何首乌致药物性肝损伤的病理学特点

目的了解何首乌致药物性肝损伤(Polygonum multiflorum-associated drug induce liver injury,PM-DILI)的临床病理学特点。方法收集2019年3月1日至2021年3月1日深圳市第三人民医院收治的8例PM-DILI患者临床资料。肝穿组织进行苏木素-伊红染色、网状纤维染色、Masson三色染色、铁、铜特殊染色和免疫组织化学染色,显微镜下观察分析。结果8例PM-DILI患者男女比为1∶1,平均年龄43岁,其中6例为急性PM-DILI,2例慢性为PM-DILI。入院血清学检查异常主要包括转氨酶升高和淤胆均为7例。主要组织病理学改变为点灶状坏死8例、界面炎5例、融合坏死4例,融合坏死以肝腺泡3带为主,不伴或伴少数炎细胞浸润;胆汁淤积5例,为肝腺泡3带的肝细胞、毛细胆管内淤胆,不伴或伴少数炎细胞浸润;中央静脉炎3例;病程长者可发生肝纤维化,甚至肝硬化2例。结论肝腺泡3带为主的急性淤胆和肝细胞坏死是PM-DILI主要组织学表现,严重者可发生静脉炎等血管损伤。     

Open, Double-Blind and Long-Term Study of Vigabatrin in Chronic Epilepsy

We performed an open, double-blind, and long-term study of vigabatrin (gamma-vinyl-GABA, GVG) in patients with treatment-resistant epilepsy who were receiving only one or at most two standard antiepileptic drugs (AEDs). The novel design included a parallel, double-blind, placebo-controlled phase that minimized the number of patients receiving placebo and allowed determination of the optimum dose of GVG for each patient before initiation of the double-blind phase. The study was divided into four phases. The first phase was a 6-week period of baseline observation. In the second phase, GVG was added openly to previous AEDs for 8 weeks. During the first 2 weeks of this phase, the dose of GVG was increased weekly and then, in the absence of adverse effects, was held constant for the next 6 weeks. At the end of this open phase, seizure frequency during the 6 weeks of constant treatment was compared with the baseline seizure frequency for each patient. Patients who experienced reduction greater than 50% in the frequency of any seizure type during the open phase were defined as responders. These responders were then entered into the third and double-blind phase, in which they were randomly allocated wither to continue active GVG treatment or placebo for 8 weeks. Thirty-three patients entered the study; 31 of 33 patients completed the initial open phase. Twenty patients achieved a reduction greater than or equal to 50% in the frequency of one or more seizure types and were eligible for the double-blind phase; 10 were randomized to continue GVG and 10 were randomized to placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of drug-induced hematotoxicity: from in vivo to in vitro assessment

As part of the early preclinical development of a new antipsychotic compound, Wistar rats of both sexes were dosed orally for upto 7 days. At high doses, expected changes in appearance and behavior, decreases in bodyweight gain and feed intake but also a fluid and pale bone marrow (BM) were observed. Blood cell counts were normal as were clinical chemical values. BM sections showed a red cell hypoplasia. Circulating reticulocytes and erythroblasts on BM smears were decreased suggesting that the compound might have a selective toxicity for the erythroid lineage. In a mechanistic experiment, rats were dosed for 9 days and phlebotomized after 7 days of exposure to stimulate erythroid regeneration. Red-blood cell mass, reticulocytes and erythropoietin (EPO) levels were monitored before and upto 48 h after bleeding. Results showed that an EPO-mediated pathogenesis could be excluded. The effect of the drug on the formation of Colony-forming units (CFU)-E and CFU-GM was then quantitatively measured in vitro after direct exposure to the compound. In two successive assays, rat or human BM cells were incubated with the drug dissolved in the collection medium at final concentrations of 0.3×10^–7 –3×10^–5 M. In the presence of adequate growth factors, CFU-E and CFU-GM were cultured and cell proliferation was compared between treated and control groups. Our results showed an expected inhibition by the drug of the growth of erythroid progenitors associated to a similar effect on myeloid progenitors. The CFU-E and CFU-GM of both human and rat sources were totally inhibited from the concentration of 3×10^–5 M. The IC₅₀ values were consistent with rat peak plasma levels reached in vivo by the drug. Therefore, the short-term cloning assays performed on rat BM cells were sensitive indicators of the hematotoxicity of the compound and were considered as predictive for human toxicity.     

Reproductive Function in Epilepsy

Summary: : The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.     

Directional running in mice: effects of cocaine and chlorpromazine

Mice ran in a circular runway. Some received milk at every third circuit in a designated direction, clockwise or counterclockwise, in daily 1000-s sessions. Under control conditions, about 10 times as many circuits were made in the reinforced direction as in the non-reinforced direction. Cocaine (10, 30, 100 µM/kg) had little effect on the total number of circuits, but progressively increased the number in the non-reinforced direction. Chlorpromazine (1, 3, 10, 30 µM/kg) caused a monotonic decrease in total number of circuits and in number in non-reinforced direction. At the highest doses the proportion in the non-reinforced direction was increased. Mice, untrained in the runway and with no reinforcement of circuits in either direction, made many fewer total circuits than when running was reinforced and about equal numbers were in clockwise and in counterclockwise directions. Cocaine greatly increased the total number of circuits. As in the subjects whose running was reinforced, cocaine led to a much higher tendency for mice to run in a single direction. The similarities between the tendency to run in one direction after cocaine and the rotational behavior of rodents seen after cocaine and amphetamine suggest a common mechanism.     

Flow cytometry analysis of platelet antibodies

We have devised assays to detect both circulating alloantibodies to platelets (indirect assay) and platelet-association IgG and IgM (direct assay) using a flow cytometric technique. A variety of patients with immune thrombocytopenia were studied. Employment of a confocal lens in the flow cytometer increased the discrimination power of the instrument. Patients with autoimmune thrombocytopenia (idiopathic thrombocytic purpura [ITP], systemic lupus erythematosus (SLE), lymphoma, leukemia, and drug-induced thrombocytopenia showed a significant increase in platelet-associated antibody. Circulating antibodies to platelets (alloantibodies) were demonstrated in cases of platelet refractoriness and neonatal isoimmune purpura. Day-today precision of the assays ranged from 3% to 6% (coefficient of variation). No interference was shown in the presence of hemoglobin (5 g/L), triglycerides (10 g/L), or polyclonal and monoclonal immunoglobulinemia (50 g/L: IgG, IgA, IgM). The sensitivity of the direct assay was 500 attograms of IgG or IgM platelet.