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1.
PLoS Negl Trop Dis ; 18(8): e0012351, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39102440

RESUMEN

Moxidectin is approved by the US Food and Drug Administration (US FDA) for the treatment of onchocerciasis (river-blindness) due to Onchocerca volvulus in patients aged 12 years and older. In onchocerciasis-endemic areas, mass drug administration (MDA) programs with ivermectin, with or without vector control, aim to control the disease, reduce morbidity, interrupt transmission, and more recently, achieve elimination. Moxidectin has the potential to be used in MDA programs. In countries where onchocerciasis is endemic, infants are often breastfed up to the age of 2 years, suggesting that some women are likely to be lactating during such periodic MDA programs. Quantitative analyses of non-clinical and clinical data using non-compartmental analysis and population based pharmacokinetic (popPK) modeling as well as physiologically based pharmacokinetic modeling (PBPK) were performed to determine the amount of moxidectin excreted in breast milk and subsequent exposures in the infant. The results of the analyses were similar. Concentrations of moxidectin in breast milk followed a similar pattern to those in plasma, with maximum concentrations occurring approximately 4 hours after dosing followed by a rapid decline in both breast milk and plasma. As early as two days after dosing, concentrations of moxidectin in breast milk were below the threshold for acceptable daily intake levels established by the European Medicines Agency (EMA) and FDA for secondary exposures from veterinary use, and below the WHO recommended relative infant dose (RID) safety threshold. The analyses were conducted to support prescribers and policy makers on dosing recommendations for moxidectin in lactation.


Asunto(s)
Lactancia , Macrólidos , Humanos , Macrólidos/farmacocinética , Macrólidos/administración & dosificación , Femenino , Oncocercosis/tratamiento farmacológico , Leche Humana/química , Lactante , Adulto , Filaricidas/farmacocinética , Filaricidas/administración & dosificación
2.
ACS Infect Dis ; 6(2): 180-185, 2020 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-31876143

RESUMEN

The optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, 21 (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound 21was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.


Asunto(s)
Bencimidazoles/uso terapéutico , Compuestos de Boro/uso terapéutico , Cetonas/química , Oncocercosis Ocular/tratamiento farmacológico , Administración Oral , Animales , Bencimidazoles/farmacocinética , Compuestos de Boro/farmacocinética , Modelos Animales de Enfermedad , Femenino , Filaricidas/farmacocinética , Filaricidas/uso terapéutico , Gerbillinae , Masculino
3.
ACS Infect Dis ; 6(2): 173-179, 2020 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-31876154

RESUMEN

A series of benzimidazole-benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.


Asunto(s)
Bencimidazoles/uso terapéutico , Compuestos de Boro/uso terapéutico , Brugia/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Amidas , Animales , Bencimidazoles/farmacocinética , Compuestos de Boro/farmacocinética , Femenino , Filaricidas/farmacocinética , Filaricidas/uso terapéutico , Gerbillinae , Masculino , Onchocerca volvulus/efectos de los fármacos
4.
J Control Release ; 316: 34-52, 2019 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-31655132

RESUMEN

Conventional oral therapy of lymphatic filariasis drugs is only effective to kill microfilariae in the bloodstream, but is often ineffective to kill adult filarial (macrofilariae) in the complex anatomy of the lymphatic system. The encapsulation of drugs into lipid-based nanoparticles with sizes of <100nm, and administration intradermally, could be used to enhance lymphatic uptake. Therefore, we developed an innovative approach, using solid lipid nanoparticles (SLNs) and dissolving microneedles (MNs) to deliver antifilariasis drugs, namely doxycycline, diethylcarbamazine and albendazole, intradermally. The SLNs were prepared from Geleol® and Tween®80 as a lipid matrix and stabilizer, respectively. The formulations were optimized using a central composite design, producing SLNs with sizes of <100nm. Drug release was sustained over 48h from SLNs, compared to pure drugs. The SLNs were then incorporated into a polymeric hydrogel which was casted to form SLNs-loaded MNs. SLNs-loaded MNs exhibited sufficient mechanical and insertion properties. Importantly, dermatokinetic studies showed that>40% of drugs were retained in the dermis of excised neonatal porcine skin up to 24h post-MN application, indicating the high possibility of the SLNs to be taken by the lymphatic system. In in vivo studies, the maximal lymph concentrations of the three drugs in rat, achieved following intradermal delivery, ranged between 4- and 7-fold higher than that recorded after oral administration. Additionally, compared to oral administration, despite the lower plasma Cmax and organ-distribution, the AUC and relative bioavailability of the three drugs in rat plasma was also higher using our delivery approach. Accordingly, this delivery approach could maximize the drugs concentrations in the lymph system without essentially increasing their plasma concentrations. This could potentially deliver the drugs efficiently to the bloodstream, where the microfilariae reside, while also targeting drug to the lymph nodes, where filarial nematodes reside in infected patients, leading to an effective therapy for lymphatic filariasis.


Asunto(s)
Sistemas de Liberación de Medicamentos , Filariasis Linfática/tratamiento farmacológico , Filaricidas/administración & dosificación , Nanopartículas , Albendazol/administración & dosificación , Animales , Preparaciones de Acción Retardada , Dietilcarbamazina/administración & dosificación , Doxiciclina/administración & dosificación , Portadores de Fármacos/química , Liberación de Fármacos , Femenino , Filaricidas/farmacocinética , Lípidos/química , Sistema Linfático/metabolismo , Agujas , Ratas , Ratas Sprague-Dawley , Piel/metabolismo , Porcinos
5.
PLoS Negl Trop Dis ; 13(5): e0007325, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31107869

RESUMEN

BACKGROUND: A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa. METHODS: In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d'Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants' infection status. FINDINGS: There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment. CONCLUSIONS: Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845713.


Asunto(s)
Albendazol/administración & dosificación , Dietilcarbamazina/administración & dosificación , Filariasis Linfática/tratamiento farmacológico , Filaricidas/administración & dosificación , Ivermectina/administración & dosificación , Wuchereria bancrofti/efectos de los fármacos , Adolescente , Adulto , Anciano , Albendazol/efectos adversos , Albendazol/farmacocinética , Animales , Estudios de Cohortes , Côte d'Ivoire , Dietilcarbamazina/efectos adversos , Dietilcarbamazina/farmacocinética , Combinación de Medicamentos , Filariasis Linfática/parasitología , Femenino , Filaricidas/efectos adversos , Filaricidas/farmacocinética , Humanos , Ivermectina/efectos adversos , Ivermectina/farmacocinética , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Wuchereria bancrofti/fisiología , Adulto Joven
6.
PLoS Negl Trop Dis ; 13(2): e0007159, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30818326

RESUMEN

There is a significant need for improved treatments for onchocerciasis and lymphatic filariasis, diseases caused by filarial worm infection. In particular, an agent able to selectively kill adult worms (macrofilaricide) would be expected to substantially augment the benefits of mass drug administration (MDA) with current microfilaricides, and to provide a solution to treatment of onchocerciasis / loiasis co-infection, where MDA is restricted. We have identified a novel macrofilaricidal agent, Tylosin A (TylA), which acts by targeting the worm-symbiont Wolbachia bacterium. Chemical modification of TylA leads to improvements in anti-Wolbachia activity and oral pharmacokinetic properties; an optimized analog (ABBV-4083) has been selected for clinical evaluation.


Asunto(s)
Antibacterianos/farmacología , Descubrimiento de Drogas , Filaricidas/farmacología , Tilosina/análogos & derivados , Tilosina/farmacología , Wolbachia/efectos de los fármacos , Animales , Antibacterianos/farmacocinética , Filariasis Linfática/tratamiento farmacológico , Femenino , Filaricidas/farmacocinética , Filarioidea/efectos de los fármacos , Filarioidea/microbiología , Gerbillinae , Ratones , Ratones Endogámicos BALB C , Oncocercosis/tratamiento farmacológico , Simbiosis/efectos de los fármacos
7.
J Med Chem ; 62(5): 2521-2540, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30730745

RESUMEN

A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti- Wolbachia antibiotics and, as such, may be useful in the treatment of filarial infections caused by Onchocerca volvulus, resulting in Onchocerciasis or river blindness, or Wuchereria bancrofti and Brugia malayi and related parasitic nematodes resulting in lymphatic filariasis. These two important neglected tropical diseases disproportionately impact patients in the developing world. The lead preclinical candidate compound containing 7-fluoro-6-oxybenzoxaborole (15, AN11251) was shown to have good in vitro anti- Wolbachia activity and physicochemical and pharmacokinetic properties providing high exposure in plasma. The lead was effective in reducing the Wolbachia load in filarial worms following oral administration to mice.


Asunto(s)
Boro/farmacología , Diterpenos/farmacología , Filariasis Linfática/tratamiento farmacológico , Filaricidas/uso terapéutico , Oncocercosis/tratamiento farmacológico , Compuestos Policíclicos/farmacología , Wolbachia/efectos de los fármacos , Wuchereria bancrofti/efectos de los fármacos , Animales , Boro/química , Diterpenos/química , Filaricidas/farmacocinética , Filaricidas/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Compuestos Policíclicos/química , Pleuromutilinas
8.
PLoS Negl Trop Dis ; 13(1): e0006320, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30650105

RESUMEN

Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect.


Asunto(s)
Filariasis/tratamiento farmacológico , Filaricidas/farmacología , Filaricidas/farmacocinética , Filarioidea/efectos de los fármacos , Mebendazol/análogos & derivados , Administración Oral , Animales , Modelos Animales de Enfermedad , Desarrollo Embrionario/efectos de los fármacos , Femenino , Filariasis/parasitología , Filaricidas/administración & dosificación , Filarioidea/embriología , Gerbillinae/parasitología , Mebendazol/administración & dosificación , Mebendazol/farmacocinética , Mebendazol/farmacología , Carga de Parásitos
9.
Clin Infect Dis ; 62(3): 334-341, 2016 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-26486704

RESUMEN

BACKGROUND: Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown. METHODS: We performed a pilot study to test the efficacy, safety, and pharmacokinetics of single-dose DEC, IVM, and ALB in Wuchereria bancrofti-infected Papua New Guineans. Adults were randomized into 2 treatment arms, DEC 6 mg/kg + ALB 400 mg (N = 12) or DEC 6 mg/kg + ALB 400 mg + IVM 200 µg/kg (N = 12), and monitored for microfilaria, parasite antigenemia, adverse events (AEs), and serum drug levels. RESULTS: Triple-drug therapy induced >2-log reductions in microfilaria levels at 36 and 168 hours after treatment compared with approximately 1-log reduction with 2 drugs. All 12 individuals who received 3 drugs were microfilaria negative 1 year after treatment, whereas 11 of 12 individuals in the 2-drug regimen were microfilaria positive. In 6 participants followed 2 years after treatment, those who received 3 drugs remained microfilaria negative. AEs, particularly fever, myalgias, pruritus, and proteinuria/hematuria, occurred in 83% vs 50% of those receiving triple-drug compared to 2-drug treatment respectively (P = .021); all resolved within 7 days after treatment. No serious AEs were observed in either group. There was no significant effect of IVM on DEC or ALB drug levels. CONCLUSIONS: Triple-drug therapy is safe and more effective than DEC + ALB for Bancroftian filariasis and has the potential to accelerate elimination of lymphatic filariasis. CLINICAL TRIALS REGISTRATION: NCT01975441.


Asunto(s)
Albendazol/administración & dosificación , Dietilcarbamazina/administración & dosificación , Filariasis Linfática/tratamiento farmacológico , Filaricidas/administración & dosificación , Ivermectina/administración & dosificación , Adulto , Albendazol/efectos adversos , Albendazol/farmacocinética , Animales , Dietilcarbamazina/efectos adversos , Dietilcarbamazina/farmacocinética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Filaricidas/efectos adversos , Filaricidas/farmacocinética , Humanos , Ivermectina/efectos adversos , Ivermectina/farmacocinética , Masculino , Persona de Mediana Edad , Papúa Nueva Guinea , Parasitemia/tratamiento farmacológico , Proyectos Piloto , Suero/química , Método Simple Ciego , Resultado del Tratamiento , Wuchereria bancrofti/aislamiento & purificación , Adulto Joven
10.
Parasitol Res ; 113(2): 681-91, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24366812

RESUMEN

The present study reports on the antifilarial activity of poly (lactic-co-glycolic acid) nanoparticles encapsulated ivermectin (nano-IVM) against human lymphatic filariid Brugia malayi in rodent host Mastomys coucha. Nano-IVM was prepared and optimized by nanoprecipitation method. The selected nano-IVM (F5) showed a uniform spherical shape with 96 nm diameter and 74.12 % entrapment efficiency, and when used at a suboptimal dose of 100 µg/kg body weight, completely eliminated filarial parasites from systemic circulation on 60 days post-infection in animals inflicted with B. malayi. In contrast, the coadministration of nano-IVM (F5) along with standard filaricide diethylcarbamazine (DEC) was found to be competent enough to suppress microfilarial stage of parasites and successfully eliminated microfilaria at 45 days posttreatment. However, the free form of both the drugs alone or in combination was unable to impart such suppression and followed by recurrence of the infection. Interestingly, nano-IVM (F5) was also found to be effective against adult stage parasites causing 36.67 % worm mortality and 75.89 % in combination with DEC; however, female sterilization remain almost similar. Thus, the combination of entrapped IVM with DEC exhibited enhanced microfilaricidal and marginally better macrofilaricidal efficacy than any of the single formulation or drugs combination.


Asunto(s)
Brugia Malayi/efectos de los fármacos , Filariasis/tratamiento farmacológico , Filaricidas/administración & dosificación , Ivermectina/administración & dosificación , Ácido Láctico , Nanocápsulas , Ácido Poliglicólico , Animales , Dietilcarbamazina/administración & dosificación , Dietilcarbamazina/farmacocinética , Dietilcarbamazina/farmacología , Dietilcarbamazina/uso terapéutico , Femenino , Filariasis/parasitología , Filaricidas/farmacocinética , Filaricidas/farmacología , Ivermectina/farmacocinética , Ivermectina/farmacología , Masculino , Microfilarias/efectos de los fármacos , Murinae , Nanocápsulas/ultraestructura , Carga de Parásitos , Pruebas de Sensibilidad Parasitaria , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Alcohol Polivinílico
11.
J Drug Target ; 22(1): 1-13, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24004100

RESUMEN

INTRODUCTION: Growing interest in the application of nanotechnology to treat lymphatic filariasis (LF) implies that the imminent medical arsenal of this interesting technology is attractive for health authorities. Currently, they are completely dependent on friendly oral mass drug (anti-filarials) administration to eliminate this morbid disease and are now looking for new alternatives to bring about further improvements. AREAS COVERED: A plethora of issues affecting the oral bioavailability of the mainstay human lymphatic filarial drugs, leading to meager pharmacokinetics and pharmacodynamics issues in anti-filarial chemotherapy are identified. Various important nanomedical drug delivery systems are highlighted and their solutions provided. A conceptual resolution to strictly arrest the transmission of LF in endemic areas is also presented. FUTURE PERSPECTIVES: Unless the solutions for pharmacokinetic tribulations and the measurement of factual pharmacodynamic endpoints for the existing anti-filarial drugs are evaluated using relevant approaches, health authorities will not be able to devise optimal treatment regimens for affected patients. Contemporary therapeutic paradigms need to be shifted toward the upcoming schemes of nanopharmaceutical sciences, which have enormous potential to advance the community-directed management of this tropical disease by improving the pharmacokinetic and pharmacodynamic properties of the filaricidal agents.


Asunto(s)
Filariasis Linfática/tratamiento farmacológico , Filaricidas/farmacología , Filaricidas/uso terapéutico , Animales , Sistemas de Liberación de Medicamentos/métodos , Filaricidas/farmacocinética , Humanos
12.
Parasitol Res ; 112(8): 2933-43, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23828187

RESUMEN

The current antifilarial treatments are not up to the mark partly due to deep location of filarial parasites in the human lymphatic system. We report here on the improvement in the antifilarial activity of ivermectin (IVM) using chitosan-alginate nanoparticles prepared by modified complex coacervation method. The nanoparticles were spherical having 155 nm size and 4.56 and 75.67% loading and entrapment efficiency respectively for IVM. The delivery system maintained the sustained release and significantly augmented the microfilaricidal (MIF) activity at a single low dose (200 µg/kg body weight, subcutaneously) in contrast to much higher dose of free ivermectin (400 µg/kg body weight, subcutaneously) against human lymphatic filariid, Brugia malayi in rodent host, Mastomys coucha. To substantiate increase in MIF activity, pharmacokinetics study was designed on Wistar rats which revealed a greater peak plasma concentration (45.3 ± 1.79 ng/ml), area under the concentration curve (298 ± 38.7 ng d/ml) and extended mean residence time (23.4 ± 8.56 days)of IVM in chitosan-alginate nanoparticles. Administration of 25 mg/kg of diethylcarbamazine following nanoparticle therapy significantly improved the MIF and macrofilaricidal action of encapsulated drug and was considered superior in this study.


Asunto(s)
Alginatos/química , Brugia Malayi/efectos de los fármacos , Quitosano/química , Ivermectina/farmacología , Nanopartículas/química , Animales , Área Bajo la Curva , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Filaricidas/química , Filaricidas/farmacocinética , Filaricidas/farmacología , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Humanos , Ivermectina/administración & dosificación , Ivermectina/farmacocinética , Masculino , Murinae , Ratas , Ratas Wistar , Espectroscopía Infrarroja por Transformada de Fourier , Tiempo
14.
Biopharm Drug Dispos ; 28(8): 431-8, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17847063

RESUMEN

This study compares plasma disposition kinetics of ivermectin and moxidectin after oral administration to beagle dogs experimentally infected with the filarial parasite, Brugia pahangi. Sixteen dogs were selected and randomly allocated into two groups of eight dogs each. Animals in each group received either ivermectin or moxidectin by oral route at a dose of 250 microg/kg. Blood samples were collected from 0.5 h up to 56 days post-treatment and the plasma was analysed by high performance liquid chromatography (HPLC). The obtained data were analysed by compartmental and non-compartmental pharmacokinetic techniques. Peak plasma concentrations (C(max)) of 234.0 +/- 64.3 ng/ml (mean +/- SD) were obtained for moxidectin and 132.6 +/- 43.0 ng/ml for ivermectin. The terminal elimination half-life was significantly (p<0.01) longer in the moxidectin treated group (621.3 +/- 149.3 h) than for ivermectin treated group (80.3 +/- 29.8 h). A significantly (p< 0.01) larger V(ss)/F was obtained for moxidectin (19.21 +/- 3.61 l/kg) compared with ivermectin (5.35 +/- 1.29 l/kg). The mean estimates of CL/F of moxidectin and ivermectin were 0.0220 +/- 0.00381 and 0.0498 +/- 0.0179 l/h/kg, respectively. The comparative plasma disposition kinetics of ivermectin and moxidectin in dogs is reported for the first time.


Asunto(s)
Filaricidas/farmacocinética , Ivermectina/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Brugia pahangi , Cromatografía Líquida de Alta Presión , Interpretación Estadística de Datos , Perros , Femenino , Filariasis/metabolismo , Semivida , Indicadores y Reactivos , Macrólidos/farmacocinética , Masculino , Espectrometría de Fluorescencia
15.
J Parasitol ; 92(5): 1075-80, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17152953

RESUMEN

A single-dose treatment with diethylcarbamazine (DEC) reduced microfilaria (mf) counts of Brugia pahangi by >90% at 30 min post-treatment in Mongolian jirds (Meriones unguiculatus). The reduction was followed by a rapid increase in microfilaremia, with the count reaching pretreatment level in 3 hr. The mechanisms behind this temporary reduction of mf were investigated. Without treatment, mf accumulated in the lungs. At 30 min post-treatment, they had moved from the lungs and accumulated in the muscle. At the same time, electron microscopy revealed many mf in the muscle interstitium. DEC concentrations at 30 min were much lower in the muscle (12.2 microg/g of tissue) than in the lungs, liver, and kidneys (19.8-40.7 microg/g), all of which declined to < 0.6 microg/g by 3 hr. The presence of mf in the muscle would be advantageous for avoiding high DEC concentrations, and their extravascular location could prevent attack by host effector cells.


Asunto(s)
Brugia pahangi/efectos de los fármacos , Dietilcarbamazina/farmacología , Filaricidas/farmacología , Pulmón/parasitología , Músculo Esquelético/parasitología , Animales , Vasos Sanguíneos/parasitología , Vasos Sanguíneos/ultraestructura , Brugia pahangi/fisiología , Brugia pahangi/ultraestructura , Dietilcarbamazina/sangre , Dietilcarbamazina/farmacocinética , Modelos Animales de Enfermedad , Filaricidas/sangre , Filaricidas/farmacocinética , Gerbillinae , Corazón/parasitología , Riñón/metabolismo , Riñón/parasitología , Hígado/metabolismo , Hígado/parasitología , Pulmón/metabolismo , Masculino , Microfilarias/efectos de los fármacos , Microfilarias/fisiología , Microfilarias/ultraestructura , Microscopía Electrónica de Transmisión , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Miocardio/metabolismo
16.
Ann Trop Med Parasitol ; 97(2): 165-78, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12803872

RESUMEN

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.


Asunto(s)
Albendazol/análogos & derivados , Albendazol/administración & dosificación , Antihelmínticos/administración & dosificación , Filaricidas/administración & dosificación , Ivermectina/administración & dosificación , Onchocerca volvulus/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Administración Oral , Adulto , Albendazol/efectos adversos , Albendazol/sangre , Albendazol/farmacocinética , Animales , Antihelmínticos/efectos adversos , Antihelmínticos/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Filaricidas/efectos adversos , Filaricidas/farmacocinética , Humanos , Ivermectina/efectos adversos , Ivermectina/farmacocinética , Masculino , Microfilarias/efectos de los fármacos , Persona de Mediana Edad
17.
J Clin Pharmacol ; 42(3): 327-31, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11865970

RESUMEN

In most Wuchereria bancrofti and Brugia malayi infections, the microfilaria are found in the blood in greatest number between 10 p.m. and 2 a.m., indicating that chronotherapy may be beneficial in treating such infections. This study reports the influence of time of administration on the pharmacokinetics of diethylcarbamazine (DEC) in healthy volunteers. The study was conducted in 12 healthy volunteers by administering a 150 mg single oral dose of diethylcarbamazine citrate at 0600 or 1800 h in a balanced crossover design with the approval of an institutional ethics committee. The subjects fasted for about 10 hours before and 3 hours after drug treatment. Blood samples were collected at predetermined time intervals, and the drug content in the serum was estimated using HPLC with an electrochemical detector. Pharmacokinetic analysis was performed using noncompartmental methods employing WinNonlin (version 3.1), and the means of various pharmacokinetic parameters were compared for any dosing time-related changes using a paired t-test at a probability level of 95%. The mean +/- SD values of pharmacokinetic parameters of DEC for the treatments at 0600 versus 1800 h were as follows: Cmax, 500+/-227 versus 637+/-401 ng/ml; tmax, 2.3+/-0.7 versus 2.7+/-1 h; Ka, 2.23+/-0.72 versus 1.96+/-0.97 h(-1); t1/2, 14.6+/-6.7 versus 11.4+/-4.9 h; AUC0-t, 5,334+/-1,853 versus 6,901+/-4,203 ng x h/ml; AUC0-infinity, 5,840+/-1,922 versus 7,220+/-4,205 ng x h/ml; CL/F, 36,058+/-19,011 versus 32,189+/-25,293 ml/h/kg; Vd/F, 570+/-225 versus 533+/-447 L; and MRT 17.7+/-5.9 versus 15.3+/-5.2 h. None of the parameters was significantly changed (p > 0.05) as a function of time of administration.


Asunto(s)
Cronoterapia/métodos , Dietilcarbamazina/administración & dosificación , Dietilcarbamazina/farmacocinética , Filaricidas/administración & dosificación , Filaricidas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Cronoterapia/estadística & datos numéricos , Estudios Cruzados , Dietilcarbamazina/sangre , Filaricidas/sangre , Humanos
18.
Am J Ther ; 8(1): 7-9, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11304652

RESUMEN

We investigated the effect of the oral binder-activated charcoal on the excretion of diethylcarbamazine. Six healthy volunteers were given 150 mg diethylcarbamazine with 350 mL water each. One and 2 weeks later, they received 150 mg diethylcarbamazine plus 7.5 and 15 g activated charcoal, respectively, in 350 mL water as a charcoal slurry. Urinary levels of diethylcarbamazine were measured spectrophotometrically from 1 to 72 hours after ingestion in three different periods. Treatment with activated charcoal led to 5.4% urinary recovery of diethylcarbamazine, decreased excretion rate, and a much lower plateau indicator of reduced absorption. Activated charcoal reduces the absorption and urinary excretion rate of diethylcarbamazine by adsorbing it in the gastrointestinal tract.


Asunto(s)
Carbón Orgánico/farmacología , Dietilcarbamazina/farmacocinética , Filaricidas/farmacocinética , Absorción , Administración Oral , Adulto , Dietilcarbamazina/orina , Sistema Digestivo/efectos de los fármacos , Filaricidas/orina , Humanos , Masculino
19.
Physiol Chem Phys Med NMR ; 32(1): 1-12, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10970042

RESUMEN

A well known glucose antimetabolite, 2-deoxy glucose (2DG) widely used in chemotherapy of cancer along with radiation, was evaluated as an antifilarial agent by nuclear magnetic resonance. The uptake and metabolism of 2DG in the experimental filarial infection Acanthocheilonema viteae was studied by in vivo multinuclear NMR. An unusually long retention time of 2DG6P within these parasites was observed on continuous 31P NMR monitoring, along with a decrease in ATP levels. These results led to therapeutic investigation in A. viteae infected host Mastomys coucha. 2DG showed a remarkable adulticidal activity (73.6%) with 50% sterilization of surviving female worms at a dose of 250 mg/kg x 5, p.o. NMR observations and activity profile substantiate the findings of one another, directed towards the hitting of bioenergetic machinery of A. viteae by macrofilaricidal agent (2DG).


Asunto(s)
Desoxiglucosa/farmacología , Dipetalonema/efectos de los fármacos , Dipetalonema/metabolismo , Filaricidas/farmacología , Espectroscopía de Resonancia Magnética/métodos , Ratones/parasitología , Administración Oral , Animales , Antimetabolitos/administración & dosificación , Antimetabolitos/farmacocinética , Desoxiglucosa/farmacocinética , Infecciones por Dipetalonema/tratamiento farmacológico , Infecciones por Dipetalonema/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Metabolismo Energético/efectos de los fármacos , Filaricidas/farmacocinética , Interacciones Huésped-Parásitos , Lactatos/metabolismo , Resultado del Tratamiento
20.
Pharmacol Res ; 42(2): 167-70, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10887047

RESUMEN

The effect of activated charcoal (AC) on body clearance of diethylcarbamazine (DEC) was investigated in six healthy volunteers. On three occasions at weekly intervals, each subject received 150 mg of DEC with 350 ml of water. One and two weeks later, 150 mg of DEC plus 7.5 g and 15 g of AC, respectively, in 350 ml of water as a charcoal slurry. The non-renal clearance of DEC expressed as the total body clearance of DEC was increased after treatment with AC. The 45.2, 79.6 percent and 58.6, 81.6 percent reductions in maximum concentration and area under the concentration-time curve, respectively, suggest an appreciable adsorption of DEC by AC (7.5 and 15 g) in the gut. Serum eliminating half-life was decreased upon treatment with AC (7.5 and 15 g). These results indicate that AC accelerates the body clearance of DEC by increasing non-renal elimination of the drug.


Asunto(s)
Carbón Orgánico/farmacología , Dietilcarbamazina/farmacocinética , Filaricidas/farmacocinética , Administración Oral , Adulto , Antídotos/farmacología , Estudios Cruzados , Dietilcarbamazina/efectos adversos , Dietilcarbamazina/sangre , Interacciones Farmacológicas , Filaricidas/efectos adversos , Filaricidas/sangre , Humanos , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos
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