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Different modes of inhibition of rat gastric mucosal 6-keto-PGF1 alpha production by indomethacin, aspirin and aminopyrine.

The actions of aminopyrine on rat gastric mucosal cyclooxygenase activity in vitro were investigated and compared with those of the cyclooxygenase inhibitors indomethacin and aspirin. Aminopyrine is a phenyl-pyrazolone derivative with potent analgesic and antipyretic properties, but is weakly ulcerogenic, while indomethacin and aspirin are known to cause considerable ulcerogenesis. Aminopyrine was less potent in its ability to inhibit cyclooxygenase activity. The inhibition by all three drugs decreased with an increase in the substrate concentration. Pre-incubation with the enzymes greatly increased the inhibitory action of indomethacin and aspirin, but only slightly increased that of aminopyrine. The inhibitory action of aminopyrine was reversible, whereas those of indomethacin and aspirin were irreversible. These findings are discussed in relation to the low incidence of gastrointestinal irritation caused by aminopyrine.

6-Ketoprostaglandin F1 alpha↗

Formation of 4-ethoxy-4'-nitrosodiphenylamine in the reaction of the phenacetin metabolite 4-nitrosophenetol with glutathione.

Phenacetin, a constituent of several analgesic and antipyretic formulations has been made responsible for a variety of toxic and carcinogenic actions. 4-Nitrosophenetol, the N-oxydation product of intermediate 4-phenetidine, forms methemoglobin and binds covalently to sulfhydryl groups of proteins and glutathione. In the reaction of 4-nitrosophenetol with glutathione and other thiols an intermediate so-called "semimercaptal" is formed from which N-(thiol-S-yl)-4-phenetidine S-oxide, N-(thiol-S-yl)-4-phenetidine and 4-phenetidine derive. Besides thiol adducts, a yellow compound is formed which was isolated as a pure crystalline product (elemental analysis) and identified by FAB-MS, EI-MS, 13C-, 1H-NMR, and UV-VIS spectroscopy as 4-ethoxy-4'-nitrosodiphenylamine. This nitrosoarene is formed by an unknown mechanism from 4-nitrosophenetol and 4-phenetidine under liberation of ethanol. In human erythrocytes this compound is easily reduced to 4-amino-4'-ethoxydiphenylamine (FAB-MS, EI-MS, 13C-NMR). During the reaction of 4-nitrosophenetol with red cells only traces of 4-ethoxy-4'-nitrosodiphenylamine were formed, whereas up to 10% appeared as the reduction product 4-amino-4'-ethoxydiphenylamine. This latter compound is unstable in red cells and is metabolized further to unidentified products.

Chemical Phenomena↗

The contributions of various chloroquine salts to the biliary and urinary execretion of hepatic paracetamol conjugation metabolites in the rat.

As an approach to explain the possible in vivo interaction of paracetamol (acetaminophen) with various chloroquine salts that are often administered during malaria tropica, the effects of these salts (chloroquine sulphate, chloroquine phosphate, chloroquine hydrochloride and ferrous sulphate) were examined in male rats. The coadministration of chloroquine salts with paracetamol for 7 days showed varied effects on urinary and biliary excretion of paracetamol sulphate and paracetamol glucuronide conjugates--the major metabolites of paracetamol metabolism. These findings suggest that chloroquine sulphate and ferrous sulphate may enhance the sulphation pathway in paracetamol metabolism and influence detoxification of paracetamol in the liver and thus protect the liver. Chloroquine sulphate is therefore a better choice compared to other chloroquine salts in the treatment of malaria with paracetamol as an antipyretic and analgesic.

Acetaminophen↗

Nimesulide: an NSAID that preferentially inhibits COX-2, and has various unique pharmacological activities.

Nimesulide is a NSAID with good anti-inflammatory, analgesic and antipyretic activities expected of such compounds. However, in addition it has some unique therapeutic and pharmacological activities. The novel therapeutic aspects include a relatively low toxicity to the gastrointestinal tract and kidneys, it can be given to most patients who experience respiratory problems with other NSAIDs, and the onset of analgesia is comparatively quick. The main novel pharmacological actions obtained using nimesulide in vivo at therapeutic doses, or in vitro at concentrations within the therapeutic range of free (unbound) drug, include: a preferential inhibition of prostaglandin synthesis via COX-2, and reductions in cytokine action/release, histamine release, the release of enzymes that degrade cartilage, and the release of superoxide anions and other toxic substances from neutrophils. Interactions with other drugs are few and of little or no clinical significance.

Animals↗

Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis.

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.

Absorption↗

Meloxicam: a reappraisal of pharmacokinetics, efficacy and safety.

The discovery of two distinct isoenzymes of COX has led to the development and clinical introduction of COX-2 inhibitors with increased selectivity onto the market. Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class, and is a preferential inhibitor of COX-2, demonstrating effectiveness with anti-inflammatory, analgesic and antipyretic activity. Meloxicam is therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. Trials have examined the risk of gastrointestinal ulceration of meloxicam when compared with traditional non-specific COX-inhibiting NSAIDs with mixed results; meloxicam seems to have a greater gastrointestinal risk than the highly specific COX-2 NSAIDs. Meloxicam has a plasma half-life of approximately 20 h and is convenient for once daily administration. Neither moderate renal nor hepatic insufficiency significantly alters the pharmacokinetics of meloxicam in short-term studies. Furthermore, dose adjustment is not required in the elderly. Recent drug-drug interaction studies have demonstrated that meloxicam interacts with some medications, including cholestyramine, lithium and some inhibitors of cytochrome P450 -2C9 and -3A4. Consequently, increased clinical vigilance should be maintained when coprescribing some medications with meloxicam. Concentration-dependent therapeutic and toxicological effects have yet to be extensively elucidated for meloxicam. Long-term safety in various organ systems, especially in the heart and vascular system and with concomitant drug administration, remains to be proven. The pharmacokinetics of meloxicam enables once daily application, which increases compliance compared with some shorter acting NSAIDs; however, long-term clinical data clearly demonstrating safety and efficacy advantages are lacking.

Anti-Inflammatory Agents, Non-Steroidal↗

Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children.

OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAIDs), mainly ibuprofen, are used extensively among children as analgesic and antipyretic agents. Our initial survey in the Kendang Kerbau Children's Hospital in Singapore showed NSAIDs to be the second most common adverse drug reaction-causing medications among children of Asian descent. We attempted to characterize the clinical and epidemiologic profile of NSAID reactions in this group of patients. METHODS: A retrospective case series from a hospital-based pediatric drug allergy clinic was studied. A diagnosis of NSAID hypersensitivity was made with a modified oral provocation test. Atopy was evaluated clinically and tested with a standard panel of skin-prick tests. We excluded from analysis patients with any unprovoked episodes of urticaria and/or angioedema, patients < 1 year of age, and patients who refused a diagnostic challenge test. RESULTS: Between March 1, 2003, and February 28, 2004, 24 patients, including 14 male patients (58%) and 18 Chinese patients (75%), with a mean age of 7.4 years (range: 1.4-14.4 years), were diagnosed as having cross-reactive NSAID hypersensitivity. A family history consistent with NSAID hypersensitivity was elicited for 17% of patients. None of the patients reported any episodes of angioedema/urticaria unrelated to NSAIDs. The median cumulative reaction-eliciting dose was 7.1 mg/kg. Facial angioedema developed for all patients (100%) and generalized urticaria for 38% of challenged patients, irrespective of age. There was no circulatory compromise, but respiratory symptoms of tachypnea, wheezing, and/or cough were documented for 42% of patients. A cross-reactive hypersensitivity response to acetaminophen was documented for 46% of our patients through their history and for 25% through diagnostic challenge. Compared with patients with suspected adverse drug reactions to antibiotics, patients in the NSAID group were older (7.4 vs 4.8 years) and more likely to have a diagnosis of asthma (odds ratio: 7.5; 95% confidence interval: 3.1-19). CONCLUSIONS: Early presentations of facial angioedema and urticaria are key features of dose- and potency-dependent, cross-reactive reactions to NSAIDs in a subpopulation of young, Asian, atopic children. Significant overlap with acetaminophen hypersensitivity, especially among very young patients, for whom the use of a cyclooxygenase-2-specific medication may not be feasible, severely limits options for medical antipyretic treatment.

Acetaminophen↗

[Non-prescription drugs in Brazil].

In this study we examined the 100 over-the-counter drugs that were most widely sold in Brazil from June 1992 to June 1993. We excluded 23 food products that were classified as medicinal. The sample, which included 77 drugs, was representative of about 67% of all sales in monetary value, and 76.8% of all units sold of the different classes of over-the-counter drugs. The anatomical-therapeutic-chemical (ATC) system was used to classify the various drugs; each class of drugs was also graded according to a scale of its intrinsic value, taking into account effectiveness and risks. Most classes of drugs (91%) showed "little intrinsic value" (that is, were of questionable or no value, of relative value, or unacceptable), and 70% were fixed-dose combinations. Only 10 classes of drugs were included in the Ministry of Health's National Drug List, and four appeared in WHO's list of essential drugs. The therapeutic classes to which the drugs belonged were, in descending order of frequency, for the digestive tract, skin, genitourinary system, musculo-skeletal system, central nervous system, parasitic diseases, respiratory tract, and sensory system. The therapeutic subgroup that commanded the highest sales was that of the non-opiate analgesics and antipyretics. Our results confirm the hypothesis that over-the-counter drugs in Brazil are of poor therapeutic quality and that the use of many such drugs is a source of unnecessary expense for the population. Some of them should not be accessible to individuals who lack current knowledge of their side effects, since 25% of all cases of poisoning in the country are related to self-medication. Modifying the public's perception of the need for taking drugs to relieve their ailments is one approach that may improve their use of medications in the long term.

Brazil↗

Neutropenia, agranulocytosis and dipyrone.

CONTEXT: Neutropenia and agranulocytosis may be defined as granulocyte counts of less than 1,500/mm3 and 500/mm3, respectively. Agranulocytosis is a rare and serious disease often caused by drugs. Its mortality rate is around 10%. The most common manifestations are infections such as tonsillitis, pharyngitis, stomatitis or pneumonia. Although dipyrone is one of the drugs known to be associated with agranulocytosis, the strength of the association has been a matter of much debate. Moreover, alternative analgesic and antipyretic agents are not devoid of serious side effects. CONCLUSIONS: It is therefore necessary to establish the incidence of agranulocytosis in Latin America and the role of dipyrone. The ongoing LATIN Study is a multicenter international case-control study that will provide answers for these questions.

Agranulocytosis↗

Dipyrone-induced granulocytopenia: a case for awareness.

Dipyrone, also known as metamizole, is an analgesic and antipyretic drug that was banned by the United States Food and Drug Administration because of its association with agranulocytosis. However, it is still produced and marketed in several countries in Central and South America as well as in Europe, Asia, and Africa. It can also be found in the United States, where illegal sales have been reported in California gift shops, markets, bakeries, and other retail establishments. Dipyrone is commonly found in the homes of families who are originally from areas where it is still lawfully marketed. We describe a patient who developed granulocytopenia and fever after taking dipyrone and discuss the available literature. Our aim is to raise awareness of this drug, which is commonly used outside the United States, and to call attention to its well-known and potentially lethal side effect.

Adult↗

A population-based case-control teratologic study of oral dipyrone treatment during pregnancy.

OBJECTIVE: To study the possible human teratogenic effect of oral dipyrone, an antipyretic and analgesic drug treatment during pregnancy. DESIGN AND SETTING: The analysis of cases with different congenital abnormalities and their matched population controls without congenital abnormalities, in addition to a comparison between cases and malformation controls (Down's syndrome) in the population-based, large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. STUDY PARTICIPANTS: 22 843 neonates or fetuses with congenital abnormalities (cases), 38 151 matched newborns without congenital abnormalities (population controls) and 834 neonates or fetuses with Down's syndrome (malformation controls). MAIN OUTCOME MEASURES: 25 congenital abnormality groups. RESULTS: 1382 (6%) cases, 1911 (5%) population controls and 74 (8.9%) malformation controls were born to mothers treated with dipyrone during pregnancy. The case-matched population control analysis showed a higher rate of diaphragmatic defect (adjusted prevalence odds ratio [POR] 2.7; 95% CI 1.0, 6.8), cardiovascular malformations (POR 1.3; 95% CI 1.0, 1.7) and other isolated congenital abnormalities (POR 1.8; 95% CI 1.1, 2.9) after oral dipyrone treatment during the second and third months of gestation, i.e. in the critical period for most major congenital abnormalities. However, the evaluation of only medically recorded dipyrone use did not confirm these possible associations. The comparison of dipyrone treatment between 25 congenital abnormalities groups and malformation controls as the referent group also did not show any difference in the dipyrone use during the second and third months of gestation. CONCLUSIONS: The higher occurrence of dipyrone treatment in the case mothers compared with population control mothers can be explained by recall bias and/or chance. However, the higher rate of diaphragmatic congenital abnormalities can be considered as a signal and merits further investigation.

Abnormalities, Drug-Induced↗

Pharmacokinetics of oxicam nonsteroidal anti-inflammatory agents.

Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of structurally closely related substances with anti-inflammatory, analgesic and antipyretic activities. They have a weakly acidic character and are extensively bound to plasma proteins. Piroxicam, the most widely used oxicam, is well absorbed after oral administration. Peak plasma concentrations (Cmax) of the drug are reached within 2 to 4 hours. Piroxicam has a small volume of distribution and a low plasma clearance. It undergoes hepatic metabolism and only 5 to 10% is excreted unchanged in urine. The elimination half-life varies between 30 and 70 hours. Age of the patient and renal or hepatic dysfunction do not seem to have any major effect on the pharmacokinetics of piroxicam. The drug reduces the renal excretion of lithium to a clinically significant extent, but the clinical significance of piroxicam-aspirin (acetylsalicylic-acid) and piroxicam-acenocoumarol interaction has not been established. Ampiroxicam, droxicam and pivoxicam are prodrugs of piroxicam that have been synthesised to reduce piroxicam-related gastrointestinal irritation. All prodrugs are well absorbed, but Cmax values are reached later than those following administration of piroxicam. Tenoxicam is used in the management of rheumatic and inflammatory diseases. Mean Cmax values are achieved 2 hours postdose. Food reduces the rate but not the extent of absorption. The oral bioavailability of tenoxicam is 100% and rectal bioavailability is 80%. Like piroxicam, tenoxicam has a low volume of distribution and low plasma clearance. It is eliminated through hepatic metabolism. The mean elimination half-life is 60 to 75 hours. The pharmacokinetics of tenoxicam are independent of patient age, or concurrent liver or renal diseases. High doses of aspirin have been shown to increase the elimination of tenoxicam, but this has little clinical significance. Isoxicam was in widespread clinical use until its worldwide marketing was suspended because of fatal skin reactions. Isoxicam is completely absorbed, but Cmax values are not reached until 10 hours postdose. It has a low plasma clearance, approximately 5 ml/min (0.3 L/h), and low volume of distribution. The mean elimination half-life is 30 hours and does not appear to be affected by the age of the patient. Isoxicam potentiated the anticoagulant effect of warfarin, necessitating a 20% dosage reduction. Lornoxicam differs from other oxicam NSAIDs because it has a short elimination half-life of 3 to 4 hours. On the basis of limited data, some individuals seem to eliminate lornoxicam very slowly, suggesting the presence of polymorphic metabolism. The pharmacokinetics of cinnoxicam and sudoxicam have not been studied thoroughly.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

Clinical pharmacokinetics of ibuprofen. The first 30 years.

Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2 arylpropionic acid (2-APA) class. A common structural feature of 2-APANSAIDs is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side chain moiety with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its pharmacokinetics. Substantial unidirectional inversion of the R-(-) to the S-(+) enantiomer occurs and thus, data generated using nonstereospecific assays may not be extrapolated to explain the disposition of the individual enantiomers. The absorption of ibuprofen is rapid and complete when given orally. The area under the plasma concentration-time curve (AUC) of ibuprofen is dose-dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to plasma albumin. At doses greater than 600mg there is an increase in the unbound fraction of the drug, leading to an increased clearance of ibuprofen and a reduced AUC of the total drug. Substantial concentrations of ibuprofen are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Ibuprofen is eliminated following biotransformation to glucuronide conjugate metabolites that are excreted in urine, with little of the drug being eliminated unchanged. The excretion of conjugates may be tied to renal function and the accumulation of conjugates occurs in end-stage renal disease. Hepatic disease and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not excreted in substantial concentrations into breast milk. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), cholestyramine and methotrexate. A relationship between ibuprofen plasma concentrations and analgesic and antipyretic effects has been elucidated.

Animals↗

The effect of nimesulide on prostanoid formation.

Nimesulide (4-nitro-2-phenoxy-methansulfonanilide) is a weak acidic (pKa = 6.50) nonsteroidal anti-inflammatory drug (NSAID) belonging to a new chemical class, the sulfonanilide derivatives, and does not contain the carboxylic group. It exhibits potent anti-inflammatory, analgesic and antipyretic activities. Although nimesulide is not a cyclo-oxygenase inhibitor in gastric tissues or bovine seminal vesicle microsomes, it inhibits prostaglandin synthesis in zymosan-stimulated murine macrophages in inflammatory exudate. Nimesulide significantly antagonises the immune formation of thromboxane B2 in lung tissue. It neither induces gastrointestinal lesions nor affects renal function in animal models.

Animals↗

Recent contributions to knowledge of the mechanism of action of nimesulide.

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) of the sulfonanilide class. Its anti-inflammatory, analgesic and antipyretic activities have been demonstrated in several widely used animal experimental models and in numerous clinical trials. Nimesulide only weakly inhibits prostaglandin synthesis and appears to exert its effects through various mechanisms. It inhibits the release of oxidants from activated neutrophils and has a scavenging effect on hypochlorous acid without affecting neutrophil function. Nimesulide also decreases histamine release from tissue mast cells and inhibits the production of platelet-activating factor by human basophils. Furthermore, when added in vitro to cultures of human articular chondrocytes, nimesulide inhibits the release of stromelysin and blocks metalloproteinase activity.

Animals↗

Effect of age and disease on the pharmacokinetics of nimesulide.

Nimesulide is a nonsteroidal anti-inflammatory agent with additional antipyretic and analgesic activity. The recommended dosage is 100 to 200 mg twice daily orally or rectally. The pharmacokinetics profile of nimesulide has been studied in patients with a predisposition for altered pharmacokinetics. The pharmacokinetic profile of nimesulide and its hydroxy metabolite was not altered when the drug was administered in a standard regimen (100mg twice daily) to elderly patients aged < 80 years, suggesting that dosage adjustment is not necessary for such patients. In children aged 7 to 9 years, nimesulide 50mg administered in a granular formulation showed a tendency for greater absorption and elimination than that recorded for adults administered nimesulide in tablet form. These results suggest that the pharmacokinetic profile of this paediatric formulation should be assessed in children aged < 7 years to determine whether their dosage should be adjusted. In patients with moderate renal insufficiency, the pharmacokinetic profile of nimesulide was not altered even though the terminal elimination half-life of its hydroxy metabolite was greater and this resulted in slight accumulation with multiple dose administration in a standard regimen. This slight effect was not considered to be clinically significant and therefore dosage adjustment for patients with moderate renal impairment appears unnecessary. Administration of nimesulide to patients with severe renal failure should be avoided until the propensity and significance of hydroxy-nimesulide accumulation is quantified in this patient group. The pharmacokinetic profile of nimesulide has not been determined in patients with hepatic disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

An assessment of the efficacy and tolerability of nimesulide vs paracetamol in children after adenotonsillectomy.

The efficacy and tolerability of nimesulide were assessed and compared with those of paracetamol in the treatment of 35 children with pain and inflammation following adenotonsillectomy. The antipyretic and analgesic efficacy of the 2 drugs was similar, although more patients had complete remission of pain after 4 days of treatment with nimesulide. Both drugs were well tolerated, even though occasional elevation of transaminase enzymes and alkaline phosphatase was noted in the nimesulide-treated group. It is postulated that this effect may have been attributable to the volatile anaesthetics used during surgery.

Acetaminophen↗

Diclofenac-potassium in migraine: a review.

UNLABELLED: The NSAID diclofenac is a potent inhibitor of prostaglandin synthesis and an established antipyretic and analgesic agent. Diclofenac-potassium was developed as an immediate-release tablet with the aim of providing rapid onset of action after oral administration. This formulation has been investigated in the acute treatment of migraine. Data from available placebo-controlled clinical trials indicate that diclofenac-potassium 50 or 100mg as an immediate-release tablet is more effective than placebo and as effective as oral sumatriptan 100mg and ergotamine plus caffeine at reducing pain intensity in patients with migraine 2 hours after initial administration. Duration of pain relief is similar for the 3 drugs but onset appears to be faster with diclofenac-potassium than with oral sumatriptan or ergotamine plus caffeine. Diclofenac-potassium appears to have favourable effects on some accompanying symptoms such as nausea and vomiting. The frequency of these symptoms was significantly lower with diclofenac-potassium than with sumatriptan in 1 study, although only a few patients had vomiting at baseline. Effects on phonophobia or photophobia did not differ between diclofenac-potassium, sumatriptan and ergotamine plus caffeine. The need for rescue medication is consistently less with diclofenac-potassium than with placebo. Data are inconsistent or scarce regarding the effects of diclofenac-potassium versus placebo on other measures such as headache recurrence and working ability. Diclofenac-potassium was generally well tolerated in clinical trials in patients with migraine. Adverse events reported most frequently (abdominal pain, tiredness and fatigue and nausea) were typically mild to moderate. CONCLUSION: Diclofenac-potassium provides rapid pain relief (within 60 to 90 minutes), is well tolerated and reduces the frequency of some of the accompanying symptoms in patients with migraine. Available trials indicate that diclofenac-potassium provides similar pain relief to sumatriptan and is at least as effective as ergotamine plus caffeine, but appears to have a greater effect on nausea and vomiting than sumatriptan and a faster onset of action than both drugs. Comparisons with other NSAIDs are lacking. Diclofenac-potassium is likely to find a role as a useful first-line option in the acute treatment of migraine.

Anti-Inflammatory Agents, Non-Steroidal↗