Analgesic Anti-inflammatory Agents Research Articles

Calcitonin

Calcitonin is a polypeptide hormone that bone resorption-inhibitory and analgesic effects, and has been used over many decades as a drug for the treatment of osteoporosis in Japan and overseas. Reports of large-scale studies of this hormone therefore as yet are few, compared to recently introduced drugs. Calcitonin is prescribed in injectable form in Japan while nasal spray preparations are widely used in Europe and the Unites States. Its characteristic effect of analgesia is slow in onset as compared with anti-inflammatory analgesic agents. A mechanism of action involving its serotonin receptor expression-mediated effect on pain impulse transmission has been demonstrated. On account of this effect, calcitonin is recommended for use in the management of pain in patients with fresh vertebral fractures.

Preparation of 5-aryl-3-alkylthio-l,2,4-triazoles and corresponding sulfones with antiinflammatory–analgesic activity

In this study, a series of 5-aryl-3-alkylthio-1,2,4-triazoles and corresponding sulfones were prepared with the objective of developing better analgesic–antiinflammatory compounds with minimum ulcerogenic risk. The structures of the compounds were elucidated by spectral and elemental analysis. The compounds were assayed per os in mice for their antiinflammatory and analgesic activity as well as the ulcerogenic risk and acute toxicity. Several of these compounds showed significant activity. Alkylsulfone derivatives were found to be much more potent analgesic–antiinflammatory agents than the corresponding alkylthio analogs. Compounds 9 and 11 were the most active of the series in both analgesic and antiinflammatory activity tests. In contrast to reference compound acetyl salicylic acid, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic/antiinflammatory activity.

Determination of nonsteroidal anti-inflammatory drugs in human specimens by capillary zone electrophoresis and micellar electrokinetic chromatography.

Therapeutic drug monitoring of anti-inflammatory drugs is necessary for the identification of the agents that cause toxic events and for the decision on the treatment for intoxication. Recently, capillary electrophoresis (CE) has been developed for the simple and rapid analyses of a variety of chemical agents. Micellar electrokinetic chromatography (MEKC) can separate acidic, neutral and basic anti-inflammatory drugs in serum. Furthermore, serum samples are directly applied to the CE system without any pretreatments, and some anti-inflammatory drugs can be separated from serum albumin in the MEKC analysis. On the other hand, capillary zone electrophoresis (CZE) enables us to determine a few microg/mL levels of acidic anti-inflammatory drugs with simple running buffer and stacking technique. A rapid and simultaneous determination of several analgesic anti-inflammatory agents, including ibuprofen, acetaminophen, indomethacin, and salicylic acid in human serum has been developed by using CZE. Therefore, the CZE and MEKC analysis may become a potentially useful alternative to high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) for therapeutic drug monitoring, particularly in serum of patients suffering from intoxication by overdosage of nonsteroidal anti-inflammatory agents.

A rapid and simultaneous determination of several analgesic antiinflammatory agents by capillary zone electrophoresis.

A rapid and simultaneous determination of several analgesic antiinflammatory agents--ibuprofen, acetaminophen, indomethacin, and salicylic acid--in human serum was developed by using capillary zone electrophoresis (CZE) coupled with diode-array ultraviolet detection. After precipitation of serum protein with acetonitrile containing 3-isobutyl-1-methylxanthine as the internal standard, an aliquot of deproteinized samples was applied directly to the CZE system. It enabled us to measure all of these four agents within 6 min, and there were no peaks interfering with the assay of these agents or 3-isobutyl-1-methylxanthine. Both the separation and quantification of these agents in human serum were reproducible after repeated analysis within a day or day-to-day analysis. In addition, there was a good correlation for each drug (r = 0.997-0.999) between the values in serum determined by CZE analysis and those measured either by high-performance liquid chromatography with ultraviolet detection (ibuprofen and indomethacin) or by fluorescence polarization immunoassay (acetaminophen and salicylic acid). Therefore, the present CZE analysis could provide a simple, rapid, and efficient method for the identification as well as monitoring of analgesic antiinflammatory agents, particularly in serum of patients suffering from intoxication by overdosage of these agents.

Pain Responses in Methadone-Maintained Opioid Abusers

Providing pain management for known opioid abusers is a challenging clinical task, in part because little is known about their pain experience and analgesic requirements. This study was designed to describe pain tolerance and analgesic response in a sample of opioid addicts stabilized in methadone-maintenance (MM) treatment (n = 60) in comparison to matched nondependent control subjects (n = 60). By using a placebo-controlled, two-way factorial design, tolerance to cold-pressor (CP) pain was examined, both before and after oral administration of therapeutic doses of common opioid (hydromorphone 2 mg) and nonsteroidal anti-inflammatory (ketorolac 10 mg) analgesic agents. Results showed that MM individuals were significantly less tolerant of CP pain than control subjects, replicating previous work. Analgesic effects were significant neither for medication nor group. These data indicate that MM opioid abusers represent a pain-intolerant subset of clinical patients. Their complaints of pain should be evaluated seriously and managed aggressively.

Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

A group of methyl 2-methyl-2-[2-(4-benzoyl-5-phenyl-7-halo-2-azabicyclo[4.1.0]hept-3-ene)]acetates (10-15), and the related acetamide derivative (16), that possess a variety of C-7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic-antiinflammatory agents. The effect of the C-7 substituent(s) and the nature of the acetic acid ester (R 1 = OMe) or acetamide (R 1 = NH 2 ) moiety on analgesic activity was determined using a 4% NaCI-induced abdominal constriction assay. Compounds 10-16 inhibited writhing by 36-82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C-7 substituents was a determinant of analgesic activity in the 7,7-dihalo group of compounds where the relative activity profile was 7-Cl 2 > 7-Br 2 > 7-F 2 > 7-Cl,7-F, and for 7-monohalo compounds where the potency order was 7-Br > 7-Cl. Elaboration of the 7,7-dibromo methyl acetate ester (10) to the corresponding acetamide derivative (16) enhanced analgesic activity. The nature of the 7-halo substituent(s) in the 7,7-dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan-induced rat paw edema assay, where the relative potency order was 7-Br 2 > 7-Cl 2 > 7-F 2 > 7-Cl,7-F. The most potent 7,7-dibromo compound (10) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX-2 (IC 50 = 26.4 μM) and COX-1 (IC 50 = 227 μM) for a COX-2 selectivity index of 8.6. Docking 10 in the active site of human COX-2 showed it binds in the center of the COX-2 binding site with the C-5 phenyl ring oriented toward the acetylation site (Ser 530 ), and the phenyl group of the C-4 benzoyl moiety oriented in the vicinity of the COX-2 secondary binding pocket near Val 523 .

Voltammetric Behaviour of Ketorolac and Its HPLC-EC Determination in Tablets.

ABSTRACT Ketorolac is an antiinflammatory-analgesic agent that is oxidizable at the glassy carbon electrode. The voltammetric oxidation produces two well resolved pH-dependent peaks, that are overlapped at pH>10. Using this voltammetric response a HPLC procedure with electrochemical detection in order to quantify ketorolac in pharmaceutical dosage forms is presented. Furthermore comparative methods using UV spectrophotometry and HPLC with photodiode array detector were used.

Synthesis and antiinflammatory—analgesic profile of 1-methyl-2-(4-X-benzoyl) imidazole-5-carboxylic acids

A set of 1-methyl-2-(4-X-benzoyl)imidazole-5-carboxylic acids, designed as antiinflammatory—analgesic agents, were synthesized and biologically evaluated in vivo (writhing test and the carrageenen rat pleurisy) using tolmetin as a reference drug. The compounds were also tested in vitro on the cyclooxygenase enzyme of sheep vescicular microsome. Distribution coefficients in the octanol-buffer system at different pH values have been determined for their potential influence on activity. Although the investigated compounds exhibited moderate or no inhibitory activity against cyclooxygenase in in vitro and in vivo assays, two of them (the 4-nitrobenzoyl and the 4-chlorobenzoyl derivatives 1e and 1b) were found to be more active than tolmetin in the writhing test. Moreover, 1b also showed higher activity in the pleurisy assay.

Manipulative physiotherapy for spinal problems in primary care: outcomes of care.

Outcome measures for physiotherapy in a primary health care setting should be evaluated before physiotherapy becomes widely available in general practice. The aim of this study was to assess changes in outcome measures in patients with spinal problems treated with bed rest, advice and analgesia ('traditional' treatment) and with manual/manipulative physiotherapy ('active' treatment). A retrospective analysis was carried out of computerized records of patients treated in primary care with manual and manipulative physiotherapy for spinal problems and a group with a similar age/sex/diagnosis profile who were given traditional treatment. Outcome measures in the 12 months following the initial diagnosis were: referrals, recurrences, casualty attendances, X-rays and number of prescribed analgesic and non-steroidal anti-inflammatory agents (NSAIDs). In the active group, there were 231 lumbar and 154 cervical patients, and 82 and 75, respectively, in the traditional group. There was a significant decrease in the recurrence rate [odds ratio (OR) = 0.56, 95% confidence interval (CI) 0.37-0.84] and in the numbers attending casualty (OR = 0.19, 95% CI 0.04-0.76) for 'active' compared with 'traditional' patients. For patients with cervical problems, there was a significant decrease in the active group of NSAIDs prescribed (P < 0.05). Certain outcomes of spinal problems are improved by the provision of manipulative physiotherapy in general practice.

Rapid and Sensitive Liquid Chromatographic Assay of Mefenamic Acid in Plasma

Mefenamic acid (MA) is a nonsteroidal antiinflammatory analgesic agent widely used clinically. A simple and sensitive liquid-chromatographic assay has been developed for the quantitative determination of MA in human plasma. A reverse phase, 10-microns cyano column (25 x 0.4 cm), a mobile phase of water-acetonitrile-methanol-17 M acetic acid (69:15:15:1 by volume), and an ultraviolet detection (290 nm) are used for the separation of MA and internal standard (methyl-clonazepam). MA and internal standard are extracted from acidified plasma into diethyl ether and after evaporation of the organic phase, the residue is redissolved in methanol. Calibration curves are linear in the range 0.05-3.20 micrograms/ml, and at the plasma level corresponding to the quantification limit (0.05 microgram/ml) coefficients of variation are 7.5% and 10.2% for repeatability and reproducibility studies, respectively. This assay was successfully used in the study of pharmacokinetics of MA in human plasma after a single oral administration of a low MA dose.

Nimesulide. A preliminary review of its pharmacological properties and therapeutic efficacy in inflammation and pain states.

Nimesulide is a new non-steroidal anti-inflammatory analgesic agent given orally or rectally on a twice daily basis in a number of inflammatory and pain states. Although still at an early stage of clinical assessment, preliminary evidence suggests that nimesulide 200 to 400mg daily is significantly more effective than placebo in reducing the pain, fever and inflammatory symptoms of chronic rheumatoid arthritis or osteoarthritis, respiratory tract infections, otorhinolaryngological diseases, soft tissue and oral cavity inflammation, dysmenorrhoea, phlebitis/thrombosis, urogenital disease and postoperative pain states. In a number of comparative studies, nimesulide has also been shown to be more effective than piroxicam (in osteoarthritis), paracetamol (acetaminophen) [in respiratory tract inflammation], benzydamine or naproxen (in otorhinolaryngological disease), phenylprenazone (in laryngotracheitis/bronchitis, respiratory inflammation and otorhinolaryngological disease), Serratia peptidases (in postoperative or dental pain, trauma and phlebitis), ketoprofen (in postoperative dental pain) and mefenamic acid (in dysmenorrhoea). In addition, the efficacy of nimesulide has been observed to be comparable with that of aspirin, with or without vitamin C, and mefenamic acid (in respiratory tract infection), ibuprofen (in soft tissue disease), naproxen (in respiratory tract inflammation, dysmenorrhoea and postoperative pain states), suprofen and paracetamol (in postoperative pain states), benzydamine (in genitourinary tract inflammation) and dipyrone, paracetamol or diclofenac (in fever). The safety profile of nimesulide has yet to be fully established, although initial evidence suggests the usual adverse effects associated with non-steroidal anti-inflammatory drugs occur, possibly with a lower incidence of gastrointestinal problems than with other members in its therapeutic class. Nimesulide, therefore, appears to offer a useful alternative to other non-steroidal anti-inflammatory drugs in the treatment of patients with inflammatory conditions and/or pain and fever states. However, further definition of its efficacy and tolerability is clearly required, particularly in comparison with established or other new drugs in its therapeutic class.

Pharmacokinetics and metabolism of tomoxiprole, a new analgesic antiinflammatory agent, in the rat.

The pharmacokinetics and the metabolic profile of tomoxiprole, a new analgesic antiinflammatory agent belonging to the class of 3-alkyl-2-aryl-3H-naphth (1,2-d)imidazoles, were studied in the rat. After oral administration (5 mg/kg) to male rats, tomoxiprole was rapidly absorbed, mostly by the gut, and reached maximum plasma levels of about 0.5 microgram/ml in 0.25-2 h. A metabolic first pass reduced the extent of oral bioavailability of the parent compound to about half, while absorption (total 14C data) was estimated to be complete. After intravenous injection (2.5 mg/kg), the plasma kinetics of tomoxiprole in male rats showed a bi-exponential profile, and the terminal elimination half-life was 4.2 h. The apparent volume of distribution was high, suggesting a wide distribution of the drug. Increasing the oral dose by ten times (50 mg/kg), resulted in linear kinetics with a proportional increase of the C max and AUC values and the same value of terminal elimination half-life. In females given a 5 mg/kg dose, the plasma levels of 14C, tomoxiprole and AUC values were somewhat higher than in males. The plasma levels of total 14C after iv or po treatments were higher and more sustained than those of tomoxiprole. The kinetic profile after iv administration was described by a three exponential terms equation and the terminal elimination half-life was 38.7 h. Upon iv administration, total 14C was rapidly distributed in highly vascularized tissues while in others, like the bone, fat, gonads, pancreas and skin the equilibrium with the central compartment was attained later. Target organs were the adrenals, liver, lungs, pancreas, thyroid, stomach and above all the fat tissue. Elimination from tissues was almost complete 48 h after the treatment. 14C was eliminated mainly in the feces (80% of dose) as metabolites. In the bile, five polar metabolites were detected; one of them, desmethyl tomoxiprole glucuronide, accounting alone for more than 80% of the total biliary radioactivity; was purified and its structure assigned.

High-Performance Liquid Chromatography of MDL-035 in the Plasma of Rats, Dogs and Humans

Abstract A sensitive and reproducible high performance liquid chromatographic method was set up for the assay of MDL-035, a new non-steroidal, nonacidic analgesic antiinflammatory agent, in the plasma of rats, dogs and humans. Plasma samples (0.5ml) containing flurazepam as the internal standard, were diluted and extracted with ethyl ether. After centrifugation, the organic phase was taken to dryness, the residue was redissolved and injected into an RP-2 column. The elution was made in isocratic conditions using a CH.CN/phosphate buffer solution as mobile phase. The UV detection was made at 320 nm. The method was validated for the concentration range from 0.05 to 10 ug/ml, and applied to pharmacokinetic studies. A typical plasma concentration-time profile in the rat after an oral administration is here presented.

Chemical and Pharmacological Properties of Diflunisal.

Diflunisal, 5-(2',4'-difluorophenyl) salicylic acid, was discovered as a potent antiinflammatory analgesic agent after an extensive investigation of more than 500 salicylic acid analogs. The addition of a difluorophenyl substituent at the C5 position of salicylic acid yielded a new molecule with much improved lipophilicity, a longer duration of action, and a molecular configuration that is optimal for greater antiinflammatory and analgesic activities. The difluorophenyl group is metabolically stable; the acyl and phenolic glucuronides of the intact diflunisal are major urinary metabolites. The absence of an O-acetyl group in this novel salicylate analog circumvents the well-known in vivo acylation potential of aspirin and renders diflunisal a reversible cyclooxygenase inhibitor with a secondary oxygen radical scavenging effect. In a variety of analgesic, acute, and chronic antiinflammatory models, diflunisal is active at 10 mg/kg, approximately 5 to 10 times more potent than aspirin. It has a relatively low potential to cause gastrointestinal irritation as indicated by the lack of acute effect on the integrity of gastric mucosal barrier, no change of intragastric potential, and no disturbance of prostaglandin production by the gastric tissue. Diflunisal holds promise as a new clinically useful analgesic and antiinflammatory drug with good tolerance and a long duration of action.

A double blind comparative study of a new non-steroidal anti-inflammatory analgesic agent, Suprofen after tooth extraction

A double blind comparative study of a new non-steroidal anti-inflammatory analgesic agent, Suprofen after tooth extraction

Augmentation of allergic histamine release from human leukocytes by nonsteroidal anti-inflammatory—analgesic agents

Augmentation of allergic histamine release in vitro with human leukocytes was produced by numerous nonsteroidal anti-inflammatory—analgesic agents, primarily the arylalkanoic and anthranilic acids. Augmentation occurred without release of histamine by the agents in the absence of the allergen (ragweed) and only under conditions of an accompanying release by the allergen. As a consequence of augmentation, less allergen was necessary to produce a given response in the presence of these agents. It is suggested that some of these agents might enhance mediator release in immediate-type hypersensitivity reactions. The same agents reported to exacerbate chronic urticaria, i.e., indomethacin, mefenamic acid, sodium salicylate, aspirin, sodium benzoate, and tartrazine, also augmented allergic histamine release. Pharmacologically mediated augmentation of mediator release from stimulated cells is suggested to be involved in the exacerbation of existing chronic urticaria by the acidic nonsteroidal anti-inflammatory—analgesic agents.

4-Ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone(M73101)の薬理学的研究

The anti-inflammatory activity and the mode of action of M73101, a new non-steroid analgesic anti-inflammatory agent, were investigated in experimental animals and compared with those of reference drugs. M73101 inhibited the increase in vascular permeability induced by acetic acid and its activity was more potent than that of phenylbutazone. M73101 showed a marked inhibitory effect against rat paw edema induced by various phlogistic agents (carrageenin, dextran, histamine, serotonin and bradykinin) and the activities were equal to or more potent than those of aminopyrine, mepirizole and tiaramide HCl. M73101 also inhibited the edema induced by mustard, scalding and anti-rat rabbit serum in rats. In addition, the anti-edematous effect of M73101 on carrageenin-induced rat paw edema was not influenced by spinalectomy or adrenalectomy, indicating that the anti-inflammatory action of M73101 was not mediated by the central nervous system and the adrenals. Local and oral administration of M73101 inhibited significantly the leucocyte migration into the fluid of CMC pouch in rats and the activity was more potent than phenylbutazone, suggesting that the anti-inflammatory effect of M73101 was due to the direct action at the inflamed site. On the other hand, M73101 did not show any marked activities on the experimental chronic inflammatory models. From these results, it is suggested that M73101 may be useful for clinical application as a basic analgesic, anti-inflammatory drug with remarkable anti-inflammatory activity in acute and subacute cases. The mechanism of the anti-inflammatory action of M73101 probably involves inhibition of an increase in vascular permeability and leucocyte migration.

Pharmacological studies of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101). (1). Analgesic activity (author's transl)

The analgesic activity and the mode of action of M73101, a new analgesic anti-inflammatory agent, were investigated in mice and rats and compared to those of reference drugs. M73101 showed a marked analgesic activity against noxious stimuli induced by pressure (Haffner method and Randall-Selitto method), thermal (hot plate method), electric and chemical (acetic acid-stretching method and bradykinin-induced responses) stimulation, in a manner similar to those of basic anti-inflammatory drugs (BAD) such as aminopyrine, mepirizole, tiaramide HCl, and benzydamine HCl. The activities of M73101 were equal to and/or more potent than those of BAD, and more potent than those of acidic anti-inflammatory drugs. In addition, the analgesic activity of M73101 was not decreased by the pretreatment with levallorphan and showed no cross-tolerance to morphine in mice, indicating that the analgesic properties of M73101 differ from those of morphine. On the other hand, the analgesic activity of M73101 as well as BAD was decreased by repeated oral administration in mice, and the potency was weaker than mepirizole. Furthermore, the muscle relaxant effect of M73101 obtained by inclined screen test in mice was the weakest among the BAD, suggesting that analgesic activity of M73101 is not related to the muscle relaxant property. These results indicate that M73101 may be useful for clinical application as an anti-inflammatory drug possessing remarkable analgesic activity.

Effects of 4-Ethoxy-2-methyl-5-morpholino-3 (2H) -pyridazinone (M73101) on Healthy Man. I. Physiological Function

Clinico-pharmacological effects of 4-ethoxy-2-methyl-5-morpholino-3 (2H) -pyridazinone (M73101), a new anti-inflammatory analgesic agent synthesized at the Research Laboratories of Morishita Pharmaceutical Co., Ltd., were studied in twenty-one healthy male volunteers aged 25-42.Nineteen volunteers were administered oral single dose of M73101 as follows: one volunteer with 0.5 mg/kg, 3 with 1.0 mg/kg, 5 with 2.5mg/kg, 3 with 5.0mg/kg, 5 with 10.0mg/kg and 2 with 15.0mg/kg. Two volunteers were medicated with oral repeated dose, three times of 5.0mg/kg at intervals of 4 hours.The physiological function tests by means of a polygraph were done in single dose group except 8 volunteers. In all volunteers, analgesic effects of M73101 on electrically evoked pain responses were studied, and clinical symptoms, side effects and laboratory tests were checked before and after medications.It was observed that the medication with M73101 in a dose range of 0.5-15.0mg/kg had no significant influences on blood pressure, heart rate, blood flow in the forehead skin, respiration and GSR, while the blood flow in the buccal skin was increased in a few volunteers. Bowel sounds as representative of the intestinal motility were increased except three volunteers medicated with 1.0, 2.5 and 15.0mg/kg. On the other hand, no abnormal findings in hematological tests, urinalysis and biochemical tests were observed after medication in all volunteers. The analgesic effect was expressed as the average of 5 volunteers. The administration of 5.0 and 10.0 mg/kg manifested an analgesic effect in 15 minutes, which lasted for 3-4 hoursorevenlonger.

Flurbiprofen: An interim report on the long-term study

SummaryA multi-centre, computer based study of flurbiprofen was started in 1971 to provide extensive and regular clinical and laboratory data on patients with a variety of arthritic conditions. To date, 828 patients have been studied, some of whom have received flurbiprofen continuously for up to 3 years in dosage ranging from 75 mg. to 250 mg. daily.The cumulative evidence of objective and subjective clinical assessments indicates that flurbiprofen is an effective anti-inflammatory analgesic agent which is well tolerated by the majority of patients: only 108 patients have been withdrawn from the study because of side-effects and many of the patients were receiving concomitant therapy known to cause side-effects. Measurements of conventional haematological and biochemical parameters have revealedno untoward efects of flurbiprofen therapy.