The safety of vedolizumab for the treatment of ulcerative colitis

Introduction: Vedolizumab is a humanized monoclonal antibody to the α4β7-integrin that blocks lymphocyte trafficking to the gut and is approved for treatment of patients with moderate-to-severe ulcerative colitis (UC). The gut-selective mechanism of action has the potential to improve vedolizumab’s safety profile compared to other approved biologic drugs.

Areas covered: We review the mechanism of action, efficacy and safety of vedolizumab treatment for UC. The positioning of vedolizumab in management algorithms is also discussed.

Expert opinion: The highly selective mechanism of action of vedolizumab restricts immunosuppressive effects to the gut. Vedolizumab is efficacious as induction and maintenance therapy in UC patients who are naïve or refractory to tumor necrosis factor antagonists. No clinically important safety signals have been identified. Infusion reactions are reported in <5% of cases. The rates of adverse events (AE), serious AEs, and serious infections were not different between patients treated with placebo and those who received vedolizumab in a pooled analysis of six randomized controlled trials. Rates of malignancy and mortality in vedolizumab-exposed patients are similar to those of the general UC patient population. Progressive multifocal leukoencephalopathy has not been observed. Vedolizumab is a safe and effective therapy for UC with a unique mechanism of action.     

Alicaforsen for the treatment of inflammatory bowel disease

Introduction: Intracellular adhesion molecule-1 (ICAM-1), is a transmembrane glycoprotein of the immunoglobulin family, constitutively expressed on vascular endothelial cells and upregulated in inflamed colonic tissue. Alicaforsen, a 20 base ICAM-1 anti-sense oligonucleotide and highly selective ICAM-1 inhibitor, down-regulates ICAM-1 mRNA.

Areas covered: We review mechanism of action, pharmacokinetics, pre-clinical, clinical and safety data of alicaforsen for the treatment of ulcerative colitis (UC), pouchitis and Crohn’s disease (CD).

Expert opinion: After 6 weeks of treatment, topical alicaforsen was significantly more effective than placebo in inducing remission in patients with moderate-severe distal UC, with treatment effects lasting up to 30 weeks. No difference was observed in head-head comparison with mesalamine topical enema, although alicaforsen appeared to have more durable treatment effect. Clinical trials of an intravenous formulation in Crohn’s disease showed no significant treatment effect compared to placebo. An open-label trial in alicaforsen for pouchitis demonstrated encouraging results, now being assessed in a multi-national phase 3 trial. No major safety signals have been observed in UC patients treated with alicaforsen enemas. The potential as a novel therapy for pouchitis has led to orphan designation for this indication by the FDA and European Medicines Agency.     

Treatment of steroid-naive ulcerative colitis

The introduction of steroid therapy by Truelove and Witts in the 1950s revolutionized the treatment of ulcerative colitis. Corticosteroids are potent inhibitors of T-cell activation and proinflammatory cytokines and still represent the mainstay of therapy of patients with ulcerative colitis. About 15% of patients are resistant to steroids, and about a quarter of patients become dependent within 1 year of therapy. Steroid-related adverse events are numerous and occur frequently. So, new steroids with low systemic absorption and better safety profile have been studied, but they show an overall lower efficacy compared with traditional steroids. A new drug-delivery system based on the use of autologous erythrocytes loaded with dexamethasone 21-phosphate has been recently developed. Several studies have demonstrated its efficacy in steroid-dependent patients leading to complete withdrawal of oral steroids and disappearance of the most steroid-related adverse events. In this review we elaborate on the role of steroids in the treatment of ulcerative colitis, focusing on the aspects related to the mechanisms of action and resistance to the steroids, and their secondary effects. Moreover, we analyse the alternatives to traditional systemic steroids such as the new steroids with low bioavailability and the steroids encapsulated into erythrocytes.     

Budesonide for the treatment of ulcerative colitis

Introduction: Budesonide is a synthetic corticosteroid characterized by enhanced topical potency and limited systemic bioavailability. Its use in ulcerative colitis (UC) was limited to rectal preparations until recently when the new oral budesonide formulation incorporating the multi-matrix system technology was introduced. The purpose of this review is to evaluate the current role of oral and rectal budesonide in managing UC patients

Areas covered: In this paper, we described the chemical structure and pharmacologic characteristics of the different oral and rectal budesonide preparations, provided a summary of the published trials that evaluated the efficacy and safety of budesonide in UC, and discussed the current status of its use in this population

Expert opinion: Budesonide is effective in inducing remission in a subset of patients with mild-moderate UC. Nevertheless, the current evidence suggests inferiority of oral budesonide to 5-aminosalisylates (5-ASA) and systemic steroids, whereas rectal applications are comparable to other rectal steroid preparations, but still inferior to rectal 5-ASA. In clinical practice, several issues need clarification including, its exact position in the line of induction agents; the role of combining budesonide and 5-ASAs; the role of combining oral and rectal budesonide; and the role of budesonide in maintenance therapy.     

The safety of biological pharmacotherapy for the treatment of ulcerative colitis

Introduction: Biological agents are effective in ulcerative colitis (UC). Currently, 3 anti-TNF agents (infliximab, adalimumab, and golimumab) and 1 anti-integrin agent (vedolizumab) are approved for the treatment of UC. The mechanism of action of biologic agents can also give rise to several side effects, some even serious. It remains uncertain to what extent biologic treatments may be associated with an increased rate of infections, malignancies and other adverse events

Areas covered: Our aim is to review the relevant data available in the literature and briefly summarize the safety profile of biological therapy in UC. We performed a literature search using the OVID, MEDLINE, PUBMED and EMBASE databases. Also other relevant sources of safety data were also used.

Expert opinion: All biological agents currently used in UC are relatively safe. Accurate prevention measures and screening prior to start such therapies, and regular surveillance programs are strongly recommend to minimize any risk of infections, malignancy and other adverse events related to the use of monoclonal antibodies in UC patients.     

Pharmacodynamic assessment of vedolizumab for the treatment of ulcerative colitis

Introduction: Vedolizumab is an anti-integrin approved for the treatment of Crohn’s disease and ulcerative colitis. By binding the α4β7-integrin heterodimer, vedolizumab blocks leukocyte translocation into gastrointestinal tissue.

Areas covered: This review discusses the chemistry, pharmacologic properties, clinical efficacy, and safety of vedolizumab in ulcerative colitis. Other medications available for the treatment of ulcerative colitis are also discussed.

Expert opinion: Vedolizumab is a promising new agent for the treatment of ulcerative colitis. Its mechanism of action differs from TNF-α inhibitors and immune suppressants, allowing it to be used in cases of TNF-α inhibitor failure or non-response, or as a first-line biologic drug. Available safety data suggests that vedolizumab is not associated with an increased risk of infection or malignancy; however, additional post-marketing data are required to confirm these initial reports. Vedolizumab is likely to be used in growing numbers of patients over the coming years.     

The treatment of ulcerative colitis with balsalazide sodium

Balsalazide sodium (5-aminosalicylic acid [5-ASA] linked to 4-aminobenzyl-β-alanine) was designed to deliver 5-ASA to the colonie mucosa without the sulphapyridine-associated side-effects seen with sulphasalazine. Studies amounting to some 450 patient-years exposure to balsalazide in patients with ulcerative colitis have so far confirmed the expectation of higher efficacy and high patient tolerance of balsalazide.     

Mesalamine in the treatment and maintenance of remission of ulcerative colitis

Ulcerative colitis (UC) is a chronic disease of the GI tract that is characterized by mucosal inflammation in the colon. Mesalamine (mesalazine) is a 5-aminosalicylic acid compound that is the first-line treatment for patients with mild-to-moderate UC. There are multiple formulations of mesalamine available, primarily differentiated by their means of delivering active mesalamine to the colon. Mesalamine has been demonstrated in randomized controlled trials to induce both clinical response and remission, and maintain clinical remission, in these patients. It has few serious adverse effects and is generally well tolerated by patients. The main areas of uncertainty with use of mesalamine in patients with UC center on the optimal dose for induction of response, how to maintain patient adherence and the role of mesalamine in cancer chemoprophylaxis. Generic forms of mesalamine have yet to be approved by regulatory bodies in the USA.     

A placebo-controlled,blind comparison of nedocromil sodium and beclomethasone dipropionate in bronchial asthma

Summary

A multi-centre, randomized, blind comparative group study was carried out in 202 adult patients, who had suffered from asthma for at least 2 years, to assess the effectiveness and tolerability of maintenance treatment with either 4?mg nedocromil sodium 4-times daily, 0.1?mg beclomethasone dipropionate 4-times daily or 2 puffs of placebo 4-times daily, given by inhalation. Lung function (FEY₁ and sRaw) measurements were made at the beginning and end of a 2-week baseline period and then after 3 and 6 weeks of treatment: assessments were also made of asthma severity. Patients recorded daily on diary cards details of morning and evening PEFR, usage of inhaled bronchodilators, severity of dyspnoea, cough and morning tightness. The results showed that, compared with placebo, both nedocromil sodium and beclomethasone dipropionate-treated patients showed an improvement in FEY₁and a reduction in sRaw values: PEFR increased slightly in all three groups. There was an improvement in asthma severity, diminished rate of dyspnoea and cough, and reduced usage of inhaled bronchodilators in patients receiving active treatment but not in those on placebo. Overall assessment of treatment efficacy by both investigators and patients showed that opinions were significantly in favour of active treatment over placebo. Treatment was well tolerated and no serious side-effects were reported. It was concluded that at the dosages used nedocromil sodium was comparable with and equivalent to inhaled beclomethasone dipropionate in nearly all of the parameters assessed, and both drugs were superior to placebo in the maintenance treatment of asthma in adult patients.     

Severe ulcerative colitis: present medical treatment strategies

A total of 15 – 19% of ulcerative colitis patients have a severe attack at some time during their illness. As a consequence of its high associated mortality and morbidity rates, a close collaboration between gastroenterologists and surgeons in their management is mandatory, in order to define, as best as possible, the timing of surgery (i.e., colectomy) when patients fail to respond to medical treatment or worsen despite optimal medical treatment. The first step in medical treatment consists of using intravenous corticosteroids as they have been demonstrated to reduce drastically the mortality rates. However, at 1 year approximately 25% of patients become corticosteroid dependent and 30% require colectomy, which can consistently affect their quality of life. Therefore, intravenous ciclosporin has been proposed as a rescue therapy, with a further improvement of short-term efficacy and reduction of surgery requirement. Nevertheless, its use is associated with a risk of toxicity and intravenous ciclosporin is not easy to use in non-specialised centres. In addition, long-term studies suggest that colectomy is often only delayed and relapse frequent. Consequently, some authors evaluate the potential use of infliximab. Available data are encouraging, reporting a significant short-term reduction in colectomy rate. Nevertheless, additional trials are required to better define the more effective and safe treatment option(s), for both the short- and long-term, in this patient setting; a question addressed in ongoing trials.     

Comparison of flunisolide and beclomethasone dipropionate in seasonal allergic rhinitis

Summary

Sixty-nine patients were entered into a randomized, single-blind, parallel group study. Patients had a history of moderate to severe seasonal allergic rhinitis and all patients commenced treatment before the start of the pollen season. Treatment was with either flunisolide or beclomethasone dipropionate, both being administered as 2 sprays to each nostril twice daily for 7 weeks. Assessments of signs and symptoms of hay fever were made at admission and after 3 and 7-weeks' treatment. Patients were asked to keep a daily record of the severity of their symptoms. The overall effect of treatment was evaluated by both the patient and physician. Side-effects were elicited by indirect questioning. Sixty patients completed the study. Four patients from the flunisolide group and 2 from the beclomethasone group were lost to follow-up. Two further patients withdrew from the flunisolide group and 1 from the beclomethasone group. Analysis of results did not reveal any statistically significant differences between the treatments. Minor side-effects were reported by 1 patient from each treatment group. Both treatments proved to be effective in the treatment of hay fever and were equally well tolerated.     

The gastrointestinal passage and release of beclomethasone dipropionate from oral delivery systems in ileostomy volunteers

Aims To study the delivery of 15  mg beclomethasone 17,21-dipropionate (BDP) to the distal part of the small bowel for three oral sustained-release formulations (I-III) and a reference capsule in volunteer ileostomists, and to compare these findings with the in vitro dissolution profiles.
Methods Two groups of nine ileostomy volunteers (aged 20–61 years), who were otherwise healthy, were enrolled in the study. The recovery of BDP and its metabolite beclomethasone 17-monopropionate (B17P) in ileostomy effluent was investigated in a cross-over study after administration of formulations I or II or a reference capsule containing micronised BDP, and in a second open study after administration of formulation III. Radio-opaque granules were coadministered for evaluation of gastrointestinal passage. Ileostomy effluents were collected hourly for 10–12  h following drug intake. After marker beads had been counted on X-rays, ileostomy collections were analysed for BDP and its metabolites. Cumulative recovery, lag-time and mean transit time were determined for drug and marker beads.
Results Gastrointestinal passage characteristics were similar for all treatments. Total drug recovery was approximately three times higher for the sustained-release formulations than for the reference capsule. Recovery of B17P from stoma fluid samples was significantly lower for formulation III than for formulations I and II.
Conclusions The novel oral formulations delivered substantial amounts of steroid drug at the distal small bowel/proximal colon, which may warrant further studies to evaluate clinical applicability.     

Drug treatment of ulcerative colitis: unfractionated heparin,low molecular weight heparins and beyond

Ulcerative colitis (UC) is characterised by chronic inflammation of the colon of unknown aetiology. Medical treatment of UC is complex and sometimes unsatisfactory. A total of 75% of patients experience relapses during the course of their illness and 20 – 25% require a colostomy. Recent years have witnessed a paradigm shift in the way UC is medically treated. The focus has now shifted to newer forms of therapy along with the older established drugs such as sulfasalazine and corticosteroids. Unfractionated heparin and low molecular weight heparins have been tested for their efficacy in patients with UC with conflicting results in various studies. Immunosuppressive and immune-based therapies, drugs modifying biological responses, prebiotics, probiotics, symbiotics, melatonin and topical butyrate have all been testedwith variable success. The current review delineates the recent therapeutic alternatives in UC with main emphasis on heparins.     

Pharmacokinetics of chlorofluorocarbon and hydrofluoroalkane metered-dose inhaler formulations of beclomethasone dipropionate

AIMS: To compare the pharmacokinetic profile of Beclazone (beclomethasone dipropionate) in its chlorofluorocarbon (CFC)-based and CFC-free formulations. METHODS: Ten healthy adults received a single 1,000 microg nominal dose (ex-valve) of beclomethasone dipropionate from a CFC inhaler (BEC-CFC) or from a CFC-free inhaler containing hydrofluoroalkane (HFA)-134a (BEC-HFA) in an open-label, randomized, two-way, crossover study. Blood samples were collected predose and over 12 h after inhalation. Comparisons were made of maximum plasma concentration of beclomethasone 17-monopropionate (17-BMP) (Cmax), and area under the plasma concentration vs time curve (AUC). RESULTS: The tmax was significantly (P<0.05) earlier with BEC-HFA and plasma levels were significantly higher following administration of BEC-HFA than BEC-CFC. Geometric mean values for AUC were 1.5 fold greater (90% CI 1.3-1.9) and for Cmax were 1.9 fold greater (90% CI 1.6-2.6) following BEC-HFA than BEC-CFC. CONCLUSIONS: Our data in healthy volunteers would not be consistent with the manufacturers' recommendation for a microgram equivalent (1:1) nominal dose switch between these HFA and CFC formulations. Further well designed trials are required in asthmatic patients to properly define their respective dose-response relationships for antiasthmatic and systemic adverse effects.     

Pharmacokinetics and dose proportionality of beclomethasone from three strengths of a CFC-free beclomethasone dipropionate metered-dose inhaler

As part of a development program to offer alternatives to chlorofluorocarbon (CFC) containing metered-dose inhalers, beclomethasone dipropionate has been formulated in a CFC-free system at three strengths: 50, 100, and 200 μg/actuation ex valve. To measure serum levels and dose proportionality of the beclomethasone derived from beclomethasone dipropionate, 13 mild to moderate asthmatic patients received a single dose of eight inhalations from each strength according to a double-blind crossover design. Seven patients were studied over 4 h and six patients over 12 h. For the total doses of 400, 800, and 1600 μg studied over 12 h, C_max and AUC increased in a ratio of 1:1·8:3·1. A good correlation was seen between the fine-particle mass delivered and the in vivo performance of the three strengths. From a clinical point of view, the predictable increases in serum levels with an increase in dose will permit the clinician to effectively titrate a patient with this product. © 1997 John Wiley & Sons, Ltd.     

高效液相色谱内标法测定无极膏中丙酸倍氯米松的含量

目的建立测定无极膏中丙酸倍氯米松含量的方法。方法采用C18柱（4．6mm×250mm,5um）,以甲醇·水（75：25）为流动相,流速为1．0ml·min^-1,检测波长240nm,用内标法测定,内标物为醋酸氯地孕酮。结果丙酸倍氯米松在2．09—41．76mg·L^-1范内呈良好线性关系（r=1）,平均回收率为100．96％,RSD为1．6％。结论该方法准确,可靠,可用于无极膏的质量控制。     

Novel therapies in the treatment of ulcerative colitis

Ulcerative colitis is a chronic inflammatory disease of unknown cause. Its course is one of relapse and remission and requires therapy for both the induction and maintenance of remission. The progress in the fields of genetics and immunology has afforded important advances in our understanding of the inflammatory process. Traditional therapy with non-specific anti-inflammatories for ulcerative colitis remains our gold standard as newer targeted therapies have failed to provide any improved efficacy. This review examines the most recent compounds in development for the treatment of ulcerative colitis, including data from early clinical trials and the potential clinical impact of future entities.     

Novel therapies in the treatment of ulcerative colitis

Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause. Its course is one of relapse and remission and requires therapy for both the induction and maintenance of remission. Progress in the fields of genetics and immunology affords important advances in our understanding of the inflammatory process. Traditional therapy for ulcerative colitis with nonspecific anti-inflammatories remains our gold standard. This review examines the most recent compounds in development for the treatment of ulcerative colitis, including data from early clinical trials and the potential clinical impact of future entities.     

A safety evaluation of budesonide MMX for the treatment of ulcerative colitis

Introduction: Budesonide belongs to low-bioavailability steroids class. A novel oral formulation of budesonide, which uses the Multi-Matrix System (MMX) for delivering drugs to the colon, is now available as a possible treatment of ulcerative colitis patients intolerant or not-responding to first-line therapy with 5-ASA.

Areas covered: in this review we present information about the development and the use of budesonide MMX and we provide data about its mechanism of action as well as, pharmacodynamics and pharmacokynetics. Moreover, we present the available literature data about the efficacy and, mainly, the safety of budesonide-MMX.

Expert opinion: budesonide-MMX is a new therapeutic option in mild-to-moderate UC patients. Its good safety profile in clinical trials undoubtedly represents a strength for a possible wide use in clinical practice, mainly if it will be confirmed by post-marketing data. Other indications, such as treatment of colonic Crohn’s disease, could theoretically be considered, if sustained by reliable scientific data.     

Efficacy and safety of drugs for ulcerative colitis

Importance of the field: Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon that carries considerable burden and morbidity for patients and presents a constant challenge in management for gastroenterologists. Continued advances in medical therapies provide a range of treatment options for patients, but with this is the need to balance the potential benefits of a particular medication with its side effect profile in both the short and the long term.

Areas covered in this review: This article will review the current drugs used in the treatment of UC, including 5-amninosalicylates, antibiotics, steroids, immunomodulators and biologics, with particular attention to their indications, efficacy and toxicity profile.

What the reader will gain: The reader will gain a comprehensive understanding of the various medical therapies used in the treatment of UC with focus on efficacy and toxicity profiles, allowing providers to choose appropriate medical therapies for their patients.

Take home message: The particular agent used depends upon the extent and severity of disease, with mild-to-moderate disease treated with conventional therapy including 5-amninosalicylates. Steroids are used in the short term to bring active disease into remission, and the more aggressive immunomodulators and biologics are reserved for more severe disease given their toxicity profiles.