Luteinized unruptured follicle syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies.

PubMed

Micu, Mihaela C; Micu, Romeo; Ostensen, Monika

2011-09-01

Administration of nonsteroidal antiinflammatory drugs (NSAIDs) may impair fertility. The occurrence of the luteinized unruptured follicle (LUF) syndrome was assessed in women with inflammatory arthropathies exposed to NSAIDs and compared to that in nonexposed women. Fourteen patients with inflammatory rheumatic disease, 29 women with noninflammatory musculoskeletal conditions, and 449 women not exposed to NSAIDs were studied by intravaginal ultrasound monitoring for follicular development and ovulation in 1 or more menstrual cycles. Disease activity was assessed in inflammatory rheumatic disease. In 59 monitored cycles of patients with continuous NSAID exposure, 35.6% of LUF syndromes occurred compared to 3.4% of LUF syndromes in untreated women (P < 0.001). Etoricoxib was responsible for 75% of LUF syndromes in patients exposed continuously, whereas diclofenac generated 15% of LUF syndromes. An ibuprofen dosage of 1,600 mg/day did not induce LUF syndrome either at continuous periovulatory or discontinuous exposure. Interestingly, the frequency of LUF syndrome was 46.2% in patients with inactive inflammatory disease compared to 15% in patients with active disease (P = 0.023). Etoricoxib generated LUF syndrome in 94.2% of the cases with inactive disease versus 28.6% in patients with active disease (P = 0.003). NSAIDs increased the risk of the LUF syndrome, particularly in patients with inactive disease. The selective cyclooxygenase 2 (COX-2) inhibitor etoricoxib was a more potent inductor of LUF syndrome than nonselective COX inhibitors. Continuous periovulatory exposure to NSAIDs should be avoided when planning a pregnancy in patients with rheumatic diseases. Copyright © 2011 by the American College of Rheumatology.

Upregulation of intrinsic apoptotic pathway in NSAIDs mediated chemoprevention of experimental lung carcinogenesis.

PubMed

Setia, Shruti; Sanyal, Sankar N

2012-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer. The role of COX-2 and apoptosis were evaluated in 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung cancer in rat and chemoprevention with indomethacin, a traditional NSAID and etoricoxib, a selective COX-2 inhibitor. The animals were divided into Control, DMBA, DMBA+ indomethacin and DMBA+ etoricoxib groups. They received a single intratracheal instillation of DMBA while NSAIDs were given orally daily for 32 weeks. Besides morphology and histology of lungs, RT-PCR, western blots and immunohistochemistry were performed for the expression of apoptotic proteins and COX enzymes. Apoptosis was studied by DNA fragmentation and fluorescent staining. The occurrence of tumors and lesions was noted in the DMBA animals, besides constricted alveolar spaces and hyperplasia. COX-1 was found to be uniformly expressed while COX-2 level was raised significantly in DMBA group. The apoptotic proteins, apaf-1, caspase-9 and caspase-3 were highly diminished in DMBA group but restored to normal level in NSAIDs groups. Also, apoptosis was suppressed in carcinogen group by DNA fragmentation analysis and fluorescent staining of the lung cells while co-administration of NSAIDs along with DMBA led to the restoration of apoptosis. DMBA administration to the rats led to tumorigenesis in the lungs, had no effects on COX-1 expression, while elevating the COX-2 levels and suppressing apoptosis. The treatment with NSAIDs led to the amelioration of these effects. However, etoricoxib which is a COX-2 specific inhibitor, was found to be more effective than the traditional NSAID, indomethacin.

Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis.

PubMed

van Walsem, Anneloes; Pandhi, Shaloo; Nixon, Richard M; Guyot, Patricia; Karabis, Andreas; Moore, R Andrew

2015-03-19

There is argument over the benefits and risks of drugs for treating chronic musculoskeletal pain. This study compared the efficacy, safety, and tolerability of diclofenac, ibuprofen, naproxen, celecoxib, and etoricoxib for patients with pain caused by osteoarthritis (OA) or rheumatoid arthritis (RA). A systematic literature review used Medline and EMBASE to identify randomised controlled trials. Efficacy outcomes assessed included: pain relief measured by visual analogue scale (VAS); Western Ontario McMaster Universities Arthritis Index (WOMAC) VAS or WOMAC Likert scale; physical functioning measured by WOMAC VAS or Likert scale; and patient global assessment (PGA) of disease severity measured on VAS or 5-point Likert scale. Safety outcomes included: Antiplatelet Trialists' Collaboration (APTC), major cardiovascular (CV) and major upper gastrointestinal (GI) events, and withdrawals. Data for each outcome were synthesized by a Bayesian network meta-analysis (NMA). For efficacy assessments, labelled doses for OA treatment were used for the base case while labelled doses for RA treatment were also included in the sensitivity analysis. Pooled data across dose ranges were used for safety. Efficacy, safety, and tolerability data were found for 146,524 patients in 176 studies included in the NMA. Diclofenac (150 mg/day) was likely to be more effective in alleviating pain than celecoxib (200 mg/day), naproxen (1000 mg/day), and ibuprofen (2400 mg/day), and similar to etoricoxib (60 mg/day); a lower dose of diclofenac (100 mg/day) was comparable to all other treatments in alleviating pain. Improved physical function with diclofenac (100 and 150 mg/day) was mostly comparable to all other treatments. PGA with diclofenac (100 and 150 mg/day) was likely to be more effective or comparable to all other treatments. All active treatments were similar for APTC and major CV events. Major upper GI events with diclofenac were lower compared to naproxen and ibuprofen, comparable to celecoxib, and higher than etoricoxib. Risk of withdrawal with diclofenac was lower compared to ibuprofen, similar to celecoxib and naproxen, and higher than etoricoxib. The benefit-risk profile of diclofenac was comparable to other treatments used for pain relief in OA and RA; benefits and risks vary in individuals and need consideration when making treatment decisions.

Downregulation of NF-κB and PCNA in the regulatory pathways of apoptosis by cyclooxygenase-2 inhibitors in experimental lung cancer.

PubMed

Setia, Shruti; Sanyal, Sankar Nath

2012-10-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation, angiogenesis and by promoting apoptosis. The present study further explored the comparative role of a traditional NSAID, indomethacin and a newly developed coxib, etoricoxib against 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung carcinogenesis in rats. Morphological and histological analysis revealed the occurrence of tumors and lesions along with constricted alveolar spaces in the DMBA treated animals which were largely corrected both by indomethacin and etoricoxib. COX-1 was found to be uniformly expressed in all the groups while COX-2 levels were raised prominently in the DMBA treated animals. Proliferation, as studied by PCNA expression was found to be markedly increased in the DMBA group as compared to the others. Increased NF-κB expression in the DMBA group was found to correct with the co-administration of NSAIDs. Also, fluorescent co-staining of the isolated lung cells revealed a significantly decreased apoptosis and altered mitochondrial membrane potential. In conclusion, these parameters indicate to the chemopreventive action of the two NSAIDs studied in lung cancer and as their mechanism of action suggests, can be achievable both by COX-dependent and COX-independent pathways.

Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies.

PubMed

McGettigan, Patricia; Henry, David

2011-09-01

Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings. We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment. This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Please see later in the article for the Editors' Summary.

Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies

PubMed Central

McGettigan, Patricia; Henry, David

2011-01-01

Background Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings. Methods and Findings We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment. Conclusions This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Please see later in the article for the Editors' Summary PMID:21980265

The effect of anti-rheumatic medications for coronary artery diseases risk in patients with rheumatoid arthritis might be changed over time: A nationwide population-based cohort study

PubMed Central

Lin, Lichi; Chen, Chyong-Mei; Chiou, Jeng-Yuan; Wang, Yu-Hsun; Wang, Paul Yung-Pou; Wei, James Cheng-Chung

2017-01-01

Objectives To determine whether anti-rheumatic drug usage is associated with risk of coronary artery diseases (CAD) in incident Rheumatoid Arthritis (RA) patients. Methods Data were obtained from the Taiwan National Health Insurance Research Database. The study cohort comprised 6260 patients who were newly diagnosed with RA between 2001–2010. The study endpoint was occurrence of CAD according to the ICD-9-CM codes. We used the WHO Defined Daily Dose (DDD) as a tool to assess the drugs exposure. The Cox proportional hazards regression model was used to estimate the hazard ratio (HR) of disease after controlling for demographic and other co-morbidities. When the proportionality assumption is violated, a spline curve of the Scaled Schoenfeld residuals is fitted to demonstrate the estimated effect on CAD over time for drug usage. Results Among RA patients, use of celecoxib, and etoricoxib was associated with significantly decreased incidence of CAD. The adjusted HR(95% CI) of CAD for low-dose celecoxib (DDD≦1) and high-dose user were 0.47(0.34, 0.65) and 0.37(0.24, 0.58) during the 4 year follow-up time; however, it became 0.98(0.70, 1.37) and1.29(0.85, 1.95). Adjusted HR(95% CI) of CAD for etoricoxib users remained 0.47(0.26, 0.84). Conclusions This study revealed association of decreased CAD risk in RA patients taking 2 different kinds of COX-2i in comparison with nonusers. The effect might be changed over time, after about 4 years. PMID:28658301

Treatment of Chronic Plantar Fasciitis with Noninvasive Interactive Neurostimulation: A Prospective Randomized Controlled Study.

PubMed

Razzano, Cristina; Carbone, Stefano; Mangone, Massimiliano; Iannotta, M Raffaella; Battaglia, Alessandro; Santilli, Valter

The initial treatment of plantar fasciitis should be conservative, with most cases responding to standard physiotherapy, nonsteroidal anti-inflammatory drugs (NSAIDs), heel pads, and stretching. In cases of chronic refractory symptoms, more invasive treatment could be necessary. Noninvasive interactive neurostimulation (NIN) is a form of electric therapy that works by locating areas of lower skin impedance. The objective of the present prospective randomized controlled study was to evaluate whether the use of NIN for chronic plantar fasciitis could result in greater improvement in a foot functional score, lower levels of reported pain, reduced patient consumption of NSAIDs, and greater patient satisfaction compared with electric shockwave therapy in patients without a response to standard conservative treatment. The patients were randomized using random blocks to the NIN program (group 1) or electric shockwave therapy (group 2). The outcome measurements were the pain subscale of the validated Foot Function Index (PS-FFI), patient-reported subjective assessment of the level of pain using a standard visual analog scale, and daily intake of NSAID tablets (etoricoxib 60 mg). The study group was evaluated at baseline (time 0), week 4 (time 1), and week 12 (final follow-up point). Group 1 (55 patients) experienced significantly better results compared with group 2 (49 patients) in term of the PS-FFI score, visual analog scale score, and daily intake of etoricoxib 60 mg. NIN was an effective treatment of chronic resistant plantar fasciitis, with full patient satisfaction in >90% of cases. The present prospective randomized controlled study showed superior results for noninvasive neurostimulation compared with electric shockwave therapy, in terms of the functional score, pain improvement, and use of NSAIDs. Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries

PubMed Central

McGettigan, Patricia; Henry, David

2013-01-01

Background Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries. Methods and Findings Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7–58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%. Conclusions Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs. Please see later in the article for the Editors' Summary PMID:23424288

Adoption of new drugs by physicians: a survival analysis.

PubMed

Garjón, Francisco Javier; Azparren, Ana; Vergara, Iván; Azaola, Borja; Loayssa, Jose Ramón

2012-03-08

New drugs often substitute others cheaper and with a risk-benefit balance better established. Our aim was to analyse the diffusion of new drugs during the first months of use, examining the differences between family physicians and specialists. Prescription data were obtained of cefditoren, duloxetine, etoricoxib, ezetimibe, levocetirizine, olmesartan, pregabalin and tiotropium 36 months after their launching. We obtained the monthly number of prescriptions per doctor and the number prescribers of each drug by specialty. After discarding those with less than 10 prescriptions during this period, physicians were defined as adopters if the number of prescriptions was over the 25th percentile for each drug and level (primary or secondary care). The diffusion of each drug was studied by determining the number of adopter family physicians throughout the study period. Among the group of adopters, we compared the month of the first prescription by family physicians to that of other specialists using the Kaplan-Meier method. The adoption of the drugs in primary care follows an exponential diffusion curve that reaches a plateau at month 6 to 23. Tiotropium was the most rapidly and widely adopted drug. Cefditoren spread at a slower rate and was the least adopted. The diffusion of etoricoxib was initially slowed down due to administrative requirements for its prescription. The median time of adoption in the case of family physicians was 4-6 months. For each of the drugs, physicians of a specialty other than family physicians adopted it first. The number of adopters of a new drug increases quickly in the first months and reaches a plateau. The number of adopter family physicians varies considerably for different drugs. The adoption of new drugs is faster in specialists. The time of adoption should be considered to promote rational prescribing by providing timely information about new drugs and independent medical education.

Adoption of new drugs by physicians: a survival analysis

PubMed Central

2012-01-01

Background New drugs often substitute others cheaper and with a risk-benefit balance better established. Our aim was to analyse the diffusion of new drugs during the first months of use, examining the differences between family physicians and specialists. Methods Prescription data were obtained of cefditoren, duloxetine, etoricoxib, ezetimibe, levocetirizine, olmesartan, pregabalin and tiotropium 36 months after their launching. We obtained the monthly number of prescriptions per doctor and the number prescribers of each drug by specialty. After discarding those with less than 10 prescriptions during this period, physicians were defined as adopters if the number of prescriptions was over the 25th percentile for each drug and level (primary or secondary care). The diffusion of each drug was studied by determining the number of adopter family physicians throughout the study period. Among the group of adopters, we compared the month of the first prescription by family physicians to that of other specialists using the Kaplan-Meier method. Results The adoption of the drugs in primary care follows an exponential diffusion curve that reaches a plateau at month 6 to 23. Tiotropium was the most rapidly and widely adopted drug. Cefditoren spread at a slower rate and was the least adopted. The diffusion of etoricoxib was initially slowed down due to administrative requirements for its prescription. The median time of adoption in the case of family physicians was 4-6 months. For each of the drugs, physicians of a specialty other than family physicians adopted it first. Conclusions The number of adopters of a new drug increases quickly in the first months and reaches a plateau. The number of adopter family physicians varies considerably for different drugs. The adoption of new drugs is faster in specialists. The time of adoption should be considered to promote rational prescribing by providing timely information about new drugs and independent medical education. PMID:22401169

Pharmacokinetic and pharmacodynamic herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide with etoricoxib after oral administration in rats.

PubMed

Balap, Aishwarya; Atre, Bhagyashri; Lohidasan, Sathiyanarayanan; Sinnathambi, Arulmozhi; Mahadik, Kakasaheb

2016-05-13

Andrographis paniculata Nees (Acanthacae) is commonly used medicinal plant in the traditional. Unani and Ayurvedic medicinal systems. It has broad range of pharmacological effects such as hepatoprotective, antioxidant, antivenom, antifertility, inhibition of replication of the HIV virus, antimalarial, antifungal, antibacterial, antidiabetic, suppression of various cancer cells and anti-inflammatory properties. Andrographolide (AN) is one of the active constituent of the A. paniculata Nees extract (APE). They have been found in many traditional herbal formulations in India and proven to be effective as anti-inflammatory drug To evaluate the pharmacokinetic and pharmacodynamic (anti-arthritic) herb-drug interactions of A. paniculata Nees extract (APE) and pure andrographolide (AN) with etoricoxib (ETO) after oral co-administration in wistar rats. After oral co-administration of APE (200mg/Kg) and AN (60mg/kg) with ETO (10mg/kg) in rats, drug concentrations in plasma were determined using HPLC method. The main pharmacokinetic parameters of Cmax, tmax, t1/2, MRT, Vd, CL, and AUC were calculated by non-compartment model. Change in paw volume, mechanical nociceptive threshold, mechanical hyperalgesia, histopathology and hematological parameters were evaluated to study antiarthritic activity. Co-administration of ETO with APE and pure AN decreased systemic exposure level of each compound in vivo. The Cmax, AUC, t1/2 of ETO was decreased whereas Vd and CL of ETO was increased significantly after co-administration of ETO with pure AN and APE. In pharmacodynamic study, ETO alone and ETO+APE (10+200mg/kg) groups exhibited significant synergistic anti-arthritic activity as compared to groups ETO+AN, APE and AN alone. The results obtained from this study suggested that ETO, APE and pure AN existed pharmacokinetic herb-drug interactions in rat which is correlated with anti-arthritic study. Physicians and patients using A. paniculata should have the knowledge about its possible herb-drug interaction with ETO. Copyright © 2016. Published by Elsevier Ireland Ltd.

An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UV(B)-inflamed and normal skin.

PubMed

Schaffler, Klaus; Reeh, Peter; Duan, W Rachel; Best, Andrea E; Othman, Ahmed A; Faltynek, Connie R; Locke, Charles; Nothaft, Wolfram

2013-02-01

Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UV(B)-inflamed skin. This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg and placebo. Painful stimuli were induced by CO(2) -laser on normal and UV(B) -inflamed skin. LEPs and visual analogue scale (VAS-pain) ratings were taken at baseline and hourly up to 8 h post-dose from both skin types. Compared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UV(B)-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8 h period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8 h period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared with placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4 and 9.4 ng ml(-1) for the 0.5, 2 and 6 mg doses, respectively. There were no clinically significant safety findings. TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation. © 2012 Abbott. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries.

PubMed

McGettigan, Patricia; Henry, David

2013-01-01

Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries. Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7-58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%. Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs.

An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UVB-inflamed and normal skin

PubMed Central

Schaffler, Klaus; Reeh, Peter; Duan, W Rachel; Best, Andrea E; Othman, Ahmed A; Faltynek, Connie R; Locke, Charles; Nothaft, Wolfram

2013-01-01

Aims Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UVB-inflamed skin. Methods This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg and placebo. Painful stimuli were induced by CO2-laser on normal and UVB-inflamed skin. LEPs and visual analogue scale (VAS-pain) ratings were taken at baseline and hourly up to 8 h post-dose from both skin types. Results Compared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UVB-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8 h period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8 h period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared with placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4 and 9.4 ng ml−1 for the 0.5, 2 and 6 mg doses, respectively. There were no clinically significant safety findings. Conclusions TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation. PMID:22775239

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-10-01

[Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Design and synthesis of some new 2,3'-bipyridine-5-carbonitriles as potential anti-inflammatory/antimicrobial agents.

PubMed

Elzahhar, Perihan A; Elkazaz, Salwa; Soliman, Raafat; El-Tombary, Alaa A; Shaltout, Hossam A; El-Ashmawy, Ibrahim M; Abdel Wahab, Abeer E; El-Hawash, Soad A

2017-08-01

Inflammation may cause accumulation of fluid in the injured area, which may promote bacterial growth. Other reports disclosed that non-steroidal anti-inflammatory drugs may enhance progression of bacterial infection. This work describes synthesis of new series of 2,3'-bipyridine-5-carbonitriles as structural analogs of etoricoxib, linked at position-6 to variously substituted thio or oxo moieties. Biological screening results revealed that compounds 2b, 4b, 7e and 8 showed significant acute and chronic AI activities and broad spectrum of antimicrobial activity. In addition, similarity ensemble approach was applied to predict potential biological targets of the tested compounds. Then, pharmacophore modeling study was employed to determine the most important structural parameters controlling bioactivity. Moreover, title compounds showed physicochemical properties within those considered adequate for drug candidates. This study explored the potential of such series of compounds as structural leads for further modification to develop a new class of dual AI-antimicrobial agents.

Thermodynamic behavior of glassy state of structurally related compounds.

PubMed

Kaushal, Aditya Mohan; Bansal, Arvind Kumar

2008-08-01

Thermodynamic properties of amorphous pharmaceutical forms are responsible for enhanced solubility as well as poor physical stability. The present study was designed to investigate the differences in thermodynamic parameters arising out of disparate molecular structures and associations for four structurally related pharmaceutical compounds--celecoxib, valdecoxib, rofecoxib, and etoricoxib. Conventional and modulated temperature differential scanning calorimetry were employed to study glass forming ability and thermodynamic behavior of the glassy state of model compounds. Glass transition temperature of four glassy compounds was in a close range of 327.6-331.8 K, however, other thermodynamic parameters varied considerably. Kauzmann temperature, strength parameter and fragility parameter showed rofecoxib glass to be most fragile of the four compounds. Glass forming ability of the compounds fared similar in the critical cooling rate experiments, suggesting that different factors were determining the glass forming ability and subsequent behavior of the compounds in glassy state. A comprehensive understanding of such thermodynamic facets of amorphous form would help in rationalizing the approaches towards development of stable glassy pharmaceuticals.

Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Acute Myocardial Infarction in the General German Population: A Nested Case-Control Study.

PubMed

Thöne, Kathrin; Kollhorst, Bianca; Schink, Tania

2017-09-01

Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased relative risk of acute myocardial infarction (AMI), but the label warnings refer particularly to patients with cardiovascular risk factors. The magnitude of relative AMI risk for patients with and without cardiovascular risk factors varies between studies depending on the drugs and doses studied. The aim of our study was to estimate population-based relative AMI risks for individual and widely used NSAIDs, for a cumulative amount of NSAID use, and for patients with and without a prior history of cardiovascular risk factors. Based on data from the German Pharmacoepidemiological Research Database (GePaRD) of about 17 million insurance members from four statutory health insurance providers, for the years 2004-2009, a nested case-control study was conducted within a cohort of 3,476,931 new NSAID users classified into current, recent, or past users. Up to 100 controls were matched to each case by age, sex, and length of follow-up using risk set sampling. Multivariable conditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Duration of NSAID use was calculated by the cumulative amount of dispensed defined daily doses (DDDs), and stratified analyses were conducted for potential effect modifiers. Overall, 17,236 AMI cases were matched to 1,714,006 controls. Elevated relative AMI risks were seen for current users of fixed combinations of diclofenac with misoprostol (OR 1.76, 95% CI 1.26-2.45), indometacin (1.69, 1.22-2.35), ibuprofen (1.54, 1.43-1.65), etoricoxib (1.52, 1.24-1.87), and diclofenac (1.43, 1.34-1.52) compared with past use. A low cumulative NSAID amount was associated with a higher relative AMI risk for ibuprofen, diclofenac, and indometacin. The relative risk associated with current use of diclofenac, fixed combinations of diclofenac with misoprostol, etoricoxib, and ibuprofen was highest in the younger age group (<60 years) and similar for patients with or without major cardiovascular risk factors. Relative AMI risk estimates differed among the 15 investigated individual NSAIDs. Diclofenac and ibuprofen, the most frequently used NSAIDs, were associated with a 40-50% increased relative risk of AMI, even for low cumulative NSAID amounts. The relative AMI risk in patients with and without cardiovascular risk factors was similarly elevated.

Single dose oral analgesics for acute postoperative pain in adults

PubMed Central

Moore, R Andrew; Derry, Sheena; McQuay, Henry J; Wiffen, Philip J

2014-01-01

Background Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data. Objectives To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone. Methods We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event. Main results The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken. There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen, and indometacin. Where there was adequate information for drug/dose combinations (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. Reliable results were obtained for 46 drug/dose combinations in all painful postsurgical conditions; 45 in dental pain and 14 in other painful conditions. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours in the same pain condition. Participants reporting at least one adverse event were few and generally no different between active drug and placebo, with a few exceptions, principally for aspirin and opioids. Drug/dose combinations with good (low) NNTs were ibuprofen 400 mg (2.5; 95% confidence interval (CI) 2.4 to 2.6), diclofenac 50 mg (2.7; 95% CI 2.4 to 3.0), etoricoxib 120 mg (1.9; 95% CI 1.7 to 2.1), codeine 60 mg + paracetamol 1000 mg (2.2; 95% CI 1.8 to 2.9), celecoxib 400 mg (2.5; 95% CI 2.2 to 2.9), and naproxen 500/550 mg (2.7; 95% CI 2.3 to 3.3). Long duration of action (8 hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg + paracetamol 650 mg, naproxen 500/550 mg, and celecoxib 400 mg. Not all participants had good pain relief and for many drug/dose combinations 50% or more did not achieve at last 50% maximum pain relief over four to six hours. Authors’ conclusions There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers. PMID:21901726

[The assessment of oral NSAID use in patients with rheumatoid arthritis in Hungary--a cross sectional non interventional study].

PubMed

Inotai, András; Rojkovich, Bernadette; Mészáros, Agnes

2010-01-01

Continuous NSAID (nonsteroidal anti-inflammatory drug) therapy is associated with gastrointestinal (GI) and cardiovascular (CV) side effects. In this paper, the oral NSAID use of 143 patients with rheumatoid arthritis was assessed focusing on safety and farmacoeconomic aspects in a cross sectional non interventional study. The most widely used NSAIDs were meloxicam (n = 55, 38.5%) and diclofenac (n = 30, 21%). We found that coxibs were overused (n = 13, 9.1%) compared with the average total coxib consumption in Hungary. According to our results, drugs associated with GI friend side effect profile (meloxicam, celecoxib, etoricoxib) were much preferred in patients with previous GI events, than in patients with low GI risk. The previous occurrence of GI events were significantly higher (p = 0.019) in patients currently treated with safer NSAIDs, probably because of the so-called 'indication bias'. No statistically significant difference in patient's quality of life could be proved between NSAID drug groups. The uses of NSAIDs were considered to be rational concerning CV and GI risk as well as cost-effectiveness.

Intensive Care in a Patient with Toxic Epidermal Necrolysis

PubMed Central

Fischer, M.

2017-01-01

Toxic epidermal necrolysis (TEN) is a serious adverse drug reaction with high lethality, which usually requires intensive-medical care. A 44-year-old man developed generalized exanthema with increasing exfoliation and mucosal involvement after taking allopurinol, ibuprofen, and etoricoxib. The clinical diagnosis of TEN was histologically confirmed. Prednisolone therapy with 3 mg/kg body weight (BW) was not able to prevent further progress to finally 80% of the body surface, and infliximab 5 mg/kg BW was given as a single dose. This prevented further progression of the TEN. Despite marked improvement in skin findings, the ICU stay was prolonged by a complex analgosedation, transient kidney failure, volume management, positioning therapy, and vegetatively impeded weaning. Moreover, there was colonization with multiresistant bacteria (MRSA and VRE). Nonetheless, the patient could be restored to health and was released after four weeks. Infliximab seems to be effective in the treatment of TEN, especially in cases of rapid progression. Moreover, patients with TEN are difficult to handle in intensive-medical care, whereby attention should especially be paid to sufficient pain therapy, and the positioning of the patient is a particular challenge. PMID:29225976

Design, synthesis and biological screening of some novel celecoxib and etoricoxib analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile.

PubMed

Alsayed, Shahinda S R; Elshemy, Heba A H; Abdelgawad, Mohamed A; Abdel-Latif, Mahmoud S; Abdellatif, Khaled R A

2017-02-01

Two new series of 4,6-diaryl-3-cyanopyridine 4a-r and 1,3,5-triaryl-2-pyrazolines 6a-f and were prepared. The new compounds were evaluated for their in vitro COX-2 selectivity and in vivo anti-inflammatory activity. Compounds 4o,r and 6d,f had moderate to high selectivity index (S.I.) compared to celecoxib (selectivity indexes of 4.5, 3.14, 4.79 and 3.21, respectively) and also, showed in vivo anti-inflammatory activity approximately equal to or higher than celecoxib (edema inhibition %=60.5, 64.5, 59.3 and 59.3, after 3h, respectively) and the effective anti-inflammatory doses were (ED 50 =10.1, 7.8, 8.46 and 10.7mg/kg respectively, celecoxib ED 50 =10.8mg/kg) and ulcerogenic liability were determined for these compounds which showed promising activity by being more potent than celecoxib with nearly negligible ulcerogenic liability compared to celecoxib (reduction in ulcerogenic liability versus celecoxib=85, 82, 74 and 67%, respectively). Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibitory effect of selective cyclooxygenase-2 inhibitor lumiracoxib on human organic anion transporters hOAT1 and hOAT3.

PubMed

Uwai, Yuichi; Honjo, Hiroaki; Iwamoto, Kikuo

2010-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) delay renal excretion of antifolate methotrexate by inhibiting human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8). In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effect of selective cyclooxygenase-2 inhibitors on hOAT1 and hOAT3. The uptake of methotrexate into oocytes was increased by the injection of hOAT1 and hOAT3 cRNA, and transport was strongly inhibited by lumiracoxib. The apparent 50% inhibitory concentrations of lumiracoxib were estimated to be 3.3 µM and 1.9 µM for uptake of p-aminohippurate by hOAT1 and of estrone sulfate by hOAT3, respectively. Eadie-Hofstee plot analysis showed that lumiracoxib inhibited hOAT1 and hOAT3 in a competitive manner. For other cyclooxygenase-2 inhibitors celecoxib, etoricoxib, rofecoxib and valdecoxib, slight to moderate inhibition of hOAT3 only was observed. These findings show that lumiracoxib has inhibitory potential toward hOAT1 and hOAT3, comparable to that of nonselective NSAIDs.

A Distonic Radical-Ion for Detection of Traces of Adventitious Molecular Oxygen (O2) in Collision Gases Used in Tandem Mass Spectrometers

NASA Astrophysics Data System (ADS)

Jariwala, Freneil B.; Hibbs, John A.; Weisbecker, Carl S.; Ressler, John; Khade, Rahul L.; Zhang, Yong; Attygalle, Athula B.

2014-09-01

We describe a diagnostic ion that enables rapid semiquantitative evaluation of the degree of oxygen contamination in the collision gases used in tandem mass spectrometers. Upon collision-induced dissociation (CID), the m/z 359 positive ion generated from the analgesic etoricoxib undergoes a facile loss of a methyl sulfone radical [•SO2(CH3); 79-Da] to produce a distonic radical cation of m/z 280. The product-ion spectrum of this m/z 280 ion, recorded under low-energy activation on tandem-in-space QqQ or QqTof mass spectrometers using nitrogen from a generator as the collision gas, or tandem-in-time ion-trap (LCQ, LTQ) mass spectrometers using purified helium as the buffer gas, showed two unexpected peaks at m/z 312 and 295. This enigmatic m/z 312 ion, which bears a mass-to-charge ratio higher than that of the precursor ion, represented an addition of molecular oxygen (O2) to the precursor ion. The exceptional affinity of the m/z 280 radical cation towards oxygen was deployed to develop a method to determine the oxygen content in collision gases.

Nuclear factor kappa B: a pro-inflammatory, transcription factor-mediated signalling pathway in lung carcinogenesis and its inhibition by nonsteroidal anti-inflammatory drugs.

PubMed

Setia, Shruti; Sanyal, Sankar Nath

2012-01-01

9,10-Dimethyl benz(a)anthracene (DMBA), when injected intratracheally once at a dose of 20 mg/kg body weight, is found to induce lung cancer in rats. Two nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and etoricoxib, are given orally daily as chemopreventive agents at a dose of 0.6 mg/kg body weight and 2 mg/kg body weight, respectively, along with DMBA. Morphologic and histologic analysis revealed the occurence of tumors and intense cellular proliferation in the DMBA-treated animals, whereas no such features were observed in the other groups. Nuclear factor κB, a nuclear transcription factor, and proliferating cell nuclear antigen, a cell proliferation antigen, were studied by immunoblotting and immunohistochemistry and their levels were markedly elevated in the DMBA group compared with the others. Oxidative stress parameters, as studied by the inducible nitric oxide synthase activity, and the levels of reactive oxygen and nitrogen species were found to be suppressed in the DMBA group. Furthermore, fluorescent staining of the isolated lung cells from bronchoalveolar lavage was performed to study apoptosis and alterations in the mitochondrial membrane potential, and the DMBA-induced lung cancer was found to be associated with high inner mitochondrial membrane potential and a suppressed level of apoptosis.

Optimal management of orthodontic pain.

PubMed

Topolski, Francielle; Moro, Alexandre; Correr, Gisele Maria; Schimim, Sasha Cristina

2018-01-01

Pain is an undesirable side effect of orthodontic tooth movement, which causes many patients to give up orthodontic treatment or avoid it altogether. The aim of this study was to investigate, through an analysis of the scientific literature, the best method for managing orthodontic pain. The methodological aspects involved careful definition of keywords and diligent search in databases of scientific articles published in the English language, without any restriction of publication date. We recovered 1281 articles. After the filtering and classification of these articles, 56 randomized clinical trials were selected. Of these, 19 evaluated the effects of different types of drugs for the control of orthodontic pain, 16 evaluated the effects of low-level laser therapy on orthodontic pain, and 21 evaluated other methods of pain control. Drugs reported as effective in orthodontic pain control included ibuprofen, paracetamol, naproxen sodium, aspirin, etoricoxib, meloxicam, piroxicam, and tenoxicam. Most studies report favorable outcomes in terms of alleviation of orthodontic pain with the use of low-level laser therapy. Nevertheless, we noticed that there is no consensus, both for the drug and for laser therapy, on the doses and clinical protocols most appropriate for orthodontic pain management. Alternative methods for orthodontic pain control can also broaden the clinician's range of options in the search for better patient care.

Optimal management of orthodontic pain

PubMed Central

Topolski, Francielle; Moro, Alexandre; Correr, Gisele Maria; Schimim, Sasha Cristina

2018-01-01

Pain is an undesirable side effect of orthodontic tooth movement, which causes many patients to give up orthodontic treatment or avoid it altogether. The aim of this study was to investigate, through an analysis of the scientific literature, the best method for managing orthodontic pain. The methodological aspects involved careful definition of keywords and diligent search in databases of scientific articles published in the English language, without any restriction of publication date. We recovered 1281 articles. After the filtering and classification of these articles, 56 randomized clinical trials were selected. Of these, 19 evaluated the effects of different types of drugs for the control of orthodontic pain, 16 evaluated the effects of low-level laser therapy on orthodontic pain, and 21 evaluated other methods of pain control. Drugs reported as effective in orthodontic pain control included ibuprofen, paracetamol, naproxen sodium, aspirin, etoricoxib, meloxicam, piroxicam, and tenoxicam. Most studies report favorable outcomes in terms of alleviation of orthodontic pain with the use of low-level laser therapy. Nevertheless, we noticed that there is no consensus, both for the drug and for laser therapy, on the doses and clinical protocols most appropriate for orthodontic pain management. Alternative methods for orthodontic pain control can also broaden the clinician’s range of options in the search for better patient care. PMID:29588616

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2003-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AdGVVEGF121.10, anakinra, andolast, anidulafungin, APC-2059, l-arginine hydrochloride, aripiprazole, arzoxifene hydrochloride, asimadoline; Bexarotene, bimatoprost, bimosiamose, bizelesin, BMS-188667, botulinum toxin type B, bromfenac sodium, bryostatin 1; Cannabidiol, cariporide mesilate, CCI-1004, CDP-571, cerivastatin sodium, clevudine; Dalbavancin, darbepoetin alfa, decitabine, deligoparin sodium, diethylnorspermine, drotrecogin alfa (activated), DTaP-HBV-IPV/Hib-vaccine; E-5564, eculizumab, edodekin alfa, emtricitabine, enfuvirtide, (-)-epigallocatechin gallate, eplerenone, esomeprazole magnesium, etaquine, etoricoxib, ezetimibe; Fesoterodine, fipamezole hydrochloride, fondaparinux sodium, fosamprenavir calcium, frovatriptan, fulvestrant; Gadofosveset sodium, galiximab, ghrelin (human), glufosfamide; Homoharringtonine; Idraparinux sodium, imatinib mesylate, INS-37217; KRN-7000; L-651582, lafutidine, lanthanum carbonate, lenercept, levetiracetam, lusupultide; Magnesium sulfate, melatonin, mepolizumab, midostaurin, morphine hydrochloride, mozavaptan; Natalizumab, nesiritide; OPC-51803, oregovomab, oritavancin; Peginterferon alfa-2(a), pleconaril, plevitrexed, prasterone, pregabalin; Ranibizumab, Ro-31-7453, roxifiban acetate, rubitecan; SCV-07, SHL-749, sho-saiko-to, soblidotin, solifenacin succinate; Tegaserod maleate, telithromycin, tenecteplase, theraCIM, tipifarnib, travoprost; Valdecoxib, vardenafil hydrochloride hydrate, voriconazole; Ximelagatran; Ziprasidone hydrochloride, ZYC-00101. (c) 2003 Prous Science. All rights reserved.

Enthalpy relaxation studies of two structurally related amorphous drugs and their binary dispersions.

PubMed

Bansal, Shyam Sunder; Kaushal, Aditya Mohan; Bansal, Arvind Kumar

2010-11-01

The purpose of the current study was to evaluate the enthalpy relaxation behavior of valdecoxib (VLB) and etoricoxib (ETB) and their binary dispersions to derive relaxation constants and to understand their molecular mobilities. Solid dispersions of VLB and ETB were prepared with 1%, 2%, 5%, 10%, 15%, and 20% (w/w) concentrations of polyvinylpyrrolidone (PVP) in situ using differential scanning calorimetry (DSC). Enthalpy relaxation studies were carried out with isothermal storage periods of 1, 2, 4, 6, 16, and 24 hours at 40°C and 0% relative humidity (RH). PVP increased the glass transition temperature (T(g)) and decreased the enthalpy relaxation. Significant differences between two drugs were observed with respect to their relaxation behavior which may be due to differences in intermolecular interactions as predicted by Couchman-Karasz equation and molecular mobility. Kohlrausch-Williams-Watts equation was found to be inadequate in describing complex molecular relaxations in binary dispersions. The enthalpy relaxation behavior of VLB and ETB was found to be significantly different. PVP stabilized VLB significantly; however, its effect on ETB was negligible. The extent of enthalpy relaxation was found to correlate with hydrogen bonding tendency of the drug molecules. The outcome can help in rational designing of amorphous systems with optimal performance.

Safe adalimumab therapy for rheumatoid arthritis in a patient with pre-existing multiple myeloma.

PubMed

Mielke, Frank; Schweigert, Marcus

2008-04-01

We report on a patient with rheumatoid arthritis (RA) who was treated with adalimumab and retrospectively diagnosed as having a multiple myeloma. In addition to the determination of clinical symptoms, investigations included radiography of the thorax, spine, hands and feet, arthrosonography, determination of laboratory parameters (including C-reactive protein levels and presence of antibodies against cyclic citrullinated peptide), cytogenetics and electrocardiography. RA was initially diagnosed in 1988. Stage II and stage III RA were diagnosed for the left and right foot, respectively, in 1996. Joints of both hands were diagnosed with stage I RA; both wrists and some finger joints showed signs of synovitis. Plasmocytoma was diagnosed in 2004; however, investigation of medical records revealed evidence of multiple myeloma 8 years earlier, in 1996. RA was originally treated with gold, sulfasalazine, azathioprin and glucocorticoid. Methotrexate was later used in addition to cortisone and then in combination with a selective cyclo-oxygenase-2 inhibitor. A combination therapy consisting of adalimumab (40 mg every 2 weeks), methotrexate (15 mg weekly) and a cyclo-oxygenase-2 inhibitor (rofecoxib 25 mg daily until July 2004, etoricoxib 90 mg daily from October 2004) was started in November 2003. Adalimumab therapy was interrupted for 6 months owing to safety concerns, but was resumed after a careful risk-benefit assessment.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2003-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 2F5, 2G12, abetimus sodium, ABI-007, adalimumab, adefovir dipivoxil, AE-941, alefacept, altropane, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminopterin, anakinra, aprinocarsen sodium, atazanavir, atlizumab, atomoxetine hydrochloride; B7-1 vaccine, bevacizumab, biricodar dicitrate, BMS-188667, brasofensine sulfate, bryostatin 1; cantuzumab mertansine, CHS-828, cinacalcet hydrochloride, cipamfylline, creatine, CVT-3146; darbepoetin alfa, DITPA, drotrecogin alfa (activated), duloxetine hydrochloride; edatrexate, efalizumab, ENMD-0997, epoetin, erlosamide, esomeprazole magnesium, etiprednol dicloacetate, etoricoxib, everolimus, ezetimibe; fampridine, fenretinide, FTY-720; IGF-I/IGFBP-3, IL-1 cytokine trap, ilodecakin, interferon beta, ISIS-104838, ISIS-2503, ISIS-5132, ivabradine hydrochloride; lafutidine, lanthanum carbonate, l-Arginine hydrochloride, LEA29Y, lerdelimumab, levetiracetam, levobupivacaine hydrochloride, levosimendan, lopinavir; melagatran, mibefradil hydrochloride, miglustat, morphine-6-glucuronide; nesiritide; omalizumab, omapatrilat; p24-VLP, parecoxib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pitavastatin calcium, plevitrexed, prasterone, pregabalin, PRO-2000, prucalopride; rapacuronium bromide, rebimastat, RGA-0853, rubitecan, ruboxistaurin mesilate hydrate, RWJ-67657; S-16020-2, sarizotan, SLV-306, stiripentol; TA-CIN, tenecteplase, teriparatide, tezacitabine, tipifarnib, trabectedin, troglitazone; valdecoxib, vardenafil; Z-338, ziconotide.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-05-01

O(6)-Benzylguanine; (-)-Gossypol; Abatacept, AC-2592, Adalimumab, AIDSVAX gp120 B/E, Alemtuzumab, Aliskiren fumarate, ALVAC E120TMG, Ambrisentan, Amlodipine, Anakinra, Aripiprazole, Armodafinil, Atomoxetine hydrochloride, Avotermin; Bevacizumab, BIBW-2992, Bortezomib, Bosentan, Botulinum toxin type B; Canakinumab, CAT-354, Ciclesonide, CMV gB vaccine, Corifollitropin alfa, Daptomycin, Darbepoetin alfa, Dasatinib, Denosumab; EndoTAG-1, Eplerenone, Esomeprazole sodium, Eszopiclone, Etoricoxib, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; F-50040, Fesoterodine fumavate, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, Golimumab; Imatinib mesylate, Inhalable human insulin, Insulin glargine, Ivabradine hydrochloride; Lercanidipine hydrochloride/enalapril maleate, Levosimendan, Liposomal vincristine sulfate, Liraglutide; MDV-3100, Mometasone furoate/formoterol fumavate, Multiepitope CTL peptide vaccine, Mycophenolic acid sodium salt, Nabiximols, Natalizumab, Nesiritide; Obeticholic acid, Olmesartan medoxomil, Omalizumab, Omecamtiv mecarbil; Paclitaxel-eluting stent, Paliperidone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, Polymyxin B nonapeptide, PORxin-302, Prasugrel, Pregabalin, Pridopidine; Ranelic acid distrontium salt, Rasagiline mesilate, rDEN4delta30-4995, Recombinant human relaxin H2, rhFSH, Rilonacept, Rolofylline, Rosiglitazone maleate/metformin hydrochloride, Rosuvastatin calcium, Rotigotine; Salcaprozic acid sodium salt, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, Temsirolimus, Tenofovir, Tenofovir disoproxil fumarate, Teriparatide, Tiotropium bromide, Tocilizumab, Tolvaptan, Tozasertib, Treprostinil sodium; Ustekinumab; Vardenafil hydrochloride hydrate, Varenicline tartrate, Vatalanib succinate, Voriconazole, Vorinostat; Zotarolimus-eluting stent. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Chemopreventive effects of NSAIDs as inhibitors of cyclooxygenase-2 and inducers of apoptosis in experimental lung carcinogenesis.

PubMed

Setia, Shruti; Vaish, Vivek; Sanyal, Sankar Nath

2012-07-01

Roles of cyclooxygenase (COX) enzyme and intrinsic pathway of apoptosis have been explored for the chemopreventive effects of non-steroidal anti-inflammatory drugs (NSAIDs) on 9,10-dimethyl benz(a)anthracene (DMBA)-induced lung cancer in rat model. 16 weeks after the administration of DMBA, morphological analysis revealed the occurrences of tumours and lesions, which were regressed considerably with the co-administration of indomethacin and etoricoxib, the two NSAIDs under investigation. DMBA group was marked by hyperplasia and dysplasia as observed by histological examination, and these features were corrected to a large extent by the two NSAIDs. Elevated levels of COX-2 were seen in the DMBA group, the enzyme responsible for prostaglandin synthesis during inflammation and cancer, whilst the expression of the constitutive isoform, COX-1, was equally expressed in all the groups. Apoptosis was quantified by studying the activities of apaf-1, caspase-9, and 3 by immunofluorescence and western blots. Their activities were found to diminish in the DMBA-treated animals as compared to the other groups. Fluorescent co-staining of the isolated broncho-alveolar lavage cells showed reduced number of apoptotic cells in the DMBA group, indicating decrease in apoptosis after carcinogen administration. The present results thus suggest that the mechanism of cancer chemoprevention of NSAIDs may include the suppression of COX-2 and the induction of apoptosis.

Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1.

PubMed

Schellhorn, Melina; Haustein, Maria; Frank, Marcus; Linnebacher, Michael; Hinz, Burkhard

2015-11-17

The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. Finally, celecoxib elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate celecoxib-induced upregulation of ICAM-1 on lung cancer cells to be responsible for intercellular ICAM-1/LFA-1 crosslink that confers increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of celecoxib.

Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1

PubMed Central

Frank, Marcus; Linnebacher, Michael; Hinz, Burkhard

2015-01-01

The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. Finally, celecoxib elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate celecoxib-induced upregulation of ICAM-1 on lung cancer cells to be responsible for intercellular ICAM-1/LFA-1 crosslink that confers increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of celecoxib. PMID:26513172

Combination Therapies of Diacerein and Febuxostat Inhibit IL-1β Responses and Improve Clinical Symptoms in Patients With Refractory Gout.

PubMed

Yu, Yi-Kai; Yu, Fei; Ye, Cong; Shen, Gui-Fen; Lei, Xiao-Mei; Zhang, Sheng-Tao; Hu, Shao-Xian

2017-05-01

There are several therapeutic strategies available for the treatment of an acute gout attack and the prevention of recurrent gout flares, and they include nonsteroid anti-inflammatory drugs. This prospective study was aimed at evaluating the efficiency and safety of diacerein in combination with febuxostat on urate control, global assessments of disease activity, self-monitored gouty acute flare times, inflammatory markers, and clinical symptoms associated with their life quantity in patients with refractory gout. A total of 64 patients with refractory gout were sequentially recruited and prescribed with oral febuxostat alone or febuxostat plus diacerein daily for 12 weeks. The intensity of joint pain, numbers of acute flare, disease activity and the levels of serum amyloid A, mature IL-1β, IL-18, C-reactive protein, and urate in individual subjects were routine analyzed. In comparison with that treatment with febuxostat alone, treatment with both drugs for 12 weeks had a better therapeutic effect on reducing the values of visual analog scales, acute flares, and healthy assessment questionnaire scores in these gout patients. Furthermore, treatment with both drugs also significantly reduced the mean daily dose of etoricoxib and the levels of serum IL-1β and serum amyloid A. There was no significant difference in the frequency of patients with adverse effect between these 2 groups of patients. In conclusion, combination of diacerein and febuxostat had better therapeutic effect on reducing acute gout flares, inflammation, and clinical symptoms in patients with refractory gout.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2007-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide, Uracil, Ustekinumab; V-260, Vandetanib, Vatalanib succinate, Vernakalant hydrochloride, Vorinostat; YM-155; Zileuton, Zoledronic acid monohydrate.

Quantitation of itopride in human serum by high-performance liquid chromatography with fluorescence detection and its application to a bioequivalence study.

PubMed

Singh, Sonu Sundd; Jain, Manish; Sharma, Kuldeep; Shah, Bhavin; Vyas, Meghna; Thakkar, Purav; Shah, Ruchy; Singh, Shriprakash; Lohray, Brajbhushan

2005-04-25

A new method was developed for determination of itopride in human serum by reversed phase high-performance liquid chromatography (HPLC) with fluorescence detection (excitation at 291 nm and emission at 342 nm). The method employed one-step extraction of itopride from serum matrix with a mixture of tert-butyl methyl ether and dichloromethane (70:30, v/v) using etoricoxib as an internal standard. Chromatographic separation was obtained within 12.0 min using a reverse phase YMC-Pack AM ODS column (250 mm x 4.6 mm, 5 microm) and an isocratic mobile phase constituting of a mixture of 0.05% tri-fluoro acetic acid in water and acetonitrile (75:25, v/v) flowing at a flow rate of 1.0 ml/min. The method was linear in the range of 14.0 ng/ml to 1000.0 ng/ml. The lower limit of quantitation (LLOQ) was 14.0 ng/ml. Average recovery of itopride and the internal standard from the biological matrix was more than 66.04 and 64.57%, respectively. The inter-day accuracy of the drug containing serum samples was more than 97.81% with a precision of 2.31-3.68%. The intra-day accuracy was 96.91% or more with a precision of 5.17-9.50%. Serum samples containing itopride were stable for 180.0 days at -70+/-5 degrees C and for 24.0 h at ambient temperature (25+/-5 degrees C). The method was successfully applied to the bioequivalence study of itopride in healthy, male human subjects.

[Human Single Drug Exposures to Non-opioid Analgesics Reported to the Poisons Information Centre Erfurt from 2003 to 2012].

PubMed

Hentschel, H; Prasa, D; Bergmann, I; Enden, G; Plenert, B; Frimlova, G; Just, S; Liebetrau, G; Stürzebecher, A; Deters, M

2016-01-01

Because of their frequency, non-opioid analgesics (NOA) single drug exposures registered by Poisons Information Centre (PIC) Erfurt have been studied over a decade. A retrospective analysis of frequencies, circumstances of exposure, symptom severity, and age groups in NOA single drug exposures received by the PIC Erfurt from the beginning of 2003 to the end of 2012 was undertaken. Of all 4749 NOA single drug exposures, the 10 most frequent were caused by paracetamol (n=1 686), ibuprofen (n=1 439), acetylsalicylic acid (n=456), dipyrone (n=274), diclofenac (n=267), flupirtine (n=138), naproxen (n=41), etoricoxib (n=36), indomethacin (n=24), and dexketoprofen (n=19). Paracetamol single drug exposures increased from 158 in 2003 to 216 in 2007 and fell afterwards to 133 in 2012. Ibuprofen single drug exposures continously rose from 57 in 2003 to 258 in 2012. Adults were more often involved in NOA (53.8%) and all single drug exposures (54.1%) than children (45.9% and 45.6%, respectively). Suicidal attempts were more frequent in NOA (43.1%) than in all single drug exposures (34.2%), whereas accidental exposures or exposures in abuse were less often (33.4 and 0.2%, 46.0 and 0.9% respectively). NOA single drug exposures resulted mostly in none to minor symptoms (77.0%) and rarely in moderate (2.1%) or severe symptoms (1.0%). One adult was found dead after probable ingestion of 32 g of acetylsalicylic acid in suicidal intention. Because many NOA are over-the-counter drugs, it is difficult to obtain data on their use. PIC data could provide information on the NOA use in the population. © Georg Thieme Verlag KG Stuttgart · New York.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-01-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs:(R)-Flurbiprofen, 90Yttrium-DOTA-huJ591; ABT-510, ACP-103, Ad5-FGF4, adalimumab, ademetionine, AG-7352, alemtuzumab, Amb a 1 ISS-DNA, anakinra, apaziquone, aprepitant, aripiprazole, atazanavir sulfate; BAL-8557, bevacizumab, BMS-188797, bortezomib, bosentan, brivudine; Calcipotriol/betamethasone dipropionate, cannabidiol, caspofungin acetate, catumaxomab, CERE-120, cetuximab, ciclesonide, cilomilast, cizolirtine citrate, Cypher, cystemustine; Dalbavancin, darifenacin hydrobromide, dasatinib, deferasirox, denosumab, desmoteplase, dihydrexidine, dimethyl fumarate, dutasteride, DW-166HC; Eculizumab, enfuvirtide, entecavir, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, eszopiclone, etoricoxib, everolimus; Fallypride, febuxostat, fenretinide, fesoterodine, fingolimod hydrochloride; Gabapentin enacarbil, gefitinib; hMaxi-K, human papillomavirus vaccine, HYAL-CT1101; Imatinib mesylate, indiplon, inolimomab, ISAtx-247; J591; Lacosamide, landiolol, lasofoxifene tartrate, lestaurtinib, lidocaine/prilocaine, linezolid, lixivaptan, lonafarnib, lopinavir, lopinavir/ritonavir, lumiracoxib; Natalizumab, nesiritide; OC-108, omalizumab, onercept, OSC; Palifermin, palonosetron hydrochloride, parathyroid hormone (human recombinant), parecoxib sodium, PD-MAGE-3 vaccine, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pelitinib, pitavastatin calcium, plerixafor hydrochloride, posaconazole, prasterone sulfate, pregabalin; Ramelteon, ranelic acid distrontium salt, rasburicase, rosuvastatin calcium, rotigotine, RSD-1235, rufinamide, rupatadine fumarate; Sarizotan hydrochloride, SHL-749, sirolimus-eluting stent, solifenacin succinate, sunitinib malate; Tadalafil, talampanel, tasidotin hydrochloride, Taxus, tegaserod maleate, telavancin hydrochloride, tenofovir disoproxil fumarate, tiotropium bromide, tocilizumab, tositumomab, treprostinil sodium, tridolgosir hydrochloride, TTS-CD3; Ularitide; Valdecoxib, Val-Tyr sardine peptidase, vardenafil hydrochloride hydrate, voriconazole; Yttrium (90Y) edotreotide, Yttrium 90 (90Y) ibritumomab tiuxetan; Zileuton, zucapsaicin.

Matrix solid-phase dispersion followed by liquid chromatography tandem mass spectrometry for the determination of selective ciclooxygenase-2 inhibitors in sewage sludge samples.

PubMed

Triñanes, Sara; Casais, M Carmen; Mejuto, M Carmen; Cela, Rafael

2016-09-02

A straightforward single-step extraction method based on matrix solid-phase dispersion (MSPD), followed by high-performance liquid chromatography with hybrid quadrupole time of flight mass spectrometry (LC-QTOF-MS), was developed and optimized to determine five non-steroidal anti-inflammatory drugs (Valdecoxib, Etoricoxib, Parecoxib, Celecoxib and 2,5-Dimethylcelecoxib) in sewage sludge samples. The influence of different operational parameters on the extraction efficiency a well as in the matrix effects of the produced extracts was evaluated in detail. Under final working conditions, freeze dried samples (0.2g) were first soaked with 100μL of aqueous potassium hydroxide solution (60%, w/v), mixed with 1g of anhydrous sodium sulfate and dispersed with 1g of Florisil. This blend was transferred to the top of a polypropylene column cartridge containing 3g of silica. Analytes were recovered using 15mL of hexane/acetone (1:2, v/v) mixture. The extracts were concentrated by evaporation and reconstituted with 1mL of methanol/water (1:1, v/v), filtered and injected in the LC system. Quantification limits from 0.005 and 0.05ngg(-1) and absolute recoveries between 86 and 105% were achieved. Results indicated the presence of two of the targeted COXIBs in real samples of sewage sludge, the highest average concentration (22ngg(-1)) corresponding to celecoxib. Moreover, the screening capabilities of the LC-QTOF-MS system demonstrated that the developed MSPD extraction procedure might be useful for the selective extraction of some other pharmaceuticals (e.g. amiodarone and their metabolite N-desethylamiodarone, miconazole, clotrimazole and ketoprofen) from sludge samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Gender bias in clinical research, pharmaceutical marketing, and the prescription of drugs

PubMed Central

Chilet-Rosell, Elisa

2014-01-01

This thesis is part of the studies of gender bias in health which together with the paradigm of evidence-based medicine shares the empirical assumption that there are inaccuracies in medical practice, in addition to a lack of rigour and transparency. It worked with the distinction between the concepts of sex and gender and between the concepts of sex-related differences and gender inequalities, in terms of applying a gender perspective in the study design and the subsequent analysis. This PhD review presents the research process conducted in Spain, which can provide an example for future research. Study I described a review of 58 clinical trials (CTs) of etoricoxib to assess its compliance with the Recommendations of Evaluation of Gender Differences in the Clinical Evaluation of Drugs. In Study II, key informants from professions related to different areas in drug development and pharmacovigilance held a working meeting to reach a consensus document on recommendations for the study and evaluation of gender differences in CTs in Spain. In Study III, the websites of the eight best-selling hormone replacement therapy drugs in Spain on Google first page of results were analysed. In Study IV, a logistic regression analysis was performed to compare analgesic prescription by sex in regions with a higher or lower Gender Development Index (GDI) than the Spanish average. Gender biases identified in this thesis limited the legitimacy of medicine, which is not based on the best possible evidence. The results also demonstrate the existence of inequalities between men and women that are not due merely to biological differences, but are gender inequalities stemming from the social differences that exist between both sexes. PMID:25498360

Pain Management After Outpatient Shoulder Arthroscopy: A Systematic Review of Randomized Controlled Trials.

PubMed

Warrender, William J; Syed, Usman Ali M; Hammoud, Sommer; Emper, William; Ciccotti, Michael G; Abboud, Joseph A; Freedman, Kevin B

2017-06-01

Effective postoperative pain management after shoulder arthroscopy is a critical component to recovery, rehabilitation, and patient satisfaction. This systematic review provides a comprehensive overview of level 1 and level 2 evidence regarding postoperative pain management for outpatient arthroscopic shoulder surgery. Systematic review. We performed a systematic review of the various modalities reported in the literature for postoperative pain control after outpatient shoulder arthroscopy and analyzed their outcomes. Analgesic regimens reviewed include regional nerve blocks/infusions, subacromial/intra-articular injections or infusions, cryotherapy, and oral medications. Only randomized control trials with level 1 or level 2 evidence that compared 2 or more pain management modalities or placebo were included. We excluded studies without objective measures to quantify postoperative pain within the first postoperative month, subjective pain scale measurements, or narcotic consumption as outcome measures. A combined total of 40 randomized control trials met our inclusion criteria. Of the 40 included studies, 15 examined nerve blocks, 4 studied oral medication regimens, 12 studied subacromial infusion, 8 compared multiple modalities, and 1 evaluated cryotherapy. Interscalene nerve blocks (ISBs) were found to be the most effective method to control postoperative pain after shoulder arthroscopy. Increasing concentrations, continuous infusions, and patient-controlled methods can be effective for more aggressively controlling pain. Dexamethasone, clonidine, intrabursal oxycodone, and magnesium have all been shown to successfully improve the duration and adequacy of ISBs when used as adjuvants. Oral pregabalin and etoricoxib administered preoperatively have evidence supporting decreased postoperative pain and increased patient satisfaction. On the basis of the evidence in this review, we recommend the use of ISBs as the most effective analgesic for outpatient arthroscopic shoulder surgery.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-04-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort extract, synthetic human secretin; Taxus, telavancin hydrochloride, telithromycin, temoporfin, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate/emtricitabine, teriparatide, testosterone gel, TG-1024, tirapazamine, travoprost, travoprost/timolol; Valdecoxib, valganciclovir hydrochloride, voriconazole; Ximelagatran.

Prescribing potentially inappropriate medication (PIM) in Germany's elderly as indicated by the PRISCUS list. An analysis based on regional claims data.

PubMed

Schubert, Ingrid; Küpper-Nybelen, Jutta; Ihle, Peter; Thürmann, Petra

2013-07-01

The aim of this study was to estimate the prevalence of potentially inappropriate medication (PIM) in the elderly as indicated by Germany's recently published list (PRISCUS) and to assess factors independently associated with PIM prescribing, both overall and separately for therapeutic groups. Claims data analysis (Health Insurance Sample AOK Hesse/KV Hesse, 18.75% random sample of insurants from AOK Hesse, Germany) is used in the study. The study population is composed of 73,665 insurants >64 years of age continuously insured in the last quarter of 2009 and either continuously insured or deceased in 2010. Prevalence estimates are standardized to the population of Germany (31 December 2010). The variables age, sex, polypharmacy, hospital stay and nursing care are assessed for their independent association with general PIM prescription and among 11 therapeutic subgroups using multivariate logistic regression analysis. In 2010, 22.0% of the elderly received at least one PIM prescription (men: 18.3%, women: 24.8%). The highest PIM prevalence was observed for antidepressants (6.5%), antihypertensives (3.8%) and antiarrhythmic drugs (3.5%). Amitriptyline, tetrazepam, doxepin, acetyldigoxin, doxazosin and etoricoxib were the most frequently prescribed PIMs. Multivariate analyses indicate that women (OR 1.39; 95% CI: 1.34-1.44) and persons with extreme polypharmacy (≥10 vs. <5 drugs: OR 5.16; 95% CI: 4.87-5.47) were at higher risk for receiving a PRISCUS-PIM. Risk analysis for therapeutic groups shows divergent associations. PRISCUS-PIMs are widely used. Educational programs should focus on drugs with high treatment prevalence and call professionals' attention to those elderly patients who are at special risk for inappropriate medication. Copyright © 2013 John Wiley & Sons, Ltd.

Gender bias in clinical research, pharmaceutical marketing, and the prescription of drugs.

PubMed

Chilet-Rosell, Elisa

2014-01-01

This thesis is part of the studies of gender bias in health which together with the paradigm of evidence-based medicine shares the empirical assumption that there are inaccuracies in medical practice, in addition to a lack of rigour and transparency. It worked with the distinction between the concepts of sex and gender and between the concepts of sex-related differences and gender inequalities, in terms of applying a gender perspective in the study design and the subsequent analysis. This PhD review presents the research process conducted in Spain, which can provide an example for future research. Study I described a review of 58 clinical trials (CTs) of etoricoxib to assess its compliance with the Recommendations of Evaluation of Gender Differences in the Clinical Evaluation of Drugs. In Study II, key informants from professions related to different areas in drug development and pharmacovigilance held a working meeting to reach a consensus document on recommendations for the study and evaluation of gender differences in CTs in Spain. In Study III, the websites of the eight best-selling hormone replacement therapy drugs in Spain on Google first page of results were analysed. In Study IV, a logistic regression analysis was performed to compare analgesic prescription by sex in regions with a higher or lower Gender Development Index (GDI) than the Spanish average. Gender biases identified in this thesis limited the legitimacy of medicine, which is not based on the best possible evidence. The results also demonstrate the existence of inequalities between men and women that are not due merely to biological differences, but are gender inequalities stemming from the social differences that exist between both sexes.

Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews.

PubMed

Moore, R Andrew; Derry, Sheena; Aldington, Dominic; Wiffen, Philip J

2015-09-28

This is an updated version of the original Cochrane overview published in Issue 9, 2011. That overview considered both efficacy and adverse events, but adverse events are now dealt with in a separate overview.Thirty-nine Cochrane reviews of randomised trials have examined the analgesic efficacy of individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews and assesses the reliability of available data. To summarise the efficacy of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery who have been given a single dose of oral analgesic. We identified systematic reviews in the Cochrane Database of Systematic Reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group, had a standard title, and had as their primary outcome the number of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews, we extracted the number needed to treat for an additional beneficial outcome (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, and the percentage of participants remedicating by six, eight, 12, or 24 hours. Where there was adequate information for pairs of drug and dose (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. The overview included 39 separate Cochrane Reviews with 41 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 50,000 participants in approximately 460 individual studies. The individual reviews included only high-quality trials of standardised design, methods, and efficacy outcome reporting. No statistical comparison was undertaken.Reliable results (high quality information) were obtained for 53 pairs of drug and dose in painful postsurgical conditions; these included various fixed dose combinations, and fast acting formulations of some analgesics. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours. Good (low) NNTs were obtained with ibuprofen 200 mg plus paracetamol (acetaminophen) 500 mg (NNT compared with placebo 1.6; 95% confidence interval 1.5 to 1.8), ibuprofen fast acting 200 mg (2.1; 1.9 to 2.3); ibuprofen 200 mg plus caffeine 100 mg (2.1; 1.9 to 3.1), diclofenac potassium 50 mg (2.1; 1.9 to 2.5), and etoricoxib 120 mg (1.8; 1.7 to 2.0). For comparison, ibuprofen acid 400 mg had an NNT of 2.5 (2.4 to 2.6). Not all participants had good pain relief and, for many pairs of drug and dose, 50% or more did not achieve at least 50% maximum pain relief over four to six hours.Long duration of action (eight hours or greater) was found for etoricoxib 120 mg, diflunisal 500 mg, paracetamol 650 mg plus oxycodone 10 mg, naproxen 500/550 mg, celecoxib 400 mg, and ibuprofen 400 mg plus paracetamol 1000 mg.There was no evidence of analgesic effect for aceclofenac 150 mg, aspirin 500 mg, and oxycodone 5 mg (low quality evidence). No trial data were available in reviews of acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for nine drugs and doses, and data potentially susceptible to publication bias for 13 drugs and doses (very low quality evidence). There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.

Evaluation of rational nonsteroidal anti-inflammatory drugs and gastro-protective agents use; association rule data mining using outpatient prescription patterns.

PubMed

Pattanaprateep, Oraluck; McEvoy, Mark; Attia, John; Thakkinstian, Ammarin

2017-07-04

Nonsteroidal anti-inflammatory drugs (NSAIDs) and gastro-protective agents should be co-prescribed following a standard clinical practice guideline; however, adherence to this guideline in routine practice is unknown. This study applied an association rule model (ARM) to estimate rational NSAIDs and gastro-protective agents use in an outpatient prescriptions dataset. A database of hospital outpatients from October 1st, 2013 to September 30th, 2015 was searched for any of following drugs: oral antacids (A02A), peptic ulcer and gastro-oesophageal reflux disease drugs (GORD, A02B), and anti-inflammatory and anti-rheumatic products, non-steroids or NSAIDs (M01A). Data including patient demographics, diagnoses, and drug utilization were also retrieved. An association rule model was used to analyze co-prescription of the same drug class (i.e., prescriptions within A02A-A02B, M01A) and between drug classes (A02A-A02B & M01A) using the Apriori algorithm in R. The lift value, was calculated by a ratio of confidence to expected confidence, which gave information about the association between drugs in the prescription. We identified a total of 404,273 patients with 2,575,331 outpatient visits in 2 fiscal years. Mean age was 48 years and 34% were male. Among A02A, A02B and M01A drug classes, 12 rules of associations were discovered with support and confidence thresholds of 1% and 50%. The highest lift was between Omeprazole and Ranitidine (340 visits); about one-third of these visits (118) were prescriptions to non-GORD patients, contrary to guidelines. Another finding was the concomitant use of COX-2 inhibitors (Etoricoxib or Celecoxib) and PPIs. 35.6% of these were for patients aged less than 60 years with no GI complication and no Aspirin, inconsistent with guidelines. Around one-third of occasions where these medications were co-prescribed were inconsistent with guidelines. With the rapid growth of health datasets, data mining methods may help assess quality of care and concordance with guidelines and best evidence.

Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations. Implications for COX-2 cardiovascular profile.

PubMed

Arellano, Félix M; Yood, Marianne Ulcickas; Wentworth, Charles E; Oliveria, Susan A; Rivero, Elena; Verma, Anila; Rothman, Kenneth J

2006-12-01

COX-2 and NSAIDS differ in their gastrointestinal (GI) and cardiovascular (CV) toxicity from pharmacological, clinical and epidemiologic point of views. Describe the patterns of use of NSAIDS and COX-2 in The Health Improvement Network (THIN) database in UK and the PharMetrics database in USA. We examined the experience of 10 distinct cohorts of new users of diclofenac, naproxen, ibuprofen, piroxicam, other NSAIDS, meloxicam, celecoxib, etoricoxib, rofecoxib and valdecoxib. The study period was 1 January 1995 through 2004 (31 March in UK and 28 February in USA). We collected information on covariates including history of upper GI disease, CV disease, hepatic disease, dosage, concomitant medication, and visits to a rheumatologist. We identified 486 076 unique patient-drug pairs in UK and 1 533 239 in USA. In UK population 78 201 (16%) were COX-2 users and in PharMetrics 324 206 (21%) were COX-2 users. Diclofenac and ibuprofen (NSAIDS), and celecoxib and rofecoxib (COX-2) were the agents prescribed most frequently. The duration of therapy was longer among celecoxib and rofecoxib users than among other users. More COX-2 users than NSAIDS users received concomitant gastroprotective agents (GPA), corticosteroids and anti-platelet therapy, and had a history of thromboembolic events and hypertension. PharMetrics patients were prescribed higher doses of NSAIDS and COX-2. The use of any single agent for more than 90 days was uncommon, but more frequent in PharMetrics. Switching was uncommon and was generally to a NSAID. Our results confirm some previous findings from other authors such as the presence of both GI and CV channelling to COX-2 agents but refute others, such as the frequency of drug switching between these agents. The typical use of COX-2 agents in practice is for shorter duration, and at lower doses, than was employed in randomized clinical trials. This difference may help clarify the apparent discrepancy with respect to CV toxicity between the results from clinical trials, which showed a higher CV risk with these drugs, and non-experimental epidemiologic studies, which showed lower or no increase in risk.

Prescribing patterns of non-steroidal anti-inflammatory drugs in chronic kidney disease patients in the South African private sector.

PubMed

Meuwesen, Willem P; du Plessis, Jesslee M; Burger, Johanita R; Lubbe, Martie S; Cockeran, Marike

2016-08-01

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used pharmaceutical agents worldwide. NSAIDs are considered nephrotoxic and should therefore be used with caution or be avoided completely in high risk patients, such as chronic kidney disease (CKD) patients. Objective This study aimed to investigate the prescribing of NSAIDs in CKD patients in order to generate awareness and improve the outcome of these patients. Setting The study was conducted using medicine claims data in the private health sector of South Africa. Method A descriptive, quantitative study was performed, using retrospective data obtained from a Pharmaceutical Benefit Management company. Data from 1 January 2009 to 31 December 2013 were analysed. The study population consisted of all patients with an ICD-10 code for a CKD (N18), in association with a paid claim for an NSAID. Main outcome measure The stratification of NSAID prescribing volume among the CKD population in terms of gender, age, NSAID type, dosage and prescriber type. Results The prescribing of NSAIDs in CKD patients varied between 26 and 40 % over the 5 year study period. No association between gender and CKD patients who received NSAIDs versus those who did not was found, with p > 0.05 and Cramer's V < 0.1 for each year of the study. The association between age groups and CKD patients who received NSAIDs versus those who did not was statistically significant, but practically weak (p < 0.05; Cramer's V ≥ 0.1). Most NSAID prescriptions (52-63 %) were for patients aged 35-64 years. Diclofenac (34.25 %) was the single most frequently prescribed NSAID, but the COX-2-inhibitors (celecoxib, meloxicam and etoricoxib) were the preferred NSAID class to be prescribed. The majority (61.6 %) of the NSAIDs were prescribed by general medical practitioners in dosages meeting and even exceeding the recommended daily dosage of patients with normal kidney function. Conclusions Even though NSAIDs are regarded as nephrotoxic drugs, they are still being prescribed to at-risk CKD patients, in particular, the elderly.

Pain control in first-trimester surgical abortion: a systematic review of randomized controlled trials.

PubMed

Renner, Regina M; Jensen, Jeffrey T; Nichols, Mark D; Edelman, Alison B

2010-05-01

First-trimester abortions especially cervical dilation and suction aspiration are associated with pain despite various methods of pain control. Following the guidelines for a Cochrane review, we systematically searched for and reviewed randomized controlled trials comparing methods of pain control in first-trimester surgical abortion at less than 14 weeks gestational age using electric or manual suction aspiration. Outcomes included intra- and postoperative pain, side effects, recovery measures and satisfaction. We included 40 trials with 5131 participants. Because of heterogeneity, we divided studies into seven groups: Local anesthesia: Data were insufficient to show a clear benefit of a paracervical block (PCB) compared to no PCB. Reported mean pain scores (10-point scale) during dilation and aspiration were improved with carbonated lidocaine [weighted mean difference (WMD), -0.80; 95% confidence interval (CI), -0.89 to -0.71; WMD, -0.96; 95% CI, -1.67 to -0.25], deep injection (WMD, -1.64; 95% CI, -3.21 to -0.08; WMD, 1.00; 95% CI, 1.09 to 0.91), and with adding a 4% intrauterine lidocaine infusion (WMD, -2.0; 95% CI, -3.29 to -0.71; WMD, -2.8; 95% CI, -3.95 to -1.65). PCB with premedication: Ibuprofen and naproxen resulted in small reduction of intra- and postoperative pain. Conscious sedation: The addition of conscious intravenous sedation using diazepam and fentanyl to PCB decreased procedural pain. General anesthesia: Conscious sedation increased intraoperative but decreased postoperative pain compared to general anesthesia (GA) [Peto odds ratio (Peto OR) 14.77 (95%, CI 4.91-44.38) and Peto OR 7.47 (95% CI, 2.2-25.36) for dilation and aspiration, respectively, and WMD -1.00 (95% CI, -1.77 to -0.23) postoperatively). Inhalation anesthetics are associated with increased blood loss (p<0.001). GA with premedication: The cyclooxygenase (COX)-2 inhibitor etoricoxib; the nonselective COX inhibitors lornoxicam, diclofenac and ketorolac IM; and the opioid nalbuphine improved postoperative pain. Nonpharmacological intervention: Listening to music decreased procedural pain. No major complication was observed. Conscious sedation, GA and some nonpharmacological interventions decreased procedural and postoperative pain, while being safe and satisfactory to patients. Data on the widely used PCB are inadequate to support its use, and it needs to be further studied to determine any benefit.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2006-10-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (-)-gossypol, 2-deoxyglucose, 3,4-DAP, 7-monohydroxyethylrutoside; Ad5CMV-p53, adalimumab, adefovir dipivoxil, ADH-1, alemtuzumab, aliskiren fumarate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, amrubicin hydrochloride, AN-152, anakinra, anecortave acetate, antiasthma herbal medicine intervention, AP-12009, AP-23573, apaziquone, aprinocarsen sodium, AR-C126532, AR-H065522, aripiprazole, armodafinil, arzoxifene hydrochloride, atazanavir sulfate, atilmotin, atomoxetine hydrochloride, atorvastatin, avanafil, azimilide hydrochloride; Bevacizumab, biphasic insulin aspart, BMS-214662, BN-83495, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, cetuximab, chrysin, ciclesonide, clevudine, clofarabine, clopidogrel, CNF-1010, CNTO-328, CP-751871, CX-717, Cypher; Dapoxetine hydrochloride, darifenacin hydrobromide, dasatinib, deferasirox, dextofisopam, dextromethorphan/quinidine sulfate, diclofenac, dronedarone hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Edaravone, efaproxiral sodium, emtricitabine, entecavir, eplerenone, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, ezetimibe, ezetimibe/simvastatin; Finrozole, fipamezole hydrochloride, fondaparinux sodium, fulvestrant; Gabapentin enacarbil, gaboxadol, gefitinib, gestodene, ghrelin (human); Human insulin, human papillomavirus vaccine; Imatinib mesylate, immunoglobulin intravenous (human), indiplon, insulin detemir, insulin glargine, insulin glulisine, intranasal insulin, istradefylline, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; LA-419, lacosamide, landiolol, lanthanum carbonate, lidocaine/prilocaine, liposomal cisplatin, lutropin alfa; Matuzumab, MBP(82-98), mecasermin, MGCD-0103, MMR-V, morphine hydrochloride, mycophenolic acid sodium salt; Natalizumab, NCX-4016, neridronic acid, nesiritide, nilotinib, NSC-330507; O6-benzylguanine, olanzapine/fluoxetine hydrochloride, omalizumab; Panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant, pemetrexed disodium, perospirone hydrochloride, pexelizumab, phorbol 12-myristate 13-acetate, pneumococcal 7-valent conjugate vaccine, posaconazole, pramiconazole, prasugrel, pregabalin, prilocaine; rAAV-GAD65, raclopride, rasagiline mesilate, retapamulin, rosuvastatin calcium, rotigotine, rufinamide; SarCNU, SB-743921, SHL-749, sirolimus-eluting stent, sitaxsentan sodium, sorafenib; TachoSil, tadalafil, talampanel, Taxus, tegaserod maleate, telithromycin, telmisartan/hydrochlorothiazide, temsirolimus, tenatoprazole, teriflunomide, tetrathiomolybdate, ticilimumab, timcodar dimesilate, tipifarnib, tirapazamine, TPI, tramiprosate, trifluridine/TPI, trimethoprim; Ularitide, Urocortin 2; Valdecoxib, valganciclovir hydrochloride, valproate magnesium, valspodar, vardenafil hydrochloride hydrate, vitespen, vofopitant hydrochloride, volociximab, vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, zotarolimus, zotarolimus-eluting stent.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2005-01-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate; ACP-103, Ad.Egr.TNF.11 D, adalimumab, AF-IL 12, AIDSVAX gp120 B/B, alefacept, alemtuzumab, a-Galactosylceramide, ALVAC vCP 1452, alvimopan hydrate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anidulafungin, antarelix, aprepitant, aripiprazole, arsenic sulfide, asoprisnil, atazanavir sulfate, atomoxetine hydrochloride; Bevacizumab, bimatoprost, BMS-184476, bortezomib, bosentan, botulinum toxin type B, BrachySil, brivudine; Caffeine, calcipotriol/betamethasone dipropionate, cannabidiol, capsaicin for injection, caspofungin acetate, CC-4047, cetuximab, CGP-36742, clofazimine, CpG-7909, Cypher; Darbepoetin alfa, dextromethorphan/quinidine sulfate, dimethylfumarate, dronabinol/cannabidiol, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecogramostim, efalizumab, eletriptan, emtricitabine, enfuvirtide, eplerenone, esomeprazole magnesium, estradiol acetate, eszopiclone, etoricoxib, exenatide, ezetimibe, ezetimibe/simvastatin; Fampridine, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GPI-0100; hA 20, HTU-PA, human insulin, HuOKT 3 gamma 1(Ala 234-Ala 235), hyaluronic acid; Icatibant, imatinib mesylate, Indiplon, INKP-100, INKP-102, iodine (I131) tositumomab, istradefylline, IV gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, landiolol, lanthanum carbonate, lasofoxifene tartrate, LB-80380, lenalidomide, lidocaine/tetracaine, linezolid, liposomal doxorubicin, liposomal vincristine sulfate, lopinavir, lopinavir/ritonavir, lumiracoxib, lurtotecan; Maribavir, morphine glucuronide, MVA-5 T 4; NBI-56418, NCX-4016, nesiritide, nicotine conjugate vaccine, NSC-330507; Oglufanide, omalizumab, oxipurinol; Palifermin, palonosetron hydrochloride, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, PEGylated interferon alfacon-1, perospirone hydrochloride, pimecrolimus, pixantrone maleate, plerixafor hydrochloride, PowderJect lidocaine, pradefovir mesylate, prasterone, pregabalin, Prostvac VF, PT-141, PTC-124, pyridoxamine; QS-21, quercetin; R-126638, R-411, ralfinamide, rasagiline mesilate, rF-PSA, RG-2077, rhThrombin, rimonabant hydrochloride, rofecoxib, rosuvastatin calcium, rotigotine hydrochloride, rV-PSA; S-18886, S-303, seocalcitol, SGN-40, sitaxsentan sodium, SPP-301, St. John's Wort extract; Tadalafil, taxus, telithromycin, tenatoprazole, tenofovir disoproxil fumarate, testosterone MDTS, testosterone transdermal patch, tgAAC-09, TH-9507, thioacetazone, tipifarnib, TQ-1011, trabectedin, travoprost, trimethoprim; Valdecoxib, valganciclovir hydrochloride, valopicitabine, voriconazole; Xcellerated T cells. (c) 2005 Prous Science. All rights reserved.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-06-01

[¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab, Nemonoxacin, Norelgestromin/ethinyl estradiol; Oblimersen sodium, Ocriplasmin, Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Pagoclone, Paliperidone, Panitumumab, Pazopanib hydrochloride, PCV7, Pegaptanib octasodium, Peginterferon alfa-2a, Peginterferon alfa-2b/ ribavirin, Pegvisomant, Pemetrexed disodium, Perifosine, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Plitidepsin, Posaconazole, Pregabalin, Progesterone capriate; Raltegravir potassium, Ramucirumab, Ranelic acid distrontium salt, Rasburicase, Recombinant Bet V1, Recombinant human insulin, rhFSH, Rolofylline, Romidepsin, Romiplostim, Rosuvastatin calcium; Sapacitabine, Sevelamer carbonate, Sinecatechins, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, SN-29244, Sorafenib, Sugammadex sodium, Sunitinib malate; Tadalafil, Tafenoquine, Talnetant, Tanezumab, Tapentadol hydrochloride, Tasocitinib citrate, Technosphere/Insulin, Telcagepant, Tenofovir disoproxil fumarate, Teriparatide, Ticagrelor, Tigecycline, Tiotropium bromide, Tipifarnib, Tocilizumab, TS-041; Ulipristal acetate, Urtoxazumab, Ustekinumab; Vandetanib, Varenicline tartrate, Vicriviroc, Voriconazole, Vorinostat, VRC-HIVADV014-00-VP, VRC-HIVDNA016-00-VP; Zoledronic acid monohydrate. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Celecoxib and sulfasalazine had negative association with coronary artery diseases in patients with ankylosing spondylitis

PubMed Central

Wu, Li-Chih; Leong, Pui-Ying; Yeo, Kai-Jieh; Li, Ting-Yu; Wang, Yu-Hsun; Chiou, Jeng-Yuan; Wei, James Cheng-Chung

2016-01-01

Abstract The aim of the study is to assess the effects of celecoxib and sulfasalazine on the risk of coronary artery disease (CAD) in patients with ankylosing spondylitis (AS). Using the claims data of Taiwan National Health Insurance (NHI) database, a nationally representative data that contain the medical records of 23 million Taiwan residents, we randomly selected 1 million cohort from the database, and then we enrolled only patients who were newly diagnosed with AS (n = 4829) between year 2001 and 2010, excluding patients who had CAD (ICD-9- CM codes: 410–414) before the diagnosis of AS (n = 4112). According to propensity score matched 1:2 on age, gender, AS duration, Charlson comorbidity index, hypertension, and hyperlipidemia, 236 and 472 patients were included in the case (AS with CAD) and control (AS without CAD) groups, respectively. We used the WHO defined daily dose (DDD) as a tool to assess the dosage of sulfasalazine and celecoxib exposure. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (ORs) and 95% confidence interval (CI) for the risk of CAD associated with use of sulfasalazine and celecoxib. Among 4112 AS patients, 8.4% (346/4112) developed CAD. CAD in AS patients were positively associated with age of 35 to 65, Charlson comorbidities index (CCI), hypertension, and hyperlipidemia. There was no gender difference between case and control groups. After adjustment for age, gender, CCI, hypertension, and hyperlipidemia, sulfasalazine users with an average daily dose ≥ 0.5 DDD (0.5 gm/day) had negative association with CAD events as compared to sulfasalazine nonusers (OR 0.63; 95% CI, 0.40–0.99, P < 0.05). NSAIDs, including celecoxib, etoricoxib, but no naproxen and diclofenac were negatively associated with CAD. Celecoxib users, with an average daily dose > 1.5 DDD, were negatively associated with CAD events, compared to celecoxib nonusers (OR 0.34; 95% CI, 0.13–0.89; P < 0.05). In this 10-year population-based case-control study, 8.4% of AS patients developed CAD. Sulfasalazine usage at an average dose of ≥ 0.5 gm/day demonstrated negative association with CAD events in patients with AS. PMID:27603385

Pain control in first trimester surgical abortion.

PubMed

Renner, Regina-Maria; Jensen, Jeffrey T J; Nichols, Mark D N; Edelman, Alison

2009-04-15

First trimester abortions especially cervical dilation and suction aspiration are associated with pain, despite various methods of pain control. Compare different methods of pain control during first trimester surgical abortion. We searched multiple electronic databases with the appropriate key words, as well as reference lists of articles, and contacted professionals to seek other trials. Randomized controlled trials comparing methods of pain control in first trimester surgical abortion at less than 14 weeks gestational age using electric or manual suction aspiration. Outcomes included intra- and postoperative pain, side effects, recovery measures and satisfaction. Two reviewers independently extracted data. Meta-analysis results are expressed as weighted mean difference (WMD) or Peto Odds ratio with 95% confidence interval (CI). We included forty studies with 5131 participants. Due to heterogeneity we divided studies into 7 groups:Local anesthesia: Data was insufficient to show a clear benefit of a paracervical block (PCB) compared to no PCB or a PCB with bacteriostatic saline. Pain scores during dilation and aspiration were improved with deep injection (WMD -1.64 95% CI -3.21 to -0.08; WMD 1.00 95% CI 1.09 to 0.91), and with adding a 4% intrauterine lidocaine infusion (WMD -2.0 95% CI -3.29 to -0.71, WMD -2.8 95% CI -3.95 to -1.65 with dilation and aspiration respectively).PCB with premedication: Ibuprofen and naproxen resulted in small reduction of intra- and post-operative pain.Analgesia: Diclofenac-sodium did not reduce pain.Conscious sedation: The addition of conscious intravenous sedation using diazepam and fentanyl to PCB decreased procedural pain.General anesthesia (GA): Conscious sedation increased intraoperative but decreased postoperative pain compared to GA (Peto OR 14.77 95% CI 4.91 to 44.38, and Peto OR 7.47 95% CI 2.2 to 25.36 for dilation and aspiration respectively, and WMD 1.00 95% CI 1.77 to 0.23 postoperatively). Inhalation anesthetics are associated with increased blood loss (p<0.001).GA with premedication: The COX 2 inhibitor etoricoxib, the non-selective COX inhibitors lornoxicam, diclofenac and ketorolac IM, and the opioid nalbuphine were improved postoperative pain.Non-pharmacological intervention: Listening to music decreased procedural pain.No major complication was observed. Conscious sedation, GA and some non-pharmacological interventions decreased procedural and postoperative pain, while being safe and satisfactory to patients. Data on the widely used PCB is inadequate to support its use, and it needs to be further studied to determine any benefit.

Oral nonsteroidal anti-inflammatory drugs for fibromyalgia in adults.

PubMed

Derry, Sheena; Wiffen, Philip J; Häuser, Winfried; Mücke, Martin; Tölle, Thomas Rudolf; Bell, Rae F; Moore, R Andrew

2017-03-27

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain in fibromyalgia, despite being considered not to be effective. To assess the analgesic efficacy, tolerability (drop-out due to adverse events), and safety (serious adverse events) of oral nonsteroidal anti-inflammatory drugs for fibromyalgia in adults. We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from inception to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. We included randomised, double-blind trials of two weeks' duration or longer, comparing any oral NSAID with placebo or another active treatment for relief of pain in fibromyalgia, with subjective pain assessment by the participant. Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)) or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC), serious adverse events, and withdrawals due to adverse events; secondary outcomes were adverse events, withdrawals due to lack of efficacy, and outcomes relating to sleep, fatigue, and quality of life. Where pooled analysis was possible, we used dichotomous data to calculate risk difference (RD) and number needed to treat for an additional beneficial outcome (NNT), using standard methods. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. Our searches identified six randomised, double-blind studies involving 292 participants in suitably characterised fibromyalgia. The mean age of participants was between 39 and 50 years, and 89% to 100% were women. The initial pain intensity was around 7/10 on a 0 to 10 pain scale, indicating severe pain. NSAIDs tested were etoricoxib 90 mg daily, ibuprofen 2400 mg daily, naproxen 1000 mg daily, and tenoxicam 20 mg daily; 146 participants received NSAID and 146 placebo. The duration of treatment in the double-blind phase varied between three and eight weeks.Not all studies reported all the outcomes of interest. Analyses consistently showed no significant difference between NSAID and placebo: substantial benefit (at least 50% pain intensity reduction) (risk difference (RD) -0.07 (95% confidence interval (CI) -0.18 to 0.04) 2 studies, 146 participants; moderate benefit (at least 30% pain intensity reduction) (RD -0.04 (95% CI -0.16 to 0.08) 3 studies, 192 participants; withdrawals due to adverse events (RD 0.04 (95% CI -0.02 to 0.09) 4 studies, 230 participants; participants experiencing any adverse event (RD 0.08 (95% CI -0.03 to 0.19) 4 studies, 230 participants; all-cause withdrawals (RD 0.03 (95% CI -0.07 to 0.14) 3 studies, 192 participants. There were no serious adverse events or deaths. Although most studies had some measures of health-related quality of life, fibromyalgia impact, or other outcomes, none reported the outcomes beyond saying that there was no or little difference between the treatment groups.We downgraded evidence on all outcomes to very low quality, meaning that this research does not provide a reliable indication of the likely effect. The likelihood that the effect could be substantially different is very high. This is based on the small numbers of studies, participants, and events, as well as other deficiencies of reporting study quality allowing possible risks of bias. There is only a modest amount of very low-quality evidence about the use of NSAIDs in fibromyalgia, and that comes from small, largely inadequate studies with potential risk of bias. That bias would normally be to increase the apparent benefits of NSAIDs, but no such benefits were seen. Consequently, NSAIDs cannot be regarded as useful for treating fibromyalgia.

Nonsteroidal anti-inflammatory drugs for dysmenorrhoea.

PubMed

Marjoribanks, Jane; Ayeleke, Reuben Olugbenga; Farquhar, Cindy; Proctor, Michelle

2015-07-30

Dysmenorrhoea is a common gynaecological problem consisting of painful cramps accompanying menstruation, which in the absence of any underlying abnormality is known as primary dysmenorrhoea. Research has shown that women with dysmenorrhoea have high levels of prostaglandins, hormones known to cause cramping abdominal pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs that act by blocking prostaglandin production. They inhibit the action of cyclooxygenase (COX), an enzyme responsible for the formation of prostaglandins. The COX enzyme exists in two forms, COX-1 and COX-2. Traditional NSAIDs are considered 'non-selective' because they inhibit both COX-1 and COX-2 enzymes. More selective NSAIDs that solely target COX-2 enzymes (COX-2-specific inhibitors) were launched in 1999 with the aim of reducing side effects commonly reported in association with NSAIDs, such as indigestion, headaches and drowsiness. To determine the effectiveness and safety of NSAIDs in the treatment of primary dysmenorrhoea. We searched the following databases in January 2015: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, November 2014 issue), MEDLINE, EMBASE and Web of Science. We also searched clinical trials registers (ClinicalTrials.gov and ICTRP). We checked the abstracts of major scientific meetings and the reference lists of relevant articles. All randomised controlled trial (RCT) comparisons of NSAIDs versus placebo, other NSAIDs or paracetamol, when used to treat primary dysmenorrhoea. Two review authors independently selected the studies, assessed their risk of bias and extracted data, calculating odds ratios (ORs) for dichotomous outcomes and mean differences for continuous outcomes, with 95% confidence intervals (CIs). We used inverse variance methods to combine data. We assessed the overall quality of the evidence using GRADE methods. We included 80 randomised controlled trials (5820 women). They compared 20 different NSAIDs (18 non-selective and two COX-2-specific) versus placebo, paracetamol or each other. NSAIDs versus placeboAmong women with primary dysmenorrhoea, NSAIDs were more effective for pain relief than placebo (OR 4.37, 95% CI 3.76 to 5.09; 35 RCTs, I(2) = 53%, low quality evidence). This suggests that if 18% of women taking placebo achieve moderate or excellent pain relief, between 45% and 53% taking NSAIDs will do so.However, NSAIDs were associated with more adverse effects (overall adverse effects: OR 1.29, 95% CI 1.11 to 1.51, 25 RCTs, I(2) = 0%, low quality evidence; gastrointestinal adverse effects: OR 1.58, 95% CI 1.12 to 2.23, 14 RCTs, I(2) = 30%; neurological adverse effects: OR 2.74, 95% CI 1.66 to 4.53, seven RCTs, I(2) = 0%, low quality evidence). The evidence suggests that if 10% of women taking placebo experience side effects, between 11% and 14% of women taking NSAIDs will do so. NSAIDs versus other NSAIDsWhen NSAIDs were compared with each other there was little evidence of the superiority of any individual NSAID for either pain relief or safety. However, the available evidence had little power to detect such differences, as most individual comparisons were based on very few small trials. Non-selective NSAIDs versus COX-2-specific selectorsOnly two of the included studies utilised COX-2-specific inhibitors (etoricoxib and celecoxib). There was no evidence that COX-2-specific inhibitors were more effective or tolerable for the treatment of dysmenorrhoea than traditional NSAIDs; however data were very scanty. NSAIDs versus paracetamolNSAIDs appeared to be more effective for pain relief than paracetamol (OR 1.89, 95% CI 1.05 to 3.43, three RCTs, I(2) = 0%, low quality evidence). There was no evidence of a difference with regard to adverse effects, though data were very scanty.Most of the studies were commercially funded (59%); a further 31% failed to state their source of funding. NSAIDs appear to be a very effective treatment for dysmenorrhoea, though women using them need to be aware of the substantial risk of adverse effects. There is insufficient evidence to determine which (if any) individual NSAID is the safest and most effective for the treatment of dysmenorrhoea. We rated the quality of the evidence as low for most comparisons, mainly due to poor reporting of study methods.