Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases

1. Ibuprofen enantiomers and their respective coenzyme A thioesters were tested in human platelets and blood monocytes to determine their selectivity and potency as inhibitors of cyclo-oxygenase activity of prostaglandin endoperoxide synthase-1 (PGHS-1) and PGHS-2.
2. Human blood from volunteers was drawn and allowed to clot at 37°C for 1 h in the presence of increasing concentrations of the test compounds (R-ibuprofen, S-ibuprofen, R-ibuprofenoyl-CoA, S-ibuprofenoyl-CoA, NS-398). Immunoreactive (ir) thromboxane B₂ (TXB₂) concentrations in serum were determined by a specific EIA assay as an index of the cyclo-oxygenase activity of platelet PGHS-1.
3. Heparin-treated blood from the same donors was incubated at 37°C for 24 h with the same concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 μg ml⁻¹). The contribution of PGHS-1 was suppressed by pretreatment of the volunteers with aspirin (500 mg; 48 h before venepuncture). As a measure of LPS induced PGHS-2 activity immunoreactive prostaglandin E₂ (irPGE₂) plasma concentrations were determined by a specific EIA assay.
4. S-ibuprofen inhibited the activity of PGHS-1 (IC₅₀ 2.1 μM) and PGHS-2 (IC₅₀ 1.6 μM) equally. R-ibuprofen inhibited PGHS-1 (IC₅₀ 34.9) less potently than S-ibuprofen and showed no inhibition of PGHS-2 up to 250 μM. By contrast R-ibuprofenoyl-CoA thioester inhibited PGE₂ production from LPS-stimulated monocytes almost two orders of magnitude more potently than the generation of TXB₂ (IC₅₀ 5.6 vs 219 μM).
5. Western blotting of PGHS-2 after LPS induction of blood monocytes showed a concentration-dependent inhibition of PGHS-2 protein expression by ibuprofenoyl-CoA thioesters.
6. These data confirm that S-ibuprofen represents the active entity in the racemate with respect to cyclo-oxygenase activity. More importantly the data suggest a contribution of the R-enantiomer to therapeutic effects not only by chiral inversion to S-ibuprofen but also via inhibition of induction of PGHS-2 mediated by R-ibuprofenoyl-CoA thioester.
7. The data may explain why racemic ibuprofen is ranked as one of the safest non-steroidal anti-inflammatory drugs (NSAIDs) so far determined in epidemiological studies.

     

儿科各种退热疗法临床效果比较

目的:探讨不同退热药物的退热效果,总结各种措施的副作用及儿科医生首选用药。方法:对210例病毒性呼吸道感染所致861例次高热(>39℃)患儿,分别予不同的退热药物及各自联合物理降温治疗,观察用药1h后的退热效果。结果:安乃近、复方阿斯匹林、对乙酰氨基酚糖浆与布洛芬混悬液退热总有效率分别为78%、76%、81%与89%(χ2为6.81、8.64、3.97,P<0.05)。布洛芬混悬液退热效果显著优于安乃近、复方阿斯匹林、对乙酰氨基酚糖浆,且不良反应最少,联合物理降温有协同效应。结论:布洛芬混悬液退热效果肯定,不良反应少,值得临床应用。     

布洛芬软胶囊治疗偏头痛的临床试验

目的 评价布洛芬软胶囊治疗偏头痛急性发作的疗效和安全性。方法 随机、双盲、安慰剂交叉对照的多中心临床试验。共入组偏头痛病例120例,实际完成病例数为111例,其中先服布洛芬后服安慰剂组55例;先服安慰剂后服布洛芬组56例。治疗前两组的一般资料、临床评价和实验室指标无显著性差异。结果 布洛芬组和安慰剂组2小时内头痛消失率分别为(48.65±4.74)%和(19.82±3.78)%(P<0.01)。布洛芬组和安慰剂组2小时内头痛缓解率分别为(79.28±3.85)%和(45.05±4.72)%(P<0.01)。结论 布洛芬治疗偏头痛安全性好,可作为治疗偏头痛急性发作的有效药物。     

Section 2 Thrombophlebitis of the lower limbs: therapy with2-(4-isobutylphenyl)propionic acid

Summary

A trial was carried out to assess the value of ibuprofen in relieving the symptoms and signs in 40 patients suffering from inflammatory phlebopathies of the lower limbs. Ibuprofen was given in a dosage of 900?mg. daily for periods ranging from 7 to 28 days. Spontaneous pain, redness and oedema showed a marked reduction, on average by the third day, although pain on pressure persisted for about 10 days. Body temperature returned to normal within a few hours. The results were assessed as excellent in 10, good in 19,fair in 8, and poor in 3 patients. Side-effects were reported inonly 3 patients and were mild.     

Section 1 The effect of ibuprofen on lymphocyte stimulation by phytohaemagglutillin in Vitro

Summary

A study was carried out to determine the effects of ibuprofen, phenylbutazone and indomethacin at different concentrations on phytohaemagglutinin-induced stimulation of lymphocytes in vitro. The results indicate that all three drugs inhibit lymphocyte stimulation, and at concentrations achieved by ibuprofen and phenylbutazone in vivo. It may be, therefore, that part of the effect of ibuprofen in rheumatoid arthritis is due to inhibition of lymphocyte function.     

Common cold and influenza symptom management: the use of pharmacokinetic considerations to predict the efficacy of a twice-daily treatment for colds and flu

SUMMARY

Objective: The objective of the two pharmacokinetic studies reported here was to compare the relative bioavailability of an ibuprofen/pseudoephedrine modified-release capsule with each of the active ingredients given alone as standard formulations.

Study design: Evaluation of two open, randomised, cross-over studies, one single dose and one multiple dose, in healthy male volunteers.

Methods: Healthy volunteers were randomised in a cross-over design to single or multiple doses of a combination of ibuprofen (600 mg) plus pseudoephedrine (90 mg) in a slow-release formulation and the individual active products alone as standard formulations; ibuprofen 400mg, pseudoephedrine 60 mg.

Results: The single-dose study demonstrated that the bioavailabilities of ibuprofen and pseudoephedrine achieved with the slow-release formulation were not significantly different from those with standard tablets of each ingredient alone. In addition, mean plasma levels of ibuprofen predictive of clinical efficacy were achieved within 0.5-1 h and lasted for 10-12 h thereafter. The time required to reach clinically effective blood levels of pseudoephedrine was longer, starting at approximately 2 h. However, the plasma levels predicted that the clinical effect would then last for at least a further 12 h. Trough levels from the multiple-dose study showed that clinically relevant analgesic and decongestant plasma levels were maintained for 24 h during twice-daily dosing. The slow-release formulation was well tolerated with only mild adverse events.

Conclusion: Blood levels would predict that the present slow-release fo rmulation of ibuprofen plus pseudoephedrine should offer reliable day and night control of cold and flu and sinus symptoms and be associated with a favourable safety profile.     

Section 2 Long-term ibuprofen therapy of rheumatic disease in patients with a past history of peptic Ulceration

Summary

Thirty patients with chronic rheumatic conditions and a known history of peptic ulceration were treated with ibuprofen, 600?mg. to 1200?mg. daily. Six patients withdrew from the study. In the remaining 24 patients, ibuprofen gave effective relief of symptoms and did not aggravate the gastro-intestinal pathology.     

Reducing postoperative pain by changing the process

Untreated postoperative pain is an important ethical and financial issue that can lead to unnecessary suffering and prolonged stays in hospital. Despite the availability of effective analgesics and a growing body of published material that supports their use, postoperative pain remains a problem worldwide. To reduce acute postoperative pain, we introduced an intervention combining evidence-based analgesic protocols with the education of staff and patients on a surgical ward. The experiences of 68 patients before and 80 patients after the intervention were compared (worst pain scores, duration of pain, and satisfaction). Inadequately controlled pain was significantly reduced after the intervention, which suggests that the introduction of analgesic protocols supported by the education of staff and patients can be beneficial. Despite this, severe pain remained relatively common, indicating room for improvement. Duration of pain and patient satisfaction were not affected by the intervention, and patient satisfaction remained high throughout the study.     

Section 2 The comparison of four non-steroidal antirheumatic agents in the treatment of rheumatic diseases

Summary

A comparative open study was made of the effectiveness of four antirheumatic agents in the treatment of 69 hospitalised patients with rheumatic diseases who had failed to respond satisfactorily to previous therapies. Simple subjective and objective assessments showed that approximately half the patients treated with ibuprofen, oxyphen-butazone or mefenamic acid showed improvement, but that fewer did so with flufenamic acid. Full therapeutic effect of the drugs was evident in approximately 3 weeks.