Pentoxifylline: A New Drug for the Treatment of Intermittent Claudication; Mechanism of Action, Pharmacokinetics, Clinical Efficacy and Adverse Effects

Pharmacotherapy - Tập 4 Số 6 - Trang 297-306 - 1984
Domingo M. Aviado1,2, John M. Porter1,2
1Atmospheric Health Sciences, Inc., Pharmacology Research Group, Short Hills, New Jersey
2Division of Vascular Surgery, University of Oregon Health Science Center, Portland.

Tóm tắt

During the past decade, the effectiveness of peripheral vasodilator drugs in the treatment of chronic occlusive arterial disease has been questioned. Pentoxifylline is a hemorheologic agent with primary actions that include increasing erythrocyte flexibility, reducing blood viscosity and increasing microcirculatory flow and tissue perfusion. The result is improved supply of oxygen to ischemic muscles of the limbs. In several double‐blind studies, pentoxifylline increased walking distance of patients with intermittent claudication in comparison to placebo or vasodilators. Like other methylxanthines, pentoxifylline is well absorbed in the gastrointestinal tract, almost completely metabolized in the body and excreted in the urine. The most significant difference in its pharmacokinetics is that, unlike other methylxanthines, it is bound to the erythrocytic membrane where it is initially metabolized. Although pentoxifylline has been shown to be effective in the treatment of intermittent claudication, additional research is needed to determine its use as adjunctive therapy in patients with concurrent coronary or cerebrovascular disease.

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Tài liệu tham khảo

Aviado DM., 1976, New antihypertensive drugs, 505

Food and Drug Administration., 1971, Peripheral vasodilators for oral administration, Federal Register, 36, 13347

10.1016/S0140-6736(59)91467-9

Hamilton M, 1952, The treatment of intermittent claudication, Q J Med, 21, 169

10.1056/NEJM197903293001305

Coffman JD., 1983, Pharmacologic approach to treatment of limb ischemia, 43

10.1172/JCI100749

Mohler W, 1971, Zuer Chemie und Synthese von 3,7‐Dimethyl‐1‐(5‐oxo‐hexyl)‐xanthin, (On chemistry and synthesis of 3.7-dimethyl-1-(5-oxo-hexyl)-xanthine.) Arzneimittelforsch, 21, 1159

Hinze HJ., 1971, Zur Analytik von 3,7‐Dimethyl‐1‐(5‐oxo‐hexyl)‐xanthin. 1. Mitteilung: Zur Spektroskopie von 3.7‐dimethyl‐1‐(5‐oxo‐hexyl)‐xanthin. (Analysis of 3,7‐dimethyl‐1‐(5‐oxo‐hexyl)‐xanthine. 1, Spectroscopy of 3,7-dimethyl-1-(5-oxo-hexyl)-xanthine.) Arzneimittelforsch, 21, 1456

Hinze HJ., 1971, Zur Analytik von 3,7‐Dimethyl‐1‐(5‐oxo‐hexyl)‐xanthin (BL 191). 2. Mitteilung: Zur Chromatographie und quantitativen Bestimmung von BL 191. (Analysis of 3,7‐Dimethyl‐1‐(5‐oxo‐hexyl)‐xanthin. 2, Chromatography and quantitative estimation of BL 191.) Arzneimittelforsch, 21, 2045

Komarek J, 1977, Der Effekt von Pentoxifyllin, Xantinol‐nicotinat und Theophyllin auf das Kreislaufsystem, die myokariale Dynamik und die linksventriculäre Kontraktilität beim Hund im akuten Experiment, (Acute effect of pentoxifylline, theophylline, and xanthinol nicotinate on the circulatory system, myocardial dynamics, and left ventricular contractility in dogs.) Arzneimittelforsch, 27, 1932

10.1038/icb.1975.29

Boksay I, 1971, The effect of 3,7‐dimethyl‐1‐(5′‐oxohexyl)‐xanthin on the β‐adrenergic receptors and on the activity of isoprenaline, Arch Int Pharmacodyn Ther, 194, 174

10.1536/ihj.23.235

Heidrich H, 1976, The effect of pentoxifylline on central and peripheral haemodynamics—an experimental clinical study, Z Kardiol, 65, 385

Baumann JC., 1977, Erweiterte Möglichkeiten zur konservativen Behandlung arterieller Durchblutungstörungen, (Increase possibilities for conservative treatment of arterial circulatory distrubances.) Therapiewoche, 27, 5872

10.1016/S0140-6736(76)92778-1

10.1177/000331977602700306

Kuzuya F., 1977, Influence of pentoxifylline (Trental) on platelet aggregation (Japanese), Gendai no Shrinryo, 19, 1567

10.1185/03007997909109432

10.1185/03007997709115279

Ehrly AM., 1982, Effects of orally administered pentoxifylline on muscular oxygen pressure in patients with intermittent claudication, IRCS Med Sci, 10, 401

Hess HV, 1973, Medikamentöse Verbesserung der Flieseigenschaften des Blutes. Aine wirksames Prinzip zur Behandlung von arteriellen Durchblutungstorungen. (Improvement of the fluidity of the blood with medication, An effective principle for the treatment of disturbances of the arterial blood flow.) Fortschr Med, 91, 743

Völker D., 1978, Behandlung von Arteriopathien mit Trental 400. Ergebnisse einer Doppelblidstudie, (Treatment of arteriopathies with Trental 400.) Med Welt, 29, 1244

10.1007/BF00498562

Lusov VA, 1978, The treatment of peripheral atherosclerosis with pentoxifylline, Pharmatherapeutica, 2, 123

Smud R, 1976, Changes in blood viscosity induced by pentoxifylline, Pharmatherapeutica, 1, 229

Schmid‐Schönbein H., 1977, Microcirculation

Müller R., 1981, Hemorrheology and peripheral vascular diseases. A new therapeutic approach, J Med, 12, 209

Herger R., 1972, Erfahrungen mit dem neuen Vasotherapeutikum Trental in der dermatologischen Fachpraxis, (New vasotherapy with Trental in cutaneous ulcer.) Fortsch Med, 24, 865

Mund‐Hoym WD., 1978, Zur Behandlung chronischer arterieller Angiopathien mit Pentoxifyllin (Trental), (The treatment of chronic arterial blood circulatory interference.) Schweiz Rundschau Med, 67, 1593

Brevetti G, 1979, La pentossifillina nel trattamento delle arteriopatie obliteranti al secondo stadio (Pentoxifylline in the treatment of state II obliterative arteriopathy.), Prog Med (Rome), 35, 563

Hoechst‐Roussel Pharmaceuticals, Inc., 1980, Doppler pressure measurements in multicenter study

10.1016/0002-8703(82)90401-X

Rudofsky G, 1979, Behandlung von Patienten mit arterieller verschluskrankheit (Stadium II) mit Pentoxifylline. Hämodynamische und ergometrische Befunde. (The influence of chronic pentoxifylline medication on ergometric and hemodynamic parameters in intermittent claudication.), Med Klin, 74, 1093

Pupita F, 1981, Farmacologia clinica delle sostanze vasoattive: studi sulla pentoxifyllina. (Clinical pharmacology of a vasoactive substance: pentoxifylline.), Ric Clin Lab, 11, 293

Angelkort B, 1978, Zur Behandlung der chronischen arteriellen Verschluskankheit. Klinische Studie mit einer neuen galenischem Zubereitung von Pentoxifyllin (Trental 400). (Treatment of chronic arterial occlusive disease. Clinical study with a new galenic preparation of pentoxifylline. Trental 400.), Med Klin, 73, 791

Aviado DM., 1983, Peripheral vasodilators versus pentoxifylline for the treatment of intermittent claudication, Ric Clin Lab, 13, 263

10.1177/000331978403500703

Lewis T, 1931, Observations upon muscular pain in intermittent claudication, Heart, 15, 359

Spittell JA, 1982, Peripheral vascular disorders, Geriatrics, 37, 55

Spittell JA, 1983, Pharmacologic approach to treatment of limb ischemia, 87

Ehrly AM, 1976, Altered deformability of erythrocytes from patients with chronic occlusive arterial disease, Vasa, 5, 319

Dormandy JA, 1981, Erythrocyte deformability in the pathophysiology of the microcirculation, Ric Clin Lab, 11, 35

10.1111/j.1749-6632.1983.tb35214.x

Cicardo VH., 1980, Inhibicion de la fosfodiestererasa central y periferico y la pression arterial del perro, (Central and peripheral inhibition of phosphodiesterases and arterial blood pressure in the dog.) Medicina, 40, 423

Steffanovich V., 1975, Effect of pentoxifylline on energy‐rich rat's erythrocytes, Res Commun Chem Pathol Pharmacol, 10, 747

Kramer JJ, 1983, Effects of pentoxifylline on membrane protein phosphorylation in rat erythrocytes, Vasc Med, 1, 159

Hinze HJ., 1972, Zur pharmakokinetic von 3,7‐Dimethyl‐1‐(5′‐oxo‐hexyl)‐xanthin (BL 191) am Menschen, (Pharmacokinetic of 3,7‐dimethyl‐1‐(5′‐oxo‐hexyl)‐xanthine (BL 191) in man.), Arzneimittelforsch, 22, 1492

Hinze HJ, 1972, Struktür der Ausscheidungsprodukte des 3,7‐Dimethyl‐1‐(5′‐oxo‐hexyl)‐xanthin (BL 191) beim Menschen, (Structure of metabolites of BL 191 in man.) Arzneimittelforsch, 22, 1144

Hinze HJ, 1976, Bioavailability and pharmacokinetics of pentoxifylline from “Trental 400” in man, Pharmatherapeutica, 1, 160

Hoechst‐Roussel Pharmaceuticals, Inc., 1982, Trental tablet dissolution

Hinze HJ, 1982, Binding of pentoxifylline and metabolite M‐I to human erythrocytes. An in vitro study

Christ O, 1972, Pharmakokinetische Untersuchungen nach oraler Verabreichung von 3,7‐Dimethyl‐1‐(5′‐oxohexyl)‐xanthin‐14C (BL 191‐14C) an Ratten, Hunde und Menschen, (Pharmacokinetic investigations after oral administration of 3,7-dimethyl-1-(5′-oxo-hexyl)-xanthine-14C (BL 191)-14C) to rats, dogs and humans.) Arzneimittelforsch, 22, 1933

10.3109/03639048109057718

Juergens JL, 1980, Allen‐Barker‐Hines' peripheral vascular diseases

10.1016/0002-8703(82)90642-1

Food and Drug Administration., 1976, Peripheral vascular diseases—intermittent claudication study protocol. Draft guidelines from cardio‐renal section, 1

Porter JM, 1982, Pharmacologic treatment of intermittent claudication, Surgery, 92, 966

Buckert B, 1976, Trials of 3,7‐Dimethyl‐1‐(5′‐oxo‐hexyl)‐xanthine (BL 191) in double‐blind tests, Farmaco (Prat), 31, 264

Tonak J, 1977, Zur Behandlung von Durchblutungstorungen mit Pentoxifyllin. Eine Doppelblindstudie mit Trental. (Treatment of circulatory disturbances with pentoxifylline. Double‐blind trial with Trental.), Med Monatsschr Pharm, 31, 467

Bollinger A, 1977, Double‐blind study of pentoxifylline against placebo in patients with intermittent claudication, Pharmatherapeutica, 1, 557

Schubotz R., 1976, Double‐blind trial of pentoxifylline in diabetics with peripheral vascular disorders, Pharmatherapeutica, 1, 172

Kelllner H., 1976, Zur Behandlung chronischer arterieller Diurchblutungstorungen. Doppelblindversuch mit Trental 400. (Treatment of chronic arterial circulatory disorders, Double-blind trial with Trental 400.) Münch Med Wochenschr, 118, 1399

Roekaerts F, 1982, La pentoxifylline 400 dans le traitement de l'arterite obliterante. Résultats préliminaires d'une étude randomisée et croisée à long terme versus Placebo. (Pentoxifylline 400 in the treatment of atherosclerosis obliterans, Preliminary results in a randomized double-blind placebo-controlled study.) Actual Angeiologie, 8, 35

10.1177/000331978303400105

10.1177/000331978403500709

Feine‐Haake G., 1977, Zur objektivierung der therapeutischen Wirksamkeit von Trental 400. (Assessment of therapeutic efficiency of Trental 400; double‐blind trial in geriatric patients with vascular disorders.), Fortschr Med, 95, 48

DonaldsonDR KesterRC RusselCW WigginsPA HallTJ Does oxpentifylline (Trental) have a place in the treatment of intermittent claudication?Third European conference on clinical pharmacology (London)1981;(abstract 164):82.

Mayer H, 1975, Behandlung arterieller und arteriovenöser Durchlutungsstörungen mit Trental, Therapiewoche, 25, 4941

Angelkort B., 1977, Influence of pentoxifylline (Trental 400) on microcirculation, poststenotic blood pressure and walking capacity in patients with chronic occlusive arterial disease, IRCS Med Sci, 5, 370

Westphalen JG., 1977, Zur klinischen Erprobung von Trental 400 bei Gefäskranken mit peripherer arterieller Verschluskrankheit, (Clinical trial of Trental 400 in patients with peripheral arterial occlusive disease.) Munch Med Wochenschr, 119, 901

Berke E, 1978, Periphere Angiopathie—Besteigerung der Mikrozirkulation. Argebnisse der ambulanten Behandlung in einer orthopädischen Fachpraxis. (Peripheral angiopathy—enhancement of the microcirculation, Results of ambulant treatment in an orthopedic consulting practice.) Arztl Prax, 30, 1235

Sondern W, 1979, Erfahrungen mit Pentoxifyllin bei charonischobliterierenden Erkrankungen der Beini‐arterien in Klinik und Praxis, (Experiences with pentoxifylline in chronic obliterating diseases of the leg arteries in clinic and practice.) Med Welt, 30, 1367

Dembowski U, 1979, Angioneuropathien, Angiopathien und andere Durchblutungstorungen Behandlung bein ambulanten Patienten. (Angioneuropathies, angiolopathies and other circulatory disorders, Treatment of outpatients.) Z Allg Med, 55, 1583

Pemler K, 1979, Pentoxifyllin‐Medikation im Rahmen der Ulcus cruris‐Behandlung. Ergebnisse einer Feldstudie mit Trental 400. (Pentoxifylline medication within the scope of leg‐ulcer therapy. Results of a field study using Trental 400.), Fortschr Med, 97, 1019

Mattern H, 1979, Durchblutungsförderung durch verbesserte mikrozirkulation, (Enhanced blood circulation as a result of improved microcirculation.) Arztl Praxis, 31, 2638

Tannenberg G., 1980, Zur medikamentosen Behandlung von Arteiopathien. Studie mit Trental 400. (Drug therapy of arterial diseases, A study with Trental 400.) Fortschr Med, 98, 1795

10.1177/000331978403500701

Komarov FI, 1978, Pentoxifylline in the treatment of peripheral vascular disease, Pharmatherapeutica, 2, 82

Schindler H., 1978, The clinical use of pentoxifylline, Pharmatherapeutica, 2, 66

Koppenhagen K, 1979, Wirkung von pentoxifyllin auf die Leber‐durchblutung, (Effects of pentoxifylline in hepatic circulation.) Med Klin, 74, 1254

Schaefer K, 1977, Untersuchungen zur Pharmakokinetik von Pentoxifyllin bei chronischer Niereninsuffizienz. (Investigations on the pharmacokinetics of pentoxifylline in chronic renal failures.), Med Klin, 42, 204

Hoechst‐Roussel Pharmaceuticals, Inc., 1980, Chronic animal studies on Trental

Hoechst‐Roussel Pharmaceuticals, Inc., 1984, Trental. Physician's and package insert monograph