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PubMed1994

Salicylamide reverses the aspirin-antagonistic effect of salicylic acid on rat platelet cyclooxygenase.

The antagonistic effect of salicylic acid (SA), the major metabolite of aspirin, on aspirin (ASA)-induced inhibition of cyclooxygenase has been recognized in vivo and in vitro. Salicylamide is available with aspirin in some analgesic preparations. Salicylamide shares important characteristics with salicylic acid including the lack of effect on cyclooxygenase and platelet aggregation as well as a close structural resemblance. This prompted us to study the interaction of salicylamide with aspirin and/or SA on rat platelet and cyclooxygenase. Our results showed that salicylamide has, unlike SA, no blocking effect on the anticyclooxygenase effect of aspirin in vitro. Moreover, salicylamide could dose-dependently prevent the aspirin-blocking effect of SA on platelet cyclooxygenase. These results suggest that salicylamide and SA compete for a receptor on cyclooxygenase different to that of aspirin. A functional model of cyclooxygenase enzyme is proposed.

Animals↗

PubMed1972

The influence of pyrogen-induced fever on salicylamide metabolism in man.

Salicylamide is metabolized in man by biotransformation to salicylamide glucuronide, salicylamide sulfate, and gentisamide glucuronide. The metabolites are quantitatively and rapidly excreted in urine. Study of the metabolism of this drug in volunteers during episodes of pyrogen-induced fever shows a significant reduction in the half-life (t(1/2)) of the excretion of the drug metabolites. The proportion of the drug transformed to its major metabolite, salicylamide glucuronide, is significantly reduced by fever, with concomitant increase in the proportion of one or both of the other metabolites. Thus, the pattern of urinary metabolites of salicylamide is altered. The shortened t(1/2) of the metabolite excretion is probably due to increased hepatic and renal blood flow known to accompany pyrogen-induced fever. This concept was supported by the observation that when two subjects were placed in a high-temperature environmental chamber, a condition in which hepatic and renal blood flows are known to diminish, the t(1/2) of salicylamide metabolite excretion actually increased. No simple explanation exists to explain the changed metabolite pattern noted during febrile periods. It is most likely to be due to complex interactions between the direct or indirect effects of the pyrogens and the factors affecting the hepatic biotransformation of drugs.

Adult↗

PubMed1988

Non-linear hepatic first-pass metabolism of salicylamide in dogs after portacaval transposition.

The effect of the rate of input of salicylamide into the portal vein of dogs on the clearance and bioavailability of the drug was examined. The four dogs had undergone portacaval transposition so that a hindlimb infusion delivered the drug directly and only into the liver. On separate occasions, salicylamide, 20 mg/kg, was infused into a hindlimb vein at three different rates, the duration of each infusion was 3, 10, and 30 min. Simultaneously, to measure the bioavailability, 14C-salicylamide was infused at the same rate into a forelimb vein. As the duration of the infusion was increased from 3 to 30 min, the clearance of salicylamide increased significantly from 1.05 +/- 0.21 (mean +/- SD) to 1.57 +/- 0.38 L/min and the half-life decreased significantly from 14.66 +/- 3.60 to 9.09 +/- 2.42 min. Bioavailability decreased from 0.84 +/- 0.11 to 0.61 +/- 0.61, but the differences were not statistically significant. As predicted for a drug that has nonlinear clearance and bioavailability, the rate of infusion of salicylamide affects the values of these parameters.

Animals↗

PubMed1991

Bioavailability of aspirin and salicylamide following oral co-administration in human volunteers.

BC powder (I) is a commercially available analgesic containing the active ingredients aspirin and salicylamide. The kinetics of I, BC powder minus aspirin (II), and BC powder minus salicylamide (III) were evaluated in 13 volunteers. Ten minutes after administration of I, aspirin reached a maximum concentration of 12.9 micrograms/mL, while salicylamide concentration reached a peak value of 3.4 micrograms/mL. However, when III was administered, aspirin was not detected at 10 min and only reached a concentration of 0.4 microgram/mL at 2 and 6 h. Furthermore, the area under the plasma concentration versus time curve for aspirin when III was administered was sixfold less compared with treatment with I. The area under the curve for aspirin metabolites was significantly different in I versus III. After treatment with II, a delay in salicylamide peak concentration was observed. Gentisamide was not detected throughout the study. This study demonstrates that salicylamide significantly enhances plasma levels of aspirin with potential therapeutic implications.

Adult↗

PubMed1981

Spectrofluorometric determination of acetylsalicylic acid, salicylamide, and salicyclic acid as an impurity in pharmaceutical preparations.

Spectrofluorometry, either direct or in combination with a separation technique, provides a sensitive and accurate method for the determination of certain extent fluorescent analgesic drugs and the determination of impurities in many combination preparations. A critical examination of the UV spectra of common analgesics and related compounds indicates that the fluorescence inner filter effect should be negligible below 10(-5) M and that selective excitation and emission wavelengths should minimize interference from other fluorescent species. Fluorometric procedures are presented for the determination of salicylamide, acetylsalicylic acid, and salicylic acid, as an impurity, in preparations containing salicylamide, acetylsalicylic acid, acetaminophen, caffeine, and phenacetin as major constituents. Inner filtering is the limiting factor only for the direct and indirect determination of salicylamide and the direct determination of acetylsalicylic acid. Results of fluorometric determinations compare favorably with other reference methods. Salicylic acid is determined in the 10(-7) M concentration range after separation from salicylamide, acetaminophen, and caffeine.

Acetaminophen↗

PubMed1990

Solubilization of salicylamide and acetaminophen by antihistamines in aqueous solution.

The effect of self-association of the antihistaminic drugs pheniramine, chlorpheniramine, and brompheniramine as their maleate salts on the solubilization of salicylamide and acetaminophen in aqueous solution has been investigated. The total solubility of salicylamide increased nonlinearly at lower antihistamine concentrations (less than 0.4 M), but reached limiting linearity (slope = 0.34 mol/mol of antihistamine) at higher concentrations (up to 0.8 M). Salicylamide solubility increases are approximately 10-fold at high concentrations (0.6-0.8 M) of antihistamine, while acetaminophen solubility increases are about fivefold at similar antihistamine concentrations. The solubilization data were analyzed with a stepwise self-association model. Based on a dimer model, the experimental and theoretical log excess salicylamide solubility profiles were in good agreement (r2 = 0.982) except at the lowest chlorpheniramine maleate concentrations. Such deviation at the lowest concentrations increased when trimer and 11-mer models were utilized. To account for this deviation, a monomer-dimer model based on interaction with both the chlorpheniramine maleate monomer and dimer was proposed. This model was in excellent agreement (r2 = 0.996) with the solubility data.

Acetaminophen↗

PubMed1981

Release of mutagenic metabolites of benzo[a]pyrene from the perfused rat liver after inhibition of glucuronidation and sulfation by salicylamide.

The role of glucuronide and sulfate conjugation in presystemic inactivation of benzo[a]pyrene (BP) metabolites was investigated with rat livers perfused with BP (12 mumol). Comparisons were made between metabolite profiles and mutagenicity of medium from perfusions with and without salicylamide, a selective inhibitor of glucuronide and sulfate conjugation. After 4 h perfusion in the presence of salicylamide, certain BP metabolites (diols, quinones, phenols, and metabolites more polar than BP-9,10-diol) were significantly increased at the expense of quinones and phenols in the glucuronide fraction. Mutagenicity of medium (detected by the Ames test, using tester strains TA98 and TA100) was low in perfusion without salicylamide. Mutagenicity detected with tester strain TA98 was significantly increased in perfusions with salicylamide. Involvement of glucuronidation in BP inactivation was also observed at the subcellular level; when cofactors of glucuronidation were added to liver homogenates along with the NADPH regenerating system in the Ames test, BP mutagenicity was markedly decreased. Both the activation of BP to mutagenic metabolites and the inactivation of BP metabolites by glucuronidation was much more pronounced with liver homogenates from 3-methylcholanthrene-treated rats than with those from phenobarbital-treated animals or untreated controls. The results suggest an important role for glucuronidation and sulfation in the inactivation and elimination of polycyclic aromatic hydrocarbons.

Animals↗

PubMed1977

Age-related differences in salicylamide and acetaminophen conjugation in man.

Following a concomitant oral dose of salicylamide and acetaminophen (5 mg/kg of each) the urinary excretion of glucuronide and sulfate conjugates of the drugs were followed in children (ages seven to ten years) and adults. No significant difference were observed between the two age groups in the half-lives for appearance of salicylamide conjugates in urine. Age-related changes in the metabolic pathways, however, were observed. The mean percentage of dose excreted as salicylamide sulfate was significantly higher in children (78%) than in adults (36%). In contrast, salicylamide glucuronide was the major excretory product in adults. Similar age-related differences were observed for acetaminophen conjugation. Pharmacokinetic analysis indicated that the deficiency in glucuronide conjugation of these drugs in children is accompanied by a higher rate of sulfate formation.

Acetaminophen↗

PubMed1992

The aminoquinazoline group as a replacement for the salicylamide group: the design and synthesis of a novel highly selective beta 1 adrenoceptor partial agonist.

The high potency at beta 1 receptors, excellent selectivity (beta 1/beta 2) and high degree of agonism displayed by compounds such as 1 is believed to be due in part to the salicylamide side chain. Two conformations of salicylamide are known to exist in the crystal state (2 and 3), but ab initio calculations suggest that in the absence of crystal packing forces 2 should be more stable. The aminoquinazoline group was judged to be a good replacement for salicylamide in 1, and consequently the oxypropanolamine derivative 4 was prepared. 4 shows extremely high potency at the beta 1 receptor, and excellent beta 1/beta 2 selectivity. It has comparable in vitro activity to 1, although it displays a lower degree of agonism. These results suggest that in this system aminoquinazoline appears to be an excellent mimic of the salicylamide group.

Adrenergic beta-Agonists↗

PubMed1991

Hydrolysis kinetics of 1,3-benzoxazine-2,4-dione (a potential salicylamide prodrug) and various N-substituted derivatives.

The kinetics and mechanism of hydrolysis of 1,3-benzoxazine-2,4-dione and its N-methyl and N-benzoyl derivatives were studied in aqueous solution to provide basic information on the reactivity of the benzoxazinedione structure and to assess the potential of unsubstituted 1,3-benzoxazine-2,4-dione as a prodrug for salicylamide. The compounds were found to hydrolyze quantitatively to the parent salicylamide. The pH-rate profiles obtained at pH 1-11 were accounted for by a spontaneous or water-catalyzed reaction which predominated at pH 1-4 and a hydroxide ion-catalyzed reaction. The rates of hydrolysis were catalyzed slightly in the presence of human plasma and rat liver homogenate, the exception being the N-benzoyl derivative which was hydrolyzed very fast in plasma solutions to N-benzoylsalicylamide. The aqueous solubility and lipophilicity characteristics of 1,3-benzoxazine-2,4-dione were determined. The results obtained suggest that the latter may function as a prodrug for salicylamide with the potential of depressing the extensive first-pass metabolism of salicylamide following oral or rectal administration.

Animals↗

PubMed1983

Effect of salicylamide on the growth of a Morris hepatoma in rats fed 8% and 25% casein diets.

To investigate the effect of 2% salicylamide and protein feeding levels on animal and tumor growth, male ACI rats were injected with Morris hepatoma #3924A (1 X 10(6) cells) 1 week following the conversion to diets containing 8% or 25% casein (+/- 2% salicylamide). The animals were sacrificed on day 19 after tumor transplantation. Tumor area and tumor weight were significantly higher in animals on the 25% versus the 8% casein diets. Reduction in body weight gain and protein efficiency ratio (PER) were observed in drug-treated and tumor-bearing animals. Total serum protein and liver protein were significantly reduced in all tumor-bearing animals when compared to non-tumor-bearing rats. Liver protein from animals with tumors was significantly higher among those fed salicylamide, in comparison with the tumor bearing non-drug-treated animals. Overall, these results show that the growth of Morris hepatoma #3924A in ACI rats is enhanced by increased dietary protein and is significantly reduced by a low-protein diet and/or a salicylamide dietary supplement.

Animals↗

PubMedDate not supplied

Salicylamide pharmacokinetics in healthy males: dietary effect.

The effect of diet on the absorption, metabolism, and elimination of salicylamide (SAM), in man was studied in five healthy male volunteers. In a three-way cross-over study, 300 mg SAM capsules were administered under fasting, carbohydrate, and lipid diet conditions. Total urinary salicylates, salicylamide glucuronide (SAMG), and salicylamide sulphate (SAMS) were determined at different time intervals. Diet was found to have no significant effect on the extent of SAM absorption or on its apparent elimination half-life. A significant increase (P less than 0.001) in the fraction excreted as SAMS in the lipid diet trial compared to the fasting or carbohydrate trials is observed. In the lipid diet trial, the ratio (R) of the cumulative urinary SAMS/SAMG was found to be 15-3 times the ratio obtained under fasting or carbohydrate diet conditions. The equilibrium solubilities of SAM under physiologic conditions in water (W), simulated intestinal fluid (M), and corn oil (O) were 4.08, and 4.81, and 12.5 mg ml-1, respectively. The equilibrium apparent distribution coefficients KO/W, KO/M, and KM/W were 3.1, 2.6 and 1.18, respectively. The increase in R is probably due to a decrease in free SAM concentration at the absorption site (intestinal mucosa) in the presence of lipids. A model for drug distribution in the gastrointestinal tract during lipid digestion is proposed and discussed.

Absorption↗

PubMed1976

Rapid spectrophotometric determination of salicylamide in analgesic tablets.

An independent, simple, and rapid procedure is suggested for the routine analysis of salicylamide in analgesic tablets containing acetaminophen, phenobarbital, caffeine, codeine phosphate, prednisone, ascorbic acid, and chloroquine phosphate. The method does not require the preliminary separation of salicylamide from other constituents by the time-consuming solvent extraction technique or by chromatography prior to determination. The absorbance was linear for investigated concentrations of salicylamide from 0 to 4.0 mg/100 ml of solution at 308 nm.

Analgesics↗

PubMed1993

Preparation and evaluation of Eudragit gels. VI: In vivo evaluation of Eudispert rectal hydrogel and xerogel containing salicylamide.

Eudispert hv hydrogel and xerogel preparations containing salicylamide displayed sustained-release plasma profiles when compared with other conventional rectal preparations. The absolute bioavailability of salicylamide was 97.3% for the hydrogel preparation and 98.4% for the xerogel preparation. These results may arise because the gel preparation stays at the application site, the lower part of the rectum, over a fairly long period because of its bioadhesive force. Furthermore, the gastrointestinal and hepatic first-pass elimination of salicylamide can be avoided completely by rectal administration of these preparations. Visual and optical microscopic observation of rectal membranes indicated no irritation or abnormality after administration of Eudispert hv hydrogel and xerogel.

Acrylic Resins↗

PubMed1978

Effects of salicylamide and protein restriction on the skeletal development of the rat fetus.

Salicylamide has previously been shown to be teratogenic to the rat. Aims of the present study were to examine separate effects and interactions of salicylamide administration and protein restriction on development of the rat fetus. In experiments using Holtzman rats,the percentage of fetal resorptions was significantly increased by drug treatment and by protein restriction. Malformations were seen in fetuses from dams given the drug from the fifth to eleventh days of gestation; the inicdence of these malformations being independent of the diet. Factors affecting appearance of ossification centers included drug dosage, placental and fetal weight and litter size. Protein restriction had no significant effect on the development of centers of ossification. It is concluded that salicylamide, as well as protein restriction, produces adverse effects on pregnancy outcome in the rat.

Abnormalities, Drug-Induced↗

PubMed1998

Simultaneous determination of salicylamide and salsalate in serum and urine by first derivative variable-angle synchronous fluorescence spectrometry.

The determination of salicylamide and salsalate in human serum and urine is performed using a simple, rapid, sensitive, and selective method. The broad-band overlapping conventional spectra of both compounds are resolved by means of first derivative variable-angle synchronous fluorescence spectrometry. The method is based on the intrinsic fluorescence of both drugs in chloroformic solution. The measurements are performed in an alkaline medium, which is adjusted by adding 0.40 M pyrrolidine chloroformic solution to the organic phase. The method was applied for the simultaneous determination of salicylamide and salsalate, at concentrations between 0.100 and 1. 000 microg mL-1 for both components, by means of absolute values of a first derivative variable-angle synchronous scan at the emission/excitation wavelengths of 410/299 nm for salicylamide and 440/307 nm for salsalate. Serum and urine are extracted with chloroform, by adding acetate buffer solution to provide pH 4.8 in the aqueous phase. Finally, pyrrolidine chloroformic solution is added to organic phase, where both components are determined, without the need for a reextraction step to an aqueous phase.

Humans↗

PubMed1987

High-performance liquid chromatographic method for the quantitation of salicylamide and its metabolites in biological fluids.

A high-performance liquid chromatographic (HPLC) assay is described for the determination of salicylamide (SAM) and its metabolites in biological fluids obtained from an in situ rat liver preparation and rat in vivo. SAM and its six metabolites, salicylamide sulphate, salicylamide glucuronide, gentisamide (GAM), gentisamide 2-sulphate, gentisamide 5-sulphate and gentisamide 5-glucuronide, were separated on a mu Bondapak C18 column with 0.085 M potassium dihydrogenphosphate pH 3.35, as mobile phase and by using a flow gradient. Enriched recovery of SAM and GAM from blood was achieved by extraction followed by a second HPLC procedure with a mobile phase consisting of acetic acid and methanol. Furthermore, the reproducibility and the stability of the samples under assay conditions were investigated.

Animals↗

PubMed1983

Human platelet phenolsulphotransferase M and P: substrate specificities and correlation with in vivo sulphoconjugation of paracetamol and salicylamide.

Human platelet phenolsulphotransferase exists in two functional forms. M and P. In this study the substrate specificity of the two forms has been further delineated by correlating activities in different individuals with various substrates. m-Tyramine, noradrenaline, adrenaline, 5-hydroxytryptamine, p-hydroxyamphetamine, isoprenaline, salbutamol and l-naphthol were all specific substrates for the M form of the enzyme. Paracetamol, a mixed substrate, was predominantly metabolized by the M form. Salicylamide at 5 microM was a substrate for the P form but became and M substrate at higher concentration. Phenol itself, a specific substrate for phenolsulphotransferase P at 10 microM, also became an M substrate at 1 mM concentration. These substrate specificities were confirmed with the selective inhibitor, dichloronitrophenol. In this study, we measured phenolsulphotransferase activity in platelets from 13 individuals selected on the basis of their wide variation in ability to sulphoconjugate paracetamol and salicylamide in vivo. There was no significant relationship between the in vivo pattern with either drug and the activity of platelet phenolsulphotransferase assayed with paracetamol or salicylamide respectively.

Acetaminophen↗