Cesium Carbonate Promoted Direct Amidation of Unactivated Esters with Amino Alcohol Derivatives.

Cesium carbonate promoted direct amidation of unactivated esters with amino alcohols was developed without the use of transition-metal catalysts and coupling reagents. This method enabled the synthesis of several serine-containing oligopeptides and benzamide derivatives with yields up to 90%. The methodology proceeds under mild reaction conditions and exhibits no racemization for most naturally occurring amino acid substrates. The reaction demonstrates good compatibility with primary alkyl and benzyl esters and broad tolerance for a range of amino acid substrates with nonpolar and protected side chains. The hydroxy group on the amine nucleophile was found to be critical for the reaction to be successful. A likely mechanism involving cesium coordination to the substrates enabling the subsequent proximity-driven acyl transfer was proposed. The practicality of this approach was demonstrated in the preparation of a biologically active nicotinamide derivative in a reasonable yield.

Duloxetine improves oxaliplatin-induced neuropathy in patients with colorectal cancer: an open-label pilot study.

BACKGROUND: This open-label pilot study is aimed to evaluate the efficacy and tolerability of the antidepressant duloxetine, which is effective for diabetic neuropathic pain, in the treatment of chronic oxaliplatin-induced peripheral neuropathy (OIPN). METHODS: We enrolled a total of 39 patients with stage III or IV colorectal cancer with chronic OIPN. They were treated with duloxetine by increasing the dose from 30 mg/day to 60 mg/day. Patients' pain intensity was rated at baseline and 12 weeks after duloxetine administration. The severity of neuropathic pain was evaluated using the visual analog scale (VAS) score and the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3 (NCI-CTCAE v3.0). RESULTS: Nine patients (23.1%) discontinued duloxetine before the end of treatment because of adverse events. Of the remaining 30 patients, 19 patients (63.3%) had a VAS score improvement. Among them, nine (47.4%) showed a simultaneous grade improvement, and the other 10 patients (52.6%) had a stable grade according to NCI-CTCAE v3.0. Treatment with duloxetine did not impair renal or liver function and did not interfere with chemotherapy. CONCLUSIONS: Duloxetine is feasible in treating chronic OIPN with tolerable toxicity at a daily dose of 60 mg/day.

High early mortality rate in elderly patients with multiple myeloma receiving a vincristine-doxorubicin-dexamethasone regimen.

Treatment-related mortality (TRM) is not uncommon in patients after the first course of vincristine-doxorubicin-dexamethasone (VAD) chemotherapy,but quite rare after melphalan-prednisolone (MP). This motivated us to compare the rates of TRM after the first course of VAD with those after the first course of MP. We retrospectively assessed survival and TRM in 179 patients treated for multiple myeloma with either MP or VAD. Survival was similar in two groups (P 50.463 in log-rank test). However, TRM was significantly higher inpatients after the first course of VAD (11 in 100 patients, 11.0%) than that after the first course of MP (1 in 79, 1.3%; P 5 0.010). Poor performance status (P 5 0.004) and advanced age (P 5 0.009) before treatment were independent significant factors associated with TRM after the first course of induction therapy. Pyogenic infection was the major cause of TRM after VAD (9 in 11, 81.8%). We concluded that VAD should be cautiously used as induction therapy in multiple myeloma patients, especially in elderly and/or those with poor performance status.

Aspirin and Risk of Dementia in Patients with Late-Onset Depression: A Population-Based Cohort Study.

BACKGROUND: Late onset depression (LOD) often occurs in the context of vascular disease and may be associated with risk of dementia. Aspirin is widely used to reduce the risk of cardiovascular disease and stroke. However, its role in patients with LOD and risk of dementia remains inconclusive. Materials and Methods. A population-based study was conducted using data from National Health Insurance of Taiwan during 1996-2009. Patients fulfil diagnostic criteria for LOD with or without subsequent dementia (incident dementia) and among whom users of aspirin (75 mg daily for at least 6 months) were identified. The time-dependent Cox proportional hazards model was applied for multivariate analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matching patients. Cumulative incidence of incident dementia after diagnosis of LOD was calculated by Kaplan-Meier Method. RESULTS: A total of 6028 (13.4%) and 40,411 (86.6%) patients were defined as, with and without diagnosis of LOD, among whom 2,424 (41.9%) were aspirin users. Patients with LOD had more comorbidities such as cardiovascular diseases, diabetes, and hypertension comparing to those without LOD. Among patients with LOD, aspirin users had lower incidence of subsequent incident dementia than non-users (Hazard Ratio = 0.734, 95% CI 0.641-0.841, p < 0.001). After matching aspirin users with non-users by propensity scores-matching method, the cumulative incidence of incident dementia was significantly lower in aspirin users of LOD patients (p < 0.001). After matching aspirin users with non-users by propensity scores-matching method, the cumulative incidence of incident dementia was significantly lower in aspirin users of LOD patients (. CONCLUSIONS: Aspirin may be associated with a lower risk of incident dementia in patients with LOD. This beneficial effect of aspirin in LOD patients needs validation in prospective clinical trials and our results should be interpreted with caution.

The prolonged activated partial thromboplastin time at diagnosis indicates less favorable prognosis in IgA myeloma.

BACKGROUND: The impact of coagulopathy on survival of patients with myeloma has not been studied in detail. We aimed to assess the correlation between activated partial thromboplastin time/prothrombin time at diagnosis and overall survival in myeloma patients. METHODS: Data including activated partial thromboplastin time and prothrombin time obtained before treatment and at the time of diagnosis of multiple myeloma (excluding monoclonal gammopathy of undetermined significance, POEMS syndrome, IgM myeloma and myeloma with amyloidosis) collected from 222 patients were analyzed. RESULTS: Twenty-one patients (9.5%) had prolonged activated partial thromboplastin time (nine with prolonged a activated partial thromboplastin time alone, 12 with both prolonged activated partial thromboplastin time and prothrombin time) and 10 (4.5%) had prolonged prothrombin time alone. Coagulopathy occurred only in patients with IgA and IgG myeloma but not light-chain disease. Prolonged activated partial thromboplastin time was an independent prognostic factor in IgA and IgG myeloma (median survival = 12.7 months, P = 0.004), while prolonged prothrombin time alone had no impact on survival. Subgroup analysis revealed that prolonged activated partial thromboplastin time indicated less favorable survival in IgA myeloma (P = 0.001), but not the IgG myeloma (P = 0.341). This observation still holds true in IgA myeloma with Durie-Salmon stage II or III (P = 0.002). CONCLUSIONS: The presence of prolonged activated partial thromboplastin time at diagnosis is a prognostic factor indicating poor outcome in the IgA myeloma.

Methionine synthase 2756AA polymorphism is associated with the risk of cognitive impairment in patients with late-life depression.

BACKGROUNDS: Apolipoprotein E epsilon-4 (APOE ε4) allele, methylenetetrahydrofolate reductase (MTHFR C677T), and methionine synthase (MTR A2756G) were tested their associations with cognitive impairment in people with late-life depression (LLD). METHODS: People with LLD were assessed by mini-mental state examination and were examined the distribution of APOE ε4 allele, MTHFR, and MTR polymorphisms. RESULTS: Odds ratio of MTR 2756 AA to MTR 2756 AG and GG genotypes for the risk of cognitive impairment was 5.80 (95% confidence interval = 1.18-28.50; P = 0.03). CONCLUSION: People with LLD carrying MTR2756 AA genotype have higher risk of cognitive impairment than those carrying G allele.

Shift from darbepoetin-α to continuous erythropoietin receptor activator decreases serum aluminium concentration in patients on hemodialysis.

OBJECTIVE: The response of erythropoietic stimulating agents (ESA) in uremic patients may be associated with the changes of biochemical parameters, metal elements and inflammation status during the shift from one ESA to another. METHOD: We compared changes in above mentioned factors after switching from darbepoetin-α (DPO) 20µg weekly for 10 weeks to continuous erythropoietin receptor activator (CERA) 100µg monthly for 10 weeks in uremic patients on hemodialysis. The haematocrit (Hct), metal elements and inflammation status are the primary outcome. Subjects included 54 patients without transfusion or bleeding or additional ESAs. Responders (IR, n=36) were defined as patients with an increase in Hct after the swtich. RESULT: Although there was no significant difference in overall mean Hct after the switch (p=0.135), there are significantly greater mean number of red blood cells (RBC) (p=0.006), higher platelet numbers (p=0.001), larger RBCs (p=0.017) and higher creatinine (p=0.04) and total cholesterol (T-CHOL) (p=0.003) levels. Mean overall aluminium (Al) level decreased significantly (p=0.001). C-reactive protein (CRP) also decreased (p=0.016). The overall LDH increased (p=0.049) and potassium decreased significantly (p=0.036), which indicating active erythropoiesis. The calcium (Ca) level was significantly higher (p=0.034) and phosphate was significantly lower (p=0.028) after the shift. Although there was no significant increase in overall levels of parathyroid hormone (PTH) after the shift (p=0.061), but the pre-shift and post-shift PTH level was significantly higher in IRs than in non-IRs (p=0.003 and p=0.027, respectively). IRs had a significantly lower initial T-CHOL (p=0.03) and initial CRP (p=0.012) than non-responders, which may be related to lower inflammation. CONCLUSION: We found the shift from DPO to CERA results in lower Al levels, a reduced inflammatory response, and an increase in RBC number and PTH level in uremic patients on hemodialysis.

Statins Reduces the Risk of Dementia in Patients with Late-Onset Depression: A Retrospective Cohort Study.

OBJECTIVE: Patients with late-onset depression (LOD) have been reported to run a higher risk of subsequent dementia. The present study was conducted to assess whether statins can reduce the risk of dementia in these patients. METHODS: We used the data from National Health Insurance of Taiwan during 1996-2009. Standardized Incidence Ratios (SIRs) were calculated for LOD and subsequent dementia. The criteria for LOD diagnoses included age ≥65 years, diagnosis of depression after 65 years of age, at least three service claims, and treatment with antidepressants. The time-dependent Cox proportional hazards model was applied for multivariate analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matching patients for validation studies. Kaplan-Meier curve estimate was used to measure the group of patients with dementia living after diagnosis of LOD. RESULTS: Totally 45,973 patients aged ≥65 years were enrolled. The prevalence of LOD was 12.9% (5,952/45,973). Patients with LOD showed to have a higher incidence of subsequent dementia compared with those without LOD (Odds Ratio: 2.785; 95% CI 2.619-2.958). Among patients with LOD, lipid lowering agent (LLA) users (for at least 3 months) had lower incidence of subsequent dementia than non-users (Hazard Ratio = 0.781, 95% CI 0.685-0.891). Nevertheless, only statins users showed to have reduced risk of dementia (Hazard Ratio = 0.674, 95% CI 0.547-0.832) while other LLAs did not, which was further validated by Kaplan-Meier estimates after we used the propensity scores with the one-to-one nearest-neighbor matching model to control the confounding factors. CONCLUSIONS: Statins may reduce the risk of subsequent dementia in patients with LOD.

A new model for predicting the timing of leukapheresis on the basis of CD34+ cell and hematopoietic progenitor cell levels.

We developed a model (depending on peripheral CD34(+) cell count and hematopoietic progenitor cell count) to determine the optimal timing of 3-day leukapheresis in patients pretreated with chemotherapy and G-CSF. Marrow potentials were identified on the basis of three patterns of leukapheretic yield. Pattern 1 predicted good marrow potential. The positive predictive value of a first-day leukapheretic yield of >1 x 10(6) CD34(+) cells/kg (mean 3-day yield = 8.18 x 10(6) CD34(+) cells/kg, n = 11) was 100%. Pattern 2 predicted poor marrow potential. The negative predictive value of a 3-day leukapheretic yield of >1 x 10(6) CD34(+) cells/kg (3-day yield = 0.26 x 10(6) CD34(+) cells/kg, n = 1) was 100%. Pattern 3 met neither of the above criteria (mean 3-day yield = 1.37 x 10(6) CD34(+) cells/kg, n = 19). The marrow potential was borderline and patients could be further divided into two subgroups according to peripheral CD34(+) cell counts when WBC reached >10,000/microl. The mean yield differed significantly between pattern 1 and 3 (P < 0.001). For patients with good marrow potential, leukapheresis should begin as soon as the WBC count is >5,000/microl. Patients with borderline marrow potential may benefit from delaying leukapheresis until the WBC level is >10,000/microl and leukapheresis extended more than 3 days.