ELLIPSE Study: A Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia

Background: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable. Primary objective: To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray. Methodology: Phase 1, randomized, double-blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg. Results: A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study. Conclusion: Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy. Trial Registration: ClinicalTrials.gov Identifier #{"type":"clinical-trial","attrs":{"text":"NCT01507480","term_id":"NCT01507480"}}NCT01507480     

Dose – response relationship of bevacizumab in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI <4 L/min/m² at 24 months, respectively. The fraction of patients with <20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis.     

Dose – response relationship of bevacizumab in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI <4 L/min/m² at 24 months, respectively. The fraction of patients with <20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis.     

Systemic Effects of Fluticasone Nasal Spray: Report of 2 Cases

ObjectiveTo describe two clinical cases of systemic side effects from use of fluticasone nasal spray.MethodsA retrospective review of medical records of two patients using this drug was undertaken, and their clinical presentations and laboratory data are summarized.ResultsDespite many clinical reports about the potential side effects from inhaled corticosteroids, no previously published clinical reports or studies have addressed such problems with the use of potent glucocorticoid nasal sprays. Two patients are described in whom different clinical problems developed after overuse of fluticasone nasal spray, a commonly advertised and prescribed drug. One patient was admitted to the hospital with symptoms of adrenal insufficiency. In the other patient, bone mineral density decreased substantially in 1 to 2 years despite preventive estrogen therapy. These patients had suppressed plasma or urinary cortisol, a low plasma adrenocorticotropic hormone (corticotropin) level, or an abnormal response to a cosyntropin stimulation test.ConclusionPatients should be clearly warned that the prescribed dosing for fluticasone nasal spray should be carefully followed because overuse may cause serious side effects. (Endocr Pract. 2005;11:194-196)     

Bevacizumab,an anti-vascular endothelial growth factor antibody,inhibits osteoarthritis

Introduction

Angiogenesis is an important factor in the development of osteoarthritis (OA). We investigated the efficacy of bevacizumab, an antibody against vascular endothelial growth factor and an inhibitor of angiogenesis, in the treatment of OA using a rabbit model of anterior cruciate ligament transection.

Methods

First, we evaluated the response of gene expression and histology of the normal joint to bevacizumab treatment. Next, in a rabbit model of OA induced by anterior cruciate ligament transection, we used macroscopic and histological evaluations and real-time polymerase chain reaction (PCR) to examine the responses to intravenous (systemic) administration of bevacizumab (OAB IV group). We also investigated the efficacy of intra-articular (local) administration of bevacizumab in OA-induced rabbits (OAB IA group).

Results

Histologically, bevacizumab had no negative effect in normal joints. Bevacizumab did not increase the expression of genes for catabolic factors in the synovium, subchondral bone, or articular cartilage, but it increased the expression of collagen type 2 in the articular cartilage. Macroscopically and histologically, the OAB IV group exhibited a reduction in articular cartilage degeneration and less osteophyte formation and synovitis compared with the control group (no bevacizumab; OA group). Real-time PCR showed significantly lower expression of catabolic factors in the synovium in the OAB IV group compared with the OA group. In articular cartilage, expression levels of aggrecan, collagen type 2, and chondromodulin-1 were higher in the OAB IV group than in the OA group. Histological evaluation and assessment of pain behaviour showed a superior effect in the OAB IA group compared with the OAB IV group 12 weeks after administration of bevacizumab, even though the total dosage given to the OAB IA group was half that received by the OAB IV group.

Conclusions

Considering the dosage and potential adverse effects of bevacizumab, the local administration of bevacizumab is a more advantageous approach than systemic administration. Our results suggest that intra-articular bevacizumab may offer a new therapeutic approach for patients with post-traumatic OA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0427-y) contains supplementary material, which is available to authorized users.     

Nicotine nasal spray with nicotine patch for smoking cessation: randomised trial with six year follow up

ObjectiveTo evaluate the efficacy of using a nicotine patch for 5 months with a nicotine nasal spray for 1 year.DesignPlacebo controlled, double blind trial.SettingReykjavik health centre.Subjects237 smokers aged 22-66 years living in or around Reykjavik.InterventionsNicotine patch for 5 months with nicotine nasal spray for 1 year (n=118) or nicotine patch with placebo spray (n=119). Treatment with patches included 15 mg of nicotine for 3 months, 10 mg for the fourth month, and 5 mg for the fifth month, whereas nicotine in the nasal spray was available for up to 1 year. Both groups received supportive treatment.ResultsThe log rank test for 6 years (χ²=8.5, P=0.004) shows a significant association between abstinence from smoking and type of treatment. Sustained abstinence rates for the patch and nasal spray group and patch only group were 51% v 35% after 6 weeks (P=0.011 (χ²), 95% confidence interval 1.17% to 3.32%), 37% v 25% after 3 months (P=0.045, 1.01% to 3.08%), 31% v 16% after 6 months (P=0.005, 1.27% to 4.50%), 27% v 11% after 12 months (P=0.001, 1.50% to 6.14%), and 16% v 9% after 6 years (P=0.077, 0.93% to 4.72%).ConclusionsShort and long term abstinence rates show that the combination of using a nicotine patch for 5 months with a nicotine nasal spray for 1 year is a more effective method of stopping smoking than using a patch only. The low percentage of participants using the nasal spray at 1 year, and the few relapses during the second year, suggest that it is not cost effective to use a nasal spray for longer than 7 months after stopping a patch.

Key messages

• Combined methods of nicotine replacement therapy have a potential advantage over one method because of high levels of substitution
• Nicotine patches release nicotine slowly, but nicotine nasal spray delivers nicotine more rapidly, enabling the smoker to respond quickly to any smoking urges
• Treatment with a patch and nicotine nasal spray was significantly more effective than patch and placebo from day 15 after stopping smoking
• Using a patch for 5 months with a nicotine nasal spray for 1 year provides a more effective means of stopping smoking than using a patch only
• It is not cost effective to use a nicotine nasal spray for longer than 7 months after stopping a patch

     

基于血清IgE水平及嗅功能变化探究奥马珠单抗在变应性鼻炎患者中的应用价值

摘要 目的：探究基于血清IgE水平及嗅功能变化探究奥马珠单抗在变应性鼻炎患者中的应用价值。方法：选取2021年1月-2022年12月期间我院就诊80例的变应性鼻炎患者,并按照单双号法随机分为观察组（应用奥马珠单抗治疗,40例）和对照组（应用常规药物治疗,40例）。比较两组患者治疗3个月后的临床疗效及治疗期间不良反应（鼻出血、口咽干、鼻腔干）;比较两组患者治疗前和治疗3个月后的免疫功能（血清IgE、CD3⁺、CD4⁺、CD8⁺）、鼻内镜检查结果（炎性渗出、水肿、囊泡）、嗅功能变化和生活质量[鼻结膜炎生活质量量表（RQLQ）]。结果：治疗3个月后,观察组的临床疗效显著高于对照组（P<0.05）;两组不良反应发生率比较差异无统计学意义（P>0.05）。治疗3个月后,两组的IgE、CD8⁺水平、鼻内镜检查结果和RQLQ评分均较治疗前显著降低,且观察组显著低于对照组（P均<0.05）;两组的CD3⁺、CD4⁺水平和嗅功能均较治疗前显著提高,且观察组显著高于对照组（P均<0.05）。结论：奥马珠单抗能够有效减轻患者的症状、改善免疫功能,同时显著提高患者的嗅功能,具有良好的安全性,对患者的生活质量有着积极的影响。     

Efficacy and tolerability of levocabastine and azelastine nasal sprays for the treatment of allergic rhinitis

Levocabastine and azelastine are currently the only antihistamines available as nasal sprays for the topical therapy of seasonal allergic rhinitis. The present study was undertaken to compare the onset of action, efficacy and tolerability of these two agents in a total of 242 patients with this condition. This was an international, multicentre, open-label, randomized, parallel-group trial with 123 patients treated with levocabastine (0.5 mg/ml, two puffs per nostril twice daily) and 119 with azelastine (1 mg/ml, one puff per nostril twice daily). Onset of action was comparable for the two drugs with over 50% of patients in each group reporting significant symptomatic relief within 30 min of administration of the first dose of study medication. Therapeutic efficacy was also found to be comparable in the two groups with no statistically significant intergroup differences reported for any of the parameters evaluated, although assessments of global therapeutic efficacy revealed a trend favouring levocabastine. Levocabastine appeared to be better tolerated than azelastine (p = 0.06), with the incidence of the most common adverse experiences, application site reactions and taste disturbances, significantly higher on azelastine than with levocabastine (5% versus 1%; p = 0.05 and 5% versus 0%; p = 0.01, respectively). In conclusion, levocabastine nasal spray appears to be at least as effective as, but better tolerated than, azelastine nasal spray for the treatment of seasonal allergic rhinitis.     

Monitoring Monoclonal Antibody Delivery in Oncology: The Example of Bevacizumab

Developing therapeutic monoclonal antibodies paves the way for new strategies in oncology using targeted therapy which should improve specificity. However, due to a lack of biomarkers, a personalized therapy scheme cannot always be applied with monoclonal antibodies. As a consequence, the efficacy or side effects associated with this type of treatment often appear to be sporadic. Bevacizumab is a therapeutic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). It is used to limit tumor vascularization. No prognosis or response biomarker is associated with this antibody, we therefore assessed whether the administration protocol could be a possible cause of heterogeneous responses (or variable efficacy). To do this, we developed a bevacizumab assay with a broad sensitivity range to measure blood bevacizumab concentrations. We then analyzed bevacizumab concentrations in 17 patients throughout the first quarter of treatment. In line with previously published data, average blood concentrations were 88+/−27 mg/L following the first dose administered, and 213+/−105 mg/L after the last (6^th) dose administered. However, the individual values were scattered, with a mean 4-fold difference between the lowest and the highest concentration for each dose administered. We demonstrated that the bevacizumab administration schedule results in a high inter-individual variability in terms of blood concentrations. Comparison of assay data with clinical data indicates that blood concentrations above the median are associated with side effects, whereas values below the median favor inefficacy. In conclusion, bevacizumab-based therapy could benefit from a personalized administration schedule including follow-up and adjustment of circulating bevacizumab concentrations.     

孟鲁司特钠联合左卡巴斯汀鼻喷剂治疗小儿过敏性鼻炎的疗效评价及对血清ECP、EOS及CRP水平的影响

目的:探讨孟鲁司特钠联合左卡巴斯汀鼻喷剂治疗小儿过敏性鼻炎的疗效及对血清嗜酸性粒细胞阳离子蛋白(ECP)、嗜酸性粒细胞(EOS)及C反应蛋白(CRP)水平的影响。方法:选择我院2016年7月～2018年7月收治的151例过敏性鼻炎患儿,按随机数字表法分为69例对照组和82例观察组,对照组采用左卡巴斯汀鼻喷剂治疗,观察组在对照组基础上联合孟鲁司特钠治疗,比较两组临床疗效,治疗前后症状及体征评分,生活质量评分,血清ECP、EOS及CRP、总免疫球蛋白E(TIg E)和特异性免疫球蛋白E(Sig E)水平,和不良反应发生情况。结果:观察组总有效率高于对照组,差异有统计学意义(P0.05)。治疗前,两组症状及体征评分,生活质量评分,血清ECP、EOS及CRP、总免疫球蛋白E(TIg E)和特异性免疫球蛋白E(Sig E)水平比较差异无统计学意义(P0.05);治疗后,两组以上指标均下降,观察组低于对照组,差异均有统计学意义(均P0.05)。两组均有胃肠道反应、口干、头痛发生,组间总不良反应发生率比较无统计学差异(P0.05)。结论:孟鲁司特钠联合左卡巴斯汀鼻喷剂治疗小儿过敏性鼻炎安全有效,能够降低血清ECP、EOS及CRP水平,促进患儿恢复。     

Clinical Implication of UGT1A1 Promoter Polymorphism for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Patients Treated with Bevacizumab Combined with FOLFIRI in the First-line Setting

PURPOSE: This study aimed to identify the efficacy and toxicity of the FOLFIRI regimen (fluorouracil, leucovorin, and irinotecan) with irinotecan dose escalation plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC) via UGT1A1 genotyping. METHODS: We administered bevacizumab plus FOLFIRI with irinotecan dose escalation to treat 70 mCRC patients. The UGT1A1 *1/*1 and *1/*28 genotypes started with a 180-mg/m² dose of irinotecan, and UGT1A1 *28/*28 genotype started with a dose of 120 mg/m². The dose of irinotecan was escalated at increasing intervals of 20 to 30 mg/m² until grade 3/4 adverse events (AEs) occurred. The clinical response rate, toxicity, and survival were analyzed. RESULTS: The clinical response and disease control rates of mCRC patients treated with FOLFIRI plus bevacizumab were significantly better in patients with UGT1A1 *1/*1 and *1/*28 genotypes than in patients with UGT1A1 *28/*28 (P = .006 and P < .001, respectively). Grade 3/4 AEs were significantly more common in mCRC patients with the UGT1A1 *28/*28 genotype (P < .001). Progression-free survival was significantly higher in UGT1A1 *1/*1 and *1/*28 patients (P = .002). mCRC patients who underwent metastasectomy achieved better overall survival than those who did not undergo metastasectomy (P = .015). CONCLUSIONS: Our study showed that mCRC patients with UGT1A1 *1/*1 and *1/*28 genotypes could receive escalated doses of irinotecan to obtain a more favorable clinical outcome without significant AEs.     

西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的有效性和安全性比较

目的:比较西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的有效性和安全性。方法:选取2014年1月～2017年8月我院收治的晚期结直肠癌患者100例,根据患者入院先后顺序随机分为两组,所有患者均给予FOLFIRI方案进行化疗,A组在化疗的基础上给予贝伐珠单抗进行治疗,B组在化疗的基础上给予西妥昔单抗进行治疗。比较两组患者临床治疗的缓解率、控制率及不良反应的发生情况,对所有患者随访1年,记录并比较两组患者的无进展生存期。结果:两组患者的缓解率、控制率、恶心呕吐、头晕、延迟性腹泻、肝肾损伤、白细胞减少、血小板减少和尿蛋白的发生率相比均无统计学差异(P0.05),但B组患者骨髓抑制和皮疹的发生率显著高于A组(P0.05);两组患者的无进展生存期相比无统计学差异(P0.05)。结论:西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的临床效果相当,且不良反应较轻,以Ⅰ～Ⅱ度为主,患者均可耐受,对症治疗后均有所缓解。西妥昔单抗易引发骨髓抑制和皮疹,在临床应用过程中需注意并进行有效预防和积极处理。     

Effects of Nasal Corticosteroids on Boosts of Systemic Allergen-Specific IgE Production Induced by Nasal Allergen Exposure

BackgroundAllergen exposure via the respiratory tract and in particular via the nasal mucosa boosts systemic allergen-specific IgE production. Intranasal corticosteroids (INCS) represent a first line treatment of allergic rhinitis but their effects on this boost of allergen-specific IgE production are unclear.AimHere we aimed to determine in a double-blind, placebo-controlled study whether therapeutic doses of an INCS preparation, i.e., nasal fluticasone propionate, have effects on boosts of allergen-specific IgE following nasal allergen exposure.MethodsSubjects (n = 48) suffering from grass and birch pollen allergy were treated with daily fluticasone propionate or placebo nasal spray for four weeks. After two weeks of treatment, subjects underwent nasal provocation with either birch pollen allergen Bet v 1 or grass pollen allergen Phl p 5. Bet v 1 and Phl p 5-specific IgE, IgG_1–4, IgM and IgA levels were measured in serum samples obtained at the time of provocation and one, two, four, six and eight weeks thereafter.ResultsNasal allergen provocation induced a median increase to 141.1% of serum IgE levels to allergens used for provocation but not to control allergens 4 weeks after provocation. There were no significant differences regarding the boosts of allergen-specific IgE between INCS- and placebo-treated subjects.ConclusionIn conclusion, the application of fluticasone propionate had no significant effects on the boosts of systemic allergen-specific IgE production following nasal allergen exposure.

Trial Registration

http://clinicaltrials.gov/ {"type":"clinical-trial","attrs":{"text":"NCT00755066","term_id":"NCT00755066"}}NCT00755066     

鼻内镜术与鼻息肉摘除术对鼻窦炎合并鼻息肉患者的鼻腔通气功能、嗅觉功能和生活质量的影响

目的:探讨鼻内镜术与鼻息肉摘除术对鼻窦炎合并鼻息肉患者的鼻腔通气功能、嗅觉功能和生活质量的影响。方法:选取2016年1月-2017年8月期间我院收治的94例鼻窦炎合并鼻息肉患者。根据数表法将患者随机分为对照组(n=47)与研究组(n=47),其中对照组患者行传统鼻息肉摘除术,研究组则行鼻内镜术。观察两组患者临床疗效、临床指标及并发症发生情况,比较两组患者术前、术后6个月鼻腔通气功能、嗅觉功能和生活质量评分。结果:研究组临床总有效率为91.49%(43/47),高于对照组的65.96%(31/47)(P0.05)。研究组患者手术时间、术后住院时间、术中出血量均低于对照组(P0.05)。两组患者术后6个月鼻腔通气功能、嗅觉功能评分均较术前降低,且研究组低于对照组(P0.05)。两组患者术后6个月躯体功能(PF)、躯体角色(RP)、躯体疼痛(BP)、总体健康(GH)、情感角色(RE)以及心理健康(MH)均较术前升高,且研究组高于对照组(P0.05)。研究组头晕、头痛、流脓涕、鼻塞、复发等并发症发生率均低于对照组(P0.05)。结论:鼻窦炎合并鼻息肉患者采用鼻内镜术治疗,疗效确切,可显著改善患者临床指标、生活质量,对患者鼻腔通气功能、嗅觉功能均有促进作用,且术后并发症少,值得临床推广。     

Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis

IntroductionRecently, studies have demonstrated that the addition of bevacizumab to chemotherapy could be associated with better outcomes in patients with advanced non-small cell lung cancer (NSCLC). However, the benefit seems to be dependent on the drugs used in the chemotherapy regimens. This systematic review evaluated the strength of data on efficacy of the addition of bevacizumab to chemotherapy in advanced NSCLC.MethodsPubMed, EMBASE, and Cochrane databases were searched. Eligible studies were randomized clinical trials (RCTs) that evaluated chemotherapy with or without bevacizumab in patients with advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS), response rate (RR), toxicities and treatment related mortality. Hazard ratios (HR) and odds ratios (OR) were used for the meta-analysis and were expressed with 95% confidence intervals (CI).ResultsWe included results reported from five RCTs, with a total of 2,252 patients included in the primary analysis, all of them using platinum-based chemotherapy regimens. Compared to chemotherapy alone, the addition of bevacizumab to chemotherapy resulted in a significant longer OS (HR 0.89; 95% CI 0.79 to 0.99; p = 0.04), longer PFS (HR 0.73; 95% CI 0.66 to 0.82; p<0.00001) and higher response rates (OR 2.34; 95% CI 1.89 to 2.89; p<0.00001). We found no heterogeneity between trials, in all comparisons. There was a slight increase in toxicities in bevacizumab group, as well as an increased rate of treatment-related mortality.ConclusionsThe addition of bevacizumab to chemotherapy in patients with advanced NSCLC prolongs OS, PFS and RR. Considering the toxicities added, and the small absolute benefits found, bevacizumab plus platinum-based chemotherapy can be considered an option in selected patients with advanced NSCLC. However, risks and benefits should be discussed with patients before decision making.     

Efficacy of a Carrageenan nasal spray in patients with common cold: a randomized controlled trial

Background

The common cold is the most widespread viral infection in humans. Iota-carrageenan has previously shown antiviral effectiveness against cold viruses in clinical trials. This study investigated the efficacy of a carrageenan-containing nasal spray on the duration of the common cold and nasal fluid viral load in adult patients.

Methods

In a randomized, double-blind, placebo-controlled trial, 211 patients suffering from early symptoms of the common cold were treated for seven days. Application was performed three times daily with either a carrageenan-supplemented nasal spray or saline solution as placebo with an overall observation period of 21 days. The primary endpoint was the duration of disease defined as the time until the last day with symptoms followed by all other days in the study period without symptoms. During the study, but prior unblinding, the definition of disease duration was adapted from the original protocol that defines disease duration as the time period of symptoms followed by 48 hours without symptoms.

Results

In patients showing a laboratory-confirmed cold virus infection and adherence to the protocol, alleviation of symptoms was 2.1 days faster in the carrageenan group in comparison to placebo (p = 0.037). The primary endpoint that had been prespecified but was changed before unblinding was not met. Viral titers in nasal fluids showed a significantly greater decrease in carrageenan patients in the intention-to-treat population (p = 0.024) and in the per protocol population (p = 0.018) between days 1 and 3/4.

Conclusions

In adults with common cold virus infections, direct local administration of carrageenan with nasal sprays reduced the duration of cold symptoms. A significant reduction of viral load in the nasal wash fluids of patients confirmed similar findings from earlier trials in children and adults.

Trial registration

Current Controlled Trials ISRCTN80148028     

A Safety Review and Meta-Analyses of Bevacizumab and Ranibizumab: Off-Label versus Goldstandard

Background

We set out a systemic review to evaluate whether off-label bevacizumab is as safe as licensed ranibizumab, and whether bevacizumab can be justifiably offered to patients as a treatment for age-related macular degeneration with robust evidence of no differential risk.

Methods and Findings

Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. We included RCTs with a minimum follow-up of one year which investigated bevacizumab or ranibizumab in direct comparison or against any other control group (indirect comparison). Direct comparison (3 trials, 1333 patients): The one year data show a significantly higher rate of ocular adverse effects (AE) with bevacizumab compared to ranibizumab (RR = 2.8; 95% CI 1.2–6.5). The proportion of patients with serious infections and gastrointestinal disorders was also higher with bevacizumab than with ranibizumab (RR = 1.3; 95% CI 1.0–1.7). Arterial thromboembolic events were equally distributed among the groups. Indirect comparison: Ranibizumab versus any control (5 trials, 4054 patients): The two year results of three landmark trials showed that while absolute rates of serious ocular AE were low (≤2.1%), relative harm was significantly raised (RR = 3.1; 95% CI 1.1–8.9). A significant increase in nonocular haemorrhage was also observed with ranibizumab (RR = 1.7; 95% CI 1.1–2.7). Bevacizumab versus any control (3 trials, 244 patients): We were unable to judge the safety profile of bevacizumab due to the poor quality of AE monitoring and reporting in the trials.

Conclusions

Evidence from head-to-head trials raises concern about an increased risk of ocular and multiple systemic AE with bevacizumab. Therefore, clinicians and patients should continue to carefully weight up the benefits and harms when choosing between the two treatment options. We also emphasize the need for studies that are powered not just for efficacy, but for defined safety outcomes based on the signals detected in this systematic review.     

鼻窦内镜术治疗鼻窦炎合并鼻息肉的疗效及对鼻腔通气和嗅觉功能的影响

目的:探讨鼻窦内镜术治疗鼻窦炎合并鼻息肉的临床疗效及对鼻腔通气和嗅觉功能的影响。方法:选取2014年1月至2016年6月我院收治的鼻窦炎合并鼻息肉患者80例。根据随机数字表法分为观察组和对照组,各40例。对照组给予传统摘除术治疗,观察组则行鼻窦内镜术治疗。比较两组临床疗效以及治疗前、治疗后3个月症状评分、鼻气道总阻力、嗅觉功能评分。结果:观察组治疗总有效率为95.00%,显著高于对照组的77.50%(P0.05)。治疗前两组患者鼻塞、脓涕、嗅觉障碍、疼痛及总症状评分比较无统计学差异(P0.05),治疗后3个月两组患者鼻塞、脓涕、嗅觉障碍、疼痛及总症状评分均低于治疗前,且观察组患者鼻塞、脓涕、嗅觉障碍、疼痛及总症状评分低于对照组(P0.05)。治疗前两组患者鼻气道总阻力、嗅觉功能评分比较无统计学差异(P0.05),治疗后3个月两组患者鼻气道总阻力、嗅觉功能评分均低于治疗前,且观察组低于对照组(均P0.05)。结论:鼻窦内镜术治疗鼻窦炎合并鼻息肉有利于改善患者临床症状,促进患者嗅觉功能以及鼻腔通气的恢复,是治疗鼻窦炎合并鼻息肉的有效方法。     

鼻内镜下电凝结合微填塞治疗难治性鼻出血

目的：探讨鼻内镜下电凝止血结合明胶海绵微填塞治疗难治性鼻出血的临床特征和疗效。方法：回顾性分析我院2011 年1 月至2015 年1 月收治的203 例难治性鼻出血患者的临床资料,探讨发病季节、发病年龄、出血部位以及发病年龄与出血部位的 相关性。结果：203 例患者经鼻内镜下电凝止血结合明胶海绵微填塞治疗,全部治愈,其发病特征具有明显的季节性,40~60 岁多 见（41.9%）,下鼻道出血最常见（30.0%）,老年人以鼻腔后下部位出血为主,青中年以鼻腔前上部位出血为主。结论：鼻内镜下电凝 结合微填塞治疗难治性鼻出血微创、安全、有效,值得推广。     

Faster onset of action with topical levocabastine than with oral cetirizine

This international multicentre, open-label, parallel-group trial was undertaken to compare the therapeutic efficacy and tolerability of topical levocabastine and oral cetirizine in patients with perennial allergic rhinoconjunctivitis, with particular reference to the comparative onset of action of the two drugs. A total of 207 patients were randomized to receive either levocabastine nasal spray (0.5 mg/ml, two sprays in each nostril twice daily) plus levocabastine eye drops as required (0.5 mg/ml, one drop in each eye twice daily p.r.n.) or cetirizine orally (10 mg once daily) with a treatment duration of 2 weeks. Onset of action was found to be significantly more rapid with levocabastine than with cetirizine for both nasal and ocular symptoms (p < 0.001). Within 15 min of study drug administration, 36% of levocabastine-treated patients reported relief from nasal symptoms and 32% relief from ocular symptoms compared with 10% and 17% of patients on cetirizine, respectively. At 1 h, the percentages of patients reporting relief were 76% and 38% for nasal symptoms, and 81% and 48% for ocular symptoms in the levocabastine and cetirizine treatment groups, respectively. At 8 h there were no differences between the two treatments. Overall therapeutic efficacy was found to be comparable in the two treatment groups over the 2-week study period with no significant intergroup differences in symptom severity or global therapeutic efficacy. Both drugs were well tolerated with no significant differences in the incidence or type of adverse reactions between the two groups. In conclusion, levocabastine eye drops and nasal spray are as effective and well tolerated as oral cetirizine for the treatment of perennial allergic rhinoconjunctivitis with the advantage of a significantly faster onset of action for both nasal and ocular symptoms.