Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042961 (volvulus)
 4,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of single and multiple doses of ivermectin on mortality and morphology were assessed in over 700 female Onchocerca volvulus worms and the effects on embryogenesis were assessed in 490. Nodules were surgically removed from Sierra Leoneans recruited from a double-blind placebo controlled study of ivermectin given at six-monthly intervals. Nodules were digested in collagenase to isolate whole adult worms. After four or five doses of ivermectin there were significant increases in the numbers of discoloured and calcified worms and possibly a trend towards increased mortality, but this was not seen consistently. There was no evidence of a prophylactic effect of the drug. Worms were then homogenised and embryograms constructed. A single dose of ivermectin produced large numbers of degenerating intrauterine microfilariae, but embryonic development occurred normally. After multiple doses we observed almost complete cessation of embryogenesis, with a highly significant decrease in the numbers of viable multicellular embryonic stages, while oocytes appeared to be produced normally. Development is probably impeded at the single cell stage, possibly because of reduced fertilization. In planning the future role of ivermectin as a control measure for onchocerciasis it is crucial to determine if these effects on embryogenesis are reversible.
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PMID:The effect of repeated doses of ivermectin on adult female Onchocerca volvulus in Sierra Leone. 129 32

The effects of co-culture with monkey kidney cells (LLCMK2), cell-conditioned medium and decreased atmospheric oxygen on the in vitro molting and viability of infective stage larvae (L3) of Onchocerca lienalis and O. volvulus were examined. O. lienalis L3 were cultured in an RPMI 1640-based medium in the presence of an LLCMK2 cell monolayer or in medium which had been conditioned for three days by cells. In paired experiments cell conditioned medium alone in 95% air/5% CO2 produced molting levels of 54 +/- 14% which increased to 67 +/- 20% in treatments cultured under decreased oxygen; this value equalled the level of molting of worms cocultured with LLCMK2 cells. Worm survival in the three environments was similar. In seven additional experiments using O. lienalis (n = 186), overall levels of 74 +/- 12 percent molting and 75 +/- 7% viability on days 21-33 were obtained. Worms increased in length from 503 +/- 50 mu as L3 to 638 +/- 74 mu as L4 on day 21 (p = 0.0001, n = 42-44). Ultrastructural comparison of an in vitro derived L4, (39 days in culture) vs a vector-derived L3 revealed fewer annulations and decreased osmiophilia on the epicuticle of the L4 while the hypodermis showed increased morphogenetic definition. O. volvulus molted at an average rate of 74% (n = 40) with a mean viability on day 28 of 95%. L3 increased in length from a mean of 635 +/- 50 mu to 775 +/- 45 mu as L4 on day 28 (p = 0.0001). Larvae of both species were cultured under these conditions for periods of time exceeding 100 days.
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PMID:The use of cell-conditioned medium for the in vitro culture of Onchocerca spp. larvae (Nematoda: Filarioidea). 233 42

A range of culture conditions were examined to optimize parasite maintenance. Using male worms in a cell-free system, good results were obtained with medium NCTC 135 + 10% inactivated calf serum (IFCS) in an atmosphere of 95% N2/5% CO2 (median survival time 45 days). Survival was increased to 6-7 months using medium MEM + 10% IFCS + LLCMK2 (monkey kidney) feeder cells in a gas phase of 5% CO2 in air. Worms exposed to collagenase solution (5 mg/ml) were subsequently less motile and survived shorter periods compared to unexposed controls. The drug responses of worms (in vitro) were examined using 13 antiparasitic compounds. Ivermectin and CGP 6140 were among the most active, with the majority of drugs significantly affecting motility levels at a concentration of 5 x 10(-5) M or less. This system may provide useful information on the intrinsic activity of new compounds. A technique was developed for the successful cryopreservation of males in liquid nitrogen using ethanediol as a cryoprotectant in a 2-step incubation procedure, thereby enabling the long-term storage and transportation of worms. In conclusion, the common bovine parasite O. gutturosa provides a practical alternative for research in the absence of O. volvulus.
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PMID:The development of a laboratory model for onchocerciasis using Onchocerca gutturosa: in vitro culture, collagenase effects, drug studies and cryopreservation. 285 98

The composition of proteins and antigens of female Onchocerca volvulus from one focus of transmission was studied by SDS-PAGE and immunoblotting. Worms that had been exposed to collagenase digestion of onchocercomata for different periods of time and parasites of different age and status of reproduction were tested. Some O. volvulus antigens were found to be sensible to prolonged digestion (molecular weights: 18 KD, 21 KD, 24 KD) but the majority of the antigens was stable up to 64 hours of incubation at 34 degrees C. The composition of proteins and antigens varied with the age and the status of reproduction of the worms. Slight differences between individual filariae were found, even when worms of comparable age and status of reproduction were tested that had been exposed to nodule digestion for comparable time.
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PMID:Studies on the protein and antigen composition of individual female Onchocerca volvulus after collagenase digestion. 300 80

An in vitro system for chemotherapeutic research using adult male Onchocerca gutturosa has been developed as a model for O. volvulus. Using a culture system consisting of medium MEM + 10% heat inactivated foetal calf serum (IFCS) + LLCMK2 (monkey kidney) feeder cells in an atmosphere of 5% CO2 in air, we examined the effects of a range of antiparasitic drugs on worm motility. Ivermectin, levamisole, furapyrimidone, Mel W, chloroquine, metrifonate, flubendazole, amoscanate and the Ciba-Geigy compounds CGP 6140, CGP 20'376 and CGI 17658 either immobilized or significantly reduced motility levels at a concentration of 5 X 10(-5) M or less within a 7-day period. Worms were affected at very low concentrations by ivermectin (effective conc. to reduce motility levels to 50% of controls, 3.14 X 10(-8) M), levamisole (7.95 X 10(-8) M), CGP 6140 (8.87 X 10(-9) M) and CGP 20'376 (2.78 X 10(-8) M). Difficulties were experienced in accurately repeating the immotile endpoint for levamisole due to an inconsistent partial recovery of motility. Over a 7-day period diethylcarbamazine had little effect on motility levels, while suramin caused a slight increase in activity compared to controls at some timepoints. Subsequent experiments demonstrated some differences in drug efficacy depending on the presence or absence of serum and feeder cells in the culture system probably because of drug avidly binding to serum proteins. However, serum and cells were found to be essential ingredients of the culture system to maintain worms in good condition, indicating that new drugs should be evaluated both in the presence and absence of serum and cells. Comparisons were made between the responses of O. gutturosa and Brugia pahangi to certain drugs and these species were found to significantly differ in their sensitivities to ivermectin and a novel compound (Wellcome), indicating that Onchocerca parasites should be used wherever possible for compound identification and development intended for the treatment of onchocerciasis. The in vitro system described here, using male O. gutturosa, provides a basis for further research and a practical alternative to O. volvulus.
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PMID:Drug activity against Onchocerca gutturosa males in vitro: a model for chemotherapeutic research on onchocerciasis. 343 7

Thirty-eight nodules containing adults of Onchocerca volvulus were removed from 36 patients who had no detectable microfilariae in skin snips. Worms were digested from nodules in collagenase solution, maintained alive in vitro, and the number, sex, and state of fecundity were recorded. A total of 48 female and 8 male worms were recovered; 39 females were in the nodules without the presence of a male. Eleven females (22.9%) had microfilariae in utero or produced microfilariae in vitro; seven of these were found together with males in the nodules while four were not. No nodules were found around male worms unless a female was also present. These observations indicate that the nodule forms only around female worms and that mating probably occurs before or early during nodule formation. Furthermore, the production of microfilariae by the the female is not essential for nodule formation since many nodules contained non-fecund, living females.
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PMID:Early formation of the nodule in Guatemalan onchocerciasis. 707 89

Onchocerca volvulus nodules were removed from 77 fully compliant patients in a longitudinal study of ivermectin treatment in Sierra Leone. The patients had participated in a randomized controlled trial and received either 4 annual doses of ivermectin or 10 6-monthly doses over 6 years. Worms were examined 9 months after the last treatment for evidence of changes in morphology, viability and reproductivity. The findings were compared with results for the 2 groups obtained at earlier surveys of the same study population. Repeated treatment at 6 and 12-month intervals has resulted in a marked ageing of the male worm population profile and a significant reduction in the proportion of live female worms found in the nodules. In addition, there has been a reduction in reproductivity of 90% or more. However, most of the worms found were still alive and potentially fertile, underlining the need for the continuation of regular ivermectin treatment to maintain the benefits achieved.
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PMID:Viability and fertility of adult Onchocerca volvulus after 6 years of treatment with ivermectin. 891 42

An electron microscopy study was performed to evaluate the feasibility of the use of the anterior nerve ring of male Onchocerca volvulus for the assessment of early drug effects. Worms were exposed to new and known compounds at reasonable concentrations of 1 microM and less for 6, 12, 18, and 36 h in an established in vitro system. The anterior end of the filariae up to a length of 1 mm was examined and the morphological findings were compared with motility and reduction of a tetrazolium sat to formazan by live but not dead worms. The nerve fibers were more susceptible to the chemotherapeutic intervention then the other tissues in the anteriormost part of the worms. The alterations depended on the duration of exposure and the chemical nature of the compounds used. Morphological changes in the nervous tissue and the inhibition of motility and formazan production corresponded well for the arsenical mel w, used as an active standard, two pyrimidinyl-guanidines (PD 105482 and PD 105666), and an imidazolinylhydrazone (WR 251993).
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PMID:The anterior central nervous system of male Onchocerca volvulus (Nematoda:Filarioidea) as a target for chemotherapy: results of an electron microscopy study. 921 5

Ivermectin (IVM) was first developed for use with livestock. It is now the only drug used for mass treatment of onchocerciasis. It is difficult to prove whether reports of sub-optimal responses to IVM in some Onchocerca volvulus infected patients are a result of drug resistance, as procedures typically used to examine IVM efficacy in livestock can not be performed on humans. To determine the effects of IVM on O. volvulus, one approach is to examine allele frequencies before and after treatment. Allele(s) linked to resistance may increase in frequency after repeated treatment. Mass treatment of large human populations to reduce transmission of O. volvulus will impose selection pressure for resistance. P-glycoprotein has been implicated as a candidate IVM resistance gene in nematodes. In this study, the intron-exon structure of O. volvulus P-glycoprotein (OvPGP) has been defined. The gene spans 10.6 kb, is AT-rich, contains 24 exons and a high proportion of class 0 introns. The genetic diversity of 28 loci spanning the entire OvPGP gene was examined in four O. volvulus populations from the Volta Region of Ghana. Worms collected in 1999 and 2002 from IVM treated patients showed reduced genetic polymorphism and an increase in the number of loci not in Hardy-Weinberg equilibrium. Changes in allelic patterns and a reduction in diversity at many loci in P-glycoprotein in the parasites from IVM treated patients in 1999 and 2002 suggest that IVM is imposing selection on this gene, consistent with a possible development of IVM resistance.
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PMID:Genomic organization and effects of ivermectin selection on Onchocerca volvulus P-glycoprotein. 1599 57

ATP-binding cassette (ABC) transporters comprise a large paralogous protein family and several confer drug resistance. Ivermectin (IVM) is the only drug approved for treatment of onchocerciasis and is a substrate for some ABC transporters. Furthermore, there is accumulating evidence that IVM selects on some ABC transporter genes in Onchocerca volvulus and other parasitic nematodes. The onchocerciasis control programs rely on community based treatment with IVM each year to reduce morbidity and decrease parasite transmission. This appears to be imposing selection pressure on O. volvulus. A half-size ABC transporter cDNA has previously been reported for O. volvulus, however, the full length gene has not been previously characterized and investigated for possible selection by IVM. Genes under selection may be identified by patterns of linkage disequilibrium (LD) and a loss of genetic polymorphism at physically linked loci. Twelve genetic markers spanning the full gene were examined in O. volvulus from non-treated and IVM treated populations in Ghana. Analysis of the genomic organization of the half-size ABC transporter (OvPLP) indicates that it spans approximately 3.8 kb comprising nine exons. Worms from treated people showed a reduction in gene diversity, a loss of genetic polymorphism at several markers, a selection for specific alleles, and a reduction in the number of regions in LD; these effects were more pronounced as treatment increased. These changes suggest that IVM is imposing selection pressure on this gene. The region between transmembrane domains four and five may be a useful marker for IVM selection in O. volvulus.
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PMID:Characterization of a half-size ATP-binding cassette transporter gene which may be a useful marker for ivermectin selection in Onchocerca volvulus. 1625 66


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