Etanercept-induced injection site reactions: potential pathomechanisms and clinical assessment

Introduction: Etanercept (ETN) is a tumor necrosis factor alpha (TNF-α) antagonist used for the treatment of chronic inflammatory disorders. Injection site reactions (ISRs) are reported to be the most common adverse event of ETN therapy. While their mechanisms are not completely understood, the occurrence of ETN-ISRs could indicate a risk of systemic immune-mediated severe adverse drug reactions.

Areas covered: Based on two cases and a review of the literature, the characteristics and frequency of ETN-ISRs were assessed. This article discusses their potential mechanisms and clinical relevance, and provides recommendations for the management of patients presenting with ETN-ISRs.

Expert opinion: Basically, irritative and immune-mediated ISRs may be distinguished. The formation of anti-drug antibodies (ADAs) may promote immune-mediated ISRs that likely represent either anaphylactic type I reactions, or cutaneous Arthus-like type III reactions according to the Coombs and Gell classification. A differentiation between these reactions by clinical course and etanercept-skin testing may help to decide if ETN treatment should be stopped to avoid the development of more severe adverse drug reactions if ISRs occur.     

Subcutaneous delivery of biotherapeutics: challenges at the injection site

Introduction: Biotherapeutics are primarily delivered subcutaneously due to better compliance and prolonged rate of absorption compared to other parenteral administration routes. Recent research has allowed for the development of biotherapeutic formulations for subcutaneous delivery that require a lower frequency of administration by increasing drug half-life. Formulations determine shelf-life stability as well as features and transient behaviors that influence stability once implanted in the subcutaneous space.

Areas covered: This review provides an overview of the factors affecting subcutaneous absorption with a focus on transient effects at the injection site following administration of biotherapeutics and the subsequent impact on absorption and stability.

Expert opinion: Advances have been made in understanding subcutaneous tissue and the complex interplay of factors that regulate its homeostasis. The issue of poor stability after injection has been neglected, and many biotherapeutics are hampered by low bioavailability. With the advent of new in vitro techniques that account for properties of the injection site, stability studies evaluating subcutaneous tissues and impacts on pharmacokinetics of biotherapeutics may be useful in the development of new formulations.     

Insulin administration: selecting the appropriate needle and individualizing the injection technique

INTRODUCTION: Patients with diabetes who receive insulin therapy often fail to meet their targets for metabolic control with insulin injections. Their inadequate glycemic control may be related to incorrect injection procedure. AREAS COVERED: This review examines the latest data related to insulin injection and needle characteristics, which play an integral role in patient satisfaction. Searches of Medline and Cumulative Index to Nursing and Allied Health Literature databases were conducted. Results show that optimal insulin injection can facilitate glycemic control in pediatric and adult patients. In general, needles shorter than 8 mm are appropriate for normal weight, obese pediatric and adult patients. However, body mass index, gender, race, age and injection site can influence the depth of subcutaneous tissue and thus, the desired needle size and injection technique. Although the abdomen, thighs and buttocks are all recommended injection sites, abdominal injections disperse insulin slightly more rapidly than thigh injections. EXPERT OPINION: Wider acceptance of needles shorter than 6 mm will occur with more evidence of their safety and efficacy, particularly in children. Development of shorter and thinner needles to make injections even easier and less burdensome may be expected in the future.     

Insulin administration: selecting the appropriate needle and individualizing the injection technique

Introduction: Patients with diabetes who receive insulin therapy often fail to meet their targets for metabolic control with insulin injections. Their inadequate glycemic control may be related to incorrect injection procedure.

Areas covered: This review examines the latest data related to insulin injection and needle characteristics, which play an integral role in patient satisfaction. Searches of Medline and Cumulative Index to Nursing and Allied Health Literature databases were conducted. Results show that optimal insulin injection can facilitate glycemic control in pediatric and adult patients. In general, needles shorter than 8 mm are appropriate for normal weight, obese pediatric and adult patients. However, body mass index, gender, race, age and injection site can influence the depth of subcutaneous tissue and thus, the desired needle size and injection technique. Although the abdomen, thighs and buttocks are all recommended injection sites, abdominal injections disperse insulin slightly more rapidly than thigh injections.

Expert opinion: Wider acceptance of needles shorter than 6 mm will occur with more evidence of their safety and efficacy, particularly in children. Development of shorter and thinner needles to make injections even easier and less burdensome may be expected in the future.     

Identification and determination of GnRH antagonist gelling at injection site

The purpose of this study was to first observe whether orntide, a GnRH antagonist, gels at the injection site and if so, to develop and validate an extraction method to quantitate the peptide amount as well as assess chemical stability in the gel. After subcutaneous injection of a large dose of orntide acetate solution, a white gel and local traumatized effect were observed at the injection site. Orntide remaining at the injection site was recovered by tissue excision, homogenization and tissue protein precipitation with perchloric acid and quantified by high performance liquid chromatography (HPLC) following separation on a C18 column. The standard curve was linear in the detection range and there was no interference from either blank tissue or excipients of the orntide formulation. The recovery from spiked tissue or that immediately following injection was in the range of 90-110%. MALDI-FT mass spectrometry (MS) of the peak fraction indicated that the orntide recovered from the injection site was in the intact form. The results showed that orntide solution, when injected at a large dose, formed a gel at the injection site. The gel delayed the release from the injection site and caused discernible tissue reaction.     

The ever-changing narrative: Supervised injection site policy making in Ontario,Canada

BackgroundWe analyze the ongoing debate surrounding supervised injection sites in Ontario, Canada and changing policies that impact host communities. Despite a plethora of evidence proving the effectiveness of supervised injection sites on harm reduction strategy, the topic remains highly controversial with constantly changing rhetoric in the Ontario drug policy landscape.MethodsWe reviewed government reports, policies, and media sources spanning from prior to the establishment of the first Canadian supervised injection site in 2000 to early 2019, adopting an advocacy coalition framework approach to this policy analysis. Various advocacy coalitions emerge from this analysis, including all three levels of government, law enforcement, health practitioners, and community groups. We describe the narratives constructed by these coalitions, analyzing the supervised injection site model as a harm reduction strategy within a continually shifting socio-political landscape.ResultsEmerging from the analysis are competing narratives put forward by various stakeholders within the policy subsystem. We find policy-makers tend to leverage scientific uncertainty as a tool to defend the interests of the most powerful actor in the subsystem. Despite an increase in the number of deaths due to the opioid crisis and evidence highlighting the efficacy of supervised injection sites as a harm reduction tool, various stakeholders are locked in a battle of claims and counter-claims about the appropriate policy response to opioids.ConclusionsThese findings have broad implications for drug policy in other contexts. Our case study demonstrates the strength of stopgap measures, like supervised injection, to reduce harm from controlled substances.     

苯胺洛芬注射液镇痛作用及镇痛部位研究

目的研究苯胺洛芬注射液对大鼠单足致炎急性炎症模型和大鼠单发性关节慢性病理性炎症模型的镇痛作用,并对其镇痛部位进行分析。方法通过角叉菜胶致大鼠单足致炎后的后肢压痛实验和完全弗氏佐剂致大鼠单发性关节炎性疼痛实验,测定致炎足和非致炎足痛阈值和屈伸关节评分。结果在大鼠急性炎症模型和慢性病理性炎症模型中,苯胺洛芬注射液25.2、75.6 mg·kg-1可提升致炎足的痛阈值,但对非致炎足的痛阈值无明显影响,致炎足和非致炎足痛阈值变化情况与氟比洛芬酯注射液相当,而喷他佐辛注射液对致炎足和非致炎足均有镇痛作用。结论苯胺洛芬注射液发挥镇痛作用的部位主要在外周,这与非甾体类抗炎镇痛药的作用部位相似。     

Worsening injection site reactions with continued use of etanercept

We report the case of a patient with persistent and worsening injection site reactions associated with subcutaneous etanercept therapy. Injection site reactions are well documented to occur early in therapy; however they typically decrease in frequency over time. This patient developed early injection site reactions that have persisted and worsened into his tenth month of treatment with etanercept.     

Recurrent injection site reactions from interferon beta 1-b

Recombinant human interferon beta-1b is an immune-modulatory drug used for a variety of conditions including multiple sclerosis (MS). Skin reactions to therapeutic use of injectable interferon beta-lb are relatively common, including injection site reactions and exacerbation of underlying skin disease. Injection site reactions are seen much more frequently in females. We discuss a case of prolonged susceptibility to injection site reaction with over a decade of use of interferon beta 1-b for MS. Given the prevalence of such reactions, the dermatologist should be aware of the phenomenon and that it frequently does not necessitate discontinuation of therapy.     

The tower technique and vertical supraperiosteal depot technique: novel vertical injection techniques for volume-efficient subcutaneous tissue support and volumetric augmentation

A 55-year-old Caucasian female with a past history of face-lifting surgery presented with early signs of soft tissue elastosis, volumetric deficiency in the periocular region, the nasolabial folds, the lips, and the lower face. Hyaluronic acid (HA) filler injections were performed with two novel vertical injection techniques that support and tense the subcutaneous connective tissue--the Tower Technique (TT) and the Vertical Supraperiosteal Depot Technique (VSDT). Vertical injection techniques are a volume-efficient means of delivering excellent, long-lasting results and patient satisfaction with minimal recovery time and are appropriate for volumetric augmentation even in patients who have subdermal fibrosis due to previous facial surgery.     

留置气泡技术在临床药物皮内试验操作中的运用观察

目的：通过对常规皮内注射方法与留置气泡（A-h）皮内注射法在药物皮内试验操作后并发症的对比,为临床皮内注射技术选择和改进提供依据。方法：选用需做药物皮内试验操作住的院患者126例,分别使用常规皮内注射法和A—b皮内注射法,观察并记录注射后药（血）液外溢、疼痛等不良反应发生率的情况。结果：126例患者中,A-b皮内注射法给药不良反应发生率低于常规皮内注射法给药（P〈0．05）。结论：A—b皮内注射法较常规皮内注射法所致局部不良反应发生率低,药物利用度高,更适合于临床应用。     

Insulin injection technique can be taught without hospitalization

Although hospitalization of the diabetic may be seen as a failure of management, and places the patient in an artificial situation, admission for initiation of insulin therapy is the custom in most Ethiopian hospitals. From January 1987 to January 1988, 144 diabetics were taught insulin injection technique in the Diabetic Clinic of Yekatit 12 Hospital in Addis Ababa, Ethiopia, by two nurses in early morning, six days weekly, sessions. Of these, 85 were inpatients aged 6 to 73 years from all wards, admitted because of ketoacidosis, intercurrent illnesses or rural home. The 59 outpatients, aged 7 to 70 years, attended each morning, and started therapy with 8 to 12 units of Lente insulin daily, the dose being increased every 2 or 3 days by small increments until control was attained. These outpatients needed an average of 4.7 mornings (range 1-13) to learn the technique, and an additional 3 to 4 weeks of frequent checkup to achieve control: several continued their jobs while learning. The method failed with 2 very symptomatic patients; there were no severe hypoglycaemic reactions or other complications. In addition to the financial saving for patients, and reduction of hospital bed use by diabetics, the patients helped and encouraged each other, learning faster than when taught individually as "ill" inpatients.     

克班宁注射剂原料药的质量标准研究

建立克班宁(crebanine)注射剂原料药的质量控制方法.方法:采用TLC进行定性鉴别.以RP-HPLC法Zirchrom ODS柱(250 mm×4.6 mm,15 μm)定量测定,流动相为甲醇-水-三乙胺(88:12:0.05),流速:1.0 mL·min-1,检测波长282 nm.结果:供试品与对照品在薄层板相同位置上显相同斑点;克班宁的峰面积与浓度呈线性关系,线性范围为0.9～10.8μg,r=0.999 7,平均加样回收率为99.4%～102.7%,RSD为1.3%～1.9%,10批样品含量均大于90%.结论:本法简便、准确、可靠,可作为该原料药的质量控制方法.     

Antinociceptive synergy between diclofenac and morphine after local injection into the inflamed site

BackgroundCombinations of non-steroidal anti-inflammatory drugs with opioids are frequently used to reduce opioid doses required in the clinical management of acute pain. The present study was designed to evaluate the possible antinociceptive interaction between morphine and diclofenac at peripheral level in male rats.MethodsDrugs were chosen based of their efficacy in the treatment of this kind of pain and as representative drugs of their respective analgesic groups. For the formalin test, 50 μl of 1% formalin solution was injected subcutaneously into the right hind paw. The interaction between morphine and diclofenac was evaluated by using isobolographic analysis and interaction index. Drug interaction was examined by administering fixed-ratio combinations of morphine-diclofenac (1 : 1 and 3 : 1) of their respective ED₃₀ fractions.ResultsDiclofenac and morphine reduced flinching behavior in a dose-dependent manner during phase 2 but not phase 1 of the formalin test. Isobolographic analysis showed a synergistic interaction for the combination of morphine and diclofenac after local peripheral administration.ConclusionsData suggest that the combination of morphine with diclofenac at the site of injury is synergistic and could be useful in the treatment of wounds, bruises, rheumatisms and other painful peripheral conditions associated with an inflammatory process.