Pharmacokinetics and pharmacodynamics of SB 209670, an endothelin receptor antagonist: effects on the regulation of renal vascular tone.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SB 209670, a non-peptide endothelin-A/endothelin-B receptor antagonist. METHODS: The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SB 209670 infused at doses that ranged from 0.2 to 1.5 mirog kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SB 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study. RESULTS: SB 209670 appeared to display linear kinetics over the dose range from 0.2 to 1.5 microg kg(-1) min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-1 increased in an apparent dose-dependent manner. Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007). Renal sodium excretion was similar during SB 209670 and placebo infusion. CONCLUSION: The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-1. The lack of anti-natriuretic effect and the renal vasodilator response observed in this study indicate that SB 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.     

Effects of methylene blue-treated plasma on red cells and stored platelet concentrates

BACKGROUND: Photochemical methods can effectively inactivate extracellular viruses and bacteria found in blood components. Treatment of plasma with methylene blue (MB), a phenothiazine dye, and visible light inactivates enveloped viruses including HIV-1. The effects of MB- treated plasma on cellular components stored in vitro have not been well characterized. STUDY DESIGN AND METHODS: MB-treated plasma (83 microg MB/250 mL plasma) was added to single-donor platelets, stored AS- 1 red cells (RBCs), irradiated RBCs, and frozen-deglycerolized RBCs. In vitro platelet assays performed after 1 and 5 days of storage in MB- treated plasma included pH, pO2, pCO2, HCO3, platelet number, lactate dehydrogenase, glucose, osmotic recovery, and CD62 expression. RBC components were examined at specific intervals for leakage of potassium, plasma hemoglobin level, and percentage of hemolysis. Direct antiglobulin tests, osmotic fragilities, and RBC antigen stability tests were also performed on RBCs stored in MB-treated plasma. Components stored with autologous plasma or nontreated allogeneic plasma served as controls. RESULTS: Similar storage-induced changes in pH, glucose, and platelet numbers, as well as increases in lactate dehydrogenase, CD62 expression, and lactate were seen in single-donor platelets stored with MB-treated and control plasma. Platelet morphology scores and osmotic recoveries were not altered. Plasma hemoglobin and potassium and percentage of hemolysis increased equally in the various RBC components stored with MB-treated or nontreated plasma. Osmotic fragility and RBC antigen stability were not appreciably altered by MB-treated plasma. CONCLUSION: Plasma treated by MB photoinactivation can be used for in vitro resuspension and storage of platelets or RBCs, because of the lack of influence of MB-treated plasma on a variety of in vitro platelet and RBC assays.     

Collapsin-1/semaphorin-III/D is regulated developmentally in Purkinje cells and collapses pontocerebellar mossy fiber neuronal growth cones

Most axons in the CNS innervate specific subregions or layers of their target regions and form contacts with specific types of target neurons, but the molecular basis of this process is not well understood. To determine whether collapsin-1/semaphorin-III/D, a molecule known to repel specific axons, might guide afferent axons within their cerebellar targets, we characterized its expression by in situ hybridization and observed its effects on mossy and climbing fiber extension and growth cone size in vitro. In newborn mice sema-D is expressed by cerebellar Purkinje cells in parasagittal bands located medially and in some cells of the cerebellar nuclei. Later, sema-D expression in Purkinje cells broadens such that banded expression is no longer prominent, and expression is detected in progressively more lateral regions. By postnatal day 16, expression is observed throughout the cerebellar mediolateral axis. Collapsin-1 protein, the chick ortholog of sema-D, did not inhibit the extension of neurites from explants of inferior olivary nuclei, the source of climbing fibers that innervate Purkinje cells. In contrast, when it was applied to axons extending from basilar pontine explants, a source of mossy fiber afferents of granule cells, collapsin-1 caused most pontine growth cones to collapse, as evidenced by a reduction in growth cone size of up to 59%. Moreover, 63% of pontine growth cones arrested their extension or retracted. Its effects on mossy fiber extension and its distribution suggest that sema-D prevents mossy fibers from innervating inappropriate cerebellar target regions and cell types.     

HPLC法测定地西泮和艾司唑仑的血药浓度

建立ＨＰＬＣ法同时测定地西泮和艾司唑仑血药浓度。方法：以Ｕｌｔｒａｓｐｈｅｒｅ－ＯＤＳ５μｍ４．６ｍｍ＊２５ｃｍ色谱柱为分离柱,流动相：甲醇－乙腈－水（４０：２０：４０）;检测波长为２５４ｎｍ,以外标法峰面积定量。结论本法可用于血药浓度测定。     

Evaluation design of a reactivation care program to prevent functional loss in hospitalised elderly: A cohort study including a randomised controlled trial

Background

Elderly persons admitted to the hospital are at risk for hospital related functional loss. This evaluation aims to compare the effects of different levels of (integrated) health intervention care programs on preventing hospital related functional loss among elderly patients by comparing a new intervention program to two usual care programs.

Methods/Design

This study will include an effect, process and cost evaluation using a mixed methods design of quantitative and qualitative methods. Three hospitals in the Netherlands with different levels of integrated geriatric health care will be evaluated using a quasi-experimental study design. Data collection on outcomes will take place through a prospective cohort study, which will incorporate a nested randomised controlled trial to evaluate the effects of a stay at the centre for prevention and reactivation for patients with complex problems. The study population will consist of elderly persons (65 years or older) at risk for functional loss who are admitted to one of the three hospitals. Data is prospectively collected at time of hospital admission (T0), three months (T1), and twelve months (T2) after hospital admission. Patient and informal caregiver outcomes (e.g. health related quality of life, activities of daily living, burden of care, (re-) admission in hospital or nursing homes, mortality) as well as process measures (e.g. the cooperation and collaboration of multidisciplinary teams, patient and informal caregiver satisfaction with care) will be measured. A qualitative analysis will determine the fidelity of intervention implementation as well as provide further context and explanation for quantitative outcomes. Finally, costs will be determined from a societal viewpoint to allow for cost effectiveness calculations.

Discussion

It is anticipated that higher levels of integrated hospital health care for at risk elderly will result in prevention of loss of functioning and loss of quality of life after hospital discharge as well as in lower burden of care and higher quality of life for informal caregivers. Ultimately, the results of this study may contribute to the implementation of a national integrated health care program to prevent hospital related functional loss among elderly patients.

Trial registration

The Netherlands National Trial Register: NTR2317     

Dual effect of quercetin on rat isolated portal vein smooth muscle contractility

Summary

This study examined the effects of quercetin on spontaneously contracting portal veins isolated from healthy young adult male and female Wistar rats (250–300 g). Quercetin (10^-7–10^-4 M) always produced significant biphasic effects, comprising an initial brief stimulant effect (rise in basal tone), followed by a sustained, longer-lasting secondary relaxant (inhibitory) effect on the venous tissues. The initial brief contractions of the venous muscle preparations were not modified by preincubation of the tissues with prazosin (10^-6 M), suggesting that the initial upsurge in basal tone and increases in contractile frequencies of the venous tissues were probably not mediated via alpha₁-adrenoceptor stimulation. However, preincubation of the tissues with nifedipine (10^-7 M) significantly suppressed (p < 0.05) or attenuated the initial stimulant effect of quercetin, suggesting that the flavonoid might be activating L-type voltage-dependent calcium channels. The vasorelaxant effect of quercetin was partially but not significantly (p > 0.05) inhibited by L-NAME (100 μM) or indomethacin (10 μM), suggesting that the vasorelaxant effect of the flavonoid was unlikely to be mediated via endothelium-dependent relaxing factor (EDRF), or through prostacyclin (PGI₂) pathways. N-p-tosyl-l-phenylalanine-chloromethyl-ketone (TPCK, 3 μM) significantly (p < 0.01) antagonised quercetin-induced relaxations, suggesting that cAMP-dependent protein kinases might have contributed, at least in part, towards the vasorelaxant effect of quercetin on rat isolated portal veins.     

Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer

BACKGROUND:

Preoperative chemoradiation improves survival in esophageal and gastroesophageal junction (GEJ) cancer. We evaluated irinotecan and cisplatin as induction chemotherapy followed by concurrent chemoradiation in esophageal cancer.

METHODS:

Patients with uT1N1M0 or uT2‐4NanyM0 resectable squamous cancer or adenocarcinoma of the esophagus or GEJ received irinotecan 65 mg/m² and cisplatin 30 mg/m² for 4 treatments in weeks 1 through 5, followed by 4 treatments in weeks 7 through 11 with 50.4 Gy in daily fractions, followed by surgery. The primary endpoint was pathologic complete response (pCR). Positron emission tomography (PET) scan was performed prior to chemotherapy and as restaging prior to radiotherapy.

RESULTS:

Fifty‐five patients were evaluable, 75% of whom had adenocarcinoma and 65% of whom had uT3N1 disease. Thirty‐eight patients underwent R0 resection (69%). The incidence of pCR was 16% (95% confidence interval, 8%‐29%). Median overall survival was 31.7 months. An exploratory analysis of PET response to induction chemotherapy indicated a correlation with pCR (32% vs 4%), R0 resection (84% vs 57%), progression‐free survival (24.1 vs 7.7 months), and overall survival (40.2 vs 25.5 months).

CONCLUSIONS:

Weekly treatment with irinotecan, cisplatin, and radiation achieved results no better and potentially inferior to other phase 2 chemoradiotherapy trials with a low rate of pCR. The use of PET scan after induction chemotherapy to direct chemotherapy during subsequent radiotherapy merits further study. Cancer 2011. © 2011 American Cancer Society.