Effect of digoxin, sodium valproate, and celecoxib on the cerebral cyclooxygenase pathway and neuron-specific enolase under the pentylenetetrazole-induced kindling in mice.

Neuroinflammation plays an important role in the pathogenesis of epilepsy, so it is necessary to clarify the influence of standard antiepileptic drugs as well as adjuvant agents (e.g., cardiac glycoside digoxin, which previously showed a clear anticonvulsant potential) on cyclooxygenase pathway and neuron-specific enolase under the conditions of chronic epileptogenesis. The aim of the article is to determine the effect of digoxin, sodium valproate, and celecoxib per se, as well as the combination of digoxin with sodium valproate on the content of cyclooxygenase 1 and 2 types, prostaglandins E2, F2α, I2, thromboxane B2, 8-isoprostane and neuron-specific enolase in the brain of mice in the pentylenetetrazole-induced kindling model. It was found that only the combination of sodium valproate with digoxin provides a complete protective effect (absence of seizures) and shows the clearest influence on neuroinflammation markers and neuronal damage than monotherapy with each of these drugs and celecoxib, which appeared to be an ineffective anticonvulsant. The obtained results indicate that digoxin is a promising adjuvant drug to classical antiepileptic drugs (mostly sodium valproate) in epilepsy treatment.c.

HPLC and GC Characterization of Dicliptera bupleuroides Aerial Parts and Evaluation of Its Anti-Inflammatory Potential in Vitro, in silico and in Vivo Using Carrageenan and Formalin Induced Inflammation in Rat Models.

The current study aimed to evaluate the anti-inflammatory activity of Dicliptera bupleuroides Nees aerial parts methanol extract and its different fractions namely hexane, chloroform, ethyl acetate and butanol in vitro using cyclooxygenase inhibitory assay (COX-2). In vivo anti-inflammatory evaluation was performed using carrageenan and formalin induced inflammation in rat models followed by molecular docking. High performance liquid chromatography (HPLC) and gas chromatography coupled with mass chromatography (GC/MS) analyses were used for chemical analyses of the tested samples. The tested samples showed significant inhibition in COX-2 inhibitory assay where methanol extract (DBM) showed the highest inhibitory potential at 100 µg/mL estimated by 67.86 %. At a dose of 400 mg/kg, all of the examined samples showed pronounced results in carrageenan induced acute inflammation in rat model at 4th h interval with DBM showed the highest efficiency displaying 65.32 % inhibition as compared to the untreated rats. Formalin model was employed for seven days and DBM exhibited 65.33 % and 69.39 % inhibition at 200 and 400 mg/kg, respectively approaching that of the standard on the 7th day. HPLC revealed the presence of caffeic acid, gallic acid and sinapic acid, quercetin and myricetin in DBM. GC/MS analysis of its hexane fraction revealed the presence of 16 compounds belonging mainly to fatty acids and sterols that account for 85.26 % of the total detected compounds. Molecular docking showed that hexadecanoic acid followed by decanedioic acid and isopropyl myristate showed the best fitting within cyclooxygenase-II (COX-II) while nonacosane followed by hexatriacontane and isopropyl myristate revealed the most pronounced fitting within the 5-lipoxygenase (5-LOX) active sites. Absorption, metabolism, distribution and excretion and toxicity prediction (ADMET/ TOPKAT) concluded that most of the detected compounds showed reasonable pharmacokinetic, pharmacodynamic and toxicity properties that could be further modified to be more suitable for incorporation in pharmaceutical dosage forms combating inflammation and its undesirable consequences.

Aspirin in essential thrombocythemia. For whom? What formulation? What regimen?

Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm, the most common clinical manifestations of which include arterial and venous thrombosis, bleeding and vasomotor/microvascular disturbances. Low-dose (81-100 mg) aspirin once daily, which irreversibly inhibits platelet thromboxane A2 (TxA2) production by acetylating cyclo-oxygenase-1, is the recommended treatment for the control of vascular events in all ET risk categories, except patients at very low risk, who need aspirin for treatment of vasomotor/microvascular disturbances only. Simple observation should be preferred over aspirin prophylaxis in low-risk patients with platelet counts >1,000x109/L or harboring CALR mutations. Plain aspirin should be preferred over enteric coated aspirin because some ET patients display poor responsiveness ("resistance") to the latter. When treated with a once daily aspirin regimen, adequate inhibition of platelet TxA2 production (measured as serum thromboxane B2 level) does not persist for 24 h in most patients. This phenomenon is associated with the patients' platelet count and the number (but not the fraction) of circulating immature reticulated platelets with non-acetylated cyclo-oxygenase-1 and is therefore consequent to high platelet production (the hallmark of ET), rather than increased platelet turnover (which is normal in ET). Twice daily aspirin administration overcame this problem and proved safe in small studies. Although additional data on gastrointestinal tolerability will be useful, the twice daily regimen could already be implemented in clinical practice, considering its favorable risk/benefit profile. However, patients whose platelet count has been normalized could still be treated with the once daily regimen, because they would otherwise be unnecessarily exposed to a potential small risk of gastrointestinal discomfort.

Does Early Neonatal Thrombocytopenia Affect Ductal Therapeutic Response to Acetaminophen in Preterm Neonates?

OBJECTIVE: Perinatal thrombocytopenia has been shown to affect responsiveness to therapeutic ductal closure with cyclooxygenase (COX) inhibitors. This has not been studied in responsiveness to acetaminophen, which has less effect on platelet function. The objective of this study was to evaluate whether thrombocytopenia affects ductal responsiveness to acetaminophen. STUDY DESIGN: This study was a retrospective review of preterm neonates <1,500 g. Echocardiograms were performed within the first week of life; if ductal status was found to be hemodynamically significant, infants were treated with acetaminophen. RESULTS: We studied 254 infants. Fifty-seven of these (22%) had a hemodynamically significant patent ductus arteriosus (hsPDA) and were treated with acetaminophen. Forty (70%) of those treated responded with ductal closure after one to two courses of acetaminophen. Seventeen infants were considered nonresponsive, requiring the addition of ibuprofen and/or surgical ligation. Sixty seven of the 254 infants (26%) developed moderate thrombocytopenia (platelets <100,000) within the first 10 days of life, more within the hsPDA group (54 vs. 18% p < 0.001); however, no differences in platelet-related parameters were observed between those who did and did not respond to acetaminophen treatment when comparing infants with hsPDA. Twenty-six of the 67 thrombocytopenic infants were already thrombocytopenic prior to acetaminophen treatment, and 19 of these 26 (73%) with pretreatment thrombocytopenia responded to acetaminophen treatment-with the overall response rate of 70%. CONCLUSIONS: This study is the first to document that, in contrast to the COX inhibitors, there is no association between early neonatal thrombocytopenia and ductal therapeutic responsiveness to acetaminophen. KEY POINTS: · Perinatal thrombocytopenia affects ductal closure with COX inhibitors.. · In contrast to the COX inhibitors, acetaminophen responsiveness is not affected by thrombocytopenia.. · Acetaminophen can be recommended to close hsPDA in the presence of thrombocytopenia..

Ciclooxigenasa 2 y cáncer colorrectal: implicaciones terapéuticas / Cyclooxygenase 2 and colorectal cancer: therapeutic implications

Diversas evidencias epidemiológicas sugieren una asociación inversa entre el consumo de antiinflamatorios no esteroideos (AINE) y el riesgo de desarrollar determinadas neoplasias. Esta asociación condujo a la identificación de la diana terapéutica de estos fármacos, la isoenzima 2 de la ciclooxigenasa (COX-2). Estudios posteriores han demostrado que COX-2 se halla sobreexpresada en múltiples lesiones malignas y premalignas de diversos orígenes, entre las que se incluyen las neoplasias colorrectales. Esta circunstancia explica el efecto beneficioso observado con el uso de AINE clásicos y, más recientemente, con los inhibidores selectivos de la COX-2 (coxibs), en el tratamiento y/o prevención de diversas neoplasias

There is epidemiological evidence that suggests an inverse association between the consumption of non-steroidal anti-inflammatories (NSAIDs) and the risk of developing certain neoplasms. This association led to the identification of the therapeutic target of these drugs, cyclooxygenase type 2 (COX-2). Later studies have demonstrated that COX-2 is over-expressed in many malignant and pre-malignant lesions of different origins, among which are included colorectal neoplasms. This factor explains the beneficial effect observed with the use of classic NSAIDs and more recently, with selective COX-2 inhibitors (coxibs), in the treatment and/or prevention of several neoplasms

Quimioprevenção do câncer de mama / Current status of breast cancer chemoprevention

Quimioprevenção é definida como o uso de agentes químicos naturais ou sintéticos para reverter, suprimir ou prevenir a progressão carcinogênica para carcinoma invasor. Os fármacos que agem como agentes quimiopreventivos contra o câncer de mama são divididos em dois grupos principais: os que previnem cânceres de mama receptor de estrogênio (RE) positivos, como os moduladores seletivos do receptor de estrogênio (SERM), inibidores de aromatase, agonistas de GnRH e fitoestrogênios; e os fármacos que previnem os cânceres RE-negativos, como os inibidores da ciclooxigenase-2 (COX-2), retinóides, as estatinas, os inibidores do receptor tirosina quinase, o anticorpo monoclonal contra HER-2 e os inbidores da telomerase. Resultados do estudo conduzido pelo NSABP que comparou o tamoxifeno com o raloxifeno (STAR), avaliando a eficácia na redução de risco, assim como a toxicidade desses dois SERMs em uma população similar e de alto risco para câncer de mama, demonstrou que o raloxifeno é tão efetivo quanto o tamoxifeno na redução de risco de câncer de mama invasor (p=0,83) e apresentou menor risco de eventos tromboembólicos e catarata; todavia, exibiu maior risco de carcinoma não invasor, porém sem significância estatística. Baseado nos dados promissores que revelaram diminuição de risco de câncer de mama contralateral em estudos de adjuvância, alguns inibidores de aromatase, incluindo o letrozol, anastrazol e exemestane, estão sendo incorporados em investigações para avaliar sua eficácia como agentes preventivos de alto risco em mulheres. Os inibidores de COX-2 demonstraram sua eficácia na prevenção do câncer de mama em estudos caso-controle e coorte, sendo necessários estudos aleatórios para atestar sua eficácia. O resultado positivo de alguns ensaios clínicos na prevenção do câncer de mama em populações de alto risco sugere que a quimioprevenção é uma estratégia racional e atraente.

Chemoprevention is defined as the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic progression of invasive cancer. Drugs that act as chemoprevention agents for breast cancer are divided into two major groups: drugs that prevent Estrogen Receptor (ER) - positive breast cancers [selective estrogen receptor modulators (SERM), aromatase inhibitors GnKH agonists and phytoestrogens] and drugs that prevent ER - negative breast cancers [cyclooxygenase-2 (COX-2) inhibitors, retinoids, statins, receptor tyrosine, kinase inhibitors, monoclonal antibody against HER-2 and telomerase inhibitors]. Results from the NSABP Study of Tamoxifen and Raloxifene (STAR), which compared the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk for breast cancer population, showed that Raloxifene is as effective as Tamoxifen in reducing the risk of non-invasive breast cancer (p=.83). It has a statistically significant lower risk of thromboembolic events and cataracts, however a non- statistically significant higher risk of noninvasive breast cancer. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole and exemestane, are being included in trials to evaluate their efficacy in breast cancer prevention in both case-control and cohort studies As such randomized studies to confirm this efficacy are needed. Positive results of several recent clinical trials for preventing breast cancer in high-risk populations suggest that chemoprevention is a rational and attractive strategy.

[Current status of breast cancer chemoprevention]. / Quimioprevenção do câncer de mama.

Chemoprevention is defined as the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic progression of invasive cancer. Drugs that act as chemoprevention agents for breast cancer are divided into two major groups: drugs that prevent Estrogen Receptor (ER)-positive breast cancers [selective estrogen receptor modulators (SERM), aromatase inhibitors GnKH agonists and phytoestrogens] and drugs that prevent ER-negative breast cancers [cyclooxygenase-2 (COX-2) inhibitors, retinoids, statins, receptor tyrosine, kinase inhibitors, monoclonal antibody against HER-2 and telomerase inhibitors]. Results from the NSABP Study of Tamoxifen and Raloxifene (STAR), which compared the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk for breast cancer population, showed that Raloxifene is as effective as Tamoxifen in reducing the risk of non-invasive breast cancer (p=.83). It has a statistically significant lower risk of thromboembolic events and cataracts, however a non- statistically significant higher risk of noninvasive breast cancer. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole and exemestane, are being included in trials to evaluate their efficacy in breast cancer prevention in both case-control and cohort studies As such randomized studies to confirm this efficacy are needed. Positive results of several recent clinical trials for preventing breast cancer in high-risk populations suggest that chemoprevention is a rational and attractive strategy.

The antinociceptive effect of local or systemic parecoxib combined with lidocaine/clonidine intravenous regional analgesia for complex regional pain syndrome type I in the arm.

We evaluated the efficacy of local or systemic parecoxib combined with lidocaine/clonidine IV regional analgesia in complex regional pain syndrome (CRPS) type 1 in a dominant upper limb. Thirty patients with CRPS type 1 were divided into three groups. The control group (CG) received both IV saline in the healthy limb and IV loco-regional 1 mg/kg of lidocaine + 30 mug of clonidine, diluted to a 10-mL volume with saline. The systemic parecoxib group (SPG) received a regional block similar to that administered to the CG but with systemic 20 mg of parecoxib, whereas the IV regional anesthesia with parecoxib group (IVRAPG) received an extra IV 5 mg of loco-regional parecoxib compared with the CG. The block was performed once a week for 3 consecutive weeks. Analgesia was evaluated by the 10-cm visual analog scale (VAS) and rescue analgesic consumption. The IVRAPG showed less daily ketoprofen (milligrams) consumption in the second and third weeks compared with the other groups (P < 0.05). The IVRAPG also showed less ketoprofen consumption when comparing the first and second week with the third week (P < 0.05). The VAS score comparison among groups revealed that groups were similar during the first and second week observation, although the IVRAPG showed smaller VAS scores in the third week compared with both CG and SPG (P < 0.05). We conclude the IV 5 mg of parecoxib was an effective antiinflammatory drug combined with clonidine/lidocaine loco-regional block in CRPS type 1.

[Is there a future for COX-2 inhibitors?].

The two cyclooxygenase isoforms (COX-1 and COX-2--coxibs) have overlapping functions and both are involved in the regulation of homeostatic and inflammatory processes in the various tissues. Treatment with highly selective COX-2 inhibitors is associated with significantly fewer serious adverse gastrointestinal events than is treatment with the dual inhibitors--the non-selective NSAIDs. Of the two coxibs, rofecoxib was shown to be much more selective than celecoxib and with less interaction with other drugs. Various clinical studies have demonstrated that the coxibs are equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator non-selective NSAIDs in osteoarthritis, rheumatoid arthritis, post surgery pain and dysmenorrhea. Perioperative use of coxibs reduces pain, opioid consumption and the risk of bleeding caused by the non-selective NSAIDs. The coxibs show similar tolerability for renal, liver and cardiothrombotic events as compared to the non-selective NSAIDs. Coxibs are contraindicated in pregnancy, in nursing mothers and pediatric patients and should be used with caution in patients with asthma. The impact of the coxibs on the cardiovascular system is controversial. However, coxibs should be used in caution and at the lowest recommended dose in patients with hypertension, ischemic heart disease and heart failure. These drugs do not interfere with the aspirin anti-platelet aggregation activity. Emerging evidence suggest that the coxibs may also find potential use as supportive therapy in various malignant tumors and intestinal polyps where COX-2 is overly expressed.

Management of pelvic pain from dysmenorrhea or endometriosis.

Many women suffer from pelvic pain, and a great many visit their family doctor for diagnosis and treatment. Two common causes are primary dysmenorrhea and endometriosis. Primary dysmenorrhea is best treated by prostaglandin inhibition from nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2)-specific inhibitors. Oral contraceptives can be added to improve pain control. Endometriosis can be treated with NSAIDs and COX-2-specific inhibitors as well but can also be treated with hormonal manipulation or surgery. Empiric treatment for endometriosis in selected patients is now accepted, making the disorder easier for family physicians to manage.

Cyclooxygenase and nitric oxide systems in the gut as therapeutic targets for safer anti-inflammatory drugs.

After a decade of intense pharmacological and drug development activity by the pharmaceutical industry, compounds derived from two key strategies for reducing gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs) have been subjected to rigorous clinical appraisal. Despite the undoubted therapeutic and commercial success of the selective cyclooxygenase (COX)-2 inhibitors, known as the coxibs, with second-generation compounds already approved and launched, some concerns over their full gastrointestinal profile still linger, while the cardiovascular safety of this class has become a key issue. Likewise, Phase II evaluation of compounds incorporating a nitric oxide (NO)-donating moiety into standard NSAIDs (the NO-NSAIDs or CINODs) has created recent controversy over the full clinical profile of these compounds. Other approaches such as NO-COX-2 inhibitors and dual COX-lipoxygenase inhibitors are already warranting interest. It might therefore be too early to predict the eventual winning strategy for safer anti-inflammatory drugs.

Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: Effects on survival, metabolism, and function.

BACKGROUND: The role of nutrition in the palliative treatment of patients with malignancy-related cachexia is unclear. The goal of the current study was to determine whether specialized, nutrition-focused patient care could improve integrated whole-body metabolism and functional outcome in unselected weight-losing patients with malignant disease who were receiving systemic antiinflammatory (cyclooxygenase [COX]-inhibitory) treatment along with erythropoietin (EPO) support. METHODS: Three hundred nine patients with malignant disease who experienced progressive cachexia due to solid tumors (primarily gastrointestinal lesions) were randomized to receive a COX inhibitor (indomethacin, 50 mg twice daily) and EPO (15-40,000 units per week) along with specialized, nutrition-focused patient care (oral nutritional support and home total parenteral nutrition [TPN]) provided on a patient-by-patient basis to attenuate inflammation, prevent anemia, and improve nutritional status. Control patients received the same indomethacin and EPO doses that study patients received without the added nutritional support. All patients were treated and followed until death. Biochemical assays (blood, liver, kidney, and thyroid), nutritional state assessment (food intake and body composition), and exercise testing with simultaneous measurement of whole-body respiratory gas exchange before and during exercise were performed before the start of treatment and then at regular intervals during the treatment period (every 2-30 months after treatment initiation). Statistical analyses were performed on 'intention-to-treat' and 'as-treated' bases. RESULTS: Home TPN was provided to approximately 50% of the study patients without severe complications. Over the entire observation period, rhEPO prevented the development of anemia in both study patients and control patients. Intention-to-treat analysis revealed an improvement in energy balance for nutritionally supported patients (P < 0.03); no other significant differences in outcome between study patients and control patients were observed. As-treated analysis demonstrated that patients receiving nutrition experienced prolonged survival (P < 0.01), which was accompanied by improved energy balance (P < 0.001), increasing body fat (P < 0.05), and a greater maximum exercise capacity (P < 0.04). A trend toward increased metabolic efficiency at maximum exercise (P < 0.06) for study patients relative to control patients also was observed. CONCLUSIONS: The results of the current study strongly support that nutrition is a limiting factor influencing survival and that nutritional support protects integrated metabolism and metabolic function in patients with progressive cachexia secondary to malignant disease.

Uptake of COX-2 selective inhibitors and influence on NSAID prescribing in Northern Ireland.

PURPOSE: Rofecoxib and celecoxib have been recently introduced and promoted as 'safer' non-steroidal anti-inflammatory drugs (NSAIDs) regarding gastric toxicity. The primary aim was to measure their uptake and any impact on conventional NSAID prescribing. A secondary aim was to assess any change in proton pump inhibitor (PPI) prescribing. METHODS: Prescribing data in terms of defined daily doses (DDDs) were pooled from 1997 onwards. Linear trends in the data were tested for using regression analyses. Direct comparisons were made between the April-June quarter of the year 1999 (i.e. before the introduction of rofecoxib and celecoxib) and the same quarter 3 years later. RESULTS: Overall NSAID prescribing in Northern Ireland was found to be increasing linearly at an estimated rate of 154,000 DDDs per quarter since the introduction of celecoxib and rofecoxib. The rate of increase in the volume of prescribing of the two new drugs was found to be four times the rate of decrease in prescribing of the 'older' NSAIDs. Overall prescribing of anti-inflammatory agents had increased from 37.8 to 47.7 DDDs/1000 patients/day over 3 years with no effect on the upward trend in PPI prescribing. CONCLUSIONS: The introduction of rofecoxib and celecoxib has increased prescribing volume of anti-inflammatory agents by 26% in Northern Ireland over the 3-year period. This could pose safety problems in the future as more people are being prescribed anti-inflammatory agents.

New dogmas or old?

Recent experimental studies may undermine our understanding of the gastrointestinal side effects of non-steroidal anti-inflammatory drugs and cast a shadow on the original concept that underpins the development of the recent addition to the clinical anti-inflammatory armamentarium, the COX-2 selective inhibitors. But is this just a passing cloud or a total eclipse of the COX theory?

NSAIDs: the emperor's new dogma?

The spectacular marketing success of the selective cyclooxygenase 2 (COX-2) inhibitors is largely based on efficacy comparable with conventional non-steroidal anti-inflammatory drugs (NSAIDs) with vastly improved gastrointestinal safety. The additional key to the marketing success is the purity and simplicity of the message-that is, COX-1 inhibition causes the gastrointestinal side effects of NSAIDs (COX-1 dogma) while COX-2 blocking confers the therapeutic benefits (COX-2 dogma). Adherence to the COX dogmas with development of COX-2 selective agents has undoubtedly benefited many patients, but ironically their scientific basis is now seriously challenged by experimentation.

Implicación de ciclooxigenasa 2 en el cáncer: utilidad de los coxib / Implication of cyclooxygenase 2 in cancer: utility of coxibs

No disponible

Potential effect of cyclooxygenase-2-specific inhibitors on the prevention of colorectal cancer: a cost-effectiveness analysis.

PURPOSE: To estimate the potential cost-effectiveness of colorectal cancer chemoprevention with cyclooxygenase-2-specific inhibitors (COX-2 inhibitors). METHODS: Using a decision analytic Markov model, we estimated the discounted cost per life-year saved for three strategies: a COX-2 inhibitor alone; as an adjunct to colonoscopy every 10 years in persons at average risk of colorectal cancer; and as an adjunct to colonoscopy every 5 years in persons with first-degree relatives who had colorectal cancer. RESULTS: In the base case, the incremental cost per life-year saved with a COX-2 inhibitor alone compared with no screening was 233,300 dollars in persons at average risk of colorectal cancer and 56,700 dollars in persons with 2 first-degree relatives who had the disease. Chemoprevention was both less effective and more costly than screening. The incremental cost per life-year saved with a COX-2 inhibitor as an adjunct to screening was 823,800 dollars in persons at average risk and 404,700 dollars in persons with 2 first-degree relatives who had colorectal cancer. Combining a COX-2 inhibitor with less frequent screening was not as cost-effective as screening at currently recommended intervals. Cost-effectiveness estimates were highly sensitive to the cost of COX-2 inhibitors and their effect on the risk of cancer. CONCLUSION: Chemoprevention of colorectal cancer with COX-2 inhibitors is likely to incur substantially higher costs per life-year saved than are currently recommended screening strategies. COX-2 inhibitor use as an adjunct to screening may increase life expectancy, although at prohibitive costs, and is unlikely to result in less frequent screening.

COX-2: where are we in 2003?--distinction from NSAIDs becoming blurred.

The distinction between cyclooxygenase-2-selective inhibitors (CSIs) and nonsteroidal anti-inflammatory drugs ultimately must be clinical and must be clinically and economically relevant. This distinction needs to be demonstrated in a substantial and clinically relevant difference in the respective rates of serious adverse reactions of the upper gastrointestinal tract. Event-driven, randomized, blinded, controlled trials with sufficient power are required to resolve uncertainties concerning the relative risk of thrombotic cardiovascular events in patients taking CSIs who have risk factors for these events. Patients and situations more representative of those in primary-care practice - elderly, comorbidities, comedication - need to be included in larger studies to provide a better understanding of the risks and benefits of CSIs.