salicylates and salicylamide

The purpose was to investigate the in vivo skin penetration of four 14C-salicylic compounds using microdialysis and to relate dermal concentrations to structural features. Furthermore, to compare two in vivo retrodialysis recovery methods for estimation of true unbound extracellular concentrations. Microdialysis probes were inserted in the dermis of hairless rats. Equimolal 14C-salicylic formulations were applied topically and dialysate sampled consecutively for 4h. True extracellular concentrations were estimated by retrodialysis by drug method (the 14C-salicylic compounds themselves) and by retrodialysis by calibrator method (3H-salicylic acid as internal standard). Probe depth was measured by ultrasound scanning. High dermal concentrations were found after application of 14C-salicylamide (low protein-binding) and the lipophilic ester 14C-butyl salicylate, which was completely hydrolysed to 14C-salicylic acid during skin diffusion. Protein binding and dissociation may explain the lower dermal concentrations of 14C-salicylic acid and 14C-diethylamine salicylate, respectively. Probe depth did not significantly influence dialysate concentrations. The two in vivo recovery correction methods did not reduce the variation in concentration-time curves. In conclusion, differentiated penetration kinetics was found ranking: 14C-salicylamide >/= 14C-butyl salicylate > 14C-salicylic acid > 14C-diethylamine salicylate. Dermal concentrations were related to structural features of the model compounds. The two correction methods performed alike; however, the calibrator method has the advantage of serving as a quality control during experiments.

Topics: Administration, Cutaneous; Animals; Female; In Vitro Techniques; Microdialysis; Models, Biological; Permeability; Rats; Rats, Sprague-Dawley; Salicylamides; Salicylates; Skin; Skin Absorption; Time Factors

Gentisamide (GAM, 2,5-dihydroxybenzamide), a minor first-pass metabolite of salicylamide (SAM, 2-hydroxybenzamide), was studied using FT-IR, 1D and 2D homo- and heteronuclear 1H and 13C NMR spectroscopy. GAM was isolated from human urine eight hours after oral administration of SAM. FT-IR, 1H and 13C NMR spectra unequivocally confirmed the chemical structure of GAM through chemical and substituent shifts, coupling constants and connectivities in COSY, NOESY, HETCOR and HBMC spectra. From NOESY spectra of GAM in DMSO-d6, it was concluded that the amide protons are oriented toward the ortho-proton at C-6. Obtained results indicate that the presence of the additional phenol group at C-5 in GAM favours the formation of intramolecular hydrogen bonding of the O...HO type between C2-OH proton and oxygen atom of the amide group.

Topics: Benzamides; Carbon Isotopes; Chemistry, Pharmaceutical; Croatia; Deuterium; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Salicylamides; Salicylates; Spectroscopy, Fourier Transform Infrared

There is a strong need for antipruritic substances for treating itch in clinical dermatology. In one recent human study, topically applied acetylsalicylic acid has been described to rapidly decrease histamine-induced itch. We have established a model for periferally elicited pruritus by injecting serotonin into the rostral back area (neck) in rats. Using this model, we aimed to investigate the antipruritic potential of four different salicylic compounds, which all possess different skin penetration characteristics. Eighteen rats were studied for 6 weeks. Prior to serotonin injections (2 mg/ml, 50 micro l), 10 micro l of test substances was applied to a circular area 18 mm in diameter. The four substances were salicylic acid, butyl salicylate, diethylamine salicylate and salicylamide, all solubilized in dimethyl isosorbide to a concentration of 5% w/w. Diethylamine salicylate and salicylamide were previously shown to be slowly absorbed through rat skin in contrast to salicylic acid and butyl salicylate. After serotonin injections, scratching was monitored by video recording for 1.5 h. Compared with the vehicle, a lower number of scratch sequences were seen when diethylamine salicylate (P < 0.001) and salicylamide (P = 0.005) had been applied. The numbers of scratch sequences were lower with diethylamine salicylate and salicylamide than with the vehicle throughout the 1.5-h study period. We conclude that topical application of diethylamine salicylate and salicylamide could suppress serotonin-induced scratching in rats. The antipruritic effect seems to be related to the slow drug release of the two substances. The results may be clinically relevant as serotonin induces itch in humans.

Topics: Administration, Topical; Animals; Antipruritics; Female; Pruritus; Rats; Rats, Mutant Strains; Salicylamides; Salicylates; Salicylic Acid; Serotonin

Salicylamide, sodium salicylate and acetylsalicylic acid are salicylic acid derivates. They differ in their substitution on the benzene ring and may have different effects on membranes. Red blood cells were used as a prototypical cellular system regarding drug mediated plasma bilayer effects. Established photometric methods sensing tiny changes of red blood cell morphology at rest (red blood cell shape) and at very low shear forces (red blood cell stiffness, red blood cell relaxation time) were applied. The derivative induced effects were detected in a time- and dose-dependent manner. Salicylamide induced a most pronounced echinocytic shape at 5 mM. The shape effect was smaller above as well as below 5 mM. Sodium salicylate induced echinocytes with increasing concentrations showing a saturation above 10 mM. In contrast, the shape was not affected by acetylsalicylic acid. All shape changes occurred within 2 min, and were reversible. The above tendencies were in parallel to a slight red blood cell stiffening. The relaxation time continuously increased with increasing concentrations in both salicylamide and sodium salicylate, with salicylamide always acting stronger. Acetylsalicylic acid again showed no effect. We hypothesize that the observed effects of sodium salicylate and salicylamide are due to their phenolic character mediating a molecular hydrophobicity. According to the bilayer couple hypothesis this would lead to an insertion into the red blood cells outer plasma bilayer leaflet. The extension induced here would cause a positive membrane bending leading to echinocytic shapes and the observed loss of red blood cell fluidity. In contrast, the hydrophilic aspirin would penetrate and thus not affect the red blood cell plasma membrane.

Topics: Aspirin; Cell Membrane; Cell Size; Dose-Response Relationship, Drug; Erythrocyte Membrane; Humans; In Vitro Techniques; Photometry; Salicylamides; Salicylates; Sodium Salicylate; Time Factors

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.

Topics: Humans; Salicylamides; Salicylates; Spectrometry, Fluorescence

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.

Topics: Animals; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Male; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Salicylamides; Salicylates; Salicylic Acid; Thromboxane B2

An assessment of salicylic acid-induced mucosal damage in vivo by measuring the metabolism of salicylamide (SAM) was investigated in rabbit intestine. The intestinal first-pass metabolism of SAM was studied using in situ intestinal sacs with complete mesenteric venous blood collection. The appearance of both SAM and its metabolites into the mesenteric venous blood was measured directly by cannulating the mesenteric vein of exposed intestine and collecting all venous blood draining from the absorbing region. Following oral pretreatment with salicylic acid, the appearance of SAM glucuronide (SAMG) in the mesenteric venous blood was significantly increased compared with the control. The increased blood concentration of SAMG following intraduodenal administration of SAM in vivo was observed in rabbits pretreated with salicylic acid orally. The blood concentration of SAMG after the intravenous administration of SAM was not increased compared with the control. We suggest that the change in the intestinal first-pass metabolism of SAM may be due to the intestinal mucosal damage induced by oral pretreatment with salicylic acid. The measurement of SAM metabolites may be of value in the assessment of intestinal mucosal damage in vivo.

Topics: Animals; Intestinal Mucosa; Male; Rabbits; Salicylamides; Salicylates; Salicylic Acid; Spectrometry, Fluorescence

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.

Topics: Animals; Carbamates; Chromatography, High Pressure Liquid; Fluorides; Male; Mitochondria, Liver; Oxazines; Potassium; Potassium Compounds; Prodrugs; Rats; Salicylamides; Salicylates; Salicylic Acid

Topics: Animals; Drug Interactions; Kinetics; Male; Rabbits; Salicylamides; Salicylates; Salicylic Acid; Sulfisoxazole

In vitro salicylates /aspirin, salicylic acid, salicylamide and gentisic acid/ inhibited formation of 12-lipoxygenase products in intact human washed platelets which were stimulated with thrombin or arachidonic acid. Salicylates did not affect 12-lipoxygenase activity in platelet lysates. Ex vivo aspirin or salicylamide at a dose of 1 g given orally to healthy volunteers potentiated formation of 12-lipoxygenase products in washed platelets. It is concluded that the effect of salicylates on 12-lipoxygenase pathway is independent from their influence on cyclooxygenase activity in platelets and aspirin cannot be considered as a selective inhibitor of platelet cyclooxygenase.

Topics: Adult; Arachidonate 12-Lipoxygenase; Arachidonate Lipoxygenases; Aspirin; Blood Platelets; Chromatography, High Pressure Liquid; Gentisates; Humans; Hydroxybenzoates; In Vitro Techniques; Lipoxygenase Inhibitors; Salicylamides; Salicylates; Salicylic Acid

Salicylate (1-5 mM) had no effect on the peak amplitude (Pt) of twitches elicited at 0.05 to 0.05 Hz, but depressed the Pt in frog and toad "toe" muscles stimulated at 5 to 10 Hz. The maximal tetanic tension (Po) was not reduced significantly by salicylate, but the time to reach Po was increased to several seconds. K-induced contractures were reduced by ca 40 and 50%, respectively, in the presence of 5 and 10 mM salicylate. Pretreatment with salicylate (5 mM) reduced the twitch potentiation by quinine, shortened the duration of twitches in caffeine-treated muscles and inhibited the caffeine- and the quinine-induced contractures. Muscles in contracture because of a previous exposure to quinine relaxed promptly upon addition of salicylate to the bathing medium. The inhibitory effects of salicylate on Pt, on Po and on K- or drug-induced contractures were reversible and were not affected by changes in pH between 7.5 and 6.5. Salicylate depressed the caffeine-rapid cooling contractures (RCC). In toad muscles, this effect was affected markedly by the order in which caffeine and salicylate were applied. Blockade of the caffeine-RCC by salicylate was enhanced by lowering the pH of the medium. Salicylamide (1-5 mM) reproduced the effects of salicylate on the caffeine- and the quinine-induced contractures and the caffeine-RCC. In addition, salicylamide reduced the twitch tension. It is proposed that salicylate and salicylamide affect Casequestration by the sarcoplasmic reticulum.

Topics: Animals; Bufo marinus; Caffeine; Calcium; Hydrogen-Ion Concentration; Membrane Potentials; Muscle Contraction; Potassium; Quinine; Ranidae; Salicylamides; Salicylates; Salicylic Acid

The dissolution rates of each component in compressed spheres consisting of three components were measured under sink conditions. The observed dissolution rates of benzoic acid, salicylic acid, and salicylamide compare favorably to the predicted dissolution rates according to a previously presented kinetic model.

Topics: Benzoates; Benzoic Acid; Kinetics; Models, Chemical; Salicylamides; Salicylates; Salicylic Acid; Solubility; Spectrophotometry, Ultraviolet

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.

Topics: Acetaminophen; Aspirin; Buffers; Caffeine; Drug Combinations; Drug Contamination; Salicylamides; Salicylates; Salicylic Acid; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet

Topics: Humans; Metabolism; Salicylamides; Salicylates

Topics: Aspirin; Salicylamides; Salicylates; Salicylic Acid

Topics: Animals; Cats; Salicylamides; Salicylates; Salicylic Acid

Topics: Fungi; In Vitro Techniques; Salicylamides; Salicylates

Topics: Aspirin; Calculi; Humans; Salicylamides; Salicylates; Urinary Calculi; Urinary Tract

Topics: Aminopyrine; Analgesics; Humans; Rheumatic Diseases; Salicylamides; Salicylates

Topics: Analgesics; Antirheumatic Agents; Rheumatic Diseases; Salicylamides; Salicylates

Topics: Animals; Cats; Salicylamides; Salicylates; Salicylic Acid

Topics: Humans; Salicylamides; Salicylates; Urine

Topics: Purpura; Purpura, Thrombocytopenic; Salicylamides; Salicylates

Topics: Blood; Body Fluids; Humans; Salicylamides; Salicylates; Urine

Topics: 4-Aminobenzoic Acid; Adrenal Glands; Animals; Ascorbic Acid; Cholesterol; Rats; Salicylamides; Salicylates; Sodium Salicylate

Topics: Arthritis; Arthritis, Rheumatoid; Disease; Humans; Neuritis; Peripheral Nerves; Salicylamides; Salicylates

Topics: Animals; Cats; Felis; Rabbits; Salicylamides; Salicylates; Salicylic Acid; Sodium Salicylate

Topics: Anthelmintics; Enzymes; Salicylamides; Salicylates

Topics: Anthelmintics; Salicylamides; Salicylates

Topics: Anthelmintics; Salicylamides; Salicylates

Topics: Biological Transport; Blood; Humans; Salicylamides; Salicylates

Topics: Adrenal Cortex; Animals; Ascorbic Acid; Eosinophils; Leukocyte Count; Rats; Salicylamides; Salicylates

Topics: Administration, Rectal; Rheumatic Diseases; Salicylamides; Salicylates; Sciatica

Topics: Combined Modality Therapy; Hypnotics and Sedatives; Phenacetin; Salicylamides; Salicylates

Topics: 4-Aminobenzoic Acid; Analgesics; Humans; para-Aminobenzoates; Salicylamides; Salicylates; Sodium; Tonsillitis

Topics: Anthelmintics; Salicylamides; Salicylates

Topics: Analgesics; Rheumatic Diseases; Salicylamides; Salicylates

Topics: Anthelmintics; Rheumatic Diseases; Salicylamides; Salicylates; Salicylic Acid

Topics: Analgesics; Aspirin; Salicylamides; Salicylates

Topics: Salicylamides; Salicylates

Topics: Injections, Intramuscular; Salicylamides; Salicylates

Topics: Salicylamides; Salicylates

Topics: Anthelmintics; Salicylamides; Salicylates

Topics: Nervous System Diseases; Salicylamides; Salicylates

Topics: Salicylamides; Salicylates

Topics: Analgesics; Antipyretics; Salicylamides; Salicylates

Topics: Anthelmintics; Salicylamides; Salicylates

Topics: Arthritis; Arthritis, Rheumatoid; Humans; Hypersensitivity; Salicylamides; Salicylates

Topics: Anthelmintics; Salicylamides; Salicylates

Topics: Anesthesia; Animals; Bile; Chloralose; Diuresis; Diuretics; Dogs; Salicylamides; Salicylates

Topics: Body Fluids; Humans; Salicylamides; Salicylates; Urine

Topics: Animals; Anthelmintics; Aspirin; Mice; Salicylamides; Salicylates; Sodium Salicylate

Topics: Anthelmintics; Salicylamides; Salicylates; Sodium Salicylate

Topics: 4-Aminobenzoic Acid; Animals; Benzoates; Benzoic Acid; Body Temperature; Metabolism; Oxygen Consumption; Rats; Salicylamides; Salicylates; Salts; Sodium

Topics: Analgesics; Salicylamides; Salicylates

Topics: Anthelmintics; Salicylamides; Salicylates

Topics: Salicylamides; Salicylates

Topics: Salicylamides; Salicylates

Topics: Rheumatic Diseases; Rheumatic Fever; Salicylamides; Salicylates

Topics: Antipyretics; Humans; Salicylamides; Salicylates

Topics: Analgesics; Antipyretics; Hyperthermia, Induced; Salicylamides; Salicylates