First-line Symptomatic Treatment Research Articles

Anti-edematous effects of epinastine, cetirizine and its enantiomers in λ-carrageenan-induced edema in rat hind paw.

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1 -receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers' ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ -carrageenan injection, all second-generation histamine H1 -receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ -carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1 -receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine's anti-edematous activity.

Generalized myasthenia gravis with acetylcholine receptor antibodies: A guidance for treatment.

Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research. MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings. Pyridostigmine represents the first-line symptomatic treatment, while ambenonium and beta adrenergic agonists are second-line options. Early thymectomy should be undertaken if a thymoma, and in non-thymoma patients up to the age of 50-65 years if not obtaining remission on symptomatic treatment. Most patients need immunosuppressive drug treatment. Combining corticosteroids at the lowest possible dose with azathioprine is recommended, rituximab being an alternative first-line option. Mycophenolate, methotrexate, and tacrolimus represent second-line immunosuppression. Plasma exchange and intravenous immunoglobulin are used for myasthenic crises and acute exacerbations. Novel complement inhibitors and FcRn blockers are effective and fast-acting treatments with promising safety profiles. Their use depends on local availability, refunding policies, and cost-benefit analyses. Adapted physical training is recommended. Planning of pregnancies with optimal treatment, information, and awareness of neonatal MG is necessary. Social support and adaptation of work and daily life activities are recommended. Successful treatment of MG rests on timely combination of different interventions. Due to spontaneous disease fluctuations, comorbidities, and changes in life conditions, regular long-term specialized follow-up is needed. Most patients do reasonably well but there is room for further improvement. Novel treatments are promising, though subject to restricted access due to costs.

2018 APLAR axial spondyloarthritis treatment recommendations

Despite the availability of axial spondyloarthritis (SpA) recommendations proposed by various rheumatology societies, we considered that a region-specific guideline was of substantial added value to clinicians of the Asia-Pacific region, given the wide variations in predisposition to infections and other patient factors, local practice patterns, and access to treatment across countries. Systematic reviews were undertaken of English-language articles published between 2000 and 2016, identified from MEDLINE using PubMed, EMBASE and Cochrane databases. The strength of available evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Recommendations were developed through consensus using the Delphi technique. Fourteen axial SpA treatment recommendations were developed based on evidence summaries and consensus. The first 2 recommendations cover non-pharmacological approaches to management. Recommendations 3 to 5 describe the following: the use of non-steroidal anti-inflammatory drugs as first-line symptomatic treatment; the avoidance of long-term corticosteroid use; and the utility of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for peripheral or extra-articular manifestations. Recommendation 6 refers to the indications for biological DMARDs (bDMARDs). Recommendation 7 deals specifically with screening for infections endemic to Asia, prior to use of bDMARDs. Recommendations 7 to 13 cover the role of bDMARDs in the treatment of active axial SpA and include related issues such as continuing therapy and use in special populations. Recommendation 14 deals with the utility of surgical intervention in axial SpA. These recommendations provide up-to-date guidance for treatment of axial SpA to help meet the needs of patients and clinicians in the Asia-Pacific region.

Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamine.

The second-generation H1-antihistamines (sgAH) are the first-line symptomatic treatment of patients with chronic spontaneous urticaria (CSU). Up to 50% of the patients will not respond to licensed doses of sgAH. According to the guidelines, the dose of sgAH may be increased up to 4 times the conventional dose. However, even at higher doses, there is a subgroup of patients refractory to the antihistamine treatment. The purpose of this article was to review the different treatment options of antihistamine-refractory CSU patients. This revision examines the available literature for therapies used in chronic urticaria, including omalizumab, ciclosporin A, oral glucocorticoids, leukotriene receptor antagonists, H2 antihistamines, doxepin, dapsone, hydroxychloroquine, phototherapy, methotrexate, mycophenolate mofetil, azathioprine, autohemotherapy, intravenous immunoglobulins and rituximab, between others. After the exhaustive review of the medical literature only few high-quality studies have been identified, mostly for omalizumab. Omalizumab is an anti-immunoglobulin E monoclonal antibody, approved for the treatment of CSU, that has radically changed the management of the patients without good response to sgAH, allowing to reach complete responses in a high percentage of patients. Although actually the therapeutic management of CSU is more effective and safer than before 2014, there is place even for new and more effective treatments. A good number of partial responders and slow responders to omalizumab and a little percentage still of non-responders to available therapies stimulate the development of new drugs that will also be discussed.

Treatment use in a prospective naturalistic cohort of children and adolescents with catatonia.

We aimed to (1) describe the treatment used in a large sample of young inpatients with catatonia, (2) determine which factors were associated with improvement and (3) benzodiazepine (BZD) efficacy. From 1993 to 2011, 66 patients between the ages of 9 and 19 years were consecutively hospitalized for a catatonic syndrome. We prospectively collected sociodemographic, clinical and treatment data. In total, 51 (77%) patients underwent a BZD trial. BZDs were effective in 33 (65%) patients, who were associated with significantly fewer severe adverse events (p = 0.013) and resulted in fewer referrals for electroconvulsive therapy (ECT) (p = 0.037). Other treatments included ECT (N = 12, 18%); antipsychotic medications, mostly in combination; and treatment of an underlying medical condition, when possible. For 10 patients, four different trials were needed to achieve clinical improvement. When all treatments were combined, there was a better clinical response in acute-onset catatonia (p = 0.032). In contrast, the response was lower in boys (p = 0.044) and when posturing (p = 0.04) and mannerisms (p = 0.008) were present as catatonic symptoms. The treatment response was independent of the underlying psychiatric or systemic medical condition. As in adults, BZDs should be the first-line symptomatic treatment for catatonia in young patients, and ECT should be a second option. Additionally, the absence of an association between the response to treatment and the underlying psychiatric condition suggests that catatonia should be considered as a syndrome.

Profile of aminopyridines for Lambert–Eaton myasthenic syndrome

Profile of aminopyridines for Lambert–Eaton myasthenic syndrome Paul Maddison,1 Michael J Keogh,2 Saam Sedehizadeh11Department of Clinical Neurology, Queen's Medical Centre, Nottingham, UK; 2Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Newcastle upon Tyne, UKAbstract: 3,4-diaminopyridine (3,4-DAP) is an effective, symptomatic treatment for Lambert–Eaton myasthenic syndrome (LEMS). Several trials have studied the effects of 3,4-DAP in small numbers of LEMS patients. We systematically reviewed all randomized trials of 3,4-DAP in LEMS to determine the efficacy of this treatment using meta-analysis of clinical and electrophysiological end points. Data from four randomized, placebo-controlled trials revealed that muscle-strength scores increased significantly with 3,4-DAP. Limited meta-analysis performed on two trials using the quantitative myasthenia gravis score indicated that the clinical benefits seen were modest, with an improvement in quantitative myasthenia gravis score of 2.44 points (95% confidence interval: 1.2–3.6). Meta-analysis of the mean change in compound muscle action potential amplitude following 3,4-DAP treatment revealed a significant improvement compared to placebo (1.36 mV, 95% confidence interval: 0.99–1.72). 3,4-DAP is an effective, safe, first-line symptomatic treatment for LEMS, with significant clinical and electrophysiological benefits demonstrated by meta-analysis.Keywords: Lambert–Eaton myasthenic syndrome, 3,4-diaminopyridine, meta-analysis

Allergic diseases of the skin and drug allergies – 2022. Consensus statement on management of urticaria in India

Background Urticaria, a heterogeneous group of diseases, often cannot be recognized by its morphology. Due to non-specific and non-affordable diagnosis, management of urticaria, especially chronic urticaria, is very challenging. This guideline includes definition, causes, classification and management of urticaria. Urticaria has a profound impact on the quality of life and causes immense distress to patients, necessitating effective treatment. One approach to manage urticaria is identification and elimination of the underlying cause(s) and/or eliciting trigger (s), while the second one is treatment aimed at providing symptomatic relief. This guideline recommends use of second-generation non-sedating H1 antihistamines as the first-line treatment. The dose can be increased up to four times to meet the expected results. In case patients still do not respond, appropriate treatment options can be selected depending on the cost. First-generation antihistamines can interfere with rapid eye movement (REM) sleep and impact on learning and performance. New GA²LEN/EDF/EAACI/WAO guidelines do not recommend the use of these sedating antihistamines for the routine management of CU as the firstline agents. Second-generation antihistamines should be considered as the first-line symptomatic treatment for urticaria because of their good safety and tolerability pro

Paraneoplastic Syndromes of the Neuromuscular Junction: Therapeutic Options in Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome, and Neuromyotonia

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia are neuromuscular transmission disorders occurring with or without associated malignancy. Due to the common antibody-mediated pathophysiology, immunosuppression has an important role in the treatment of each of these disorders. Symptomatic treatment is more variable. Pyridostigmine is first-line treatment in generalized MG. Response seems to be better in patients with acetylcholine receptor (AChR) antibodies than in patients with antibodies against muscle-specific tyrosine kinase (MuSK). Pyridostigmine can be sufficient in mild MG, although most patients need additional immunosuppressive therapy. If so, prednisolone is efficient in the majority of the patients, with a relatively early onset of clinical effect. High drug dosage and treatment duration should be limited as much as possible because of serious corticosteroid-related side effects. As long-term treatment is needed in most patients for sustainable remission, adding non-steroid immunosuppressive drugs should be considered. Their therapeutic response is usually delayed and often takes a period of several months. In the meantime, corticosteroids are continued and doses are tapered down over a period of several months. There are no trials comparing different immunosuppressive drugs. Choice is mainly based on the clinician's familiarity with certain drugs and their side effects, combined with patients' characteristics. Most commonly used is azathioprine. Alternatively, tacrolimus, cyclosporine A, mycophenolate mofetil or rituximab can be used. The use of cyclophosphamide is limited to refractory cases, due to serious side effects. Plasma exchange and intravenous immunoglobulin induce rapid but temporary improvement, and are reserved for severe disease exacerbations because of high costs of treatment. It is recommended that computed tomography (CT) of the thorax is performed in every AChR-positive MG patient, and that patients are referred for thymectomy in case of thymoma. In patients without thymoma, thymectomy can be considered as well, especially in younger, AChR-positive patients with severe disease. However, definite proof of benefit is lacking and an international randomized trial to clarify this topic is currently ongoing. When LEMS is suspected, always search for malignancy, especially small cell lung carcinoma with continued screening up to two years. In paraneoplastic LEMS, cancer treatment usually results in clinical improvement of the myasthenic symptoms. 3,4-Diaminopyridine is first-line symptomatic treatment in LEMS. It is usually well tolerated and effective. When immunosuppressive therapy is needed, the same considerations apply to LEMS as described for MG. Peripheral nerve hyperexcitability in neuromyotonia can be treated with anticonvulsant drugs such as phenytoin, valproic acid or carbamazepine. When response in insufficient, start prednisolone in mild disease and consider the addition of azathioprine. Plasma exchange or intravenous immunoglobulin is indicated in severe neuromyotonia and in patients with neuromyotonia combined with central nervous system symptoms, a clinical picture known as Morvan's syndrome.

Does concomitant use of paracetamol potentiate the gastroduodenal mucosal injury associated with aspirin? A prospective, randomised, pilot study

Paracetamol is commonly prescribed for first-line symptomatic treatment in patients with osteoarthritis and aspirin is often co-administered for cardiovascular prophylaxis. It is not known if an interaction exists between aspirin and paracetamol in regards to gastroduodenal mucosal injury. To investigate whether or not co-administered aspirin with paracetamol results in an increased rate of endoscopic gastroduodenal mucosal injury as compared to either agent alone. In this prospective, double-blind, randomised, three-arm, placebo- and active-controlled, parallel-group pilot study healthy adult subjects (18-75years old) with a normal baseline trans-nasal oesophagogastroduodenoscopy (TN-EGD), received oral paracetamol 4000mg q.d.s. (n=21), aspirin 325mg q.d.s. (n=19) or paracetamol 4000mg q.d.s. and aspirin 325mg q.d.s. (n=20). Upper gastrointestinal mucosal injury was evaluated after 7days of treatment with TN-EGD. The rate of gastric ulcers in subjects receiving paracetamol (0/21, 0%) alone or aspirin (3/19, 16%) or both (2/20, 10%) was not different. There were, however, significantly more subjects with one or more lesions (erosion or ulcer) per subject in the paracetamol and aspirin (16/20, 80%) treated subjects as compared to the aspirin (8/19, 42%, P<0.001) or the paracetamol (3/21, 14%, P<0.01) exposed subjects. The mean number of lesions per subject was also greater (7.9 vs. 0.7, P<0.01) in those treated with aspirin and paracetamol compared to paracetamol alone. Co-administration of paracetamol and aspirin was not associated with a significant difference in endoscopic ulcer rates compared to either drug alone. There was a strong signal for increased endoscopic erosions and ulcers in the combined group compared to either aspirin or paracetamol alone.

The impact of beta-blockers on mortality in stable angina: a meta-analysis

Beta-blockers are recommended as first-line symptomatic treatment for stable angina. However, their impact on mortality outside the context of myocardial infarction is unknown. We performed a meta-analysis of all randomized trials of beta-blockers in stable angina. Medical databases and cardiology journals were searched for relevant randomized clinical trials. The primary outcome was cardiovascular mortality, separately considering trials of beta-blockers versus placebo and beta-blockers versus other antianginals. We conducted a subgroup analysis on cardioselective versus non-cardioselective beta-blockers and calcium channel antagonists versus nitrates. We calculated odds ratios (ORs) and confidence intervals (CIs) using Peto's method. We found no statistically significant evidence that beta-blockers impact on mortality when compared with placebo (OR, 0.42; CI, 0.15-1.21) or other antianginals (OR, 0.98; CI, 0.86-1.10), or all others (OR, 0.97; CI, 0.86-1.09). There was a trend for cardioselective beta-blockers to have a greater improvement in mortality when compared with placebo and to have greater impact than non-calcium channel antagonists. Beta-blockers do not have statistically significant impact on mortality versus placebo or versus other active comparators. The findings exclude a benefit of 15% or greater and a hazard of 10% or greater. The impact of cardioselectivity requires further study.

Pharmacological rationale for the treatment of chronic urticaria with second‐generation non‐sedating antihistamines at higher‐than‐standard doses

Chronic urticaria (CU) is a long-lasting and distressing condition that impairs patient quality of life (QoL) by disrupting sleep and diminishing work/school productivity. Thus treatment should not only be safe and effective but also not add to this impairment or increase risks to health or safety. Non-sedating second-generation antihistamines, with their long duration of action, pharmacodynamic properties that allow once-daily dosing and lack of drug-drug interactions and sedative effects, are the first-line symptomatic treatment option, but some patients have no adequate response to standard doses of these medications. Other therapeutic approaches to refractory urticaria have been suggested but have been limited by sparse clinical data and/or significant adverse effect profiles. Although discouraged by treatment guidelines, sedating antihistamines are frequently prescribed for nighttime use when urticaria symptoms are severe as add-on therapy to a non-sedating antihistamine. However, their pronounced effects on rapid eye movement sleep and hangover negatively impact QoL, learning and performance, and limit their use for patients in occupations that require alertness. For patients who do not respond adequately to standard doses of non-sedating second-generation antihistamines, increasing the dose of non-sedating antihistamines thus may represent the safest therapeutic approach. Given the fact that only few controlled studies have assessed the efficacy and safety of high-dose non-sedating antihistamines in CU, patient safety should be a key consideration when choosing a specific antihistamine.

The use of a responder analysis to identify clinically meaningful differences in chronic urticaria patients following placebo- controlled treatment with rupatadine 10 and 20 mg

According to the EAACI/GA(2)LEN/EDF guidelines for urticaria management, modern non-sedating H1-antihistamines are the first-line symptomatic treatment for chronic urticaria. Two previous randomized clinical trials demonstrated rupatadine efficacy and safety in chronic urticaria treatment. However, a responder analysis to identify clinically meaningful differences in patients with chronic urticaria has not yet been performed. This analysis includes the pooled data from two randomized, double-blind, placebo-controlled, multicentre studies in which chronic urticaria patients were treated with rupatadine at different doses. Responder rates were defined as the percentage of patients after 4 weeks of treatment who exhibited a reduction of symptoms by at least 50% or 75% as compared to baseline. The variables analysed were as follows: Mean Pruritus Score (MPS), Mean Number of Wheals (MNW), and Mean Urticaria Activity Score (UAS). A total of 538 patients were included. This responder analysis, using different response levels, shows that the efficacy of rupatadine 10 mg and 20 mg is significantly better as compared to placebo in the treatment of chronic urticaria patients. Notably, treatment with rupatadine 20 mg daily resulted in a higher percentage of patients with response of 75% symptom reduction or better than rupatadine 10 mg. Our results support the use of higher than standard doses of non sedating antihistamines in chronic urticaria. We strongly recommend performing and reporting responder analyses for established and new drugs used by patients with chronic urticaria.

Update on chronic urticaria: focusing on mechanisms

This review discusses some of the recent advances in basic and clinical research focused on chronic urticaria. It is a concise summary of issues that occupied researchers' attention in the previous year, and it discusses a selection of novel findings that further our understanding of the pathomechanism of this disease. Particular consideration is given to the role of basophils, the coagulation cascade, fibrinolysis, and hormonal pathways in chronic urticaria pathogenesis. The description of clinical data is focused on prognostic issues, disease severity, and the effects of the disease on patients' quality of life. Mast cells are the key elements in chronic urticaria pathogenesis, whereas basophils should be regarded as bystanders and serve as biomarkers in some chronic urticaria subsets. The coagulation cascade, hormonal factors, and the psychological status of the patients seem to contribute substantially to the course and activity of the disease. Nonsedating second-generation antihistamines should be considered as first-line symptomatic treatment for chronic urticaria. Of note, the dosage should be increased up to four-fold if required before switching to second-line therapies.

Optimising the use of beta-blockers in older patients with heart failure.

Heart failure is predominantly a disease of the older person with half of all patients with the condition aged >75 years. Diuretics are the first-line symptomatic treatment for heart failure. beta-blockers should be initiated on an outpatient basis once the patient is stable, euvolaemic (by means of a diuretic) and established on an angiotensin converting enzyme (ACE) inhibitor. Large trials have demonstrated the beneficial effects of the beta-blockers carvedilol, metoprolol and bisoprolol in patients with heart failure, most of whom were also receiving ACE inhibitors. However, the mean age of patients in these trials was generally 60 to 65 years, with very few patients aged >75 years being recruited. It is, thus, not immediately clear how to apply these trial results to older patients with heart failure. Subgroup analyses from these large beta-blocker heart failure trials suggest that older patients gain similar benefit from beta-blocker treatment to younger patients. The trials, however, give no guidance as to whether older patients should receive the same target dosage or titration regimen as younger patients. It is suggested that a less aggressive titration regimen may be more appropriate for older patients while still attempting to achieve the trial target dosages. Titration can be safely achieved on an outpatient basis. In particular, a period of observation in the clinic after initiation of treatment does not appear to be necessary. The survival benefit resulting from the use of a beta-blocker in patients with heart failure is modest (months rather than years). It is, thus important not to neglect the effects of treatment on quality of life. A proportion of patients experience adverse effects with a beta-blocker. For such patients a balance needs to be made between the adverse effects on quality of life and the likely extension of life from the use of a beta-blocker. For patients who can tolerate a beta-blocker, the available evidence suggests that it can improve quality of life. The evidence currently available does not support the use of an angiotensin II receptor blocker (ARB) in addition to an ACE inhibitor and beta-blocker. For patients unable to tolerate an ACE inhibitor or beta-blocker, the use of an ARB may confer some advantage.

Pathophysiology and management of self-poisoning with beta-blockers.

The prognosis of self-poisoning with beta-blockers is excellent, especially if medical management is started immediately but the wide variety of clinical symptoms and proposed treatments complicate the therapeutic strategy. Beta-blockers that are liposoluble or have marked anti-arrhythmic activity are more lethal (e.g. propranolol, sotalol). Similarly, pre-existing cardiac pathology or co-ingestion of psychotropic or cardioactive drugs increases mortality. The first-line symptomatic treatment is administration of atropine and volume-expanding fluids to treat bradycardia and hypotension, respectively. However atropine is often unsuccessful in reversing beta-blocker-induced bradycardia and repeated doses can provoke atropine poisoning. If symptomatic treatment fails, then antidotes should be administered in a precise order: first, high doses of glucagon, followed by isoproterenol, epinephrine, and the new inhibitors of phosphodiesterases. Mechanical ventilation should be started at the same time as pharmacological treatment in cases of severe collapse or prolonged QRS.