scholarly journals The Effect of Long-Term Low-Dose Atropine on Refractive Progression in Myopic Australian School Children

2021 ◽  
Vol 10 (7) ◽  
pp. 1444
Author(s):  
William Myles ◽  
Catherine Dunlop ◽  
Sally A. McFadden
Keyword(s):  
Low Dose ◽  
High Dose ◽  
Eye Drops ◽  
Myopia Progression ◽  
At Risk Children ◽  
Slow Group ◽  
Blue Eyes ◽  
Global Population ◽  
Axial Growth

Myopia will affect half the global population by 2050 and is a leading cause of vision impairment. High-dose atropine slows myopia progression but with undesirable side-effects. Low-dose atropine is an alternative. We report the effects of 0.01% or 0.005% atropine eye drops on myopia progression in 13 Australian children aged between 2 and 18 years and observed for 2 years without and up to 5 years (mean 2.8 years) with treatment. Prior to treatment, myopia progression was either ‘slow’ (more positive than −0.5D/year; mean −0.19D/year) or ‘fast’ (more negative than −0.5D/year; mean −1.01D/year). Atropine reduced myopic progression rates (slow: −0.07D/year, fast: −0.25D/year, combined: before: −0.74, during: −0.18D/year, p = 0.03). Rebound occurred in 3/4 eyes that ceased atropine. Atropine halved axial growth in the ‘Slow’ group relative to an age-matched model of untreated myopes (0.098 vs. 0.196mm/year, p < 0.001) but was double that in emmetropes (0.051mm/year, p < 0.01). Atropine did not slow axial growth in ‘fast’ progressors compared to the age-matched untreated myope model (0.265 vs. 0.245mm/year, p = 0.754, Power = 0.8). Adverse effects (69% of patients) included dilated pupils (6/13) more common in children with blue eyes (5/7, p = 0.04). Low-dose atropine could not remove initial myopia offsets suggesting treatment should commence in at-risk children as young as possible.

scholarly journals The Effects of 0.01% Atropine on Adult Myopes’ Contrast Sensitivity

2021 ◽  
Vol 15 ◽  
Author(s):  
Ziyun Cheng ◽  
Jianhui Mei ◽  
Suqi Cao ◽  
Ran Zhang ◽  
Jiawei Zhou ◽  
...  
Keyword(s):  
Contrast Sensitivity ◽  
Low Dose ◽  
Randomized Study ◽  
Eye Drops ◽  
Short Term ◽  
Myopia Progression ◽  
Significant Interaction Effect ◽  
Corrected Visual Acuity ◽  
To Receive

PurposeAtropine at a low concentration is considered a safe and effective treatment to mitigate myopia progression. However, the potential unwanted side effects of administering atropine at a low dose on visual functions other than best corrected visual acuity has not been investigated. In this study, we investigate the short-term (12,16, and 20 h) and long-term (1, 2, and 4 weeks) effects of 0.01% atropine (i.e., 0.1 mg/ml) on contrast sensitivity (CS) in patients with myopia.MethodsThirty adults (23.33 ± 2.93 years old) with myopia between -1.00 and -6.00 diopters (D), astigmatism of -1.50 D or less, and anisometropia of 1.00 D or less, participated in this prospective, masked, placebo-controlled, randomized study. The participants were randomly assigned to receive 0.01% atropine or polyvinyl alcohol eye drops once nightly to both eyes for four weeks. CS was measured binocularly at baseline and 12, 16, 20 h, 1, 2, and 4 weeks after the first use of the eye drops.ResultsThere was no statistically significant differences of CS found between atropine and placebo-controlled groups in both short-term and long-term. There was no statistically significant interaction effect found between the time and group.ConclusionWe demonstrated no significant deleterious effect of 0.01% atropine on adult myopes’ CS.

Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers

1987 ◽  
Vol 17 (4) ◽  
pp. 869-873 ◽  
Author(s):  
C. Schmauss ◽  
J.-C. Krieg
Keyword(s):  
Low Dose ◽  
Matched Control ◽  
Control Group ◽  
High Dose ◽  
Withdrawal Therapy ◽  
The Mean ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Age And Sex

SynopsisIn 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients (N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients (N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.

Case Report: Rapid Response to Low-Dose Thalidomide in a Case of Severe Steroid Recalcitrant Erythema Nodosum Leprosum

2021 ◽  
Author(s):  
B. Savitha ◽  
Kabir Sardana ◽  
Ritu Kumari ◽  
Ananta Khurana ◽  
Surabhi Sinha ◽  
...  
Keyword(s):  
Low Dose ◽  
Erythema Nodosum ◽  
Lepromatous Leprosy ◽  
High Dose ◽  
Effective Treatment Option ◽  
Steroid Dependence ◽  
Erythema Nodosum Leprosum ◽  
Organ Specific ◽  
Inflammatory Drugs

Erythema nodosum leprosum (ENL), or type 2 lepra reaction, presents with crops of evanescent, tender erythematous nodules accompanied by fever, arthralgia, weight loss, malaise, and organ-specific manifestations, and is seen in borderline and lepromatous leprosy. The drugs approved for ENL include nonsteroidal anti-inflammatory drugs, systemic steroids, thalidomide, and clofazimine. The management of ENL is challenging because long-term steroid use leads to steroid dependence. Our patient had severe steroid recalcitrant ENL with vesicular and pustular lesions mimicking Sweet’s syndrome, and was treated effectively with a low-dose thalidomide regimen (100 mg/d) as opposed to the high dose (400 mg/d) recommended in the literature. We discuss the patho-mechanics and clinical utility of a low-dose thalidomide regimen as an effective treatment option for ENL.

Effects of long-term continuous GnRH administration on the pituitary–gonadal axis in Eld's deer stags (Cervus eldi thamin)

1995 ◽  
Vol 73 (9) ◽  
pp. 1609-1619 ◽  
Author(s):  
S. L. Monfort ◽  
J. L. Brown ◽  
T. C. Wood ◽  
M. Bush ◽  
L. R. Williamson ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Fertile Period ◽  
Nonbreeding Season ◽  
Testosterone Secretion ◽  
High Doses ◽  
Seasonal Decline ◽  
Seasonally Breeding

Eld's deer stags (Cervus eldi thamin) (in groups of three) were continuously administered gonadotropin-releasing hormone (GnRH) in control, low, medium, or high doses (0, 20.1 ± 0.7, 83.3 ± 2.6, and 292.9 ± 4.9 ng∙kg−1∙d−1, respectively) via osmotic minipumps for ~80 d to investigate the potential for precociously reactivating the pituitary–testicular axis during the nonbreeding season. Secretory patterns of LH, FSH, and testosterone concentrations were qualitatively similar among treatments. However, in the low-dose group, basal LH and FSH concentrations were both increased (p < 0.05) and pituitary responsiveness to a superimposed GnRH challenge was augmented (p < 0.05) after 12 weeks of treatment compared with all other groups. Despite these endocrine changes, continuous low-dose GnRH administration was not effective for precociously inducing testicular activity in this seasonally breeding species. High-dose GnRH administration initially induced a transient increase in LH, FSH, and testosterone secretion and delayed, but did not prevent, the seasonal decline in spermatogenesis. After 6–12 weeks of high-dose GnRH administration, however, attenuated pituitary responsiveness appeared to delay the normal seasonal reactivation of the pituitary–gonadal axis. In conclusion, prolonged, continuous low-dose GnRH administration did not effectively translate into a precocious onset of testicular activity; therefore, this specific approach is unlikely to be useful for prolonging the fertile period in this seasonally breeding species.

scholarly journals Effect of low-dose atropine on myopia progression, pupil diameter and accommodative amplitude: low-dose atropine and myopia progression

2020 ◽  
pp. bjophthalmol-2019-315440 ◽  
Author(s):  
Aicun Fu ◽  
Fiona Stapleton ◽  
Li Wei ◽  
Weiqun Wang ◽  
Bingxin Zhao ◽  
...  
Keyword(s):  
Low Dose ◽  
Pupil Diameter ◽  
Repeated Measurements ◽  
Control Group ◽  
Eye Drops ◽  
Control Groups ◽  
Myopia Progression ◽  
Registration Number ◽  
And Control ◽  
Accommodative Amplitude

PurposeTo evaluate the effects of 0.01% and 0.02% atropine eye drops on myopia progression, pupil diameter and accommodative amplitude in myopic children.MethodsA cohort study assessed 400 myopic children divided into three groups: 138 and 142 children were randomised to use either 0.02% or 0.01% atropine eye drops, respectively. They wore single-vision (SV) spectacles, with one drop of atropine eye drop applied to both eyes once nightly. Control children (n=120) only wore SV spectacles. Repeated measurements of spherical equivalent refractive errors (SERs), axial length (AL), pupil diameter and accommodative amplitude were performed at baseline, and 4, 8 and 12 months after treatment.ResultsAfter 12 months, the SER change was −0.38±0.35D, −0.47±0.45D, −0.70±0.60D and AL change was 0.30±0.21 mm, 0.37±0.22 mm, 0.46±0.35 mm in the 0.02%, 0.01% atropine and control groups, respectively. There were significant differences in the change in AL and SER between three groups (all p<0.001). Between baseline and the 12-month visit, the overall change in accommodative amplitude was 1.50±0.25D, 1.61±0.31D and change in pupil diameter was 0.78±0.42 mm, 0.69±0.39 mm, with 0.02% and 0.01% atropine, respectively. Accommodative amplitude significantly decreased and pupil diameter significantly increased in two atropine groups (all p<0.001). Moreover, there was no statistical difference in the change difference in accommodative amplitude and pupil diameter between two atropine groups (p=0.24, p=0.38), whereas the accommodative amplitude (p=0.45) and pupil diameter (p=0.39) in the control group remained stable.Conclusions0.02% atropine eye drops had a better effect on myopia progression than 0.01% atropine, but 0.02% and 0.01% atropine showed similar effects on pupil diameter and accommodative amplitude after 12 months of treatment.Trial registration numberChiCTR-IPD-16008844.

Successful Long Term Therapeutic Expression of Factor VIII in Hemophilia A Dogs After Administration of AAV-cFVIII Using a Two-Chain or Single Chain Delivery Approach.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 546-546
Author(s):  
Denise E. Sabatino ◽  
Ekaterina Altynova ◽  
Amy M. Lange ◽  
Shangzhen Zhou ◽  
Elizabeth P. Merricks ◽  
...  
Keyword(s):  
Low Dose ◽  
Hemophilia A ◽  
High Dose ◽  
Dependent Manner ◽  
Igg Antibodies ◽  
Single Chain ◽  
Spontaneous Bleeding ◽  
Aav Vector ◽  
Bleeding Episodes

Abstract Abstract 546 While adeno-associated virus (AAV) is a promising gene delivery vector, it has been challenging to deliver FVIII due to the large size of the FVIII cDNA and the high frequency of FVIII antibody formation in hemophilia A (HA) patients. We used two approaches to overcome the size limitation of AAV for FVIII: (1) two-chain delivery in which the canine FVIII (cFVIII) heavy chain (HC) is delivered in one AAV vector and the cFVIII light chain (LC) is delivered in a second AAV vector and (2) single chain delivery in which the B-domain deleted cFVIII cDNA with minimal regulatory elements is within one AAV vector. In the two-chain approach AAV-HC (4.0 Kb) and AAV-LC (3.9 Kb) with a liver specific promoter was co-injected at a dose of 6×1012 vector genomes/vector/kg or 1.25×1013vg/vector/kg using AAV8 or AAV9 via hepatic infusion. Five hemophilia A dogs treated with AAV-HC and AAV-LC expressed 0.5-11% cFVIII in a dose-dependent manner. The mean cFVIII activity based on Coatest assay for the low dose was 1.3% (>1220d)(Linus)(AAV8) and 0.6% (>1770d)(H19)(AAV9), while for the high dose it was 5.2% (800d)(F24)(AAV8) and 2.4% (>1270d)(Woodstock)(AAV9). One dog (J60) had a splenectomy due to a complication at the time of surgery and has maintained high levels of expression (mean 11.0%; >820d). The WBCT consistently remained at a mean of 17.6 min for low dose dogs and 13.7 min for high dose dogs compared to 8-12 min in normal dogs. Using novel reagents that we generated specific to cFVIII, we developed assays to detect cFVIII antigen levels and IgG antibodies. Despite receiving equal doses of each vector, at day 85 the cFVIII-LC antigen levels (71.7 ± 19.2 ng/ml) were >10-fold higher than would be predicted based on activity while the cFVIII-HC antigen levels (14.6 ± 9.2 ng/ml) were >3-fold higher than activity. Since functional FVIII synthesis relies on the co-transduction of AAV-HC and AAV-LC in the same cell, this suggests that only a portion of the vector co-transduces and expresses cFVIII in the same cell and that the light chain is secreted more efficiently than the HC. No IgG antibodies to cFVIII were detected at any time point in these dogs. Three dogs have maintained FVIII expression for >3.5 years and two dogs for >2 years with ongoing observation. No spontaneous bleeding episodes have been observed in these dogs for a cumulative observation of >16 years while >80 bleeding episodes would be expected during this time period. The second approach, the single chain delivery, overcomes the co-transduction requirement of the two-chain approach by ensuring that each transduced cell expresses functional FVIII. However, it is difficult to efficiently package the large 5.2 Kb single chain construct into an AAV vector. Since no significant differences were observed between AAV8 and AAV9 using the two-chain approach, we used AAV8 to deliver the single chain cFVIII by peripheral vein infusion at 2×1013vg/kg or 4×1013vg/kg. The mean cFVIII activity was 0.7% (>430d) for the low dose dog (L51) and 6.8% (>290d) and 2.2% (>110d) for the high dose dogs (M06, M50). cFVIII HC and LC ELISA showed that cFVIII antigen levels correlated with activity. WBCT was a mean of 19.1 min for L51, 15.3 min for M06 and 11.6 min for M50. No spontaneous bleeding episodes have been observed in these dogs. The high dose dogs had no IgG antibodies to FVIII. L51 had transient IgG antibodies to FVIII until d52 in the absence of a Bethesda titer. A rise in FVIII expression in L51 coincided with the disappearance of anti-cFVIII antibodies. Comparison of single chain and two-chain delivery of FVIII reveals that (1) long term therapeutic levels of cFVIII in a dose-dependent manner can be obtained with both delivery approaches; (2) circulating cFVIII antigen levels are >10-fold higher than activity in the two-chain delivery in contrast to single chain delivery in which antigen correlates with activity; and (3) high antigen levels may facilitate tolerance to FVIII in the setting of liver-directed gene transfer, since a transient non-inhibitory antibody was observed in only one dog with very low FVIII levels. Notably, no cellular toxicity due to continuous expression of various forms of FVIII was found in these animals based on long-term sustained FVIII expression levels and normal liver enzymes in all eight HA dogs. Further studies to characterize the immune responses to the transgene will define the optimal vector approach. These data will form the basis for clinical studies in humans with severe HA. Disclosures: No relevant conflicts of interest to declare.

Maintenance Low Dose 13 Cis-Retinoic Acid and Alpha Tocopherol Improves Survival Compared to High Dose Therapy for 6 Months In LOW and INT-1/2 Stage MDS: Role for Prevention Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5053-5053
Author(s):  
Emmanuel C. Besa ◽  
Joseph Vadakara
Keyword(s):  
Retinoic Acid ◽  
Retrospective Study ◽  
Side Effects ◽  
Low Dose ◽  
Low Risk ◽  
Alpha Tocopherol ◽  
High Dose ◽  
Off Label ◽  
Stage Disease

Abstract Abstract 5053 There are no current therapies or preventative strategies other than transfusion support and possibly growth factor support for the management of low risk and INT 1 Myelodysplasia. There have been a few studies that looked into the effect of 13 cis-retinoic acid (13CRA) by itself and in combination with other drugs that showed some benefits to the use of 13CRA in MDS. A randomized blinded study failed to show any benefit of 13CRA over placebo; however in this study many of the patients discontinued therapy due to side effects of the 13CRA and significant number of the patients had advanced stage disease and either had CMML, RAEB, and RAEB-t based on the classification in use then. Other studies have suggested that the beneficial effect of 13CRA is possibly seen in early stage disease and in low risk Refractory Anemia patients. To look into the benefit that 13CRA might have on IPSS low risk, INT-1 and INT-2 MDS patients we conducted a retrospective study that looked at the effect of 13CRA given in two different doses and durations. Methods: This was a retrospective study that looked at patients with IPSS low risk and INT-1 and INT-2. The patients were divided into two groups. One group was treated with a dose of 13CRA at a dose of 100mg/m2/day for 6 months. The second cohort was treated with a dose of 40mg of 13CRA until disease progression. Disease progression was then compared in the two groups to see if there was any statistical difference in the treatment arms. One of the patients did not seem to have any side effects of 13CRA and it was later found that that patient was on alpha tocopherol, once this was realized then all the patients were given Alpha tocopherol (AT) at a dose 800mg per day along with 13CRA. Results: Twenty patients were identified in the high dose short term arm, and 29 patients in the low dose long term arm. Both groups were similar in age (mean, range) in years, male/female ratio, duration from diagnosis to treatment. IPSS scores and transfusion requirements were comparable. Responses were observed in both groups with an overall response rate of 44.8% in HDST and 75% in LDLT with similar, low AML transformation in INT-1-2 patients of 15% in LDLT and 13.7% in HDST. A better median survival was observed with 5 patients still alive at 72 months in LDLT compared to 30 months in HDST group with a difference of 42 months (3.5 years) (Log-rank p value= 0.0099). The patients who were on the LDLT arm with alpha tocopherol had a much better toxicity profile with only 5% developing skin toxicity compared to as high as 27% in HDST arm and 100% in patients who only received 13CRA, similarly triglyceride changes were seen in 5%, 20%, and 52% respectively, AST elevations were seen in 0%, 2% and 19 % respectively. This suggest that lack of toxicity and good tolerance using 13 CRA at 40 mg/d with 800 mg of AT for long term preventive measure in early phase MDS may result in prolonged survival and may be used as basis for a prospective prevention trial. Disclosures: Off Label Use: 13 cis retinoic acid is used off label.

Long Term Efficacy and Safety Results and Analysis of Dose Correlations from the Phase I/II Peginvera Study of Ropeginterferon Alfa-2b, a Novel IFNa-2b, in Polycythemia Vera Patient

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4056-4056
Author(s):  
Heinz Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
Josef Thaler ◽  
Ernst Schlögl ◽  
Gunther Gastl ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Group ◽  
Low Dose ◽  
Term Treatment ◽  
High Dose ◽  
Individual Response ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Long Term Treatment

Abstract Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, composed of mainly one isoform, resulting in longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design Efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of ropeginterferon alfa-2b, administered subcutaneously every 14 to 28 days, has been defined earlier. Patients with confirmed diagnosis of PV, age ≥18 years, both naïve and cytoreductively pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by hematocrit (Hct)<45%, platelet count≤400*109/L, WBC count≤10*109/L, normal spleen size by sonography, and absence of thromboembolic events. Partial response (PR) is defined as Hct<45% without phlebotomy but with persistent splenomegaly or elevated (>400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Complete molecular response has been defined as reduction of any molecular abnormality to undetectable levels; partial molecular response as: reduction ≥ 50% in patients with < 50% mutant allele burden, or a reduction ≥ 25% in patients with > 50% mutant allele burden. The present analysis was focused on long-term tolerability and safety in correlation with the dose of ropeginterferon alfa-2b in PV. Results Data on treatment as by July, 24, 2015, are covered by the current analysis. Baseline characteristics of the study cohort during short-term treatment were already presented earlier (Gisslinger et al, ASH 2013). The full analysis set and efficacy set were composed of 51 and 47 patients, respectively. Currently, the median reported treatment duration is 138 weeks, 33 patients completed their follow up for two years, 19 for three years. Starting with the week 10, Hct-level, platelet- and WBC-counts could be constantly maintained within normal range in the majority of patients. In a group of patients with the mean administered dose of <300 µg ("low dose", n=36), CR as best individual response was achieved in 20 (56%) patients, and PR in 14 (39%) compared to the CR and PR in the high dose (>300 µg, n=11) group of 8 (73%) and 3 (27%) respectively. However, no statistical significance can be observed if correlation between the dose and response status was analyzed. 30 patients are still being treated in the study. Similarly, no association between the dose and occurrence of adverse events in the study could be observed. Complete molecular response as best individual response was observed more frequently in the high dose group 4 (36%) compared to 8 (23%) in the low dose group, while partial molecular responses were equally frequent in both dose groups (in 6/55% and 20/57%, respectively). 21 patients discontinued the study, 18 being treated with AOP2014 doses corresponding to low, and 3 to the high dose arms, corresponding to the drop-out rate of 50% and 27% in the respective arms. Interestingly, all discontinuations in the high dose group occurred within the first year of treatment (at weeks 16, 18 and 32), while the drop-outs in the low dose group (6 patients, 33%) discontinued the study after completion of their first year of treatment. Conclusions Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. Overall response rate of >80% with cumulative CRs in 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients have been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. No significant difference between the two mean dose levels regarding response rates or adverse events even during long-term treatment and observation could be observed. These finding are to be further verified in a larger prospective setting. Disclosures Gisslinger: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Janssen Cilag: Honoraria, Speakers Bureau. Buxhofer-Ausch:AOP Orphan: Research Funding. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Research Funding. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Willenbacher:COMET Center ONCOTYROL: Research Funding; AOP Orphan: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Pfizer: Honoraria, Research Funding; GSK: Research Funding; Boehringer-Ingelheim: Honoraria; AOP Orphan: Research Funding; Celgene: Consultancy; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding.

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