A model for the study of nonocclusive intestinal ischaemia.

The effects of mesenteric ischaemia have till now been studied in the laboratory by two methods: mechanical occlusion of the proximal superior mesenteric artery, which is followed by functionally reduced bloodflow in the terminal branches; and reduction in cardiac output (leading to shock) brought about by induced atrial fibrillation of cardiac tamponade, this leading to reflex mesenteric vasoconstriction. A new method is described in which noradrenaline is infused into the mesenteric circulation of anaesthetized dogs to produce vasoconstriction. The immediate effects are emptying of the normally full vessels, spasm of the midgut smooth muscle, and pallor with deepening cyanosis. After 60 min subserosal ecchymoses, and haemorrhages into the mucosa and submucosa appear, with sero-sanguinious transudate into the bowel lumen and, eventually, mucosal necrosis. The model described here may facilitate further study of the regulatory mechanisms underlying "nonocclusive" mesenteric ischaemia.     

Ixekizumab for treatment of psoriasis

Psoriasis is a prevalent chronic inflammatory skin disease of unknown etiology. Recent advances in understanding the pathogenesis of psoriasis suggest that IL-17 is a key proinflammatory mediator present in the skin. Several agents targeting IL-17 or its receptor are in clinical trials for the treatment of psoriasis. This review focuses on the biological rationale and the results of clinical trials with ixekizumab, a humanized IgG4 monoclonal antibody. Ixekizumab binds the IL-17A homodimer, thereby blocking the binding of IL-17A to the IL-17 receptor. The currently available Phase I–III data indicate that ixekizumab is a promising drug, although long-term data of efficacy and safety are needed before ixekizumab and other IL-17 targeting therapeutics can find their place in clinical practice.     

Ustekinumab for the treatment of psoriasis

Management of psoriasis over the last decade has changed significantly with the introduction of biological therapies. Ustekinumab is a first-in-class biological agent, inhibiting the action of IL-12 and IL-23, and has provided further evidence for the role of Th1 and Th17 lymphocytes in the pathogenesis of psoriasis. Efficacy has been clearly demonstrated in three Phase III clinical trials. Week 12 Psoriasis Area and Severity Index (PASI) 75 was observed in 66.4–75.7% of patients with PASI 90 achieved in 36.7–50.9%. This marked clinical response is also reflected in a significant improvement in quality of life. The most recent Phase III clinical trial has demonstrated the superior efficacy of ustekinumab (regardless of dosing regimen) compared with high-dose etanercept at week 12. Long-term efficacy has been demonstrated over 148 weeks with 64–76% of patients maintaining PASI 75. The role of ustekinumab in the treatment of psoriatic arthritis has shown some benefit in Phase II clinical trials. Phase III clinical trials are pending and will provide further guidance on management of concurrent disease. The currently available safety data are on the whole reassuring, although ongoing vigilance remains central to the detection of rare or late sequelae.     

Brodalumab for the treatment of psoriasis

Introduction: Psoriasis is a complex disease in which the alteration of the IL-23/Th17 axis appears to be crucial for its pathogenic mechanisms, and anti-IL17 agents are rapidly becoming important therapeutic tools. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab.

Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association.

Expert commentary: By blocking the IL-17 receptor A, brodalumab antagonizes signaling from IL-17A, IL-17F, IL-17A/F and IL-25, and this probably contributes to the high efficacy observed in clinical trials. Considering the different therapeutic target and the potential biological implications that blocking IL-17RA instead of IL-17A might have, brodalumab may not necessarily belong to the same class that includes secukinumab and ixekizumab, but it may be classified in a distinct group.     

Tildrakizumab for the treatment of psoriasis

Introduction: Psoriasis is an immune-mediated skin disease amenable to targeted immunotherapy. Tildrakizumab is a humanized IgG1 monoclonal antibody targeting interleukin-23 p19 and is approved for use in moderate to severe psoriasis.

Areas covered: This article reviews the mechanism of action, pharmacokinetics, safety, tolerability, and clinical efficacy of tildrakizumab, administered subcutaneously every 12 weeks, in treatment of moderate to severe psoriasis.

Expert commentary: In two phase 3 clinical trials, tildrakizumab showed a consistent low occurrence of adverse events, underlining safety and tolerance. The long half-life permits subcutaneous injections every 12 weeks. Seventy eight percent of patients achieved PASI 75 (a > 75% improvement from baseline PASI) at 28 weeks, 58% achieved PASI 90, 29% achieved PASI 100 and 70% achieved a Physician’s Global Assessment score of clear or almost clear. A high proportion of patients maintained PASI response after 2 years of treatment. Tildrakizumab improved Dermatology Life Quality Index, psoriasis-related personal relationship problems and sexual difficulties. Baseline PASI score, PGA, and BMI were not predictive of PASI 90 response at week 12, however achievement of PASI 50 by week 8 was predictive of a PASI 90 response at week 12.     

Ustekinumab for the treatment of psoriasis

Management of psoriasis over the last decade has changed significantly with the introduction of biological therapies. Ustekinumab is a first-in-class biological agent, inhibiting the action of IL-12 and IL-23, and has provided further evidence for the role of Th1 and Th17 lymphocytes in the pathogenesis of psoriasis. Efficacy has been clearly demonstrated in three Phase III clinical trials. Week 12 Psoriasis Area and Severity Index (PASI) 75 was observed in 66.4-75.7% of patients with PASI 90 achieved in 36.7-50.9%. This marked clinical response is also reflected in a significant improvement in quality of life. The most recent Phase III clinical trial has demonstrated the superior efficacy of ustekinumab (regardless of dosing regimen) compared with high-dose etanercept at week 12. Long-term efficacy has been demonstrated over 148 weeks with 64-76% of patients maintaining PASI 75. The role of ustekinumab in the treatment of psoriatic arthritis has shown some benefit in Phase II clinical trials. Phase III clinical trials are pending and will provide further guidance on management of concurrent disease. The currently available safety data are on the whole reassuring, although ongoing vigilance remains central to the detection of rare or late sequelae.     

Tofacitinib for the treatment of moderate-to-severe psoriasis

Because of the increased knowledge about the underlying cytokine network in psoriasis, selective systemic agents for the treatment of moderate-to-severe psoriasis have been developed during the past decade. The marked upregulation of JAK/STAT pathways in psoriasis and the identification of multiple key mediators in psoriasis pathogenesis that signal through JAK/STAT pathways led to investigation of JAK proteins as potential therapeutic targets for psoriasis treatment. A novel JAK-STAT inhibitor, tofacitinib, has been tested in preclinical studies for the treatment of psoriasis. Considering the satisfactory safety profile and the encouraging efficacy observed in the Phase II and Phase III trials, tofacitinib may represent an important therapeutic to be included into the psoriasis paradigm.     

Spectinomycin versus tetracycline for the treatment of gonorrhea.

Spectinomycin and tetracycline are alternative drugs to penicillin in the treatment of gonorrhea. To compare the efficacy of these agents and their propensity to select resistant gonococci, we treated 4043 patients randomly with either 2 or 4 g of spectinomycin once or 9 g of oral tetracycline for four days. Minimum cure rate for anogenital gonorrhea was 94 per cent with either drug. Oropharyngeal infection responded poorly to spectinomycin in men, with failure of therapy in six of 11. Postgonococcal urethritis in men was less common after tetracycline than after spectinomycin (P less than 0.005). Spectinomycin failure was not related to drug resistance. Tetracycline failure correlated with resistance (P less than 0.0002); one fifth of the isolates resistant to 1.0 mug per milliter of tetracycline were not eradicated. For several reasons, including the appearance of beta-lactamase-producing gonococci, it is no longer clear that penicillin G is the "drug of choice" for gonorrhea. Spectinomycin and tetracycline are equally acceptable alternatives, each with distinct advantages and disadvantages.     

Novel immunotherapies for psoriasis.

New insights into the pathophysiology of psoriasis have suggested possibilities for targeted therapeutic intervention. Several novel, systemic immunomodulatory therapies are currently in clinical development and results of recent clinical trials are remarkable. These include approaches targeting antigen presentation and costimulation, T-cell activation and leukocyte adhesion, the action of proinflammatory mediators and the administration of anti-inflammatory cytokines. These trials contribute to our further understanding of the disease, indicating which mechanisms play a greater or lesser part in its development. Moreover, they will lead to new therapeutic options. If psoriasis is considered as a visible model disease for T-cell-mediated disorders characterized by a type-1 cytokine pattern these recent findings might have a more general impact on the treatment of autoimmune disorders.     

Tofacitinib for the treatment of psoriasis and psoriatic arthritis

Introduction: Psoriasis and psoriatic arthritis (PsA) are inflammatory immune-mediated conditions which can cause considerable disability and reduced quality of life. Management can be complex as clinical heterogeneity may lead to different treatment pathways. Tofacitinib is a novel, oral Janus Kinase (JAK) inhibitor with proven efficacy in rheumatoid arthritis.

Areas covered: This review analyzes recent studies of tofacitinib in psoriatic disease treatment. The relevant literature was identified using clinicaltrials.gov, PubMed, and Google Scholar. Tofacitinib efficacy was demonstrated in PsA by the OPAL Broaden and OPAL Beyond phase-III studies, and received FDA and EMA approval. Tofacitinib was superior to placebo for the treatment of moderate-to-severe plaque psoriasis in the OPT Pivotal 1 and 2, OPT Retreatment studies, but FDA approval was declined for this indication based on issues of clinical efficacy and long-term safety.

Expert commentary: Tofacitinib is an important oral drug for the treatment of PsA. However, the long-term safety data require further evaluation. Tofacitinib and other JAK inhibitors show potential to broaden the treatment options in PsA and other inflammatory conditions.     

Co-morbidity in psoriasis: mechanisms and implications for treatment

Introduction: Psoriasis is a common, chronic, immune-mediated inflammatory disorder. The disease is associated with several co-morbidities including cardiovascular disease, metabolic syndrome, and psychiatric disorders. It is important to identify and treat these co-morbidities because they have a strongly negative effect on the overall health of patients with psoriasis. Unfortunately, these co-morbidities are often overlooked and/or left untreated. Therefore, the aim of this review is to discuss the mechanisms of how co-morbidities are associated with psoriasis as well as implications for the clinic to be able to recognize such co-morbidities.

Areas covered: This is a review of studies investigating and discussing co-morbidities of psoriasis and screening. Literature was retrieved by searching on the PubMed database using individual and combined search terms related to relevant co-morbidities.

Expert commentary: Effective management of psoriasis involves targeting of both psoriasis and co-morbidities.     

2% Crisaborole topical ointment for the treatment of mild-to-moderate atopic dermatitis

Introduction: Crisaborole 2% topical ointment is an anti-inflammatory, non-steroidal phosphodiesterase 4 inhibitor which is currently under investigation for its potential role in the treatment of atopic dermatitis and psoriasis.

Areas covered: So far, 7 trials have been completed in atopic dermatitis. The 2% strength appeared to be the superior dosing regimen. Pruritus improved significantly within one week. The improvements in objective efficacy assessments in crisaborole-treated patients were also statistically significant compared to the vehicle.

Expert commentary: Crisaborole has several key features in its mode of action which distinguish it from existing treatments for atopic dermatitis (AD), notably its activity against the phosphodiesterase E4 (PDE4) pathway, regulating cyclic AMP (cAMP) levels. This is less immunosuppressive than other pathways and has no effect on skin thinning. The pathway interrupts the itch sensation (pruritus) which means that the itch-scratch cycle, the bane in the life of patients with AD, is interrupted, usually as early as a few days into treatment. Hence, with the promising safety profile demonstrated, early treatment of mild to moderate AD patients might help to control AD better and improve quality of life for patients.     

Secukinumab (AIN457) for the treatment of psoriasis

Psoriasis is a chronic inflammatory disease with a multifactorial origin that appears in patients with genetic predisposition and is induced by environmental factors, and characterized by alterations in the innate and adaptive immunity. IL-17A is one of the specific cytokines involved in the pathogenesis of psoriasis and its inhibition is highly effective in the treatment of patients with moderate and severe psoriasis. Secukinumab is a monoclonal antibody that specifically binds to IL-17A and inhibits the interaction to its receptor, and it has demonstrated its efficacy and safety in the treatment of psoriasis. Phase II and III clinical trials indicate that > 80% of the patients receiving secukinumab achieve Psoriasis Area Severity Index (PASI) 75 at week 12. In the Phase III efficacy of response and safety of two fixed secukinumab regimens in psoriasis trial, PASI 75 rates were 81.6% with 300 mg secukinumab, 71.6% with 150 mg secukinumab and 4.5% with placebo, and responses were maintained up to 52 weeks in the majority of patients. In the Phase III Full Year Investigative Examination Of Secukinumab versus Etanercept Using Two Dosing Regimens To Determine Efficacy in Psoriasis study, the efficacy of secukinumab was compared to etanercept. The results indicate that both doses of secukinumab (150 and 300 mg) showed superior efficacy compared with etanercept throughout the study; PASI 75 rates at week 12 were 77.1% with 300 mg secukinumab, 67% with 150 mg of secukinumab, 44% with etanercept and 4.9% with placebo. PASI 90 and PASI 100 were 54 and 24% with secukinumab 300 mg and 21 and 4% with etanercept at week 12. At week 52, PASI 90 continued to be higher in the secukinumab group (65%) compared with the etanercept group (33%). Regarding safety, the most common side effects were nasopharyngitis and headache. The rate of infections was higher with secukinumab than placebo. This was especially the case for Candida infections, which were more common in the secukinumab group (4.7% with secukinumab 300 mg and 2.3% with secukinumab 150 mg), but all cases were resolved with conventional treatment. Secukinumab is a well-tolerated treatment that has demonstrated efficacy in treating moderate-to-severe plaque psoriasis. Nevertheless, long-term studies are necessary to confirm Phase II and Phase III data.     

A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure.

BACKGROUND AND METHODS: Lateral internal sphincterotomy, the most common treatment for chronic anal fissure, may cause permanent injury to the anal sphincter, which can lead to fecal incontinence. We compared two nonsurgical treatments that avert the risk of fecal incontinence. We randomly assigned 50 adults with symptomatic chronic posterior anal fissures to receive treatment with either a total of 20 U of botulinum toxin injected into the internal anal sphincter on each side of the anterior midline or 0.2 percent nitroglycerin ointment applied twice daily for six weeks. RESULTS: After two months, the fissures were healed in 24 of the 25 patients (96 percent) in the botulinum-toxin group and in 15 of the 25 (60 percent) in the nitroglycerin group (P=0.005). No patient in either group had fecal incontinence. At some time during treatment, five patients in the nitroglycerin group had transient, moderate-to-severe headaches that were related to treatment. None of the patients in the botulinum-toxin group reported adverse effects. Ten patients who did not have a response to the assigned treatment - 1 in the botulinum-toxin group and 9 in the nitroglycerin group - crossed over to the other treatment; the fissures subsequently healed in all 10 patients. There were no relapses during an average of about 15 months of follow-up. CONCLUSIONS: Although treatment with either topical nitroglycerin or botulinum toxin is effective as an alternative to surgery for patients with chronic anal fissure, botulinum toxin is the more effective nonsurgical treatment.