Contribution of Irf-1 promoter polymorphisms to the Th1-type cell response and interferon-beta monotherapy for chronic hepatitis C.

We recently reported promoter polymorphisms in the IRF-1 gene, an interferon-inducible gene that plays an important role in host antiviral function. The promoter activity was shown to be different between different polymorphisms. In this study, we investigated the relationship between IRF-1 promoter polymorphisms and the response to interferon monotherapy for chronic hepatitis C. Eighteen patients with a low initial viral load or hepatitis C virus (HCV) genotype non-1b received 6-months course of interferon-beta monotherapy. IRF-1 gene mutations and the treatment response were investigated. The IRF-1 promoter type possessing a higher promoter activity (-415C/-410A/-300A) was found in only three patients, all of which had a lower viral load than those with other promoter types and were able to obtain a sustained viral response. Flow cytometric analysis of peripheral blood mononuclear cells showed that the patients with a higher promoter activity of the IRF-1 had a significantly higher proportion of T helper 1-type CD4(+) cells after interferon administration than those of other promoter types. These results suggest that IRF-1 promoter polymorphisms may contribute, at least partially, to host antiviral activity for chronic hepatitis C.     

Combining Antidepressants in Acute Treatment of Depression: A Meta-Analysis of 38 Studies Including 4511 Patients

Objective:

Combining antidepressants (ADs) for therapy of acute depression is frequently employed, but randomized studies have yielded conflicting results. We conducted a systematic review and meta-analysis aimed at determining efficacy and tolerability of combination therapy.

Methods:

MEDLINE, Embase, PsycINFO, and CENTRAL databases were systematically searched through March 2014 for controlled studies comparing combinations of ADs with AD monotherapy in adult patients suffering from acute depression. The prespecified primary outcome was standardized mean difference (SMD), secondary outcomes were response, remission, and dropouts.

Results:

Among 8688 articles screened, 38 studies were eligible, including 4511 patients. Combination treatment was statistically, significantly superior to monotherapy (SMD 0.29; 95% CI 0.16 to 0.42). During monotherapy, slightly fewer patients dropped out due to adverse events (OR 0.90; 95% CI 0.53 to 1.53). Studies were heterogeneous (I² = 63%), and there was indication of moderate publication bias (fail-safe N for an effect of 0.1:44), but results remained robust across prespecified secondary outcomes and subgroups, including analyses restricted to randomized controlled trials and low risk of bias studies. Meta-regression revealed an association of SMD with difference in imipramine-equivalent dose. Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations.

Conclusion:

Combining ADs seems to be superior to monotherapy with only slightly more patients dropping out. Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors seems to be significantly more effective than other combinations. Overall, our search revealed a dearth of well-designed studies.     

Sirolimus monotherapy as maintenance immunosuppression: a multicenter experience

The aim of this study was to retrospectively evaluate safety and feasibility of sirolimus (SRL) monotherapy in kidney transplant recipients. Patients older than 18 years, with monotherapy prescribed for more than 1 month and at least 6 months of follow‐up were included. We analysed the data from 138 patients. Mean time period between transplantation and start of monotherapy was 6.5 ± 4.1 years.The most frequent reason was minimization of immunosuppression followed by malignancy. Acute rejection rate was 1.4% at 12 months (two episodes). Graft and patient survival were 94.2% and 97.1% respectively. Mean follow‐up after initiation of monotherapy was 29.4 months. Two patients died as a result of cardiovascular diseases and two because of malignancy. Percentage of withdrawal from monotherapy was 14%. SRL trough levels were 10.2 ± 2.3 ng/ml at baseline and 9.6 6 ± 3.3 ng/ml at 12 months. Mean glomerular filtration rate was 48.4 ml/min/1.73 m² at baseline and 47.7 ml/min/1.73 m² at 12 months. Proteinuria was 499.7 mg/24 h at baseline and 543 ± 794 mg/24 h at 12 months. No significant changes in lipids, glucose, or hemoglobin occurred, although the percentage of patients treated with statins and Epo increased at the end of the follow‐up. SRL monotherapy is suitable as long‐term immunosuppression in selected patients with no significantly increased risk of late acute rejection.     

Do the old psychostimulant drugs have a role in managing treatment‐resistant depression?

Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment‐resistant depression? Objective: As the authors have observed clinical benefit from the psychostimulants methylphenidate and dexamphetamine for treating resistant melancholic and bipolar depression, those drugs were evaluated in a consecutively recruited sample of 50 such patients. Method: Patients (27 bipolar, 23 unipolar) received either methylphenidate (n = 44) or dexamphetamine (n = 6), with 30 having it prescribed as an augmenting drug and 20 as monotherapy. At the final review, ranging from 6 weeks to 62 months (mean 57 weeks), 52% were still receiving their psychostimulant. Results: Thirty‐four per cent reported the psychostimulant as distinctly improving their depression, 30% reported some level of improvement and 36% reported no improvement and/or side‐effects. For improvers, the modal dose of methylphenidate was 20 mg. Significant side‐effects were reported by 18% (including one manic response), switching was rare and limited to the bipolar subjects, and most side‐effects were minor. Any positive response occurred rapidly and loss of efficacy was rare. Testing of tricyclic levels in some patients suggested that stimulant drugs may raise tricyclic levels in those who are rapid metabolizers. Conclusion: Although this study was not controlled, the high success rate in a diagnostically refined sample implies that the psychostimulants may be efficacious for patients with melancholic and bipolar depression who have failed to respond to orthodox antidepressant drugs.     

3种抗精神病药物对精神分裂症患者糖代谢的影响

目的探讨3种非典型抗精神病药物对精神分裂症患者糖代谢的影响。方法将270例精神分裂症患者随机分成3组,测定单药治疗前后8周空腹血糖和血清胰岛素及餐后2小时血糖和血清胰岛素。结果利培酮、阿立哌唑、齐拉西酮对糖代谢均有影响,其中空腹胰岛素和餐后2h血糖的改变有统计学意义。结论非典型抗精神病药物中利培酮、阿立哌唑和齐拉西酮对糖代谢均有影响。     

Topiramate monotherapy in infantile spasm

Infantile spasm is an age-related refractory epilepsy. Topiramate is a new anticonvulsant with multiple mechanisms of action, and it may be effective for treating pediatric epilepsies. To evaluate the efficacy and tolerability of first-line topiramate treatment for infantile spasm, 20 patients received topiramate monotherapy during this study. They were treated with an initial dose of 1mg/kg/day, with a progressive titration of 1 mg/kg a week until their spasms were controlled and a maximum dose of 12 mg/kg/day was achieved. The evaluation of the treatment efficacy was based on the spasm frequency data that was obtained by the scalp and video-EEG, and by the parental count of spasm. Thirty percent of the subjects became spasm-free during the study. Six of 20 subjects (30%) had cessation of spasm and disappearance of hypsarrhythmia as seen via the video EEG; four (50%) of eight idiopathic patients had a response, whereas two (17%) of 12 patients with symptomatic infantile spasm responded. Seventy of the patients, including the spasm-free patients, had a reduction in their seizure frequency of more than 50%, and 10% of the patients had a reduction in their seizure frequency of less than 50%. The clusters of spasm frequency decreased from 10.6 +/- 8.5 to 3.5 +/- 1.4 clusters/day. Topiramate is effective and tolerated in those patients suffering from infantile spasm. Our results suggest that this drug should be considered as a new first-line drug for treating infantile spasm.     

抗高血压药物的联合应用

血压达标可明显降低心血管病发病率和死亡率;然而在我国,人群高血压的控制率仅为6.1%.联合降压治疗,如固定剂量复方制剂的联合治疗与单药降压治疗比较,可明显降低血压和减少药物不良反应的发生.由于联合降压治疗可能减少不良事件的发生、提高患者的依从性、降低治疗成本和改善血压的达标率,因此联合降压治疗对高危高血压患者是一项有价值的选择.     

Phase II study of oxaliplatin in japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines

BACKGROUND: Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m2 every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines. METHODS: Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m2 every 3 weeks. RESULTS: Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1-6). The overall response rate was 9% (5/57, 95% CI: 4-19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living. CONCLUSIONS: The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients.     

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.