Onchocercacidal effects of amocarzine (CGP 6140) in Latin America

Poltera, A. A.; Moran, Maureen; F, Zak; Striebel, H.P.; Zea-Flores, Guillermo; Guderian, Ronald H.; Beltranena, F.; Proaño, Roberto

doi:10.1016/0140-6736(91)91642-8

Cited by 26 publications

(5 citation statements)

References 6 publications

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“…The compounds tested included a range of test antibiotics (Tables 1 , 2 and 3 ), both individually and in combination. The amoscanate derivative CGP 6140 (Amocarzine) was used as a positive control since it is macrofilaricidal against Onchocerca parasites [ 28 ], reviewed by [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

Onchocerca parasites and Wolbachia endosymbionts: evaluation of a spectrum of antibiotic types for activity against Onchocerca gutturosa in vitro

et al. 2006

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BackgroundThe filarial parasites of major importance in humans contain the symbiotic bacterium Wolbachia and recent studies have shown that targeting of these bacteria with antibiotics results in a reduction in worm viability, development, embryogenesis, and survival. Doxycycline has been effective in human trials, but there is a need to develop drugs that can be given for shorter periods and to pregnant women and children. The World Health Organisation-approved assay to screen for anti-filarial activity in vitro uses male Onchocerca gutturosa, with effects being determined by worm motility and viability as measured by reduction of MTT to MTT formazan. Here we have used this system to screen antibiotics for anti-filarial activity. In addition we have determined the contribution of Wolbachia depletion to the MTT reduction assay.MethodsAdult male O. gutturosa were cultured on a monkey kidney cell (LLCMK 2) feeder layer in 24-well plates with antibiotics and antibiotic combinations (6 to 10 worms per group). The macrofilaricide CGP 6140 (Amocarzine) was used as a positive control. Worm viability was assessed by two methods, (i) motility levels and (ii) MTT/formazan colorimetry. Worm motility was scored on a scale of 0 (immotile) to 10 (maximum) every 5 days up to 40 days. On day 40 worm viability was evaluated by MTT/formazan colorimetry, and results were expressed as a mean percentage reduction compared with untreated control values at day 40. To determine the contribution of Wolbachia to the MTT assay, the MTT formazan formation of an insect cell-line (C6/36) with or without insect Wolbachia infection and treated or untreated with tetracycline was compared.ResultsAntibiotics with known anti-Wolbachia activity were efficacious in this system. Rifampicin (5 × 10-5M) was the most effective anti-mycobacterial agent; clofazimine (1.25 × 10-5M and 3.13 × 10-6M) produced a gradual reduction in motility and by 40 days had reduced worm viability. The other anti-mycobacterial drugs tested had limited or no activity. Doxycycline (5 × 10-5M) was filaricidal, but minocycline was more effective and at a lower concentration (5 × 10-5M and 1.25 × 10-5M). Inactive compounds included erythromycin, oxytetracycline, trimethoprim and sulphamethoxazole. The MTT assay on the insect cell-line showed that Wolbachia made a significant contribution to the metabolic activity within the cells, which could be reduced when they were exposed to tetracycline.ConclusionThe O. gutturosa adult male screen for anti-filarial drug activity is also valid for the screening of antibiotics for anti-Wolbachia activity. In agreement with previous findings, rifampicin and doxycycline were effective; however, the most active antibiotic was minocycline. Wolbachia contributed to the formation of MTT formazan in the MTT assay of viability and is therefore not exclusively a measure of worm viability and indicates that Wolbachia contributes directly to the metabolic activity of the nematode.

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Section: Methodsmentioning

confidence: 99%

Onchocerca parasites and Wolbachia endosymbionts: evaluation of a spectrum of antibiotic types for activity against Onchocerca gutturosa in vitro

et al. 2006

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“…None of these compounds was advanced to human testing, although some were efficacious in animal models. 38 Other candidate macrofilaricides were tested in the 1980s in human trials, including compounds from formerly Ciba-Geigy, now Novartis International AG (Basel, Switzerland) 39 and antiparasitic drugs such as chloroquine and the organophosphate metrifonate. 40,41 None were sufficiently safe or effective to warrant further development.…”

Section: History Of Onchocerciasis Treatmentmentioning

confidence: 99%

Chemotherapy in the treatment, control, and elimination of human onchocerciasis

Higazi¹,

Geary²,

Mackenzie³

2014

RRTM

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Onchocerciasis treatment is one of the most positive stories in tropical medicine although major challenges remain to reaching the ultimate goal of disease elimination. Such challenges are to be expected when the therapeutic goal is to kill and safely remove a large multistage, efficient, metazoan infectious agent such as Onchocerca volvulus that has an exceptionally complicated relationship with its host. Successful control of onchocerciasis has often been hampered by host reactions following chemotherapy, that can sometimes cause significant tissue pathology. Presence of other filariae, particularly Loa loa, in endemic onchocerciasis-treatment areas also poses severe problems due to adverse reactions caused by drug-induced death of the coincident microfilariae of this usually clinically benign species. Although ivermectin has been very successful, there is a need to enhance the progress toward elimination of onchocerciasis; new drugs and their efficient use are keys to this. The permanent absence of Onchocerca microfilaridermia, defined as the lack of resurgence of skin microfilarial loads after treatment, is the ultimate characteristic of a useful new chemotherapeutic agent. Several drugs are under investigation to achieve this, including the reassessment of currently available and previously tested agents, such as the antibiotic, doxycycline, which targets the adult parasites through its anti-Wolbachia endosymbiont activity. Flubendazole, a benzimidazole derivative approved for treatment of human gastrointestinal nematodes, is also being considered for repurposing as a macrofilaricide to aid in the achievement of eradication. The managerial challenges existing at the population level also need to be addressed; these include drug-distribution fatigue, the need to include noncompliant people, civil unrest in endemic areas, political cross-border issues, restrictions of age and pregnancy, and complications due to integration with other treatment programs. It is likely that a panel of chemotherapeutic options, new and old, supported by strong and effective distribution systems will be the best way to address challenges of treatment and elimination of this infection. Future research should also address management of treatment and control, and consider how new treatment paradigms can be incorporated to meet time lines set for global elimination by 2025.

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“…Some success was obtained with amocarzine, although its macrofilaricidal properties were not optimal [21]. Several other compounds are currently under consideration.…”

Section: Introductionmentioning

confidence: 99%

Macrofilaricides and onchocerciasis control, mathematical modelling of the prospects for elimination

Alley¹,

Oortmarssen

Boatin³

et al. 2001

BMC Public Health

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BackgroundIn most endemic parts of the world, onchocerciasis (river blindness) control relies, or will soon rely, exclusively on mass treatment with the microfilaricide ivermectin. Worldwide eradication of the parasite by means of this drug is unlikely. Macrofilaricidal drugs are currently being developed for human use.MethodsWe used ONCHOSIM, a microsimulation mathematical model of the dynamics of onchocerciasis transmission, to explore the potentials of a hypothetical macrofilaricidal drug for the elimination of onchocerciasis under different epidemiological conditions, as characterized by previous intervention strategies, vectorial capacity and levels of coverage.ResultsWith a high vector biting rate and poor coverage, a very effective macrofilaricide would appear to have a substantially higher potential for achieving elimination of the parasite than does ivermectin.ConclusionsMacrofilaricides have a substantially higher potential for achieving onchocerciasis elimination than ivermectin, but high coverage levels are still key. When these drugs become available, onchocerciasis elimination strategies should be reconsidered. In view of the impact of control efforts preceding the introduction of macrofilaricides on the success of elimination, it is important to sustain current control efforts.

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Onchocercacidal effects of amocarzine (CGP 6140) in Latin America

Cited by 26 publications

References 6 publications

Onchocerca parasites and Wolbachia endosymbionts: evaluation of a spectrum of antibiotic types for activity against Onchocerca gutturosa in vitro

Onchocerca parasites and Wolbachia endosymbionts: evaluation of a spectrum of antibiotic types for activity against Onchocerca gutturosa in vitro

Chemotherapy in the treatment, control, and elimination of human onchocerciasis

Macrofilaricides and onchocerciasis control, mathematical modelling of the prospects for elimination

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