Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors

Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field.     

Single and multiple dose pharmacokinetics of enteric coated ketoprofen: Effect of cimetidine

Summary The effect of cimetidine on the single and multiple dose pharmacokinetics of enteric coated ketoprofen was studied in 12 healthy volunteers. Each subject completed two 8-day study treatment periods: either ketoprofen alone (100 mg p.o. twice daily), or co-administered with cimetidine (600 mg twice daily). t_lag, C_max, t_max, t_1/2, and k for ketoprofen were not significantly different between single and multiple dose administration. AUC of ketoprofen was slightly but significantly larger following multiple (21.2 µg·h·ml^–1) as compared to single dose administration (19.0 µg·h· ml^–1). As a result, plasma clearance of ketoprofen was slightly but significantly reduced following multiple dose administration (80.6 ml/min vs 89.3 ml/min). Cimetidine had no effect on the single or multiple dose pharmacokinetics of enteric coated ketoprofen. Total 12-h urinary recovery of ketoprofen (mostly in the form of ketoprofen glucuronide) was 83.5% of the dose following single dose administration and was significantly greater following multiple dose administration (93.1%). Again cimetidine co-administration had no effect on the single and multiple dose urinary recovery.The results of this study show that cimetidine is not affecting the oral pharmacokinetics of enteric coated ketoprofen.     

Does gabapentin lead to early symptom improvement in obsessive-compulsive disorder?

OBJECTIVE: The aim of this study was to compare efficacy of fluoxetine alone and co-administration of gabapentin and fluoxetine in patients with obsessive compulsive disorder (OCD). METHODS: Forty outpatients with a DSM-IV diagnosis of OCD were randomized to open label treatment, 20 of whom were treated with fluoxetine alone and the remaining 20 with fluoxetine plus gabapentin during 8 weeks. The severity was assessed by Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and Clinical Global Impression (CGI). RESULTS: Final CGI-I and Y-BOCS scores were not significantly different in both groups. However, in repeated measures ANOVA, compared to fluoxetine group, we found significantly a better improvement in the fluoxetine plus gabapentin group at week 2 by means of YBOCS and CGI-I scores. Comparisons on weeks 4, 6 and 8 revealed no statistical differences between the groups. There was no significant difference of adverse effects between two groups. CONCLUSIONS: Adding gabapentin to fluoxetine in the treatment of OCD seems to shorten the time to onset of fluoxetine's anti-obsessive effect without a significant increase in adverse effects. In order to accelerate the clinical response, co-administration of fluoxetine and gabapentin may be a preferable strategy. On the other hand, further controlled studies are needed to support this finding.     

依折麦布联合降脂治疗及其多效性研究进展

肠道胆固醇吸收抑制剂依折麦布(ezetimibe)联合他汀类药物降脂具有良好的安全性及疗效,联合其他降脂药物如氯贝丁酯类、烟酸类、胆酸螯合树脂类同样具有良好的耐受性及疗效。同时依折麦布联合他汀类药物具有降低高敏C反应蛋白、降低血小板聚集、保护内皮功能、抗动脉硬化等作用。文中综述了依折麦布联合他汀类药物和其他类药物降脂治疗的临床研究进展及其多效性研究进展。     

溴泰君与阿霉素单用和联合应用在Beagle犬的毒代动力学研究

目的:研究溴泰君(W198)在Beagle犬体内毒代动力学,为临床试验提供依据。方法:采用HPLC紫外或荧光检测方法测定Beagle犬静脉注射溴泰君、阿霉素以及溴泰君与阿霉素联合给药后生物样品中溴泰君和阿霉素的浓度。结果:Beagle犬静脉注射溴泰君15 mg·kg-1·d-1,第1次、第3次、第72次给药后的血清药物浓度-时间曲线下的面积(AUC0-24h)分别为6.15±0.66、26.55±9.43和33.63±2.31 mg·h-1·L-1。Beagle犬静脉注射阿霉素每次1.5mg·kg-1,第1次和第3次给药后的血清药物AUC0-24h分别为0.70±0.21和1.19±0.19mg·h-1·L-1。溴泰君与阿霉素联合给药时,溴泰君连续给药3次、阿霉素给药1次和溴泰君连续给药39次、阿霉素给药3次后溴泰君的血清药物AUC0-24h分别为 25.52±6.04和42.60±4.14 mg.h-1·L-1;阿霉素的血清药物AUC0-24h分别为0.39±0.05和0.77±0.19 mg·h-1·L-1。结论:溴泰君和阿霉素连续多次给药后药物在动物体内均有明显蓄积作用。联合给药后溴泰君对阿霉素的消除似有促进作用,揭示溴泰君可以使阿霉素的系统暴露量减低,有利于降低阿霉素的毒性。     

Effect of Co-Administration of Curcumin with Amlodipine in Hypertension

Curcumin, a curcuminoid known as the main bioactive compound of turmeric, is used in foods, cosmetics, and pharmaceutical products. Amlodipine is a general antihypertensive drug used in combination with various other antihypertensive agents. To date, no studies have examined the effects of the co-administration of amlodipine with curcumin. In this study, the vasodilatory effects of curcumin, amlodipine, and the co-administration of curcumin with amlodipine on isolated rat aortic rings pre-contracted with phenylephrine were evaluated, and the hypotensive effects were evaluated using the tail cuff method. To measure blood pressure, male spontaneously hypertensive rats were divided into four groups, each containing six rats, as follows: amlodipine 1 mg/kg alone treated, amlodipine 1 mg/kg with curcumin 30 mg/kg treated, amlodipine 1 mg/kg with curcumin 100 mg/kg treated, and amlodipine 1 mg/kg with curcumin 300 mg/kg treated groups. Amlodipine and curcumin were intraperitoneally injected, and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at 1, 2, 4, and 8 h after administration. The combined administration of curcumin and amlodipine induced a stronger vasorelaxant effect than amlodipine alone. However, co-administration did not significantly lower SBP and DBP compared to the single administration of amlodipine. The results of this study suggest that hypertensive patients taking amlodipine can consume curcumin or turmeric for food or other medical purposes without inhibiting the blood pressure-lowering effect of amlodipine.     

Are herbal medicines alone or in combination for diabetic peripheral neuropathy more effective than methylcobalamin alone? A systematic review and meta-analysis

Background and purposeIn Asian countries, herbal medicines have been used to treat diabetic peripheral neuropathy (DPN) as an adjunctive therapy. This review aims to assess the effectiveness and safety of herbal medicines for the treatment of DPN.MethodsA literature search was conducted on PubMed, Embase, CENTRAL, Scopus, CINAHL, CNKI, DBPIA, and OASIS for randomized controlled trials that evaluated the effects of herbal medicines on DPN. The oral methylcobalamin administered group was selected as the control. The primary outcome measure was nerve conduction velocity (NCV), and the secondary outcome measure was the total efficacy rate (TER). The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. A meta-analysis was conducted using Review Manager 5.4.1 software.ResultsSeventy-two RCTs with a total of 6260 patients were included. The meta-analysis showed that herbal medicine and co-administration of herbal medicine and methylcobalamin (CHM) treatment for DPN significantly increased the sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) of the median and common peroneal nerves than methylcobalamin treatment alone. Herbal medicine and CHM treatment for DPN also significantly improved the TER compared to the control group. Herbal medicine and CHM treatment was found to be relatively safe.ConclusionOur study suggests that herbal medicine and CHM might be more effective than methylcobalamin alone in the management of DPN. Further rigorous studies should be conducted to make more definite conclusions.     

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice

Summary. The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30 mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in co-administration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder. Received May 29, 2000; accepted September 13, 2000     

16种具有P-gp抑制作用的上市药物对吉非替尼口服生物利用度和脑通透性的影响

采用LC-MS/MS法研究16种具有P-gp抑制作用的上市药物对吉非替尼口服生物利用度和脑通透性的影响。对照组ICR小鼠灌胃给予CMC-Na混悬液和吉非替尼混悬液,抑制剂组ICR小鼠分别灌胃给予16种上市药物混悬液和吉非替尼混悬液,血浆样品和脑匀浆样品经乙腈沉淀后,用LC-MS/MS法测定药物浓度。结果发现16种药物中利托那韦能够明显增加吉非替尼的口服生物利用度,吉非替尼血药浓度-时间曲线下面积(AUC)增加了2倍,同时增加了吉非替尼的脑暴露量,但是没有增加吉非替尼的脑通透性;部分其他药物也能增加吉非替尼的血浆AUC,不能增加吉非替尼的脑通透性;游离分数校正脑浓度发现对照组和给予利托那韦后,脑内游离药物浓度均不能达到体外抑制非小细胞肺癌(NSCLC)细胞生长的IC₅₀。本研究结果表明,临床剂量的16种具有P-gp抑制作用的上市药物虽然能够增加吉非替尼的口服生物利用度,但是不能特异性提高脑组织暴露量,需要研发特异性更强和更安全的P-gp抑制剂;用脑部药物游离分数校正脑浓度后,临床前研究发现脑暴露量不足可能是吉非替尼治疗脑转移疗效不理想的原因之一。