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Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis
- Source :
- PLoS Pathogens, Vol 2, Iss 9, p e92 (2006), Scopus-Elsevier, PLoS Pathogens, PLOS PATHOGENS
- Publication Year :
- 2006
- Publisher :
- Public Library of Science (PLoS), 2006.
-
Abstract
- 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 μg/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.<br />Synopsis Lymphatic filariasis, caused by filarial worms, is transmitted by mosquitoes. The infection leads to pathology such as edema of the legs (lymphedema) or the scrotum (hydrocele). About 120 million people are estimated to be infected, and 1.2 billion are at risk of infection. The currently used drugs (diethylcarbamazine [DEC] or ivermectin plus albendazole) to treat the disease are able to kill most of the larval stage (microfilariae) in the blood but have either no (ivermectin) or partial (DEC) effect on the adult worms that cause the pathology. They also do not sufficiently halt the progression of pathology, such as, lymph vessel dilation, hydrocele, and lymphedema. In search of a more effective drug capable of killing the adult worms, and also of halting the progression of the disease in already infected individuals, the authors recruited, in an endemic area in Ghana, 33 people who were infected with the worm and microfilaremic but had not yet developed the disease, as well as 18 lymphedema patients, and treated them with either 200 mg/d doxycycline or matching placebo for 6 wk. The findings presented here reveal that doxycycline is able to kill the adult worms, improves lymphatic vessel dilation, and ameliorates the conditions of lymphedema patients significantly. This suggests that doxycycline can be used to treat lymphatic filarial infections and pathology, making doxycycline the first drug already approved for human use and considered for use as an adjunct to current control programs, which in addition to parasite control achieves improvement of the quality of life of persons with pathology.
- Subjects :
- Male
Pathology
Nematodes
Vascular Endothelial Growth Factor C
Parasitemia
Ivermectin
Homo (Human)
Testis
Medicine
Biology (General)
Microfilariae
Lymphatic filariasis
Ultrasonography
Doxycycline
Middle Aged
Testicular Hydrocele
Lymphatic system
Lymphedema
Infectious Diseases
Treatment Outcome
Vascular endothelial growth factor C
Intercellular Signaling Peptides and Proteins
Female
Wolbachia
medicine.drug
Research Article
Adult
medicine.medical_specialty
wc_880
QH301-705.5
Immunology
Molecular Sequence Data
Microbiology
Microfilaria
Albendazole
qv_34
Lymphatic System
Elephantiasis, Filarial
Virology
Genetics
Animals
Humans
Molecular Biology
business.industry
RC581-607
medicine.disease
Vascular Endothelial Growth Factor Receptor-3
Eubacteria
Filaricides
Parasitology
Immunologic diseases. Allergy
business
RB
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 2
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....63b9f73657448669a44763113a276f13