The role of dose size in a chemotherapy regimen (ProMECE-CytaBOM) for the first-line treatment of large B-cell lymphomas: a randomized trial by the Gruppo Italiano Studio Linfomi (GISL).

BACKGROUND: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas. METHODS: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine. RESULTS: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent. CONCLUSIONS: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS--at least within the limits clinically attainable without stem cell rescue--does not improve results.

Abnormal regulation of HFE mRNA expression does not contribute to primary iron overload.

BACKGROUND AND OBJECTIVES: Hereditary hemochromatosis (HHC) is a common, recessively inherited, genetic disorder associated with an abnormality of the HFE gene. Subjects homozygous for a point mutation in the gene coding sequence, leading to the amino acid substitution C282Y, are usually affected by the disease. A second point mutation, causing the amino acid substitution H63D, has been described, and compound heterozygotes for the two mutations or homozygotes for the H63D mutation are at risk of developing a milder form of HHC. In populations of northern European origin the C282Y substitution accounts for more than 90% of cases of HHC. In Italy, however, fewer than 70% of patients with HHC are homozygous or compound heterozygous for HFE mutations. Even in the absence of mutations in its coding region, the HFE gene might be involved in the pathogenesis of HHC through inhibition of transcription of the gene or reduced stability of its mRNA. DESIGN AND METHODS: Since little is known about the regulation of HFE expression, we investigated 17 subjects heterozygous for one of the HFE mutations and with biochemical evidence of iron overload and compared the levels of wild type and mutated mRNAs in their peripheral blood cells. c-DNA regions flanking the mutated codons were amplified by reverse transcriptase polymerase chain reaction (PCR). PCR products derived from the two alleles were differentiated and quantified by digestion with restriction enzymes, electrophoresis in an agarose gel stained with ethidium bromide and densitometric scanning of the gel. RESULTS: In all cases wild type and mutated mRNAs were expressed at similar levels, suggesting that reduced expression of an HFE allele coding a normal protein is not involved in the pathogenesis of iron overload. However, we can not rule out that a tissue specific regulation of HFE expression in the cells directly involved in iron absorption is altered and contributes to the pathogenesis of the disease. E INTERPRETATION AND CONCLUSIONS: Our results suggest that primary iron overload is a multigenic syndrome; this hypothesis is strongly supported by the recent demonstration that the juvenile hemochromatosis locus maps to human chromosome 1q.

Red blood cell precursor mass as an independent determinant of serum erythropoietin level.

Serum erythropoietin (sEpo) concentration is primarily related to the rate of renal production and, under the stimulus of hypoxia, increases exponentially as hemoglobin (Hb) decreases. Additional factors, however, appear to influence sEpo, and in this work, we performed studies to evaluate the role of the red blood cell precursor mass. We first compared the relationship of sEpo with Hb in patients with low versus high erythroid activity. The first group included 27 patients with erythroid aplasia or hypoplasia having serum transferrin receptor (sTfR) levels < 3 mg/L (erythroid activity < 0.6 times normal), while the second one included 28 patients with beta-thalassemia intermedia having sTfR levels > 10 mg/L (erythroid activity > 2 times normal). There was no difference between the two groups with respect to Hb (8.3 +/- 1.6 v 8.0 +/- 1.3 g/dL, P > .05), but sEpo levels were notably higher in patients with low erythroid activity (1,601 +/- 1,542 v 235 +/- 143 mU/mL, P < . 001). In fact, multivariate analysis of variance (ANOVA) showed that, at any given Hb level, sEpo was higher in patients with low erythroid activity (P < .0001). Twenty patients undergoing allogeneic or autologous bone marrow transplantation (BMT) were then investigated. A marked increase in sEpo was seen in all cases at the time of marrow aplasia, disproportionately high when compared with the small decrease in Hb level. Sequential studies were also performed in five patients with iron deficiency anemia undergoing intravenous (IV) iron therapy. Within 24 to 72 hours after starting iron treatment, marked decreases in sEpo (up to one log magnitude) were found before any change in Hb level. Similar observations were made in patients with megaloblastic anemia and in a case of pure red blood cell aplasia. These findings point to an inverse relationship between red blood cell precursor mass and sEpo: at any given Hb level, the higher the number of red blood cell precursors, the lower the sEpo concentration. The most likely explanation for this is that sEpo levels are regulated not only by the rate of renal production, but also by the rate of utilization by erythroid cells.

Prediction of response to recombinant human erythropoietin (rHuEpo) in anemia of malignancy.

BACKGROUND: Since only a portion of anemic patients outside the uremia setting benefit from erythropoietin treatment, a reliable means of predicting potential responders and nonresponders would be very useful. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 58 patients with refractory anemia associated with various malignant disorders who had been treated with subcutaneous rHuEpo. The starting rHuEpo dose was 375 U/kg/week for 4 weeks, and was increased to 750 U/kg/week for another 4 weeks if no response was observed. Response was defined as a Hb increase > or = 2 g/dL with no need for blood transfusion. We examined the value of various laboratory parameters (baseline levels, 2-week and 4-week changes) as predictors of response. Endogenous erythropoietin production was evaluated by its serum level and erythroid activity was assessed through reticulocyte count and circulating transferrin receptor. RESULTS: Forty-eight individuals were evaluable, 58% of whom responded to rHuEpo within 8 weeks. Multiple regression analysis showed that 53% of the variation in the 8-week Hb concentration was explained by variations in baseline serum erythropoietin and the 2-week change in serum transferrin receptor (p < 0.001). Based on these two parameters, response prediction in individual patients would have resulted in a sensitivity of 96%, a specificity of 79% and an overall accuracy of 88%. In addition, 58% of the variation in the 8-week Hb was explained by variations in the 4-week changes in Hb and reticulocyte count (p < 0.001). Utilizing these latter parameters and baseline serum erythropoietin, response prediction in individual patients would have resulted in a sensitivity of 92%, a specificity of 82% and an overall accuracy of 88%. CONCLUSIONS: This retrospective analysis suggests that response to rHuEpo can be reasonably predicted by pretreatment serum erythropoietin together with early changes in simple laboratory parameters.

Successful pregnancy following gonadotropin therapy in a young female with juvenile idiopathic hemochromatosis and secondary hypogonadotropic hypogonadism.

Heart failure and hypogonadotropic hypogonadism are the most frequent clinical problems encountered in patients with juvenile idiopathic hemochromatosis (JIH). In this context, amenorrhea is one of the first symptoms in female patients, and hormone therapy must be added to phlebotomy to restore menstrual cycles. Here we report the case of a woman in childbearing age with hypogonadotropic hypogonadism due to JIH. Following therapy with gonadotropinic hormones the patient had a twin pregnancy with term delivery. The newborns presented a normal iron status. This confirms that early diagnosis and treatment of JIH are important to prevent irreversible organ damage and shows that the female reproductive function can be preserved in adequately treated patients.

Effects of digoxin, placebo and ibopamine on exercise tolerance and cardiac rhythm of patients with chronic post-infarct left ventricular failure.

This study compares the effects of digoxin, placebo and ibopamine (SB-7505), the orally active 3,4-diisobutyryl ester of N-methyl-dopamine, on exercise tolerance and cardiac rhythm of 14 patients whose left ventricular heart failure (end-diastolic pressure, 26.3 +/- 5.9 mmHg; ejection fraction, 0.42 +/- 0.10%) depended on a previous myocardial infarction. Patients were admitted to the study while on chronic oral digoxin treatment (serum levels between 1.1 and 1.9 ng/ml). Placebo instead of digoxin was given for the following month. Thereafter ibopamine 50 mg t.i.d. for one month was given. A sequence of one-month treatments with digoxin, placebo and ibopamine was repeated, then ibopamine was administered continuously for the next two months. The concurrent treatment (diuretics in all patients, nitroderivates in twelve, calcium antagonists in two) remained unchanged during the observation period. Symptoms-limited exercise tests and 24-h Holter recordings were obtained at admission, at the end of each one-month treatment and at the end of the observation period. Two patients developed unstable angina without increase of serum creatine phosphokinase while on ibopamine and were withdrawn. Out of the 12 patients that concluded the trial, one required supplementary doses of diuretic at the end of the second period on placebo. The results obtained during the trial suggest that: a) therapeutic plasma levels of digoxin have no deleterious effect on cardiac rhythm nor significantly increase exercise tolerance as compared with placebo; b) diuretics and nitrates appear to sustain the clinical stability of these patients as a group.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the mechanism of action of protacine (CR 604), a new non-steroidal anti-inflammatory agent.

3'-(4-[2-(1-P-Chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropyl-glutaramate(+/-)dimaleate (protacine, CR 604), a new non-steroidal compound active on experimental inflammation, in vitro inhibits prostaglandin synthesis from arachidonic acid and platelet aggregation. When administered p.o., it prevents ex vivo platelet aggregation and in vivo arachidonate-induced thrombosis in rabbits. The cAMP levels of rat leucocytes are significantly reduced after treatment in vivo with protacine, even under maximum PGE-mediated stimulation. These effects, the inhibition of the proteolytic activity of trypsin and the fibrinolytic properties evidenced on recalcified plasma clots, contribute to explain the anti-inflammatory activity of protacine.

Pharmacological study of a new non-steroidal anti-inflammatory drug: protacine (CR 604).

The pharmacological activities of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropylglutaramate(+/-)dimaleate (protacine, CR 604), a new indolyl derivative with strong anti-inflammatory, analgesic and antipyretic activities, are described. The dose-dependent activity of protacine on inflammation has been shown both in short-term experiments, like the hind paw edema induced by carrageenin and several other irritants, and long-term tests, like the aminoacetonitrile-induced osteolathyrism, the adjuvant-induced arthritis and the cotton pellet-induced granuloma. The analgesic activity of the drug has been evidenced in the phenylquinone-induced writhing and the Randall-Selitto tests, and the antipyretic effects in the yeast-induced hyperthermia in rats. Other general pharmacological effects have been studied, too. Contrarily to several other anti-inflammatory drugs, including indometacin, showing advers effects at doses which are in the same range of those active on experimental inflammation, protacine shows these effects to a minor degree and at doses which are much larger than those pharmacologically active. The therapeutic index of protacine therefore is superior to that of other anti-inflammatory drugs.

Pharmacokinetic approach to proglumide long-term activity.

In order to explain the long-term therapeutic activity of (+/-)-4-benzamide-N,-di-n-propylglutaramic acid (proglumide, Milid) a pharmacokinetic study was carried out in rats by three administration routes. As a result, experimental data could have been fitted to a tri- or tetra-exponential equation, with terminal half-life of about 24 h. Since human pharmacokinetics was found to be rather similar to that in rats, it can be extrapolated that steady state plasma level of drug during therapeutic dosage regimen should range around 60% of peak level of single administration.