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Branford, Susan,Yeung, David T.,Prime, Jodi A.,Choi, Soo-Young,Bang, Ju-hee,Park, Jin Eok,Kim, Dong-Wook,Ross, David M.,Hughes, Timothy P. American Society of Hematology 2012 Blood Vol.119 No.18
<B>Abstract</B><P>Rising BCR-ABL1 transcripts indicate potential loss of imatinib response in CML. We determined whether the BCR-ABL1 doubling time could distinguish nonadherence from resistance as the cause of lost response. Distinct groups were examined: (1) acquired clinical resistance because of blast crisis and/or BCR-ABL1 mutations; and (2) documented imatinib discontinuation/interruption. Short doubling times occurred with blast crisis (median, 9.0 days; range, 6.1-17.6 days; n = 12 patients), relapse after imatinib discontinuation in complete molecular response (median, 9.0 days; range, 6.9-26.5 days; n = 17), and imatinib interruption during an entire measurement interval (median, 9.4 days; range, 4.2-17.6 days; n = 12; P = .72). Whereas these doubling times were consistently short and indicated rapid leukemic expansion, fold rises were highly variable: 71-, 9.5-, and 10.5-fold, respectively. The fold rise depended on the measurement interval, whereas the doubling time was independent of the interval. Longer doubling times occurred for patients with mutations who maintained chronic phase (CP: median, 48 days; range, 17.3-143 days; n = 29; P < .0001). Predicted short and long doubling times were validated on an independent cohort monitored elsewhere. The doubling time revealed major differences in kinetics according to clinical context. Long doubling times observed with mutations in CP allow time for intervention. A short doubling time for a patient in CP should raise the suspicion of nonadherence.</P>
Hughes, Timothy,Saglio, Giuseppe,Branford, Susan,Soverini, Simona,Kim, Dong-Wook,Mü,ller, Martin C,Martinelli, Giovanni,Cortes, Jorge,Beppu, Lan,Gottardi, Enrico,Kim, Dongho,Erben, Philipp,Shou, Y Grune Stratton ; American Society of Clinical Onco 2009 Journal of clinical oncology Vol.27 No.25
<P>PURPOSE: Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. PATIENTS AND METHODS: Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. RESULTS: Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC(50)] <or= 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC(50) > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. CONCLUSION: For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.</P>
Baccarani, Michele,Druker, Brian J,Branford, Susan,Kim, Dong-Wook,Pane, Fabrizio,Mongay, Lidia,Mone, Manisha,Ortmann, Christine-Elke,Kantarjian, Hagop M,Radich, Jerald P,Hughes, Timothy P,Cortes, Jorg Elsevier Science Publishers 2014 INTERNATIONAL JOURNAL OF HEMATOLOGY Vol.99 No.5
<P>The TOPS trial evaluated high- (800 mg/day; n = 319) versus standard-dose (400 mg/day; n = 157) imatinib in patients newly diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Patients had a minimum follow-up of 42 months or discontinued early. Major molecular response (MMR) rates were similar between arms at (51.6 vs 50.2 % for 400 and 800 mg/day, respectively; P = 0.77) and by (75.8 vs 79.0 %; P = 0.4807) 42 months. There were no differences in event-free survival (EFS), progression-free survival(PFS), or overall survival (OS) between arms. The estimated rates of PFS on treatment and OS at 42 months were significantly higher in patients with MMR at 6, 12, and 18 months compared with those without MMR.Adverse events were more frequent with high-dose imatinib. Patients with B1 treatment interruption (vs [1) and those able to maintain imatinib C600 mg/day (vs\600 mg/day) in the first year of treatment had faster and higher response rates, but no improvement in EFS or PFS. Adherence to prescribed dose without interruption may be more important than initiation of therapy with higher doses of imatinib. Achievement of MMR correlated with longterm clinical outcomes.</P>
Cortes, Jorge E.,Baccarani, Michele,Guilhot, Franç,ois,Druker, Brian J.,Branford, Susan,Kim, Dong-Wook,Pane, Fabrizio,Pasquini, Ricardo,Goldberg, Stuart L.,Kalaycio, Matt,Moiraghi, Beatriz,Rowe, American Society of Clinical Oncology 2010 Journal of clinical oncology Vol.28 No.3
<B>Purpose</B><P>To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase.</P><B>Patients and Methods</B><P>A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months.</P><B>Results</B><P>At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d.</P><B>Conclusion</B><P>MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.</P>
Wang, Chang-Hong,Cheng, Xue-Mei,He, Yu-Qi,White, Kenneth N.,Bligh, S.W.Annie,Branford-White, Christopher J.,Wang, Zheng-Tao 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.9
The pharmacokinetics in rats of gentiopicroside (GPS) from orally administered decoctions of Radix Gentianae (DRG) and Gentiana macrophlla (DGM) were compared with that of GPS alone administered at 150 mg/kg orally and 30 mg/kg intravenously. The metabolic profile of GPS after intravenous injection could be fitted to two-compartment model whereas oral administration decoctions DRG or DGM, or GPS alone, could all be fitted to a one-compartment model. After oral administration of GPS alone, GPS was absorbed quickly and reached a maximum plasma concentration ($C_{max}$) value, 5.78 ${\pm}$ 2.24 ${\mu}g/mL$ within 0.75 ${\pm}$ 0.62 h. The plasma level of GPS declined with a $T_{1/2ke}$, 3.35 ${\pm}$ 0.76 h. After oral administration of decoctions DRG and DGM, GPS was absorbed and reached significantly higher maximum concentrations of 10.53 ${\pm}$ 3.20 ${\mu}g/mL$ (p < 0.01) and 7.43 ${\pm}$ 1.64 ${\mu}g/mL$ (p < 0.05) at later time points 1.60 ${\pm}$ 0.76 (p < 0.01) and 2.08${\pm}$0.74 h (p < 0.05), for DRG and DGM respectively, compared with oral GPS alone. Significantly larger AUC values were found for decoctions of GPS (83.49 ${\pm}$ 20.8 ${\mu}g{\cdot}h/mL$ for DRG and 59.43 ${\pm}$ 12.9 ${\mu}g{\cdot}h/mL$ for DGM) compared with oral GPS alone (32.67 ${\pm}$ 12.9 ${\mu}g{\cdot}h/mL$. The results demonstrate that the bioavailability of GPS was markedly improved when administered as a decoction than as purified GPS. The decoction from Radix Gentianae provided 2.5 times better bioavailability and that from Gentiana macrophlla 1.8 times higher. The study confirms the importance of careful pharmacokinetic analysis in the characterization of herbal medicines when applied for future clinical applications.
Pharmacokinetic Behavior of Gentiopicroside From Decoction of Radix Gentianae,
Chang-hong Wang,Xue-mei Cheng,Yu-qi He,Kenneth N. White,S. W. Annie Bligh,Christopher J. Branford-White,Zheng-tao Wang 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.9
The pharmacokinetics in rats of gentiopicroside (GPS) from orally administered decoctions of Radix Gentianae (DRG) and Gentiana macrophlla (DGM) were compared with that of GPS alone administered at 150 mg/kg orally and 30 mg/kg intravenously. The metabolic profile of GPS after intravenous injection could be fitted to two-compartment model whereas oral administration decoctions DRG or DGM, or GPS alone, could all be fitted to a one-compartment model. After oral administration of GPS alone, GPS was absorbed quickly and reached a maximum plasma concentration (Cmax) value, 5.78 ± 2.24 µg/mL within 0.75 ± 0.62 h. The plasma level of GPS declined with a T1/2ke, 3.35 ± 0.76 h. After oral administration of decoctions DRG and DGM, GPS was absorbed and reached significantly higher maximum concentrations of 10.53 ± 3.20 µg/mL (p < 0.01) and 7.43 ± 1.64 µg/mL (p < 0.05) at later time points 1.60 ± 0.76 (p < 0.01) and 2.08±0.74 h (p < 0.05), for DRG and DGM respectively, compared with oral GPS alone. Significantly larger AUC values were found for decoctions of GPS (83.49 ± 20.8 µg·h/mL for DRG and 59.43 ± 12.9 µg·h/mL for DGM) compared with oral GPS alone (32.67 ± 12.9 µg·h/mL). The results demonstrate that the bioavailability of GPS was markedly improved when administered as a decoction than as purified GPS. The decoction from Radix Gentianae provided 2.5 times better bioavailability and that from Gentiana macrophlla 1.8 times higher. The study confirms the importance of careful pharmacokinetic analysis in the characterization of herbal medicines when applied for future clinical applications.
Mü,ller, Martin C.,Cortes, Jorge E.,Kim, Dong-Wook,Druker, Brian J.,Erben, Philipp,Pasquini, Ricardo,Branford, Susan,Hughes, Timothy P.,Radich, Jerald P.,Ploughman, Lynn,Mukhopadhyay, Jaydip,Hochh American Society of Hematology 2009 Blood Vol.114 No.24
<B>Abstract</B><P>Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC50) greater than 3nM; among patients with mutations with lower or unknown IC50, efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844.</P>
Photoproduction ofπ+π−meson pairs on the proton
Battaglieri, M.,De Vita, R.,Szczepaniak, A. P.,Adhikari, K. P.,Amaryan, M. J.,Anghinolfi, M.,Baghdasaryan, H.,Bedlinskiy, I.,Bellis, M.,Bibrzycki, L.,Biselli, A. S.,Bookwalter, C.,Branford, D.,Briscoe American Physical Society 2009 PHYSICAL REVIEW D - Vol.80 No.7