Analysis of imatinib in bone marrow and plasma samples of chronic myeloid leukaemia patients using solid phase extraction LC-ESI-MS

The LC-ESI-MS was developed and validated for the analysis of imatinib in plasma and bone marrow samples using deuterated imatinib [D[8]-IM] as an internal standard. The biological samples were extracted using Strata-X-C SPE cartridges and separated on C[8] column [50 x 3 mm, 3 microm], and methanol: 0.1% formic acid [70:30] was delivered at the rate of 0.7 ml/min as a mobile phase. Imatinib was quantified in samples by monitoring the ions m/z 494.3 for imatinib and 502.3 for D[8]-imatinib on mass spectrometer. The method was linear in the concentration range of 1-1500 ng/250 microl in spiked human plasma samples and limit of quantification was 5 ng/mL. Inter-day and intra-day variations in spiked human plasma spiked with 50, 250 and 500 ng /mL were less than 3.16%. The repeatability and reproducibility and other parameters of the methods were also validated. The method was employed for the analysis of the imatinib in human plasma and bone marrow samples. The drug levels in bone marrow and plasma samples were correlated to the degree of cytogenetic response. No significant difference of imatinib level between blood and bone marrow in IM-treated patients dosed to steady state was observed

Repercussão cardiovascular, com e sem álcool, do carbonato de lodenafila, um novo inibidor da PDE5 / Repercusión cardiovascular, con y sin alcohol, del carbonato de lodenafila, un nuevo inhibidor de la PDE5 / Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption

FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5) estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, assim como as alterações na farmacocinética que esta associação possa determinar. MÉTODOS: Estudo realizado com 15 voluntários sadios que receberam em momentos diferentes o carbonato de lodenafila (CL) na dose de 160 mg em jejum, CL (160 mg) com álcool, ou somente placebo. Esses pacientes foram monitorados por 24 horas, sendo avaliado o quadro clínico, a pressão arterial (PA), a frequência cardíaca (FC), o intervalo QT e também os dados de farmacocinética. RESULTADOS: O carbonato de lodenafila, isoladamente ou associado com álcool, não determinou alterações clínicas significativas na PA ou FC, embora tenha ocorrido diminuição da PA estatisticamente significativa após 4 horas, nos voluntários que receberam medicamento e álcool, assim como um aumento da FC após 6 horas nos pacientes que receberam o CL. A análise do intervalo QT corrigido não mostrou alteração significativa. O álcool aumentou a biodisponibilidade do medicamento em 74 por cento. Houve somente 2 queixas de cefaleia leve, possivelmente associada ao medicamento. CONCLUSÃO: O carbonato de lodenafila, mesmo associado ao álcool, não determinou repercussões clínicas importantes na PA, FC, ou alterações no intervalo QTc; a ingestão com álcool, por sua vez, aumentou significativamente sua biodisponibilidade.

BACKGROUND: Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. OBJECTIVE: This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. METHODS: Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. RESULTS: Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74 percent when drug intake was associated with alcohol. CONCLUSION: These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

FUNDAMENTO: La disfunción eréctil afecta a un gran número de hombres en el mundo y los inhibidores de PDE5 (iPDE5) están entre los principales métodos de tratamiento de estos pacientes. El consumo social de alcohol y el acto sexual presentan una relación considerable. Por lo tanto, puede ocurrir una asociación entre alcohol e iPDE5. El carbonato de lodenafila es un nuevo iPDE5 desarrollado por una empresa brasileña. OBJETIVO: Evaluar la repercusión cardiovascular del carbonato de lodenafila, asociado o no al alcohol, así como las alteraciones en la farmacocinética que esta asociación pueda determinar. MÉTODOS: Estudio realizado con 15 voluntarios sanos que recibieron en momentos diferentes el carbonato de lodenafila (CL) en la dosis de 160mg en ayunas, CL (160 mg) con alcohol, o solamente placebo. Estos pacientes fueron monitoreados por 24 horas, siendo evaluado el cuadro clínico, la presión arterial (PA), la frecuencia cardíaca (FC), el intervalo QT y también los datos de farmacocinética. RESULTADOS: El carbonato de lodenafila, aisladamente o asociado con alcohol, no determinó alteraciones clínicas significativas en la PA o FC, aunque se haya registrado una disminución de la PA estadísticamente significativa después de 4 horas en los voluntarios que recibieron medicamento y alcohol, así como un aumento de la FC después de 6 horas en los pacientes que recibieron el CL. El análisis del intervalo QT corregido no mostró alteración significativa. El alcohol aumentó la biodisponibilidad del medicamento en un 74 por ciento. Se registraron sólo 2 quejas de cefalea leve, posiblemente asociada al medicamento. CONCLUSIÓN: El carbonato de lodenafila, aun asociado al alcohol, no determinó repercusiones clínicas importantes en la PA, FC, o alteraciones en el intervalo QTc; la ingestión con alcohol, a su vez, aumentó significativamente su biodisponibilidad.

HPLC determination of imatinib in plasma and tissues after multiple oral dose administration to mice

Imatinib inhibits Bcr-Abl, c-KIT and PDGFR kinases. It is approved for the treatment of chronic myeloid leukemia [CML], gastrointestinal stromal tumors [GIST] and has further therapeutic potential. Male ICR mice were given imatinib PO [50 or 25 mg/kg, 5 doses every 2 h]; euthanized 2 h after the last dose administration; plasma, liver, brain, spleen and kidney were collected and imatinib concentration measured by an optimized HPLC method for quantification in tissues. Methanol [1:1 v/v plasma] and pH 4, 40:30:30 [v/v/v] water-methanol-acetonitrile at 5 ml/g [brain] and 10 ml/g [spleen, kidney, liver] ratio was added to the samples, homogenized, sonicated, centrifuged [15, 000 rpm, 5 min, 2°C] and the supernatant injected into an Inertsil CN-3 column [4.6 mm x 150 mm, 5 micro m] using 64:35:1 [v/v/v] water-methanol-triethylamine [pH 4.8], flow rate 1 ml/min, 25°C. Imatinib eluted at 7.5 min [268 nm]. Linearity: 0.1-50 micro g/ml; precision, accuracy, inter- and intra-day variability was within 15%. Recovery was above 95% [plasma], 80% [brain] and 90% [kidney, liver, spleen]. Imatinib tissue concentrations were 6-8 folds higher than plasma except brain, where the ratio decreased from 0.24 to 0.08 suggesting limited brain penetration, likely due to blood brain barrier efflux transporters. The extensive distribution supports the expansion of therapeutic applications

Brief report on Ziprasidone.

Ziprasidone is a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. The initial evidence suggests an effective dosage range of 80-160 mg/day. Clinical trials suggest that the drug is an effective antipsychotic in schizophrenia and schizo-affective disorder with a beneficial effect on negative symptoms and symptoms of depression. The main adverse effects appear to be somnolence (14%) and nausea (10%). Ziprasidone has relatively fewer side effects and yet has at least equivalent efficacy for florid 'positive' symptoms compared to conventional anti psychotics. The additional serotonergic actions deliver further efficacy against 'negative' and affective symptoms of schizophrenia. Reduced effects on cognitive abilities compared to conventional anti psychotics make Ziprasidone more attractive.