Category Prednisone Side Effect

Treatment of chronic non-infectious uveitis and scleritis

<h1>Treatment of chronic non-infectious uveitis and scleritis</h1>

Treatment of chronic non-infectious uveitis and scleritis

a Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Ophthalmology Department, University of Lausanne, Switzerland b Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, Switzerland Summary Ocular inflammations such as uveitis and scleritis can lead to significant visual impairment if not treated properly. To limit potentially sight-threatening complications, good control of the inflammation in the acute phase is necessary. Corticosteroids have been the mainstay of ocular therapies for many years, but high doses of corticosteroids, which are required to maintain quiescence in severe uveitis, can be associated with many systemic and ocular complications. In order to limit steroid side-effects, classic immunosuppressant and immunobiologic agents have been widely used as steroid-sparing agents. In this review, we summarise the immunosuppressive drug therapy utilised in the treatment of ocular inflammatory diseases. Keywords: uveitis, scleritis, azathioprine, methotrexate, mycophenolate mofetil, immunosuppressive agents, anti-TNF agents, biological therapy Introduction Ocular inflammatory diseases, such as severe uveitis and scleritis, may require intense immunosuppressive therapy to control ocular inflammation and prevent irreversible visual impairment. Non-infectious uveitis consists of a wide group of ocular inflammatory diseases and ocular complications and accounts for 10‒15% of preventable blindness in developed countries [ 1 , 2 ]. Ocular inflammation may be restricted to the eye or can be associated with systemic disease. According to the Standardization of Uveitis Nomenclature (SUN) working group, uveitis can be classified, according to the primary anatomical location of the inflammation, as anterior, intermediate, posterior, or panuveitis when affecting all three areas [ 3 ]. Intermediate, posterior and panuveitic disease have a higher risk of vision loss compared to anterior uveitis. Recent epidemiological data give yearly incidences of uveitis of between 14 and 17 per 100,000. The prevalence is between 58 and 115 per 100,000 [ 4 – 6 ]. The large variation in prevalence is due to variation in diagnostic workup, heterogeneity of the disease, lack of uniform classification and referral or selection bias [ 7 ]. The median age of onset of uveitis is around 35 years [ 8 ]. About 35% of all uveitis patients have been reported to suffer significant visual impairment or legal blindness [ 1 , 9 ]. Prompt therapy and rapid control of ocular inflammation are the key to maintaining good visual acuity. Uveitis and scleritis can have a devastating effect on visual acuity. Before the era of corticosteroids, about 50% of juvenile idiopathic arthritis-associated uveitis cases had a poor visual outcome of legal blindness [ 10 , 11 ]. Corticosteroids have been the mainstay of ocular therapies for many years, but high doses of corticosteroids are necessary to maintain quiescence in severe uveitis, particularly in severe ocular inflammatory diseases. However, their long-term use is associated with many systemic and ocular complications. Common systemic complications include cortico-induced diabetes, systemic hypertension, osteoporosis and mood disorders [ 12 ]. Ocular complications include cataracts and a rise of ocular pressure in steroid responder patients. The risk of ocular hypertension increases with the potency of the steroids and is directly related to the administered dose. In order to limit steroid side-effects, classic immunosuppressant agents have been widely used as steroid-sparing agents, particularly with steroid doses still over 10mg/day after six months of therapy [ 13 – 15 ]. Current disease-modifying antirheumatic drugs (DMARDs) include methotrexate, mycophenolate mofetil, cyclosporine A and azathioprine. However, in severe uveitis, systemic steroid therapy remains necessary to control ocular inflammation. The recent development of biological agents, particularly anti-TNFα agents, has opened up a new era in the treatment of uveitis. The aim of this paper is to review recent ophthalmological literature concerning new treatment modalities for non-infectious uveitis and scleritis, and to offer a practical guide for internists and general practitioners. Uveitis generalities The standardization of uveitis nomenclature (SUN) project considerably improved the assessment of drug efficacy in uveitis, with classification based on the primary site of inflammation within the eye and standardised use of clinical grading as a tool for assessing the degree of inflammation [ 3 ]. Uveitis can be classified as anterior, intermediate or posterior uveitis, according to the primary site of inflammation [ 3 ]. In anterior uveitis, the anterior chamber is the main site of inflammation and it includes iritis, iridocyclitis and anterior cyclitis. In intermediate uveitis, the vitreous is the main site of inflammation and it includes posterior cyclitis, hyalitis and pars planitis. Finally, posterior uveitis affects the retina and/or choroid. If all three eye segments are involved, the term panuveitis is used. Uveitis can also be classified, according to the type of presentation, as acute, recurrent or chronic [ 3 ]. In terms of etiology, the two major categories are infectious and non-infectious uveitis. The latter includes the following etiologies: sarcoidosis, Behçet’s disease, ankylosing spondylitis, inflammatory bowel disease, Juvenile idiopathic arthritis, seronegative arthropathy, reactive arthritis, multiple sclerosis and Vogt-Koyanagi-Harada syndrome. Scleritis generalities Scleritis is associated with a systemic inflammatory disease in over 50% of cases [ 16 ]. The disease is classified as anterior or posterior, diffuse or nodular, necrotising or non-necrotising and infectious or non-infectious [ 17 ]. In severe, non-infectious scleritis, therapy is mostly guided by the presence of an underlying systemic disease, mainly rheumatoid arthritis, relapsing polychondritis, granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and systemic lupus erythematosus. According to Baeten et al, disease entities should be classified by pathogenesis rather than phenotypic disease classification [ 18 ], but anatomical localisation of inflammation will also guide the speed of introduction of therapies. Necrotising scleritis (also referred to as scleromalacia perforans) associated with granulomatosis with polyangiitis or rheumatoid arthritis requires the introduction of bDMARDs such as rituximab at an early stage to avoid ocular perforation [ 19 ]. Treatments generalities To limit potentially sight-threatening complications, good control of the inflammation in the acute phase is necessary. Two strategies can be used to control intraocular inflammation, the classical “step-up” approach and the “top-down” approach. In the step-up approach, therapies are progressively introduced in a stepladder fashion until sufficient control of the intraocular inflammation is reached [ 20 ]. First-line therapy consists of topical corticosteroids. In the absence of response or if topical corticosteroids induce ocular hypertension/glaucoma or cataracts, systemic corticosteroids are introduced at an initial dosage of 1 mg/kg/day, followed by immunosuppressive drugs 2–3 months later, in an attempt to minimise corticosteroid systemic side effects (steroid-sparing agents) [ 20 ]. Immunosuppressive therapy is introduced in the following cases: to control inflammation in the case of failure of or insufficient response to treatment with corticosteroids, particularly in the case of high-risk uveitis syndrome, and/or to prevent cortico-induced toxicity (steroid-sparing agents). It should be noted that, despite an increasing number of randomised clinical trials studying the effectiveness of immunosuppressive therapies in uveitis, most of our knowledge in this area comes from retrospective studies. This is principally due to the large heterogeneity, and also the relative rarity, of uveitides. Several promising new treatments for inflammatory ocular diseases are under investigation, such as JAK inhibitors [ 21 ], but here we shall mainly focus on the currently approved treatments for inflammatory eye diseases, namely glucocorticoids, anti-metabolites (azathioprine, methotrexate and mycophenolate mofetil), T cell/calcineurin inhibitors (cyclosporine A) and biologics. Glucocorticoids Corticosteroids have inhibitory effects on a broad range of immune responses, via inhibitory effects on the gene transcription of several pro-inflammatory cytokines, effects on post-translational events, including the suppression of COX-2 synthesis, and also through the non-genomic activation of anti-inflammatory proteins [ 22 ]. In uveitis, corticosteroids can be used topically, periocularly, intraocularly or systemically. The limits and risks of local therapies compared to systemic therapies are the key factors determining the therapeutic decision. Local corticosteroids have an efficacy mainly on anterior uveitis, with poor efficacy on the posterior segment of the eye. Corticosteroids are associated with multiple ocular complications, such as ocular hypertension in steroid responder patients. Amarly et al demonstrated that about one third of patients had an increased ocular pressure after initiation of topical dexamethasone drops TID [ 23 ]. The severity of ocular hypertension is directly correlated with the potency of corticosteroids. The two topical steroids with the greatest potency, 0.1% dexamethasone and 1% prednisolone acetate, had the greatest effect on ocular pressure, with rises in IOP of 22.9 ± 2.9 and 10 ± 1.7 mmHg respectively [ 24 ]. A recent study was able to stratify the relative risk of ocular hypertension, which was directly correlated with the number of daily doses administered. With a mean administration of eight drops per day, the adjusted hazard ratio (HR) of increase in IOP was around eight in children, while one drop daily had almost no effect on ocular pressure, with an HR of 1 [ 25 ]. In the adult population, the same trend was observed but with lower limits, eight drops a day producing an HR of about 3 [ 26 ]. Periocular administration of corticosteroids is particularly interesting for the avoidance of systemic side effects. This consists of the subconjunctival injection of betamethasone, the sub-tenon injection of triamcinolone acetonide suspension and the intravitreal injection of a long-term dexamethasone delivery system, used for inflammatory cystoid macular edema in particular [ 27 ]. Periocular or intraocular steroid injections are, however, mainly used as adjuvant therapy to systemic therapies [ 28 ]. Systemic steroid therapy is reserved for bilateral, intermediate and posterior uveitis, panuveitis, or any form of sight-threatening uveitis. The classical dosage is 1–1.5 mg/kg/day of prednisone/prednisolone p.o. or 250‒1,000 mg of methylprednisolone IV daily for three days, followed by oral therapy [ 29 ]. The rate of corticosteroid decrease should be adapted by ophthalmologists according to the uveitis activity and should not be more than 10% every 2-3 weeks to avoid a relapse of inflammation. Cyclosporine A Cyclosporine A (CycA) is a lipophilic cyclic peptide, comprised of 11 amino acids and derived from fungi, which selectively inhibits calcineurin, thereby impairing the transcription of interleukin-2, TNFα and several other cytokines in T lymphocytes. Unlike other immunosuppressive agents such as azathioprine and the alkylating agents, CycA lacks clinically significant myelosuppressive activity [ 30 ]. Calcineurin inhibitors have been used for immunosuppression in solid organ transplantation for over three decades. Nephrotoxicity and arterial hypertension represent the major side effects of cyclosporine [ 31 ]. Classical dosage for ophthalmologic indications is 150–200 mg/day (2.5–5 mg/kg/day). Typical ocular indications for CycA are ocular Behçet’s disease, birdshot chorioretinopathy, ocular sarcoidosis, pars planitis, VKH syndrome, tubulointerstitial nephritis and uveitis syndrome (TINU), sympathetic ophthalmia, idiopathic posterior uveitis, peripheral ulcerative keratitis and scleritis (particularly in GPA) [ 20 ]. However, in recent studies, biological therapies such as anti-TNFα agents were preferred for first-line therapy in sight-threatening uveitis, and cyclosporine was usually used as second- or third-line therapy [ 20 , 32 , 33 ]. Interestingly, CycA was shown to selectively attenuate Th17 cells, a T-helper memory-derived cell population that seems to play an important role in the mechanism of corticosteroid-resistance in inflammatory conditions. This finding opens up new possibilities for the development of drugs that could be used in cases of corticosteroid-resistant intraocular inflammation [ 34 ]. Azathioprine The prodrug azathioprine (AZA) is an immunosuppressive agent, metabolised in the liver to its active form 6-mercapto-purine, that inhibits maturation of B and T lymphocytes through its activity as an antagonist of purine metabolism, resulting in the inhibition of DNA, RNA, and consequently protein synthesis. AZA is widely used in the management of uveitis [ 35 , 36 ]. AZA is generally used at an initial dose of 1mg/kg/day, and the dose is then progressively increased to 2‒2.5mg/day in the absence of haematological and hepatic adverse events. AZA has been shown to successfully controlled ocular inflammatory disease in 62% of patients [ 37 ]. As AZA is moderately effective for controlling inflammation when used in monotherapy, it is typically used in combination with other immunosuppressive agents. AZA seems to be more effective in patients with intermediate uveitis (90% with sustained inactivity within one year) [ 37 ]. AZA is typically prescribed for juvenile idiopathic arthritis (JIA) iridocyclitis, Behçet’s disease, GPA, sympathetic ophthalmia, VKH’s syndrome, ocular sarcoidosis and pars planitis. Patients under AZA should be regularly monitored with a complete blood counts and hepatic tests. Both AZA and CicA are considered safe options for pregnant women that need to pursue treatment in sight-threatening ocular inflammatory disease. Methotrexate Methotrexate (MTX) is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR), thereby interfering with purine and pyrimidine metabolism and therefore inhibiting DNA and RNA synthesis, DNA repair and cell division. At lower doses MTX achieves anti-inflammatory effects. MTX can be administered for ocular sarcoidosis, JIA-associated uveitis, reactive arthritis-, ankylosing spondylitis- and inflammatory bowel disease (IBD)-associated uveitis, scleritis, and sympathetic ophthalmia [ 20 ]. It can be used as a first-line corticosteroid-sparing drug or in combined therapy. MTX has been shown to successfully control ocular inflammation in 66-76.2% of patients in combination with low doses of corticosteroids (<10 mg/day) [ 38 , 39 ]. In a prospective study of a large cohort of 3,512 JIA patients, Tappeiner et al. showed that the early use of MTX or MTX + TNFα inhibitors within the first year of active arthritis has a highly protective effect against development of uveitis [ 40 ]. In adults, MTX should be preferentially administered as weekly subcutaneous injections. Biodisponibility of oral MTX is erratic, digestive side-effects are common and there is a risk of accidental daily intake. Subcutaneous MTX is started at an initial dose of 7.5–15 mg/week and may be increased to 20–25 mg/week. Five mg of oral folic acid is administered the day after the weekly MTX injection to limit haematologic toxicity. The main side effects of MTX include myelosuppression (leucopenia and thrombocytopenia) due to folic acid antagonism, infections, liver toxicity and pneumonitis. MTX is contra-indicated in pregnancy. Mycophenolate mofetil Mycophenolate mofetil (MMF) is a selective inhibitor of inosine monophosphate dehydrogenase that interrupts guanosine synthesis. It suppresses T and B lymphocyte proliferation, reduces antibody production and inhibits transmigration of leukocytes. This drug is used as an anti-rejection drug in transplant patients and has shown efficacy in the treatment of systemic autoimmune disease [ 41 ]. MMF has been widely tested for treating refractory uveitis and severe scleritis [ 42 ]. Complete control of inflammation was achieved in 53% of patients at six months and 73% within one year [ 43 , 44 ]. MMF is teratogenic, and contraceptive measures are needed in women of child-bearing age. Anti-TNFα TNFα is a pleiotropic, pro-inflammatory cytokine which plays an important role not only in host defence against intracellular pathogens, but also in the pathogenesis of numerous inflammatory diseases such as non-infectious uveitis (NIU). TNFα was shown to be up-regulated in the aqueous humour and serum of patients with uveitis and is thought to play a key role in the physiopathology of uveitic inflammation [ 45 ]. At the molecular level, TNFα is synthetised as a transmembrane protein that is then cleaved by a TNFα converting enzyme (TACE) to release soluble TNFα. TNFα exerts its function by acting on two distinct receptors: TNF receptor 1 (TNFR1) and TNFR2. The understanding of TNFα-induced signalling has been enriched in the last few decades, revealing the formation of distinct signalling protein complexes that lead to different functional outcomes such as inflammation, apoptosis and necroptosis [ 46 ]. Interestingly, TNFR1 binds both soluble (sTNFα) and membrane bound TNFα (mTNFα), and principally mediates inflammation and cell death. In contrast, TNFR2 binds only mTNFα and plays a role in tissue homeostasis, regeneration and immune regulation. The current approved anti-TNFα treatments inhibit both pathways and therefore interfere with the homeostatic functions of TNFα. A new concept in the therapeutics of TNF-mediated diseases is to selectively inhibit the pathogenic effects of TNFα, preserving its homeostatic functions by targeting specifically sTNFα or TNFR1 [ 47 ]. Currently, five biologic agents targeting TNFα are approved for the treatment of rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis and juvenile idiopathic arthritis (JIA). These are infliximab (Remicade ® ), adalimumab (Humira ® ), certolizumab pegol (Cimzia ® ), golimumab (Simponi ® ) and etanercept (Enbrel ® ) [ 46 ]. In addition to the approved indications, anti-TNFα is also used, off-label, in sarcoidosis, Behçet disease, non-infectious ocular inflammation, pyoderma gangrenosum and in patients with TNF receptor-associated periodic fever syndrome (TRAPS) and adult-onset Still’s disease [ 48 ]. To date, adalimumab (Humira ® ) is the only immunobiologic agent that has been approved in Switzerland in the indication of non-infectious intermediate or posterior uveitis, or panuveitis, as a corticosteroid sparing agent in the absence of adequate response to corticosteroids with or without immunosuppressive agents. Recent studies have shown the beneficial role of the anti-TNFα adalimumab in active and inactive, non-infectious intermediate and posterior uveitis and panuveitis (NIIPPU). The VISUAL I study, a multicentre, double-masked, randomised, placebo-controlled phase 3 trial, showed that patients with active NIIPPU who were treated with adalimumab presented a lower risk of uveitic flare or visual impairment than patients who received a placebo [ 49 ]. The parallel study, VISUAL II, a multicentre, double-masked, randomised, placebo-controlled phase 3 trial, showed that adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive NIIPPU controlled by systemic corticosteroids [ 50 ]. VISUAL III is the open label extension of VISUAL I and II. This study was able to demonstrate a numerical improvement in steroid-free quiescence and steroid dose reduction [ 51 ]. Finally, among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate, the SYCAMORE study showed control of inflammation in the adalimumab treated group compared with a placebo, as observed in the adult population [ 52 ]. Anti-TNFα represents an extraordinarily effective treatment for many auto-immune diseases, including NIIPPU, even though these compounds may, in rare cases, cause autoimmune conditions such as drug-induced lupus (DIL), demyelinating disease, autoimmune hepatitis, psoriasis and even uveitis [ 53 ]. The mechanisms underlying these auto-immune conditions is unclear, but could be partially due to the TNFα antagonists-induced production of autoantibodies such as antinuclear antibodies (ANA) and anti-double-stranded DNA antibodies (anti-dsDNA) [ 54 , 55 ]. The risk of developing auto-antibodies is lower if TNFα antagonists are administered in combination with an immunosuppressive treatment, such as MTX. The exact molecular mechanisms responsible for autoantibody formation remain unknown. Multiple sclerosis-associated uveitis (MS-associated uveitis) may be present in 5-16% of intermediate uveitis cases [ 56 ]. A brain MRI should be performed in the presence of uveitis associated with neurologic systemic symptoms in order to rule out the presence of MS before the introduction of an anti-TNF agent. According to the SABER Study, a retrospective, population-based cohort study, optic neuritis is rare among patients who initiate anti-TNF therapy, and occurs with similar frequency among those with classic immunosuppressant exposure [ 57 ]. Finally, the use of monoclonal antibody therapies targeting TNFα can result in immunisation, with the apparition of anti-drug antibodies. The latter may give rise to low serum drug levels, loss of therapeutic response, and adverse events such as infusion reactions. The use of concomitant MTX may attenuate the frequency of anti-drug antibodies (ADA) [ 58 ]. The ARMADA trial showed an incidence of anti-adalimumab antibodies lower than 1% in rheumatoid arthritis patients who were taking concomitant MTX, compared to an incidence of 12% in patients treated with adalimumab as monotherapy [ 59 , 60 ]. Conclusion In summary, non-infectious uveitides represent a heterogenous group of ocular inflammatory diseases affecting a broad range of age groups, with a high potential for blindness if not treated adequately. Increasing evidence supports the effectiveness and safety of using immunosuppressive drug therapy to treat ocular inflammatory diseases. The antimetabolites (AZA, MTX) and the biologics (anti-TNFα), in particular, appear to offer the best balance between effectiveness and safety, and represent an excellent alternative to corticosteroid therapy. 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Ophthalmology. 2009;116(11):2188–98.e1. doi:. http://dx.doi.org/10.1016/j.ophtha.2009.04.020 PubMed 39 Samson CM, Waheed N, Baltatzis S, Foster CS. Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients. Ophthalmology. 2001;108(6):1134–9. doi:. http://dx.doi.org/10.1016/S0161-6420(01)00576-0 PubMed 40 Tappeiner C, Schenck S, Niewerth M, Heiligenhaus A, Minden K, Klotsche J. Impact of Antiinflammatory Treatment on the Onset of Uveitis in Juvenile Idiopathic Arthritis: Longitudinal Analysis From a Nationwide Pediatric Rheumatology Database. Arthritis Care Res (Hoboken). 2016 ;68(1):46–54. 41 Lipsky JJ. Mycophenolate mofetil. Lancet. 1996;348(9038):1357–9. doi:. http://dx.doi.org/10.1016/S0140-6736(96)10310-X PubMed 42 Kilmartin DJ, Forrester JV, Dick AD. Rescue therapy with mycophenolate mofetil in refractory uveitis. Lancet. 1998;352(9121):35–6. doi:. http://dx.doi.org/10.1016/S0140-6736(05)79515-5 PubMed 43 Sobrin L, Christen W, Foster CS. Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis. Ophthalmology. 2008 Aug;115(8):1416–21–1421. 44 Teoh SC, Hogan AC, Dick AD, Lee RWJ. Mycophenolate mofetil for the treatment of uveitis. Am J Ophthalmol. 2008 Nov;146(5):752–60–760. 45 Santos Lacomba M, Marcos Martín C, Gallardo Galera JM, Gómez Vidal MA, Collantes Estévez E, Ramírez Chamond R, et al.Aqueous humor and serum tumor necrosis factor-alpha in clinical uveitis. Ophthalmic Res. 2001;33(5):251–5. doi:. http://dx.doi.org/10.1159/000055677 PubMed 46 Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12(1):49–62. doi:. http://dx.doi.org/10.1038/nrrheum.2015.169 PubMed 47 Fischer R, Kontermann R, Maier O. Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy. Antibodies. Multidisciplinary Digital Publishing Institute. 2015;4(1):48–70. 48 Karampetsou MP, Liossis S-NC, Sfikakis PP. TNF-α antagonists beyond approved indications: stories of success and prospects for the future. QJM. 2010;103(12):917–28. doi:. http://dx.doi.org/10.1093/qjmed/hcq152 PubMed 49 Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in Patients with Active Noninfectious Uveitis. N Engl J Med. 2016 Sep 8;375(10):932–43. 50 Nguyen QD, Merrill PT, Jaffe GJ, Dick AD, Kurup SK, Sheppard J, et al.Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388(10050):1183–92. doi:. http://dx.doi.org/10.1016/S0140-6736(16)31339-3 PubMed 51 Suhler EB, Adán A, Brézin AP, Fortin E, Goto H, Jaffe GJ, et al.Safety and Efficacy of Adalimumab in Patients with Noninfectious Uveitis in an Ongoing Open-Label Study: VISUAL III. Ophthalmology. 2018;125(7):1075–87. doi:. http://dx.doi.org/10.1016/j.ophtha.2017.12.039 PubMed 52 Ramanan AV, Dick AD, Jones AP, McKay A, Williamson PR, Compeyrot-Lacassagne S, et al.; SYCAMORE Study Group. Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis. N Engl J Med. 2017;376(17):1637–46. doi:. http://dx.doi.org/10.1056/NEJMoa1614160 PubMed 53 Alessandri C, Scrivo R, Spinelli FR, Ceccarelli F, Magrini L, Priori R, et al. Autoantibody production in anti-TNF-alpha-treated patients. Ann N Y Acad Sci. 2007 Sep;1110(1):319–29. 54 Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum. 2000 Nov;43(11):2383–90. 55 De Rycke L, Kruithof E, Van Damme N, Hoffman IEA, Van den Bossche N, Van den Bosch F, et al. Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy. Arthritis Rheum. Wiley-Blackwell; 2003 Apr;48(4):1015–23. 56 Zein G, Berta A, Foster CS. Multiple sclerosis-associated uveitis. Ocul Immunol Inflamm. 2004;12(2):137–42. doi:. http://dx.doi.org/10.1080/09273940490895344 PubMed 57 Winthrop KL, Chen L, Fraunfelder FW, Ku JH, Varley CD, Suhler E, et al.Initiation of anti-TNF therapy and the risk of optic neuritis: from the safety assessment of biologic ThERapy (SABER) Study. Am J Ophthalmol. 2013;155(1):183–189.e1. doi:. http://dx.doi.org/10.1016/j.ajo.2012.06.023 PubMed 58 Jani M, Barton A, Warren RB, Griffiths CEM, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford). 2014;53(2):213–22. doi:. http://dx.doi.org/10.1093/rheumatology/ket260 PubMed 59 Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003 Jan;48(1):35–45. 60 van de Putte LBA, Atkins C, Malaise M, Sany J, Russell AS, van Riel PLCM, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis. 2004 May;63(5):508–16. Copyright
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Comment on Understanding asthma pathophysiology, diagnosis, and management by Sagar

<h1>Comment on Understanding asthma pathophysiology, diagnosis, and management by Sagar</h1>

Comment on Understanding asthma pathophysiology, diagnosis, and management by Sagar

Understanding asthma pathophysiology, diagnosis, and management July 2015 Vol. 10 No. 7
Author(s):
A chronic inflammatory airway disorder, asthma is marked by airway hyperresponsiveness with recurrent episodes of wheezing, coughing, tightness of the chest, and shortness of breath. Typically, these episodes are associated with airflow obstruction that may be reversed spontaneously or with treatment.
Asthma affects approximately 300 million people around the world. In children, males have a higher asthma risk; in adults, females have a higher prevalence.
Experts believe asthma results from various host factors, environmental factors, or a combination. Host factors include gender, obesity, and genetics. Genetic factors include atopy. Defined as a genetic tendency to develop allergic diseases, such as asthma and allergic rhinitis, atopy commonly is linked to an immunoglobulin E (IgE)–mediated response to allergens. Pathophysiology
Understanding asthma pathophysiology helps you understand how the condition is diagnosed and treated. Our knowledge of asthma pathogenesis has changed dramatically in the last 25 years, as researchers have found various asthma phenotypes.
Asthma involves many pathophysiologic factors, including bronchiolar inflammation with airway constriction and resistance that manifests as epi­sodes of coughing, shortness of breath, and wheezing. Asthma can affect the trachea, bronchi, and bronchioles. Inflammation can exist even though obvious signs and symptoms of asthma may not always occur.
Bronchospasms, edema, excessive mucus, and epithelial and muscle damage can lead to bronchoconstriction with broncho­spasm. Defined as sharp contractions of bronchial smooth muscle, bronchospasm causes the airways to narrow; edema from microvascular leakage contributes to airway narrowing. Airway capillaries may dilate and leak, increasing secretions, which in turn causes edema and impairs mucus clearance. (See How bronchospasm constricts the airway .)
Asthma also may lead to an increase in mucus-secreting cells with expansion of mucus-secreting glands. Increased mucus secretion can cause thick mucus plugs that block the airway. Injury to the epithelium may cause epithelial peeling, which may result in extreme airway impairment. Loss of the epithelium’s barrier function allows allergens to penetrate, causing the airways to become hyperresponsive—a major feature of asthma. The degree of hyperresponsiveness depends largely on the extent of inflammation and the individual’s immunologic response.
Asthma also causes loss of enzymes that normally break down inflammatory mediators, with ensuing reflexive neural effects from sensory nerve exposure. Without proper treatment and control, asthma may cause airway remodeling leading to changes to cells and tissues in the lower respiratory tract; these changes cause permanent fibrotic damage. Such remodeling may be irreversible, resulting in progressive loss of lung function and decreased response to therapy. Classifying asthma
Asthma may be atopic, nonatopic, or a combination. Atopic asthma begins in childhood and is linked to triggers that initiate wheezing. It may arise after exposure and response to a specific allergen, such as dust mites, grass or tree pollen, pet dander, smoke, or certain drugs or foods. On exposure to a trigger, excessive release of IgE occurs, which initiates B-lymphocyte activation. IgE binds to cells related to inflammation. This action causes release of inflammatory mediators (such as chemokines, nitric oxide, prostaglandin D2, cyto­kines, histamine, and leuko­trienes), in turn triggering airway inflammation and bronchoconstriction. Women who smoke during pregnancy may predispose their unborn children to higher IgE levels, causing hyperresponsiveness and asthma development. Exposure to pollution may have the same effect. Nonatopic asthma doesn’t involve an IgE response. It may have fewer obvious triggers and usually occurs in adults, possibly secondary to a viral infection. Diagnosis
Asthma diagnosis goes beyond symptoms, such as coughing, chest tightness, wheezing, and dyspnea—and even beyond signs and symptoms that worsen at night and improve after treatment. Diagnosis may require pulmonary function tests (PFTs) and peak expiratory flow (PEF) measurements. With asthma, the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC, also called FEV1%) typically declines.
Asthma symptoms can be reversed by a rapid-acting beta2-agonist, such as albuterol, as measured by spirometry. The generally acceptable response to beta2-agonists is a 12% or 200-mL increase in FEV1 or FVC. PEF measurements not only aid diagnosis but also help clinicians monitor the disease.
Some patients with asthma signs and symptoms may have normal PFT results. They may need further diagnostic testing, such as airway response testing using a bron­chial challenge. (See Bronchial challenge .)
Clinicians must rule out other conditions that may decrease FEV1 and cause signs and symptoms that mimic asthma. These conditions include vocal cord dysfunction, gastroesophageal reflux disease, ischemic cardiac pain, chronic obstructive pulmonary disease, heart failure, upper-airway obstruction, cystic fibrosis, hyperventilation, and foreign-body aspiration. Viral respiratory infections may lead to asthma exacerbations or contribute to eventual development of the disorder. Management
Asthma management involves both acute and long-term treatment. Medication selection hinges on the patient’s age, disease severity, and comorbidities.
Be sure to obtain a complete medication history before the patient starts taking asthma medications. Some drugs, including beta-blockers, angiotensin-converting enzyme inhibitors, cholinergics, and nonpotassium-sparing diuretics, may be contraindicated for patients receiving certain asthma agents. Rescue (quick-relief) drugs
Meant for short-term symptom relief, rescue drugs cause bronchodilation and are used mainly to prevent or treat an asthma attack. They begin working within minutes and may remain effective for up to 6 hours. Potential side effects include jitteriness and palpitations. Rescue drugs include ipratropium bromide inhaler (Atrovent), short-acting beta2-agonists, and oral corticosteroids. Ipratropium bromide, an anticholinergic, may be given in combination with short-acting beta2-agonists in some cases. Beta2-agonists used for quick relief include albuterol, levalbuterol, metaproterenol, and terbutaline. Oral corticosteroids, such as prednisone and methylprednisolone, sometimes are used for brief periods during acute asthma attacks that don’t respond to usual treatments. Long-term use can lead to high blood pressure, muscle weakness, cataracts, osteoporosis, decreased ability to resist infection, and reduced growth in children. Long-term control agents
Used to prevent asthma attacks and control chronic symptoms, these agents include inhaled corticosteroids, leukotriene modifiers, long-acting beta-agonists (LABAs), theophylline, and combination inhalers that contain both a corticosteroid and an LABA. These drugs may take days or weeks to reach maximal effect.
Leukotriene modifiers help prevent symptoms for up to 24 hours. LABAs, which may last up to 12 hours, usually are given in combination with an inhaled corticosteroid, because when used alone they may lead to a severe asthma attack. LABAs also are prescribed to prevent nocturnal asthma symptoms, such as coughing. Theoph­ylline, given orally, acts as a bronchodilator and also is used to treat nocturnal symptoms. Patient education
Patient education is crucial in asthma management. Teach patients and their families how to use a peak flow meter, optimize environmental controls, and recognize asthma signs and symptoms. Stress the importance of smoking cessation. Urge patients to receive annual vaccinations, as asthma increases the risk of complications from respiratory diseases, such as pneumonia and influenza.
Selected references Asthma overview. American Academy of Allergy Asthma and Immunology. http://www.aaaai.org/conditions-and-treatments/asthma
Corbridge S, Corbridge TC. Asthma in adolescents and adults. Am J Nurs . 2010; 110(5):28-38.
Fanta CH. Treatment of acute exacerbation of asthma in adults. Last updated February 5, 2015. www.uptodate.com/contents/treatment-of-acute-exacerbations-of-asthma-in-adults
Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention (for Adults and Children Older than 5 Years). Updated 2015. www.ginasthma.org/local/uploads/files/GINA_Pocket_2015.pdf
Johnson J. Asthma assessment tips. J Nurse Pract . 2010;6(5):383-4.
Kaufman G. Asthma: pathophysiology, diagnosis and management. Nurs Stand . 2011; 26(5):48-56.
Martinez FD, Vercelli D. Asthma. Lancet Sem . 2013;382(9901):1360-72.
National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Section 2: Definition, pathophysiology and pathogenesis of asthma and natural history of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007; 1-24.
Pruitt B, Lawson R. Assessing and managing asthma: a Global Initiative for Asthma update. Nursing. 2011;41(5):46-52.
Shari J. Lynn and Kathryn Kushto-Reese are instructors at the Johns Hopkins University School of Nursing in Baltimore, Maryland. Related Articles:

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Myasthenia Gravis: Symptoms, Causes, Complications & Treatment

<h1>Myasthenia Gravis: Symptoms, Causes, Complications & Treatment</h1>

Myasthenia Gravis: Symptoms, Causes, Complications & Treatment

Chewing Causes Of Myasthenia Gravis
The disease is caused due to an autoimmune problem which occurs when your immune system mistakenly attacks the healthy tissue [11] [12] [13] . 1. Antibodies
For an individual suffering from myasthenia gravis, the antibodies (proteins) which are usually supposed to attack the foreign, harmful substances in the body will attack the neuromuscular junction. This damages the neuromuscular membrane, thereby reducing the effect of the neurotransmitter substance acetylcholine (a critical substance required for communication between nerve cells and muscles). As the antibodies block the function of the protein, it will lead to the development of myasthenia gravis. 2. Thymus gland
According to it some studies, it has been pointed out that the gland which is a part of the immune system can trigger as well as maintain the production of antibodies that block acetylcholine. The thymus gland is large in infancy and becomes smaller as one age. However, in adults with myasthenia gravis, the gland is abnormally large. 3. Other causes
In some people, myasthenia gravis is not caused by the antibodies blocking acetylcholine and is termed as antibody-negative myasthenia gravis. It is caused by antibodies that destroy the protein lipoprotein-related protein 4.
Genetic factors are also linked with the development of the condition. Rare cases have been reported where mothers with myasthenia gravis have children who are born with myasthenia gravis, which is also called as neonatal myasthenia gravis [14] . Risk Factors Of Myasthenia Gravis
Certain factors can worsen the symptoms of the condition. The risk factors pertaining to myasthenia gravis are as follows [15] : Stress Illness Fatigue Some medications such as beta blockers, quinidine gluconate, quinidine sulfate, quinine, phenytoin, and certain anaesthetics and antibiotics Complications Of Myasthenia Gravis
Though treatable, some of the complications pertaining to the condition have been deemed life-threatening [16] [17] . 1. Thymus tumours
Studies have revealed that about 15 per cent of individuals suffering from myasthenia gravis have a tumour in their thymus. The tumours are termed as thymomas and most are not cancerous. 2. Myasthenic crisis
A life-threatening condition, this occurs to people when their muscles that control the breathing becomes weak and thus, fails to function. If a person is suffering from the myasthenic crisis, emergency treatment is required so as to assist their breathing. 3. Other complications
Individuals suffering from the condition can develop complications such as underactive or overactive thyroid. If the thyroid is underactive, you may develop difficulties dealing with cold, weight gain and other issues. Likewise, if your thyroid is overactive, it can cause difficulties dealing with heat, weight loss etc. Apart from this, they can also develop autoimmune conditions such as rheumatoid arthritis or lupus. Diagnosis Of Myasthenia Gravis
In order to understand and examine your condition, the doctor will first review your symptoms and medical history. Then, the doctor will carry out a physical examination, and the following tests will be carried out [18] [19] [20] . 1. Neurological examination
Under this, the doctor will examine your neurological health by testing your reflexes, muscle strength, muscle tone, senses of touch and sight, coordination and balance. The neurological examination will test sensation in different areas of your body, as well as the motor functions, like touching your finger to your nose so as to understand if muscle weakness is there. 2. Ice pack test
Your doctor can conduct an ice pack test if you have a droopy eyelid. Under this test, the doctor will place a bag filled with ice on your eyelid. After a short span of two minutes, the doctor will remove the bag and analyse your droopy eyelid for any signs of improvement. 3. Edrophonium test
Under this test, the doctor will inject a chemical called edrophonium chloride. This is done so as to understand whether the muscle weakness is caused as a result of myasthenia gravis. If there is an improvement in your muscle movements, the doctor may conclude that the individual has myasthenia gravis. 4. Repetitive nerve stimulation
A nerve conduction study, this involves the doctors attaching the electrodes to your skin over the muscles so as to carry out the test. Small pulses of electricity will be sent through the electrodes in order to measure the nerve’s ability to send a signal to the muscles. 5. Blood analysis
Carrying out a blood test will help understand the doctor if there are any abnormal antibodies present, that can disrupt the receptor sites (where the nerve impulses signal the muscles to move). 6. Single-fibre electromyography (EMG)
This method will measure the electrical activity travelling between your brain and muscles. EMG involves inserting a thin wire electrode through the skin and into a muscle, so as to test a single muscle fibre. 7. Pulmonary function tests
This test is carried out by your doctor to examine whether your condition is affecting your breathing. Treatment For Myasthenia Gravis
As there is no significant cure for the condition, the goal is to manage and control the symptoms [21] [22] . 1. Medications
Your doctor will prescribe medications (cholinesterase inhibitors) such as pyridostigmine so as to improve the communication between your nerves and muscles. Corticosteroids such as prednisone will help in protecting the immune system by limiting the production of antibodies. Immunosuppressants such as azathioprine, mycophenolate mofetil, cyclosporine, methotrexate or tacrolimus will be prescribed to improve your immune system.
However, prolonged use of these medications can cause side effects such as gastrointestinal upset, nausea, and excessive salivation, sweating (cholinesterase inhibitors), bone thinning, weight gain, diabetes and increased risk of infections (corticosteroids), and vomiting, gastrointestinal upset, nausea, liver damage, increased risk of infection, and kidney damage (immunosuppressants). 2. Intravenous therapy
Under this, various procedures such as plasmapheresis, intravenous immunoglobulin (IVIg) and monoclonal antibody will be carried out. Plasmapheresis is similar to dialysis and helps in removing the antibodies that block transmission of signals. This will help the doctors in gaining access to your veins. IVIg and monoclonal antibody help in altering your immune system and thereby improving the symptoms pertaining to myasthenia gravis.
IVIg has certain mild side effects such as chills, dizziness, headaches and fluid retention. 3. Surgery
As aforementioned, about 15 per cent of people with myasthenia gravis have a tumour in the thymus gland (a gland under the breastbone that is involved with the immune system). If there is no tumour in the thymus gland, the surgery will help in improving your myasthenia gravis symptoms and help eliminate the symptoms. This can help you in stopping the medications.
The surgeries involved in the process are video-assisted thymectomy and robot-assisted thymectomy. These surgery methods in comparison to other methods are easy and better because it includes less blood loss, less pain, lower mortality rates and shorter hospital stay [23] .
*The treatment method suitable for you will be decided by your doctor. Certain factors such as your age, severity of your condition, the location of the muscles affected and other existing medical conditions have to be taken into consideration before finalising on the treatment method [24] . Lifestyle Changes And Home Remedies
Along with the medications prescribed for the condition, doctors advise that it is beneficial to take up measures which will help in dealing with the symptoms [25] .
Wear an eye patch : If you have double vision, the best measure is to wear an eye patch as it can help relieve the problem. Wear the patch while you write, read or watch television. Also, switch the eye patch to the other eye to help reduce the strain on your eyes, periodically.
Use safety precautions at home : Install support measures such as grab bars or railings in places around your house where you may need support (bathrooms, staircase). Keep your sidewalks and paths outside home clear of dried leaves or dirt, or any sort of debris that can cause a fall.
Adjust your eating routine : Try consuming food when you have muscle strength. Chew your food slowly, and take breaks in between. It is better to eat small meals and incorporate soft foods into your diet.
Use electric appliances and power tools : This will help you in reducing the time taken to cook or wash. Using appliances like an electric toothbrush can make your daily tasks easier [26] . View Article References [1] Jaretzki, A., Barohn, R. J., Ernstoff, R. M., Kaminski, H. J., Keesey, J. C., Penn, A. S., & Sanders, D. B. (2000). Myasthenia gravis: recommendations for clinical research standards. Neurology, 55(1), 16-23. [2] Lindstrom, J. M., Seybold, M. E., Lennon, V. A., Whittingham, S., & Duane, D. D. (1998). Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value. Neurology, 51(4), 933-933. [3] Simpson, J. A. (1960). Myasthenia gravis: a new hypothesis. Scottish Medical Journal, 5(10), 419-436. [4] Fambrough, D. M., Drachman, D. B., & Satyamurti, S. (1973). Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science, 182(4109), 293-295. [5] Jaretzki 3rd, A., Penn, A. S., Younger, D. S., Wolff, M., Olarte, M. R., Lovelace, R. E., & Rowland, L. P. (1988). ” Maximal” thymectomy for myasthenia gravis. Results. The Journal of thoracic and cardiovascular surgery, 95(5), 747. [6] Castleman, B. (1966). The pathology of the thymus gland in myasthenia gravis. Annals of the New York Academy of Sciences, 135(1), 496-503. [7] Bhanushali, M. J., Wuu, J., & Benatar, M. (2008). Treatment of ocular symptoms in myasthenia gravis. Neurology, 71(17), 1335-1341. [8] Gilhus, N. E., & Verschuuren, J. J. (2015). Myasthenia gravis: subgroup classification and therapeutic strategies. The Lancet Neurology, 14(10), 1023-1036. [9] Dau, P. C., Lindstrom, J. M., Cassel, C. K., Denys, E. H., Shev, E. E., & Spitler, L. E. (1977). Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. New England Journal of Medicine, 297(21), 1134-1140. [10] Lefvert, A. K., Bergström, K., Matell, G., Osterman, P. O., & Pirskanen, R. (1978). Determination of acetylcholine receptor antibody in myasthenia gravis: clinical usefulness and pathogenetic implications. Journal of Neurology, Neurosurgery & Psychiatry, 41(5), 394-403. [11] Yan, M., Liu, Z., Fei, E., Chen, W., Lai, X., Luo, B., … & Xiong, W. C. (2018). Induction of anti-agrin antibodies causes myasthenia gravis in mice. Neuroscience, 373, 113-121. [12] Phillips, W. D., & Vincent, A. (2016). Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Research, 5. [13] Sussman, J., Farrugia, M. E., Maddison, P., Hill, M., Leite, M. I., & Hilton-Jones, D. (2015). Myasthenia gravis: Association of British Neurologists’ management guidelines. Practical neurology, 15(3), 199-206. [14] Cron, M. A., Maillard, S., TRUFFAULT, F., Gualeni, A. V., Gloghini, A., Fadel, E., … & Le Panse, R. (2019). Causes and consequences of miR-150-5p dysregulation in Myasthenia Gravis. Frontiers in Immunology, 10, 539. [15] Hamed, S. A. (2016). Sleep Related Conditions with Myasthenia Gravis: Evidence, Causes and Implications. Science, 4(2-1), 6-16. [16] Singh, T., Huttinger, F., Brown, M., & Jones, L. (2018). Pre-operative Management of Myasthenia Gravis in Patients Undergoing Surgery (P6. 430). [17] Zavala, L., Fernandez, V., Melamud, L., Manin, A., Aguirre, F., & Villa, A. (2018). Myasthenia Gravis: Pregnancy and Neonatal Complications in Argentina.(P6. 434). [18] Wolfe, G. I., Kaminski, H. J., Aban, I. B., Minisman, G., Kuo, H. C., Marx, A., … & Heckmann, J. M. (2016). Randomized trial of thymectomy in myasthenia gravis. New England Journal of Medicine, 375(6), 511-522. [19] Oger, J., & Frykman, H. (2015). An update on laboratory diagnosis in myasthenia gravis. Clinica Chimica Acta, 449, 43-48. [20] Pasnoor, M., Dimachkie, M. M., Farmakidis, C., & Barohn, R. J. (2018). Diagnosis of myasthenia gravis. Neurologic clinics, 36(2), 261-274. [21] Tandan, R., Hehir, M. K., Waheed, W., & Howard, D. B. (2017). Rituximab treatment of myasthenia gravis: a systematic review. Muscle & nerve, 56(2), 185-196. [22] Kaminski, H. J., & Kusner, L. L. (Eds.). (2018). Myasthenia gravis and related disorders. Humana Press. [23] Filosso, P. L., Ruffini, E., Lausi, P. O., Lyberis, P., Costardi, L., Olivetti, S., … & Guerrera, F. (2018). Minimally-invasive surgery for non-thymomatous myasthenia gravis. Shanghai Chest, 2(4). [24] Sonett, J. R., Magee, M. J., & Gorenstein, L. (2017). Thymectomy and myasthenia gravis: A history of surgical passion and scientific excellence. The Journal of thoracic and cardiovascular surgery, 154(1), 306-309. [25] Mann-Segal, D. D., Shanahan, E. A., Jones, B., & Ramasamy, D. (1996). Purulent pericarditis: rediscovery of an old remedy. The Journal of thoracic and cardiovascular surgery, 111(2), 487-488. [26] Jacobs, P., Dubovsky, D., & Ferguson, A. (1978). Plasmapheresis and myasthenia gravis. British medical journal, 1(6106), 177.

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Trovagene Announces Fourth Quarter and Full-Year 2018 Results

<h1>Trovagene Announces Fourth Quarter and Full-Year 2018 Results</h1>

Trovagene Announces Fourth Quarter and Full-Year 2018 Results

SAN DIEGO Trovagene, Inc. (Nasdaq: TROV), a clinical-stage oncology therapeutics company, using a precision medicine approach to develop drugs that target cell division (mitosis) for the treatment of leukemias, lymphomas and solid tumor cancers, today announced company highlights and financial results for the fourth quarter and full-year ended December 31, 2018 . The company is issuing this press release in lieu of conducting a conference call.
“We are pleased with the progress we are making in the clinical development of onvansertib for the treatment of cancers and indications where there is a significant need to bring new therapeutic options to physicians and their patients – Acute Myeloid Leukemia (AML), metastatic Castration-Resistant Prostate Cancer (mCRPC) and metastatic Colorectal Cancer (mCRC),” said Dr. Thomas Adams , Chief Executive Officer and Chairman of Trovagene. “Our AML trial continues to advance and data shows that the combination of onvansertib and standard-of-care chemotherapy is demonstrating both a favorable safety profile and showing activity in greater than 88% of evaluable patients treated to-date, which is very encouraging. In January, we received a “study may proceed” notification from the FDA for our Phase 1b /2 trial in mCRC and expect that enrollment in this trial, which is being funded by PoC Capital, will begin mid-year. We anticipate having data readouts from our Phase 2 trial in mCRPC throughout 2019, and recently presented a poster at the Genitourinary Cancers Symposium (ASCO-GU), overviewing the trial and confirming the safety of the combination of onvansertib and Zytiga®. We will also be presenting safety and preliminary clinical data from our Phase 1b /2 trial in AML and Phase 2 trial in mCRPC at the American Association for Cancer Research (AACR) annual conference in early April, 2019.”
Dr. Adams added, “We achieved a number of key milestones in 2018, including: Successful completion of the first three dose levels, without any dose-limiting toxicities, in the Phase 1b segment of our AML trial; granting of Orphan Drug Designation in Europe for the treatment of AML; presentation of preliminary clinical data from our AML trial at the American Society of Hematology (ASH) conference in December; opening of our mCRPC Phase 2 trial to full enrollment, following confirmation that the combination of onvansertib and Zytiga® is safe and well tolerated in the safety lead-in phase; submission of a new IND and protocol for our Phase 1b /2 trial in mCRC in December; strengthening of our patent portfolio around our drug candidate, onvansertib, with the issuance of two new patents; and entering into an exclusive license agreement with MIT to develop combination therapies that include anti-androgen or androgen antagonist and a Polo-like Kinase (PLK) inhibitor (onvansertib) for the treatment of cancer.”
The Company has advanced its business in 2018, and to-date in 2019, with the following activities and milestone achievements:
Announced Presentation Update on Phase 2 Study of Onvansertib in Combination with Zytiga ® in Patients with mCRPC at ASCO-GU On February 14, 2019 , Trovagene announced the presentation of a poster reviewing its ongoing Phase 2 study evaluating onvansertib in combination with Zytiga® (abiraterone acetate)/prednisone in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) at the Genitourinary Cancers Symposium (ASCO-GU) in San Francisco, CA. The data featured demonstrates the safety and tolerability of onvansertib in combination with Zytiga® which was confirmed in the safety lead-in portion of the trial that was completed prior to opening the trial to full enrollment. In addition, a second arm is planned with the goal of maximizing clinical activity by reducing the dosing schedule from the current 21-day cycle to a 14-day cycle.
Announced that Trovagene and PoC Capital Entered into an Agreement to Fund Clinical Development of Onvansertib in metastatic Coloreactal Cancer (mCRC) On January 29, 2019 , Trovagene announced an agreement with PoC Capital to fund its Phase 1b /2 trial of onvansertib in combination with FOLFIRI and Avastin in patients with mCRC with a KRAS mutation. Trovagene submitted an Investigational New Drug (IND) application and protocol to the FDA on December 19, 2018 , and received a “study may proceed” notification from the FDA, 28-days later, on January 16, 2019 . The trial will be conducted at two prestigious cancer centers in the U.S.; USC Norris Comprehensive Cancer Center and The Mayo Clinic.
Announced New Patent Issued for Combination of Onvansertib and Ant–Androgen Drugs to Treat Non-Metastatic and Metastatic Prostate Cancer On January 23, 2019 , Trovagene announced the issuance of a new patent (10,155,006), entitled Combination Therapies and Methods of Use Thereof for Treating Cancer , by the U.S. Patent and Trademark Office (USPTO). This patent broadens previously issued patent (9,566,280), by expanding the use of Onvansertib to encompass combination therapies with any anti-androgen and androgen antagonist drug, such as Zytiga®, Xtandi® and Erleada® for the treatment of metastatic and non-metastatic castrate-resistant prostate cancer. The issuance of this patent further strengthens Trovagene’s existing intellectual property portfolio obtained with the licensing of exclusive global development and commercialization rights to onvansertib from Nerviano Medical Sciences in March, 2017.
Announced New Data from Phase 1b /2 Study of Onvansertib in Combination with LDAC or Decitabine Demonstrated Response to Treatment in Relapsed/Refractory AML On December 3, 2018 , Trovagene announced presentation of data from its ongoing Phase 1b /2 study evaluating onvansertib in combination with standard-of-care chemotherapy in Acute Myeloid Leukemia (AML) at the 60 th American Society of Hematology (ASH) annual meeting. The date presented in a poster demonstrated that onvansertib, in combination with LDAC or decitabine is benefiting patients who have relapsed/refractory AML and that the combination is safe and well tolerated, with no serious adverse events (SAEs) reported to-date.
Announced New Patent Claim Allowances Affirming Broad Patent Portfolio Coverage of NPM1 Mutations by U.S. Patent and Trademark Office On October 24, 2018 , Trovagene announced that the U.S. Patent and Trademark Office (USPTO) has allowed claims that affirms broad coverage of NPM1 mutation testing; Patent Application 14/750331, entitled “Nucleophosmin Protein (NPM) Mutants, Corresponding Gene Sequences and Uses Thereof.” This patent encompasses broad claims around the assessment of NPM1 mutational status in any cancer type, including acute myeloid leukemia (AML). This not only aligns with the Company’s current biomarker strategy and clinical development of onvansertib in AML, but also strengthens the revenue generating potential for Trovagene.
Announced Exclusive License Agreement with MIT for Combination Therapy of Anti-Androgens and Polo-like Kinase Inhibitors in Prostate Cancer On October 3, 2018 , Trovagene announced that it has entered into an exclusive patent license agreement with the Massachusetts Institute of Technology ( MIT ). Under the agreement, Trovagene has exclusive rights to develop combination therapies that include anti-androgen or androgen antagonist and a Polo-like Kinase (PLK) inhibitor for the treatment of cancer. The exclusive license agreement is part of Trovagene’s strategy to explore the efficacy of Onvansertib, its first-in-class, 3rd generation, highly-selective, oral PLK1 inhibitor, in combination with anti-androgen drugs in cancers including prostate, breast, pancreatic, lung and gastrointestinal. There is a need for new therapies that effectively treat cancers that depend on internal androgen signaling, such as castration-resistant prostate cancer, as well as cancers which over-express androgen receptor (AR), or are otherwise dependent on the synthesis of steroid hormones for their growth, such as some breast cancers. In-vitro and in-vivo preclinical research demonstrates a unique synergistic effect with the combination of PLK inhibitors and anti-androgens, which was the precursor that led to the current Phase 2 trial of onvansertib in combination with Zytiga® (abiraterone acetate)/prednisone that is being conducted at the three Harvard Medical Cancer Centers.
Announced Completion of Dosing Cohort of Patients Treated with Onvansertib in Combination with Decitabine in Ongoing Phase 1b /2 AML Trial On September 27, 2018 , Trovagene announced completion of the second dosing cohort of onvansertib, its first-in-class, 3rd generation, highly-selective oral Polo-like Kinase 1 (PLK1) Inhibitor, in combination with standard-of-care decitabine, in its Phase 1b /2 clinical trial in patients with Acute Myeloid Leukemia (AML). All three patients in the cohort successfully completed treatment with onvansertib at 18mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with decitabine and the combination was well tolerated. The Safety Review Committee (SRC) has recommended escalating to the next dose level of onvansertib at 27mg/m2 (approximately a 50% increase) in combination with decitabine.
Announced Predictive Clinical Biomarker Approach to Identify Acute Myeloid Leukemia (AML) Patients Most Likely to Respond to Onvansertib On September 5, 2018 , Trovagene announced it has developed a method for predicting response to treatment by measuring the ability of onvansertib, a first-in-class, 3rd generation, oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor, to inhibit PLK1 in patients with Acute Myeloid Leukemia (AML). PLK1 uniquely phosphorylates translational control tumor protein (TCTP) to form pTCTP and inhibition of this enzymatic activity by onvansertib appears to be predictive of patient response to treatment. In the ongoing Phase 1b /2 open label clinical trial in AML, PLK1 inhibition is being assessed 3-hours following administration, at the approximate peak concentration (C max ) of onvansertib. In the first six patients treated, the greatest target engagement, or inhibition of PLK1, was observed in the three patients who showed a response to treatment.
Announced European Commission Grants Orphan Drug Designation to Onvansertib (PCM-075) for Treatment of Acute Myeloid Leukemia in Europe On August 29, 2018 , Trovagene announced that the European Commission (EC) has endorsed the positive opinion of the Committee for Orphan Medicinal Products (COMP) and has granted Orphan Drug Designation (ODD) for onvansertib, a first-in-class, 3rd generation, oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor, for the treatment of patients with Acute Myeloid Leukemia (AML). Orphan drug designation by the EC provides regulatory and financial incentives to Trovagene, including reduced fees during the product development phase, direct access to centralized marketing authorization in the EU, and 10-year market exclusivity following product approval.
Announced Completion of Second Dosing Cohort of Patients Treated with Onvansertib (PCM-075) in Ongoing Phase 1b /2 AML Trial On August 16, 2018 , Trovagene announced completion of the second dosing cohort of onvansertib, a first-in-class, 3rd generation, highly-selective oral Polo-like Kinase 1 (PLK1) Inhibitor, in combination with standard-of-care low-dose cytarabine (LDAC), in its Phase 1b /2 clinical trial in patients with Acute Myeloid Leukemia (AML). All three patients in the cohort successfully completed treatment with onvansertib at 18 mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with LDAC and the combination was well tolerated. The Safety Review Committee (SRC) has recommended escalating to the next dose level of onvansertib at 27 mg/m2 (approximately a 50% increase) in combination with LDAC. Additionally, two patients in the three-patient cohort of onvansertib at 18 mg/m2 in combination with decitabine have also successfully completed at least one cycle of treatment and recruitment of the third patient to complete this cohort is in process. Four of the eleven patients treated to-date remain on treatment, three are currently receiving a second cycle of treatment and one patient is scheduled to start a fifth cycle of treatment.
Fourth Quarter 2018 Financial Results
Total operating expenses were approximately $4.2 million for the three months ended December 31, 2018 , an increase of million $0.2 million from $4.0 million for the same period in 2017. The increase in operating expenses is attributed to advancing the onvansertib clinical development programs.
Net cash used in operating activities in the fourth quarter of 2018 was $3.6 million , compared to $3.3 million in the fourth quarter of 2017. The year-over-year increase of $0.3 million can be attributed primarily to progress made with the clinical development of its drug candidate, onvansertib.
Research and development expenses increased by approximately $1.3 million to $2.5 million for the three months ended December 31, 2018 from $1.2 million for the same period in 2017. The overall increase in research and development expenses was primarily due to the increased outside service costs for clinical studies related to the development of our drug candidate, onvansertib. We expect increases in research and development costs to continue as we advance the onvansertib clinical development programs in AML, mCRPC and mCRC.
Selling, general and administrative expenses decreased by approximately $0.2 million to $1.7 million for the three months ended December 31, 2018 from $1.9 million for the same period in 2017. The reduction is primarily due to a decrease in stock-based compensation.
The weighted average diluted shares of common stock outstanding used to calculate per share results for the three months ended December 31, 2018 was 3.8 million.
As of December 31, 2018 , Trovagene had approximately $11.5 million of cash and cash equivalents.
About Trovagene, Inc.
Trovagene is a clinical-stage, oncology therapeutics company, taking a precision medicine approach to develop drugs that target mitosis (cell division) to treat various types of cancer, including leukemias, lymphomas and solid tumors. Trovagene has intellectual property and proprietary technology that enables the Company to analyze circulating tumor DNA (ctDNA) and clinically actionable markers to identify patients most likely to respond to specific cancer therapies. Trovagene plans to continue to vertically integrate its tumor genomics technology with the development of targeted cancer therapeutics. For more information, please visit https://www.trovageneoncology.com .
Forward-Looking Statements
Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of words such as “anticipate,” “believe,” “forecast,” “estimated” and “intend” or other similar terms or expressions that concern Trovagene’s expectations, strategy, plans or intentions. These forward-looking statements are based on Trovagene’s current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, our need for additional financing; our ability to continue as a going concern; clinical trials involve a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results; our clinical trials may be suspended or discontinued due to unexpected side effects or other safety risks that could preclude approval of our product candidates; uncertainties of government or third party payer reimbursement; dependence on key personnel; limited experience in marketing and sales; substantial competition; uncertainties of patent protection and litigation; dependence upon third parties; our ability to develop tests, kits and systems and the success of those products; regulatory, financial and business risks related to our international expansion and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. There are no guarantees that any of our technology or products will be utilized or prove to be commercially successful. Additionally, there are no guarantees that future clinical trials will be completed or successful or that any precision medicine therapeutics will receive regulatory approval for any indication or prove to be commercially successful. Investors should read the risk factors set forth in Trovagene’s Form 10-K for the year ended December 31, 2018, and other periodic reports filed with the Securities and Exchange Commission. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and Trovagene does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances.
Trovagene Contact:
Vicki Kelemen
VP, Clinical Development
858-952-7652
vkelemen@trovagene.com
Trovagene, Inc.
Condensed Consolidated Statements of Operations
(in thousands, except for per share amounts)
Three Months Ended
December 31,
Years Ended
December 31 ,
2018
2017
2018
2017
(unaudited)
Revenues:
Royalties
$
76
$
116
$
251
$
286
Services
2
69
127
219
Total revenues
78
185
378
505
Costs and expenses:
Cost of revenues

383
597
1,811
Research and development
2,497
1,207
8,164
7,883
Selling, general and administrative
1,685
1,874
8,006
14,232
Restructuring charges

505
664
2,175
Total operating expenses
4,182
3,969
17,431
26,101
Loss from operations
(4,104)
(3,784)
(17,053)
(25,596)
Net interest income (expense)
75
(9)
194
(886)
Gain on change in fair value of derivative financial instruments- warrants
38
1,388
617
3,401
Gain (loss) on extinguishment of debt


18
(1,656)
Other loss, net
(168)
(165)
(237)
(170)
Net loss
(4,159)
(2,570)
(16,461)
(24,907)
Preferred stock dividend
(6)
(6)
(2,794)
(24)
Net loss attributable to common stockholders
$
(4,165)
$
(2,576)
$
(19,255)
$
(24,931)
Net loss per common share – basic and diluted
$
(1.09)
$
(4.61)
$
(8.26)
$
(51.76)
Weighted average shares outstanding – basic and diluted
3,832
558
2,330
482
Trovagene, Inc.
Condensed Consolidated Balance Sheets
(in thousands)
December 31,
2018
December 31,
2017
Assets
Current assets:
Cash and cash equivalents
$
11,453
$
8,226
Accounts receivable and unbilled receivable
168
77
Prepaid expense
1,144
1,166
Total current assets
12,765
9,469
Property and equipment, net
1,304
2,426
Other assets
103
390
Total Assets
$
14,172
$
12,285
Liabilities and Stockholders’ Equity
Current liabilities:
Accounts payable
$
665
$
825
Accrued expenses
1,814
1,455
Deferred rent
486
334
Current portion of long-term debt

1,332
Total current liabilities
2,965
3,946
Derivative financial instruments – warrants
32
649
Deferred rent, net of current portion
1,091
1,184
Total Liabilities
4,088
5,779
Stockholders’ equity
10,084
6,506
Total liabilities and stockholders’ equity
$
14,172
$
12,285
Trovagene, Inc.
Condensed Consolidated Statements of Cash Flows
(in thousands)
Years Ended
December 31,
2018
2017
Operating activities
Net loss
$ (16,461)
$ (24,907)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization
859
1,248
Stock based compensation expense
2,175
4,013
Change in fair value of derivative financial instruments – warrants
(617)
(3,401)
(Gain) loss on extinguishment of debt
(18)
1,656
Other non-cash items
764
1,236
Changes in operating assets and liabilities
98
(3,126)
Net cash used in operating activities
(13,200)
(23,281)
Investing activities:
Net proceeds from disposal (purchase) of capital equipment
23
(100)
Net sales and maturities of short-term investments

24,062
Net cash provided by investing activities
23
23,926
Financing activities:
Proceeds from sales of common stock and warrants, net of expenses
11,779
10,861
Proceeds from sales of Series B Convertible Preferred Stock, net of expenses
4,387

Proceeds from exercise of warrants
1,613

Net repayment of debt
(1,375)
(17,239)
Net cash provided by (used in) financing activities
16,404
(6,378)
Effect of exchange rate changes on cash and cash equivalents

8
Net change in cash and equivalents
3,227
(5,689)
Cash and cash equivalents—Beginning of period
8,226
13,915
Cash and cash equivalents—End of period
$11,453
$8,226
</

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Do you know Ibuprofen Could cause Kidney Damage?

<h1>Do you know Ibuprofen Could cause Kidney Damage?</h1>

Do you know Ibuprofen Could cause Kidney Damage?

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Trovagene Announces Fourth Quarter and Full-Year 2018 Results

<h1>Trovagene Announces Fourth Quarter and Full-Year 2018 Results</h1>

Trovagene Announces Fourth Quarter and Full-Year 2018 Results

SAN DIEGO, March 6, 2019 /PRNewswire/ — Trovagene, Inc. (Nasdaq: TROV), a clinical-stage oncology therapeutics company, using a precision medicine approach to develop drugs that target cell division (mitosis) for the treatment of leukemias, lymphomas and sol…

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Trovagene Announces Fourth Quarter and Full-Year 2018 Results

<h1>Trovagene Announces Fourth Quarter and Full-Year 2018 Results</h1>

Trovagene Announces Fourth Quarter and Full-Year 2018 Results

SAN DIEGO , March 6, 2019 /PRNewswire/ — Trovagene, Inc. (Nasdaq: TROV), a clinical-stage oncology therapeutics company, using a precision medicine approach to develop drugs that target cell division (mitosis) for the treatment of leukemias, lymphomas and solid tumor cancers, today announced company highlights and financial results for the fourth quarter and full-year ended December 31, 2018 . The company is issuing this press release in lieu of conducting a conference call.
“We are pleased with the progress we are making in the clinical development of onvansertib for the treatment of cancers and indications where there is a significant need to bring new therapeutic options to physicians and their patients – Acute Myeloid Leukemia (AML), metastatic Castration-Resistant Prostate Cancer (mCRPC) and metastatic Colorectal Cancer (mCRC),” said Dr. Thomas Adams , Chief Executive Officer and Chairman of Trovagene. “Our AML trial continues to advance and data shows that the combination of onvansertib and standard-of-care chemotherapy is demonstrating both a favorable safety profile and showing activity in greater than 88% of evaluable patients treated to-date, which is very encouraging. In January, we received a “study may proceed” notification from the FDA for our Phase 1b /2 trial in mCRC and expect that enrollment in this trial, which is being funded by PoC Capital, will begin mid-year. We anticipate having data readouts from our Phase 2 trial in mCRPC throughout 2019, and recently presented a poster at the Genitourinary Cancers Symposium (ASCO-GU), overviewing the trial and confirming the safety of the combination of onvansertib and Zytiga®. We will also be presenting safety and preliminary clinical data from our Phase 1b /2 trial in AML and Phase 2 trial in mCRPC at the American Association for Cancer Research (AACR) annual conference in early April, 2019.”
Dr. Adams added, “We achieved a number of key milestones in 2018, including: Successful completion of the first three dose levels, without any dose-limiting toxicities, in the Phase 1b segment of our AML trial; granting of Orphan Drug Designation in Europe for the treatment of AML; presentation of preliminary clinical data from our AML trial at the American Society of Hematology (ASH) conference in December; opening of our mCRPC Phase 2 trial to full enrollment, following confirmation that the combination of onvansertib and Zytiga® is safe and well tolerated in the safety lead-in phase; submission of a new IND and protocol for our Phase 1b /2 trial in mCRC in December; strengthening of our patent portfolio around our drug candidate, onvansertib, with the issuance of two new patents; and entering into an exclusive license agreement with MIT to develop combination therapies that include anti-androgen or androgen antagonist and a Polo-like Kinase (PLK) inhibitor (onvansertib) for the treatment of cancer.”
The Company has advanced its business in 2018, and to-date in 2019, with the following activities and milestone achievements:
Announced Presentation Update on Phase 2 Study of Onvansertib in Combination with Zytiga ® in Patients with mCRPC at ASCO-GU On February 14, 2019 , Trovagene announced the presentation of a poster reviewing its ongoing Phase 2 study evaluating onvansertib in combination with Zytiga® (abiraterone acetate)/prednisone in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) at the Genitourinary Cancers Symposium (ASCO-GU) in San Francisco, CA. The data featured demonstrates the safety and tolerability of onvansertib in combination with Zytiga® which was confirmed in the safety lead-in portion of the trial that was completed prior to opening the trial to full enrollment. In addition, a second arm is planned with the goal of maximizing clinical activity by reducing the dosing schedule from the current 21-day cycle to a 14-day cycle.
Announced that Trovagene and PoC Capital Entered into an Agreement to Fund Clinical Development of Onvansertib in metastatic Coloreactal Cancer (mCRC) On January 29, 2019 , Trovagene announced an agreement with PoC Capital to fund its Phase 1b /2 trial of onvansertib in combination with FOLFIRI and Avastin in patients with mCRC with a KRAS mutation. Trovagene submitted an Investigational New Drug (IND) application and protocol to the FDA on December 19, 2018 , and received a “study may proceed” notification from the FDA, 28-days later, on January 16, 2019 . The trial will be conducted at two prestigious cancer centers in the U.S.; USC Norris Comprehensive Cancer Center and The Mayo Clinic.
Announced New Patent Issued for Combination of Onvansertib and Ant–Androgen Drugs to Treat Non-Metastatic and Metastatic Prostate Cancer On January 23, 2019 , Trovagene announced the issuance of a new patent (10,155,006), entitled Combination Therapies and Methods of Use Thereof for Treating Cancer , by the U.S. Patent and Trademark Office (USPTO). This patent broadens previously issued patent (9,566,280), by expanding the use of Onvansertib to encompass combination therapies with any anti-androgen and androgen antagonist drug, such as Zytiga®, Xtandi® and Erleada® for the treatment of metastatic and non-metastatic castrate-resistant prostate cancer. The issuance of this patent further strengthens Trovagene’s existing intellectual property portfolio obtained with the licensing of exclusive global development and commercialization rights to onvansertib from Nerviano Medical Sciences in March, 2017.
Announced New Data from Phase 1b /2 Study of Onvansertib in Combination with LDAC or Decitabine Demonstrated Response to Treatment in Relapsed/Refractory AML On December 3, 2018 , Trovagene announced presentation of data from its ongoing Phase 1b /2 study evaluating onvansertib in combination with standard-of-care chemotherapy in Acute Myeloid Leukemia (AML) at the 60 th American Society of Hematology (ASH) annual meeting. The date presented in a poster demonstrated that onvansertib, in combination with LDAC or decitabine is benefiting patients who have relapsed/refractory AML and that the combination is safe and well tolerated, with no serious adverse events (SAEs) reported to-date.
Announced New Patent Claim Allowances Affirming Broad Patent Portfolio Coverage of NPM1 Mutations by U.S. Patent and Trademark Office On October 24, 2018 , Trovagene announced that the U.S. Patent and Trademark Office (USPTO) has allowed claims that affirms broad coverage of NPM1 mutation testing; Patent Application 14/750331, entitled “Nucleophosmin Protein (NPM) Mutants, Corresponding Gene Sequences and Uses Thereof.” This patent encompasses broad claims around the assessment of NPM1 mutational status in any cancer type, including acute myeloid leukemia (AML). This not only aligns with the Company’s current biomarker strategy and clinical development of onvansertib in AML, but also strengthens the revenue generating potential for Trovagene.
Announced Exclusive License Agreement with MIT for Combination Therapy of Anti-Androgens and Polo-like Kinase Inhibitors in Prostate Cancer On October 3, 2018 , Trovagene announced that it has entered into an exclusive patent license agreement with the Massachusetts Institute of Technology ( MIT ). Under the agreement, Trovagene has exclusive rights to develop combination therapies that include anti-androgen or androgen antagonist and a Polo-like Kinase (PLK) inhibitor for the treatment of cancer. The exclusive license agreement is part of Trovagene’s strategy to explore the efficacy of Onvansertib, its first-in-class, 3rd generation, highly-selective, oral PLK1 inhibitor, in combination with anti-androgen drugs in cancers including prostate, breast, pancreatic, lung and gastrointestinal. There is a need for new therapies that effectively treat cancers that depend on internal androgen signaling, such as castration-resistant prostate cancer, as well as cancers which over-express androgen receptor (AR), or are otherwise dependent on the synthesis of steroid hormones for their growth, such as some breast cancers. In-vitro and in-vivo preclinical research demonstrates a unique synergistic effect with the combination of PLK inhibitors and anti-androgens, which was the precursor that led to the current Phase 2 trial of onvansertib in combination with Zytiga® (abiraterone acetate)/prednisone that is being conducted at the three Harvard Medical Cancer Centers.
Announced Completion of Dosing Cohort of Patients Treated with Onvansertib in Combination with Decitabine in Ongoing Phase 1b /2 AML Trial On September 27, 2018 , Trovagene announced completion of the second dosing cohort of onvansertib, its first-in-class, 3rd generation, highly-selective oral Polo-like Kinase 1 (PLK1) Inhibitor, in combination with standard-of-care decitabine, in its Phase 1b /2 clinical trial in patients with Acute Myeloid Leukemia (AML). All three patients in the cohort successfully completed treatment with onvansertib at 18mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with decitabine and the combination was well tolerated. The Safety Review Committee (SRC) has recommended escalating to the next dose level of onvansertib at 27mg/m2 (approximately a 50% increase) in combination with decitabine.
Announced Predictive Clinical Biomarker Approach to Identify Acute Myeloid Leukemia (AML) Patients Most Likely to Respond to Onvansertib On September 5, 2018 , Trovagene announced it has developed a method for predicting response to treatment by measuring the ability of onvansertib, a first-in-class, 3rd generation, oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor, to inhibit PLK1 in patients with Acute Myeloid Leukemia (AML). PLK1 uniquely phosphorylates translational control tumor protein (TCTP) to form pTCTP and inhibition of this enzymatic activity by onvansertib appears to be predictive of patient response to treatment. In the ongoing Phase 1b /2 open label clinical trial in AML, PLK1 inhibition is being assessed 3-hours following administration, at the approximate peak concentration (C max ) of onvansertib. In the first six patients treated, the greatest target engagement, or inhibition of PLK1, was observed in the three patients who showed a response to treatment.
Announced European Commission Grants Orphan Drug Designation to Onvansertib (PCM-075) for Treatment of Acute Myeloid Leukemia in Europe On August 29, 2018 , Trovagene announced that the European Commission (EC) has endorsed the positive opinion of the Committee for Orphan Medicinal Products (COMP) and has granted Orphan Drug Designation (ODD) for onvansertib, a first-in-class, 3rd generation, oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor, for the treatment of patients with Acute Myeloid Leukemia (AML). Orphan drug designation by the EC provides regulatory and financial incentives to Trovagene, including reduced fees during the product development phase, direct access to centralized marketing authorization in the EU, and 10-year market exclusivity following product approval.
Announced Completion of Second Dosing Cohort of Patients Treated with Onvansertib (PCM-075) in Ongoing Phase 1b /2 AML Trial On August 16, 2018 , Trovagene announced completion of the second dosing cohort of onvansertib, a first-in-class, 3rd generation, highly-selective oral Polo-like Kinase 1 (PLK1) Inhibitor, in combination with standard-of-care low-dose cytarabine (LDAC), in its Phase 1b /2 clinical trial in patients with Acute Myeloid Leukemia (AML). All three patients in the cohort successfully completed treatment with onvansertib at 18 mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with LDAC and the combination was well tolerated. The Safety Review Committee (SRC) has recommended escalating to the next dose level of onvansertib at 27 mg/m2 (approximately a 50% increase) in combination with LDAC. Additionally, two patients in the three-patient cohort of onvansertib at 18 mg/m2 in combination with decitabine have also successfully completed at least one cycle of treatment and recruitment of the third patient to complete this cohort is in process. Four of the eleven patients treated to-date remain on treatment, three are currently receiving a second cycle of treatment and one patient is scheduled to start a fifth cycle of treatment.
Fourth Quarter 2018 Financial Results
Total operating expenses were approximately $4.2 million for the three months ended December 31, 2018 , an increase of million $0.2 million from $4.0 million for the same period in 2017. The increase in operating expenses is attributed to advancing the onvansertib clinical development programs.
Net cash used in operating activities in the fourth quarter of 2018 was $3.6 million , compared to $3.3 million in the fourth quarter of 2017. The year-over-year increase of $0.3 million can be attributed primarily to progress made with the clinical development of its drug candidate, onvansertib.
Research and development expenses increased by approximately $1.3 million to $2.5 million for the three months ended December 31, 2018 from $1.2 million for the same period in 2017. The overall increase in research and development expenses was primarily due to the increased outside service costs for clinical studies related to the development of our drug candidate, onvansertib. We expect increases in research and development costs to continue as we advance the onvansertib clinical development programs in AML, mCRPC and mCRC.
Selling, general and administrative expenses decreased by approximately $0.2 million to $1.7 million for the three months ended December 31, 2018 from $1.9 million for the same period in 2017. The reduction is primarily due to a decrease in stock-based compensation.
The weighted average diluted shares of common stock outstanding used to calculate per share results for the three months ended December 31, 2018 was 3.8 million.
As of December 31, 2018 , Trovagene had approximately $11.5 million of cash and cash equivalents.
About Trovagene, Inc.
Trovagene is a clinical-stage, oncology therapeutics company, taking a precision medicine approach to develop drugs that target mitosis (cell division) to treat various types of cancer, including leukemias, lymphomas and solid tumors. Trovagene has intellectual property and proprietary technology that enables the Company to analyze circulating tumor DNA (ctDNA) and clinically actionable markers to identify patients most likely to respond to specific cancer therapies. Trovagene plans to continue to vertically integrate its tumor genomics technology with the development of targeted cancer therapeutics. For more information, please visit https://www.trovageneoncology.com .
Forward-Looking Statements
Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of words such as “anticipate,” “believe,” “forecast,” “estimated” and “intend” or other similar terms or expressions that concern Trovagene’s expectations, strategy, plans or intentions. These forward-looking statements are based on Trovagene’s current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, our need for additional financing; our ability to continue as a going concern; clinical trials involve a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results; our clinical trials may be suspended or discontinued due to unexpected side effects or other safety risks that could preclude approval of our product candidates; uncertainties of government or third party payer reimbursement; dependence on key personnel; limited experience in marketing and sales; substantial competition; uncertainties of patent protection and litigation; dependence upon third parties; our ability to develop tests, kits and systems and the success of those products; regulatory, financial and business risks related to our international expansion and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. There are no guarantees that any of our technology or products will be utilized or prove to be commercially successful. Additionally, there are no guarantees that future clinical trials will be completed or successful or that any precision medicine therapeutics will receive regulatory approval for any indication or prove to be commercially successful. Investors should read the risk factors set forth in Trovagene’s Form 10-K for the year ended December 31, 2018, and other periodic reports filed with the Securities and Exchange Commission. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and Trovagene does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances.
Trovagene Contact: Vicki Kelemen VP, Clinical Development 858-952-7652 vkelemen@trovagene.com
Trovagene, Inc.
Condensed Consolidated Statements of Operations
(in thousands, except for per share amounts)
Three Months Ended
December 31,
Years Ended
December 31 ,
2018
2017
2018
2017
(unaudited)
Revenues:
Royalties
$
76
$
116
$
251
$
286
Services
2
69
127
219
Total revenues
78
185
378
505
Costs and expenses:
Cost of revenues

383
597
1,811
Research and development
2,497
1,207
8,164
7,883
Selling, general and administrative
1,685
1,874
8,006
14,232
Restructuring charges

505
664
2,175
Total operating expenses
4,182
3,969
17,431
26,101
Loss from operations
(4,104)
(3,784)
(17,053)
(25,596)
Net interest income (expense)
75
(9)
194
(886)
Gain on change in fair value of derivative financial instruments- warrants
38
1,388
617
3,401
Gain (loss) on extinguishment of debt


18
(1,656)
Other loss, net
(168)
(165)
(237)
(170)
Net loss
(4,159)
(2,570)
(16,461)
(24,907)
Preferred stock dividend
(6)
(6)
(2,794)
(24)
Net loss attributable to common stockholders
$
(4,165)
$
(2,576)
$
(19,255)
$
(24,931)
Net loss per common share – basic and diluted
$
(1.09)
$
(4.61)
$
(8.26)
$
(51.76)
Weighted average shares outstanding – basic and diluted
3,832
558
2,330
482
Trovagene, Inc.
Condensed Consolidated Balance Sheets
(in thousands)
December 31,
2018
December 31, 2017
Assets
Current assets:
Cash and cash equivalents
$
11,453
$
8,226
Accounts receivable and unbilled receivable
168
77
Prepaid expense
1,144
1,166
Total current assets
12,765
9,469
Property and equipment, net
1,304
2,426
Other assets
103
390
Total Assets
$
14,172
$
12,285
Liabilities and Stockholders’ Equity
Current liabilities:
Accounts payable
$
665
$
825
Accrued expenses
1,814
1,455
Deferred rent
486
334
Current portion of long-term debt

1,332
Total current liabilities
2,965
3,946
Derivative financial instruments – warrants
32
649
Deferred rent, net of current portion
1,091
1,184
Total Liabilities
4,088
5,779
Stockholders’ equity
10,084
6,506
Total liabilities and stockholders’ equity
$
14,172
$
12,285
Trovagene, Inc.
Condensed Consolidated Statements of Cash Flows
(in thousands)
Years Ended
December 31,
2018
2017
Operating activities
Net loss
$ (16,461)
$ (24,907)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization
859
1,248
Stock based compensation expense
2,175
4,013
Change in fair value of derivative financial instruments – warrants
(617)
(3,401)
(Gain) loss on extinguishment of debt
(18)
1,656
Other non-cash items
764
1,236
Changes in operating assets and liabilities
98
(3,126)
Net cash used in operating activities
(13,200)
(23,281)
Investing activities:
Net proceeds from disposal (purchase) of capital equipment
23
(100)
Net sales and maturities of short-term investments

24,062
Net cash provided by investing activities
23
23,926
Financing activities:
Proceeds from sales of common stock and warrants, net of expenses
11,779
10,861
Proceeds from sales of Series B Convertible Preferred Stock, net of expenses
4,387

Proceeds from exercise of warrants
1,613

Net repayment of debt
(1,375)
(17,239)
Net cash provided by (used in) financing activities
16,404
(6,378)
Effect of exchange rate changes on cash and cash equivalents

8
Net change in cash and equivalents
3,227
(5,689)
Cash and cash equivalents—Beginning of period
8,226
13,915
Cash and cash equivalents—End of period
$11,453
$8,226
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SOURCE Trovagene, Inc.

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Medicine For Hair Loss

<h1>Medicine For Hair Loss</h1>

Medicine For Hair Loss

Like 2 views https://lnky.ml/httpultimatemuskyguidecomforumindexphpphpsessidj82ia5s42f4ifq9l1s23ema637topic1217440868431 – https://lnky.ml/httpultimatemuskyguidecomforumindexphpphpsessidj82ia5s42f4ifq9l1s23ema637topic1217440868431 . Dysmenorrhea is handled with 250 mg each 6 to eight hours after an initial dose of 500 mg. Typically, prednisone can provoke hypertension (excessive blood) and trigger an excruciating headache, tinnitus (ringing in your ears), chest pain, confusion, arrythmia (irregular heartbeat) and seizure. Don’t double the subsequent dose to catch up. They are estimated to trigger at least 16,000 deaths per 12 months and send 100,000 people to the emergency room in the U. High colleges are allowed with the disease, and just like the common cold virus or influenza. In 1992, Proscar, a day by day drug for males over 60 years of age, during which the lively ingredient is 5mg of Finasteride, was licensed in the UK for the prevention of Benign Prostate Hyperplasia (BPH). 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Ranbaxy Restarts Generic Lipitor Production

<h1>Ranbaxy Restarts Generic Lipitor Production</h1>

Ranbaxy Restarts Generic Lipitor Production

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