平律复方对大鼠心肌缺血-再灌注心律失常的影响

目的研究平律复方对大鼠心肌缺血-再灌注心律失常的影响。方法采用结扎冠状动脉左前降支15m in,再灌注45 m in造成大鼠心肌缺血-再灌注模型,监测标准Ⅱ导联心电图变化,测定心肌细胞膜C a2 -ATP酶、M g2 -ATP酶及N a ,K -ATP酶的活力,采用RP-HPLC法检测心肌组织ATP水平、腺苷酸池(TAN)水平和能量负荷值(EC)。结果平律复方(ig,0.04、0.20、1.00 g/kg)能有效降低大鼠心肌缺血-再灌注心律失常的发生率,显著缩短室性心律失常的持续时间;能对抗缺血-再灌注心肌ATP酶活力的异常变化;各剂量组心肌组织ATP水平恢复为正常对照组的58%、68%和86%,TAN水平和EC值比模型对照组分别增加了25%、49%、66%和24%、27%、29%。结论平律复方具有抗大鼠心肌缺血-再灌注心律失常的作用,其机制可能与改善心肌组织的能量代谢有关。     

Lipidic prodrug approach for improved oral drug delivery and therapy

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.     

μ-Opioid receptor activation enhances DNA synthesis in immature oligodendrocytes

Opioids disrupt nervous system development by inhibiting the proliferation of neuronal and glial progenitors. These studies explored the hypothesis that μ opioid receptors are expressed by immature oligodendrocytes (OLs) and are functionally related to growth. Antibodies identifying the cloned μ opioid receptor demonstrated that cultured OLs expressed μ opioid receptor immunoreactivity very early during development. Cultures were treated with the selective μ opioid receptor agonist H-Tyr-Pro-Phe (N-Me)- -Pro-NH₂ (PL017; 1 μM), or PL017 (1 μM) plus the antagonist naloxone (3 μM). Opioid-dependent changes in DNA synthesis were assessed by determining the proportion of bromodeoxyuridine (BrdU)-labeled O4-immunoreactive OLs. Treatment with PL017 caused a 311% increase in the proportion of O4-immunoreactive OLs incorporating BrdU compared to untreated controls, and these effects were prevented by co-administering naloxone. These preliminary results indicate that (i) immature OLs express μ opioid receptors and that (ii) the activation of this receptor type is functionally coupled to DNA synthesis and the cell division cycle. The expression of opioid receptors by OLs suggests that the endogenous opioid system is widely distributed among glial types.     

Lymphocyte blast transformation responses and viral antibodies in relation to HLA antigens in multiple sclerosis

Fifty four clinically stable multiple sclerosis (MS) patients and 54 age- and sex-matched control subjects were HLA-typed, and their responses to herpes simplex, measles, mumps and rubella antigens were examined by the lymphocyte blast transformation test and by serum antibody titrations. Blast transformation response to purified tuberculin (PPD), mitogen phytohaemagglutinin (PHA), pokeweed mitogen (PWN) and concanavalin A (Con A) and spontaneous proliferation of lymphocytes were also studied. MS patients differed from controls by higher antibody levels to measles and rubella viruses and by lower specific blast transformation responses to rubella and measles antigens. When the relative strength of transformation responses was measured, mumps and herpes simplex responses were also lower in MS patients than in controls. In addition, spontaneous lymphocyte proliferation of MS patients in 6-day cultures was lower than that of control lymphocytes. In mitogen stimulations there were no differences between whole groups, but the oldest patients had lower responses to PHA and Con A than their matched controls. The frequency of HLA-Dw2 was 56.6% in MS patients and 32.1% in controls. The patients with and without Dw2 differed from each other only by a lower specific response to PPD in the Dw2-positive group. The immunological response of Dw2-positive controls resembled that of MS patients: low transformation response to viral antigens, low spontaneous proliferation and elevated measles antibodies. This finding supports the function of a genetically determined type of immune responsiveness with low cell-mediated immunity and high levels of certain viral antibodies as one susceptibility factor in multiple sclerosis.     

Chlorphentermine uptake by rabbit lung slices

Slices of rabbit lung tissue (～ 150 mg; 0.5 mm) were incubated in 5 ml of Krebs-Ringer phosphate buffer, in the presence of 0.25 mM [¹⁴C] chlorphentermine (CP) with shaking at 37°C and under an atmosphere of an O₂/CO₂ mixture (95 : 5). Incubation medium (M) and tissue (T)_were analyzed for radioactivity. Uptake of CP reached a plateau after 30 min at a T/M ratio of 20. Upon varying the concentration of [¹⁴C] CP from 0.125 mM to 2 mM, the concentration-response curve was seen to saturate and the T/M ratio decreased with increasing concentration. Substituting LiCl for NaCl or increasing the K⁺ content in the medium decreased CP uptake. Incubation of slices with Na⁺-pump inhibitors, harmaline and iodoacetate, significantly decreased CP uptake. Chloroamphetamine, desimipramine, imipramine, morphine, chlorpromazine, dieldrin, methadone, amphetamine (each at 1 mM) and incubation at 10°C inhibited CP uptake. Imipramine and amphetamine were both effective in displacing previously accumulated CP from the tissue slices. Efflux of CP from the lung slices was biphasic and was not affected by removal of Na⁺ from the medium. Binding of CP to lung homogenate was unaffected by substituting LiCl for NaCl or by the presence of 1 mM iodoacetate. However, 1 mM harmaline or 1 mM imipramine decreased CP binding. These studies offer evidence for a partially Na⁺-dependent, active uptake process for pulmonary sequestration of CP compatible with earlier findings obtained with perfused intact lung preparations.