Impact of cyclosporine 2-h level and mycophenolate mofetil dose on clinical outcomes in de novo heart transplant patients receiving anti-thymocyte globulin induction

BACKGROUND: Cyclosporine (CsA) 2-h post-dose level (C2) correlates better than trough levels (C0) with the area under the curve. We evaluated the clinical impact of C2 and mycophenolate mofetil (MMF) dose in adult heart transplant patients receiving anti-thymocyte globulin (ATG) induction. METHODS: Two immunosuppressive strategies were sequentially evaluated. In Group 1 (13 patients), simultaneous C0/C2 (ng/mL) were analyzed. CsA dose monitoring was initially based on C0 : <3 months: 200-300, 4-6 months: 150-250, 6-9 months: 100-200, and on C2 thereafter (as in Group 2). In Group 2 (nine patients), C2 monitoring was implemented: <3 months: 600-800, 4-6 months: 500-700, >6 months: 400-600. All patients received ATG induction, corticosteroids, and MMF (1.0 g b.i.d. in Group 1 and 1.5 g b.i.d. in Group 2). RESULTS: Patients in Group 2 received higher MMF doses during the first trimester. C2 at 1, 3, 6, 12, 24, and 36 months was, respectively, 1199 +/- 476, 1202 +/- 587, 999 +/- 467, 664 +/- 203, 593 +/- 208, and 561 +/- 147 in Group 1, and 809 +/- 160 (p = 0.02), 644 +/- 178 (p = 0.003), 664 +/- 169 (p = 0.02), 616 +/- 221, 464 +/- 234, and 451 +/- 165 in Group 2. The incidence of acute rejection (grade > or =3A) at 6, 12, 24, and 36 months was, respectively, 38.5, 38.5, 46, and 54% in Group 1, and 11, 44, 56, and 56% in Group 2 (p = NS). At 3 months, the creatinine clearance was 25% lower in Group 1. Thereafter, renal function remained stable in both groups. CONCLUSION: Our results suggest that heart transplant patients receiving ATG induction may experience similar outcomes with either a higher C2 and a lower MMF dose or a lower C2 and a higher MMF dose. These results could be considered to design prospective studies to optimize C2 monitoring, to reduce the incidence of acute rejection without increasing the risk of renal dysfunction.     

Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59, P < 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73, P < 0.0001). In particular, CL/F values in children aged less than 10 years (112 +/- 82 mL/kg/h, mean +/- SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 +/- 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 +/- 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 +/- 2.2 micrograms/mL, n = 30) and those having no clinical improvement (5.2 +/- 2.2 micrograms/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.     

High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence

BACKGROUND: The objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high-dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL). METHODS: Data were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty-four patients had primary refractory HL, 59 patients had their first recurrence of HL (within 1 year in 32 patients and > 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high-dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L-phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease. RESULTS: Ninety-two patients (90%) completed the HDS program. There were five toxic deaths (treatment-related mortality rate, 4.9%) and six secondary malignan cies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow-up of 5 years, the 5-year overall survival (OS) and event-free survival (EFS) projections were 64% (95% confidence interval [95% CI], 54-74%) and 53% (95% CI, 43-63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5-year OS and EFS projections of 77% (95% CI, 66-88%) and 63% (95% CI, 50-76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5-year OS and EFS projections of 36% (95% CI, 16-55%) and 33% (95% CI, 14-52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS. CONCLUSIONS: The use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL.     

Novel sst(4)-selective somatostatin (SRIF) agonists. 3. Analogues amenable to radiolabeling

After our discovery that H-c[Cys-Phe-Phe-DNal-Lys-Thr-Phe-Cys]-OH (ODN-8) had high affinity and marginal selectivity for human sst(3) (part 2 of this series: Erchegyi et al. J. Med. Chem., preceding paper in this issue)(11) and that H-c[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-OH (ODT-8, 3) had high affinity and marginal selectivity for human sst(4), that H-c[Cys-Phe-Tyr-D-threo-beta-Me2Nal-Lys-Thr-Phe-Cys]-OH had high affinity for all sst's except for sst(1), and that H-c[Cys-Phe-Tyr-L-threo-beta-Me2Nal-Lys-Thr-Phe-Cys]-OH had high affinity for sst(4) (IC(50) = 2.1 nM), with more than 50-fold selectivity toward the other receptors (parts 1 and 2 of this series: Rivier et al. and Erchegyi et al. J. Med. Chem., preceding papers in this issue), we found H-c[Cys-Phe-Phe-Trp-Lys-Thr-Phe-Cys]-OH (OLT-8, 2), H-c[Cys-Phe-Phe-L-threo-beta-MeTrp-Lys-Thr-Phe-Cys]-OH (4) and H-c[Cys-Phe-Phe-D-threo-beta-MeTrp-Lys-Thr-Phe-Cys]-OH (5) to have very high affinity for sst(4) (IC(50) = 0.7, 1.8, and 4.0 nM, respectively) and 5- to 10-fold selectivity versus the other sst's. From earlier work, we concluded that an l-amino acid at position 8 and a tyrosine or 4-aminophenylalanine substitution at position 7 may lead to high sst(4) selectivity. In fact, [Tyr(7)]-2 (6) and [Tyr(7)]-3 (7) show ca. 5-fold selectivity for sst(4), and [Aph(7)]-2 (8) and [Aph(7)]-3 (9) have high sst(4) affinity (IC(50) = 1.2 and 0.88 nM, respectively) and selectivity, suggesting that indeed an l-residue at position 8 will direct selectivity toward sst(4). Unexpectedly, [Ala(7)]-2 (10) and [Ala(7)]-3 (11) have very high sst(4) affinity (IC(50) = 0.84 and 0.98 nM, respectively) and selectivity (>600- and 200-fold, respectively). The combination of Tyr(2) and dTrp(8) in analogues 14 and 22 did not affect the affinity of the analogues for sst(4) (IC(50) = 1.2 and 1.1 nM, respectively) but resulted in loss of selectivity, whereas the combination of Tyr(2) and LTrp(8) in H-Tyr-c[Cys-Phe-Aph-Trp-Lys-Thr-Phe-Cys]-OH (13) and H-Tyr-c[Cys-Phe-Ala-Trp-Lys-Thr-Phe-Cys]-OH(19) retained high affinity (IC(50) = 1.9 and 1.98 nM, respectively) and sst(4) selectivity (>50 and >250, respectively). Interestingly, the same substitutions at positions 2 and 7, with l-threo-beta-MeTrp at position 8, yielded a much less selective analogue (20). Carbamoylation of the N-terminus of most of these analogues resulted in slightly improved affinity, selectivity, or both. Other amino acid substitutions in this series, such as those with Amp (25, 26), Orn (27), or IAmp (29) at position 7, were also tolerated but with a 2- to 3-fold loss of affinity and concomitant loss of selectivity. Analogous peptides with a tyrosine at position 11 (31-36) were less selective than the corresponding peptides with a tyrosine at position 2. Several analogues in this series compared favorably with the non-peptide L-803,087 (37) in terms of affinity and selectivity. Analogues 8, 10, and 21 potently inhibited the forskolin-stimulated cAMP production in sst(4)-transfected cells, therefore acting as full agonists. Cold monoiodination of 19 yielded 21, with retention of high sst(4) selectivity and affinity (IC(50) = 3.5 nM). (125)Iodinated 19 selectively binds to sst(4)-transfected cells but not to sst(1-3)- or sst(5)-transfected cells. Binding in sst(4)-transfected cells was completely displaced by SRIF-28 or the sst(4)-selective L-803,087.     

Increased proportion of CD8+ T-lymphocytes in the paratracheal lymph nodes of smokers with mild COPD

Previous studies have shown an increased number of inflammatory cells and, in particular, of CD8+ T lymphocytes, in central airways, peripheral airways, lung parenchyma and pulmonary arteries of smokers with COPD. In this study we investigated whether this inflammatory process is restricted to the lung tissue or whether a similar process is also present in the lymph nodes of these subjects. We examined paratracheal lymph nodes obtained from 6 smokers with COPD (FEV1/VC < 88% predicted and FEV1/FVC < 70% both before and after 200 microg of inhaled salbutamol) and 6 smokers without COPD (FEV1/VC > 88% predicted and FEV1/FVC > 70%) undergoing lung resection for localised pulmonary lesions. By immunohistochemistry we quantified CD4+ and CD8+ T-lymphocytes in the lymph nodes. Smokers with COPD had a decreased ratio CD4/CD8 compared to smokers without COPD. When all subjects were considered together, the ratio CD4/CD8 showed a positive correlation with the values of FEV1/VC and a negative correlation with cigarette consumption. In conclusion, smokers with COPD have an increased proportion of CD8+ cells in the lymph nodes, indicating that a T-lymphocyte pattern similar to that present in the lung tissue is also present in the lymph nodes of these subjects. This finding suggests that, in COPD, the polarisation of the immune response may occur in the regional lymph nodes, possibly as a consequence of the presentation of an endogenous antigen that remains unknown.     

A prospective randomized study comparing intramuscular progesterone and 17alpha-hydroxyprogesterone caproate in patients undergoing in vitro fertilization-embryo transfer cycles

OBJECTIVE: To compare the effectiveness of i.m. P and 17alpha-hydroxyprogesterone caproate (17-HPC) for luteal phase support, in patients undergoing IVF-ET cycles. DESIGN: Prospective, randomized study. SETTING: Patients undergoing IVF-ET in our Centers. PATIENT(S): The inclusion criteria were the use of GnRH down-regulation and aged <40 years. INTERVENTION(S): A total of 300 cycles were randomly treated with either 17-HPC (341 mg every 3 days) or P (50 mg daily). MAIN OUTCOME MEASURE(S): The outcomes of IVF in both study groups were evaluated for biochemical pregnancy, miscarriage, clinical pregnancy, and ongoing pregnancy. RESULT(S): No difference was found in the main outcome parameters considered. CONCLUSION(S): Although the results of the study encourage the use of 17-HPC for luteal phase support in patients undergoing IVF-ET program, more studies are necessary to support the hypothesis that it can replace i.m. P-in-oil.     

Low dose of ethinyl estradiol can reverse the antiestrogenic effects of clomiphene citrate on endometrium

Fifty healthy, voluntary patients aged between 20 and 30 years with regular menstruation and plasmatic progesterone level >10 ng/ml at the midluteal phase have been enrolled in this study. They were randomly treated with clomiphene citrate (CC; group A) or CC + ethinyl estradiol (0.05 mg group B, or 0.02 mg group C). We estimated the difference in uterine artery pulsatily index, endometrial thickness and histological dating and morphometric analysis of endometrium. No significant differences in Pulsatility Index values and in the number of preovulatory follicles were noted. The difference between endometrial thickness, histological dating and morphometric analysis of the endometrium were statistically different between groups B and C vs. A. Our study shows that CC has a deleterious effect on endometrium maturity and that adding ethinyl-E(2) produces a favorable endometrial response even with very low doses.