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1.
Pediatr Crit Care Med ; 12(6): e237-41, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21057354

ABSTRACT

OBJECTIVE: Terlipressin has been successfully used as rescue treatment in hypotensive adults and children with septic shock, but only exceptionally in neonates. The aim of this study is to describe original clinical scenarios in which terlipressin, in newborns and infants, resolved the catecholamine-refractory hypotension. DESIGN: Retrospective study. SETTING: Neonatal intensive care unit. PATIENTS: All newborns with hypotension unresponsive to volume replacement and catecholamines, and treated with terlipressin, from January 2008 to December 2009. In this study, also an infant (11 months old) born extremely preterm was included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four hypotensive patients received as rescue therapy terlipressin, which produced a dramatic increase in mean arterial pressure, diuresis, and reduction of lactate levels. In three newborns, hypotension, associated with pulmonary hypertension, was resolved with terlipressin. Two of them (one with systemic inflammatory response syndrome, the other with congenital diaphragmatic hernia) died in the following days for causes unrelated to hypotension; the third (on mild hypothermia for hypoxic-ischemic encephalopathy) recovered. We report furthermore an infant with septic shock and on treatment with ß-blockers in whom terlipressin normalized blood pressure. In two patients, cranial Doppler ultrasonography showed the recovery of diastolic cerebral flow in the anterior cerebral artery and the normalization of resistance index within 30 mins from the first dose of terlipressin. In two infants, hyponatremia was detected. CONCLUSION: Although the number of reported infants is little, terlipressin appears to be an effective rescue treatment in different scenarios of refractory neonatal hypotension. Further controlled studies are required to confirm its efficacy and safety.


Subject(s)
Hypotension/drug therapy , Lypressin/analogs & derivatives , Vasoconstrictor Agents/therapeutic use , Catecholamines/therapeutic use , Female , Humans , Hypotension/diagnostic imaging , Infant , Infant, Newborn , Intensive Care Units, Neonatal , Italy , Lypressin/administration & dosage , Lypressin/therapeutic use , Male , Medical Audit , Retrospective Studies , Shock, Septic , Terlipressin , Ultrasonography , Vasoconstrictor Agents/administration & dosage
3.
Bioorg Med Chem ; 15(21): 6748-57, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17765552

ABSTRACT

Steganacin and podophyllotoxin are two naturally occurring lignans first isolated from plant sources, which share the capability to disrupt tubulin assembly. Although not strictly essential for its activity, the lactone ring on both structures represents Achilles' heel, as it is a potential site of metabolic degradation and epimerization on its C2 carbon brings about a significant loss in potency. In the present manuscript, we have used the ruthenium-catalyzed [3+2] azide-alkyne cycloaddition, a click-chemistry reaction, to replace the lactone ring with a 1,5-disubstituted triazole in few synthetic steps. The compounds were cytotoxic, although to a lesser degree compared to podophyllotoxin, while retaining antitubulin activity. The present structures might therefore represent a good platform for the fast generation of metabolically stable compounds with few stereogenic centers that might be of value from a medicinal chemistry point of view.


Subject(s)
4-Butyrolactone/analogs & derivatives , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Lactones/chemistry , Lignans/chemistry , Lignans/pharmacology , Podophyllotoxin/analogs & derivatives , 4-Butyrolactone/chemistry , Antineoplastic Agents/chemical synthesis , Catalysis , Cell Line, Tumor , Humans , Lignans/chemical synthesis , Molecular Conformation , Ruthenium/chemistry , Triazoles/chemistry , Tubulin/drug effects
4.
Transfusion ; 47(12): 2202-6, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17714421

ABSTRACT

BACKGROUND: Controlled-rate freezing (CRF) followed by storage in liquid nitrogen is employed by most centers as the standard procedure for peripheral blood progenitor cell (PBPC) cryopreservation. Uncontrolled-rate freezing (URF) at -80 degrees C is more simple, time-saving, less expensive, and, possibly, as effective as CRF. The aim of this retrospective analysis was to compare CRF and URF in childhood transplantation. STUDY DESIGN AND METHODS: A total of 54 PBPC transplants performed in 39 children aged 3 to 16 years (median, 9.5 years) were analyzed: 23 transplants in 16 children with CRF versus 31 transplants performed in 23 children with -80 degrees C URF. All grafts contained at least 2 x 10(6) per kg unselected CD34+ cells, enumerated before freezing. Nucleated cells infused ranged from 1.32 x 10(8) to 4.3 x 10(8) per mL with a median of 3.1 x 10(8) per mL. Cryoprotectant solution consisted of a final dimethyl sulfoxide (DMSO) concentration of 10 percent DMSO with autologous plasma. RESULTS: The two study groups did not differ in terms of timing of neutrophil and platelet recovery or transfusion requirements. Adverse events related to graft infusion, severe complications, and transplant-related mortality were not significantly different between CRF and URF groups. In both groups only mild adverse events were observed during graft administration. URF procedures, however, were simpler and less expensive. At a median follow-up of 72 months, no secondary myelodysplasia was observed in either group. CONCLUSION: Our analysis suggests that URF is safe and effective in the pediatric population.


Subject(s)
Blood Preservation/methods , Cryopreservation/methods , Peripheral Blood Stem Cell Transplantation/methods , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Male , Reproducibility of Results , Treatment Outcome
5.
J Med Chem ; 49(17): 5372-6, 2006 Aug 24.
Article in English | MEDLINE | ID: mdl-16913727

ABSTRACT

We have synthesized rigid analogues of combretastatin bearing a furan ring in place of the olefinic bridge. These compounds are cytotoxic at nanomolar concentrations in neuroblastoma cells, display a similar structure-activity relationship compared to combretastatin A4, and inhibit tubulin polymerization. We also show that the furan ring can be further functionalized. Thus, it is possible that combretafurans could act as scaffolds for the development of dual-action antitumoral agents.


Subject(s)
Anisoles/chemical synthesis , Anisoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Bibenzyls/chemical synthesis , Bibenzyls/pharmacology , Furans/chemistry , Neuroblastoma/drug therapy , Stilbenes/chemical synthesis , Stilbenes/pharmacology , Anisoles/chemistry , Antineoplastic Agents/chemistry , Bibenzyls/chemistry , Cell Death/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Stilbenes/chemistry , Structure-Activity Relationship , Tubulin/drug effects
7.
J Med Chem ; 49(2): 467-70, 2006 Jan 26.
Article in English | MEDLINE | ID: mdl-16420033

ABSTRACT

Resveratrol is a phytoalexin able to display an array of biological activities. We decided to replace the double bond with a triazole ring using the archetypical click reaction: the Huisgen [3 + 2] cycloaddition. Seventy-two triazole derivatives were synthesized via a parallel combinatorial approach. Preliminary data suggest that this procedure can lead to the synthesis of compounds that display some, but not all, of resveratrol's actions with increased potency.


Subject(s)
Antineoplastic Agents/chemical synthesis , Stilbenes/chemical synthesis , Triazoles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Resveratrol , Stereoisomerism , Stilbenes/chemistry , Stilbenes/pharmacology , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology
8.
Bioorg Med Chem Lett ; 15(15): 3551-4, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15963722

ABSTRACT

A series of chimeric compounds bearing the combretastatin and the nitrogen mustard cores were synthesized. All the compounds were cytotoxic and inhibited tubulin polymerization. When combretastatin was joined to chlorambucil via an ester linkage, the resultant compound proved to be significantly more potent than the two compounds put together. When combretastatin was joined to nitrogen mustard via an ether linkage or when a true hybrid was synthesized, loss of potency was observed. Nonetheless, these latter compounds appeared to be more efficacious and surprisingly were able to inhibit tubulin depolymerization at high concentrations.


Subject(s)
Antineoplastic Agents/chemical synthesis , Bibenzyls/chemical synthesis , Mustard Plant/chemistry , Stilbenes/chemical synthesis , Antineoplastic Agents/pharmacology , Bibenzyls/pharmacology , Humans , Inhibitory Concentration 50 , Neuroblastoma/metabolism , Neuroblastoma/pathology , Nitrogen/chemistry , Polymers/chemistry , Stilbenes/pharmacology , Structure-Activity Relationship , Tubulin/chemistry , Tubulin Modulators , Tumor Cells, Cultured
9.
J Med Chem ; 48(9): 3260-8, 2005 May 05.
Article in English | MEDLINE | ID: mdl-15857132

ABSTRACT

Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins embodying a furazan ring (combretafurazans). To achieve this, we have developed a new strategy that exploits the dehydration of vicinal dioximes using the Mitsunobu reaction. Among the advantages of following such a strategy are the mild conditions used for the construction of the diarylfurazan derivatives, allowing for the presence of highly functionalized substrates and deactivated aromatic rings. Combretafurazans are more potent in vitro cytotoxic compounds compared to combretastatins in neuroblastoma cells, yet maintaining similar structure-activity relationship and pharmacodynamic profiles.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzene Derivatives/chemical synthesis , Oxadiazoles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Biopolymers , Cell Line, Tumor , Drug Screening Assays, Antitumor , Fluorescent Antibody Technique , Humans , Molecular Conformation , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Structure-Activity Relationship , Tubulin/chemistry
10.
Blood ; 105(6): 2601-7, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15546956

ABSTRACT

Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non-primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.


Subject(s)
Hematopoietic Stem Cell Mobilization , Multiple Sclerosis/therapy , Peripheral Blood Stem Cell Transplantation , Transplantation Conditioning , Adult , Antilymphocyte Serum/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carmustine/administration & dosage , Cytarabine/administration & dosage , Female , Follow-Up Studies , Humans , Male , Melphalan/administration & dosage , Middle Aged , Multiple Sclerosis/complications , Multiple Sclerosis/diagnostic imaging , Peripheral Blood Stem Cell Transplantation/adverse effects , Podophyllotoxin/administration & dosage , Quality of Life , Radiography , Retrospective Studies , Transplantation, Autologous , Treatment Outcome
11.
Leuk Lymphoma ; 44(11): 2015-8, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14738158

ABSTRACT

We report the case of a 31-year-old man with anaplastic large-cell lymphoma successfully treated with chemotherapy who showed mediastinal widening 5 months after autologous stem-cell transplantation. CT scan and PET evaluations were consistent with the diagnosis of benign thymic hyperplasia. Because of the rapid and aggressive course of this type of lymphoma, and the progressive widening of the mass at CT scan, we performed a mediastinal biopsy that confirmed these findings, showing normal thymic tissue. This is the first case of benign thymic hyperplasia defined with FDG-PET and confirmed by histologic evaluation.


Subject(s)
Carcinoma/therapy , Lymphoma, Non-Hodgkin/therapy , Peripheral Blood Stem Cell Transplantation/adverse effects , Thymus Hyperplasia/etiology , Tomography, Emission-Computed/methods , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/complications , Fluorine Radioisotopes , Fluorodeoxyglucose F18 , Humans , Lymphoma, Non-Hodgkin/complications , Male , Radiopharmaceuticals , Thymus Hyperplasia/diagnostic imaging , Thymus Hyperplasia/pathology , Transplantation, Autologous
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