Pharmacokinetic–Pharmacodynamic Analysis of the Static Allodynia Response to Pregabalin and Sildenafil in a Rat Model of Neuropathic Pain
| العنوان: | Pharmacokinetic–Pharmacodynamic Analysis of the Static Allodynia Response to Pregabalin and Sildenafil in a Rat Model of Neuropathic Pain |
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| المؤلفون: | Stephen Bramwell, Robert R. Bies, Meindert Danhof, Gregor Bender, Keith Tan, Scott Marshall, Mark J. Field, Joost DeJongh, Jeffry A. Florian |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 334:599-608 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Male, Pain Threshold, Sildenafil, Population, Pregabalin, Pain, Ligands, Models, Biological, Loading dose, Piperazines, Sildenafil Citrate, Rats, Sprague-Dawley, chemistry.chemical_compound, medicine, Animals, Drug Interactions, Sulfones, education, gamma-Aminobutyric Acid, Pharmacology, Analgesics, education.field_of_study, Pharmacokinetic pharmacodynamic, business.industry, Phosphodiesterase 5 Inhibitors, Rats, Allodynia, chemistry, Hyperalgesia, Purines, Anesthesia, Concomitant, Chronic Disease, Neuropathic pain, Molecular Medicine, Calcium Channels, medicine.symptom, business, Ion Channel Gating, medicine.drug |
| الوصف: | The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC(50) of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC(50), whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil. |
| تدمد: | 1521-0103 0022-3565 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::43268025817c406f840c2065c0b9ee72 https://doi.org/10.1124/jpet.110.166074 |
| رقم الأكسشن: | edsair.doi.dedup.....43268025817c406f840c2065c0b9ee72 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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