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PubMedDate not supplied

First-pass elimination of salicylamide in man following oral and rectal administration.

In order to study the avoidance of hepatic first-pass elimination following rectal administration, 500 mg of salicylamide (SAM) were given orally and rectally to man. Plasma SAM concentrations were measurable following oral administration, but following rectal administration SAM concentrations were either very low or not detectable. The mean excretion of SAM sulphate (SAMS) and SAM glucuronide (SAMG) in the urine following oral and rectal administration was 71.3 per cent and 45.6 per cent respectively. Increasing the oral and rectal dose (1500 mg of SAM, solution) showed that the mean AUC values were 911 and 144 micrograms min ml-1, respectively. The mean urinary excretion of SAMS plus SAMG following oral and rectal administration was 82.0 and 75.6 per cent respectively; the mean plasma elimination half-lives were 31 and 40 min, respectively, while the mean urinary elimination half-lives were 63 and 73 min, respectively.

Administration, Oral↗
PubMed1975

Differentiating nonaqueous titration of aspirin, acetaminophen, and salicylamide mixtures.

Mixtures containing aspirin, acetaminophen, and salicylamide were assayed potentiometrically by nonaqueous titration. The difference in pKa values for these weak acids was sufficient to permit successful differentiation. The titrant was tetrabutylammonium hydroxide, and the titration solvent was dimethylformamide. The procedure was applied to commercial dosage forms.

Acetaminophen↗
PubMed1978

Estimation of dissolution rate of salicylamide in complexing media using a theoretical diffusion model.

Dissolution rates of salicylamide in water and caffeine solutions under perfect sink conditions were predicted by theoretical diffusion equations applicable to dissolution in complexing media. Experimental dissolution rates were measured using a compartmentalized rotating-basket apparatus under two sets of conditions. Agreement was found between experimental and predicted rates. Use of the theoretical equation for estimating dissolution rates involves simple calculations of diffusion coefficients and diffusion layer thickness under the operative dissolution conditions. The increase in dissolution rate caused by addition of the complexant can be calculated for diffusion-controlled dissolution directly if the stability constant and the drug solubility in water are known or measured.

Caffeine↗
PubMed1980

Simultaneous quantitation of acetaminophen, aspirin, caffeine, codeine phosphate, phenacetin, and salicylamide by high-pressure liquid chromatography.

A method for the simultaneous quantitation of acetaminophen, aspirin, caffeine, codeine phosphate, phenacetin, and salicylamide was developed. The method is based on reversed-phase high-pressure liquid chromatography with a mobile phase buffered with phosphate (pH 2.3). The procedure not only separated these six active ingredients but also salicylic acid, the major decomposition product of aspirin. The method gave excellent results for three commercial products and a synthetic mixture containing four active ingredients. Lowering the pH increased the retention time of some weak acids and decreased that of some weak bases. Only these changes in the retention times made the separation possible.

Acetaminophen↗
PubMed1980

Simultaneous GLC analysis of salicylamide, phenylpropanolamine hydrochloride, caffeine, chlorpheniramine maleate, phenylephrine hydrochloride, and pyrilamine maleate in capsule preparations.

A GLC method is described for the quantitative determination of salicylamide, phenylpropanolamine hydrochloride, caffeine, chlorpheniramine maleate, phenylephrine hydrochloride, and pyrilamine maleate. The sample was dissolved in ethanol, and an aliquot of the solution was brought to dryness and treated with 0.1 ml of 4-(dimethyl-amino)pyridine in pyridine-acetic anhydride (1:1). The components were isolated and measured by applying 1 microliter of the reaction mixture to a chromatograph equipped with a flame-ionization detector and fitted with 8% OV-101 glass columns. The accuracy was good. Dicyclohexylphthalate was used as the internal standard.

Aminopyridines↗
PubMed1982

Effect of polyisobutylene on ethyl cellulose-walled microcapsules: wall structure and thickness of salicylamide and theophylline microcapsules.

Microcapsules were prepared by the ethylcellulose coacervation process which is based on the differential thermal solubility in cyclohexane. When a protective colloid, polyisobutylene, was present in adequate concentration, individually film-coated core particles formed. However, they were accompanied by small empty coacervate droplets, detectable by microscopic observation. Below the critical colloid concentration, the product had the form of aggregate, in contrast to individual film-coated microcapsules. Increase of colloid concentration yielded microcapsules of higher drug content, because coating became progressively thinner; there was a corresponding increase in the release rate of drugs from the microcapsules. Since the initial wall polymer/drug ratio and the particle size are constant, the drug content varied with the thicknesses of the wall membrane. This is shown here by removal of empty coacervate droplets by repeated decantations, enabling determination of drug content by chemical analysis. In contrast to results reported in the literature, in the presence of a protective colloid, microcapsule drug content decreased with decreasing particle size of the drug. This was caused by more complete uptake of the wall polymer on the increased surface of core material. The effect of protective colloid concentration on the apparent loss of wall polymer as empty droplets closely paralleled its effect on the size of stabilized droplet formation is a side reaction when core material is present, causing changes in wall thickness. This reaction not only affects the efficiency of the coating process but may be utilized to control wall thickness. First-order constants for drug release from salicylamide and theophylline microcapsules followed the same pattern as wall thickness and confirmed the validity of the measurements.

Capsules↗
PubMed1985

Pharmacodynamics of the hypnotic effect of salicylamide in rats.

Salicylamide (SAM) can produce sedation and sleep in humans and animals. To explore the potential utility of the drug as a research tool for assessing disease effects on the response of the central nervous system to depressant drugs, and to obtain a better understanding of the clinically evident sedative action of SAM, studies were performed to characterize the relationship between the concentrations and hypnotic effect of this drug in rats. Female Lewis rats weighing 170-200 g received SAM by intravenous infusion at a rate of 0.49, 1.22, or 2.47 mg/min until the onset of loss of the righting reflex. This well-defined pharmacological endpoint occurred from 16.7 +/- 2.3 min (fastest infusion rate) to 110 +/- 27 min (slowest infusion rate) after the start of the infusion. SAM concentrations at that time in serum, serum water, brain, and cerebrospinal fluid (CSF) were similar in animals that had received the 1.22- or 2.47-mg/min infusion and lower in animals that were infused at a rate of 0.49 mg/min. The slowest infusion rate group also exhibited increased serum protein binding of the drug. The SAM concentration ratio, CSF-serum water, was essentially unity in all three groups, indicative of rapid equilibration of the drug across the blood-CSF barrier. Gentisamide, the hydroxylated metabolite of SAM, was found in serum, CSF, and brain, but in low concentrations at which this metabolite alone had no hypnotic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Concurrent determination of hepatic bioavailability of salicylamide by three techniques in the dog.

Three methods of measuring hepatic first-pass metabolism of salicylamide in dogs that had undergone portacaval transposition were compared. The drug in both its radiolabeled (0.74 MBq) and unlabeled (20 mg/kg) forms was infused concurrently into forelimb and hindlimb veins, respectively. Because of the transposition, drug from the hindlimb is subject to first-pass metabolism in the liver. Bioavailability is a complementary measure of the extent of this metabolism. The three methods of determining bioavailability were continuous withdrawal of blood to determine the ratio of the areas under the plasma concentration versus time curves, ratio of specific activities in plasma after all the drug had been administered, and the conventional method, measurement of the ratio of areas determined from sequential plasma concentrations. The three techniques were found to give virtually identical values for bioavailability. Each method has its own advantages, limitations, and possible applications. The continuous withdrawal technique is potentially most applicable for drugs with short half-lives. The ratio of specific activities may be the preferred method for drugs with long half-lives. The conventional method is limited by the number of samples needed, but is potentially useful under those conditions in which data following test and intravenous routes of administration are available.

Animals↗
PubMed1989

Hepatic modeling of metabolite kinetics in sequential and parallel pathways: salicylamide and gentisamide metabolism in perfused rat liver.

Previous data on salicylamide (SAM) metabolism in the perfused rat liver had indicated that SAM was metabolized by three parallel (competing) pathways: sulfation, glucuronidation, and hydroxylation, whereas sequential metabolism of the hydroxylated metabolite, gentisamide (GAM), was solely via 5-glucuronidation to form GAM-5G. However, under comparable conditions, preformed GAM formed mainly two monosulfate conjugates at the 2- and 5-positions (GAM-2S and GAM-5S); 5-glucuronidation was a minor pathway. In the present study, the techniques of normal (N) and retrograde (R) rat liver perfusion with SAM and mathematic modeling on SAM and GAM metabolism were used to explore the role of enzymic distributions in determining the dissimilar fates of GAM, as a generated metabolite of SAM or as preformed GAM. Changes in the steady-state extraction ratio of SAM (E) and metabolite formation ratios between N and R perfusions were used as indices of the uneven distribution of enzyme activities. Two SAM concentrations (134 and 295 microM) were used for single-pass perfusion: the lower SAM concentration exceeded the apparent Km for SAM sulfation but was less than those for SAM glucuronidation and hydroxylation; the higher concentration exceeded the apparent Km's for SAM sulfation and glucuronidation but was less than the Km for hydroxylations. Simulation of SAM metabolism data was carried out with various enzyme distribution patterns and extended to include GAM metabolism. At both input concentrations, E was high (0.94 at 134 microM and 0.7 at 295 microM) and unchanged during N and R, with SAM-sulfate (SAM-S) as the major metabolite and GAM-5G as the only detectable metabolite of GAM. Saturation of SAM sulfation occurred at the higher input SAM concentration as shown by a decrease in E and a proportionally less increase in sulfation rates and proportionally more than expected increases in SAM hydroxylation and glucuronidation rates. At both SAM concentrations, the steady-state ratio of metabolite formation rates for SAM-S/SAM-G decreased when flow direction changed from N to R. An insignificant decrease in SAM-S/SAM-OH was observed at the low input SAM concentration, due to the small amount of SAM-OH formed and hence large variation in the ratio among the preparations, whereas at the high input SAM concentration, the decrease in SAM-S/SAM-OH with a change in flow direction from N to R was evident. The metabolite formation ratio, SAM-G/SAM-OH, however, was unchanged at both input concentrations and flow directions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Synthesis and evaluation of the analgesic and antiinflammatory activities of O-substituted salicylamides.

The present investigation deals with the synthesis of some new salicylamidoacetyl sulfonamides 3a,b, salicylamido ethylacetate 4, salicylamido acetic acid hydrazide 5, which is considered as the key intermediate for the synthesis of several series of new compounds such as salicylamido pyrazol 6 and pyrazolone 7. N-imido-derivatives 9, 10, 11, thiadiazole 13, oxadiazole 14, 15, Schiffs bases 16a-f. Cyclocondensation of Schiffs bases with thioglycolic acid gave thiazolidinone 18a-c while with acetylchloride afforded azitidinones 19a-c and with acetic anhydride gave 1,4-benzoxazepine-3,5-dione. Some of the compounds were tested for their analgesic and antiinflammatory activities as well as ulcerogenic effects. Some derivatives were more effective than salicylamide and ulcerogenic activity was variably lowered.

Analgesics, Non-Narcotic↗
PubMed2001

Synthesis of new salicylamide derivatives with evaluation of their antiinflammatory, analgesic and antipyretic activities.

A new series of pyridazine, pyrazoles, pyrazolidine-3,5-dione, Semicarbazide, thiosemicarbazides, hydantoin, thiohydantoins, 1,2,4-triazoles, S-triazolo[3,4-b]-1,3,4-thiadiazoles incorporated indirectly into salicylamide moiety at position 2 were synthesized. Also the synthesis of novel series of 3-salicylamido-2-hydroxypropyl-amine derivatives were prepared. Several of these compounds were screened for antiinflammatory, analgesic, antipyretic and ulcerogenic activities.

Analgesics, Non-Narcotic↗
PubMed1990

Metabolism of ethyl 2-carbamoyloxybenzoate (4003/2), a prodrug of salicylic acid, carsalam and salicylamide.

The metabolites of 4003/2 observed in vivo have been produced by incubation in vitro of 4003/2 with liver post-mitochondrial supernatants from rat, rabbit and dog. The metabolites were characterized by UV, i.r., NMR, MS and HPLC. All the metabolites detected have been or are in use as drugs for the relief of pain and inflammation. Hence, the new drug 4003/2 is a pro-drug of salicylic acid, carsalam and salicylamide.

Animals↗
PubMed1991

A comparative PET-study of five carbon-11 or fluorine-18 labelled salicylamides. Preparation and in vitro dopamine D-2 receptor binding.

Five 11C- or 18F-labelled salicylamides ([11C]raclopride (I), [11C]eticlopride (II), [18F]NCQ 258 (III), [18F]NCQ 134 (IV) and [18F]NCQ 135 (V] were prepared. The total radiochemical yields of I-V from EOB were 3-30% (decay-corrected) with an overall synthesis time of 40-110 min. All compounds were isolated by semi-preparative HPLC and the radiochemical purity was greater than 99%. I-V were in separate experiments injected into Cynomolgus monkeys for PET-examination of ligand distribution in brain in vivo. I-V passed rapidly across the blood-brain barrier. With both analogs I and II there was a high uptake in the striatum, a region with a high density of dopamine D-2 receptors. With the 18F-labelled analogs III and IV, the uptake in the striatum was almost identical to that in the dopamine receptor poor cerebellum whereas the striatal uptake of V was clearly higher than in the cerebellum. Unlabelled I-V (raclopride, eticlopride, NCQ 258 (VII), NCQ 134 (VIII) and NCQ 135 (IX)) were also prepared and examined in vitro using [3H]raclopride and [3H]spiperone binding to rat striatal dopamine D-2 receptors. A significantly lower affinity was shown for NCQ 258 and NCQ 134 (5 times) compared to that of raclopride and eticlopride, respectively, whereas the affinity of NCQ 135 was similar to that of eticlopride.

Animals↗
PubMed2004

Effects of Sho-saiko-to extract and its components, Baicalin, baicalein, glycyrrhizin and glycyrrhetic acid, on pharmacokinetic behavior of salicylamide in carbon tetrachloride intoxicated rats.

To elucidate the effects of Sho-saiko-to extract and its components, baicalin, baicalein, glycyrrhizin and glycyrrhetic acid, against the effects of longer periods of acute hepatic injury induced by CCl4, we measured serum ALT activity in male Wistar rats for five days after ip administration of CCl4 (0.2 ml/kg), and examined the daily changes of the pharmacokinetic behavior of salicylamide (SAM) for five days. Serum ALT activity rose to a maximum level within a day after administration of CCl4 and then decreased to the control level after three. Sho-saiko-to extract and its components could suppress this acute change in serum ALT activity to less than 50% of CCl4 alone. However, the pharmacokinetics of SAM showed that liver function recovers in a biphasic manner, so that plasma clearance (CL) decreased significantly at days 1 and 3 after administration of CCl4 (P<0.05). We concluded that the CL change at day 1 corresponds to the acute action of CCl4 intoxication, and that the change at day 3 is effect of physiologically reduced liver function due to the liver regeneration for tissue repair after the CCl4 hepatic injury. Sho-saiko-to extract and its components were shown to suppress acute hepatic injury induced by CCl4, and to bring about an early recovery in liver function.

Alanine Transaminase↗
PubMed2006

Protective role of 3-nitro-N-methyl-salicylamide on isolated rat heart during 4 hours of cold storage and reperfusion.

OBJECTIVE: Cardiac ischemia/reperfusion (I/R) injury, a necessary consequence of transplantation, is probably related to the formation of reactive oxygen species (ROS). The ROS burst within the first moments of reperfusion is associated with injury, continuously generate O2- at about 3% to 5% of total O2 consumption owing to electron leak by mitochondrial oxidoreductases, especially complexes I and III. 3-nitro-N-methyl-salicylamide (NNMS) displays inhibitory effects on succinate-cytochrome C reductase, but also reduces effects on creation of O2- radical and H2O2 by isolated rat mitochondria. Presumably NNMS inhibits electron leakage from the mitochondrial respiratory chain. We investigated effect of NNMS on heart protection after hypothermic ischemia. METHODS: A Langendorff-prepared rat heart model was employed after the heart had been preserved for 4 hours under hypothermic conditions of ischemia with subsequent reperfusion/rewarming for 60 minutes. RESULTS: The group of hearts treated with NNMS showed increased recovery of heart function compared with a group of mEC. The lactate dehydrogenase (LDH) activity in coronary flow (CF) by hearts treated with NNMS was lower than that with mECs, as was the content of malonedialdehyde (MDA) and conjugated diene (CD). CONCLUSIONS: NNMS improved heart physiology after reperfusion following 4 hours of hypothermic ischemia.

Animals↗
PubMed1984

Inhibition studies of microsomal UDP-glucuronosyltransferase activities by furosemide and salicylamide.

Contrarily to cytochrome P-450, a few inhibitors of UDP-glucuronosyltransferase have been described. We verified the nature of the in vitro inhibition due to furosemide, using 4 different aglycones (morphine, p-nitrophenol, borneol and eugenol) presumably belong may to different clusters of UDP-glucuronosyltransferase activities. The variations of these corresponding kinetic parameters (Km, Vmax, specific activities) must correspond to different inhibition mechanisms of furosemide, for example different site(s) of fixation in the area of the active site of UDPGT. Because these variations were not as classically described, we checked the impact of furosemide pretreatment on in vitro levels of different UDPGT activities. We compared these result, with another inhibitor (salicylamide). The apparent induction due to the both molecules enforced the hypothesis of a complexe inhibition mechanism.

Animals↗
PubMed1999

Novel quinolizidine salicylamide influenza fusion inhibitors.

A novel series of quinolizidine salicylamides was synthesized as specific inhibitors of the H1 subtype of influenza A viruses. These inhibitors inhibit the pH-induced fusion process, thereby blocking viral entry into host cells. Compound 16 was the most active inhibitor in this series with an EC50 of 0.25 microg/mL in plaque reduction assay. The synthesis and the SAR of these compounds are discussed.

Animals↗