derivatives of Zeise’s salt were synthesized in this structure–activity relationship study. Surprisingly, not only these Zeise–aspirin compounds but also Zeise’s salt itself showed high inhibitory potency against COX enzymes in in vitro assays. In contrast, potassium tetrachloroplatinate and cisplatin did not influence the enzyme activity at equimolar concentrations. It was demonstrated by LC‐ESI tandem‐mass spectrometry that Zeise’s salt platinates the essential amino acids Tyr385 (active site of the enzyme) and Ser516 (will be acetylated by aspirin) of COX‐1, thereby strongly impairing the function of the enzyme. This finding demonstrates for the first time that Zeise’s salt is pharmacologically active and is a potent enzyme inhibitor.     

Study of intramolecular interactions in aspirin

A detailed quantum chemical study of the solvent effects in the intramolecular hydrogen bonding, conformational stability, and reactivity of aspirin has been performed using density functional theory (DFT) at the B3LYP/6‐31G(d) theory level. Seven conformational isomers, three of them presenting intramolecular hydrogen bonds, have been located. Thermochemical functions have been computed, and relative energies and free enthalpies have been determined in gas and aqueous phases. Several molecular properties have been calculated to predict the ability of aspirin to acylate cyclooxygenase (COX) enzymes. A six‐membered‐ring hydrogen‐bonded conformer was found to be the most reactive species. The solvation in aqueous phase increases the reactivity and strengthens intramolecular hydrogen bonding.     

Catalytic Method for Synthesis of Aspirin by a Green,Efficient and Recyclable Solid Acid Catalyst (Preyssler's Anion) at Room Temperature

Synthesis of aspirin at room temperature via O‐acetylation of salicylic acid in the presence of Preyssler type heteropolyacids has been investigated in order to contribute toward clean technology, which is the most important need of the society. All of the catalysts are recyclable and reusable.     

Low dose aspirin estimation: an application to a human pharmacokinetic study

Low dose to very high dose aspirin is used to prevent heart attack. We have developed and validated a sensitive and robust method that could detect low levels of aspirin and salicylic acid in plasma and also a novel sample collection procedure to carry out sample preparation at room temperature. The total run time was 3.00 min; the developed method was validated in human plasma with a lower limit of quantitation of 0.99 ng/mL for aspirin and 2.01 ng/mL for salicylic acid. A linear response function was established for the range of concentrations 0.99–756.20 ng/mL (r > 0.998) for aspirin and 2.01–2486.86 ng/mL for salicylic acid. The intra‐ and inter‐day precision values for aspirin and salicylic acid met the acceptance as per FDA guidelines. The developed assay method was applied to an oral pharmacokinetic study in humans. Copyright © 2012 John Wiley & Sons, Ltd.     

Polycyclic N‐Heterocyclic Compounds. Part 82: Synthesis and Evaluation of Anti‐Platelet Aggregation Activity of 2,4‐Disubstituted 5,6‐Dihydro[1]benzothiepino[5,4‐d]pyrimidine and Related Compounds

We have synthesized a large number of tricyclic 2‐substituted 4‐alkylamino‐5,6‐dihydro[1]benzothiepino[5,4‐d]pyrimidines as part of our research to develop new effective anti‐platelet drugs. A variety of alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising anti‐platelet candidates with potencies superior to aspirin.     

Fullerene Black Modified Screen Printed Electrodes for the Quantification of Acetaminophen and Guanine

Fullerene Black (FB) and Extracted Fullerene Black (EFB) were used in modified screen‐printed electrodes producing electrochemical transducers (FB‐SPEs and EFB‐SPEs). A complete electrochemical study was performed and the best results are obtained working with FB‐SPEs, especially in terms of: 1. improved electron‐transfer kinetic mechanisms and 2. sensitivity and selectivity toward Acetaminophen (Ac) and Guanine (G). These latter represent two important electro‐active targets to quantify in medicine field application, because: Ac is a preferred alternative (as analgesic‐antipyretic agent) to aspirin, particularly for patients who cannot tolerate aspirin; the oxidation signal of G is useful for the fabrication of emerging analytical tools, such as DNA chipsand user‐friendly diagnostic devices. Ac and G are quantify by using FB‐SPEs electrochemical devices, with an extended linearity (1–300 μM for Ac; 0.1–300 μM for G), an excellent sensitivity (2.82 μA μM⁻¹ cm⁻² in the case of Ac; and 0.183 μA μM⁻¹ cm⁻² in the case of G), a low detection limit (0.01 μM for Ac; 0.005 μM for G), a very good reproducibility (both: intra‐; inter‐electrodes reproducibility RSD % ranging from 0.3–0.5 for Ac; and 0.50–0.85 for G) and a very fast response time (6 s for Ac; 5 s in the case of G). In addition, high selectivity is obtained at FB‐SPEs, meaning that the FB‐SPEs electrochemical transducers are suitable to simultaneously quantify Ac and G in real samples, having several different (highly concentrated) interference.     

Polycyclic N‐Heterocyclic Compounds. Part 85: Synthesis and Evaluation of Antiplatelet Aggregation Activity of 2,4‐Disubstituted 5,6‐Dihydro[1]benzazepino[5,4‐d]pyrimidine and Related Compounds

We have synthesized a large number of tricyclic 2‐substituted 4‐alkylamino‐5,6‐dihydro[1]benzazepino[5,4‐d]pyrimidines as part of our research to develop new effective antiplatelet drugs. A variety of alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Polycyclic N‐Heterocyclic Compounds. Part 79: Synthesis of 2,4‐Disubstituted 6,7‐Dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidines as Potential Antiplatelet Aggregators

Libraries of tricyclic 2‐substituted 4‐alkylamino‐6,7‐dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Crystallisation of aspirin via simulated pulmonary surfactant monolayers and lung‐specific additives

Pain is a prevalent condition that can have a serious impact upon the socioeconomic function of a population. Numerous methods exist to administer analgesic medication (e.g. aspirin) to the body however inherent drawbacks limit patient acceptability. The inhaled route offers promise to facilitate the administration of medication to the body. Here, we consider the crystallisation behaviour of aspirin, our model therapeutic agent, when in contact with material of relevance to the lung. Thus, our approach aims to better understand the interaction between drug substances and the respiratory tract. Langmuir monolayers composed of a mixed surfactant system were supported on an aqueous subphase containing aspirin (7.5 mg/ml). The surfactant film was compressed to either 5mN/m (i.e. inhalation end point) or 50 mN/m (i.e. exhalation end point), whilst located within a humid environment for 16 h. Standard cooling crystallisation procedures were employed to produce control samples. Antisolvent crystallisation in the presence or absence of lung‐specific additives was conducted. All samples were analysed via scanning electron microscopy and X‐ray diffraction. Drug‐surfactant interactions were confirmed via condensed Langmuir isotherms. Scanning electron microscopy analysis revealed plate‐like morphology. The crystallisation route dictated both the crystal habit and particle size distribution. Dominant reflections were the (100) and (200) aspects. The main modes of interaction were hydrogen bonding, hydrophobic associations, and van der Waals forces. Here, we have demonstrated the potential of antisolvent crystallisation with lung‐specific additives to achieve control over drug crystal morphology. The approach taken can be applied in respirable formulation engineering. Copyright © 2017 John Wiley & Sons, Ltd.     

Polycyclic N‐Heterocyclic Compounds. Part 75: Synthesis of 2,4‐Disubstituted 5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and 12‐Substituted 1,2,4,5‐Tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines as Potential Antiplatelet Aggregators

Libraries of tricyclic 2‐substituted 4‐alkylamino‐5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and tetracyclic 12‐substituted 1,2,4,5‐tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Polycyclic N‐Heterocyclic Compounds. Part 86: Synthesis and Evaluation of Antiplatelet Aggregation Activity of 2,4‐Disubstituted 9‐Chloro‐5,6‐dihydropyrimido[5,4‐d]benzazepine and Related Compounds

Libraries of tricyclic 2‐substituted 4‐alkylamino‐9‐chloro‐5,6‐dihydropyrimido[5,4‐d]benzazepines and tetracyclic 12‐substituted 8‐chloro‐1,2,5,6‐tetrahydro‐4H‐imidazo[1′,2′:1,6]pyrimido[5,4‐d]benzazepines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Stability‐indicating HPLC method for simultaneous quantification of 14 impurities in excedrin tablet formulations and identification of new impurity by LC–MS in accelerated stability studies

We developed novel stability‐indicating HPLC method for simultaneous estimation of 14 impurities in excedrin tablet, a formulation with a combination of acetaminophen, aspirin, and caffeine. In addition, a new impurity that was generated through degradation of aspirin at high temperatures during the accelerated stability conditions was positively identified and confirmed, using liquid chromatography–mass spectrometry technique. The HPLC method was optimized using the Inertsustain C₁₈, 250 × 4.6 mm, 5.0 μm column, employing simple gradient method. Forced degradation studies were performed under acidic, basic, oxidative and thermal conditions to prove the scope and stability‐indicating the nature of the method. The optimized method was validated as per the International Conference on Harmonization guidelines. The HPLC method showed linearity from LOQ concentration to 21 μg mL^?1. Precision and intermediate precision values were <5% RSD. The validated HPLC method is currently applied for the routine testing of excedrin tablet formulations in quality control laboratories.     

Deposition and aggregation of aspirin molecules on a phospholipid bilayer pattern

Aspirin and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) are deposited from their alcoholic mixed solution onto highly oriented pyrolytic graphite (HOPG) by spin coating. The film structure and morphology are characterized by atomic force microscopy (AFM). The barely soluble DMPE forms a highly oriented stripe phase as a result of its one-dimensional epitaxy with the HOPG lattice. The bilayer stripe pattern exposes the cross section of the lipid bilayer lamellae and enables the direct visualization of the molecular interactions of drug or biological molecules with either the hydrophobic or the hydrophilic part of the phospholipid bilayer. The bilayer pattern affects the aspirin molecular deposition and aggregation. AFM shows that the aspirin molecules prefer to deposit and aggregate along the aliphatic interior part of the bilayer pattern, giving rise to parallel dimer rods in registry with the underlying pattern. The nonpolar interactions between aspirin and the phospholipid bilayer are consistent with the lipophilic nature of aspirin. The bilayer pattern not only stabilizes the rodlike aggregate structure of aspirin at low aspirin concentration but also inhibits crystallization of aspirin at high aspirin concentration. Molecular models show that the width of the DMPE aliphatic chain interior can accommodate no more than two aspirin dimers. The bilayer confinement may prevent aspirin from reaching its critical nucleus size. This study illustrates a general method to induce a metastable or amorphous form of an active pharmaceutical ingredient (API) by chemical confinement under high undercooling conditions. Metastable and amorphous solids often display better solubility and bioavailability than the stable crystalline form of the API.     

Reinvestigation of the paracetamol–caffeine,aspirin–caffeine,and paracetamol–aspirin phase equilibria diagrams

Many drug candidates are poorly soluble. The formation of solid dispersion can improve their solubility, consequently their bioavailability. For this purpose, the use of eutectic mixtures is well known in the pharmaceutical field. At the eutectic composition, both components are in reduced particle size and well dispersed. In this work, we focus on the combination of paracetamol, aspirin, and caffeine, which is highly effective for the treatment of migraine headache pain. We have reinvestigated the paracetamol–caffeine, aspirin–caffeine, and paracetamol–aspirin phase equilibria diagrams taking into account the polymorphism of caffeine, paracetamol, and aspirin. The three phase diagrams are determined using X-ray diffraction and the differential scanning calorimetry from the binary mixtures. It is concluded that the paracetamol–caffeine and aspirin–caffeine systems are similar and exhibit two invariants, one eutectic and one metatectic. The paracetamol–aspirin phase diagram reveals the formation of one eutectic. The composition of the three eutectics formed is confirmed by the related Tamman’s triangles. No compound formation is found in the three systems.     

Quantitative non-destructive determination of salicylic acid acetate in aspirin tablets by Raman spectroscopy

Laser Raman spectroscopy was used for the quantitative determination of aspirin in aspirin-maize starch tablets. A calibration curve was constructed from spectra obtained from tablets with known quantities of aspirin and starch. The calibration curve is given from the relationship: I(552)/I(478) = (W(aspirin)/W(starch)) x 4.21, where I(552) and I(478) are the relative Raman intensities for the 552 and 478 cm(-1) Raman shift, respectively. W(aspirin) and W(starch) represent the weight of aspirin and starch in a pellet.