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PubMed2001

Suppression by a sesquiterpene lactone from Carpesium divaricatum of inducible nitric oxide synthase by inhibiting nuclear factor-kappaB activation.

Excessive nitric oxide (NO) produced by inducible NO synthase (iNOS) acts as a causative regulator in various inflammatory disease states. Carpesium divaricatum has been used in Korean traditional herbal medicine for its antipyretic, analgesic, vermifugic, and anti-inflammatory properties. We investigated the molecular mechanism for the suppression of lipopolysaccharide/interferon-gamma (LPS/IFN-gamma)-induced NO production in RAW 264.7 macrophages by the sesquiterpene lactone 2beta,5-epoxy-5,10-dihydroxy-6alpha-angeloyloxy-9beta-isobutyloxy-germacran-8alpha,12-olide (C-1), which has been identified recently as a new compound from C. divaricatum. C-1 decreased NO production in LPS/IFN-gamma-stimulated RAW 264.7 cells in a concentration-dependent manner, with an IC50 of approximately 2.16 microM; however, it had no direct effect on the iNOS activity of fully LPS/IFN-gamma-stimulated RAW 264.7 cells. Furthermore, treatment with C-1 led to a decrease in iNOS protein and mRNA. These effects appear to be due to inhibition of nuclear factor-kappaB (NF-kappaB) activation through a mechanism involving stabilization of the NF-kappaB/inhibitor of the kappaB (I-kappaB) complex, since inhibition of NF-kappaB DNA binding activity by C-1 was accompanied by a parallel reduction of nuclear translocation of subunit p65 of NF-kappaB and I-kappaBalpha degradation. Taken together, the results suggest that the ability of C-1 to inhibit iNOS gene expression may be responsible, in part, for its anti-inflammatory effects.

Animals↗

PubMedDate not supplied

Synthesis of angelicin heteroanalogues: preliminary photobiological and pharmacological studies.

A series of angelicin heteroanalogues, in which the furan was replaced by thiophene or a 1-substituted pyrazole moiety, was synthesised in order to obtain potential therapeutic agents with antiproliferative and/or other biological activities. In general, the antiproliferative activity of the new thioangelicin, tested in different biological substrates, appeared to be higher than that of the angelicin, the natural parent compound, but lower than that of 8-MOP, the furocoumarin ordinarily used in PUVA therapy and photopheresis. Thioangelicin 6 induced strong inhibition of T2 bacteriophage infectivity and was able to significantly repress the DNA synthesis in Ehrlich ascites cells and the clonal growth in HeLa cells. The pyrazolocoumarins did not show any noticeable effect upon UVA irradiation in all the biological systems considered. All the new angelicin heteroanalogues appeared to be free of the known phototoxicity of furocoumarins on the skin. The pyrazolocoumarins have also been tested as anti-inflammatory, analgesic, antipyretic, local anaesthetic, anti-arrhythmic and platelet anti-aggregating agents by standard procedures. In this class of derivatives, 10a showed good anti-inflammatory and antipyretic properties, while 9a and 11a showed significant local anaesthetic activity.

Animals↗

PubMed2003

Cyclooxygenases in the skin: pharmacological and toxicological implications.

Cyclooxygenase (COX), a prostaglandin-endoperoxide synthase (PTGS), catalyzes the formation of prostaglandins from arachidonic acid. Prostaglandins are lipid signaling mediators that play a central role in a broad range of diverse physiological and pathophysiological processes, including inflammation, reproduction, nocioception, and gastrointestinal protection. Inhibition of cyclooxygenase activity is the mechanism by which nonsteroidal antiinflammatory drugs (NSAIDS) exert their analgesic, antipyretic, antiinflammatory, and antithrombotic effects. COX is currently believed to exist in three isoforms. In this review, we provide a concise state-of-the-art description of the role of COX in pharmacology and toxicology of skin including its involvement in normal physiology, cutaneous inflammation, nociception, wound healing, and tumorigenesis. COX-dependent pathways influence keratinocyte differentiation, hair follicle development, and hair growth. The critical role of COX-2 in pathophysiology of skin is also addressed. COX-2 mediates inflammatory processes in skin, including inflammatory hyperalgesia and nociception, and administration of specific COX-2 inhibitors reduces edema, vascular permeability, and other markers of cutaneous inflammation. A number of studies in animal models and in humans show that COX-2 inhibitors possess cancer chemopreventive properties. Selective COX-2 inhibitors have a more favorable side-effect profile. Topical formulations of COX-2 inhibitors are being developed as a novel pharmacologic approach for the treatment of COX-2 mediated skin diseases.

Animals↗

PubMed1998

Practical approach to analgesia and sedation in the neonatal intensive care unit.

The anatomic and physiological bases for nociception are present even in very preterm neonates. Neonates show the same behavioral, endocrine, and metabolic responses to noxious stimuli as older subjects. Preterm infants appear to be more sensitive to painful stimuli and have heightened responses to successive stimuli. Infants receiving intensive care are subjected to frequent stressful procedures and also chronic noxious influences related to the environment of care. Inflammatory conditions such as necrotizing enterocolitis may also cause pain. Untreated pain in babies is associated with increased major morbidity and mortality. Nonpharmacological interventions, including environmental modification and comforting during procedures reduce stress. Intravenous opiates are the mainstay of pharmacological analgesia. A pure sedative agent can provide physiological stability in settings in which there are less acutely painful stimuli or when there are adverse effects from, or tolerance to, opiates. Local anesthesia of skin and mucous membranes is helpful for invasive procedures. Antipyretic analgesics such as acetaminophen have a role in inflammatory pain.

Analgesia↗

PubMed1997

Pharmacological investigation of Cassia italica.

In the present study, the ethanolic extract of the whole plant parts (root, stem leaves and pods) of Cassia italica (Mill.) Lam. ex F.W. Ander (Leguminosae) was investigated for bioactivities: namely anti-inflammatory, antipyretic, analgesic and prostaglandin (PG) release by rat peritoneal leucocytes, antineoplastic and antiviral. In rats, the extracts reduced carrageenin-induced paw swelling (100 mg/kg bw-31%) and fever (100 mg/kg bw-37%). The extract showed weak effect on writhing induced by acetic acid. A dose-dependent inhibition of PG release effect was observed using rat peritoneal leucocytes.

Animals↗

PubMed2000

Determination of nimesulide in pharmaceutical dosage forms by second order derivative UV spectrophotometry.

In this study, nimesulide which has been used as an analgesic, antipyretic and anti-inflammatory agent, was analyzed by using second order derivative UV spectrophotometry. The solvent, the degree of derivation, ranges of wavelength and n-value were chosen in order to optimize the conditions. The concentration of nimesulide in its solutions in ethanol and chloroform were determined between the wavelength ranges of 200 and 500 nm (n = 6, delta lambda = 21) and in the linearity ranges of 2.0-90.0 microg ml(-1) in ethanol and 2.0-50.0 microg ml(-1) in chloroform by using the values obtained from the second derivative UV spectrum of the substance. The developed second derivative UV spectrophotometric method was applied to the pharmaceutical preparations such as tablet, sachet (granule) and suspension. Tablet and sachet were analysed in ethanol while the suspension was analysed in chloroform. The results obtained from derivative UV spectrophotometry were compared with those obtained by using HPLC. It was found that the difference was not statistically important between these methods. It was concluded that developed derivative UV spectrophotometric method was accurate, sensitive, precise, reproducible and could be applied directly and easily to the pharmaceutical preparations.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1994

Use of topical nonsteroidal anti-inflammatory drugs in excimer laser photorefractive keratectomy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce potent analgesic, antipyretic, and anti-inflammatory effects. We studied postoperative pain in 97 consecutive patients having photorefractive keratectomy (PRK) by an excimer laser with different topical NSAID protocols. Treatment with topical homatropine hydrobromide, either diclofenac sodium (Voltaren Ophthalmic) or ketorolac tromethamine (Acular), and a soft contact lens was most effective in achieving post-PRK analgesia. We also studied post-PRK myopic regression in 68 consecutive patients and found that flurbiprofen sodium (Ocufen), when added to topical steroid protocols, significantly reduced myopic regression for one year postoperatively more than steroids alone or steroids and diclofenac sodium. Diclofenac, used with topical steroids, had less of an additive effect on myopic regression than did flurbiprofen. Topical NSAIDs are useful adjuncts to PRK therapy, both to eliminate postoperative pain and to control post-PRK myopic regression.

Administration, Topical↗

PubMed1996

Naproxen sodium.

Naproxen sodium possesses analgesic, antipyretic, and anti-inflammatory effects. Adverse effects of naproxen sodium include gastrointestinal effects, precipitation of allergic symptoms, and potential for hepatotoxicity. Naproxen sodium is contraindicated in patients with known sensitivity and those with heart failure, hypertension, or other conditions associated with fluid retention. Nonprescription products of naproxen sodium, ibuprofen, ketoprofen, acetaminophen, and salicylates are all similarly effective in treating mild aches and pains and reducing fever.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2003

Dexamethasone for morbidity after subdural electrode insertion--a randomized controlled trial.

BACKGROUND: Invasive monitoring with subdural electrodes (SDE) for investigation of medically intractable epilepsy may be associated with undesirable immediate postoperative morbidity such as headache, nausea, vomiting, fever, and meningism. We undertook to evaluate the potential beneficial role of perioperative dexamethasone in reducing these symptoms. METHODS: In a double-blind placebo controlled clinical trial 30 patients undergoing SDE insertion were randomized to receive either placebo or a course of dexamethasone beginning one hour prior to surgery and tapering to discontinue over 72 hours postoperatively. Pain, pain relief, nausea, nausea relief, temperature, and meningism were assessed regularly in the postoperative period, and analgesic, antipyretic, and antiemetic drug requirements were tabulated. RESULTS: One patient was withdrawn from the dexamethasone group due to lack of data. With regards to postoperative pain, the direction of benefit favoured dexamethasone but a significant treatment by time interaction prevented further analysis of treatment effect. The dexamethasone group did have significantly lower temperatures and higher nausea relief scores. There was no statistically significant difference between the groups with regards to pain relief, nausea, and meningism scores. The beneficial effects of dexamethasone were delayed in onset, of limited duration, and not uniform over the observation period. CONCLUSION: Dexamethasone appears to have a role in reducing immediate morbidity following SDE insertion but its effect is not uniform in the postoperative period; it appears to be delayed in onset, and of limited duration. Further study is necessary to determine the ideal dosing schedule.

Adult↗

PubMed2001

Treatment with paracetamol in infants.

BACKGROUND: Paracetamol (N-acetyl-p-amino-phenol) or acetaminophen has become the most widely used analgesic and antipyretic in children. However, there is a wide discrepancy between the extent to which paracetamol is used and the limited available pharmacological data in small infants. The purpose of this article is to present a review of the current literature regarding the use of paracetamol in neonates and infants with a particular emphasis on pharmacological issues. METHODS: A MEDLINE search (up to March 2000) was conducted to identify relevant English-language publications using paracetamol, children, infants and neonates as search terms. Additional studies were identified from bibliographies of the reviewed literature. RESULTS: Pharmacological studies on paracetamol in infants are few. Most studies have focused on the administration of one single paracetamol dose, and the problem of cumulative toxicity with repeated dosing has not been addressed. Plasma paracetamol concentration should be 10-20 mg ml(-1) to achieve antipyretic and analgesic effects. The bioavailability of the different formulations and routes of administration vary with age. Rectal absorption is slower and more erratic than the oral; however, in the very young, rectal bioavailability is higher than in older patients. Volume of distribution seems to be age-independent, whereas clearance is reduced in neonates and particularly in preterm babies. Neonates and infants are capable of forming the reactive intermediate metabolite that causes hepatocellular damage, particularly after multiple doses. They have an immature glucuronide conjugation system, but the rate constant for the sulphation metabolic pathway is larger than in older children, and this is the most important route of metabolism. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of paracetamol differ substantially in neonates and infants from those in older children and adults; hence, dosing should be adjusted accordingly.

Acetaminophen↗

PubMed1992

Hyperpyrexia in spinal injury patients.

We studied 13 spinal injury patients who had hyperpyrexia during an 18 month period (September 1984-March 1986) to discover if differences existed in the core temperature of patients with tetraplegia and those with paraplegia, and the contribution of these differences to the final outcome. Children were excluded from this study as well as patients with any sign of infection on first admission, patients with multiple injuries, and those referred from peripheral hospitals more than one week after injury. Patients with tetraplegia (C3-C7) had persistently high and uncontrollable core temperatures (average 39.5 degrees C) while those with paraplegia (T4-L5) showed lower core temperatures which were still high (average 38.1 degrees C). The difference in the average high core temperature (1.4 degrees C) is statistically significant. The lowest average core temperatures were about the same in tetraplegics and paraplegics (just over 35 degrees C). Four patients died: 3 tetraplegics and one paraplegic. Antipyretic analgesics were ineffective in reducing the high core temperatures.

Adolescent↗

PubMed2004

2-hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation.

Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog and the 4-NHMe-phenyl analog with a CF3, and the 4-OEt-phenyl analog with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.

Animals↗

PubMed1992

Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs.

Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase (AICAR transformylase, EC 2.1.2.3) and bovine liver dihydrofolate reductase (EC 1.5.1.3). In contrast, aspirin and the antipyretic-analgesic drugs acetaminophen and antipyrine were weak inhibitors of these enzymes. Structure-activity correlation suggests that an aromatic ring with a side chain containing a carboxylic acid is a requirement for competitive inhibition of the transformylase. The above-listed NSAIDs also inhibited the folate-coenzyme-mediated biosynthesis of serine from glycine and formate (i.e., the C1 index) by human blood mononuclear cells (BMCs) in experiments where the drug was added to a culture of BMCs. Acetaminophen had a weak inhibitory effect on the C1 index. Consistent with the results obtained in vitro is the observation that the C1 index of BMCs from rheumatoid-arthritis patients treated with drugs which possess little antifolate activity (e.g. acetaminophen) is higher than the C1 index of BMCs from rheumatoid-arthritis patients treated with NSAIDs possessing more potent antifolate activity (e.g. sulindac, sulphasalazine, naproxen and ibuprofen). The mean activity of the transformylase in BMCs taken from healthy humans was 1.98 nmol of product/h per 10(6) cells and the activity was positively correlated with BMC folate levels. These results are consistent with the hypothesis that (1) the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and (2) aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound.

Acyltransferases↗

PubMed2003

Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract.

Aspirin is widely prescribed and confers considerable benefit to patients by reducing cardiovascular and cerebrovascular morbidity and mortality. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective analgesics, antipyretics and reduce the inflammatory component in conditions such as rheumatoid arthritis. However, both agents are associated with an increased risk of gastrointestinal symptoms and the potentially serious consequences of gastroduodenal ulceration, bleeding and perforation. The introduction of highly selective cyclo-oxygenase (COX)-2 inhibitors or the coprescription gastroprotective agents with nonselective NSAIDs have offered strategies to reduce the incidence of such events. This review article analyzes the quantitative techniques that can be employed by clinical pharmacologists and the clinical studies performed to assess NSAID damage in the gastrointestinal tract.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals.

Recently, it has been reported that inflammatory processes are associated with the pathophysiology of Alzheimer's disease and that treatment of non-steroidal anti-inflammatory drugs reduce the risk for Alzheimer's disease. In the present study, we examined nitric oxide radical quenching activity of non-steroidal anti-inflammatory drugs and steroidal drugs using our established direct in vitro nitric oxide radical detecting system by electron spin resonance spectrometry. The non-steroidal anti-inflammatory drugs, aspirin, mefenamic acid, indomethacin and ketoprofen directly and dose-dependently scavenged generated nitric oxide radicals. In experiments of nitric oxide radical donor, NOC18-induced neuronal damage, these four non-steroidal drugs significantly prevented the NOC18-induced reduction of cell viability and apoptotic nuclear changes in neuronal cells without affecting the induction of inducible nitric oxide synthase-like immunoreactivity. However, ibuprofen, naproxen or steroidal drugs, which had less or no scavenging effects in vitro, showed almost no protective effects against NOC18-induced cell toxicity. These results suggest that the protective effects of the former four non-steroidal anti-inflammatory drugs against apoptosis might be mainly due to their direct nitric oxide radical scavenging activities in neuronal cells. These direct NO. quenching activities represent novel effects of non-steroidal anti-inflammatory drugs. Our findings identified novel pharmacological mechanisms of these drugs to exert not only their anti-inflammatory, analgesic, antipyretic activities but also neuroprotective activities against neurodegeneration.

Alzheimer Disease↗

PubMed2004

Is licofelone, a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase, a promising alternative in anti-inflammatory therapy?

As prostaglandins and leukotrienes are critical in inflammation, dual cyclo-oxygenase and 5-lipoxygenase enzymes inhibitors, especially licofelone, are being developed by pharmaceutical companies. Experimental data indicate that licofelone shares the antipyretic, analgesic, anti-inflammatory and anti-platelet activities of conventional nonsteroidal anti-inflammatory drugs (NSAIDs), and exhibits anti-allergic properties. Although licofelone may lead to similar adverse effects on the kidney than available NSAIDs, it appeared to induce less gastrointestinal damaging effects than nonselective NSAIDs in animals. Unfortunately, preliminary clinical studies provided less impressive data with respect to efficacy. Finally, the experimental promise of licofelone as a safe and potent anti-inflammatory and analgesic agent remains to be proved in humans.

Acetates↗

PubMed2004

Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein.

Acetaminophen is a widely used antipyretic analgesic, reducing fever caused by bacterial and viral infections and by clinical trauma such as cancer or stroke. In rare cases in humans, e.g., in febrile children or HIV or stroke patients, acetaminophen causes hypothermia while therapeutic blood levels of the drug are maintained. In C57/BL6 mice, acetaminophen caused hypothermia that was dose related and maximum (>2 degrees C below normal) with a dose of 300 mg/kg. The reduction and recovery of body temperature was paralleled by a fall of >90% and a subsequent rise of prostaglandin (PG)E(2) concentrations in the brain. In cyclooxygenase (COX)-2(-/-) mice, acetaminophen (300 mg/kg) produced hypothermia accompanied by a reduction in brain PGE(2) levels, whereas in COX-1(-/-) mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1(-/-) mice had approximately 70% lower levels of PGE(2) than those of WT animals, and these levels were not reduced further by acetaminophen. The putative selective COX-3 inhibitors antipyrine and aminopyrine also reduced basal body temperature and brain PGE(2) levels in normal mice. We propose that acetaminophen is a selective inhibitor of a COX-1 variant and this enzyme is involved in the continual synthesis of PGE(2) that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.

Acetaminophen↗

PubMed2001

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells.

Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by approximately 50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G(1) and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.

Acetaminophen↗