Nonelectrolyte fluxes across gastric mucosa in relation to gastric stimulation

The effects of histamine and thiocyanate, added to the serosal bathing solution, on unidirectional fluxes of some nonelectrolytes (thiourea, methylated thiourea derivates, mannitol), and on H⁺, pepsinogen and mucous secretion were investigated in frog (Rana esculenta) fundic gastric mucosa. Histamine (10^–4 M) increases significantly the outfluxes (serosa to mucosa fluxes) of only thiourea and its derivates (but not mannitol) and the stimulation is the greater the more lipidsoluble the nonelectrolyte is. Influxes (mucosa to serosa fluxes) of the same molecules are not affected. In parallel histamine stimulates H⁺-secretion but does not modify pepsinogen and mucous secretion.SCN^– (10^–2M) inhibits the histamine effect on thiourea outfluxes and on H⁺-secretion, while pepsinogen and mucous secretion are not affected.Colchicine (10^–4 M) pretreatment inhibits the histamine effect on outfluxes and H⁺-secretion.It is concluded that: (1) histamine induces a secretion of nonelectrolytes towards the lumen; (2) such secretion is correlated with the hormone-induced secretion of HCl and fluid; (3) this process is mediated by an exocytotic mechanism.     

Effects of cytochalasin B and dihydrocytochalasin B on calcium transport by intestinal absorptive cells

Summary In vivo calcium absorption was studied in normal and rachitic chicks. Cytochalasin B (CB) at a concentration of 25 μg/ml added to the medium inside the duodenal lumen inhibited calcium absorption (20 min) from 82.5±1.9% of calcium absorbed in the controls to 59.2±3% in normal and from 70.0±2.3% to 47.0±2.1% in rachitic chicks. In vitro studies by everted ileal sacs of young rabbits also showed an inhibition of active transport of calcium due to CB. Whereas in the controls the ratio of⁴⁵Ca concentrations in serosal and mucosal media (60 min) was 7.2±0.32, the ratios were 5.24±0.52; 4.40±0.36; 3.40±0.42; 5.77±0.52; 1.38±0.08; and 1.06±0.02 in the presence of CB at concentrations of 5, 10 and 25 μg/ml; colchicine 10⁻⁴M, Na citrate 0.02M, and heat-devitalized conditions, respectively.⁴⁵Ca concentration in the mucosal scrapings was also affected. It showed an increase from controls (15,101±404 cpm/mg) and correlated with CB concentration: 17,378±489, 19,015±1000, and 20,201±362 at 5, 10, and 25 μg/ml, respectively. Dihydrocytochalasin B also inhibited active calcium transport and caused an increase in⁴⁵Ca concentration in the mucosal scrapings. Correlated electron microscopic studies showed certain changes in the brush border, especially in some actin microfilaments in the terminal web region. It seems that these morphological alterations may be related to transcytoplasmic movement of calcium.     

Spread of herpes simplex virus in peripheral nerves

Summary Suckling mice were inoculated intradermally with herpes simplex virus into the sole of the hind foot. Titrations for infective virus from different levels of the sciatic nerve, dorsal ganglia, and spinal cord showed that virus was already present in the spinal cord two days after inoculation, and before virus could be recovered from the examined levels of the sciatic nerve. Ligatures, freezing, and local treatment with colchicine of the sciatic nerve could prevent the spread of infection. The ultrastructural features of nerves soaked with mitosis inhibitors are described. Extensive changes with ultimate collapse of axons and disintegration of myelin sheaths were found, while the Schwann cells showed no obvious degenerative changes and the endoneurial spaces were wide. It is considered that the infectious agent travels inside the axons to the CNS, and that a spread of virus in endoneurial spaces or by propagation in Schwann cells, as recently has been suggested, is of minor importance. The study seems to provide evidence that inside the axons a transport of materials directed disto-proximally all the way to the nerve cell body exists.This study was supported by grants B 70-12X-82-06, B 70-13X-2226-04 B and B 70-14X-2728-02B from the Swedish Medical Research Council.     

Ultrastructural changes induced in the rat retina by treatment with colchicine

Colchicine, 0.05 g to 10 g dissolved in 1 l water, was injected in the vitreous body in the eye of adult albino rats. The animals were fixed by perfusion via the aorta or by immersion at varying time intervals and examined by electron microscopy.Ultrastructural changes were observed within a few hours after intraocular injection of 0.2 g colchicine. All the different types of retinal cells showed a common main mode of reaction. The nucleolus appeared to increase in size and density during the first days. The chromatine became dispersed and the components in the nucleus increased. Rodlets of 70 Å filaments appeared in an increased number of the nuclei of the neuroectodermal cells. The number of cell organelles increased i.e. mitochondria, lysosomes, ribosomes arranged as polyribosomes, in the vicinity of the nuclear infoldings. The profiles of the endoplasmic reticulum became short and tubulo-saccular. The number of filaments increased only in those cells which normally are rich in that structure.The retinal nerve cells in the ganglion cell layer and inner nuclear layer showed signs of disintegration of their Nissl substance but no proliferation of filaments. No apparent changes were observed with regard to the neurotubuli in these neurons. Many synaptic bodies degenerated and several nerve cell processes were retracted. There was an accumulation of especially synaptic vesicles in the distended terminals.The inner segments of the photoreceptor cells were retracted and became filled with amorphous material. The outer segments decreased gradually in length during the first week and only a rudiment remained thereafter. The Müller neuroglial cells showed a marked increase in the number of filaments and a slight of the tubuli.The ultrastructural findings are discussed especially with respect to the mechanisms of intracellular transport. It is proposed that the heavy increase in the number of filaments in nerve cells in certain regions of the nervous system does reflect an inbalance between formation and intracellular transport of filaments. The possibility is discussed that colchicine inhibits not only the cytoplasmic but also the intranuclear transport of cell constituents.This study was supported by grants from the Swedish Medical Research Council (B71-12X-2543-03 and B71-13X-2226-05) and Riksföreningen mot Cancer (265-B70-02X).     

不同基质和透皮促进剂对秋水仙碱凝胶剂体外透皮特性的影响

目的优选秋水仙碱凝胶剂基质和相应的透皮促进剂,为制备秋水仙碱透皮给药新制剂提供参考资料。方法采用改良的Franz扩散池法,并通过RP-HPLC法测定接收液中秋水仙碱的含量。结果3种基质的秋水仙碱凝胶体外透皮比率为Carbopol基质凝胶>HPMC基质凝胶>CMC-Na基质凝胶。以Carbopol为基质,加入几种透皮促进剂后,秋水仙碱凝胶的体外透皮速率为丙二醇>冰片>氮酮>薄荷油。结论凝胶剂作为秋水仙碱透皮吸收新剂型可行。     

Colchicine in experimental alkaline burns of the rat esophagus: an old drug, a new indication?

Aim: An experimental study was performed to investigate the efficacy of colchicine in the prevention of fibrosis in the alkaline burn of the esophagus in rats. Method: A standard esophageal alkaline burn was produced by the application of 37.5% NaOH for a period of 90 s to the distal esophagus followed by a water rinse. The experiments were conducted twice with two different dosages of colchicine. In the first experiment, colchicine 1 mg/kg (i.p.) was applied once, on the first day. Group A (n:8), the sham laparotomy group; group B (n:8), the untreated group (positive control group); Group C (n:16), where the standard esophageal burn was induced and colchicine applied at a dose of 1 mg/kg i.p. in 1 ml volume, and group D (n:14), where the rats did not have any operation, but were treated with colchicine (1 mg/kg, i.p.) as in group C. In the second experiment, colchicine was applied at repeated doses of 100 μg/kg (i.p.) on the first, 7th, 14th, and 21st days. Twenty-five rats were divided into groups. Group AA (n:8), the sham laparotomy group; group BB (n:9), the untreated group (positive control group); and group CC (n:8), where the standard esophageal burn was induced and colchicine was applied at repeated doses. All the rats were killed on the 28th day and evaluated for esophageal tissue hydroxyproline content and histopathologic damage score. Results: Colchicine treatment at a dose of 1 mg/kg significantly reduced the quantity of hydroxyproline in the esophageal tissue in groups C and D compared with the positive control group B (P<0.05). However, it is associated with a mortality rate of 60%. Colchicine at repeated doses of 100 μg/kg showed no significant effect in group CC compared to the untreated group BB and in the quantity tissue of hydroxyproline content (P>0.05). Conclusion: At non-toxic doses, colchicine was not effective in the treatment of alkaline esophageal burn in rats. Colchicine-like molecules with less adverse effects or colchicine itself in titrated doses may be hopeful in preventing the development of fibrosis in the alkaline burns of the esophagus.     

小剂量秋水仙碱与吲哚美辛联合中药方剂治疗风湿热痹型痛风性关节炎的疗效观察

目的:探讨小剂量秋水仙碱与吲哚美辛联合中药方剂治疗风湿热痹型痛风性关节炎的临床疗效。方法:以2018年10月至2019年9月在解放军桂林康复疗养中心门诊就诊的风湿热痹型痛风性关节炎患者120例作为研究对象,按照数字表法随机分为研究组和对照组,两组均为60例。研究组患者给予小剂量秋水仙碱与吲哚美辛联合中药方剂治疗,对照组患者给予常规剂量秋水仙碱与吲哚美辛治疗。对比两组患者的总体疗效、血尿指标[血清尿酸(UA)、血清C反应蛋白(CRP)及尿比重]水平及不良反应发生情况。结果:研究组患者的总有效率为76.7%(46/60),与对照组的51.7%(31/60)比较,差异有统计学意义(χ²=10.00,P<0.05)。治疗后,两组患者各项血尿指标均有不同程度的好转,但相比之下,研究组患者UA、CRP及尿比重的恢复情况明显优于对照组,差异均有统计学意义(P<0.05)。两组患者在治疗过程中均未出现严重不良反应。结论:对风湿热痹型痛风性关节炎患者给予小剂量秋水仙碱与吲哚美辛联合中药方剂治疗具有明显优势,疗效显著,值得进一步研究。     

Management of complex gout in clinical practice: Update on therapeutic approaches

Increasing therapeutic options are available for gout management. Anti-inflammatory agents are used in the acute management of gout flares, and interleukin-1 inhibitors are effective for those unable to take conventional anti-inflammatory treatments. Lowering of serum urate remains the cornerstone of effective long-term management. Allopurinol is the first-line urate-lowering therapy, and a gradual dose-escalation strategy to serum urate target is recommended. Febuxostat and lesinurad have been approved more recently. In a large cardiovascular outcomes trial, higher all-cause and cardiovascular mortality was observed with febuxostat than with allopurinol. Lesinurad should be co-prescribed with a xanthine oxidase inhibitor, and close monitoring of kidney function is required. Evidence for non-pharmacological management is limited, but personalised lifestyle modification may reduce associated cardiovascular risk. In this review, we discuss current principles in the gout management paradigm, consider strategies for managing complex, clinical scenarios, and review emerging therapies.