High-dose Tolerance Research Articles

Гормональний статус пацієнток після хірургічного лікування фіброзно-кістозної мастопатії та можливості його корекції

The purpose of the study was to investigate the efficacy of Mastodynon in terms of indications in elevated doses versus the standard dose. Materials and methods. Data were analyzed for 60 patients after surgical treatment of fibro-cystic mastopathy. Depending on the postoperative therapy received by the patients, they were divided into three groups. Group I (n = 20): patients were observed in accordance with the standards established in mammal practice and did not receive special agents that affect hormonal homeostasis. Group II (n = 20): In addition to observation, patients received Mastodynon® (1 tablet or 30 drops 2 times a day) for 6 months. Group III (n = 20): Patients were given for a post-operative rehabilitation Mastodynon® in a double dose (2 tablets or 60 drops 2 times a day) for 6 months. Results Surgical treatment without conservative therapy eliminates organic changes in the thoracic glands (GH), but hormonal disorders that have led to pathologic and histological changes in the tissues of GZ continue to exist for a long time and can lead to repeated nodal formations. In group І, 25% of patients within 2 years performed repeated sectoral resections on recurrence of nodule formation. In group І, 25% of patients within 2 years performed repeated sectoral resections on recurrence of nodule formation. The use of Mastodynon® in standard doses (group II) for postoperative rehabilitation contributes to a significant improvement in hormonal homeostasis (normalization of prolactin, estradiol and progesterone levels), a 24.7 mm decrease in the degree of cyclic mastodynia according to the visual analog scale (VAS), and the improvement of ultrasound scan Pictures of GZ in 75% of patients. The most pronounced effect of this rehabilitation approach after the surgical treatment phase was noted for the use of Mastodynone in doble doses (2 tablets or 60 drops 2 times a day) in Group III. In these patients, the degree of reduction of cyclic mastodynia was 30 mm for VAS and positive changes in the tissues of GH were noted in 85% of patients. However, the highest incidence of adverse events was also noted in Group III, although they were temporary in nature and did not require withdrawal or dose reduction. Conclusion. Despite the presence of short-term side effects and rapid rebounding in the double-dose Mastodynon® group, our study showed better results than standard doses, faster and more stable therapeutic effect. Taking into account the results obtained, it can be argued that the use of high doses of Mastodynon® may be recommended to patients for the treatment of mastopathy. For a more complete study of such an important aspect as the tolerability of high doses of Mastodynon®, it is advisable to conduct more extensive studies, taking into account the dosage form and the use of other drugs. Key words: mastopathy, postoperative rehabilitation, Mastodynon®, mastodynia.

A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.

2591 Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS > 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.

Histopathological Analysis of Naïve Swine Esophagus Irradiated with a Brachytherapy Stent Demonstrated Favorable Tissue Tolerance of High Mucosal Tissue Doses

Self-expanding metal stents (SEMS) appear to be the most effective treatment for dysphagia in palliative patients suffering from malignant esophageal cancers (EC), providing immediate relief to dysphagia in a single treatment step. Recent recommendations from the European Society of Gastrointestinal Endoscopy further recommend the use of brachytherapy in addition to stenting in patients with longer life expectancies due to possible improved survival advantage and quality of life [Spaanderet al. Endoscopy 48, 939-948 (2016)]. However, the equipment and clinical expertise necessary for intraluminal brachytherapy is not readily available in most communities. In this study we present a brachytherapy stent designed to deliver clinically relevant radiation doses to ECs using commercially available brachytherapy sources. This pilot study aimed to assess the histopathological effects of the radioactive SEMS in the naïve porcine esophagus.

The Balance between CD8+ T Cell-Mediated Clearance of AAV-Encoded Antigen in the Liver and Tolerance Is Dependent on the Vector Dose

The liver continuously receives antigens from circulation and the gastrointestinal tract. A complex immune regulatory system has evolved in order to both limit inflammation and promote tolerance in the liver. Although insitu immune tolerance mechanisms enable successful gene therapy and liver transplantation, at the same time they facilitate chronic infections by pathogens such as hepatitis viruses. It is, however, poorly understood why hepatocytes infected with hepatitis viruses or transduced with adeno-associated virus (AAV)-based vectors may be rejected by CD8+ Tcells several months later. We found that hepatic transfer of limited doses of an AAV-ovalbumin vector rapidly induced antigen-specific CD8+ Tcells that only became functionally competent after >2months. At this time, CD8+ Tcells had downregulated negative checkpoint markers, e.g., the programmed death 1 [PD-1] receptor, and upregulated expression of relevant cytokines. At further reduced vector dose, only intrahepatic rather than systemic CD8+ Tcell responses occurred, showing identical delay in antigen clearance. In contrast, PD-1-deficient mice rapidly cleared ovalbumin. Interestingly, higher vector dose directed sustained transgene expression without CD8+ Tcell responses. Regulatory Tcells, IL-10 expression, and Fas-L contributed to high-dose tolerance. Thus, viral vector doses profoundly impact CD8+ Tcell responses.

Tolerability of effective high doses of paliperidone palmitate in patients with severe resistant schizophrenia.

The aim of the study was to evaluate the effectiveness and tolerability of doses of paliperidone palmitate (PP) of 175 mgEq and over/28 days in patients with severe schizophrenia [Clinical Global Impression-Severity scale (CGI-S)≥5] and their retention in treatment. A 36-month prospective, observational study was carried out of patients with severe schizophrenia who were treated with 175 mg and over every 28 days of PP to achieve clinical stabilization (N=30). Assessment included CGI-S, WHO Disability Assessment Schedule, Camberwell Assessment of Need, and Medication Adherence Report Scale. Laboratory tests, weight, side effects, reasons for discharge, and hospital admissions were measured. The average dose of PP was 228.7 (11.9) mgEq/28 days. There was one discharge because of side effects. Weight and prolactin levels decreased. After 3 years, CGI-S (P<0.01), Camberwell Assessment of Need (P<0.01), and WHO Disability Assessment Schedule in the four areas (P<0.05) decreased. The Medication Adherence Report Scale increased (P<0.001). There were fewer hospital admissions (P<0.001). Retention in treatment after 36 months was 90%. Tolerability of 175 mgEq/28 days and over of PP was very good, being useful in improving treatment adherence in severely ill patients and helping in this way to achieve clinical stabilization and better social functioning. These patients were clozapine candidates; thus, high doses of PP could be an alternative for them.

Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a frequent developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and nonverbal communication, and stereotyped patterns of interests and activities. It has been previously reported that there is vitamin D deficiency in autistic children; however, there is a lack of randomized controlled trials of vitamin D supplementation in ASD children. This study is a double-blinded, randomized clinical trial (RCT) that was conducted on 109 children with ASD (85 boys and 24 girls; aged 3-10years). The aim of this study was to assess the effects of vitamin D supplementation on the core symptoms of autism in children. ASD patients were randomized to receive vitamin D3 or placebo for 4months. The serum levels of 25-hydroxycholecalciferol (25 (OH)D) were measured at the beginning and at the end of the study. The autism severity and social maturity of the children were assessed by the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and the Autism Treatment Evaluation Checklist (ATEC). UMIN-CTR Study Design: trial number: UMIN000020281. Supplementation of vitamin D was well tolerated by the ASD children. The daily doses used in the therapy group was 300IU vitamin D3/kg/day, not to exceed 5,000IU/day. The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group. This study demonstrates the efficacy and tolerability of high doses of vitamin D3 in children with ASD. This study is the first double-blinded RCT proving the efficacy of vitamin D3 in ASD patients. Depending on the parameters measured in the study, oral vitamin D supplementation may safely improve signs and symptoms of ASD and could be recommended for children with ASD. At this stage, this study is a single RCT with a small number of patients, and a great deal of additional wide-scale studies are needed to critically validate the efficacy of vitamin D in ASD.

R04 - High dosages of the fixed combination OXYCODONE/NALOXONE in cancer pain: mid-term efficacy and tolerability

Background: Treatment of moderate-to-severe chronic cancer pain with opioids is often associated with central and gastrointestinal side effects.Oral combination oxycodone-naloxone strongly attenuates gastrointestinal side effects.Aim of this study was to evaluate efficacy and tolerability of high doses of OXN-PR on middle-term in patients with cancer pain. Material and Methods: multicenter prospective observation on consecutive cancer pts with uncontrolled moderate-severe pain or intolerant to analgesics,who were “switched” to OXN-PR. Pts rotated at entry to OXN-PR = 80mg daily were selected.All pts were reevaluated after 15,30,45 and 60 days.Primary end point was analgesic response rate[Responders:pts achieving a decrease of average pain intensity(API,measured by NRS)= 30% at T30]. Other end-points were:impact of pain on daily quality of life(BPI-SF 7 items),bowel dysfunction BFI,other side effects. Results: of 351 pts enrolled,123 were prescribed OXN-PR = 80mg daily at T0(age 63.9 ±12,males 61%;metastatic disease in 88.6%).At T0,the majority of pts had severe pain(NRS = 7 in 80.4%)with neuropathic features(82.1%); 96.7% were rotated from other strong opioids,30.0%were also taking rapid fentanyl for BTCP episodes.There were 22(17.9%)pts who discontinued prematurely OXN-PR(exitus n.6; disease progression 2;side effects7;lack of efficacy 3;lost at f.u. 4);the remaining 101(82.1%)completed the 60-day study.OXN-PR resulted in a significant reduction in pain over time(NRS:from 7.3 ±1.8 at T0 to 3.2 ±2.4 at T60, p <0.001),and the number of daily BTCP declined(1.3 ±2 at T0 vs 0.6 ±1 at T60, p <0.001).A response rate was achieved in 96 pts(78.0%).Daily dosage of OXN-PR increased only slightly during the observation(81.3 ±6 at T0 vs 91.7 ± 32 mg at T60, P <0.001).The impact of pain on QoL abated (BPI-SF from 7.7 ± 1.4 to 2.6 ±1.9 at T60, P <0.0001).OXN-PR did not worsen bowel function,BFI improved markedly (from 54.6 ± 33 at T0 to 27.9 ± 22 at T60, P <0.001).The number of patients who complained for other opioid side effects decreased overtime(confusion 24.9% at T0 vs13.8% at T60;nausea/vomiting 33.3%vs7.3%;itching 13%vs5.7%; dry mouth 32.3%vs18.9%; tremor17.0%vs8.1%; dizziness31.7%vs8.9%; diarrhea4.9%vs2.4%atT60(overall:p < 0.01). Conclusions: OXN-PR was highly effective and well tolerated even at high doses in cancer patients with pain:the agonist-antagonist combination rapidly alleviated pain and its impact on life style,reducing the number of BTCP and improving opioid side effects.

Could Adult European Pharmacoresistant Epilepsy Patients Be Treated With Higher Doses of Zonisamide?

To examine the clinical effect (efficacy and tolerability) of high doses of zonisamide (ZNS) (>500 mg/d) in adult patients with pharmacoresistant epilepsy. Between 2006 and 2013, all epileptic outpatients treated with high doses of ZNS were selected. Safety and efficacy were assessed based on patient and caregiver reports. Serum levels of ZNS and other concomitant antiepileptic drugs were evaluated if available. Nine patients (5 female): 8 focal/1 generalized pharmacoresistant epilepsy. Mean age: 34 years. Most frequent seizure type: complex partial seizures; other seizure types: generalized tonic-clonic, tonic, myoclonia. Zonisamide in polytherapy in all (100%), administered in tritherapy in 3 (33%) of 9 patients; mean dose: 633 (600-700) mg/d; efficacy (>50% seizure reduction) was observed in 5 (55%) of 9 patients. Five of 9 patients are still taking high doses of ZNS (more than 1 year). Adverse events were observed in 3 (37%) of 8 patients. Good tolerance to high doses of other antiepileptic drugs had been observed in 6 (66%) of 9 patients. Plasma levels of ZNS were only available in 2 patients; both were in the therapeutic range (34.95, 30.91) (10-40 mg/L). High doses of ZNS are effective and safe in pharmacoresistant epileptic patients. Therapeutic drug monitoring of ZNS may be considered at therapeutic failure.

79. Vector Dose Delineates Between Chronic, Non-Functional CD8+ T Cell Response and Tolerance to the Transgene Product Upon Liver Gene Transfer

The liver is characterized by a microenvironment that promotes immune tolerance, which can be exploited by gene therapy. In the case of hepatitis viral infections such as HBV or HCV however, ineffective or non-functional responses can result in chronic disease. To understand the parameters and mechanisms that govern the CD8+ T cell response to a virally encoded antigen expressed in the liver, we administered an adeno-associated virus expressing ovalbumin (AAV8-EF1α-ovalbumin) to immune competent C57BL/6J mice at various doses (low: 1×108 vg, medium: 1×109 vg, and high: 1×1010 vg). Interestingly, all doses resulted in sustained vector-dose dependent systemic ova expression, albeit with distinct immune profiles. At the low dose and the high doses, no response to ova was observed. At the medium dose, circulating ova-specific CD8+ T cells were detected in 40-50% of mice at high frequency (5-35%) by tetramer stain. These emerged within 1 month and, while declining in frequency over time, can persist for up to one year. Despite their inefficiency in eliminating vector-derived ova expression, functional assays demonstrated that induced CD8+ T cells retained cytolytic activity to SIINFEKL (the dominant ovalbumin MHC class I epitope in C57BL/6J mice) peptide-loaded target cells in vivo or in vitro, and that they produced Th1 type cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in response to ex vivo stimulation with SIINFEKL epitope. Further phenotypic characterization revealed that most of these cells expressed PD-1 and 2B4. Other markers of exhaustion such as CD160, LAG3 and TIM3 were expressed to a lesser extent. Cells acquired memory phenotype over time as judged by CD44, CD62L, and CCR7 markers. Since higher vector doses failed to induce the CD8+ T cell response entirely, a potent antigen-dependent “off switch” has to exist in the liver. Previously, we and others identified FoxP3+ Treg, activation induced apoptotic cell death, and expression of the immune suppressive cytokine IL-10 as contributors to immune tolerance induction by hepatic gene transfer. Therefore, we used Foxp3-DTR mice (for transient depletion of Treg), FasL−/−, and IL-10−/− mice to determine if these pathways were required in preventing ova-specific CD8+ T cell activation in the high-dose group. Transient depletion of Foxp3+ Treg in Foxp3-DTR mice led to a low but detectable CD8+ T cell response in all animals. In contrast, only 1/5 (20%) of FasL−/− or IL-10−/− mice developed a response. Therefore, it is likely that multiple (and perhaps redundant) mechanisms work in concert to achieve high-dose tolerance to proteins expressed in the liver. These results have implications for viral infections of the liver and for gene and cell therapies, illustrating the potential for chronic albeit only partially functional T cell responses at low doses, which can be entirely prevented at sufficient antigen doses.

Safety and tolerability of high doses of glucocorticoides

Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone), which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L), in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

Abstract 644: Impact of conjugation site on pharmacokinetics and off-target toxicity of site-specific antibody drug conjugates

Abstract Site-specific conjugation of toxic payload to antibody yields homogeneous ADCs resulting in improved therapeutic index over conventional conjugation. To understand the role of conjugation site on pharmacokinetics, off-target toxicity, cysteine(cys) was engineered into a humanized anti-IL13Rα2 antibody, hAB08, at various sites within the IgG1/k constant domains. Single cys mutants L443C and Q347C with DAR 2, and double cys mutants K392C+L443C, L443C/kK183C and Q347C/kK183C with DAR 4 were conjugated using auristatin 0101 via maleimidocapronic - valine-citruline-p-aminobenzyloxycarbonyl (vc, cleavable linker). All cys mutants and their conjugates maintained their binding properties compared to parental hAb08. Cysteine substitution sites were selected based on conjugation efficiency and in vitro stability. In vivo efficacy was evaluated in mouse xenograph tumor models. Pharmacokinetics (PK) and off target toxicity (TOX) were assessed in both mouse and rat in vivo studies. Our data demonstrate that that all site specific conjugates show improved in vitro stability, comparable or better in vivo efficacy in mice xenograph models and in vivo stability (ratio of ADC-AUC/Ab-AUC) compared to conventional conjugates. However PK and off-target toxicity of antibody drug conjugates had been significantly impacted by conjugation site and animal species. L443 mutants show higher ADC-AUC, lower clearance and longer half life than Q347 mutants in mice while a reverse TK behavior was observed in rat. All site specific conjugates show higher dose tolerance and less off-target toxicity relative to conventional conjugates in rat. This off-target toxicity improvement depends on sites of conjugation. The L443 mutants exhibited a better off-target TOX profile relative to Q347 mutants. Taken together, site-specific conjugation improved in vivo efficacy and off-target toxicity relative to conventionally conjugated ADC. PK differences and off-target toxicity improvements depend on conjugation sites and animal species. Note: This abstract was not presented at the meeting. Citation Format: Dangshe Ma, Fang Jin, Frank Barletta, George Hu, Nathan Tumey, Haige Zhang, Tao He, Eric Sousa, Manoj Charti, Kiran Khadke, Judy Lucas, Darren Ferguson, Christoper Brown, Weijun Ma, Scott Gatto, William Brady, Edmund Graziani, Hans-Peter Gerber, Puja Sapra, Lioudmila Tchistikova. Impact of conjugation site on pharmacokinetics and off-target toxicity of site-specific antibody drug conjugates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 644. doi:10.1158/1538-7445.AM2015-644

Evaluation of the toxicology and pharmacokinetics of recombinant factor VIII Fc fusion protein in animals

IntroductionRecombinant factor VIII Fc fusion protein (rFVIIIFc) is a novel recombinant factor VIII with a prolonged half-life, developed for the treatment of hemophilia A. Studies that evaluated the toxicological effects of rFVIIIFc in 2 pharmacologically relevant species, cynomolgus monkeys and Sprague Dawley rats, are reported here. Materials and MethodsIn repeat-dose toxicology studies, rats and monkeys received 0, 50, 250, or 1000IU/kg rFVIIIFc every other day for 4weeks. In a high-dose tolerance study, monkeys received 1 rFVIIIFc dose of 3000, 10,000, or 20,000IU/kg. Evaluations included in-life observations, laboratory and post-mortem evaluations, pharmacokinetics, and local tolerance. Allometric scaling, using data from 4 animal species and humans, was used to evaluate the relationship between animal and human pharmacokinetics. ResultsrFVIIIFc was well tolerated with no adverse toxicological findings directly attributable to rFVIIIFc. As expected, antibodies to this fully human protein developed in rats and monkeys in a time-dependent fashion following repeated dosing, leading to increased clearance in both species. There were no local reactions (infusion site) or evidence of thrombosis at high doses in rats and monkeys. Allometric scaling demonstrated more rapid clearance in small animals compared with humans and a volume of distribution (steady state) proportional to body weight across species, suggesting that animal pharmacokinetics are predictive of human pharmacokinetics. ConclusionsRepeated doses of rFVIIIFc in 2 relevant animal species and high doses of rFVIIIFc in monkeys were well tolerated. These results supported the clinical safety of rFVIIIFc observed in phase 1/2a and phase 3 clinical trials.

TWO METHODS OF ORAL DELIVERY OF RESVERATROL: A CASE STUDY

Background: Resveratrol is one of the most popular nutrition supplements, especially in the older population segment, yet its safety and health benefits are not fully established. This study aimed at determining bioavailability and the physiological effects of resveratrol delivered by 2 methods in a one senior patient case study. Methods: Bioavailability of resveratrol and blood chemistry parameters following the gastrointestinal and transbuccal intake were measured, respectively, by HPLC in blood and urine, and by blood chemistry analyzer. Results: The fraction of the initially administered resveratrol detected in the blood was over 15 times higher following transbuccal intake than through the gastrointestinal tract. About 36% of the ingested resveratrol was excreted in urine as 3 major metabolites, while only 11% were secreted as major metabolites following the transbuccal intake. The major metabolite in urine peaked at the same time regardless of the method of delivery. Three long-term (31 day) cycles of resveratrol supplementation by transbuccal mucoadhesive film or by ingestion did not result in any noticeable (over 5%) variation of blood chemistry, blood pressure or the overall physical condition of the patient. Conclusion: Bioavailability of resveratrol delivered through oral mucosa may be over one log higher than by swallowing, as determined by the fraction of the initial resveratrol intake in the blood and, under metabolized form, in urine. Lack of resveratrol-associated changes in blood pressure and chemistry following long term supplementation demonstrates good tolerance to high doses of resveratrol in this senior patient case study.

Phase 2 Trial of Nab-Paclitaxel Plus Carboplatin for Advanced NSCLC in Patients at Risk of Bleeding From VEGF Directed Therapies: Metastatic Non-Small Cell Lung Cancer

The addition of bevacizumab (Bev) to platinum based chemotherapy results in higher response rate (RR), progression-free survival (PFS), and overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Due to bleeding risk, Bev is contraindicated in patients (pts) with squamous histology or with hemoptysis. Nab-paclitaxel is a novel formulation of paclitaxel with higher dose tolerance and potentially improved efficacy. We hypothesized that in pts with advanced NSCLC ineligible for bevacizumab therapy (squamous histology, history of hemoptysis, requirement for anticoagulation) the combination of nab-paclitaxel and carboplatin would be superior to alternative doublets.

Tolerability of High Doses of Daptomycin in the Treatment of Prosthetic Vascular Graft Infection: A Retrospective Study.

IntroductionIn treatment of prosthetic vascular graft infection (PVGI), appropriate antimicrobial treatment is crucial for controlling the septic process and preventing re-infection of the new graft. Glycopeptides are the mainstay of treatment for device-related infections by methicillin-resistant Staphylococcus aureus strains, but with some limitations, especially concerning vancomycin-intermediate and glycopeptide-intermediate S. aureus. We report our experience using a high dose of daptomycin (DAP) for treatment of PVGI.MethodsWe reviewed medical reports of 26 patients treated with high doses of DAP (>8 mg/kg) and beta-lactams/aminosides for PVGI, defined as positive bacterial culture of intraoperative specimens or blood samples and/or clinical, biological, and radiological signs of infection. Clinical success was defined by resolution of all clinical signs at the end of follow-up, without the need for additional antibiotic therapy, and/or negative culture in case of new surgery.ResultsCultures of intraoperative samples were positive in 21 patients (80.8%). Blood and intraoperative cultures were concomitantly positive in 10 patients. The main microorganism identified in microbiological samples was S. aureus (n = 18). Surgery was performed in 23 patients (88.4%). The mean duration of the DAP regimen was 12.3 ± 11.9 days. DAP was discontinued in 26 patients [need to switch to microbiological results (n = 19), bacterial pneumonia (n = 2), and increased creatine phosphokinase levels (n = 4)]. One patient had myalgia, while 9 received concomitant statins.ConclusionHigh-dose DAP therapy shows a satisfactory toxicity profile even in severely ill patients with multiple comorbidities, and may favorably compete with vancomycin, especially concerning the risk of induced nephrotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0035-9) contains supplementary material, which is available to authorized users.

P-102: Bioavailability and tolerance of high doses vitamin D in children with newly diagnosed Crohn’s disease

Methods: We conducted an open label pilot study aiming to investigate the bioavailability and tolerance of high doses of vitamin D3 as an adjunct therapy in children with newly diagnosed pediatric CD. Vitamin D was administered orally at doses of 3,000 IU/day (in children with enteral nutrition therapy) or 4,000 IU/day (in children with corticosteroids). The primary objective was to document the lack of adverse effects (such as hypercalcemia or hypercalciuria). The secondary objective was to investigate the bioavailability of vitamin D, as assessed by the blood levels of 25OHD measured weekly up to one month. Results: A total of 20 children (9 girls, 11 17 years) were included in the study. CD localization at diagnosis was ileal (n = 5), colic (n = 5) and ileocolic (n = 10). All patients had active inflammatory phenotype. The median (range) level of 25(OH)D at baseline was 51 nmol/L (20 77). Vitamin D supplementation resulted in a gradual increase of 25(OH)D: slower during the first two weeks followed by a plateau by the end of the fourth week. All patients with a daily dose of 4,000 IU D3 reached a 25(OH)D blood level of 100 nmol/L. No patient had a serum level of vitamin D above 220 nmol/L (toxic level). We did not observe any adverse clinical or biological event during followup. Conclusion: In children with active CD at diagnosis, a daily dose of 4,000 IU of vitamin D is well tolerated and quickly increases the blood levels of 25OHD3 to 100 nmol/L or above in all cases.

Diffraction before destruction.

X-ray free-electron lasers have opened up the possibility of structure determination of protein crystals at room temperature, free of radiation damage. The femtosecond-duration pulses of these sources enable diffraction signals to be collected from samples at doses of 1000 MGy or higher. The sample is vaporized by the intense pulse, but not before the scattering that gives rise to the diffraction pattern takes place. Consequently, only a single flash diffraction pattern can be recorded from a crystal, giving rise to the method of serial crystallography where tens of thousands of patterns are collected from individual crystals that flow across the beam and the patterns are indexed and aggregated into a set of structure factors. The high-dose tolerance and the many-crystal averaging approach allow data to be collected from much smaller crystals than have been examined at synchrotron radiation facilities, even from radiation-sensitive samples. Here, we review the interaction of intense femtosecond X-ray pulses with materials and discuss the implications for structure determination. We identify various dose regimes and conclude that the strongest achievable signals for a given sample are attained at the highest possible dose rates, from highest possible pulse intensities.

Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers

Previous studies have indicated that ticagrelor is well tolerated and exhibits linear pharmacokinetics up to doses of 600 mg/day. The safety, tolerability, pharmacokinetics and pharmacodynamics (bleeding times and pulmonary function tests) of high single-ascending doses of ticagrelor were assessed to determine the maximum tolerated dose of ticagrelor. This was a randomized, double-blind, placebo-controlled study. Eight healthy volunteers were planned for enrollment in each of 3 dose groups, ticagrelor 900 mg, 1,260 mg, and 1,620 mg (6 : 2 ratio ticagrelor : placebo). The study stopping criteria were met when 3 of the 6 volunteers receiving ticagrelor 1,260 mg experienced moderate gastrointestinal adverse events (AE); none were observed with placebo. One volunteer receiving ticagrelor 1,260 mg had a serious AE - sinus arrest, high-grade atrioventricular block, and ventricular escape rhythm with syncope - and another volunteer had brief, mild dyspnea. Ticagrelor 900 mg was well tolerated. Total exposure to ticagrelor increased dose proportionally. Peak plasma concentration (Cmax) for ticagrelor did not increase much, most likely due to delayed absorption. There were no relevant changes in respiratory parameters. Bleeding times were prolonged in those receiving ticagrelor with respect to placebo, with longer bleeding times in volunteers receiving ticagrelor 1,260 mg than in volunteers receiving 900 mg; no bleeding events were reported. These results indicate that the maximum tolerated single dose of ticagrelor is 900 mg in healthy volunteers.

Selective Internal Radiation Therapy to the Liver: High Tumor Dose and Normal Liver Tolerance

Selective Internal Radiation Therapy to the Liver: High Tumor Dose and Normal Liver Tolerance

Dose-ranging randomized pharmacokinetic (PK) and pharmacodynamic (PD) study of vorinostat in patients with advanced solid tumors.

2571 Background: Continuous 400 mg daily vorinostat (V) is effective treatment for cutaneous T-cell lymphoma, but has displayed erratic activity in combination therapy for solid tumors. Short-course high-dose vorinostat may have a better therapeutic index for solid tumors, but dose/exposure/PD relationships have not been tested in sufficiently powered studies. Methods: Patients (pts) were randomized to either V 1600 mg daily, days (d) 1-3 then 400 mg d8-10 or 400 mg d1-3 then 1600 mg d8-10 with complete PK sampling on d3 and d10 to determine the increase in Cmax upon increasing V from 400 to1600 mg. To assess safety and tolerability of high dose V added to carboplatin, pts then received high dose V d15-17 with carboplatin AUC 5 on d17; this combination was repeated every 21d thereafter. Platelet counts were determined weekly. To detect with 80% power a difference in vorinostat Cmax between 400 and 1600 mg required at least 10 pts in each sequence. In vitro studies of gene expression in solid tumors suggested as a secondary endpoint the frequency of pts achieving Cmax &gt; 1000 ng/mL. Results: 24 pts (11 men/13 women) enrolled between April 2011 and March 2012 and were evaluable for study endpoints. No sequence dependence of change in Cmax was detected. Cmax for V 1600 mg was nearly double that for 400 mg (1184+/-631 vs. 616+/-442 ng/mL, p &lt; 0.001). The PD effect on platelets (d10) was greater for the higher dose (median -76 vs. -14 K/µL, p= 0.02). There were no dose limiting toxicities. Of 24 pts, 11 achieved Cmax &gt; 1000 ng/mL. Conclusions: The 1600 mg dose of vorinostat results in a higher Cmax than 400 mg and greater PD effect than 400 mg and is tolerable in combination with carboplatin. The carboplatin/vorinostat doublet serves as a DNA-damaging/epigenetic modifier module to be combined in more complex regimens. Clinical trial information: NCT01281176.