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PubMed2006

Determination of fourteen non-steroidal anti-inflammatory drugs in animal serum and plasma by liquid chromatography/mass spectrometry.

The European Union has regulated the use of non-steroidal anti-inflammatory drugs (NSAIDs) in animal production and requires its member states to detect their residues in different matrices. In this work, a detailed MS and MS/MS study by ion-trap mass spectrometry of fourteen NSAIDs is described. Two multi-residue reversed-phase LC/ESI-MS/MS methods were developed, one for the determination of salicylic acid, naproxen, carprofen, flurbiprofen, ibuprofen, niflumic acid and meclofenamic acid in the negative ion mode, and the other for the determination of ketoprofen, suxibutazone, diclofenac, mefenamic acid, tolfenamic acid, phenylbutazone and its metabolite oxyphenbutazone in the positive ion mode. It was thus possible to confirm up to 14 different NSAID residues in serum and plasma samples of farmed animals, after chromatographic separation by a linear gradient. These substances were chosen as representative of different chemical subclasses of NSAIDs. The two methods were also validated in-house at three contamination levels, evaluating specificity and calculating mean recoveries, repeatability and within-laboratory reproducibility. The MS/MS product ion spectra were successfully used for the qualitative identification of all the drugs tested. All the NSAIDs, apart from salicylic acid, were recovered in high amounts, ranging between 71.6% and 100.9%.

Animals↗
PubMed1987

High-performance liquid chromatographic assay of a new non-steroidal anti-inflammatory agent, 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid, in human plasma and urine.

A high-performance liquid chromatographic method for the quantitation of a new anti-inflammatory agent, 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid (CN-100; I), has been developed. The assay consists in extracting samples containing I and mefenamic acid, the internal standard, under acidic conditions and analysis by reversed-phase chromatography using ultraviolet detection at 330 nm. Preliminary plasma concentration-time and cumulative urinary excretion profiles from a healthy subject following oral administration of the tablet formulation are presented. This method is simple, sensitive and reproducible and is applicable to studies of the pharmacokinetic behaviour of I in humans.

Administration, Oral↗
PubMed1989

Endogenous inhibition of arachidonic acid metabolism in the endometrium of the sheep.

Arachidonic acid is metabolised via the cyclo-oxygenase pathway to several biologically active metabolites. These metabolites control important reproductive functions like luteolysis of the corpus luteum. The metabolism of arachidonic acid was studied by the enzymatic conversion of [1-14C]-labelled arachidonic acid in sheep endometrial tissue. The inhibitory capacity of sheep endometrial tissue was measured by the enzymatic conversion of [1-14C]-arachidonic acid by sheep seminal vesicular gland microsomes. Endometrial microsomes converted arachidonic acid into different prostaglandins and monohydroxy acids but at a low rate. A factor(s) inhibiting both prostaglandin and monohydroxy acid synthesis was found in both the microsomal and cytosolic fractions of endometrial tissue. A very high inhibitory potency of prostaglandin and monohydroxy acid synthesis, calculated as IC50 values, was found in cytosolic fractions. For comparison IC50 values of indomethacin, mefenamic acid, carprofen and acetylsalicylic acid were also calculated in this in vitro system. These data indicate that both prostaglandin and monohydroxy acid synthesizing capacities and an inhibitory factor(s) are present in sheep endometrium and possibly regulate arachidonic acid metabolism in this tissue.

Animals↗
PubMed2006

PAMPA - excipient classification gradient map.

The effect of excipients on the artificial membrane permeability (Double-Sink PAMPA) properties of eight sparingly soluble drugs was studied. Quantities of excipient were selected to match the concentrations expected in the gastrointestinal fluid under clinically relevant conditions. Over 1,200 measurements were performed. To correct for the effects of the aqueous boundary layer and determine the intrinsic permeability, precisely measured ionization constants were used. The intrinsic permeability of weak acids was enhanced (up to 100 fold) but that of weak bases depressed (up to 270 fold) by the excipients: mefenamic acid > glybenclamide > progesterone > griseofulvin > clotrimazole > astemizole > dipyridamole > butacaine. Excipient enhancement ranked: 3 mM NaTC > 0.24% PEG400 > 0.2 M KCl > 0.24% NMP > 5% PEG400 > 0.24% PG > 1% PEG400 > 0.1M KCl > 1% PG > 1% NMP > 5% PG > 0.24% HP-beta-CD > 1% HP-beta-CD > 15 mM NaTC. The study clearly indicates that the method is suitable for use in preclinical development to assess the effect of excipients on the permeability of sparingly soluble drug candidates. The method is quick, cost-effective, and reasonably accurate. The self-rank-ordered PAMPA-Mapping may be a helpful visualization tool for delivery screening.

Cell Membrane Permeability↗
PubMed1994

Modulation of three types of K+ currents in canine coronary artery smooth muscle cells by NS-004, or 1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone.

The effects of the cardioprotective, vasorelaxant agent NS-004 [1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone] on K+ currents of freshly isolated canine coronary artery smooth muscle cells were examined using the suction pipette method. The Ca(++)-sensitive K+ current (IK, Ca) was isolated by using a holding potential of 0 mV and 5 mM ATP in the internal perfusate. The voltage-dependent delayed rectifier K+ current (IK, DR) was recorded at potentials below 20 mV in internal solution containing 5 mM ATP. The ATP-sensitive K+ current (IK, ATP) was induced by removing ATP in the pipette solution and was measured at potentials negative to -30 mV where IK, Ca and IK, DR were absent. External application of NS-004 activated IK, Ca, which, at 80 mV, was increased from 0.28 +/- 0.03 to 1.1 +/- 0.2, to 3.2 +/- 1.0, to 5.6 +/- 1.6 and to 8.5 +/- 1.6 nA, respectively, by 12.5, 25, 50 and 100 microM NS-004. Structurally related flufenamic, niflumic and mefenamic acids, at 100 microM, also enhanced IK, Ca. The order of potency for IK, Ca activation was NS-004 >> flufenamic = niflumic > mefenamic. In contrast, NS-004 blocked IK, DR, beginning at 2 microM with 50% inhibition at 22 microM. NS-004 also inhibited IK, ATP with a Ki value of 2.4 microM and a Hill coefficient of 1.3 in 0 mM intracellular ATP. These results demonstrate that NS-004 is a more potent activator of IK, Ca than the fenamates and that it is also a relatively potent blocker of IK, DR and IK, ATP in canine coronary artery smooth muscle cells.

Animals↗
PubMed2004

The "high solubility" definition of the current FDA Guidance on Biopharmaceutical Classification System may be too strict for acidic drugs.

PURPOSE: The purpose of this study was to assess if the definition of high solubility as proposed in the FDA Guidance on Biopharmaceutical Classification System (BCS) is too strict for highly permeable acidic drugs. METHODS: The solubility and permeability values of 20 (18 acidic and 2 non-acidic) nonsteroidal anti-inflammatory drugs (NSAID) were determined. The NSAIDs were grouped into three different sets having acetic acid, propionic acid, or other acidic moieties such as fenamate, oxicam, and salicylate. Two nonacidic NSAIDs (celecoxib and rofecoxib) were also included for comparison purposes. Equilibrium solubility values were determined at pH 1.2, 5.0, 7.4, and in biorelevant media simulating fed intestinal fluid at pH 5.0. For a select number of acids, we also measured solubility values in media simulating gastric and fasted intestinal fluids. Permeability classification was established relative to that of reference drugs in the Caco-2 cell permeability model. Permeability coefficients for all drugs were measured at concentrations corresponding to the lowest and highest marketed dose strengths dissolved in 250 ml volume, and their potential interaction with cellular efflux pumps was investigated. RESULTS: All NSAIDs with different acidic functional groups were classified as highly permeable based on their Caco-2 cell permeability. Only ketorolac appeared to have a potential for interaction with cellular efflux pumps. Solubility classification was based on comparison of equilibrium solubility at pH 1.2, 5.0. and 7.4 relative to marketed dose strengths in 250 ml. The pKa values for the acidic NSAIDs studied were between 3.5 and 5.1. and, as expected, their solubility increased dramatically at pH 7.4 compared to pH 1.2. Only three NSAIDs, ketorolac, ketoprofen. and acetyl salicylic acid, meet the current criteria for high solubility over the entire pH range. However, with the exception of ibuprofen, oxaprozin, and mefenamic acid, the remaining compounds can be classified as Class I drugs (high solubility-high permeability) relative to solubility at pH 7.4. The use of bio-relevant media simulating gastric and intestinal milieu for solubility measurements or increasing the dose volume to 500 ml did not provide for a better boundary for solubility classification. CONCLUSIONS: Based on the current definition of solubility, 15 of the 18 acidic NSAIDs in this study will be classified as Class II compounds as the solubility criteria applies to the entire pH range of 1.2 to 7.4, although the low solubility criteria does not hold true over the entire pH range. Whence, of the 18 acidic drugs, 15 can be classified as Class I based on the pH 7.4 solubility alone. This finding is intriguing because these drugs exhibit Class I behavior as their absorption does not seem to be dissolution or solubility limited. It could then be argued that for acidic drugs, the boundaries for solubility are too restrictive. Solubility at pH > 5 (pH in duodenum) may be more appropriate because most compounds are mainly absorbed in the intestinal region. Consideration for an intermediate solubility classification for highly permeable ionizable compounds that reflects physiological conditions seems warranted.

Acids↗
PubMed2003

Demographics, assessment and management of pain in the elderly.

The prevalence of pain increases with each decade of life. Pain in the elderly is distinctly different from pain experienced by younger individuals. Cancer is a leading cause of pain; however, other conditions that cause pain such as facet joint arthritis (causing low back pain), polymyalgia rheumatica, Paget's disease, neuropathies, peripheral vascular disease and coronary disease most commonly occur in patients over the age of 50 years. Poorly controlled pain in the elderly leads to cognitive failure, depression and mood disturbance and reduces activities of daily living. Barriers to pain management include a sense of fatalism, denial, the desire to be 'the good patient', geographical barriers and financial limitations. Aging causes physiological changes that alter the pharmacokinetics and pharmacodynamics of analgesics, narrowing their therapeutic index and increasing the risk of toxicity and drug-drug interactions. CNS changes lead to an increased risk of delirium. Assessment among the verbal but cognitively impaired elderly is satisfactorily accomplished with the help of unidimensional and multidimensional pain scales. A comprehensive physical examination and pain history is essential, as well as a review of cognitive function and activities of daily living. The goal of pain management among the elderly is improvement in pain and optimisation of activities of daily living, not complete eradication of pain nor the lowest possible drug dosages. Most successful management strategies combine pharmacological and nonpharmacological (home remedies, massage, topical agents, heat and cold packs and informal cognitive strategies) therapies. A basic principle of the pharmacological approach in the elderly is to start analgesics at low dosages and titrate slowly. The WHO's three-step guideline to pain management should guide prescribing. Opioid choices necessitate an understanding of pharmacology to ensure safe administration in end-organ failure and avoidance of drug interactions. Adjuvant analgesics are used to reduce opioid adverse effects or improve poorly controlled pain. Adjuvant analgesics (NSAIDs, tricyclic antidepressants and antiepileptic drugs) are initiated prior to opioids for nociceptive and neuropathic pain. Preferred adjuvants for nociceptive pain are short-acting paracetamol (acetaminophen), NSAIDs, cyclo-oxygenase-2 inhibitors and corticosteroids (short-term). Preferred drugs for neuropathic pain include desipramine, nortriptyline, gabapentin and valproic acid. Drugs to avoid are pentazocine, pethidine (meperidine), dextropropoxyphene and opioids that are both an agonist and antagonist, ketorolac, indomethacin, piroxicam, mefenamic acid, amitriptyline and doxepin. The type of pain, and renal and hepatic function, alter the preferred adjuvant and opioid choices. Selection of the appropriate analgesics is also influenced by versatility, polypharmacy, severity and type of pain, drug availability, associated symptoms and cost.

Acetaminophen↗
PubMed1983

Antipyretic analgesics and the allergic patient.

Recent studies of idiosyncratic reactions to analgesics have revealed several clinical patterns with different pathogeneses. In the common type of asthma precipitated by aspirin, inhibition of cyclooxygenase leads to disturbances in the metabolism of arachidonic acid. Drugs that precipitate possibly life-threatening bronchoconstriction and are absolutely contraindicated in patients with aspirin-induced asthma include indomethacin, mefenamic acid, flufenamic and meclofenamic acids, ibuprofen, fenoprofen, ketoprofen, naproxen, diclofenac, amidopyrine, noramidopyrine, phenylbutazone, flumizole, and ditazol. If necessary, patients with aspirin-induced asthma can safely take, even on a long-term basis, salicylamide, dextropropoxyphene, benzydamine, guaiacolic ester of salicylic acid, and chloroquine. In some patients with urticaria/angioedema, symptoms are due to inhibition of cyclooxygenase by analgesics; in others, the cause may be impurities in commercial preparations of aspirin; and in still others, the mechanisms remain unknown.

Acute Disease↗
PubMed2002

The enhancing effect of a triethanolamine-ethanol-isopropyl myristate mixed system on the skin permeation of acidic drugs.

The effect of a TEI enhancer mixed system consisting of triethanolamine (T), ethanol (E) and isopropyl myristate (IPM) on the skin permeation of acidic, basic and neutral drugs were evaluated in vitro using excised hairless rat skin. The binary enhancer system consisting of IPM and ethanol (El) produced marked improvement on the penetration of all the drugs tested. When T was added to the EI system, a greater enhancing effect was found only on acidic drugs with a carboxyl group, compared with the flux in the EI system. On addition of another amine to the EI system, instead of T, mefenamic acid (MA), which exhibited the highest enhancing effect of the model drugs, showed an approximately 14-180 times greater flux than when delivered by the EI system. On simultaneous application of isosorbide dinitrate (ISDN) with MA in the TEI system, the flux of MA increased on increasing the T concentration in the TEI system, while, the flux of ISDN, a neutral drug, was unaffected by the T concentration. Application of MA in the EI system after pretreatment of the TEI system showed that the residual amount of T in the skin plays an important role in the skin permeation of MA. Furthermore, at a fixed concentration of MA, the flux of MA increased on increasing the T concentration in the TEI system, while the flux of E remained unchanged. Finally, the infrared spectrum of MA with amine in the E solution indicated that the carboxyl group of MA was ionized. These results demonstrated that the formation of an ion pair between MA and T, but not the effect of T on the skin, may be responsible for the enhanced skin permeation of MA using the TEI system.

Animals↗
PubMed2003

Effects of anti-inflammatory drugs on convulsant activity of quinolones: a comparative study of drug interaction between quinolones and anti-inflammatory drugs.

Quinolones have been reported to possess potent convulsant activity, which is enhanced when they are administered concurrently with anti-inflammatory drugs. To define the individual drug interactions of quinolones with anti-inflammatory drugs, we studied the convulsant activity of six quinolones with or without 13 anti-inflammatory drugs and 3 analgesic/antipyretic drugs in mice. Intraventricular injections of norfloxacin (NFLX), enoxacin (ENX), ciprofloxacin, lomefloxacin (LFLX), levofloxacin, and gatifloxacin induced convulsions in mice in a dose-dependent manner. Concurrent administration of biphenylacetic acid strongly enhanced the convulsant activity of NFLX, ENX, and LFLX. Flurbiprofen also strongly enhanced the activity of NFLX and ENX, and ketoprofen strongly enhanced the activity of ENX. However, mefenamic acid, piroxicam, tenoxicam, meloxicam, etodolac, sulpyrine, isopropylantipyrine, and acetaminophen had no effect on the convulsant activity of quinolones. These results suggest that each quinolone has an individual drug interaction with each anti-inflammatory drug. It was suggested that we should know which anti-inflammatory drugs enhance the convulsant activity of individual quinolones, and which quinolone has no/weak drug interaction with different anti-inflammatory drugs when these drugs are used concurrently for the treatment of patients with infectious diseases.

Animals↗
PubMed1992

Prostaglandin-related microvascular dilation in pentobarbital- and etomidate-anesthetized rats.

Etomidate is characterized by minimal systemic cardiovascular effects, but its effect on the microvasculature has not been assessed. We compared the microvasculature of etomidate-anesthetized animals to that of animals anesthetized with pentobarbital, since its effects on the microvasculature are known. Male Sprague-Dawley rats were anesthetized with etomidate or pentobarbital. The cremaster muscle was prepared for microscopic viewing, leaving the neural and vascular supply intact. Small arterioles were near their maximal diameters in etomidate-anesthetized rats, whereas the pentobarbital group had a large dilator capacity (maximal diameter-basal diameter/basal diameter). The effect on resting arteriolar diameters of endothelium-derived relaxing factor (EDRF) and prostaglandin synthesis inhibitors was tested. Dilator capacity was not affected by the EDRF inhibitor nitro-L-arginine, but it was significantly increased by mefenamic acid and ibuprofen in etomidate-anesthetized animals. To test whether dilator and constrictor mechanisms were normal, serotonin concentration-response curves were obtained in pentobarbital and etomidate-anesthetized animals with and without mefenamate or ibuprofen present. The dilation of small arterioles to serotonin in the etomidate groups with mefenamate or ibuprofen was not significantly different from that of the pentobarbital groups. Serotonin produced a comparable constriction of large arterioles in both anesthetic groups. The topical application of etomidate to the cremaster muscle did not affect arteriolar diameters. Thus, etomidate appears to trigger the release of dilator prostaglandins in striated muscle through a central or indirect mechanism.

Anesthesia, Intravenous↗
PubMed1977

Does diaminobenzidine demonstrate prostaglandin synthetase? A study on polyunsaturated fatty acid-induced DAB oxidation in sheep vesicular glands and rabbit kidney medulla.

A method histochemical localization of prostaglandin synthetase using DAB, potassium cyanide and polyunsaturated fatty acid has been revised. The arachidonic acid-induced DAB oxidation observed in the secretory epithelium of sheep vesicular glands and in collecting tubules as well as intersititial cells of rabbit kidney medulla was found to be insensitive to antiinflammatory cyclooxygenase (formerly referred as prostaglandin synthetase) inhibitors, such as indomethacin, aspirin, mefenamic acid and paracetamol, whereas aminotriazole caused complete inhibition of the reaction. Furthermore, DAB was oxidized in the presence of polyunsaturated fatty acids inconvertible to prostaglandins (linoleic and linolenic acid) as well as in the presence of H2O2--in the latter case reaction possessed identical features with that induced by fatty acids. Ultrastructurally, the reaction product was localized on the membranes of nuclear envelope and endoplasmic reticulum. On the ground of the results obtained a hypothesis is presented, that the polyunsaturated fatty acid-induced DAB oxidation is due to a peroxidatic activity of the investigated tissues. Possible relations between such peroxidatic activity and prostaglandin biosynthesis are discussed.

3,3'-Diaminobenzidine↗
PubMedDate not supplied

Aspirin-induced asthma in children.

Since Cooke first described bronchospasm induced by acetyl salicylic acid in asthmatic patients in 1919, numerous studies have been done with the objective of understanding the pathology, treatment and incidence of aspirin-induced asthma. The incidence is difficult to establish but according to two recent studies, the percentage in the infantile asthmatic population was estimated at 13% and 28%. This prevalence is greater than that suspected at first and reveals the necessity of reviewing this problem. In this study we present 4 pediatric patients, 2 atopics and 2 non-atopics affected with aspirin-induced asthma. A detailed clinical history, oral provocation test to acetyl salicylic acid, other non-steroid anti-inflammatory analgesics and additives was performed. The oral provocation test with acetyl salicylic acid was positive in all 4 cases. The oral provocation with non-steroid anti-inflammatory analgesics and other additives was negative in 2 patients. In the remaining 2 patients, one demonstrated sensitivity only to tartrazine and the other to tartrazine, red coccine, mefenamic acid and benorylate. In conclusion, aspirin-induced asthma is not infrequent in infancy. Therefore, it is important to bear it always in mind and to diagnose it through oral provocation besides looking for possible cross reactions.

Aspirin↗
PubMedDate not supplied

[Effect of nonsteroidal anti-inflammatory agents on protein and nucleic acid levels in a focus of aseptic proliferative inflammation].

In experiments on albino rats on the model of "cotton wool granuloma" it was found that non-steroidal anti-inflammatory agents inhibited the growth of the granulation and fibrous tissue that was followed by a normal decrease of contents of protein and RNA but not DNA in it. By their effect on RNA and granuloma weight butadione and mefenamic acid are significantly more active than antipyrine.

Animals↗
PubMed2003

Simultaneous determination of arylpropionic acidic non-steroidal anti-inflammatory drugs in pharmaceutical formulations and human plasma by HPLC with UV detection.

A simple and sensitive high-performance liquid chromatography-UV detection method was developed for the simultaneous determination of non-steroidal anti-inflammatory drugs (NSAIDs) having an arylpropionic acid moiety in pharmaceutical formulations and human plasma. Isocratic separation was employed on ODS column (250 x 4.6 mm i.d., 5 microm) at ambient temperature. The mobile phase consisted of acetonitrile, phosphate buffer (pH 3.5; 50 mM), methanol and tetrahydrofuran. The NSAIDs in the eluent were monitored under a wavelength-programme to provide their maximum absorbance. Mefenamic acid was used as an internal standard. Drugs were found to be 96.8-101.9% of their label claim in pharmaceutical formulations. One hundred microliters of human plasma samples were pretreated with a simple liquid-liquid extraction using ethyl acetate. The detection limits of compounds studied at a signal-to-noise ratio of 3 were 11.5-75 ng/ml in human plasma samples. The proposed method is simple, selective and could be applicable for routine analysis of arylpropionic acidic NSAIDs in pharmaceutical as well as in human plasma samples.

Anti-Inflammatory Agents, Non-Steroidal↗