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[
Trans R Soc Trop Med Hyg
]
Ivermectin, at the standard dose of 150 micrograms/kg bodyweight, does not kill the adult worms of Onchocerca volvulus and does not disrupt embryogenesis or spermatogenesis. Repeated standard doses, if maintained, arrest microfilarial production but result in only a mild-to-modest macrofilaricidal effect. We investigated whether high doses would effectively kill the adult worms, and whether cessation of microfilarial production could be reproduced by an equivalent, single, high dose. One hundred men participated in a double-blind placebo-controlled trial and received increasing doses of ivermectin from 150 micrograms/kg to 1600 micrograms/kg bodyweight. Nodules were excised at day 180 and examined by histopathology. Total doses of ivermectin up to 1600 micrograms/kg were not significantly more effective than 150 micrograms/kg. Moreover, they did not reproduce the marked inhibitory effects of the repeat standard-dose regimens on embryogenesis, nor the modest effect on adult worm viability, at comparable total doses. These effects may be functions of multiplicities of dosages rather than of the total dose. Our findings also suggest that repeated high-dose regimens are unlikely to be more effective than a similar number of 150 micrograms/kg doses. This deficiency of ivermectin requires that the search for macrofilaricides remains a top priority.
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[
Trop Med Parasitol,
1995]
Ivermectin is a potent microfilaricide that also blocks microfilarial release while albendazole is toxic to all intrauterine stages. We investigated whether their combination would permanently sterilize the adult worms. In the first open phase, all 69 patients received 150 micrograms/kg of ivermectin. In the second double-blind phase one week later, 35 patients were randomized to receive 800 mg of albendazole with a fatty breakfast for three consecutive days while 34 patients received matching placebo tablets. Detailed clinical and laboratory examinations were done before treatment and were repeated at intervals over one year. Nodules were excised at three and six months. There was a rapid reduction in skin microfilariae, maximal at four weeks (99.9%). Counts increased subsequently and were between 11 and 18% of initial values at one year. Nodule histology showed no macrofilaricidal activity of the combination. A high proportion of the stretched intrauterine microfilariae were degenerate in both groups. Anterior chamber microfilarial counts were unchanged until day 18 and then fell successively. Low levels persisted in several patients at one year. Dead corneal microfilariae and corneal punctate opacities increased initially, fell with time and then disappeared in most patients. Systemic and ocular reactions were mild to moderate and biochemical abnormalities were minor. A pronounced posttreatment eosinophilia subsided by day 30. There was no significant difference between the two groups in clinical and laboratory tolerance or in alterations in skin and ocular parasites and no important differences in the effect on the adult worms. The combination of ivermectin with albendazole given one week apart is well tolerated but produces no additional effect against Onchocerca volvulus when compared to ivermectin given alone.
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[
Ann Trop Med Parasitol,
2003]
A randomized, double-blind, placebo-controlled trial was conducted, to determine whether the co-administration of ivermectin with albendazole is safe and more effective against Onchocerca volvulus than ivermectin alone, and whether a significant pharmacokinetic interaction occurs. Forty-two male onchocerciasis patients received ivermectin (200 mug/kg) alone, albendazole (400 mg) alone or the combination. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. Microfilaricidal efficacy was estimated from the reductions in skin counts between day 0 (pretreatment) and day 30. To determine efficacy against the adult worms, two independent observers examined histology slides prepared from nodules excised on day 180; changes in the skin counts of skin microfilariae between days 30 and 365 provided additional indicators of the level of adulticidal activity. Pharmacokinetic parameters for ivermectin and albendazole sulphoxide were defined over 72 h post-treatment. The co-administration of ivermectin with albendazole did not produce more severe adverse effects than ivermectin alone. Both nodule examiners found that the combination was not macrofilaricidal and that it was not clearly superior to ivermectin alone in the effects on reproductive activity; this was supported by the similar efficacy of the two regimens in the suppression of skin microfilariae. There was no significant pharmacokinetic interaction. Although the co-administration of ivermectin with albendazole appears safe, it offers no advantage over ivermectin alone in the control of onchocerciasis. The combination does not require an alteration in the dosage of either component.
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[
Ann Trop Med Parasitol,
2004]
Two randomized, double-blind, placebo-controlled trials, in which levamisole (2.5 mg/kg) was given alone or co-administered with ivermectin (200 microg/kg) or albendazole (400 mg), were conducted. In Trial 1, safety and drug-drug interaction were explored in 42 healthy male volunteers. During Trial 2, the safety of the same treatment regimens and their efficacy against the adult worms and microfilariae of Onchocerca volvulus were investigated in 66 infected subjects of both sexes. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. The pharmacokinetic parameters for levamisole alone and the combinations were determined in Trial 1 and then compared with historical data for ivermectin and albendazole, given as single agents, to determine if drug-drug interaction had occurred. The level of efficacy against the adult worms was determined by the examination of histology sections of nodules excised 6 months posttreatment and from the changes seen in the levels of microfilaridermia within a year of treatment. Microfilaricidal efficacy was estimated from the reductions in the levels of microfilaridermia between day 0 (1 day pre-treatment) and day 30. Although the regimens were generally well tolerated, there were unexpected adverse effects in both healthy volunteers and infected subjects. Clinically significant drug-drug interactions resulted in an increase in the bio-availability of ivermectin but a reduction in that of albendazole when these drugs were co-administered with levamisole. Levamisole given alone or with albendazole had little effect on O. volvulus. The combination of levamisole with ivermectin was neither macrofilaricidal nor more effective against the microfilariae and the adult worms than ivermectin alone. The pathogenesis of the adverse events and the drug-drug interactions are discussed.
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de Bono, Mario, Amin-Wetzel, Niko, Sengupta, Piali, Philbrook, Alison, Kazatskaya, Anna, Yuan, Lisa
[
MicroPubl Biol,
2020]
A subset of sensory neurons in C. elegans contains compartmentalized sensory structures termed cilia at their distal dendritic ends (Ward et al. 1975; Perkins et al. 1986; Doroquez et al. 2014). Cilia present on different sensory neuron types are specialized both in morphology and function, and are generated and maintained via shared and cell-specific molecules and mechanisms (Perkins et al. 1986; Evans et al. 2006; Mukhopadhyay et al. 2007; Mukhopadhyay et al. 2008; Morsci and Barr 2011; Doroquez et al. 2014; Silva et al. 2017). The bilaterally symmetric pair of URX oxygen-sensing neurons in the C. elegans head (Figure 1A) is thought to be non-ciliated (Ward et al. 1975; Doroquez et al. 2014) but nevertheless exhibits intriguing morphological similarities with ciliated sensory neurons. URX dendrites extend to the nose where they terminate in large bulb-like complex structures (Ward et al. 1975; Doroquez et al. 2014; Cebul et al. 2020) (Figure 1A). These structures concentrate oxygen-sensing signaling molecules (Gross et al. 2014; Mclachlan et al. 2018) suggesting that similar to cilia, these structures are specialized for sensory functions. Microtubule growth events similar to those observed in ciliated sensory neurons were also reported at the distal dendritic regions of URX, implying the presence of a microtubule organizer such as a remodeled basal body (Harterink et al. 2018). Moreover, a subset of ciliary genes is expressed in URX (Kunitomo et al. 2005; Harterink et al. 2018; Mclachlan et al. 2018). We tested the hypothesis that URX dendrites contain cilia at their distal ends.
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[
Mol Cell,
2009]
Three recent papers (Gu et al., 2009; Claycomb et al., 2009; van Wolfswinkel et al., 2009) provide evidence that links a new class of small RNAs and Argonaute-associated complexes to centromere function and genome surveillance.
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[
MicroPubl Biol,
2021]
Like other animals, the nematode C. elegans exhibits reduced movement and sleep in response to sickness, which can be induced by exposure to high temperatures (Hill et al. 2014; Nelson et al. 2014) ultraviolet light (DeBardeleben et al. 2017), and other stressful exposures (Hill et al. 2014; Goetting et al. 2020). This response has been termed Stress/Sickness-Induced Sleep (SIS) (Hill et al. 2014; Trojanowski and Raizen 2016). Exposure to the stressor leads to quiescence in part via release of the cytokine Epidermal Growth Factor (EGF) (Hill et al. 2014; Konietzka et al. 2020), which is encoded by the gene
lin-3 (Hill and Sternberg 1992). EGF activates the ALA and RIS neurons, which then release their respective neuropeptides to effect reduced movement and behavioral quiescence (Konietzka et al. 2020).
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[
MicroPubl Biol,
2021]
Neuronal networks can achieve similar outputs via distinct underlying circuit mechanisms (Beverly et al., 2011; Marder et al., 2015; Saideman et al., 2007; Trojanowski et al., 2014; Wang et al., 2019). This degeneracy allows networks to maintain robustness without compromising functional flexibility (Cropper et al., 2016; Edelman and Gally, 2001). Since the contribution of degenerate neuronal pathways is likely to be revealed under defined genetic or environmental conditions, it is challenging to identify and describe the contributions of such pathways to neuronal circuit function.
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[
MicroPubl Biol,
2021]
MEC-4 and UNC-8 are subunits of the DEG/ENaC family of voltage-independent Na+ channels in C. elegans (Driscoll and Chalfie 1991, Canessa, Horisberger et al. 1993, Waldmann, Champigny et al. 1996, Waldmann, Champigny et al. 1997, de Weille, Bassilana et al. 1998, Waldmann and Lazdunski 1998). While MEC-4 is expressed in body touch neurons where it mediates the transduction of gentle touch sensation (Driscoll and Chalfie 1991, O'Hagan, Chalfie et al. 2005), UNC-8 is primarily expressed in motoneurons where it is involved in synaptic remodeling during development (Tavernarakis, Shreffler et al. 1997, Miller-Fleming, Petersen et al. 2016). Both MEC-4 and UNC-8 can be hyperactivated by genetic mutations that hinder channel closing, called (d) mutations (Driscoll and Chalfie 1991, Shreffler, Magardino et al. 1995, Goodman, Ernstrom et al. 2002, Wang, Matthewman et al. 2013). C. elegans neurons and Xenopus oocytes expressing these hyperactive variants of MEC-4 and UNC-8 undergo cell death due to uncontrolled flux of ions into the cell. Cell death in Xenopus oocytes and in cultured C. elegans neurons can be prevented by incubation with the DEG/ENaC channel blocker amiloride (Goodman, Ernstrom et al. 2002, Suzuki, Kerr et al. 2003, Wang, Matthewman et al. 2013).
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[
MicroPubl Biol,
2022]
The Q system is a genetic tool developed to deliver spatiotemporal control over gene expression (Giles et al. 1991; Potter et al. 2010; Wei et al. 2012). Although it has already been adapted for use in C. elegans by Wei et al. in 2012, to date, the Q system has not been applied extensively in this nematode. In the relatively few available reports, it is mainly used to constitutively restrict gene expression in a spatial manner (e.g. Schild et al. 2014; Schild and Glauser 2015; Jee et al. 2016; Tolstenkov et al. 2018; Chiyoda et al. 2021), while but a handful of studies also explore the temporal aspect of the system (Matus et al. 2015; Yuan et al. 2016; Cottee et al. 2017; Hoang and Miller 2017). We aimed to apply this tool in the C. elegans nervous system to gain both spatial and temporal control over expression of a gene encoding a reporter protein that is targeted to the secretory pathway. Despite our efforts, we here report that in our hands, the Q system is not suitable for application in the neurons due to a lack of dynamic range.