Long-term follow-up of a phase I study of high-dose decitabine,busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias

BACKGROUND: Decitabine is a hypomethylating agent that has activity in patients with leukemia. The authors combined decitabine with busulfan and cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. METHODS: Patients with high-risk acute myeloid leukemia (AML) (n = 12 patients); chronic myelomonocytic leukemia (CMML) (n = 1 patient); acute lymphocytic leukemia (ALL) (n = 1 patient); or late chronic phase, accelerated, or blastic phase chronic myelogenous leukemia (n = 9 patients) were eligible for the study. The treatment plan was comprised of busulfan, 12 mg/kg orally; cyclophosphamide, 100 mg/kg (n = 4 patients) or 120 mg/kg (n = 19 patients); and decitabine, intravenously at 3 dose levels: 400 mg/m(2) (n = 10 patients), 600 mg/m(2) (n = 8 patients), and 800 mg/m(2) (n = 5 patients). Donors were human leukocyte antigen-identical siblings in all cases, and all but one patient received peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus based in all but one patient. RESULTS: The median time to neutrophil and platelet engraftment was 12.5 days and 17.5 days, respectively. Twenty-one patients were engrafted and achieved disease remission. At a median of 3.3 years posttransplantation, 26% of patients (40% of patients with AML) were alive and disease free. The median survival for the group was 17.2 months, and the disease free survival for the group was 8.9 months. Causes of death were disease recurrence (nine patients), chronic GVHD (four patients), infections (three patients), and acute GVHD (one patient). The 100-day mortality rate was 9%. No decitabine dose-limiting toxicity was documented. The treatment-related mortality rate at 3 years was 35%. Responders were treated at all three decitabine dose levels, and no dose-response correlation was observed. CONCLUSIONS: There was a high response rate with low treatment-related mortality, with 26% of patients alive in remission 3.3 years after transplantation.     

Long‐term effects of chronic nicotine on emotional and cognitive behaviors and hippocampus cell morphology in mice: comparisons of adult and adolescent nicotine exposure

Nicotine dependence is associated with increased risk for emotional, cognitive and neurological impairments later in life. This study investigated the long‐term effects of nicotine exposure during adolescence and adulthood on measures of depression, anxiety, learning and hippocampal pyramidal cell morphology. Mice (C57BL/6J) received saline or nicotine for 12 days via pumps implanted on postnatal day 32 (adolescent) or 54 (adults). Thirty days after cessation of nicotine/saline, mice were tested for learning using contextual fear conditioning, depression‐like behaviors using the forced swim test or anxiety‐like behaviors with the elevated plus maze. Brains from nicotine‐ or saline‐exposed mice were processed with Golgi stain for whole neuron reconstruction in the CA1 and CA3 regions of the hippocampus. Results demonstrate higher depression‐like responses in both adolescent and adult mice when tested during acute nicotine withdrawal. Heightened depression‐like behaviors persisted when tested after 30 days of nicotine abstinence in mice exposed as adolescents, but not adults. Adult, but not adolescent, exposure to nicotine resulted in increased open‐arm time when tested after 30 days of abstinence. Nicotine exposure during adolescence caused deficits in contextual fear learning indicated by lower levels of freezing to the context as compared with controls when tested 30 days later. In addition, reduced dendritic length and complexity in the apical CA1 branches in adult mice exposed to nicotine during adolescence were found. These results demonstrate that nicotine exposure and withdrawal can have long‐term effects on emotional and cognitive functioning, particularly when nicotine exposure occurs during the critical period of adolescence.     

Assessment of Segregation Potential of Powder Blends

Pharmaceutical blends consist of several components each with its own unique characteristics, with different size, shape, density, and particle-particle interactions. With so many degrees of complexity, prediction of segregation behavior becomes intractable. The objective of this study was to develop a segregation test method or a segregation tool that would assess the segregation potential of blends. Literature reports generally seek to predict the segregation behavior based on only one mechanism by which the segregation occurs, primarily sifting or fluidization. This study makes an attempt to combine both of these mechanisms by which segregation occurs. A test is developed and used to assess the segregation behavior of blends at large scale and compare the content uniformity results of tablets with the results of the segregation test. The segregation testing model was successful in predicting the segregation tendency of the formulation and also in rank ordering large scale formulation blends based on their segregation potential. A segregation risk classification system is proposed to assess the potential of segregation at large scale.     

Investigating the Impact of Cu2+ Doping on the Morphological,Structural, Optical,and Electrical Properties of CoFe2O4 Nanoparticles for Use in Electrical Devices

This study investigated the production of Cu²⁺-doped CoFe₂O₄ nanoparticles (CFO NPs) using a facile sol−gel technique. The impact of Cu²⁺ doping on the lattice parameters, morphology, optical properties, and electrical properties of CFO NPs was investigated for applications in electrical devices. The XRD analysis revealed the formation of spinel-phased crystalline structures of the specimens with no impurity phases. The average grain size, lattice constant, cell volume, and porosity were measured in the range of 4.55–7.07 nm, 8.1770–8.1097 Å, 546.7414–533.3525 ų, and 8.77–6.93%, respectively. The SEM analysis revealed a change in morphology of the specimens with a rise in Cu²⁺ content. The particles started gaining a defined shape and size with a rise in Cu²⁺ doping. The Cu_0.12Co_0.88Fe₂O₄ NPs revealed clear grain boundaries with the least agglomeration. The energy band gap declined from 3.98 eV to 3.21 eV with a shift in Cu²⁺ concentration from 0.4 to 0.12. The electrical studies showed that doping a trace amount of Cu²⁺ improved the electrical properties of the CFO NPs without producing any structural distortions. The conductivity of the Cu²⁺-doped CFO NPs increased from 6.66 × 10⁻¹⁰ to 5.26 × 10⁻⁶ ℧ cm⁻¹ with a rise in Cu²⁺ concentration. The improved structural and electrical characteristics of the prepared Cu²⁺-doped CFO NPs made them a suitable candidate for electrical devices, diodes, and sensor technology applications.     

Influence of salbutamol on the anticonvulsant potency of the antiepileptic drugs in the maximal electroshock-induced seizures in mice

Backgroundβ₂-Adrenergic receptor agonists are widely used agents in the treatment of asthma or preterm labor. Since prevalence of asthma was shown to be higher in patients with epilepsy and modulation of noradrenergic system activity may modify epilepsy course, the aim of the present study was to examine the effect of salbutamol (SALB), one of the most commonly used β₂-adrenergic receptor agonist on the anticonvulsant potency of four classical antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB) in mice subjected to the maximal electroshock (MES)-induced seizures.MethodsSeizures were caused by a current delivered through ear-clip electrodes. The influence of AEDs and SALB on animals’ motor coordination and memory processes was also evaluated.ResultsSingle SALB injection did not change, whereas 7 days SALB administration decreased seizure threshold in the MES-induced seizures in mice. Moreover, SALB injected ip for 1 day and for 7 days lowered the antiepileptic activity of PB in the MES-induced seizures in mice, but did not change the effect of other analyzed AEDs: VPA, CBZ or DPH. Butoxamine, a selective β₂-adrenergic receptor antagonist, reversed SALB influence on the activity of PB. SALB given alone or in combination with the tested AEDs did not affect animals’ motor performance and memory after both single and 7 days administration.ConclusionsPresented results show that SALB may decrease the antiepileptic efficacy of PB. A special caution is advised to patients with epilepsy receiving β₂-adrenergic receptors agonists in the pharmacotherapy of pulmonary and obstetrical disorders.     

Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases.

The aim of this study was to elucidate the metabolic pathways for dihydroartemisinin (DHA), the active metabolite of the artemisinin derivative artesunate (ARTS). Urine was collected from 17 Vietnamese adults with falciparum malaria who had received 120 mg of ARTS i.v., and metabolites were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Human liver microsomes were incubated with [12-(3)H]DHA and cofactors for either glucuronidation or cytochrome P450-catalyzed oxidation. Human liver cytosol was incubated with cofactor for sulfation. Metabolites were detected by HPLC-MS and/or HPLC with radiochemical detection. Metabolism of DHA by recombinant human UDP-glucuronosyltransferases (UGTs) was studied. HPLC-MS analysis of urine identified alpha-DHA-beta-glucuronide (alpha-DHA-G) and a product characterized as the tetrahydrofuran isomer of alpha-DHA-G. DHA was present only in very small amounts. The ratio of the tetrahydrofuran isomer, alpha-DHA-G, was highly variable (median 0.75; range 0.09-64). Nevertheless, alpha-DHA-G was generally the major urinary product of DHA glucuronidation in patients. The tetrahydrofuran isomer appeared to be at least partly a product of nonenzymic reactions occurring in urine and was readily formed from alpha-DHA-G by iron-mediated isomerization. In human liver microsomal incubations, DHA-G (diastereomer unspecified) was the only metabolite found (V(max) 177 +/- 47 pmol min(-1) mg(-1), K(m) 90 +/- 16 microM). Alpha-DHA-G was formed in incubations of DHA with expressed UGT1A9 (K(m) 32 microM, V(max) 8.9 pmol min(-1) mg(-1)) or UGT2B7 (K(m) 438 microM, V(max) 10.9 pmol mg(-1) min(-1)) but not with UGT1A1 or UGT1A6. There was no significant metabolism of DHA by cytochrome-P450 oxidation or by cytosolic sulfotransferases. We conclude that alpha-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.