Doxycycline reduces plasma VEGF-c/sVEGFR-3 and improves pathology in lymphatic filariasis
Doxycycline reduces plasma VEGF-c/sVEGFR-3 and improves pathology in lymphatic filariasis
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DOI：
10.1371/journal.ppat.0020092
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发表时间：
2006-09-01
期刊：
影响因子：
6.7
通讯作者：
Hoerauf, Achim
中科院分区：
文献类型：
--
作者：
Debrah, Alexander Yaw;Mand, Sabine;Hoerauf, Achim
淋巴丝虫病是热带地区一种具有相当大社会经济负担的疾病。目前使用的抗丝虫病药物能够有力地减少传播，从而最终将降低与感染相关的发病率负担，然而，直接导致已经感染的个人的发病率停止或改善的化疗原则将是主要的先导。为了寻找这样一种更有效的药物来补充现有的药物，在加纳班克罗夫斯坦丝虫病流行的地区，33名微丝虫病患者和18名淋巴水肿症患者参加了一项为期6周的双盲安慰剂对照试验，剂量为200毫克/天。多西环素治疗4个月后，所有患者均给予伊维菌素150~200 mg/kg和阿苯达唑400 mg。监测患者的沃尔巴克氏菌和微丝虫载量、抗原血症、丝虫舞动征、睾丸上淋巴管扩张和血浆淋巴管生成因子水平(血管内皮生长因子-C和可溶性血管内皮生长因子受体-3[(S)血管内皮生长因子受体-3])。淋巴水肿患者还被监测淋巴水肿的分期(分级)和患肢的周长。与安慰剂组相比，服用多西环素治疗24个月的微丝虫病患者沃尔巴克氏菌载量、微丝虫病、抗原血症和FDS频率显著降低。在服用多西环素的患者中，睾丸上淋巴管的平均扩张在24个月时显著减少，而安慰剂组没有改善。在临床改善之前，在12个月时，服用多西环素的患者的平均血浆VEGF-C和sVEGFR-3水平显著下降，接近地方性正常值，而安慰剂患者的水平没有明显下降。经多西环素治疗后，淋巴水肿患者的病情明显改善，治疗12个月后，接受多西环素治疗的患者的平均淋巴水肿期明显低于安慰剂患者。分期减少表现为皮肤质地较好，深层皱纹减少，深层皱纹较少。综上所述，多西环素抗班氏丝虫病6wk方案显示出较强的大丝虫杀灭活性和血浆中VEGF-C/sVEGFR-3水平的降低，后者与改善睾丸上扩张的淋巴管和改善淋巴丝虫病患者的病理有关。
Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150 -200 mu g/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogenic factors (vascular endothelial growth factor-C [VEGF-C] and soluble vascular endothelial growth factor receptor-3 [(s) VEGFR-3]). Lymphedema patients were additionally monitored for stage (grade) of lymphedema and the circumferences of affected legs. Wolbachia load, microfilaremia, antigenemia, and frequency of FDS were significantly reduced in microfilaremic patients up to 24 mo in the doxycycline group compared to the placebo group. The mean dilation of supratesticular lymphatic vessels in doxycycline-treated patients was reduced significantly at 24 mo, whereas there was no improvement in the placebo group. Preceding clinical improvement, at 12 mo, the mean plasma levels of VEGF-C and sVEGFR-3 decreased significantly in the doxycycline-treated patients to a level close to that of endemic normal values, whereas there was no significant reduction in the placebo patients. The extent of disease in lymphedema patients significantly improved following doxycycline, with the mean stage of lymphedema in the doxycycline-treated patients being significantly lower compared to placebo patients 12 mo after treatment. The reduction in the stages manifested as better skin texture, a reduction of deep folds, and fewer deep skin folds. In conclusion, a 6-wk regimen of antifilarial treatment with doxycycline against W. bancrofti showed a strong macrofilaricidal activity and reduction in plasma levels of VEGF-C/sVEGFR-3, the latter being associated with amelioration of supratesticular dilated lymphatic vessels and with an improvement of pathology in lymphatic filariasis patients.