Pharmacokinetics of Orally Administered Pentoxifylline in Humans

Smith, Robert V.; Waller, Elaine S.; Doluisio, James T.; Bauza, Michael T.; Puri, Surendra K.; Ho, Irwin; Lassman, Howard B.

doi:10.1002/jps.2600750111

Cited by 97 publications

(72 citation statements)

References 9 publications

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“…Also, combinations that employ apraclonidine, which does not cross the blood brain barrier 83 , would further reduce the potential systemic side-effects of α 2A receptor agonists, which lower blood pressure largely by actions at α 2A and/or imidazoline receptors in the brain stem 88 . Furthermore, although the half-life of some of the agents when given systemically is fairly short (e.g., pentoxifylline: 0.84 h; linsidomine: 1.0 h) 80,81 , slow skin penetration after topical administration is known to produce a prolongation of drug half-life by 5-10 fold 26 . This likely explains our finding that topical treatment with combinations including these agents produced anti-allodynic effects lasting up to 6 hours in CIPN rats, and why the combinations were effective when tested 3 hours post-application during chronic dosing trials in CIPN rats.…”

Section: Discussionmentioning

confidence: 99%

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

Ragavendran

Laferrière

Xiao

et al. 2013

The Journal of Pain

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Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α 2 -adrenergic (α 2A ) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent anti-allodynic effects in rats with chronic post- CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript ischemia pain, and the anti-allodynic dose-response curves of PDE and PA inhibitors were shifted 2.5-10 fold leftward when combined with non-analgesic doses of α 2A receptor agonists or NO donors. Topical combinations also produced significant anti-allodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 h after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α 2A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain.Perspective-This article presents the synergistic anti-allodynic effects of combinations of α 2A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.

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Section: Discussionmentioning

confidence: 99%

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

Ragavendran

Laferrière

Xiao

et al. 2013

The Journal of Pain

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“…PX is hepatically metabolized by hydroxylation and demethylation to six renally excreted metabolites (Smith et al, 1986). The presence of high test formulation PX levels may alter the mechanism of metabolizing enzymes by saturation, which may lead to increased bioavailability.…”

Section: Discussionmentioning

confidence: 99%

“…Reference It was shown that PX was rapidly cleared from plasma; it undergoes extensive first pass metabolism (Hinze et al, 1976;Smith et al, 1986). Oral bioavailability of PX tablet was found to be 20-30 % (Beerman et al, 1985).…”

Section: Testmentioning

confidence: 99%

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Bioavailability of Pentoxifylline-Chitosan Oral Matrix Tablet in Healthy Subjects

Teksin¹,

Ağabeyoğlu²

2009

JBB

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Pentoxifylline (PX) is a highly water-soluble, hemorheologic drug that undergoes first-pass effect with 20 % bioavailability. Chitosan (CH), a biocompatible and biodegradable natural polymer, is used to increase drug bioavailability, as well as prolonging release. The aim of this study was to investigate the feasibility of enhancement of oral bioavailability of PX using CH. CH was used as an absorption enhancer for preparing the matrix tablet. The in vitro release and bioavailability of PX-CH tablet was compared with the reference product (Trental ® -400, Sanofi-Aventis, Turkey). PX-CH tablets were prepared by the slugging method. The in vitro release studies were performed by a flow-through cell apparatus (USP Apparatus IV). A randomized, two-way crossover bioavailability study was conducted in 12 fasting, healthy male volunteers to compare PX-CH and reference tablets; both of them containing 400 mg PX. One tablet of either formulation was administered after a 12 h overnight fast. After dosing, serial blood samples were collected during a period of 12 hours. Plasma samples were analyzed for PX by a validated UV-HPLC method. The pharmacokinetic parameters AUC 0-12 , AUC 0-inf , C max , t max , λ z , t 1/2 , Vd and CL were determined from plasma concentration-time profiles for both formulations. A higher in vitro release rate of PX was observed using acidic dissolution medium. The total in vitro release of PX was 104 % for PX-CH and 78.7 % for the reference after 12 hours. The mean maximum plasma concentration (C max ) of PX-CH tablets was 1260±910 ng/mL after a t max of 0.784±0.406 h. For the reference, they were 67.9±33.7 ng/mL and a t max of 1.48±0.79 h, respectively. It was found that the relative bioavailability of PTX was significantly increased with CH, compared to reference. AUC 0-inf values for test and reference were 1740±850 ng.h/ mL and 1270±780 ng.h/mL, respectively. Enhancement of the bioavailability of PX would suggest that CH could be used to improve oral bioavailability of PX.

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“…At this plasma concentration, PENT potentiated the antitumor effect of ET in vivo. In humans, the highest plasma PENT concentration including active metabolite was 2,400 ng/ ml (0.009 mM ) [21]. A higher concentration of PENT is probably achievable and tolerable in humans.…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline Potentiates the Antitumor Effect of Cisplatin and Etoposide on Human Lung Cancer Cell Lines

et al. 1996

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The effect of pentoxifylline (PENT) on the sensitivity of two human lung adenocarcinoma cell lines, PC-9 and PC-14, to cisplatin (CDDP) and etoposide (ET) was studied. PENT at 0.5 and 1 mM enhanced the cytotoxicity of CDDP and ET on PC-14 and PC-9, respectively. Isobologram analyses of IC₅₀ data, as well as combination index calculations, revealed that PENT had an additive or a synergistic effect when applied in combination with CDDP or ET, respectively. PENT potentiated the antitumor effect of ET in a nude-mouse xenograft model using PC-14 cells, when PENT was administered at 150 mg/kg subcutaneously for 6 days. Flow cytometry revealed that PENT decreased the accumulation of cells in the G₂+M phase caused by CDDP when using PC-9 cells. However, PENT did not remarkably alter the accumulation of cells in G₂+M caused by ET. These results suggest that PENT enhanced the antitumor effects of CDDP additively and those of ET synergistically. The enhancement mechanism probably differs between CDDP and ET. PENT needs more study to elucidate its potency as a new agent for combination chemotherapy.

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Pharmacokinetics of Orally Administered Pentoxifylline in Humans

Cited by 97 publications

References 9 publications

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

Bioavailability of Pentoxifylline-Chitosan Oral Matrix Tablet in Healthy Subjects

Pentoxifylline Potentiates the Antitumor Effect of Cisplatin and Etoposide on Human Lung Cancer Cell Lines

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