Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.     

A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice

AIMS: The new cyclooxygenase-2 (COX-2) selective inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx), have been widely prescribed since their launch. No reviews currently appear in the literature of prescribing patterns in Australia. This paper describes a self-audit of the clinical use of selective COX-2 inhibitor therapy undertaken with rural general practitioners (GPs) in Australia. METHODS: A structured audit form was developed and distributed to interested GPs. The form was self-administered and focused on issues about COX-2 inhibitors and the types of patients who were receiving them, e.g. indications, patient demographics, risk factors and drug interactions. RESULTS: A total of 627 patients were recruited (569 celecoxib and 58 rofecoxib). A range of doses was prescribed. Osteoarthritis was the most common indication (68.1%). Risk factors known for the nonselective nonsteroidal anti-inflammatory drugs were identified in 65.1% of patients, with the most common being advanced age, hypertension and previous peptic ulcer disease. Potential drug interactions were common. A variety of reasons for initiation of therapy was identified; these included perceived increased efficacy, safety and failure of other treatment. CONCLUSIONS: These results show that COX-2 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a COX-2 inhibitor. The perception of improved safety and efficacy was common and is of concern. Limitations of the study include the reliance on self-reporting.     

Nimesulide: an NSAID that preferentially inhibits COX-2, and has various unique pharmacological activities

Nimesulide is a NSAID with good anti-inflammatory, analgesic and antipyretic activities expected of such compounds. However, in addition it has some unique therapeutic and pharmacological activities. The novel therapeutic aspects include a relatively low toxicity to the gastrointestinal tract and kidneys, it can be given to most patients who experience respiratory problems with other NSAIDs, and the onset of analgesia is comparatively quick. The main novel pharmacological actions obtained using nimesulide in vivo at therapeutic doses, or in vitro at concentrations within the therapeutic range of free (unbound) drug, include: a preferential inhibition of prostaglandin synthesis via COX-2, and reductions in cytokine action/release, histamine release, the release of enzymes that degrade cartilage, and the release of superoxide anions and other toxic substances from neutrophils. Interactions with other drugs are few and of little or no clinical significance.     

Colon-specific delivery of celecoxib is a potential strategy to improve toxicological and pharmacological properties of the selective Cox-2 inhibitor: implication in treatment of familiar adenomatous polyposis

In general, colon-specific delivery of a drug decreases systemic absorption and increases therapeutic concentration of the drug at the target site. N-succinylglutam-1 or 5-yl celecoxib (SG1C and SG5C) were prepared as a colon-specific prodrug of celecoxib, a selective Cox-2 inhibitor, and investigated whether the celecoxib derivatives could deliver celecoxib to the target site and improve cardiovascular toxicity and therapeutic effectiveness for the treatment of familiar adenomatous polyposis. SG1C and SA5C were cleaved to release celecoxib in the cecal contents while stable in small intestinal contents. The cecal release of celecoxib was much greater for SG1C than SG5C. SG1C administered orally was barely detected in the blood and urine. SG1C delivered much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level compared with oral administration of free celecoxib. Consistent with these pharmacokinetic results, SG1C supplied a greater concentration of celecoxib for the entire colonic tissue and did not change the serum level of 6-keto-PGF_1α whose decrease is associated with the cardiovascular toxicity of celecoxib. Taken together, colon-specific delivery of celecoxib using a prodrug approach may be a useful strategy to improve toxicological and pharmacological properties of celecoxib.     

Development of intestinal, but not gastric damage caused by a low dose of indomethacin in the presence of rofecoxib

The ulcerogenic effect of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the gastrointestinal mucosa was investigated in the presence of a low dose of indomethacin. Indomethacin at 3 mg/kg did not cause any damage in both the stomach and small intestine, despite inhibiting prostaglandin (PG) production. Rofecoxib had no effect on PG production and did not cause any damage in these tissues. In the presence of indomethacin, however, rofecoxib provoked damage in the small intestine but not the stomach. Indomethacin at 3 mg/kg induced hypermotility and COX-2 expression in the intestine but not in the stomach, both in an atropine-sensitive manner. These results suggest that a low dose of indomethacin produces damage in the small intestine but not in the stomach when administered together with rofecoxib. The PG deficiency caused by a low dose of indomethacin produces hypermotility and COX-2 expression in the small intestine, and results in damage when COX-2 is inhibited. It is assumed that the hypermotility response is a key event in the expression of COX-2 and thereby important in the development of mucosal damage in the gastrointestinal tract.     

Effect of benzydamine,a topically administered NSAID onin vitro prostanoid synthesis by human and rat gastric mucosa and rat kidney,aorta and urinary bladder: Lack of effect on cyclooxygenase but potent inhibition of receptor-linked prostanoid synthesis

Orally administered NSAIDs are notorious for their frequent and severe side-effects in the gastrointestinal tract and kidney, whereas topically administered NSAIDs may avoid these untoward effects. Since NSAID-induced side-effects are largely prostaglandin (PG)-mediated, the effects of the topically administered NSAID, benzydamine, onin vitro PGI₂ and PGE₂ synthesis by the rat and human gastric mucosa and rat kidney slices was investigated. The effect on receptor-linked PG synthesis in the isolated rat aorta (adrenergic) and urinary bladder (cholinergic) was also investigated since NSAIDs may disrupt mobilization of calcium therein. Benzydamine was a very weak inhibitor of spontaneous PGI₂ and PGE₂ synthesis by human and rat gastric mucosa and rat kidney. In contrast, benzydamine was a potent inhibitor of noradrenaline- and carbachol-stimulated (but not arachidonate- or trauma-stimulated) PGI₂ synthesis. It is concluded that: a) benzydamine is unlikely to elicit cyclooxygenase-mediated side-effects on the gastrointestinal tract or kidney, b) the anti-inflammatory action of benzydamine is mediated by disruption of calcium linked to receptor-PG synthesis coupling, and c) calcium-dependent inflammatory processes may also be affected by benzydamine.     

Patent Update: Antibacterial Patents Appearing in the Third Quarter of 1991

The sulfonamides constitute an important class of drugs, with several types of clinically used agents, possessing antibacterial, anticarbonic anhydrase (CA), diuretic, hypoglycaemic, anti-thyroid, protease inhibitory, anticancer and cyclooxygenase (COX) inhibitory activities, among others. A recently developed class of such pharmacological agents, incorporating primary sulfamoyl moieties in their molecule, is constituted by the COX-2 selective inhibitors, with at least two clinically used drugs, celecoxib and valdecoxib, discovered by Pharmacia Corp. It was recently shown that the sulfonamide COX-2-selective inhibitors (but not the methylsulfone ones, such as rofecoxib developed by Merck and Co.) also act as nanomolar inhibitors of CAs, some of which are strongly involved in tumorigenesis. In consequence, the potent anticancer effects of the sulfonamide COX-2-selective inhibitors and the much weaker effects of rofecoxib, reported ultimately by many researchers, may be explained by the contribution of CA inhibition to such processes in addition to COX-2 inhibition. In these two patents, Pharmacia Corp. claim the use of their sulfonamide COX-2 inhibitory compounds (celecoxib, valdecoxib and their many congeners), alone or in combination with classical sulfonamide CA inhibitors (acetazolamide, methazolamide, dichlorophenamide, dorzolamide, brinzolamide and their congeners, as well as structurally-related derivatives) for the treatment of CA-mediated disorders, including glaucoma and neoplasia. The patents do not contain any experimental evidence for the potential use of such compounds/combinations for the management of these pathologies, but are based on literature data from other laboratories.     

盐酸乙哌立松联合塞来昔布治疗颈肩腰背痛75例疗效分析

目的评价盐酸乙哌立松联合应用塞来昔布对常见颈肩腰背痛的临床疗效。方法收集150例门诊颈肩腰背痛患者,随机分成单用药组(单独口服塞来昔布)和联合用药组(盐酸乙哌立松联合塞来昔布),采用VAS方法进行疗效评价,并观察2组的不良反应。结果联合用药组的总有效率为84%,显著高于单用药组的65.33%(P<0.05);联合用药组对急慢性颈肩软组织劳损、肩关节周围炎和急慢性腰肌劳损引起疼痛的疗效优于单用药组,但对腰椎间盘突出症引起疼痛的疗效与单用药组相当。2组发生不良反应的患者均为1例(1.33%)。结论盐酸乙哌立松联合塞来昔布治疗颈肩腰背痛可获得较好的镇痛疗效,优于单纯应用塞来昔布胶囊。     

Efficacy of a phenol derivative,isopropyl vanillate,as an anti-inflammatory agent: A new small molecule inhibitor of COX and neutrophil migration

Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti-inflammatory effects. The objective of this study was to investigate the anti-inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP-VT), in mice. The results of this study indicated that ISP-VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP-VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor-α and interleukin-6), and vascular permeability. ISP-VT also significantly reduced the expression of cyclooxygenase-2 (COX-2) in subplantar tissue of mice. ISP-VT inhibited COX-2 selectively compared to the standard drug. Our results showed that although ISP-VT binds to COX-1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP-VT significantly reduced rectal temperature in yeast-induced hyperthermia in mice. Our results showed that the main mechanism ISP-VT-induced anti-inflammatory activity is by inhibition of COX-2. In conclusion, our results indicate that ISP-VT has potential as an anti-inflammatory and antipyretic therapeutic compound.     

Efficacy and safety of etoricoxib in the treatment of osteoarthritis

Osteoarthritis is a progressive disease that affects millions of people worldwide, but for which there are no curative options and indeed a limited number of medical treatment options. The American College of Rheumatology recommendations suggest administering either a traditional NSAID or a COX-2-selective inhibitor for pain relief. Traditional NSAIDs, such as naproxen, may have a higher risk of gastrointestinal (GI) events, while COX-2-selective inhibitors may have a higher risk of thrombotic cardiovascular (CV) events (with traditional NSAIDs and COX-2-selective agents appearing to have a similar CV risk). Etoricoxib, introduced in 2002, has been approved in over 60 countries worldwide for osteoarthritis. Large-scale studies addressing the efficacy, GI tolerability and potential for CV events with etoricoxib have now been published. Several patient types appear to benefit from etoricoxib, including those with CV risk factors and those requiring gastroprotective agents. In patients with CV risk factors, the benefits and risks of all NSAIDs should be weighed carefully in each patient, balancing the potential risks of treatment against the potential relief for pain and disability.     

Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans

AIMS: The cytochrome P450 enzyme CYP2C9 catalyses the 4'-hydroxylation of the nonsteroidal analgesic drug diclofenac in humans. We studied the influences of the known amino acid variants, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), on diclofenac pharmacokinetics after a 50-mg oral dose of diclofenac in healthy volunteers. As a surrogate marker of diclofenac activity, the ex vivo formation of prostaglandin E2 and thromboxane B2, which reflects COX-2 and COX-1 activity, was measured. METHODS: Genotyping was performed in 516 healthy volunteers to obtain 20 participants with all allelic combinations of the two CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Diclofenac and 4'-hydroxydiclofenac were quantified in plasma by reversed phase h.p.l.c. after oral intake of 50 mg diclofenac. Concentrations of thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) were measured by immunoassays. RESULTS: There was no evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles *2 and *3 compared with the wild type (mean CL/F (95% CI) 20.5 (11, 30) l h-1 for *1/*1, 29.9 (19, 40) l h-1 for *1/*2, 30.0 (4, 56) l h-1 for *2/*2, 22.6 (12, 33) l h-1 for *1/*3, 23.5 (11, 37) l h-1 for *3/*3 and 37.3 (-15, 89) l h-1 in *2/*3). Furthermore, plasma concentrations of the metabolite 4'-hydroxydiclofenac were not lower in carriers of the CYP2C9 low-activity alleles *2 and *3 compared with carriers of the CYP2C9*1/*1 genotype. Marked diclofenac mediated inhibition of COX-1- and COX-2 activity was detected in all individuals independent of CYP2C9 genotype. CONCLUSIONS: Polymorphisms of the CYP2C9 gene had no discernible effect on the pharmacokinetics and pharmacodynamics of diclofenac. The question of whether enzymes other than CYP2C9 play a major role in diclofenac 4'-hydroxylation in vivo or whether 4'-hydroxylation is not a rate-limiting step in diclofenac elimination in vivo, or whether the effect of the CYP2C9 polymorphisms is substrate-dependent, needs further investigation.     

XELOX与FLO方案治疗晚期胃癌的近期疗效及毒副反应比较

目的比较奥沙利铂联合卡培他滨方案(XELOX)与奥沙利铂联合5-FU/LV(FLO)方案治疗的晚期胃癌的近期疗效和毒副反应。方法通过查阅病例资料回顾分析2007年5月～2009年4月期间该科收治的62例采用XELOX和FLO化疗方案治疗的晚期胃癌,其中奥沙利铂联合卡培他滨(XELOX)A组33例,奥沙利铂联合5-FU/LV(FLO组)B组29例。结果 A组总有效率48.48%,疾病进展时间5.92个月,B组为44.83%和5.70个月,两组之间差异无统计学意义;A组中性粒细胞减少发生率15.2%,明显低于B组48.3%(P=0.006<0.01);A组神经毒性发生率15.2%明显低于B组58.6%(P=0.000<0.01);A组的手足综合症发生率(48.5%)明显高于B组13.8%(P=0.006<0.01),大多数为轻度,主要为I～Ⅱ度。结论 XELOX方案与FLO方案的疗效相近,但XELOX方案毒副反应较轻、耐受性良好、临床使用方便等优点。     

F 15845, a new blocker of the persistent sodium current prevents consequences of hypoxia in rat femoral artery

Background and purpose:

Selective cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx) and celecoxib (Celebrex) were developed as NSAIDs with reduced gastric side effects. Celecoxib has now been shown to affect cellular physiology via an unexpected, COX-independent, pathway – by inhibiting K_v2.1 and other ion channels. In this study, we investigated the mechanism of the action of celecoxib on K_v2.1 channels.

Experimental approach:

The mode of action of celecoxib on rat K_v2.1 channels was studied by whole-cell patch-clamping to record currents from channels expressed in HEK-293 cells.

Key results:

Celecoxib reduced current through K_v2.1 channels when applied from the extracellular side. At low concentrations (≤3 µM), celecoxib accelerated kinetics of activation, deactivation and inactivation. Recovery of rat K_v2.1 channels from inactivation could be characterized by two components, with celecoxib selectively accelerating the slow component of recovery at ≤10 µM. At >3 µM, celecoxib led to closed-channel block with relative slowing of activation. At 30 µM, it additionally induced open-channel block that manifested in use-dependent inhibition and slower recovery from inactivation.

Conclusions and implications:

Celecoxib reduced current through K_v2.1 channels by modifying gating and inducing closed- and open-channel block, with the three effects manifesting at different concentrations. These data will help to elucidate the mechanisms of action of this widely prescribed drug on ion channels and those underlying its neurological, cardiovascular and other effects.     

Advances in the treatment of rheumatoid arthritis: old versus new therapies

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.     

A correlation between a proteomic evaluation and conventional measurements in the assessment of renal proximal tubular toxicity.

4-Aminophenol (4-AP), D-serine, and cisplatin are established rodent nephrotoxins that damage proximal tubules within the renal cortex. Using high throughput 2D gel proteomics to profile protein changes in the plasma of compound-treated animals, we identified several markers of kidney toxicity. Male F344 and Alpk rats were treated with increasing doses of 4-AP, D-serine, or cisplatin, and plasma samples were collected over time. Control groups received saline or nontoxic isomers, L-serine, and transplatin. Plasma proteins that displayed dose- and temporal-dependent regulation in each study were further characterized by mass spectrometry to elucidate the protein identity. Several isoforms of the rat-specific T-kininogen protein were identified in each study. T-kininogen was elevated in the plasma of 4-AP-, D-serine-, and cisplatin-treated animals at early time points, returning to baseline levels 3 weeks after treatment. The protein was not elevated in the plasma of control animals or those treated with nontoxic compounds. We propose that T-kininogen may be required to counteract apoptosis in proximal tubular cells in order to minimize tissue damage following a toxic insult. In addition, T-kininogen may be required to stimulate localized inflammation to aid tissue repair. We also identified several isoforms of the inter-alpha inhibitor H4P heavy chain in the 4-AP and D-serine studies. In each case, the protein expression levels in the blood samples paralleled the extent of kidney toxicity, highlighting the correlation between protein alterations and clinical chemistry endpoints. A further set of proteins correlating with kidney damage was found to be a component of the complement cascade and other blood clotting factors, indicating a contribution of the immune system to the observed toxicity. These observations underscore the value of proteomics in identifying new biomarkers and in the elucidation of mechanisms of toxicity.     

神经性疼痛和癫治疗新药普瑞巴林

美国FDA于2004年批准普瑞巴林作为治疗糖尿病性周围神经性疼痛和带状疱疹神经痛的药物。本文综述了近年来的相关临床研究情况,并总结了普瑞巴林的药理学、药动学、疗效及耐受性。     

Antinociceptive and anti‐inflammatory properties of 7‐hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain

Objectives In the present study we investigated the antinociceptive, anti‐inflammatory and antipyretic effects of 7‐hydroxycoumarin (7‐HC) in animal models. Methods The effects of oral 7‐HC were tested against acetic acid‐induced writhing, formalin test, tail flick test, complete Freund's adjuvant (CFA)‐induced hypernociception, carrageenan‐induced paw oedema, lipopolysaccharide‐induced fever and the rota rod test. Key findings 7‐HC (3–60 mg/kg) produced a dose‐related antinociception against acetic acid‐induced writhing in mice and in the formalin test. In contrast, treatment with 7‐HC did not prevent thermal nociception in the tail flick test. A single treatment with 7‐HC, 60 mg/kg, produced a long‐lasting antinociceptive effect against CFA‐induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7‐HC produced a continuous antinociceptive effect against CFA‐induced hypernociception. 7‐HC (30–120 mg/kg) produced anti‐inflammatory and antipyretic effects against carrageenan‐induced inflammation and lipopolysaccharide‐induced fever, respectively. Moreover, 7‐HC was found to be safe with respect to ulcer induction. In the rota rod test, 7‐HC‐treated mice did not show any motor performance alterations. Conclusions The prolonged antinociceptive and anti‐inflammatory effects of 7‐HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.