scholarly journals Chloroquine Is Grossly Overdosed and Overused but Well Tolerated in Guinea-Bissau

2008 ◽  
Vol 53 (1) ◽  
pp. 180-185 ◽  
Author(s):  
Johan Ursing ◽  
Poul-Erik Kofoed ◽  
Amabelia Rodrigues ◽  
Yngve Bergqvist ◽  
Lars Rombo
Keyword(s):  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Standard Dose ◽  
High Dose ◽  
Routine Practice ◽  
Double Dose ◽  
Normal Dose ◽  
Guinea Bissau ◽  
High Doses ◽  
Low Prevalence

ABSTRACT High chloroquine doses are commonly prescribed in Guinea-Bissau. Double-dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed, and it was not known if the high doses prescribed in Guinea-Bissau were taken or whether they caused adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken, and whether concentration-dependent adverse events occurred in routine practice. Chloroquine prescriptions by eight physicians and chloroquine intake by 102 children were recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations in whole blood were measured. The median total chloroquine dose prescribed and that reportedly taken were 81 and 77 mg kg−1, respectively. The total dose was usually split into two to three daily doses of 6.6 mg kg−1 each. These were taken unsupervised for a median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50 mg kg−1) of chloroquine was taken. Only 3/102 children had Plasmodium falciparum in the blood at the time of diagnosis and treatment. No severe adverse events were reported. No adverse events were associated with higher chloroquine concentrations. High doses of chloroquine are commonly taken and well tolerated in Guinea-Bissau. Malaria diagnostics are poor, and chloroquine is commonly prescribed to children without parasitemia. Use of high-dose chloroquine is concurrent with an exceptionally low prevalence of chloroquine-resistant P. falciparum.

scholarly journals High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Johan Ursing ◽  
Lars Rombo ◽  
Staffan Eksborg ◽  
Lena Larson ◽  
Anita Bruvoll ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Standard Dose ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Chloroquine Resistance ◽  
High Dose ◽  
Qtc Interval ◽  
Content Type ◽  
Qt Interval Prolongation

ABSTRACT Higher chloroquine doses can effectively treat up to 93 to 96% of malaria infections caused by Plasmodium falciparum carrying the resistance-conferring chloroquine resistance transporter (pfcrt) 76T allele. The tolerability of 50 (double the standard dose) and 70 mg/kg total chloroquine doses were assessed in this study. Fifteen 4- to 8-year-old children with uncomplicated malaria were given 10 mg/kg of chloroquine twice daily for 2 days and 5 mg/kg twice daily on the third day. Fifteen additional children were given 5 mg/kg twice daily for 2 more days. Chloroquine concentrations, blood pressure, electrocardiograms (ECGs), parasite density, and adverse events were assessed until day 28. Both dosages were well tolerated, and symptoms resolved by day 3 in parallel with increasing chloroquine concentrations. The median corrected QT (QTc) interval was 12 to 26 ms higher at expected peak concentrations than at day 0 (P < 0.001). Pfcrt 76T was associated with delayed parasite clearance. Day 28 clinical and parasitological responses against P. falciparum with pfcrt 76T were 57% (4/7) and 67% (4/6) after treatment with 50 and 70 mg/kg, respectively. Dosages were well tolerated, and no severe cardiac adverse events occurred. The QTc interval increase was similar to that found in adults taking 25 mg/kg of chloroquine. (This study has been registered at ClinicalTrials.gov under identifier NCT01814423.)

scholarly journals Gastrointestinal Events in High-Dose vs Standard-Dose Influenza Vaccine Recipients

2018 ◽  
Vol 5 (6) ◽  
Author(s):  
H Keipp Talbot ◽  
Andrew J Dunning ◽  
Corwin A Robertson ◽  
Victoria A Landolfi ◽  
David P Greenberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Influenza Vaccine ◽  
Randomized Clinical Trial ◽  
Standard Dose ◽  
High Dose ◽  
Passive Surveillance ◽  
Prospective Randomized Clinical Trial ◽  
Gastrointestinal Events ◽  
Gastrointestinal Adverse Events

Abstract Passive surveillance data had signaled the possibility of gastrointestinal adverse events occurring after the administration of high-dose inactivated influenza vaccine (IIV-HD). However, in a large, prospective randomized clinical trial, rates of serious gastrointestinal events were no greater among IIV-HD recipients than among those who received a standard-dose influenza vaccine.

scholarly journals Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Standard Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Area ◽  
Double Blind ◽  
Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

Hormonal status of patients after surgical treatment of fibrocystic mastopathy and possibilityes of its corrections

2017 ◽  
pp. 128-131
Author(s):  
Yu.Ya. Pryshash ◽  
Keyword(s):  
Surgical Treatment ◽  
Standard Dose ◽  
Treatment Phase ◽  
Nodule Formation ◽  
Double Dose ◽  
Postoperative Rehabilitation ◽  
Group Iii ◽  
Group I ◽  
Group Ii ◽  
High Doses

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.

scholarly journals Efficacy and Safety of High Vs Standard Daptomycin Doses Examined in Chinese Patients With Severe Burn Injuries by Pharmacokinetic Evaluation

2020 ◽  
Vol 41 (3) ◽  
pp. 705-713
Author(s):  
Yingzi Huang ◽  
Guozhong Lv ◽  
Linlin Hu ◽  
Yunfu Wu ◽  
Nan Guo ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Burn Injury ◽  
Standard Dose ◽  
Burn Injuries ◽  
Chinese Patients ◽  
High Dose ◽  
Severe Burn ◽  
Serious Adverse Events ◽  
Severe Burn Injuries ◽  
High Doses

Abstract Previous studies and the concentration-dependent antibacterial actions of daptomycin suggested that a high dose would be needed for difficult-to-treat infections in burn patients. Here, we evaluated the effects of administration of low and high doses of daptomycin in patients with severe burn injuries. The study retrospectively analyzed 10 patients with severe burn injuries, using pharmacokinetic (PK) and pharmacodynamic (PD) evaluations of daptomycin doses given to combat serious infections. Daptomycin was administered as a single dose or by multiple doses intravenously at a standard dose of 6 mg/kg/d or a high dose of 12 mg/kg/d for 7 to 14 days. The serum concentrations of daptomycin from patients were analyzed by liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS). Burn injury patients treated with high-dose daptomycin had a linear PK profile and a negative correlation between the AUC0–24 and Baux score (R2 = .953 and R2 = .801). The Cmax, AUC0–24, and t(h)½ increased significantly compared with patients given a standard dose. The efficacy of daptomycin against Staphylococcus aureus showed significantly higher rates of (AUC0–24)/MIC and Cmax/MIC after high-dose daptomycin compared with the standard dose, reflected in a significant correlation between a high dose and the Baux score (r = .976, P &lt; .001). Positive S. aureus cultures from two of three high-dose and none of two daptomycin low-dose patients converted from positive to negative after therapy. No serious adverse events or discontinuation of the drug occurred during the treatment period. Daptomycin doses up to 12 mg/kg/d were well tolerated in Chinese patients with severe burn injuries, which were complicated by infections with S. aureus.

High Dose Plerixafor Is Safe and Mobilizes Higher Numbers of CD34+ Cells Compared with Standard Dose Plerixafor

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 585-585
Author(s):  
Jeremy M Pantin ◽  
Xin Tian ◽  
Matthew M. Hsieh ◽  
Lisa Cook ◽  
Theresa Donohue ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Dose ◽  
Adverse Events ◽  
Dose Level ◽  
Peripheral Blood ◽  
Standard Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cell Numbers ◽  
Cd34 Cells

Abstract Abstract 585 Introduction Plerixafor is a bicyclam compound that inhibits the binding of stromal cell derived factor-1 (SDF-1) to its cognate receptor CXCR4. This results in therapid release of CD34+ cells into circulation, which can then be collected by apheresis. Plerixafor is FDA approved at the 240 μg/kg dose to be used in conjunction with G-CSF to mobilize autografts for transplantation. Allogeneic grafts can also be mobilized using single agent plerixafor without G-CSF, and following transplantation, result in sustained donor derived hematopoiesis. However, when the 240 μg/kg dose is used, 1/3 of donors fail to mobilize minimally acceptable doses of CD34+ cells. Recently, we demonstrated the safety of administration of a single dose of 480 μg/kg of subcutaneous (sc) plerixafor in humans. We subsequently conducted a randomized cross-over trial comparing CD34+ mobilization in healthy subjects mobilized with a single dose of sc plerixafor given at either a high dose (480 μg/kg) or a conventional dose (240 μg/kg). Methods Twenty normal healthy volunteers were randomized and received either a 240 or 480 μg/kg dose of sc plerixafor followed by at least a 2 week wash out period then were administered the other dose of plerixafor. Circulating numbers of leukocytes and CD34+ cells/μlwere measured at multiple time points for 24 hours following each plerixafor injection and the CD34+ AUC over 24 hours was calculated for each subject at each dose level. Peripheral blood colony forming unit (CFU) assays were performed at baseline and 6 hours after plerixafor dosing. Adverse events were graded using CTCAE version 3.A sample size of 20 subjects was determined to have over 90% power to detect an absolute CD34+ count difference of 10/μl using this crossover design and a two-sidedpaired t-test at the 0.05 level. Results Twenty-three subjects were enrolled and 20 completed administration of both doses. Peak circulating CD34+ cell numbers (median 31.5 vs 25, p=0.0009), circulating CD34+ cell numbers at 24hrs (median 15.5 vs 9, p<0.0001), and the CD34+ AUC over 24 hours (median 543 vs 411, p<0.0001) were all significantly higher following the administration of the 480 μg/kg plerixafor dose compared to the 240 μg/kg dose. The time to peak CD34+ was also slightly longer after the 480 μg/kg dose (median 10 vs 8 hrs, p=0.011). These differences were not related to the order of administration of the 2 different plerixafor doses. Although GM-CFUs from the peripheral blood at 6hrs following plerixafor were significantly higher compared to baseline levels at both plerixafordoses, there was no dose-effect relationship observed between drug dose and fold increase in GM-CFUs. The incidence and severity of AE's did not differ between lower and higher doses of plerixafor and no grade 3 or greater adverse events occurred at either dose level. Conclusion These preliminary data suggest high dose plerixafor can be administered safely and may mobilize more CD34+ cells than standard dose plerixafor. Furthermore, these data suggest mobilization following a single dose of plerixafor and a single apheresis procedure would result in graft collections containing higher CD34+ cell numbers when allogeneic stem cell donors are mobilized with high-dose plerixafor compared to standard-dose. Disclosures: Off Label Use: Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).

Phase II dosing study of cytarabine chemotherapy in combination with cenersen (EL625) and idarubicin in refractory and relapsed acute myelogenous leukemia (AML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7070-7070
Author(s):  
Y. Alvarado ◽  
H. Kantarjian ◽  
E. J. Freireich ◽  
G. Garcia-Manero ◽  
A. Ferrajoli ◽  
...  
Keyword(s):  
Adverse Events ◽  
Standard Dose ◽  
Package Insert ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Literature Report ◽  
Remission Duration ◽  
Similar Patient ◽  
Acute Myelogenous

7070 Background: Cenersen is an antisense oligonucleotide that blocks production of p53. It sensitizes acute myeloid leukemia (AML) stem cells in vitro to DNA damage. Methods: Thirty-seven patients (13 refractory, 24 relapsed) with AML have been enrolled in the ongoing trial. All patients received cenersen (0.1 mg/kg/hr continuous intravenous infusion over 4 days [d]) plus Idarubicin (12mg/m2/dx3). Cytarabine was administered as follows: group (1) no cytarabine; (2) 100mg/m2/dx7; (3) 1g/m2/dx4 (3d > 60y). Chemotherapy started day 2. Results: Eighteen patients were treated per protocol and 19 were inevaluable to include 16 who received prohibited substances that block the action of cenersen (acetaminophen and/or high dose antioxidants). Six (33%) of those treated per protocol achieved CR compared to none of the 16 who received prohibited substances (p=0.02). This rate compares favorably to a literature report of a similar patient population (14%; Estey 1996). There were 2 patients who achieved a CRp, one of whom received acetaminophen on day 7. No significant differences in response occurred between the three treatment arms. The remission duration for 7 of the 8 responding patients was longer than the prior remission duration for the same patients. Several adverse events (AEs) (infection, bleeding, mucositis and hair loss) were significantly (p<0.001) less common for patients in this trial compared to the AE frequency described in the package insert for Idarubicin for its use in combination with standard dose Cytarabine. No adverse events attributable to cenersen were identified. Conclusions: We conclude that cenersen in combination with chemotherapy may improve the response rate compared to that expected with chemotherapy alone. No significant financial relationships to disclose.

scholarly journals Severe Infusion-Related Adverse Events and Renal Failure in Patients Receiving High-Dose Intravenous Polymyxin B

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Josiane F. John ◽  
Diego R. Falci ◽  
Maria Helena Rigatto ◽  
Renata D. Oliveira ◽  
Thaysa G. Kremer ◽  
...  
Keyword(s):  
Renal Failure ◽  
Adverse Event ◽  
Body Weight ◽  
Adverse Events ◽  
Total Dose ◽  
Polymyxin B ◽  
High Dose ◽  
Daily Dose ◽  
High Doses ◽  
Very High

ABSTRACT The use of very high doses of polymyxin B (PMB) against carbapenem-resistant Gram-negative bacilli has been addressed in in vitro experiments as a strategy to improve bacterial killing and suppress resistance emergence. However, the toxicities of very high doses in patients are unknown. We conducted a retrospective cohort study assessing patients receiving PMB at >3 mg/kg of body weight/day or a total dose of ≥250 mg/day. The main outcomes were severe infusion-related adverse events according to the Common Terminology Criteria for Adverse Events and the renal failure category of RIFLE criteria for acute kidney injury (AKI) during treatment. A total of 222 patients were included for analysis of infusion-related events. The mean PMB dose was 3.61 ± 0.97 mg/kg/day (median total dose/day = 268 mg). Severe infusion-related adverse events occurred in two patients, resulting in an incidence of 0.9% (95% confidence interval, 0.2 to 3.2%); one was classified as a life-threatening adverse event, and one was classified as a severe adverse event. Renal failure was analyzed in 115 patients, and 25 (21.7%) patients presented renal failure (54 [47.0%] developed any degree of AKI, categorized as risk [27.8%], injury [25.9%], and failure [46.3%]). Treatment with a vasoactive drug, concomitant treatment with nephrotoxic drugs, and baseline creatinine clearance were independent risk factors for renal failure. Neither the PMB daily dose scaled by body weight nor the total daily dose was associated with renal failure. The in-hospital mortality rate was 60% (134 patients): 26% of deaths (57 patients) occurred during treatment, and none occurred during infusion. Our data suggest that high-dose schemes have an acceptable safety profile and could be further tested in clinical trials assessing strategies to improve patient outcomes and minimize the emergence of PMB resistance.

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