Double-blind Cross-over Study of Ketoprofen and Ibuprofen in Management of Rheumatoid Arthritis

A double-blind cross-over study of ketoprofen (Orudis) 150 mg daily and ibuprofen (Brufen) 1,200 mg daily was carried out in 35 outpatients with rheumatoid arthritis. Results suggest that analgesic and anti-inflammatory activity of ketoprofen is superior to that of ibuprofen. Significantly greater pain relief (P < 0·05) and reduction in joint circumference (P < 0·01) was obtained with ketoprofen than with ibuprofen. Side effects of the drugs were comparable and not serious.     

Challenging inflammatory process at molecular,cellular and in vivo levels via some new pyrazolyl thiazolones

The work reported herein describes the synthesis of a new series of anti-inflammatory pyrazolyl thiazolones. In addition to COX-2/15-LOX inhibition, these hybrids exerted their anti-inflammatory actions through novel mechanisms. The most active compounds possessed COX-2 inhibitory activities comparable to celecoxib (IC₅₀ values of 0.09–0.14 µM) with significant 15-LOX inhibitory activities (IC₅₀s 1.96 to 3.52 µM). Upon investigation of their in vivo anti-inflammatory activities and ulcerogenic profiles, these compounds showed activity patterns equivalent or more superior to diclofenac and/or celecoxib. Intriguingly, the most active compounds were more effective than diclofenac in suppressing monocyte-to-macrophage differentiation and inflammatory cytokine production by activated macrophages, as well as their ability to induce macrophage apoptosis. The latter finding potentially adds a new dimension to the previously reported anti-inflammatory mechanisms of similar compounds. These compounds were effectively docked into COX-2 and 15-LOX active sites. Also, in silico predictions confirmed the appropriateness of these compounds as drug-like candidates.     

A Preliminary Pilot Randomized Crossover Study of Uzara (Xysmalobium undulatum) versus Ibuprofen in the Treatment of Primary Dysmenorrhea

Objective

Preliminary evaluation of efficacy and safety of uzara use in treatment of moderate and severe primary dysmenorrhea in comparison to ibuprofen.

Materials and Methods

This randomized, comparative two way cross-over study comprised 60 single female students at Faculty of Medicine, Ain Shams University, Egypt, aged 19–28 years with moderate (n = 46) or severe (n = 14) primary dysmenorrhea. Participants were randomized to take either uzara (80 mg/8 hours for two doses, then 40 mg/8 hours) then ibuprofen (400 mg/6 hours) in two subsequent cycles or vice versa. The pain intensity, using VAS, was recorded immediately before taking the medication (0 hour) and after 4, 12, 24, 48–60, 96–120 hours. Main outcome measures included effectiveness of pain relief defined as drop of VAS to 3 or less, patient''s global evaluation of the drug, absence from school, the use of a rescue medication, and, in those who continued the treatment, the pain intensity difference (PID) at different points after start of medication and its sum (SPID).

Results

Uzara was comparably effective to ibuprofen (78.3% vs. 86.7% of cycles; respectively), with comparable rates of effectiveness on global evaluation (being around 50% for either drug), and rates of school absences (11.7% vs. 13.3%; respectively). The need for rescue medication was different (18.3% and 10%; respectively), albeit with no statistical significance. The means of PID at different time points and SPID were comparable, with significantly lower average mean of VAS scores compared to that felt with no medication (1.6 vs. 6.8, p<0.001). Side effects were less with uzara than ibuprofen (0% vs. 8.3%, p<0.05).

Conclusions

Uzara might be as effective as ibuprofen in management of primary dysmenorrhea but with less side effects. These findings need to be confirmed by a properly designed trial with a larger sample size.

Trial Registration

Current Controlled Trials ISRCTN25618258     

High-performance liquid chromatographic determination of naproxen, ibuprofen and diclofenac in plasma and synovial fluid in man

High-performance liquid chromatographic assay procedures have been developed for naproxen, ibuprofen and diclofenac in human plasma and synovial fluid samples. A single liquid—liquid extraction procedure was used to isolate each compound from acidified biological matrix prior to the quantitative analysis. A Spherisorb ODS column (12.5 cm × 4.6 mm I.D.) was used for all the chromatography. Naproxen was eluted with a mobile phase of methanol—Sörensen's buffer at pH 7 (37:63, v/v). Ibuprofen and diclofenac were eluted using mobile phases of methanol—water at pH 3.3 (65:35, v/v and 63:37, v/v, respectively). Diphenylacetic acid was used as the internal standard for the assay of naproxen and flurbiprofen was used in the analysis of ibuprofen and diclofenac. Inter- and intra-day coefficients of variation were less than 7%. The assays were used in clinical studies of the three drugs in osteo- and rheumatoid arthritis patients.     

Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis

Aims To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin.Design Nested case-control study.Setting 367 general practices contributing to the UK QRESEARCH database and spread throughout every strategic health authority and health board in England, Wales, and Scotland.Subjects 9218 cases with a first ever diagnosis of myocardial infarction during the four year study period; 86 349 controls matched for age, calendar year, sex, and practice.Outcome measures Unadjusted and adjusted odds ratios with 95% confidence intervals for myocardial infarction associated with rofecoxib, celecoxib, naproxen, ibuprofen, diclofenac, and other selective and non-selective NSAIDS. Odds ratios were adjusted for smoking status, comorbidity, deprivation, and use of statins, aspirin, and antidepressants.Results A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39). Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease.Conclusion These results suggest an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen despite adjustment for many potential confounders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. This is an observational study and may be subject to residual confounding that cannot be fully corrected for. However, enough concerns may exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs.     

Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study

Objective To determine whether older patients with chronic knee pain should be advised to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs).Design Randomised controlled trial and patient preference study.Setting 26 general practices.Participants People aged ≥50 with knee pain: 282 in randomised trial and 303 in preference study. Interventions Advice to use topical or oral ibuprofen.Primary outcome measures WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, major and minor adverse effects.Results Changes in global WOMAC scores at 12 months were equivalent. In the randomised trial the difference (topical minus oral) was two points (95% confidence interval −2 to 6); in the preference study, it was one point (−4 to 6). There were no differences in major adverse effects in the trial or study. The only significant differences in secondary outcomes were in the randomised trial. The oral group had more respiratory adverse effects (17% v 7%,95% confidence interval for difference −17% to −2%), the change in serum creatinine was 3.7 mmol/l less favourable (0.9 µmol/l to 6.5 µmol/l); and more participants changed treatments because of adverse effects (16% v 1%, −16% to −5%). In the topical group more participants had chronic pain grade III or IV at three months, and more participants changed treatment because of ineffectiveness.Conclusions Advice to use oral or topical preparations has an equivalent effect on knee pain over one year, and there are more minor side effects with oral NSAIDs. Topical NSAIDs may be a useful alternative to oral NSAIDs.Trial registration ISRCTN 79353052.     

Proteomic analysis in NSAIDs-treated primary cardiomyocytes

NSAIDs (non-steroidal anti-inflammatory drugs) are widely used for the treatment of a variety of inflammatory diseases, but many of them were withdrawn from the market due to their cardiovascular toxicity. In this study, we tried to identify proteins responding to the cellular toxicity in NSAIDs-treated primarily cultured cardiomyocytes using 2-D proteomic analysis. We used seven different NSAIDs (celecoxib, rofecoxib, valdecoxib, diclofenac, naproxen, ibuprofen, and meloxicam) possessing each different degree of cardiovascular risk. Overall protein spots were similar in all NSAIDs-treated cells although numbers of decreased proteins were about 2-fold higher in celecoxib or rofecoxib-treated cells than in cells incubated with other NSAIDs. Many stress-related proteins, cardiac muscle movement proteins and proteins involved in membrane organization have been isolated. Among them, Septin-8, a filament scaffolding protein, showed its specific expression pattern depending on the extent of drug toxicity. Its expression level was low in cells treated by relatively high toxic drugs such as celecoxib, diclofenac, valdecoxib, and rofecoxib. On the contrary, Septin-8 was similarly expressed in control cells in the presence of less toxic drugs such ibuprofen, naproxen, and meloxicam. This data suggests that Septin-8 differentially responds to each NSAID.     

Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports

The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.     

First-dose analgesic effect of the cyclo-oxygenase-2 selective inhibitor lumiracoxib in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled comparison with celecoxib [NCT00267215]

Cyclo-oxygenase-2 selective inhibitors are frequently used to manage osteoarthritis. We compared the analgesic efficacy of the novel cyclo-oxygenase-2 selective inhibitor lumiracoxib (Prexige) versus placebo and celecoxib in patients with knee osteoarthritis. This seven day, double-blind, placebo and active comparator controlled, parallel group study included 364 patients aged > or = 50 years with moderate-to-severe symptomatic knee osteoarthritis. Patients received lumiracoxib 400 mg/day (four times the recommended chronic dose in osteoarthritis; n = 144), placebo (n = 75), or celecoxib 200 mg twice daily (n = 145). The primary variable was actual pain intensity difference (100 mm visual-analogue scale) between baseline and the mean of three hour and five hour assessments after the first dose. Actual pain intensity difference, average and worst pain, pain relief and functional status (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) were measured over seven days. Patients also completed a global evaluation of treatment effect at study end or premature discontinuation. For the primary variable, the superiority of lumiracoxib versus placebo, the noninferiority of lumiracoxib versus celecoxib, and the superiority of lumiracoxib versus celecoxib were assessed by closed test procedure adjusting for multiplicity, thereby maintaining the overall 5% significance level. In addition, celecoxib was assessed versus placebo in a predefined exploratory manner to assess trial sensitivity. Lumiracoxib provided better analgesia than placebo 3-5 hours after the first dose (P = 0.004) through to study end. The estimated difference between lumiracoxib and celecoxib 3-5 hours after the first dose was not significant (P = 0.185). Celecoxib was not significantly different from placebo in this analysis (P = 0.069). At study end 13.9% of lumiracoxib-treated patients reported complete pain relief versus 5.5% and 5.3% of celecoxib and placebo recipients, respectively. WOMAC total and subscales improved for both active treatments versus placebo except for difficulty in performing daily activities, for which celecoxib just failed to achieve significance (P = 0.056). In the patient's global evaluation of treatment effect, 58.1% of patients receiving lumiracoxib rated treatment as 'excellent' or 'good', versus 48.6% of celecoxib and 25.3% of placebo patients. Lumiracoxib was well tolerated. The overall incidence of adverse events was similar across treatment groups.     

Effect of Formulation Variables on Preparation of Celecoxib Loaded Polylactide-Co-Glycolide Nanoparticles

Polymer based nanoparticle formulations have been shown to increase drug bioavailability and/or reduce drug adverse effects. Nonsteroidal anti-inflammatory drugs (e.g. celecoxib) reduce prostaglandin synthesis and cause side effects such as gastrointestinal and renal complications. The aim of this study was to formulate celecoxib entrapped poly lactide-co-glycolide based nanoparticles through a solvent evaporation process using didodecyldimethylammonium bromide or poly vinyl alcohol as stabilizer. Nanoparticles were characterized for zeta potential, particle size, entrapment efficiency, and morphology. Effects of stabilizer concentration (0.1, 0.25, 0.5, and 1% w/v), drug amount (5, 10, 15, and 20 mg), and emulsifier (lecithin) on nanoparticle characterization were examined for formula optimization. The use of 0.1, 0.25, and 0.5% w/v didodecyldimethylammonium bromide resulted in a more than 5-fold increase in zeta potential and a more than 1.5-fold increase in entrapment efficiency with a reduction in particle size over 35%, when compared to stabilizer free formulation. Nanoparticle formulations were also highly influenced by emulsifier and drug amount. Using 0.25% w/v didodecyldimethylammonium bromide NP formulations, peak zeta potential was achieved using 15 mg celecoxib with emulsifier (17.15±0.36 mV) and 20 mg celecoxib without emulsifier (25.00±0.18 mV). Peak NP size reduction and entrapment efficiency was achieved using 5 mg celecoxib formulations with (70.87±1.24 nm and 95.55±0.66%, respectively) and without (92.97±0.51 nm and 95.93±0.27%, respectively) emulsifier. In conclusion, formulations using 5 mg celecoxib with 0.25% w/v didodecyldimethylammonium bromide concentrations produced nanoparticles exhibiting enhanced size reduction and entrapment efficiency. Furthermore, emulsifier free formulations demonstrated improved zeta potential when compared to formulations containing emulsifier (p<0.01). Therefore, our results suggest the use of emulsifier free 5 mg celecoxib drug formulations containing 0.25% w/v didodecyldimethylammonium bromide for production of polymeric NPs that demonstrate enhanced zeta potential, small particle size, and high entrapment efficiency.     

Combined Treatment of Xenon and Hypothermia in Newborn Rats - Additive or Synergistic Effect?

BackgroundBreathing the inert gas Xenon (Xe) enhances hypothermic (HT) neuroprotection after hypoxia-ischemia (HI) in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added) or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7) rats, showed that the combination of mild HT (35°C) and low Xe concentration (20%), both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.Design/MethodsAfter the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT) NT_37°C, HT_35°C, HT_32°C) or Xe concentrations (0%, 20% or 50%) starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101) of P7 pups were exposed to either HT_35°C+Xe_0%, NT+Xe_20% or a combination of HT_35°C+Xe_20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side) brain tissue area loss after seven day survival.ResultsImmediate HT_32°C (p = 0.042), but not HT_35°C significantly reduced brain injury compared to NT_37°C. As previously shown, adding immediate Xe_50% to HT_32°C increased protection. Neither 4 h-delayed Xe_20%, nor Xe_50% at 37°C significantly reduced brain injury (p>0.050). In addition, neither 4 h-delayed HT_35°C alone, nor HT_35°C+Xe_20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.ConclusionsCombining two treatments that individually were ineffective (delayed HT_35°C and delayed Xe_20%) did not exert neuroprotection when combined, and therefore did not show a synergistic treatment effect.     

Safety, efficacy and anti-inflammatory activity of rho iso-alpha-acids from hops

A defined mixture of rho iso-alpha-acids (RIAA), a modified hop extract, was evaluated for anti-inflammatory efficacy and safety. RIAA inhibited LPS-stimulated PGE(2) formation with >200-fold selectivity of COX-2 (IC(50)=1.3 microg/ml) over COX-1 (IC(50)>289 microg/ml). This occurred only when RIAA was added prior to, but not post, LPS stimulation. Consistent with this observation, RIAA produced no physiologically relevant, direct inhibition of COX-1 or COX-2 peroxidase activity. This suggests that RIAA inhibits inducible but not constitutive COX-2. In support, we found RIAA showed minimal PGE(2) inhibition (IC(50)=21mug/ml) relative to celecoxib (IC(50)=0.024 microg/ml), aspirin (IC(50)=0.52 microg/ml) or ibuprofen (IC(50)=0.57 microg/ml) in the AGS gastric mucosal model, where COX-1 and -2 are expressed constitutively. Taken together these results predict RIAA may have lower potential for gastrointestinal and cardiovascular toxicity observed with COX enzyme inhibitors. Following confirmation of bioavailable RIAA administered orally, gastrointestinal safety was assessed using the fecal calprotectin biomarker in a 14-day human clinical study; RIAA (900 mg/day) produced no change compared to naproxen (1000 mg/day), which increased fecal calprotectin 200%. Cardiovascular safety was addressed by PGI-M measurements where RIAA (1000 mg) did not reduce PGI-M or affect the urinary PGI-M/TXB(2) ratio. Drug interaction potential was evaluated against six major CYPs; of relevance, RIAA inhibited CYP2C9. Toxicity was assessed in a 21-day oral, mouse subchronic toxicity study where no dose dependent histopathological effects were noted. Clinically, RIAA (1000 mg/day) produced a 54% reduction in WOMAC Global scores in a 6-week, open-label trial of human subjects exhibiting knee osteoarthritis.     

温针灸联合塞来昔布胶囊对膝骨关节炎患者骨代谢指标和血清IL-6、IL-17、IL-18水平的影响

摘要 目的：观察温针灸联合塞来昔布胶囊对膝骨关节炎（KOA）患者骨代谢指标和血清白介素-6（IL-6）、白介素-17（IL-17）、白介素-18（IL-18）水平的影响。方法：纳入我院2017年4月~2020年12月间针灸科接收的KOA患者80例,将患者采用信封抽签法分为对照组和研究组,各为40例。对照组给予塞来昔布胶囊进行治疗,研究组给予温针灸联合塞来昔布胶囊进行治疗,均连续治疗8周。观察两组疗效、骨代谢指标[骨保护素（OPG）、降钙素（CT）、骨钙素（BGP）]、炎性因子、量表评分[视觉模拟评分法（VAS）、骨关节炎指数评分表（WOMAC）、Lysholm膝关节评分]等情况,记录治疗期间的不良反应发生率。结果：研究组的临床总有效率高于对照组（P<0.05）。研究组治疗8周后VAS、WOMAC较对照组低,Lysholm膝关节评分较对照组高（P<0.05）。研究组治疗8周后血清OPG、BGP较对照组高（P<0.05）。两组血清CT水平治疗8周后对比差异无统计学意义（P>0.05）。研究组治疗8周后血清IL-6、IL-17、IL-18较对照组低（P<0.05）。两组不良反应总发生率组间对比差异无统计学意义（P>0.05）。结论：温针灸联合塞来昔布胶囊治疗KOA患者,可有效减轻疼痛,促进膝关节功能恢复,同时还可抑制炎症因子,改善骨代谢指标,优化治疗效果。     

Results of a proof of concept,double-blind,randomized trial of a second generation antisense oligonucleotide targeting high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis

IntroductionThis randomized, double-blind, phase II study evaluated the pharmacodynamics, safety and tolerability of ISIS 329993 (ISIS-CRP_Rx), an antisense oligonucleotide, in patients with active rheumatoid arthritis (RA).MethodsPatients with active RA of at least six months duration were randomized into three cohorts to receive ISIS-CRP_Rx (100 mg, 200 mg or 400 mg) or placebo (3 active:1 placebo within each cohort) via subcutaneous (SC) injection on Days 1, 3, 5 and 8 and then once weekly for the next 11 weeks. The effects of study treatment on high-sensitivity C-reactive protein (hs-CRP) level were evaluated. An exploratory analysis on disease activity was assessed via the American College of Rheumatology 20% improvement criteria (ACR20). Safety was evaluated via adverse events and laboratory measures.ResultsFifty-one patients received one of the following treatments: ISIS-CRP_Rx 100 mg, n = 12; 200 mg, n = 13, 400 mg, n = 14; placebo n = 12. In the ISIS-CRP_Rx treatment groups there were dose-dependent reductions in hs-CRP. At Day 36 the mean percent change from baseline was: placebo: −14.4%; ISIS-CRP_Rx 100 mg: −19.5%; 200 mg: −56.6% and 400 mg: −76.7%, (P = 0.0015 placebo compared to 400 mg). There were no differences between treatment groups and placebo in the ACR20 at Day 36 or Day 92. There were no serious infections and no elevations in liver function tests, lipids, creatinine or other lab abnormalities related to ISIS-CRP_Rx.ConclusionsIn this study, ISIS-CRP_Rx selectively reduced hs-CRP in a dose-dependent manner, and was well-tolerated in patients with RA. Its utility as a therapy in RA remains unclear.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01414101","term_id":"NCT01414101"}}NCT01414101. Registered 21 July 2011.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0578-5) contains supplementary material, which is available to authorized users.     

Bony Healing of Unstable Thoracolumbar Burst Fractures in the Elderly Using Percutaneously Applied Titanium Mesh Cages and a Transpedicular Fixation System with Expandable Screws

IntroductionThere is a high incidence of vertebral burst fractures following low velocity trauma in the elderly. Treatment of unstable vertebral burst fractures using the same principles like in stable vertebral burst fractures may show less favourable results in terms of fracture reduction, maintenance of reduction and cement leakage. In order to address these shortcomings this study introduces cementless fixation of unstable vertebral burst fractures using internal fixators and expandable intravertebral titanium mesh cages in a one-stage procedure via minimum-invasive techniques.ResultsStabilization of the collapsed vertebral body was achieved in all 16 cases without any intraoperative complication. Surgical time averaged 102±6.6 minutes (71–194). The postoperative kyphotic angle (KA) and Cobb angle revealed significant improvements (KA 13.7° to 7.4°, p<0.001; Cobb 9.6° to 6.0°, p<0.002) with partial loss of reduction at final follow-up (KA 8.3°, Cobb 8.7°). VAS (Visual Analogue Scale) improved from 7.6 to 2.6 (p<0.001). Adjacent fractures were not observed. One minor (malposition of pedicle screw) complication was encountered.ConclusionCementless fixation of osteoporotic burst fractures revealed substantial pain relief, adequate maintenance of reduction and a low complication rate. Bony healing after unstable osteoporotic burst fractures is possible.

Trial Registration

www.germanctr.de DRKS00005657     

Emergency medical services evaluations for chest pain during first COVID-19 lockdown in Hollands-Midden,the Netherlands

ObjectiveTo assess whether the COVID-19 lockdown in 2020 had negative indirect health effects, as people seem to have been reluctant to seek medical care.MethodsAll emergency medical services (EMS) transports for chest pain or out-of-hospital cardiac arrest (OHCA) in the Dutch region Hollands-Midden (population served > 800,000) were evaluated during the initial 6 weeks of the COVID-19 lockdown and during the same time period in 2019. The primary endpoint was the number of evaluated chest pain patients in both cohorts. In addition, the number of EMS evaluations of ST-elevation myocardial infarction (STEMI) and OHCA were assessed.ResultsDuring the COVID-19 lockdown period, the EMS evaluated 927 chest pain patients (49% male, age 62 ± 17 years) compared with 1041 patients (51% male, 63 ± 17 years) in the same period in 2019, which corresponded with a significant relative risk (RR) reduction of 0.88 (95% confidence interval (CI) 0.81–0.96). Similarly, there was a significant reduction in the number of STEMI patients (RR 0.52, 95% CI 0.32–0.85), the incidence of OHCA remained unchanged (RR 1.23, 95% CI 0.83–1.83).ConclusionDuring the first COVID-19 lockdown, there was a significant reduction in the number of patients with chest pain or STEMI evaluated by the EMS, while the incidence of OHCA remained similar. Although the reason for the decrease in chest pain and STEMI consultations is not entirely clear, more attention should be paid to the importance of contacting the EMS in case of suspected cardiac symptoms in possible future lockdowns.Supplementary InformationThe online version of this article (10.1007/s12471-021-01545-y) contains supplementary material, which is available to authorized users.     

The Safety and Pharmacokinetics of Carprofen,Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure

The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern.     

Safety and feasibility of umbilical cord mesenchymal stem cells in patients with COVID‐19 pneumonia: A pilot study

ObjectivesWe aim to explore the safety and feasibility of umbilical cord mesenchymal stem cells (UC‐MSCs) transplantation in patients with severe and critically severe coronavirus disease‐2019 (COVID‐19).MethodsWe conducted a small sample, single arm, pilot trial. In addition to standard therapy, we performed four rounds of transplantation of UC‐MSCs in sixteen patients with severe and critically severe COVID‐19. We recorded adverse events from enrolment to Day 28. We evaluated the oxygenation index, inflammatory biomarkers, radiological presentations of the disease and lymphocyte subsets count on the 7th day (D7 ± 1 day), the 14th day (D14 ± 1 day) and the 28th day (D28 ± 3 days).ResultsThere were no infusion‐related or allergic reactions. The oxygenation index was improved after transplantation. The mortality of enrolled patients was 6.25%, whereas the historical mortality rate was 45.4%. The level of cytokines estimated varied in the normal range, the radiological presentations (ground glass opacity) were improved and the lymphocyte count and lymphocyte subsets (CD4⁺ T cells, CD8⁺ T cells and NK cells) count showed recovery after transplantation.ConclusionsIntravenous transplantation of UC‐MSCs was safe and feasible for treatment of patients with severe and critically severe COVID‐19 pneumonia.