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FTY720 is a recently approved first line therapy for relapsing forms of multiple sclerosis. In this context, FTY720 is a pro-drug, with its anti-multiple sclerosis, immunosuppressive effects largely elicited following its phosphorylation by sphingosine kinase 2 and subsequent modulation of G protein-coupled sphingosine 1-phosphate (S1P) receptor 1 that induces lymphopenia by altering lymphocyte trafficking. A number of other biological effects of FTY720 have, however, been described, including considerable evidence that this drug also has anti-cancer properties. These other effects of FTY720 are independent of S1P receptors, and appear facilitated by modulation of a range of other recently described protein targets by nonphosphorylated FTY720. Here, we review the direct targets of FTY720 that contribute to its anti-cancer properties. We also discuss other recently described protein effectors that, in combination with S1P receptors, appear to contribute to its immunosuppressive effects.

Fingolimod is a sphingosine-1 phosphate receptor modulator, which is effective in the treatment of severe relapsing-remitting form of multiple sclerosis. Once daily oral use of fingolimod decreased the annualized relapse rate, inflammatory brain lesion activity and the rate of brain atrophy compared both to placebo and intramuscular administered interferon beta-1a. The drug targets the cardiovascular system as well via sphingosine-1 phosphate receptors. After initiation of fingolimod therapy transient sinus bradycardia and slowing of the atrioventricular conduction develops. The onset of the effect is as early as 1 hour post administration, while heart rate and conduction normalized in 24 hours in most of the cases. According to the clinical trials symptomatic bradycardia developed in 0.5% of the cases, responding to the appropriate therapy. The incidence of Mobitz I type II atrioventricular blocks and blocks with 2:1 atrioventricular conduction was 0.2% and 0.1%, respectively. All of these cardiovascular events showed regression during observation and no higher degree atrioventricular blocks were detected at the approved therapeutic dose. Following the first dose effect, fingolimod had a moderate hypertensive effect on long-term. For the safety of fingolimod treatment detailed cardiovascular risk stratification of all patients, adequate patient monitoring after the first dose and competency in treating the possible side effects is necessary. In patients with increased cardiovascular risks, treatment should be considered only if anticipated benefits outweigh potential risks and extended monitoring is required.

The availability of the second-generation therapies for relapsing multiple sclerosis (MS), natalizumab and fingolimod, provides new treatment options for MS but also presents new challenges. Both natalizumab and fingolimod appear to be more effective than the interferon beta products and glatiramer acetate, but both have more safety problems than do the first-generation therapies. Treatment with natalizumab is associated with a significant risk of patients developing progressive multifocal leukoencephalopathy (PML), which the JC virus causes. We now are able to risk stratify MS patients into high- and low-risk groups for developing PML on the basis of the presence or absence of antibodies to the JC virus, history of prior use of immunosuppressants, and duration of therapy with natalizumab. Fingolimod appears to be associated with a risk of asystole and sudden death. It may also increase the risk of serious herpes infections and paradoxical activation of MS. More information is needed about these serious side effects from fingolimod to allow us to use it safely in patients.

Cough in children is among the most common problems managed by pediatricians, and occurs more frequently in preschool than in older children. Most acute episodes of cough are due to viral upper respiratory tract infections. The morbidity associated with acute cough in a child extends also to parents, teachers, and other family members and caregivers. Unfortunately, therapeutic options for acute cough in children are severely limited due to the absence of drugs shown to be effective antitussives with an acceptable safety profile. Agents used in the management of adult cough, such as narcotics (codeine, hydrocodone), the non-narcotic opioid dextromethorphan, first-generation, potentially sedating antihistamines, and decongestants such as pseudoephedrine, have all been deemed inadequate for treatment of acute pediatric cough on a risk/benefit basis. A growing body of evidence suggests that the peripherally acting antitussive, levodropropizine, may be an attractive alternative for the treatment of bothersome acute cough in children., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Fumonisin B(1) (FB(1)) is a mycotoxin produced by a common fungal contaminant of corn. Ingestion of FB(1)-contaminated food is associated with increased risk for neural tube defects (NTDs). FB(1) induces NTDs in inbred LM/Bc mice. FB(1) inhibits ceramide synthase in de novo sphingolipid biosynthesis, resulting in accumulation of sphinganine and sphinganine-1-phosphate (Sa1P). Sa1P functions as a ligand for a family of G protein-coupled S1P receptors., Methods: Pregnant SWV and LM/Bc mice were treated with FB(1) (20 mg/kg/day intraperitoneally on embryonic day (ED) 7.5-8.5) or the known S1P receptor agonist FTY720 (10 mg/kg/day oral gavage on ED 6.5-8.5). LC/MS was used to detect sphingoid base-1-phosphates in maternal blood spots, plasma, and embryonic tissue. Strain-specific SWV and LM/Bc mouse embryonic fibroblasts (MEFs) and serum free mouse embryo (SFME) neural progenitor cells were treated with FB(1) (40 μM for 24 hr) and LC/MS was used to detect sphingoid base-1-phosphates., Results: FTY720 induced NTDs in both the SWV and the LM/Bc strains of mice. Sphinganine-1-P (Sa1P) and FTY720-P were elevated in the blood spots and plasma of mice treated with FB(1) or FTY720, respectively. FTY720-P was elevated in ED 9.5 exencephalic embryos. Sa1P was elevated in SFME and MEF cells treated with FB(1), and Sa1P was higher in MEFs generated from the FB(1)-NTD-susceptible LM/Bc strain., Conclusions: Elevated sphingoid base-1-P after FB(1) or FTY720 suggest a potential role for these bioactive lipid ligands and activation of S1P receptor signaling pathways in the failure of neural tube closure after FB(1) or FTY720. Sa1P may represent a biomarker for FB(1)-NTD risk assessment., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Fingolimod (FTY720) has previously shown clinical efficacy in phase II/III studies of predominantly Caucasian populations with multiple sclerosis (MS)., Objectives: To report six-month efficacy and safety outcomes in Japanese patients with relapsing MS treated with fingolimod., Methods: In this double-blind, parallel-group, phase II study, 171 Japanese patients with relapsing MS were randomized to receive once-daily fingolimod 0.5 mg or 1.25 mg, or matching placebo for six months. The primary and secondary endpoints were the percentages of patients free from gadolinium (Gd)-enhanced lesions at months 3 and 6, and relapses over six months, respectively; safety outcomes were also assessed., Results: 147 patients completed the study. Higher proportions of patients were free from Gd-enhanced lesions at months 3 and 6 with fingolimod (0.5 mg: 70%, p = 0.004; 1.25 mg: 86%, p < 0.001) than with placebo (40%). Odds ratios for the proportions of relapse-free patients over six months favoured fingolimod versus placebo but were not significant. Adverse events related to fingolimod included transient bradycardia and atrioventricular block at treatment initiation, and elevated liver enzyme levels., Conclusions: This study demonstrated the clinical efficacy of fingolimod for the first time in Japanese patients with MS, consistent with the established effects of fingolimod in Caucasian patients.

The paper describes the case of a patient affected by a combination of genetic and autoimmune diseases (multiple sclerosis, psoriatic arthritis, Leiden V mutation, and sicca syndrome) and hypertension. The psoriatic arthritis was treated with celecoxib and multiple sclerosis with fingolimod. The patient developed high fever and endocarditis, resulting in severe mitral regurgitation, atrial fibrillation, and congestive heart failure. Evidence is suggestive of adverse effects of potent immunosuppressive and anti-inflammatory therapies with biologic agents and the cardiovascular system. Fingolimod increases susceptibility to infections and induced endocarditis resulting in severe mitral regurgitation, atrial fibrillation, and congestive heart failure. Managed care systems limit the contact among basic care physicians and specialists. However, the process by which the optimal decision may be reached for a patient with a complex pathology is shared decision making, where the risk of severe complications and medical expenses may be reduced.

Introduction: Fingolimod is the first approved drug with oral availability for the treatment of relapsing multiple sclerosis., Aims: To review the mechanism of action of fingolimod and its relationship with the development of infections. To propose preventive measures for those patients who are receiving the drug or will initiate a new treatment. In addition, the role of fingolimod in the development of progressive multifocal leukoencephalopathy on the basis of recent knowledge of its pathophysiology will be discussed., Development: The mechanism of action of fingolimod is based on an antagonic effect on the sphingosine 1-phospate receptors that will generate an inhibition of the egress of naive and central memory lymphocytes into the bloodstream, allowing the free recirculation of memory effectors T lymphocytes. This effect will produce lymphopenia. Fingolimod-associated lymphopenia is a consequence of lymphocyte redistribution, and it is selective and reversible. There is no evidence of higher number of opportunistic and non-opportunistic infections in comparison to placebo or interferon beta-1a in patients receiving fingolimod. However, two patients developed severe herpetic infections under fingolimod., Conclusions: Fingolimod induce a selective and reversible lymphopenia that, taking into account the most recent available data, does not seem to be associated with higher risk of opportunistic infections due to a preservation of immuno-surveillance. The risk of herpesvirus infection should be taken into consideration and more studies are warranted to confirm if an association of these infections with the use of fingolimod exists.

Fingolimod is the first oral treatment of multiple sclerosis. It is the first-in-class sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phophate receptors on lymphocytes and via downregulation of the receptor prevents lymphocyte egress from lymphoid tissues into the circulation. This mechanism reduces the infiltration of potentially auto-aggressive lymphocytes into the central nervous system. Two large phase III studies with fingolimod have shown superior efficacy of the drug in two dosages compared to placebo and to weekly intramuscular injections of Interferon beta-1a. Among possible side effects of the drug is a transient bradycardia after the first dose of fingolimod including possible AV blockade and therefore monitoring of pulse rate and blood pressure for 6 h following the first application is needed. During treatment, attention has to be given to specific infections, elevated liver enzymes, and ophthalmologic changes. Recommendations on the use of fingolimod including safety aspects are given in this article.

Background and Purpose: FTY720 (Fingolimod) is a recently approved orally administered drug for the treatment of multiple sclerosis. Phase II and III clinical trials have demonstrated that this drug modestly increases BP. We previously showed that inhibition of sphingosine kinase increases vascular tone and BP in hypertensive, but not normotensive rats. Since FTY720 is reported to have inhibitory effects on sphingosine kinase, we investigated whether FTY720 increases vascular tone and BP only in hypertensive rats via this mechanism., Experimental Approach: The contractile and BP modulating effects of FTY720 were studied in vivo and ex vivo (wire myography) in age-matched normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs)., Key Results: Oral administration of FTY720 induced an increase in mean arterial pressure in SHR, whereas a decrease in BP was observed in WKY rats, as measured 24 h after administration. Similar to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced large contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions were inhibited by endothelium denudation, COX and thromboxane synthase inhibitors, and by thromboxane receptor antagonism, indicating that (like DMS-induced contractions) they were endothelium-dependent and mediated by thromboxane A₂., Conclusions and Implications: These data demonstrate that FTY720 increases vascular tone and BP only in hypertensive rats, most likely as a result of its inhibitory effect on sphingosine kinase., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background: Fingolimod 0·5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics., Methods: We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0·5 mg or 1·25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978., Findings: Treatment with fingolimod 0·5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0·76 (95% CI 0·54-1·09; p=0·13) in patients aged over 40 years to 0·29 (0·16-0·52; p<0·0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0·5 mg versus placebo ranged from 0·85 (95% CI 0·53-1·36; p=0·50) in patients with a T2 lesion volume of 3300 mm(3) or less to 0·32 (0·14-0·73; p=0·0066) in patients with an EDSS over 3·5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0·5 mg versus placebo was 0·38 (95% CI 0·21-0·68, p=0·0011), and for treatment-naive patients with rapidly evolving severe disease it was 0·33 (0·18-0·62, p=0·0006). Hazard ratios for confirmed disability progression over 24 months were 0·68 (0·29-1·62; p=0·39) and 0·73 (0·25-2·07; p=0·55), respectively, in these groups., Interpretation: Patients with relapsing-remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0·5 mg fingolimod., Funding: Novartis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Fingolimod (FTY-720), a sphingosine-1-phosphate receptor modulator, is the first US Food and Drug Administration (FDA)-approved oral agent for the treatment of relapsing forms of multiple sclerosis (MS). Two recent phase III clinical studies (TRANSFORMS [Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS] and FREEDOMS [FTY720 Research Evaluating Effects of Daily Oral Therapy in MS]) demonstrated a significant reduction in the annualized relapse rate in patients with relapsing-remitting MS, compared to once weekly interferon β-1a and placebo. Macular edema was a prominent adverse event reported in these and prior studies of fingolimod. Thirteen of 2,564 (0.5%) patients treated with fingolimod in FREEDOMS and TRANSFORMS developed macular edema. Fingolimod-associated macular edema (FAME) appears to be dose-dependent (observed in only 2 patients taking the FDA-approved 0.5 mg dose) and typically resolves upon cessation of therapy. Although a relatively common condition in ophthalmology, most neurologists have not encountered macular edema in clinical practice. The purpose of this review is to educate the neurologist on the etiology, clinical manifestations, diagnostic modalities, and treatment approaches in patients with FAME. We also discuss the use of fingolimod in patients with uveitis and diabetes mellitus, highlight the guidelines for surveillance ophthalmic examination, and outline the key distinguishing features between FAME and optic neuritis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system and is the common cause of optic neuritis. Fingolimod, an immunosuppressive agent, is used in MS to prevent acute exacerbations. We report a case of relapsing-remitting MS treated with fingolimod. The patient presented with an acute decrease in vision in the left eye. Eye examination showed clinical macular edema (ME) in the left eye, which was confirmed on fluorescein angiogram and optical coherence tomography (OCT). After discontinuation of fingolimod and treatment with topical corticosteroid medication, there was complete resolution of the ME. The ME as a side-effect of fingolimod is reversible after discontinuing, which was seen on OCT.

Since April 2011 fingolimod (FTY 720, Gilenya®), a new oral treatment, is available for relapsing-remitting multiple sclerosis (MS) in Germany. Adverse effects in pre-marketing clinical controlled multicenter studies have led to specific precautions that have to be followed before initiating treatment. According to the European Union prescribing information fingolimod is not to be used as a first-line treatment, but is licensed as a second-line option or escalating therapy of MS. During treatment physical and neurological examinations as well as regular blood counts should be performed. The immunosuppressive mode of action of fingolimod requires increased awareness of infectious complications. Due to two fatal herpetic infections during the TRANSFORMS trial all patients without a history of chicken pox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. Comparably to other immunosuppressive treatment strategies the immune response to vaccines may be hampered during treatment with fingolimod. Thus, on the one hand, vaccination gaps should be closed before initiation of fingolimod treatment and, on the other hand, success of vaccinations during fingolimod therapy may have to be checked by antibody titre assessment.

Fingolimod (Gilenya--Novartis) is a new treatment for patients with highly active relapsing-remitting multiple sclerosis. It is the first oral disease-modifying drug for the treatment of patients with multiple sclerosis. Here we assess the place of this drug.

We report the case of a patient who developed extensive brain lesions during fingolimod (FTY720) treatment in the TRANSFORMS study. His initial diagnosis was multiple sclerosis, but after encephalopathy anti-aquaporin4 antibody (anti-AQP4 Ab) was detected, it was changed to neuromyelitis optica spectrum disorder. After treatment with fingolimod, he developed bilateral extensive brain lesions. The brain MRI showed lesions predominantly involving the right frontal and parietal lobes, with vasogenic edema and enhancement. He had residual encephalomalacia and no recurrence with steroid treatment over 3 years following withdrawal of fingolimod.

Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P₁,₅ agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation.

Balancing efficacy versus burden of therapy is essential for the choice of disease-modifying therapy in every MS patient. The first-line therapies, interferon-? and glatiramer acetate, have well-established efficacy and present no major safety concerns. Certain second-line therapies, such as natalizumab, offer potentially greater efficacy, but are associated with an increased level of risk. Over the last year, the first two oral treatments of relapsing-remitting multiple sclerosis, cladribine and fingolimod, have been marketed in certain countries, although cladribine was subsequently withdrawn. In the Phase III clinical development programme, both drugs appeared effective and reasonably safe. However, there were cases of serious adverse events (malignancies and fatal infections) whose relationship with treatment was unclear. Specific postmarketing studies will be necessary to assess the risks of these new oral therapies. Indeed, both natalizumab and mitoxantrone are known today to be associated with rare adverse drug reactions (progressive multifocal leukoencephalopathy for natalizumab and treatment-related leukaemia for mitoxantrone), which were not identified before the treatments were approved. The use of therapies carrying potential serious risks is justified in patients who cannot be treated effectively with safe first-line therapies, but probably not in the average relapsing-remitting multiple sclerosis or clinical isolated syndrome patient. Pivotal Phase III clinical trials, on which basis drug approval is generally granted, are designed to demonstrate clinical efficacy and reveal frequently occurring adverse effects of a new drug. However, post-approval trials with extensive patient exposure are needed to generate knowledge of more patient-specific clinical effectiveness and long-term safety, in particular with respect to rare adverse reactions. Other post-approval measures, such as risk management programmes, pharmacovigilance studies, or phased launch of the drug, may be useful to ensure that risks associated with new treatments are identified and minimised. The final evaluation of the benefits to risks balance of a drug should be made in every patient by weighing benefits in disease activity and progression, quality of life and health economy against both commonly occurring mild side-effects and rare potentially life-threatening adverse drug effects. This decision should be shared between the physician and patient, who may not share the same perceptions of acceptable risk., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Oral fingolimod (Gilenya) is a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Fingolimod reduces relapses and delays disability progression in patients with relapsing forms of multiple sclerosis (MS). We report a patient with MS who developed asystole and sustained bradycardia 21 hours after the first dose of fingolimod.

Objectives: Reports about the nature of the ingredients responsible for allergic contact dermatitis caused by specific cosmetic products are scarce., Methods: Between January 2000 and December 2010, the specific cosmetic products having caused allergic contact dermatitis, as well as the individual allergenic cosmetic ingredients present in them, were recorded by use of a standardized form., Results: Among 11 different categories of cosmetic product, skin care products, followed by hair care and body-cleansing products, were most often involved. The presence of the allergenic ingredient(s) in a specific cosmetic product was confirmed according to the ingredient label in 959 of 1448 records. Six hundred and twenty-one of 959 concerned non-fragrance components, preservatives being responsible for 58% of them. Reactions to formaldehyde and formaldehyde-releasers were most often correlated with body-cleansing products, particularly 2-bromo-2-nitropropane-1,3-diol and skin care products. They were followed by the methylchloroisothiazolinone/methylisothiazolinone mixture, most frequently found as allergens in hair care and intimate hygiene products, and facial cleansers (in the last category together with diazolidinyl urea). Octocrylene was by far the most frequent (photo)allergen in sun care products., Conclusions: This study provides information on the presence and frequency of allergens in specific causal cosmetic products., (© 2011 John Wiley & Sons A/S.)

Background: Formaldehyde and formaldehyde-releasers are common causes of allergic contact dermatitis., Objectives: To determine the frequency of sensitization to formaldehyde and seven formaldehyde-releasers. To establish and characterize groups of patients according to the results of patch testing., Materials and Methods: We performed a 5-year retrospective study, in six Spanish hospitals, of patients with positive patch test reactions to formaldehyde or any of seven formaldehyde-releasers., Results: The most frequent allergens were formaldehyde (1.72%), imidazolidinyl urea (1.05%), quaternium-15 (0.88%), and diazolidinyl urea (0.79%). Patients with sensitization to only formaldehyde had a higher frequency of occupational dermatitis (25%) than patients with sensitization to only formaldehyde-releasers (9.5%). The most common sites of dermatitis were the hands (31.7%) in patients with sensitization to only formaldehyde and the face and legs (31.3% and 24.6%) in patients with sensitization to only formaldehyde-releasers. We found a subgroup of 25 patients who were sensitized to both imidazolidinyl urea and diazolidinyl urea, and only 6 of these (24%) were also sensitized to formaldehyde., Conclusions: The inclusion of imidazolidinyl urea and diazolidinyl urea in the baseline series of the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) should enable better classification of patients allergic to formaldehyde, and could aid in their management., (© 2011 John Wiley & Sons A/S.)

Background: Allergic contact dermatitis in children is less recognized than in adults. However, recently, allergic contact dermatitis has started to attract more interest as a cause of or contributor to eczema in children, and patch testing has been gaining in recognition as a useful diagnostic tool in this group., Objectives: The aim of this analysis was to investigate the results of patch testing of selected children with eczema of various types (mostly atopic dermatitis) attending the Sheffield Children's Hospital, and to assess potential allergens that might elicit allergic contact dermatitis., Patients and Methods: We analysed retrospectively the patch test results in 110 children aged between 2 and 18 years, referred to a contact dermatitis clinic between April 2002 and December 2008. We looked at the percentages of relevant positive reactions in boys and girls, by age groups, and recorded the outcome of treatment following patch testing., Results: One or more positive allergic reactions of current or past relevance was found in 48/110 children (44%; 29 females and 19 males). There were 94 allergy-positive patch test reactions in 110 patients: 81 had a reaction of current or past relevance, 12 had a reaction of unknown relevance, and 1 had reaction that was a cross-reaction. The commonest allergens with present or past relevance were medicaments, plant allergens, house dust mite, nickel, Amerchol® L101 (a lanolin derivative), and 2-bromo-2-nitropropane-1,3-diol. However, finding a positive allergen was not associated with a better clinical outcome., Conclusions: We have shown that patch testing can identify relevant allergens in 44% of children with eczema. The commonest relevant allergens were medicament allergens, plant allergens, house dust mite, nickel, Amerchol® L101, and 2-bromo-2-nitropropane-1,3-diol. Patch testing can be performed in children as young as 2 years with the proper preparation., (© 2011 John Wiley & Sons A/S.)

Implantable disks for glaucoma treatment were prepared by blending poly(ɛ-caprolactone), PCL, poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) and dorzolamide. Their in vivo performance was assessed by their capacity to decrease intraocular pressure (IOP) in normotensive and hypertensive eyes. Drug mapping showed that release was complete from blend disks and the low molecular weight (MW) PCL after 1 month in vivo. The high MW PCL showed non-cumulative release rates above the therapeutic level during 3 months in vitro. In vivo, the fibrous capsule formation around the implant controls the drug release, working as a barrier membrane. Histologic analysis showed normal foreign body reaction response to the implants. In normotensive eyes, a 20% decrease in IOP obtained with the disks during 1 month was similar to Trusopt eyedrops treatment. In hypertensive eyes, the most sustained decrease was shown by the high MW PCL (40% after 1 month, 30% after 2 months). It was shown that the implants can lower IOP in sustained manner in a rabbit glaucoma model., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral treatment approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis (MS). The aim of this review was to provide a concise, comprehensive overview of the clinically relevant mechanism of action, efficacy and safety information available for fingolimod. Key data were derived from two international, Phase III, double-blind, randomised trials (TRANSFORMS and FREEDOMS) performed over 12 and 24 months, respectively, which evaluated fingolimod 0.5 and 1.25 mg daily in 1703 patients with relapsing forms of MS. In TRANSFORMS, there was a 52% reduction in the annualised relapse rate (ARR) with fingolimod 0.5 mg vs. 30 μg intramuscular interferon beta-1a (0.16 vs. 0.33; p < 0.001) at 1 year. In FREEDOMS, there was a 55% decrease in ARR at 2 years with fingolimod 0.5 mg vs. placebo (0.18 vs. 0.40; p < 0.001). Risk of disability progression, confirmed at 3 months, was also reduced by 30% over the 2-year study period with fingolimod vs. placebo (p = 0.02). Significantly fewer new or enlarged lesions on T(2) -weighted images were seen in both studies (TRANSFORMS, p = 0.002 vs. interferon beta-1a at 1 year; FREEDOMS, p < 0.001 vs. placebo at 2 years). Overall, fingolimod 0.5 mg was well tolerated by patients. Transient, generally asymptomatic bradycardia and infrequent atrioventricular block were seen with the administration of the first dose. Macular oedema and serious infections occurred infrequently. Reversible, asymptomatic elevations of liver enzymes could also occur. As the first approved oral disease-modifying treatment, fingolimod offers patients a convenient alternative to regular self-injection for the treatment of relapsing forms of MS. In addition to high efficacy with a relatively acceptable safety profile, fingolimod provides a therapy with a new mechanism of action., (© 2011 Blackwell Publishing Ltd.)

Oral fingolimod (Gilenya™), a sphingosine 1-phosphate (S1P) receptor agonist, is the first oral agent and the first in a novel class of disease-modifying therapies (DMTs) to be approved for use in the US for the treatment of relapsing forms of multiple sclerosis (MS). In the EU, fingolimod is approved for use as a single-agent DMT in selected patients with highly-active, relapsing-remitting (RR) MS. This article reviews the pharmacological properties and clinical use of the drug in patients with RRMS. Fingolimod is rapidly converted in vivo to the active moiety S-fingolimod-phosphate, which binds with high affinity to S1P receptors, thereby sequestering lymphocytes in the lymph nodes and preventing their egress into the peripheral circulation. As a consequence, there is a reduction in the infiltration of autoaggressive lymphocytes into the CNS. Fingolimod-phosphate also acts as a functional antagonist, as its binding to S1P receptors results in their internalization and degradation, thereby downregulating S1P receptors on the lymphocyte cell surface. Since fingolimod crosses the blood : brain barrier, it also potentially acts at S1P receptors on neural cells in the CNS to mitigate neuropathological processes associated with MS. In large multinational trials in adult patients with RRMS, oral fingolimod 0.5 mg/day was more effective than oral placebo (FREEDOMS) and recommended dosages of intramuscular interferon-β (IFNβ)-1a (TRANSFORMS) in reducing the annualized relapse rate and was also generally more effective at slowing progression of neurological disability and at reducing the burden and activity of disease. Fingolimod was generally well tolerated in these trials of up to 2 years' duration, with most adverse events being manageable and of mild to moderate severity; there were two deaths from opportunistic infections, albeit these occurred with fingolimod 1.25 mg/day (higher than the recommended dosage). Limited long-term data indicated that no new safety concerns had arisen after 5 years of fingolimod treatment. However, further clinical experience is required to fully determine the long-term safety profile of fingolimod, particularly with regard to any potentially serious or life-threatening adverse events. In the absence of robust pharmacoeconomic studies and of head-to-head trials comparing fingolimod with other formulations of IFNβ and glatiramer acetate, the relative position of fingolimod with respect to other DMTs remains to be fully determined. In the meantime, given its convenient once-daily oral treatment regimen and better efficacy than intramuscular IFNβ-1a, fingolimod is a valuable emerging option for the treatment of adult patients with relapsing forms of MS.

In the absence of a better alternative, subcutaneous interferon beta is the standard first-line treatment for relapsing-remitting multiple sclerosis. Fingolimod, an oral immunosuppressant that reduces the circulating lymphocyte count, is in the process of receiving marketing authorisation for this use in the European Union. Initial clinical evaluation is based on 2 trials. In a 12-month, comparative, double-blind, randomised trial including 1292 patients daily treatment with oral fingolimod (0.5 mg or 1.25 mg) modestly prolonged the interval between exacerbations compared to weekly intramuscular injections of interferon beta-1a: about one exacerbation prevented every 6 years. No tangible impact on progression of disability was observed. A double-blind placebo-controlled trial that lasted 2 years also showed a statistically significant reduction in the annual frequency of exacerbations. There was no firm evidence that fingolimod had a tangible effect on progression of disability. An indirect comparison suggests that the impact of fingolimod on exacerbations is roughly similar to that of cladribine, another oral immunosuppressant that received a negative opinion in this indication from the European Medicines Agency. Several short-term adverse effects consistent with the pharmacological action of fingolimod and the results of animal pharmacology studies were observed in clinical trials, including infections (especially herpetic), pulmonary disorders, cardiac conduction disorders and macular oedema. A risk of lymphoma and heart failure is possible in the longer term. Given the modest gain in efficacy compared with interferon beta (based on weak supporting evidence) and the major adverse effects of fingolimod, it is better to continue to use interferon beta for initial treatment of relapsing-remitting multiple sclerosis, and to reserve fingolimod for use in clinical trials in which patients are closely monitored.

Oral fingolimod signals the sphingosine 1-phosphate receptor and this in turn mediates immunomodulatory activity. No data of fingolimod in any pediatric population existed before this study. We put our study results in perspective against data from adult renal transplant patients. We investigated pharmacokinetics and pharmacodynamics of single-dose fingolimod (0.07 mg/kg) and its effects on lymphocytes and heart rate in seven adolescents (14.1 ± 1.6 yr) with stable renal transplants. Blood samples for pharmacokinetics and lymphocytes were collected at screening, baseline, and up to 28 days post-dosing. Cardiac monitoring included 12-lead ECG, 24-h Holter monitoring, and echocardiography. A fingolimod dose of 0.07 mg/kg resulted in mean AUC of 731 ± 240 ng·h/mL and C(max) of 3.6 ± 0.6 ng/mL. Drug exposure was nearly identical to adults receiving the same dose. Absolute lymphocyte count decreased 85% from baseline; average nadir occurred by six h post-dose. Heart rate decreased from 74 bpm (predose mean) to 53 bpm (nadir) three h post-dose. Mean heart rates recovered by Day 14 (75 bpm). Weight-adjusted doses of fingolimod in adolescents resulted in drug exposure similar to adults. Adolescents and adults shared comparable negative chronotropic effects and decreased lymphocyte count. Recovery trajectories of these parameters back to baseline were similar between age groups., (© 2011 John Wiley & Sons A/S.)

Purpose: This scoping review assesses the literature and summarizes the current evidence on sclerotherapy for the treatment of lymphatic malformations in pediatric patients., Methods: A comprehensive search of published and unpublished literature was conducted using multiple databases. Title, abstract, and full-text screening was conducted by 2 independent clinicians. All discrepancies were resolved during consensus meetings., Results: A total of 182 articles were retrieved. Forty-four articles were removed as duplicates, and 11 articles were added after reviewing prominent studies. After full-text abstraction, 44 articles and 2 conference proceedings (N = 882 patients) were included in the final results. Twelve articles were classified as level II and 34 articles as level IV evidence. Picibanil (OK-432) was the primary agent used in most included studies. Postinjection symptoms with OK-432 were primarily fever, swelling, and erythema at the site. Life-threatening complications were uncommon and involved postinjection swelling of cervical lesions causing airway compromise., Conclusions: The literature regarding sclerotherapy for lymphatic malformations is of a low level of evidence and suffers from a lack of standardization. Randomized clinical trials focused on OK-432, bleomycin, or alcoholic solution of zein; standardized dosing protocols; and consistent and reliable outcome reporting will be necessary for further development of treatment guidelines., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod-phosphate (fingolimod-P), is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod-P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P₁ S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti-inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10x the approved 0.5 mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies., (Copyright © 2011 American Neurological Association.)

This paper presents a summary of the current knowledge of the mechanism of action of fingolimod (FTY720; Gilenya®; Novartis Pharma Stein AG, Stein, Switzerland) and the phase 2 and 3 studies that have been performed on the drug. This study will discuss specific safety issues that should be considered when initiating this therapy. Multiple sclerosis (MS), an inflammatory disease of the central nervous system, is considered to be a leading cause of neurologic disability in young adults, and predominantly affects young women. The past two decades have seen significant growth in therapeutic options for relapsing forms of MS, including FTY720. Fingolimod (FTY720) is a sphingosine-1-phosphate receptor modulator, and currently the approved dosage is 0.5 mg daily. Notable side effects include bradycardia in the first hours after administration and macular edema. There may be an increased risk of herpetic infections (varicella zoster virus and herpes simplex virus) associated with this medication. This oral therapy has been shown to be effective in double-blind, placebo-controlled studies, and in trials comparing it to weekly interferon beta-1a therapy. However, the long-term efficacy and safety of this oral medication in relapsing MS, including the effect on reduction of disability progression and cognitive decline, remains to be established.