Brain uptake of radiolabeled N‐oleoyl‐dopamine in the rat

N‐acyl‐dopamines are a novel class of biologically active lipids that have recently been identified in the brain and have the potential to interact with neural signaling pathways. This study seeks to determine the ability of N‐oleoyl‐dopamine, a synthetic amide of oleic acid and dopamine, to cross the blood brain barrier. We determined the tissue content of radioactivity in selected brain regions, in a short‐run study design, following injections of [³H]N‐oleoyl‐dopamine (0.4 µCi) into the internal carotid artery in the rat. These results were compared with intracarotid injections of [³H]dopamine and with intravenous injections of both radiolabeled compounds. The level of radioactivity was determined using liquid scintillation and was expressed as the percentage of its total dose injected per gram of tissue. We found that the 15‐min brain uptake of radioactivity, with no distinct regional variations, amounted to about 6% following the intracarotid [³H]N‐oleoyl‐dopamine, which was a significant 3–4‐fold increase over that following similar administration of [³H]dopamine. Intravenous injections of [³H]N‐oleoyl‐dopamine gave a much smaller yield of radioactivity in brain tissue samples which was still severalfold greater than that for intravenous [³H]dopamine. Qualitative thin‐layered chromatography screening showed the presence of unchanged N‐oleoyl‐dopamine in the brain following injections. We conclude that N‐oleoyl‐dopamine has an appreciable ability to cross the blood‐brain barrier, which contrasts the limited transfer of dopamine alone. N‐oleoyl‐dopamine might exert physiological effects due to its known affinity for the central vanilloid receptors or to better satisfying the brain tissue demand for dopamine. The study suggests a potential pharmacological role for N‐oleoyl‐dopamine delivered exogenously in helping regulate the brain function. Drug Dev. Res. 60:217–224, 2003. © 2003 Wiley‐Liss, Inc.     

The influence of erythropoietin on cytokines in haemodialysis patients

Summary: In this study, the administration of erythropoietin to haemodialysis patients revealed its immunomodulating properties. to dissociate the immunological effects of erythropoietin action from its haematological effects the patients in our study were administered recombinant human erythropoietin (rhEpo) at the doses that would not affect erythropoiesis. After baseline data had been obtained, six haemodialysis patients were given rhEpo (Eprex-Cilag) at the dose 7-10 U/kg bodyweight/s.c., three times a week, for 12 weeks. All patients maintained a stable haemoglobin concentration; no blood transfusions were required. Serum levels of tumour necrosis factor (TNF), IL-2 and IL-6 levels of the study patients and the four control patients, not receiving rhEpo, were monitored every 2 weeks. the levels of IL-6 and TNF remained unchanged; however, a low serum level of IL-2, recorded before therapy, increased gradually for 10 weeks until it reached the values observed in normal healthy humans (P<0.01). After that it dropped to the initial values. During the study the red blood cell numbers did not change. This study supports the thesis that erythropoietin administered to haemodialysis patients not only corrects anaemia but also independently modulates immunological response.     

A retrospective comparative study of surgery followed by chemotherapy vs. non-surgical management in limited-disease small cell lung cancer.

OBJECTIVE: The role of surgery in limited SCLC is still a matter of controversy. Even though the response rates to chemotherapy are very high, prognosis of SCLC patients has remained poor with a median survival of only 12-14 months for limited disease. High incidence of local relapses after chemotherapy in limited-stage SCLC led to reassessment of the role of local treatment in the multimodality management of this tumor. METHODS: We performed retrospective comparative analysis of survival in a series of 134 limited-stage SCLC patients treated between 1984 and 1996 with either complete resection followed by chemotherapy (67 patients), or with conventional non-surgical management (67 patients). In all patients who underwent resection, the diagnosis of SCLC was established only postoperatively. The control (non-surgical) group was selected using 'pair-matched case-control' methodology, out of 176 limited-stage patients potentially suitable for surgery (i.e. with no pleural effusion or other local advancement, no supraclavicular lymph node involvement and good performance status), but treated without resection. The major prognostic factors were well balanced between these two groups. Total series included 109 males and 25 females, 20 patients with T1 and 114 patients with T2 disease, 51 N0, 43 N1 and 40 N2 disease. RESULTS: Median survival in patients treated with and without surgery was 22 months and 11 months, respectively, (P < 0.001). The two-year and five-year survival probabilities were 43 and 27%, respectively, in the surgical group, and 17 and 4%, respectively, in the non-surgical group. Subset analysis confirmed significantly longer survival with surgery in all T and N categories, except for N2 disease. Local relapse occurred in 15 and 55% of patients treated with and without surgery, respectively, (P < 0.001). Distant relapse probabilities were similar in both groups (36 and 40%, respectively). The most common site of metastases in the entire series was brain, followed by liver, lymph nodes, bone, lung and skin. CONCLUSIONS: Our results suggest a possible role of surgery in limited-stage SCLC. Thus, a randomised study addressing this issue seems to be justified.     

Utilization of a sol-gel method for encapsulation of doxorubicin

The sol-gel pre-doping method was used to encapsulate doxorubicin in silica gels and optimum conditions of preparation of drug-loaded gel were established, ensuring both reproducible and effective results of quantitative encapsulation of doxorubicin and its gradual but complete release. Doxorubicin was encapsulated in polysiloxane polymers using the method based on sol-gel encapsulation without a catalyst, with an acid catalyst (HCl) and a base catalyst (NH3). The time of gelation of the gel loaded with doxorubicin, encapsulation efficiency of the drug and the degree of release of the drug from the gel are all affected by the kind of catalyst (acidic or basic) or its absence at the gel preparation stage, and the temperature of the gelation process. The time of sol gelation when using the NH3 or HCl catalyst was 9 days at 21 degrees C, 2 days at 30 degrees C and 1.5 days at 37 degrees C, while for the gel prepared without a catalyst it was 90 days at 21 degrees C, 75 days at 30 degrees C and 70 days at 37 degrees C. The efficiency of doxorubicin encapsulation was 99.5 +/- 0.5% (w/w) for acid-catalyzed gel, 98.9 +/- 1.01% (w/w) for base-catalyzed gel and 86.4 +/- 11.6% (w/w) for non-catalyzed gel. A 100% (w/w) release of doxorubicin by diffusion through pores was found only in the case of base-catalyzed gel after a 140-h incubation time. For acid-catalyzed gel and non-catalyzed gel, the total amounts of released doxorubicin after 140 h of incubation were 3-5% (w/w) and 9-11% (w/w), respectively. The stability of doxorubicin encapsulated in the three kinds of gel matrices was found to be improved compared to the stability of a free form of the drug in solution.     

Alternating copolymerization of carbon dioxide and propylene oxide in the presence of organometallic catalysts

Carbon dioxide and propylene oxide (PO) were copolymerized using diethylzinc in addition with benzenedi- and triols, aliphatic diols and triols, and aminophenols as catalyst systems. A large amount of CO₂/PO alternating copolymer, {poly(propylene carbonate), poly(oxycarbonyloxypropylene), of high molecular weight was obtained using the homogeneous (C₂H₅)₂Zn/pyrogallol (2:1 by mole) system ( 1 ). The (C₂H₅)₂Zn/o-aminophenol system ( 2 ) (also homogeneous) appeared to be much less active in the copolymerization of CO₂ with PO than the former one. From the other studied systems, that appeared to be heterogeneous, (C₂H₅)₂Zn/resorcinol (1:1 by mole) was the most active one, but less active than the system 1 . Further, the copolymerization of CO₂ and PO was studied in the presence of the (C₂H₅)₂Zn/resorcinol (1:1 by mole) system at various temperatures and in reaction media of different basicity. On the basis of the obtained results of the copolymerization of CO₂ with PO and of measurements of the quantity of ethane evolved in the reactions between the catalytic systems' components, structures of several catalysts, particularly homogeneous ones, are suggested and some aspects of the copolymerization mechanism are discussed.     

Nasal versus bronchial and nasal response to oral aspirin challenge: Clinical and biochemical differences between patients with aspirin-induced asthma/rhinitis

BACKGROUND: Aspirin-induced asthma/rhinitis (AIAR) is characterized by the altered metabolism of leukotrienes and proinflammatory prostaglandins. The basal and postchallenge levels of eicosanoids might reflect the clinical and biochemical characteristics of patients with distinct types of hypersensitive responses to aspirin. OBJECTIVE: We compared clinical and eicosanoid profiles of patients with AIAR showing both bronchial and nasal versus isolated nasal responses to aspirin challenge. METHODS: Twenty-three patients with AIAR underwent the single-blind, oral, placebo-controlled aspirin challenge. The bronchial response (BR) was evidenced by dyspnea and spirometry, whereas the nasal response (NR) was evidenced by nasal symptoms and acoustic rhinometry and/or rhinomanometry. Urinary leukotriene E4 (uLTE4), serum and urinary stable prostaglandin D2 metabolite, and 9alpha,11beta-prostaglandin F2 (9alpha,11beta-PGF2), were determined at baseline and after the aspirin challenge. RESULTS: Fifteen subjects showed BR and NR (BNR), whereas 8 showed NR only. Basal uLTE4 in the BNR group was significantly higher than in the NR group. After aspirin challenge, it increased significantly in both groups. Serum 9alpha,11beta-PGF2 increased after aspirin challenge in the BNR group only. The patients with BNR had more severe AIAR. CONCLUSIONS: BNR to aspirin in AIAR indicates a more advanced disease and more profound underlying eicosanoid metabolism disturbances.     

Increase of interleukin 6 and decrease of interleukin 2 production during the ageing process are influenced by the health status

The ageing process is accompanied by the disregulation of interleukin 2 (IL2) and interleukin 6 (IL6) production. In our paper, we asked whether the age between 60 and 70 years is a turning point for the disregulation of both IL2 and IL6 production. Fifty volunteers 60–70 years old, 25 aged 36–59, and 50 of 20–35 years old were enrolled into the study. Their health status was graded according to the criteria of the Senieur Protocol (SP) as ‘healthy' and ‘almost-healthy'. The cytokines level was determined in the sera of the volunteers. Moreover, the spontaneous release of IL6 by peripheral blood mononuclear cells (PBMC) and the activity of the IL6 gene in non-stimulated PBMC were also analysed. Cytokine levels were measured by biological assays, mRNA for IL6 was detected by RT-PCR method. The results showed that the production of IL2 is not disregulated in the ‘healthy' people until the age of 60–70. People not fulfilling all SP criteria are characterised by a lower level of IL2 in the sera. The overproduction of IL6 into the sera and supernatants from non-stimulated PBMC and PBL as well as the activation of IL6 gene start between the ages 36 and 59 and is more pronounced in the ‘almost-healthy'.     

Anionic polymerization of exo-3,4,5-trithiatetracyclo[5.5.1.O2,6.O8,12]tridec-10-ene (dicyclopentadiene trisulfide)

The anionic polymerization of exo-3,4,5-trithiatetracyclo[5.5.1.O^2,6.O^8,12]tridec-10-ene ( 1 ) in bulk and/or in aromatic solvents (benzene, toluene) was studied. The polymerization was initiated with sodium benzenethiolate (sodium cation complexed with dibenzo-18-crown-6). Polymers with high-molecular weights were obtained (M _n ≈ 10⁵, osmometrically). The polymerization was found to be living and reversible; the equilibrium monomer concentration increases with the temperature. The ceilling temperature was estimated as 167°C. The thermodynamic data of the polymerization in toluene was determined and compared with those of the polymerization of exo-3,4,5-trithiatricyclo[5.2.O^2,6]decane. The standard enthalpy ΔH = ?(6,6 ± 0,6)kJ · mol ¹ and entropy ΔS = ?(29,3 ± 2,1)J · mol ¹ · K ¹ of the polymerization of 1 were evaluated from the temperature dependence of the equilibrium monomer concentration, determined dilatometrically.     

The soluble tumor necrosis factor receptor I is an early predictor of local infective complications after colorectal surgery

The clinical implications of increased cytokine levels after major surgery remain unclear. In this study, systemic concentration of a spectrum of cytokines, including interleukins IL-6, IL-8, IL-10, IL-1ra, and soluble tumor necrosis factor receptor-I (sTNF-RI) was examined in patients with and without postoperative septic complications following colorectal surgery. Although there were no significant changes in IL-1, TNF-, and IL-8 serum levels during the observation period, there was a significant rise in IL-6, IL-1ra, and sTNF-RI concentrations in the entire group of patients between postoperative day 1 and 14. There were no differences between the group without and with local complications when IL-6, IL-1ra, and IL-10 were examined. The serum levels of sTNF-RI, IL-1ra, and IL-6 were found to be sensitive indicators of the pro- and anti-inflammatory response to the surgical trauma, but only sTNF-RI turned out to be a sensitive early marker of local septic postoperative complications in patients with colorectal carcinoma.