Increased Hemolysis after Intramuscular Iron Administration in Patients with Paroxysmal Nocturnal Hemoglobinuria: Report of Six Occurrences in Four Patients, and Speculations on a Possible Mechanism

Four patients with PNH were described who developed accelerated activityof their disease after the intramuscular administration of iron-dextran fortreatment of iron deficiency. This was considered to reflect a unique effect ofiron on PNH erythrocytes. It was postulated that this effect resulted from celldamage caused by iron catalyzed peroxidation of erythrocyte lipids, a reaction to which PNH erythrocytes could be unusually susceptible by virtue ofan increased content of unsaturated fatty acids or pro-oxidants or decreasedcontent of antioxidants.

Submitted on August 13, 1964 Accepted on November 11, 1964     

DFP Labeling of Platelets During Recovery from Thrombocytopenia

Rat platelets were labeled with tritiated diisopropylfluorophosphate(³H-DFP) during recovery from acute thrombocytopenia. The results indicated that there was significant labeling of megakaryocytes by ³H-DFPwhich, in the presence of an increased rate of platelet production, resulted inmaintenance of relatively constant values for platelet-bound radioactivity during the period of maximum platelet production and reactive thrombocytosis.Significant random loss of platelets was apparent, and, when a cohort ofyoung platelets was transfused to normal recipients, they were destroyed at anormal rate.

     

Effects of growth hormone deficiency and rhGH replacement therapy on the 6β-hydroxycortisol/free cortisol ratio,a marker of CYP3A activity,in growth hormone-deficient children

Objective To determine the effect of both growth hormone deficiency (GHD) and rhGH replacement therapy on CYP3A activity as well as the potential influence of gender.Methods The sample consisted of 35 GHD children (16 males and 19 females), aged 2.9–13.1 years, and a control group of 35 healthy children matched for age and sex. The urinary ratio 6-hydroxycortisol/free cortisol was used as a marker of CYP3A activity. In patients, urine samples were collected at two times, prior to starting rhGH replacement treatment and 30 days after beginning therapy.Results A significantly higher metabolic activity in GHD children was observed in relation to controls (P=0.0001) without sex differences. Paired comparisons demonstrated a sexually dimorphic effect of rhGH therapy on the CYP3A activity. While boys displayed a significant decrease (P=0.003), girls showed no significantly different values of CYP3A marker (P>0.05). Unpaired comparison between controls and GHD children after therapy demonstrated absence of significant differences in boys (P>0.05) and a strikingly higher activity in girls (P=0.0001).Conclusions The data suggests that: (a) GHD in children increases CYP3A activity in a non-sex-dependent manner, (b) rhGH treatment for 30 days to GHD children results in a sexually dimorphic effect on CYP3A activity, with a significant decrease in males toward normalization in relation to controls and non-significant changes in females. The results of this study may have important clinical implications for GHD children, since changes in CYP3A activity importantly affect the metabolism of both steroid hormones and CYP3A substrate drugs.     

A randomized,double-blind,placebo-controlled,phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.