Pentoxifylline

doi:10.1016/S0190-9622(94)70069-9

Journal of the American Academy of Dermatology

Volume 30, Issue 4, April 1994, Pages 603-621

https://doi.org/10.1016/S0190-9622(94)70069-9 Get rights and content

Pentoxifylline (oxpentifylline) is a methylxanthine derivative with potent hemorrheologic properties. In the United States it is marketed for the treatment of intermittent claudication. Human and animal studies have shown that pentoxifylline therapy results in a variety of physiologic changes at the cellular level, which may be important in treating a diverse group of human afflictions. Immune modulation includes increased leukocyte deformability and Chemotaxis, decreased endothelial leukocyte adhesion, decreased neutrophil degranulation and release of superoxides, decreased production of monocyte-derived tumor necrosis factor, decreased leukocyte responsiveness to interleukin 1 and tumor necrosis factor, inhibition of T and B lymphocyte activation, and decreased natural killer cell activity. Hypercoagulable states improve through decreased platelet aggregation and adhesion, increased plasminogen activator, increased plasmin, increased antithrombin III, decreased fibrinogen, decreased α₂-antiplasmin, decreased α₁-antitrypsin, and decreased α₂-macroglobulin. Wound healing and connective tissue disorders may respond to an increase in fibroblast collagenases and decreased collagen, fibronectin, and glycosaminoglycan production. Fibroblast responsiveness to tumor necrosis factor is also diminished. Potential medical uses of pentoxifylline are reviewed.

References (203)

H Ely
Pentoxifylline therapy in dermatology: a review of localized hyperviscosity and its effects on the skin
Dermatol Clin
(1988)
EA Schmalzer et al.
Filterability of subpopulations of leukocytes: effect of pentoxifylline
Blood
(1984)
CP Samlaska et al.
Superficial thrombophlebitis. I. Primary hypercoagulable states
J Am Acad Dermatol
(1990)
PE Wakefield et al.
Tumor necrosis factor
J Am Acad Dermatol
(1991)
RM Strieter et al.
Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline
Biochem Biophys Res Commun
(1988)
LA Rosenthal et al.
Methylxan-thine-induced inhibition of antigen- and superantigen-specific activation of T and B lymphocytes
Immunopharmacology
(1992)
M Michal et al.
Reduced thrombus formation in vivo after administration of pentoxifylline (Trental)
Thromb Res
(1989)
HP Klöcking et al.
Release of plasminogen activator by pentoxifylline and its major metabolite
Thromb Res
(1987)
B Berman et al.
Pentoxifylline inhibits normal human dermal fibroblast in vitro proliferation, collagen, glycosaminoglycan, and fibronectin production, and increases collagenase activity
J Invest Dermatol
(1989)
B Berman et al.
Pentoxifylline inhibits certain constitutive and tumor necrosis factor-α-induced activities of human normal dermal fibroblasts
J Invest Dermatol
(1992)

AV Wahba-Yahav

Chronic leukocytoclastic vasculitis associated with polycythemia vera: effective control with pentoxifylline

J Am Acad Dermatol

(1992)

F Fazely et al.

Pentoxifylline (trental) decreases the replication of the human immunodeficiency virus type 1 in human peripheral blood mononuclear cells and incultured T cells

Blood

(1991)

JL Ambrus et al.

Pentoxifylline in treatment of acquired immunodeficiency syndrome?

[Letter] Blood

(1992)

GL Mandell et al.

Pentoxifylline and leukocyte function: foreword and overview

J Hakim et al.

Preface

A Ward et al.

Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy

Drugs

(1987)

P Zabiel et al.

Oxpenti-fylline in endotoxaemia

Lancet

(1989)

GM Maxwell

The effects of a new xanthine derivative 3,7-dimethyl-1 (5-oxo-hexyl)-xanthine (pentoxifylline) on the general and cardiac hemodynamics of the intact animal

Aust J Exp Biol Med Sci

(1975)

N Tranquille et al.

The effect of pentoxifylline (trental) and two analogues, BL 194 and HWA 448, on the release of plasminogen activators and von Willebrand factor in rats

J Cardiovasc Pharmacol

(1991)

AM Ehrly

Improvements in the flow properties of blood: a new therapeutical approach in occlusive arterial disease

Angiology

(1976)

E Porsche et al.

The influence of pentoxifylline on ATPase activity of human erythrocyte membranes: IRCS

J Med Sci

(1978)

NW Seidler et al.

The effects of pentoxifylline on the plasma membrane Ca²⁺ ATPase in age-separated rat andhuman erythrocytes

J Clin Pharmacol

(1992)

Y Sato et al.

Interaction of pentoxifylline with human erythrocytes. II Effects of pentoxifylline on the erythrocyte membrane

Chem Pharm Bull

(1990)

Y Sato et al.

Interaction of pentoxifylline with human erythrocytes, III. Comparison of fluidity change of erythrocyte membrane caused by S-adenosyl-L-methionine with that by pentoxifylline

Chem Pharm Bull

(1991)

DM Cummings et al.

Lack of effect of pentoxifylline on red blood cell deformability

J Clin Pharmacol

(1992)

M Hayakawa

Comparative efficacy of vinpocetine, pentoxifylline and nicergoline on red blood cell deformability

Arzneimittelforschung

(1992)

PL Sonkin et al.

Vasodilator action of pentoxifylline on microcirculation of rat cremaster muscle

Angiology

(1992)

M Schönharting et al.

The haemorheo-logical and antithrombotic potential of pentoxifylline (‘Trental’): a review

Pharmatherapeutica

(1988)

DE Hammerschmidt et al.

Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor

J Lab Clin Med

(1988)

PH Ely

White blood cells as mediators of hyperviscosity-induced tissue damage in neutrophilic vascular reactions: therapy of pentoxifylline

J Am Acad Dermatol

(1989)

F Bertocchi et al.

The effect of pentoxifylline on polymorphonuclear cell adhesion to cultured endothelial cells

GW Sullivan et al.

Pentoxifylline inhibits the inflammatory effects of endotoxin and endotoxin-induced cytokines on neutrophil function

D Tighe et al.

Pentoxifylline decreases neutrophil adhesion and reverses hemodynamic and histological changes associated with peritonitis in pigs

JL Salyer et al.

Mechanisms of tumor necrosis factor-α alteration of PMN adhesion and migration

Am J Pathol

(1990)

CA Dinarello et al.

Lymphokines

N Engl J Med

(1987)

MP Bevilacqua et al.

Interleu-kin-1 acts on cultured human vascular endothelial cells to increase the adhesion of polymorphonuclear leukocytes, monocytes and-related leukocyte cell lines

J Clin Invest

(1985)

JI Gallin et al.

Role of the neutrophil in host defense and inflammation

MS Currie et al.

Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, de-granulation; and superoxide production

J Leukoc Biol

(1990)

G Freyburger et al.

Leukocyte activation and rheological changes: effect of pentoxifylline

H Bessler et al.

Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells

J Leukoc Biol

(1986)

P Sourbier et al.

In vitro effect of pentoxifylline on human neutrophil function

GW Sullivan et al.

Enhancement of Chemotaxis and protection of mice from infection

Trans Assoc Am Physicians

(1984)

GW Sullivan et al.

Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline

Infect Immun

(1988)

S Endres et al.

Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-α and interleukin-1β by human mononuclear cells

Immunology

(1991)

H Zheng et al.

Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

Am Rev Respir Dis

(1990)

L Schandené et al.

Differential effects of pentoxifylline on the production of tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) by monocytes and T cells

Immunology

(1992)

WR Reed et al.

Suppressive effect of pentoxifylline on natural killer cell activity

J Lab Clin Med

(1992)

P Knox

Leukocyte activation and rheological changes: effect of pentoxifylline

JL Ambrus et al.

Studies on platelet aggregation with pentoxifylline: effect in neoplastic disorders and other new indications

J Med

(1979)

R Müller et al.

Haemorheological role of platelet aggregation and hypercoagulability in microcirculation: theoretical approach with pentoxifylline

Pharmatherapeutica

(1980)

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^*: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of the Defense.

^**: No reprints available.

^a: From the Dermatology Service, Tripler Army Medical Center.

^b: From the Transitional Medicine Service, Tripler Army Medical Center.

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Pentoxifylline*,**

Dermatol Clin

Blood

J Am Acad Dermatol

J Am Acad Dermatol

Biochem Biophys Res Commun

Immunopharmacology

Thromb Res

Thromb Res

J Invest Dermatol

J Invest Dermatol

J Am Acad Dermatol

Blood

[Letter] Blood

Pentoxifylline and leukocyte function: foreword and overview

Preface

Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy

Drugs

Oxpenti-fylline in endotoxaemia

Lancet

The effects of a new xanthine derivative 3,7-dimethyl-1 (5-oxo-hexyl)-xanthine (pentoxifylline) on the general and cardiac hemodynamics of the intact animal

Aust J Exp Biol Med Sci

The effect of pentoxifylline (trental) and two analogues, BL 194 and HWA 448, on the release of plasminogen activators and von Willebrand factor in rats

J Cardiovasc Pharmacol

Improvements in the flow properties of blood: a new therapeutical approach in occlusive arterial disease

Angiology

The influence of pentoxifylline on ATPase activity of human erythrocyte membranes: IRCS

J Med Sci

The effects of pentoxifylline on the plasma membrane Ca2+ ATPase in age-separated rat andhuman erythrocytes

J Clin Pharmacol

Interaction of pentoxifylline with human erythrocytes. II Effects of pentoxifylline on the erythrocyte membrane

Chem Pharm Bull

Interaction of pentoxifylline with human erythrocytes, III. Comparison of fluidity change of erythrocyte membrane caused by S-adenosyl-L-methionine with that by pentoxifylline

Chem Pharm Bull

Lack of effect of pentoxifylline on red blood cell deformability

J Clin Pharmacol

Comparative efficacy of vinpocetine, pentoxifylline and nicergoline on red blood cell deformability

Arzneimittelforschung

Vasodilator action of pentoxifylline on microcirculation of rat cremaster muscle

Angiology

The haemorheo-logical and antithrombotic potential of pentoxifylline (‘Trental’): a review

Pharmatherapeutica

Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor

J Lab Clin Med

White blood cells as mediators of hyperviscosity-induced tissue damage in neutrophilic vascular reactions: therapy of pentoxifylline

J Am Acad Dermatol

The effect of pentoxifylline on polymorphonuclear cell adhesion to cultured endothelial cells

Pentoxifylline inhibits the inflammatory effects of endotoxin and endotoxin-induced cytokines on neutrophil function

Pentoxifylline decreases neutrophil adhesion and reverses hemodynamic and histological changes associated with peritonitis in pigs

Mechanisms of tumor necrosis factor-α alteration of PMN adhesion and migration

Am J Pathol

Lymphokines

N Engl J Med

Interleu-kin-1 acts on cultured human vascular endothelial cells to increase the adhesion of polymorphonuclear leukocytes, monocytes and-related leukocyte cell lines

J Clin Invest

Role of the neutrophil in host defense and inflammation

Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, de-granulation; and superoxide production

J Leukoc Biol

Leukocyte activation and rheological changes: effect of pentoxifylline

Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells

J Leukoc Biol

In vitro effect of pentoxifylline on human neutrophil function

Enhancement of Chemotaxis and protection of mice from infection

Trans Assoc Am Physicians

Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline

Infect Immun

Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-α and interleukin-1β by human mononuclear cells

Immunology

Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

Am Rev Respir Dis

Differential effects of pentoxifylline on the production of tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) by monocytes and T cells

Immunology

Suppressive effect of pentoxifylline on natural killer cell activity

J Lab Clin Med

Leukocyte activation and rheological changes: effect of pentoxifylline

Studies on platelet aggregation with pentoxifylline: effect in neoplastic disorders and other new indications

J Med

Haemorheological role of platelet aggregation and hypercoagulability in microcirculation: theoretical approach with pentoxifylline

Pharmatherapeutica

The effects of pentoxifylline on the plasma membrane Ca²⁺ ATPase in age-separated rat andhuman erythrocytes