Further studies on the antipyretic action of polymyxin B in pyrogen-induced fever.

A study of the antipyretic effect of polymyxin B was undertaken to determine how this agent reduces fever in rabbits. It involved the effects of the drug: (1) on fever induced by exogenous pyrogenes (E. coli lipopolysaccharide, synthetic double-stranded ribonucleic acid, sodium nucleinate from yeast) and leucocytic pyrogen, (2) on the release of endogenous pyrogen in vivo and in vitro, and (3) on leucocytic and exogenous pyrogens in vitro. The results indicate that polymyxin B produces an antipyretic effect in endotoxin-induced fever primarily by an interaction of this cationic macromolecule with the anionic endotoxin molecule. Further it is likely that polymyxin B inhibits endogenous pyrogen synthesis and/or release from polymorphonuclear leucocytes.     

Pyrogenic fever and blood plasma glucocorticoids after nonsteroid anti-inflammatory drugs

Rabbits were injected with the lipopolysaccharide from E. coli (LPS) and received orally nonsteroid anti-inflammatory drugs (NSAIDs): acetylsalicylic acid, indomethacin, mefenamic acid, ibuprofen, aminophenazone, metamizole sodium, and phenylbutazone. These NSAIDs exerted antipyretic action without inhibiting the increase in the level of plasma glucocorticoids induced by LPS. This finding indicates the lack of correlation between the pyrogenic action of bacterial pyrogen and pyrogenic increase in the plasma glucocorticoid level. The investigated NSAIDs when given alone to normothermic rabbits differently affected the plasma glucocorticoid level: acetylsalicylic acid, indomethacin and ibuprofen depressed the plasma level of these hormones, mefenamic acid and phenylbutazone elevated it, and aminophenazone and metamizole sodium did not alter it significantly.     

Antipyretic activity of SL-573 (II) (author's transl)]

Antipyretic activity of SL-573 was not influenced by age and sex difference in rats. The combined effect of other drugs on antipyretic activity of SL-573 was examined, using several drugs which might be clinically applicable. Cefazolin sodium, ampicillin sodium, codeine phosphate, hydrochlorothiazide and haloperidol did not show any significant effect on antipyretic activity of SL-573. Diazepam itself showed antipyretic activity, and its combined use with SL-573 resulted in an additive effect. SL-573 also showed antipyretic activity in mice with fever induced by yeast, as was seen in rats. SL-573 diminished the hyperthermic response to bacterial endotoxin and leucocytic pyrogen in rats, but not to 2, 4-dinitrophenol. Additionally, SL-573 did not inhibit the bacterial endotoxin-induced production of leucocytic pyrogen and its release in saline medium. SL-573, therefore, is considered to be a centrally acting antipyretic. Intraventricular injection of prostaglandin E2 and arachidonic acid induced a hyperthermia in mice. SL-573 clearly inhibited arachidonic acid-induced hyperthermia, but not prostaglandin E2-induced hyperthermia. Since SL-573 is known to inhibit prostaglandin biosynthesis from arachidonic acid, the prostaglandin biosynthesis inhibition may be one of the main mechanisms of antipyretic action of SL-573.     

AD-1590, a potent antagonist of lipopolysaccharide-induced fever in rabbits

The antipyretic activity of AD-1590 (2-[8-methyl-10,11-oxodibenz[b,f]oxepin-2-yl]propionic acid), a non-steroidal anti-inflammatory drug with a novel chemical structure, was investigated in rabbits with lipopolysaccharide (LPS)-induced fever and monkeys with leucocytic pyrogen-induced fever. AD-1590 produced a dose-related inhibition of the LPS-fever at oral doses of 0·1 mg kg⁻¹ or more (ED50 = 0·089 mg kg⁻¹). Its potency was 10–12, 20–35, 100–170, 400–540, >1500 and >2000 times that of ketoprofen, diclofenac sodium, indomethacin, ibuprofen, mefenamic acid and aspirin, respectively. The fever caused by leucocytic pyrogen was significantly inhibited by intravenous administration of 0·1–0·2 mg kg⁻¹ of AD-1590. AD-1590 (10 mg kg⁻¹ oral or i.v.) did not affect body temperature in afebrile rabbits or monkeys. These results suggest that AD-1590 shows a potent antipyretic activity in the rabbit and monkey and is a potent antagonist of LPS-fever.     

Flurbiprofen: a review of its pharmacological properties and therapeutic use in rheumatic diseases.

Flurbiprofen, a phenylalkanoic acid derivative, is a non-steroidal anti-inflammatory, antipyretic, analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and allied conditions. Published data suggest that flurbiprofen 120 to 150 mg daily is comparable in effectiveness with therapeutic doses of aspirin (3 to 4 g) in rheumatoid arthritis, but generally causes fewer side effects. Flurbiprofen 150 to 300 mg appears to be comparable with 75 to 150 mg of indomethacin in rheumatoid arthritis and degenerative joint disease, and comparable with phenylbutazone or indomethacin in ankylosing spondylitis. In comparison with other non-steroidal agents, flurbiprofen appears to be at least as effective as naproxen, ibuprofen or sulindac, but generally causes more side effects than these drugs. However, as no one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, flurbiprofen should be considered along with other drugs of its type in the arthritic patient.     

The antipyretic effect of tilorone hydrochloride in the cat.

1 The antipyretic activity of tilorone hydrochloride was studied in conscious, unrestrained cats provided with implanted jugular venous catheters, third cerebral ventricular (i.c.v.) cannulae and retroperitoneal thermocouples. 2 In afebrile animals, 10 mg/kg i.v. or 1 mg i.c.v. tilorone hydrochloride did not alter body temperature, but 20 mg/kg i.v. or 2 to 5 mg i.c.v. caused hypothermia and various behavioural responses. 3 Non-hypothermogenic doses of tilorone (i.v. or i.c.v.) antagonized hyperthermic responses to leucocytic pyrogen (i.v. or i.c.v.), bacterial pyrogen (i.c.v.) and sodium arachidonate (i.c.v.) but did not antagonize prostaglandin E1 (i.c.v.). 4 These results indicate that tilorone has an antipyretic action within the central nervous system that is distinct from its hypothermogenic action. Although there is no published evidence to indicate that tilorone can inhibit prostaglandin synthesis peripherally, its ability to reduce hyperthermic responses to arachidonate suggests that it can inhibit prostaglandin synthesis within the brain.     

Central versus peripheral sites of antipyretic action of a non-steroidal anti-inflammatory agent, AD-1590, in rabbits

The site of antipyretic action of AD-1590 in the sequential process involved in the development of fever caused by bacterial pyrogen (LPS) was investigated in rabbits. AD-1590 (1 microgram/ml) did not inactivate both LPS and leucocytic pyrogen (LP) and did not affect the generation of LP in the in vitro test. AD-1590 (0.1 mg/kg i.v.) prevented the fever caused by LP as well as LPS, but did not prevent the fever by PGE2 (100 ng/rabbit) injected into the preoptic anterior hypothalamic (PO/AH) regions. A significant antipyretic effect of AD-1590 on LPS-fever was found when AD-1590 (4 micrograms/rabbit) was injected into the PO/AH regions. AD-1590 (0.4 mg/kg i.v.) did not produce anti-pyretic activity against 2,4-dinitrophenol-hyperthermia; the monoamine levels in the brain were not affected with AD-1590 (10 mg/kg p.o.). These results suggest that AD-1590, like acidic non-steroidal anti-inflammatory drugs, produces its antipyretic action through the central mechanisms.     

Assessment of in vitro genotoxic and cytotoxic effects of flurbiprofen on human cultured lymphocytes

Flurbiprofen is non-steroidal anti-inflammatory drug which is commonly used for its analgesic, antipyretic, and anti-inflammatory effects. The purpose of the study was to explore the genotoxic and cytotoxic effects of flurbiprofen in human cultured lymphocytes by sister chromatid exchange, chromosome aberration, and cytokinesis-blocked micronucleus tests. 10, 20, 30, and 40?μg/mL concentrations of flurbiprofen (solvent is DMSO) were used to treatment of human cultured lymphocytes at two different treatment periods (24 and 48 h). Flurbiprofen had no significant genotoxic effect in any of these tests. But exposing to flurbiprofen for 24 and 48 h led to significant decrease on proliferation index, mitotic index, and nuclear division index (NDI). Also, all decreases were concentration-dependent (except NDI at 24 h treatment period). Consequently, the findings of this research showed that flurbiprofen had cytotoxic effects in human blood lymphocytes.     

茴香注射液热原检查方法学研究

目的:验证红茴香注射液热原检查的适用性。方法:参考《中国药典》2010年版一部附录中药注射剂安全性检查法应用指导原则,对红茴香注射液进行热原检查的方法学验证。结果:红茴香注射液原液在剂量为1 mL.kg-1有一定的毒性反应,不适宜进行热原试验;10倍稀释液对热原检查无干扰。结论:可用热原检查法检查红茴香注射液中可能存在的热原,浓度为其10倍稀释液,剂量为1 mL.kg-1。     

Liver function and pyrexia caused by a pyrogen from Escherichia coli, lysergic acid diethylamide and dinitrophenol

Rabbits with liver damaged by carbon tetrachloride do not respond with hyperthermia to a lipopolysaccharide pyrogen from Escherichia coli or dinitrophenol, but lysergic acid diethylamide develops its usual effect. Rabbits with obstructive liver damage react with hyperthermia to all three pyrogenic factors. The results support the concept of a peripheral action of pyrogen. It is suggested that the liver plays a rôle in the process of transforming the bacterial pyrogen into the endogenous pyrogen.     

Naloxone does not antagonize leukocytic pyrogen

In a crossover experiment, cats were given third cerebral ventricular injections of 500 microgram naloxone hydrochloride or saline vehicle followed in 15 min by i.v. injections of saline solution or leukocytic pyrogen. The pyrogen produced comparable fevers after both saline and naloxone pretreatment. Intravenous administration of naloxone hydrochloride (5 mg/kg) likewise did not prevent febrile responses to leukocytic pyrogen. These results indicate that endogenous opioid peptides are not likely central mediators of pyrogen-induced fevers.     

Carbonic anhydrase inhibition by flurbiprofen and related agents.

Flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), reduces bone resorption in periodontal disease. This therapeutic effect has been attributed to inhibition of prostaglandin synthesis. In view of the importance of carbonic anhydrase (CA) in bone resorption, we examined the CA-inhibitory properties of flurbiprofen using bovine and human CA II and compared them with those of acetazolamide and two other NSAIDs, ibuprofen and indomethacin. Flurbiprofen inhibited both human and bovine erythrocyte CA II but to a much lesser degree than acetazolamide. Ibuprofen and indomethacin were much less active in inhibiting CA II than flurbiprofen.     

Differentiation between formation,in plasma,of anaphylatoxin and of endogenous pyrogen

Summary Two anaphylatoxin-forming agents have been investigated with respect to possible pyrogenic effects: the AT forming fraction of cobra venom and agar.The cobra venom fraction produced fever in rabbits. The pyrogenic principle is, however, not identical with the AT forming enzyme. Unlike the latter the pyrogenic principle is stable in acidic solution and destroyed by periodate. It may be a lipopolysaccharide.Rabbit plasma, incubated with agar caused fever in rabbits. Agar also induced pyrogenic activity in saline after it had been incubated in that medium. The active principle proved to be agaropectin, the water-soluble acidic fraction of agar. Agarose was inert. In contrast, anaphylatoxin formation is induced by agarose, not by agaropectin.In rabbit plasma, agaropectin induces the formation of an endogenous pyrogen. This principle can be separated from the agaropectin by DEAE cellulose chromatography. It is further distinguished from the latter by being heat-labile.Besides being activated by different agents the processes of pyrogen and AT formation differ in their requirement for cations. AT formation is blocked by EDTA but pyrogen formation is not. It is concluded that in spite of similarities and common activation by endotoxins the processes of AT and pyrogen formation are different and independent events.     

Albumin‐binding of diclofenac and the effect of a site II inhibitor in the aqueous humor of cataract patients with the instillation of diclofenac

Diclofenac instillation has been used widely in cataract surgery to prevent postoperative inflammation. Since diclofenac binds strongly to albumin in the circulation, it does not have a sufficient effect on patients in whom diclofenac binds strongly to albumin in the aqueous humor. A decrease in diclofenac binding and an increase in free diclofenac levels are necessary in these patients. The binding of diclofenac to albumin was investigated in the aqueous humor. In a diclofenac binding assay with albumin in the aqueous humor of individual patients, diclofenac was extracted from aliquots of the aqueous humor, and its total levels were measured using ultra high performance liquid chromatography (UHPLC). Free diclofenac levels were measured using ultrafiltration and UHPLC. The albumin‐binding fraction of diclofenac was 0.8 or higher in the aqueous humor of some patients. Ibuprofen significantly inhibited diclofenac binding to site II of albumin in mimic aqueous humor, but not in pooled aqueous humor. This difference may have been due to the weak binding of diclofenac to site II in the pooled aqueous humor. Flurbiprofen was used instead of diclofenac. Flurbiprofen has been shown to bind more strongly than diclofenac to the same site of albumin. Thus, the inhibitory effect of ibuprofen on the binding of flurbiprofen to albumin was investigated in pooled aqueous humor. The results indicated that ibuprofen significantly inhibited the flurbiprofen binding. An effective diclofenac administration method may be established for clinical application by the instillation of an appropriate inhibitor of binding to the albumin site II. Copyright © 2014 John Wiley & Sons, Ltd.     

Uridine-induced hyperthermia in the rabbit

Uridine injection in 0.6% saline elevated rabbit temperatures (mean = 0.9 °C) in the USP XX pyrogen test. Hyperthermia was delayed in onset and peaking 3–4 h post injection, but the injection was negative in the limulus amoebocyte lysate (LAL) assay. Uridine from five lots of different sources exceeded USP XX limits in the rabbit pyrogen test and proved negative in the LAL assay. Because the dose of uridine was high, several procedures were used to determine if an impurity was the cause of temperature elevation. Uridine remained pyrogenic in spite of ultrafiltration (10 000 nominal mol. wt), recrystallization and preparative scale HPLC. Sterile filtration and autoclaving also did not affect the response. Hyperthermia, therefore, appears to be an inherent property of uridine. Uridine was also found to release endogenous pyrogen in-vitro from human mononuclear cells. Uridine has been reported to induce fever in man, thus the USP rabbit pyrogen test predicted for the clinical response.     

Absorption through human skin of ibuprofen and flurbiprofen; effect of dose variation, deposited drug films, occlusion and the penetration enhancer N-methyl-2-pyrrolidone

The penetration of ibuprofen and flurbiprofen, non-steroidal anti-inflammatory agents, was investigated from drug films deposited by acetone evaporation on cadaver skin in an open cell 'in-vivo mimic' design. Increased dosage did not produce a proportional increase in the permeation and maximizing the skin-drug contact did not increase penetration: both factors indicate that absorption from deposited drug films was dissolution rate-limited. Occlusion of the skin did not increase the dissolution rate of the deposited drug film, but did elevate the penetration of drug already present within the skin at the time of occlusion. The diffusion coefficients for both drugs were calculated by two methods, yielding 1.8 +/- 1.3 X 10(-11) cm2 s-1 and 1.0 +/- 0.56 X 10(-11) cm2 s-1 for ibuprofen and 1.9 +/- 0.59 X 10(-11) cm2 s-1 and 0.77 +/- 0.23 X 10(-11) cm2 s-1 for flurbiprofen. Increasing the acetone-skin contact time from 2 min to 2 h did not significantly alter the permeability of the skin. Absorption of flurbiprofen was similar from 10 and 100% saturated aqueous solutions, suggesting that the skin has a limited capacity for flurbiprofen transport beyond which further increase in drug penetration may be difficult. N-Methyl-2-pyrrolidone enhanced the penetration flux of ibuprofen sixteenfold and flurbiprofen, over threefold. The 'in-vivo mimic' design for permeation experiments has thus proved to be useful for evaluating the kinetics of topical therapy and the mechanism of action of potential penetration enhancers.     

柴黄颗粒对内毒素致热新西兰兔脑脊液中发热介质的影响

目的:研究柴黄颗粒对内毒素致热新西兰兔的解热作用及其对脑脊液中内生致热原和中枢性发热介质的影响。方法:用内毒素复制发热模型,新西兰兔随机分为对照组、发热组、柴黄1组、柴黄2组、柴黄3组。观察用药后每1 h的体温变化,共5 h;用放射免疫法和ELISA法测定发热高峰新西兰兔脑脊液中白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)含量及促肾上腺皮质激素释放激素(CRH)、前列腺素E2(PGE2)、精氨酸加压素(AVP)和黑素细胞刺激素(α-MSH)含量;并将柴黄3个剂量组的温度变化抑制率与IL-1β、TNF-α、IL-6、CRH、PGE2、AVP和α-MSH含量变化抑制率分别作相关性分析。结果:柴黄颗粒不同剂量组均具有降低发热新西兰兔体温的作用,具有降低脑脊液中IL-1β、TNF-α和IL-6含量及CRH、PGE2含量的作用,具有升高脑脊液中AVP和α-MSH含量的作用。相关分析表明在两个发热高峰,即致热后1 h和3 h,柴黄颗粒对新西兰兔的体温变化抑制率与脑脊液中内生致热原IL-1β、TNF-α、IL-6变化抑制率呈正相关;在第一个发热高峰,即致热后1 h,可能与降低中枢性发热介质CRH、PGE2有关;在第二个发热高峰,即致热后3 h,可能与降低中枢性发热介质CRH、PGE2,增加中枢性发热介质AVP、α-MSH有关。结论:柴黄颗粒有明显的解热作用,其作用机制可能与减少脑脊液中内生致热原IL-1β、TNF-α和IL-6的含量有关;同时与减少脑脊液中中枢性正调节介质PGE2、CRH及增加中枢性负调节介质AVP、α-MSH的含量有关。     

The analgesic and antipyretic effects of a non-steroidal antiinflammatory agent, EB-382, in experimental animals

The analgesic and antipyretic effects of EB-382 as a new non-steroidal antiinflammatory agent were examined in mice and rats. EB-382 had an equipotent inhibition to ibuprofen on the writhing syndrome caused by acetic acid, phenylquinone and acetylcholine in mice, but phenylbutazone was less potent in these experiments. EB-382 had a much more potent inhibition on the pain by the Randall-Selitto method and silver nitrate-induced arthritic pain in rats than ibuprofen and phenylbutazone. EB-382 had no analgesic effect on the pain of non-treated foot by the Randall-Selitto method in rats and by the hot-plate method in mice. EB-382 had a much more potent inhibition on the yeast-induced chronic inflammatory and adjuvant arthritic pains in rats than ibuprofen and phenylbutazone. The antipyretic activity of EB-382 was almost equipotent to that of ibuprofen in rats. EB-382 had no effect on the normal body temperature in rats, which was different from aminopyrine. The above results suggest that EB-382 will be a useful analgesic agent with an antipyretic antiinflammatory activity in clinical studies.     

Treatment of rheumatoid arthritis with flurbiprofen or ibuprofen.

Flurbiprofen and ibuprofen were compared in a six-week double-blind randomized study in 208 patients with rheumatoid arthritis. Daily dosages were 120 mg flurbiprofen and 2400 mg ibuprofen for six weeks. Both drugs were effective in providing partial control of RA symptoms. Either or both drugs produced statistically significant improvement in mean values of time of onset of fatigue, grip strength and tender and swollen joint counts. All other standard endpoints of efficacy (except ESR) were improved but not at a statistically significant level. Slightly more than half of the patients improved during the trial. There was no statistically significant difference in the efficacy of the drugs. The incidence of side effects was low with both drugs. Most side effects were related to gastrointestinal tract irritation.     

Effects of diflunisal on fever in the rabbit and the rat

The antipyretic efficacy of diflunisal was assessed in rats made febrile by yeast and in rabbits made febrile by bacterial endotoxin. Diflunisal was a more potent antipyretic than aspirin in rats, reducing a maximum fever in doses not producing overt toxic effects. In contrast, submaximal fever in rabbits was not reduced by diflunisal. Fatal hyperthermia of rapid onset was observed in rats and rabbits receiving high doses of diflunisal after administration of microbial pyrogen but not in control animals. These data indicate the toxicity of diflunisal may be potentiated by the presence of pyrogens. It is concluded that the apparent antipyretic efficacy of a drug can depend on the species-pyrogen combination used to screen for antipyresis.