Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation

Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean ± SD, 1.21 ± 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4–12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis.     

Improved rapid methods for the determination of iron content and binding capacity of serum

Improved methods are described for the determination of serum iron (SeFe) and latent iron-binding capacity under controlled conditions of pH. As before, no precipitation or heating of the serum is required, and controls are not used. Unbuffered sulphonated bathophenanthroline is employed for colour development. Statistical data for 40 normals are presented and comparisons with other data are given; the effects of ageing of serum are studied.     

The short term outcome of elderly patients with hip fractures

A prospective outcome study was performed of 100 hip fracture patients at an urban medical center in the United States. After hospitalization 19% were discharged to a rehabilitation facility and 59% were discharged home. At a mean follow-up of 8 months, 81% of patients lived at home, compared to 89% who lived at home prior to the fracture. At follow-up 71% of the patients were able to walk outside with one cane or no aids at all, and 81% were able to perform basic activities of daily living. Half of all patients did not require any home assistance at follow-up. Ten patients had died at follow-up. The goal of operatively treating the patient with a hip fracture is fixation of the fracture with a return to the patient’s pre-fracture functional ability. This study illustrates that patients with hip fractures can be effectively treated and discharged home or to a short-term rehabilitation facility with restoration of their pre-fracture functional status.

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Résumé  Une étude prospective sur le devenir de 100 patients présentant une fracture de la hanche a été faite dans un Centre Médical Urbain des USA. Après l’hospitalisation, 19% des patients sont allés en structure de rééducation et 59% ont regagné leur domicile. A un délai moyen de 8 mois, 81% des patients vivent à domicile alors qu’il y en avait 89% avant la fracture. Au délai d’observation, 71% des patients marchent à l’extérieur avec une canne ou sans aide et 81% sont capables des activités habituelles de la vie quotidienne. La moitié des patients n’ont besoin d’aucune assistance à domicile. 10 patients sont morts. Le but du traitement opératoire des patients présentant une fracture de la hanche est la fixation de la fracture pour permettre un retour au niveau de fonction pré-traumatique. Cette étude confirma la possibilité d’un retour à l’état fonctionnel antérieur avec, aprés le traitement, un retour à domicile ou un court séjour en Centre de réadaptation.

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Accepted: 8 August 1999     

Deletion of 7p or monosomy 7 in pediatric acute lymphoblastic leukemia is an adverse prognostic factor: a report from the Children's Cancer Group.

Monosomy 7 or deletions of 7q are associated with many myeloid disorders; however, the significance of such abnormalities in childhood acute lymphoblastic leukemia (ALL) is unknown. Among 1880 children with ALL, 75 (4%) had losses involving chromosome 7, 16 (21%) with monosomy 7, 41 (55%) with losses of 7p (del(7p)), 16 (21%) with losses of 7q (del(7q)), and two (3%) with losses involving both arms. Patients with losses involving chromosome 7 were more likely to be > or =10 years old, National Cancer Institute (NCI) poor risk, and hypodiploid than patients lacking this abnormality. Patients with or without these abnormalities had similar early response to induction therapy. Event-free survival (EFS) and survival for patients with monosomy 7 (P<0.0001 and P=0.0007, respectively) or del(7p) (P<0.0001 and P=0.0001, respectively), but not of patients with del(7q), were significantly worse than those of patients lacking these abnormalities. The poorer EFS was maintained after adjustment for a Philadelphia (Ph) chromosome, NCI risk status, ploidy, or an abnormal 9p. However, the impact on survival was not maintained for monosomy 7 after adjustment for a Ph. These results indicate that the critical region of loss of chromosome 7 in pediatric ALL may be on the p-arm.     

Has Tranexamic Acid in Total Knee Arthroplasty Made Tourniquet Use Obsolete?

The application of tranexamic acid (TXA) in total joint arthroplasty has dramatically improved peri-operative blood management. In light of these benefits, a study by Huang et al., “Intravenous and Topical Tranexamic Acid Alone Are Superior to Tourniquet Use for Primary Total Knee Arthroplasty,” evaluates the need for continued use of the intra-operative tourniquet, which remains a routine practice with documented benefits and adverse effects. This review evaluates the study’s design and critically interprets its findings for clinical practice. Through a prospective, randomized trial, Huang et al. demonstrated that among selected patients undergoing primary total knee arthroplasty, the use of a tourniquet results in no reduction in blood loss beyond that provided by TXA alone. Moreover, the use of TXA without a tourniquet led to improved early clinical outcomes such as reduced post-operative swelling, improved knee range of motion at discharge, and enhanced patient satisfaction. As medicine is practiced in an increasingly value-driven environment, this study provides a useful method for evaluating the utility of commonly used interventions. Its findings highlight the need for future investigations into the optimal administration of TXA in total knee arthroplasty.     

Submaximal early exercise test compared to clinical findings for evaluation of short- and long-term prognosis after the first myocardial infarction

Clinical and ergometric data were derived from 1098 consecutiveexercise tests in patients with a first acute myocardial infarctionbetween 1974–1983. In 1992 a follow-up was performed inorder to analyse the importance of a submaximal early exercisetest, in combination with clinical data, for the predictionof short- and long-term prognosis of cardiovascular death. The relative value of 20 clinical variables, including medicalhistory, markers of infarction size, medication etc., and 28variables at exercise test were studied. Univariate, multivariateand survival analysis, for estimation of prognosis and independentprediction of cardiovascular death was used. Independent clinical risk factors for cardiovascular death were(1) Within 1 year: relative heart volume (ml.m^–2 bodysurface area) on chest X-ray. (2) Long-term mortality: maximumheart rate and relative heart volume, diabetes, age and digitalismedication. Independent exercise risk factors were: (1) Within1 year: heart rate, ventricular arrhythmia and ST depression 1 mm before exercise, diastolic blood pressure at maximum exerciseand target heart rate. (2) Long-term mortality: angina pectorisand/or ST depression 1 mm at maximum exercise. In subgroupsof patients with clinical risk factors, mortality risk increasedif there were signs of angina pectoris and/or ST depression 1 mm during exercise. The risk increased 100% in diabetics,91% with age >70 years, 58% with relative heart volume 500ml.m^–2 body surface area, 42% with heart rate 100 atadmission, and 34% with digitalis medication. No increase wasfound in the subgroup of patients without clinical risk factors. Thus, submaximal early exercise stress testing provides importantinformation for short- and long-term prognosis in patients afterthe first acute myocardial infarction compared to clinical evaluationalone.     

Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Addition of a delayed-intensification (DI) phase after standard induction/consolidation therapy was previously shown to improve outcome for patients younger than 10 years of age with intermediate-risk acute lymphoblastic leukemia (ALL). The current trial randomized 1204 patients to regimens containing a single DI phase (405 patients), 2 DI phases (DDI) (402 patients), or a single DI phase in conjunction with increased vincristine and prednisone pulses during maintenance (DIVPI) (397 patients). Estimates of event-free survival (EFS) and survival at 6 years are 79% +/- 1% and 89% +/- 1%, respectively. EFS was improved on DDI compared with either DI (log-rank P =.04; Kaplan-Meier [KM] P =.04; relative risk [RR] = 1.38) or DIVPI (log-rank P =.04; KM P =.01; RR = 1.39).There was no difference in EFS for the DI and DIVPI regimens (log-rank P =.96; KM P =.75). Survival estimates at 6 years were 87% (SD = 2%) for DI; 91% (SD = 2%) for DDI; and 90% (SD = 2%) for DIVPI (P =.17). Significant univariate risk factors for the overall cohort included poor day-7 marrow response, black race, and age of at least 5 years. These data demonstrate that DDI improves EFS of patients younger than 10 years of age with intermediate-risk ALL.     

Intermittent PTH administration and mechanical loading are anabolic for periprosthetic cancellous bone

The purpose of this study was to determine the individual and combined effects on periprosthetic cancellous bone of intermittent parathyroid hormone administration (iPTH) and mechanical loading at the cellular, molecular, and tissue levels. Porous titanium implants were inserted bilaterally on the cancellous bone of adult rabbits beneath a loading device attached to the distal lateral femur. The left femur received a sham loading device. The right femur was loaded daily, and half of the rabbits received daily PTH. Periprosthetic bone was evaluated up to 28 days for gene expression, histology, and µCT analysis. Loading and iPTH increased bone mass by a combination of two mechanisms: (1) Altering cell populations in a pro‐osteoblastic/anti‐adipocytic direction, and (2) controlling bone turnover by modulating the RANKL‐OPG ratio. At the tissue level, BV/TV increased with both loading (+53%, p < 0.05) and iPTH (+54%, p < 0.05). Combined treatment showed only small additional effects at the cellular and molecular levels that corresponded to a small additive effect on bone volume (+13% compared to iPTH alone, p > 0.05). This study suggests that iPTH and loading are potential therapies for enhancing periprosthetic bone formation. The elucidation of the cellular and molecular response may help further enhance the combined therapy and related targeted treatment strategies. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:163–173, 2015.