Studies on Combination Dosing (III) Aspirin and Ethenzamide

Abstract

Abstract-In our studies with drug combinations, we searched for mixtures which would enhance the effectiveness of the related active substances. Ethenzamide was found to possess a specific suppressive effect on the gastric damage induced by aspirin.Such effect could not be demonstrated in analgesic agents such as salicylamide, bucetin, acetaminophen and phenacetin. The combination of aspirin with ethenzamide had a potentiating effect on analgesic activity and reduced motor incoordination and loss of righting reflex.We calculated the safety margins of various ratios of combinations and concluded that the best was aspirin and ethenzamide at a ratio of 2:3.The general principle in considering drug combinations containing two or more in gredients is to evaluate not only the enhancement of the main effect and/or the magnification of the pharmacological spectrum of each ingredient but also the usefulness of the combi nation from the standpoint of total effect. We further propose that this principle should include increasing the safety margin so that drug combinations have greater safety margins than do the ingredients as single entities (1, 2, 3).Aspirin although in wide use does induce gastrointestinal damage. As such an untoward effect often limits extensive clinical application, we searched for a compound which would enhance the usefulness of aspirin when used in combination with other agents. MATERIALS AND METHODSAspirin, ethenzamide, salicylamide, bucetin, acetaminophen, phenacetin and five mixtures of aspirin and ethenzamide were used. Such were prepared in accordance with the ratios shown in Table 1. All orally administered test agents were suspended in I gum arabic solution. SLC-ddY male mice weighing 24±2 g were used.For each dose studied, a group of either 5 or 10 mice was employed in each experiment. Gastric damages induced by aspirin combined with various mild analgesicsThe method of Fiikawa et al (4) was followed. The mice were deprived of solid food but allowed free access to drinking water for 18 hr prior to experiments. The animals were sacrificed by cervical dislocation 4 hr after administration of drugs. The stomachs were rapidly exposed and fixed with 5 % formalin for 3 min. Gastric damages were observed under a stereoscopic microscope, and the length of erosive lesions (L.E.) was measured.The cumulative frequency was obtained from frequency distribution of 10 mice by L.E.

Cocrystals of Ethenzamide: Study of Structural and Physicochemical Properties

“…28−30 It is mainly used in combination with other active ingredients such as acetaminophen, aspirin, dipyrone, allyl iso-propyl acetyl urea, caffeine, and ibuprofen. 31,32 The crystal structure of the ETZ molecule was reported recently in the literature. 33 The main drawback of this drug is the lower solubility and bioavailability, which makes it a superior challenge to enhance its solubility behavior through cocrystallization.…”

“…Coformers used in the present study were gallic acid hydrate (GA), 2-nitrobenzoic acid (2NB), 3-nitrobenzoic acid (3NB), 2,4-dinitrobenzoic acid (DNB), and 3-toluic acid (3TA) as shown in Scheme . Ethenzamide is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. − It is mainly used in combination with other active ingredients such as acetaminophen, aspirin, dipyrone, allyl iso-propyl acetyl urea, caffeine, and ibuprofen. , The crystal structure of the ETZ molecule was reported recently in the literature . The main drawback of this drug is the lower solubility and bioavailability, which makes it a superior challenge to enhance its solubility behavior through cocrystallization.…”

Herringbone array of hydrogen-bonded ribbons in 2-ethoxybenzamide from high-resolution X-ray powder diffraction

“…The ribbons are arranged in a T-shaped herringbone pattern and cohesion between them is achieved by van der Waals forces. Comment 2-Ethoxybenzamide, (I), also called ethenzamide, is a compound with pharmaceutical applications as an analgesic and antipyretic (Kawano et al, 1978;Darias et al, 1992) in cold medications (Okamoto et al, 2005). Besides its medicinal use, it is interesting from the crystal engineering point of view for the analysis of the usual packing modes of benzamides, which often involve the formation of head-to-head hydrogen-bonded dimers (Braga et al, 1999).…”

Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical

“…Ethenzamide is BCS Class II analgesic drug (solubility of 8.8 mM in deionized water 13 ) commonly coadministered with NSAIDs such as acetaminophen or aspirin. 14,15 Delivery of ethenzamide in its amorphous phase will increase solubility; however, polymer stabilizers are necessary to prevent precipitation in aqueous media at elevated supersaturation. 7 It has been observed in other systems that polymers of moderate hydrophobicity are more potent inhibitors of crystallization from aqueous solution than hydrophobic or hydrophilic polymers.…”

“…The influence of polymer hydrophobicity on the ability of a class of poly­( N -hydroxyethyl acrylamide) (PHEAM) polymers to inhibit crystallization of ethenzamide was examined in both aqueous solution and in the amorphous phase. Ethenzamide is BCS Class II analgesic drug (solubility of 8.8 mM in deionized water) commonly coadministered with NSAIDs such as acetaminophen or aspirin. , Delivery of ethenzamide in its amorphous phase will increase solubility; however, polymer stabilizers are necessary to prevent precipitation in aqueous media at elevated supersaturation . It has been observed in other systems that polymers of moderate hydrophobicity are more potent inhibitors of crystallization from aqueous solution than hydrophobic or hydrophilic polymers. ,− Completely hydrophilic polymers more favorably interact with solvent over solute, yet fully hydrophobic polymers form insoluble globules in aqueous solution .…”