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Paracetamol is an analgesic and antipyretic agent which was first marketed for use as a drug in the U.K. in 1956. It has since become popular with the medical profession and the general public as an alternative to aspirin.
The aqueous extracts of Acacia nilotica and Hibiscus sabdariffa were tested for anti-inflammatory, analgesic and antipyretic activities in animal models. Acacia nilotica extract had an inhibitory effect on carrageenan induced paw edema and yeast-induced pyrexia in rats. It also produced a significant increase in the hot plate reaction time in mice. Hibiscus sabdariffa extract had no effect on paw edema but had an inhibitory effect on yeast induced pyrexia and a significant effect on the hot plate reaction time. Among the phytoconstituents found in both plants, flavanoids, polysaccharides and organic acids may be mainly responsible for their pharmacological activities.
Acetaminophen is a widely used antipyretic and analgesic drug whose mechanism of action has recently been suggested to involve inhibitory effects on prostaglandin synthesis via a newly discovered cyclooxygenase variant (COX-3). Because COX-3 expression is high in cerebral endothelium, we investigated the effect of acetaminophen on the prostaglandin production of cultured rat cerebral endothelial cells (CECs). Acetaminophen dose-dependently inhibited both basal and LPS-induced PGE(2) production in CECs with IC(50) values of 15.5 and 6.9 microM, respectively. Acetaminophen also similarly inhibited the synthesis of 6-keto-PGF(1alpha) and thromboxane B(2). LPS stimulation increased the expression of COX-2 but not COX-1 or COX-3. In addition, the selective COX-2 inhibitor NS398 (1 microM) was equally as effective as acetaminophen in blocking LPS-induced PGE(2) production. Acetaminophen did not influence the expression of the three COX isoforms and the inducible nitric oxide synthase. In LPS-stimulated isolated cerebral microvessels, acetaminophen also significantly inhibited PGE(2) production. Our results show that prostaglandin production in CECs during basal and stimulated conditions is very sensitive to inhibition by acetaminophen and suggest that acetaminophen acts against COX-2 and not COX-1 or COX-3. Furthermore, our findings support a critical role for cerebral endothelium in the therapeutic actions of acetaminophen in the central nervous system.
BACKGROUND: Nimesulide is a cyclooxygenase (COX) inhibitor with a high degree of selectivity to COX-2. It is a widely used and well tolerated nonsteroidal antiinflammatory drug that also has analgesic and antipyretic properties. The most frequently reported side effects concern the gastrointestinal tract. Pruritus and skin rash are the most common cutaneous adverse reactions. There are only eight cases of fixed drug eruptions due to nimesulide, described in the literature. CASE REPORT: The authors report a case of a patient with a history of antihistamine hypersensitivity who developed a bullous form of pigmented fixed drug eruption after nimesulide ingestion. Patch tests performed on residual skin lesion were positive to nimesulide, confirming that this was the culprit drug. CONCLUSIONS: Fixed drug eruptions are common cutaneous drug reactions, often misdiagnosed. A detailed anamnesis and physical examination are the key to suspect this condition.
We examined the effect of acetaminophen, an analgesic and antipyretic drug, on acute gastric mucosal injury induced by ischemia-reperfusion in rats. Ischemia-reperfusion was induced by clamping the celiac artery for 30 min with a small clip. Sixty minutes after reperfusion, the total area of erosions was measured. Acetaminophen (300 and 500 mg/kg) administered intraperitoneally 90 min before the ischemia significantly reduced the total area of erosions. The drug also inhibited the increase in lipid peroxide levels induced by ischemia-reperfusion in the gastric tissue and the increase in lipid peroxidation caused by the hydroxyl radical, OH., in vitro. Gastric prostaglandin E2 (PGE2) contents tended to increase after ischemia-reperfusion in both control and acetaminophen-treated groups. A significant difference in gastric PGE2 contents between control and acetaminophen-treated groups was not observed. The results indicate that acetaminophen may protect the gastric mucosa against ischemia-reperfusion injury, probably by blocking hydroxyl-radical-induced membrane damage.
Compared to intravesical chemotherapy, instillations with bacillus Calmette-Guérin (BCG) may provoke more frequently local and systemic reactions. As well as irritative bladder symptoms, BCG therapy may cause systemic side-effects, such as mild malaise, fever and, less commonly, life-threatening sepsis. It is important that risk factors for these adverse events are recognized, and that traumatic catheterization and instillations in inflamed or damaged bladders are avoided. Once recognized, virtually all side-effects can be treated successfully. Treatment options may include delaying or withholding BCG instillations, or using antipyretics and analgesics for reducing bladder symptoms. Treatment with tuberculostatic drugs for up to 6 months may be necessary in cases of severe systemic or local toxicity. In vitro, BCG is very susceptible to most antibiotics and tuberculostatic agents. Clinical trials are currently investigating whether the prophylactic use of tuberculostatic agents, such as isoniazid, or dose reduction in BCG can prevent adverse effects without impairing the antitumour efficacy of BCG.
Paracetamol and salicylate are weak inhibitors of both isolated cyclooxygenase-1 (COX-1) and COX-2 but are potent inhibitors of prostaglandin (PG) synthesis in intact cells if low concentrations of arachidonic acid are available. The effects of both drugs are overcome by increased levels of hydroperoxides. At low concentrations of arachidonic acid, COX-2 is the major isoenzyme involved in PG synthesis when both COX-1 and COX-2 are present in cells. Therefore, paracetamol and salicylate may selectively inhibit PG synthesis involving COX-2 because the lower flux through this pathway produces lesser levels of the hydroperoxide, PGG(2), than the pathway involving COX-1. Apart from the lack of anti-inflammatory effect of paracetamol in rheumatoid arthritis, the clinical effects of paracetamol and salicylate are very similar and resemble those of the selective COX-2 inhibitors. A splice variant of COX-1, termed COX-3, may be a site of action of these drugs but, further work, particularly at low concentrations of arachidonic acid is required. We suggest that paracetamol, salicylate and, possibly, the pyrazolone drugs, such as dipyrone, may represent a distinct class of atypical NSAIDs which could be termed peroxide sensitive analgesic and antipyretic drugs (PSAADs).
The aim of this study was to examine salivary flow rate and its association with the use of medication in a representative sample of 76-, 81-, and 86-year-old subjects, totaling 368. In this study, 23% (n = 80) of the subjects were unmedicated. From one to three daily medications were used by 47% (n = 168) and more than four medications by 30% (n = 104). The most commonly used medications were nitrates, digitalis or anti-arrhythmic drugs (47.7%), analgesics and antipyretics (32.6%), and diuretics (29.5%). The mean number used daily was significantly higher in 86-year-olds than in the two younger age groups (p < 0.01). No significant differences in this respect were found between genders. Among the unmedicated subjects, 76-year-olds had significantly higher stimulated salivary flow rates than did the 81-year-olds (p < 0.05). Unmedicated women showed significantly lower unstimulated (p < 0.01) and stimulated flow rates than did men (p < 0.05). Stimulated salivary flow rate was also significantly higher in the 76-year-old medicated subjects than in the medicated 86-year-old subjects (p < 0.05). No statistically significant differences were found in unstimulated salivary flow rates among the three age groups. Medicated women showed significantly lower unstimulated salivary flow rates than men (p < 0.001), although the difference in stimulated saliva flow was not significant. A statistically significant difference in unstimulated and stimulated salivary flow rates was found between unmedicated persons and those who took from four to six, or more than seven, prescribed medications daily.
Nimesulide, 4-nitro-2-phenoxymethanesulphonanilide, a new non-steroidal anti-inflammatory drug endowed with potent anti-inflammatory, analgesic and antipyretic activities, was tested at a daily dose of 200 mg b.i.d. against Benzydamine on a double-blind basis, in a randomized trial with fifty out-patients suffering from inflammatory ear, nose and throat diseases (otitis media, sinusitis, rhinitis). Nimesulide treatment brought about an immediate and significant improvement in over-all pain, exudation, oedema and headache and produced a rapid lowering in body temperature. The recovery was more rapid and significant in patients with Nimesulide than in those with Benzydamine. The signs and symptoms under consideration reached almost complete resolution within the set treatment-period of 10 days. Clinical tolerability of Nimesulide was better than that of Benzydamine: one case of moderate gastric pyrosis and drowsiness was complained of by the Nimesulide-treated patients versus eleven cases of gastro-intestinal discomfort, mouth dryness, and/or drowsiness which were complained of by the Benzydamine-treated patients.
Five hundred and sixty-three university students were interviewed to survey the practice of self-medication which was found to be very prevalent (94.0%). The most commonly used items included remedies for cough and cold, antipyretics and analgesics. Topical preparations and Chinese herbal medicines were also frequently consumed. Self-medication items were mostly obtained from home medicine cabinets and pharmacy shops (not necessarily staffed by registered pharmacists) and they also relied heavily on family members and previous illness experience for information on the medications they took. The healthcare professionals only played a minor role in the provision of drug information. Nevertheless, the concept of self-medication is well-established among these university students as they recognised that minor illness could be cared for without seeing a doctor. Healthcare professionals should assume more active roles in the provision of drug information and counselling so that a good self-care programme could be established.
It has been more than 30 years since Sir John Vane first reported that the pharmacological actions of aspirin-like drugs could be explained by their ability to inhibit cyclooxygenase (COX). Since then, a second isoform of COX, named COX-2, has been discovered and highly selective inhibitors of this isoform have been marketed. Most recently, a splice variant of COX-1 mRNA, retaining intron 1, and given the names COX-3, COX-1b or COX-1v, has been described. Non-selective NSAIDs such as ibuprofen and naproxen, which inhibit both COX-1 and COX-2, have proven highly effective and safe in the short-term management of acute pain. Highly selective COX-2 inhibitors including celecoxib, rofecoxib, valdecoxib, lumiracoxib, and etoricoxib were developed with the hope of significantly reducing the serious gastrointestinal toxicities associated with chronic high-dose NSAID use. While long-term studies demonstrated that rofecoxib and lumiracoxib reduced the incidence of GI perforations, ulcerations and bleeds by approximately 60% compared to non-selective NSAIDs, recent reports also demonstrated that the chronic use of rofecoxib and celecoxib in arthritis and colorectal polyp patients, and the short-term use of parecoxib and valdecoxib in patients who had undergone coronary artery bypass surgery, resulted in a significant increase in serious cardiovascular events, including myocardial infarction and stroke compared to naproxen or placebo. COX-3 mRNA has been isolated in many tissues including canine and human cerebral cortex, human aorta, and rodent cerebral endothelium, heart, kidney and neuronal tissues. In transfected insect cells, canine COX-3 protein is expressed and was selectively inhibited by acetaminophen. However, in humans and rodents an acetaminophen sensitive COX-3 protein is not expressed because the retention of intron-1 adds 94 and 98 nucleotides to the COX-3 mRNA structure respectively. Since the genetic code is a triplicate code (3 nucleotides to form one amino acid), the retention of the intron in both species results in a frame shift in the RNA message and the production of a truncated protein with a completely different amino acid sequence than COX-1 or COX-2 lacking acetaminophen sensitivity. Advances made through a combination of basic molecular biological and pharmacological techniques, and well designed randomized controlled clinical trials have demonstrated that the apparent gastrointestinal advantage of selective COX-2 inhibitors appears to be outweighed by their potential for cardiovascular toxicity and that acetaminophen's analgesic and antipyretic effects do not involve the inhibition of the COX-1 splice variant protein, putative COX-3.
Acetaminophen is the most widely used antipyretic and analgesic drug in the world. Acetaminophen poisoning and the following hepatic failure are not rare and are the most common indications of liver transplantation in the USA and Europe. In this case report, the patient was a 25-year old woman with hepatic failure who was brought to Loghman-Hakim Poison Centre 24 hours after attempted suicide with 100 tablets of acetaminophen, 325 mg. She was treated with N-acetylcysteine (NAC) and discharged from the hospital 12 days after admission and followed up for 1 month. In conclusion, acetaminophen poisoning should be considered in the differential diagnoses of hepatic failure. In acetaminophen-induced hepatic damage the administration of NAC must always be considered even after 24 hours of overdose.
Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for their antiinflammatory, antipyretic, and analgesic properties. The molecular basis for the therapeutic action of NSAIDs is believed to be in their ability to inhibit cyclooxygenase (COX) activity and thereby blocking the production of prostaglandins. Emerging evidence now suggests that NSAIDs can exert their pharmacological effects through other mechanisms. This study investigated the influence of a nonselective COX-inhibitor ketorolac on IL-1beta- and TNFalpha-induced expression of proinflammatory genes in the brain. Systemic injection of both cytokines caused a rapid and transient transcriptional activation of COX-2 gene within the cerebral microvasculature, which was significantly enhanced by ketorolac. Expression of genes encoding the index of nuclear factor kappaB activity and the chemokine monocyte chemoattractant protein-1 was also increased by the NSAID. We speculated here that such effect was indirectly mediated via an altered secretion of plasma glucocorticoids because ketorolac is a potent inhibitor of the hypothalamic-pituitary-adrenal axis during systemic inflammation. As expected, pretreatment with the glucocorticoid receptor antagonist RU-486 exacerbated the influence of systemic immune stimuli on proinflammatory signaling. In contrast, exogenous corticosterone abolished the effects of ketorolac on IL-1beta-induced COX-2 and monocyte chemoattractant protein-1 gene expression in the cerebral endothelium. This drug plays therefore a paradoxical role in its ability to inhibit the circulating levels of glucocorticoids that are essential inhibitory feedback on the proinflammatory signal transduction pathways and gene transcription. In altering the production of key prostaglandins that are involved in the control of hypothalamic-pituitary-adrenal axis, ketorolac may have proinflammatory properties in the central nervous system during systemic immune stimuli.
Dipyrone is a non-narcotic analgesic and antipyretic drug used in both pediatric and adult patients. Dipyrone solution can be used intranasally as an antipyretic agent for infants. However, dipyrone is not stable in liquid state. Therefore, a stable dipyrone formulation was developed and the antipyretic effect of the formulation was studied after intranasal administration in rabbits and rats, respectively. To guarantee dose accuracy in animal studies, effect of dose volume on the distribution of dipyrone solution in rabbit nasal cavities were studied, using gentian violet as an indicator. Animal fever model and intranasal administration methods were established. In addition, the potential toxicity of the dipyrone formulation was studied. It was shown that the nasal volume of rabbits is large enough to hold 100 microl solution. After intranasal administration, improved pharmacodynamics was obtained with the new developed dipyrone formulation compared to the normal dipyrone solution, and significantly decreased body temperature was observed 10 min after dosing. The toxicity was negligible. In conclusion, the dipyrone formulation is effective and safe for clinical medication.
General pharmacological studies were performed on (6)-gingerol and (6)-shogaol which are the pungent constituents of ginger (Zingiber officinale Roscoe). Intravenous (i.v.) administration of (6)-gingerol (at 1.75-3.5 mg/kg) or (6)-shogaol (at 1.75-3.5 mg/kg) and oral administration of them (at 70-140 mg/kg) produced an inhibition of spontaneous motor activity, an antipyretic and analgesic effects, prolonged hexobarbital-induced sleeping time, and these effects of (6)-shogaol were mostly more intensive than that of (6)-gingerol. (6)-Shogaol showed an intense antitussive effect in comparison with dihydrocodeine phosphate. In the electro-encephalogram of cortex, the low amplitude fast wave pattern was observed for 5 min after i.v. administration of (6)-shogaol, and then changed to the drowsy pattern, which was restored after 60 min. In the gastro-intestinal system, (6)-shogaol intensively inhibited the traverse of charcoal meal through the intestine in contrast with (6)-gingerol after i.v. administration of 3.5 mg/kg, but (6)-shogaol facilitated such an intestinal function after oral administration of 35 mg/kg. Both (6)-shogaol and (6)-gingerol suppressed gastric contraction in situ, and the suppression by the former was more intensive than that by the latter. In the cardiovascular system, both (6)-shogaol and (6)-gingerol produced depressor response at lower doses on the blood pressure. At high doses, both drugs produced three phase pattern.
The analgesic, anti-pyretic and anti-inflammatory effects of FI-302, N-(3-piperidinopropyl)-4-methyl-6-trifluoromethyl-furo [3,2-b]indole-2-carboxamide, a newly synthesized tricyclic compound, were investigated in comparison with those of nonsteroidal anti-inflammatory drugs (NSAIDs). FI-302 showed potent analgesic and antipyretic effects in the various models used. FI-302 showed an inhibitory effect on acute inflammatory response such as carrageenin-induced edema, but did not show any effect on chronic inflammatory response such as cotton pellet granuloma. These effects of FI-302 were about 2 to 7 times more potent than those of non-acidic NSAIDs such as mepirizole and tiaramide. Moreover, FI-302 had little or no ulcerogenic activity. From these results, it is conceivable that the spectrum of FI-302's activities is similar to those of non-acidic NSAIDs such as mepirizole and tiaramide. These results suggest that FI-302 is a new non-ulcerogenic anti-inflammatory compound, and should be suitably applicable for clinical purposes.
In order to examine analgesic and antiinflammatory activities of the position isomers of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (1, emorfazone), an analgesic-antiinflammatory drug, 5-ethoxy-2-methyl-4-morpholino-3(2H)-pyridazinone (2), 6-ethoxy-2-methyl-4-morpholino-3(2H)-pyridazinone (3) and 6-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (4) were prepared. Since 4 showed the most strong activity among the compounds tested, various 6-alkoxy- or 6-allyloxy-2-alkyl- or 2-cyclohexyl- or 2-phenyl-5-substituted amino-3(2H)-pyridazinones (15, 16) were prepared and examined for their activities. As a result, 4 and 2-methyl-5-morpholino-6-n-propoxy- or 6-n-butoxy-3(2H)-pyridazinone (15b, c) and 6-ethoxy-2-ethyl-5-morpholino-3(2H)-pyridazinone (15 l) were revealed to be more potent in analgesic and antipyretic activities than commercial drugs (1, aminopyrine, mepirizole, tiaramide HCl, phenylbutazone, mefenamic acid). On the basis of the available data, the structure-activity relationship in a series of 6-alkoxy-2-alkyl-5-substituted amino-3(2H)-pyridazinones (15, 16) was also discussed.
Cimicifugae Rhizoma have been used as an anti-inflammatory, analgesic and antipyretic remedy in the traditional Chinese medicines. Many 9,19-cyclolanostane glycosides have been isolated from Cimicifuga and related genera. Two biogenetically key compounds, acetylshengmanol xyloside and cimicifugoside H-1, were isolated and their chemical structures were elucidated by our group. The former compound seems to be the parent component of the other glycosides such as cimigenol xyloside from C. dahurica, C. iaponica and C. acerina. The latter glycoside, cimicifugoside H-1 was isolated together with cimicifugosides H-2-H-6 from commercial Cimicifugae Rhizoma. They are novel glycosides having a hydroxyl group ay C-11, and cimicifugosides H-3, H-4 and H-6 were trinor-triterpenol glycosides. Cimicifugoside H-1 changed into H-2, H-3 and H-4 under acidic or alkaline conditions. In this review, the structure elucidation of the above glycosides and their chemical transformation into other Cimicifuga glycosides are described.