Part Of Combination Therapy Research Articles

Abstract B25: BRD4 inhibition improves the efficacy of ABT-199 in T-cell acute lymphoblastic leukemia

Abstract Introduction: Despite the improved survival of patients with T-cell acute lymphoblastic leukemia (T-ALL), therapy-resistant or refractory T-ALL remains a major clinical challenge. Recently, we and others reported promising therapeutic activity for ABT-199, a highly specific inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2), especially in immature T-ALL. Nevertheless, the occurrence of dose-limiting toxicities and the emergence of therapy resistance provides a rationale for the evaluation of ABT-199 as part of combination therapies. Indeed, previous studies have shown that ABT-199 can synergize with conventional chemotherapeutic agents in human T-ALL. BRD4 is an important bromodomain and extra-terminal (BET) protein that facilitates the recruitment of the transcriptional apparatus to acetylated chromatin. Small molecule inhibitors that target BET-bromodomain proteins, such as JQ1, can broadly affect oncogenic gene transcription and have recently emerged as powerful anti-cancer agents in a variety of hematological malignancies, including T-ALL. Here, we evaluated JQ1 and ABT-199 combination therapy and provide in vitro and in vivo evidence that combined BCL-2 and BRD4 inhibition synergistically affects leukemic tumor growth in T-ALL. Experimental Procedures: In vitro synergism between ABT-199 and JQ1 in a panel of T-ALL cell lines was determined by the combination index (CI) based on cell viability 48h after compound administration. For in vivo evaluation of the ABT-199/JQ1 combination therapy, luciferase-labeled T-ALL cells were administered by tail vein injection in immune compromised NOD scid gamma mice. Upon engraftment of leukemic cells, mice were divided into four groups and treated daily with 50mg ABT-199/kg body weight and/or 50mg JQ1/kg body weight for 13 days. The percentage of leukemic cells in the blood and bone marrow after treatment was analyzed using FACS analysis upon staining with an anti-human CD45 antibody. Results: In vitro evaluation of ABT-199 and JQ1 combination therapy revealed strong synergism (CI<0.5) in the T-ALL cell lines LOUCY, DND-41, ALL-SIL and TALL-1. In contrast, no or only slight synergistic effects (CI>0.5) were observed in other T-ALL lines, including KOPTK1, JURKAT, PEER and HPB-ALL. Notably, the degree of synergism was not defined by the IC50 values for ABT-199 or JQ1, but was significantly correlated with BCL-2 expression levels. Next, in vivo drug treatment experiments using luciferase-positive LOUCY T-ALL cells confirmed the synergistic activity of the JQ1/ABT-199 combination therapy as evaluated by bioluminescence, percentage of leukemic blasts in blood or bone marrow and spleen size. Interestingly, although ABT-199 strongly reduced the leukemic burden during the first days of treatment, the therapeutic response of single ABT-199 therapy was not durable. In contrast, JQ1/ABT-199 combination therapy resulted in a sustained therapeutic response associated with tumor regression. As expected, combination therapy resulted in enhanced levels of cleaved PARP and increased caspase activity in synergistic T-ALL cell lines, in line with induction of cellular apoptosis upon ABT-199/JQ1 treatment. To better understand the molecular mechanism by which JQ1 enhances the anti-leukemic properties of ABT-199, we defined its effect on gene expression in T-ALL cell lines. Notably, this analysis showed that the balance of pro- and anti-apoptotic BCL2 family factors was affected by JQ1 treatment. For example, JQ1 treatment caused a significant reduction in BCL2 levels, but also induced a concomitant increase in anti-apoptotic MCL1. In addition, pro-apoptotic factors, such as BIM, were also upregulated upon JQ1 treatment. Conclusions: Here, we show that BET-bromodomain inhibition can sensitize BCL2-positive human T-ALL to ABT-199 treatment by interfering with the balance of pro- and anti-apoptotic BCL2 family members. Citation Format: Sofie Peirs, Filip Matthijssens, Tim Pieters, Niels Vandamme, Geert Berx, Bruce Poppe, Pieter Van Vlierberghe. BRD4 inhibition improves the efficacy of ABT-199 in T-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B25.

Possibilities of using essential oils in the combination therapy of acute respiratory diseases in children

Acute respiratory infections remain one of the most common diseases in children. In spite of a huge range of medications available to treat and prevent acute respiratory diseases, investigations, the objective of which is to enhance therapeutic efficiency in children with acute respiratory diseases, are being continued. Objective: to enhance the clinical efficiency of treatment using the warming gel “Dyshi” in children with acute rhinosinusitis. A total of 60 children aged 3 to 7 years with mild acute rhinosinusitis were followed up. The children were divided into 2 groups of 30 in each. Group 1 received the warming gel “Dyshi” for children in addition to standard combination therapy; Group 2 had standard combination therapy alone. The clinical efficiency was evaluated based on the changes in rating scores of the severity of the major symptoms of the disease. The application of the warming gel “Dyshi” for children as part of combination therapy enhances the clinical efficiency of therapy for mild acute rhinosinusitis can more promptly ease the major symptoms of the disease, shorten the duration of therapy, and reduce the number of used decongestants and the risk of complications. There was no case of intolerance or allergy due to the application of the gel “Dyshi”. The latter alleviates nasal breathing and causes reductions in nasal swelling and the magnitude of cough, which may be recommended for use in the combination therapy of rhinosinusitis in children.

Cost-effectiveness of Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the Republic of Korea

PurposeBedaquiline is a new drug used for the treatment of multidrug-resistant tuberculosis (MDR-TB). This study aimed to evaluate the cost-effectiveness of adding bedaquiline to a standard regimen (SR) for treating patients with MDR-TB, including extensively drug-resistant (XDR)-TB, in the Republic of Korea. MethodsA cohort-based decision-analytic model developed in a previously published study from the United Kingdom was used, with a 20-year time horizon and a 5% discount rate for cost and effectiveness, to evaluate the incremental cost-effectiveness ratios of bedaquiline + SR and SR only. The key parameters regarding the clinical data were available via the published Phase II trial of bedaquiline. Additional parameters for recurrence, cure status, loss to follow-up, surgery, death, cost, and health utility were based on Korean data if available; otherwise the international literature data were applied. Univariate and probabilistic sensitivity analyses were conducted. FindingsBased on the analysis, a patient on bedaquiline + SR would gain 1.20 quality-adjusted life-years (QALYs) at 13,961,659 Korean won (KRW) (1100 KRW = US $1) of additional cost compared with a patient administered SR only, with an incremental cost/utility ratio of 11,638,656 KRW/QALY. Bedaquiline + SR had an 80% probability of being cost-effective, at a willingness-to-pay threshold of 26 million KRW, compared with SR only. ImplicationsThe results of this study suggest that, in the Republic of Korea, bedaquiline, as a part of combination therapy with SR, is a cost-effective option for the treatment of MDR-TB (including XDR-TB) compared with SR only.

CORRECTION OF DYSBIOTIC ABNORMALITIES IN CHILDREN WITH ACUTE RESPIRATORY DISORDERS

Background: A special attention in the treatment of acute respiratory disorders (ARD) in children should be paid to correction of defense mechanisms of the body, including elimination of dysbiotic abnormalities. The use of probiotics, whose mechanism of action is directed to restoration of qualitative and quantitative composition of normal microbiota, is considered to be perspective in the combination therapy of ARD patients. Aim: to assess clinical and laboratory efficacy of probiotic Florin forte in children with ARD. Materials and methods: One hundred and eleven children aged from3 months to 14 years with ARD were included into the study. In 81.1% of cases they had concomitant obstruction of upper respiratory ways. From day1 after admission to the hospital, 81 patients (the main group) were administered probiotic Florin forte as a part of combination therapy for 5 to7 days, and 30 children (the comparator group) were administered the standard treatment without probiotics. Parameters of oropharyngeal and mucosal microflora, immune parameters of anti-infectious resistance (phagocytic activity, phagocytic index, neutrophilic index of digestion), as well as secretory immunoglobulin A levels in saliva were measured during the course of the illness. Results: In the patients of the main group under the combination therapy, there was a significantly more rapid elimination of respiratory symptoms and intoxication (p 0.05). Improvements of immune parameters of the anti-infectious resistance system were found only in the main group: the phagocytic index at 120 minutes after incubation of neutrophils was 4.26 ± 0.04 before treatment and 3.94 ± 0.09 after treatment (р < 0.05); the neutrophil digestion index, 5.70 ± 0.71 and10.83 ± 0.94 (р < 0.01), and secretory IgA level in saliva, 0.05 ± 0.03 and 0.125 ± 0.03 mcg/mL, respectively (р < 0.05). Conclusion: Inclusion of probiotic Florin forte into combination therapy of ARD patients promoted more rapid clinical recovery, improvement of biocenotic parameters in oropharyngeal and gut mucosa and an increase in anti-infectious resistance of the host.

Vedolizumab in the treatment of Crohn’s disease

ABSTRACTVedolizumab, a recent addition to the therapeutic armamentarium in Crohn’s disease, is promising in efficacy, durability of remission and safety. It is the first gut selective biologic treatment, acting by targeting α4β7-integrin, a receptor expressed on activated lymphocytes and binding to MAdCAM1, a cell adhesion molecule selectively expressed in the circulatory system of the digestive tract, preventing trafficking of lymphocytes to the gut. The pivotal GEMINI studies have demonstrated the efficacy and safety of vedolizumab in achieving clinical response and clinical remission in patients with moderately to severely active CD who are naïve or have previously failed therapy with TNF-antagonists, immunomodulators or dependent on steroids. Vedolizumab had a favorable safety profile and specifically showed no evidence of PML, reactivation of latent TB or hepatitis B. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Vedolizumab can be given as a first-line therapy or following treatment failure, and was tolerated as part of combination therapy. More medications with similar and novel therapeutic mechanisms are anticipated in the coming years.

Abstract B39: BRD4 inhibition improves the efficacy of ABT-199 in T-cell acute lymphoblastic leukemia

Abstract Introduction: Despite the improved survival of patients with T-cell acute lymphoblastic leukemia (T-ALL), therapy-resistant or refractory T-ALL remains a major clinical challenge. Recently, we and others reported promising therapeutic activity for ABT-199, a highly specific inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2), especially in immature T-ALL. Nevertheless, the occurrence of dose-limiting toxicities and the emergence of therapy resistance provides a rationale for the evaluation of ABT-199 as part of combination therapies. Indeed, previous studies have shown that ABT-199 can synergize with conventional chemotherapeutic agents in human T-ALL. BRD4 is an important bromodomain and extra-terminal (BET) protein that facilitates the recruitment of the transcriptional apparatus to acetylated chromatin. Small molecule inhibitors that target BET-bromodomain proteins, such as JQ1, can broadly affect oncogenic gene transcription and have recently emerged as powerful anti-cancer agents in a variety of hematological malignancies, including T-ALL. Here, we evaluated JQ1 and ABT-199 combination therapy and provide in vitro and in vivo evidence that combined BCL-2 and BRD4 inhibition synergistically affects leukemic tumor growth in T-ALL. Experimental Procedures: In vitro synergism between ABT-199 and JQ1 in a panel of T-ALL cell lines was determined by the combination index (CI) based on cell viability 48h after compound administration. For in vivo evaluation of the ABT-199/JQ1 combination therapy, luciferase-labeled T-ALL cells were administered by tail vein injection in immune compromised NOD scid gamma mice. Upon engraftment of leukemic cells, mice were divided into four groups and treated daily with 50mg ABT-199/kg body weight and/or 50mg JQ1/kg body weight for 13 days. The percentage of leukemic cells in the blood and bone marrow after treatment was analyzed using FACS analysis upon staining with an anti-human CD45 antibody. Results: In vitro evaluation of ABT-199 and JQ1 combination therapy revealed strong synergism (CI&amp;lt;0.5) in the T-ALL cell lines LOUCY, DND-41, ALL-SIL and TALL-1. In contrast, no or only slight synergistic effects (CI&amp;gt;0.5) were observed in other T-ALL lines, including KOPTK1, JURKAT, PEER and HPB-ALL. Notably, the degree of synergism was not defined by the IC50 values for ABT-199 or JQ1, but was significantly correlated with BCL-2 expression levels. Next, in vivo drug treatment experiments using luciferase-positive LOUCY T-ALL cells confirmed the synergistic activity of the JQ1/ABT-199 combination therapy as evaluated by bioluminescence, percentage of leukemic blasts in blood or bone marrow and spleen size. Interestingly, although ABT-199 strongly reduced the leukemic burden during the first days of treatment, the therapeutic response of single ABT-199 therapy was not durable. In contrast, JQ1/ABT-199 combination therapy resulted in a sustained therapeutic response associated with tumor regression. As expected, combination therapy resulted in enhanced levels of cleaved PARP and increased caspase activity in synergistic T-ALL cell lines, in line with induction of cellular apoptosis upon ABT-199/JQ1 treatment. To better understand the molecular mechanism by which JQ1 enhances the anti-leukemic properties of ABT-199, we defined its effect on gene expression in T-ALL cell lines. Notably, this analysis showed that the balance of pro- and anti-apoptotic BCL2 family factors was affected by JQ1 treatment. For example, JQ1 treatment caused a significant reduction in BCL2 levels, but also induced a concomitant increase in anti-apoptotic MCL1. In addition, pro-apoptotic factors, such as BIM, were also upregulated upon JQ1 treatment. Conclusions: Here, we show that BET-bromodomain inhibition can sensitize BCL2-positive human T-ALL to ABT-199 treatment by interfering with the balance of pro- and anti-apoptotic BCL2 family members. Citation Format: Sofie Peirs, Filip Matthijssens, Tim Pieters, Niels Vandamme, Geert Berx, Bruce Poppe, Pieter Van Vlierberghe. BRD4 inhibition improves the efficacy of ABT-199 in T-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B39.

Necitumumab: First Global Approval.

Eli Lilly is developing necitumumab (Portrazza™), an intravenously administered fully human IgG monoclonal antibody directed against the epidermal growth factor receptor (EGFR), which is expressed in a variety of solid tumours and has been implicated in promoting oncogenesis and tumour progression. Necitumumab is approved as a part of combination therapy (with gemcitabine and cisplatin) in the USA for the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), and regulatory submissions have been made in the EU for this same indication. Necitumumab was derived from the proprietary phage display library of Dyax Corp, and originated with ImClone Systems, which was acquired by Eli Lilly in November 2008. Necitumumab was also under phase II development for colorectal cancer in Belgium and Spain; however, no recent development has been reported for this indication. This article summarizes the milestones in the development of necitumumab leading to this first approval for the first-line treatment of metastatic squamous NSCLC, in combination with gemcitabine and cisplatin.

Регуляторно-адаптивный статус в определении эффективности небиволола и соталола у пациентов c гипертонической болезнью и пароксизмальной фибрилляцией предсердий

Aim: compare the effectiveness of treatment with nebivololum or sotalolum in patients with hypertensive disease (HD) and paroxysmal atral fibrillation (AF) taking into account quantitative evaluation of the regulatory adaptive status (RAS). Materials and methods. 50 patients with HD of stages II-III and paroxysmal AF took part in the research, they were randomized into two groups for treatment with nebivololum (5.6±1.6 mg/day n=25) or sotalolum (157.0±38.3 mg/day, n=25). As part of combination therapy, patients were administered lisinoprilum (14.3±3.7 mg/day and 14.4±3.9 mg/day), when required alsoatorvastatinum (18.8±4.4 mg/day, n=11 and 16.0±5.1 mg/day, n=12), acetylsalicylic acid (91.2±14.1 mg/day, n=11and 92.1±16.8 mg/day, n=11), respectively. Initially and 6 months after therapy, the following was done: quantitative assessment of RAS (by cardio-respiratory synchronism test), echocardiography, triplex scanning of brachiocephalic arteries, treadmill test, six-minute walk test, all-day monitoring of blood pressure and electrocardiogram, subjective assessment of quality of life. Results. Both drug regimens comparably improved structural and functional condition of the heart, controlled arterial hypertension, effectively suppressed paroxysms of AF, improved the quality of life. At the same time, the use of nebivololum increased the RAS and increased exercise tolerance, to a lesser degree than the use of sotalolum. Conclusion. In patients with HD of stages II-III and paroxysmal AF the use of nebivololum as part of combination therapy may be preferable to sotalolum due to its positive impact on the RAS.

Регуляторно-адаптивный статус в определении эффективности бисопролола и соталола у пациентов с гипертонической болезнью и желудочковыми нарушениями ритма сердца

Aim. Compare the effectiveness of treatment with bisoprololum or sotalolum in patients with hypertensive disease (HD) and ventricular arrhythmias (VA) taking into account quantitative evaluation of the regulatory adaptive status (RAS).Materials and methods. 48 patients with HD of stages II-III and VA of grade I-IV based on the В.Lown grading system, II-III groups based on J.Bigger grading system took part in the research, they were randomized into two groups for treatment with bisoprololum (6.2±1.7 mg/day) or sotalolum (159.1±47.4 mg/day). As part of combination therapy, patients were administered lisinoprilum (12.8±4.2 mg/day and 13.7±4.5 mg/day), acetylsalicylic acid when required (93.1±19.0 and 95.0±16.2 mg/day), atorvastatinum (15.9±4.6 mg/day and 15.6±4.9 mg/day), respectively. Initially and 6 months after therapy, the following was done: quantitative assessment of RAS (by cardio-respiratory synchronism test), echocardiography, triplex scanning of brachiocephalic arteries, treadmill test, six-minute walk test, all-day monitoring of blood pressure and electrocardiogram, subjective assessment of quality of life.Results. Both drug regimens comparably improved structural and functional condition of the heart, increased exercise tolerance, controlled arterial hypertension, effectively suppressed ventricular arrhythmia, improved the quality of life. At the same time, the use of sotalolum decreased the RAS to a lesser degree than the use of bisoprololum.Conclusion. In patients with HD of stages II-III and VA the use of sotalolum as part of combination therapy may be preferable to bisoprololum due to its less negative impact on the RAS.

Regulatory and adaptive status: bisoprolol vs sotalol in co-existent hypertension and paroxysmal atrial fibrillation

Background. Atrial fibrillation (AF) is associated with the increase in mortality from cardiovascular causes, systemic thromboembolism, congestive heart failure, high rate of hospitalization and deterioration of quality of life. Hypertension (HTN) is the most common cause of AF. Beta-blockers are the therapy of choice for AF prevention. To predict the therapy efficiency, one should assess the regulatory and adaptive status (RAS). The aim of our study was to compare bisoprolol vs sotalol in patients with HTn and paroxysmal AF taking into account quantitative indices of the regulatory adaptive status (RAS). Design and methods. We included 50 patients with HTN stages II–III and paroxysmal AF and randomized them into two groups for treatment with bisoprolol (6,4 ± 1,8 mg/day, n = 25) or sotalol (157,0 ± 38,3 mg/day, n = 25). As part of combination therapy, lisinopril (14,2 ± 3,8 and 14,0 ± 4,8 mg/day), atorvastatin (17,1 ± 3,7 mg/day, n = 11 and 16,0 ± 5,1 mg/day, n = 11), acetylsalicylic acid were prescribed (90,0 ± 14,6 mg/day, n = 12 and 92,1 ± 16,8 mg/day, n = 12), respectively. At baseline and 6 months after therapy, quantitative assessment of RAS (by cardio-respiratory synchronism test), echocardiography, triplex scanning of brachiocephalic arteries, treadmill test, six-minute walk test, 24‑hour blood pressure and electrocardiogram monitoring, subjective assessment of quality of life. Results. Both schemes comparably improved structural and functional parameters of the heart, increased exercise tolerance, controlled arterial hypertension, effectively suppressed AF paroxysms, improved quality of life. At the same time, sotalol led to the decrease of RAS to a lesser degree than bisoprolol. Conclusions . In patients with HTN stages II–III and paroxysmal AF sotalol as a component of the combination therapy may be preferable to bisoprolol due to its lower impact on the RAS.

Bedaquiline: A new hope in treatment of tuberculosis

Multidrug resistant tuberculosis is defined as resistance to at least isoniazid and rifampicin. Multidrug resistant Tuberculosis is one of the most challenging health problem being faced by the medical fraternity. An urgent need for newer and more effective drugs is relies to combat this Drug Resistant Tuberculosis menance. Bedaquiline, first in a new class of drug , has been approved by the US Food and Drug Association, the first time in 40 years that a drug has been approved that attacked Tuberculosis. In phase III trials Bedaquiline was found to bring about faster culture conversion and significantly more culture conversions. Accordingly, the FDA has approved bedaquiline as part of combination therapy to treat adults with MDR pulmonary TB when other alternatives are not available. Bedaquiline has a promising potential and has a favourable outcome in Drug Resistant Tuberculosis.

Long-term follow-up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases

To describe the long-term outcomes of intravitreal bevacizumab (IVB) for the treatment of pediatric retinal and choroidal diseases. This was a multicenter, retrospective, consecutive case series of patients <18 years of age treated with IVB from 2005 to 2013. Primary outcome measures included visual acuity and central macular thickness at 12 months' follow-up. A total of 95 eyes of 90 patients (average age, 8.7 years [range, 0.33-17 years]) were included, in which 352 injections (average, 3.7/eye) were administered for choroidal neovascular membrane (CNVM, n = 35), Coats disease (n = 35), familial exudative vitreoretinopathy (FEVR, n = 13), cystoid macular edema (CME, n = 6), and other (n = 6). Mean follow-up was 679 ± 581 days. IVB was used as monotherapy in 27 eyes and as part of combination therapy in 68. Mean Snellen equivalent visual acuity improved from 20/224 at baseline to 20/120 at 6 months (P = 0.034) and 20/108 at 12 months (P = 0.005). Mean central macular thickness improved from 426 μm to 349 μm at 6 months (P = 0.025) and 340 μm at 12 months (P = 0.002). Statistically significant visual acuity gains at 12 months were achieved in patients with CNVM (P = 0.009) but not in eyes with CME (P = 0.06), Coats disease (P = 0.15), or FEVR (P = 0.93). Adverse effects included ocular hypertension in 8 eyes and worsening tractional retinal detachment in 3 eyes. Patients receiving IVB as part of the treatment for pediatric retinal and choroidal diseases experienced significant visual acuity gains and reductions in central macular thickness. IVB was generally well tolerated, although safety concerns persist.

Polypharmacy: a risk factor to consider in valproate‐induced hyperammonaemic encephalopathy

AbstractBackgroundValproate is commonly prescribed as part of combination therapy in antiepileptic or mood stabilising regimens. Although generally well tolerated, valproate has potential to cause serious adverse effects, one of which is valproate‐induced hyperammonaemic encephalopathy (VHE). The risk of developing VHE is rare; however, this can increase when valproate is used in conjunction with other medications.AimThis report aims to highlight the importance of early diagnosis of VHE and emphasise the potential deleterious effects of polypharmacy and certain hazardous drug combinations.Clinical detailsA 58‐year‐old woman with a 1‐week history of increasing lethargy, confusion and drowsiness presented to the emergency department. Blood tests showed a raised ammonia level and liver function test (LFT) derangement. She had been on a long‐term antiepileptic regimen which included sodium valproate. The only recent change to her medications was the introduction of atorvastatin. A diagnosis of VHE was made and valproate was discontinued. Atorvastatin was also stopped on account of its likely role in LFT derangement.OutcomesAfter discontinuation of both agents attributed to her presentation, serum ammonia and LFTs returned to within normal range. The patient also gradually resumed her usual level of alertness and functional state.ConclusionThis report describes a case of VHE and emphasises the detrimental role of polypharmacy associated with this presentation. This illustrates the potentially complex pharmacy issues that must be considered in the management of a patient on chronic valproate therapy.

ADRENORECEPTORS BLOCKING: RECENT DATA ON URAPIDIL USAGE

The article is focused on recent (last two years) data from the trials of alphaadrenoblocker urapidil as a drug of choice for severe refractory hypertension, for controlled hypotension, and for outpatient care as part of combination therapy.

Фармакоэкономический анализ использования канаглифлозина (инвокана) в составе комбинированной терапии в лечении сахарного диабета 2 типа

Фармакоэкономический анализ использования канаглифлозина (инвокана) в составе комбинированной терапии в лечении сахарного диабета 2 типа

4E-BP1 as an oncotarget

The cap-dependent mRNA translation process that enables post-transcriptional control of gene expression and protein synthesis is tightly regulated in eukaryotes. Deregulation of this process, particularly in the formation of the eIF4F translation initiation complex—comprising the eIF4E mRNA cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase—is associated with cancer development and progression. It is widely believed that translation of certain key oncogenic mRNAs is strongly dependent on the level of eIF4E. Consequently, expression of these oncogenic mRNAs is preferentially and dis-proportionately affected by eIF4E availability and is sensitive to alteration of its level. Free eIF4E level can be increased substantially in cancer cells by a number of mechanisms, including elevated eIF4E expression, decreased expression of eIF4E inhibitory binding proteins, 4E-BPs, and release of eIF4E from 4E-BPs by inactivating phosphorylation of 4E-BPs results from the oncogenic activation of PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways. Our recent studies have revealed that 4E-BP1 is a critical regulatory node that integrates oncogenic signals of the P3K/AKT and RAS/RAF/MEK/ERK pathways for cancer progression and metastasis [1-3]. Mutations in genes that encode components of these two pathways occur at high frequency in cancer. Moreover, the AKT and ERK pathways are often concurrently activated by separate mutations in many human tumors. For instance, KRAS and PIK3CA mutation occur simultaneously in colorectal carcinoma; BRAF and PIK3CA mutation in thyroid carcinoma; and BRAF and PTEN mutation occur simultaneously in melanoma. A number of small molecule inhibitors targeting components of these two pathways have been tested for the treatment of cancer in preclinical and clinical studies, but have shown only limited activity as a single agent. Our work demonstrated that in tumors such as colorectal cancer (CRC) with coexistent activation of both PI3K/AKT and RAS/ERK pathways, drug resistance, following inhibition of either pathway, is associated with redundant activation of eIF4E-initiated cap-dependent translation through convergent phosphorylation of the translational repressor 4E-BP1 mediated by the AKT and ERK pathways. We found that combined inhibition of both pathways is required to maximally inhibit 4E-BP1 phosphorylation and subsequent induction of 4E-BP1 binding to eIF4E to prevent cap-dependent translation of oncogenic mRNAs (e.g. survivin) and ultimately achieve antitumor activity. Furthermore, we showed that a genetically-modified non-phosphorylated 4E-BP1 mutant that binds constitutively to eIF4E and represses eIF4E-dependent oncogene expression exerts similar inhibitory effects on tumor growth and metastasis as the combined pharmacological inhibition of AKT and ERK pathways, whereas loss of 4E-BP1 expression induces epithelial-mesenchymal transition through translational control of snail expression and its activity to promote metastatic progression of CRC and reduce CRC dependence on AKT/ERK signaling for translation, survival and motility. Collectively, these findings support the conclusion that deregulation of 4E-BP1 phosphorylation-mediated assembly of eIF4F translation initiation complex causes CRC resistance to its upstream kinase targeted therapies and thus maintain the transformed phenotype for CRC progression and metastasis. Of notice, several lines of evidence have also established incomplete inhibition of 4E-BP1 phosphorylation, amplification of eIF4E or increased eIF4E/4E-BP ratio as a mechanism of primary resistance to anti-PI3K/AKT/mTOR and anti-BRAF/MEK/ERK pathway inhibitors in a variety of cancers [4-6]. Our data and others strongly suggest that 4E-BP1 phosphorylation is an important biomarker and therapeutic target in cancer. It is well know that mTOR kinase complex 1 (mTORC1) phosphorylates 4E-BP1, which in turn, activates cap-dependent translation and promotes protein synthesis. Our recent studies demonstrated that the effects of AKT and ERK activation on translational regulation of CRC progression are largely mediated by mTORC1 [2], suggesting that targeting mTOR is an attractive strategy for cancer therapy. Nevertheless, incomplete inhibition of 4E-BP1 phosphorylation and a concomitant activation of AKT via loss of a negative feedback mechanism by mTOR inhibitors, including rapalogs and mTOR kinase inhibitors, have been implicated in reduction of their therapeutic efficacy. Our most recent findings revealed a critical role of PRAS40, a mTORC1 inhibitor, as a key integrator of mTORC1 and AKT signaling for 4E-BP1-mediated translational regulation of tumor progression, and indicated that the redundant phosphorylation of PRAS40 on Ser183 and Thr246 sites by both mTORC1 and AKT signaling is a novel mechanistic basis for the acquired resistance to mTOR inhibitors in cancer cells [7]. Our findings further suggest that directly targeting the convergence of multiple oncogenic signals on eIF4F translation initiation complex may provide a promising strategy for improving cancer therapy. Several translation initiation inhibitors, including eIF4E antisense-oligonucleotides and the eIF4A inhibitor silvestrol, have recently produced encouraging anti-tumor effects with limited toxicity. Future works require additional clinical correlative studies and await the development of clinically effective translation initiation inhibitors for cancer treatment, either as single agents or as part of combination therapy.

BEDAQUILINE: A long but much fruitful wait since seventies

Tuberculosis (TB) is a major health problem in developing countries one of the leading cause of deaths due to infectious disease in the world. Drug treatment had being successful with anti-tubercular drugs available, but Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are serious forms of TB which have emerged as real concern. Bedaquiline (TMC-207 or R207910), is a new anti TB agent been approved as a part of drug regimen therapy in pulmonary MDR-TB. Bedaquiline acts on energy metabolism of the bacteria. It acts as a bactericidal drug. There are two important black box warnings for this drug, firstly prolongation of QT interval and secondly increased risk of death with bedaquiline as compared to placebo treatment. Fast track approval for bedaquiline was based on two phase 2 trials. The FDA has approved bedaquiline on Dec 2012, for the treatment of MDR-TB in adults (&gt;18 years) as part of combination therapy under the fast track designation, priority review and orphan-product designation based on two Phase II trials. Careful use of this drug along with monitoring of the potential adverse effects and drug interactions becomes very important, as this new anti-tubercular drug has being approved after forty years, since last anti tubercular drug was approved.doi: http://dx.doi.org/10.3126/mjsbh.v13i1.13000

TYPICAL ABSENCES: RESULTS OF OWN INVESTIGATIONS

Typical absences (TA) are brief primary generalized epileptic seizures characterized by sudden onset and termination. According to their definition, absences consist of impairment of consciousness that is synchronously accompanied by electroencephalographic (EEG) changes as generalized spike–slow wave discharges of 3 or more Hz. The authors conducted an investigation of 1261 patients with different forms of epilepsy with onset of seizures from the first days of life to the age of 18 years. The patients were followed up from 1990 to 2010. Absence seizures were detected in 231 patients, which accounts for 18.3 % of all the epileptic patients. TA were found in 102 patients, which constitutes 8.1 % of all cases of epilepsy with onset of seizures beyond the age of 18 years. The paper provides a detailed analysis of a group of patients with TA in terms of anamnestic, clinical, electroencephalographic, and neuroimaging features and the results of therapy with antiepileptic drugs (AEDs). The age of onset of TA-associated epilepsy was from 9 months to 17 years (mean 9.4 ± 4.06 years). The disease occurred most frequently in young school-age children (41.2 %). Isolated TA as the only type of seizures were observed in the clinical picture of 28 (27.5 %) patients. TA were concurrent with other types of seizures in other cases. The investigators have identified 4 types of seizures which TA (generalized convulsions, myoclonic seizures, febrile seizures, and eyelid myoclonia) may be concurrent with. Neuroimaging stated there were no brain changes in 85.3 % of TA-associated epilepsy cases. Moderate diffuse subatrophic changes were detected in other cases (14.7 %). Local cerebral structural abnormalities were absent. The use of antiepileptic therapy as both monotherapy and polytherapy using different combinations showed the high efficacy of AEDs. Complete remission was achieved in 84.3 % of TA-associated epilepsy cases. An AED-induced reduction in the frequency of seizures was observed in 15.7 % of the patients. No one case – without effect. The greatest success in relieving seizures was seen in juvenile myoclonic epilepsy; childhood absence epilepsy was intermediate; the lowest percentage of remission was noted in juvenile absence epilepsy. The most effective drugs were valproic acid and ethosuximide used both alone and in combination. Lamotrigine, topiramate, and levetiracetam were used as part of combination therapy.

Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions.

Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT) and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence.

Tumor-associated macrophages and heparanase in lung cancer microenvironment. (TUM6P.970)

Abstract Tumor-associated macrophages promote aspects of tumor initiation, growth, and progression. Tumor growth takes place in a complex microenvironment of stromal cells and extracellular matrix. Heparanase is the only known mammalian glycosidase capable of cleaving heparan sulfate. Its expression has been associated with tumor development. Immunohistochemistry and immunofluorescence were performed in samples of 37 lung cancer patients to assess heparanase, macrophages and lymphocytes presence and localization. All types of tumors expressed heparanase within the cytoplasm and nucleus. Adenocarcinoma showed the highest intensity and widespread distribution. The other types had similar intensity with a less widespread distribution. Tumor surroundings also presented heparanase co-expression with fibroblast, macrophages and epithelial cells. Heparanase expression correlates to TNM staging. The heparanase possesses a different distribution according to the type of lung tumor. Heparanase from fibroblasts might regulate the tumor microenvironment through HS cleavage, by enabling invasion and release of growth factors from extracellular matrix. We showed lung cancer TAMs expressing heparanase and described heparanase localization in the tumor microenvironment providing knowledge concerning lung cancer. Therefore, we suggest that heparanase can constitute a possible therapeutic target for lung carcinoma and that macrophages are attractive targets as part of combination therapy in cancer.