Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “SALICYLAMIDE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed1986

Depletion of hepatic UDP-glucuronic acid by drugs that are glucuronidated.

Salicylamide, clofibric acid, valproic acid and chloramphenicol are all known to be glucuronidated. The effects of these compounds on the hepatic concentration of UDP-glucuronic acid, the cosubstrate for glucuronidation, were studied in mice and found to lower hepatic UDP-glucuronic acid in a dose- and time-dependent fashion. Valproic acid, chloramphenicol, salicylamide and clofibric acid depleted hepatic UDP-glucuronic acid significantly at dosages as low as 0.5, 0.5, 0.75 and 4.0 mmol/kg, respectively. Hepatic UDP-glucuronic acid was decreased by 90% by valproic acid, 91% by chloramphenicol, 98% by salicylamide and 41% by clofibric acid (after dosages of 4, 2, 1 and 5 mmol/kg, respectively). UDP-glucuronic acid was depleted maximally by 15 after drug administration. Salicylamide also was used as a model compound to study the effect of drug loading on the hepatic concentrations of UDP-glucose and glycogen, precursors of UDP-glucuronic acid. It was found that, in addition to UDP-glucuronic acid, salicylamide (4 mmol/kg) also depleted UDP-glucose and glycogen by about 50%. These data suggest that large drug loads cause an increase flux through the glucuronic acid pathway and that hepatic UDP-glucuronic acid is consumed more rapidly than it is produced.

Animals↗
PubMedDate not supplied

Effect of product inhibition on elimination kinetics of ethoxybenzamide in rabbits. Analysis by physiological pharmacokinetic model.

In our previous study [Lin, Sugiyama, Awazu, and Hanano: J. Pharmacokin. Biopharm. 10,649 (1982)], we successfully applied a physiological pharmacokinetic model to quantitative prediction of the elimination and distribution kinetics of ethoxybenzamide in rats and rabbits. The predictions of the time course of ethoxybenzamide concentrations in plasma were good at lower doses (10 and 20 mg/kg), whereas those at high dose (80 mg/kg) were poor. In the present study, therefore, product inhibition was suspected and examined. Product inhibition of ethoxybenzamide deethylation by its metabolite, salicylamide, was demonstrated both in vivo and in vitro studies. The plasma disappearances of ethoxybenzamide after a 20 mg/kg iv injection were determined both in the control and the salicylamide-treated rabbits. In the salicylamide-treated rabbits, the plasma disappearance of ethoxybenzamide was significantly delayed compared to that in control rabbits. This delay was quantitatively explained by the physiological pharmacokinetic model taking the competitive-type of product inhibition into consideration. The apparent dissociation constant for the salicylamide-enzyme complex in vivo was estimated as 0.14 mM. The inhibition of ethoxybenzamide de-ethylation by salicylamide was observed also in in vitro study using liver microsome of rabbits.

Animals↗
PubMed1991

Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides. Relations to other side chain congeners.

A number of substituted N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides and -salicylamides have been prepared and investigated as dopamine D-2 receptor antagonists in vitro and in vivo. The affinity was found to be confined to the R enantiomer, in contrast to the corresponding N-ethyl or N-allyl derivatives. The X-ray structure of one of the compounds (15) confirmed the R stereochemistry. This compound (15) was found to adopt a solid-state conformation in which the 4-fluorobenzyl group is folded over the salicylamide moiety. Benzamides having a 2,3-dimethoxy substitution pattern (24 and 26) or salicylamides with a 5,6-dimethoxy grouping (21 and 22) were especially potent, in that they inhibited [3H]spiperone binding to rat striatal dopamine D-2 receptors in vitro with IC50 values of about 1 nM. The new compounds' ability to block apomorphine-induced stereotypies correlated with the affinity for the [3H]spiperone binding site. Higher dose levels were necessary to induce catalepsy than to block the apomorphine-induced responses. The influence of the aromatic substituents on the potency of substituted benzamides with three types of side chains, i.e. (R)-(1-benzyl-2-pyrrolidinyl)methyl, (S)-(1-ethyl-2-pyrrolidinyl)methyl and 1-benzyl-4-piperidinyl, was compared. The 3-bromo-5,6-dimethoxysalicylamide substitution pattern was found to be the most general since it gave very potent compounds in all series. The substituted (R)-N-[(1-(4-fluoro-benzyl)-2-pyrrolidinyl)methyl]benzamides (26) and -salicylamides (22) are suitable for development into 18F radioligands without altering the parent structure.

Animals↗
PubMed1980

Tocainide kinetics and metabolism: effects of phenobarbital and substrates of glucuronyl transferase.

Tocainide, a lidocaine congener with low hepatic clearance, is eliminated predominantly by formation of a novel glucuronide conjugate. This suggested the possibility of metabolic interactions with enzyme inducers or competitive substrates for glucuronyl transferase. The time course of tocainide blood concentration as well as the urinary excretion-time profiles of drug and principal metabolite (a glucuronide of tocainide carbaminic acid, TOCG) were examined in six subjects before and after 15 days on phenobarbital (100 mg/day). In another study, the effect of salicylamide and clofibrate on the time courses of tocainide and TOCG urinary excretion were examined in four of the same six subjects. After 600 mg tocainide HCl by mouth, the area under the tocainide blood concentration-time curve was 48.2 +/- 11.9 hr micrograms/ml for the control dose and 49.6 +/- 4.2 hr micrograms/ml (mean = SD) after phenobarbital. Percent of dose excreted unchanged in urine (46.0 +/- 4.9 and 43.4 +/- 5.6) and percent of dose excreted as TOCG (30.6 +/0 3.3 and 27.7 +/- 7.2) were not affected by phenobarbital (data presented as control and after phenobarbital). Because salicylamide has been reported to be a potent inhibitor of the glucuronidation of some drugs and because clofibrate yields metabolites that may be competitive inhibitors of tocainide conjugation, the two were given together with tocainide. Average percent of dose recovered in urine as unchanged tocainide in 24 hr was 26.8%, 28.3%, and 29.7% in the control, salicylamide, and clofibrate studies. The urinary excretion of TOCG was also not affected. It is concluded that under the conditions of our investigation, the principal urinary metabolite of tocainide, a glucuronide of tocainide carbaminic acid, is formed by a mechanism not subject to induction by phenobarbital or competitive inhibition by salicylamide or clofibrate.

Adult↗
PubMed1990

Potential antipsychotic agents 5. Synthesis and antidopaminergic properties of substituted 5,6-dimethoxysalicylamides and related compounds.

A series of 3-substituted 5,6-dimethoxysalicylamides III (9-13 and 15) has been synthesized from the corresponding 2,5,6-trimethoxybenzoic acids. Relaxation times T1 and carbon chemical shifts of the methoxy groups in III showed that the 6-methoxy group adopts a nearly perpendicular orientation and the 5-methoxy group takes on a more coplanar orientation with respect to the ring plane in solution. The salicylamides III display a very high and stereoselective affinity for the [3H]spiperone and [3H]raclopride binding sites in vitro. Regioisomeric salicylamides IV also exhibit pronounced, but lower than III, affinity for the [3H]spiperone binding site. The structural requirements were further assessed by studies of the related amino analogues 23 and 24 and hydroxy analogue 27. The 3-bromo compound 11 (FLB 463) was studied in various in vivo models and compared with the dopamine-D2 antagonists sulpiride, raclopride, eticlopride, and haloperidol. The high potency of 11 to selectively block dopamine-D2 receptors in vitro and in vivo combined with indications on a low potential for motor side effects makes it a very interesting new member of the class of substituted salicylamides.

Animals↗
PubMed1990

Potential antipsychotic agents. 7. Synthesis and antidopaminergic properties of the atypical highly potent (S)-5-bromo-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide and related compounds. A comparative study.

(S)-5-Bromo-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide (6) and some related compounds, i.e. the R isomer 7, the 3-hydroxy analogue 8, the desbromo derivative 9, the monomethoxy compound 10, and the 2,4-dimethoxy analogue 11, have been synthesized from the corresponding benzoic acids. The benzamides, lacking o-hydroxy groups, were evaluated for their affinity for the [3H]spiperone binding site and for their inhibition of apomorphine-induced behavioral responses in relation to the effect of the corresponding salicylamides. Besides the 2-hydroxy-3-methoxybenzamide 12 and the related 1,4-benzodioxane (13) and 2,3-dihydrobenzofuran (14), carboxamides were investigated in order to evaluate the stereoelectronic requirements on the 2-methoxy group for the receptor interaction. The study supports the view that the o-methoxy group may adopt coplanar, as well as perpendicular orientations, and maintain the intramolecular hydrogen bonding required in the bioactive conformation. The benzamide 6 was found to be equipotent with the analogous highly active salicylamide 3 (FLB 463) both in vitro and in vivo. In addition, 6 displayed a preferential inhibition of the hyperactivity component of the behavioral syndrome, which is regarded to indicate a low tendency to induce extrapyramidal side effects in man at antipsychotically effective doses. The benzamide class of compounds (6-10) were found to be somewhat more sensitive to the structural modifications than the salicylamide class, i.e. the o-hydroxy-substituted benzamides (2-5). The potent and selective benzamide 6 (FLB 457) is highly suitable for investigations of dopamine D-2 mediated responses and, in radiolabeled form, for receptor binding studies in vitro and in vivo.

Animals↗
PubMedDate not supplied

Phenolic compounds, sodium salicylate and related compounds, as inhibitors of tumor cell growth and inducers of apoptosis in mouse leukemia L1210 cells.

The effects of a series of phenolic compounds were compared to the effects of sodium salicylate (2-hydroxybenzoate) on the growth, cell cycle and apoptotic effects in wild-type (WT) and deoxyadenosine-resistant (Y8) L1210 leukemia cells. These compounds included: salicylaldehyde, salicylaldoxime, salicylhydroxamic acid, salicylamide, 5-aminosalicylate and 5-sulfosalicylate. The IC50 values for inhibition of tumor cell growth ranged from 40 microM for salicylaldhyde to greater than 4 mM for 5-sulfosalicylate. There appeared to be an excellent correlation between the IC50 value for a compound and the ratio of octanol/aqueous distribution. Salicylamide caused a G2/M block in both the WT and Y8 L1210 cells, while salicylalehyde caused a G0/G1 block in both the WT and Y8 cells. Salicylamide and salicylaldoxime caused a much greater apoptotic effect in the Y8 cells than in the parental WT L210 cells. These data suggest that salicylaldehyde and salicylaldoxime, the most active compounds in this series, may provide the lead chemicals from which other more active drugs can be synthesized.

Aldehydes↗
PubMed1984

Inhibitory effects of salicylate on contractility in skeletal muscle.

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.

Animals↗
PubMed1995

Depletion of hepatic 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and sulfate in rats by xenobiotics that are sulfated.

Sulfation is considered a high-affinity but low-capacity conjugation mechanism that is limited by the availability of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the cosubstrate for sulfation. Salicylamide, phenol and 1-naphthol are all known substrates for the sulfation reaction. This study was conducted to determine whether the xenobiotics that are sulfated when administered to rats will lower hepatic PAPS and its precursor, sulfate. Urinary sulfate excretion was reduced 85% to 95% by these compounds. Hepatic PAPS was reduced 73%, 39%, and 87% by salicylamide, phenol and naphthol, respectively, 2 hr after administration of 2 mmol/kg. These compounds also decreased serum sulfate concentrations by 45% to 86% and lowered hepatic sulfate concentrations. In summary, these studies demonstrate that salicylamide, phenol and 1-naphthol lower hepatic PAPS and sulfate concentrations, as well as serum sulfate concentrations. These findings imply that increased sulfation, as a result of the sulfation of xenobiotics, results in depletion of hepatic PAPS concentrations, possibly because the utilization of PAPS by the sulfotransferases exceeds its generation via sulfate activation. Thus the capacity-limited sulfation of high dosages of xenobiotics appears to be due to the reduced availability of hepatic PAPS, which in turn is limited by the availability of sulfate.

Animals↗
PubMed2000

Amidation of salicyluric acid and gentisuric acid: a possible role for peptidylglycine alpha-amidating monooxygenase in the metabolism of aspirin.

Bifunctional peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the copper-, ascorbate-, and O2-dependent cleavage of C-terminal glycine-extended peptides, N-acylglycines, and the bile acid glycine conjugates to the corresponding amides and glyoxylate. Two known metabolites of aspirin, salicyluric acid and gentisuric acid, are also substrates for PAM, leading to the formation of salicylamide and gentisamide. The time course for O2 consumption and glyoxylate production indicates that salicylurate amidation is a two-step reaction. Salicylurate is first converted to N-salicyl-alpha-hydroxyglycine, which is ultimately dealkylated to salicylamide and glyoxylate. The enzymatically generated salicylamide and N-salicyl-alpha-hydroxyglycine were characterized by mass spectrometry and two-dimensional 1H-13C heteronuclear multiple quantum coherence NMR.

Animals↗
PubMed2002

In vivo skin penetration of salicylic compounds in hairless rats.

The in vivo skin penetration of four salicylic compounds was investigated using a hairless rat model, which allowed for non-occluded, finite dose application, and free mobility of the rats throughout the test period. The model compounds were applied in equimolal concentrations of 0.4 mmol/g dimethyl isosorbide. At certain times (0.5-24 h) the rats were killed, and the amount of test compound on the skin surface, in the stratum corneum, and in the deeper viable skin layers was determined. Significant different skin concentrations were found with the following ranking: [(14)C]diethylamine salicylate>[(14)C]salicylic acid>[(14)C]salicylamide>[(14)C]butyl salicylate. In addition, the in vivo percutaneous rate of absorption was in the following order: [(14)C]butyl salicylate>[(14)C]salicylic acid> or =[(14)C]salicylamide>[(14)C]diethylamine salicylate. [(14)C]Butyl salicylate was rapidly absorbed and completely depleted from the surface 3 h post application. In comparison with [(14)C]salicylic acid, the ionic [(14)C]diethylamine salicylate had larger surface depots and penetrated the skin at a lower rate. The relatively hydrophilic [(14)C]salicylamide also had larger surface depots but much lower skin levels. For comparison, the in vitro permeation of the formulations was studied through freshly excised hairless rat skin using Franz diffusions cells, and an agreement between the techniques was found.

Animals↗
PubMed2003

Rational design and synthesis of androgen receptor-targeted nonsteroidal anti-androgen ligands for the tumor-specific delivery of a doxorubicin-formaldehyde conjugate.

The synthesis and preliminary evaluation of a doxorubicin-formaldehyde conjugate tethered to the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostate cancer are reported. The relative ability of the targeting group to bind to the human androgen receptor was studied as a function of tether. The tether served to attach the antiandrogen to the doxorubicin-formaldehyde conjugate via an N-Mannich base of a salicylamide derivative. The salicylamide was selected to serve as a trigger release mechanism to separate the doxorubicin-formaldehyde conjugate from the targeting group after it has bound to the androgen receptor. The remaining part of the tether consisted of a linear group that spanned from the 5-position of the salicylamide to the 3'-position of cyanonilutamide. The structures explored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethylene glycol), N,N'-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of the tethers bound to the targeting group for human androgen receptor were measured using a (3)H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeted drug with the butynediol-based linear region has a relative binding affinity of 10%. This relative binding affinity is encouraging in light of the cocrystal structure of human androgen receptor ligand binding domain bound to the steroid Metribolone which predicts very limited space for a tether connecting the antiandrogen on the inside to the cytotoxin on the outside.

Androgen Antagonists↗
PubMed1989

Drug interactions involving aspirin (acetylsalicylic acid) and salicylic acid.

Aspirin (acetylsalicylic acid) is metabolically converted to salicyclic acid by the action of carboxylesterases. Although metabolic drug interactions involving aspirin are theoretically possible, there appear to have been no studies to date which have shown conclusively that aspirin hydrolysis is altered by coadministered drugs. However, a number of treatments are known to affect the rate or extent of aspirin absorption, including activated charcoal, antacids, cholestyramine and metoclopramide. Caffeine and metoprolol have been reported to increase peak salicylic acid concentration following aspirin administration, and coadministration of dipyridamole and aspirin results in higher plasma aspirin concentrations. The mechanism(s) responsible for these latter observations remains unknown. Salicylic acid is extensively bound to plasma albumin, and many of the reported drug interactions involve displacement of the coadministered drug from plasma protein. Protein binding displacement appears to be the basis of salicylic acid interactions with diclofenac, flurbiprofen, ibuprofen, isoxicam, ketoprofen, naproxen, phenytoin and tolmetin. Following displacement of these agents increased clearance of total drug occurs, and consequently the plasma concentration of total drug decreases. Although generally not measured, unbound concentration of the interacting drug should not be markedly altered. Salicylic acid also increases total plasma clearance of fenoprofen but, unlike the interactions with the other propionic acid non-steroidals, plasma protein binding displacement does not appear to be involved. Induction of fenoprofen metabolism is a possibility, although there is no firm evidence from other studies that salicylate is able to induce the metabolism of coadministered drugs. Since salicylic acid is extensively metabolised, it is not surprising that it is able to inhibit the metabolism of certain coadministered drugs and chemicals, an effect which has been reported for salicylamide, valproic acid, m-xylene, and zomepirac. The interactions with salicylamide, m-xylene and zomepirac are probably competitive in nature since mutual inhibition of salicylic acid metabolism occurs. There is an additional component of protein binding displacement in the interactions with valproic acid and zomepirac, resulting in increased unbound drug concentration. Certain coadministered drugs (or chemicals) may alter the metabolism of salicylic acid; inhibition of its metabolism has been demonstrated following treatment with benzoic acid, salicylamide, m-xylene, zomepirac and possibly cimetidine. In contrast, salicylic acid elimination is enhanced in oral contraceptive steroid users and by corticosteroid treatment. Oral contraceptive steroids induce both salicylic acid glucuronidation and salicylurate formation. Induction of metabolism has also been proposed to account for the effects of corticosteroids, but this is still to be proven.(ABSTRACT TRUNCATED AT 400 WORDS)

Antacids↗
PubMedDate not supplied

Glucuronidation of morphine and six beta 2-sympathomimetics in isolated rat intestinal epithelial cells.

The metabolism of morphine and six beta 2-sympathomimetics (orciprenaline, terbutaline, fenoterol, salbutamol, ritodrine, and bamethan) in isolated rat intestinal epithelial cells was investigated. Only conjugates with glucuronic acid were detected. With regard to observed Vmax values the beta 2-sympathomimetics can be divided in two groups. The three resorcinols (orciprenaline, terbutaline, fenoterol) have a Vmax value comparable to that of morphine (70-230 pmol/min X mg cell protein). The phenolic beta 2-sympathomimetics (salbutamol, ritodrine, bamethan) exhibit a Vmax value comparable to the Vmax value of 1-naphthol (500-1100 pmol/min X mg cell protein). Calculation of intestinal intrinsic (metabolic) clearance and intestinal first pass extraction ratios from Vmax and Kappm values suggests that most of these drugs may undergo substantial intestinal first pass metabolism after oral administration. The glucuronidation of morphine in isolated mucosal cells could be completely inhibited by addition of 1-naphthol (50 microM), salicylamide (5 mM), or fenoterol (5 mM). Glucuronidation of fenoterol could be partially inhibited by 1-naphthol, salicylamide, and morphine. Preliminary data obtained with microsomes suggest that 1-naphthol and morphine are metabolized by different forms of the intestinal microsomal UDP-glucuronosyltransferase. Fenoterol and ritodrine are probably glucuronidated by the form, which also glucuronidates morphine. The results demonstrate that rat intestinal epithelial cells can be used to predict intestinal metabolism of morphine and other drugs at least qualitatively and that phenolic food constituents (e.g. 1-naphthol) and non-prescription drugs (e.g. salicylamide) may affect the intestinal first pass metabolism of morphine and fenoterol.

Adrenergic beta-Agonists↗
PubMed2006

Towards an understanding of the structurally based potential for mechanically activated disordering of small molecule organic crystals.

The potential for various small molecule organic crystals to undergo complete mechanically induced disordering is investigated. A model is proposed, which considers changes in free energy required for lattice incorporation of a critical dislocation density. Application requires knowledge of a few physical properties, namely the elastic shear modulus, Burgers vector magnitude, molar volume, melting temperature, and heat of fusion. The model was tested using seven compounds; acetaminophen, aspirin, gamma-indomethacin, salicylamide, sucrose, and two proprietary drug compounds, PFZ1 and PFZ2. Crystalline solids were subjected to high shear, controlled temperature comminution for various durations, after which the samples were examined using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The results verified that acetaminophen, aspirin, and salicylamide, which were suggested by the model to be resistant to complete mechanical disordering, remained fully crystalline, even after 5 h of milling. Sucrose and gamma-indomethacin were both predicted to be susceptible to amorphization, which was confirmed by physical characterization. Single, 3-h grinding experiments were performed on two proprietary compounds, PFZ1 and PFZ2. The model indicated that each should be resistant to complete disordering, a trend held by PFZ1. Evidence of partial disordering of PFZ2 was unexpected and is discussed with respect to possible temperature effects.

Acetaminophen↗
PubMed2003

Evaluation of in vitro antifungal activity of N-benzylsalicylamide derivatives.

A series of 65 derivatives of N-benzylsalicylamide was tested against eight potentially human pathogenic fungi by microdilution broth method modified according to M27-A standard. The majority of these compounds showed only weak in vitro antifungal activity. The most significant effect was observed against filamentous fungi Trichophyton mentagrophytes, Absidia corymbifera, and Aspergillus fumigatus while yeasts, in general, were less susceptible. N-(4'-Chlorobenzyl) salicylamides, N-(3',4'-dichlorobenzyl)-salicylamides, and partially N-benzylsalicylamides exhibited relatively high in vitro antifungal activity. The most efficient derivatives had MIC < or = 7.8 mumol/L against T. mentagrophytes. Regression analysis suggested an indirect relationship between MIC values and lipophilicity (log P).

Antifungal Agents↗
PubMed1986

Salicylates and 12-lipoxygenase activity in human washed platelets.

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.

Adult↗
PubMed2004

Differentiated in vivo skin penetration of salicylic compounds in hairless rats measured by cutaneous microdialysis.

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.

Administration, Cutaneous↗