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The anti-inflammatory profile of proquazone.

Proquazone, 1-isopropyl-4-phenyl-7-methyl-2(1H)-quinazolinone is an orally effective anti-inflammatory analgesic and antipyretic compound in animal models. The compound is less ulcerogenic than indomethacin in the rat and appears to potentiate the anti-inflammatory and thymus involution effects of hydrocortisone in this species. That a nonacidic nonsteroidal compound would display a spectrum of anti-inflammatory activity similar to that previously found only with acidic compounds will be the subject of further investigations.

Analgesics↗

[New esters of N-arylanthranilic acids].

A series of acyloxy- and alkyloxymethyl esters of meclofenamic, flufenamic and mefenamic acids has been synthesized and its antiinflammatory, analgesic and antipyretic activities have been compared with those of the corresponding acids and the methyl, beta,gamma-isopropylidene-dioxypropyl, N,N-diethylaminoethyl esters. The acyloxy- and alkyloxymethyl esters are the most interesting compounds, because they possess pharmacological activity of the same order as that of the corresponding acids and a lower toxicity. The ethoxymethyl ester of the N-(2,6-dichloro-m-tolyl)anthranilic acid is presently under clinical investigation.

Analgesics↗

Paediatric prescribing in Karachi.

To assess amount of drug overuse we studied drug prescribing for common childhood problems by 65 general practitioners (GPs) and 29 paediatricians. A total of 2433 encounters between GPs or paediatricians and children under five years of age were observed. The presenting complaints were fever in 18%, cough in 9%, both fever and cough in 21%, vomiting in 20% and diarrhoea in 41% of encounters. Antibacterials were prescribed in 49% of encounters, analgesics and antipyretics in 29%, antiemetics in 8% and injectables in 15%. Antidiarrhoeals were prescribed in 41% encounters with children reported to have diarrhoea. Ampicillin and cotrimoxazole were the two common antibacterials prescribed by both GPs and paediatricians. Antibacterials were prescribed in significantly larger number of encounters with GPs than in those with paediatricians. Mean encounter time of patients with GPs was 3.4+/-2.7 minutes and with paediatricians 9.7+/-4.1 minutes.

Ampicillin↗

Induction of chromosome aberrations in vivo in bone-marrow cells of mice by paracetamol.

The induction of chromosome aberrations by a common analgesic with antipyretic activity, Paracetamol, was investigated in vivo on bone-marrow cells of albino male mice. The drug was given orally or intraperitoneally in a single and cumulative dose series. The doses were the serial dilution of the highest one (400 mg/kg for intraperitoneal administration and 800 mg/kg for oral administration). Our study indicates that the cellular damage induced by Paracetamol leads to expression in chromosome aberrations such as gaps, chromatid breaks, acentric fragments and polyploid metaphases.

Acetaminophen↗

[3,3'-bi-1,3-thiazolidine]-4,4'-dione system. I. Synthesis, conformational analysis and pharmacological activities of 2,2'-diaryl derivatives.

The two configurational isomers, d1, and meso, of some 2,2'-diaryl-[3,3'-bi-1,3-thiazolidine]-4,4'-dione derivatives have been obtained and characterized. The 1H-N.M.R. spectra of both stereoisomers in DMSO-d6 solution are temperature-dependent and their dynamic behaviour has been related to the hindered rotation of the N--N bond. Evidence for an orthogonal disposition of the two heterocyclic rings, in the ground state, is presented. These new bicyclic compounds possess interesting antiinflammatory, analgesic and antipyretic activities as well as low acute toxicity and ulcerogenicity. The antiinflammatory effect, which in some compounds is higher than that of indomethacin and phenylbutazone, appears to be a function of the relative disposition of the substituents at position 2 and 2': generally the meso isomers are more active than the d1 ones. The lipophilicity of the tested compounds was determined by reversed-phase thin-layer chromatography.

Analgesics↗

Ketorolac, an injectable nonnarcotic analgesic.

Clinical studies of the injectable nonsteroidal anti-inflammatory agent (NSAIA) ketorolac tromethamine are reviewed, and the chemistry, pharmacology, pharmacokinetics, drug interactions, and adverse effects of ketorolac are described. Ketorolac exhibits anti-inflammatory, analgesic, and antipyretic activity. Although the exact mechanisms of action have not been determined, its effects appear to be associated principally with the inhibition of prostaglandin synthesis. After oral, i.m., or i.v. administration, ketorolac and its metabolites are excreted mainly in urine. Ketorolac tromethamine has been used for the symptomatic relief of moderate to severe postoperative pain, including that associated with abdominal, gynecologic, oral, orthopedic, or urologic surgery. Ketorolac has also been used for the relief of acute renal colic, pain associated with trauma, and visceral pain associated with cancer. When administered i.m., ketorolac produced analgesia comparable to that of i.m. doses of meperidine, pentazocine, or morphine. The most common adverse effects associated with short-term administration are nervous system and gastrointestinal effects; these are usually mild and occur in about 39% of patients. Unlike opiate analgesics, ketorolac does not appear to cause tolerance or physical dependence in patients receiving long-term therapy. Ketorolac tromethamine has been administered concomitantly with morphine or meperidine without apparent adverse interaction. For short-term pain management, an initial i.m. ketorolac tromethamine loading dose of 30 or 60 mg is recommended. Ketorolac tromethamine appears to be as effective as morphine or meperidine for short-term management of moderate to severe postoperative pain. It lacks the respiratory depressant effects of opiate analgesics but shares the toxic potentials of other NSAIAs.

Animals↗

Drug hoarding in a rural community in Israel. Results of a pilot epidemiologic investigation.

The total quantity of drugs hoarded in a rural village in Israel was established as a result of a comprehensive house-to-house search. In 43 of the 44 houses in the village, hoarded drugs were found. The average number of different drugs found per household was 15.5 and the median number, 9.5. Analgesic and antipyretic drugs, topical skin preparations and antibiotics were found most frequently among a total of 166 identifiable medicines. The drugs found included 5,998 tablets and capsules, 3,327 ml of liquid preparations, 1,290 g of creams and powders and 369 suppositories and pessaries. These findings are discussed in relation to the drug expenditure of the largest Israel health insurance fund, the serious health hazards which they present, and their possible relevance to the total Israel population. The possibility of a "hoarding-prone" personality is raised.

Analgesics↗

Paracetamol toxicity: epidemiology, prevention and costs to the health-care system.

Paracetamol has been used as an analgesic and antipyretic for many years, with toxicity first noted in the 1960s. Since then the incidence of poisoning has increased, and paracetamol is now the most common drug in self-poisoning, with a high rate of morbidity and mortality. The use, abuse and ways of reducing paracetamol toxicity are reviewed, but in view of the potential for harm, serious consideration should be given to changing the legal status of paracetamol, possibly to a prescription-only medicine.

Acetaminophen↗

Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system.

Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase. AM404 also inhibits purified cyclooxygenase (COX)-1 and COX-2 and prostaglandin synthesis in lipopolysaccharide-stimulated RAW264.7 macrophages. This novel metabolite of acetaminophen also acts on the endogenous cannabinoid system, which, together with TRPV1 and COX, is present in the pain and thermoregulatory pathways. These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen.

Acetaminophen↗

[About paracetamol again].

The mechanism of hepatotoxicity caused by paracetamol (acetaminophen) overdose and the treatment of patients is reviewed. Paracetamol is widely used over-the-counter drug with analgesic and antipyretic properties. Although it is considered to be safe at therapeutic doses, the incidence of hepatotoxicity caused by overdose or inadvertent application has been increasing lately. N-acetyl-p-benzoquinonimine, one of the metabolites formed from paracetamol is responsible for the hepatotoxicity. Until now there is no complete therapeutic strategy for the effective treatment of hepatotoxicity caused by paracetamol. Gut decontamination, N-acetylcysteine antidote administration and enhancement of elimination is used for the management of paracetamol overdose. Those with severe hepatotoxicity and neurological symptoms can benefit from removal of necrotic liver and undergo transplantation.

Acetaminophen↗

[Combined use of bucolome and pyrazolone derivatives (II). Complex formation due to interaction between bucolome and pyrazolones].

We have already reported that bucolome (BCP), a non-steroidal anti-inflammatory agent, potentiates significantly the analgesic and antipyretic effects of pyrazolones which are substituted by alkylamino group at 4-position of the pyrazolone ring. Physical and quantum chemistry were applied to the mechanism of this synergistic action. The solubility of BCP was markedly increased in proportion to elevation of aminopyrine (AM) concentration, but not by a combination with isopropylantipyrine (IP). The binding of BCP to bovine serum albumin was slightly inhibited by AM, but not by IP. The mixture of AM and BCP in aqueous media generated optical absorption in the ultraviolet differential spectrum, due to the charge transfer interaction. The results of the infrared or NMR spectrum demonstrated the formation of a hydrogen binding in non-aqueous media between BCP and AM. From the calculation of the charge on an atom, the energy of the highest occupied molecular orbital and the frontier electron density, BCP is considered to be a good electron acceptor. The beta-units of Mho of pyrazolones were found to correlate with the potentiation coefficient of analgesic activity in combination drugs. These results suggest that the complex formation between BCP and pyrazolones is an important factor for the synergism of action and is due to the charge transfer interaction and the hydrogen binding of both molecules.

Barbiturates↗

Acetaminophen toxicity.

Acetaminophen is the most widely used and recommended nonprescription analgesic and antipyretic medication in the United States (Rose, 1994). Because acetaminophen is widely advertised and readily available over the counter, consumers as well as health care professionals perceive this medication to be nontoxic. Large or repeated doses of acetaminophen can produce hepatotoxicity, which can occur within 24 hours of an overdose. However, because the signs and symptoms of acetaminophen overdose mimic common illnesses, the real diagnosis may go undetected (Baer & Williams, 1996). Early detection and treatment of acetaminophen overdose is imperative to avoid hepatotoxicity. Nurses play a key role in early identification of both recommended dosages and the clinical features that are associated with acetaminophen toxicity.

Acetaminophen↗

Anti-inflammatory, analgesic and other related actions of 4'-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9).

4'-Chloro-5-methoxy-3-biphenylylacetic acid (DKA-9) is a novel phenylacetic acid derivative with marked anti-inflammatory, analgesic and antipyretic activities. DKA-9 was approximately 2 times and 25 times more effective than ibuprofen in inhibiting carrageenin-induced paw edema and adjuvant-induced arthritis, respectively, in rats. The anti-inflammatory effect of DKA-9 was observed also in adrenalectomized rats. In the Randall-Selitto test in rats, DKA-9 was about 2 times more potent than ibuprofen and equipotent to indometacin. In lowering brewer's yeast-induced fever in rats, DKA-9 was almost 1/2 times more effective than ibuprofen. Considering from therapeutic index (ED50 in ulcerogenic effect/ED50 in carrageenin-induced edema), DKA-9 was found to be much superior to indometacin or ibuprofen.

Analgesics↗

Prolongation of antipyretic action and reduction of gastric ulcerogenicity in the rat by controlled-release granules of bermoprofen, a new nonsteroidal anti-inflammatory drug.

While bermoprofen [(+-)-10,11-dihydro-alpha,8-dimethyl-11- oxodibenz[b,f]oxepin-2-acetic acid], a new nonsteroidal antiinflammatory drug (NSAID), has potent antipyretic and analgesic activities with a short biological half-life, it shows ulcerogenic activity as a side-effect like other nonsteroidal anti-inflammatory drugs. A bermoprofen preparation was specially designed to prolong its duration of action and to reduce its side effect. Immediate-release granules (IRGs) were prepared by coating particles of Nonpareil 103 with bermoprofen. The IRGs were also coated by spraying a film solution composed of ethylcellulose and hydroxypropylmethylcellulose (3:2), and, thereby, three kinds of retard-release granules (RRGs) were obtained with the coating amounts of 1.5, 2.5, and 4%. Peak plasma bermoprofen levels were seen 0.5, 1, 2, and 3 h after single oral administrations of IRG, RRG(1.5%), RRG (2.5%), and RRG(4%), respectively, in rats. The potency order in ulcerogenic activity was RRG(1.5%) greater than IRG greater than RRG(2.5%) greater than RRG(4%) after a single oral dosage in rats. Then, IRG and RRG(4%) were mixed (in the ratio 3:7, which was calculated from their simulated plasma bermoprofen profiles) in order to get fast onset and long duration of antipyretic action. These mixed granules [i.e., the sustained-release granules (SRGs)] exhibited a falt plasma bermoprofen profile, and longer lasting antipyretic and lower ulcerogenic activities in rats in comparison with IRG or bermoprofen. From these results, it is suggested that a bermoprofen SRG preparation has more durable therapeutic activity and lower side-effects as a NSAID.

Animals↗

A gastroprotective anti-inflammatory agent: the beta-morpholinoethyl ester of niflumic acid (morniflumate).

In several animal models orally administered morniflumate, the beta-morpholinoethyl ester of niflumic acid, proved almost equal to the parent compound in anti-inflammatory, analgesic and antipyretic activity with the advantage of complete freedom from the ulcerogenic effects of the acidic parent compound. Further, it was 5 times less active in intestinal perforation experiments and 10 times less toxic in acute toxicity experiments than niflumic acid. Bioavailability and pharmacokinetics tests after oral and intravenous administration suggest that morniflumate is absorbed as such from the gastrointestinal tract and then undergoes rapid hydrolysis in the plasma, releasing the free acidic form, the molecule responsible for the pharmacological effects. In addition to being free from ulcerogenic effects, the ester actually displayed a gastroprotective effect against the ulcerogenic effects of niflumic acid; this finding is discussed in the light of the concept of 'cytoprotection' recently reported for a series of mild gastric irritants.

Analgesics↗

Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen.

Acetaminophen is a mild analgesic and antipyretic agent that is safe and effective when taken in therapeutic doses. Ingestion of overdoses, however, may lead to acute liver failure accompanied by centrilobular degeneration and necrosis. Although the toxicity of acetaminophen is generally thought to be caused by direct interaction of its reactive metabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirectly through the release of cytotoxic mediators. We analyzed the potential role of hepatic macrophages in acetaminophen hepatotoxicity by examining the effects of modulating the activity of these cells on tissue injury. Treatment of male Long Evans Hooded rats with acetaminophen (800 mg/kg) was found to induce extensive centrilobular hepatic necrosis. Pretreatment of the rats with either dextran sulfate or gadolinium chloride, two inhibitors of hepatic macrophage functioning, completely blocked hepatic necrosis, as well as increases in serum transaminase levels induced by acetaminophen. Interestingly, treatment of rats with the macrophage activator, lipopolysaccharide (LPS), also reduced tissue injury induced by acetaminophen. To exclude the possibility that the effects of gadolinium chloride, dextran sulfate, or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of these agents on various pharmacokinetic properties of this analgesic. Dextran sulfate and gadolinium chloride had no effect on the half-life of a low dose of acetaminophen (20 mg/kg), or on the activity of any of its individual pathways of metabolism, including the formation of acetaminophen-mercapturic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin.

Omeprazole, a widely used and potent gastric proton pump inhibitor, induces cytochrome P450 (CYP) 1A2 in humans. Induction is most pronounced in slow metabolizers of S-mephenytoin because CYP2C19 (S-mephenytoin hydroxylase) is responsible for the elimination of omeprazole. Acetaminophen (INN, paracetamol), a widely used and effective analgesic and antipyretic agent, causes serious hepatic and renal toxicity at high doses by conversion of acetaminophen to the toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) through CYP1A2, CYP2E1, and CYP3A4. This study evaluated whether omeprazole pretreatment in five rapid and five slow metabolizers of S-mephenytoin could increase thioether (an estimate of NAPQI production) metabolite formation from acetaminophen. The results of this study show that, despite induction of CYP1A2 activity in slow metabolizers (a 75% increase in plasma clearance of caffeine), the formation of NAPQI from acetaminophen was not increased after 7 days of omeprazole administration (40 mg/day). This suggests that induction of CYP1A2 activity by omeprazole is unlikely to increase the risk of acetaminophen hepatotoxicity.

Acetaminophen↗

Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone.

OBJECTIVE: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically. METHODS: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly. RESULTS: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA. CONCLUSION: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

Administration, Oral↗