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Etoclofene, the ethoxy methyl ester of N-(2,6-dichloro-m-tolyl)anthranilic acid, showed potent anti-inflammatory, anti-pyretic and peripheral analgesic activity in several experimental models of inflammation. There was no evidence of adrenal dependence or corticoid-like effects at effective and non-toxic dose levels. Etoclofene showed a low level of toxicity and was well tolerated in animals.
A dual-labelling technique has been used to establish that partial hepatectomy has no effect on the degradation of poly (A)+mRNA and confirms that the increased incorporation of precursor into mRNA during early prereplicative development reflects an actual increase in mRNA biosynthesis. Simultaneous studies on the changes in nuclear RNA metabolism support the conclusion that an increase in gene transcription does occur. Colchicine, at concentrations known to disrupt microtubules, has no effect on this increase in gene transcription but prevents the translation of the gene products by promoting polysome disaggregation transiently during a critical stage of prereplicative development. Studies with mefenamic acid and hydrocortisone, specific inhibitors of prostaglandin metabolism, have ruled out any involvement of prostaglandins in the induction of prereplicative mRNA synthesis.
OBJECTIVE: The nature of the enzyme(s) catalysing the biotransformation of lornoxicam to one of its major metabolites, 5'-hydroxy-lornoxicam, has been investigated in human liver microsomes. The reaction kinetics were characterised, the affinity of lornoxicam for three major human drug metabolising cytochrome P-450 isozymes (CYP2C9, CYP2D6 and CYP3A4) was determined, and inhibition of the reaction by known substrates (diclofenac, ibuprofen, mefenamic acid, phenytoin, tolbutamide and warfarin) and the prototype inhibitor (sulphaphenazole) of CYP2C9 was investigated. RESULTS: Lornoxicam 5'-hydroxylation displayed single enzyme Michaelis-Menten kinetics, with a KM of 3.6 mu mol center dot l-1 and a Vmax of 2.6 nmol center dot h-1 center dot mg-1 microsomal protein. The apparent affinity of lornoxicam was high for CYP2C9, but negligible for CYP3A4 and CYP2D6. Inhibition of lornoxicam 5'-hydroxylation by CYP2C9 substrates and sulphaphenazole competitively and completely inhibited lornoxicam 5'-hydroxylation (Ki = 0.31 mu mol center dot l-1 as well as lornoxicam clearance (Ki = 0.33 mu mol center dot l-1), partial metabolic clearance (fm) = 0.95). CONCLUSION: 5'-Hydroxylation appears to be the only cytochrome P-450 catalysed metabolic reaction of lornoxicam by human liver microsomes and this major in vivo biotransformation pathway is catalysed virtually exclusively by CYP2C9.
Like many clinical non-small-cell lung cancers, the Lewis lung carcinoma produces prostaglandins. The Lewis lung carcinoma was used as a model of both primary and metastatic disease to assess the ability of cyclooxygenase inhibitors (mefenamic acid, diflunisal, sulindac, and indomethacin), the collagenase inhibitor minocycline, and the lipoxygenase inhibitor phenidone to act as modulators of cytotoxic cancer therapies. Although none of the single modulators given i.p. daily on days 4-18 altered tumor growth or the number of metastases found on day 20, modulator combinations consisting of minocycline/a cyclooxygenase inhibitor and, especially, of phenidone/a cyclooxygenase inhibitor resulted in modest tumor growth delay and a decreased number of lung metastases on day 20. The most effective modulators of cisplatin (CDDP) were phenidone/sulindac and phenidone/indomethacin, which led to 2.4- to 2.5-fold increases in the tumor growth delay produced by CDDP. The most effective modulations of cyclophosphamide resulted from administration of minocycline, minocycline/sulindac, or phenidone/sulindac and led to 2.0- to 2.1-fold increases in tumor growth delay by cyclophosphamide. The most effective modulators of melphalan produced 4.5- to 4.7-fold increases in tumor growth delay by the drug and were minocycline/sulindac, minocycline/mefenamic acid, and phenidone/sulindac. The most effective modulation of carmustine (BCNU) was obtained with minocycline/sulindac and minocycline/diflunisal leading to 2.8- to 3.1-fold increases in tumor growth delay by BCNU. Finally, the most effective modulation of radiation was obtained with minocycline/sulindac and phenidone/sulindac and resulted in 2.8- to 3.3-fold increases in tumor growth delay by radiation. The modulator combination that along with the cytotoxic therapies was most effective against metastatic disease was phenidone/mefenamic acid. There was no clear relationship between effective modulation of the cancer therapies and the degree of reduction in serum levels of prostaglandin E2 and leukotriene B4 by the agents in Lewis lung tumor bearing mice.
Orpanoxin, a nonsteroidal anti-inflammatory drug (NSAID) lacking gastric ulcerogenic effects in the therapeutic dose range in rats, was compared with six reference NSAIDs for oral activity in the rat paw carrageenin-induced edema assay. Tested NSAIDs were ranked on the basis of oral mg/kg ED50 values: piroxicam, 0.55; orpanoxin, 35.6; diflunisal, 59.6; benoxaprofen, greater than 300; tolmetin sodium, greater than 300; and sulindac, greater than 300. Zomepirac sodium was inactive. Only the three most potent compounds produced greater than 60% inhibition of edema. Inhibition was generally greater at 4 h than at 6 h post carrageenin for all compounds. Oral activity of orpanoxin was also demonstrated in the guinea-pig u.v.-induced erythema model (ED50 = 24.2 mg/kg p.o. when given 1 h before irradiation) and in the mouse ear croton oil induced edema test (ED50 value = 131 mg/kg p.o.). Topical activity of orpanoxin was assessed in both the guinea-pig and mouse models. In the guinea-pig u.v.-induced erythema model, application (1 h after u.v.) of 1, 5, and 10% (w/v) orpanoxin creams (containing 10% urea) significantly inhibited erythema at 2, 3, and 4 h post-irradiation. Orpanoxin, mefenamic acid, and indomethacin as 1% creams inhibited total erythema scores 70, 92 and 74%, respectively. Evidence for topical activity in the mouse ear assay was also obtained for orpanoxin in diethyl ether or 10% urea cream, but not in dimethylsulfoxide. It was concluded that orpanoxin has anti-inflammatory activity comparable to reference NSAIDs in the rat paw edema test, is active orally in rat, mouse, and guinea-pig models, and shows topical activity in the guinea-pig and the mouse.
The helper function of macrophages in lymphocyte stimulation is well known, but there are indications that macrophages may also exert a suppressor effect on lymphocytes. This effect might be due to prostaglandins secreted by the macrophages. In order to test this hypothesis anti-inflammatory drugs, some of which are known inhibitors of prostaglandin synthesis, were added to a series of phytohaemagglutinin (PHA)-stimulated lymphocyte cultures containing different proportions of macrophages and lymphocytes. The experiments showed that high concentrations of all drugs were inhibitory. Moderate concentrations of some of the PG-synthesis-inhibiting drugs (like indomethacin and mefenamic acid), however, appeared to have a stimulatory effect. The stimulation was more pronounced in cultures containing a high proportion of macrophages. These results support the assumption that macrophages release prostaglandins, which suppress PHA-induced lymphocyte proliferation.
PURPOSE: Children scheduled to undergo otoplasty experience severe pain postoperatively. Nausea and vomiting is also a problem. This study was designed to compare two analgesic techniques (i) regional nerve blockade (ii) local anaesthetic infiltration, with respect to quality and duration of analgesia, opioid requirements and the incidence of postoperative nausea and vomiting (PONV). METHODS: Forty three children, ASA I-II, aged 3-15 yr, were studied and followed for 24 hr postoperatively. Patients were randomised into two groups. Patients in Group A received local infiltration with lidocaine 1% with adrenaline 1:200,000 0.4 ml.kg-1 (n = 21). Patients in Group B (n = 22) received nerve blockade, bupivacaine 0.5%, 0.4 ml.kg-1. No other form of analgesia was used intraoperatively. Quality and duration of analgesia were assessed using pain and sedation scores recorded by a blinded observer at 0, 5, 10, 15, 30, 45 min with Recovery Room, and at 0, 30, 60, 90, 120, 180, 240, 360, 480 min on the ward. Pain score > 6 was treated with fentanyl 1 microgram.kg-1 iv (recovery) and morphine 0.2 mg.kg-1 im or mefenamic acid 8 mg.kg-1 po on the ward. Time to first supplemental analgesia was noted. Mean duration of analgesia was 8.6 (1.1-24) hr, Group A and 10.5 (1.3-24) hr, Group B (P > 0.7). 24% per cent of children (Group A) and 27% (Group B) required no supplemental analgesia (P > 0.6). The degree of pain control resulted in a low requirement for opioids, Group A: 24%, Group B: 14% (P:NS). The overall incidence of PONV was 43% (Group A) and 36% (Group B) (P:NS): PONV correlated with opioid use. There were no differences between the groups with regard to pain/sedation scores, quality/duration of analgesia, opioid requirements and incidence of PONV. CONCLUSION: Both techniques provided excellent postoperative analgesia. Lidocaine 1% infiltration (adrenaline 1:200,000) has the added advantage of improving surgical field and haemostasis. Thus, we advocate use of the simpler technique.
AIM OF INVESTIGATION: We examined whether a pre-emptive analgesic effect could be achieved with ropivacaine, which has less cardiovascular and central nervous system toxicity than bupivacaine, in adults undergoing tonsillectomy. METHODS: The study was carried out in 80 patients in a randomised, double-blind fashion. The patients were randomly assigned to one of four groups. In group I, 3 ml ropivacaine 7.5 mg/ml were injected pre-operatively 5 minutes before the start of OR into each tonsil bed. In group II, 3 ml ropivacaine 7.5 mg/ml were injected post-operatively into each tonsil bed. In group III, 3 ml NaCl were injected pre-operatively 5 minutes before the start of OR into each tonsil bed. In group IV, 3 ml NaCl were injected post-operatively into each tonsil bed. The analgesic effectiveness was measured post-operatively by the use of a visual analogue scale, a numeric rating scale (at rest and during activity) and by measuring the total analgesic consumption (mefenamic acid) in the first 192 hours. In addition the time of first analgesic request was noted. Vital parameters and side-effects were documented. RESULTS: There was no significant difference between the groups in the time of first analgesic request. Likewise, there was no significant difference in the post-operative cumulative analgesic consumption between the four groups. The post-operative administration of ropivacaine resulted in significantly lower pain scores at certain time points compared with the other groups as measured both with the visual analogue scale and the numeric rating scale (at rest). It must be emphasized, that the pain scores both at rest and with exertion remain high and that the net analgesic consumption (per day) remains constant for the first 8 post-operative days. CONCLUSIONS: We could demonstrate no significant pre-emptive analgesic effect with ropivacaine in adults undergoing tonsillectomy in our study. One can, however, recommend the administration of ropivacaine post-operatively after tonsillectomy, since a reduction of pain scores can thereby be achieved. For post-operative analgesia we recommend the combination of a non-opioid analgesic with a weak opioid.
Pharmaceutical substances have been detected in sewage effluents as well as receiving waters in many parts of the world. To assess the fate and removal of these compounds within sewage treatment plants, an understanding of their partitioning behavior between the solid and aqueous phases is critical. Therefore, a preliminary study was conducted to ascertain an understanding of the binding behavior of five drug substances sorbing to the solid phase in a laboratory scale-activated sludge plant (Husmann unit). For comparison, uncontaminated river sediment was also used as a substrate. All of the compounds tested partitioned more readily to the sludge than the sediment, likely because of the former's higher organic carbon content. Partitioning to the solid phase correlated roughly with predicted log Kow values. A period of initial sorption was followed by a phase of desorption, and net absorption of the selected drugs (with the exception of mefenamic acid) after 5 hours of mixing was minimal.
In a medline search (covering 1966 to Sept. 1996) 32 clinical studies were identified, in which the efficacy of paracetamol or matamizol per se, or in comparison to other analgesics, in various chronic pain states, such as migraine, dysmenorrhoea, arthritis and osteoarthritis pain and cancer pain had been examined. In patients with migraine (4 studies) several other analgesics (ibuprofen, mefenamic acid, flupirtin) were slightly more effective than paracetamol, however, the efficacy of paracetamol itself had not been assessed. In patients with chronic tension headache (1 study) paracetamol was superior to placebo, but less effective than naproxen. Pain of dysmenorrhoea was not, or only marginally improved by paracetamol in 3 studies, efficacy was reported in 1 study. Similarly, pain in rheumatoid arthritis was not significantly alleviated when paracetamol was given alone (3 studies) and marginally improved, when combined with naproxen and tested against naproxen alone (1 study). Some improvement by paracetamol of pain scores in patients with osteoarthritis (5 studies) requires further clinical confirmation. No studies were found, in which metamizol had been studied in chronic non-cancer pain. Paracetamol and/or metamizol have been included in 14 studies on cancer pain, most of these studies attempting to validate the WHO analgesic ladder for cancer pain treatment. However, except for one study, in which metamizol was comparable in efficacy to morphine, all other publications do not provide detailed information on the efficacy of individual analgesics. Therefore it is not possible at present, to assess the possible merits of paracetamol or metamizol in the treatment of cancer pain from published studies.
Aspirin intolerance manifests itself as an acute urticaria-angioedema, bronchospasm, severe rhinitis, or shock occurring within three hours of aspirin ingestion. Aspirin intolerance occurs most commonly in patients with chronic urticaria (23 percent), in whom it is mostly manifested by the urticarial type of aspirin intolerance, and in asthmatic persons (4 to 19 percent), in whom it is mostly manifested by the bronchospastic type. The frequency of aspirin intolerance in patients with nasal polyps is about 23 percent, and consists of the bronchospastic type of intolerance. There is no definite evidence that aspirin intolerance is mediated by an immunologic reaction. In the bronchospastic type, an association between prostaglandins and the slow-reacting substance of anaphylaxis seems likely. The pathogenic mechanism for the urticarial type of aspirin intolerance is unknown. Under carefully controlled conditions, a transient desensitization to aspirin is possible. Various drugs, most of which are prostaglandin inhibitors, cross-react with aspirin in intolerant persons. They are, in decreasing order of frequency, as follows: indomethacin (100 percent), ibuprofen, mefenamic acid, phenylbutazone, sodium benzoate, tartrazine and acetaminophen (5 percent). Aspirin is an efficacious drug with increasing therapeutic use. In order to minimize its risk and increase its safety, physicians should familiarize themselves with those high-risk conditions where aspirin therapy should be avoided, or at least used cautiously.
Several candidate mediators of acute inflammation such as E-type prostaglandins, histamine and bradykinin are potent pro-diarrhoeal colonic secretagogues. They act to increase serosal to mucosal transport of chloride and passive water efflux. We investigated the effects of platelet activating factor (PAF) on muscle-stripped rat colon, measuring transepithelial potential difference (p.d.) and, under voltage clamp conditions, short circuit current (Isc). PAF induced dose-dependent increases in p.d. and Isc, with an approximate EC50 of 1.5 X 10(-10) M; similar concentrations of lyso-PAF had a much smaller but discernible effect. PAF and lyso-PAF both displayed 'sidedness' with serosal application effective and mucosal application ineffective. Inhibitor studies suggest that chloride is the principal ion carrier, but the specific PAF receptor antagonists kadsurenone, L652731, CV 3988 and WEB 2086 did not block the response. Unlike bradykinin, PAF did not cause the release of PGE2 into the serosal bathing fluid, and its action was not attenuated by the cyclo-oxygenase inhibitors piroxicam, mefenamic acid or flurbiprofen. We conclude that PAF has a powerful pro-diarrhoeal secretory action on colonic epithelium which is not mediated by the previously defined PAF receptor(s) and is independent of prostanoid generation.
Regulation of avidin accumulation by prostaglandins (PGs) and their inhibitors was studied in chick oviduct organ culture. Avidin was induced neither by progesterone nor PGF2 alpha in the oviduct of immature chicks. By progesterone and PGs, a high avidin synthesis was induced when the chicks received diethylstilbestrol (DES) for 7 days. Enhanced avidin production was observed by PGF2 alpha, PGE1 and PGE2, whereas PGA2 and PGB2 had a slight inhibitory effect and PGA1 and PGB1 had no effect on avidin production. PGF2 alpha was most effective at a concentration of 10-20 micrograms/ml. The effects of progesterone and PGF2 alpha were not additive. Mefenamic acid, at concentrations of 40 and 60 micrograms/ml, inhibited 50 and 85%, respectively, of the avidin synthesis induced by progesterone, whereas the inhibition of the total protein synthesis was only 20%, and this only by the higher concentration of the drug. Tolfenamic and meclofenamic acid were also inhibitory in the case of progestin-induced avidin synthesis. These studies indicate that the PGs (F2 alpha, E1 and E2) might be involved in the avidin induction in the chick differentiated oviduct. The specific inhibition of the progesterone-dependent avidin synthesis by the PG inhibitors suggests that PGs may be connected with the progesterone action in the oviduct. We propose that the avidin synthesis by the chick oviduct might be considered as a model system for studying PG effects on the synthesis of a specific protein.
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The purpose of the present investigation was to evaluate whether antiinflammatory drugs affect the pharmacodynamics of theophylline-induced seizures. Adult male Lewis rats were treated with either dexamethasone (DEX), hydrocortisone (HYD), ibuprofen (IBU), or mefenamic acid (MFA), for 4 consecutive days. On the fourth day they received a constant infusion of theophylline (2 mg/min IV) until the onset of maximal seizures. Then, blood and cerebrospinal fluid (CSF) were obtained for theophylline concentration determinations by HPLC. It was found that pretreatment with the corticosteroids DEX and HYD elevated the CSF theophylline concentration required to induce maximal seizures in comparison to the untreated rats (242 +/- 6, 232 +/- 6, and 203 +/- 10 mg/l, respectively, n = 10, p < 0.05). MFA also increased the CSF theophylline concentration at that end-point in comparison to the controls (p < 0.01), whereas pretreatment with IBU had no effect (280 +/- 10 MFA, 225 +/- 9 IBU vs. 220 +/- 8 controls, n = 12). The data suggests that concomitant treatment with antiinflammatory drugs, together with theophylline, do not increase the risk for theophylline-induced seizures. Moreover, in certain cases they may elevate the seizure threshold and protect against these hazardous episodes.
Triphasic depressor-pressor-depressor blood pressure responses to neurotensin (NT: 1.67 micrograms/kg i.v.) in anesthetized rats were not elicited when the second dose of NT was administered 20 min after the first injection. Pretreatment of animals with histamine markedly reduced the depressor response to NT, and vice versa. The triphasic blood pressure pattern remained unaffected with acetylcholine and serotonin treatment, and hypotensive effects of acetylcholine and serotonin were not modified by NT. Attenuation of depressor response induced by the second injection of NT was antagonized by pretreatment with prostaglandin synthesis inhibitors such as indomethacin, mefenamic acid and acetylsalicylic acid. These results suggest that histamine and prostaglandins play a role in the development of desensitization to NT in rat blood pressure.
A simple, sensitive, accurate, and rapid method for the quantitative determination of naproxen, oxyphenbutazone, mefenamic acid, indomethacin, and diclofenac sodium in pharmaceutical preparations is proposed. The method is based on the formation of blue complexes with Folin-Ciocalteu reagent.
A modified formalin test in mice was investigated. The pain response curve induced by 0.5% formalin was biphasic, having 2 peaks, from 0 to 5 min (first phase) and from 15 to 20 min (second phase). A low concentration of formalin was used, allowing the effects of weak analgesics to be detected. Centrally acting drugs such as narcotics inhibited both phases equally. Peripherally acting drugs such as aspirin, oxyphenbutazone, hydrocortisone and dexamethasone only inhibited the second phase. Aminopyrine and mefenamic acid which acted on both central and peripheral sites inhibited both phases, but the second phase was inhibited by lower doses. Thus, this method enables one to easily distinguish the site of action of analgesics. Furthermore, pain response in the first phase was inhibited by capsaicin-treated desensitization and Des-Arg9-(Leu8)-bradykinin (bradykinin inhibitor). The second phase was inhibited by compound 48/80 pretreatment, indomethacin and bradykinin inhibitor. Therefore, it is suggested that substance P and bradykinin participate in the manifestation of the first phase response, and histamine, serotonin, prostaglandin and bradykinin are involved in the second phase. These results indicate that the first and second phase responses induced by formalin have distinct characteristic properties, and it is a very useful method for examining pain, nociception and its modulation by pharmacological or other means.