Biomedical subjects

Marco Gobbi

Publications and source records attributed to Marco Gobbi.

At least 19 recordsLinked to original sources

PubMed2007

Case-control study of multidrug resistance phenotype and response to induction treatment including or not fludarabine in newly diagnosed acute myeloid leukaemia patients.

One hundred and six patients aged </=60 years with newly diagnosed acute myeloid leukaemia (AML) treated with fludarabine-based regimens (cases) were matched with 106 AML patients treated with conventional non-fludarabine-based regimens (controls). The cases and controls were matched by expression of the multidrug resistance P-glycoprotein (MDR-Pgp), measured by flow cytometry as mean fluorescence index (MFI), cytogenetics, and age. The complete remission (CR) rate of the cases was 61% among the MDR-Pgp-positive (pos(ve)) patients (MFI >/= 6) vs. 75% among the MDR-Pgp-negative (neg(ve)) ones (MFI < 6) (P = 0.16). Conversely, in the controls, the CR rate was 44% among the MDR-Pgp-pos(ve) patients vs. 67% among the MDR-Pgp-neg(ve) ones (P = 0.02). The 4-year disease-free survival (DFS) and overall survival (OS) of MDR-Pgp-pos(ve) cases were significantly longer than those of MDR-Pgp-pos(ve) controls (DFS, 28.1% vs. 6.5%, P = 0.004; OS, 33.5% vs. 9.6%, P = 0.01). This difference was not found among the MDR-Pgp-neg(ve) patients. By univariate (P = 0.007) and multivariate (P = 0.007) analysis, the MDR-Pgp-pos(ve) phenotype was negatively correlated with CR and it emerged as the most important independent negative prognostic factor, after cytogenetics. Our study confirms the prognostic impact of the MDR phenotype in AML and strongly suggests fludarabine-based induction treatments as a promising strategy for MDR-Pgp-pos(ve) AML patients. In this setting of patients, large prospective randomised studies should be planned.

Acute Disease↗

PubMed2006

Gene therapy in epilepsy: the focus on NPY.

Gene therapy represents an innovative and promising alternative for the treatment of epileptic patients who are resistant to conventional antiepileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant viral vectors have been most widely used so far. Several gene targets could be used to correct the compromized balance between inhibitory and excitatory transmission in epilepsy. Transduction of neuropeptide genes such as galanin and neuropeptide Y (NPY) in specific brain areas in experimental models of seizures resulted in significant anticonvulsant effects. In particular, the long-lasting NPY over-expression obtained in the rat hippocampus using intracerebral application of recombinant adeno-associated viral (AAV) vectors reduced the generalization of seizures from their site of onset, delayed acquisition of fully kindled seizures and afforded neuroprotection. These results establish a proof-of-principle for the applicability of AAV-NPY vectors for the inhibition of seizures in epilepsy. Additional investigations are required to demonstrate a therapeutic role of gene therapy in chronic models of seizures and to address in more detail safety concerns and possible side-effects.

Epilepsy↗

PubMed2006

WB4101-related compounds: new, subtype-selective alpha1-adrenoreceptor antagonists (or inverse agonists?).

Our previous structure-affinity relationship study had considered the enantiomers of the naphthodioxane, tetrahydronaphthodioxane, and 2-methoxy-1-naphthoxy analogues (compounds 1, 3, and 2, respectively) of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane, the well-known alpha1-adrenoceptor (alpha1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha1-AR subtypes and 5-HT1A receptor. Here, we extend investigations to antagonist activity enclosing new enantiomeric pairs, namely those of the methoxytetrahydronaphthoxy and methoxybiphenyloxy WB4101 analogues (4 and 5-7, respectively) and of a double-modified WB4101 derivative (8) resulting from hybridization between 2 and 3. We found that (S)-2 is a very potent (pA2 10.68) and moderately selective alpha1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective alpha1A-AR antagonist. Both of these compounds and (S)-WB4101 seem to act as inverse agonists in a vascular model. The results, which generally validate the logic we followed in designing these eight compounds, are acceptably rationalized by comparative SAR analysis of binding and functional affinities.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2006

Expansion of Vdelta1 T lymphocytes producing IL-4 in low-grade non-Hodgkin lymphomas expressing UL-16-binding proteins.

Data on 23 patients with low-grade non-Hodgkin lymphomas (NHLs), 4 mantle (MT), 4 marginal zone (MZ), and 15 follicular (FL), were analyzed and compared with 10 high-risk (HR) B-cell chronic lymphocytic leukemias (B-CLLs) with lymph node involvement and 4 diffuse large-cell lymphomas (DLCLs). A significant increase in circulating Vdelta1 T lymphocytes producing interleukin-4 (IL-4) was found in patients with FL, MT, and MZ NHL, at variance with DLCL and HR B-CLL. IL-4 was also detectable in the sera and lymph nodes of the same patients. In 19 of the 23 patients with NHL with increased circulating Vdelta1 T lymphocytes, B cells expressing the UL-16-binding proteins (ULBPs) ULBP2 or ULBP3 or both were found in peripheral blood, bone marrow, or lymph nodes. Of note, in HR B-CLL or in DLCL, where leukemic cells were negative for ULBPs, no Vdelta1 T-cell increase was found. Moreover, Vdelta1 T lymphocytes from patients with FL NHL proliferate in response to ULBP2+ and ULBP3+ lymphoma cells. Finally, patients with high expression of ULBPs, increased circulating Vdelta1 T lymphocytes, and high levels of serum IL-4 showed stable disease in a 1-year follow-up in contrast to patients with low circulating Vdelta1 T cells and undetectable IL-4 or ULBPs.

Adult↗

PubMed2006

Comparison between patients with Philadelphia-positive chronic phase chronic myeloid leukemia who obtained a complete cytogenetic response within 1 year of imatinib therapy and those who achieved such a response after 12 months of treatment.

PURPOSE: Imatinib mesylate is a potent inhibitor of BCR-ABL, the constitutively active tyrosine kinase protein critical for the pathogenesis of chronic myeloid leukemia. PATIENTS AND METHODS: We reviewed 284 patients with late chronic-phase Philadelphia chromosome (Ph) -positive chronic myeloid leukemia treated with imatinib 400 mg daily after interferon-alpha failure. In a retrospective study, we evaluated the pattern and rapidity of the response to imatinib, comparing the cytogenetic and molecular responses, progression-free and overall survival rates in patients who obtained a complete cytogenetic response within 1 year of treatment (early responders), and in patients where a complete cytogenetic response was detected after 12 months (late responders). RESULTS: After 3 or 4 years of treatment, the molecular response of the late cytogenetic responders was similar to that of the early cytogenetic responders. At 36 months of treatment the amount of residual disease measured by standardized quantitative reverse-transcriptase polymerase chain reaction was 0.00047 in late responders versus 0.00022 in early responders, and at 48 months it was 0.00019 versus 0.00026 (median values, P value = nonsignificant). The estimated 4-year progression-free survival rate was 88% for early responders and 100% for late responders, while the estimated 4-year overall survival rates were 92% and 100% for early and late responders, respectively. CONCLUSION: The sensitivity and the response (cytogenic and molecular) to imatinib may require 1 year or more. Long-term follow-up results continue to improve in terms of rates and durability of the complete cytogenetic response, major or complete molecular response, and progression-free and overall survival.

Adult↗

PubMed2006

Erythropoietin plus granulocyte colony-stimulating factor is better than erythropoietin alone to treat anemia in low-risk myelodysplastic syndromes: results from a randomized single-centre study.

Haemopoietic growth factors (HGF), i.e. erythropoietin [recombinant human erythropoietin (rHEPO)] or granulocyte colony stimulating factor (G-CSF), alone or in combination, have largely been used to treat anemia in myelodysplastic syndromes (MDS), but whether combined rHEPO and G-CSF is really superior to rHEPO alone is still under debate. In particular, randomized studies comparing front-line rHEPO vs rHEPO+G-CSF are still lacking. The aim of this study was to compare the effects of "standard" doses of rHEPO with the combination of rHEPO and G-CSF in the treatment of anemic patients with low-risk MDS in a prospective randomized trial. Anemic patients with low-risk MDS were randomly assigned to receive either rHEPO (10,000 IU s.c. three times a week) or the same dosage of rHEPO+G-CSF (300 mug s.c. twice a week) for a minimum of 8 weeks. Patients who were unresponsive to rHEPO were offered the combination therapy for another 8 weeks, whereas non-responders to rHEPO+G-CSF were considered "off study". Responders continued the treatment indefinitely. Both haematological response and changes in quality-of-life (QoL) scores (Functional Assessment of Cancer Therapy-Anemia) were recorded and evaluated. Thirty consecutive patients [10 refractory anemia (RA), 5 RA with ringed sideroblasts, 7 refractory cytopenia with multilineage dysplasia, 5 RA with less than 10% blasts and 3 5q-syndrome] were enrolled in the study. All of them (15 in the rHEPO arm and 15 in the rHEPO+G-CSF arm) were valuable after the first 8 weeks of treatment. Erythroid response was observed in 6/15 (40%) patients in the rHEPO arm and in 11/15 (73.3%) patients in the rHEPO+G-CSF arm. In 4/9 (44.4%) patients who were unresponsive to rHEPO, the addition of G-CSF induced erythroid response at 16 weeks. No relevant adverse effects were recorded for either treatment in any of the study patients. Erythroid response to HGF was associated with a relevant improvement in QoL. Twenty responders continued the treatment. Afterwards, 8/20 (40%) discontinued therapy because of the following: losing response (2), progression to high-risk MDS (3) and death due to other causes (3). The remaining 12 are still responding and continuing treatment, with a median follow-up of 28 months. Progression to acute leukemia was cumulatively observed in 4/30 (13.3%) patients (2 in each arm). Although our data were obtained from a relatively small cohort of patients, they indicate that the rHEPO+G-CSF treatment is more effective than rHEPO alone for correcting anemia in low-risk MDS patients and for making a relevant improvement in their QoL.

Aged↗

PubMed2006

Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells.

Interleukin-21 (IL-21) is a member of the IL-2 cytokine family, which mediates proliferation or growth arrest and apoptosis of normal B cells, depending on their activation state. Here we demonstrate that surface IL-21 receptor (R) is expressed at variable levels by chronic lymphocytic leukemia (CLL) B cells freshly isolated from 33 different patients. IL-21R expression was up-regulated following cell stimulation via surface CD40. Therefore, IL-21 effects were more evident in CD40-activated CLL B cells. IL-21 induced an early signaling cascade in CLL B cells, which included JAK-1 and JAK-3 autophosphorylation and tyrosine phosphorylation of STAT-1, STAT-3, and STAT-5. IL-21 signaling failed to stimulate CLL B-cell proliferation, but induced their apoptosis. In addition, IL-21 counteracted the proliferative and antiapoptotic signals delivered by IL-15 to CLL B cells. IL-21-mediated apoptosis involved activation of caspase-8 and caspase-3, cleavage of Bid to its active form t-Bid, and cleavage of PARP and of p27Kip-1. Recent data indicate that CLL B cells require interaction with the microenvironment for their survival and expansion. The present findings thus provide a set of new mechanisms involved in the balance between cell-survival and apoptotic signals in CLL B cells.

Animals↗

PubMed2006

Molecular analysis of the Imatinib-induced complete cytogenetic response in chronic myelogenous leukemia.

The aim of this study was to elucidate the relationship between clonal and normal haematopoiesis in chronic myelogenous leukemia (CML). Thirteen female patients who reached complete cytogenetic response (CCR) after Imatinib treatment were studied. Although all the study patients exhibited a polyclonal pattern of X inactivation, p210 BCR/ABL transcript remained detectable in all cases by nested RT-PCR. This study also demonstrated the presence of p190 transcript in nine out of 13 study patients. A longer follow-up analysis is needed to clarify the prognostic value of these results. The recent observation that clonal cytogenetic abnormalities may occur in CML patients in polyclonal remission after imatinib suggests that a neoplastic stem cell lacking BCR/ABL rearrangement may acquire further cytogenetic alterations other than Philadelphia chromosome.

Adult↗

PubMed2005

Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors.

In this study we have analyzed the interaction between in vitro cultured bone marrow stromal cells (BMSC) and NK cells. Ex vivo-isolated NK cells neoexpressed the activation Ag CD69 and released IFN-gamma and TNF-alpha upon binding with BMSC. Production of these proinflammatory cytokines was dependent on ligation of ICAM1 expressed on BMSC and its receptor LFA1 on NK cells. Furthermore, the NKp30, among natural cytotoxicity receptors, appeared to be primarily involved in triggering NK cells upon interaction with BMSC. Unexpectedly, autologous IL-2-activated NK cells killed BMSC. Again, LFA1/ICAM1 interaction plays a key role in NK/BMSC interaction; this interaction is followed by a strong intracellular calcium increase in NK cells. More importantly, NKG2D/MHC-I-related stress-inducible molecule A and/or NKG2D/UL-16 binding protein 3 engagement is responsible for the delivery of a lethal hit. It appears that HLA-I molecules do not protect BMSC from NK cell-mediated injury. Thus, NK cells, activated upon binding with BMSC, may regulate BMSC survival.

Antigens, CD↗

PubMed2005

Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.

Prion protein (PrP) amyloid formation is a central feature of genetic and acquired prion diseases such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. The major component of GSS amyloid is a PrP fragment spanning residues approximately 82-146, which when synthesized as a peptide, readily forms fibrils featuring GSS amyloid. The present study employed surface plasmon resonance (SPR) to characterize the binding events underlying PrP82-146 oligomerization at the first stages of fibrillization, according to evidence suggesting a pathogenic role of prefibrillar oligomers rather than mature amyloid fibrils. We followed in real time the binding reactions occurring during short term (seconds) addition of PrP82-146 small oligomers (1-5-mers, flowing species) onto soluble prefibrillar PrP82-146 aggregates immobilized on the sensor surface. SPR data confirmed very efficient aggregation/elongation, consistent with the hypothesis of nucleation-dependent polymerization process. Much lower binding was observed when PrP82-146 flowed onto the scrambled sequence of PrP82-146 or onto prefibrillar Abeta42 aggregates. As previously found with Abeta40, SPR data could be adequately fitted by equations modeling the "dock-and-lock" mechanism, in which the "locking" step is due to sequential conformational changes, each increasing the affinity of the monomer for the fibril until a condition of irreversible binding is reached. However, these conformational changes (i.e. the locking steps) appear to be faster and easier with PrP82-146 than with Abeta40. Such differences suggest that PrP82-146 has a greater propensity to polymerize and greater stability of the aggregates.

Amyloid↗

PubMed2005

QSAR study for a novel series of ortho monosubstituted phenoxy analogues of alpha1-adrenoceptor antagonist WB4101.

A number of (S)- and (R)-2-[(2-phenoxyethyl)aminomethyl]-1,4-benzodioxanes unsubstituted or ortho monosubstituted at the phenoxy moiety were synthesized and tested in binding assays on the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR and the 5-HT(1A) receptor. The affinity values of the new compounds 1-16 were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known alpha(1) antagonist WB4101, finding that the unsubstituted derivative (S)-1 and the o-methyl, the o-t-butyl, the o-fluoro and the o-methoxy derivatives, (S)-2, (S)-4, (S)-8 and (S)-16, respectively, display a significantly specific 5-HT(1A) affinity, very close, with the exception of (S)-4, to the almost nanomolar one of (S)-WB4101. Otherwise, sensible affinity decreases were recorded for the three alpha(1)-AR subtypes. A classical quantitative structure-activity relationship (Hansch) analysis was successfully applied to compounds (S)-1 to (S)-16 and (S)-WB4101 to rationalize such binding data.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2005

Antiepileptic effects of botulinum neurotoxin E.

Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/E-injected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.

Animals↗

PubMed2005

Potential antidepressant properties of IDN 5491 (hyperforin-trimethoxybenzoate), a semisynthetic ester of hyperforin.

Hyperforin is one of the possible active principles mediating the antidepressant activity of Hypericum perforatum L. extracts. The ester derivative IDN 5491 (hyperforin-trimethoxybenzoate) showed antidepressant-like properties in the forced swimming test (FST) in rats, with no effect on open-field activity, when given as three intraperitoneal injections in 24 h at 3.125 and 6.25 mg/kg. The plasma concentrations of IDN 5491 were 30-50 microM, and those of hyperforin much lower but still close to those after effective doses of hyperforin-dicyclohexylammonium and Hypericum extract. This suggests that hyperforin plays a role in the antidepressant-like effect of the ester and of Hypericum extract. In vitro binding and uptake data showed that IDN 5491 is inactive on a wide panel of CNS targets at a concentration (14 microM) much higher than that measured in the brain of treated rats (0.3 microM). Like the extract, the antidepressant-like effect of IDN 5491 was blocked by (-)-sulpiride, a selective D2 receptor antagonist and by BD-1047, a selective sigma1 antagonist. Ex-vivo binding studies showed that brain sigma1 receptors are occupied after in vivo treatment with IDN 5491, possibly by an unknown metabolite or by endogenous ligand induced by hyperforin.

Animals↗

PubMed2005

Ifosfamide, epirubicin, etoposide (IEV) and autologous peripheral blood progenitor cell transplant: a feasible and effective salvage treatment for lymphoid malignancies.

The IEV schedule consisted of epirubicin 100 mg/m2 on day 1, etoposide 150 mg/m2 on days 1-3, and ifosfamide 2.5 g/m2 on days 1-3. Patients who proceeded to haematopoietic stem cell transplants (HDTs) received conditioning therapy with BEAM [for the Hodgkin's Lymphoma (HL) and non-Hodgkin's Lymphoma (NHL) groups], or melphalan 100 mg/m2 and mitoxantrone [for the multiple myeloma (MM) patients]. The study consisted of 65 patients with a median age of 53 years: 27 had aggressive NHL, 20 had HL, 7 had indolent NHL, and 11 had MM. Fifty-five patients received IEV for a disease that was refractory to conventional induction regimens, or that was in first or second relapse; 4 patients were treated with IEV while in complete response (CR) after chemotherapy in order to mobilise peripheral blood stem cells (PBSCs). Ninety percent of patients with HL responded to IEV, and 85% achieved CR. Both aggressive and indolent NHLs were less responsive (ORR 50 and 33%, respectively; CRR 41 and 16.5%, respectively). MM patients displayed an intermediate responsiveness (ORR 50% and CRR 30%). IEV was well tolerated in most patients. No life- threatening infections were recorded. PBSC mobilisation was successful in 37 out of 39 patients (95%) and led to the collection of a median of 16, 12, and 13.7 x 10(6) CD34+ cells/kg in patients with HL, NHL, and MM, respectively. All 37 patients underwent an autologous stem cell transplant following a 1 to 2 month interval after the end of IEV. Two patients were submitted to an allogeneic transplant. The median overall survival rate in HL, aggressive NHL, and indolent NHL is 32 (5-60), 16 (2-46), and 14 (4-42) months, respectively. Median EFS is 31 (5-60), 7 (2-46), and 7.5 (4-42) months, respectively. In conclusion, our study confirms that IEV +/- HDT is a well-tolerated and effective salvage treatment for lymphoid malignancies, and that IEV acts as an excellent stem cell mobiliser.

Adult↗

PubMed2004

Vdelta1 T lymphocytes from B-CLL patients recognize ULBP3 expressed on leukemic B cells and up-regulated by trans-retinoic acid.

We analyzed 38 untreated patients with chronic lymphocytic leukemia of B-cell type (B-CLL): 24 low-, 8 intermediate-, and 6 high-risk stage. In 15 patients (13 low risk and 2 intermediate risk), circulating Vdelta1 T lymphocytes were significantly increased (100 to 300 cells/muL) compared with most intermediate, all high-risk stage, and 15 healthy donors (50 to 100 cells/muL). We studied these Vdelta1 T lymphocytes and observed that they proliferated in vitro and produced tumor necrosis factor alpha or IFN-gamma in response to autologous leukemic B cells but not to normal lymphocytes. However, they were unable to kill resting autologous B cells, which lack the MHC-related MIC-A antigen and express low levels of the UL16-binding protein (ULBP) 3 and undetectable levels of ULBP1, ULBP2, and ULBP4. All these molecules are reported ligands for the NKG2D receptor, which is expressed by gammadelta T cells and activates their cytolytic function. The Vdelta1 T lymphocytes studied were able to lyse the ULBP3(+) C1R B-cell line upon transfection with MIC-A. More importantly, they also lysed autologous B-CLL cells when transcription and expression of MIC-A or up-regulation of ULBP3 were achieved either by activation or by exposure to trans-retinoic acid. The NKG2D receptor expressed on Vdelta1 T cells was involved in the recognition of B-CLL. Finally, in six patients with low numbers of circulating Vdelta1 T cells and undetectable ULBP3, the disease progressed over 1 year, whereas no progression occurred in patients with high Vdelta1 T lymphocytes and detectable/inducible ULBP3. These data suggest that Vdelta1 T lymphocytes may play a role in limiting the progression of B-CLL.

Aged↗

PubMed2004

Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of alpha 1 antagonist WB-4101.

A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the alpha(1a)-AR with respect to the other two alpha(1) subtypes and the 5-HT(1A) receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR, and the 5-HT(1A) receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific alpha(1a) affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high alpha(1a) affinity of (S)-1 and its alpha(1a) versus alpha(1b) selectivity slightly increasing the alpha(1a)/alpha(1d) and alpha(1a)/5HT(1A) affinity ratios. The SAR data were evaluated in the light of known alpha(1) subtype pharmacophores and of the alpha(1a)-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2004

Combination of liposomal daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia.

Sixty-two patients with high-risk acute leukemia were treated with the FLAD regimen [3 days of treatment with fludarabine 30 mg/m(2), cytarabine (AraC) 2 g/m(2), and liposomal daunorubicin 80 mg/m(2)]. The acute myeloid leukemia (AML) patients were either refractory to standard induction regimens (8), were in first or second relapse (13), or received therapy as first-line treatment [21 patients, 16 were above 60 years of age and 5 had post-myelodysplastic syndrome (MDS) AML]. The acute lymphoblastic leukemia (ALL) patients were treated for relapsed (7) or refractory disease (10). Three patients had chronic myeloid leukemia (CML) in the blastic phase. FLAD was well tolerated by most patients. Ten major infectious complications were recorded while no signs of cardiac toxicity were observed. Five patients (8%) died before day 28 with hypocellular marrow, mainly of infection or hemorrhage, and response could not be evaluated. Complete response rate was 62% and 69% among AML patients treated at diagnosis or for relapsed disease, respectively, and 59% among the ALL patients. Furthermore, FLAD managed to overcome the negative impact of poor prognosis karyotype in ALL patients, since five of the seven patients with t(9;22) or complex karyotype achieved complete remission (CR). Nine patients underwent bone marrow transplantation (BMT). Among the AML patients who were treated at diagnosis or for relapse, the median duration of CR was 7 months (range: 2-18) and 8 months (range: 2-26), respectively. Median survival among these patients was 8 (range: 1-40) and 12 (range: 1-30) months, respectively. Similar values were found in ALL patients. In conclusion, FLAD may be an effective alternative treatment for patients with relapsed AML and for patients with ALL who failed first-line therapy.

Acute Disease↗

PubMed2004

The antidepressant mechanism of Hypericum perforatum.

Clinical data indicate that hydroalcoholic extracts of Hypericum perforatum might be as valuable as conventional antidepressants in mild-to-moderate depression, with fewer side effects. One clinical trial using two extracts with different hyperforin contents indicated it as the main active principle responsible for the antidepressant activity. Behavioural models in rodents confirm the antidepressant-like effect of Hypericum extracts and also of pure hyperforin and hypericin. A hydroalcoholic extract lacking hyperforin also lacks the antidepressant-like effect. According to pharmacokinetic data and binding studies, it appears that the antidepressant effect of Hypericum extract is unlikely be due to an interaction of hypericin with central neurotransmitter receptors. The main in vitro effects of hyperforin (at concentrations of 0.1-1 microM) are non-specific presynaptic effects, resulting in the non-selective inhibition of the uptake of many neurotransmitters, and the interaction with dopamine D1 and opioid receptors. However, it is still not clear whether these mechanisms can be activated in vivo, since after administration of Hypericum extract brain concentrations of hyperforin are well below those active in vitro. In the rat, Hypericum extract might indirectly activate sigma receptors in vivo (through the formation of an unknown metabolite or production of an endogenous ligand), suggesting a new target for its antidepressant effects.

Animals↗