Clinical pharmacokinetic and pharmacodynamic analysis of daptomycin and the necessity of high-dose regimen in Japanese adult patients

2019 ◽  
Vol 25 (6) ◽  
pp. 437-443 ◽  
Author(s):  
Toshiharu Urakami ◽  
Yohei Hamada ◽  
Yusuke Oka ◽  
Tomohide Okinaka ◽  
Hiroki Yamakuchi ◽  
...  
1988 ◽  
Vol 6 (6) ◽  
pp. 1031-1040 ◽  
Author(s):  
R F Ozols ◽  
D C Ihde ◽  
W M Linehan ◽  
J Jacob ◽  
Y Ostchega ◽  
...  

We performed a prospective randomized trial of a high-dose chemotherapy regimen v standard cisplatin-based chemotherapy in poor prognosis nonseminomatous germ-cell cancer patients. The high-dose regimen consisting of twice the standard dose of cisplatin (P), along with vinblastine (Ve), bleomycin (B), and the epipodophylotoxin etoposide (VP-16) (V) (PVeBV) was compared to the classic regimen with normal dose cisplatin, vinblastine, and bleomycin (PVeB). Eligibility criteria included large abdominal masses, liver metastases, multiple pulmonary metastases, brain metastases, marked elevations in serum tumor markers (alpha-fetoprotein greater than 1,000 ng/mL or the beta-subunit of human chorionic gonadotropin greater than 10,000 mIU), unfavorable histology (pure choriocarcinoma), or extragonadal germ-cell tumors. Fifty-two consecutive patients with poor prognostic features were randomized to receive either PVeBV or PVeB. The median follow-up is 4 years. Treatment with the high-dose regimen increased the complete remission rate (88% v 67%, P = .14) and was associated with a lower relapse rate (17% v 41%, P = .2). The median survival of patients receiving standard therapy was 30 months, while the median survival for patients receiving the high-dose regimen has not been reached. Actuarial 5-year survival for patients treated with the high-dose regimen is 78%, compared with 48% for patients receiving standard therapy (two-sided Mantel-Cox test = .06). Disease-free survival was also superior for patients randomized to PVeBV (P = .03). Sixty-eight percent of patients (23 of 34) randomized to PVeBV are alive and continuously disease-free, compared with 33% (six of 18) for PVeB (P = .02). The major difference in toxicity between the high-dose regimen and standard therapy was the severity of myelosuppression and the incidence of severe hearing loss. Ninety-one percent of patients treated with PVeBV had a WBC count less than 1,000/microL, compared with 50% of patients receiving PVeB (P less than .05). Hearing aids were recommended for 12 patients who received PVeBV and two who received PVeB. The increased effectiveness of the PVeBV regimen in poor prognosis germ-cell cancer patients may relate to the double-dose cisplatin, the addition of VP-16, or to a synergistic effect of these two drugs.


1988 ◽  
Vol 6 (9) ◽  
pp. 1491-1500 ◽  
Author(s):  
A E Chang ◽  
T Kinsella ◽  
E Glatstein ◽  
A R Baker ◽  
W F Sindelar ◽  
...  

We have previously reported the results of a randomized trial that demonstrated the survival benefit of adjuvant chemotherapy in the treatment of patients with high-grade extremity sarcomas compared with no chemotherapy. This regimen included doxorubicin, cyclophosphamide, and methotrexate. This report updates and extends our experience. The median follow-up of this trial is now 7.1 years and reveals a 5-year disease-free survival of 75% and 54% for chemotherapy and no chemotherapy groups, respectively (two-sided P [P2] = .037). The 5-year overall survival for patients in this trial was 83% and 60% for the chemotherapy and no chemotherapy groups, respectively, with a trend towards improved survival in the chemotherapy arm (P2 = .124). Because of doxorubicin-induced cardiomyopathy we performed a subsequent randomized trial comparing this high-dose regimen to reduced cumulative doses of doxorubicin and cyclophosphamide without methotrexate. Eighty-eight patients were entered into this trial which has a median follow-up of 4.4 years. The 5-year disease-free and overall survival for patients treated with the reduced doses of chemotherapy was 72% and 75%, respectively, and was not significantly different from the high-dose regimen. No patients developed congestive heart failure on this study. We conclude that adjuvant chemotherapy improves disease-free survival in patients with extremity soft-tissue sarcomas. The overall survival advantage in patients receiving adjuvant chemotherapy in our initial randomized high-dose chemotherapy trial has diminished though it continues to favor the chemotherapy group. A reduced-dose chemotherapy regimen was found to be comparable to the high-dose regimen.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2257-2257 ◽  
Author(s):  
Kai Huebel ◽  
Alessandro Re ◽  
Ariane Boumendil ◽  
Herve Finel ◽  
Marcus Hentrich ◽  
...  

Abstract Introduction: Patients infected with HIV have an increased risk of developing aggressive B-cell non-Hodgkin lymphoma and Hodgkin lymphoma (HL). The continuous development of cART during the last decade has improved the prognosis of HIV-associated lymphoma considerably. However, a significant proportion of these patients will experience lymphoma relapse and may be candidates for autoSCT. The purpose of the present study was to investigate if recent advances in anti-lymphoma therapy and anti-infectious strategies have influenced the outcome of autoSCT for HIV-related lymphoma. Patients and methods: For this retrospective study, all EBMT-registered patients aged 18 years or older with HIV-positive serostatus who were treated with a first autoSCT between 2007 and 2013 were eligible. Baseline patient, disease, and transplant data were collected from MED-A forms. Centers were requested to provide additional HIV and lymphoma treatment and follow-up information. Statistical analysis used log rank test to assess the impact of baseline characteristics on survival endpoints. In multivariate analysis, the relevance of prognostic factors was estimated using Cox regression models. Curves of cumulative incidence of relapse (IR) and non-relapse mortality (NRM) were compared by Gray's test. Results: 138 patients from 25 European centers met the eligibility criteria and had the full data set required for this analysis available. 86% were male, median age was 44 years (range 24-69). Underlying diagnoses were diffuse large B cell lymphoma (DLBCL) in 46%, HL in 21%, Burkitt lymphoma in 14%, plasmablastic lymphoma (PBL) in 10%, and other lymphoma in 9% of the patients. Disease status at autoSCT was complete remission (CR) in 51%, partial remission (PR) in 33%, and less than PR in 16% of the patients, achieved after 1 (28%), 2 (58%), or more than 2 lines of chemotherapy (14%). With HIV load below the threshold of detection in 74% of the patients, the median CD4+ cell count was 187/µl (range 0-800) at transplant. 95% of the patients continued with cART during salvage and high-dose chemotherapy. BEAM was used as high-dose regimen in 77% of the patients. With a median follow-up of 4 years, 2-year NRM, IR, progression-free survival (PFS) and overall survival for the whole series were 9%, 23%, 68% and 70%, respectively. By multivariate analysis, diagnosis DLBCL or PBL (vs HL), increasing number of chemotherapy pretreatment lines, and less than PR at autoSCT were significant predictors of an unfavorable PFS; whilst age, high-dose regimen, performance status, and viral load had no significant impact. 2-year PFS in patients with 1st-line CR, later CR, PR, or less than PR at autoSCT was 91%, 80%, 64%, and 23%, respectively. Conclusions: This series, which is the largest ever on lymphoma transplants in HIV+ patients, suggests that in the cART / chemoimmunotherapy era, the outcome of autoSCT for HIV-related lymphoma is driven by lymphoma-dependent risk factors rather than by characteristics of HIV infection. AutoSCT under ongoing cART therapy remains the treatment of choice for HIV+ patients with PBL or recurrent DLBCL or HL. Disclosures Kröger: Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Montoto:Roche: Honoraria; Gilead: Research Funding. Dreger:Novartis: Consultancy; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy.


Author(s):  
Paridhi Gupta ◽  
Indu Chawla ◽  
Sonal Gupta

ABSTRACTBackground: Induction of labour is an indispensable part of modern obstetrics and certainly one of the most frequently performed obstetric procedure in the world. Oxytocin, being the most common inducing agent with multiple protocols being practiced, further research is required for the establishment of better protocol with optimal maternal and neonatal outcomes.Methods: Randomized comparative study including 100 term nulliparous women (randomized into high dose, group-I and low dose, group-II with 50 patients in each group) was done. High dose regimen was started with 4mu/min with increment of 4mu/min up to a maximum of 32mu/min and low dose regimen was started with 2mu/min with increment of 2mu/min up to a maximum of 32mu/min. Induction to delivery interval was the primary outcome. Secondary outcomes noted were rate of caesarean section, tachysytole with or without fetal distress, failed induction, maternal outcomes like need for instrumental vaginal delivery, PPH and choriamnionitis, neonatal outcomes like NICU admission, umbilical cord pH and apgar score.Results: There was significant reduction seen in induction to delivery interval among those induced with high dose oxytocin regimen. It was found to be 6.96±3.77 hours in group-I and 9.05±4.65 hours in group-II (p value 0.034). Though incidence of tachysystole was more in high dose regimen, it was not statistically significant. No significant difference was seen in secondary outcomes.Conclusions: On the basis of present study, high dose oxytocin regimen can be considered for induction of labour as it has same effects as that of low dose regimen with lesser induction to delivery interval.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 323-323
Author(s):  
Elena Santagostino ◽  
Maria E. Mancuso ◽  
Angiola Rocino ◽  
Giacomo Mancuso ◽  
Francesco A. Scaraggi ◽  
...  

Abstract A multicenter randomized crossover trial was designed to compare efficacy, safety, feasibility and cost associated with standard- and high-dosages of rFVIIa for home treatment of hemarthroses in hemophiliacs with inhibitors. Enrolled patients were instructed to treat within 6 hours from the onset of bleeding 4 consecutive haemarthroses of ankles, knees or elbows either with the rFVIIa standard dose of 90 mcg/kg (repeated as necessary every 3 hours) or with a single high dose of 270 mcg/kg. Patients who did not achieve a success within 9 hours continued rFVIIa treatment with repeated standard doses. The response to treatment was assessed for up to 48 hours by patients/caregivers who reported on a visual analogic scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the response as effective, partially effective or ineffective. Success was defined a treatment rated as effective and VAS score ≥70 and failure a treatment rated as ineffective and VAS score ≤30, responses that did not fulfil these criteria being considered a partial response. Of 20 hemophiliacs with inhibitors enrolled (median age: 27 years), 18 treated 32 hemarthroses assigned to the standard- and 36 to the high-dose regimen during the study period of 18 months. Forty-eight hemarthroses (71%) occurred in target joints. Success rates for standard- and high-dose regimens were similar: 31% and 25% at 9 hours, 53% and 50% at 24 hours, 66% and 64% at 48 hours. Recurrence rates were identical (3%). The median number of rFVIIa boluses needed to achieve a successful course was 3 for the standard-dose and 1 for the high-dose regimen, and the median amount of rFVIIa used per successful course was identical (270 mcg/kg). Our results indicate that the use of a high-dose regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of boluses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.


1999 ◽  
Vol 17 (6) ◽  
pp. 1736-1736 ◽  
Author(s):  
J. Tate Thigpen ◽  
Mark F. Brady ◽  
Ronald D. Alvarez ◽  
Mark D. Adelson ◽  
Howard D. Homesley ◽  
...  

PURPOSE: Progestins have definite activity against advanced or recurrent endometrial carcinoma. Both parenteral and oral progestins yield similar serum levels and response rates, which range from 18% to 34%. The one major study that used oral medroxyprogesterone acetate (MPA) noted a response rate at the lower end of the range (18%) and much poorer progression-free and overall survival times (4 and 10.5 months, respectively) than previously reported. The present study sought to confirm this earlier study of oral MPA, to assess the importance of prognostic factors such as histologic grade and receptor levels, and to determine whether a higher dose of MPA would yield a higher response rate. PATIENTS AND METHODS: Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were randomized to receive oral MPA either 200 mg/d or 1,000 mg/d until unacceptable toxicity intervened or their disease progressed. RESULTS: Among 145 patients receiving the low-dose regimen, there were 25 complete (17%) and 11 partial (8%) responses for an overall response rate of 25%. The 154 patients receiving the high-dose regimen experienced 14 (9%) complete and 10 (6%) partial responses for an overall response rate of 15%. Median durations of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens, respectively. Median survival durations were 11.1 months and 7.0 months, respectively. The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 (90% confidence interval, 0.36 to 1.04). Prognostic factors having a significant impact on the probability of response included initial performance status, age, histologic grade, and progesterone receptor concentration. Compliance with oral therapy was documented with serum levels 1 month after starting therapy, when possible. MPA levels were commensurate with the assigned dose and schedule. CONCLUSION: Oral MPA is active against endometrial carcinoma. Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status. This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally. In fact, the trends suggest the opposite. The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma, particularly those lesions that are well-differentiated and/or progesterone receptor-positive (> 50 fmol/mg cytosol protein). Patients with poorly differentiated and/or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8% to 9% response rate.


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